6

Drug-Resistant Tuberculosis in Pediatric Populations

Key Messagesa

•   The burden of DR TB in children, the number of children being treated, and the gaps in delivering both treatment and prevention to children are unknown.

•   Children can act as sentinels for DR TB, helping countries improve diagnosis and treatment while identifying gaps in knowledge.

•   Timely detection and proper treatment of the disease in adults are crucial for protecting children from infection.

•   When children are treated with regimens tailored to the susceptibility profile of their strain or of the strain of the most likely source case, they have excellent outcomes.

•   Better treatment of TB in children requires new tests and diagnostic tools and more and better drugs that are available in pediatric formulations.

__________________

a Identified by individual speakers.

Four speakers at the workshop looked specifically at the issue of DR TB in children. Pediatric DR TB is a silent epidemic, they said, and is often overlooked in policy responses. But it reflects the broader spread of MDR TB and offers valuable lessons in how to prevent and treat the disease.



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6 Drug-Resistant Tuberculosis in Pediatric Populations Key Messagesa • The burden of DR TB in children, the number of children being treated, and the gaps in delivering both treatment and prevention to children are unknown. • Children can act as sentinels for DR TB, helping countries improve diagnosis and treatment while identifying gaps in knowledge. • Timely detection and proper treatment of the disease in adults are crucial for protecting children from infection. • When children are treated with regimens tailored to the susceptibility profile of their strain or of the strain of the most likely source case, they have excellent outcomes. • Better treatment of TB in children requires new tests and diagnos­ tic tools and more and better drugs that are available in pediatric formulations. a Identified by individual speakers. Four speakers at the workshop looked specifically at the issue of DR TB in children. Pediatric DR TB is a silent epidemic, they said, and is often overlooked in policy responses. But it reflects the broader spread of MDR TB and offers valuable lessons in how to prevent and treat the disease. 55

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56 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS Children as Sentinels for Transmission and Policy Response1 “We simply do not know what the disease burden of drug-resistant TB is in children or how it varies across the globe,” said Mercedes C. Becerra, Associate Professor, Department of Global Health and Social Medicine, Harvard Medical School. Although HIV specialists have estimated the burden of HIV disease in children, the number of children being treated, and the gaps in delivering both treatment and prevention to children, “we have not generated these estimates at all” for DR TB. Most current data represent TB cases in adults who have been diag- nosed using smear microscopy tests. But because children often have forms of TB that are not detected by a smear test, the existing data are a poor gauge of the extent of pediatric TB cases and the success of treatment. Children typically have a lower bacillary load than adults, they are more likely to develop extrapulmonary forms of the disease, and obtaining test- able samples from them is difficult. “Together, this is the perfect recipe for making children invisible,” Becerra said. Recent attempts to describe the pediatric TB burden produced estimates of 500,000 cases per year, but many TB specialists believe that the actual number could be at least twice as high. HIV treatment has been supported by clear estimates showing the need for treatment and global advocacy efforts, but that has not been the case for pediatric TB. The recommended design for national TB surveys excludes anyone under age 15, and children made up less than 2 percent of the more than 300,000 patients included in the Global Drug-Resistant Surveillance Project Surveys (Zignol et al., 2013). “We literally have no sense of where we are and how far we need to go to meet the needs of this vulnerable population across the globe,” Becerra said. “The situation is frustrating for us, and it is deadly for children.” Children with DR TB can act as sentinels for the disease, she explained. Children progress more quickly than adults through the stages of the disease, which means they reflect recent transmission and make it easier to identify a source patient. Childhood TB cases, if reported, could help countries progress in diagnosis and treatment of all TB while also identify- ing gaps in treatment and knowledge. In the past 4 years, 4 reports of XDR TB in 1 or more children were published in Greece, Peru, South Africa, and the United States, respectively, and 1 each in Beijing and Mumbai, said Becerra, and more than 10 groups in the past 10 years have reported treating children for MDR TB. Thus, the 1 This section is based on the presentation by Mercedes C. Becerra, Associate Professor, Department of Global Health and Social Medicine, Harvard Medical School.

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DRUG-RESISTANT TUBERCULOSIS IN PEDIATRIC POPULATIONS 57 problem is not limited to a particular part of the world. “These are surely just the tip of the iceberg of undetected resistant TB in children in all of these places.” Similarly, Becerra and her colleagues found that reports of resistance to isoniazid, either alone or in combination with other drugs, are wide- spread in children. In more than half of the studies they reviewed, isoniazid resistance was more than 5 percent, suggesting that many children will not benefit from empirical treatments that rely on isoniazid (Yuen et al., 2013). However, when children are treated with regimens tailored to the suscepti- bility profile of their strain or the strain of the most likely source case, they have excellent outcomes. More than 80 percent of those who have accessed complete regimens have been cured. At the fourth workshop in this series, held in New Delhi, India, in 2011, the idea emerged of forming a virtual network of collaborators, including researchers, caregivers, and advocates, who would work together with the goal of ending childhood deaths from DR TB. The resulting Sentinel ­ ­ roject on Pediatric Drug-Resistant Tuberculosis2 now includes more than P 250 individuals from more than 50 countries who are working to raise the visibility of this vulnerable population, share knowledge and best practices, and formulate a scientific agenda that gives priority to children. Since form- ing, one task force has gathered short stories detailing the experiences of almost 70 children with DR TB in more than 30 countries (“Being Brave: Stories of Children with Drug-Resistant Tuberculosis,” 2012; “We Can Heal: Prevention, Diagnosis, Treatment, Care, and Support: Addressing Drug-Resistant Tuberculosis in Children,” 2013). Another task force, made up of providers with extensive experience treating drug-resistant pediatric TB, has written a 50-page practical field handbook (Management of Drug- Resistant Tuberculosis in Children: A Field Guide, 2012) based on state- of-the-art knowledge in the field (Seddon et al., 2012b). The next steps for the network, Becerra said, are to articulate a scientific agenda and initiate multisite research projects that can identify targets for monitoring. ­ Children with DR TB also can serve as sentinels for policy responses, said Becerra. Where DR TB occurs in adults, children also are likely to be exposed. For example, children living with DR TB patients in Peru had 30 times the risk of disease of the general pediatric population. Screening of household contacts is known to be a best practice in TB care, and if it were performed as a standard practice, could contribute to diagnosis of more pediatric cases. “If we want to find children with drug-resistant TB, we have to look for them where they live,” said Becerra. Becerra proposed a way of beginning to estimate the number of chil- dren at risk. Estimates of patients with DR TB, she said, can be multiplied 2  See http://www.sentinel-project.org (accessed April 15, 2013).

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58 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS by the average number of children in those households, yielding an absolute number of children that need to be evaluated. That target number comes to nearly 800,000 in a single year, based on recent WHO data. Using an average risk statistic, Becerra calculated the number of children expected to already be sick as 3.4 percent of the total (Fox et al., 2013)—an absolute number of more than 25,000 children currently needing treatment. This approach, Becerra explained, can begin to focus attention on the treat- ment gap and what can be done in the short term to serve the pediatric population. Finally, better treatment of TB in children requires new tests and diag- nostic tools and more and better drugs that are available in pediatric for- mulations. A framework that highlights basic treatment targets can be used as scaffolding for a scientific agenda that makes children a priority and can provide benchmarks for refining treatment and delivery strategies so as to increase the number of children treated. Pediatric Drug-Resistant TB in China3 Tao Li, Attending Physician, and Assistant Director, Department of Tuberculosis, Shanghai Public Health Clinical Center, Fudan University, began his presentation with the story of 4-year-old boy who has spent virtually his entire life in the hospital with DR TB. Pediatric TB has been neglected, Tao Li said, pointing out that the first WHO report, including estimates of children’s TB—490,000 new cases and 64,000 deaths per year—was published in 2012. In China, TB infection rates among children were last updated 12 years ago, showing a rate of 25 percent. According to the China CDC, 1,996 cases of new smear-positive TB occurred in children in 2004. From 1996 to 2006, the number of pediatric TB cases increased gradu- ally at Beijing Children’s Hospital. However, the number increased rapidly in Shanghai, where the Shanghai Public Health Clinical Center, the only des- ignated hospital for children’s TB, draws children from all over the country. For a doctor, Tao Li explained, the biggest challenge posed by children’s TB is diagnosis. Most children have TB that is difficult to diagnose with a smear culture, and good samples are challenging to collect. In addition, diagnosing extrapulmonary TB requires special services that often cannot be provided in general hospitals. Among 211 cases of children’s TB at the Shanghai center admitted between June 2010 and December 2011, a retrospective study showed extensive involvement of the lymphatic system in 48 percent of patients and 3  Thissection is based on the presentation by Tao Li, Attending Physician, and Assistant Di- rector, Department of Tuberculosis, Shanghai Public Health Clinical Center, Fudan University.

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DRUG-RESISTANT TUBERCULOSIS IN PEDIATRIC POPULATIONS 59 a low coinfection rate with HIV of only 1.6 percent. Only 6.6 percent of the children had a history of close contact with TB patients. Two-thirds were susceptible to all four FLDs, one-third were resistant to at least one FLD, and 5 percent had MDR TB. Only one child had an unfavorable outcome. Performing multiple tests increases the chances that a child will be diagnosed and treated effectively. In that regard, a multicenter, prospective cohort study showed that collecting a variety of specimens increases the chances of an accurate diagnosis. Specimen types included cerebrospinal fluid, pleural fluid, and lymph node aspirates. Children are the future, Tao Li concluded, and knowing that those with DR TB have favorable outcomes when treated is comforting. For example, the child he described at the beginning of his talk has recently shown improvement. Persistence in diagnosis and treatment will pay off in the long run, said Tao Li. Drug-resistant TB Meningitis in Children4 Tuberculous meningitis (TBM), which is more common in children than in adults, is the most severe type of TB, noted Huimin Li, who presented a talk prepared by Shunying Zhao, Beijing Children’s Hospital. Diagnosis of TBM in children is difficult and often delayed, and about 80 percent of children with stage II and III TBM develop neurologic sequelae. TB in children is usually paucibacillary, and microbiologic diagnosis can be made in only 20 to 40 percent of cases. Furthermore, many hospitals, including Beijing Children’s Hospital, cannot perform DST. As a result, the diagnosis of MDR TB in children is often made presumptively. According to Huimin Li, MDR TB therapy should be considered if a patient has a history of TB, has an MDR TB contact, or has a poor clinical response to first-line TB therapy within 2 weeks despite adequate adherence to treatment. Treatment of drug-resistant TBM should be based on the results of DST, testing of the source case if possible, the prevailing patterns of drug- resistant strains in the region, or the experience of practitioners. The rec- ommended treatment regimen is the combination of at least four drugs to which TBM is likely to be susceptible. Although data on drug-resistant TBM in children are limited, Huimin Li presented the results of two earlier studies. In the first study (­ adayatchi P et al., 2006), eight children from South Africa were studied between 1992 and 2003, six of whom were HIV positive and two of whom were not. Only one of these children survived. In the second study (Seddon et al., 2012a), 16 of 123 children with TBM from South Africa, studied from 4  Thissection is based on the presentation by Huimin Li and Shunying Zhao, Beijing Chil- dren’s Hospital.

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60 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS January 2003 to April 2009, had any form of drug resistance, and 4 per- cent (5 of 123) had MDR TB. MDR TB was strongly associated with both unfavorable outcomes and death. No differences were found between the outcomes of children with isoniazid-monoresistant TBM and children with drug-susceptible TBM. Huimin Li presented clinical data from 210 children with TBM in B ­ eijing Children’s Hospital from January 2002 to June 2010. These children had a high incidence of possible drug resistance, and most were at stage II or III of the disease. With treatment, 80.5 percent improved, 18.1 percent had an exacerbation of their condition or no improvement, and three died. Huimin Li emphasized that it is essential to perform drug resistance testing in children with TBM in the future, including DST and tests using molecular biology methods, to rapidly diagnose drug resistance. Results can help determine the choice of TB drugs and improve the prognosis for these patients. Huimin Li also presented the results of treating children with MDR TBM with linezolid, which has high in vitro antibacterial activity against TB. Research in adults has shown that linezolid is effective against MDR TB but also has a high incidence of serious adverse events, including neuropathies and bone marrow suppression. Among 10 children with clinically diagnosed drug-resistant TBM treated with linezolid for 1 to 3 months, none had adverse events, 9 improved, and 1 changed to a different treatment. Future research is needed to determine the best treatment regimen for linezolid, Huimin Li concluded, and to further assess its efficacy and safety in children with MDR TBM. Nonetheless, these results indicate that linezolid has better efficacy and safety in treating drug-resistant TBM in children than in adults. Pediatric MDR and XDR TB in the Russian Federation and Other Countries of the former Soviet Union5 TB is challenging to Russian pulmonologists, explained Valentina Aksenova, Head, Children and Adolescents Department, Research Institute of Physiopulmonology of the First Sechenov Moscow State Medical Uni- versity; and Chief Freelance Expert Pediatrician-Physiologist of the Russian Health Ministry. This is the case for many reasons, including late detection, undiagnosed cases of extrapulmonary TB, drug resistance, and coinfection with HIV. In Russia, 100 of every 100,000 adults and 16 of every 100,000 children have TB. Morbidity is highest in those aged 25 to 34. 5  This section is based on the presentation by Valentina Aksenova, Head, Children and Adolescents Department, Research Institute of Physiopulmonology of the First Sechenov Moscow State Medical University; and Chief Freelance Expert Pediatrician-Physiologist of the Russian Health Ministry.

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DRUG-RESISTANT TUBERCULOSIS IN PEDIATRIC POPULATIONS 61 Approximately 60 percent of the Russian population has regular occu- pational health exams, which help increase the likelihood of diagnosing TB cases. Of those diagnosed, 44.4 percent have bacterial excretion, 47.3 per- cent have degraded lung tissue, and 10.7 percent have MDR TB. Pulmonologists who treat children and adults face similar challenges, but particular challenges are posed by pediatric TB. It is more difficult to diagnose than TB in adults, so it is detected in more advanced stages, and inefficient infection control measures are in place. In 2011, 234,000 chil- dren in Russia were infected, 2,818 were diagnosed with active TB, and 1,437 were diagnosed with latent forms of the disease. Drug resistance is found in more than 50 percent of pediatric cases, Aksenova added. TB is often found in the lymph glands of children, and teenagers frequently present with complex forms of secondary TB. Aksenova described a study of 65 children with DR TB and a control group of 95 children with drug-susceptible TB (Aksenova, 2013). The study found that contact with someone who had active TB was a primary risk factor for the development of drug resistance in children, along with an interrupted course of chemoprophylaxis. Analysis of the forms of drug resistance in pediatric TB showed gen- eralized resistance to FLDs in 89 percent of children. Forty percent were resistant to kanamycin, and 38.5 percent had MDR TB. One child in the group was resistant to all drugs. In the study, 9.2 percent of children with drug-resistant forms of the disease were resistant to a single drug, and 52 percent had polyresistance. Children with DR TB were 1.8 times more likely to have acute onset of the disease and 2.2 times more likely to have significant symptoms, Aksenova said, while children from the control group were three times as likely to have multiple symptoms at the outset. Accelerated disease was typical for children with drug-resistant strains but was seen less often in those in the control group. The type of treatment needs to be based on the resistance, Aksenova said. In addition, children who have contact with patients with MDR TB should take preventive therapy with two anti-TB drugs for 6 months, which is compulsory in pediatric sanatoria in Russia. Prevention is also key. Timely detection and proper treatment of the disease in adults are crucial for protecting children from infection. For chronic forms of TB, reliable isolation of children from the patient is prefer- able. Better continuity between adult and pediatric services could contribute to tracking and preventing the spread of infection. Recommendations for preventing transmission should be distributed to patients who have contact with children, Aksenova said. Refusal of treatment and lack of isolation are challenges for doctors, and outreach is

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62 DRUG-RESISTANT TUBERCULOSIS IN CHINA AND THE BRICS necessary to explain the value of preventive care, regular exams, and proper treatment protocols. Improving the socioeconomic situation, providing effective drugs, using modern treatment methods, and ensuring that patients adhere to their treat- ment would help control the spread of resistant TB strains in Russia. Russia has both a federal target program for preventing socially significant diseases and a subprogram for urgent measures to address TB. Aksenova concluded her presentation with a quote from Lucica Ditiu, executive secretary of the Stop TB Partnership: “Every day TB kills 200 children. And this is despite the fact that the therapy which prevents disease in children is less than 3 cents a day, and treatment of the disease costs 50 cents a day. But before we can provide prevention and treatment, we have to find those at risk of TB, and this is possible only when governments, civil society and the private sector work together.”