*4.5.6. Treatment of extrapulmonary paeditric PTB*

Treatment is as for pulmonary disease, with isoniazid, rifampicin, pyrazinamide and etham‐ butol for two months followed by isoniazid and rifampicin for four months, except for CNS disease when treatment should be continued for a full year. Steroids may be used in pericardial and meningeal disease. Surgery is usually unnecessary, especially where lymph glands and abscess are present, as long term discharging sinuses may result. Surgery is sometimes necessary in spinal TB where there is instability and may be needed to overcome strictures in genito-urinary or gastro-intestinal disease. Occasionally pericardectomy may be required when pericardial disease causes tamponade.

response to initial treatment. Acquired resistance is well described in HIV co-infected adults previously treated for TB, possibly due to malabsorption of anti-TB drugs (Wells, et al., 2007). The presence of acquired resistance in the paediatric population is reported and in particular

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Although the principles of DOTS Plus have been put forward for the management of MDR TB, at the moment, there is no consensus for any regimen or optimal treatment that should be used for persons with known exposure to MDR-TB. The recommendation by CDC is a combination of pyrazinamide and ethambutol, with either pyrazinamide or a fluoroquinolone and that immunocompetent contacts should be treated for 6 months while immunocompro‐ mised contacts should be treated for 12 months. Current guidelines recommend using at least four drugs to which the patient is naïve, including an injectable and a fluoroquinolone, in an initial phase of at least 6 months; followed by at least three of the most active and best tolerated

Standardised regimens have been developed for settings where drug susceptibility testing is not available (WHO, 2006). Six classes of second-line drugs (SLDs) are available (WHO, 2003) but experience in children is limited for the majority and multi-centre paediatric trials are needed. Under optimum circumstances MDR-TB responds well to appropriate therapy. However delays in diagnosis and treatment, adherence issues, and a lack of child-friendly formulations and strategies for DOTS all frequently complicate management and contribute

The WHO currently recommends avoidance of chemoprophylaxis in cases of contact with known MDR-TB and to observe for 2 years if clinically asymptomatic. Children with latent MDR-TB infection become the reservoir for future transmission following disease reactivation in adulthood, emphasizing the need to further research and improved management of MDR-

According to the European Centre for Disease Prevention and Control (ECDC) 2012 Guide‐ lines, there are two valid options to consider for the management of MDR TB and XDR TB contacts; preventive treatment or follow-up by careful clinical observation. The purpose of preventive therapy is to prevent the progression of LTBI to TB disease in an individual who has been exposed to MDR/XDR TB. The concept of preventive therapy has been shown to be effective for LTBI after contact with drug-susceptible TB but corresponding evidence for preventive therapy of MDR TB and XDR TB contacts is very scarce. Although for children there are indications of a positive effect of preventive therapy, for other groups of contacts, the necessary body of evidence has yet to be generated, and there are ongoing studies to collect

evidence in support of the use of preventive therapy in contacts of MDR TB cases.

There is currently no evidence available on the optimal follow-up time in contacts of MDR TB or XDR TB with regard to patient benefits and costs of the intervention. In young children under five years of age the majority ( over 90%) of TB disease will devel‐ op within 12 months of infection. Infants and children under five years of age, immuno‐ compromised individuals due to HIV infection or TNF-antagonist treatment are at increased risk of progression from LTBI to TB disease. These individuals as well as other

children with TB/HIV co-infection should be closely monitored (Soeters et al., 2005).

drugs in a 12-18 month continuation phase.

to a high morbidity and mortality (Drobac et al., 2006).

TB infection in children, both at the clinical and operational level.

#### *4.5.7. Treatment of latent paediatric TB infection*

Treatment of LTBI, also known as chemoprophylaxis, is important to prevent future disease activation. The fact that over 50% of hospitalized children with culture-confirmed TB have a reported close TB contact and do not receive chemoprophylaxis, is an indication of the important missed opportunities using existing public health interventions. For the last 20 years the WHO guidelines recommended all children under 5 years in close contact with an infectious (usually smear positive) case receive 6 months isoniazid. Once active disease has been excluded, isoniazid monotherapy for 6-9 months has been proven to reduce the TB risk in exposed children by over 90% with good adherence. More recent studies suggest that 3 months of combined isoniazid and rifampicin are equally effective (Ena and Valls, 2005). In a recent study with very short follow-up, continuous isoniazid prophylaxis for HIV-infected children without documented evidence of latent infection, but living in an environment of high exposure, has also been shown to reduce overall morbidity and mortality from TB and other infections (Zar et al., 2007). Further trials in HIV-infected children receiving ART are ongoing.

Recommendations for chemoprophylaxis will continue to differ in TB-endemic and nonendemic settings, because of the perceived risk of exposure. Whilst most paediatricians in Europe and North America would advocate chemoprophylaxis for HIV infected, TB-exposed children only, this needs to be interpreted with caution if the exposure is potentially ongoing or recurrent, and the ability to distinguish LTBI from active disease is limited. In this context, many practitioners in TB-endemic settings are reluctant to place children on chemoprophylaxis because of the potential emergence of resistant strains, if indeed the child has active disease instead of LTBI.

#### *4.5.8. Treatment of drug resistant paediatric TB*

Acquisition of resistance rarely occurs in children due to the paucibacillary nature of their disease but overall, children may also be subject to less selection pressure from anti TB therapy. Thus most resistance in children is due to primary transmission of a resistant organism, and MDR /XDR-TB rates in children reflect community transmission rates. Diagnosis requires a high index of suspicion as the culture yield in children makes definitive microbiological confirmation difficult. Resistance should be suspected if an index case has known resistant TB; the child shows initial improvement on anti-TB therapy and then deteriorates; or there is no response to initial treatment. Acquired resistance is well described in HIV co-infected adults previously treated for TB, possibly due to malabsorption of anti-TB drugs (Wells, et al., 2007). The presence of acquired resistance in the paediatric population is reported and in particular children with TB/HIV co-infection should be closely monitored (Soeters et al., 2005).

*4.5.6. Treatment of extrapulmonary paeditric PTB*

410 Tuberculosis - Current Issues in Diagnosis and Management

when pericardial disease causes tamponade.

*4.5.7. Treatment of latent paediatric TB infection*

instead of LTBI.

*4.5.8. Treatment of drug resistant paediatric TB*

Treatment is as for pulmonary disease, with isoniazid, rifampicin, pyrazinamide and etham‐ butol for two months followed by isoniazid and rifampicin for four months, except for CNS disease when treatment should be continued for a full year. Steroids may be used in pericardial and meningeal disease. Surgery is usually unnecessary, especially where lymph glands and abscess are present, as long term discharging sinuses may result. Surgery is sometimes necessary in spinal TB where there is instability and may be needed to overcome strictures in genito-urinary or gastro-intestinal disease. Occasionally pericardectomy may be required

Treatment of LTBI, also known as chemoprophylaxis, is important to prevent future disease activation. The fact that over 50% of hospitalized children with culture-confirmed TB have a reported close TB contact and do not receive chemoprophylaxis, is an indication of the important missed opportunities using existing public health interventions. For the last 20 years the WHO guidelines recommended all children under 5 years in close contact with an infectious (usually smear positive) case receive 6 months isoniazid. Once active disease has been excluded, isoniazid monotherapy for 6-9 months has been proven to reduce the TB risk in exposed children by over 90% with good adherence. More recent studies suggest that 3 months of combined isoniazid and rifampicin are equally effective (Ena and Valls, 2005). In a recent study with very short follow-up, continuous isoniazid prophylaxis for HIV-infected children without documented evidence of latent infection, but living in an environment of high exposure, has also been shown to reduce overall morbidity and mortality from TB and other infections (Zar et al., 2007). Further trials in HIV-infected children receiving ART are ongoing.

Recommendations for chemoprophylaxis will continue to differ in TB-endemic and nonendemic settings, because of the perceived risk of exposure. Whilst most paediatricians in Europe and North America would advocate chemoprophylaxis for HIV infected, TB-exposed children only, this needs to be interpreted with caution if the exposure is potentially ongoing or recurrent, and the ability to distinguish LTBI from active disease is limited. In this context, many practitioners in TB-endemic settings are reluctant to place children on chemoprophylaxis because of the potential emergence of resistant strains, if indeed the child has active disease

Acquisition of resistance rarely occurs in children due to the paucibacillary nature of their disease but overall, children may also be subject to less selection pressure from anti TB therapy. Thus most resistance in children is due to primary transmission of a resistant organism, and MDR /XDR-TB rates in children reflect community transmission rates. Diagnosis requires a high index of suspicion as the culture yield in children makes definitive microbiological confirmation difficult. Resistance should be suspected if an index case has known resistant TB; the child shows initial improvement on anti-TB therapy and then deteriorates; or there is no

Although the principles of DOTS Plus have been put forward for the management of MDR TB, at the moment, there is no consensus for any regimen or optimal treatment that should be used for persons with known exposure to MDR-TB. The recommendation by CDC is a combination of pyrazinamide and ethambutol, with either pyrazinamide or a fluoroquinolone and that immunocompetent contacts should be treated for 6 months while immunocompro‐ mised contacts should be treated for 12 months. Current guidelines recommend using at least four drugs to which the patient is naïve, including an injectable and a fluoroquinolone, in an initial phase of at least 6 months; followed by at least three of the most active and best tolerated drugs in a 12-18 month continuation phase.

Standardised regimens have been developed for settings where drug susceptibility testing is not available (WHO, 2006). Six classes of second-line drugs (SLDs) are available (WHO, 2003) but experience in children is limited for the majority and multi-centre paediatric trials are needed. Under optimum circumstances MDR-TB responds well to appropriate therapy. However delays in diagnosis and treatment, adherence issues, and a lack of child-friendly formulations and strategies for DOTS all frequently complicate management and contribute to a high morbidity and mortality (Drobac et al., 2006).

The WHO currently recommends avoidance of chemoprophylaxis in cases of contact with known MDR-TB and to observe for 2 years if clinically asymptomatic. Children with latent MDR-TB infection become the reservoir for future transmission following disease reactivation in adulthood, emphasizing the need to further research and improved management of MDR-TB infection in children, both at the clinical and operational level.

According to the European Centre for Disease Prevention and Control (ECDC) 2012 Guide‐ lines, there are two valid options to consider for the management of MDR TB and XDR TB contacts; preventive treatment or follow-up by careful clinical observation. The purpose of preventive therapy is to prevent the progression of LTBI to TB disease in an individual who has been exposed to MDR/XDR TB. The concept of preventive therapy has been shown to be effective for LTBI after contact with drug-susceptible TB but corresponding evidence for preventive therapy of MDR TB and XDR TB contacts is very scarce. Although for children there are indications of a positive effect of preventive therapy, for other groups of contacts, the necessary body of evidence has yet to be generated, and there are ongoing studies to collect evidence in support of the use of preventive therapy in contacts of MDR TB cases.

There is currently no evidence available on the optimal follow-up time in contacts of MDR TB or XDR TB with regard to patient benefits and costs of the intervention. In young children under five years of age the majority ( over 90%) of TB disease will devel‐ op within 12 months of infection. Infants and children under five years of age, immuno‐ compromised individuals due to HIV infection or TNF-antagonist treatment are at increased risk of progression from LTBI to TB disease. These individuals as well as other identified risk groups require special attention as part of the individual risk assessment (WHO, 2007; Salgado and Solovic et al., 2010).

disseminated forms of TB in young children, with a protective estimate ranging from 67%– 79% against TB meningitis and 58%–87% against miliary disease. A theoretical model esti‐ mated that a universal BCG vaccine program would have a beneficial impact in settings with prevalence rates of greater than 30 sputum smear-positive cases/100,000 population (WHO, 2007). However, there is no evidence of any BCG-induced protective effect in HIV-infected children. On the contrary, studies have documented BCG-induced disseminated disease and adverse reactions. Therefore, the WHO recommendations have been revised, making HIV infection a contraindication for BCG vaccination, even in settings where TB is highly endemic. Strategies required for effective implementation of this policy change include high uptake of maternal HIV testing coupled with implementation of proven strategies to prevent mother-tochild HIV transmission, including maternal treatment with HAART and early virological

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The revised recommendations present a dilemma for national programs. Although the benefits of BCG vaccine far outweigh the risk among HIV-uninfected children living in high areas with a high prevalence of TB, the risk is higher among HIV-infected infants with or without symptoms at the time of vaccination. National recommendations will need to consider a variety of factors, including the prevalence of TB in the population, the prevalence of HIV infection, the availability of HIV testing and facilities for prevention of mother-to-child transmission during pregnancy, the capacity to conduct follow-up of vaccinated children, and the availa‐ bility of early infant diagnosis of HIV infection. Abandoning the use of BCG vaccine before newer vaccines become available may put millions of young children at risk of TB. There is an urgent need for operational research in TB endemic countries to determine the best way to

The global commitment of the WHO and the Stop TB (WHO, 2005) campaign has spurred on the efforts of the international research community to develop a more effective anti-TB vaccine by the year 2015. In view of the proven efficacy of existing BCG vaccine in preventing disse‐ minated TB in children and reducing child mortality (Roth et al., 2006) two conceptually different strategies have been pursued: firstly, the development of 'priming vaccines', which, it is hoped, will replace BCG by providing better and longer protection; secondly, the design of 'booster vaccines' to boost pre-existing BCG-derived immunity. Novel vaccines currently under development all use a "booster-strategy" after priming with BCG in infancy (Doherty et al, 2007). As the current candidates are progressing through phase I and II trials, including studies in HIV-infected individuals and age-de-escalation, it is most likely that more than one

The most advanced vaccine candidate is MVA- 85A, currently in phase II under a prime-boost strategy with BCG. Four products are in phase I (72f, Hybrid 1, Aeras 402, rBCG-UreC-Hly), each stemming from PPPs. Many of the candidates are results from the EU FP6 projects, i.e.

diagnosis of HIV infection in infants, followed by treatment.

**5. On-going research targeting paediatric TB**

manage this issue programmatically.

vaccine will progress into phase III.

**5.1. New vaccine pipelines**

The optimal duration of MDR-TB treatment in children is not known. World Health Or‐ ganization guidelines recommend treatment until 18 months after the first negative cul‐ ture (24 months in XDR-TB). As children often have paucibacillary disease, documenting a culture conversion is usually difficult. Thus, the same duration as in adults would ap‐ ply. The duration of the intensive phase of treatment (when an injectable drug is given) should be at least 6 months. Surgical resection should be considered when the patient has localized lesions and has persistently positive smear or culture results inspite of ag‐ gressive chemotherapy (Shah, 2012).
