TB AND M/XDR-TB: FROM CLINICAL MANAGEMENT TO CONTROL AND ELIMINATION

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1 ersnet.org/school TB AND M/XDR-TB: FROM CLINICAL MANAGEMENT TO CONTROL AND ELIMINATION May Bucharest, Romania SCHOOL COURSE 2012 Educational Material Thank you for viewing this document. We would like to remind you that this material is the property of the author. It is provided to you by the ERS for your personal use only, as submitted by the author by the author

2 TB in children: still a real problem? Dr. G.B. Migliori WHO Collaborating Centre for TB and Lung Diseases Fondazione S. Maugeri Care and Research Institute Via Roncaccio Tradate Italy giovannibattista.migliori@fsm.it Aims By the end of this Unit, participants will be able to: Discuss the special features of TB in children. Describe the strategic approaches to preventing and managing TB in children. Describe the main activities to be carried out by the NTP for implementation of interventions to prevent and manage TB in children. Identify suitable strategies for increasing children s visibility in NTP guidelines in line with International Standards in own setting. Summary The key intervention to achieve TB control is represented by rapid identification and effective treatment of infectious (e.g. sputum smear positive) cases. As diagnosis and treatment of TB in children is difficult, and children were considered not relevant for transmission, this specific area has been neglected by National TB Programmes. Presently, the WHO Stop TB Strategy clearly emphasises the importance of managing children based on quality standards, and the ISTC and ESTC underlines how to act in practice. This presentation will systematically revise the existing recommendations for diagnosis, treatment and prevention of TB in childhood. The presentation is composed of four sections: 1. The first section is aimed at introducing the topic, describing the special features of TB in children. 2. The second section, describes the strategic approaches to preventing and managing TB in children, with special focus on diagnosis and treatment. 3. The third section introduces the main activities to be carried out by the NTP for implementation of interventions to prevent and manage TB in children. 4. The fourth section identifies suitable strategies for increasing children s visibility in NTP guidelines in line with International Standards in own setting. Several pictures are included to allow further discussion of the topic presented. Introducing the topic: the special features of TB in children Tuberculosis (TB) is difficult to manage in children. In terms of diagnosis TB is often paucibacillary, so that the traditional bacteriological diagnosis is difficult. The known difficulty infants have in producing sputum further complicates things. In addition, chest radiography is often negative and, generally, difficult to read as small children do not collaborate much. The available tests to diagnose TB infection (TST and IGRAs) are difficult to interpret. Overall, evidence on new tests is less brilliant in children than in adults. Although evidence is growing on the use of GeneXpert in children, much should be done in terms of operational research to answer the still unanswered questions. In terms of treatment, less evidence is available on treatment of HIV and M/XDR-TB and there is a lack of paediatric formulations. 225

3 Strategic approaches to preventing and managing TB in children, with special focus on diagnosis and treatment This presentation will discuss in detail the principles for diagnosis, treatment and prevention, including the use of score methods. The risk of TB is significantly increased when there is an active, infectious TB case (SS+) in the household, or when the child is malnourished, HIV infected, or has had measles in the past few months. Therefore, TB should be suspected in any child with: 1. A history of: Unexplained weight loss or failure to grow normally Unexplained fever, especially when it continues for >2 weeks Chronic cough for >2/3 weeks Exposure to an adult with probable or definite SS + pulmonary TB 2. An examination with: Fluid on one side of the chest (reduced air entry, dullness to percussion) Enlarged non-tender lymph nodes or a lymph node abscess, especially in the neck Signs of meningitis, especially when these develop over several days and the spinal fluid contains mostly lymphocytes and elevated protein Abdominal swelling, with or without palpable lumps Progressive swelling or deformity in the bone or a joint, including the spine A diagnosis of TB is strongly suggested in the presence of three or more of the following: chronic symptoms suggestive of tuberculosis physical signs highly suggestive of tuberculosis a positive tuberculin skin test chest X-ray suggestive of TB. The recommended approach for diagnosis of tuberculosis in children includes the following: 1. Careful history (including history of TB contact and symptoms consistent with TB) 2. Clinical examination (including growth assessment) 3. Tuberculin skin testing (or IGRAs) 4. Bacteriological confirmation whenever possible 5. Investigations relevant for suspected pulmonary or extrapulmonary TB 6. HIV testing (in areas of high HIV prevalence). As a rule, a paediatric case of TB should be treated with a four drug regimen (HRZE) for 2 months followed by a two drug regimen (HR) for 4 months at the following doses: H - 10 mg kg -1 (range mg kg -1 ); maximum dose 300 mg day -1 R - 15 mg kg -1 (range mg kg -1 ); maximum dose: 600 mg day -1 Z - 35 mg kg -1 (30 40 mg kg -1 ) E - 20 mg kg -1 (15 25 mg kg -1 ) Only in areas with a very low prevalence of HIV and isoniazid resistance the 3 drug regimen (HRZ) is presently recommended during the intensive phase of treatment. Main activities to be carried out by the NTP for implementation of interventions to prevent and manage TB in children Strategies for increasing children s visibility in NTP guidelines in line with International Standards in own setting The old style statement, Little transmission, little priority! has greatly influenced the present position of childhood TB in the public health agenda. Fortunately the ISTC and ESTC documents have made it very clear that children are just as important as all the other TB patients. Therefore several ACSM (Advocacy, Communication and Social Mobilization) initiatives have been undertaken by the Stop TB Partnership through its Childlhood TB sub-group and by ECDC to advocate for an increased visibility of this important topic. 226

4 Finally, there is a need for a specific research agenda, able to answer the many unanswered queries which are still pending. Conclusions The epidemiologic evidence indicates that children account for a significant fraction of the overall incidence of mortality for TB. All efforts should be made to ensure the highest possible visibility for this delicate topic. References 1. Raviglione MC, Uplekar MW. WHO s new Stop TB Strategy. Lancet 2006; 367: This key article introduces the WHO s New Stop TB Strategy. Note that DOTS is the first element of it. Reading of this article is highly recommended to all participants 2. World Health Organization. Global tuberculosis control: WHO report World Health Organization Document 2011, Publication No. WHO/HTM/TB/ The document provides information on the present status of TB control worldwide, with the main focus on the high burden countries (Russia being the only one in Europe). The key TB control indicators are presented by WHO Region and by country. A more detailed Country presentation sheet has been developed for high burden countries. The new 2011 WHO report includes new information on children, and new improved estimates from Africa (including better estimates on children orphaned by AIDS and TB). 3. Tuberculosis Coalition for Technical Assistance. International Standards for Tuberculosis Care (ISTC), 2nd Edn. Tuberculosis Coalition for Technical Assistance, The Hague, The International Standards for TB Care is a pivotal document presenting the key standards for diagnosis, treatment and public health. Each standard is explained synthetically, while the rationale and its scientific background are also available. The Standards represent a practical guide for the clinician, to be used daily. The ISTC are complementary to the existing guidelines. The 2nd edition of the ISTC include a specific standard for children. 4. Migliori GB, Zellweger JP, Abubakar I, et al. European Union Standards for Tuberculosis Care. Eur Respir J; In press. 5. Migliori GB, Sotgiu G, Blasi F, et al. Towards the development of EU/EEA Standards for Tuberculosis Care (ESTC). Eur Respir J 2011; 38: These articles, the ESTC (EU Standards for TB Care) and the Editorial, introduce the results from a collaboration between ECDC and ERS. The ISTC have been adapted to the EU context, with explicit reference to the need to implement new rapid diagnostics without delay. They refer to both adults and children. ERS has designed the clinical standards, while ECDC has coordinated the public health ones, the documents are available online. 6. World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children. World Health Organization Document 2010, Publication No. WHO/HTM/TB/ This WHO guideline gives all the details necessary to address adequate diagnosis, treatment and prevention of TB in children. 7. World Health Organization. Rapid advice: treatment of tuberculosis in children. World Health Organization Document 2010, Publication No. WHO/HTM/TB/ This new evidence-based document answers a few specific questions on regimen and drug dosage choice in childhood. The results of the systematic reviews performed to inform the guidelines are reported in a synthetic manner. 8. World Health Organization Stop TB Partnership Childhood TB Subgroup. Chapter 4: childhood contact screening and management. Int J Tuberc Lung Dis 2007; 11: This article summarises the evidence available up until 2007 on contact screening and management. The document is produced by the Stop TB Partnership Childhood sub-group. 9. Fourie PB, Becker PJ, Festenstein F, et al. Procedures for developing a simple scoring method based on unsophisticated criteria for screening children for tuberculosis. Int J Tuberc Lung Dis 1998; 2: Edwards DJ, Kitetele F, Van Rie A. Agreement between clinical scoring systems used for the diagnosis of pediatric tuberculosis in the HIV era. Int J Tuberc Lung Dis 2007; 11:

5 These two articles summarise the status of the art of the scoring system, a useful support to diagnose TB in childhood. Useful for clinicians looking for a score method. 11. Donald PR, Maher D, Qazi S. A research agenda to promote the management of childhood tuberculosis within national tuberculosis programmes. Int J Tuberc Lung Dis 2007; 11: This article summarises the research priorities for childhood TB management. Evaluation 1. How many cases of TB in children are notified every year? And how many deaths? 2. Why is TB management difficult in children? 3. What is the ISTC document? 4. What is the ESTC document? 5. What are the criteria to pose diagnosis of TB in childhood? 6. What is a score method? Can you give an example? 7. What is the WHO-recommended regimen to treat TB in childhood? 228

6 TB in children: still a real problem? GB Migliori WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Tradate Italy Learning objectives By the end of this Unit, participants will be able to: Discuss the special features of TB in children. Describe the strategic approaches to preventing and managing TB in children. Describe the main activities to be carried out by the NTP for implementation of interventions to prevent and manage TB in children. Identify suitable strategies for increasing children s visibility in NTP guidelines in line with International Standards in own setting. Special features of TB in children -1 About 1.5 million cases (10-15% of the total burden, 95% in DC) in children aged under 15 years, with 450,000 deaths Children with TB differ from adults in their response to the disease: this may have important implications for the prevention, diagnosis and treatment of TB. Increased risk of progression of primary M. tuberculosis infection to disease (target group for preventive treatment). Development of primary TB: more commonly than adults. Bacteriological confirmation of TB is often not possible in young children with pulmonary TB who usually cannot produce a sputum sample. 229

7 Special features of TB in children -2 Higher risk of developing TB meningitis and miliary TB (see the recommended treatment regimens in Guidance for national tuberculosis programmes on the management of tuberculosis in children). Co infection with HIV- clinically very difficult to distinguish Remains a diagnostic challenge Paucibacillary, rarely culture confirmed : Sputum smear positive in 10.3% (10 14 yr), 1.8% (5 9 yr) and 1.6% (<5 yr) Cultures positive 21% (10 14 yr), 5% (5 9 yr) and 4.2% (<5 yr) Special features of TB in children - 3 Immune responses are age-dependent: following infection, 40% < 2 yr, 25% 2-5 yr and 5-15% of older children will develop disease within 2 years TB: more likely to be extrapulmonary and disseminated, particularly in infants Newton, Kampmann The Lancet Infectious Diseases, August 2008; Vol 8: Special features of TB in children -4 There is an urgent need to improve the prevention, diagnosis and treatment of TB in children, by ensuring their inclusion in NTPs in line with international standards and guidelines Evidence-based approaches should be incorporated into existing NTP guidelines and strategies Care providers (paediatricians and other clinicians) engagement is crucial Changing and improving practices as contact investigation, R&R system and operational research is necessary for NTPs to prevent and manage TB in children 230

8 Strategic approach to preventing and managing tuberculosis in children 1. Prevention of TB. Screening children who are the household contacts of a TB case (usually an adult family member) to treat them or to start IPT. 2. Management of TB. Routine diagnosis, treatment, and recording and reporting of TB in children as part of routine NTP activities. Drug-resistant TB diagnosis and treatment in children should be carried out at referral centres. Prevention of TB in children TST and IGRAs are the best way to detect M. tuberculosis infection Chest X-ray (CXR) is the best method to screen for TB disease among contacts These tests should be used to screen exposed contacts When even TST and CXR, are not readily available, contact screening and management should be based on simplified algorithms (see next slide) Contact tracing when CXR and TST are not easily available 231

9 The problem: how to manage? Diagnosis Paucibacillary disease Difficulty in producing sputum CXR often negative, difficult to read TST (and IGRAs) difficult to interpret Limited evidence on new tests Treatment Less evidence on treatment of HIV and M/XDR-TB Lack of paediatric formulations Children and NTPs Little transmission, little priority! ISTC document: children are important Need for a research agenda The risk of TB is increased when there is an active case (SS+) in the household, or when the child is malnourished, HIV infected, or has had measles in the past few months. TB to be suspected in any child with: A history of: Unexplained weight loss or failure to grow normally Unexplained fever, especially when it continues > 2 weeks Chronic cough Exposure to an adult with probable or definite SS+ PTB On examination: Fluid on one side of the chest (reduced air entry, dullness to percussion) Enlarged non-tender lymph nodes or a lymph node abscess, especially in the neck Signs of meningitis, especially when these develop over several days and the spinal fluid contains mostly lymphocytes and elevated protein Abdominal swelling, with or without palpable lumps Progressive swelling or deformity in the bone or a joint, including the spine 232

10 ISTC: Treatment A patient-centered, gender-sensitive, age-specific individualized approach to treatment should be developed for all patients. A central element is direct observation by a treatment supporter 233

11 ESTC S 1: All persons presenting with signs, symptoms, history or risk factors compatible with TB should be evaluated for pulmonary and / or extrapulmonary TB S 2: All patients (adults, adolescents, and children who are capable of producing sputum) suspected of having pulmonary TB should have at least two sputum specimens submitted for SS, C and DST in a quality-assured laboratory. When possible, at least one early morning specimen should be obtained. In countries, settings or populations in which MDR-TB is suspected in a patient, rapid testing for the identification of R-resistance and when possible H-resistance, using validated tools in a quality-assured laboratory, should be done. ESTC S 6: In all children, suspected of having intrathoracic (i.e., pulmonary, pleural, and mediastinal or hilar lymph node) TB, bacteriological confirmation should be sought through examination of appropriate biological samples (by expectoration or induced sputum, bronchial secretions, pleural fluid or gastric washings) for SS, C and DST in a quality-assured laboratory. In the event of negative bacteriological results, a diagnosis of TB should be based on the presence of abnormalities consistent with TB on chest radiography, a history of exposure to an infectious case, evidence of TB infection (positive tuberculin skin test-tst and/or interferon-gamma release assay- IGRA), and clinical findings suggestive of TB. For children suspected of having extrapulmonary TB, appropriate specimens from the suspected sites of involvement should be obtained for microscopy and for culture and histopathological examination. 234

12 Diagnosis -1 Different criteria and definitions used (e.g. chronic cough: duration not specified, < 2 w, >3 w, 4 w or > 4 w) Waiting for a gold standard, standard approach relies on clinical criteria, CXR and TST Key definitions Close contact: living in the same household or frequent contact with SS+ TB Chronic cough: unremitting cough, not improving, present for > 21 days Fever: body temp >38 C for 14 days after common causes (malaria, pneumonia) have been excluded 235

13 Diagnosis 2 Diagnosis - 3 CXR: reading complicated by technical factors (inspiration, rotation) and inter-observer variation TST: different kind, dose, reading methods, cut-offs Recommended: RT 23 Copenhagen 2 TU induration (experienced readers) 10 mm, 5 mm high risk groups (malnutrition, HIV) Diagnosis

14 Diagnosis: score methods - 5 Direct smear is positive in <10-15%, culture <30-40%, through gastric lavage, sputum induction or nasopharyngeal aspiration The triad 1) known contact with adult index case; 2) positive TST; 3) suggestive signs on CXR is recommended by ISTC for low incidence countries A UNION study demonstrated that the weight of each criterion included in the score method depends on the setting (3 settings identified: high, intermediate and low incidence countries) Diagnosis: score methods - 6 In children 3 yrs a 2006 community-based study by Marais in HIV- children demonstrated that chronic cough+failure to thrive during preceding 3 Months +fatigue had 82.3% Sensitivity and 90.2% Specificity Clinical presentation of TB is not substantially different between HIV+ and HIV- children (HIV+ more likely to have malnutrition+lymphadenopathy+history of TB, reaching higher scores) Existing score methods: Sens 56-91%, Spec 25-97% 1 out of 7 children would not have received treatment according to at least 1 of the 8 major scales compared 237

15 Diagnosis of TB in children (Summary) -7 Key risk factors for tuberculosis Household contact of a newly diagnosed smear-positive case Age <5 years HIV infection Severe malnutrition A diagnosis of tuberculosis is strongly suggested in the presence of three or more of the following: 1. chronic symptoms suggestive of tuberculosis 2. physical signs highly suggestive of tuberculosis 3. a positive tuberculin skin test 4. chest X-ray suggestive of TB. Diagnosis of TB in children - 8 Recommended approach for diagnosis of tuberculosis in children: 1. Careful history (including history of TB contact and symptoms consistent with TB) 2. Clinical examination (including growth assessment) 3. Tuberculin skin testing (or IGRAs) 4. Bacteriological confirmation whenever possible 5. Investigations relevant for suspected pulmonary or extrapulmonary TB 6. HIV testing (in areas of high HIV prevalence) Diagnosis of TB in children in Kenya Presence of 2 or more of the following symptoms Cough > 2weeks Weight loss or poor weight gain Persistent fever and/or night sweats > 2 weeks Fatigue, reduced playfulness, less active PLUS: Presence of 2 or more of the following: Positive contact history Respiratory signs CXR suggestive of PTB (where available) Positive Mantoux test (where available) THEN: PTB is likely, and treatment is justified 238

16 Diagnosis of TB in children Features in the source case suggestive of drug-resistant TB contact with a known case of drug-resistant TB; remains sputum smear-positive after three months of treatment; history of previously treated TB; history of treatment interruption. 2. Features of a child suspected of having drug-resistant TB contact with a known case of drug-resistant TB; not responding to the anti-tb regimen; recurrence of TB after adherence to treatment. TB treatment in children Treatment regimens are adopted from adult schemes Children respond very well to treatment Dosages need to be adjusted for weight: Pharmakokinetics in children differ from adults - INH mg/kg, rapid acetylators (1) - Ethambutol mg/kg (2) Problems with treating TB in the HIV-infected child on ART 1: Schaaf et al, Arch Dis Child 2005; 90:614 2: Donald et al, Int J Tuberc Lung Dis 2006; 10:1318 Treatment of TB in children - 1 Children living in settings with high HIV prevalence and/or high H resistance, with suspected or confirmed PTB or peripheral lymphadenitis, or children with extensive pulmonary disease living in low HIV prevalent or low H resistance settings should be treated with a four drug regimen (HRZE) for 2 months followed by a two drug regimen (HR) for 4 months at the following doses: H - 10 mg/kg (range mg/kg); maximum dose 300 mg/day R - 15 mg/kg (range mg/kg); maximum dose: 600 mg/day Z - 35 mg/kg (30-40 mg/kg) E - 20 mg/kg (15-25 mg/kg) Strong recommendation, moderate quality evidence If meningitis & Pott s Disease; continuationphase: 10 months 239

17 Treatment of TB in children -2 Children with suspected or confirmed pulmonary TB or TB peripheral lymphadenitis who live in a setting with a low HIV prevalence and/or low H resistance and children who are HIV negative can be treated with a three drug regimen (HRZ) for 2 months followed by a two drug (HR) regimen for 4 months at the following doses: H - 10 mg/kg (range mg/kg); maximum dose 300 mg/day R - 15 mg/kg (range mg/kg); maximum dose: 600 mg/day Z - 35 mg/kg (30-40 mg/kg) Strong recommendation, moderate level of evidence Use of FQ Children with proven or suspected PTB or TB meningitis caused by MDR bacilli can be treated with a fluoroquinolone in the context of a well functioning MDR-TB programme and within an appropriate MDR-TB regimen. This should be done by a clinician experienced in the management of paediatric TB Strong recommendation, very low quality evidence) Second-line anti-tb drugs

18 Use of corticosteroids Use: for some complicated forms of TB (TB meningitis, complications of airway obstruction by TB lymph glands and pericardial TB). If advanced TB meningitis: corticosteroids improve survival and decrease morbidity. Corticosteroids may be useful in some cases of immune reconstitution. Treatment support Education about TB and the importance of completing treatment is necessary. Support from the child s parents and immediate family is vital to ensure a satisfactory treatment outcome. A trained community member (preferably someone other than the child s parent or immediate family) can be responsible for TB management instead of a healthcare worker. All children should receive treatment free of charge. Patient treatment cards are recommended for documenting treatment adherence. Hospital care Conditions that need hospitalization include: TB meningitis and miliary TB, preferably for at least the first two months; Respiratory distress; Spinal TB; Severe adverse events, such as clinical signs of hepatotoxicity (e.g. jaundice). Some children may require hospitalization for social or logistic reasons. 241

19 HIV-infected children TB in children infected with HIV should be treated, as for children who are not infected with HIV, with a 6-month regimen. Where possible, treat HIV-infected children with rifampicin for the entire duration of treatment. Most children with TB, including the HIV-infected ones, have a good response to the 6-month regimen. Possible causes of failure: non-compliance with therapy poor drug absorption drug resistance alternative diagnoses HIV-infected children Evaluate all children with HIV and TB co-infection to determine whether ART is indicated during the TB treatment. Arrange access to ARV drugs for patients who meet indications for treatment. Consultation with an expert in HIV/TB treatment is recommended before initiation of concurrent treatment. Initiation of TB treatment should not be delayed. Children with TB and HIV co-infection should also receive co-trimoxazole as prophylaxis for other infections. HIV-infected children Anti-TB treatment is the priority; however, the optimal timing for ART initiation is not known. When to start ART: balance between the child s age, pill burden, potential drug interactions, overlapping toxicities and possible SIRS versus the risk of further progression of immune suppression with its associated increase in mortality and morbidity. Many clinicians start ART 2 8 weeks after starting anti-tb treatment. 242

20 Main activities to be carried out by the NTPs for implementation of interventions to prevent and manage tuberculosis in children 1. Preparations: Advocate to health authorities for mainstreaming of childhood TB interventions as part of routine NTP activities, in collaboration with the maternal and child health programme; Conduct a situation analysis of the extent to which childhood TB interventions are mainstreamed as part of routine NTP activities, of currently available data on prevention, case finding and treatment outcome, and of resources available for implementation of childhood TB interventions; Main activities to be carried out by the NTPs for implementation of interventions to prevent and manage tuberculosis in children Adapt NTP guidelines to reflect childhood TB interventions; Adapt maternal and child health guidelines to reflect childhood TB policies; Engage with key community stakeholders (academics, activists, etc.) to develop appropriate information, education and communication (IEC) material; Ensure effective linkages with HIV control services in settings with high HIV prevalence. Main activities to be carried out by the NTPs for implementation of interventions to prevent and manage tuberculosis in children 2. Facilitate meetings with relevant health and other authorities at national, regional or provincial and district level to ensure engagement of all health providers: - Government - NGOs - Private sector - Religious and charity organizations 243

21 Main activities to be carried out by the NTPs for implementation of interventions to prevent and manage tuberculosis in children 3. Training to implement childhood TB interventions: Develop and produce training material for health staff based on national guidelines; Develop and produce training material for community participants (e.g. those involved in contact tracing and case-finding, and in promoting and encouraging adherence as treatment supporters ); Sensitize health staff and relevant community members regarding the nature and extent of the problem of childhood TB, and motivate them to share responsibility for contact tracing, casefinding and treatment support. Main activities to be carried out by the NTPs for implementation of interventions to prevent and manage tuberculosis in children 4. Delivery of childhood TB interventions as part of routine NTP activities Assess drug procurement system for effectiveness in ensuring availability of quality-assured formulations of anti-tb drugs for children (and consider obtaining these drugs through the GDF); Monitor results of contact tracing, case-finding and treatment support; Check how effectively the routine NTP recording and reporting system is capturing the data on case-finding and treatment outcomes; Evaluate how effectively the full range of health providers is mobilized to contribute to making high-quality childhood TB interventions universally accessible; Assess effectiveness of the system of tuberculin procurement. Main activities to be carried out by the NTPs for implementation of interventions to prevent and manage tuberculosis in children 5. Advocacy, communications and social mobilization (ACSM) activities Incorporate messages about childhood TB in ACSM activities for health promotion; Advocate for commitment and funds to ensure universal access to high-quality childhood TB interventions as part of routine NTP activities. 244

22 Policy changes related to children R&R: NTPs should record and report 0 4 and 5 14 yrs age groups - To differentiate 2 main NTP targets in the paediatric age - To specifically analyse trends and outcomes - To target guidelines (e.g. 0-4 yrs: score methods; gastric washing; specific drug formulations, etc) - To improve procurement of child-friendly formulations - To be consistent with age groupings used in the Integrated Management of Childhood Illness (IMCI). Dose of Ethambutol: revised recommended dose is 20 mg/kg (range mg/kg) daily. A literature review indicates that ethambutol is safe in children of all ages at this dose Children and TB programmes: Indicators for NTP -1 Children and TB programmes: Recommendations to NTPs - 2 NTPs should R&R 2 age groups for children (0 4 yrs and 5 14 yrs) using the quarterly reporting form Revised recommended daily dose E: 20 mg/kg (15 25 mg/kg) All children to be managed by NTPs under the STB Strategy Basic tools for diagnosis should be available (e.g. CXR,TST) Contacts of SS+ cases should undergo contact investigations Diagnosis and treatment of TB in children infected with HIV merits special consideration (e.g. HIV testing and counselling) Special care for diagnosis/management of DR children BCG at birth in countries with a high TB prevalence 245

23 Children and TB programmes: priorities for research- 3. To improve: Understanding of the epidemiology of childhood TB and monitoring of NTPs performances Criteria to suspect and diagnose paediatric TB, based on agreedupon definitions Knowledge on pharmacokinetics and toxicity of drugs leading to better formulations and long-term treatment outcomes Access to contact screening and TLTI for contacts of both susceptible and DR cases with effective regimens Quality management by staff and families within STB Strategy New drugs, diagnostics and vaccines CALL TO ACTION for CHILDHOOD TB We, participants gathered at the International Childhood Tuberculosis Meeting held March 17-18, 2011 in Stockholm, Sweden recognize that: Worldwide, about 1 million TB cases occur each year in children under 15 years of age. The true burden of TB in children is unknown because of the lack of child-friendly diagnostic tools and inadequate surveillance and reporting of childhood TB cases. Children with TB infection today represent the reservoir of TB disease tomorrow. Children are more likely to develop more serious forms of TB such as miliary TB and TB meningitis resulting in high morbidity and mortality. Despite policy guidelines, the implementation of contact tracing and delivery of isoniazid preventive therapy (IPT) to young and HIV-infected children is often neglected by public health programmes. Most public health programs have limited capacity to meet the demand for care and high-quality services for childhood TB. TB care for children is not consistently integrated into HIV and care and maternal and child health programs. BCG, the only licenced TB vaccine, has limited efficacy against the most common forms of childhood TB and its effect is of limited duration. Due to inadequate case detection it is estimated that a large number of children suffering from TB are not appropriately treated. This is further compounded by drug stock outs and the lack of child-friendly formulations of drugs for TB treatment and prevention. Children are rarely included in clinical trials to evaluate new TB drugs, diagnostics or preventive strategies. To address this current situation, we call for: NTPs to include and prioritize childhood TB in their national strategic plans to address MDGs for children and pregnant women. All health care providers to integrate childhood TB into their services. The scientific community to include children (all ages) in clinical and operational studies. TB drug and diagnostic product developers to specifically include children in development plans and implementation of research at an early stage. Donors to encourage collaboration with researchers, local communities, NTPs and other stakeholders to address the growing problem of childhood TB concentrating on: Innovative research to develop child-friendly TB diagnostics, drugs, biomarkers and vaccines The strengthening of public health facilities and services so that mothers and children with and without HIV can receive appropriate TB care Providers of technical assistance to invest in building local technical and programmatic capacity to prevent, diagnose and treat TB in children in all age groups. The WHO to accelerate in-country adoption and use of childhood TB guidelines. Policy makers to adopt the existing and new WHO recommendations for childhood TB, evaluate implementation, scale-up and assess the impact of implementation strategies. Civil society to demand equitable prevention, diagnostics, treatment and care services for childhood TB and to monitor the scale- up of these services. 246