Second editionSecond editionGuidance for national tuberculosis programmes on the management of tuberculosis in children -2 nd ed.#
Children living with HIV infection have increased risk of TB exposure, infection, progression to disease, and TB-related morbidity and mortality. This risk is influenced by the degree of immune suppression. All children living with HIV infection in a TB-endemic setting should therefore be regularly screened for TB by clinical assessment at each visit to a health facility or contact with a health worker. Evaluation should aim to identify those patients who are likely to have TB disease, requiring anti-TB treatment, and those who should start IPT. Suspicion of TB disease in children with HIV is initially based on the presence of clinical symptoms. Clinical evaluation may be followed up with further investigations as appropriate (e.g. chest radiography). As for any child with suspected TB, attempts should be made to confirm diagnosis (e.g. culture, Xpert MTB/RIF assay) whenever possible (1).
Childhood HIV infection is particularly common in settings where antenatal HIV prevalence is high and PMTCT interventions are not widely implemented. The prevalence of HIV is therefore particularly high among infants and young children, an age-group also at risk for TB. In regions endemic for TB/HIV, TB is common in children living with HIV, and HIV infection is common in children with TB (1).
It is recommended that HIV testing be routinely offered to all children with suspected or diagnosed TB (1) -see also Recommendation 7, Chapter 3.

# aPProach to Diagnosis
The approach to diagnosing TB in children living with HIV is essentially the same as for diagnosis in HIV-negative children, as described in Chapter 3. This approach can be challenging in children living with HIV for the following reasons (2):
l Clinical features consistent with pulmonary TB are common in children living with HIV but may be due to other diseases and therefore lack specificity for a diagnosis of TB.
l Most children living with HIV are infected by mother-to-child transmission. The peak age prevalence for HIV is therefore in infants and young children (<5 years), who also make up the age group in which it is most difficult to confirm the cause of acute or chronic lung disease, including TB.
l TST is less sensitive in children living with HIV than in HIV-negative children; induration of >5 mm is considered positive if the child is living with HIV. Children living with HIV have a very high incidence of acute and chronic lung diseases other than TB.
l Children living with HIV may have lung disease of more than one cause (co-infection), which can mask response to therapy.
There is an overlap of radiographic findings in TB and other HIV-related lung disease.
Table 6 summarizes the impact of HIV infection on the approach to diagnosis of TB in children (2).

# Prevention of tb
Global efforts to control the co-epidemics of TB and HIV will benefit children. They include the expansion of PMTCT programmes, which will reduce the number of new HIV infections in young children. However, additional specific strategies are needed. As a minimum, all children living with HIV should be screened for TB and all children (and their families) with TB should be offered HIV testing and counselling in settings of high HIV prevalence (1).
Irrespective of age, all children living with HIV who are household contacts of infectious TB cases should be evaluated for TB disease and either treated for TB or given preventive therapy if screening finds that they are unlikely to have TB disease (see Chapter 5).
Innovative approaches are needed to ensure that co-infected children are identified and that, where possible, disease is prevented. This requires integration of services and collaborative TB/HIV activities by national TB and HIV programmes as well as other stakeholders (1).

# BCG vaccination
BCG vaccination should not be given to infants or children with known HIV infection because of the risk of disseminated BCG disease (3). This is discussed in more detail in Chapter 5.

# Contact screening and case-finding
The approach to screening and management of children who are contacts of a TB case and living with HIV is outlined in Chapter 5. A child living with HIV who is exposed to an infectious case of TB is at particular high risk of developing TB disease (1,4).
Current WHO recommendations (4) are that all household contacts of an infectious case of TB should be screened for symptoms of TB and that, if TB is excluded, preventive therapy should be offered to:
-HIV-negative children aged less than 5 years; and, -HIV-positive contacts of any age.
Recommendations for preventing TB in children living with HIV have not changed since the 2006 edition of the guidance (5) and remain consistent with recent guidelines (6). Symptom-based screening is recommended because children living with HIV who do not have suggestive symptoms such as poor weight gain, fever or current cough are unlikely to have TB disease (1,(6)(7)(8). Children living with HIV who are close contacts of an active TB case and with no evidence of TB disease should begin IPT regardless of age. The recommended dose of isoniazid for preventive therapy is 10 mg/kg (range 7-15 mg/kg, maximum 300 mg/day) daily for at least 6 months. Providing IPT to people living with HIV does not increase the risk of developing isoniazid-resistant TB: concerns regarding the development of isoniazid resistance should not be a barrier to providing IPT (2,8,9).

# Primary prophylaxis
Recommendations have also been made for IPT for infants and children living with HIV who are considered unlikely to have TB and with no known exposure to TB; this is also known as primary prophylaxis (6,7,10,11).
n Recommendation 25

# Children living with HIV who are more than 12 months of age and who are unlikely to have TB disease on symptom-based screening and have no contact with a TB case:
should be offered 6 months of IPT (10 mg/kg per day, range 7-15 mg/ kg, maximum dose 300 mg/day) as part of a comprehensive package of HIV prevention and care services if living in settings with a high TB prevalence (Strong recommendation, low quality of evidence)
might be offered 6 months of IPT (10 mg/kg per day, range Remark a: The Panel considered recent evidence (7, 10) that was not published at the time of the development of the 2011 Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resourceconstrained settings (6). The Panel noted that this large, prospective, randomized, controlled trial did not show any benefit of primary prophylaxis.

# Remark b:
Reviewing the original trial that was the basis for the 2011 recommendations (6) and that showed the benefit of primary prophylaxis, the Panel found that it represented an epidemiological context that may not be widely representative (coming from one of the highest TB burden settings). In addition, the Panel noted that the epidemiological context of that trial predated the introduction of ART in children living with HIV, and would therefore not be representative of the situation in 2013. Finally, that study had been stopped early, following interim analysis. There was also an acknowledged difficulty in interpreting the study: the reduced mortality reported was not a reduction in deaths attributed primarily to TB.
These findings were discussed in a subsequent conference call between the Panel of this guidance and the Panel of the 2011 guidelines; both Panels suggested that the original recommendation, from the 2011 document, should be split into two separate recommendations as above.
In high TB prevalence settings, 6 months of IPT may have additional benefits to that of ART in protecting against TB. However, in settings with a medium to low prevalence of TB, IPT might be offered considering resource implications. The Panel recommended further research in this area.
WHO recommends symptom-based screening, which is presented schematically in Figure 3.  Children living in settings where the prevalence of HIV is high should be treated with a four-drug regimen (HRZE) for 2 months followed by a two-drug regimen (HR) for 4 months at the dosages specified in Recommendation 8 (see Recommendation 8). Children with suspected or confirmed pulmonary TB or tuberculous peripheral lymphadenitis in settings with a high HIV prevalence (or with confirmed HIV infection) should not be treated with intermittent regimens (that is, twice-or thrice-weekly doses) (see Recommendation 26).
Each child should be assessed 2 weeks after the start of TB treatment then reviewed monthly with clinical monitoring, which should include symptom assessment, weight measurement, assessment of adherence to treatment and enquiry about any adverse events. Dosages of anti-TB drugs should be adjusted to account for any weight gain.
Most children living with HIV with drug-sensitive TB who are compliant with therapy have a good response to the 6-month regimen. Possible reasons for treatment failure are non-compliance with therapy, drug-resistant TB or alternative diagnoses (incorrect diagnosis of TB).
All children living with HIV who have successfully completed treatment for TB disease should receive isoniazid for an additional 6 months (6).
When compared with HIV-negative children, responses to TB treatment and outcome are poorer for children living with HIV. Before the availability of ART, many deaths in children with TB/HIV occurred in the first 2 months following the start of TB treatment. Medical risk factors for poor treatment response and mortality include severe malnutrition, coinfections, severe immunosuppression and high viral load.
Additional therapy recommended for HIV-infected children with TB, which may help to improve TB treatment outcomes, includes co-trimoxazole preventive therapy, the early start of ART (see below) and pyridoxine supplementation along with nutritional support (see details in Chapter 4).

# Co-trimoxazole preventive therapy
Co-trimoxazole is a broad-spectrum antimicrobial agent that prevents a range of secondary bacterial and parasitic infections in eligible adults and children living with HIV. Daily prophylaxis -co-trimoxazole preventive therapy (CPT) -prolongs survival in children living with HIV and reduces the incidence of co-morbidities. It also reduces the risk of co-infections such as pneumocystis pneumonia in HIV-exposed infants. CPT is therefore recommended for all HIV-exposed infants and children living with HIV, including those with TB (1), and should be implemented as an integral component of a package of HIVrelated services (13).
The indications for initiating, discontinuing and monitoring CPT are included in the 2006 WHO guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults: recommendations for a public health approach (14).

# Antiretroviral therapy
Antiretroviral therapy (ART) in children living with HIV aims to improve the length and quality of life, reduce HIV-related morbidity and mortality by reducing the incidence of opportunistic infections (including TB), reduce the viral load, restore and preserve immune function, and restore and preserve normal growth and development. ART improves TB treatment outcomes for children living with HIV.
WHO (13) recommends that ART be provided to all people with a confirmed HIV diagnosis and a CD4 count of 500 cells/mm3 or less, giving priority to those with severe/advanced HIV disease or a CD4 count of 350 cells/mm3 or less. WHO also recommends that ART be initiated in people with active TB and HBV co-infection with severe liver disease, all pregnant and breastfeeding women with HIV, all children younger than 5 years living with HIV and all individuals with HIV in serodiscordant relationships, regardless of CD4 cell count.
TB treatment should be started first, followed by ART as soon as possible thereafter (and within 8 weeks of the start of TB treatment). For those with a CD4 count below 50 cells/ mm3, ART should be provided within 2 weeks of the start of TB treatment (13). Table 7 summarizes the recommendations on when to start ART in children.
For first-line ART, use of simplified and less toxic regimens -as fixed-dose combinations whenever possible -is recommended as the most effective and convenient approach.
Regimens comprising a non-thymidine nucleoside reverse-transcriptase inhibitor (NRTI) backbone (tenofovir disoproxil fumarate (TDF) or abacavir (ABC) + lamivudine (3TC)) and one non-nucleoside reverse-transcriptase inhibitor (NNRTI) efavirenz (EFV) are maintained as the preferred choices in adolescents and children older than 3 years. For children younger than 3 years, a protease inhibitor (PI)-based regimen is the preferred approach in combination with ABC or zidovudine (AZT) (13). Selecting ARV regimens that are compatible with TB therapy is essential. Interactions between rifampicin and lopinavir/ritonavir (LPV/r) or nevirapine (NVP) mean that cotreatment in children under three years is challenging, but a recent large randomized controlled trial of ART in children has generated preliminary evidence on the efficacy of triple nucleoside therapy which, despite limited data in the context of TB co-treatment, offers a suitable option for children who require TB treatment while already receiving ART (13,15).
Table 8 below gives a summary of recommended ART regimens for children in need of TB treatment (13).
WHO also recommends ART for all patients with HIV and drug-resistant TB requiring second-line anti-TB drugs, irrespective of CD4 count, as early as possible (within the first 8 weeks) following the start of anti-TB treatment (13).  (15) this regimen should be considered as the preferred option for children less than 3 years on LPV/r-based regimen when starting TB treatment. It should also be considered as the preferred regimen for children older than 3 years with history of NNRTI failure.
e Increase RTV until same dose as LPV in mg, in a ratio of 1:1.
f Change to EFV should be considered as the preferred option ( 16) and EFV could be maintained after termination of TB treatment to allow simplification and harmonization with ARVs regimen in use in older children.

# Implementation considerations

# Adherence to ART
Adherence among children is a special challenge. The limited choice of paediatric formulations, poor palatability of liquid formulations, high pill or liquid volume burden, large pill size, frequent dosing requirements, dietary restrictions, loss of primary caregiver, difficulties in swallowing tablets and adverse effects may all affect adherence. Successfully treating a child requires the commitment and involvement of a responsible caregiver. Parents and other family members of children living with HIV may themselves be living with HIV; suboptimal HIV care and treatment for family members could result in suboptimal care for the child (13).

# Immune reconstitution inflammatory syndrome
Sometimes known as a paradoxical reaction, immune reconstitution inflammatory syndrome (IRIS) is a temporary clinical deterioration that may occur within 3 months of starting ART and most commonly within the first month. It is the result of reconstitution of cell-mediated immunity in response to mycobacterial antigens and can give rise to diagnostic and management challenges. This chapter describes recurring TB or drug-resistant TB (DR-TB) and the challenges of diagnosing and treating DR-TB in children.
WHO has published guidelines for the approach to diagnosis and treatment of DR-TB, based on experience in adults; the most recent version was updated in 2011 (1,2). The grade of evidence for all recommendations was very low. Available data to inform management guidelines specific for children are even more limited, although pragmatic guides based on clinical experience have been published (3)(4)(5)(6). There is no consensus on preventive therapy for high-risk contacts of MDR-TB cases.
Drug-resistant TB should be suspected when:
there is contact with known DR-TB;
there is contact with suspected DR-TB, i.e. source case is a treatment failure or a retreatment case or recently died from TB;
a child with TB is not responding to first-line therapy despite adherence;
a child previously treated for TB presents with recurrence of disease.
When DR-TB is suspected, every effort should be made to confirm the diagnosis by obtaining specimens for culture and drug susceptibility testing (DST). Rapid DST of isoniazid and rifampicin or of rifampicin alone is recommended over conventional testing or no testing at the time of diagnosis. The use of molecular tests (line probe assay and Xpert MTB/RIF) may provide evidence of resistance within hours to 1-2 days of specimen testing and is endorsed by WHO (see Chapter 3); conventional DST, by contrast, may take 1-3 months to yield results. Rapid DST may therefore provide a costeffective means of achieving early treatment, increased cure rates, reduced mortality, reduced development of additional drug resistance and a lowered probability of failure and relapse. In all cases of confirmed MDR-TB, second-line DST should be performed to exclude XDR-TB and to help establish an effective treatment regimen.
Figure 4 shows a diagnostic algorithm for the diagnosis of DR-TB in children (4).

# Prevention of tb Disease in chilD contacts of Drug-resistant tb
Current WHO guidelines do not recommend preventive therapy for contacts of DR-TB patients. No clinical trials have been done to inform policy, but observational studies have been reported. The management of contacts of DR-TB cases, whether the contacts are children or adults, is an important research topic.
Close contacts of DR-TB patients who develop TB disease usually have drug-resistant disease.
All children with an infectious TB contact should be screened for TB disease, especially children living with HIV and child household contacts of DR-TB (7). Careful clinical follow-up of asymptomatic children (every 2-3 months for the first 6 months, then 6-monthly for at least 2 years) is recommended. If TB disease develops, treatment with an appropriate DR-TB regimen based on the DST pattern of the presumed source case should be initiated.
Care providers should note that younger children are more at risk of progressing to TB disease.
The treatment of MDR-TB and XDR-TB in children is guided by the same principles and uses the same second-line drugs as the treatment in adults, although optimal durations of regimens are not known. MDR-TB is associated with poorer treatment outcomes and higher mortality than drug-sensitive TB in children (8,9).

# Treatment of monoresistant TB
Where monoresistance to isoniazid is known or suspected when treatment is initiated, or when there is high background prevalence of isoniazid resistance, 1 the addition of ethambutol to isoniazid, rifampicin and pyrazinamide in the intensive phase is recommended (see Chapter 4). For patients with more extensive disease, consideration should be given to the addition of a fluoroquinolone and to prolonging treatment to a minimum of 9 months. Monoresistance to rifampicin should be treated with isoniazid, ethambutol and a fluoroquinolone for at least 12-18 months, with the addition of pyrazinamide for at least the first 2 months (10).

# Treatment of polyresistant TB
Polyresistance refers to resistance to two or more first-line drugs but not to both isoniazid and rifampicin. Suggested treatment regimens are available (10).

# Treatment of multidrug-resistant TB
Children with MDR-TB are treated in a similar way to adults with MDR-TB (2). One practical difference is that confirmation and DST may not possible, so that empirical treatment is often required for children with suspected MDR-TB. Although outcome data in children are limited, the available evidence suggests that outcomes at least as good as those reported in adults can be achieved (10,11).
Management should adhere to the following principles:
l Never add a single drug to a failing regimen; this may lead to amplification of resistance.
l All treatment should be given daily and under direct observation.
l Treat the child according to the DST results from the likely source case, unless M. tuberculosis culture and DST results are available from the child.
l Do second-line DST in all MDR-TB cases to exclude resistance to the fluoroquinolones and/or second-line injectables, as this may call for additional drugs early in therapy.
l Give at least three (only in early primary disease) or preferably four drugs to which the patient or adult source case is naive or their isolates susceptible.
l Caregivers need counselling and support at every follow-up visit regarding adverse effects, treatment duration and importance of adherence. In addition, the following assessment of the child should be undertaken as a minimum:
assessment of treatment adherence;
enquiry about any adverse events; and
Drug dosages should be adjusted to account for any weight gain.
l Clinical, radiographic and culture response to treatment should be monitored.
Monthly smear microscopy and cultures should be done until confirmed negative on three consecutive occasions; thereafter, follow-up cultures can be done every 2-3 months.
Clinical monitoring for adverse effects should be done at every visit. Special investigations should be guided by the adverse effect profile of the drugs used.
While any of the drugs described in Table 9

# imPlementation consiDerations

# Building a treatment regimen for MDR-TB
Treatment regimens for children with MDR-TB follow the same principles as in adults (2,4). With extensive pulmonary or disseminated extrapulmonary disease, a minimum of four to six drugs should be included in the regimen, based on susceptibilities of the isolate, as outlined in the following progression (10):
1) Use any Group 1 first-line oral drugs (see Table 9) that have certain, or almost certain, efficacy, for example, drugs showing susceptibility in DST. These drugs should be administered for the duration of therapy.
2) Add one Group 2 injectable agent based on DST results and treatment history. This agent is normally given for a minimum of 6 months and for 4 months after culture conversion. Preferably, it should be an aminoglycoside such as amikacin. Do not use streptomycin (unless other Group 2 drugs are unavailable) because of high rates of resistance with DR-TB strains and higher incidence of ototoxicity.
3) Add one Group 3 fluoroquinolone based on DST results and treatment history, for the duration of therapy. Levofloxacin and moxifloxacin are preferred to ofloxacin. Note that ciprofloxacin is not recommended.
4) Group 4 second-line oral drugs should be added for the duration of therapy, until there are at least four drugs in the regimen to which the isolate is likely to be susceptible. The Group 4 drugs should be chosen on the basis of treatment history, adverse effect profile and cost. DST is not standardized for Group 4 drugs.
If a regimen of four effective drugs cannot be built from Groups 1-4, consider adding, in consultation with an MDR-TB expert, at least two Group 5 third-line drugs. DST is not standardized for Group 5 drugs.
Drug groups used to treat drug-resistant TB are summarized in Table 9.  a In children, doses of all drugs, including the fluoroquinolones, should be at the higher end of the recommended ranges wherever possible, except ethambutol. Ethambutol should be dosed at 15 mg/kg, and not at 25 mg/kg as sometimes used in adults with DR-TB, as monitoring for optic neuritis is more difficult in children.
b DST could be unreliable -use an additional drug if DST is not done or result is susceptible.
c Choose one drug in each of these groups; amikacin is preferred to kanamycin in children. Intramuscular injection of amikacin is very painful -intravenous infusion should be preferred.
d Choose one or more of these drugs to make up total of four new drugs e PAS (including PAS Na) is administered in acidic medium (e.g. yoghurt or orange juice) for improved absorption.
f Consider use of these drugs if there are insufficient drugs in other groups to build an acceptable regimen. Each drug is considered as only half a drug -therefore two drugs in this group count as one additional drug.
g In adults, high-dose isoniazid is defined as 16-20 mg/kg per day.
h Linezolid dosage for TB is uncertain, but lower doses (300 mg twice daily or even 300 mg daily in adults) cause fewer adverse effects and still seem effective.
i Thioacetazone should not be used in people living with HIV because of the serious risk of life-threatening adverse reaction.
Very few second-line drugs are produced in paediatric formulations, and the pharmacokinetics are incompletely studied in children. This means that optimal dosing of second-line drugs is unknown and that tablets must be broken or cut, potentially leading to inaccurate dosages and blood concentrations that are sub-therapeutic or toxic. The taste of medications is often unpalatable and a number of the drugs can cause vomiting and diarrhoea. This may affect the amount of drug absorbed. Daily injectable drugs are usually given for the first few months of treatment and the pill burden can be vast. In the experience of a group of multidisciplinary health care professionals and epidemiologists working within the "The Sentinel Project on Pediatric Drug-Resistant Tuberculosis" (5,6), spreading the total daily dose over the course of the day can improve tolerability but makes directly observed therapy (DOT) challenging.
Drugs can be mixed with different foods or drinks and, in some situations, nasogastric or percutaneous endoscopic gastrostomy feeding may be appropriate.
The number of drugs needed to treat MDR-TB in children has not been prospectively evaluated. Some experts suggest that early (paucibacillary) disease, e.g. mediastinal or hilar lymphadenopathy, with or without limited lung infiltrates, could be treated with fewer drugs and shorter duration of treatment (13,14). However, extensive pulmonary TB, with or without cavitation, and disseminated extrapulmonary disease should be treated with four or more drugs (4).

# Duration of treatment
There is little evidence on treatment of MDR-TB in children; typically, therefore, programmes treating children with MDR-TB use WHO guidelines for treatment of adult patients (2,10). Treatment duration depends on the extent of the disease; in most cases the intensive phase will last at least 8 months and total duration of treatment will be at least 10 months (2). All treatment should be given daily and under direct observation.
The optimal duration of treatment for MDR-TB in children is unknown. It may be that children with early, non-extensive disease require treatment for shorter periods than adults, but this is an area that requires research (4,11,13,14).

# Adverse effects
Adverse effects occur less frequently in children than in adults (4,15). The risks and benefits of each drug should be carefully considered when designing a regimen (Table 10). Caregivers should be made aware of possible adverse events and told to report immediately any that occur. No second-line anti-TB drugs are absolutely contraindicated in children. Second-line drugs should not be withheld from children unless hypersensitivity or an intractable adverse reaction has been documented. Children who have received treatment for DR-TB generally tolerate the second-line drugs well. Regular monitoring of body weight is important: drug doses need regular adjustment as the child gains weight. Baseline audiometry and monthly hearing tests are mandatory if the child is given any Group 2 injectable agents (particularly if aminoglycosides are administered for a prolonged period), as there is a risk of ototoxicity (4,10). This is especially important in high-risk patients who are diabetic, living with HIV or have renal insufficiency (10).
Adherence is critical for both anti-TB treatment and ART. Some drugs in both regimens have a profoundly unpleasant taste and many of the drugs can cause nausea and vomiting. The number of drugs taken orally is a further complicating factor. If home treatment is not possible, injectables should be given daily at the local health clinic. In the treatment of DR-TB, directly observed therapy is essential; in some cases, hospitalization until completion of injectables is necessary. Vomiting caused by the thioamides and PAS can often be overcome by initially splitting the daily dose or starting with a lower dose and increasing to full dose in 1-2 weeks, but single daily doses should be reinstituted when vomiting stops (4).
Children should be monitored for three reasons: to determine response to therapy; to identify adverse events early; and to promote adherence. Seddon et al (5) have suggested a monitoring schedule which can be adapted to local conditions and resources.

# imPlementation anD management by ntP; integrateD care 8.1 chaPter objectives
Chapter 8 outlines the responsibilities of the NTP for implementing childhood TB activities according to national guidelines and in line with this second edition of Guidance for national tuberculosis programmes on the management of tuberculosis in children. It outlines actions needed at global and national levels and discusses the importance of an integrated, family-oriented approach to TB in children.

# action at the global level
At the global level, implementation and evaluation of this updated guidance may include the following: l WHO and partners providing training and monitoring tools for child TB and child contact management, and fostering their uptake and use.
l WHO adjusting indicators to capture the data needed to evaluate child TB activities, including contact investigation and outcomes.
l WHO and partners facilitating access to diagnostic tools for children, and fostering their uptake and use.
l WHO and partners assisting countries to establish drug resistance surveys of new patients, including all children of all ages and adolescents.
The Global Drug Facility (GDF) responding to the need for anti-TB drugs and preventive therapy for children, providing guidance to countries on the transition from old to new dosages and regimens.
l WHO and partners assisting countries in securing funding for, planning, implementing and evaluating these activities.

# next stePs at national level

# NTP actions at the national level l
Development of national child TB guidelines, either as one section of the NTP guidelines or as separate guidelines, linking them with Integrated Management of Childhood Illness and translating them into appropriate languages as needed.
l Formation of a child TB working group within the NTP, with representation from community and national child TB experts as well as from the NTP.
l Evaluation of surveillance data to target particular settings for implementation and assessment of specific activities.
is initiated must be entered into the facility-based TB register. All fields in the register should be completed, including the age of the child, type of TB, HIV status and use of CPT and ART if the child is HIV-positive.
Evaluation of treatment outcome by cohort analysis in children is a valuable indicator of programme quality for child TB patients. Table 11 provides examples of indicators for routine NTP recording and recording and describes their significance for programme performance evaluation. In addition to recording in the local TB treatment register, it is important to maintain facility medical records and to include information on TB screening, results and treatment (preventive or curative) in child health documents. 1 This will improve continuity of care and communication between health services. Children should also be included in integrated TB/HIV activities. It is important to establish and maintain linkages between TB and HIV care, recording and reporting in HIV care and treatment settings; ART registers should include records of TB screening and IPT as well as CPT.
The use of a contact screening register, as suggested in Chapter 5, should be encouraged. Important screening indicators include the number of children screened, symptoms suggestive of TB, the age and HIV status of child contacts, and the type of treatment each child has received (IPT or anti-TB treatment). The ratio of the number of sputum smear-positive pulmonary TB cases to the number of HIV-positive children or children 5 years of age screened could be used as an indicator of the effectiveness of contact tracing.
BCG adverse events must also be reported -in most countries, to the Expanded Programme on Immunization.

# Training and evaluation
Training and supervision of public and private health workers will be needed to: increase case finding of child TB cases in the community; improve the management of children with TB; increase child contact screening and preventive therapy; and improve recording and reporting practices so that better data will become available for monitoring progress.
Training is a critical tool for addressing the wide policy-practice gap that currently exists. WHO has developed and field-tested training and evaluation tools that are consistent with this updated guidance and are freely available on-line www.who.int/tb/challenges/ children/en/.
Important objectives of training are to:
increase case-finding of child TB cases in the community;
improve the management of children with TB;
increase implementation of child contact screening and preventive therapy;
provide accurate data on childhood TB for NTPs for purposes of monitoring and evaluation.
The main focus of the training is for three likely common scenarios:
the child with suspected TB disease;
the child treated for TB in the community;
the child who is a close contact of a TB case.
The NTP needs to facilitate training for the following target audiences to enable them to implement childhood TB activities:
health workers at secondary-and primary-level facilities that provide care for sick children;
health workers involved in the management of adult TB cases in the community;
health workers who are involved in the management of mothers and children with HIV;
community health workers and volunteers and treatment support groups (who carry out contact tracing in the community).

# integrateD care
Children with TB often do not present, and are not managed, within the context of specific TB care services but rather in the context of services that provide care to the sick child, including maternal and child health services and HIV care services. An important step towards improving the prevention and management of TB in children is the provision of integrated care.

# an integrateD family-orienteD aPProach to aDDressing tb in chilDren

# TB in pregnancy and management of the newborn of a mother with TB disease
Pregnancy is associated with an increased risk for previously infected women of developing TB disease, particularly in the last trimester or the early postnatal period. The burden of maternal TB and TB in pregnant women has increased substantially since the start of the HIV pandemic (2): around 2% of HIV-positive pregnant mothers are diagnosed with TB, and TB is a major cause of maternal mortality in TB/HIV-endemic settings.
The increased risks for the newborns of mothers with TB and TB/HIV include (2-5):
infection and disease with TB;
mother-to-child transmission of HIV;
preterm delivery and low birth weight;
perinatal and infant mortality being orphaned.

# Management of TB in pregnancy
The symptoms of TB disease in pregnancy are similar to those in non-pregnant women, with pulmonary TB being the commonest form of disease. Disseminated TB occurs in 5-10% of pregnant woman suffering from TB, and this is a particular risk for congenital TB (2). All pregnant women in regions endemic for TB/HIV should therefore be screened for symptoms of TB. It is equally important that a pregnant woman with suspected TB be tested for HIV.
Maternal TB increases the risk of mother-to-child transmission (MTCT) of HIV (3). If TB is diagnosed, treatment must be started promptly to prevent transmission and improve outcome. The treatment of TB in pregnant women is similar to that for nonpregnant women (with the exception of streptomycin, which is not recommended in pregnancy) (6).
HIV-positive pregnant women with TB are treated with ART according to WHO guidelines (7).

# Congenital and neonatal TB
Congenital TB is TB acquired in utero, through haematogenous spread via the umbilical vessels, or at the time of delivery through aspiration or ingestion of infected amniotic fluid or cervico-vaginal secretions. Congenital TB usually presents in the first 3 weeks of life and mortality is high.
Neonatal TB is TB acquired after birth through exposure to an infectious case of TBusually the mother but sometimes another close contact.
It is often difficult to distinguish between congenital and neonatal TB but management is the same for both. Both forms will be referred to here as neonatal TB. The TB-exposed neonate may be asymptomatic or symptomatic.
Symptoms of neonatal TB are usually nonspecific and include lethargy, fever, poor feeding, low birth weight and poor weight gain. The clinical signs are also nonspecific and can include respiratory distress, non-resolving pneumonia, hepatosplenomegaly, lymphadenopathy, abdominal distension with ascites, or a clinical picture of "neonatal sepsis" with disseminated TB.
The diagnosis of TB should be included in the differential diagnosis of chronic neonatal infection with a poor response to antimicrobial therapy, congenital infections and atypical pneumonia. The most important clue to the diagnosis of neonatal TB is a maternal history of TB or HIV infection. Critical points in the maternal history include non-resolving pneumonia, past treatment for TB, contact with an index case of TB and recent initiation of treatment for TB (8).

# Management of the asymptomatic neonate exposed to maternal TB
TB disease should be excluded in a neonate born to a mother with suspected or confirmed TB. Maternal infectiousness and drug susceptibility should be determined. It is not necessary to separate the neonate from the mother if the mother does not have (or is not suspected of having) MDR-TB. It is not necessary to stop breast-feeding (3,4). While screening for TB disease or latent TB infection, BCG should not be given to neonates exposed to TB; the main reason for this is that BCG will interfere with the interpretation of TST, reducing the effectiveness of the test for diagnosing infection. Further, as discussed in Chapter 5, BCG should not be given if the newborn or infant is confirmed to be HIV-positive.
Asymptomatic neonates born to mothers with confirmed or suspected infectious drugsusceptible TB should receive isoniazid (10 mg/kg) for 6 months daily once TB disease has been excluded (9, 10) and should be regularly followed up to ensure that TB disease does not develop.
If an infant remains asymptomatic at the end of 6 months, treatment with isoniazid is stopped and a TST is performed. Usual practice is that BCG is given after 2 weeks if the TST remains negative and the baby is HIV-negative.
If the mother is non-infectious, the infant should be screened for TB. If there is no evidence of active TB, the infant should be regularly followed up to ensure that TB disease does not develop, and IPT should be considered.
If a diagnosis of TB is confirmed or the infant develops clinical signs suggestive of TB, treatment should be started under specialist care.
Neonates born to mothers with MDR-TB or XDR-TB should be referred to a local expert in the management of this complicated problem. Infection control measures, such as wearing a mask, are required to reduce the likelihood of MTCT.

# Management of the neonate with TB disease
The treatment of congenital TB and neonatal TB is the same and should be carried out by a clinician experienced in the management of paediatric TB. A complete investigation of mother and neonate should be undertaken. Chest X-rays should be done and specimens collected from appropriate sites to confirm the diagnosis of TB in the neonate. Treatment should be started on suspicion, while bacteriological confirmation is awaited, as TB progresses rapidly in the neonate. Standard WHO-recommended drug regimens for drug-susceptible and drug-resistant TB are used -see Chapters 4 and 7.
Drug dosages must take account of body weight and of weight gain, which can be rapid in young infants. Pharmacokinetic data to inform appropriate dosages of anti-TB drugs in neonates, especially preterm neonates, are currently very limited.
A favourable response to therapy is indicated by increased appetite, weight gain and radiographic resolution. Breastfeeding is recommended, irrespective of the TB status of the mother; the risk of TB transmission through breast milk is negligible and, although the most commonly used anti-TB drugs are excreted into breast milk in small amounts, there is no evidence that this induces drug resistance. Separation from the mother is not advised, especially in resource-limited settings where establishing breastfeeding can be critical for child survival. However, when TB is suspected or confirmed in the mother of an acutely ill neonate, the mother and her baby should be separated from the neonatal unit as soon as possible to prevent other neonates contracting the infection.

# Integration of maternal/infant TB/HIV care
National tuberculosis programmes, in particular in settings with a high burden of tuberculosis and HIV, should reach out to maternal, neonatal, and child health care services to ensure the mainstreaming of tuberculosis prevention, diagnosis and treatment (11). Table 12 includes key actions suggested to address the impact of tuberculosis on maternal, neonatal, and child health through integrating tuberculosis prevention and care services (11).
Table 12. Key programmatic actions to address the impact of TB on maternal, neonatal and child health a

# Integrated management of pregnancy and child health services n
Include TB prevention, diagnosis and treatment as core component of the integrated management of pregnancy and child health package.
n TB prevention, diagnosis and treatment should be included as key interventions at all stages of pregnancy, neonatal, postpartum and postnatal care, particularly in high HIV and TB prevalence settings.

# Prevention of mother-to-child HIV transmission services n
Pregnant women living with HIV should be screened regularly using a symptom-based screening algorithm at each of their encounters with health workers and based on the outcome of the screening should either be provided with IPT or be further investigated for TB.
n Facilitate implementation of the integrated patient monitoring system of HIV (pre-ART and ART), PMTCT and TB care recommended by WHO, UNICEF and the Global Fund to Fight AIDS, Malaria and Tuberculosis with standardized indicators.
n Integrated management of childhood illnesses (IMCI) services strengthen TB prevention, case-finding, diagnosis, and treatment for children less than 5 years old.

# Family planning and infertility services n
Include tuberculosis prevention, diagnosis and treatment services to family planning and infertility services.
n Establish effective referral mechanisms with tuberculosis services if inclusion is not possible.

# Tuberculosis and HIV programme services n
Improve the recording and reporting of tuberculosis data by sex and age.
n Encourage the use of case-based electronic recording and reporting systems and mobile phones and other e-health communications and processes.
a Reproduced from reference 11 by kind permission of the publisher.

# Patient and family support for children with TB
When a child is diagnosed with TB, he or she should also be tested for HIV (if HIV status is unknown). In many settings, the diagnosis of TB and/or of HIV can result in stigma and discrimination; the impact of this on the family unit adds to the burden of caring for children with TB or TB/HIV during physical illness and death.
The model of family-centred care -an approach that focuses on the continuum of care for the whole family rather than the individual -requires a multidisciplinary approach to address all the needs of the family. Basic principles of this continuum of care (12) include:
integration of care with prevention for the provision of a comprehensive, holistic system of TB and TB/HIV management;
provision of non-discriminatory/non-judgemental care and prevention;
maintenance of confidentiality and respect for basic rights;
provision of clinical and nursing care and home-based care to alleviate symptoms of TB and HIV and prevent opportunistic infections;
provision of counselling and psychosocial support services;
community mobilization of resources for cost-effective comprehensive and holistic care;
provision of education, supervision and support for staff and volunteers.

# The child as the "index" case of TB or HIV
When a child is diagnosed with TB, it is common to find others in the family with TB who may also need further assessment. When a child is diagnosed as HIV-positive, the mother will almost certainly also be HIV-positive, the father probably and other siblings possibly. Assessment for TB (and HIV) should be recommended to parents and siblings of children with TB (and TB/HIV).

# Support for the family
The health care worker needs to determine how much care can be expected from family members and what must be obtained from other sources. This requires the following information:
what the family knows about TB;
whether the family has acknowledged that the child has TB (and HIV);
the parents' state of health and their psychological condition;
whether the parents are capable of providing physical care for the child;
the individuals who can offer support to the family, their age and health status;
whether the individuals identified are willing and able to help care for the child;
the social services available to the family in their community.
In practical terms, support for a family with a child with TB should include:
l Psychological support to family members receiving test results showing that their child has TB disease. This must allow time for the family to ask any questions they may have regarding diagnosis and management.
l Support in assisting the family to understand their child's TB through appropriate information and educational materials about the treatment, including:
the actual treatment for TB that the child will receive;
the frequency and duration of treatment;
the health services that are available for TB (and HIV) treatment;
what is required from the family in relation to continuing care;
planning a schedule of clinical monitoring;
simple infection control measures at home;
plans to return to school.
l Support to help address issues for older children and adolescents with TB and TB/ HIV.
l Referral for screening for TB of other family members, especially siblings, and other close contacts.

# suggestions for future research 9.1 chaPter objectives
Although TB is common in children, there is little research that investigates the issues related to this field. Indeed, children are often excluded from research.
During the development of this second edition of Guidance for national tuberculosis programmes on the management of childhood tuberculosis, it became clear that insufficient evidence is available to allow formulation of recommendations on every aspect of the management of children with TB and children in families with TB. The Steering Committee and the Panel therefore compiled a list of research priorities that could guide future revisions of this document. This is not meant to be a comprehensive list of the research required but complements a research agenda for child TB published by WHO in 2007 and 2011 (1,2). The Childhood TB roadmap also highlights research priorities (3).
This chapter summarizes and highlights important research priorities identified by all those involved in the process of preparing this guidance (see "Acknowledgements" section).

# suggestions for future research

# Diagnosis of TB in children

# Treatment of TB in children l
Pharmacokinetic trials to determine optimal dosages of second-line and novel anti-TB drugs, including in HIV-positive children and especially in children under 2 years of age.
l Pharmacokinetic trials to determine optimal dosages of anti-TB drugs in newborn, including preterm, infants in the first week of life. A systematic review of the literature was conducted for each topic relevant to the recommendations and the evidence was synthesized and presented in a table available on WHO website www.who.int/tb/challenges/children/en/.
For each recommendation, any recent evidence is summarized, followed by a description of the benefits, harms and other considerations used in reviewing the recommendation and its grading (see text below for definitions of the strength levels of the recommendation).
New evidence showed that the existing recommendations were still valid.
The final decisions are listed in the Executive summary. This annex provides more detail about the evidence considered and the discussions that took place during the Panel meeting in July 2012. Where evidence is weak or lacking, future research is suggested (see Chapter 9).
In the GRADE assessment process, the quality of a body of evidence is defined as the level of confidence that the estimates of effect reported in the literature are the same as the actual effects of the intervention being studied. The value of an estimate of the effect of a given intervention depends on the level of confidence in that estimate. The higher the quality of evidence, the more likely it is that a strong recommendation can be made; however, the decision regarding the strength of the recommendation also depends on other factors.
In the GRADE profiles, the following levels of assessment of the quality of evidence are used:
Further research is very unlikely to affect confidence in the estimate of effect
Further research is likely to have an important impact on confidence in the estimate of effect
Further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the existing estimate

# Very low
Any estimate of effect is very uncertain
The strength levels of the recommendations (including those from the other documents approved by the WHO Guidelines Review Committee) are defined as follows:
The Panel is confident that the desirable effects of adherence to the recommendation outweigh the undesirable effects Conditional The Panel concludes that the desirable effects of adherence to the recommendation probably outweigh the undesirable effects. However:
data to support the recommendation are scarce; or the recommendation is applicable only to a specific group, population or setting; or new evidence may result in a change to the risk-benefit balance; or the benefits may not warrant the cost or resource requirements in all settings.
summary of eviDence anD consiDerations unDerlying each recommenDation

# Diagnosis of TB in children (Chapter 3)

# Source of recommendations

# Summary of recent evidence
The Panel has evaluated WHO 2011 recommendations and more recent evidence (published up to July 2012). The Panel recognized that data on diagnostic performance of Xpert MTB/RIF in children are emerging (and will continue to emerge). Recently published data were considered and are encouraging; they included four studies comparing Xpert with liquid culture on respiratory samples. All studies were from highburden TB settings and two were from the same study population. There were almost no published data on the use of non-respiratory samples from children (although Panel was aware that studies were ongoing). Thus far, the data for children indicated that Xpert MTB/RIF has much higher sensitivity than sputum microscopy. Use of two samples increases sensitivity, although it also increases the cost of the test. Sensitivity and specificity compared with M. tuberculosis culture and the rapid results (especially crucial in MDR-TB or HIV-associated TB) are similar to those reported from the studies in adults.

# Panel decision
At the time of its meeting (July 2012), the Panel was aware that WHO commissioned three systematic reviews to update and revise the 2011 Policy guidance on the utility of Xpert MTB/Rif for the diagnosis of tuberculosis and Rifampicin resistance in pulmonary, extrapulmonary and childhood TB. Therefore, the Panel recommended that WHO use the newest recommendations as approved by the WHO Guideline Review Committee in 2013.

# Summary of recent evidence
The Panel considered recent published data, including original studies and systematic reviews. Four recently published systematic reviews included studies that evaluated IGRAs in children in the context of TB infection and disease. The reference test was TST. The "gold standard" for diagnosis of TB disease was M. tuberculosis culture confirmation. Studies reviewed reported low numbers of culture confirmed, and some studies included a clinical "probable" TB diagnosis for comparison. There was marked heterogeneity of methodology between studies that further limited comparability and interpretation of results. Indeterminate results were especially common in young children. Most studies have been done in the high-resource, low-TB-burden setting and there are limited data from children with HIV infection or severe malnutrition. Overall, IGRAs had similar accuracy to TST in children with TB infection and disease, with methodological limitations of interpretation and comparison being recognized.
Studies that were not included in these systematic reviews because they have been published more recently were subject to the same limitations of heterogeneous methodology, small numbers of confirmed cases for disease, and high numbers of indeterminate results.
The largest and highest-quality of the recent studies was conducted in a setting of high TB burden; it reported a low sensitivity of the commercial IGRA evaluated, even in cases with confirmed disease, and lower sensitivity than TST. It is consistently clear that a negative IGRA, like a negative TST, cannot exclude TB disease. The consistent findings from review of data in children published since the original recommendations were considered and the Panel agreed to revise the quality of evidence from very low to low.

# Other considerations
Like TST, IGRAs are able to indicate infection and are not a diagnostic test for disease. The reference test is TST -and TST also has limitations.
IGRAs are expensive and technically challenging, requiring sophisticated laboratory support. Even in the context of research, it was reported that the tests are technically difficult to implement and that indeterminate results are common. Technical difficulties were reported by Panel members with experience of using IGRAs in low-income settings, even in a research context.
Limited data are available from children in TB-endemic settings, especially from key populations with diagnostic challenges, i.e. young, HIV-positive and malnourished.

# Panel decision
Endorsed, but the quality of the evidence was changed from very low to low because of consistent findings in recent studies that IGRAs have lower sensitivity than TST.

# Commercial serodiagnostics

# Source of recommendation

# Summary of recent evidence
The Panel found no recent data to consider.

# Other considerations

# Panel decision
Endorsed. No change was made to the recommendation except to include children specifically in the recommendation, which was therefore rephrased as follows:
n Recommendation 6

# Summary of recent evidence
There are no studies that compare the value of testing versus not testing for HIV in various endemic settings. There are strong and consistent data that being HIV-positive affects the individual's risk of TB disease, TB-related mortality and most TB management issues, as well as requiring management of HIV. It is therefore an extremely important test to consider in the diagnostic approach to a child with suspected TB.

# Other considerations
None n Given the risk of drug-induced hepatotoxicity, WHO recommends the following dosages of anti-TB medicines for the treatment of TB in children:

# Summary of recent evidence
The Panel considered recent pharmacokinetic data 1 showing that the serum levels achieved in infants and young children under 2 years of age using the dosages listed above (2010) were higher than when using the previous (2006) dosages in the same child. This is thus the most recent pharmacokinetic evidence to support the revisions.
The Panel then considered the ranges as recommended above, especially that for isoniazid, where the lower end of the range is the same as the actual recommended dosage of 10 mg/kg. Because of implementation difficulties for the 2012 recommendation, the Panel considered recent pharmacokinetic data on isoniazid in young children and recent analysis of existing data.
It was recognized (and supported by evidence) that a dosage of 7 mg/kg and above for isoniazid will provide adequate serum levels in almost all children. Even children who are younger than 2 years and/or are isoniazid fast acetylators (the two subgroups most likely to not reach optimal levels for drug action) will respond well to this dosage.
It was also recognized that around half of the same young children failed to reach adequate serum levels of isoniazid when receiving the previously (2006) recommended dosage of 5 mg/kg.

# Other considerations
The Panel noted the difficulties of implementing the 2010 revised dosages using either currently available fixed-dose combinations (FDCs) or the FDC proposed for paediatric use in the future. The critical difficulty is that the recommended dosage for isoniazid (10 mg/kg) is the same as the lower limit of the range (10-15 mg/kg) recommended in 2010. Using FDCs of three essential drugs (rifampicin, isoniazid and pyrazinamide), for many children it would be impossible to provide a dosage of isoniazid in the range 10-15 mg/kg without using a dosage of pyrazinamide that exceeded the recommended range (thereby increasing the risk of hepatotoxicity) or without requiring additional tablets of isoniazid alone (thereby imposing an additional pill burden and increasing the risk of incorrect dosing). not received BCG in the first few weeks of life, since clinical manifestations of HIV infection typically occur after 3 months of age. If infection status can be established with early virological testing, BCG may then be administered once HIV infection has been ruled out.
The Panel noted that these recommendations were reconsidered in 2010 with new data, and it was concluded that the new data did not provide arguments for modifying the current policy as stated in: Global Advisory Committee on Vaccine Safety, 3-4 December 2009. Use of BCG vaccine in HIV-infected infants. Weekly Epidemiological Record, 2010, 85:32-33.
The Panel noted that the application of the recommendation depends on many circumstances that vary between settings and that this was acknowledged and addressed in some detail in: Revised BCG vaccination guidelines for infants at risk for HIV infection. Weekly Epidemiological Record, 2007, 82:193-196. The text of this document is reproduced in full above.

# Summary of recent evidence
A systematic review that considered all cases of BCG disease reported in the literature up to 2009 was considered by the Panel. Since publication of the review, there has been one additional study that reported no cases of BCG disease (regional or disseminated) among HIV-positive and exposed infants; however, the number of participants in this study was small.
Consideration was given to the observed possible variation in risk between settings and between different BCG strains.

# Other considerations
The Panel also noted that the epidemiology has changed since 2006 and continues to change, so that BCG disease is now less common than it was in 2006. Today, the implementation of more prevention of mother-to-child transmission (PMTCT) programmes is resulting in fewer infants born with HIV infection; there is also increased access to early ART for HIV-positive infants, which reduces risk of BCG disease.
The Panel noted the risk of BCG-IRIS in HIV-positive infants receiving ART, and that the risk of death is far lower for BCG-IRIS than for disseminated BCG disease.
Finally, the Panel noted that the Global Advisory Committee on Vaccine Safety (GACVS) does not use the GRADE methodology for evaluating the quality of evidence; the BCGrelated recommendations were therefore left ungraded.

# Panel decision
No change to recommendations or to the application of recommendations, but a change to the wording was suggested: The Panel considered the eight recommendations in this recent document that relate to children. All of these recent recommendations are consistent with the 2006 guidance.

# Summary of recent evidence
There was no additional data to be considered that would change the quality of evidence or strength of recommendation.

# Other considerations
The 2006 guidance introduced a symptom-based screening approach for evaluating child TB contacts. This is an approach that has since been adopted for implementing IPT in settings of high HIV prevalence and that has been evaluated in that context. However, no prospective studies in children have yet been published.

# Panel decision
No changes were made to the recommendations but the wording was altered to be more specific for children for the purposes of this guidance. As noted above, the recommended dosage for isoniazid in children, including for IPT, is 10 mg/kg with a range of 7-15 mg/kg. The recommendations now read as follows:
n Recommendation 18

# Infection control

# Source of recommendations
WHO policy on TB infection control in health-care facilities, congregate settings and households. Geneva, World Health Organization, 2009

# Other considerations
The recommendations that relate to infection control do not specifically mention children but are relevant to all TB patients.
The Panel noted that the recommendations are related to health service strengthening and implementation of activities at various levels of the health service, and that the principles of infection control outlined in this document are all relevant to children.
The Panel recognized that there are certain facility-based settings, for example neonatal care settings, where the risk for children is very high.

# Panel decision
No recommendations specific to children were made.

# Management of TB in children living with HIV (Chapter 6)
Isoniazid preventive therapy for HIV-positive children

# Source of recommendation

# Summary of recent evidence
The Panel considered recent evidence that was not published at the time of the development of this recommendation (although it was taken into account in the unpublished format) and noted that a large, prospective, randomized controlled trial (Madhi et al., 2012 1 did not show any benefit of primary prophylaxis.

# Other considerations
Review of the original trial (Zar et al., 2006 2, which did show benefit, found that it represented an epidemiological context that may not be widely representative (coming from one of the highest TB burden settings). In addition, the Panel noted that the epidemiological context of that trial predated the introduction of ART in children living with HIV, and is therefore not representative of the situation in 2013. Finally, that study was stopped early, following interim analysis. There was also an acknowledged difficulty in interpreting that study: the reduced mortality reported was not a reduction in deaths attributed primarily to TB.
A recent publication (Frigati et al., 2011 3 that was reviewed was an observational cohort study of the survivors of the original trial, all started on IPT and with ART introduced over time. IPT was reported as providing benefit additional to that of ART in protecting against TB, but the quality of evidence was considered low because of study design and other confounders changing over time.
These findings were discussed in a subsequent conference call between the Panel of this guidance and the Panel of the 2011 Guidelines for intensified case-finding for tuberculosis and isoniazid preventive therapy for people living with HIV in resourceconstrained settings.
During the conference call with the two panels, it was agreed to split the recommendation for two different settings (settings with a high TB prevalence and settings with a medium or low TB prevalence).
In high TB prevalence settings, 6 months of IPT may have additional benefits to that of ART in protecting against TB. However, in settings with a medium to low prevalence of TB, IPT might be offered considering resource implications. The Panel recommended further research in this area.

# Panel decision
Split the recommendation into two separate recommendations for the two different settings as follows:
n Recommendation 25
Children living with HIV who are more than 12 months of age and who are unlikely to have TB disease on symptom-based screening and have no contact with a TB case:
should be offered 6 months of IPT (10 mg/kg per day, range 7-15 mg/ kg, maximum dose 300 mg/day) as part of a comprehensive package of HIV prevention and care services if living in settings with a high TB prevalence (Strong recommendation, low quality of evidence)
might be offered 6 months of IPT (10 mg/kg per day, range 7-15 mg/ kg, maximum dose 300 mg/day) as part of a comprehensive package of HIV prevention and care services if living in settings with a medium or low TB prevalence (Conditional recommendation acknowledging resource implications, low quality of evidence)
Frigati LJ et al. The impact of isoniazid preventive therapy and antiretroviral therapy on tuberculosis in children infected with HIV in a high tuberculosis incidence setting. Thorax, 2011, 66(6):496-501.
for MDR-TB in children are at least as good as those in adults, and that treatment for drug-resistant TB in children is tolerated at least as well as in adults.
The Panel noted that the principles of drug-resistant TB management, as listed in the 2006 guidance, were essentially unchanged, including in recent reviews by experts in the field.

# Panel decision
No additional recommendations specific to children were made.

# Implementation and management by NTP; integrated care (Chapter 8)
Recording and reporting

# Sources of recommendation
Guidance This section describes the recently revised definitions of TB cases, their classification and the treatment outcome categories (1).
Presumptive TB refers to a patient who presents with symptoms or signs suggestive of TB (previously known as a TB suspect).
Bacteriologically confirmed or clinically diagnosed cases of TB (Box A2.1) are also classified according to:
anatomical site of disease;
history of previous treatment;

# Box A2.1 TB case definitions
-A bacteriologically confirmed TB case is one from whom a biological specimen is positive by smear microscopy, culture or WHO-approved rapid diagnostics (such as Xpert MTB/RIF). All such cases should be notified, regardless of whether TB treatment has started.
-A clinically diagnosed TB case is one who does not fulfil the criteria for bacteriological confirmation but who has been diagnosed with active TB by a clinician or other medical practitioner who has decided to give the patient a full course of TB treatment. This definition includes cases diagnosed on the basis of X-ray abnormalities or suggestive histology and extrapulmonary cases without laboratory confirmation. Clinically diagnosed cases subsequently found to be bacteriologically positive (before or after starting treatment) should be reclassified as bacteriologically confirmed.

# Classification based on anatomical site of disease
Pulmonary TB (PTB) refers to any bacteriologically confirmed or clinically diagnosed case of TB involving the lung parenchyma or the tracheobronchial tree. Miliary TB is classified as PTB because there are lesions in the lungs. Tuberculous intrathoracic lymphadenopathy (mediastinal and/or hilar) or tuberculous pleural effusion, without radiographic abnormalities in the lungs, constitutes a case of extrapulmonary TB. A patient with both pulmonary and extrapulmonary TB should be classified as a case of PTB.
Extrapulmonary TB (EPTB) refers to any bacteriologically confirmed or clinically diagnosed case of TB involving organs other than the lungs, e.g. pleura, lymph nodes, abdomen, genitourinary tract, skin, joints and bones, meninges.

# Classification based on history of previous TB treatment (patient registration group)
Classifications based on history of previous TB treatment are slightly different from those previously published. They focus only on history of previous treatment and are independent of bacteriological confirmation or site of disease. Note also that the registration groups for DR-TB are slightly different (1,2).
New patients have never been treated for TB or have taken anti-TB drugs for less than 1 month.
Previously treated patients have received 1 month or more of anti-TB drugs in the past. They are further classified by the outcome of their most recent course of treatment as follows:
Relapse patients have previously been treated for TB, were declared cured or treatment completed at the end of their most recent course of treatment, and are now diagnosed with a recurrent episode of TB (either a true relapse or a new episode of TB caused by reinfection).
Treatment after failure patients are those who have previously been treated for TB and whose treatment failed at the end of their most recent course of treatment.
Treatment after loss to follow-up patients have previously been treated for TB and were declared lost to follow-up at the end of their most recent course of treatment. (These were previously known as treatment after default patients.)
Other previously treated patients are those who have previously been treated for TB but whose outcome after their most recent course of treatment is unknown or undocumented.
Patients with unknown previous TB treatment history do not fit into any of the categories listed above.
New and relapse cases of TB are incident TB cases.

# Classification based on HIV status
HIV-positive TB patient refers to any bacteriologically confirmed or clinically diagnosed case of TB who has a positive result from HIV testing conducted at the time of TB diagnosis or other documented evidence of enrolment in HIV care, such as enrolment in the pre-ART register or in the ART register once ART has been started.
HIV-negative TB patient refers to any bacteriologically confirmed or clinically diagnosed case of TB who has a negative result from HIV testing conducted at the time of TB diagnosis. Any HIV-negative TB patient subsequently found to be HIV-positive should be reclassified accordingly.
HIV status unknown TB patient refers to any bacteriologically confirmed or clinically diagnosed case of TB who has no result of HIV testing and no other documented evidence of enrolment in HIV care. If the HIV status is subsequently determined, the patient should be reclassified accordingly.

# Classification based on drug resistance
Cases are classified on the basis of drug susceptibility testing (DST) of clinical isolates confirmed to be M. tuberculosis:
Monoresistance: resistance to one first-line anti-TB drug only.
l Polydrug resistance: resistance to more than one first-line anti-TB drug (other than both isoniazid and rifampicin).
l Multidrug resistance: resistance to at least both isoniazid and rifampicin.
l Extensive drug resistance: resistance to any fluoroquinolone and to at least one of three second-line injectable drugs (capreomycin, kanamycin and amikacin), in addition to multidrug resistance.
l Rifampicin resistance: resistance to rifampicin detected using phenotypic or genotypic methods, with or without resistance to other anti-TB drugs. It includes any resistance to rifampicin, whether monoresistance, multidrug resistance, polydrug resistance or extensive drug resistance.
These categories are not all mutually exclusive. When enumerating rifampicin-resistant TB (RR-TB), for instance, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) are also included. While it has been the practice until now to limit the definitions of monoresistance and polydrug resistance to first-line drugs only, future drug regimens may make it important to classify patients by their strain resistance patterns to fluoroquinolones, second-line injectable agents and any other anti-TB drug for which reliable DST becomes available.

# treatment outcome Definitions
For purposes of consistency of reporting by NTPs, the same outcome definitions apply for children as for adults.
Treatment response in a child with sputum smear-negative PTB, smear not done PTB or EPTB is assessed through regular monthly assessment and recording of weight gain and symptom improvement. In children with smear-positive TB, sputum smears should be repeated at 2 and 5 months.
The new treatment outcome definitions make a clear distinction between two types of patients:
patients treated for drug-susceptible TB;
patients treated for drug-resistant TB using second-line treatment (defined as combination chemotherapy for drug-resistant TB, which includes drugs other than those in Group 1.
The two groups are mutually exclusive. Any patient found to have drug-resistant TB and placed on second-line treatment is removed from the drug-susceptible TB outcome cohort. This means that management of the standard TB register and of the secondline TB treatment register needs to be coordinated to ensure proper accounting of the outcomes of treatment.
All bacteriologically confirmed and clinically diagnosed TB cases should be assigned an outcome from the list in Table A2.1, except those with RR-TB or MDR-TB, who are placed on a second-line drug regimen (Table A2.2).
Patients found to have an RR-TB or MDR-TB strain at any point in time should be started on an adequate second-line drug regimen. These cases are excluded from the main TB cohort when calculating treatment outcomes and included only in the second-line TB treatment cohort analysis (Table A2.2). If treatment with a second-line drug regimen is not possible, the patient is kept in the main TB cohort and assigned an outcome from among those in Table A2.1.  Treatment completed Treatment completed as recommended by the national policy without evidence of failure BUT no record that three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase a
Treatment failed Treatment terminated or need for permanent regimen change of at least two anti-TB drugs because of:
lack of conversion b by the end of the intensive phase a or bacteriological reversion b in the continuation phase after conversion b to negative, or evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs, or adverse drug reactions (ADRs) Died A patient who dies for any reason during the course of treatment.
Lost to follow-up A patient whose treatment was interrupted for 2 consecutive months or more.

# Not evaluated
A patient for whom no treatment outcome is assigned. This includes cases "transferred out" to another treatment unit and whose treatment outcome is unknown.

# Treatment success
The sum of cured and treatment completed a For treatment failed, lack of conversion by the end of the intensive phase implies that the patient does not convert within the maximum duration of the intensive phase applied by the programme. If no maximum duration is defined, an 8-month cut-off is proposed. For regimens without a clear distinction between intensive and continuation phases, a cut-off 8 months after the start of treatment is suggested to determine when the criteria for Cured, Treatment completed and Treatment failed start to apply.
The terms "conversion" and "reversion" of culture as used here are defined as follows:
Conversion (to negative): culture is considered to have converted to negative when two consecutive cultures, taken at least 30 days apart, are found to be negative. In such a case, the specimen collection date of the first negative culture is used as the date of conversion.
Reversion (to positive): culture is considered to have reverted to positive when, after an initial conversion, two consecutive cultures, taken at least 30 days apart, are found to be positive. For the purpose of defining Treatment failed, reversion is considered only when it occurs in the continuation phase. ProceDures for obtaining clinical samPles for smear microscoPy
This annex reviews basic procedures for the more common methods of obtaining clinical samples from children for smear microscopy: expectoration, gastric aspiration and sputum induction.
All sputum specimens produced by children should be sent for smear microscopy and, where available, mycobacterial culture. Children who can produce a sputum specimen may be infectious, so, as with adults, they should be asked to do this outside and not in enclosed spaces (such as toilets) unless there is a room especially equipped for this purpose. Two sputum specimens should be obtained: an on-the-spot specimen (at first evaluation) and an early morning specimen (collected at home by the patient).
Procedure (adapted from reference 1)
- Give the child confidence by explaining to him or her (and any family members) the reason for sputum collection.
- Instruct the child to rinse his or her mouth with water before producing the specimen. This will help to remove food and any contaminating bacteria in the mouth.
- Instruct the child to take two deep breaths, holding the breath for a few seconds after each inhalation and then exhaling slowly. Ask him or her to breathe in a third time and then forcefully blow the air out. Ask him or her to breathe in again and then cough. This should produce sputum from deep in the lungs. Ask the child to hold the sputum container close to the lips and to spit into it gently after a productive cough.
- If the amount of sputum is insufficient, encourage the patient to cough again until a satisfactory specimen is obtained. Remember that many patients cannot produce sputum from deep in the respiratory track in only a few minutes. Give the child sufficient time to produce an expectoration that he or she feels is produced by a deep cough.
- If there is no expectoration, treat the container as used and dispose of it in the appropriate manner.
Gastric aspiration is generally not an aerosol-generating procedure. As young children are also at low risk of transmitting infection, gastric aspiration can be considered a low risk procedure for TB transmission and can safely be performed at the child's bedside or in a routine procedure room.

# Sputum induction
It is important to note that, unlike gastric aspiration, sputum induction is an aerosolgenerating procedure. Where possible, therefore, this procedure should be performed in an isolation room that has adequate infection control precautions (negative pressure, ultraviolet light (turned on when room is not in use) and extractor fan).
Sputum induction is regarded as a low-risk procedure for the child to be evaluated for TB. The very few adverse events that have been reported include coughing spells, mild wheezing and nosebleeds. Recent studies have shown that this procedure can safely be performed even in young infants (2), although staff will need to have specialized training and equipment to perform this procedure in such patients.
Examine children in advance to ensure they are well enough to undergo the procedure.
Children with the following characteristics should not undergo sputum induction:
inadequate fasting: if a child has not been fasting for at least 3 hours, postpone the procedure until the appropriate time;
severe respiratory distress (including rapid breathing, wheezing, hypoxia);
bleeding: low platelet count, bleeding tendency, severe nosebleeds (symptomatic or platelet count <50/ml blood);
reduced level of consciousness;
history of significant asthma (diagnosed and treated by a clinician).
- Administer a bronchodilator (e.g. salbutamol) to reduce the risk of wheezing.
- Administer nebulized hypertonic saline (3% NaCl) for 15 minutes or until 5 ml of solution have been fully administered.
- Carry out chest physiotherapy if necessary; this is useful to mobilize secretions.
- For older children who are able to expectorate, follow procedures as described under "Expectoration" above to collect sputum.
For children who are unable to expectorate (e.g. young children), carry out either:
suction of the nasal passages to remove nasal secretions; or nasopharyngeal aspiration to collect a suitable specimen.