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Chapter 15

TB in children
Elizabeth Whittaker*, Christine Jones* and Beate Kampmann*,#
SUMMARY: Tuberculosis (TB) in childhood is under reported but represents a sentinel event of transmission in the community. Susceptibility to TB is age-dependent with young children at highest risk of disseminated disease. Age-related differences in immune responses to mycobacteria underlie this phenomenon. Since childhood TB tends to be paucibacillary, bacteriological confirmation is more difficult to achieve and accurate diagnosis remains a challenge. Diagnostics include measures of host sensitisation, such as the tuberculin skin test (TST) and interferon-c release assay (IGRA), but their performance varies between children and adults and in the context rin (BCG) vaccination. Therapeutic of bacille Calmette-Gue regimens are based on adult studies but increased doses have recently been recommended by the World Health Organization (WHO), following pharmacokinetic studies in children. TB/ HIV co-infection adds complexity to diagnosis and management, much like in adults. The BCG vaccine is not fully protective and is not recommended for HIV-infected children. New vaccines are currently under investigation, with trials including infants and adolescents. KEYWORDS: Age-related immune responses, diagnostics, epidemiology, novel vaccines, therapy, tuberculosis/HIV co-infection
*Dept of Paediatrics, St. Marys Campus, Imperial College of Science, Technology and Medicine, London, UK. # Medical Research Council Unit, The Gambia, Fajara, The Gambia. Correspondence: E. Whittaker, Dept of Paediatrics, St. Marys Campus, Imperial College of Science, Technology and Medicine, Norfolk Place, London W2 1PG, UK. Email: e.whittaker@imperial.ac.uk

TB IN CHILDREN

Eur Respir Monogr 2012; 58: 206218. Copyright ERS 2012. DOI: 10.1183/1025448x.10023811 Print ISBN: 978-1-84984-027-9 Online ISBN: 978-1-84984-028-6 Print ISSN: 1025-448x Online ISSN: 2075-6674

hildhood tuberculosis (TB) presents a unique spectrum of disease with its own distinct challenges for diagnosis, prevention and treatment. Herein, we highlight the major differences between adult and childhood TB.

Epidemiology
In 2010, there were 8.8 million incident cases of TB worldwide, of which 5% were in Europe. 22 high-burden countries account for 81% of all estimated cases and, overall, the TB incidence rates have fallen by 3.4% per year between 1990 and 2010 [1]. However, childhood TB remains an overlooked area within global TB control. It has been estimated that overall, children account for 10% of all TB cases worldwide, but they may account for between 15% and 25% in high-incidence countries [2]. Estimations are difficult, as until recently only smear-positive cases were reported for children under the World Health Organization (WHO) DOTS (directly observed therapy, short course) programme, yet most children present with smear-negative TB and a bacteriological confirmation is rarely sought. Notification is now based on the decision to treat for TB, and data

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regarding smear-positive cases is collected separately. A recent European surveillance report identified that paediatric cases account for 4.3% of the total burden of TB in the European Union (EU)/European Economic Area [3]. Children under 5 years of age represent 48% of all paediatric cases (defined as those in children ,14 years of age) and the notification rates are highest in this age group (5.429.21 per 100,000 in the ,5 year olds versus 3.033.91 per 100,000 in the 514 year olds), in line with previous reports [4]. Of note, only 42.3% of the reported paediatric cases were tested by culture, demonstrating suboptimal diagnostic practices; of these, 39.9% were culture positive. The overall culture confirmation rate was 16.9% over the 9-year period of the report (but 19.2% in 2009). The mortality rate was 1.6% of all culture confirmed cases and the overall treatment outcome was successful in 75%. Transmission within a community is measured by the annual risk of infection [5]. As 95% of children develop disease within 12 months of being infected, recording data on childhood TB give an indication of recent transmission within communities, and confirms that TB infection and disease in children are sentinel events indicating the burden of TB and the effects of control strategies in a community. Infection rates rise with increased exposure, with the highest probability of developing infection between the ages of 5 and 7 years in association with school and increased social mobility. Annual risk of infection is traditionally estimated by use of childhood tuberculin surveys, although this has limitations resulting from the poor specificity of rin (BCG) vaccine is given the tuberculin skin test (TST), particularly where bacille Calmette-Gue at birth and non-tuberculous mycobacteria (NTM) are endemic. T-cell-based interferon-c release assays (IGRAs) could offer a more specific alternative, but have not yet found a use in this context because of their high cost, ethical concerns about venepuncture in healthy children, and uncertainty about the association between a positive result and later development of active disease.
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A decrease in the number of childhood cases, especially in children under 5 years of age who are mostly infected in their households, would be the first indication that transmission is decreasing in a community, emphasising the importance of the recording of TB in children. In the EU/European Economic Area, notification rates in this age group appear to be decreasing [3]. The majority of very young children (,3 years) are infected by a household source case and prudent public health policy should encourage active case finding amongst household contacts of young children with proven infection or disease. This type of reverse contact tracing can be expanded to children of all ages in low-prevalence areas, where household exposure is the most probably the source and is recommended by the WHO. It is estimated that the majority of children (6080%) exposed in a household to a sputum-smear positive case of TB become infected [4]. The probability varies with age, immunological status, environmental factors and socioeconomic status, as well as the duration and proximity of exposure and infectiousness of the contact. The risk of developing disease following infection is greatest in the immediate period following infection and declines with time; 95% of children develop disease within 12 months of being infected. The risk of developing disease is influenced by age, and nutritional, vaccination and immunological status. The progression from infection to disease, and particularly severe disease such as disseminated TB and TB meningitis, is substantially higher in infants and young children; most probably due to an immaturity in the cellular immune response, although factors such as host genetics, microbial virulence and impaired immune competence due to HIV or malnutrition can also play a role, particularly in resource-poor settings. Some active contact tracing studies including chest radiography have identified radiographic changes in 5060% of children who underwent TST conversion. The majority of these were transient changes and the children did not develop disease, suggesting disease was possibly controlled by the host immune response. These data have implications for case definitions based on radiological findings alone [6].

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Based on historical data, the highest risk of TB-related mortality following primary infection occurs during infancy (510% in natural history studies); this risk declines to 1% between the ages

of 14 years and ,0.5% from 5 to 14 years, before increasing to adult levels of 2% from 15 years of age upwards [7].

Differences in the childhood immune response to TB


As mentioned earlier, very young children are usually infected by their caregiver and it would appear that the determining factor for the higher susceptibility to disease in children is prolonged, intimate contact between the child and the index case, which might lead to a larger inoculum of Mycobacterium tuberculosis. However, there is little evidence to support this assumption, since the mycobacterial load in children is notoriously low, which lies at the root of the problem of bacteriological confirmation of primary TB. It therefore appears that even low bacillary loads in very young children can lead to acute and severe illness, be it respiratory or disseminated. The generally accepted assumption is that qualitative and quantitative differences in the immune responses to M. tuberculosis infection between adults and children determine outcome. As described elsewhere, the host immune response to M. tuberculosis infection involves both the innate and adaptive immune system, starting with antimicrobial peptides and neutrophils, followed by the interaction between the antigen presenting cells and the bacteria and granuloma formation, followed by a more targeted approach by CD4 and CD8 T-cells [8]. There is a paucity of studies examining the differences in age-related immune responses to TB, but a number of recent reviews have examined the current literature [8, 9]. Neutrophils are rapidly recruited to the site of mycobacterial infection, but studies have shown conflicting reports of their contribution to protection and pathology to date [10]. Following inhalation of mycobacterial bacilli, these are taken up by antigen presenting cells (macrophages and dendritic cells), processed and presented to T-cells causing proliferation and activation of T-helper (Th) type 1 cells in particular. A comparison of infant and adult M. tuberculosis-infected macrophages demonstrated poorer phagocytosis, but similar intracellular killing [11]. Additionally, neonates have fewer dendritic cells and their ability to synthesise interleukin (IL)-12 is impaired [12]. These functional impairments lead to poor T-cell priming and consequently impaired immunity to TB. CD4 T-cells are known to be of importance in protection against TB and children with TB have lower interferon (IFN)-c responses to M. tuberculosis than children with latent TB infection (LTBI). Such responses are further impaired in severe disease. Other T-cells, including CD8, cd, Th17 and regulatory T-cells have been studied in the context of TB infection, but comprehensive data are lacking and these paediatric studies are currently ongoing.

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Clinical spectrum of disease


The clinical spectrum of TB disease in children is diverse and spans from primary disease which is cleared without treatment, to severe forms such as miliary TB and TB meningitis. Whilst the majority of immunocompetent children with primary infection do not progress to disease, young children aged ,2 years and adolescents have an increased rate of progression and death, with the highest risk seen in infancy (table 1) [4]. Intrathoracic disease manifestations are the most common at all ages; however, disseminated TB or TB meningitis represent a considerable burden of disease in infants. School-aged children have the lowest rates of disease. Age is therefore a vital determinant of disease manifestation. Immune status also influences the rate and severity of clinical disease; HIV-infected children or those on immunosuppressive therapy have increased rates of TB disease and an increased risk of severe disease [13]. In common with adults, initiation of highly active antiretroviral treatment (ART) can be associated with the development of immune reconstitution inflammatory syndrome (IRIS).

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Intrathoracic pulmonary disease is the most common disease manifestation and has four potential outcomes: 1) M. tuberculosis may be contained and the child may be asymptomatic;

Table 1. Average age-specific risk of progression from primary infection to disease


Age at primary infection years ,1 12 25 510 .10 No disease 50 7580 95 98 8090 Pulmonary disease 3040 1020 5 2 1020 Disseminated TB/ TBM 1020 2.5 0.5 ,0.5 ,0.5 Most common disease manifestation Pulmonary: Ghon focus, lymph node or bronchial Pulmonary: Ghon focus, lymph node or bronchial Pulmonary: lymph node or bronchial Pulmonary: lymph node, bronchial, effusion or adult type Pulmonary: effusion or adult type

Data are presented as %. TB: tuberculosis; TBM: tuberculosis meningitis. Reproduced and modified from [7] with permission from the publisher.

2) parenchymal disease with associated intrathoracic adenopathy; 3) progressive primary disease with caseation and cavity formation; or 4) reactivation in adolescence. Pleural effusions complicate pulmonary TB in up to 40% of children [14]. Disease progression can result from either poor or over-exuberant containment. In young infants and in immunocompromised individuals, poor containment with unrestrained proliferation of M. tuberculosis causes parenchymal breakdown and an increased risk of dissemination. In adolescence, an over-exuberant immune response results in adult-type cavetating disease. Children over the age of 10 years with adult-type cavetating disease are frequently smear positive and, therefore, represent a transmission risk to the community [15]. Of the extrathoracic manifestations, superficial lymphadenopathy is the most common. Left untreated, it can caseate and spread to other structures through sinus tracts. Disseminated forms such as miliary TB are not common but are severe and are frequently associated with multi-organ involvement. Central nervous system disease is uncommon but complicates miliary TB in up to 50% of cases. Lumbar punctures and imaging of the central nervous system should, therefore, be carried out in such cases. High levels of mortality or long-term neurological sequlae are associated with central nervous system disease. Manifestations, such as skeletal, abdominal, skin and renal manifestations, are less common but ought to be considered, especially in immunocompromised and/or very young children.
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Diagnostic difficulties and differences in children


Despite recent advances in TB diagnosis, it remains a huge challenge in children. TB can mimic many common childhood diseases, including pneumonia, generalised bacterial and viral infections, malnutrition, and HIV. However, the main impediment to the accurate diagnosis of active TB is the paucibacillary nature of the disease in young children, and an accelerated disease progression adds to an already urgent need for rapid diagnosis. Bacteriological confirmation is the exception rather than the rule. Consequently, unlike adults, the standard for diagnosis in children has been based on clinical history, TB contact history, TST and radiological findings rather than microbiological confirmation. A number of scoring systems or algorithms have been developed to improve and standardise diagnosis, with mixed success. A recent evaluation of nine structured approaches identified a difference in case yield that ranged from 6.9% to 89.2% and concluded that although they may have some use as screening tools, they were inadequate for identifying definite TB [16]. In particular, these scoring systems are poorly adapted for the highest risk groups, HIV-infected children and children under 3 years of age, both of whom are particularly at risk of rapidly developing severe disease. The TST is an important component of many scoring systems; however, it lacks sensitivity and specificity. Furthermore, radiological findings can be difficult to interpret, and wide inter- and intra-observer variability is well described. Radiological evidence of pulmonary TB usually includes lymphadenopathy (hilar or mediastinal) and lung

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parenchymal changes. The most common parenchymal changes are segmental hyperinflation, atelectasis, alveolar consolidation, pleural effusion/empyema and, rarely, a focal mass. Cavitation is rare in young children but is more common in adolescents, who may develop adult-type postprimary disease. Miliary TB is characterised by fine bilateral reticular shadowing. Computed tomography (CT) imaging may be helpful in demonstrating pulmonary disease such as endobronchial disease, early cavitation and bronchiectasis following pulmonary TB where chest radiographs are normal or unhelpful. CT imaging, and increasingly magnetic resonance imaging (MRI), is also useful in investigating central nervous system disease, such as TB meningitis, tuberculoma or bone abnormalities. Ultrasound of the abdomen may identify lymphadenopathy, hepatic/splenic lesions or ascites. The efficacy of diagnostic testing depends on both the quality of the sample and, most importantly in children, a high index of suspicion. Unlike adults, children often swallow rather than expectorate sputum and young children are unable to produce a sample upon request. Traditionally this has led to the collection of samples directly from the stomach in the form of a gastric aspirate or lavage. In order to maximise yield, samples are collected following an overnight fast on three consecutive mornings, which has obvious disadvantages. An alternative method of obtaining a lower respiratory sample is sputum induction. A bronchodilator is inhaled, followed by nebulisation with hypertonic (35%) saline and then collection of secretions by suction or expectoration in co-operative older children. There are advantages to induced sputum including no requirements for an overnight fast as it can be conducted at any time of the day following fasting for only 23 hours, potentially as an outpatient procedure. A number of studies have demonstrated that this collection method is effective, well tolerated and has low adverse event rates, even if there is moderate-to-severe lung disease, with limited disease spread if effective infection control measures are applied [1719]. A comparative study showed an equivalent diagnostic yield between gastric lavage and induced sputum in a mixed population of children either with suspected TB or those exposed to a household contact. Collection of one gastric lavage and one induced sputum specimen on the same day had a similar yield to two consecutive day gastric lavage collections. This may represent a practical diagnostic approach with appropriate infection control measures in place. It is vital to increase the acceptability and rate of sample collection in children with suspected TB and to overcome the perception amongst health workers that a microbiologically confirmed diagnosis is neither possible nor useful in children, especially in the day and age of potentially drug-resistant (DR)-TB. Other methods of sputum collection have also been investigated in children, such as bronchoalveolar lavage (BAL), the string test and nasopharyngeal aspirate, with limited improvement over gastric aspirate/induced sputum [2022]. Bronchoscopy, with an experienced operator, enables visualisation of the bronchial tree, which can provide clues such as caseation, allows transbronchial lymph node biopsy and may also provide an alternative diagnosis. It should not be recommended for routine diagnosis of TB, but has a role in intubated children or if otherwise clinically indicated. As most children swallow their sputum, mycobacterial DNA may survive the transit of the gastrointestinal tract allowing molecular testing of stools. Initial work in Peru demonstrated a low sensitivity and high specificity of stool PCR; however, a further study using GeneXpert1 MTB/RIF (Cepheid, Sunnyvale, CA, USA) was more promising with 100% sensitivity in stool samples, but the sample size was small and further studies are required [23]. TB lymphadenitis is a common form of extrathoracic TB and children with pulmonary TB have concomitant TB lymphadenitis in 1030% of cases; fine-needle aspirate biopsy of accessible cervical or axillary lymph nodes has been shown to have both a greater yield and a decreased time to bacteriological diagnosis compared to other specimens (7 days compared to 22 days) [24]. Further paediatric studies, including the use of GeneXpert1 on these samples is warranted.

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Commercial PCR tests are showing increasing promise for the diagnosis of TB and the GeneXpert1 MTB/RIF, an integrated sample processing and nucleic acid amplification test for

detection of M. tuberculosis and resistance to rifampicin, was recently studied in a large South African paediatric study comparing the yield on induced sputum to a standard reference of liquid mycobacterial culture [25]. One sample produced a sensitivity of 84.6% for smear-positive disease and 33.3% for smear-negative disease. The yield was doubled with the addition of a second sputum sample, increasing the sensitivity by 28% to 61.1%. A second study in Tanzania of 164 children of whom 51% were HIV infected showed a sensitivity of 66.6% in smear-negative/ culture-positive children. They did not identify any difference in performance due to HIV infection [26]. The results of both studies suggest the benefits of multiple-sample testing, which is not currently recommended by WHO guidelines, but this would need to be balanced against the increased costs. Culture remains important and, in fact, is more sensitive than the GeneXpert1 for both identifying those children who are PCR negative but culture positive and for complete drugsusceptibility testing (DST) in those children with DR-TB. A recent Italian study of the GeneXpert1 in extrapulmonary (EP) TB, using a variety of samples including pleural fluid, cerebrospinal fluid, gastric aspirates, biopsies, urine, pus and FNA samples including 494 out of 1,476 samples from paediatric cases, showed great promise. GeneXpert1 had a higher sensitivity and specificity in paediatric compared to adult samples. The highest sensitivity for paediatric samples was in biopsies, pus or pleural fluid while gastric lavage and cerebrospinal fluid had a sensitivity of 81% and 75%, respectively, compared to culture and clinical diagnosis [27]. A metaanalysis of the performance of GeneXpert1 for diagnosis of EPTB reported an overall pooled sensitivity of 80% and a specificity of 86% compared to a gold standard of culture [28]. The TST and IGRAs are immunology-based diagnostic tests of mycobacterial sensitisation. It is important to remember that neither test proves the presence of mycobacteria and that IGRA were not designed for the diagnosis of active TB but rather as an indicator of LTBI. They have, however, been widely applied to diagnose active TB. Two meta-analyses to appraise their role in the diagnosis of TB disease in children have recently been published [29, 30]. MACHINGAIDZE et al. [30] included 20 studies and looked at the performance of the QuantiFERON1-TB Gold In-Tube (QFT-GIT; Cellestis, Carnegie, Australia) assay exclusively. MANDALAKAS et al. [29] included 32 studies with a total of 4,122 children and assessed both the QFT-GIT and T-SPOT1.TB test (Oxford Immunotec, Oxford, UK). Both identified that the sensitivity of the IGRA for TB disease was similar to the TST, with lower sensitivities reported for high-burden TB countries. The specificity for detection of TB disease was 91% for QFT-GIT and 94% for T-SPOT1.TB (compared to 88% for TST). All diagnostic assays, the TST, QFT-GIT and T-SPOT1.TB, had reduced sensitivity in three groups: those aged ,5 years, HIV-infected individuals and those with BCG vaccination rates .50%. Individual studies reviewed in the latter meta-analysis found associations between indeterminate results and young age, helminth infections and immune suppression, although significant associations could not be confirmed in the stratified analysis. At best, the IGRAs represent a rule-in rather than a rule-out test for TB disease; using TST and IGRAs in combination can increase sensitivity to up to 93% [31] and should be interpreted as an additional piece of evidence. However, given the current evidence, WHO has not endorsed their use for the diagnosis of active TB. However, differences appear to exist depending on the epidemiological context. MANDALAKAS et al. [29] found increased sensitivity for diagnosing LTBI in countries with a TB incidence f25 per 100,000. Sensitivity in low- versus high-incidence settings was 83% versus 68%, 86% versus 68% and 87% versus 73% for TST, QFT-GIT and T-SPOT1.TB, respectively [29]. In the 2010 updated guidelines, the Centers for Disease Control and Prevention caution against the use of IGRAs in children less than 5 years of age. Lack of performance data, potential for progression to disease and concern of attenuated IFN-c responses in this age group influenced this decision. The 2011 guidelines from the National Institute for Health and Clinical Excellence (NICE) in the UK recommend a dual strategy (IGRAs should be used to confirm a positive TST) for diagnosing LTBI in children aged 515 years. In children younger than 5 years of age, the TST is recommended. However, in household contacts of TB cases aged 25 years of age, when the initial TST is negative, an IGRA may be used along with a TST in repeat testing to increase sensitivity. In outbreak situations, IGRAs can be used alone for those older than 5 years of age. GRAHAM [32]

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identified a low level of indeterminate results from IGRAs overall (1.8%) in a study of 1,128 European children assessed for LTBI, but it was 3.6% in the children younger than 5 years of age. The concordance between the IGRA and TST was fair (k50.34) and both age and BCG vaccination record correlated with positivity of TST. In this cohort, BCG vaccinated children were less likely to have a positive IGRA, indicating a possibly protective effect of BCG vaccination against TB infection. Of note, when the TST was interpreted as negative, a positive IGRA was found in between 3.5% and 23.9% of cases depending on the TST cut-off, highlighting the importance of performing an IGRA in both TST-positive and -negative individuals, if used as part of guidelines.

Treatment of TB in children
In general, the principals of treatment and recommended regimens are entirely derived from adult regimens, since, unfortunately, there are no studies of TB drug efficacy in children with TB. Therefore, the same four-drug regimen (HRZE (isoniazid-rifampicin-pyrazinamide-ethambutol)) for 2 months followed by a two-drug regimen (HR) for 4 months is recommended. A three-drug regimen (without ethambutol) for 2 months followed by HR for 4 months can also be used for HIV-negative children with suspected or confirmed pulmonary TB or tuberculous peripheral lymphadenitis who live in settings with low HIV prevalence or low isoniazid resistance. The exception is TB of the central nervous system, bones and joints for which 12 months of treatment with a four-drug regimen (HRZE) is recommended in the first 2 months, followed by HR for 10 months. Several recent studies and re-analysis of previously published studies have led to changes in dosing guidelines for several of the first-line anti-TB drugs, notably isoniazid and ethambutol. In general, these studies have shown that for children older than 3 months of age, larger per kilogram doses are required to achieve adequate serum levels of the drug (table 2). Remarkably, there remains a dearth of data for determining optimal drug doses in infants. The absence of child-friendly fixed dose combinations of TB medications is a challenge in many settings.

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Multidrug-resistant/extensively drug-resistant TB
Multidrug-resistant (MDR)-TB is defined as M. tuberculosis resistant to the most potent first-line anti-TB medications, isoniazid and rifampicin, while extensively drug-resistant (XDR)-TB has additional resistance to the most active second-line agents, injectable drugs (aminoglycosides and/ or cyclic polypeptides) and fluoroquinolones. Since most children are treated for primary TB, DRTB is usually acquired from infection with an already drug-resistant strain, rather than developing due to poor adherence to therapy. In children, there is an increased risk of DR-TB infection in the following circumstances: 1) exposure to a known drug-resistant case; 2) exposure to a case who has had treatment failure or relapse; 3) exposure to a case who remains sputum smear-positive
Table 2. Changes in the dosing of first-line anti-tuberculosis drugs for children
Drug Isoniazid+ Rifampicin 03 months .3 months Pyrazinamide 03 months .3 months Ethambutol
#

Previous daily dosing (range)# mg?kg-1 5 (46) 10 (812) 10 (812) 25 (2030) 25 (2030) 20 (1525)

Revised daily dosing (range)" mg?kg-1 10 (1015) No change 15 (1020) No change 35 (3040) No change

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: based on the 2006 World Health Organization guidelines; ": based on the 2010 World Health Organization guidelines; +: recommended for prophylaxis and treatment. Reproduced and modified from [32] with permission from the publisher.

Table 3. Adverse effects associated with first- and second-line anti-tuberculosis agents
Drug Isoniazid Rifampicin Pyrazinamide Ethambutol Kanamycin/amikacin/capreomycin Fluroquinolones Ethionamide/prothionamide Cycloserine/terizidone PAS Clofazimine Linezolid Clarithromycin Thiacetazone Main adverse effects Hepatitis, peripheral neuropathy Hepatitis Hepatitis Optic neuritis Ototoxicity, nephrotoxicity Sleep disturbance, GI disturbance, arthritis, peripheral neuropathy GI disturbance, hypothyroidism, metallic taste Neurological and psychological effects GI disturbance, hypothyroidism, hepatitis Skin discolouration GI disturbance, headache, myelosuppression, neurotoxicity, lactic acidosis, pancreatitis GI disturbance, rash, hepatitis, prolonged QT syndrome, ventricular arrhythmias StevensJohnson syndrome in HIV-infected patients, GI disturbance, hepatitis, skin reactions

PAS: para-aminosalicylic acid; GI: gastrointestinal. Data from [34].

after 2 months of therapy; 4) exposure to a case from an area with high prevalence of resistance; and 5) travel to an area with high drug resistance [33]. Both DST and rates of resistance have increased in the EU/European Economic Area over the last 10 years [3].
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Few studies have examined the management of children with MDR-TB. Children are typically diagnosed with either confirmed or, more often, presumed MDR-TB in the absence of available culture confirmation. Treatment in such cases should be based on the DST of the confirmed index case, or the source of the presumed case. If no DST is available and the child is failing therapy, treatment decisions should be based on the prevailing DST pattern of MDR-TB strains circulating in the region. Designing a treatment regimen is based on the same recommendations as for adults, using at least four drugs, preferably five, to which the organism is susceptible. Additional challenges to treating MDR-TB in children arise from the uncertainty about activity and safety of the available drugs. The second-line drugs are rarely produced in paediatric formulations or appropriate tablet sizes, necessitating breaking, splitting, crushing or grinding. Hence dosing may be inaccurate and sub-therapeutic or toxic levels are possible. The taste of the medications is often unpalatable. A number of the drugs cause vomiting and diarrhoea that may affect the amount absorbed and possibly sub-optimal doses. The daily pill burden can be vast as the child may require multiple TB medications plus ART and other antibiotics, as well as supplements of vitamins and calories in some settings. The pharmacokinetic parameters of most of the second-line anti-TB agents in children of various ages are unknown, and optimal regimens for specific patterns of drug resistance are undefined. This is an important area for further research, since licensing of formulations in Europe now require a paediatric investigation plan and specific paediatric studies. The adverse effects of the first-line medications have been well described and are less common in children than in adults. A list of the adverse effects of the anti-TB agents is given in table 3. Children should be screened for optic neuritis, oto-toxicity and hypothyroidism as appropriate whilst on treatment for MDR-TB.

TB/HIV co-infection
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Expert advice should be sought for management of all children co-infected with TB and HIV. The incidence of TB disease in HIV-infected children is reported to be as high as 20 times that in

non-HIV-infected children [35]. Similar to adults, treatment outcomes for TB are poorer in children with HIV compared with HIV-uninfected children [36]. HIV-infected children also experience greater morbidity and mortality from TB disease and have an increased risk of relapse [37]. Some postulated reasons for this include underlying immunosuppression, the presence of coinfections, underlying chronic lung disease, malnutrition and poor drug absorption. Unlike other opportunistic infections, children with HIV are at risk of TB disease even when they have a relatively high CD4 count. All children diagnosed with TB should be screened for HIV. Children newly diagnosed with HIV should be screened for TB by clinical history and chest radiograph. There are conflicting reports of the role of routine isoniazid prophylaxis in children with HIV, with one study showing a decrease from 23.4% to 7.2% of TB disease compared to placebo in the absence of ART [38]. These findings were not confirmed in a larger study in the same population [39]. There were low rates of adverse events in this study and, of note, both highly active ART and isoniazid independently decreased the risk of TB disease. Contact tracing in households affected by TB-HIV co-infection is of particular importance. Screening for TB is especially important in HIV-infected children, both because of the risk for rapid disease progression and the complexities of adding a TB therapy to a regimen of antiretroviral therapy. The drug interactions between ART and first-line TB drugs have been extensively reviewed in adults. Rifampicin reduces the concentrations of many concomitantly administered drugs including the key antiretroviral non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Low serum protease inhibitor concentrations can be partially overcome with the use of high doses of ritonavir or by doubling the usual dose of the co-formulated form of lopinavir/ ritonavir, but subsequent hepatotoxicity is a common adverse effect. Efavirenz serum concentrations are lowered modestly by rifampin, but this does not appear to affect the efficacy of antiretrovirals. The combination of efavirenz-based ART and rifampin-based TB treatment, at their standard doses, is usually the preferred treatment for HIV-related TB in children older than 3 years of age. For children aged less than 3 years of age with prior exposure to a non-nucleoside reverse transcriptase inhibitor, a regimen of two nucleoside reverse transcriptase inhibitors plus super boosted lopinavir and ritonavir is recommended. Rifabutin, when available, may be substituted for rifampin when ART using protease inhibitors must be used, but the data for outcomes in children are extremely limited. A complete review of recommended approaches to managing dual HIV/TB infections in children can be found in the 2010 WHO guidelines. IRIS is characterised by an acute worsening of signs and symptoms of disease that occurs with immune recovery. In the setting of HIV, this correlates with the start of antiretrovirals. IRIS has been associated with the following risk factors (significant immunosuppression as measured by CD4 count, HIV viral load, severe TB disease, and early start and rapid response to antiretrovirals) and is found in up to 29% of cases in children with low CD4 counts. Due to the potential for IRIS in these risk groups, it is recommended that ART be delayed by 28 weeks after the start of antiTB therapy in all children with EPTB. Additionally, antiretrovirals should be delayed by 28 weeks in children with pulmonary disease or lymphadenitis with a CD4 count below the WHO threshold. In children with pulmonary disease or lymphadenitis with CD4 counts above the threshold that have a good response to TB therapy, antiretrovirals can be started once TB therapy is completed. It should be remembered that IRIS can occur due to BCG or NTM and is not necessarily TB.

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TB control and prevention


The BCG vaccine is the only currently licensed TB vaccine. It is a live attenuated vaccine that is administered at or near birth in most countries worldwide [40] and has been in existence since 1921. It became integrated into the Expanded Programme on Immunization infant vaccination schedule in 1974.

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The BCG is administered to an estimated 100 million infants worldwide every year, making it one of the most widely used of all vaccines [41]. Whilst it affords significant protection against disseminated disease and TB meningitis, the protection against pulmonary TB is inconsistent, with the most limited protection in geographical areas where TB is most prevalent [41, 42]. The poor protection against adult-type disease is evident since the global TB epidemic has occurred despite the majority of the world receiving the BCG. BCG vaccination of HIV-infected children is associated with disseminated BCG disease and the benefit conferred is questionable; the BCG is therefore no longer recommended in individuals known to be infected with HIV [43]. The need for a new vaccine is evident and urgent. There are 14 candidate vaccines currently in clinical trials; however, the challenges facing the development of new vaccines are significant [44]. The aim is to produce a vaccine that is efficacious against all forms of TB in all age groups and that is safe in the context of HIV infection. A further obstacle to the vaccine pipeline is that there is no defined correlate of protection against TB; clinical trials currently measure vaccine take. Using clinical disease as an end-point necessitates large sample sizes and prolonged follow-up. Active case finding, prophylaxis of household contacts and effective treatment coupled with a paucity of highly sensitive and specific diagnostic tools makes this task very difficult. The main vaccine approaches are: 1) pre-exposure vaccines, which aim to prevent infection and primary disease prior to exposure; 2) post-exposure vaccines, which aim to prevent reactivation after infection; and 3) immunotherapeutic vaccines, which could be used to shorten duration of TB treatment. Pre-exposure vaccines are most likely to be of benefit to infants and young children, where the highest rate of progression from primary infection to disseminated disease is seen. Such vaccines may not eradicate M. tuberculosis but rather elicit a cell-mediated immune response containing M. tuberculosis at the site of primary infection. They employ a heterologous prime-boost strategy [45]. BCG is retained due to efficacy against severe forms of childhood TB or a recombinant BCG vaccine may serve as the priming vaccine. A second boost vaccine is then used to expand memory T-cells common to the prime and boost vaccines. There are two such vaccines currently in phase IIb clinical trials enrolling large numbers of infants: MVA85A/Aeras485 and AERAS-402/Crucell Ad35 [46, 47]. Another adjuvant recombinant fusion protein vaccine, M72, is currently in phase II trials. Post-exposure and immunotherapeutic vaccines are more likely to be used in adolescence to prevent reactivation of latent disease. Whilst a new improved TB vaccine in early childhood is important to prevent the burden of disease in children, it is unlikely to effect a rapid reduction in TB incidence. Rather, the combination of a pre- and postexposure vaccine administered in mass campaigns, targeting adults, it most likely to achieve a substantial effect [44]. Prevention of TB or a shortened period of infectivity in adults would have the benefit to children of preventing transmission and thus would protect infants and children as well. The ideal vaccine for TB control should also be able to prevent infection. Although primary prevention, giving isoniazid to young children recently exposed to a case of TB, has been recommended by the WHO for decades, it has rarely been used in the high-burden settings of disease. There are conflicting data on the role of primary prevention in children with HIV infection who live in high-burden TB settings. It is becoming clear that the IGRAs may have great utility in low-burden settings,

HIV
Signs and symptoms

History TST Active TB

Radiology Microbiology

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Figure 1. The pieces of the jigsaw that might be required to make a diagnosis of childhood tuberculosis (TB). TST: tuberculin skin test.

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especially for children who have received the BCG vaccine, where specificity in detecting TB infection (to avoid false-positive TST results and unnecessary treatment of patients) is important [48]. Finally, although the standard 6 months of isoniazid therapy for TB infection in children is very safe and effective, adherence rates are often very low. The role of chemoprophylaxis in the setting of MDR-TB is less clear and opinions differ as to whether to watch closely and wait once disease has been ruled out by clinical examination and chest radiograph, or to give at least two drugs to which the strain of a presumed index case is sensitive. However, there are no evidencebased guidelines at present and paediatric household contacts should be closely monitored in an outpatient setting for 2 years. Further research is urgently required to determine the right approach at a given age group and potential length of prophylactic therapy. In summary, childhood TB remains a challenge for clinicians, epidemiologists and researchers with progress required in all three main areas: prevention, diagnosis and therapy. However, it is important to consider the diagnosis of TB in children in the context of any family or known TB contact, and to carefully evaluate all children potentially affected. In the absence of bacteriological confirmation, a jigsaw approach might be required, as illustrated in figure 1. International Standards for Tuberculosis Care and EU Standards for Tuberculosis Care have made the current research relevant and accessible to the practicing clinician to ensure optimal diagnosis, treatment and prevention of TB [49, 50]. However, given the specific challenges of childhood TB, a set of specific European standards of care for children is still outstanding. To make further progress in practical management and research and advocate for childhood TB we must continue to raise the profile of children and families affected by TB in European and international forums and via networked activities [51].
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Statement of Interest
B. Kampmanns laboratory has previously received a discount on consumables to conduct either IGRA from both Cellestis (Carnegie, Australia) and Oxford Immunotec (Oxford, UK). However, neither company has ever been involved in the analysis or interpretation of the data.

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