Changing Trends in Childhood Tuberculosis
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- Mukherjee, A., Lodha, R. & Kabra, S.K. Indian J Pediatr (2011) 78: 328. doi:10.1007/s12098-010-0298-4
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Several changes have been observed in the epidemiology, clinical manifestations, diagnostic modalities and treatment of tuberculosis. Emergence of HIV epidemic and drug resistance have posed significant challenges. With increase in the number of diseased adults and spread of HIV infection, the infection rates in children are likely to increase. It is estimated that in developing countries, the annual risk of tuberculosis infection in children is 2.5%. Nearly 8–20% of the deaths caused by tuberculosis occur in children. Extra pulmonary tuberculosis has increased over last two decades. HIV infected children are at an increased risk of tuberculosis, particularly disseminated disease. In last two decades, drug resistant tuberculosis has increased gradually with emergence of MDR and XDR-TB. The rate of drug resistance to any drug varied from 20% to 80% in different geographic regions. Significant changes have occurred in TB diagnostics. Various diagnostic techniques such as flourescence LED microscopy, improved culture techniques, antigen detection, nucleic acid amplification, line probe assays and IGRAs have been developed and evaluated to improve diagnosis of childhood tuberculosis. Serodiagnosis is an attractive investigation but till date none of the tests have desirable sensitivity and specificity. Tests based on nucleic acid amplification are a promising advance but relatively less experience in children, need for technical expertise and high cost are limiting factors for their use in children with tuberculosis. Short-course chemotherapy for childhood tuberculosis is well established. Directly observed treatment strategy (DOTS) have shown encouraging result. DOTS plus strategy has been introduced for MDR TB.
KeywordsChildhood tuberculosisEpidemiologyFlourescence LED microscopyNucleic acid amplification testsLine probe assayIGRADOTSDOTS plus
Tuberculosis infection and disease among children are much more prevalent in developing countries, where resources for control are scarce. Of the 9 million annual TB cases, about 1 million (11%) occur in children under 15 years of age. Of these childhood cases, 75% occur annually in 22 high-burden countries . It is estimated that in developing countries the annual risk of tuberculosis infection in children is 2.5%. In India, the overall estimates of average annual risk of infection in children 1–9 years of age was computed as 1.5%. It was higher in urban areas, at 2.2%, than in rural areas, at 1.3% . Nearly 8%–20% of the deaths caused by tuberculosis occur in children . There is no indication that tuberculosis rates among children in developing nations are declining. With increase in number of diseased adults and spread of HIV infection, the infections in children are likely to increase.
Widespread coverage with BCG vaccine has possibly led to modification in the pattern of clinical manifestations. It has been suggested that BCG vaccination is responsible for decrease in the occurrence of disseminated and severe disease. Localized forms of illness, e.g., intrathoracic lymphadenopathy, and localized CNS disease have been reported to occur with greater frequency . However, this observation needs confirmation from epidemiological studies.
A study from Spain reported an increase in the number of children with single hilar adenopathy (32% for the period 1978–1987 to 43.4% for the period 1988–1997) in comparison to those with parenchymal involvement or a mixed pattern (62% vs 45%).The authors also reported a non-significant trend towards a lower rate of tubercular meningitis in the last decade .
Changing spectrum of tuberculosis over last 4 decades in TB clinic of a tertiary care referral hospital (AIIMS)
Type of extra pulmonary TB
HIV and Tuberculosis
It has been reported that HIV infection is probably one of the most important factors for the resurgence of tuberculosis in adults as well as in children. In 2008, WHO reported a global estimate of 1.4 million of HIV–TB co-infection amongst 9.4 million new TB cases. Of the 108 million mortalities, approximately 5,00,000 were in HIV infected individuals .
Adults with HIV infection are 20–40 times more likely to develop tuberculosis from latent infection as compared to individuals without HIV infection, and those, who encounter Mycobacterium tuberculosis after HIV related immune suppression has progressed have a more rapid progression of the disease . The HIV epidemic can increase the incidence of tuberculosis in children by two major mechanisms (a) HIV-infected adults with tuberculosis disease may transmit Mycobacterium tuberculosis to children, a proportion of whom may develop tuberculosis disease and (b) Children with HIV infection are at increased risk of developing tuberculosis disease after infection has occurred. The impact of HIV epidemic on pediatric tuberculosis has been reported in several studies. In Abidjan, Cot d Iovire and in Lusaka, Zambia, a higher rate of pediatric tuberculosis was more commonly observed in HIV infected children [8, 9]. In India, the proportion of HIV infected children who also developed tuberculosis was 16%–68% [10–12].
Clinical features of tuberculosis in HIV infected children are similar to those in immunocompetent children; however, they are at risk of disseminated disease and higher mortality.
Drug Resistant Tuberculosis
Pattern of drug resistance among children with tuberculosis tends to reflect those found among adults in the same population. Since 1970s, drug resistant tuberculosis has increased gradually. As per WHO update, 5% of all TB cases have MDR-TB, based on data from more than 100 countries collected during the last decade. In 2008, WHO reported highest rates of MDR-TB ever recorded, with peaks of up to 22% of new TB cases in some regions. 85% of all MDR-TB cases are reported from 27 countries across the world; India being amongst the top five .
The rates of drug resistance to any drug vary from 20% to 80% . In India (Delhi region), the prevalence of resistance to any drug was 32.4%, while that of multidrug resistance was 13.3%, during the years 1991–1997 . Exact figures for the pediatric population are not documented. In unpublished data from our center, MDR TB was diagnosed in 21 children out of 1579 registered (1.32%) over last eight years. Various reports across the world have stated mono-resistance to INH and MDR—TB in children to be in the range of 10%–14% and 1.6%–2.3% respectively [15, 16].
XDR-TB or extensively drug-resistant tuberculosis, defined as MDR-TB plus resistance to a fluoroquinolone and at least one second-line injectable agent: amikacin, kanamycin and/or capreomycin. Worldwide, an estimated 5.4% of MDR-TB have been diagnosed as XDR-TB. As of January 2010, 58 countries have reported at least one case of XDR-TB to WHO . Again the exact numbers in children are yet to be computed. At our center, out of 21 MDR tuberculosis in children, one patient fulfilled case definition of XDR TB.
Optimal TB smear microscopy
Rapid solid and liquid culture
Nucleic acid amplification tests
Molecular drug resistance testing
Antibody detection tests
Antigen detection tests
T-cell-based interferon-gamma release assays
Since children do not expectorate enough sputum, traditionally 3 consecutive gastric lavages have been used. Reports now suggest that two or even one gastric aspirate may yield optimal results. According to the revised WHO and RNTCP policies, 2 instead of 3 sputum samples are now sufficient to screen possible pulmonary tuberculosis. New sputum smear positive pulmonary TB case is now defined as presence of at least one acid-fast bacillus (AFB) in at least one sputum sample .
There has been considerable interest in hypertonic saline induced sputum collection as this is less invasive than gastric lavage . Further trials are required before it can be conclusively stated that induced sputum is a better source of sample for AFB smear/culture than gastric aspirate. Bronchoalveolar lavage for obtaining samples for demonstration of Mycobacterium tuberculosis has been used with variable results .
Examination of smear from respiratory samples under light microscopy after Ziehl–Neelson staining is still the most widely accessible investigation in majority of high burden areas. A systematic review concluded that fluorescence microscopy with auramine staining was 10% more sensitive and as specific as conventional microscopy and was less time consuming (2 min vs 5 min for each slide) . But the pitfalls are the high cost of maintenance, requirement of dark room and the short life span of the machines. To address these issues, fluorescent light emitting diode (LED) microscopy has been developed which is less expensive, require less power, is able to run on batteries with long half-life, does not pose the risk of releasing potentially toxic products if broken and can function even in absence of dark rooms. A systematic review has demonstrated that LED microscopy can impart a statistically significant increase in sensitivity of 6% and 5%, with no appreciable loss in specificity, when compared to direct ZN microscopy and conventional fluorescence microscopy respectively .
Culture of Mycobacterium tuberculosis
LJ medium is most widely used media for determination of characteristic features of colonial morphology, growth rate and pigment production. Microscopic examination of thin layer culture plate may lead to detection of micro colonies of M tuberculosis as early as 7 days .
The BACTEC system improves the yield of positive cultures from clinical specimen and lessens the time taken to 9–14 days for detecting M. tuberculosis.  The capability of performing rapid mycobacterial drug sensitivity is an additional advantage of the BACTEC system .
Septi-Chek AFB system requires about 3 weeks incubation. Studies carried out in adults have suggested that Septi-Chek system was more sensitive than LJ Media/7 H 11 and BACTEC in percentage of isolates recovered .
Mycobacterial growth indicator tube system (MGIT) uses a fluorescent compound embedded in silicone on the bottom of the tube containing modified 7 H 11 broth with antibiotic mixture and growth supplements for mycobacteria. As this fluorescent compound is sensitive to oxygen, depletion of the latter by growth of mycobacteria, unmasks the fluorescence, which can be detected by observing the tube under long wave ultraviolet light. Available literature suggests that this method is as sensitive as the BACTEC system .
The Microscopic Observation Drug Susceptibility (MODS) assay is an inexpensive, rapid and sensitive diagnostic method utilizing manual liquid culture method (Middlebrook 7H9 broth culture) and an inverted light microscope to detect growth of Mycobacterium tuberculosis in the form of ‘tangles or cords’. It is found to be more sensitive than LJ media culture .
Nucleic Acid Amplification Tests
Nucleic acid amplification is a rapid and relatively easy method for detecting M. tuberculosis. Out of the various techniques available polymerase chain reaction (PCR), fully automated platform of real time PCR and Loop-mediated isothermal amplification (LAMP) platform are noteworthy.
Polymerase Chain Reaction
Polymerase chain reaction is the most commonly used technique of nucleic acid amplification. In children, the results of PCR have been compared with clinical diagnosis and not culture. The most commonly used target for detection of M tuberculosis is the insertion sequence IS6110. The sensitivity ranges from 4%–80% and the specificity 80%–100% .These results are not very promising. A blinded study comparing results obtained on specially prepared standardized samples by 7 different laboratories, demonstrated significant differences in the results obtained . It appears the PCR has a limited role in evaluating children for tuberculosis.
Loop Mediated Isothermal Amplification Technology Platform (LAMP)
Loop-mediated isothermal amplification (LAMP) technology is a novel method of nucleic acid amplification which is still in the early phase of development and validation. A LAMP-based assay has been developed with a set of six specific primers that target the M.tuberculosis 16 S rRNA gene to detect M. tuberculosis complex bacteria in respiratory specimens. It is a rapid test, allowing for a 109–1010 fold increase in target DNA within 30 min and can be performed in peripheral microscopy laboratories with less intense training of the personnel. The large amount of DNA generated and the high specificity of the reaction makes it possible to detect amplification by visual inspection of fluorescence or turbidity; thermocyclers are not needed as reaction is carried out in isothermal conditions. These features make LAMP a promising platform for the molecular detection of TB in peripheral, less sophisticated laboratories. . No pediatric data is available on this.
Fully Automated NAAT Platforms
Fully automated nucleic acid amplification platform (e.g. GeneExpert) that integrate sample preparation with real-time PCR amplification and detection of MTB and rifampicin resistance are being evaluated. They are rapid and simple to use, but their cost effectiveness and accuracy needs to be validated in field setting . There are no studies on the samples obtained from children with tuberculosis.
Molecular Drug Resistance Testing-Line Probe Assays
Molecular line probe assays are strip tests that simultaneously detect M. tuberculosis bacteria as well as genetic mutations that indicate isoniazid and/or rifampicin resistance. Line probe assay technology incorporates DNA extraction from M.tuberculosis isolates or directly from clinical specimens followed by polymerase chain reaction (PCR) amplification of the resistance-determining region of the gene under question and hybridization with specific oligonucleotide probes immobilized on a strip. Captured labeled hybrids are then detected by colorimetric development, enabling detection of the presence of M. tuberculosis complex, as well as the presence of wild-type and mutation probes for resistance. There are two commercially available probes which are being evaluated for rapid detection of MDR-TB in both resource-rich and resource-limited settings. Both the assays can detect M. tuberculosis complex and specific mutations in the rpoB gene conferring rifampicin resistance. The Genotype MTBDRplus assay also simultaneously detects specific mutations in the katG gene conferring high-level isoniazid resistance and in the inhA gene conferring low-level isoniazid resistance . No studies have been conducted on childhood tuberculosis.
ELISA has been used in children to detect antibodies to various purified or complex antigens of M .tuberculosis. Despite a large number of studies published over the past several years, serology has found little place in the routine diagnosis of tuberculosis in children, even though it is rapid and does not require specimen from the site of disease. A systematic review suggests that the commercial antibody detection tests are not particularly useful in diagnosis of TB disease as compared to other tests, such as sputum smear and bacterial culture . At present, serodiagnosis does not have any role in diagnosis of childhood pulmonary tuberculosis.
Lipoarabinomannans (LAM) are phosphorylated lipopolysaccharides, which are a major cell wall component of bacteria of the genus Mycobacterium. Antigen detection assays based on capture ELISA format to detect LAM in urine holds promise as an easy, point of care, non-invasive tool for diagnosing active tuberculosis. However, the low sensitivity of urinary LAM (17%–50%) as compared with the gold standard of culture offsets the advantages. The specificity is acceptable (88%–95%). This diagnostic tool may be particularly helpful in the selected subset of patients with HIV/TB co-infection, where the sensitivity increases . There are no studies on childhood tuberculosis.
T-Cell-Based Interferon-Gamma Release Assays
Interferon gamma release assays (IGRA) are in-vitro tests of cell mediated immune response which are mostly helpful in detecting latent tuberculosis infection. The two commercially available IGRAs are the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay (Cellestis Ltd, Carnegie, Australia) and the T-SPOT.TB assay (Oxford Immunotec, Oxford, UK).
The advantage of these assays lies in the fact that they are not affected by previous BCG vaccination, do not cross-react with most of the non- tubercular mycobacterium (except M. kansasii, M. szulgai, and M. marinum),are not affected by the observers’ bias and require only one visit for testing. The shortcomings of these assays include inability to distinguish between latent and active tuberculosis and high cost. More research is essential to outline the implementation of these tests in clinical settings, especially in high incidence countries. The immune response leading to release of IFN-γ is inconsistent in children below 4 year of age and hence, interpretation of IGRA may be difficult in this age group .
Mycobacteriophages have been used to detect the presence of M. tuberculosis complex and determine drug susceptibility from clinical specimens and isolates. They have a quick turn around time of 2–3 days, good specificity, but variable sensitivity. No data exists for their utility in childhood tuberculosis. At this point of time they are not good enough to replace conventional microscopy and culture/DST .
During the past three decades, dramatic changes in the therapeutic approaches to childhood tuberculosis have occurred as a result of large number of treatment trials for children and increased concerns about the development of resistance to antituberculosus drugs. Short-course chemotherapy, with the treatment duration as short as 6 months, has become the standard practice. Intermittent antituberculosis therapy is being used in National Programs in India and China successfully . A recent review on long term efficacy of DOTS regimens for tuberculosis in adults concludes: although several clinical trials supported the use of daily treatment regimens, studies reporting tuberculosis recurrence after intermittent regimens were limited. Overall there was wide variation in recurrence after successful treatment, ranging from 0% to 14%. Considerable heterogeneity across studies precluded the systematic assessment of factors contributing to tuberculosis recurrence . There are no pediatric studies to compare efficacy of thrice weekly intermittent therapy to daily therapy. A recent meta-analysis concluded that twice weekly intermittent short course therapy is less likely to cure tuberculosis in children as compared to daily therapy .
Classification and treatment of pediatric tuberculosis patients, according to the category based regime of WHO, in a prospective study has showed the feasibility of adapting the adult guidelines for categorizing the children . Review of studies on use of ethambutol in children suggest that it can be used in all children with some precaution . Pharmacokinetic studies of various antituberculosus drugs primarily in adults and to a lesser extent in children have led to determination of their optimal doses. The dose of isoniazid had decreased from 20 mg/kg/day in seventies to 5 mg/kg/day at present. But now some recent studies have shown suboptimal serum concentration of all the four first line anti tubercular drugs in children when the dose/kg body weight, as derived from adult standards, were used [39, 40].An expert panel from WHO has also expressed concern over the proper dosing schedule in children and suggested some increment in the standard recommended dosage . In the Indian DOTS program, which uses patient wise boxes, underdosing of ATT in children is a cause of concern .
Search for newer, safe and effective drugs continues in fight against tuberculosis. Some of the prospective compounds which are in phase II clinical trials mainly for treatment of drug resistant tuberculosis includes PA-824 (nitroimidazole family—inhibits synthesis of cell wall lipids), TMC-207 (diarylquinolone-inhibits ATP synthase of M Tuberculosis) and OPC-67683 (nitroimidazole family) . Immunomodulators like nebulized recombinant interferon-γ1b or Mycobacterium w (IMMUVAC®) may be helpful as an adjunctive therapy in pulmonary tuberculosis. . Larger randomized controlled trials are needed to establish their efficacy in treatment of tuberculosis.
Factors determining outcome of TB are not well understood in children. A recent study suggested that children with AFB positive, who did not receive BCG at birth or extra pulmonary TB are more likely to fail the treatment 
BCG vaccine with an efficacy ranging from 0%–80% has been the only vaccine available against tuberculosis for the last 80 years. Recently some new candidate vaccines which can be used in tandem with BCG to boost the immunity have gone into phase 1 or 2 trials e.g. MVA85A .