Pediatric tuberculosis: The way forward

Childhood tuberculosis (TB) is a grave problem, with nearly one-third of global pediatric TB cases being from India. In 2020, approximately one lakh TB cases (0–14 years of age) were reported to the National TB Elimination Program (NTEP), with around 1.4 lakh cases in the 15–18 years age group.[1] Over the last few years, childhood TB has constituted 6%–7% of all TB cases notified annually to NTEP.[2] Pulmonary TB (PTB) is the most common form of TB in children; however, the proportion of extrapulmonary TB cases is more in children as compared to adults. Despite such high figures, the estimated detection gap for TB in children is around 56%. This may be due to factors such as a lack of knowledge about presumptive TB among health-care providers, delays in seeking medical attention by caregivers, and discrepancies in the availability of diagnostic services across the country. The exact contribution of TB to under-5 mortality is unknown, as many TB-related deaths are probably reported as only “pneumonia.” There are considerable differences in host characteristics, natural history, and type of disease between children and adults, leading to challenges in the diagnosis of childhood TB.[3] Adolescents and adults have more infectious forms of TB (cavitatory) which can be easily confirmed by sputum examination as they are able to expectorate. Younger children more often have tuberculous mediastinal lymphadenopathy with or without a parenchymal focus, and they tend to swallow the sputum, making microbiological diagnosis difficult. Alternative methods of sample collection such as gastric aspirate or bronchoscopy are invasive and require trained personnel to perform. Challenges in sample collection are a major hindrance to the decentralization of diagnostic services in children. As every dark cloud has a silver lining, similarly, the new generation molecular diagnostics have revolutionized the microbiological diagnosis of TB in children. Cartridge-based nucleic acid amplification tests (Xpert-Rif™/Truenat™) and line probe assays (LPAs) have been approved and made available free of cost by NTEP, right up to the sub-district level. These tests not only detect Mycobacterumtuberculosis rapidly, with a much higher sensitivity than smear microscopy but also additionally pick up rifampicin resistance. This has greatly facilitated the universal drug susceptibility testing strategy adopted by NTEP, which refers to upfront testing of all presumptive TB cases for rifampicin resistance and further for fluoroquinolone resistance, in samples resistant to rifampicin.[4] First-line LPAs can detect resistance to rifampicin and isoniazid, whereas second-line LPAs pick up resistance to fluoroquinolones and aminoglycosides. Xpert MTB/RIF Ultra can be used on samples such as gastric aspirate, nasopharyngeal swabs, or stool; and even on cerebrospinal fluid, pleural, ascetic, or other body fluids as the sensitivity of ultra is much higher.[5] Since the yield of any microbiological test is better if performed on a good-quality clinical specimen, it is recommended to initially screen children with symptoms of PTB with a chest X-ray to prioritize cases for molecular testing. The liquid culture system (mycobacterial growth indicator tube), not only gives results in 3–6 weeks but can also test susceptibility to all anti-TB drugs. We now have the complete mapping of M. tuberculosis genome and whole genome sequencing (WGS) analyses on an appropriate clinical sample give us the entire gamut of mutations which induce resistance to various anti-TB drugs. At present, WGS is in the operational research stage under NTEP and is not recommended for routine diagnosis of TB. Several changes have come up in the treatment of drug-sensitive (DS) as well as drug-resistant (DR) TB. The doses of drugs for DSTB have increased to achieve optimal therapeutic levels. Fixed drug combinations are now available under NTEP in dispersable forms, which have simplified regimens of DSTB in children; also eliminating the risk of missing a particular drug from treatment. As there is a 12%–15% background resistance only to isoniazid in India, ethambutol is added as the third drug along with isoniazid and rifampicin in the continuation phase. Since 2018, Category II regimens for relapsed, lost to follow-up, and treatment failure cases are withdrawn and all such cases are evaluated upfront for DRTB. Recently, Phase III clinical trials have demonstrated the noninferiority of a 4-month regimen of isoniazid, rifapentine, moxifloxacin, and pyrazinamide in adolescents and adults for DS PTB.[6] The SHINE trial has demonstrated the noninferiority of a 4-month regimen for nonsevere PTB in children between 3 months and 16 years of age.[7] Similarly, the introduction of all oral regimens for DRTB has revolutionized the management in such a way that patients no longer have to take injections for 4–6 months, along with freedom from their side effects. Bedaquiline has been approved for use in children above the age of 5 years and delamanid above 6 years. Although the WHO has recommended these drugs right from newborn age, the regulatory approvals in India are still pending. The introduction of bedaquiline, delamanid, linezolid, and other potent anti-TB drugs for DRTB has not only improved outcomes but also made it possible to reduce the duration of treatment for MDR-TB to 9–11 months and XDR-TB to 18–20 months. Shorter treatments improve compliance and thereby increase cure rates in DRTB patients. Since the inclusion in WHO’s Expanded Program on Immunization in 1976, the BCG vaccine has saved millions of lives from serious forms of TB. However, immunity imparted by BCG wanes over time leaving the adolescent and adult population vulnerable. The unmet need for a newer TB vaccine has led to intense research in this field. VPM1002 and MIP vaccines are in their Phase 3 trials to evaluate efficacy and safety for preventing TB disease in healthy household contacts >6 years, of newly diagnosed sputum-positive PTB patients.[8] VPM1002 is being evaluated additionally for the prevention of infection among immunologically naïve newborns. TB preventive therapy (TPT) is recommended by WHO since 1993 to healthy individuals in contact with PTB patients for the prevention of disease in them. Isoniazid for 6 months was the initial recommended therapy for contacts of DSTB patients. The prevent TB study has demonstrated the noninferiority of a 3-month, weekly TPT with isoniazid and rifapentine and it is now being approved for use in children above 2 years of age.[9] Likewise, V-QUIN and TB-CHAMP are Phase 3 cluster randomized trials conducted for evaluating the role of 6 months of levofloxacin in children, adolescent, and adult contacts of DRTB patients. Building up patient support systems is the key to the successful management of TB and this has been aptly achieved by the NTEP in India. Diagnostics such as Xpert-Rif™/Truenat™ and medications for treatment have been made available free of cost, for both, public and private sector patients. The NIKSHAY app by Central TB Division is a one-point contact, wherein all information about test results, medications, follow-up, response to therapy, etc., is readily available. Under Nikshay Poshan Yojana, Rs. 500/- is transferred per month to all TB patients for supporting their nutritional requirements. Likewise, incentives are given to supporters of treatment helping TB patients. Since the COVID-19 pandemic, all COVID-19-positive patients are screened for TB and vice versa (bidirectional screening), to prevent missing of cases of either disease. NTEP has collaborated with Rashtriya Bal Swasthya Karyakram, Nutritional Rehabilitation Centers for early detection of TB cases. Partnerships with NGOs and private sector agencies such as SAATHI, JEET, FIND, the Union, Centers for Disease Control and Prevention, and WHO have given the necessary support and momentum to the fight against childhood TB in India. The government of India has launched the “TB Mukt Bharat Abhiyaan” to eliminate TB from India by 2025.[10] Efforts are being made under NTEP to actively engage various stakeholders including civil society organizations, elected representatives, TB-affected families, and volunteers from the general population in planning and designing the program, delivering services, and monitoring and counseling of TB patients-The Jan Andolan to End TB by 2025. Cumulative efforts from government agencies, health-care providers, and the common man, together with a strong will to eliminate TB, are the way forward to end TB.