Unmasking childhood tuberculosis – A case series with review of literature

Case 1

A 15-year-old girl presented with a 3-month history of high-grade intermittent fever, chills, productive cough, decreased appetite and weight loss. There was no history of contact with a known case of TB. She had a Bacillus CalmetteGuérin (BCG) scar and showed pallor on examination, but no lymphadenopathy or organomegaly. Respiratory examination revealed increased vocal fremitus, resonance and crepitations on the left side. Anthropometry showed normal height but low weight and body mass index (BMI). As per the WHO guidelines, the child was fitting into the criteria for active case finding for PTB. Lab tests revealed normocytic anemia, neutrophilic leucocytosis, thrombocytosis, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and a positive Mantoux test [Table 2]. Chest X-ray [Figure 1a] showed patchy opacities in the left upper zone, and the sputum acid-fast bacilli (AFB) smear was 3+ positive. Cartridge-based nucleic acid amplification test (CBNAAT) confirmed that MTB was sensitive to isoniazid (INH) and RIF. Other infectious disease workups were negative. High-resolution computed tomography (HRCT) [Figure 1b] showed left upper lobe consolidation with cavitation and tree-in-bud nodules, consistent with PTB. As per the WHO criteria, this child was defined as having extensive (or advanced) PTB disease. She was treated with INH, RIF, pyrazinamide and ethambutol (HRZE) therapy under directly observed treatment short course (DOTS), with nutritional support. Contact tracing was done, and she improved symptomatically, continuing treatment with regular follow-up.

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Figure 1:

(a) Chest X-ray of case 1 shows ill-defined confluent patchy radio-opacity in the left upper lung zone? infective aetiology, (b) high-resolution computed tomography thorax of case 1 shows ‘tree in bud’ (arrow on the right side) appearance seen in the right middle lobe and cavities (arrow on the left side) seen in the left middle lobe.

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Case 2

A 5-year-old girl undergoing treatment for primary nephrotic syndrome (PNS) developed seizures and altered consciousness during her 5^th week of steroid therapy. She had a history of pneumonia resistant to first-line antibiotics, later treated with meropenem and vancomycin. Neuroimaging was done to investigate seizures, which revealed hydrocephalus, raising suspicion for TBM, despite normal cerebrospinal fluid (CSF) findings and negative molecular tests for MTB. She was empirically started on ATT and steroids before being referred to us.

Despite treatment, her neurological status worsened with recurrent seizures and decreased consciousness. When she was received at our hospital, she was awake but unresponsive with a Glasgow coma scale of eye opening 4, motor 5 and vocal 2 (E4M5V2), with neurological signs including brisk reflexes, clonus and a positive Babinski sign. An Omaya reservoir for CSF drainage was in place due to raised intracranial pressure (ICP). Magnetic resonance imaging (MRI) revealed a tuberculoma in the parietal cortex, and CSF analysis showed elevated protein and lymphocytosis, but repeated CBNAAT tests were negative [Table 2]. Cultures from blood and CSF grew Acinetobacter baumannii sensitive only to polymyxin, which was started alongside ATT and steroids. As per the WHO criteria, this child was categorised as severe EPTB disease, TBM.

The child’s condition deteriorated with persistent seizures suggestive of epilepsia partialis continua, worsening consciousness and feeding difficulties. She required intubation and ventilatory support, with multiple anti-convulsant. Repeat imaging showed worsening hydrocephalus with multiple enlarging tuberculomas in the brainstem [Figure 2a and b]. PR is defined as an immune-mediated worsening despite therapy being suspected. Thalidomide was started as an immunomodulatory treatment alongside continued ATT and steroids. The ventriculoperitoneal shunt (VP shunt) failed and was replaced by external ventricular drainage (EVD), allowing intraventricular polymyxin administration. Persistent bloodstream infection was noted. The child needed prolonged intensive care, including tracheostomy for long-term ventilation.

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Figure 2:

(a) Magnetic resonance imaging (MRI) brain T2 flair axial section of case 2 showing hydrocephalus, exudates in the ventricles. (b) MRI brain T2 flair axial section of case 2 showing multiple tuberculomas in the brainstem (Arrow shows tuberculoma noted in the brainstem in the T2 flair images). (c) Chest X-ray of case 2 showing right mid zone infiltrate on ventilation with tracheostomy tube in situ (Ventilator-associated pneumonia). Shadow of ventriculoperitoneal shunt is also noted on the right side.

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Although the fever spikes and seizures subsided, we could not notice any neurological recovery. Unfortunately, she remained ventilator-dependent and expired due to ventilator-associated pneumonia (VAP) [Figure 2c] after 4 months of hospital stay.

Case 3

A 14-year-old girl presented with a 15-day history of low-grade intermittent fever, cough with expectoration, occasional hemoptysis, post-tussive vomiting, decreased appetite and 4 kg weight loss. Her mother had PTB 5 years prior, but the girl did not receive any preventive treatment at that point of time. She had a BCG scar on examination. Further examination showed mild cervical lymphadenopathy, increased respiratory rate, decreased air entry, crepitations and increased vocal fremitus on the right lung. Anthropometry revealed undernutrition (BMI 12.2 kg/m²). Laboratory tests showed anemia, leucocytosis, thrombocytosis, elevated ESR and CRP and a positive Mantoux test [Table 2]. Chest X-ray [Figure 3a] and HRCT [Figure 3b and c] showed bilateral cavitary lesions. Sputum smear was positive for AFB, and CBNAAT confirmed DRTB to INH by LPA. HIV and viral serologies were negative, and the abdominal ultrasound was normal. As per the WHO criteria, she was categorised as RIF-susceptible, INH-resistant advanced PTB disease. She was started on weight-based anti-tubercular therapy under DOTS as per the WHO guideline. Contact tracing was also done in this case.

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Figure 3:

(a) Chest X-ray of case 3 showing diffuse ill-defined opacities on the right side with cavity lesion beside the hilum on the right side. (b) High-resolution computed tomography (HRCT) images of case 3 showing cavity lesion depicted by arrow over the right lung upper lobe. (c) HRCT images of case 3 showing cavity lesion depicted by arrow over the left lung.

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Epidemiology and risk factors for TB

According to the WHO Global TB Report 2024,^[1] an estimated 10.8 million people developed TB globally in 2023, with 134 new cases/100,000 population. South-East Asia accounted for the highest burden, contributing 45% of global cases.^[1] In India, a national TB survey across 20 states found a prevalence of 312 cases/100,000 people.^[2,4] Children and adolescents under 15 represent 11% of global TB cases, with 7.5 million newly infected each year.^[1] Around 67 million are estimated to be latently infected, including 2 million with DR-TB and 100,000 with extensively DR-TB (XDR-TB).^[1]

Among children, the pooled prevalence of latent TB infection is defined as an immune response to MTB without active disease, ranges from 33% (5 years) to 40% (6–14 years).^[4] Approximately 5–10% of those with latent infection progress to active TB disease.

Under India’s NTEP, children make up 6–7% of patients treated annually.^[2] However, a 56% detection gap indicates significant underdiagnosis, particularly of MDR-TB, with only 3% of reported cases in children under 14 years – likely an underestimate.^[1,10,11] Paucibacillary nature of the disease, difficulties in sample collection and underuse of stool X-pert may be possible reasons for this detection gap, which still exists. Among our three cases, only one was DR-TB. Risk factors for childhood TB in India include high population density, poverty, malnutrition, exposure to tobacco and pollutants, immunodeficiency, lack of BCG vaccination and genetic susceptibility.^[2-4,11] We could notice that immunosuppression was the only risk factor in the second case. All the cases had a BCG scar on examination.

The WHO’s 2015 End TB strategy^[3] was the first to explicitly include children, leading to improved focus on paediatric TB. India’s NTEP uses standardised diagnosis, treatment and prevention protocols, supported by ‘Nikshay’, a web-based platform to monitor treatment and antibiotic use under the DOTS.^[2]

To reduce child TB mortality, 80% of which occurs in those under five, early diagnosis of infectious adults and timely screening of child contacts is essential.^[8] One study^[11] in eight high-burden countries showed that 12% of household contacts of MDR-TB cases were diagnosed through contact investigation. Systematic screening, or active case finding, is essential in closing detection gaps, especially in high HIV prevalence settings where HIV testing among TB contacts is also recommended.^[1-3]

Clinical manifestations of TB in children

TB in children can present as PTB or EPTB, with PTB being more common.^[1,20-22] Two of our cases were PTB. However, EPTB, especially TBM, is a significant cause of morbidity and mortality.^[1,16,20,23] Only one child was EPTB, that is, TBM. Across paediatric populations, no major gender differences are observed between PTB and EPTB.^[21,22] We could note that all our cases were girls. Although DR-TB is always an emerging concern,^[11] a high proportion of children with TB suffer from malnutrition in India.^[12]

PTB

Children with PTB typically present with persistent cough, poor weight gain or unexplained weight loss of more than 5% over 3 months.^[1,21,22] This is like our two cases who presented with PTB. In high-risk groups such as infants and HIV-positive children, TB may present atypically, including acute pneumonia or with persistent wheezing.^[1,24] None of our cases were HIV-positive.

The WHO guidelines^[1] recommend classifying such children as presumptive TB and initiating active case-finding using a combination of clinical examination and diagnostic tests. Chest X-ray is usually the first-line investigation in PTB, with a sensitivity of 84% and specificity of 91%. Characteristic findings include miliary shadows, hilar/mediastinal lymphadenopathy and fibro-cavitary lesions in the upper lobes.^[25] However, some radiographic patterns, such as consolidation or bronchopneumonia, are non-specific and require follow-up if symptoms persist despite antibiotics.^[1,25]

Two of the three cases (case 1 and case 3) had significant radiological findings on chest X-ray, as depicted in Table 2.

Microbiological testing using molecular WHO-recommended rapid diagnostics (mWRD)^[1,26,27], such as Xpert-MTB/RIF and AFB microscopy, should be done using sputum or gastric aspirates. In both the PTB cases presented here, we could isolate AFB and confirm the diagnosis by Xpert-MTB/RIF. These tests were done simultaneously by sending samples to the regional laboratory for TB in the district. HRCT can be used for complex cases, revealing patterns such as necrotic lymph nodes or ‘tree-in-bud’ opacities.^[28] This was very classical in our first case, where we could notice a similar HRCT appearance. Drug resistance testing is now universally recommended by WHO upfront using Xpert-MTB/RIF or Ultra, followed by LPAs for further identification of resistance to INH (H), fluoroquinolones (FQ) and second-line injectables.^[7,29] In the third case, we could confirm the drug resistance by LPA at first contact. This helped us to change the drug regime to a DR-TB regimen.

Children may also have concurrent EPTB, and diagnostic material should be collected from these sites when possible.^[27] However, due to the paucibacillary nature of TB in children, treatment should not be delayed for microbiological confirmation, especially in very young or immunocompromised children, who are at greater risk for severe and disseminated forms like TBM.^[8]

EPTB

EPTB involves sites outside the lungs and is seen in various forms, with lymph node TB being the most common, especially in children aged 5–9 years.^[10,12] Cervical lymphadenopathy is frequent, and histopathology or fine-needle aspiration cytology is used for diagnosis.^[1] The tuberculin skin test is often positive but is not diagnostic alone.^[4,6] Although we could get Mantoux positive in the PTB cases, it was negative in the EPTB case, which presented as TBM. Chest X-rays may show associated pulmonary involvement in 5–40% of lymph node TB cases.^[8]

The most severe form of EPTB is TBM, accounting for 5–10% of EPTB cases but carrying a disproportionately high mortality and morbidity,^{[14,16,20,25]} especially in children under five. This was like our second case who presented with TBM stage 3. TBM progresses through three clinical stages, with prognosis highly dependent on early detection and treatment.^[30] CSF analysis in TBM typically shows lymphocytic pleocytosis, high protein and low glucose.^[31] We could notice similar CSF findings in our second case; the findings were consistent with TBM, although we could not isolate AFB, nor we could get positivity in the molecular tests, as depicted in Table 2. CBNAAT (Xpert MTB/RIF) improves diagnostic accuracy, although the sensitivity is low, whereas X-pert Ultra has better sensitivity on CSF samples.^[1,27,31] Despite this, diagnostic yield remains limited, and lumbar puncture is often delayed due to raised ICP.^[32] Neuroimaging, including contrast-enhanced CT and MRI, is vital.^[33] Common findings include basal meningeal enhancement, hydrocephalus, tuberculomas and infarcts.^[33,34] MRI is more sensitive, particularly for brainstem lesions.^[33] Our second case did show hydrocephalus and basal exudates in the initial CT brain. After 2 months of ATT when the child’s condition worsened, we could notice several brainstem tuberculomas in the MRI [Figure 2b] despite the child being on ATT and dexamethasone. Differential diagnoses for TBM include neurocysticercosis, cryptococcal meningitis and CNS malignancies.^[13,34]

CNS-TB manifestations

TBM is the second most common EPTB form after lymphadenitis.^[16,20,30] Historical and modern data highlight its severity.^[14,15] A study published in the Indian Pediatric Journal in 1966 reported a 51% mortality in children, particularly under 5 years and in the advanced stage of TBM.^[20] TBM still contributes significantly to TB-related deaths (19.3%), with high rates of neurological sequelae (53.9%) among survivors even today.^[16] Intracranial tuberculomas, another form of CNS-TB, presents as intracranial space-occupying lesions and can cause seizures or neurological deficits.^[32-34] This was like our second case. Although rare, it can be seen in about 1% of TB cases.^[16] Risk factors for CNS-TB include young age, malnutrition, immunosuppression and malignancy.^[16,17] We did notice that our second case of TBM was immunosuppressed during steroid therapy for PNS.

TB in the setting of nephrotic syndrome

Children with PNS, especially those treated with high-dose steroids, are at risk of TB.^[9] TB incidence in this group ranges from 1.5% to 10%, mostly occurring after starting immunosuppressive therapy.^[35-37] PTB is the most common form, and frequently relapsing nephrotic syndrome on long-term steroids is particularly vulnerable.^[9,35] This was seen in our second case.

Treatment of TB

Successful TB treatment in children involves more than ATT.^[38] It also includes nutritional support, management of adverse drug reactions, comorbidity care and psychosocial support with decentralised and family-centered care recommended by WHO and integrating TB care with other health services such as maternal and child health.^[1,39] We followed this in the treatment of our patients in our hospital. All these children were attached to ‘Ni-kshay’ and treated under NTEP.

Standard treatment involves an intensive phase (2 months) and continuation phase (2–4 months).^[1] Children (3 months–16 years) with non-severe drug-susceptible TB may receive a shorter regimen of 2 months of intensive and 2 months of continuation phase (as per SHINE trial results).^[38,40] Adolescents (≥12 years and ≥40 kg) may be eligible for a 4-month rifapentine-moxifloxacin regimen^[38,40] as per the updated WHO guidelines. As these shorter regimes are still not updated in the NTEP, our first case continued with the standard treatment regime and showed good clinical improvement. Treatment for TBM requires 2 months of intensive therapy (four drugs HRZE) with steroids and 10 months of continuation phase H-Isoniazid, R-Rifampicin (HR).^[1,38] Our second case, although it was on ATT, showed worsening of symptoms after a brief period of improvement.

Corticosteroids reduce mortality and neurological disability in TBM.^[18] In severe cases, surgical interventions such as a VP shunt and endoscopic third ventriculostomy for hydrocephalus may be needed.^[41] Our second case was started on dexamethasone and was surgically treated for raised Intracranial Tension (ICT) by VP shunt initially and later by an EVD. PRs (worsening of lesions during therapy) are possible, particularly in immunocompromised children during recovery.^{[19,24,34,42]} Steroids such as prednisolone or dexamethasone are recommended for TBM, TB pericarditis, miliary TB with alveolo-capillary block, TB uveitis and Addison’s disease.^[18] They reduce inflammation, prevent complications and are typically used for 2–4 weeks before tapering. Pyridoxine (vitamin B6) is co-administered to prevent neuropathy.^[38] We did notice these PR in our second case, which was treated by thalidomide in addition to steroids.

DR-TB

DR-TB in children resembles drug-sensitive TB in presentation. It should be suspected in children exposed to DR-TB cases, non-responders to standard therapy after 2–3 months, TB relapses.^[29] Types of resistance include INHmonoresistance, MDR-TB (resistant to INH and RIF), preXDR-TB (resistant to FQ) and XDR-TB (resistant to FQ + bedaquiline/linezolid).^[1,29] Rapid tests such as GeneXpert and LPAs detect resistance in hours to days.^[27,29,31] The WHO now recommends all-oral regimens using group A drugs such as levofloxacin, bedaquiline, delamanid and linezolid, with over 78% treatment success in paediatric MDR/RR-TB.^[29]

PR^[19] and IRIS^[24] in TB both involve a worsening of TB symptoms during treatment, but they differ in their timing and underlying causes. PR occurs 3–12 weeks after starting treatment and appears as new or enlarging lesions in immunocompromised or immunocompetent children.^[13,16,19] These reactions mimic DR-TB but usually resolve on their own. Proper distinction from DR-TB is essential before labelling a case as PR. TB-IRIS is a worsening inflammatory response seen in HIV-positive children after starting antiretroviral therapy.^[24,42] Similar reactions may occur in children recovering from nephrotic syndrome during tapering of immunosuppression.^[9] These conditions usually improve with steroids but at times in a specific group of children TNF-a inhibitors such as thalidomide or infliximab, which reduce inflammation improve outcomes as shown by several studies.^{[13,18,19,43]}

Thalidomide, although it was noted to be controversial during its past obstetric use, is currently seen to be effective in treating PR and speeding radiological recovery.^[34] Infliximab, a monoclonal TNF-a inhibitor, is an alternative but has limitations due to cost and poor blood-brain barrier penetration.^[43]

Adverse effects of thalidomide include rash, neuropathy and elevated liver enzymes. It is noted that these adverse effects are often dose-dependent and seen commonly with high-dose thalidomide.^[19] A meta-analysis showed 91% clinical and 90% radiological improvement with thalidomide.^[19] Although thalidomide is not mentioned in any guidelines, strong randomised controlled trial evidence in children is still lacking. Other common drugs like aspirin have also shown benefits in PR due to their anti-thrombotic and anti-inflammatory properties.^[44] TB care is incomplete without emphasis on preventive therapy^[45] and management of malnutrition with proper nutritional and psychosocial support^[39] to the affected family as per the Nikshay Poshan Yojana of the NTEP.^[2]