35  Paediatric Tuberculosis

35.1 Definitions

Infection with Mycobacterium tuberculosis usually results from inhaling infected droplets produced by someone who has Pulmonary Tuberculosis (TB) and is coughing. The most infectious source cases are those with sputum smear-positive disease. The closer the contact with this source case, the greater the exposure and the greater the risk of getting infected with tuberculosis.

TB infection occurs when a person carries the Mycobacterium tuberculosis bacteria inside the body. Many people have TB but are well. A positive tuberculin skin test (TST) suggests infection but a negative TST does not exclude the possibility of infection.

TB disease occurs in someone with TB infection when the bacteria inside the body start to multiply and become numerous enough to damage one or more organs of the body. This damage causes clinical symptoms and signs. This is referred to as “tuberculosis” or active disease.

Close contact is defined as living in the same household as, or in frequent contact with (e.g. caregiver, school staff), a source case with PTB.

Multidrug-resistant TB (MDR-TB) is caused by M. tuberculosis strains that are resistant to both isoniazid and rifampicin.

Pre-extensively drug-resistant TB (Pre-XDR): TB caused by M. tuberculosis strains that fulfil the definition of multidrug-resistant TB (MDR-TB) or rifampicin-resistant TB (RR-TB) and that are also resistant to any fluoroquinolone.

Extensively drug-resistant TB (XDR-TB): TB caused by M. tuberculosis strains that fulfil the definition of MDR/RR-TB and that are also resistant to any fluoroquinolone and at least one additional Group A medicine. (bedaquiline and linezolid)

35.2 Incidence/prevalence

According to the 2023 WHO global TB report; globally, a total of 10.6 million people fell ill with TB in 2022 of which children less than 15 years accounted for 12%. According to WHO estimates for 2022, there were 44,000 estimated incident cases in Ghana. Of this number, Ghana notified 16,526 cases of which 10% were expected to be paediatric (0-14yrs). However, 5% of paediatric cases were notified.

35.3 Aetiology

The Mycobacterium tuberculosis complex (MTBC) constitutes a significantly genetically similar group of bacteria that cause tuberculosis in various hosts. They are rod-shaped, acid-base-fast, aerobic, slow-growing intracellular pathogens that destroy phagosomal cells to maintain and evade the immune system. The major MTBC pathogenic mycobacteria species include M. tuberculosis, M. bovis, M. africanum, and M. microti.(Zhang et al. 2022)

35.4 Pathogenesis

Following the M. tuberculosis transmission to a new host, the bacilli enter the lung and get ingested by macrophages. Further, immune cells are recruited to wall off the infected macrophages, forming granuloma, the hallmark of TB. Healthy individuals remain latently infected, and the infection is kept at bay at this stage, but it is prone to the risk of reactivation. As the granuloma develops, the bacilli emerge from the macrophages. When the reactivation occurs, M. tb proliferates, the bacterial load becomes overwhelmingly high, and the granuloma ruptures, disseminating the bacteria to the airways. The bacilli are then expectorated as contagious aerosol droplets, restarting the cycle, and infecting other individuals.(Alsayed and Gunosewoyo 2023)

35.5 Signs and symptoms

It is important to understand the risk for TB infection and TB disease. Taking the history from children and caregivers must include questions on risk factors.

For an infection to occur, there are certain factors:

1. Contact with source case (Close contact and duration of contact)
2. Source case (Smear positivity: smear positive is more infectious; Cavitation on Chest X-ray: more infectious)
3. Increased exposure (Living in high TB endemic areas; children of families living with HIV)

Factors affecting TB disease:

1. Young age ( 2 years and below)
2. HIV infection
3. Other immunosuppression (Malnutrition, Post-measles)
4. Not BCG vaccinated (Risk of disseminated TB or severe TB disease)

Pulmonary Tuberculosis

History –The major considerations

Make every effort to look for the close contact or the household contact who is the source of the infection. It is helpful to note that close contact may be at school in a classroom, dormitory/ school bus, or church. Sometimes, it may be someone who frequently visits the child’s home or a caregiver. In childhood, it may take between 3 months to 2 years from the time of exposure to develop TB disease.

History of symptoms suggestive of TB

More commonly children with TB will present with the following symptoms:

1. Cough of any duration or progressive non-remitting cough which may be dry or wet.
2. Fever (persistent or unexplained)
3. Lethargy/reduced playfulness/less active
4. Poor weight gain or weight loss or very low weight (failure to thrive), flattened growth curve is a very sensitive marker of disease. More specifically it is important to plot the measurement and compare it to previous charts on the growth charts in the child health record booklet
5. Night sweat. Since most children sweat at night, it is usually difficult to establish this symptom.

Physical Examination (Some clinical findings suggestive of PTB)

General Examination

1. Fever- Temperature that remains persistently high or irregular >37.5 (fever)
2. Weight- (confirm poor weight gain, recent weight loss): the weight should be plotted on the child’s growth curve, and any child who “falls off” or is unable to maintain their usual line of growth should be considered as having possible TB
3. Length/Height is needed to determine the weight-for-length/height Z-scores (<-3 Z indicates severe wasting)
4. MUAC -Middle upper arm circumference of < 12.5 cm
5. Respiratory rate - (fast breathing) depends on the patient’s age. (Children 0-2 months above 60cpm, 3 months to 12 months more than 50 CPM and 1-5 years more than 40 CPM)
6. Signs of respiratory distress are not specific to TB but must raise the index of suspicion e.g Low oxygen saturation, stridor, and wheezes

Physical signs suggestive of Extra Pulmonary TB (EPTB) include:

1. Enlarged cervical lymph nodes which are not painful with or without fistula formation – TB lymphadenopathy;
2. Presence of spinal kyphosis (angular swelling) – spinal TB (“gibbous”);
3. Signs of non-acute meningitis with poor response to antibiotic treatment and/or with raised intracranial pressure – TB Meningitis;
4. Pleural effusion, especially one-sided dullness with pleuritic pain in a child who is not acutely ill – pleural TB;
5. Pericardial effusion, distant or muffled heart sounds or signs of new-onset heart failure – pericardial TB;
6. Non-acute distended abdomen with or without ascites – abdominal TB;
7. Non-tender swollen joints with painful or abnormal gait – osteoarticular TB.

35.6 Investigations

In addition to a detailed history and careful physical examination, all children suspected to have TB will require additional investigations. Investigations commonly used are grouped into the following categories.

1. Bacteriological investigations
2. Radiologic investigations and
3. Immunologic investigations.

35.6.1 Bacteriological investigations

Xpert MTB/RIF Assay is the recommended first-line investigation for diagnosing TB in children. Results are rapid and determine if the patient has a drug-sensitive or resistant organism. Various specimens may be collected, including expectorated sputum, induced sputum, gastric aspirate, bronchoalveolar lavage, transbronchial biopsies, pleural aspirate urine, blood, cerebrospinal fluid tissue and, more recently, stool. Other modalities for confirming TB are smear microscopy and TB cultures.

35.6.2 Radiologic investigations

Children often have paucibacillary TB and therefore bacteriological yields are low. Various imaging modalities can be suggestive of TB. Chest X-ray is the most frequently used radiological imaging. The presence of hilar lymphadenopathy (Figure 35.1), effusions, and cavitations could all support the diagnosis of TB in children. Ultrasound, CT scan, and MRI all have roles in suspected extrapulmonary TB.

Figure 35.1: Chest X-ray showing perihilar lymphadenopathy suggestive of TB

35.6.3 Immunologic investigations

Immunological tests provide evidence for TB infection but not TB disease. Two tests are widely used namely the Tuberculin skin test and the interferon-gamma release assay.

35.7 Treatment

35.7.1 Antituberculous medications

There are two types of treatment namely TB disease treatment and TB preventive therapy. The Paediatric TB Medicines comprises of 3 different formulations as follows:

1. Rifampicin + Isoniazid + Pyrazinamide (RHZ) 75/50/150 mg
2. Ethambutol (E) 100 mg 3. Rifampicin + Isoniazid (RH) 75/50 mg

Every child receives 2RHZE ( 2 months intensive phase)/4RH (4 months continuation phase) for all forms of TB except TB meningitis and osteoarticular TB where the continuation phase is extended for 10 months (10 RH). For non-severe TB (refer to further reading) 2RHZE/2RH regimen can be applied.

Note:

Corticosteroids are often used as an adjunct in the treatment of these forms of TB to prevent complications. These include TB Meningitis; TB Pericarditis; and Pott disease/ TB Spondylitis. Pleural diseases, and Endobronchial TB
Pyridoxine (Vitamin B6) supplement is necessary in some patients to prevent peripheral neuropathy but recommended in ALL HIV-infected persons and severely acute malnourished patients on isoniazid

35.7.2 Major side effects

Potential side effects of TB medications are:

1. Rifampicin: Orange-colored urine, saliva or tears, jaundice
2. Pyrazinamide: GI disturbances, hepatotoxicity
3. Ethambutol: GI disturbances, blurred vision
4. Isoniazid: numbness and tingling in the extremities, GI disturbances, rash

35.7.3 TB Preventive Therapy

Every person living with HIV should be given TB preventive therapy (TPT) after screening and ruling out active TB disease. Other categories of children requiring TPT after ruling out TB disease are:

1. Newborns of mothers with TB,
2. All Children exposed to an index case with sputum-positive TB,
3. Long-term steroids, and immunocompromised children.

If a patient develops TB disease, the patient should be investigated, and treatment changed from TPT to full treatment. There are four(4) options for TPT in children:

1. Rifapentine + Isoniazid- weekly for 3 months
2. Rifampicin + isoniazid – daily for 3 months
3. Rifampicin- daily for 4 months
4. Isoniazid only – daily for 6 months

35.8 Complications

The most common complication is chronic lung disease. TB can affect any part of the body including the brain, spine and therefore can cause other complications such as stroke, abscesses, impaired growth and so forth.

35.9 Prognosis

With early identification and treatment, the prognosis is good.

35.10 Differential diagnosis

Common differentials are bacterial pneumonia, atypical pneumonia, brucellosis, bronchogenic carcinoma, HIV, and Hodgkin lymphoma

35.11 Further readings

WHO consolidated guidelines on tuberculosis: module 5: management of tuberculosis in children and adolescents

WHO operational handbook on tuberculosis: module 5: management of tuberculosis in children and adolescents

35.12 Sample case scenarios

Question

1. A mother delivers a newborn at 40 weeks gestation. Within the last 4 weeks of pregnancy, she started coughing. She bought cough syrup and amoxicillin at a dispensary. Her coughing got severe and she noted weight loss. At week 39, she visited the hospital and was diagnosed with TB (GeneXpert MTB positive and RIF sensitive). She was started on treatment immediately. She lives in a single room with her 3 other children who are 2 years, 8 years, and 10 years respectively who were all clinically well except the 2 years old who weighed 8 kgs.
   1. Identify risks of infection for the children
   2. Identify risks of disease in children
   3. How would you approach the management of the children

Answers

1. The risks of infection in the above scenario are sputum-positive MTB on GeneXpert tests and the single room is occupied by a single mother and her children.
2. The risk of TB disease will be in the newborn and the 2-year-old sibling who is already failing to thrive. If the mother has HIV or the children are not immunised with BCG, that would also be a risk factors for disease.
3. All the children have been exposed to TB through a close contact, who happens to be their mother. The mother has to be tested for HIV. If she is positive, all the children should also be tested. All the children would have to be screened for TB. The newborn should ideally not be given BCG vaccine but put on TPT if TB disease is excluded. The recommended TPT will depend on the HIV status of the newborn, but Isoniazid is an option for 6 months. After 6 months of INH, if there is no evidence that the newborn has been exposed to TB (Mantoux testing), the child can be given BCG vaccine. If the newborn has the disease, then full TB treatment should be given. The 2-year-old weighs 8 kg which is evidence of weight faltering. Plot the weight for age on the Z-score. Do other investigations such as Chest X-ray, stool for Xpert, and HIV testing. If the clinical, bacteriological, and imaging are suggestive of TB, treat the 2-year-old. If HIV is positive, remember to adjust the dose of ARVs that interact with rifampicin during TB treatment. If the screening of the 8 and 10 years is normal, then put them on TPT, otherwise treat them

Self-assessment questions

1. A 5-year-old boy diagnosed with TB and started on RHZE complained to his mother that he finds it difficult to see clearly what his school teacher has projected in class. Which of the following medications is likely responsible?
   1. Isoniazid
   2. Pyrazinamide
   3. Ethambutol
   4. Rifampicin
2. Explain why bacteriological yield from children with suspected PTB is often very low.

Alsayed, Shahinda S. R., and Hendra Gunosewoyo. 2023. “Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets.” International Journal of Molecular Sciences 24 (6): 5202. https://doi.org/10.3390/ijms24065202.

Zhang, Haobo, Mengda Liu, Weixing Fan, Shufang Sun, and Xiaoxu Fan. 2022. “The Impact of Mycobacterium Tuberculosis Complex in the Environment on One Health Approach.” Frontiers in Public Health 10 (September). https://doi.org/10.3389/fpubh.2022.994745.