4 Management of childhood tuberculosis
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- Planning the management of a child with tuberculosis
- Treating drug-susceptible tuberculosis
- Good adherence
- Monitoring treatment
- Drug-resistant tuberculosis
- Treating tuberculosis and HIV co-infection
- Treatment with steroids
- Good nutrition
- Case studies
When you have completed this unit you should be able to:
- Give the principles of managing a child with tuberculosis.
- Identify which children can be managed at home.
- Describe the treatment of drug-susceptible tuberculosis.
- Explain the importance of good adherence.
- Monitor a child on treatment.
- Clinically recognise drug resistance.
- Understand the role of improved nutrition.
- List the problems of treating tuberculosis and HIV co-infection.
Planning the management of a child with tuberculosis
4-1 What are the principles of managing children with tuberculosis?
- Correct treatment
- Good adherence
- Careful follow up
- Improved nutrition
- Screening for HIV
4-2 What is the difference between uncomplicated and complicated tuberculosis?
In children less than 8 years of age and under 30 kg bodyweight tuberculosis is classified as uncomplicated, complicated or TB meningitis / military TB, as the treatment differs for each of these disease categories:
- Uncomplicated TB refers to milder forms of tuberculosis in HIV uninfected children. Included are mild forms of pulmonary tuberculosis, such as limited lung (parenchymal) infection and/or limited intrathoracic lymphadenopathy, and less severe forms of extrapulmonary tuberculosis, such as TB lymphadenitis and tuberculous pleural effusion.
- By contrast, complicated TB includes: HIV-infected children with any form of pulmonary or extrapulmonary TB except for TB meningitis and military TB. HIV uninfected children with severe forms of pulmonary TB, notably extensive parenchymal, cavitatory or smear positive TB, and extrapulmonary TB, but excluding milder forms of TB, TB meningitis and military TB.
4-3 Should all children with tuberculosis be treated in hospital?
Most HIV uninfected children with uncomplicated tuberculosis and HIV-infected children with milder forms of TB do not need admission to hospital. They can be treated at home and managed from a local clinic. Usually bed rest is not required.
Children with complicated tuberculosis (severe pulmonary and extrapulmonary TB), or miliary tuberculosis or tuberculous meningitis should be admitted to hospital.
Treating drug-susceptible tuberculosis
4-4 Can tuberculosis in children be cured?
Most cases of drug-susceptible tuberculosis (more than 90%) can be cured with multiple drug treatment provided that they adhere to and complete the course of anti-tuberculous treatment.
Most patients with tuberculosis can be cured.
4-5 What are the aims of treating tuberculosis?
- To cure the tuberculosis
- To make the patient not infectious to others
- To prevent relapse of tuberculosis
- To prevent the development of drug resistance
4-6 How many drugs are used in the treatment of drug-susceptible tuberculosis?
Tuberculosis is never treated with one drug alone. The number of drugs used depends on the phase of treatment. Usually three or four drugs are used together during the intensive phase (first 2 months of treatment). During the continuation phase (last 4 months of TB treatment) 2 drugs are usually administered.
4-7 Why is more than one drug needed?
Multiple drugs are used as they are more effective than one drug alone. Using multiple drugs increases the certainty that tuberculosis will be cured.
There is less chance of drug resistance developing if multiple drugs are used. TB bacilli rapidly become resistant if only one drug is used.
- Some TB drugs kill rapidly multiplying bacilli (bactericidal drugs) while others kill slow growing bacteria (sterilising drugs).
4-8 Which drugs are used to treat drug-susceptible TB?
The four commonly used anti-tuberculous drugs used to treat drug-susceptible TB in childhood are:
- Isoniazid (INH)
- Rifampicin (RIF)
- Pyrazinamide (PZA)
- Ethambutol (EMB)
In South Africa ethionimide (Eto) is used in combination with INH, RIF and PZA to treat TB meningitis and miliary TB caused by drug-susceptible TB bacilli in children less than 8 years.
These drugs are used as they are cheap, effective and have few side effects (adverse events). All adverse events from drugs should be reported to the local authority.
4-9 What is the aim of the intensive phase of treatment?
The intensive phase usually lasts for the first 2 months of anti-tuberculous therapy. During this phase the aim is to rapidly kill as many TB bacilli as possible. To achieve this intensive treatment is needed with a number of drugs that have a high ability to kill TB bacilli. Rapidly reducing the number of TB bacilli stops the progression of the disease, makes patients less infectious and helps to prevent the development of drug resistance.
4-10 What is the aim of the continuation phase of treatment?
This longer phase of treatment is necessary to make sure that the remaining TB bacilli do not start to multiple once again. Fewer drugs are needed to achieve this.
4-11 How is uncomplicated TB treated in younger children?
For children less than 8 years of age and under 30 kg, during the intensive phase (first 2 months of anti-TB treatment) three drugs are used namely: INH, RIF and PZA. This is followed by a continuation phase (last 4 months of anti-tuberculous treatment) in which two drugs are used, namely INH and RIF. Thus for uncomplicated tuberculosis, the course of treatment usually lasts six months.
Drug treatment for many months is needed to cure tuberculosis.
4-12 How is complicated TB treated in younger children?
For children less than 8 years and under 30 kg, during the intensive phase (first 2 months of anti-TB treatment) four drugs are used namely: INH, RIF, PZA and EMB. This is followed by a continuation phase (last 4 months of anti-tuberculous treatment) in which two drugs are used, namely INH and RIF. Thus for complicated tuberculosis the total duration of treatment usually lasts six months.
- In a small proportion of young children with HIV infection, 6 months of anti-tuberculous treatment is inadequate as they may still have evidence of active tuberculosis at the end of 6 months of treatment. In this group of children, the continuation phase is often extended to 7 months thus the total duration of this group of children is 9 months. The WHO recommends that for osteoarticular tuberculosis in children and adults the continuation phase be extended to 10 months. Thus the total duration of anti-tuberculous treatment is 12 months for these children.
4-13 What is short-course treatment?
This is the modern way of treating tuberculosis where a six-month course of drug treatment is used. Before rifampicin was developed, courses of 12 to 18 months were used. However compliance was often poor with these longer courses as many patients did not take their medication regularly or stopped treatment too soon. With the introduction of rifampicin the duration of therapy was reduced to 9 months. However, after pyrazinamide was introduced and combined with isoniazid, rifampicin and/or ethambutol in the 1980s it was possible to reduce the duration of anti-tuberculous treatment further to 6 months (short-course treatment). The cure rate of tuberculosis has improved with shorter, well-monitored courses of anti-tuberculous drugs. Short-course treatment is more cost effective but must be well managed.
4-14 How are drug doses calculated in children?
Usually body weight is used to calculate drug doses in children (i.e. mg/kg). When children respond to treatment and gain weight, the dose may need to be increased even though the dose per kg body weight remains the same.
- Dosing of the TB drugs may be simplified by using a weight-band table. South Africa has adopted this approach.
4-15 How is isoniazid given?
Isoniazid (INH) is an excellent drug which is taken by mouth. It is cheap, has few adverse effects in children, and is particularly good at killing TB bacilli during the intensive phase. INH is given throughout the six-month course of treatment.
The dose of INH is 10 mg/kg/day. It is important not to use a smaller dose.
- Range is 10 to 15 mg/kg/day and the maximum daily dose is 300 mg.
4-16 How is rifampicin given?
Rifampicin is also very good at killing TB bacilli and is used throughout the six-month course. It is given by mouth and has few adverse effects in children. Rifampicin colours the urine orange but this is harmless.
The dose of rifampicin is 15 mg/kg/day.
- Range is 10 to 20 mg/kg/day and the maximum daily dose is 600 mg.
4-17 How is pyrazinamide given?
Pyrazinamide is used during the intensive phase to help kill dormant TB bacilli which are not multiplying. It is also taken by mouth.
- Note: Range is 30 to 40 mg/kg/day and the maximum daily dose is 2000 mg.
4-18 How is ethambutol given?
Ethambutol is used to treat complicated tuberculosis. It is used during the intensive phase to kill actively multiplying TB bacilli and prevent the development of resistance to the other anti-tuberculous drugs in patients more severe TB. It is taken by mouth. The dose of ethambutol is 20 mg/kg/day.
- The dosing range of ethambutol is 15 to 25 mg/kg/day and the daily maximum dose is 1200 mg.
4-19 How often are anti-tuberculous drugs taken for drug-susceptible TB?
In South Africa INH, rifampicin, pyrazinamide and ethambutol are taken by mouth at the same time once a day, usually in the morning before breakfast.
4-20 How is tuberculous meningitis and military TB treated in young children?
In South Africa, children less than 8 years of age and below 30 kg body weight with either TB meningitis or military TB are treated with four drugs, namely INH, RIF, PZA and ethionimide. All four drugs are administered for the entire duration of therapy. The duration of anti-tuberculous treatment is 6 months for HIV uninfected children and 9 months for HIV-infected children. The four drugs are administered at higher doses than other forms of tuberculosis:
- Isoniazid 20 mg/kg/day (maximum daily dose, 400 mg)
- Rifampicin 20 mg/kg/day (maximum daily dose, 600 mg)
- Pyrazinamide 40 mg/kg/day (maximum daily dose, 2000 mg)
- Ethionimide 20-25 mg/kg/day (maximum daily dose, 1000 mg).
- The WHO recommends that TB meningitis be treated with a 4-drug (INH, RIF, PZA and EMB) intensive phase of 2 months followed by a 2-drug (INH and RIF) continuation phase for a further 10 months. Unlike the South African treatment regimen, all drugs are administered at standard doses. Most countries in sub-Saharan Africa use this WHO treatment regimen.
4-21 How is drug-susceptible TB treated in older children and adolescents in South Africa?
For children older than 8 years and more than 30 kg body weight one regimen is used to treat all forms of drug-susceptible tuberculosis. The total duration of therapy is 6 months. During the intensive phase (first 2 months of anti-TB treatment) four drugs are used namely: INH, RIF, PZA and EMB. This is followed by a continuation phase lasting 4 months in which two drugs are used, namely: INH and RIF.
4-22 How are drug doses calculated for older children and adolescents?
As with younger children body weight is used to calculate drug doses (i.e. mg/kg). When children respond to treatment and gain weight, the dose may need to be increased even though the dose per kg body weight remains the same. Dosing of the TB drugs may be simplified by using a weight-band table.
- The Western Cape dosing table can be used to determine the correct doses in older children.
4-23 How does the treatment of children and adults differ?
The approach to treating adults with drug-susceptible TB is similar to that of older children and adolescents. Four drugs are used in adults during the initial, intensive phase of two months. Ethambutol is added to INH, rifampicin and pyrazinamide. This is because there are far more TB bacilli in tuberculosis with cavities which commonly occurs in adults. As young HIV uninfected children rarely have cavities, only three drugs are commonly used in the intensive phase. As with children, adults are usually treated with INH and rifampicin for the four-month continuation phase.
4-24 What are the adverse effects of drugs used for susceptible TB?
Usually there are few serious adverse effects (side effects) with children. Adverse effects are more common in adults. The organ most commonly affected by first-line anti-TB drugs is the liver. All commonly used first-line drugs can cause hepatitis. There is no need to routinely measure liver enzymes. However liver enzymes must be measured in patients who are jaundiced and all anti-TB drugs should be stopped if the enzymes are elevated more than 3 times above the upper limit of normal. These patients should be referred for investigation and review of anti-TB treatment. If a child develops hepatitis on TB treatment other common causes of hepatitis must be looked for e.g. viral hepatitis A. Nausea, vomiting, right upper quandrant pain and skin rashes may occur.
- INH may cause peripheral neuropathy, but this is very uncommon in children and routine pyridoxine supplementation is not needed. Hepatitis recovers once the drug causing the problem is stopped.
Drugs used to treat tuberculosis can cause hepatitis.
4-25 What are the advantages of fixed-dose combination drugs?
Drugs used to treat susceptible TB should ideally be given as fixed-dose combination tablets or suspensions. For some time, this has been possible for older children and adolescents over 30 kg body weight and adults. In these patients there are four-drug combined preparations, which incorporate INH, RIF PZA and EMB in a single tablet (fixed-drug combination) that is used during the intensive phase of treatment, and two-drug preparations that contain both INH and RIF in a single tablet that is used during the continuation phase. The situation for younger children was more challenging.
Until 2019 the only fixed dose preparation that was available for use in children below 30 kg body weight was a two-drug dissolvable tablet that contains equal amounts of INH and RIF (60/60 mg). This tablet was used in both intensive and continuation phases of drug-susceptible TB. All other TB drugs were administered to young children in South Africa as single-drug preparations.
In 2020, two new dissolvable fixed-drug combinations, with improved drug ratios, were added to the South African National TB programme, a rifampicin, pyrazinamide and isoniazid (75/150/50 mg) fixed-drug tablet and a rifampicin and isoniazid (75/50 mg) fixed-drug tablet. These fixed-drug combinations have been included in the TB drug dosing charts for children, further simplifying the treatment of uncomplicated TB, complicated TB and TB meningitis or miliary TB in children less than 8 years of age in South Africa.
Fixed-dose combinations reduce the number of tablets that have to be taken and prevents patients leaving out the drugs they do not like. As a result adherence is improved and the development of drug resistance reduced.
- In 2009 the WHO proposed improved 2-drug, 3-drug and 4-drug combination formulations appropriate for the treatment of drug susceptible TB in younger children. After sustained advocacy WHO announced the introduction of 2-drug (INH and RIF) and 3-drug (INH, RIF and PZA) fixed-drug formulations, and a new child-friendly dispersible ethambutol tablet in December 2015. The 2-drug and 3-drug fixed-drug combinations entered clinical practice in South Africa in 2020.
4-26 When should treatment be started?
When the diagnosis of tuberculosis is confirmed by identifying TB bacilli, usually in the sputum.
When the history, examination, skin test and chest X-ray strongly suggests tuberculosis even if the diagnosis cannot be confirmed by identifying TB bacilli. Some of these children are diagnosed after failing to respond to treatment for acute pneumonia. Therefore, some children are treated for tuberculosis without confirming the diagnosis on sputum examination. Drug treatment should be started if tuberculosis is proven or if there is a high clinical suspicion of TB.
4-27 What is good adherence?
Excellent adherence (compliance) means that every dose of medication is taken each day at the correct time. If more than 80% of the doses are taken correctly, adherence is said to be good.
4-28 Why is good adherence important?
- It greatly increases the chance for a cure.
- It greatly reduces the risk of drug resistance developing.
- It prevents the relapse (recurrence) of tuberculosis.
The most important aspect of treating a child with tuberculosis is to ensure that the medicine is taken correctly and regularly (every day including over weekends). This is often difficult as medication has to be taken for many months.
Good adherence is essential to cure the patient and prevent drug resistance.
4-29 How can adherence be improved?
- By the healthcare worker clearly explaining what tuberculosis is, and why treatment must be given for such a long time even if the child is clinically improving
- By the healthcare worker giving clear instructions on when and how to take the medication
- By a good understanding of these instructions by the child and parents
- It is essential that the clinic staff establish a good relationship with mother and child.
- With a written treatment plan
- By supporting the family
- By good follow up to check adherence
- With a treatment diary to record medication taken
- Using a daily pill box
- Using ‘DOT’
4-30 What is DOT?
‘DOT’ stands for directly observed treatment. With DOT some responsible person in the community observes the child swallowing every dose of the anti-tuberculous drugs. In practice, this is usually done from Monday to Friday with the family making sure that the drugs are taken over weekends. The DOT worker (community trained treatment supporter) does not have to be a health professional and is usually not a family member. However the DOT support person must be reliable and trained for the task. They should be encouraging and make sure that the correct dose of each drug is taken. Unfortunately DOT is often not correctly implemented.
With DOT a responsible person must see the child takes the tablets.
- In contrast to DOT, DOTS (directly observed treatment, short-course) is a strategy which has five elements: political commitment, TB DNA or culture diagnosis, regular supply of drugs, treatment supervision, and recording and reporting. DOT is only the supervision part.
4-31 What are the advantages of DOT?
DOT ensures good adherence without the child having to go to the clinic for every dose. If DOT is correctly used, the failure rate of treatment is greatly reduced and over 90% of children should be cured. The general public can play an important role in the control of TB by supporting DOT. DOT is a key factor in obtaining high cure rates and reducing the risk of drug resistance.
The success of treatment depends on good support.
- The cure rate for TB without DOT in poor countries may be as low as 40%.
4-32 How is treatment monitored?
The child should be carefully followed up at the treatment clinic (ideally a clinic close to the family home). Each child must have a treatment sheet where each visit is recorded. The child’s clinical condition, weight, drugs taken and any identified problems must be noted. A careful record of the date of the next appointment must be made. If the child fails to attend on that date, the family must be contacted by phone or by a community health worker. It is important to be aware when a child misses a clinic appointment.
4-33 How is the response to treatment monitored?
Once the child has been on triple drug or four drug treatment for a few weeks the signs and symptoms should gradually improve and the child should start to feel well and gain weight. The most reliable feature of a good response to treatment is the disappearance of symptoms and weight gain.
After starting treatment the child should be seen every two weeks for the first month and then monthly for the rest of the treatment. The child should be weighed at every visit. As the child gains weight the drug dosages must be adjusted.
In children with sputum smear-positive tuberculosis, a sputum sample for smear examination is collected at the end of the intensive phase at two months. This should be negative for TB bacilli. Sputum samples are collected again towards the end of treatment. If sputum smears or culture remain positive, drug susceptibility testing must be done to exclude drug resistance.
A definite improvement in the chest X-ray may be seen in early infections after a month. However, the X-ray changes may take a few months to improve. Therefore X-rays are not routinely used to determine if a child is responding to treatment.
4-34 What are the commonest causes of failure to cure tuberculosis?
- Failure to take the medication correctly as prescribed (non-adherence). If doses of the drugs are missed repeatedly the tuberculosis will not be cured and drug resistance may develop.
- If the treatment is stopped too soon the tuberculosis can return (relapse). In many poor countries it is common for patients with tuberculosis not to complete their full course of treatment. Once they feel well again they stop their medication. As a result, relapse of TB occurs, drug resistance develops and many people die of TB.
- The child is HIV infected and is not receiving antiretroviral treatment. Response to anti-TB treatment is usually good in children with HIV infection.
- Tuberculosis caused by multi-drug-resistant TB.
Treatment of tuberculosis is difficult as it is lengthy and requires good adherence.
4-35 What is drug-resistant tuberculosis?
This is tuberculosis where the TB bacilli are resistant to one or more of the major first-line (INH, RIF, PZA or EMB) or second-line (fluroquinolones or injectable agents) drugs. Drug-resistant tuberculosis can develop if resistant TB bacilli are transmitted from an individual (contact) with existing drug-resistant TB to an uninfected child or adult. This is referred to as primary or transmitted resistance. Alternatively, drug-resistant TB may develop in a child or adult during the course of drug-susceptible TB mainly because of poor adherence. This is referred to as secondary or acquired resistance. Transmitted drug resistance is more common than acquired resistance in children.
4-36 What are the causes of acquired drug resistance?
These patients do not have drug resistance when anti-TB treatment is started. It develops during the course of treatment mainly because of failure of good adherence due to:
- Inadequate patient education on the importance of good adherence
- Failure to understand the importance of completing the full course of treatment even if the patient is feeling much better
- Poor support (failed DOT)
- Inadequate supply of drugs (no drugs available at the clinic)
- Side effects leading to poor adherence or stopping one drug
- Poor follow up of patients on treatment
These factors are all related to the inadequate care of patients with tuberculosis. Therefore, poor management of tuberculosis in the community is the main cause of acquired drug resistance. Drug resistance is caused by poor tuberculosis management.
Acquired drug resistance is caused by poor tuberculosis management
- Although poor adherence and programmatic weaknesses are considered major reasons for the emergence of drug-resistant tuberculosis, it is becoming evident that other factors play a role in the development of acquired drug resistance such as variation in the concentration and distribution of the TB drugs in the body (due to genetic influence) and inadequate penetration of TB lesions by anti-TB drugs.
4-37 How is drug-resistant tuberculosis classified?
Resistance to one anti-TB drug is referred to as monoresistant tuberculosis. Isoniazid monoresistant tuberculosis is the most common form of drug-resistant TB. Rifampicin monoresistant TB (RR-TB) is another important form of monoresistant TB.
Multidrug resistant tuberculosis (MDR-TB) is defined as resistance to at least isoniazid and rifampicin such that treatment for drug-susceptible TB will not cure the patient.
Extensively drug-resistant tuberculosis (XDR-TB) is MDR-TB that is also resistant to any fluoroquinolone (e.g. levofloxacin and moxifloxacin) and at least one of three second-line injectable agents (amikacin, kanamycin and capreomycin).
- The term pre-extensively drug-resistant tuberculosis (pre-XDR-TB) is also used in clinical practice. It describes MDR-TB that in addition is resistant to either a fluoroquinolone or a second-line injectable agent (amikacin, kanamycin and/or capreomycin), but not both.
4-38 How important is drug-resistant tuberculosis?
Drug-resistant tuberculosis is a serious, global public health problem. It is estimated that 15 to 20% of all TB cases worldwide are resistant to at least one major first-line or second-line anti-TB drug. INH-monoresistant TB is present in approximately 10% of all TB cases and a further 5% of all patients with TB have either MDR/RR-TB or XDR-TB. Progress in controlling tuberculosis in some parts of the world is now being threatened by the growing drug-resistant crisis.
- In 2019 South Africa had 14 000 laboratory-confirmed cases of either MDR-TB or rifampicin-resistant TB (MDR/RR-TB). Although MDR/RR-TB, including XDR-TB, account for 5% of TB cases in South Africa it consumes a third of all resources and funds used in the tuberculosis programme.
4-39 How is drug resistance diagnosed in children?
- Rifampicin resistance may be diagnosed using the Xpert MTB/RIF ultra test. Further, laboratory testing of the TB bacilli in a patient with rifampicin resistance will determine whether the patient has MDR or XDR-TB.
- TB bacilli that are cultured from the sputum or another sample can be tested in the laboratory for drug-resistance. If drug-resistance is identified laboratory testing will establish whether monoresistant TB, MDR-TB or XDR-TB is present.
- Drug-resistant TB should be suspected in children if they are in contact with an adult or older child/adolescent suffering from drug-resistant pulmonary tuberculosis. If a child is in contact with drug-resistant TB and has clinical, radiological and/or Mantoux evidence of active tuberculosis the Xpert MTB/RIF ultra and TB culture results are often negative because paucibacilliary TB is common in children. However, these children should receive treatment for drug-resistant TB according to the drug-resistance test results of the adult/adolescent contact.
- Drug-resistant tuberculosis should also be considered in children with tuberculosis who fail to respond to treatment for drug-susceptible TB despite good adherence.
4-40 How are patients with drug resistance managed?
They must be managed at special TB units or clinics by doctors who are experienced in caring for these patients. There are several classes of anti-TB drugs that are used in the treatment of drug resistant TB. Many of these drugs are very expensive and have more side effects that the anti-TB drugs used to treat drug-susceptible tuberculosis. The duration of treatment for drug-resistant tuberculosis depends on the type of drug-resistance but extends for 6 to 9 months for isoniazid monoresistant TB, 9 to 11 months or more for MDR/RR-TB and 18 to 20 months or more for MDR/RR-TB with fluoroquinolone resistance. Many patients with MDR/RR-TB can be successfully treated with highly effective injectable-free drug regimens of 9 to 11 months duration.
- Drug regimens used to treat drug-resistant TB vary according to the type of drug-resistant TB and include:
- Levofloxacin or moxifloxacin
- Linezolid, clofazimine, terizidone
- Delamanid, para-aminosalicylic acid
- PZA, ethambutol, ethionimide
- High-dose INH
- Meropenem plus amoxycillin-clavulanic acid
- Injectable agents such as amikacin
4-41 What is the outcome of drug-resistant TB?
The outcome of INH monoresistant tuberculosis is similar to drug-susceptible TB. The overall success rate of MDR/RR-TB treated with an all-oral bedaquiline-containing regimen is currently at 73% in South Africa. However, children treated for MDR/RR-TB have a more favourable response with more than 80% of them achieving a good outcome.
- Up to 25% of children treated for MDR/RR-TB with an injectable agent will develop hearing loss. To prevent this complication, South Africa has introduced all-oral (injectable-free) treatment for most cases of drug-resistant TB.
Treating tuberculosis and HIV co-infection
4-42 What is the relation between tuberculosis and HIV infection?
Often both TB and HIV infections occur together. The risk of getting tuberculosis is many times higher in children who are HIV infected, especially if they are not on antiretroviral treatment. In one South African study of children under one year of age, the risk of acquiring culture-confirmed tuberculosis was 24-fold higher in HIV-infected infants compared to uninfected children of the same age.
Tuberculosis is more severe in children with an immune system weakened by HIV infection. Children with HIV infection are also more likely to develop tuberculosis if they are infected with TB bacilli.
In turn, tuberculosis speeds up the progress from asymptomatic HIV infection to severe clinical disease.
Therefore, all children with TB must be screened for HIV infection.
4-43 When does tuberculosis present in HIV-infected children?
Children may be diagnosed with TB at the same time that HIV infection is diagnosed. This is the common scenario. Alternatively, tuberculosis may develop in HIV-infected children who are already on antiretroviral treatment.
- Antiretroviral treatment significantly lowers the risk of developing tuberculosis in HIV-infected children. Therefore, the incidence of tuberculosis is lower in children on ART than in HIV-infected children who have not been started on ART.
4-44 How is tuberculosis treated in HIV-infected children?
When children with tuberculosis also have HIV infection, both infections must be treated. This should be managed at a clinic with the experience and expertise to treat children with TB and HIV co-infection. Alternatively, an experienced clinician should be consulted to assist you with the management of your patient.
- The treatment of tuberculosis always takes priority in HIV-infected children. Anti-TB treatment should be started as soon as the diagnosis of tuberculosis is made.
- In children in whom the diagnosis of HIV infection is made at the same time as the diagnosis of tuberculosis, anti-TB treatment should be started as soon as possible and antiretroviral treatment is begun within 8 weeks of commencing anti-TB treatment.
- For children with severe immunosuppression (CD4 200 or less cells/μL or below 15 %) antiretroviral treatment should ideally begin within 2 weeks of starting anti-TB treatment.
- In HIV-infected children with TB meningitis antiretroviral treatment should be deferred until 4 to 8 weeks after beginning anti-TB treatment. The antiretroviral treatment regimen may need to be adjusted to overcome the action of rifampicin on the metabolism of the antiretroviral drugs.
- For HIV-infected children who develop tuberculosis while on antiretroviral treatment, anti-TB treatment should be started as soon as possible. The antiretroviral treatment regimen may need to be adjusted to overcome the action of rifampicin on the metabolism of the antiretroviral drugs.
Tuberculosis in HIV infected children must be treated as soon as possible
4-45 How may HIV infection interfere with the drug treatment of tuberculosis?
There may be an interaction between the drugs used to treat tuberculosis and the drugs used to treat HIV infection. Adherence may also be poor as a greater number of drugs have to be taken while the risk of side effects to some of the anti-TB and antiretroviral drugs increases when both are used together.
Rifampicin significantly lowers the blood levels of some antiretroviral drugs especially nevirapine, the protease inhibitors, such as lopinavir, and the integrase inhibitors such as dolutegravir necessitating adjustment to the antiretroviral treatment regimen. Although rifampicin lowers the blood level of efavirenz its impact is moderate and therefore dose adjustment is not required for patients taking an efavirenz-containing antiretroviral treatment regimen. Rifampicin may also affect the metabolism of children treated with a 3rd antiretroviral regimen.
Rifampicin lowers blood levels of nevirapine, protease inhibitors and integrase inhibitors
4-46 What antiretroviral drug changes may be required if rifampicin is given?
- If efavirenz is being used then no change is necessary.
- If nevirapine is being used in an infant then discuss the antiretroviral treatment with an experienced clinician. If nevirapine is being used in a child more than 3 years of age, it should be replaced with efavirenz, which is less affected by rifampicin.
- If lopinavir/ritonavir is being used, it should be boosted with additional ritonavir to maintain adequate blood levels.
- If dolutegravir is being used in a child or adolescent, the dosing frequency should be increased from daily to twice daily dosing to overcome the effect of rifampicin co-administration.
- If the child is on a 3rd line or salvage antiretroviral treatment regimen, an experienced clinician should be consulted to assist you with the management of your patient.
- These decisions should be made by an experienced clinician. Not making these changes may lead to drug resistance and failure of antiretroviral treatment.
|Body weight||3-4.9 kg||5-13.9 kg||14-19.9 kg||20-24.9 kg||25-39.9 kg||40 and above kg|
|Twice daily dose||1 ml||1.5 ml||2 ml||2.5 ml||3 ml||4 ml|
4-47 What is immune reconstitution inflammatory syndrome (IRIS)?
This is the unexpected clinical deterioration in a patient who was improving on antiretroviral treatment. As the immune system starts to recover the body may have an inflammatory reaction to the TB bacilli resulting in IRIS. Two types of TB-IRIS can occur:
- Paradoxical IRIS in which new or worsening manifestations of TB develop usually within 2 to 3 months after starting antiretroviral therapy, in a child with HIV-TB co-infection who is already on TB treatment.
- Unmasking IRIS in which an HIV-infected child with silent untreated TB develops new TB symptoms usually within 2 to 3 months after starting antiretroviral therapy.
Paradoxical TB-IRIS is more common. The highest risk period for the development of TB-IRIS is the first 100 days after antiretroviral treatment is started.
Common features of TB-IRIS are unexplained fever, enlarging lymph nodes and new or worsening pulmonary disease. New or worsening abdominal signs may occur in children with abdominal TB, and new or worsening neurological signs may occur with TBM-IRIS. These children need to be referred to facilities with experience in managing TB and HIV co-infected children as the diagnosis can be difficult and other causes of deterioration such as drug resistance need to be excluded.
IRIS due to previous BCG immunisation may also occur once antiretroviral treatment is started in infants.
Treatment with steroids
4-48 When is glucocorticosteroid therapy used in the treatment of tuberculosis?
Oral steroid therapy should be added to anti-TB treatment in children with TB meningitis, TB pericarditis, when enlarged lymph nodes obstruct airways (this is confirmed on chest x-ray) and in severely ill children with disseminated or military TB. Oral steroid therapy is also used in the treatment of children with severe forms of TB-IRIS.
4-49 How is oral steroid therapy administered?
Prednisone or prednisolone is given at a dose of 2 mg/kg/day for 4 weeks (maximum daily dose is 60 mg). Thereafter, steroid therapy is tapered-off and stopped over a further 2 weeks.
4-50 Why is good nutrition important in children with tuberculosis?
- Because malnutrition and tuberculosis go ‘hand in hand’, most children with tuberculosis are underweight.
- Malnourished children with an inadequate diet have a weakened immune system and are at high risk of developing tuberculosis.
- Tuberculosis leads to poor appetite, failure to thrive and weight loss which results in malnutrition.
- Poverty and overcrowding are common factors in both malnutrition and tuberculosis.
It is therefore important to improve the nutrition of all children to help protect them against tuberculosis, and improve the nutrition in children with tuberculosis.
Malnutrition and tuberculosis are often found together.
4-51 How can the nutrition of children be assessed?
Weighing is the best method of screening children for malnutrition. All children with a weight below the normal range for their age are at high risk of malnutrition.
The weight of children with tuberculosis must be regularly recorded and plotted on a weight-for-age chart. The Road-to-Health booklet should be used in children under five years of age. Gaining weight is an important sign that the child is responding to anti-TB treatment.
Plotting weight is an important way of assessing a child’s response to treatment.
4-52 How can nutrition be improved?
By improving the child’s diet. Vegetable oil will add energy to a meal while milk powder or beans will add protein.
Once the appetite returns the amount of food eaten each day will need to be increased. Financial assistance (e.g. child support grants) or food parcels may be needed.
4-53 When is pyridoxine supplementation recommended?
Supplemental pyridoxine is recommended for children treated for drug-susceptible tuberculosis if they are malnourished, HIV-infected or pregnant adolescents. Supplemental pyridoxine is also recommended for all children treated for drug-resistant tuberculosis.
4-54 How is pyridoxine given?
For children with drug-susceptible TB the dose of pyridoxine is 12.5 mg (half a tablet) per day. For children with drug-resistant tuberculosis the recommended dose is 25 mg/day of pyridoxine if less than 5 years and 50 mg/day if older than 5 years.
Case study 1
A boy of six years old is diagnosed with uncomplicated pulmonary tuberculosis and is followed up at a district hospital. His HIV test is negative. His parents are told he will need to take medication every day for six months. They are worried that tuberculosis cannot be cured.
1. Can uncomplicated pulmonary tuberculosis be cured?
There is an excellent chance that he will be cured provided that adherence to treatment is good.
2. What drugs should be used to treat this boy?
He should receive first-line treatment of rifampicin, INH and pyrazinamide for two months followed by rifampicin and INH only for another four months. This is known as short-course treatment. The first two months of treatment is called the intensive phase while the last four months are called the continuation phase.
3. Why is he not treated with rifampicin alone?
Because TB bacilli become resistant to treatment if only a single drug is used. That is why either two or three drugs during the intensive phase or two drugs during the continuation phase are always used together as multiple-drug treatment.
4. How often should the drugs be taken?
It is best if the drugs are taken once every day of the week, usually at breakfast.
5. Are side effects to the drugs common?
Children usually have no, or only mild, side effects to the first-line drugs used to treat tuberculosis.
6. How are the doses of the drugs calculated?
The child’s body weight is used to calculate the daily dose. As the child improves and gains weight, the daily dose may have to be increased.
Case study 2
A seven-month-old child is admitted to hospital with tuberculous meningitis. One of the older children in the family is also found to have tuberculosis. The mother asks whether the infant can be treated at home as it is a long way to the hospital.
1. What drugs are used to treat tuberculous meningitis?
In South Africa isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) plus ethionamide are used in combination. Ethionimide is chosen as it crosses the blood brain barrier well. Treatment is given for six to nine months.
2. What anti-TB drugs are used to treat severe pulmonary tuberculosis?
During the intensive phase isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) plus ethambutol (EMB) are used. The intensive phase lasts for 2 months and is followed by a continuation phase of 4 months in which INH and RIF are used in combination.
3. Is streptomycin also used in children with complicated tuberculosis?
No, as it is a painful injection which has to be given daily and has serious side effects. The needles and syringes are expensive and can spread HIV if they are reused.
4. Should treatment be started if a definite diagnosis of tuberculosis cannot be made?
If there is a strong clinical suspicion of tuberculosis but TB bacilli cannot be identified, for example in the sputum, treatment should be started.
5. Can this infant with tuberculous meningitis be treated at home?
While the child remains clinically ill treatment must be given in hospital. If discharged home, it is essential that treatment is strictly supervised as a break in treatment may result in death or serious neurological damage.
6. What other infection must always be screened for in children with tuberculosis?
Case study 3
An adolescent with pulmonary tuberculosis is referred to hospital because she has not improved after six weeks of treatment. The home conditions are poor and she admits that she often does not take her medication. Her family is always fighting and is not interested in helping her with her treatment.
1. Why is she failing to respond to treatment?
Poor adherence. Not taking medication regularly every day is a common cause of treatment failure. Lack of family support is a serious problem when treating childhood illnesses such as tuberculosis.
2. How can this problem be corrected?
By using DOT (directly observed treatment). A treatment supporter must support her taking her medication each day while the importance of good adherence must be explained to her. Trained members from the community can become DOT supporters.
3. What other steps can be taken to improve adherence?
A written treatment plan, treatment diary and pill box should help to improve adherence. Support from the clinic staff is also very important.
4. What other problem may result from poor adherence?
Drug resistance to the medication used for first-line treatment.
5. What is multi-drug resistance?
Resistance to at least rifampicin and INH. This has become a major problem in South Africa.
The six most important ‘take-home’ messages
- Uncomplicated tuberculosis in HIV uninfected children is treated with three first-line drugs during the intensive phase.
- Good adherence is essential to cure tuberculosis.
- Good appetite and weight gain are early indicators of response to treatment
- Good nutrition is an important part of managing children with tuberculosis.
- Poor response to treatment in spite of good adherence suggests multi-drug resistance.
- Suspect drug resistance if the child has been in contact with an adult suffering from drug-resistant pulmonary tuberculosis.