Chapter 9: Canadian Tuberculosis Standards 7th Edition: 2014 – Pediatric Tuberculosis

Chapter 9 - Pediatric Tuberculosis

Ian Kitai, MD, BCh, FRCPC
Anne-Marie Demers, MD, FRCPC

Table of Contents

  1. Key Messages/Points
  2. Preliminary Note
  3. Introduction
  4. Pathogenesis and Definitions
  5. Clinical Presentation of TB Disease
  6. Diagnostic Tests
  7. Recommended Management of TB Disease
  8. Recommended Management of LTBI
  9. Targeted Testing for Latent TB Infection
  10. Perinatal Issues: Recommended Management of the Newborn Infant Exposed to TB
  11. Conclusions
  12. References

Key Messages/Points

  • In Canada, pediatric tuberculosis (TB) is largely a disease of Canadian-born Aboriginal and foreign-born children.
  • Active TB in children is a sentinel event that should prompt a search for the source case.
  • After infection in children under the age of 5 there is a high risk of progression to severe forms of TB.
  • Attempts should be made to collect specimens (gastric aspirates/induced sputa) for culture before therapy.
  • Sputum induction is a promising technique for diagnosis of TB disease in young children.
  • Culture yield in children is low: TB often is diagnosed by the combination of a positive TST or IGRA, abnormal chest x-ray and a history of contact with a case of infectious TB, in addition to compatible clinical signs or symptoms.
  • A negative TST or IGRA does not exclude active TB.
  • For treatment of TB disease, daily therapy is preferred over intermittent regimens.
  • Twice weekly regimens should no longer be used because each missed dose represents a larger fraction of the total number of recommended treatment doses.
  • Ethambutol (EMB) is now routinely used as part of initial empiric therapy of TB disease (pending sensitivities) in infants and children, unless contraindicated or if the source case is known to be fully susceptible.
  • Pyrazinamide (PZA) doses are higher than in the previous edition of the Standards.
  • Targeted testing for latent TB infection (LTBI) is recommended according to risk of infection and progression to disease.
  • Patients for whom therapy of LTBI is recommended should be informed of the risk of treatment and its side effects. Clear plans of action should be in place for monitoring toxicity.
  • The principal recommended regimen for LTBI is 9 months of INH.

Preliminary Note

We are fortunate to have World Health Organization (WHO) guidance documents which address the area of drug doses and initial choices of therapyFootnote 74 Footnote 88. The documents provide a summary of available evidence that is used throughout this chapter. Unless there are good grounds to differ, the recommendations in this chapter are aligned as much as possible with the WHO document and the American Academy of Pediatrics Red Book: 2012 Report of the Committee on Infectious Diseases.

Introduction

Childhood TB is a neglected disease; its true prevalence is significantly underestimated in global statisticsFootnote 1. There is a need for improved diagnostic tools, new drugs, easy-to-dose formulations and effective vaccinesFootnote 1. Pediatric tuberculosis in Canada is largely a disease of foreign-born children, the children of foreign-born parents and Aboriginal childrenFootnote 2. The incidence of TB among those <15 years of age in Canada has declined from 6.6 per 100,000 in 1970 to <2 per 100,000 in 2009 Footnote 3 (refer to Chapter 1, Epidemiology of Tuberculosis in Canada). Clinical management should take into account the global epidemiology of TB and the possibility of drug resistance in the foreign-born.

TB in children differs from that in adults in several ways: (1) diagnosis in young children may be difficult, since signs and symptoms are often nonspecific and disease is often paucibacillary; (2) TB disease in a very young child is often a sentinel event indicating recent transmission; (3) in young children, especially infants, there is a high risk of progression from latent TB infection (LTBI) to active and sometimes severe TB disease Footnote 4-7.

This chapter will cover the most important aspects of pediatric TB. Readers are encouraged to refer to other chapters of the Standards for detailed information.

Pathogenesis and Definitions

Details of the pathogenesis of TB are outlined in Chapter 2, Transmission and Pathogenesis of Tuberculosis. Children inhale Mycobacterium tuberculosis from adults or adolescents with infectious pulmonary or laryngeal TBFootnote 8. Rarely, children with cough and multibacillary disease may be infectiousFootnote 9 Footnote 10. Inhaled bacteria are taken up by alveolar macrophages and, if not immediately destroyed, result in a primary infection that consists of a small parenchymal focus that spreads via local lymphatics to regional lymph nodes. Primary infection may be associated with complications, especially in children under 5 years of ageFootnote 11. The parenchymal lesion may enlarge and caseate, or nodes may enlarge and compress or erode through a bronchus, causing wheezing, segmental pneumonia or atelectasis. The primary infection is usually accompanied by an occult, subclinical bacteremia that seeds distant sites, including the apices of the lungs, the lymph nodes and the central nervous system (CNS).This may rapidly lead to severe forms of disease, including miliary and CNS TB, especially in children younger than 5 years of ageFootnote 11. In general, the risk of progression to TB disease and of severe forms of TB disease after infection is inversely related to age (Table 1)Footnote 11. However, in most cases the primary focus heals, and the bacteria continue to survive in a dormant state that is referred to as latent TB infection (LTBI). Similar to adults, children with LTBI and an immunocompromising condition are at increased risk of TB disease.

Table 1. Average age-specific risk for disease development after untreated primary infection Footnote 11
Age at primary infection Manifestations of disease Risk of disease (%)
<12 months No disease
Pulmonary disease
TB meningitis or miliary disease
50
30-40
10-20
12-23 months No disease
Pulmonary disease
TB meningitis or miliary disease
70-80
10-20
2-5
2-4 years No disease
Pulmonary disease
TB meningitis or miliary disease
95
5
0.5
5-10 years No disease
Pulmonary disease
TB meningitis or miliary disease
98
2
<0.5
>10 years No disease
Pulmonary disease
TB meningitis or miliary disease
80-90
10-20
<0.5

There is no confirmatory test for LTBI. For practical purposes a child with LTBI is considered to have no symptoms related to the infection, a positive tuberculin skin test (TST) or interferon gamma release assay (IGRA), no clinical evidence of disease and a chest x-ray that is either normal or demonstrates evidence of remote infection, such as a calcified parenchymal nodule and/or a calcified intrathoracic lymph node Footnote 12.

Isolation of M. tuberculosis in culture from a clinical specimen confirms TB disease. However, because children may be too young to produce sputum or they have paucibacillary disease, recovery of the organism may be difficult, and confirmation is not always possible. The diagnosis of TB disease is often based on a clinical case definition, which usually relies on the triad of (1) a positive TST or IGRA, (2) either an abnormal chest x-ray and/or physical examination and (3) discovery of a link to a known or suspected case of infectious TB. Many diagnostic scoring systems have been developed but are not well validated and lack specificityFootnote 13 Footnote 14. Clinical case definitions of childhood intrathoracic TB were recently proposed by an expert panel Footnote15 these are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions.

The distinction between infection and disease is not always easy and can be somewhat artificial, since infection and primary disease are parts of a continuumFootnote 16 Footnote 17.

Clinical Presentation of TB Disease

In Canada many children with TB disease are asymptomatic at presentation. They are often identified through active case finding as contacts of patients with infectious TB and are found to have abnormal chest x-rays. This is especially true of children under 5 years of age Footnote 7.

Children may also present with symptoms or signs suggestive of diseaseFootnote 7. In young infants, these may be very nonspecific: hepatosplenomegaly, respiratory distress, fever, lymphadenopathy, abdominal distention, lethargy or irritabilityFootnote 18 Footnote 19. Older children and adolescents are more likely to experience adult-type disease and often present with the classic triad of fever, night sweats and weight loss. Those with pulmonary disease are also more likely to present with respiratory symptoms (cough, sputum and sometimes hemoptysis)Footnote 7. As in adults, their physical findings are often minimal relative to their chest x-ray abnormalitiesFootnote 20. The latter include lung infiltrates, typically but not always in the upper zone(s), that may be cavitated. TB disease in adolescents in Canada and other high-income countries is often extrapulmonaryFootnote 21. Presentation may be protean: TB may mimic inflammatory bowel disease or brain and bone tumours or involve almost any system in the body. Delay in diagnosis in adolescents is common and may reflect a lack of suspicion by cliniciansFootnote 22. Failure to send sputa for TB smear and culture from adolescents with a productive cough and epidemiologic risk factors for TB contributes to this delay.

Any extrapulmonary site may be involved, most commonly extrathoracic lymph nodes. Mycobacterial cervical lymphadenitis is commonly due to nontuberculous mycobacteria in the Canadian born but may be due to TB, especially in those with risk factors (refer to Chapter 11, Nontuberculous Mycobacteria). Miliary/disseminated disease and CNS disease, the most life-threatening forms of TB, are more likely to occur in young children and the immunocompromisedFootnote 7 Footnote 19.

Epidemiologic risk factors and/or a clinical picture compatible with TB should prompt appropriate testing.

Diagnostic Tests

Tuberculin Skin Test and Interferon Gamma Release Assays

Refer to Chapter 4, Diagnosis of Latent Tuberculosis Infection, for details about the TST and IGRAs.

In children, the TST and/or IGRA is an important part of the clinical case definition of TB disease, especially if there is a TST conversion or a new positive TST. However, a negative TST does not exclude TB disease. Furthermore, a positive TST or IGRA does not distinguish between latent TB infection and active disease.

Radiology

Chest radiography is an important part of the diagnostic workup of pediatric TB. The quality of films is crucial. The results may be difficult to interpret, especially if there is rotation of the chest relative to the x-ray beam, or there has been inadequate inspiration or overpenetration. Ideally, films should be reviewed by a radiologist experienced in reading pediatric chest x-raysFootnote 23 Footnote 24. A classification system relates radiographic appearances of primary pulmonary TB to complications of (1) the primary focus, (2) the regional lymph nodes or (3) bothFootnote 25. Useful resources with clinical examples of pediatric TB radiology are available for further informationFootnote 15 Footnote 26 Footnote 27-29.

Frontal and lateral chest radiographs are required to detect hilar and paratracheal lymphadenopathy, the most common features expected in pediatric TBFootnote 26. Parenchymal lesions may be anywhere in primary disease and are typically, but certainly not always, in the upper lobes in adolescents. Cavitation is rare in childhood TB but can be seen in children with either adult-type disease, from a progressive primary (Ghon's complex) focus in very young or immune-compromised children, or a caseating pneumonia secondary to lympho-bronchial diseaseFootnote 25 Footnote 30. Radiologic abnormalities in children may, in the short term, worsen on treatment before they improve Footnote 4.

Computed tomography (CT) scans of the chest deliver significant radiation doses; children are more vulnerable to the effects of radiation than adultsFootnote 29 Footnote 31 Footnote 32. CT may be very helpful, but its use for any case must be weighed against the likely benefits of the information gained. Magnetic resonance and CT may be very helpful in the evaluation of suspected active CNS disease, bone and joint disease, and disease at other sites, such as the intra or extrathoracic lymph nodes, pericardium and peritoneum Footnote 29.

Gastric Aspirates, Induced Sputum, and Nucleic Acid Amplification Tests

Mycobacterial confirmation of the diagnosis of pediatric TB should always be sought; this is particularly important when (1) an isolate from a source case is not available or there is a possibility of multiple sources; (2) the source case has drug-resistant TB; (3) the child is immunocompromised; or (4) the child has extrapulmonary TBFootnote 24 Footnote 33.

Gastric aspiration has traditionally been the diagnostic procedure of choice in young children who are unable to produce sputumFootnote 4 Footnote 5. Children are often hospitalized for the procedure, but it has also been successfully performed in outpatientsFootnote 34 Footnote 35 Footnote 36. Details about gastric aspiration, including a video, are available online Footnote 36 and below, under section "Gastric aspirates: some tips". The gastric aspirate material should be pH neutralized as soon as possible after aspiration, as gastric acid may kill M. tuberculosis. Unless the laboratory is available to immediately pH neutralize the sample, it should be placed in a sterile container with 100 mg of sodium carbonate Footnote 37 or a bicarbonate solutionFootnote 36. These containers may be obtained from provincial/territorial public health laboratories or made up by a hospital laboratory. The relevant laboratory should be contacted ahead of time for details regarding collection and transport of specimens. Results of acid-fast bacilli (AFB) smears of gastric aspirates usually are negative, and false-positive smear results caused by the presence of nontuberculous mycobacteria can occurFootnote 33. Although the yield of gastric aspirate cultures in infants has been reported as up to 75%Footnote 38, the overall diagnostic yield for culture is probably less than 50%Footnote 33 Footnote 35.

Gastric aspirates: some tips Footnote A Footnote B
  • During sleep the mucociliary mechanism of the respiratory tract sweeps mucus, which may contain TB bacteria, into the mouth. The material is swallowed and may be a source of organisms, especially if the stomach has not emptied.
  • Aspirates are obtained after at least 6 hours of sleep and before the stomach has emptied.
  • Patients should not drink or eat anything overnight to prevent the stomach from emptying. They should also avoid exposure to the smell or sight of food, which may encourage gastric emptying. The ideal time is just at the time of waking.
  • Aspirate the stomach contents first. Then instill no more than 50 mL of sterile distilled water - the sort used for infant feeding is suitable. Aspirate back and add the aspirate to the first specimen.
  • The fluid has to be adjusted to neutral pH within 4 hours of collection because acid is detrimental to mycobacteria. If that is not possible, it should be directly placed into a buffered solution (refer to text for details).

Sputum induction (SI) has been performed in high-burden settings as an outpatient procedure by trained personnel. Footnote 39-50. By using timed nasopharyngeal suction following administration of hypertonic saline, the technique has been safely performed in infants as young as 1 month of age. Both ultrasonic and jet nebulizers have been used. Details about the procedure Footnote 41 Footnote 51 Footnote 52 as well as a video Footnote 53 are available. The yield may be as good as or better than that of gastric aspirates, and the advantages over gastric aspirates include a shorter period of fasting, no killing of the organisms by gastric acid and higher acceptability to staff and parentsFootnote 54. Attention to safety issues, including management of bronchospasm and appropriate facilities and procedures to prevent nosocomial transmission, should be in place (refer to Chapter 15, Prevention and Control of Tuberculosis Transmission in Health Care and Other Settings). The diagnostic yield from bronchoscopy is no higher than that of gastric aspirates or SI, although it may be useful to detect possible tracheobronchial obstruction or explore alternative diagnoses Footnote 55.

Other specimens can be collected if clinically indicated: bronchial washings, pleural fluid, cerebrospinal fluid, urine, other body fluids or tissue biopsy specimens. Nasopharyngeal aspiration Footnote 43 Footnote 45 Footnote 50 Footnote 56-59 and the string test Footnote 60-62 Fine-needle aspiration biopsy has been useful in children suspected of TB who present with palpable enlarged cervical nodesFootnote 64 Footnote 65 However, surgical removal has the advantages of higher yields on culture and better outcomes, as lymph nodes may continue to enlarge and drain despite therapy to which the organism is susceptibleFootnote 66. A lumbar puncture should be performed in cases of suspected congenital or neonatal tuberculosis and in infants with disseminated diseaseFootnote 67 Footnote 68

Nucleic acid amplification (NAA) tests are useful in confirming the diagnosis in AFB smear-positive respiratory cases. Their ability to improve the sensitivity of gastric aspirates has been disappointingFootnote 31 Footnote 69-71. A study using a recently developed cartridge-based NAA test on induced sputum in children admitted for suspected TB detected all smear-positive cases but only a third of the smear-negative culture-positive cases: a second specimen increased the yield to 61%Footnote 46. More data are emerging on the type, number of specimens required and the use of NAA tests for the diagnosis of pediatric TBFootnote 50 Footnote 72 Footnote 73. Further details of microbiologic isolation, speciation and drug-resistance testing are provided in Chapter 3, Diagnosis of Active Tuberculosis and Drug Resistance.

Recommended Management of TB Disease

A diagnosis of TB infection or disease in a child should be considered a sentinel event and prompt the search for the source case, most likely an adult or adolescent in close contact with the child. Close caregivers should be evaluated to rule out TB disease. Consideration should be given to placing all close caregivers in airborne isolation until they have been evaluated (refer to Chapter 15).

The principles and phases (intensive and continuation) of TB treatment are discussed in Chapter 5, Treatment of Tuberculosis Disease. A team approach is very helpful in evaluating and treating children with TB disease. The team may include physicians and clinic nurse practitioners, public health nurses, a social worker and an interpreter. The team should, wherever possible, include or involve a pediatric TB specialist. Treatment is aimed at reducing morbidity and mortality, preventing acquired resistance and providing a lasting cure. Interruption of transmission is also important in adolescent patients with pulmonary disease who attend congregate settings, including schools. Before starting therapy for TB disease a baseline alanine aminotransferase, aspartate transaminase and bilirubin level should be obtained. HIV serology is recommended as standard practice for all children and adolescents being treated for TB disease: TB is an opportunistic infection, and the duration of treatment will be influenced by this result.

The most important element of the treatment of TB is the actual ingestion of the medication by the child, since children may not tolerate the pill burden, and the existing formulations are not particularly child friendly Footnote 4.

Individual Drugs

The drugs used in the treatment of pediatric TB, their doses and side effects are summarized in Table 2. Despite recent information about TB drug pharmacokinetics in children, more research is still needed in this areaFootnote 80. In children who are younger than 12 years or who weigh less than 35 kg, isoniazid (INH) recommended doses are 10-15 mg/kg daily (maximum 300 mg)Footnote 74 Footnote 81. Administration is affected by food: INH is better absorbed on an empty stomach. Fat reduces absorptionFootnote 82. Sugars, such as glucose, fructose and sucrose, inactivate INH by condensation. A sorbitol-based suspension avoids this problem but may cause diarrheaFootnote 75. Crushed pills are ideally mixed with water, but few children will accept this, and administration with small amounts of food is often suggestedFootnote 4 Footnote 83-87. If necessary, pills may be crushed in a small amount of a sugar-free, low-fat vehicle such as sugar-free pudding, baby food or yogurt Footnote 83.

For the older child or adolescent who weighs between 35 and 60 kg, the optimal dosing of INH is an area of uncertainty. Recommendations for adults are to use 5 mg/kg of INH (refer to Chapter 5), whereas recommendations from the American Academy of Pediatrics are to use 10 mg/kg to a maximum of 300 mgFootnote 33. On the other hand, forthcoming WHO recommendations state that at 25 kg, children can adopt adult dosage recommendations and use adult preparations, especially with fixed drug combinationsFootnote 88. There are no pharmacokinetic or toxicity data to clearly support either dose. For some patients, this results in a "grey zone" in which the dosing would be very different (e.g. a 40 kg adolescent would receive 300 mg of INH daily when dosed as per AAP recommendations and 200 mg when treated as per the adult guidelines).

Table 2. Drugs used for treatment of tuberculosis in children Footnote 33 Footnote 74 Footnote 75
Drugs Daily dose (range) Thrice weekly dose Footnote C (range) Available dosage forms Principal side effects
By weight (mg/kg) Max (mg) By weight (mg/kg) Max (mg)
CIntermittent doses should be prescribed only when directly observed therapy is available. In general daily therapy is definitely preferred over intermittent regimens.
DHepatotoxicity is greater when INH doses are more than 10-15 mg/kg daily. For older children and adolescents, the optimal dosing of INH is an area of uncertainty (refer to text).
EFor PZA: 3000 mg according to the American Thoracic Society (ATS) Footnote 75, 2000 mg according to the Red Book Footnote 33
FFor EMB: 1600 mg according to the ATS Footnote 75, 2500 mg according to the Red Book Footnote 33
GFor EMB: 2400 mg according to the ATS Footnote 75, 2500 mg according to the Red Book Footnote 33
INH  10
(10-15) Footnote D 
300 20-30 600-900 10 mg/mL suspension
100 mg tablet
300 mg tablet
  • Mild liver transaminase elevation
  • Hepatitis
  • Gastritis
  • Peripheral neuropathy
  • Hypersensitivity
 
RMP 15
(10-20)
600 10-20 600 10 mg/mL suspension
150 mg capsule
300 mg capsule
  • Orange discoloration
    of secretions
  • Vomiting
  • Hepatitis
  • Flu-like illness
 
PZA  35
(30-40)
2000 70 (60-80) Footnote E  500 mg scored tablet
  • Hepatotoxicity
  • Hyperuricemia
  • Arthralgia
 
EMB  20
(15-25)
Footnote F  40 (30-50) Footnote G  100 mg tablet
400 mg tablet
  • Optic neuritis with decreased visual acuity and decreased red-green colour discrimination
  • Gastrointestinal disturbance
 
Pyridoxine
(used to prevent INH neuropathy: has no anti-TB activity)
1 mg/kg 25     25 mg tablet
50 mg tablet
  • Few
 

Note: Information on second-line drugs for multidrug-resistant TB (MDR-TB) is available in various recent reviews Footnote 76-79 and in Chapter 8, Drug-resistant Tuberculosis.


Pyridoxine (vitamin B6) is indicated for children on meat and milk-deficient diets, breastfed infants, those with nutritional deficiencies, children with symptomatic HIV infection and adolescents who are pregnant or breastfeeding Footnote 33.

Rifampin (RMP) is frequently compounded into suspension by pharmacists. These suspensions are usually stable for at least 1 month, and unpublished experience suggests that they are effective.

Ethambutol (EMB) is now routinely used as part of initial empiric therapy of TB disease (pending sensitivities) in infants and children unless otherwise contraindicatedFootnote 33. It can cause retrobulbar neuritis, a side effect that is dose-dependent and more likely to occur with renal impairment. It is manifest as decreased visual acuity or decreased red-green colour discrimination and may be reversible upon discontinuation of the drug. EMB should be used with caution in children who are too young for monitoring, although reviews suggest that its use is safe in childrenFootnote 89 Footnote 90. When possible, baseline ophthalmological assessment should be obtained in younger children before starting EMB and be repeated regularly during treatment with the agentFootnote 75 Footnote 86 Footnote 91. Acuity and colour vision should be monitored monthly in a clinic setting using isochromatic plates; this is often possible even in young children. While optic neuritis is very uncommon at an EMB dose of 15 mg/kg dailyFootnote 89 Footnote 92 pharmacokinetic data suggest that drug levels may sometimes be subtherapeutic at this doseFootnote 52. Footnote 90 Footnote 93 In accordance with the WHO and the AAP, 20 mg/kg daily should be usedFootnote 33 Footnote 74 However, when EMB is a vital part of therapy, e.g. in drug-resistant TB, doses of 25 mg/kg daily should be used with very close monitoring of vision. Baseline serum creatinine levels should be measured to rule out occult renal impairment before initiation of therapy. EMB should be discontinued once the strain is known to be fully drug susceptible.

On the basis of pharmacokinetic dataFootnote 94, pyrazinamide (PZA) doses are higher than in the previous edition of the Canadian Tuberculosis Standards. The WHO has noted that there is insufficient high-quality evidence to assess whether these higher doses will lead to more hepatotoxicityFootnote 74 Footnote 81.

Information on second-line drugs for MDR-TB is available in various recent reviews Footnote 76-79 and in Chapter 8.

Empiric Treatment

In all suspected cases, especially those for whom no source case isolate is available, specimens should be obtained for culture and drug susceptibility testing prior to starting therapy. If there is a known source case, his/her culture and susceptibility test results may be used to guide therapy provided there is no significant possibility of alternative sources (e.g. from recent foreign travel) (refer to Diagnosis section, above). Treatment should then begin promptly when clinical and laboratory indices support a presumptive diagnosis of active tuberculosisFootnote 75. While culture and susceptibility results are pending or if empiric treatment is deemed necessary, therapy with INH, rifampin, EMB and PZA, unless contraindicated, should be startedFootnote 33 Footnote 81 If the source case is known to be fully drug susceptible, EMB can be omitted. If there is a strong possibility of drug-resistant disease, expert consultation is strongly advised (refer to section on Multidrug-resistant TB below).

Treatment modification and duration

Once the susceptibilities of the source case or the child's isolate are available, treatment should be modified as follows:

  • For fully susceptible, intrathoracic TB, INH, rifampin and PZA should be used for the first 2 months followed by 4 months of INH and rifampin. The minimum duration of therapy is 6 months in total. However, in patients with cavities on initial chest x-ray or positive sputum cultures after 2 months of treatment, the minimum duration of therapy should be 9 months Footnote 74 Footnote 75 (also, refer to Chapter 5).
  • If hilar lymphadenopathy alone is present, treatment as for pulmonary disease should be given (unless the isolate is resistant), although regimens using only INH and rifampin have been recommendedFootnote 33 Footnote 95 Footnote 96 If rifampin or pyrazinamide are discontinued because of side effects, longer durations of therapy are recommended. Rifampin is a cornerstone of anti-TB therapy and should not be discontinued because of minor side effects.

Refer to Chapter 5, Treatment of Tuberculosis Disease, for further details on drug side effects and management in cases of hepatotoxicity.

Daily vs Intermittent Regimens

There are few studies of TB treatment in children. Recent systematic reviews have found poorer cure rates with intermittent regimens and prompted the WHO to recommend daily therapy over intermittent regimens for treating pediatric TB disease, especially where HIV infection is commonFootnote 74 Footnote 97 Footnote 98 Comparing treatment studies is a challenge, considering the important differences in the epidemiology of childhood TB in industrialized countries when compared with that of low- or middle-income countries Footnote 99 and since pediatric TB disease cannot be viewed as a single entityFootnote 11. Although intermittent regimens have been successfully used in Canada and the United States, daily regimens are recommended during treatment wherever possible.

Daily regimens are strongly suggested during the intensive phase. On the basis of expert opinion the Canadian Thoracic Society suggests that when daily treatment in the initial phase is very difficult, some patients with minimal mediastinal/hilar lymphadenopathy TB or peripheral TB lymphadenitis may be treated with thrice weekly therapy (directly observed therapy [DOT]) after the first 2 weeks if they are HIV-uninfected, have a low bacillary load (i.e. have noncavitary, smear-negative disease) and have demonstrated excellent adherence to their DOT in the first 2 weeks.

Intermittent three times weekly regimens (i.e. therapy only given on three days of the week, typically with higher doses) should only be considered in the continuation phase for select HIV-uninfected children with pulmonary TB or peripheral TB lymphadenitis. These intermittent regimens should only be used under strict thrice weekly DOT. Twice weekly regimens should no longer be used because each missed dose represents a larger fraction of the total number of recommended treatment dosesFootnote 81. However, in exceptional circumstances, patients with minimal disease who are known to be reliable with DOT may be considered for twice weekly therapy in the continuation phase Footnote 33 (also, refer to Chapter 5).

Directly Observed Therapy and Adherence

A decision to initiate treatment of TB disease or latent TB should also imply a decision to monitor, minimize the risks of toxicity, follow closely and ensure that therapy is completed. If clinicians cannot achieve this they should immediately refer the patient to centres or teams that can. All patients should receive counselling about side effects and medication administration, and detection of side effects before the next scheduled appointment; access by parents and patients to clinicians and the health service should be facilitated, particularly if there are language and social barriers. If DOT is used, this involves much more than simple observation of pills taken. Integrating a liaison public health nurse into the treatment team facilitates DOT and monitoring, as well as assuring follow-up for patients. In concordance with AAP guidelines, DOT (not by the parents/guardians alone) for the full duration of therapy is strongly recommended for children and adolescents Footnote 33.

Although therapy is given on all days of the week, daily therapy can be given as five observed doses. If resources for DOT are very limited, under all circumstances DOT should always continue for the following cases: (1) Disease due to suspected or proven drug-resistant strains, (2) HIV coinfection, (3) previous treatment failure of active disease, (4) retreatment disease, (5) suspected nonadherence or previous nonadherence, (6) reasonable doubts about the ability of the parents/guardians to supervise treatment for children, (7) substance abuse in an adolescent and (8) psychopathologyFootnote 100 Footnote 101 For those not receiving daily DOT, regular supervision of therapy may help detect side effects and administration errors (also, refer to Chapter 5).

Adjunctive therapy

Corticosteroids are used as adjunctive therapy when the tuberculous inflammatory response is threatening to cause a life-endangering complication.

Corticosteroids are indicated for children with TB meningitis. In prospective, randomized trials they decreased mortality rates, and they may affect neurologic complications, neurologic sequelae and cognitive dysfunctionFootnote 102. Dexamethasone (0.3-0.4 mg/kg daily for the first week and weaning over 6 weeks) or prednisone (60 mg/day for 3 weeks tapered over the next 3 weeks) has been used in children older than 14 years of ageFootnote 102 Footnote 103 For children, the AAP Footnote 33 and other experts Footnote 104 suggest as adequate 2 mg/kg per day of prednisone (maximum, 60 mg/day) or its equivalent for 4 to 6 weeks followed by tapering. Higher prednisone doses (4 mg/kg with a taper over 4-6 weeks) have been evaluated and considered if increasing intracranial pressure continuesFootnote 102. Corticosteroids have also improved survival and reduced the need for pericardiectomy in patients with TB pericarditis (refer also to Chapter 5).

The use of corticosteroids in pleural TB is not supported by current evidence. On the basis of expert opinion, corticosteroids may have a role in endobronchial disease to relieve obstruction and atelectasisFootnote 33 Footnote 52. They may also be considered for children with severe miliary disease and in the presence of paradoxical reactions, especially when they involve airway compromiseFootnote 33. Corticosteroids should only be used in conjunction with effective antituberculosis therapy and should be tapered slowly over weeks to avoid a rebound reaction. Generally in non-meningitic conditions 2 mg/kg daily of prednisone (maximum 60 mg/day) or its equivalent is used, tapered over 6 to 8 weeksFootnote 33 Footnote 52.

While several reports suggest that a high proportion of children with TB disease and infection may have low vitamin D levelsFootnote 105, vitamin D supplementation does not affect treatment outcomesFootnote 106 Footnote 107. Existing recommendations regarding vitamin D supplementation for the population should be followed, and monitoring of serum levels in at-risk populations should be consideredFootnote 108 Footnote 109.

Side Effects and Monitoring During Treatment

Patients and their parents should be informed of the side effects indicating hepatotoxicity and other drug toxicities and should be asked to recall these at each clinic visit. They should be provided with a clear plan of action, preferably written, including contact telephone numbers, should symptoms arise.

Patients should undergo clinical evaluation at least monthlyFootnote 33 Footnote 75 Footnote 83. At each visit they should be asked about individual side effects and symptoms of TB disease, and undergo a full clinical examination. Monitoring of weight, especially in infants and young children, is especially important to the adjustment of drug doses, since children may rapidly "grow out of" the recommended dose range. On the basis of probable increases in weight some clinicians recommend prescribing 12 mg/kg of INH for infants younger than 12 months rather than 10 mg/kg. Refer to Chapter 5 for the management of common adverse reactions.

For adolescents or older children with adult-type disease, follow-up sputum examinations should be performed in the same way as for adultsFootnote 6. Repeat cultures from other clinical specimens are not necessary if the patient is improving clinically but should be strongly considered in MDR cases Footnote 110.

Chest radiography 2 months into treatment is recommended to rule out extension of diseaseFootnote 33. However, persistent radiographic signs are not an indication to change treatment if there is clinical improvementFootnote 30. At the end of a satisfactory course of treatment there may be residual lymphadenopathy or scarring that can persist for 2-3 yearsFootnote 6 Footnote 83 Normal radiography is not necessary to discontinue therapy Footnote 33.

Patients should be followed for at least 1 year after treatment completion to achieve clinical health and stability or continued resolution of radiographic findingsFootnote 4. Deteriorations (development or worsening of existing lesions and lymphadenopathy) during therapy may occur even with appropriate therapy for drug-susceptible disease in both HIV-infected and uninfected patients. Many of these reactions are paradoxical, due to immune reconstitution, but are difficult to differentiate from acquired drug resistance or clinical failureFootnote 111. Low weight and high disease burden may be associated with more reactions. Clinically significant occlusion of bronchi by enlarging intrathoracic lymph node masses may occur by this mechanism and often responds well to corticosteroid therapy. Drug resistance should be ruled out or accounted for in the treatment regimen if corticosteroids are used Footnote 111.

Treatment of Extrapulmonary TB

It is recommended that extrapulmonary TB in children be treated with the same regimens as pulmonary disease, with the exception of CNS TB, disseminated/miliary TB, and bone and joint TB, for which the recommended duration of treatment is 9 to 12 months. Refer to Chapter 7, Nonrespiratory Tuberculosis, for further details.

Treatment of MDR-TB

Refer to Chapter 8, Drug-resistant Tuberculosis. Children and adolescents at risk of drug-resistant TB include (1) those with a history of treatment of TB disease, (2) contacts of a patient with drug-resistant contagious TB disease, (3) those born in or who have resided in countries with high prevalence of drug-resistant TB and (4) infected patients whose source case has positive smear for acid-fast bacilli or cultures after 2 months of appropriate therapy or is not responding to a standard treatment regimenFootnote 33. Details of microbiologic isolation, speciation and drug-resistance testing are provided in Chapter 3, Diagnosis of Active Tuberculosis and Drug Resistance. If drug-resistant TB is isolated, an expert opinion should be obtained from a physician experienced in the management of drug-resistant TB. Recent resources summarize drug doses and side effects for the treatment of drug-resistant disease in children Footnote 76-79.

TB and HIV

Children with LTBI and HIV infection may have an accelerated progression from infection to diseaseFootnote 112 Footnote 113. The TST is often negative in HIV-coinfected children. A search for an infectious adolescent or adult is an important step towards diagnosis.

Usually the clinical features of TB in HIV-infected children are similar to those in children without HIV infection, although the disease usually is more severe and can be difficult to differentiate from illnesses caused by other opportunistic infectionsFootnote 86 Footnote 114.

The optimal treatment of pulmonary TB in children and adolescents with HIV infection is unknown. Advice from a TB expert should be sought. Refer to Chapter 10, Tuberculosis and Human Immunodeficiency Virus for further details.

Recommended Management of LTBI

In general, LTBI should be treated with INH (refer to Table 2 for doses) for 9 months unless the child has been linked to an INH-resistant source case. Routine liver function testing is not indicated for asymptomatic children who do not have underlying liver disease, do not have disseminated disease and are not taking other hepatotoxic drugs. However, although rare, severe hepatotoxicity requiring transplantation or leading to death has occurred during INH treatment of LTBI in childrenFootnote 115. Therefore, it is strongly recommended that patients receiving INH therapy be advised by the prescribing physician and other relevant health care providers to stop taking the INH immediately if they have symptoms such as anorexia, nausea, vomiting, abdominal discomfort, unexplained fatigue, dark coloured urine, scleral icterus or jaundice, and to contact them as soon as possible for further evaluation. They should be provided with a clear written plan of action, including contact telephone numbers, should symptoms arise. If symptoms occur, evaluation should include a physical examination and investigation of liver transaminase values and bilirubin levels. Patients may appear clinically well despite impending significant liver toxicity Footnote 116.

Children should be evaluated monthly, and parents should be questioned about what side effects to watch for, any side effects that have occurred, any symptoms of active TB, adherence to therapy and results of skin testing of family members and other contacts (also, refer to Chapter 6, Treatment of Latent Tuberculosis Infection). Loeffler has offered many helpful suggestions to improve adherence and completion rates (Refer to section "Recommendations to improve adherence and completion rates for TB therapy")Footnote 4. Most health departments do not have the resources for directly observed preventive therapy (DOPT). DOPT should be strongly considered for children infected with drug-resistant strains and where adherence is in doubt. DOPT can also be combined with DOT visits for household contacts of adults with TB disease.

Recommendations to improve adherence and completion rates for TB therapy Footnote 4

  • Use tablets crushed into semisoft vehicles, such as sugar-free pudding, to avoid stomach upset from the liquid preparation.
  • Warn the family that the first couple of weeks of therapy will be challenging.
  • See the patients monthly and supply only 1 month of medication at a time.
  • Provide written educational material regarding reasons for therapy and symptoms of TB and toxicity.
  • Develop a small, dedicated and enthusiastic team of staff of providers, nurses and interpreters.
  • Develop systems to encourage adherence, such as having the child put a sticker on the calendar for each dose taken.
  • Provide convenient clinic hours and short waiting times.
  • Develop a system of following up patients who have missed appointments.
  • Praise the family and child for good adherence and clinic attendance.

If the source case is INH resistant or there is epidemiologic reason to suspect that the child is infected with an INH-resistant strain, then RMP is recommended for 4 months (refer to Table 2 for doses)Footnote 117. US guidelines recommend the use of RMP daily for 6 monthsFootnote 118, but this is based on limited experience in adolescents and young adults aged 15 to 23 yearsFootnote 119. Children taking anticonvulsants and either INH or RMP should be monitored closely because both of these drugs can affect the metabolism and serum levels of anticonvulsants Footnote 75.

Children judged to be infected with a multidrug-resistant strain of M. tuberculosis should be referred to a TB specialist (refer also to Chapter 8, Drug-resistant Tuberculosis).

Rifapentine (RPT) is currently unavailable in Canada, except perhaps pursuant to a practitioner's application for the treatment of a patient under the Special Access Program (SAP) (refer to: Health Canada, Drugs and Health Products web site). If RPT is obtained through the SAP, clinicians should be aware that there have been some concerns about hypersensitivity reactions. A once-a-week RPT regimen for LTBI has recently been approved in the United States for patients >12 years of ageFootnote 120. Refer to Chapter 6 for more details on this and other alternative regimens.

A common question is whether INH, or an alternative regimen, should be given for treatment of LTBI in people who have no known contact with a drug-resistant case but have immigrated to Canada from countries with high rates of drug-resistant TB. It is important to remember that 9 months of INH has the best documented efficacy, and of foreign-born individuals less than 20%, in total, of those whose infection is reactivated in Canada have resistant strains. For these two reasons, 9 months of INH is recommended in these people (refer to Chapter 6).

Management of Contacts

The most efficient way to prevent pediatric TB is the prompt evaluation and treatment of children exposed to an infectious adult source case. Missed opportunities to prevent cases of pediatric TB include delayed diagnosis of infectious TB, delayed reporting of a source, failure to identify an exposed child during the contact investigation, failure to achieve adherence of the source case, failure to document sterilization of cultures, failure to start preventive therapy or LTBI treatment in the child and failure to ensure that the child takes the treatmentFootnote 117. With each pediatric active TB case, the case management team should determine which of these factors may have played a role in the child becoming infected with TB and take corrective action to prevent future cases.

All exposed children should have a symptom inquiry and TST. Those less than 5 years of age, all close childhood contacts and all symptomatic children should also have a physical examination and chest radiography. Children less than 5 years of age with a negative TST and no evidence of active TB by examination or radiology should be given "window" of preventive therapy to prevent the development of TB. This is because it may take up to 8 weeks after infection for the TST to convert to positive, during which time the infection may progress to disease. For children presumed to have been exposed to a drug-susceptible isolate, INH is recommended. The INH may be discontinued if, after a period of 8 weeks after the last contact, the repeat TST is negative, and the child remains asymptomatic and is immunocompetent and more than 6 months of age (for infants <6 months of age, refer to section on Perinatal Issues: Recommended Management of the Newborn Infant Exposed to TB).

In the exposed child, if the initial TST is positive (≥5 mm) and there is no clinical or radiographic evidence of disease, then a full course of treatment for LTBI is recommended. When a child with new, active TB is the index case, reverse contact tracing must be undertaken, i.e. a vigorous search should be carried out for the source case. Although most source cases are found among adolescent or adult household contacts of the child, other source cases may be found among adolescent or adult non-household contacts, such as babysitters and other caregivers either in or outside the household. Molecular characterization of M. tuberculosis isolates by genotyping can lead to identification of previously unrecognized source casesFootnote 121. If the child is hospitalized it is advisable to screen adolescent or adult visitors for evidence of active TBFootnote 122.

The optimal treatment of children in contact with patients with MDR-TB is uncertainFootnote 33 Footnote 123 Consultation with a TB specialist is recommended (refer to Chapter 8 for more details).

Targeted Testing for Latent TB Infection

Universal screening of school children and infants is not indicated. Resources should be devoted to the task of testing children at high risk of LTBI or progression of LTBI to TB diseaseFootnote 118. These include (1) contacts of a known case of TB, (2) children with suspected active disease, (3) children with known risk factors for progression of infection to disease (refer to Chapter 4, Diagnosis of Latent Tuberculosis Infection), (4) children who have travelled or resided for 3 months or longer in an area with a high incidence of TB, especially if the visit involved contact with the local population (refer to Chapter 13, Tuberculosis Surveillance and Screening in High-Risk Populations) and (5) children who arrived in Canada from countries with a high TB incidence. In the United States, risk assessment questionnaires have been developed to identify children with risk factors for TB and LTBI who should undergo a TSTFootnote 12 Footnote 118. In Canada, a school-based TB screening program and associated investigation targeting recently immigrated children have been evaluated and found to be effective Footnote 124.

Perinatal Issues: Recommended Management of the Newborn Infant Exposed to TB

Management should proceed according to the following principles:

  • Untreated TB presents a far greater hazard to a pregnant woman and her fetus than does treatment of the disease. INH, RMP and EMB are considered safe in pregnancy, and PZA is likely safe as well (refer to Chapter 5).
  • Administration of first-line TB drugs is not an indication for termination of pregnancy. If second-line drugs are needed, advice from a TB expert should be sought immediately, as several of these agents are known teratogens Footnote 125.
  • HIV-negative women receiving first-line agents, including INH and rifampin, may continue to breastfeed. While some of the drugs enter the breast milk, they are deemed safe. The concentrations of drugs in breast milk are insufficient to protect the newborn. Supplementary pyridoxine should be given to the nursing mother receiving INH and to her child Footnote 67.

Infants born to mothers with suspected/confirmed active TB or LTBI need to be managed according to the categorization of the maternal infection refer to Table 3 below.

Evaluation of an infant for congenital TB should include a clinical examination, TST, chest radiography, appropriate cultures, including a lumbar puncture, and abdominal ultrasound. A head ultrasound should also be considered. The TST result is usually negative initially, although it may become positive after 1 to 3 months of treatment. There are very few data on the utility of IGRAs in infants. Cases of infants with negative skin tests and positive IGRA whose mothers had TB have been reported Footnote 67.

Table 3. Recommended management of the newborn infant exposed to TB Footnote 33 Footnote 67
Situation 1 Evaluation of mother Evaluation of infant
Mother or household contact with clinical or radiographic evidence of infectious TB at or close to the time of delivery 
  • Evaluate for TB disease
    (refer to Chapter 3).
  • HIV testing.
  • Examine placenta for histology smears and cultures.
 
  • Evaluate for congenital TB (refer to text).
 
Separation of mother/infant Treatment of infant Breastfeeding
  • Separate mother (or household contact) and child until mother (or household contact) and infant are receiving appropriate care, tolerating medication and mother (or household contact) is noninfectious and clinically improving.
  • If the mother (or household contact) has possible MDR-TB or has poor adherence to treatment and DOT is not possible, the infant should be separated from the mother (or household contact).
 
  • If congenital TB is diagnosed, start appropriate treatment (refer to text).
  • If congenital TB is excluded, INH at a dose of 10-15 mg/kg (refer to text for duration of INH) is advised.
 
Women with TB disease who have been treated appropriately for at least 2 weeks and who are not considered infectious can breastfeed.
Situation 2 Evaluation of mother Evaluation of infant
Mother treated for TB during pregnancy 
  • Mother should have follow-up smear examinations to confirm she is no longer infectious.
  • HIV testing.
  • Examine placenta for history, smears and cultures.
 
  • Evaluate for congenital TB (refer to text).
 
Separation of mother/infant Treatment of infant Breastfeeding
  • Provided treatment has been adequate to produce clinical improvement and the mother is no longer infectious, separation is not recommended.
  • If in doubt, proceed as in Situation 1.
 
  • If congenital TB is diagnosed, start appropriate treatment (refer to text).
  • If congenital TB is excluded and mother is confirmed to be not infectious and no other household contacts have TB disease, INH is not necessary.
  • If in any doubt, proceed as in Situation 1.
 
Women with TB disease who have been treated appropriately for at least 2 weeks and who are not considered infectious can breastfeed.
Situation 3 Evaluation of mother Evaluation of infant
Mother with abnormal chest x-ray but no evidence of active disease 
  • If the chest x-ray abnormality is considered to be secondary to old, healed TB and the mother has not been previously treated, she should be evaluated, including testing of induced sputum.
  • HIV testing.
  • The mother should be treated for LTBI if not previously treated.
 
  • The infant should be evaluated clinically and radiographically at birth.
  • Consider evaluation for congenital TB (refer to text).
  • Consider a repeat TST at 3 and 6 months of age.
 
Separation of mother/infant Treatment of infant Breastfeeding
  • If the mother is no longer infectious, separation is not recommended.
  • If in doubt, proceed as in Situation 1.
 
  • If there is uncertainty about the status of the mother, the child should be provided with preventive treatment (refer to Situation 1).
 
The mother can breastfeed.
Situation 4 Evaluation of mother Evaluation of infant
Mother with LTBI and no abnormality on chest x-ray 
  • No special investigation for the newborn is recommended.
 
Separation of mother/infant Treatment of infant Breastfeeding
  • Separation of mother and infant is not recommended.
 
  • No treatment is recommended.
 
The mother can breastfeed.

The duration of INH treatment in newborns exposed to TB remains an area of uncertainty. Because of a question of the unreliability of the TST in very young infants - for which data are poor - some authorities recommend continuing an appropriate prophylactic regimen until the infant is 6 months of ageFootnote 4 Footnote 52 Footnote 126-128, when the TST can be repeated, while others recommend at least 4 monthsFootnote 33 Footnote 67 Footnote 129 Footnote 130.

Practically, according to expert opinion, if the exposure is higher risk (e.g. household or smear-positive source case) then 6 months of preventive therapy should be used, but if the source case is less infectious and there is no evidence of conversion in exposed older contacts then preventive therapy could be discontinued at 4 months if the TST is negative. The TST could be repeated at 6 months of age.

If the repeat TST is positive, the infant should be reassessed for TB disease. If TB disease is excluded, preventive therapy should be continued for a total of 9 months.

For other aspects not covered in this chapter, refer to Chapter 11, Nontuberculous Mycobacteria Chapter 12, Contact Follow-Up and Outbreak Management in Tuberculosis Control Chapter 15, Prevention and Control of Tuberculosis Transmission in Healthcare and Other Settings and Chapter 16, Bacille Calmette-Guérin (BCG) Vaccination in Canada.

Conclusions

TB continues to be an important disease in Canadian children. Canadian health care workers should use available tests (currently the TST) to screen children at high risk of infection, both to protect these children now and to avoid their becoming the next generation of adults with infectious TB.

A team approach is recommended for the treatment of pediatric TB and should take into account the possibility of drug resistance. Ultimately, elimination of pediatric TB in Canada depends on controlling the disease globally. We should all find ways to assist with that international struggle. In doing so, we will also serve the interests of present and future Canadian children Footnote 118.

References

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