Background

Tuberculosis (TB) is due to infection with Mycobacterium tuberculosis. Approximately one third of the world's population is infected, although only 5-10% of people with infection develop TB disease.¹ Transmission occurs by exposure to aerosolised droplets from people with respiratory infection.

• TB disease may be primary disease (occurring directly after initial infection) or reactivation disease (occurring after a latent period that may be many years). Primary disease is the more common form in children, reactivation disease is the more common form in adolescents and adults. Following exposure, the risk of progression to TB disease is highest in young children (<5y, especially <2y) and highest in the first 12 months following infection.
• TB disease is most commonly pulmonary disease (up to 85% of TB disease in adults and 75% in children).
  • Children are more likely to develop disseminated or non-pulmonary TB disease than adults; infants are particularly prone to miliary TB and TB meningitis.²
  • Children with pulmonary TB disease are rarely infectious due to their pattern of disease, low bacillary load and lack of coughing force.
• From November 2015, additional migration TB screening was introduced for children (if they: are applying for a Humanitarian or onshore protection visa OR from a high TB prevalence country OR declare previous household contact, using either interferon-gamma release assay IGRA or tuberculin skin test TST) with further investigation for TB if positive. Otherwise the immigration medical examination (IME - i.e. overseas visa medical) includes a chest x-ray (CXR) in everyone 11y and older.³
• Post-arrival screening for TB is part of the initial refugee health assessment.
  • TB screening requires a history, examination and a TB screening test - e.g. tuberculin skin test (TST) or interferon gamma release assay (IGRA).
    • A positive TB screening test result does not distinguish between TB infection and TB disease.
    • A negative TB screening test result does not exclude either TB infection or TB disease.
• Latent TB infection (LTBI) refers to evidence of TB infection (i.e. a positive TB screening test) without evidence of TB disease (based on history, examination, CXR and other investigations as clinically indicated). Clinically this is an asymptomatic child with a normal examination, positive screening test and a normal CXR.
  • In children with LTBI - the lifetime risk of developing TB disease is around 10%, although it is higher in young children ( <5y, especially <2y), children who have been recently exposed to TB, and children with malnutrition, immunodeficiency or poor health.
    • A 2020 meta-analysis of child and adolescent TB contacts found baseline prevalence of 34.7% positive screening tests and 1% active TB disease. In the first 90 days, prevalence of active TB disease was 6.5% in children with positive TST/IGRA and 0.8% with negative TST/IGRA. 2-year cumulative risk of active TB disease in children not receiving prevention therapy varied by age and infection status: 7.6% in all children <5y and 19.0% <5y with positive TST/IGRA.
    • A 2016 analysis of Victorian TB data found 4-year risk of TB disease after infection (positive screening test, IGRA or TST >=10mm) was 11.1% overall (14.5% with imputation), and highest in the first 5 months for children 0-14 years. Estimated 4-year risk (with imputation) was  56.0% in children <5y, 27.6% in children 5-14y and 4.7% in age 15y and older.
    • Also see online TST/IGRA interpreter and TB risk calculator for estimations age 18y+.
      

Prevalence

LTBI is common in refugee children/young people. Australian data from the 2000s suggest the prevalence of a positive TST (10mm or greater) in refugees from Africa, Europe and the Middle East was 25-55%.^4-7 More recent data from Syrian and Iraqi arrivals (2015-17) found a LTBI prevalence of 11.8%.⁸ TB disease has been found in 1.7-3.3% of refugee children attending a refugee service in NSW.^4,5

Assessment

• Contacts/previous screening: Assess past history of TB, contact history (including family/household history), pre-departure screening (both timing and results), and health undertakings (generated by offshore medical screening).
  • Often a contact history will emerge after initial screening results are positive, it is usually wise to repeat the entire TB history. Explaining that onshore screening cannot affect visa status may be important.
  • Consider additional factors that will affect TB screening tests - TST and IGRA should not be completed within 4 weeks of live viral vaccines (which may have been given pre-departure - see below).
• Symptoms: Ask about cough, other respiratory symptoms, fevers, night sweats, malaise, loss of weight/poor weight gain, other localising symptoms and BCG history.
• Consider co-morbidities that might affect the risk for disease progression (low vitamin D, HIV) or tolerance for preventive/full treatment (hepatitis, H. pylori, poor nutrition).
• Assess social circumstances and family understanding. TB is still associated with significant stigma within many communities. Families need to understand the process of screening and the next steps in management.
  
  
• Examination - perform a full physical exam.
  • Check for BCG scar; sites vary with country of origin - check deltoids, forearms, thighs, scapulae (both sides).
  • Consider TB in lymph nodes if they are >1 cm diameter in the neck, >1.5 cm in the axilla and >2 cm in the groin and do not improve with a 1 week of anti-staphylococcal antibiotics.⁹

Screening

• The TST is the preferred first line screening test in children aged <5 years, although it is less reliable in those aged <6 months. The TST can be used at all ages, and should be used in age <2y. Where TST are required for younger children in the family, it is usually efficient to use TST for all children in the family. Check for recent (within 4 weeks) live viral vaccines (see below).
  • A false negative result may occur with very recent TB exposure, active disease, immunosuppression and within 4 weeks of live attenuated vaccines (MMR, varicella, OPV, rotavirus, yellow fever).
  • A false positive result may occur as a result of previous BCG immunisation (particularly if given after early infancy) or exposure to non-tuberculous mycobacteria.
    
    
• Interferon-gamma release assays (IGRA) such as QFN-GIT® and T-SPOT-TB® are not suitable as first line screening tests in younger children. Also separate from recent (within 4 weeks) live viral vaccines.
  • Multiple studies have found a proportion of children have a negative IGRA with a positive TST.
  • IGRA tests are only Medicare billable based on certain criteria (see below), this may represent a significant cost to refugee-background families.
  • IGRA testing may be used as additional information in the specialist setting.
    
    
• Routine use of both IGRA and TST in primary screening is not recommended.
  
  
• Children aged 2-10 years may have had pre-departure (or onshore) screening for TB through the visa medical process. 
  • If screening results are available and valid (i.e. a positive or negative result for those who had IGRA screening), recent, and children are reviewed soon after arrival, they do not need repeat LTBI testing unless there are additional clinical risk factors. 
  • Repeat testing (and ideally use TST in those <5y) in children with indeterminate or failed IGRA testing.
  • Ensure testing for LTBI in children who have not had previous LTBI screening, where results are not available, or where results are not recent (e.g. more than 12m previously). 
  • Children <2y will not have had pre-arrival or onshore LTBI screening and should be screened using TST.
    
    
• All children with a positive TST or positive IGRA need a CXR, films should be sent with the child if CXR is completed in primary care.
• Children with respiratory symptoms and a normal CXR may need a CT chest (completed in the specialist setting - seek advice from TB program/service).¹⁰

TST - technical aspects

• Document presence and location of BCG scar.
• Intra-dermal injection (26-G/27-G 10 mm needle, bevel up) of 5 tuberculin units (TU) purified protein derivative (PPD).
  • 5 TU PPD = 0.1 ml of 50 TU/ml solution.
• Given in the left forearm at the junction of the upper and middle thirds.
• Read at 48 - 72 hours (up to 5 days).
  • Measure induration (not erythema) in the transverse axis.
• Less reliable in children aged <6m.
• Do not administer within 4 weeks of live attenuated vaccines (MMR, varicella, MMR-V, OPV, rotavirus, yellow fever - note MMR and other vaccines may be given during pre-arrival assessment in refugee entrants).
• Do not give if previous TB disease (likely to cause large reaction) or previous large reaction to TST, seek specialist advice if active TB infection suspected.

TST - interpretation

A positive result is:

• 5 mm or greater in children who are household contacts of someone with active TB disease, or immunosuppressed.
• 10 mm or greater in children with a history of close contact, or who are from an endemic area.
• 15 mm or greater (always considered positive).

BCG is usually given in early infancy, and almost all humanitarian arrivals have evidence of previous BCG vaccination (scar, +/- record). It is safest to ignore BCG status when interpreting the TST (and guidelines for TST interpretation no longer account for prior BCG).

IGRA - MBS guidelines

From May 2017, the MBS item 69471 for IGRA testing was amended, allowing MBS rebate for IGRA testing in the following situations:

• Exposure to confirmed case of active TB.
• HIV infection.
• Commencing/commenced TNF-inhibitor therapy.
• Commencing/commenced renal dialysis.
• Silicosis.
• Is/about to be immunocompromised (due to other condition or medical treatment).

Management

LTBI

Children <5 years who are a close contact of a confirmed TB case should start TB preventive treatment (TPT) regardless of TST results, with a 'break of contact' TST at 3 months to decide on further treatment.

Medication regimens

• The NTAC position statement on treatment of LTBI (2017), Victorian guidelines (2021), and WHO guidelines (Module 5) (2022) provide the following regimens for TPT/treatment of LTBI in children and adolescents:
  
  
• 3RH = 3 months of daily rifampicin and isoniazid, preferred option for children <30kg if dispersible fixed dose combination is available (R75mg/H50mg) - SAS required*. Dosing is:
  • 4-7 kg = 1 tablet daily (1 packet for 3m course)
  • 8-11 kg = 2 tablets daily (2 packets for 3m course)
  • 12-15 kg = 3 tablets daily (3 packets for 3m course)
  • 16-30 kg = 4 tablets (4 packets for 3m course)
    
  • Dosing is based on: rifampicin (15 mg/kg (range 10-20 mg/kg - maximum 600 mg) AND isoniazid (10 mg/kg (range 7-15 mg/kg) - maximum 300 mg). SAS prescribing - Patients will require both a script and a category B SAS form (prescribers will need to be registered/authorised on the TGA website). Packet size is 84 tablets/pack. Order in EMR under facility list/database tab.
    
    
• 4R = 4 months of daily rifampicin, preferred option for older children and adolescents - 30kg+ = 600 mg daily.  Dosing is 15 mg/kg (range 10-20 mg/kg - maximum 600 mg daily, available in 150 mg, 300 mg, 600 mg tablets and 20 mg/ml liquid).
  
  
• 3HP = 3 months of weekly rifapentine and isoniazid. Rifapentine not used in age <3 years, child dosing formulations not available in Victoria. Isoniazid (25 mg/kg age 2-11 years OR 15 mg/kg 12 years and older - maximum 900 mg) AND rifapentine (weight based dosing - 300 mg 10-14kg, OR 450 mg 14.1-25kg, OR 600 mg 25.1-32kg, OR 750 mg 32.1-50kg, OR 900 mg >50kg) 
  
  
• 6H = 6 months of daily isoniazid remains an alternative. In children with LTBI, 6 months preventive treatment with isoniazid (INH) reduces the risk of developing TB disease by 50-90%.¹¹ Dosing is 10 mg/kg (range 7-15 mg/kg, maximum 300 mg daily, available in 100 mg tablets only, no syrup form).
  • Consider vitamin B6 in addition to INH in breastfed infants, adolescents and children with poor nutrition. B6 is also used with INH in adults who have risk factors for neurotoxicity (diabetes, alcohol use, renal disease, epilepsy, HIV, pregnancy, lactation). Dose is 5-25 mg/day (not/kg).    
  • INH complications (mainly hepatitis) occur most frequently in adults >35 years, especially if co-morbid alcohol intake. It is usually well tolerated in children and adolescents. Other (rare) side effects include immediate type reactions, peripheral neuritis (prevented by B6, increased risk with poor nutrition) GIT upset and haematological problems.
  • Check hepatitis status before commencing INH - if hepatitis and abnormal LFTs discuss with a gastroenterologist and an infectious diseases specialist, alternative regimens may be considered.
  • Discuss alcohol intake with adolescents.  

General points

• Consider drug interactions and check product information - rifampicin is a cytochrome p-450 enzyme inducer, and INH inhibits the metabolism of several drugs, including anticonvulsants and benzodiazepines.  
• Seek specialist advice if unsure, and for all children with contact with resistant TB disease or HIV/complex medical conditions
• Compliance is a major issue in TPT. Discuss the risks and benefits with families, this may take some time. It is not appropriate to start treatment if the family are unsure whether they want to proceed, or they are unsure if they can manage the duration of medications.
  • If multiple children in the family require preventive treatment, it is practical to treat them all at the same time.
  • If the family declines TPT, provide information on the risks of TB disease, but no specific follow-up is required unless symptomatic, or further contact with adult with pulmonary TB disease.  
    
• Safe prescribing
  • Medications need to be clearly labelled, colour coding can be helpful.
  • Picture based dosing instructions may be helpful - see easidose.
  • All doses and medication safety issues need to be discussed with an interpreter and families need a point of contact in case they have issues with medications or compliance.
    

Other clinical scenarios

TB disease

TB disease is usually managed by a respiratory or infectious diseases physician. Standard treatment for pulmonary TB disease is 6 months of multi-agent therapy, longer durations are used for some extra-pulmonary sites and for multi-drug resistant TB disease. Tuberculosis disease is a notifiable condition. If a diagnosis of TB disease is made, perform HIV testing after appropriate counselling. See Victorian guidelines, Therapeutic guidelines (via RCH Library), and RCH Fact sheet - Tuberculosis.

TB disease in a family/household member

Discuss with infectious diseases or respiratory physician. Other family members need assessment of their TB status, this will usually occur through the TB program, check this follow-up is in place.

• The main risk is where the contact is an adult with pulmonary disease, particularly smear positive disease. Details of the index cases smear status and organism sensitivity should be recorded.
• Contacts need screening/assessment after the index case is diagnosed.
  • If the initial screen is negative; children <5y typically start prevention therapy (choice depending on the sensitivity of the index case). The TST is repeated after 10 weeks - 3 months (break of contact) to look for conversion. In children <2y a complete course of TPT may be given, regardless of the break of contact TST result.
  • Consider BCG immunisation in children with negative break of contact screening.
  • Children aged <6m should be placed on TPT and a Mantoux performed at 6m of age.
  • Refer to Victorian guidelines for further details.

Latent TB in a family/household member

• Screen other family members.
• In children <16y who have a negative screen, and have not had BCG (and who do not have contraindications) consider BCG vaccination. In children <6m old, consider TST at 6m, and BCG at that point.

BCG vaccination

Bacillus Calmette Guerin (BCG, an attenuated strain of M. bovis) has been used to vaccinate against TB since 1921 and there is 80% coverage worldwide.¹² It does not protect against infection, overall protection against all forms of disease is around 50% with greater protective effect against death from TB (71%) and TB meningitis (64%).¹³ The reported efficacy against pulmonary TB varies widely (0-~80%).¹² It offers good protection against leprosy.

• BCG vaccination causes a scar in 75-99%¹⁴ recipients.
• BCG is usually given in the neonatal period in developing countries (which has less impact on TST results compared to BCG given later in life).
• Vaccination causes a small papule which normally ulcerates in 2-3 weeks and heals in several weeks.
• Contraindications: previous TB disease, TST >5 mm diameter, HIV infection, immunosuppression, pregnancy, fever and generalised skin disease.
• Adverse events include injection site abscess in around 2.5% and lymphadenitis in around 1%, which may require anti-tuberculous drugs if severe. Adverse events are probably less likely with experienced providers.
• Further information is available in the Australian Immunisation Handbook.¹⁵
• In Victoria, BCG is available in a multi-dose vial, and only administered at RCH and MMC. See: further information about BCG clinics for children.
• Parent handout:  BCG vaccination (English only).

Resources 

• Victorian Tuberculosis Program, Victorian Tuberculosis Guidelines (2015), Victorian Child and Adolescent Tuberculosis screening (2021), Victoria DH - Tuberculosis. 
  
• CDC tuberculosis (various)
• ATS/IDSA/CDC clinical practice guidelines (2016): Diagnosis of tuberculosis in adults and children
• McGill University online TST/IGRA interpreter and TB risk calculator - for age 18y+ (likely less accurate for young children) - helpful if trying to explain risk to a family
  
• NICE tuberculosis (2016, updated 2019)
• National Tuberculosis Advisory Committee (NTAC), including policy statements
  
  • Annual reports: Tuberculosis notifications in Australia
  • Consensus statement on use of 4m treatment regimen in children <10y (2022)
  • Position statement on the use of IGRA (2017)
    
  • Policy recommendation: latent tuberculosis infection screening and treatment in children in immigration detention (2015)
    
  • National position statement for the management of latent tuberculosis infection (2017)
  • Strategic plan for control of tuberculosis in Australia, 2021-2025 (2022)
• WHO
  
  • Tuberculosis - includes consolidated guidelines:
    • Module 1: Prevention: Tuberculosis preventive treatment (2020)
    • Module 5: Management of tuberculosis in children and adolescents (2022)
  • Global tuberculosis report (2022)

References

• References

_{Immigrant health resources. Initial: Georgie Paxton and Sarath Ranganathan, January 2007. Revisions: Georgie Paxton. Last updated Oct 2023. Contact: georgia.paxton@rch.org.au}