Medical paediatrics Division E Cambridge University Hospitals NHS Foundation Trust Page 1 of 13 Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020 Guideline Tuberculosis (TB) – Management of tuberculosis in children 1 Scope Trust-wide for children <16 years old, excluding children with known HIV infection. 2 Purpose To comply with the latest NICE guidelines for the clinical diagnosis, management, prevention and control of paediatric tuberculosis To standardise and improve the care of children with suspected or confirmed tuberculosis. 3 Introduction The presentation and course of tuberculosis (TB) in children differs in many key aspects from the disease in adults. This guideline is focused on the diagnosis, screening and management of respiratory and non-respiratory TB. It is worth noting that the symptoms of tuberculosis in children are often dependent on the patient’s age. Younger children are more likely to develop clinical signs than older children. Older children may show no signs, even with extensive lung disease. Our clinical threshold for suspicion of TB should be low. Audit standards 1. 100% of children with active pulmonary TB receiving quadruple therapy, rifampicin, isoniazid, pyrazinamide and ethambutol (or other fourth drug) for the first two months of treatment, followed by four months therapy with rifampicin and isoniazid (with pyridoxine). 2. 100% of children receiving TB chemotherapy are monitored for drug toxicity (Isoniazid: liver toxicity; ethambutol: eye toxicity) 3. 100% of families are in possession of current key worker’s details. 4. 100% of cases notified to Public Health (via TB CNS) and the Enhanced Tuberculosis Surveillance (ETS) database.
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Medical paediatrics
Division E
Cambridge University Hospitals NHS Foundation Trust Page 1 of 13
Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020
Guideline
Tuberculosis (TB) –
Management of tuberculosis in children
1 Scope
Trust-wide for children <16 years old, excluding children with known HIV
infection.
2 Purpose
To comply with the latest NICE guidelines for the clinical diagnosis, management, prevention and control of paediatric tuberculosis
To standardise and improve the care of children with suspected or confirmed tuberculosis.
3 Introduction
The presentation and course of tuberculosis (TB) in children differs in many key aspects from the disease in adults. This guideline is focused on the diagnosis, screening and management of respiratory and non-respiratory TB. It is worth noting that the symptoms of tuberculosis in children are often dependent on the patient’s age. Younger children are more likely to develop clinical signs than older children. Older children may show no signs, even with extensive lung disease. Our clinical threshold for suspicion of TB should be low.
Audit standards 1. 100% of children with active pulmonary TB receiving quadruple therapy, rifampicin,
isoniazid, pyrazinamide and ethambutol (or other fourth drug) for the first two months of treatment, followed by four months therapy with rifampicin and isoniazid (with pyridoxine).
2. 100% of children receiving TB chemotherapy are monitored for drug toxicity (Isoniazid: liver toxicity; ethambutol: eye toxicity)
3. 100% of families are in possession of current key worker’s details. 4. 100% of cases notified to Public Health (via TB CNS) and the Enhanced Tuberculosis
Surveillance (ETS) database.
Medical paediatrics
Division E
Cambridge University Hospitals NHS Foundation Trust Page 2 of 13
Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020
The three most important clinical forms of TB in children are:
1. Pulmonary tuberculosis 2. Tuberculosis meningitis 3. Disseminated tuberculosis
Children with suspected tuberculosis should be managed either by a TB specialist paediatrician, or by a general paediatrician with advice from the Trust lead in TB in children (Dr Donna McShane). Children with confirmed active TB should be managed by a TB specialist paediatrician. It is standard practice to screen visitors of a child with active pulmonary TB in hospital as part of contact tracing. Children with active pulmonary TB should be kept separate from other patients until they have been excluded as the source of infection (see infection control isolation policy).
4 Latent TB: screening, diagnosis and management
For complete information on prevention and screening please refer to NICE guidelines as this is beyond the scope of this document. For dosages, see the appendix to this document or the BNF for Children.
4.1 Groups to screen
Children <2 years old who have been in close contact with a person with suspected or confirmed pulmonary or laryngeal TB who has not had at least two weeks of anti-TB treatment.
Children between 2 and 17 years old who have been in close contact with a person with confirmed or suspected pulmonary or laryngeal TB.
Immunocompromised children born in a high incidence country
Immunocompromised children who come into close contact with those with confirmed or suspected pulmonary or laryngeal TB
New entrant children from a high incidence country
4.2 Diagnosis and management of latent TB
Neonates (<28 days old) who have been in close contact with people with pulmonary or laryngeal TB who have not had at least two weeks of anti TB treatment
o Get advice from the Trust paediatric TB lead (Dr Donna McShane)
o Assess for evidence of active TB
o Start isoniazid with pyridoxine if no evidence of active TB
o Mantoux test after six weeks treatment
Medical paediatrics
Division E
Cambridge University Hospitals NHS Foundation Trust Page 3 of 13
Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020
o If Mantoux positive, reassess for and if there is no evidence of active TB, continue isoniazid with pyridoxine for six months
o If Mantoux negative, and there is no evidence of active TB, perform interferon gamma release assay
If IGRA negative, stop isoniazid and pyridoxine, give BCG vaccination
If IGRA positive, and there is no evidence of active TB, continue isoniazid and pyridoxine for a total of six months
o If Mantoux test is inconclusive refer to a TB specialist
Child between 4 weeks and 2 years been in close contact with people with pulmonary or laryngeal TB who have not had at least two weeks of anti TB treatment
o Get advice from the Trust paediatric TB lead (Dr Donna McShane)
o Assess for active TB at every stage of treatment; clinical evidence of active TB at any point necessitates full active TB treatment (see below)
o Start treatment for latent TB (rifampicin, isoniazid and pyridoxine) and perform Mantoux test
o Mantoux inconclusive; refer to a TB specialist
o Mantoux positive and no evidence of active TB, continue treating according to latent TB regimen (see below)
o Mantoux negative, continue treatment for latent TB for six weeks, then perform Mantoux test
Mantoux negative, consider IGRA
IGRA negative, stop latent TB treatment and give BCG if the child has not previously been vaccinated
Mantoux or IGRA positive, complete treatment for latent TB
Child between 2 and 17 years old who has been in close contact with a person with pulmonary or laryngeal TB
o Get advice from the Trust paediatric TB lead (Dr Donna McShane)
o Assess for active TB at every stage of treatment; clinical evidence of active TB at any point necessitates full active TB treatment (see below)
o Mantoux testing
Mantoux positive, with no evidence of active TB, offer treatment for latent TB as per protocol (rifampicin, isoniazid and pyridoxine).
Mantoux negative, perform IGRA after six weeks with a repeat Mantoux
Medical paediatrics
Division E
Cambridge University Hospitals NHS Foundation Trust Page 4 of 13
Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020
Either test is positive, and no evidence of active TB, offer treatment for latent TB as per protocol (rifampicin, isoniazid and pyridoxine)
Both tests negative, no further action required.
Immunocompromised children from a high incidence country or close contact to those with pulmonary or laryngeal TB should be referred to a TB specialist
New entrant children from a high incidence-country at first presentation to healthcare services
o Mantoux testing
Mantoux positive and no evidence of active TB, offer treatment for latent TB infection as per protocol (see below)
Mantoux negative – no action
o IGRA if Mantoux is unavailable. If large numbers of children need to be screened in an outbreak scenario, the recommendations above should be followed as per age. IGRA alone is acceptable only in adults or if Mantoux testing is not available or impractical.
4.3 Specialist diagnostic tests
4.3.1 Mantoux (tuberculin) skin test (TST)
The TST is an intradermal diagnostic test for latent and active TB performed by the TB specialist nurses. The standard dose administered is 2TU/0.1ml of Tuberculin PPD. The resultant induration is read 48-72 hours after administration: NEGATIVE <5mm diameter
POSITIVE >5mm diameter (irrespective of BCG)
Staff, appropriately trained in the administration of intra-dermal injections and interpretation of the results, can also perform the Mantoux test outside of standard working hours. Contact the TB specialist nurses or paediatric respiratory registrar. Tuberculin PPD can be requested via pharmacy or clinic 2a. TB specialist nurses can be contacted on bleep 152382, extension 216431.
4.3.2 In-vitro gamma interferon release assays (IGRA) (QuantiFERON –TB assay)
QuantiFERON-TB is an in-vitro gamma interferon release assay (IGRA) for the detection of latent TB. The assay detects interferon gamma secreted by patient T-cells after incubation with M. tuberculosis specific antigens ESAT 6, CFP10
Medical paediatrics
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Cambridge University Hospitals NHS Foundation Trust Page 5 of 13
Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020
and TB7.7. The sensitivity and specificity of this test may vary depending on clinical circumstances. Ordering QuantiFERON –TB assay:
Place order via Epic
Please provide as much clinical information as possible to assist the lab team with result interpretation.
Sample:
3ml of blood must be drawn, in the correct order as specified in test instructions, and divided equally and in the following order between the three QuantiFERON-GOLD sample bottles
o 1ml Grey Top (Nil control) o 1ml Red Top (TB antigen) o 1ml Purple top (Mitogen control)
NB no other sample bottles can be used
Samples must be shaken and kept at room temperature.
Samples must be delivered to the Immunology Lab within 12 hours of venepuncture and between the hours of 08.00- 17.00 Monday- Friday
Any queries regarding this test should be directed to Mr. Graham Wood, Lab Manager (3361), or Dr Gerald Maguire, Consultant Clinical Scientist (3159)
Results:
A report should be issued in one week. The above groups should be screened and treated, as appropriate, for latent TB as per the protocols below.
4.4 Monitoring of latent TB treatment
All children should have baseline LFT monitoring which is repeated after a minimum of two weeks therapy. If hepatotoxicity is a concern, discontinue drugs, allow liver to recover and then undertake a controlled re-introduction of the agents (as per NICE guidance).
If severe liver disease, work alongside an MDT including those with experience of managing TB in liver disease.
Screening for hepatitis B and C should be undertaken before starting treatment for latent TB. HIV screening should be undertaken at the discretion of the clinician.
Consider the drug sensitivities of the index case or the possibility of MDR-TB when making decisions about TB treatment.
Medical paediatrics
Division E
Cambridge University Hospitals NHS Foundation Trust Page 6 of 13
Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020
5 Active tuberculosis diagnosis and management
Advice should be sought from the Trust paediatric TB lead, Dr Donna McShane, when investigating or managing children with TB.
5.1 Pulmonary TB
5.1.1 Diagnosis
In children in whom active pulmonary TB is suspected, the following investigations should be performed:
Full clinical examination of the child including their BCG scar.
Mantoux skin test
Chest x-ray
Sputum samples: Send a minimum of three sputum samples before commencing treatment including 1 early morning, or within 7 days of commencing treatment if the illness is life threatening.
o Obtain sputum spontaneously if possible. If not possible use 3 gastric lavages or 3 inductions of sputum. Note that in those with suspected TB, aerosol generating procedures such as bronchoscopy, and sputum induction must be carried out in an appropriately ventilated area and appropriate infection control measures undertaken.
M.TB complex PCR including rifampicin resistance (rpoB)
QuantiFERON-TB assay
Hepatitis B and Hepatitis C screen
Consider HIV screen if at risk TB chemotherapy should be commenced before culture results are available. The standard recommended regimen should be continued in patients whose subsequent culture results are negative if there are signs and symptoms of TB.
5.1.2 Management
Children with active TB should be referred to the Trust paediatric TB lead once a diagnosis is made. Children should receive a six month, four drug regimen: two months of isoniazid (with pyridoxine), rifampicin, pyrazinamide and ethambutol. Then four months of isoniazid (with pyridoxine) and rifampicin. See appendix for dosing. Use fixed dose combination tablets if appropriate, otherwise syrups are a special order from pharmacy. Drug susceptibility testing should be used to inform modification of the treatment regimens.
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Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020
5.1.3 Assessment for necessity of directly observed therapy (DOT):
DOT should be considered based on an assessment of the likelihood of compliance. DOT should be offered to children who:
Have been treated previously for TB or have multidrug resistant TB
OR Have parents/guardian who are in any of the following groups: o Have a history of homelessness, drug or alcohol misuse o Are currently in prison, or have been in the past 5 years o Have a major psychiatric, memory or cognitive disorder o Are in denial of the TB diagnosis o Request DOT after discussion with the treatment team o Are incapable of administering the treatment, for example, through
illness or disability
5.1.4 Dosing regimens for DOT:
Use fixed dose combination tablets if appropriate
Do not dose fewer than three times per week
If DOT is required, offer daily dosing schedule unless daily DOT is not possible. In this case consider three times per week dosing. This should be done under expert supervision.
Do not routinely extend treatment beyond six months unless the child has HIV or CNS involvement (see below).
For details of drug doses please consult the appendix of this document and confirm in the BNF for Children.
5.1.5 Multi-drug resistant TB (MDR TB):
Risk factors for MDR TB include:
o Previous TB drug treatment, particularly if poor adherence was noted
o Contact with a known case of MDR TB
o Birth/ residence in a country where WHO reports that >5% of new TB cases are MDR TB
If MDR TB is suspected, start infection control measures
If positive test for Rifampicin resistance:
o Exclude pulmonary or laryngeal disease before stopping infection control measures
o Refer to specialist team with experience of MDR TB (GOSH or St Mary’s Hospital)
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Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020
o Treatment regimens should involve at least six drugs to which the mycobacterium is likely to be sensitive
o Test for resistance to second line drugs
If negative for Rifampicin resistance treat as usual drug sensitive TB (see above)
If the rapid nucleic acid amplification test is negative for M. tuberculosis but the person is at high risk of MDR TB
o Further specimens for nucleic acid amplification testing and culture are required
o Rapid rifampicin resistance on any positive tests
o If the child is well, consider waiting to start treatment for the results of susceptibility results
o If the child is unwell and urgent treatment is required, treat as MDR-TB
5.2 Management of active TB in neonates (up to four weeks of age)
5.2.1 Congenital TB
TB can be acquired from maternal extra-pulmonary sites at birth, particularly the genital tract although this is extremely rare. In-utero infection presents with gastro-intestinal disease. Guidance should be sought from a supra-regional centre (GOSH, St Mary’s London) for advice regarding length of therapy.
5.3 Non-respiratory TB
5.3.1 Diagnosis
Diagnosis of active non-respiratory TB can be difficult and is based on microscopy and culture of appropriate samples. These are site specific. Extensive guidance for site specific investigations is found in the NICE guidelines for investigation and management of Tuberculosis. No part of any sample should be placed in formalin when sent. The appropriate treatment regimen should be started without waiting for culture results if the histology and clinical picture are consistent with a diagnosis of TB. The child should be reviewed by a respiratory paediatrician. In addition all non-respiratory TB patients should have
Chest x-ray
Mantoux test
Consider TB PCR
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Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020
5.3.2 Management
The standard six month, four drug regime has been recommended for all non-respiratory TB, other than TB meningitis. This includes TB involving peripheral lymph nodes, bones and joints, spine, pericardium, and disseminated (including miliary) TB.
5.4 TB meningitis
Tuberculosis meningitis occurs when there is blood borne spread of TB bacteria to the brain. It has an insidious onset usually presenting over a few weeks. Symptoms can be vague. In infants it may present as poor feeding or failing to thrive. More classic signs include headache, vomiting, increasing drowsiness, focal neurological signs and finally coma.
5.4.1 Clinical classification
1. Stage I; no clouding of consciousness or focal neurological signs.
2. stage II; clouding of consciousness and/ or focal neurological signs
3. Stage III; comatose
5.4.2 Diagnosis
CT should be performed, with MRI imaging considered
Confirmed by demonstrating M.tuberculosis on microscopy or culture of CSF or M.tuberculosis DNA on PCR.
Diagnosis supported by basic CSF changes on LP including low glucose, raised protein and lymphocyte dominant white cell pattern.
If clinical signs and other investigations are suspicious for TB meningitis, treatment should be offered even if rapid diagnostic tests are negative.
5.4.3 Management
The recommended treatment regimen lasts 12 months
The regime comprises isoniazid (with pyridoxine), pyrazinamide, rifampicin and ethambutol for the first two months, followed by isoniazid and rifampicin for the rest of the treatment period.
In addition a glucocorticoid should be given:
o Prednisolone 1-2mg/kg once a day (max 40mg)
Dose of steroids should taper over 4-8 weeks. See BNF for Children
Surgery is indicated only in those with evidence of raised ICP.
Treatment should be led by an experienced paediatric respiratory or neurology consultant with extensive co-operation between specialties.
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Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020
The patient will need long term follow up with regards to their development and neurological function as an outpatient.
5.5 Social and statutory requirements after diagnosis
Once diagnosed with TB all children with TB at any site should receive:
A full explanation of the anti-tuberculosis treatment. This should include the side effects and the need for full compliance.
Contact tracing
A named TB case manager (usually a TB specialist respiratory nurse) within five days of diagnosis. Parents should be given the case manager’s contact details.
Individual care plan. This should include:
o If directly observed therapy (DOT) is required: details of where and by whom treatment will be observed
o Include contact details of people who might help to re-contact the child’s family should contact be lost
o Details of the support required to address the child’s unmet health and social care needs
o A commitment from the child and/or parents to complete the TB treatment regime
Referral to ophthalmology for a pre-ethambutol eye test
All cases must be notified as a statutory requirement.
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Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020
6 Monitoring compliance with and the effectiveness of the guideline
All children treated for active TB will be audited annually for the national TB data set. We would monitor compliance:
Children treated for LTB should have LFTs after two weeks of treatment initiation and screened for HepB and HCV.
Medical review at the end of treatment in latent TB and bimonthly during active TB treatment.
Monthly TB MDT will monitor the progress of all patients undergoing treatment for TB.
TB specialist nurses will monitor drug prescriptions and dispensing monthly.
Any complaints or issues with compliance will dealt with by the TB MDT.
7 References
1. NICE Guideline [NG33] Tuberculosis, January 2016
2. Online British National Formulary for Children (BNFC)
https://bnfc.nice.org.uk/
8 Associated documents
infection control isolation policy
Equality and diversity statement This document complies with the Cambridge University Hospitals NHS Foundation Trust service equality and diversity statement.
Disclaimer It is your responsibility to check against the electronic library that this printed out copy is the most recent issue of this document.
Document management Approval: 28 July 2020
Owning department: Medical paediatrics
Author(s): Donna McShane; Theo Polychronakis
Pharmacist: Stephanie Aldridge
File name: Management of TB in children Version4 July 2020
Supersedes: Version 3, June 2017
Version number: 4 Review date: July 2023
Local reference: Document ID: 13566
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Division E
Cambridge University Hospitals NHS Foundation Trust Page 12 of 13
Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020
Appendix
Dosing of TB treatment:
Taken from Online British National Formulary for Children (BNFC) https://bnfc.nice.org.uk/ viewed 30/07/2020. Please consult the online BNFC to confirm against current information.
Latent TB:
3 months of isoniazid (with pyridoxine) and rifampicin
Isoniazid, IV, IM or PO
o 1 month – 11 years old, 10mg/kg daily, maximum
300mg/dose
o 12 – 17 years old, 300mg daily
Pyridoxine, PO
o 1 month to 11 years old, 5-10mg daily
o 12 to 17 years old, 10 mg daily
Rifampicin, PO
o 1 month to 11 years old, <50kg weight, 15 mg/kg daily,
maximum 450mg/day
o 1 month to 11 years old, >50kg, 15mg/kg daily, maximum
600mg/day
o 12-17 years old, <50kg, 450mg daily
o 12-17 years old, >50kg weight, 600mg daily
OR 6 months of isoniazid (with pyridoxine)
Isoniazid, IV, IM or PO
o Neonates, 10mg/kg daily.
o 1 month – 17 years old, 10mg/kg daily, maximum
300mg/dose
Pyridoxine, PO
o Neonate, 5mg daily
o 1 month to 11 years old, 5-10mg daily
o 12 to 17 years old, 10 mg daily
Active TB:
Daily dosing for a child:
2 month initial phase:
Isoniazid, 10mg/kg (max 300mg) once daily
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Tuberculosis – Management of tuberculosis in children Version 4; Approved July 2020
Pyridoxine
o 1 month to 11 years old – 5-10mg daily
o 12 to 17 years old – 10mg daily
Rifampicin 15mg/kg once daily
o max 450mg if body weight <50kg
o max 600mg if body weight >50kg
Pyrazinamide 35mg/kg once daily
o max 1.5g if body weight <50kg
o max 2g if body weight >50kg
Ethambutol 20mg/kg once daily
4 month continuation phase:
Isoniazid 10mg/kg (max 300mg) once daily
Pyridoxine
o 1 month to 11 years old – 5-10mg daily
o 12 to 17 years old – 10mg daily
Rifampicin 15mg/kg once daily
o max 450mg if body weight <50kg;
o max 600mg if body weight >50kg
3 times weekly dosing for a child (under expert condition):
2 month initial phase:
Isoniazid, 15mg/kg (max per dose; 900mg) three times per week
Pyridoxine
o 1 month to 11 years old – 5-10mg daily
o 12 to 17 years old – 10mg daily
Rifampicin 15mg/kg, (max per dose 900mg) three times per week.
Pyrazinamide 50mg/kg three times per week
o max 2g if body weight <50kg
o max 2.5g if body weight >50kg
Ethambutol 30mg/kg three times a week
4 month continuation phase:
Isoniazid 15mg/kg (max per dose; 900mg) three times per week
Pyridoxine
o 1 month to 11 years old – 5-10mg daily
o 12 to 17 years old – 10mg daily
Rifampicin 15mg/kg (max 900mg per dose) three times per week.
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