Tuberculosis, pulmonary

A16.9

* Notifiable condition.

• Description
• Diagnostic criteria
• General and supportive measures
• Medicine treatment
• Referral

DESCRIPTION

A chronic, granulomatous disease of the lungs caused by M. tuberculosis.
Most children acquire tuberculosis from infected adults by inhalation.

Malnourished, immunosuppressed (HIV and AIDS) and children < 3 years of age with pulmonary tuberculosis (PTB) are always regarded as having a very serious disease.

Complications include:

• enlarged hilar and mediastinal lymphadenopathy with obstruction, e.g. tracheal or bronchial airway compression or occlusion with secondary atelectasis or hyperinflation;
• local spread of infection, e.g. TB bronchopneumonia, pleural effusion or cavitation;
• disseminated disease, e.g. miliary TB, TB meningitis and metastatic extrapulmonary involvement.

DIAGNOSTIC CRITERIA

Any child presenting with symptoms and signs suggestive of pulmonary TB is regarded as a case of TB if there is:

• a chest X-ray suggestive of TB,

and/or

• history of exposure to an infectious TB case and/or positive Tuberculin Skin Test (TST) e.g. Mantoux.

The diagnosis is supported by a positive M. tuberculosis PCR e.g. GeneXpert®. Culture, usually on gastric aspirates or induced sputum, is a confirmatory test.

• Signs and symptoms include:
  • unexplained weight loss or failure to thrive,
  • unexplained fever for ≥ 2 weeks,
  • chronic, unremitting cough for > 14 days,
  • lymphadenopathy (especially cervical, often matted),
  • hepatosplenomegaly,
  • consolidation and pleural effusion.
• The following may be evident on chest X-ray:
  • Direct or indirect evidence of hilar or mediastinal adenopathy with or without parenchymal opacification and/or bronchopneumonia,
  • miliary changes,
  • pleural effusions.

Note:
Miliary pattern on chest X-rays of HIV infected children may also be suggestive of a diagnosis of lymphoid interstitial pneumonitis (LIP). (The miliary pattern of TB extends into the periphery of the lungs whereas LIP usually does not).

• Exposure to an adult with pulmonary tuberculosis.
• Tuberculin skin test (TST) e.g. Mantoux.
  • A positive TST has an induration of ≥ 10 mm.
  • A TST may be falsely negative in the presence of:
    • malnutrition,
    • immunodeficiency, e.g. HIV and AIDS,
    • immunosuppression, e.g. steroid therapy, cancer chemotherapy,
    • following overwhelming viral infection, e.g. measles or post vaccination.

In these circumstances a TST induration of ≥ 5 mm may be regarded as positive. Frequently, the TST will be non-reactive in these cases and a decision not to start TB treatment should not be based on a negative TST test.

• M. tuberculosis is suggested by positive PCR and confirmed by culture on the following specimens but most children will not have microbiological confirmation of TB:
  • early morning gastric aspirate (empty stomach, no oral food intake for ≥ 4 hours),
  • sputum (older children),
  • induced sputum,
  • CSF,
  • pleural and ascitic fluids,
  • fine needle aspirate biopsies of lymph nodes,
  • ear swabs for tuberculosis culture in chronic otorrhoea.
• PCR sputum positive on molecular testing.
  • The M. tuberculosis PCR has an inferior yield to liquid culture and therefore should not replace culture.
  • Where available, the molecular M. tuberculosis PCR test should be performed on sputum and gastric aspirates in preference to fluorescent smear for acid fast bacilli as it increases the diagnostic yield and allows early identification of rifampicin resistance.
• Microscopy and culture in all cases.

GENERAL AND SUPPORTIVE MEASURES

• Identify and treat the source case.
• In case of known contact with adult MDR TB case, the child requires referral for appropriate MDR TB prophylaxis or treatment.
• Screen all contacts for TB infection.
• Monitor the nutritional status of the child to assess response to treatment.
• Only symptomatic pleural effusions should be drained via pleural aspiration (in such cases consider adjunctive steroid therapy).
• Ensure household infection control practices.

MEDICINE TREATMENT

Tuberculosis control programme drug regimens (2013)

Directly observed therapy (DOT), short-course, using fixed medicine combinations is recommended to avoid the development of antimicrobial resistance.

Give treatment daily in both the intensive (initial) and the continuation phase.

HIV infected children with tuberculosis should be treated according to the standard treatment protocol with clinical, radiologic and microbiologic follow-up to determine response to treatment.

Uncomplicated with low bacillary load

Children up to 8 years:

* For each dose, dissolve 150mg dispersible (1 tablet) in 3 mL of water to prepare a concentration of 50mg/mL(150mg/3mL)

Dosing recommendations for dispersible combinations tablets:

PLUS
If HIV infected or malnourished:

• Pyridoxine, oral, daily for 6 months:
  • < 5 years of age: 12.5 mg daily,
  • > 5 years of age: 25 mg.

Children > 8 years of age and adolescent:

PLUS
If HIV infected or malnourished:

• Pyridoxine 25mg daily for 6 months.

Complicated TB, high bacillary load

All other forms of severe TB. i.e. extensive pulmonary TB, spinal or, osteo-articular TB or abdominal TB.

Children up to 8 years of age:
Intensive phase:
Standard dose 4–drug therapy daily (RHZE) for 2 months.

Follow with:
Continuation phase:
Standard dose 2 drug therapy daily (isoniazid + rifampicin).

Notes:
* For each dose, dissolve 150mg dispersible (1 tablet) in 3mL of water to prepare a concentration of 50mg/mL(150mg/3mL).
** For each dose, crush 400mg (1 tablet) to a fine powder and dissolve in 8mL of water to prepare a concentration of 400mg/8mL. Discard unused solution.
*** Continuation phase may be prolonged to 7 months in slow responders and children with HIV.

PLUS
If HIV infected or malnourished:

• Pyridoxine, oral, daily for 6 months:
  • < 5 years of age: 12.5 mg daily,
  • > 5 years of age: 25 mg.

Children > 8 years and adolescent:

PLUS
If HIV infected or malnourished:

• Pyridoxine 25 mg daily for 6 months.

Adjust treatment dosages to body weight.
If calculating dosages, rather give ½ tablet more than ½ tablet less.

Treatment of children who were previously successfully treated for TB

(Retreatment)
A child, who was previously successfully treated for pulmonary TB, is at increased risk for re-infection with TB. It is imperative to exclude drug-resistant TB by carrying out sputum M. tuberculosis PCR plus culture with drug susceptibility testing (DST), and also determine DST of any known TB source case. If the above does not indicate resistant TB, treat as drug susceptible TB (high bacillary load) with close monitoring of response. Consider an extension of the duration of the continuation phase of therapy in these retreatment cases.

Drug resistant TB

Drug resistant TB single drug, multidrug (MDR), extensive drug resistant (XDR) is as infectious as drug susceptible TB.
Drug resistance can be primary or acquired.

MDR-TB disease indicates resistance to both rifampicin and isoniazid with/without resistance to any other antituberculosis medicine(s).
XDR-TB disease is defined as MDR-TB and in vitro resistance to any of the fluoroquinolones and any second-line injectable medicine.

Suspect DR-TB when any of the features listed below is present:

1. A known source case (or contact) with drug resistant TB or high-risk source case, e.g. on TB therapy who was recently released from prison.
2. A smear positive case after 2 months of TB treatment who failed (or deteriorated on) first-line anti-tuberculosis treatment to which they were adherent (treatment failure or relapse within 6 months of treatment).
3. Any severely ill child with TB that failed or got worse on TB treatment.
4. Defaulted TB treatment (> 2 months).
5. Treatment interruptions (< 1 month) or who relapsed while on TB treatment or at the end of treatment.
6. With recurrent TB disease after completion of TB treatment (retreatment case).

When DR-TB is suspected, submit appropriate microbiological specimens for genotypic drug sensitivity test and culture for phenotypic drug susceptibility testing. M. tuberculosis PCR tests for rifampicin resistance only while the line probe assay (LPA) tests for isoniazid and rifampicin susceptibility. Second-line LPA tests for other antimicrobial resistance including quinolones. All samples that test positive on molecular PCR testing must have samples submitted for culture and drug susceptibility testing but therapy for MDR-TB must be instituted while awaiting results. False positive results with both the M. tuberculosis PCR. and line probe assay have been recorded. Clinical and radiological correlation with molecular results must always be considered and discuss discordant results with an expert.

Manage confirmed DR-TB in a dedicated MDR-TB unit with appropriate infection control measures to prevent nosocomial transmission. Initiate treatment in consultation with a designated expert while awaiting referral to the designated MDR-TB centre. An uninterrupted medicine supply, direct supervision with proper education and counselling is necessary.

The standardised empiric treatment protocol for MDR-TB for children is 5 drugs for 6 months or more for at least 6 days a week during the intensive phase and 4 drugs for at least 6 days a week for 18 months or less during the continuation phase. Exact duration of therapy for the intensive phase is 4 months after the first date of sampling of a negative culture result while the total duration of therapy should be 18 months after the first date of sampling of a negative culture result.

Children < 8 years with MDR-TB
Intensive phase:

• Levofloxacin, oral.
  • 15–20 mg/kg/dose once daily.
  • Maximum dose: 1000 mg.
• Amikacin, IV, 15–22.5 mg/kg daily.
• Terizidone, oral, 15–20 mg/kg daily.
• Ethionamide, oral, 15–20 mg/kg daily.
• Pyrazinamide, oral, 30–40 mg/kg daily

Continuation phase:
Same as initial phase but stop amikacin.

Children >8 years with MDR-TB
Intensive phase:

• Moxifloxacin, oral, daily.
  • <25 kg: 200mg
  • >25 kg: 400mg
• Amikacin, IV, 15–22.5mg/kg daily.
• Terizidone, oral, 15–20mg/kg daily.
• Ethionamide, oral, 15–20mg/kg daily.
• Pyrazinamide, oral, 30–40mg/kg daily.

Continuation phase:
Same as intensive phase but stop amikacin.

Other agents may be substituted in special situations and in consultation with a designated expert. Cases of DR-TB must be monitored clinically, with radiology and microbiologically for response to therapy. TB culture conversion occurs when 2 consecutive TB culture results on sputum/gastric aspirates taken 30 days apart are negative and thereafter remains negative.

Disseminated (Miliary) TB

Children < 8 years
A 6-month regimen of all 4 the following medicines:

• Rifampicin, oral, 20 mg/kg as a single daily dose.
  • Maximum dose, oral, 600mg daily.

PLUS

• Isoniazid, oral, 20 mg/kg as a single daily dose.
  • Maximum dose, oral, 400mg daily.

PLUS

• Pyrazinamide, oral, 40 mg/kg as a single daily dose.
  • Maximum daily dose: 2000 mg.

PLUS

• Ethionamide, oral, 20 mg/kg as a single daily dose.
  • Maximum daily dose: 1000 mg.

PLUS

• Pyridoxine 25 mg daily for 6 months.

Note:
All cases of miliary TB should have a lumbar puncture (LP) preformed. Any abnormal CSF results or where a LP is not performed, should be treated as a patient with TBM. See Meningitis, tuberculosis (TBM) .

Preventive therapy for TB exposure/infection

Screen all children in close contact with an infectious pulmonary TB case for TB disease. Screening includes clinical history/examination and, if available, chest X-ray and tuberculin skin test (TST). Give antituberculosis treatment if the diagnosis of TB disease is confirmed or suspected.

Indications for Isoniazid Preventive Therapy (IPT):

• All asymptomatic children < 5 years of age, or HIV-infected irrespective of age, i.e. clinically normal, normal chest X-ray and TST positive or negative, in close contact with an infectious pulmonary TB case should receive isoniazid preventive therapy (IPT).
• Children < 5 years of age, or HIV-infected irrespective of age, who have had no previous TB treatment or preventive therapy, are asymptomatic without a history of close contact with an infectious pulmonary TB case but found to have a positive TST.
• Previous isoniazid preventive therapy or treatment does not protect the child against subsequent TB exposure/infection. If there is re-exposure to an infectious pulmonary TB case after completion of 6 months of chemotherapy, children (< 5 years or HIV-infected) should receive IPT after each episode of documented TB exposure for 6 months. In cases of re-exposure to infectious source cases while the child is on IPT, the duration of IPT should continue for as long as the source case remains infectious.

Preventive therapy in case of drug-susceptible TB contact:

• Isoniazid, oral, 10 mg/kg daily for 6 months.

Preventive therapy in case of drug-resistant TB contact:
Isoniazid monoresistance:

• Rifampicin, oral, 15 mg/kg daily for 4 months.

Rifampicin monoresistance:

• Isoniazid, oral, 10 mg/kg daily for 6 months.

MDR-TB:

• Isoniazid, oral, 15-20mg/kg daily for 6 months 300mg
• Ethambutol, oral, 20-25mg/kg daily for 6 months 400mg
• Levofloxacin 15-20mg/kg daily for 6 months 500mg

Refer case if simplification of prophylaxis regimen is required

XDR-TB:

• Close follow-up for two years.
• Ensure household infection control practices are observed.
• Refer all cases.

REFERRAL

• Poor response to standard TB treatment.
• Failure to exclude MDR-TB.
• Adverse drug reactions (ADR) requiring single drug combinations.
• MDR or MDR-TB contact.