Latent Tuberculosis Infection

TB Skin Testing and IGRA’s – Management and Report 

Reporting of Positive TB Skin Tests 

Under the 1990 Health Protection and Promotion Act, all positive TB Skin Tests are reportable to Public Health. The practitioner reading the test results must:

  • Report the positive test even when referring the patient to another physician or specialist for treatment.
  • Fax all positive skin test results with recent chest x-ray to 519-883-2248 with the Referral form that can be obtained on the Request a Form page.
Management of a Positive TB Skin Test 

Persons with a positive skin test should be further assessed to rule out active TB disease. This assessment should include all three of the following:

  • Assessment of symptoms suggestive of active TB (see Clinical Presentation)
  • Risk Factors for TB (i.e. contact history or other medical conditions) 
  • Chest X-Ray (Frontal and Lateral View)

In the presence of symptoms consistent with active pulmonary TB, three sputum samples for AFB smear and mycobacterial culture should be submitted to London PHL and Region of Waterloo Public Health should be notified in order to discuss possible isolation requirements (see Sputum Collection)

Source: (Canadian Tuberculosis Standards, 7th ed., 2014, Chapter 4, P.11) 

Assessment and Clinical Presentation 
  • The classic symptom of pulmonary TB disease is a chronic cough of at least three weeks duration
  • Cough is initially dry although after several weeks to months will become productive
  • Fever and night sweats are common, but may be absent in the very young and elderly
  • Hemoptysis, anorexia, weight loss, chest pain, and other symptoms are generally manifestations of more advanced disease
  • TB can be found in other parts of the body and symptoms will vary depending on location (e.g. lymphadenopathy, pleural effusion, and abdominal or bone/joint involvement)

Source: (Canadian Tuberculosis Standards, 7th ed., 2014, Chapter 3, p.3)

Interferon-Gamma Release Assays (IGRA’s) 

What is an IGRA test?

Blood test to assist in the diagnosis M. Tuberculosis infection. There are two types of IGRA tests:

  1. QuantiFERON – TB Gold
  2. T-SPOT TB

The white blood cells from persons infected with M. Tuberculosis will release interferon gamma (IFN-g) when mixed with antigens derived from M. Tuberculosis. The result is based on the amount of IFN-g produced. IGRAs are not affected by BCG vaccination status and are useful for evaluating LTBI in BCG-vaccinated individuals, specific to when BCG is administered after infancy or when multiple BCG vaccinations are received. IGRA has a specificity of >95% in diagnosis of LTBI.

(Canadian TB Standards, - 7th Edition, pg. 18)

What are the advantages of having an IGRA test?

  • IGRA test requires a single patient visit
  • Results can be available in 2-10 days
  • Prior BCG (bacille Calmette-Guérin) vaccination does not cause a false positive result
  • Results not affected by most environmental Mycobacteriae
  • Results are not affected by reader bias or error

What are the disadvantages of the IGRAs?

  • Cost is not covered by the Ontario Health Insurance Plan (OHIP)
  • QuantiFERON®-TB Gold testing can only be obtained at certain locations of Dynacare and Life Labs. Please contact Dynacare for hours and availability of test
  • Limited data on the use of IGRAs to predict who will progress to TB disease in the future
  • Limited data on the use of IGRAs for:
    • children younger than five years of age
    • persons recently exposed to M. Tuberculosis
    • immunocompromised persons
    • serial testing

When can IGRAs be considered?

  • As a confirmatory test when an individual has had a positive tuberculin skin test (TST) and when there is a low risk of the individual being infected with TB
  • For persons who have received BCG vaccination after infancy (one year of age) and/or have had BCG vaccination more than once
  • For confirmation of LTBI particularly when preventative treatment is being considered
  • For persons from groups that historically have poor rates of return for TST reading

When should IGRAs not be considered?

  • For the diagnosis of active TB
  • When serial testing is indicated such as healthcare workers or other populations (e.g. corrections staff or prison inmates) with potential for ongoing exposure
  • When a live-virus vaccine has been administered unless they are both on the same day or 4-6 weeks after receiving the live vaccine 

Diagnostics – Chest X-Rays and Sputum Collection

Chest X-Ray Interpretation 

Chest radiography (Frontal and Lateral views) is the usual first step in evaluation of an individual with pulmonary symptoms. Chest radiography cannot provide a conclusive diagnosis on its own (if abnormal) and should be followed by microbiological tests for TB (sputum testing for AFB and culture).

The interpretation of chest x-rays is highly variable between readers. About 10 per cent of persons with HIV infection and active TB disease will have a normal chest x-ray. Typical Chest X-Ray findings in immunocompetent adults:

  1. Position: infiltrates in the apical-posterior segments of upper lobes or superior segments of lower lobes in 90 per cent
  2. Volume Loss: hallmark of TB disease as a result of destructive and fibrotic nature
  3. Cavitation: seen at later stage of disease and depends upon immune response, not often seen in immunocompromised individuals

Note: Non-cavity infiltrates and lower lobe involvement may be seen in the immunocompromised, such as patients with diabetes, renal failure, HIV infection, or on corticosteroids.

Source: (Canadian Tuberculosis Standards, 7th ed., 2014, Chapter 4, p.3) 

Sputum Collection 
  • At least three sputa specimens should be collected using standard orange top urine specimen container
  • Collect 5-10 mL of sputum from deep cough (not saliva) using following:
    • three consecutive morning samples
    • three samples collected same day, at least one hour apart (must write time on bottle if collected on same day)
  • Specimens should be delivered to the laboratory within one hour of collection. If transportation of specimens is delayed, specimens should be refrigerated at 4°C and protected from light.
  • Submit samples using the Public Health Ontario General Test Requisition. Indicate AFB smear and Culture for Mycobacterium Tuberculosis

Source: (Canadian Tuberculosis Standards, 7th ed., 2014, Chapter 4, p.6)

Public Health Laboratory – Timelines and Results 
  • Smear for Acid Fast Bacilli (AFB) - result is generally available within 24 hours
  • PCR Testing for M.TB.Complex - done Monday, Wednesday, and Friday with results phoned on the same day (test is done on all new smear positive results)
  • Culture for M.Tuberculosis - results may be available anywhere from 4 days - 7 weeks
  • Susceptibility Drug Testing - results available 4 - 7 days after organism has grown in culture 

Management and Treatment Recommendations

Recommendations for Treatment of Latent Tuberculosis Infection (LTBI) 

Treatment for LTBI should be considered for those with a positive TB skin test to reduce an individual’s risk of developing active TB disease.

  • TB risk factors: See http://www.tstin3d.com to determine a person’s lifetime risk of developing active TB and the risk of adverse events from therapy with INH. A 5 per cent lifetime risk is a reasonable cut-off for consideration of LTBI treatment. The decision to treat LTBI should be made on a case-by-case basis, taking into consideration the risks of therapy from adverse events (e.g. hepatotoxicity as related to age >50 years or comorbidities), balanced against the risk of development of active TB (risk factors as outlined below). (Canadian TB Standards 7th ed., chapter 6 and chapter 13, 2014). For individual country TB incidence rates see the World Health Organization website.
  • It is essential that active TB has been ruled out prior to initiating LTBI treatment.
  • Age ≥35 years is not a contraindication to treatment of LTBI if the risk of progression to active TB disease is greater than the risk of serious adverse reactions to treatment.
  • For immunosuppressed individuals LTBI treatment should be considered in consultation with a TB expert (a Respirologist or Infectious Diseases Physician).

For assistance with assessment of risk, please see http://www.tstin3d.com 

Tuberculin Skin Test Cut-points for Treatment of LTBI

Dimensions Explanation
0-4 mm
  • In general this is considered negative and no treatment is indicated
  • Close contacts in children less than five years of age should be treated pending results of repeat skin test eight weeks after exposure
≥5 mm
  • HIV Infection
  • Contact with infectious TB within the past two years
  • Fibronodular disease on Chest X-ray
  • Organ transplantation (related to immune suppressant therapy)
  • TNF alpha inhibitors
  • Other immunosuppressive drugs, e.g. corticosteroids (equivalent of ≥ 15 mg/day of prednisone for one month)
  • End-stage renal disease
≥10 mm
  • TST conversion (within two years)
  • Diabetes, malnutrition (less than 90 per cent ideal body weight) cigarette smoking, daily alcohol consumption (more than three drinks a day)
  • Silicosis
  • Hematologic malignancies (e.g. leukemia, lymphoma) and certain carcinomas (e.g. head and neck)

Source: (Canadian Tuberculosis Standards, 7th ed., 2014, p.131) 

Latent TB Treatment Options
Drug Interval and Duration Dosage Criteria for Completion Comments
Isoniazid (INH) Daily for nine months

Adults: 5 mg/kg (Max 300 mg/day)

 

Children: 10-15 g/kg (Max 300 mg/day)

Minimum 270 doses within 9-12 months
  • Provides optimal protection
  • See effectiveness of INH
Vitamin B6

(Pyridoxine)

Daily with INH 25 mg daily Taken with INH
  • B6 indicated in HIV infection, poor nutrition, alcoholism, diabetes, uremia, neonatal period
  • May be prescribed routinely to reduce neuropathy
Rifampin (RMP) Daily for four months

Adults:10 mg/kg

(Max 600 mg/day)

Minimum 120 doses within 4-6 months

Alternate regiment for persons:

  • Who cannot tolerate INH
  • Who are contacts of INH-resistant TB
  • When INH for 9 months is not feasible

**Given the consequences of Rifampin resistance, active TB must be ruled out if Rifampin is used (i.e. assessment, CXR, sputum testing)

For treatment of LTBI in HIV positive persons refer to a Respirologist.

CDC Core Curriculum on TB, What the Clinician Should Know, 2000, p. 112, 113 (Canadian Tuberculosis Standards, 7th ed., 2014, p. 133-137)

Effectiveness of LTBI Treatment 
Effectiveness of INH Recommendations
INH, when taken for nine months, is up to 90% effective (assuming sensitive to INH and ≥ 80% compliance)

Consultation or referral to a Respirologist/TB Specialist is recommended for the following persons:

  • Abnormal CXR
  • HIV positive
  • Contacts of multidrug-resistant TB children
  • Pregnant women at high risk of TB
  • When daily therapy is not feasible, intermittent therapy is needed

Canadian Tuberculosis Standards, 7th ed., 2014, p. 133-137

 

Effectiveness of Rifampin Recommendations

Efficacy of four months of Rifampin was unknown at the time of Publication of the Canadian Tuberculosis Standards, 7th Edition

Recent study by expert group, showed that four months of Rifampin has similar efficacy of nine months of INH

Check the Study here

Consultation or referral to a Respirologist/TB Specialist is recommended for the following persons:

  • Abnormal CXR
  • HIV positive
  • Contacts of multidrug-resistant TB children
  • Pregnant women at high risk of TB
  • When daily therapy is not feasible, intermittent therapy is needed

Canadian Tuberculosis Standards, 7th ed., 2014, p. 133-137

Treatment Monitoring and Potential Adverse Reactions of LTBI Treatment

Isoniazid (INH) 

Adverse Reactions Monitoring Comments
 
  • Rash
  • Hepatic enzyme elevation
  • Hepatitis
  • Peripheral neuropathy
  • Mild CNS effects
  • Drug interactions resulting in increased levels of:
    • phenytoin (Dilantin)
    • carbamazepine (Tegretol)
    • disulfiram (Antabuse)
  • Baseline levels prior to treatment (AST, ALT, ALP, and total bilirubin)
  • Clinical monitoring generally monthly (or more/less frequent if indicated)
  • Regular ALT, AST for patients with
    • pre-existing liver disease
    • age ≥ 35
    • history of alcohol abuse
  • If ALT/AST level > 5 times upper normal level (or three times if symptomatic), then INH should be stopped and a TB specialist consulted
  • Repeat monitoring of liver enzymes for patients with symptoms consistent with hepatic side effects
 
  • Hepatitis risk correlated with age
    • Under 20 (rare)
    • 20 to 34 (risk 0.2%)
    • 35 to 49 (risk 1.5%)
    • Over 50 (risk 2.4%)
  • Hepatitis risk increases with daily alcohol consumption or viral hepatitis
  • INH induced hepatitis is almost always reversible when INH is discontinued
  • INH given alone to persons with active TB disease can lead to INH resistant TB

Rifampin (RMP)

Adverse Reactions Monitoring Comments
 
  • G.I. upset

  • Drug interactions

  • Hepatitis

  • Thrombocytopenia

  • Flu-like symptoms

  • Rash

  • Renal failure

  • Fever

Baseline CBC, platelets, and liver enzymes

Repeat measurements if:

  • Baseline results are abnormal
  • Patient has symptoms of an adverse reaction
  • Body fluid is orange
  • May permanently discolour contact lens
  • May increase clearance of drugs metabolized by the liver – estrogen, coumadin, methadone, glucocorticoids, sulfonylureas
  • By accelerating estrogen metabolism, RMP may interfere with effectiveness of birth control pills; alternative contraceptive method should be advised
  • Contraindicated in severe chronic liver disease
  • Contraindicated or used with precaution when administered with protease inhibitors, non-nucleoside reverse transcriptase inhibitors

CDC Core Curriculum on Tuberculosis, 2000, p. 120, 121 | Canadian Tuberculosis Standards, 7th ed., 2014, p. 115-116

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