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LATENT TB: FAQ's
David J. Roesel MD MPH
November/December, 2006

Table of Contents

What is latent tuberculosis?

“Latent tuberculosis” is the term used for people who test positive for tuberculosis (most commonly with a positive tuberculin skin test), but do not have any evidence of active infection. Currently one in three people worldwide are felt to harbor tuberculosis bacilli.

Tuberculosis is transmitted through airborne spread of Mycobacterium tuberculosis. When a person with active pulmonary TB coughs, aerosolized droplets containing bacilli can invade the lungs of close contacts. In 90-95% of cases, the infected person's immune system halts growth of the bacteria and active disease does not develop, although skin or serological testing for TB will convert to positive. Once positive, a person's TB test will generally remain positive for life.

Approximately one in ten latent infections will later progress to active disease unless treatment is given. Most cases of active tuberculosis result from reactivation of latent TB.

Who should be screened for latent TB?
Persons at high risk for developing TB disease should be tested for latent TB. This includes:

• Close contacts of a person with infectious TB.
• Immigrants from countries with high rates of TB.
• People who live or work in places where TB is more common, such as homeless shelters, migrant labor camps, prisons, jails, hospitals, and some nursing homes.
• Medically underserved and low-income populations.
• Children exposed to high-risk adults.
• People with chest radiographs showing healed TB.
• Patients with HIV, silicosis, malnutrition, renal failure, or other conditions placing them at higher risk for active TB.
• Patients on chronic immunosuppressive drugs.
• Injection drug users.

The CDC discourages testing of people at low risk for infection.

Which people with latent TB are at highest risk of developing active disease?

Overall, 5-10 percent of all people with latent tuberculosis will go on to develop active disease. The risk of reactivation is greatest in those with recent TB infection and in people with conditions which weaken the immune system. The following groups are considered to be at high risk:

• Recent skin test converters (within the past 2 years)
• Young children. (Infants have a 40% chance of progressing to active disease, and children are more likely to develop life-threatening forms of TB).
• Immigrants from countries with high rates of TB (within the first 5 years after immigration)
• People with the following clinical conditions:
• HIV/AIDS (10% annual risk of developing active TB)
• Diabetes mellitus
• Underweight (more than 10% below normal)
• Chronic kidney disease, esp. hemodialysis patients
• Gastrectomy or jejunoilial bypass
• Silicosis
• Head and neck cancer
• Solid organ transplant recipients
• Prolonged use of immunosuppressive drugs (prednisone 15 mg/day > 1 month, TNF-alpha antagonists)
• Leukemia or lymphoma
• Chest X-rays with evidence of prior TB
• Injection drug users

Which countries have high rates of TB?

Global TB Incidence

Cases per 100,000

Ninety-five percent of all tuberculosis cases in the world occur in developing countries. Tuberculosis is prevalent in Russia, India, Southeast Asia, sub-Saharan Africa, and parts of Latin America. Countries with a high prevalence of HIV infection have the greatest tuberculosis burden.

The following ten countries of origin account for the largest number of TB cases among immigrants:
Mexico, Philippines, Vietnam, India, China, Haiti, South Korea, Guatemala, Ethiopia, and Peru .

(Number of cases per 100,000 population)

What is the risk of tuberculosis among immigrants?

In the US, over half of all active TB cases occur in immigrants. The reported cases of active TB in foreign-born persons has remained at 7000-8000 per year, while the number of cases in US-born people has dropped from 17,000 in 1993 to 6,500 in 2005. As a result, the percentage of active TB cases in immigrants has increased steadily (from 29% of all cases in 1993 to 54% in 2005).

Cases of TB in US-born vs. Foreign-born persons:

The risk of latent disease progressing to active tuberculosis is highest in the first few years after immigration, which is why newly-arrived immigrants (within five years) are a priority for testing and treatment. However, half of all TB reactivations in immigrants occur after their first five years in the US, so testing this group should be encouraged as well.

TB Cases in Foreign-born Persons, by Duration of US residence (2005)

How do you place a TB skin test?

The Mantoux tuberculin skin test is the standard method of screening for infection with Mycobacterium tuberculosis. It is performed by placing a subcutaneous injection of 0.1 ml tuberculin purified protein derivative (PPD) into the inner surface of the forearm. The test is read 48-72 hours later by measuring in millimeters the degree of induration (not erythema) perpendicular to the long axis of the forearm. Use of controls to test for anergy is not recommended.

How is a TB skin test interpreted?

A positive test indicates TB infection, but cannot distinguish between latent and active disease. The cut-off point for a positive reaction depends on the person's overall risk:

1 . Prednisone = 15 mg/day for one month or more; TNF-alpha antagonists (Infliximab, Etanercept).
2. Hospitals, nursing homes, homeless shelters, correctional facilities.
3. Diabetes, silicosis, chronic kidney disease, leukemias and lymphomas, lung cancer, carcinomas of the head and neck, gastrectomy, jejunoileal bypass, underweight by = 10% ideal body weight.

• A skin test conversion is any increase in induration of 10 mm or more.
  
• Known contacts of an active case of tuberculosis should be tested at the time of contact, and then re-tested in 8-10 weeks if the initial test is negative.
  
• Pregnancy is not a contraindication to tuberculin skin testing.
  
• False-negative tests can occur in the setting of malnutrition, HIV infection, sarcoidosis, concurrent viral infection, and use of immunosuppressive medications. However, there is no proven benefit to anergy testing (use of controls) in immunosuppressed people, and it is not recommended.
  
• Recent administration of a live vaccine can also cause a false-negative skin test. To prevent this, the PPD should either be placed the same day as a live vaccine or at least 4 weeks afterwards.
  
• It takes 2-8 weeks after infection for the skin test to become positive after a person is infected.
  
• False-positive tests can be caused by nontuberculous mycobacteria, and recent BCG vaccination (see separate discussion).

What is two-step testing?

If it has been many years since a person was infected with TB, his or her initial skin test may be negative, because of waning immunity. Subsequent tests may be positive, however, because the initial tuberculin placement stimulates the immune response to the test. This phenomenon is referred to as the “booster effect.” The booster effect can be misinterpreted as a new skin test conversion (i.e. a recent TB infection). To avoid this problem, two-step testing should be used as the initial test in people where repeat testing is anticipated (such as hospital workers or nursing home residents).

To perform two-step testing, a second skin test is placed 1-3 weeks after the initial skin test, if the first test is negative. If the second test remains negative, the person is presumed to be negative for latent tuberculosis, and any subsequent positive tests are the result of new infection. If the second test turns positive, this is a boosted response from prior TB infection. The person should be treated for latent TB if indicated (see separate discussion).

Two-step testing may also be performed to better identify latent TB in older immigrants, who may be decades out from their initial infection and have falsely negative initial tests. One problem with this approach is that two-step testing increases the rate of false-positive results due to BCG vaccination.

There is no booster effect with the QuantiFERON® -TB Gold test, so there is no need for two-step testing if this screening method is used.

What about BCG vaccination?

BCG (Bacille Calmette-Guérin) is a vaccine made from an attenuated strain of Mycobacterium bovis. It provides protection against TB meningitis in children as well as some protection against leprosy, but its ability to protect against pulmonary TB is questionable. The use of BCG is widespread in developing countries (see map).

Prior vaccination with BCG is not a contraindication to TB skin testing, and the CDC guidelines recommend ignoring BCG status when interpreting skin test results and selecting candidates for latent TB treatment. Although BCG vaccination can turn a skin test positive, reactivity due to BCG vaccination wanes over time. If it has been more than 5 years since vaccination, a positive skin test is more likely due to TB infection than vaccination. Furthermore, the larger the size of the PPD reaction, the less likely it is due to BCG. A recent meta-analysis found that reactive skin tests more than 15 years since vaccination or with more than 15 mm of induration were unlikely to be due to prior BCG vaccination.

Interferon-based blood tests such as the QuantiFERON® -TB Gold avoid the possibility of false-positives occurring from BCG vaccination, since cross-reactivity does not occur.

How do you test for TB with QuantiFERON®-TB Gold?

The QuantiFERON®-TB Gold test (Celestis Inc, Australia) was approved by the FDA in 2005 as a means of diagnosing tuberculosis. The CDC considers the test to be an acceptable alternative to skin testing.

The test is performed by incubating the patient's blood for 16-24 hours with synthetic peptides representing two M. tuberculosis- specific antigens. In the presence of latent or active TB infection, these antigens will stimulate interferon-gamma release from the patient's white blood cells, which is then measured by ELISA. The test must be performed within 12 hours of the blood draw, and results are reported as positive, negative, or indeterminate

Advantages: The patient does not need to return for a reading. Results are available within 24 hours. There is no booster phenomenon. There is no reader bias (as can affect skin test interpretation). The result is not affected by prior BCG vaccination. Disadvantages: Limited availability. More costly. Uncertain interpretation of indeterminate tests. Limited data in children and in HIV infection. Blood must be tested within 12 hours of being drawn.

T-SPOT. TB (Oxford Immunotec, UK) is another interferon-based blood test for the detection of tuberculosis. It is currently being evaluated by the FDA.

What sort of TB screening is done prior to immigration?

Persons wishing to immigrate to the United States undergo mandatory screening for pulmonary tuberculosis prior to receiving a visa. This generally consists of a chest radiograph, with sputum microscopy for acid-fast bacilli if abnormal. The Institute of Medicine has recommended that all prospective immigrants also undergo tuberculin skin testing, and receive treatment for latent TB if they test positive, but this is not yet current practice. There are no health screening requirements for non-immigrant visas (temporary visas issued for purposes of work, study, or tourism).

Why treat latent TB?

Completing a course of treatment decreases the person's lifetime risk of developing active TB by 90%. Treatment of latent TB is also a cornerstone of efforts to eliminate TB in society, since it minimizes the number of infectious cases.

Who should be treated for latent TB?

• In general, anyone with a positive TB test who is at high risk of reactivation should be treated, regardless of age. (See above list of high-risk groups).
  
• Although the 2000 CDC guidelines seem to suggest that foreign-born persons not be treated if they have been living in the United States more than 5 years, a recent study found that 25% of all cases of active TB in the US occur in this population. Treating all foreign-born people with latent TB should be strongly considered, regardless of whenthey immigrated.
  
• Children who are close contacts to a case of infectious tuberculosis should be started empirically on treatment for latent TB. A baseline tuberculin skin test should be placed at the time of initiation of treatment, and repeated 10-12 weeks after the exposure. If the second test is negative and the child is over 6 months old, treatment can then be discontinued. A similar approach is recommended for HIV-infected patients.
  
• Prior to treatment, active disease must be ruled out by means of a thorough history, physical examination, and chest radiograph. Sputum examination for acid fast bacilli is indicated if there is an abnormal chest radiograph or respiratory symptoms. Unexplained fevers, chills, night sweats, fatigue, or weight loss should prompt a search for extra-pulmonary TB if the chest radiograph is normal.

How is latent TB treated?

PREFERRED REGIMEN
              
Isoniazid 300 mg daily x 9 months

• Nine months of isoniazid (INH) is the preferred treatment regimen for all cases of latent TB, including HIV patients, pregnant women, and children. A minimum of 270 doses must be administered within 12 months.
  
• In pregnancy, it is preferable to wait until the post-partum period to administer INH, unless the mother has HIV or a recent contact with active TB. Breastfeeding is not a contraindication to isoniazid.
  
• Supplementation with 10-50 mg/day of Pyridoxine (vitamin B6), is recommended for use in the following instances:
  • During pregnancy, lactation, and the post-partum period.
  • In people with seizures.
  • In conditions with increased risk of peripheral neuropathy: diabetes, HIV, alcoholism, renal failure, and malnutrition

ALTERNATIVE REGIMENS
          
Isoniazid 900 mg twice weekly x 9 months
              (directly-observed therapy)
Isoniazid 300 mg daily x 6 months
Isoniazid 900 mg twice weekly x 6 months
              (directly-observed therapy)
Rifampin 600 mg daily x 4 months

• Six months of isoniazid is a more cost-effective regimen for latent TB, although nine months provides better protection from active disease (90% vs. 70% risk-reduction).
• Directly-observed isoniazid therapy should be considered for persons at high risk who are suspected of nonadherence.
• Courses of INH shorter than nine months do not provide adequate treatment in patients with HIV infection, and should not be used.
• Rifampin is an acceptable alternative for those patients who cannot tolerate isoniazid. It cannot be used in patients taking protease inhibitors or non-nucleotide reverse transcriptase inhibitors. (Rifabutin 300 mg/day may be substituted). Rifampin causes orange coloration of tears, urine, and sweat, and may discolor contact lenses. It also causes increased sun sensitivity.

NOT RECOMMENDED
      
Rifamin plus pyrazinamide x 2 months

•  This regimen has been associated with an increased risk of severe hepatic injury and death, and should generally not be used.

Pediatric doses:

• Isoniazid 10-15 mg/kg/day for 9 months
• Isoniazid 20-40 mg/kg twice weekly for 9 months
• Rifampin 10-20 mg/kg/day for 6 months

What sort of monitoring is needed during treatment?

• The CDC recommends monthly clinic visits during treatment to assess adherence and identify signs or symptoms of adverse drug reactions. Treatment should be held if the patient develops anorexia, nausea, vomiting, abdominal pain, dark urine, jaundice, rash, persistent fatigue, easy bruisability, or paresthesias of the hands and feet. Patients should be advised to refrain from alcohol ingestion during treatment.
• Hepatitis is the most important adverse effect of latent TB treatment. It usually occurs within the first three months of treatment, and people with advanced age or daily alcohol consumption are at greatest risk. Overall incidence of hepatotoxicity is 0.1% with isoniazid and 0.6% with rifampin.
• Peripheral neuropathy is another known adverse effect of isoniazid. The incidence is under 0.2%, and those at highest risk are pregnant and breastfeeding women, diabetics, alcoholics, HIV patients, and patients with uremia. Pyridoxine supplementation should be provided to these high-risk groups.
• Cutaneous reactions occur in up to 6% of people taking rifampin. They are generally self-limited. Thrombocytopenia is a rare complication of rifampin therapy.
• Baseline laboratory testing and periodic laboratory monitoring are not routinely indicated during treatment of latent TB. Exceptions are the following:
• Patients with chronic liver disease (including active hepatitis B or C)
• Heavy drinkers of alcohol
• HIV infected patients
• Pregnant women
• Post-partum women for the first three months after delivery
  These persons should ALT, AST, and bilirubin measured before and during the course of treatment.
• If hepatic transaminases exceed 3 times the upper limit of normal in asymptomatic patients, or 5 times the upper limit of normal in patients with symptoms, treatment should be withheld.

Important drug-drug interactions:

Isoniazid increases the levels of:

• Phenytoin
• Carbamazepine
• Warfarin
• Benzodiazepines

Aluminum-containing antacids reduce the absorption of isoniazid.

Rifampin is a potent inducer of hepatic microsomal enzymes, and decreases the levels of several medications, including:

• Warfarin
• Oral contraceptives
• Anticonvulsants
• Sulfonylureas
• Digoxin
• Opiates
• Cyclosporine
• Ketoconazole
• Dapsone

What about HIV co-infection?

HIV infection is the greatest known risk factor for the progression of latent M. tuberculosis infection to active TB. In many African countries, 30-60% of all new TB cases occur in people with HIV, and TB is the leading cause of death globally for HIV-infected people. HIV infection is associated with a much higher risk of reactivation of latent TB, and a more rapid progression of disease. Whereas in HIV-negative people a positive TB skin test carries a 5-10% lifetime risk of reactivation, in HIV-positive people reactivation occurs at a rate of 5-7% per year.

The tuberculin skin test may provide false-negative results in HIV patients due to impaired cellular immunity. However, testing for cutaneous anergy by placing intradermal controls (such as Candida antigen) has not been shown to be of benefit, and is not recommended. The performance of TNF-based assays such as QuantiFERON® -TB Gold not yet been established.

How would you treat contacts of people with multi-drug resistant TB?

Standard latent TB treatment regimens are unlikely to be effective in high-risk contacts of people with MDR-TB. Treatment should be guided by susceptibility testing of the index case, and expert consultation should be sought.

References and links

ATS/CDC. Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection. Am J Resp Crit Care Med. April 4, 2000. 161 (4):S221-S247. http://ajrccm.atsjournals.org/cgi/content/full/161/4/S1/S221

ATS/CDC. Update: Fatal and Severe Liver Injuries Associated With Rifampin and Pyrazinamide for Latent Tuberculosis Infection, and Revisions in American Thoracic Society/ CDC Recommendations--United States, 200. Am. J. Respir. Crit. Care Med . Oct 7, 2001. 164 (7) 1319-1320. http://ajrccm.atsjournals.org/cgi/content/full/164/7/1319

Cain K et al. Tuberculosis Among Foreign-born Persons in the United States: Achieving Tuberculosis Elimination. Am J Resp Crit Care Med; Oct 12, 2006 [Epub ahead of print] http://ajrccm.atsjournals.org/cgi/content/abstract/200608-1178OCv1

CDC. Guide for Primary Health Care Providers: Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection 2005. http://www.cdc.gov/nchstp/tb/pubs//LTBI/default.htm

CDC. TB Elimination: QuantiFERON ® -TB Gold Test. March, 2006. http://www.cdc.gov/nchstp/tb/pubs/tbfactsheets/250103.htm

CDC. TB Elimination: Tuberculin Skin Testing. April 2006. http://www.cdc.gov/nchstp/tb/pubs/tbfactsheets/250140.htm

CDC. Treatment of Latent Tuberculosis Infection (LTBI). 2006. http://www.cdc.gov/nchstp/tb/pubs/tbfactsheets/250110.htm

CDC, Tubeculosis and Pregnancy. 2005. http://www.cdc.gov/nchstp/tb/pubs/tbfactsheets/250160.htm

CDC. Tuberculosis in the United States. National Tuberculosis Sur veillance System Highlights from 2005. http://www.cdc.gov/nchstp/tb/pubs/slidesets/surv/surv2005/default.htm

CDC. Questions and Answers About TB, 2005. http://www.cdc.gov/nchstp/tb/faqs/qa.htm

Marurek GH et al. Guidelines for Using the QuantiFERON ® -TB Gold Test for Detecting Mycobacterium tuberculosis Infection, United States . MMWR . Dec. 16, 2005. 54(RR15); 49-55 . http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5415a4.htm

Richeldi L. An Update on the Diagnosis of Tuberculosis Infection. Am J Respir Crit Care Med . 2006; 174:736-742