# Presentation: 290211

## Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection, 2005

**Applying CDC/ATS Guidelines in Your Clinical Practice**

**Division of Tuberculosis Elimination**
**Centers for Disease Control and Prevention**

**Notes:**
Introduction 
The Centers for Disease Control and Prevention (CDC) and American Thoracic Society (ATS) issued revised guidelines for targeted tuberculin testing and the treatment of latent tuberculosis infection (LTBI). The guidelines were published in the June 9, 2000 issue of the Morbidity and Mortality Weekly Report (MMWR) and in the American Journal of Respiratory and Critical Care Medicine (2000;161:S221–S247). In addition to changes in treatment and monitoring recommendations, an emphasis was placed on testing only those who may have recently been infected with tuberculosis (TB) and those at risk for progression from latent infection to active disease. This slide set includes the recommendations in the 2000 guidelines and updates to the recommendations published before November 2004.

Key areas covered in this slide set include: 
• Brief history of LTBI treatment
• Concept of targeted testing
• Risk factors for LTBI
• Tuberculin skin testing and QuantiFERON®-TB Test 
• Treatment recommendations for LTBI
• Case studies

Target audience:
The target audience for this slide set is the primary healthcare provider. Supporting references and resources have been included in the slide set.

Adapting the presentation:
The slide can be used in its entirety or in sections depending on audience needs. If the slides are altered, the CDC and HHS logos must be removed.

Use of case studies:
The slide set contains three case studies to reinforce the importance of targeted testing and the identification individuals at risk for LTBI. The case study slides may be incorporated at the presenter’s discretion. The question and answer slides following the case slides can be used to encourage group participation and discussion. Alternatively, the presenter can present the cases and highlight the main educational points without group discussion. 

## Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection

- As tuberculosis (TB) disease rates in the United States (U.S.) decrease, finding and treating persons at high risk for latent TB infection (LTBI) has become a priority.

## Latent TB Infection (LTBI)

- 	LTBI is the presence of *M. tuberculosis* organisms (tubercle bacilli) without symptoms or radiographic evidence of TB disease.

## Terminology

- “Treatment of latent TB infection” replaces the terms “preventive therapy” and “chemoprophylaxis*”* to promote greater understanding of the concept for both patients and providers.
- Targeted tuberculin testing is used to focus program activities and provider practices on groups at the highest risk for TB.

## LTBI vs. Pulmonary TB Disease

_**Latent TB Infection**_
- TST* or QFT† positive
- Negative chest radiograph
- No symptoms or physical findings suggestive of TB disease

_**Pulmonary TB Disease**_
- TST or QFT usually positive
- Chest radiograph may be abnormal
- Symptoms *may* include one or more of the following: fever, cough, night sweats, weight loss, fatigue, hemoptysis, decreased appetite
- Respiratory specimens *may* be smear or culture positive

- *tuberculin skin test
- †QFT (QuantiFERON-TB and QuantiFERON-Gold) is a blood test to detect *M. tuberculosis* infection.

## Targeted Tuberculin Testing

- Detects persons with LTBI who would benefit from treatment
- De-emphasizes testing of groups that are not at high risk for TB
- Can help reduce the waste of resources and prevent inappropriate treatment

## Treatment of LTBI – Milestones (1)

- For more than 3 decades, an essential component of TB prevention and control in the U.S. has been the treatment of persons with LTBI to prevent TB disease.

## Treatment of LTBI – Milestones (2)

- 1965: 	American Thoracic Society (ATS) recommends treatment of LTBI for those with previously untreated TB, tuberculin skin test (TST) converters, and young children.
- 1967: 	Recommendations expanded to include all TST positive reactors    (10 mm).

## Treatment of LTBI – Milestones (3)

- 1974:	CDC and ATS guidelines established for pretreatment screening to decrease risk of hepatitis associated with treatment
- Treatment recommended for persons ≤ 35 years of age

## Treatment of LTBI – Milestones (4)

- 1983:	CDC recommends clinical and laboratory monitoring of persons  35 who require treatment for LTBI
- 1998: 	CDC recommends 2 months of rifampin (RIF) plus pyrazinamide (PZA) as an option for HIV-infected patients (later changed)

## Treatment of LTBI – Milestones (5)

- 2000:	CDC and ATS issue updated guidelines for targeted testing and LTBI treatment1
- 9-month regimen of isoniazid (INH) is preferred
- 2-month regimen of RIF and PZA and a 4-month regimen of RIF recommended as options (later changed)
- 1 *MMWR* June 9, 2000; 49(No. RR-6)

## Treatment of LTBI – Milestones (6)

- 2001:	Owing to liver injury and death associated with 2-month regimen of RIF and PZA, use of this option de-emphasized in favor of other regimens2
- 2003:	2-month regimen of RIZ and PZA generally not recommended — to be used only if the potential benefits outweigh the risk of severe liver injury and death3
- 	 ____________________________________________________
- 	2   *MMWR *August 31, 2001; 50(34): 733-735
- 	3  * MMWR *August 8, 2003; 52(31): 735-739

## What’s New (1)

- Tuberculin skin testing
- Emphasis on targeting persons at high risk
- 5-mm induration cutoff level for organ transplant recipients and other immunosuppressed patients being treated with prednisone or TNF-α antagonists4
- Skin-test conversion defined as increase of            10 mm of induration within a 2-year period, regardless of age
- ____________________________________________________
- 4   *MMWR *August 61, 2004; 53(33): 683-686

## What’s New (2)

- Treatment of LTBI
- HIV-negative persons – INH for 9 months preferred regimen
- HIV-positive persons and those with fibrotic lesions on chest x-ray (consistent with previous TB) – INH should be given for 9 months
- For all persons – RIF for 4 months is an option

## What’s New (3)

- Clinical and laboratory monitoring
- Routine baseline and follow-up monitoring not required except for
- HIV-infected persons
- Pregnant women or those in early postpartum period
- Persons with chronic liver disease or who use alcohol regularly
- Monthly monitoring for signs or symptoms of   possible adverse effects

## Identifying Risk FactorsThat Lead to Development of TB Disease

## Persons at Risk for DevelopingTB Disease

- Those who have been recently infected
- Those with clinical conditions that increase their risk of progressing from LTBI to TB disease

- Persons at high risk for developing TB disease fall into 2 categories

## Recent Infection as a Risk Factor (1)

- Close contacts to person with infectious TB
- Skin test converters (within past 2 years)
- Recent immigrants from TB-endemic regions of the world (within 5 years of arrival to the U.S.)

- Persons more likely to have been recently infected include

## Recent Infection as a Risk Factor (2)

- Children  5 years with a positive TST
- Residents and employees of high-risk congregate settings (e.g., correctional facilities, homeless shelters, health care facilities)

##  Increased Risk for Progression toTB Disease (1)

- HIV-infected persons
- Those with a history of prior, untreated TB or fibrotic lesions on chest radiograph

- Persons more likely to progress from LTBI to TB disease include

##  Increased Risk for Progression toTB Disease (2)

- Underweight or malnourished persons
- Injection drug users
- Those receiving TNF-α antagonists for treatment of rheumatoid arthritis or Crohn’s disease

##  Increased Risk for Progression toTB Disease (3)

- Persons with certain medical conditions such as
- Silicosis
- Diabetes mellitus
- Chronic renal failure or on hemodialysis
- Solid organ transplantation (e.g., heart, kidney)
- Carcinoma of head or neck
- Gastrectomy or jejunoilial bypass

**Notes:**

Relative risk of developing active TB for persons with certain clinical conditions:
Silicosis						30 times greater
Diabetes						2-4 times greater
Chronic renal failure/hemodialysis		10-25 times greater
Gastrectomy						 2-5 times greater
Jejunoileal bypass					 27-63 times greater
Kidney transplant					 37 times greater
Heart transplant					 20-74 times greater
Cancer of head/neck				 16 times greater

## Tuberculin Testing

##  Testing for M. tuberculosis Infection

- Mantoux tuberculin skin test (TST)
- Skin test that produces delayed-type hypersensitivity reaction in persons with *M. tuberculosis* infection
- QuantiFERON® -TB test and QuantiFERON® - Gold
- Blood test that measures and compares amount of interferon-gamma (IFN-) released by blood cells in response to antigens

## Mantoux Tuberculin Skin Test

- Preferred method of skin testing for *M. tuberculosis* infection
- TST is useful for
- Determining how many people in a group are infected (e.g., contact investigation)
- Examining persons who have symptoms of TB
- Multiple puncture tests (e.g., Tine Test) are inaccurate and not recommended

## Administering the TST

- Inject 0.1 ml of 5 TU PPD tuberculin solution intradermally on volar surface of lower arm using a 27-gauge needle
- Produce a wheal 6 to 10 mm in diameter

## Reading the TST (1)

- Measure reaction in 48 to 72 hours
- Measure induration, not erythema
- Record reaction in millimeters, not “negative” or “positive”
- Ensure trained health care professional measures and interprets the TST

## Reading the TST (2)

- Educate patient and family regarding significance of a positive TST result
- Positive TST reactions can be measured accurately for up to 7 days
- Negative reactions can be read accurately for only 72 hours

## TST Interpretation (1)

**5-mm induration is interpreted as positive in**
- HIV-infected persons
- Close contacts to an infectious TB case
- Persons with chest radiographs consistent with prior untreated TB

## TST Interpretation (2)

**5-mm induration is interpreted as positive in (cont.)**
- Organ transplant recipients
- Other immunosuppressed patients (e.g., those taking the equivalent of >15 mg/d of prednisone for 1 month or those taking TNF-α antagonists)

##  TST Interpretation (3)

**10-mm induration is interpreted as positive in**
- Recent immigrants
- Injection drug users
- Residents or employees of congregate settings
- Mycobacteriology laboratory personnel

##  TST Interpretation (4)

**10-mm induration is interpreted as positive in (cont.)**
- Persons with clinical conditions that place them at high risk
- Children < 4 years; infants, children, and adolescents exposed to adults at high-risk

## TST Interpretation (5)

- Persons with no known risk factors for TB.*

- *Although skin testing programs should be conducted only among high-risk groups, certain individuals may require TST for employment or school attendance. Diagnosis and treatment of LTBI should always be tied to risk assessment.

**15-mm induration is interpreted as positive in**

- ____________________________________________________

## Factors That May Cause False-Positive TST Reactions

- Nontuberculous mycobacteria
- Reactions caused by nontuberculous  mycobacteria are usually  10 mm of induration
- BCG vaccination
- Reactivity in BCG vaccine recipients generally wanes over time; positive TST result is likely due to TB infection if risk factors are present

## Factors That May Cause False-Negative TST Reactions (1) 

- Anergy
- Inability to react to a TST because of a weakened immune system
- Usefulness of anergy testing in TST-negative persons who are HIV infected has not been demonstrated

## Factors That May Cause False-Negative TST Reactions (2) 

- Recent TB infection
- Defined as 2 to 10 weeks after exposure
- Very young age
- Newborns

## Factors That May Cause False-Negative TST Reactions (3)

- Live-virus vaccination
- For example, measles or smallpox
- Can temporarily suppress TST reactivity
- Overwhelming TB disease
- Poor TST administration technique
- For example, TST injection too shallow or too deep, or wheal is too small

## Boosting

- Some people with LTBI may have a negative skin test reaction when tested years after infection because of a waning response.
- An initial skin test may stimulate (boost) the ability to react to tuberculin.
- Positive reactions to subsequent tests may be misinterpreted as new infections rather than “boosted” reactions.

## Two-Step Testing (1) 

- A strategy to determine the difference between boosted reactions and reactions due to recent infection.
- If first TST is positive, consider the person infected
- If first TST is negative, give second TST 1–3 weeks later
- If second TST is positive, consider the person infected
- If second TST is negative, consider the person uninfected at baseline

## Two-Step Testing (2)

- Use two-step tests for initial baseline skin testing of adults who will be retested periodically (e.g., health care workers).

## QuantiFERON®-TB Test and QuantiFERON®-Gold Test (1) 

- Whole-blood test used to detect *M. tuberculosis* infection
- Approved by the U.S. Food and Drug Administration (FDA)
- Entails mixing blood samples with antigens from *M. tuberculosis, M. avium complex*, and controls and incubating for 16 to 24 hours

## QuantiFERON®-TB Test and QuantiFERON®-Gold Test (2) 

- Cells that recognize the antigen release  interferon-
- Amount of interferon released in response to tuberculin is compared to amount released in response to other antigens5

* *5*MMWR January 31*,2003; 52 (RR-02): 15-18 and CDC Fact Sheet Document # 250103, March 2003

- ____________________________________________________

## LTBI Treatment Regimens

## Initiating Treatment 

- Before initiating treatment for LTBI
- Rule out TB disease (i.e., wait for culture result if specimen obtained)
- Determine prior history of treatment for LTBI or TB disease
- Assess risks and benefits of treatment
- Determine current and previous drug therapy

## Isoniazid Regimens (1)

- 9-month regimen of isoniazid (INH) is the preferred regimen
- 6-month regimen is less effective but may be used if unable to complete 9 months
- May be given daily or intermittently (twice weekly)
- Use directly observed therapy (DOT) for intermittent regimen

## Isoniazid Regimens (2)

- INH daily for 9 months 	*(270 doses within 12 months)*
- INH twice/week for 9 months 	*(76 doses within 12 months)*
- INH daily for 6 months 	*(180 doses within 9 months)*
- INH twice/week for 6 months 	*(52 doses within 9 months)*

## Rifampin Regimens (1) 

- Rifampin (RIF) given daily for 4 months is an acceptable alternative when treatment with INH is not feasible.
- In situations where RIF cannot be used (e.g., HIV-infected persons receiving protease inhibitors), rifabutin may be substituted.

## Rifampin Regimens (2)

- RIF daily for 4 months 	*(120 doses within 6 months)*
- RIF and PZA for 2 months should generally not be offered due to risk of severe adverse events6
- _____________________________________
- 6*MMWR *August 8, 2003; 52 (31): 735-739

## Completion of Therapy

- Completion of therapy is based on the total number of doses administered, not on duration alone.

## Management of Patient Who Missed Doses

- Extend or re-start treatment if interruptions were frequent or prolonged enough to preclude completion
- When treatment has been interrupted for more than 2 months, patient should be examined to rule out TB disease
- Recommend and arrange for DOT as needed

## Monitoring During Treatment

## Clinical Monitoring (1)

- Rash
- Anorexia, nausea, vomiting, or abdominal pain in right upper quadrant
- Fatigue or weakness
- Dark urine
- Persistent numbness in hands or feet

- Instruct patient to report signs or symptoms of adverse drug reactions

## Clinical Monitoring (2)

-  Rationale for treatment
-  Adherence with therapy
-  Symptoms of adverse drug reactions
-  Plans to continue treatment

- Monthly visits should include a brief physical exam and a review of

## Clinical Monitoring (3)

- Incidence of hepatitis in persons taking INH is lower than previously thought (0.1 to 0.15%)
- Hepatitis risk increases with age
- Uncommon in persons < 20 years old
- Nearly 2% in persons 50 to 64 years old
- Risk increased with underlying liver disease or heavy alcohol consumption

##  Laboratory Monitoring (1)

- Baseline liver function tests (e.g., AST, ALT, and bilirubin) are not necessary except for patients with the following risk factors:

- HIV infection
- History of liver disease
- Alcoholism
- Pregnancy or in early postpartum period

## Laboratory Monitoring (2)

- Repeat laboratory monitoring if patient has
- Abnormal baseline results
- Current or recent pregnancy
- High risk for adverse reactions
- Symptoms of adverse reaction
- Liver enlargement or tenderness during examination

## Laboratory Monitoring (3)

- Asymptomatic elevation of hepatic enzymes seen in 10%-20% of people taking INH
- Levels usually return to normal after completion of treatment
- Some experts recommend withholding INH if transaminase level exceeds 3 times the upper limit of normal if patient has symptoms of hepatotoxicity, and 5 times the upper limit of normal if patient is asymptomatic7

- 7MMWR June 9, 2000; 49(No. RR-6): 39

## Meeting the Challenge of TB Prevention

- For every patient
- Assess TB risk factors
- If risk is present, perform TST or QFT
- If TST or QFT is positive, rule out active TB disease
- If active TB disease is ruled out, initiate treatment for LTBI
- If treatment is initiated, ensure completion

## Additional Resources

- For additional information on TB, visit the CDC Division of Tuberculosis Elimination Website at
- http://www.cdc.gov/tb

## Guidelines Available Online

- CDC’s Morbidity and Mortality Weekly Report
- 	_[http://www.cdc.gov/mmwr](http://www.cdc.gov/mmwr)_
- American Thoracic Society
- 	_[http://www.thoracic.org/statements/](http://www.thoracic.org/statements/)_

## Case Studies

## Case Study A (1)

- Patient history
- 29-year-old African-American female
- History of diabetes
- 35 weeks pregnant
- TST = 20 mm of induration
- No symptoms of TB disease
- CXR, CBC, LFTs normal
- No known contact with TB patient

## Case Study A (2)

- Questions
- What are this patient’s risk factors for TB infection or disease?
- What is the appropriate management for this patient?

## Case Study A (3)

- Discussion of risk factors
- Persons with diabetes mellitus are 2 to 4 times more likely to develop TB disease than those without diabetes
- Risk may be higher in insulin-dependent diabetics and those with poorly controlled diabetes

## Case Study A (4)

- Discussion of management
- Pregnancy has minimal influence on the pathogenesis of TB or the likelihood of LTBI progressing to disease
- Pregnant women should be targeted for TB testing only if they have specific risk factors for LTBI or progression to disease

## Case Study A (5)

- Discussion of management
- Some experts prefer to delay treatment until after the early postpartum period, unless the person has recent TB infection or HIV infection

## Case Study B (1)

- Patient history
- 47-year-old Hispanic male
- Moved to U.S. from Bolivia 4 years ago
- Known contact of infectious TB case
- TST = 5 mm of induration
- 3 months later TST = 23 mm of induration
- No symptoms of TB disease
- Normal CXR, CBC, AST, and bilirubin

## Case Study B (2)

-  Questions
- What are the patient’s risk factors for TB infection or disease?
- Has the management of this patient to date been appropriate?

## Case Study B (3)

- Discussion of risk factors
- Patient is a contact of an infectious TB case
- Recent immigrant to the U.S. from a country with a high prevalence of TB

## Case Study B (4)

- Discussion of risk factors
- If the patient had not been a contact, the recency of his immigration (less than 4 years) would have made him a candidate for TB testing, but the 5-mm reaction would not be considered positive
- Persons who immigrate from TB-endemic countries have increased rates of TB

## Case Study B (5)

- Discussion of risk factors
- Rates of TB approach those of their countries of origin for 5 years after arrival in the U.S.
- These increased rates most likely result from recent *M. tuberculosis* infection in their native country

## Case Study B (6)

- Discussion of management
- Should be treated for LTBI if TST reactions  10 mm of induration
- As a contact of an active TB case, 5 mm of induration is considered positive
- This patient should have been treated for LTBI immediately after the first TST

## Case Study C (1)

- Patient history
- 36-year-old Asian female
- Moved to U.S. from Philippines > 15 years ago
- Plans to work in a correctional facility
- TST result negative 1 year ago
- TST for pre-employment physical = 26 mm of induration
- CXR normal
- No symptoms of TB disease
- No known contact with a TB patient

## Case Study C (2)

- Questions
- What are the patient’s risk factors for TB infection or disease?
- What is the appropriate management for this patient?

## Case Study C (3)

- Discussion of risk factors
- Patient’s TST converted from negative to positive (within a 2-year period)
- TST conversion increases risk for progressing from LTBI to TB disease
- Foreign-born status is less of a risk factor, i.e., she immigrated more than 5 years ago

## Case Study C (4)

- Discussion of management
- Patient’s TST conversion indicates failure to identify this person as high risk for recent exposure to TB
- Patient may have had extended travel to her country of origin or other high-prevalence parts of the world

## Case Study C (5)

- Discussion of management
- Patient is a recent converter and, as such, is a candidate for treatment of LTBI with INH