AME Diagnosis and Treatment of Latent Tuberculosis by laa10797


									                                 AME 3.13.06 to 3.17.06:
       Screening and Treatment of Latent Tube rculosis Infection (Positive PPDs)

             Authors: Authors: Sara Luckhaupt, MD and Joel Tsevat, MD, MPH

Competencies: Medical Knowledge, Patient Care

Learning Objectives: After reading this information you should be able to:

   1. Identify who should be tested and treated for latent tuberculosis infection
      (positive PPD)
   2. List the recommended treatment regimens

Key Points

    The goal of these PPD testing is to identify people at high risk for developing
     active TB who would benefit by treatment of latent TB infection.
    Age 35 is no longer a threshold for treatment for a positive PPD.
    Anergy testing is not recommended for routine use for people who are infected
     with HIV or are otherwise immunocompromised.
    9 months of daily INH is the preferred regimen.
    Pyridoxine is recommended to be given with INH to groups of patients in which
     neuropathy is common and to pregnant women and patients with seizure

Targeted Tuberculin Testing

In April 2000, the CDC published guidelines for targeted tuberculin testing and treatment
of latent TB infection.1 The goal of these recommendations is to identify people at high
risk for developing active TB who would benefit by treatment of latent TB infection.
According to the recommendations, a decision to test is a decision to treat (if positive), so
the guidelines discourage tuberculin testing among groups that are at low risk of
developing active TB.

People at high risk for developing active TB who should be tested by PPD*:

      Those likely to have been recently infected with Mycobacterium tuberculosis
          o Close contacts of persons with infectious pulmonary TB
          o Immigrants from areas of the world with high rates of TB (e.g., SE Asia,
              Africa, Eastern Europe, Russia, and most parts of Latin America and the
Certain epidemiologically defined groups: homeless persons, those with HIV infection,
injection drug users, persons who live or work in institutional settings (hospitals,
homeless shelters, correctional facilities, nursing homes, and residential homes for
patients with AIDS))

      Those with clinical conditions that are associated with an increased risk for
       progression from latent TB infection to active TB
          o HIV
          o Injection drug use
          o Silicosis
          o Radiographic findings consistent with prior TB
          o Underweight
          o Chronic renal failure/hemodialysis
          o Diabetes mellitus
          o Gastrectomy
          o Jejunoileal bypass
          o Solid organ transplantation
          o Carcinoma of the head or neck
          o Other neoplasms
          o Prolonged therapy with corticosteroids (>15 mg/day of prednisone or
              equivalent for 2-4 weeks) and other immunosuppressive agents

*Persons whose PPDs convert from negative to positive within a period of 2 years (10
mm increase) and children, especially those younger than 4 years of age, who have a
positive PPD have an increased risk of progression from latent TB infection to active TB,
presumably due to recent infection.

Notice that age 35 is no longer mentioned as a threshold for treatment, PPDs are not
contraindicated for people who have been vaccinated with BCG, and anergy testing is not
recommended for routine use in people who are infected with HIV or otherwise

Tube rculin Skin Testing

Tuberculin skin testing is conducted by injecting 0.1 ml of 5 tuberculin units purified
protein derivative (PPD) intradermally into the dorsal or volar surface of the forearm.
Tests should be read 48-72 hours after administration, and the transverse diameter of the
induration should be recorded in millimeters. In our clinic, tuberculin skin tests can be
placed by an RN (any day except Thursday) and can be read at a follow-up nurse’s visit.
Always make sure the patient can return within 48-72 hours for a reading before
placing a PPD.
                             Crite ria for PPD Positivity by Risk Group

5 mm of induration            10 mm of induration            15 mm of induration

      HIV+                          Recent immigrants               Persons with no
      Recent contacts of             (5 yrs) from high               risk factors for TB*
       active TB cases                prevalence countries
      Fibrotic changes on           Injection drug users
       CXR consistent                Persons who live or
       with prior TB                  work in institutional
      Organ transplant               settings
       recipients                    Mycobacteriology lab
      Other                          personnel
       immunosuppressed              Persons with the
       patients                       clinical conditions
                                      listed above that
                                      increase risk
                                     Children younger
                                      than 4 yrs or infants,
                                      children, and            *The guidelines do not
                                      adolescents exposed      recommend testing these
                                      to adults at high risk   people

Pre-Treatment Evaluation

      Rule out active TB by history, physical exam, CXR, and further studies as
       indicated (sputum samples if CXR suspicious or patient is HIV+ and there is a
       high index of suspicion)
      Baseline laboratory testing (i.e., liver enzymes) is not recommended unless the
       initial evaluation suggests an underlying liver disorder or risk factors for liver
       disease; liver enzymes are recommended for patients with HIV infection, for
       pregnant women, and for women in the immediate postpartum period
      Active hepatitis and end-stage liver disease are relative contraindications to the
       use of isoniazid or pyrazinamide for the treatment of latent TB infection
                                  Treatment Regimens

       Drug         Duration       Inte rval       Adult        Rating*/        Rating*/
                                                   Dose        Evidence †      Evidence †
                                                               for HIV-        for HIV+
                                                                Patients        Patients
   Isoniazid        9 months         Daily        300 mg         A (II)          A (II)
                                   2/week        900 mg          B (II)         B (II)
   Isoniazid        6 months         Daily        300 mg          B (I)           C (I)

                                   2/week        900 mg          B (II)          C (I)
   Rifampin         4 months         Daily        600 mg          B (II)         B (III)

DOT= Directly observed therapy (for twice weekly dosing)
*A=preferred; B=acceptable alternative; C=offer when A & B cannot be given; D=should
generally not be offered
 I=randomized clinical trial data; II=data from clinical trials that were not randomized or
were conducted in other populations; III=expert opinion.

As you can see, 9 months of daily INH is the preferred regimen. The effectiveness
(relative risk reduction) of 12 months of INH has been shown to be as high as 90%
among adherent HIV- patients and 83% among HIV+ patients, and additional studies of
the effectiveness of various durations of INH therapy suggest that there is no increased
protection in going from 9 months of therapy to 12 months of therapy, but that the 9-
month regimen is more cost-effective. Idiosyncratic hepatitis (incidence of symptomatic
hepatitis is 1-3/1000 persons treated; alcohol is a co-factor) is the most severe adverse
reaction from INH, but peripheral neuropathy is also associated with INH administration
due to interference with metabolism of pyridoxine (vitamin B6). Thus, pyridoxine
therapy is recommended for groups of patients in which neuropathy is common (e.g.,
those with diabetes, uremia, alcoholism, malnutrition, and HIV infection), and for
pregnant women and patients with seizure disorders. A 4- month course of rifampin is
recommended as an alternative for patients presumed to be infected with INH-resistant
TB (e.g., close contacts of patients with INH resistant TB). A 2- month course of
rifampin and pyrazinamide is no longer recommended because of hepatotoxicity. No
other regimens are currently recommended for the treatment of latent TB.


       Patients being treated for latent TB infection should be scheduled for follow-up at
        least monthly
       Evaluation should include questioning about side effects and checking for signs of
      Laboratory testing is indicated if baseline liver enzymes were abnormal, the
       patient has other risk factors for liver disease (i.e., HIV, pregnancy, <3 months
       post-partum, heavy alcohol use, pre-existing chronic liver disease, other
       hepatotoxic drugs), or the patient reports symptoms compatible with drug toxicity
      Some experts recommend that isoniazid should be withheld if transaminase levels
       exceed 3 times the upper limit of normal if the patient is symptomatic and 5 times
       the upper limit of normal if the patient is asymptomatic

Completion of Treatment

Completion of therapy is based on total number of doses administered  not on duration
of therapy alone.

For the daily regimens:
    The 9- month regimen of isoniazid should consist of 270 doses, at minimum,
        administered within 12 months
    The 6- month regimen of isoniazid should consist of 180 doses, at minimum,
        administered within 9 months
    The 4- month regimen of rifampin should consist of 120 doses, at minimum,
        administered within 6 months
    When therapy is reinstituted after an interruption of more than 2 months, a
        medical examination to rule out active TB is indicated

Advances on the Horizon(?)

         Peripheral blood T-cell based interferon  assays are being developed and
investigated.3 These assays may offer improved sensitivity and specificity over PPD
testing, but prospective studies are still needed to evaluate the usefulness of these tests.

1. Centers for Disease Control and Prevention. Targeted tuberculin testing and
   treatment of latent tuberculosis infection. MMWR 2000;49 (No. RR-6):1-39.
2. Centers for Disease Control and Prevention. Update: adverse event data and
   revised American Thoracic Society/CDC recommendations against the use of
   rifampin and pyrazinamide for treatment of latent tuberculosis infection  United
   States, 2003. MMWR 2003;52:735-739.
3. Blumberg HM, Leonard MK Jr., Jasmer RM. Update on the treatment of
   tuberculosis and latent tuberculosis infection. JAMA 2005;293:2776-2784.


1. A 68-year-old man with hypertension and chronic renal insufficiency tells you
   that his wife has recently been diagnosed with tuberculosis, and asks you whether
   he needs to be tested.

       a. Should you order a PPD?
       b. What is the cut-off point for reading this patient’s PPD as positive?
       c. What kind of evaluation would this patient need to have before starting
          treatment for latent TB infection?

2. For which of the following patients is treatment of latent TB infection

       a. A health care worker with a PPD of 12 mm who had a negative PPD 2
          years ago
       b. An infant, born to an HIV+ mother, with a PPD of 10 mm
       c. A 70-year-old HIV- man with steroid-dependent COPD (20 mg
          prednisone/day for 2 months) with a PPD of 8 mm
       d. A 25-year-old female teacher with no significant past medical history,
          with a pre-employment PPD of 14 mm

3. Which of the following patients has most likely completed a recommended
   adequate course of therapy for latent TB infection?

       a. An HIV+ man who took 180 doses of isoniazid in a 9- month period
       b. An HIV- woman who took 180 doses of isoniazid in a 6- month period
       c. An HIV- man who completed a 2- month regimen of rifampin and

4. Which drug regimen is appropriate for a 50-year-old diabetic male with a positive

       a. 9 months of daily INH
       b. 4 months of daily rifampin
       c. 2 months of rifampin and pyrazinamide
       d. 9 months of daily INH and pyridoxine

5. Which of the following patients has a PPD that qualifies as positive?

       a. A 40-year-old asthmatic who recently finished a 5-day course of
          prednisone and who has 8 mm of induration
       b. An injection-drug user with 6 mm of induration
       c. A recent immigrant from Somalia with 12 mm of induration
       d. An HIV+ male with 3 mm of induration

6. For which of the following patients should you consider placing a PPD test?

       a. A 68-year-old woman who is beginning hemodialysis and moving into a
          nursing home
       b. A receptionist at a dentist’s office
       c. A recent immigrant from Vietnam with a history of BCG vaccination
       d. A patient with chronic silicosis who is having increased shortness of

                                    Ans wers

       1. Answers and Discussion: This patient should be tested due to his close
       contact with his wife with TB. The fact that he has renal insufficiency may
       also increase his risk of developing active TB. His PPD would be considered
       positive at 5 mm induration. Pre-treatment evaluation should include history
       and physical for symptoms or signs of active TB or liver disease and a CXR to
       look for active TB. Baseline laboratory testing is probably not necessary
       unless there is suspicion for pre-existing liver dysfunction.

       2. Answer: a, b, c
       Discussion: The CDC recommends treatment for the first three patients due to
       their combination of risk factors and PPD results. They do not recommend
       routine testing of teachers without risk factors, although this is commonly
       required for employment. You do not need to consider treating Patient D
       unless her PPD results in 15 mm induration, because otherwise it is likely a
       false positive result and her risk of developing active TB is low.

       3. Answer: b
       Discussion: The first patient has only completed the equivalent of a 6- month
       regimen, which has a C rating for HIV+ persons, so he should continue
       treatment to complete 270 doses within 12 months. The second patient has
       completed a 6- month regimen, which is rated B for HIV- persons. The third
patient has completed a regimen that followed the 2000 guidelines but is no
longer recommended due to risk of liver injury.

4. Answer: d
Discussion: It is important that a patient with diabetes receives pyridoxine
along with INH to prevent onset or worsening of peripheral neuropathy.

5. Answer: c
Discussion: Patient A is not at increased risk for developing TB because s/he
has not been on steroids long enough to be immunosuppressed. The
appropriate PPD cut-off for Patients B and C is 10mm, and the appropriate
cut-off for Patient D is 5 mm.

6. Answer: a, c, d
Discussion: Hemodialysis, residence in a nursing home, recent immigration
from SE Asia, and silicosis all increase the chance of recent infection and/or
the risk of progression from latent to active TB. Previous vaccination with
BCG is not a contraindication to PPD testing.

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