Tuberculosis Control Program

BUMEDINST 6224.8

Chief, Bureau of Medicine and Surgery
February 8, 1993

Evaluation and Preventive Therapy (Chemoprophylaxis) of Tuberculin Reactors

1. General. All tuberculin reactors (induration of 5 mm or greater to a tuberculin skin test with either 5 TU or 1 TU purified protein derivative (PPD)) must be evaluated and considered for preventive therapy with isoniazid (INH). Preventive therapy with INH, if indicated, is required for all active duty members, and should be strongly recommended for all other medical beneficiaries, unless specific medical conditions contraindicate its use.

2. Indications for Preventive Therapy (Chemoprophylaxis)

a. Tuberculin reactor on initial testing, e. g., when entering the Navy or Marine Corps.

(1) Tuberculin reactor with > 10 mm induration is a candidate for INH preventive therapy regardless of age if they have not previously received a documented course of INH.

(2) Tuberculin reactor with < 10 mm induration is a candidate for INH preventive therapy only if one of the criteria in paragraph 2b applies.

b. Tuberculin reactor identified in subsequent periodic or contact investigation testing. Table 1 summarizes the following indications for INH preventive therapy of tuberculin reactors by age, risk factors, and size of tuberculin skin test induration.

(1) Tuberculin reactor, regardless of age, with one of the following risk factors and a positive tuberculin skin test reaction is a candidate for INH preventive therapy, if not previously treated. (The amount of induration indicating a "positive" test is given in parentheses for each situation.)

(a) Persons with known or suspected HIV infection (> 5 mm).

(b) Close contact of newly diagnosed tuberculosis cases with active disease (> 5 mm).

(c) Previously untreated or inadequately treated persons with chest radiographs showing fibrotic lesions compatible with old healed tuberculosis (> 5 mm).

(d) Injecting drug users (> 10 mm).

(e) Persons with medical conditions which have been reported to increase the risk of tuberculosis (> 10 mm). These medical conditions include: silicosis; gastrectomy; jejeunoileal bypass; weight of 10 percent or more below ideal body weight; chronic renal failure; conditions requiring prolonged high dose corticosteroid therapy or other immunosuppressive therapy; some hematologic disorders (e. g., leukemia and lymphomas); and other malignancies.

(2) Tuberculin reactor less than 35 years of age with one of the following risk factors and a positive tuberculin skin test reaction is a candidate for INH preventive therapy, if not previously treated. (The amount of induration indicating a "positive" test is given in parentheses for each situation.)

(a) Foreign born person from high prevalence countries ( > 10 mm). High prevalence countries include countries in Asia, Africa, Central and South America, and Eastern Europe.

(b) Residents of correctional facilities ( > 10 mm).

(3) Tuberculin reactor less than 35 years of age, who does not have any risk factors, but has a positive tuberculin skin test reaction of > 15 mm induration is a candidate for INH preventive therapy, if not previously treated.

(4) Recent tuberculin skin test convertors ( > 10 mm increase within a 2- 3 year period for those less than 35 years old; > 15 mm increase for those age 35 years and older). (Example: 25 year old U. S.born white female had a zero mm induration 2 years ago during recruit training. Now she has a 13 mm induration on a routine screen. She is a candidate of INH even though she has no other risk factors, including a known exposure to a case of tuberculosis disease, and her reaction is less than 15 mm.)

c. Previously known tuberculin reactor (old reactor) who was not properly evaluated in the past or who did not complete an appropriate course of preventive therapy.

(1) Previously known tuberculin reactor less than 35 years of age is a candidate for INH preventive therapy following the criteria for risk groups and positive reactions listed above.

(2) Previously known tuberculin reactor equal to or greater than 35 years of age is generally not a candidate for INH preventive treatment, unless specific risk factors for active disease are present. Such risk factors are set out in paragraph 2b( 1)( e) of this enclosure.

(3) A previously known tuberculin reactor may be treated without repeat testing if a properly documented tuberculin skin test result is in the medical treatment record. If a person gives an undocumented history of a tuberculin reaction and INH preventive treatment may be indicated, follow the guidance of enclosure (1) to document the current reaction to tuberculin.

3. Dosage and Duration of Preventive Therapy

a. The antibiotic regimen of choice for tuberculosis preventive therapy is INH in an oral daily dose of 300 mg for adults and 10 mg/ kg (not to exceed 300 mg) for children.

b. The duration of preventive treatment therapy is determined by the presence or absence or risk factors for tuberculosis disease.

(1) Tuberculin reactors with no risk factors for the development of tuberculosis disease should receive 6 months of continuous therapy with INH.

(2) Tuberculin reactors with HIV infection and persons with stable abnormal chest radiographs consistent with past tuberculosis should receive 12 months of continuous therapy with INH.

c. Some individuals may also require a concomitant course of pyridoxine (vitamin B6) in an oral daily dose of 50 mg for adults. These are primarily individuals who are, or may be, malnourished or relatively malnourished, or who have certain types of neuropathies. Such individuals may include alcoholics, pregnant women, and some children.

d. An alternative dosing schedule is INH given twice weekly in a dose of 15 mg/ kg (up to 900 mg). This schedule makes directlyobserved therapy more convenient, when poor compliance with daily INH is a concern.

4. Contraindications to Preventive Therapy With INH

a. Medical Contraindications to INH Include:

(1) Previous history of INH associated liver injury.

(2) History of a severe adverse reaction to INH.

(3) Acute or active liver disease of any etiology.

b. Neither a history of viral hepatitis nor the presence of hepatitis B surface antigen (HBsAg) is a contraindications to INH preventive therapy, if there is no evidence of current liver disease (i. e., liver function tests demonstrate normal levels of liver enzymes).

5. Initial Evaluation for INH Preventive Therapy

a. Before instituting a course of INH preventive therapy, the tuberculin reactor must be examined by a medical officer or physicians assistant.

b. The evaluation must include:

(1) An appropriate history and physical examination.

(2) Chest radiograph for newly identified  tuberculin reactors with induration > 10 mm. newly identified  reactors with induration < 10 mm require a Chest radiograph only if they have risk factors for tuberculosis disease. (See paragraph 2b( 1)( e) of this enclosure.) Previously known reactors need a Chest radiograph  if one was not documented previously or if otherwise clinically indicated.

(3) Baseline liver function tests (at a minimum, ALT/ serum glutamic oxaloacetic transaminase (SGOT) or AST/ serum glutamic pyruvic transaminase (SGPT)) for all reactors 35 years old or greater who will receive INH. Baseline liver function tests are not required for INH recipients under age 35, but they should be done if clinically indicated.

(4) HIV antibody testing must be performed for all newly identified  active duty tuberculin reactors. All newly-identified dependent and civilian employee tuberculin reactors, as defined in table 1, must be queried about HIV risk behaviors per reference (e). Individuals with HIV risk factors should be counseled and offered a HIV antibody testing.  Acceptance of such testing is voluntary on their part.

c. The following decisions need to be made:

(1) Is active disease present?

(2) Are specific medical contraindications to INH present?

(3) Are risk factors for tuberculosis disease present?

(4) Should preventive therapy with INH be prescribed and for what duration?

(5) Should a concomitant course of pyridoxine be prescribed?

d. If the examining medical officer or physicians assistant recommends that an active duty member who is a newly identified  tuberculin reactor not start INH preventive therapy, although indicated by the guidelines of this instruction, the cognizant MDR must obtain and document a second professional opinion in the form of a consultation from a preventive medicine physician at the area NAVENPVNTMEDU or a qualified infectious disease or pulmonary medicine specialist.

e. A medical board or limitation of duties is not required or indicated for those with no evidence of active disease, i. e., for those whose only evidence of tuberculous infection is a positive tuberculin skin test. This is true whether such individuals are or are not undergoing a course of preventive therapy.

6. Followup Evaluations and Monitoring

a. INH Preventive Therapy Prescribed

(1) Closely monitor a person for whom INH preventive therapy is prescribed to ensure that they use the drug regularly and properly, and to prevent or minimize any side effects of treatment.

(2) Dispense only one month's supply of INH at one time, except in unusual circumstances. The patient needs to return for a clinical evaluation by a knowledgeable MDR prior to dispensing each month's supply of INH.

(3) Enclosure (4) gives guidance and contains a sample patient questionnaire to assist in careful clinical monitoring of the patient on INH. Documentation of the monthly evaluations will be maintained in the medical treatment record of each reactor.

(4) Liver Function Tests

(a) Routine liver function tests (at a minimum, serum alanine aminotransferase (ALT, SGPT) or serum aspartate amino-transferase (AST, SGOT)) should be obtained at least 1, 2, and 3 months after initiation of INH for the following categories of reactors:

1. All reactors 35 years old or greater.

2. Individuals who are also taking phenytoin (i. e., Dilantin).

3. Individuals who are heavy drinkers of alcohol.

4. Individuals with chronic liver disease or severe renal dysfunction.

5. Pregnancy.

(b) In some settings (e. g., aboard some ships) it is not practicable to obtain monthly enzyme levels. This should not preclude prescribing INH for any tuberculin reactor over age 35 who is otherwise healthy, provided very careful clinical monitoring is done.

(c) Liver function tests should be obtained on any reactor on INH if clinically indicated (i. e., jaundice, unexplained nausea, etc.).

b. INH Preventive Therapy Not Prescribed

(1) Candidate for INH preventive therapy. Monitor any newly identified tuberculin reactor who is a candidate for INH, but for whom INH is not prescribed because of medical contra-indications, for evidence of active tuberculosis disease. Such monitoring should be done monthly for 6 months, then annually thereafter. Enclosure (4) has a sample questionnaire which can assist in conducting and documenting this evaluation.

(2) Not candidate for INH preventive therapy. Any tuberculin reactor (induration > 5 mm but < 15 mm) who is not a candidate for INH per the guidelines of this instruction must return to the appropriate periodic screening program. The results of subsequent tuberculin skin tests must be evaluated per this instruction. Tuberculin reactors with induration > 15 mm who are not a candidate for INH preventive therapy must not be returned to the tuberculin skin test screening program. Such individuals must, however, undergo an annual evaluation (history and physical examination) for active disease. These individuals will only receive a chest radiograph as part of the annual evaluation if clinically indicated.

7. Patient Education. The patient must be educated as to the implications of his or her tuberculin skin test results, the benefits and risks of INH preventive treatment, and the warning signs of untoward side effects of this beneficial antibiotic. The MDR is responsible for maintaining a patient education program which ensures these goals. The necessity for faithful adherence to the prescribed course of treatment in the absence of untoward side effects must be strongly emphasized. A notation to the effect that appropriate patient education and counseling has occurred must be documented in the patient's medical treatment record (SF 600). The sample patient questionnaire included in enclosure (4) provides the basic information to be included in patient education.

8. Completion of INH Preventive Therapy. When a person completes the appropriate regimen of preventive therapy, an entry must be made in their medical treatment regimen clearly stating that they have completed the prescribed course of therapy. No additional tuberculin skin testing or chest radiograph is required or indicated. The reactor must be placed in an annual evaluation program for previously known tuberculin reactors (old reactors) who have received appropriate preventive therapy. See enclosure (4).

9. Special Situations

a. Missed doses or interrupted preventive therapy. A person who "feels" healthy (e. g., most tuberculin reactors) often finds it difficult to incorporate daily medication into his or her normal routine. Realistically, few reactors are able to complete 6 months of INH preventive therapy without missing an occasional dose. The effect of a few missed doses is usually of little significance, yet the additive effect of many missed doses may be quite detrimental to the effectiveness of preventive therapy. The necessity for strict compliance with daily INH therapy must be stressed to infected individuals during the required monthly clinical reevaluations.

(1) If the patient misses more than 1 month of therapy, but has completed more than 3 months of therapy at the beginning of the lapse, restart the program with the goal of completing at least 3 subsequent months of therapy.

(2) If the patient has completed less than 3 months at the time of the lapse of more than 1 month, therapy should be restarted under strict supervision with the goal of completing at least 6 subsequent months of therapy.

b. Dependents. Management of dependents who are tuberculin reactors or close contacts of persons with active tuberculosis disease must comply with local public health laws and regulations and with established standards of medical practice in the United States as defined in the most current guidelines of the American Academy of Pediatrics, the American Thoracic Society of the American Lung Association, or the Centers for Disease Control of the U. S. Public Health Service. In particular, as specified in reference (a), children and adolescents who are close contacts (household) of persons with active tuberculosis disease must receive INH in a dosage of 10 mg/ kg body weight (not to exceed 300 mg/ day) for 3 months, regardless of initial tuberculin skin test results. They must then be retested at the end of the 3 months and if found to be reactors must be continued on INH for a total period of 6 months. If found to be nonreactors after the initial 3 months of INH, and if exposure has ended, INH may be discontinued.

c. Civilian workers on Navy or Marine Corps activities. In areas of high tuberculosis risk in which infection of civilian workers aboard Navy or Marine Corps activities poses a continuing significant public health problem, consultation must be obtained from the area NAVENPVNTMEDU for recommendations regarding an effective local control program. Provisions of reference (a) apply, as appropriate.

d. INH resistant tuberculosis and preventive treatment of persons allergic to INH. INH is the only antibiotic with demonstrated efficacy in the prevention of tuberculosis disease among infected persons. However, resistance to INH has been increasingly recognized in some areas. Also, some persons may be allergic to INH. In cases where tuberculin reactors (or exposed children, regardless of skin test status) are known to be close contacts of a person or persons with demonstrated INH resistant tuberculosis, rifampin may be substituted for INH in an adult, daily dose of 600 mg orally. The comparable pediatric dose is 10- 15 mg/ kg body weight, not to exceed 600 mg per day. In such cases, consultation must be obtained with a qualified pulmonary medicine or infectious disease specialist. Such a course of action may also be appropriate for tuberculin reactors who are allergic to INH.

e. Persons Leaving the Service While on Preventive Therapy

(1) Retirement. Active duty and work related civil service members on INH preventive therapy who retire before completing their course of INH must be counseled, with appropriate documentation in their health records (SF 600), that continued treatment is necessary and may be obtained at most Armed Forces or Department of Veterans Affairs (DVA) medical facilities.

(2) Separation. Active duty and work related civil service members on INH preventive therapy who are discharged or released to inactive duty before the completion of their course of INH must be counseled, with appropriate documentation on a SF 600 in their medical treatment records, as to the importance of continuing the medication. Care may be provided by the DVA, public health clinics, private physicians, etc. To facilitate followup, such personnel must be provided with a statement signed by the cognizant MDR containing the date treatment was begun and the type and dosage of prescribed medication.

10. INH associated Hepatitis

a. In the past, misconceptions about tuberculosis preventive treatment have abounded. The most common error is the assumption that tuberculin reactors over 35 years of age should not be placed on tuberculosis preventive therapy. Another frequent mistake is the practice of restricting tuberculosis preventive therapy only to those tuberculin reactors who also have a chest radiograph abnormality. The risks associated with tuberculosis preventive therapy, though real, have often been grossly exaggerated. The result is that many infected individuals who might benefit from an appropriate course of tuberculosis preventive therapy are never given this preventive therapy.

b. An elevation of SGOT or SGPT up to four times normal in an otherwise asymptomatic person is not necessarily an indication for stopping preventive therapy, but rather for closer monitoring. The significance and use of these liver enzyme levels is discussed below. Most people, regardless of age, experience some elevation of hepatic enzyme levels in the blood during the first few months of INH therapy. Usually, these levels plateau at about the third month of therapy. If this pattern does not occur and hepatic enzyme levels continue to rise, or if there is a precipitous increase of more than 4 times the patient's normal baseline level, this is evidence of liver toxicity and the INH should be discontinued at once. In most people, once hepatic enzyme levels  reach a plateau, they return rapidly to normal baseline levels.

c. The cognizant MDR should be thoroughly knowledgeable of the signs and symptoms of INH hypersensitivity and toxicity states as discussed in the manufacturer's package insert or prescribing information. The cognizant MDR must STOP THE USE OF INH AT ONCE if significant untoward side effects are suspected. The patient's health status must then be very carefully evaluated to determine if the manifestations noted were induced by INH. An experienced specialist should be consulted for this evaluation.

d. The risk of INH associated hepatitis increases with age and is potentially fatal if the appropriate signs and symptoms are not monitored. This age specific risk is as follows:

The risk of active tuberculosis disease is about 50 per 1,000 among newly identified tuberculin reactors. At no age does the risk of INH associated hepatitis outweigh the risk of active tuberculosis disease in this group. Therefore, all newly-identified reactors deserve INH preventive therapy provided no specific medical contraindication exists. However, individuals over the age of 35 years should be monitored most carefully while taking INH.

e. INH preventive therapy for previously known (old) reactors. Previously-known tuberculin reactors (more than 2 to 3 years previously) who have never received a complete course of INH preventive therapy should be re-evaluated for INH preventive therapy. Unlike the situation with newly identified reactors, when the risk of active tuberculosis disease is about 5 percent and clearly outweighs the risk of INH associated liver toxicity, the situation with previously known reactors may differ, depending on age and their risk factors for tuberculosis disease. If they have no risk factors, their risk of developing active tuberculosis disease is about 1 percent. If under 35 years of age, they may benefit from a course of INH preventive therapy and should be evaluated for this antibiotic. If over 35 years of age, however, their risk of INH associated liver toxicity outweighs their risk of active tuberculosis and they should receive an annual clinical evaluation per enclosure (4) in lieu of INH preventive therapy. To reiterate, this does not apply to newly identified reactors who will be given INH preventive therapy REGARDLESS OF AGE, provided no specific medical contraindication is present.