Proceedings of UCLA Healthcare - Summer 2000, Vol. 4, No.

CLINICAL REVIEW

Tuberculosis: Review of PPD Testing and Prophylaxis

Baldeep Singh, M.D.

Introduction
fter a concerning increase in the number of tuberculosis (TB) cases early in the 90's, the trends in TB in the United States have been slowly improving. In 1998, 18,361 cases of TB were reported in the United States (6.8 cases per 100,000 population) - an 8% decline in cases from 1997 and a 31% decline in cases since 1992.1 In California specifically, there were 3,852 cases in 1998, a 28% decline from 1992. The declining national and state-wide statistics are directly related to the apparent strengthening of TB control programs since 1992. Much of the decline can also be attributed to the change in recommendations in the arena of prophylactic therapy for TB. However, the Center for Disease Control goal of decreasing TB's prevalence to 1 case in 100,000 by the year 2010 will probably not be achieved given the current rate of decrease. Therefore, the medical community must continue aggressively screening and treating patients for TB. The following article is a summary of the most recent recommendations regarding TB prophylaxis. This is not a guideline for the treatment of active TB.

(or positive tests):2 1. > 5mm induration: Household or close contacts of an active case, persons with a clinical suspicion of TB, and patients with HIV infection. 2. > 10 mm of induration: This group includes patients with the following risk factors: foreign-born persons from high prevalence countries; those from medically underserved, low-income populations including high risk ethnic minorities; intravenous drug users; the homeless; residents of facilities for long term care (nursing homes, institutions for the developmentally disabled, and correctional insti tutions); and persons with medical conditions associated with a higher risk of TB. ** The Department of Health has now classified all residents of Los Angeles county in the above category.3 3. > 15 mm induration: Low risk patient not living in Los Angeles with no risk factors The PPD is read 48 to 72 hours after placement of the test. Reading should be based on palpating the skin for induration borders. The reading should not be based on the extent of erythema on the arm. Many providers use a pen to facilitate measurement of induration. A single measurement of the induration diameter transverse to the long axis of the forearm should be recorded (eg. not a reading of 12 by 8 mm). A positive test is based on the risk factor recommendations above.

PPD Testing
The tuberculin skin test is the only available method for establishing the diagnosis of M. tuberculosis infection in the absence of clinical symptoms. The 5 tuberculin units (TU), or intermediate strength tuberculin, applied by the Mantoux (intradermal) technique should always be used. The definition of a positive test depends on one's risk factors. One must measure the amount of induration, not erythema, on the transverse axis of the arm and document it as one measurement in millimeters.

The Booster Phenomenon PPD Interpretation

The American Thoracic Society and Centers for Disease Control (ATS/CDC) recommends the following interpretation of the tuberculin test with three defined cutoff values for significant reactions Although boosting occurs in all age groups, it increases substantially with age and is most frequently encountered among persons older than 55 years of age. The difficulty of defining criteria for boosted reactions and new converters reflects the

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imperfections of the tuberculin test. A two-step tuberculin skin testing protocol is recommended for all persons who will undergo serial tuberculin skin tests. When tuberculin skin testing of adults is to be repeated periodically, the use of twostep testing initially can reduce the likelihood that a boosted reaction will be interpreted as representing recent infection. It is important to do this with the initial PPD placement so that subsequent testing is not misinterpreted as a recent conversion. If the reaction to the first test is negative, a second test should be given a week later. If the second test result remains below the cut point for a positive test, the reaction is considered to be negative. If the reaction to the second test is positive, it probably represents a boosted reaction and not a new infection. If this important step is not done, and the patient is tested the following year or two, the result may mistakenly be considered a new conversion, and thus treated inappropriately.

tion may also explain false negative tuberculin tests. Application of control skin antigens to determine anergy in ambulatory patients tested with PPD is not routinely recommended, with the exception of patients with HIV. The rate of false negative tuberculin tests among persons infected with HIV depends on the severity of immunosuppression. In patients presenting with AIDS and TB at the same time, approximately 33%-50% will have positive tuberculin tests at the time of diagnosis. However, most persons with asymptomatic HIV infection and TB will have a positive tuberculin test. The CDC recommends that all HIV infected persons be evaluated for delayed type hypersensitivity anergy at the time of tuberculin testing. Application of at least two control antigens (e.g. candida, mumps or tetanus toxoid) by the Mantoux method is recommended. Any induration measured at 48-72 hours is considered evidence of a positive response.

Positive PPD Conversion to Active TB Past BCG Innoculation

A prior history of vaccination with the Bacille Calmette-Gurian (BCG) is frequently cited as a reason not to perform a tuberculin skin test, because of problems interpreting the result. However, studies estimate that this tuberculin sensitivity wanes at a rate of 10% per year unless repeated doses of BCG (or tuberculin) are administered annually. After 10 years, the rate of false positives from BCG is quite low. Therefore, the CDC recommends ignoring a history of BCG vaccination in deciding whether to apply the tuberculin test or how to interpret it.2 Overall, between 5% and 15% of all tuberculin reactors will develop active TB during their lifetime. Thus, the decision to treat a patient is based on their cumulative risk of developing active TB versus their risk of developing an adverse reaction to isoniazid. The rates of conversion to active to TB are listed in Table 1. These data are the basis for the recommendation regarding treatment listed below.

Preventive Therapy Efficacy Anergy Testing

False negative tuberculin tests occur because of acute infections, live viral vaccines, poor nutritional status, metabolic derangements, immunosuppressive therapy, and diseases affecting the lymphoid tissue. Factors related to tuberculin used (storage, dilution, contamination, adsorption) and to the method of administraTable 1 Adults with positive PPD,normal CXR Recent converter Household contact of active case Positive PPD, abnormal CXR (inactive) Positive PPD, HIV infection 0.1%/year 3 to 5% 1st year 2 to 5% 1st year 1 to 4.5% 1st year up to 8%/year There is strong evidence to support the effectiveness of isoniazid therapy. In patients with a positive PPD and a negative chest X-ray, a consistent reduction in cases of TB was demonstrated by using isoniazid for six months. Six months of therapy was chosen after data revealed that this course conferred a 65% reduction in cases reported compared with 70% reduction at

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one year of therapy2. Given the clear improvement in patient compliance, the CDC recommendation was changed in 1993 to six months from one year.

Persons older than 65 years of age, pregnant women, diabetics, daily alcohol users, patients with chronic renal failure, poorly nourished persons and anyone with any other predisposition to peripheral neuropathy.

Risks of Isoniazid
Elevations of serum hepatic enzymes (AST or ALT) occur in 10% to 20% of persons on isoniazid. Clinical hepatitis is infrequent, and is directly related to increasing age. The age cut off of 35 was chosen based on the risk of isoniazid hepatitis in the low risk groups. Age (yrs.) < 20 20 -- 34 35 -- 49 50 -- 64 > 65 Hepatitis Risk Rare up to 0.3% up to 1.2% up to 2.3% up to 5.0%

Initiating and Monitoring Therapy

Isoniazid is administered daily in a dose of 300 mg/day. A chest X-ray showing no abnormalities consistent with active TB is mandatory prior to initiating treatment. If radiographic abnormalities are present, active disease should be ruled out with sputum cultures. One or two calcified granulomas do not usually qualify as a significant TB abnormality.

Under Age 35
Anyone under the age of 35 who meets criteria should be given isoniazid therapy unless contraindicated. Baseline liver function tests are not recommended for individuals younger than 35 years of age unless there is a history of alcohol abuse or liver disease. However, the CDC does recommend monthly evaluations of patients to monitor for adverse side effects. If the patient develops symptoms compatible with hepatitis, the isoniazid should be stopped until liver function tests can be obtained. Asymptomatic persons with AST greater than 3 - 5 times the upper limits of normal should also discontinue isoniazid. The reported deaths from isoniazid hepatitis have occurred when the patients were continued on the drug through jaundice. Women, especially during and following pregnancy, may be at increased risk of isoniazid -associated hepatitis. It is, therefore, not recommended to give isoniazid during pregnancy or up to six months postpartum to avoid this potential risk.

The risk of hepatitis is highly correlated with alcohol intake. However, persons who abuse alcohol are also at increased risk of TB, and this should not be used as a reason to not recommend isoniazid therapy. Asymptomatic chronic carriers of HBsAg do not have an increased risk of isoniazid hepatitis, and so this is not a contraindication to prophylactic therapy. Routinely following liver function tests is not recommended in low risk groups. However, serial hepatic enzyme testing is recommended in patients over age 35 and in high risk groups including alcohol users, IV drug users, and those with chronic liver disease. Additionally, there is evidence that minority women who are post-puberty are also at higher risk and should receive closer monitoring. isoniazid should NOT be used until at least six months post-partum if a pregnant woman is found to be PPD positive. Side effects from isoniazid include: somnolence, difficulties with concentration, dizziness and gastrointestinal upset. Allergic rashes occur infrequently. This may be improved by taking the medication before bed and/or with food. Isoniazid interferes with the metabolism of phenytoin, leading to an increase in the serum levels.

Over Age 35
If the patient is over age 35, the guidelines to give preventive therapy are much stricter. The criteria are as follows: 1. Household and other close contacts of potentially infectious cases of pulmonary TB regardless of age or tuberculin status 2. Newly infected persons or documented tuberculin skin test converters regardless of age (within two years of a negative PPD) 3. Persons with a positive PPD (>5 mm) and an abnormal chest radiograph without active TB

Use of Vitamin B6
Peripheral neuropathy occurs in <1% of persons on isoniazid, and is preventable with pyridoxine (vitamin B6) supplements of 10 to 25 mg/day. Routine pyridoxine is not recommended. The following risk groups are recommend for adjunctive pyridoxine therapy:

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4. Persons with positive PPD (>10 mm) and in special clinical situations: silicosis prolonged therapy with corticosteroids (equivalent of (20 mg of prednisone for at least one month) immunosuppressive therapy of other types endoreticular malignancies (leukemia, lymphoma) end stage renal disease rapid weight loss or chronic undernutrition insulin-requiring diabetes mellitus The CDC does recommend monthly liver function tests in patients over 35 since the incidence of isoniazid induced hepatitis is higher.

United States, an aggressive approach to the TB prophylaxis is warranted. REFERENCES

1. Progress toward the elimination of tuberculosis--United States, 1998. MMWR Morb Mortal Wkly Rep 1999 Aug 27; 48(33):732-6. 2. Bass JB Jr, Farer LS, Hopewell PC, O'Brien R, Jacobs RF, Ruben F, et al. Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and The Centers for Disease Control and Prevention. Am J Respir Crit Care Med 1994 May; 149(5):1359-74. 3. Los Angeles County Tuberculosis Control Program. Available from: URL: http://phps.dhs.co.la.ca.us/tb/index.htm 4. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 1998 Oct 30; 47(RR-20):1-58.

Special Cases
The CDC makes different recommendations in two specific categories: 1. Patients with the specific chest X-ray abnor malities of fibrotic nodular lesions or evidence of silicosis, without evidence of active TB (i.e. negative sputums) should receive a full 12 months isoniazid, or four months of isoniazid and rifampin. 2. HIV-infected individuals with positive PPDs should also be treated for at least nine months, or with one of the regimens listed below.

Preventive Therapy Regimens for Adults with HIV Infection

The CDC recently revised the guideline for TB prophylaxis in patient with HIV.4 The major change was to reduce the recommendation for isoniazid therapy from 12 months to nine months. Two other recommended regimens are listed on the following page. Patients must carefully adhere to the strict guidelines, paying special attention to their antiviral and antibacterial prophylactic regimen.

Conclusion
In conclusion, TB prophylaxis is an effective and underused therapy. Adherence to the CDC consensus guidelines would increase the number of patients treated. Los Angeles is now considered a high risk environment, and thus stricter adherence to treatment guidelines should be taken. If we are to continue the encouraging trend towards TB eradication in the

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Preventive Therapy Regimens for Adults with HIV Infection

Drug isoniazid Interval & Duration Comments Daily for 9 months Isoniazid can be administered concurrently with nucleoside reverse transcriptase inhibitors, protease inhibitors, or nonnucleoside reverse transcriptase inhibitors 2 times/week for 9 months Directly observed preventive therapy must be used when twice-weekly dosing is used Known exposure to person who has isoniazid-resistant TB. Chronic severe liver disease. Contraindications History of an isoniazidinduced reaction, including hepatic, skin, or other allergic reactions or neuropathy

Indications Rating HIV-infected persons A.II who are candidates for TB preventative therapy

See above

B.I

isoniazid

HIV-infected persons are candidates for TB preventive therapy

A.I

rifampin and Daily for 2 months pyrazinamide*

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HIV-infected persons known to be contacts of patientswho has isoniazidresistant, rifamycinsusceptible TB.

Protease inhibitors or nonnucleoside reverse transcriptase inhibitors should not be administered concurrently with rifampin; in this situation, an alternative is the use of rifabutin+ and pyrazinamide. If rifabutin is administered, patient should be monitored carefully for potential rifabutin drug toxicity and potential decreased antiretroviral drug activity. Dose adjustments, alternative therapies, or other precautions might be needed when rifamycins are used (e.g., patients using hormonal contraceptives must be advised to use barrier methods, and patients using methadone require dose adjustments)

History of rifamycininduced reaction, including hepatic, skin, or other who allergic reactions, or thrombocytopenia. Pregnancy, chronic severe hyperuricemia, or chronic severe liver disease

Proceedings of UCLA Healthcare - Summer 2000, Vol. 4, No. 2

* For patients with intolerance to pyrazinamide, some experts recommend the use of rifamycin (rifampin or rifabutin) alone for preventive treatment. Most experts agree that available data support the recommendation of administering this treatment for a short duration of 4 months, although some experts would administer the treatment for 6 months. + The concurrent use of rifabutin is contraindicated with ritonavir, hard-gel saquinavir (Invirase), and delavirdine. The information regarding the use of rifabutin with soft-gel saquinavir (Fortovase), amprenavir, efavirenz, and nevirapine is limited.