Mantoux Tuberculin Skin Test

The preferred method for detecting TB infection -- and the only way to diagnose TB infection before it progresses to active disease -- is a skin test using the Mantoux technique.¹¹ That technique involves the injection of a small amount of purified protein derivative (PPD) just beneath the surface of the skin of the forearm. (The PPD poses no threat of disease or TB infection to the test subject, regardless of the test subject's HIV status.) The result of the test can be read by a trained health care worker within 48 to 72 hours of the time of the injection. Generally, an immune-competent person infected with TB for more than 2 to 10 weeks will produce an immune response to the PPD that manifests itself through the development of an induration at the site of the injection. (An induration is an area of raised, swollen, or hardened skin.¹² ) A person not infected with TB will usually produce no induration in response to the PPD. Indurations are measured and recorded in millimeters.

Reading and Classifying the Tuberculin Reaction

In most cases, a positive reaction to a tuberculin skin test will show that the test subject is TB-infected. Whether a reaction is classified as positive will depend on the size of the induration and the risk factors for infection or disease of the person being tested. Thus, a reaction of 5 mm or more is positive in:

• Persons whose chest x-rays suggest previous TB disease
• Persons who are HIV-positive
• Persons with risk factors for HIV infection
• Close contacts of persons with infectious TB
• Injection drug users whose HIV status is unknown.

A reaction of 10 mm or more is positive in:

• Injection drug users who are HIV seronegative
• Persons with known medical risk factors (other than HIV disease) for developing infectious TB, e.g., diabetes mellitus
• Persons from medically underserved or low income populations, including such high-risk minority groups as Asians, Pacific Islanders, African Americans, Latinos, and Native Americans
• Immigrants from countries where TB is common
• Residents of long-term care facilities
• Health care workers in facilities where TB is present
• The homeless.

All others will be considered to have had a positive reaction to the skin test only if they develop an induration of 15 mm or more.¹³

What About Immunosuppressed Individuals?

Between 10 and 25 percent of persons with TB do not react, or react only mildly, to tuberculin skin testing.¹⁴ Thus, the fact that someone does not react to the test does not necessarily mean that he or she is not infected. In fact, about one-third of persons with HIV infection -- and 60 percent of those with AIDS -- have a reaction to tuberculin skin testing that in other circumstances would probably not be considered positive. The inability of some immunosuppressed individuals to mount a response to tests such as the tuberculin skin test is known as "anergy." Anergy can be caused by HIV infection, overwhelming miliary or pulmonary TB, severe or febrile illness, measles or other viral infections, Hodgkin's disease, sarcoidosis, live-virus vaccination, and immunosuppressive drugs. Anergy can be detected by the administration (via the Mantoux technique) of at least two additional delayed-type hypersensitivity antigens when testing with PPD. A person whose reaction to any of the three antigens measures 3 mm or more is not anergic.

Why Is Two-Step Testing Recommended?

Persons who have been infected with TB for many years may lose the ability to mount a positive reaction to tuberculin skin testing. However, a skin test will cause them to have positive reactions to subsequent tests, thus creating the possibility that the reader of the second test will identify the test subject as newly infected. To avoid that confusion, especially for individuals who are to be tested periodically, such as certain AOD employees, programs should employ a two-step testing procedure the first time they screen an individual for TB. Two-step testing calls for the administration of two tuberculin skin tests 1 to 3 weeks apart. If the first test is positive, the person is considered infected. If the first test is negative, a second test will be performed 1 to 3 weeks later. If the second test is positive, the person is probably infected; if it is negative, the person is probably not infected.

Who Should Be Screened?

High-risk persons should be screened for TB infection. These include:

• Persons with HIV infection
• Persons at risk for HIV
• Close contacts of persons with infectious TB
• Persons with certain medical conditions, such as diabetes mellitus, silicosis, or low body weight
• Persons who inject drugs
• Immigrants from areas where TB is common
• The medically underserved, the poor, and ethnic or racial minorities
• Residents of long-term care facilities
• The homeless.

Substance abuse programs should also screen employees who may be exposed to TB on the job or who would pose a danger to patients and other staff if they were to develop infectious TB. Such employees should be screened upon employment and at intervals dictated by the risk of transmission in the facility (see chapter 6). Screened persons who test positive should be evaluated for active TB disease. If no active disease is present, infected persons at high risk for disease should be considered for preventive therapy.

High-Priority Candidates for Preventive Therapy

Preventive therapy is not routine and is not indicated for all TB-infected persons. In particular, preventive therapy might not be indicated for persons at high risk for adverse reactions to INH, persons who cannot tolerate INH, persons who may have been exposed to a drug-resistant organism, pregnant women (unless they are in a high-risk group), and persons who are unlikely to follow the recommended regimen. The following are high-priority candidates for preventive therapy:

• Persons who are or may be HIV positive
• Close contacts of persons with infectious TB
• Persons whose chest x-ray suggests previous TB but who did not receive adequate treatment
• Persons who inject drugs
• Persons with certain medical conditions
• Persons infected within the preceding 2 years.

Others who should be evaluated for preventive therapy include persons who are under 35 years of age, have reacted to the tuberculin skin test with an induration of 10 or more millimeters, and who are foreign-born, poor, medically underserved, members of a minority group, homeless, or live in long-term care facilities. (Age is significant because those older than 35 years of age are at greater risk of developing INH-related hepatitis.)

What if a Person Has Been Exposed to a Drug-Resistant Organism?

High-risk patients on INH preventive therapy who are likely to have been exposed to an organism resistant to INH should receive preventive therapy with an alternative antituberculosis drug, e.g., rifampin or RIF. In cases where a patient's strain of M. tuberculosis is resistant to both INH and RIF, preventive therapy becomes more complicated. The CDC recommends that persons who are at high risk for developing TB disease, such as HIV-infected persons who may have been exposed to a multidrug-resistant strain of TB, take at least two antituberculosis drugs to which the infecting organism has shown susceptibility. For persons who are not at high risk for developing TB disease, but who may have been exposed to a multidrug-resistant strain of TB, the CDC recommends either:

1. No preventive therapy but careful monitoring for signs of TB disease, or
2. A regimen of two antituberculosis drugs to which there is demonstrated susceptibility.

In making these recommendations, the CDC cautions that the efficacy of preventive therapy with drugs other than INH and RIF has not been established and that careful monitoring for signs of TB disease is suggested in such cases. An AOD program that is managing a patient who may have been exposed to multidrug-resistant TB should consult with an expert on multidrug-resistant TB for current recommendations regarding preventive therapy. Such experts can be identified through local or State public health departments.

Do Patients on Preventive Therapy Need To Be Monitored?

Patients on INH preventive therapy must be monitored monthly for adherence to the prescribed regimen and adverse reactions, especially symptoms or signs of hepatitis or neurotoxicity. (Patients should be advised to monitor themselves for the symptoms of hepatitis, which include nausea, vomiting, and loss of appetite.) Because of the importance of adherence to a successful outcome, the responsible clinician will not hesitate to raise adherence issues with his or her patients, count pills, or even order urine tests.

Directly observed preventive therapy will increase the chances of a successful treatment outcome. Directly observed therapy means that someone actually watches the patient take his or her prescribed medication. Although this work is usually performed by local or State public health workers, it can also be done by AOD staff.

With respect to possible adverse reactions, special precautions are recommended for persons who are older than 35 years of age, abuse alcohol, have a history of side-effects with INH, inject drugs, use medications that may contraindicate INH, have chronic liver problems, are pregnant, or have peripheral neuropathy or a condition associated with its development, such as diabetes mellitus.

Preventive Therapy in AOD Programs

AOD programs that wish to set up a TB preventive therapy program should be aware of the practical difficulties involved in administering preventive therapy. Among other things, programs should bear in mind:

• The importance of proper screening for TB
• The importance of correctly identifying appropriate candidates for preventive therapy
• The need to monitor for adherence and adverse reactions
• The importance of knowing whether the patient has been exposed to a drug- resistant strain of M. tuberculosis, and, if so, the susceptibility pattern of the source case's isolate.

The issues surrounding infection control and TB-related services within AOD programs are discussed in chapter 5.

Who Should Be Evaluated?

Persons who are suspected of having TB, persons who have a positive reaction to tuberculin skin testing, and persons who present with symptoms that include a prolonged (3 or more weeks) cough, bloody sputum, chest pain, fever, night sweats, easy fatigability, loss of appetite, and weight loss should be evaluated for infectious pulmonary TB. (The index of suspicion will vary depending on the prevalence of TB in the surrounding community, the prevalence of TB in the facility itself, and individual or group risk factors.) An appropriate medical evaluation for TB disease (as opposed to infection) will include a medical history, physical examination, Mantoux tuberculin skin test, chest x-ray, and bacteriologic examination.

Medical History

A clinician will want to know whether a patient has a history of exposure to TB or a history of TB infection or disease. Where applicable, a clinician will want to know whether a prescribed regimen was adequate and whether it was followed, since inadequate or incomplete treatment may allow TB to recur and may result in drug-resistant forms of the illness. A proper history will inquire into risk factors that may increase the risk for active disease.

Physical Examination

A physical examination will not rule out or confirm TB. Nevertheless, it may yield valuable information that will help in treating the patient.

Tuberculin Skin Test

Tuberculin skin testing is discussed earlier in this chapter under "How Do We Screen for TB Infection?" It bears repeating that a negative skin test does not rule out TB, especially for persons who are immunosuppressed.

Chest X-Rays

Chest x-rays are the traditional method for detecting pulmonary TB disease in a person with a positive PPD and/or such symptoms as a persistent cough, fever, or chills. However, since a person with both HIV infection and active TB disease may have an apparently "normal" film, chest x-rays are not necessarily definitive. Further laboratory examinations of a patient's sputum or other bodily specimens need to be conducted to confirm a diagnosis of TB disease. Chest x-rays can rule out pulmonary TB in a person with a positive skin test reaction but no symptoms of disease.

Bacteriologic Examination

Persons who are suspected of having pulmonary or laryngeal TB should have a series of three sputum specimens tested for tuberculosis by smear examination and culture. (Sputum is material that is brought up from the lungs; it is different from saliva.) A smear examination involves staining a smear of the patient's sputum with a dye designed to highlight the presence of tubercle bacilli when examined under a microscope. This test can produce a presumptive diagnosis of TB within 24 hours of the specimen's collection.

A smear examination cannot provide a definitive diagnosis of TB disease because the mycobacteria it locates in the sputum may be other than M. tuberculosis. To obtain a definitive diagnosis of TB disease, a laboratory culture of M. tuberculosis must be done. Such cultures are the most accurate method for detecting the presence of TB disease. Cultures can be done on a test subject's sputum, tissues, or bodily fluids. Cultures can be ready within 10 to 14 days of specimen collection. To help prevent transmission of disease, the CDC recommends that, where clinical signs and symptoms indicate the presence of disease, clinicians should not wait for the culture results to begin treatment.

In all cases, the M. tuberculosis isolate should also be tested for drug susceptibility. New tests make it possible to get susceptibility testing results within 5 to 7 days of culture inoculation. Other tests yield results within 2 to 6 weeks.

What Is the Standard Regimen?

Treating active TB disease can take as little as 6 and as many as 24 months. For treatment to be effective, the TB organisms must be susceptible to the antituberculosis drugs used, the treatment must last long enough to be effective, and the patient must follow the prescribed regimen. The initial treatment regimen will usually consist of drugs, INH, RIF, pyrazinamide, and either ethambutol or streptomycin, and will last 6 months.¹⁸ (Single drug regimens are not used because they can lead to the development of drug-resistant strains; multiple drugs reduce the chance of drug-resistance by complementing and reinforcing one another.) Assuming patient adherence and strain susceptibility, fully 95 percent of all immune-competent persons will emerge from treatment free of TB.

Directly Observed Therapy (DOT)

Because patient adherence is the single most important factor in the success of treatment (and because about 25 percent of all TB patients do not follow the prescribed treatment regimen), the CDC recommends that treatment be administered by means of directly observed therapy or DOT. (This nonadherence is risky for both the individual concerned and for those in contact with him or her; it can lead to both TB and AOD relapse, the further transmission of TB, and the development of drug resistance.)

DOT means that a health care worker or public health employee will watch the patient to see that he or she takes the prescribed medication. As intrusive and paternalistic as this may seem, DOT has proved to be effective in reducing relapse and drug resistance. Further, it is cost-effective when used with an intermittent regimen, that is, a regimen that requires medication on a less than daily basis. Such regimens are easier to supervise than regimens that require daily medication.

For those programs wishing to employ DOT, the CDC advises that the DOT be carried out at a time and in a location that makes it as convenient as possible for the patient. In any event, all programs providing TB treatment (whether or not they use DOT) should promote adherence by doing the following:

• Developing individualized treatment plans
• Trying to provide culturally and linguistically appropriate outreach staff
• Educating patients about TB, TB treatment, and possible adverse reactions to treatment
• Using incentives
• Easing access to health and social services, where appropriate.

If necessary, the CDC recommends legal action to civilly commit nonadherent patients who are infectious, at risk for becoming infectious, or at risk for becoming drug-resistant.

Drug-Resistant TB Disease

A patient may acquire drug-resistant TB by developing drug-resistant organisms while being treated for drug-sensitive M. tuberculosis -- either because the drug therapy was inadequate or taken incorrectly -- or through primary infection, i.e., by being infected with a drug-resistant organism. The most common reason for the development of drug resistance is inadequate therapy. The most common drug resistance is to INH, one of the most effective anti-TB drugs.

Drug-resistant TB is treated through an individualized treatment plan based on the drug-susceptibility pattern of a patient's particular strain of M. tuberculosis. Because it can involve a variety of drugs, the treatment regimen for drug-resistant TB can be time-consuming, is often poorly tolerated by the patient, can result in unpleasant side effects, and may have an alarming failure rate.

In the early 1990s, the CDC investigated nine outbreaks of drug-resistant TB disease in hospitals and other institutional settings. The CDC's investigators found widespread multidrug-resistant or MDR TB disease among patients with HIV infection, a mortality rate as high as 72 to 89 percent, and a median interval of only 16 weeks from diagnosis to death.¹⁹

Monitoring Treatment for Active Disease

As with preventive therapy, treatment for TB disease must be monitored regularly for both adherence and adverse reactions. Patients should be instructed to look for signs or symptoms of adverse reactions and to report them immediately to health care workers or medical personnel. With respect to side effects, AOD programs should be aware that RIF or rifampin, one of the two key anti-tuberculosis drugs, accelerates the clearance of drugs metabolized by the liver. Thus, patients who are on methadone may require up to a 50 percent increase in their dosage of methadone. Lastly, patients need to be monitored to ensure that treatment is working and that they have not relapsed.

When May a Patient in Treatment for TB Return to the AOD Program?

To prevent the spread of TB in their facilities, AOD programs must identify, isolate (or remove), and treat (or refer for treatment), all patients and staff with active TB disease. Staff and patients with active disease may not return to the program until it is medically determined that they are not infectious. Fortunately, infectiousness in patients with TB disease declines quickly once effective therapy is implemented. TB-infected patients who have received adequate treatment for 2 to 3 weeks, have responded to the treatment, and have had three consecutive negative smear examinations from sputum taken on 3 separate days are no longer infectious. It will take about 2 months for most infectious TB patients to become noninfectious.