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Clinical Updates in Infectious Diseases

Supported by an unrestricted educational grant from Glaxo Wellcome

Volume III, Issue 3 - March 1997

Tuberculosis in the 1990s

While tuberculosis (TB) was forgotten by many in the United States (US) until this decade, TB has never ceased being a leader in worldwide mortality. It is estimated that one third of the world's population is infected with Mycobacterium tuberculosis and that there are approximately 7.5 million active cases of TB each year. The World Health Organization estimates that over 30 million people will die of TB during the 1990s.

In the US, cases of active TB decreased throughout this century due to both improvements in general public health and the development of specific antituberculous medications beginning in the 1940s and 1950s. By 1985 only 22,201 cases of active TB were reported in the US, the lowest number ever reached. Conferences were held to orchestrate the elimination of TB in the US. Beginning in 1986 and continuing into the early part of 1990s, cases of tuberculosis rebounded (Fig 1). The cause of this increase was multifactorial and included a breakdown in the public health TB infrastructure, the impact of human immunodeficiency virus (HIV) infection, and new US immigration patterns.

TB in the US is not equally distributed, either geographically or in individual demographic categories. New York, New Jersey, California, Texas, Illinois, and a number of states in the Southeast lead the nation in incidence of TB. Urban areas are particularly impacted, with many rural counties reporting no cases of active disease. Groups with higher than average rates of TB include members of racial minority groups, persons of lower socioeconomic status, and residents of long-term-care facilities such as nursing homes, shelters, and prisons. Individuals with histories of injection drug use and alcohol abuse are also considered at higher risk for TB. Foreign-born individuals account for an increasingly large percentage (about 30%) of cases in the US. The most frequent countries of origin are Latin America and Southeast Asia.

Most persons with normal immune systems who become infected with M tuberculosis never develop active disease. Because the immune system controls the infection, the only evidence of the bacillus may be a positive tuberculin skin test. In an HIV-negative person the lifetime risk of developing active disease after infection is only 5% to 10%. Persons with HIV infection are much more likely to develop active TB because of deterioration of the immune system. Persons coinfected with both HIV and M tuberculosis develop active TB at rates of up to 7% to 10% per year. In addition to a higher rate of reactivation disease, HIV-infected persons are more likely to develop primary TB if exposed. Outbreaks of primary TB have occurred among HIV-infected persons in clinics, hospital rooms, prisons, and housing facilities. Recent studies have shown up to 40% of cases in some metropolitan areas may be due to recent contact with the organism.

Diagnosis

The only tool to diagnose persons with latent infection remains the tuberculin skin test. Injecting 5 tuberculin units of purified protein derivative (PPD) intradermally is the only standardized test. The definition of a positive reaction depends on the population being tested (Table 1). Persons at highest risk are considered to have a positive test with 5 mm of induration with other individuals considered positive at 10 or 15 mm. These tests should be read 48 to 72 hours after intradermal injection, although a positive reading after that time is still significant. For persons undergoing yearly testing such as healthcare workers and nursing home residents, a second or "booster" skin test should be applied 1 to 3 weeks after the first negative test. Applying a booster test to HlV-positive patients has not proved useful.

The diagnosis of active TB requires an open mind because TB can present with a wide variety of manifestations. Classic TB with upper lobe infiltrates and cavities are still the most common radiologic diagnostic findings in both HIV-positive and HIV-negative patients. Patients with advanced HIV disease, however, frequently present with atypical manifestations including lower lobe infiltrates, pleural effusions, and up to 30% to 40% have nonpulmonary disease. Many of these latter cases can only be diagnosed with invasive techniques including Lymph node biopsies and spinal taps. Specimens should be sent for both smear and culture in all persons with suspected TB. It is important to use laboratories that employ rapid diagnostics, including broth culture techniques that reduce the time for isolating the organism from 4 to 6 weeks for such cultures to as little as 7 to 14 days. Genetic probes are currently available to discern whether cultures positive for mycobacteria are M tuberculosis or nontuberculous mycobacteria.

Recently, new probes have been approved to directly test sputum samples for the presence of M tuberculosis. To date, these probes have only been approved for use on smear-positive sputums, where the positive and negative predictive value are quite high. These new direct probes are not approved for use in smear-negative patients due to a higher (up to 50%) level of false-positive and false-negative results when compared to culture. It is hoped these direct probes will be able to assist in detecting TB in nonpulmonary specimens (such as urine, spinal fluid, and blood) but there is not enough data to date to support using them to detect nonpulmonary disease.

Blood cultures for mycobacteria are useful in detecting TB as well as in detecting M avium complex in patients with HIV infection. Up to 10% of HlV-positive patients with active TB have mycobacteria in their blood. Blood cultures are only rarely positive in HIV-negative patients with TB and should not be routinely done.

Treatment

Treatment requires commitment and education on the parts of both the healthcare workers and the patient. The drugs available are adequate to treat and cure the overwhelming majority of patients with TB when used correctly. Treatment failures are usually due to noncompliance on the part of the patient and errors in judgment on the part of the provider. These problems can be overcome with a committed, knowledgeable healthcare team.

The preferred treatment for all forms of TB is a 6-month regimen consisting of 2 months of isoniazid (INH), rifampin, and pyrazinamide (Table 2) followed by 4 additional months of INH and rifampin. For individuals living in areas where resistance to INH is >4%, a fourth drug should be added pending susceptibility testing results. This fourth drug is usually ethambutol although streptomycin is sometimes used. A less desirable alternative regimen for persons who cannot take pyrazinamide is 9 months of isoniazid and rifampin. Other drugs should be added pending susceptibility testing results if multidrug resistance is a concern.

Persons being treated for TB should be monitored for adverse drug effects. The most common adverse effects are liver toxicities, which can be associated with INH, rifampin, and pyrazinamide. Patients should be screened monthly for symptoms of hepatitis. Some clinics perform liver function tests monthly for all patients >35 years of age. Pyrazinamide is associated with an elevated uric acid but only rarely is a cause of acute gout. Persons receiving ethambutol should have a monthly review of visual acuity and ability to discriminate red from green as a clue to the development of retrobulbar neuritis. Ethambutol should only be used at a dose of 15 mg/kg/day, and should not be used for children whose visual acuity cannot be monitored (eg, those <6 years of age), to avoid this toxicity.

Drug resistance can either be primary (in a person not previously treated for TB) or secondary to prior inappropriate treatment. Rates of drug resistance have been particularly high in metropolitan New York City. A recent study National Institutes of Health (NIH) study by the Community Programs for Clinical Research on AIDS showed 37% of M tuberculosis isolates from HIV-infected patients with TB in New York City were resistant to one or more of the primary drugs. Multiple drug resistance (MDR), as defined by resistance to both INH and rifampin, is also quite high in metropolitan New York with 19.4% of HIV-positive patients having MDR isolates in the NIH study. Overall resistance and MDR rates have dropped in New York City in the last few years due to improved treatment and control policies.

Patients with drug-resistant isolates should be cared for by an infectious disease specialist. Isolates resistant to only INH can usually be treated easily with rifampin and pyrazinamide for 6 to 9 months. Isolates with rifampin resistance can be treated with INH, ethambutol, and pyrazinamide for 9 to 12 months. Close monitoring of sputum cultures and clinical monitoring is essential for these individuals. Patients with MDR TB are difficult to treat with only a 50% cure rate.

A number of drugs should be considered (Table 3) and the patient should be treated with three or more active agents based on susceptibility results. The quinolones have been a particularly useful addition to the treatment regimen of many patients with drug-resistant disease. In addition, rifabutin is effective for about 25% of patients with rifampin resistance.

Patients with HIV infection should be treated with the same regimens as HIV-negative individuals. Those who respond quickly can receive a total of only 6 months of therapy, although some physicians prefer to treat with a 9-month regimen. This longer duration of therapy is supported by a recent study from Zaire showing a higher success rate in patients treated for 6 months. It should be noted that higher rates of adverse drug effects are frequent in HIV-positive patients so modifications in treatment regimens are not uncommon.

Directly observed therapy (DOT) has now been accepted as the primary approach to treating TB to assure a successful outcome and diminish the possibility of developing drug resistance. DOT has been proven to accomplish these goals while reducing overall costs associated with TB control. Patients on DOT can be given either twice or thrice weekly therapy after an initial 2 weeks of daily therapy. For patients unable to be placed on a DOT program there are now drug combinations in single tablets. INH and rifampin have the trade name Rifamate while isoniazid, rifampin, and pyrazinamide are marketed as Rifater. These combination products preclude the patient from single drug therapy that result in development of resistance.

Prevention

Individuals already infected with M tuberculosis may be candidates for preventive therapy. Patients with a positive PPD test who are <35 years old should be offered 6 months of INH preventive therapy. Persons with a positive PPD test who are >35 years old should be offered INH if they have any condition that increases the likelihood of reactivation disease (Table 4). For those who are HIV- and PPD-positive, 12 months of INH should be given. Isoniazid is given as a 300-mg daily dose, although some programs administer INH in a dose of 900 mg twice weekly as DOT. There are no proven alternatives to INH although a study is currently being conducted to evaluate the utility of rifampin and pyrazinamide given daily for 2 months for preventive therapy. Rifampin as monotherapy for 6 months may be effective and rifabutin taken daily for 3 months is also being studied for prophylaxis.

All persons receiving preventive therapy should be seen monthly so an evaluation can be done for hepatic and other toxicities. Patients should be counseled about the symptoms of hepatitis and asked to report any suggestion of this disease immediately.

A great deal of emphasis has recently been placed on controlling TB in hospitals, nursing homes, and other facilities. These renewed efforts were driven by nosocomial TB outbreaks. Both drug-susceptible and drug-resistant strain outbreaks occurred due to inattention to diagnosing and correctly isolating patients with active disease. Many of these outbreaks occurred in HIV-positive persons because the population has a propensity to develop primary TB when exposed to the organism.

The Centers for Disease Control and Prevention (CDC) updated their guidelines for TB prevention in healthcare settings in 1994. The main emphasis of these guidelines is on correctly identifying and isolating patients. Education is therefore key to the success of any TB control program and must include all personnel who come in contact with these patients. Engineering controls should include isolation rooms with negative air flow and at least six to 12 air exchanges per hour. High-efficiency particulate air filters and UV lights may be used in situations where unidirectional negative air flow cannot be achieved. All caregivers must participate in a personal respiratory protection program. This should include PPD skin testing every 6 months for all employees with a negative test and the use of an "N-95" face mask (approved by the National Institute of Occupational Health and Safety when coming in contact with possibly contaminated air).

Conclusion

The US has seen a decrease in TB rates for the past 3 years, with 23,000 cases reported in 1995 (the last year with complete reporting). This downward trend is a direct reflection of the resources that have been put into TB treatment, research, and prevention. It is incumbent on all clinicians to recognize and treat TB correctly if this trend is to continue.

Fred M. Gordin, MD
Chief, Infectious Diseases
VA Medical Center
Associate Professor of Medicine
Georgetown University
Washington, DC

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Clinical Updates in Infectious Diseases

Tuberculosis in the 1990s

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