CHAPTER 22

TUBERCULOSIS

Ariel Pablos-Méndez, M.D., M.P.H.

Table of Contents

            A third of the world’s population is currently infected with Mycobacterium tuberculosis (MTb), 8 million new cases occur annually, and two to three million people die of tuberculosis (TB) each year. This toll is predicted to increase after the year 2000.[i] Although most cases occur in Africa and Asia (30 percent in India alone), it is estimated that 10 to 15 million people in the U.S. are infected, and almost 20,000 cases are reported a year in this country.[ii]^,[iii]^,[iv]

            TB, the “white plague,” was the leading cause of death among young people in the 19th century. During the first half of the 20th century there was a steady decline in incidence and mortality, which preceded the advent of anti-TB medication. In many industrialized nations TB was on the brink of elimination.⁴ Recently, however, we  witnessed a resurgence,³ particularly in New York City, which reports 10 percent of all U.S. cases. Poor adherence to TB treatment led to the emergence of drug-resistance,[v]^,[vi] which turned TB more threatening.

            The incidence of TB doubled in the 1980’s, peaking in 1992.[vii]^,[viii] This resurgence was attributed to HIV infection; half the cases of new TB were coinfected and there were several nosocomial outbreaks in AIDS wards.[ix]^,4 The concentration of TB among minorities,^3,9 the homeless, and injection drug users (IDUs), however, bespoke important socioeconomic factors as well. In NYC, two-thirds of the cases occur in men, 60 percent are African American, 25 percent Hispanic and 30 to 40 percent are born abroad; approximately 20 percent are homeless, 25 percent alcoholics and 25 percent IDUs.^7,8

            The tide is already being turned by physician education, hospital isolation policies and directly observed therapy (DOT) efforts spearheaded by the NYC Department of Health. From 1992 to 1997, TB incidence declined by 50 percent, particularly among US-born and HIV-infected people, while the numbers of multi-drug-resistant TB (MDR-TB) have decreased by 90 percent.⁸ Despite this success, the complacency of the 1980s and its tragic consequences must be avoided. Indeed, TB is actually increasing among foreign-born patients, and early detection and prophylaxis is the new challenge.

Prevention

            Surveillance of high risk groups (prisons, shelters, hospitals) and re-education of health care professionals are important strategies to regain control of TB. Coordinating efforts by Departments of Health are critical to the success of these and other activities (including case-finding through efficient reporting and contact investigation). Chest X-ray screening campaigns have been abandoned in favor of targeted PPD screening and isoniazid (INH) prophylaxis. Since one patient with TB will infect ten other people, the most important preventive strategy is isolating and curing infectious cases.

BCG Vaccine:

            The BCG (bacille Calmette-Guerin) vaccine (attenuated strains of M. bovis) is widely used, with 70 percent coverage of the world population, especially in developing countries.[x] BCG is safe, even among persons with asymptomatic HIV infection. The vaccination is not practiced in North America, however, because of the relatively low incidence of TB, possible interference with PPD testing,[xi] and limited efficacy. A recent meta-analysis of 14 prospective trials and 12 case-control studies of BCG vaccination, however, found that it decreased TB incidence by 50 percent and mortality by 70 percent, particularly in children.[xii] The full sequence of the 4,000 genes of M. tuberculosis in 1998 has boosted hopes for a better vaccine.[xiii] 

Workplace:

            Nurses are the health care professionals at highest risk of acquiring TB. Physicians have twice the age-specific incidence rate as the general population. Teaching hospitals care for a large proportion of TB patients in NYC and PPD conversion among junior housestaff reached 10 to 15 percent per year in 1990. Proper isolation practices at New York Presbyterian Hospital have reduced this rate to virtually zero.

PPD Screening:

            Although more than three-quarters of TB patients have contact with a health care provider within the five years preceding diagnosis, less than one-third have had PPD testing, and chemoprophylaxis was given to less than 10 percent of eligible cases. PPD reactivity from BCG vaccination (usually less than 15 mm) declines by 10 percent per year and does not explain PPD results in adults. Unless already positive or treated, PPD testing should be repeated every 6 months to two years while indicated (Table 1). People 35 years or older with no risk factors and a previously normal CXR need not be screened; on the other hand, foreign born diabetics in our clinics should not be ignored.[xiv] Always document size of induration rather than “+” or “-“.

            A positive PPD is presumptive evidence of prior mycobacterial infection and does not occur as a result of prior PPD testing or allergy to the diluent. Anergy is defined as <5 mm induration to antigens from candida, tetanus and mumps. Although not well standardized, anergy panels are useful when immunosuppression is likely in groups with a high prevalence of TB infection (among whom INH prophylaxis would be indicated).^4,11

TABLE 1: Indications for PPD screening

* Members of the immediate family, close social contacts or those sharing indoor environments with  infectious TB patients for substantial periods of time.

            Anergy occurs in regular TB (15 percent), but is more common in pleural or miliary TB (30 to 50 percent), patients with HIV infection (30 percent) or AIDS (70 percent),⁹ malnourished individuals and others with T-cell suppression. Storage problems or subcutaneous administration of PPD also lead to false-negative results.

            False positive reactions are seen in BCG-vaccinated people (within 10 years, rarely > 15mm), and in people from areas with nonpathogenic mycobacteria such as tropical countries and the southeast U.S. In our setting (NYC), positive PPD reactions in BCG-vaccinated persons usually indicate M.Tb. infection.¹¹

Boosting refers to an apparent PPD “conversion” in people who in fact were infected earlier but whose immunologic memory had faded and is then stimulated after repeat tuberculin testing. PPD testing by itself cannot sensitize a noninfected person. Boosting may last one to two years after a PPD, and it may lead to otherwise unnecessary prophylaxis and source-case investigations in congregate settings. In order to avoid such confusion, older people with indications for periodic PPD testing should have a confirmatory PPD test within a month of their first negative result (Table 3).

TABLE 2: Initial PPD strategy in patients over 55

INH Chemoprophylaxis:

            Chemoprophylaxis may prevent infection in PPD-negative contacts of contagious persons (primary prevention), abort disease in those already infected (secondary prevention), and prevent recurrences in those with lung scars from remote disease (tertiary prevention). There is no evidence that prophylactic chemotherapy fosters drug resistance. Current recommendations are based on risk/benefit yields, which vary over time and in different populations (Table 3).^14,[xv] Revised CDC guidelines are expected in spring 2000; these will  be available on the CDC website (www.CDC.gov).

            Without prophylaxis, TB undergoes clinical reactivation in five to 15 percent of PPD-positive subjects (3 percent among nursing home admissions). Since half the time TB reactivates within the first two years of infection, recent converters (or young people) and PPD-contacts of active TB cases are a good target for prophylaxis. Among HIV-infected patients, those with a positive PPD (10 to 20 percent) have a 5 to 10 percent probability of developing TB each year (compared with 0.01 percent in the general population). Asymptomatic subjects with inactive TB changes in CXR (calcified nodes, pleural thickening and lung scars), a positive PPD and no prior treatment are also at high risk for reactivation.

            INH is the most effective drug for TB prevention. In most situations, 10 mg/kg (max 300 mg/day) is used; pyridoxine (25 mg/day) may be given at the same time to avoid risk of neuropathy. The recommended duration of treatment is six months[xvi] (70 percent effective); nine-month regimens are preferred in children.[xvii] Twelve-month regimens are reserved for patients with HIV and those with abnormal CXR.^11,14,15,17  Two-month regimens with RIF/PZA are a reasonable alternative.

            Contraindications to chemoprophylaxis include: active TB, active liver disease and INH hypersensitivity (rash or fever) or hepatotoxicity. Special precautions (i.e., precise dosing and initial and monthly LFT monitoring) should be taken in patients over 35, those with a history of alcohol abuse, chronic liver disease, peripheral neuropathy and pregnancy. It is appropriate to consult the Infectious Disease service in the case of a pregnant patient with a positive PPD; prophylaxis should generally be deferred until late postpartum (3 months) except in HIV-infected patients and recent PPD-converters. INH should not be given in the first trimester of pregnancy; breast feeding is not contraindicated nor is it a substitute for the infant’s chemoprophylaxis if warranted.¹¹

Drug-resistance and INH prophylaxis:

            This is a problem with no definite answer at present. Despite INH-resistance rates of up to 20 percent in NYC, INH is still given to most patients. For PPD-positive contacts of TB patients with known INH-resistance, the 2-month regimen with RIF/PZA is appropriate. A specialist should be consulted in MDRTB cases.

TABLE 3: Indications for INH chemoprophylaxis*

*In each of these cases, active disease should be excluded by a careful history and physical exam, and by CXR (if suspicious, examine serial sputa for AFB and consider biopsy). When in doubt, do not start prophylaxis - consider instead 4-drug treatment for 4 months (appropriate for culture-neg. pulmonary TB).

Diagnosis

            There are two keys in the diagnosis of active TB. First, think TB in any patient with unexplained cough, fever or CXR abnormalities, especially if HIV-infected; and second, obtain adequate specimens before treatment is started. Confirmed or suspected cases of active TB should be placed in isolation and reported by a physician to the Department of Health within two working days [(212) 788-4162]. The PPD is positive in 90 percent of patient with active TB, but it may be negative even with positive induration to control antigens (i.e. PPD-specific anergy).

            In 90 percent of cases, reactivation TB is pulmonary. Extrapulmonary disease is the main clinical presentation in 15 percent of cases, including pleurisy, lymphadenitis (5 percent), GU tract (2-3 percent), bone (1-2 percent), miliary (1.5 percent), and intracranial forms (1 percent). Half of AIDS patients with TB have extrapulmonary involvement (lymph nodes commonly), often concurrent with pulmonary disease.

Radiology:

            The CXR may be suggestive but is never diagnostic for TB. The CXR may look like ARDS in four percent, but in five to ten percent it may be normal; lateral and lordotic views and CT scans may be necessary in some cases. Posterior apical infiltrates with or without cavitation are classical of reactivation TB in immunocompetent hosts, but as seen in Table 4, CXR can vary dramatically among patients with TB.

TABLE 4: Chest Xray patterns in pulmonary TB⁸

In HIV-infected patients, delays in treatment may double mortality.[xviii] Many cases present with primary TB, and CXR may show hilar adenopathy and apical infiltrates. Hilar adenopathy, pleural effusion, and cavitations, common in TB, are rarely seen in PCP or CMV; Kaposi’s sarcoma and lymphoma may cause this pattern but usually have extrapulmonary presentations.

Bacteriology:

            The first sputum specimen should be obtained under supervision. Specimens (>5 cc) should be placed in saline or special containers. Aerosol-induced sputum resembles saliva and will be discarded by the laboratory staff unless labeled “induced.” 

            AFB smear of sputum: Three adequate sputum samples will yield AFB in over 60 percent of cases with pulmonary TB; this figure is as high as 98 percent in those with cavitary disease, but as low as 30 percent in AIDS patients or those with primary or miliary TB. Bronchoalveolar lavage does not improve this yield (it does for culture). If AFB smears are negative in the first three specimens, three additional specimens should be collected in suspected cases.

M.Tb. cultures: Current culture techniques require three to six weeks, and cultures may be negative in up to 20 percent of sputum samples (over 50% in pleurisy, ascites or CSF). Rapid and sensitive radiometric methods expedite AFB identification, and DNA-based tests may become standard in the future (currently approved for rapid species identification in AFB smear-positive specimens).

 Treatment of Active Tuberculosis

            The classic study on the natural history of TB, conducted in India by Narain et al.[xix] during the 1960’s, showed that 30 percent of patients with active TB die in 18 months and 50 percent die in five years. Nearly one-third of the cases improved with little or no treatment; of those with spontaneous “cure,” 28 percent reactivated 15 to 25 years later. In NYC there was a high mortality rate (25 percent in 1991), particularly in those patients infected with HIV, those with MDRTB and the elderly; therapeutic delays were common then (over 1 month in 20 percent) and 90 percent lethal in HIV-positive patients.¹⁸

            Effective medical treatment was introduced  over 25 years ago; the efficacy of the so-called “second line” agents has not been appropriately evaluated, although the quinolones are very useful. In the 1980’s, the classically long treatments (one to two years) were progressively replaced by multi-drug, short-course regimens that include RIF and PZA. Tablets with fixed combinations of INH and RIF are available and recommended.

TABLE 5: Antituberculosis drugs: first-line agents

* By inducing hepatic CYP450, RIF accelerates the clearance of  oral contraceptives, coumadin, methadone (by a third), oral hypoglycemic agents, dapsone, digitalis, anticonvulsants, imidazoles,  cyclosporin, and protease inhibitors.

Hepatitis:

            One of the most feared complications of anti-TB therapy and chemoprophylaxis is hepatitis (INH > RIF), with a case-fatality rate of 7 percent if the drug is not stopped. This complication is rare in young people (0.5 percent in those under 35), but increased with age; the toxicities of INH and RIF are synergistic. Most cases are noted within the first three months of treatment. Transaminase levels up to three times baseline are common (15 percent) and, if asymptomatic, should only lead to continued monitoring. Five-fold elevation of transaminases call for action - consult a specialist before withdrawing any drug!

Drug regimens:

            As nonadherence to medication became appreciated in the 1970’s, short-course regimens emerged and became standard.[xx] Six-month regimens that include three to four drugs in the first two months have proved as effective as prolonged treatment (> 95 percent cure), with minimal increase in toxicity and improved completion rates.²⁰ Drug-therapy should not be stopped, however, before three months of documented culture conversion (six months in HIV).^2,11,17

HIV-infected patients:

            The therapeutic response is as good as in HIV-negative cases, despite disease severity and drug malabsorption; a temporary exacerbation of symptoms (‘paradoxic reaction’) may occur rarely. Although late relapse and reinfection do occur, drug interactions and toxicities are frequent problems; thus treatment should only last 6 to 9 months. Adult patients with TB and unknown HIV status should be counseled to have the test. The combination of anti-TB drugs, AZT and lamuvidine is well-tolerated. However, in patients taking protease inhibitors (or NNRTIs), RIF is contraindicated as suboptimal antiviral levels and RIF toxicity (particularly with Ritonavir) may occur; in such situations low dose rifabutin is recommended.^9,11,[xxi]

TABLE 6: Recommended regimens for treatment of active TB.^9,11,20

Routine follow-up:

            Baseline LFTs should be obtained in every patient; follow-up LFTs are warranted in older patients, those with abnormal baseline levels, and those with history of alcoholism; periodic monitoring is controversial in asymptomatic young patients, but checking LFTs one or two months after starting treatment seems reasonable. Patients who are alcoholic, diabetic, malnourished or elderly should be given pyridoxine (vitamin B6, 25 mg/day) to prevent INH peripheral neuropathy. Patients on EMB should have their color vision and visual acuity monitored monthly.

            Symptoms usually improve after one to two weeks of treatment; AFB cultures become negative after four to 10 weeks of effective treatment (90 percent). Contagiousness drops after two weeks, and isolation may be stopped then in the presence of clinical and microbiological response. CXR usually clears in three to four months and should be obtained at the end of treatment. Patients are followed by the treating physician on a monthly basis to ensure adherence, evaluated drug toxicity, make adjustments and detect recurrence of symptoms. Relapse after cure is extremely rare in HIV-negative patients with pansensitive TB (less than three percent) and continued follow-up after the first year is unnecessary.¹¹

Adherence to drug therapy:

            Adherence is a major problem with all regimens: patient default occurs in 20 to 50 percent of cases and half the time it goes unsuspected.⁶ Monitoring missed appointments, pill counting and testing urine for medication metabolites or serum for hyperuricemia (caused by PZA) may be useful.¹¹ Although patient education and incentives are useful, closely supervised treatment is the preferred strategy to ensure adherence. Directly observed therapy is mandatory in patients with MDRTB and “delinquent” cases. Supervised treatment can be arranged through the Department of Health TB clinic, which you should call for referrals or with questions (304-5420).

Drug resistant TB:

            Random mutation yields drug resistance in 1 of 10^5-8 mycobacteria. In 1950, INH/SM resistance was found in one to two percent of TB cases. In 1991, resistance to at least one anti-TB drug was found in 33 percent of patients in NYC; 19 percent had resistance to both INH and RIF (seven percent if previously untreated), making them MDR cases. After much work and 1 billion dollars, the prevalence of MDR in new patients is now less than three percent. Culturing every patient at the outset and starting a four-drug regimen are critical initial steps. Expert consultation is mandatory in the management of DRTB and treatment failures; prolonged treatment (one to two years) and complex regimens are necessary in patients with MDR-TB.¹⁰

TABLE 7: Management of patients with TB in NYC ^10,11

Table of Contents

Recommended reading:

Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998;393:537-44.

Pablos‑Mendez A, Blustein J, Knirsch CA. The role of diabetes mellitus in the higher prevalence of tuberculosis among Hispanics. Am J Public Health 1997;87:574‑9.

Halsey NA, Coberly JS, Desormameaux J, et al. Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection. Lancet 1998;351:786-92.

Gordin FM, et al. A controlled trial of isoniazid in persons with anergy and HIV infection who are at high risk for tuberculosis. N Engl J Med 1997;337:315-20.

Bishai WR, Graham NMH, Harrington S, et al. Molecular and geographic patterns of tuberculosis transmission after 15 years of directly observed therapy. JAMA 1998;280:1679-1684.

Sahai J, et al. Reduced plasma concentrations of antituberculosis drugs in patients with HIV infection. Ann Intern Med 1997;127:289-93.

Moore M, Onorato IM, McCray E, Castro KG. Trends in drug-resistant tuberculosis in the United States, 1993-1996. JAMA 1997;278:833-7.

Pablos‑Mendez A, Knirsch CA, Barr RG, Lerner BH, Frieden TR. Nonadherence in tuberculosis treatment: predictors and consequences in New York City. Am J Med 1997;102:164‑70.

Zuber PL, McKenna MT, Binkin NJ, Onorato IM, Castro KG. Long‑term risk of tuberculosis among foreign‑born persons in the United States. JAMA 1997;278:304‑7.

Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with the human immunodeficiency virus: principles of therapy and revised recommendations. MMWR 1998;Vol.47, RR-20.

Eagling VA, Back DJ, Barry MG. Differential inhibition of cytochrome P450 isoforms by protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol 1997;44:190-4.

McGregor MM, Olliaro P, Wolmarans L, et al. Efficacy and safety of rifabutin in the treatment of patients with newly diagnosed pulmonary tuberculosis. Am J Respir Crit Care Med 1996;154:1462-7.