- Email: [email protected]
Tuberculosis: From history to current management
Tuberculosis: From History to Current Management By Rob Roy MacGregor (TB) is a disease probaT UBERCULOSIS bly as old as humanity itself. Skeletal remains from the Iron Age have shown pathological lesions that are classic for the disease, and recent examinations of mummified human remains from before the time of Christ have shown acid-fast bacilli and evidence of Mycobacterium tuberculosis by polymerase chain reaction. It is fair to say that TB and man evolved together, and owing to the very high frequency of infection in the past, the human cellmediated immune system can be regarded as having developed in response to the challenge of TB. The importance of this fact has been emphasized by the recent development of epidemic immune deficiency caused by the human immunodeficiencyvirus (HIV), which is causing a secondary epidemic of TB wherever the two pathogens coexist. Thus, although an ancient disease, TB remains a formidable adversary and continues to create new challenges for the modern world. Therefore, this special issue of Seminars in Roentgenology is both timely and necessary in providing state-of-the-art information regarding diagnostic and monitoring approaches for TB. This article will review the epidemiology of TB, its microbiology and pathogenesis, diagnostic methods other than imaging, modern therapy, and the normal and abnormal course of the disease.
sures (Fig 1). 1 After 1953, with effective drugs that rendered patients noninfectious within a few weeks of initiating treatment, new cases declined at a rate of 6.7% per year until 1985 when, under the influence of the growing epidemic of acquired immunodeficiency syndrome (AIDS), new TB cases stabilized at around 22,000 nationwide. These cases have increased yearly thereafter (Fig 2). 2 An estimated 39,000 additional cases of TB have occurred between 1985 and 1991 as a result of the AIDS epidemic. The current behavior of TB in the United States reflects a number of different factors. First, clinical TB develops either because a host is unable to control primary infection (less than 20% of cases) or because an old primary infection (initially controlled by the ceil-mediated immune system) reactivates as a result of some impairment of immunity (more than 80%). Second, because the frequency of transmission within the population has decreased dramatically since the development of effective chemotherapy, most Americans with inactive infection either acquired it years ago and thus are over the age of 40 years or are members of a group with increased risk of primary infection. The latter include minority group members, substance abusers, those born in Third World countries, residents of long-term care facilities
EPIDEMIOLOGY
ABBREVIATIONS
TB, or "consumption" as it was commonly known, was the leading reported cause of death in the United States during the 19th century. In New York City, it was responsible for 19.9% of fatalities in 1800 and 10.8% in 1850, with death rates above 500 per 100,000 of the population. Both the discovery of the transmissible etiologic agent by Robert Koch in 1882 and the sanitarium movement that was established in the 1880s provided a rational approach toward treating the infected patient and reducing the risk of transmission. By 1900, the annual death rate from TB in the United States was 200 per 100,000 of the population. By 1953, the beginning of the chemotherapy era, the rate was down to 12.4, a tribute to public health mea-
AFB, acid-fast bacilli; AIDS, acquired immunodeficiency syndrome; CDC, Centers for Disease Control; CMI, cell-mediated immunity; HIV, human immunodeficiency virus; INH, isoniazid; MDR, multiply drug resistant; PZA, pyrazinamide; TB, tuberculosis
Seminars in Roentgenology, Vol XXVlII, No 2 (April), 1993: pp 101-108
From the Infectious Diseases Division, Department of Medicine, School of Medicine, Universityof Pennsylvania, Philadelphia, PA. Supported in part by US Public Health Service Grant No. 1- UO1-AI-32783. Address reprint requests to Rob Roy MacGregor, MD, Professor of Medicine, Director, Hospital of the University of Pennsylvania AIDS Clinical Trials Unit, 536 Johnson Pavilion/ 6073, University of Pennsylvania, Philadelphia, PA 19104. Copyright 9 1993 by W.B. Saunders Company 0037-198X/93/2802-000855.00/0 101
102
ROB ROY MACGREGOR
Year 1900 v
1905
1910 ,
5O0 400
1915
1920
,
1925
,
,
103Q
1935
l
!
1940
194S
1
!
1959 v
1955 9
1960
1965
!
i
1970 !
1975 !
1980 v
500 400 300
30C
200
20s Case Rate )Active and Inactive Cases)
i
loo 9O
w
5o
6
80 70 60
5O
N 40
Case Rate
30
1908
20
Oth International T8 Col~gress
20
1921 BCG
1908 Mal~tot~x Skill Test
~ria Change)
g
1907 Vor~ Pirquet
1918 1919
4
rnfruenza Epidemic
Skirl Test
3
1904
2
NTA
1961 1959 l
I
Federal TB Grants
I
I
I
I
1914.1918 World War I
Fig 1.
I
I
I
~"~"~ 1938.1945
1950 1953
World War II
Korean War
I
I
I
--
I
I
I
Vietnam War 1975
TB--Case rates and death rates in the United States since 1900.
(including prisons), the poor, and the homeless. Third, public health control of TB represents the interplay of biological, social, and economic factors. Fourth, opportunities for immune dysfunction have increased as a result of immunosuppressive medications and HIV. To see how these factors have influenced TB in the United States, statistics for 1989 should be reviewed. 3 TB differentially affects the older population: rates are 19.7% per 100,000 for people 65 years and older versus 6.6% for those 20 to 24 years of age. Minority group members are also disproportionately represented, with (Log s~le)
f
39,000 Excess Cases
incidence of 30.6% per 100,000 among nonwhites versus 9.5% for whites. Urban black men also have a premature peak of cases in the 20 to 45 year age range because of the influence of HIV. Men have an attack rate twice that for women. Twenty-three percent of cases occurred in the foreign-born, particularly those from Mexico, Haiti, and Asia. Epidemics of TB have occurred in nursing homes, facilities for the mentally retarded, prisons, migrant worker camps, and homeless shelters. Although medication-induced immunosuppression clearly contributes to reactivation of quiescent TB, HIV infection has become the major risk factor for clinical TB. In several recent studies of newly diagnosed urban cases, the frequency of positive HIV antibody tests varied from 23% to 42%, and in New York City, it was 82% among minorities with TB. Thus, in the United States today, TB is predominately a disease of the elderly, the chronically ill, and the disenfranchised. MICROBIOLOGY
i
i
i
i
Year Fig 2. Expected and observed TB cases in the United States from 1980 through 1991: O, observed rate; --expected rate.
Mycobacteria are thin, rod-shaped organisms that have a high proportion of lipids in their cell wall, making them resistant to normal Gram stain. However, they accept basic fuchsin dyes and are resistant to decolorization with acid-
TB: HISTORY AND MANAGEMENT
alcohol, thus acquiring the term "acid-fast." Most pathogenic mycobacteria grow very slowly, with doubling times of 15 to 20 hours versus less than 1 hour for Escherichia coli; thus, growth to visible colonies usually takes 3 to 4 weeks. M tuberculosis and Mycobacterium leprae are most pathogenic to humans, although nature abounds with a variety of other mycobacteria referred to as "nontuberculous mycobacteria" (also called "mycobacteria other than tuberculosis," "atypical," or "anonymous" mycobacteria) and divided by Runyon into four groups on the basis of pigment production (Groups I to III) or rapid growth (Group IV). Mycobacterium kansasii and Mycobacterium avium complex can cause pulmonary infection indistinguishable from that of M tuberculosis. Otherwise, the nontuberculous mycobacteria are generally nonpathogenic, although all groups can cause tissue infection, especially under conditions of local or generalized immune impairment. Mycobacteria can be detected by several staining approaches: the Ziehl-Neelsen stain (using carbol-fuchsin, heat, and methylene blue counterstain), has been supplanted by the Kinyoun stain, which does not require heating; fluorescent staining with auramine or auraminerhodamine emits a bright yellow-orange color that allows for more rapid and accurate scanning of slides and is the stain used most commonly in clinical laboratories. For culture, specimens are inoculated onto Lowenstein-Jensen slants (containing the inhibitor malachite green) and plates of clear Middlebrook medium (permitting inspection for colonial morphology) and examined weekly for growth. Colonies are smeared for organism staining, and recently developed DNA probes can be applied that provide immediate identification of M tuberculosis complex, M avium complex, and Mycobacterium gordonae. Two new broth culture systems can demonstrate growth of mycobacteria in sputum in 1 to 2 weeks, versus 3 to 6 weeks on standard media. In addition, polymerase chain reaction techniques for direct identification of M tuberculosis in sputum smears are under development. Alternatively, M tuberculosis is differentiated from the other mycobacteria by biochemical reactions that include niacin production and inhibition by isoniazid (INH).
103
PATHOGENESIS
M tuberculosis spreads from person to person in 1 to t0 micron-sized droplet nuclei produced when a patient with active respiratory tract infection coughs, shouts, or sings. In this form, these organisms can survive for hours suspended in the air, to be inhaled by anyone sharing the same airspace as the infected patient. The small size of the droplets allow them to evade the mucociliary defense of the upper airway and to reach the respiratory bronchioles or alveoli (usually in the lower lung fields) where they are deposited and start an infection. The proliferating organisms can survive in alveolar macrophages following phagocytosis and spread via the lymphatics to the regional nodes. From there, organisms enter circulation and are disseminated throughout the body where they are phagocytized by endovascular macrophages. During this early dissemination, cell-mediated immunity is developing against mycobacterial antigens, enhanced by the adjuvant action of the the organism's unique cell wall lipids. As a result, within 2 to 6 weeks of the primary infection, sensitized lymphocytes contacting tuberculoprotein elaborate lymphokines that activate macrophages, leading to an intense inflammatory reaction around the foci of infection. Although rarely recognized as evidence of primary TB infection, this inflammatory reaction often causes nonspecific "flu-like" symptoms such as cough, fever, and myalgias. Microscopically, this intense reaction is characterized by lymphocytic infiltration, fibroblast proliferation, and Langhans multinucleated giant cells, organized into so-called "granulomas." The inflammation leads to death of the organisms and cellular necrosis that appears grossly cheesy or "caseous." The end result in most cases is control and resolution of the infection. Nonetheless, some organisms can remain viable in granulomata, posing the risk for reactivation at some distant time when opportunity is provided by a waning of the host's cell-mediated immune response. The only signs of the resolved primary infection are a delayed hypersensitivity response to intradermally injected tuberculoprotein (a positive purified protein derivative skin test) and perhaps radiologically detectable calcification at the site of the primary lung infection
104
ROB ROY MACGREGOR
and its regional lymph nodes, a so-called primary or "Ghon complex." It is critical to understand two aspects of TB pathogenesis: 1. Primary infection is associated with an early dissemination of organisms to multiple sites in the body, creating the potential for later clinical infection of extrapulmonary sites such as bone, kidney, lymph nodes, serosal surfaces, genital tract, and meninges. 2. Cell-mediated immunity (CMI) is essential to control of the primary infection and to maintain residual organisms in a dormant state. Following primary infection, events can take one of several paths: !n a small percent of cases, insufficient immunity develops (often due to factors such as malnutrition, concomitant chronic disease, or immunosuppressive medications and diseases), allowing the primary infection to progress in the lung or disseminated, leading to rapid death unless effective chemotherapy is instituted promptly. In over 95% of cases, CMI proves sufficient, and the primary infection resolves (usually without diagnosis), leaving a lifetime risk of 5% to 8% for reactivation disease if conditions permit. The greatest risk of reactivation is within the first 5 years following infection, perhaps relating to the progressive increased competence of the antituberculous immune response and the resultant reduction in the number of viable organisms. Thereafter, the risk drops sharply, usually requiring a cofactor that impairs immune control of residual organisms, as shown in Table 1. It is estimated that over 90% of new cases of TB occurring each year in the United States represents reactivation of prior infection rather than new acquisition of primary infection. 4 In considering pathogenesis, it now is also important to stress the interaction of M tuberculosis and HIV in co-infected individuals. It has Table 1. Risk Factors for Reactivation of Quiescent Tuberculous Infection
Chronic diseases: chronic obstructive lung disease, cancer, renal failure, heart failure, malnutrition, other chronic debilitating diseases Diseases impairing cell-mediated immunity: HIV infection, lymphoma, leukemia, sarcoid Medications impairing cell-mediated immunity: glucocorticoids, cytotoxic drugs, azathiaprim, cyclosporine Radiation therapy to infected tissues
been said that both are "bad actors" and that they have a bad influence on one another. 5 The outcome of this interaction depends on which organism strikes first. 6 The risk of TB reactivation increases as the immunity of a patient who earlier sustained and controlled primary TB and then became infected with HIV becomes progressively more impaired. Clinical TB can occur with T-helper cell counts as high as 350. Although the manifestations of this reactivation can be atypical, response to treatment is usually as good as that observed in non-HIV patients. In contrast, when HIV infection comes first, immune function can be so impaired when TB is contracted that the organisms thrive and disseminate unopposed. These patients can develop overwhelming primary TB and die in 8 to 12 weeks, often before the infection is even recognized. In parts of the world where TB is endemic, the spread of HIV is causing a catastrophic secondary epidemic of TB; in subSaharan Africa, it is the leading cause of death in HIV-infected people. CLINICAL PRESENTATIONS
The manifestations of TB depend on the sites involved and on the time following reactivation when the diagnosis is made. Pulmonary TB accounts for about 80% of current new cases in the United States. It can be discovered by a chest radiograph taken for other reasons while the patient is still totally asymptomatic. At a slightly later stage, the patient may have nonspecific symptoms of malaise, weight loss, and a dry cough. When the infection is far advanced, the patient may present many of the classic signs and symptoms associated with TB such as fevers, night sweats, productive cough, hemoptysis, and marked weight loss. Only half of the patients diagnosed with pulmonary TB at our hospital presented these classic symptoms, and less than half had temperatures above 100~ 7 Many of those not detected initially had symptoms suggestive of other pulmonary diseases or of occult neoplasms. TB presenting in other organs will induce symptoms characteristic of dysfunction of these organs. For example, tuberculous meningitis presents a picture of chronic progressive lymphocytic meningitis; renal TB can cause hematuria and, in late stage, renal failure; genital TB is a cause of sterility and
TB: HISTORY AND MANAGEMENT
tubovarian abscess; TB can present as a mass lesion in brain, bone, mediastinum, retroperitoneum, and other places, mimicking cancer. It is important to remember that tuberculous infection can occur in any site in the body, owing to the dissemination that occurs early in primary infection. Therefore, the clinician must be alert to the possibility of TB as a cause of virtually any organ dysfunction in a patient with a positive TB skin test. TB in an HIV-infected patient is twice as likely to present at an extrapulmonary site than in the HIV-negative patient. 8 Thus, the symptoms are often atypical for classic TB. Moreover, when patients with far-advanced immunosuppression develop TB, pulmonary infiltrates can be more diffuse and less likely to be apical or cavitary, owing to the inability of the patient to mount an intense inflammatory response. DIAGNOSTIC METHODS
The key to diagnosing TB is a high index of suspicion. The possibility of TB should be considered in all cases of subacute pulmonary disease as well as for patients with fevers of unknown origin or failure to thrive, suggesting occult neoplasm. 7 This is particularly true for patients with an increased risk of TB: the poor, minority group members, the elderly, the foreign-born, and substance abusers. Pulmonary TB continues to account for about 80% of TB infections, and radiographic characteristics will be discussed in subsequent articles. Direct microscopical examination of sputum will disclose acid-fast organisms in about 50% of cases; the tests in use have been described earlier in this article. They are less sensitive than cultures, requiring roughly 104 organisms/ mL to be observed compared with culture sensitivity of less than 10 organisms. Clinicians must assure that true sputum, not saliva, is provided to the laboratory; specimens lacking neutrophils and alveolar macrophages should be rejected. Patients unable to raise sputum spontaneously can have induction by the inhalation of heated hypertonic saline, and fiberoptic bronchoscopy with broncho-alveolar lavage and transbronchial biopsy should be reserved for cases where these methods fail. Gastric aspirates are rarely performed currently for diagnostic material and should never be stained, owing
105
to the number of nonpathogenic acid-fast organisms in normal mouth flora. Smear examination of urine, cerebrospinal fluid, and other body fluids is usually negative because of relatively low numbers of acid-fast bacilli (AFB) present. Cultures are necessary to confirm a diagnosis of TB and to identify the specific mycobacterium responsible. It takes 3 to 4 weeks for an initial isolate to grow to visible colonies. It takes several more weeks to confirm species; as noted, new techniques involving RNA probes and radiometric detection of growth promise to speed this process in the next few years. In areas of low TB incidence, mycobacteria isolated from sputum are more likely to be nontuberculous types such as Mkansasii, Mavium complex, and M gordonae than M tuberculosis. The extended time required for laboratory diagnosis underscores the fact that the initial diagnosis and therapy must antedate microbiological confirmation, and that laboratory data subsequently accrue to support, confirm, or refute this preliminary clinical diagnosis. Biopsy material from diseased tissue will usually demonstrate classical granuloma formation, with or without caseous necrosis. Acid-fast stains of tissue are negative in the majority of cases, owing to low numbers of organisms in tissue (as opposed to sputum). Cultures of infected tissue are more sensitive, yielding mycobacteria in from 40% to 80% of cases confirmed by other criteria. Other laboratory tests are nonspecific. Patients may have an anemia of chronic inflammation, neutropenia or neutrophilia, an elevated sedimentation rate, and/or hypoalbuminemia, especially in advanced disease; however, none of these may be present. Tuberculin skin testing has two uses. First, for patients suspected of active TB, it can indicate whether or not they have ever been infected with M tuberculosis. Any reaction of greater than 5mm induration at 48 to 72 hours is consistent with prior tuberculous infection, although not diagnostic because many people with insignificant prior infections with a nontuberculous mycobacterium or bacillus CalmetteGu6rin vaccination can have reactions in the 5 to 15mm range. A negative reaction, coupled with evidence of ability to react to other antigens such as candida, mumps, or tetanus toxoid,
106
ROB ROY MACGREGOR
strongly suggests that the host's immune system has never been exposed to tuberculoprotein, hence, that the patient's syndrome is not TB. A positive reaction, or a negative one coupled with anergy to all other test antigens, means that TB can still be the proper diagnosis. The second use of tuberculin testing is for discovering healthy individuals who have controlled primary TB and who could benefit from prophylactic treatment with INH to prevent reactivation. Six to 12 months of such treatment will reduce the risk of reactivation by 75% to 90% but because the drug can cause serious hepatitis, criteria for its administration vary according to the subject's relative risks of reactivation and of hepatitis. For people at increased risk of reactivation, it is proper to treat some reactions that may be secondary to nontuberculous infection, but for those with no additional risk factors, the hope is to avoid any unnecessary risk for hepatitis. The current Centers for Disease Control (CDC) recommendations9 use a 3-tiered approach, with 5mm, 10mm, or 15mm used as the threshold for treatment, depending on other clinical factors (see Table 2). Currently, there is great emphasis on discovering HIV-infected patients with positive tuberculin reactions because of the estimated 10% per year risk of reactivation of their TB infection.
Table 2. PPD Reactions Qualifying for Preventive INH Treatment Induration >_ 5ram:
Close contacts of patients with active TEl Persons with HIV infection Persons whose chest radiographs show fibrotic lesions indicating old, untreated TB Induration _> 10ram: Persons with medical risk factors that increase the change of TB Foreign-born persons from high-prevalence countries Low-income persons, including high-risk minorities Intravenous drug users Residents of long-term c a r e facilities such as prisons and nursing homes Other high-risk populations identified locally such as health care workers in some areas Induration _> 15ram: Persons with no additional riskfactors for TB Abbreviations: PPD, purified protein derivative.
THERAPY
A number of changes have evolved in the chemotherapy of TB over the last 20 years. 1~ In addition, drug resistance is becoming an increasing problem in patients who fail to take their medication properly, as well as for their contacts. Before considering specifics of TB treatment, several broad principles are important to remember: 1. Use of antibiotic combinations reduces the likelihood of developing drug resistance. 2. Patient compliance with therapy diminishes as a function of duration on treatment and improved sense of well-being. 3. Hence, the shorter the effective treatment regimen, the better. 4. Noncompliance is strongly associated with development of drug resistance and failure of treatment. 5. Noncompliance is also strongly associated with certain patient characteristics: poverty, substance abuse, social disorder. 6. The best way to assure compliance and successful completion of a therapeutic course is to give intermittent directly observed therapy. 7. Tuberculous organisms that are multiply drug-resistant (MDR stains) are still generally uncommon, but physicians must be alert for evidence that they are present in any patient under their care. 8. MDR stains occur in areas and among patients who are noncompliant with treatment, particularly in poverty areas of large cities, in prisons, and in health-care facilities. The evolution of current TB chemotherapy began in the 1970s with studies performed by the British Medical Research Council in East Africa demonstrating that the standard treatment of TB at that time, mainly 18 to 24 months of INH + ethambutol, could be shortened to 9 months by the use of multiple drug regimens containing INH and rifampin (rif). 1233 Further studies from Africa, Hong Kong, and finally the United States have shown that 9 months of INH + rif, or 6-month courses using INH/rif plus pyrazinamide (PZA) for the first 2 months, followed by INH/rif alone for the last four all produced 97% to 98% cure rates. Finally, stud-
TB: HISTORY AND MANAGEMENT
ies have proven that use of intermittent dosing to assure compliance does not reduce the effectiveness of these short course regimens. 14 Modern chemotherapy is based on these studies. In June 1992, the CDC of the United States Public Health Service made the following recommendation for initial treatment of TB in the United States15: For the first 8 weeks: INH/rif/PZA should be administered daily (plus ethambutol or streptomycin until susceptibility to INH and rifampin is demonstrated), followed by INH/rif daily or twice weekly for 16 more weeks. Treatment should continue for at least 6 months, and 3 months after the first negative culture. Alternatively, shorter daily regimens followed by intermittent regimens are also recommended as effective and helpful in assuring compliance with therapy (Table
3). When drug resistance is suspected or known, at least two new agents to which the patient has not been exposed must be added at once; addition of a single drug to the patient's regimen presents too great a risk of inducing additional resistance. Risk factors for resistance include previous treatment, prior noncompliance, and acquisition in an area of known drug resistance (eg, certain United States cities such as New York, Newark, and Miami, third-world countries, and institutions such as prisons and homeless shelters). Other treatment modalities to be remembered include rest, diet, surgery, and glucocorticoid drugs. The first two helped many patients to control their disease in the prechemotherapy era. Surgery is still a useful option for removing foci of resistant organisms, particularly if it can be accompanied by aggressive multidrug therapy to prevent development of sinus tracts. Table 3. CDC Options for the Initial Treatment of TB First 8 weeks:
INH/rif/PZA daily [+ EMB or SM until organism proven susceptible to INH/rif] Next 16 weeks: INH/rif daily or twice weekly OR First 2 weeks: INH/rif/PZA/EMB or SM daily Next 6 weeks: INH/rif/PZA/EMB or SM twice weekly Next 16 weeks: INH/rif twice weekly OR All 24 weeks: INH/rif/PZA/EMB or SM three times weekly All intermittent administration must be directly observed.
107
Finally, steroid therapy for 4 to 6 weeks in patients receiving chemotherapy to which their organism is susceptible can reduce the period of generalized malaise (caused by the antituberculous inflammatory reaction), resulting in more rapid clinical recovery without adverse effects on bacteriological cure. PATIENT MANAGEMENT AND DISEASE COURSE
Initially, patients should be placed in respiratory isolation on the basis of a clinical picture consistent with TB; waiting for confirmation of the diagnosis will expose health care workers and fellow patients to the risk of infection. When the presentation is highly suggestive of TB, it is prudent to initiate chemotherapy as well. Thereafter, if stains of sputum demonstrate AFB, treatment can continue with confidence; if strains are negative for AFB, the diagnosis of TB is not excluded, as up to 50% of patients with active disease can have a negative AFB smear. (Contrarily, a negative smear generally is viewed as indicating a lower concentration of organisms and thus a lower degree of infectiousness to others.) Patients on effective chemotherapy will usually respond within 1 to 2 weeks with a decrease in cough, a reduction in fever, an increased appetite, and an improved sense of well-being. The decision to discontinue respiratory isolation in a patient on therapy has become more complicated with the increase in drug resistance. Prior studies have shown that patients stop transmitting the organism within 1 to 2 weeks after starting effective therapy, 16-18and so most centers had adopted an arbitrary time such as 2 weeks on therapy to discontinue respiratory isolation. CDC now recommends that three criteria be met to remove a patient from respiratory isolation in a pressure-negative room: (1) administration of chemotherapy for 2 weeks; (2) clinical evidence of a therapeutic response, such as decreased cough, fever, or malaise; and (3) microbiological evidence of a response, specifically a decrease in the number of AFB seen on sputum smear. ~7 Outpatient management of patients on therapy consists of measurement of clinical improvement and tolerance of drugs. CDC recommends
108
ROB ROY MACGREGOR
visits for questioning and examination for signs and symptoms of drug toxicity and compliance twice monthly for the first 2 months, and then once monthly. 15 Sputum smears are examined and cultured twice monthly until negative and then at monthly intervals for the treatment course. Continued smear or culture positivity after 3 months is unusual and indicates need for further evaluation. Baseline hematology and liver chemistries should be measured in patients over 35 years of age, but then should be repeated only when symptoms suggest toxicity.
Serious hepatitis is uncommon, 2~ but patients should be warned to call the physician with suspicious symptoms and should also be warned to discontinue treatment if unable to consult. Chest radiographs change slowly during therapy. Hence, many consultants advise follow-up examination at 3-month intervals. Once the treatment course is completed without complication, patients may be discharged from care with instructions to return only if symptoms suggestive of relapse occur. Routine follow-up is not cost effective.
REFERENCES
1. US Department of Health, Education, and Welfare. Extrapulmonary Tuberculosis in the United States (HEW Publication No. [CDC] 78-8360). Atlanta, GA, US Government Printing Office, September 1978 2. American Thoracic Society: Control of tuberculosis in the United States. Official American Thoracic Society Statement. Am Rev Respir Dis 146:1623-1633, 1992 3. Centers for Disease Control: Tuberculosis Statistics in the United States, 1989 (HHS Publication No. [CDC] 91-8322). Atlanta, GA, Centers for Disease Control, Division of Tuberculosis Elimination, August 1991 4. Mangura BT, Reichman LB: Pulmonary tuberculosis, in Pennington JE (ed): Respiratory Infections: Diagnosis and Management, (ed 2). New York, NY, Raven Press, 1988 5. CurranJ: Public policy implications ofthe tuberculosis/ HIV epidemics. Presented at Session 64. Tuberculosis & HIV, Eighth International Conference on AIDS/Third STD World Congress, Amsterdam, Netherlands, July 21, 1992 6. FitzGerald JM, Grzybowski S, Allen EA: The impact of human immunodeficiency virus infection on tuberculosis and its control. Chest 100:191-200, 1991 7. MacGregor RR: A year's experience with tuberculosis in a private urban teaching hospital in the postsanitorium era. Am J Med 58:221-228, 1975 8. Shafer RW, Kim DS, Weiss JP, et al: Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine 70:384-397, 1991 9. American Thoracic Society/Centers for Disease Control: Diagnostic standards and classification of tuberculosis. Am Rev Respir Dis 142:725-735, 1990 10. Dutt AK, Stead WW: Chemotherapy of tuberculosis for the 1980s. Clin Chest Med 4:243-252, 1980
11. Davidson PT, Le HQ: Drug treatment of tuberculosis-1992. Drugs 43:651-673, 1992 12. Fox W, Mitchison DA: Short-course chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 111:325352, 1975 13. Fox W: Whither short-course chemotherapy? Brit J Dis Chest 75:331-357, 1981 14. Dutt AK, Jones L, Stead WW: Short-course chemotherapy for tuberculosis with largely twice-weekly isoniadizrifampin. Chest 75:441-447, 1979 15. Prevention and control of tuberculosis in migrant farm workers. MMWR 41:1-15, June 5, 1992 (suppl RR-10) 16. Riley RL, Mills CC, O'Grady F, et al: Infectiousness of air from a tuberculosis ward. Am Rev Respir Dis 85:511-525, 1962 17. Kamat SR, Dawson JJ, Devadatta S, et al: A controlled study of the influence of segregation of tuberculosis patients for 1 year on the attack rate of tuberculosis in a five-year period in close family contacts in South India. Bull WHO 34:517-532, 1966 18. Gunnels JJ, Bates JH, Swindall H: Infectivity of sputum-positive tuberculosis patients on chemotherapy. Am Rev Respir Dis 109:323-330, 1974 19. Guidelines for preventing the transmission of tuberculosis in health care settings, with special focus on HIVrelated issues. MMWR 39:1-29, 1990 (suppl RR-17) 20. Kopanoff DE, Snider DE, Caras GJ: Isoniazidrelated hepatitis. A US Public Health Service cooperative surveillance study. Am Rev Respir Dis 117:991-1001, 1978 21. Gangadharam PRJ: Isoniazid, rifampin, and hepatotoxicity. Am Rev Respir Dis 133:963-965, 1986
sures (Fig 1). 1 After 1953, with effective drugs that rendered patients noninfectious within a few weeks of initiating treatment, new cases declined at a rate of 6.7% per year until 1985 when, under the influence of the growing epidemic of acquired immunodeficiency syndrome (AIDS), new TB cases stabilized at around 22,000 nationwide. These cases have increased yearly thereafter (Fig 2). 2 An estimated 39,000 additional cases of TB have occurred between 1985 and 1991 as a result of the AIDS epidemic. The current behavior of TB in the United States reflects a number of different factors. First, clinical TB develops either because a host is unable to control primary infection (less than 20% of cases) or because an old primary infection (initially controlled by the ceil-mediated immune system) reactivates as a result of some impairment of immunity (more than 80%). Second, because the frequency of transmission within the population has decreased dramatically since the development of effective chemotherapy, most Americans with inactive infection either acquired it years ago and thus are over the age of 40 years or are members of a group with increased risk of primary infection. The latter include minority group members, substance abusers, those born in Third World countries, residents of long-term care facilities
EPIDEMIOLOGY
ABBREVIATIONS
TB, or "consumption" as it was commonly known, was the leading reported cause of death in the United States during the 19th century. In New York City, it was responsible for 19.9% of fatalities in 1800 and 10.8% in 1850, with death rates above 500 per 100,000 of the population. Both the discovery of the transmissible etiologic agent by Robert Koch in 1882 and the sanitarium movement that was established in the 1880s provided a rational approach toward treating the infected patient and reducing the risk of transmission. By 1900, the annual death rate from TB in the United States was 200 per 100,000 of the population. By 1953, the beginning of the chemotherapy era, the rate was down to 12.4, a tribute to public health mea-
AFB, acid-fast bacilli; AIDS, acquired immunodeficiency syndrome; CDC, Centers for Disease Control; CMI, cell-mediated immunity; HIV, human immunodeficiency virus; INH, isoniazid; MDR, multiply drug resistant; PZA, pyrazinamide; TB, tuberculosis
Seminars in Roentgenology, Vol XXVlII, No 2 (April), 1993: pp 101-108
From the Infectious Diseases Division, Department of Medicine, School of Medicine, Universityof Pennsylvania, Philadelphia, PA. Supported in part by US Public Health Service Grant No. 1- UO1-AI-32783. Address reprint requests to Rob Roy MacGregor, MD, Professor of Medicine, Director, Hospital of the University of Pennsylvania AIDS Clinical Trials Unit, 536 Johnson Pavilion/ 6073, University of Pennsylvania, Philadelphia, PA 19104. Copyright 9 1993 by W.B. Saunders Company 0037-198X/93/2802-000855.00/0 101
102
ROB ROY MACGREGOR
Year 1900 v
1905
1910 ,
5O0 400
1915
1920
,
1925
,
,
103Q
1935
l
!
1940
194S
1
!
1959 v
1955 9
1960
1965
!
i
1970 !
1975 !
1980 v
500 400 300
30C
200
20s Case Rate )Active and Inactive Cases)
i
loo 9O
w
5o
6
80 70 60
5O
N 40
Case Rate
30
1908
20
Oth International T8 Col~gress
20
1921 BCG
1908 Mal~tot~x Skill Test
~ria Change)
g
1907 Vor~ Pirquet
1918 1919
4
rnfruenza Epidemic
Skirl Test
3
1904
2
NTA
1961 1959 l
I
Federal TB Grants
I
I
I
I
1914.1918 World War I
Fig 1.
I
I
I
~"~"~ 1938.1945
1950 1953
World War II
Korean War
I
I
I
--
I
I
I
Vietnam War 1975
TB--Case rates and death rates in the United States since 1900.
(including prisons), the poor, and the homeless. Third, public health control of TB represents the interplay of biological, social, and economic factors. Fourth, opportunities for immune dysfunction have increased as a result of immunosuppressive medications and HIV. To see how these factors have influenced TB in the United States, statistics for 1989 should be reviewed. 3 TB differentially affects the older population: rates are 19.7% per 100,000 for people 65 years and older versus 6.6% for those 20 to 24 years of age. Minority group members are also disproportionately represented, with (Log s~le)
f
39,000 Excess Cases
incidence of 30.6% per 100,000 among nonwhites versus 9.5% for whites. Urban black men also have a premature peak of cases in the 20 to 45 year age range because of the influence of HIV. Men have an attack rate twice that for women. Twenty-three percent of cases occurred in the foreign-born, particularly those from Mexico, Haiti, and Asia. Epidemics of TB have occurred in nursing homes, facilities for the mentally retarded, prisons, migrant worker camps, and homeless shelters. Although medication-induced immunosuppression clearly contributes to reactivation of quiescent TB, HIV infection has become the major risk factor for clinical TB. In several recent studies of newly diagnosed urban cases, the frequency of positive HIV antibody tests varied from 23% to 42%, and in New York City, it was 82% among minorities with TB. Thus, in the United States today, TB is predominately a disease of the elderly, the chronically ill, and the disenfranchised. MICROBIOLOGY
i
i
i
i
Year Fig 2. Expected and observed TB cases in the United States from 1980 through 1991: O, observed rate; --expected rate.
Mycobacteria are thin, rod-shaped organisms that have a high proportion of lipids in their cell wall, making them resistant to normal Gram stain. However, they accept basic fuchsin dyes and are resistant to decolorization with acid-
TB: HISTORY AND MANAGEMENT
alcohol, thus acquiring the term "acid-fast." Most pathogenic mycobacteria grow very slowly, with doubling times of 15 to 20 hours versus less than 1 hour for Escherichia coli; thus, growth to visible colonies usually takes 3 to 4 weeks. M tuberculosis and Mycobacterium leprae are most pathogenic to humans, although nature abounds with a variety of other mycobacteria referred to as "nontuberculous mycobacteria" (also called "mycobacteria other than tuberculosis," "atypical," or "anonymous" mycobacteria) and divided by Runyon into four groups on the basis of pigment production (Groups I to III) or rapid growth (Group IV). Mycobacterium kansasii and Mycobacterium avium complex can cause pulmonary infection indistinguishable from that of M tuberculosis. Otherwise, the nontuberculous mycobacteria are generally nonpathogenic, although all groups can cause tissue infection, especially under conditions of local or generalized immune impairment. Mycobacteria can be detected by several staining approaches: the Ziehl-Neelsen stain (using carbol-fuchsin, heat, and methylene blue counterstain), has been supplanted by the Kinyoun stain, which does not require heating; fluorescent staining with auramine or auraminerhodamine emits a bright yellow-orange color that allows for more rapid and accurate scanning of slides and is the stain used most commonly in clinical laboratories. For culture, specimens are inoculated onto Lowenstein-Jensen slants (containing the inhibitor malachite green) and plates of clear Middlebrook medium (permitting inspection for colonial morphology) and examined weekly for growth. Colonies are smeared for organism staining, and recently developed DNA probes can be applied that provide immediate identification of M tuberculosis complex, M avium complex, and Mycobacterium gordonae. Two new broth culture systems can demonstrate growth of mycobacteria in sputum in 1 to 2 weeks, versus 3 to 6 weeks on standard media. In addition, polymerase chain reaction techniques for direct identification of M tuberculosis in sputum smears are under development. Alternatively, M tuberculosis is differentiated from the other mycobacteria by biochemical reactions that include niacin production and inhibition by isoniazid (INH).
103
PATHOGENESIS
M tuberculosis spreads from person to person in 1 to t0 micron-sized droplet nuclei produced when a patient with active respiratory tract infection coughs, shouts, or sings. In this form, these organisms can survive for hours suspended in the air, to be inhaled by anyone sharing the same airspace as the infected patient. The small size of the droplets allow them to evade the mucociliary defense of the upper airway and to reach the respiratory bronchioles or alveoli (usually in the lower lung fields) where they are deposited and start an infection. The proliferating organisms can survive in alveolar macrophages following phagocytosis and spread via the lymphatics to the regional nodes. From there, organisms enter circulation and are disseminated throughout the body where they are phagocytized by endovascular macrophages. During this early dissemination, cell-mediated immunity is developing against mycobacterial antigens, enhanced by the adjuvant action of the the organism's unique cell wall lipids. As a result, within 2 to 6 weeks of the primary infection, sensitized lymphocytes contacting tuberculoprotein elaborate lymphokines that activate macrophages, leading to an intense inflammatory reaction around the foci of infection. Although rarely recognized as evidence of primary TB infection, this inflammatory reaction often causes nonspecific "flu-like" symptoms such as cough, fever, and myalgias. Microscopically, this intense reaction is characterized by lymphocytic infiltration, fibroblast proliferation, and Langhans multinucleated giant cells, organized into so-called "granulomas." The inflammation leads to death of the organisms and cellular necrosis that appears grossly cheesy or "caseous." The end result in most cases is control and resolution of the infection. Nonetheless, some organisms can remain viable in granulomata, posing the risk for reactivation at some distant time when opportunity is provided by a waning of the host's cell-mediated immune response. The only signs of the resolved primary infection are a delayed hypersensitivity response to intradermally injected tuberculoprotein (a positive purified protein derivative skin test) and perhaps radiologically detectable calcification at the site of the primary lung infection
104
ROB ROY MACGREGOR
and its regional lymph nodes, a so-called primary or "Ghon complex." It is critical to understand two aspects of TB pathogenesis: 1. Primary infection is associated with an early dissemination of organisms to multiple sites in the body, creating the potential for later clinical infection of extrapulmonary sites such as bone, kidney, lymph nodes, serosal surfaces, genital tract, and meninges. 2. Cell-mediated immunity (CMI) is essential to control of the primary infection and to maintain residual organisms in a dormant state. Following primary infection, events can take one of several paths: !n a small percent of cases, insufficient immunity develops (often due to factors such as malnutrition, concomitant chronic disease, or immunosuppressive medications and diseases), allowing the primary infection to progress in the lung or disseminated, leading to rapid death unless effective chemotherapy is instituted promptly. In over 95% of cases, CMI proves sufficient, and the primary infection resolves (usually without diagnosis), leaving a lifetime risk of 5% to 8% for reactivation disease if conditions permit. The greatest risk of reactivation is within the first 5 years following infection, perhaps relating to the progressive increased competence of the antituberculous immune response and the resultant reduction in the number of viable organisms. Thereafter, the risk drops sharply, usually requiring a cofactor that impairs immune control of residual organisms, as shown in Table 1. It is estimated that over 90% of new cases of TB occurring each year in the United States represents reactivation of prior infection rather than new acquisition of primary infection. 4 In considering pathogenesis, it now is also important to stress the interaction of M tuberculosis and HIV in co-infected individuals. It has Table 1. Risk Factors for Reactivation of Quiescent Tuberculous Infection
Chronic diseases: chronic obstructive lung disease, cancer, renal failure, heart failure, malnutrition, other chronic debilitating diseases Diseases impairing cell-mediated immunity: HIV infection, lymphoma, leukemia, sarcoid Medications impairing cell-mediated immunity: glucocorticoids, cytotoxic drugs, azathiaprim, cyclosporine Radiation therapy to infected tissues
been said that both are "bad actors" and that they have a bad influence on one another. 5 The outcome of this interaction depends on which organism strikes first. 6 The risk of TB reactivation increases as the immunity of a patient who earlier sustained and controlled primary TB and then became infected with HIV becomes progressively more impaired. Clinical TB can occur with T-helper cell counts as high as 350. Although the manifestations of this reactivation can be atypical, response to treatment is usually as good as that observed in non-HIV patients. In contrast, when HIV infection comes first, immune function can be so impaired when TB is contracted that the organisms thrive and disseminate unopposed. These patients can develop overwhelming primary TB and die in 8 to 12 weeks, often before the infection is even recognized. In parts of the world where TB is endemic, the spread of HIV is causing a catastrophic secondary epidemic of TB; in subSaharan Africa, it is the leading cause of death in HIV-infected people. CLINICAL PRESENTATIONS
The manifestations of TB depend on the sites involved and on the time following reactivation when the diagnosis is made. Pulmonary TB accounts for about 80% of current new cases in the United States. It can be discovered by a chest radiograph taken for other reasons while the patient is still totally asymptomatic. At a slightly later stage, the patient may have nonspecific symptoms of malaise, weight loss, and a dry cough. When the infection is far advanced, the patient may present many of the classic signs and symptoms associated with TB such as fevers, night sweats, productive cough, hemoptysis, and marked weight loss. Only half of the patients diagnosed with pulmonary TB at our hospital presented these classic symptoms, and less than half had temperatures above 100~ 7 Many of those not detected initially had symptoms suggestive of other pulmonary diseases or of occult neoplasms. TB presenting in other organs will induce symptoms characteristic of dysfunction of these organs. For example, tuberculous meningitis presents a picture of chronic progressive lymphocytic meningitis; renal TB can cause hematuria and, in late stage, renal failure; genital TB is a cause of sterility and
TB: HISTORY AND MANAGEMENT
tubovarian abscess; TB can present as a mass lesion in brain, bone, mediastinum, retroperitoneum, and other places, mimicking cancer. It is important to remember that tuberculous infection can occur in any site in the body, owing to the dissemination that occurs early in primary infection. Therefore, the clinician must be alert to the possibility of TB as a cause of virtually any organ dysfunction in a patient with a positive TB skin test. TB in an HIV-infected patient is twice as likely to present at an extrapulmonary site than in the HIV-negative patient. 8 Thus, the symptoms are often atypical for classic TB. Moreover, when patients with far-advanced immunosuppression develop TB, pulmonary infiltrates can be more diffuse and less likely to be apical or cavitary, owing to the inability of the patient to mount an intense inflammatory response. DIAGNOSTIC METHODS
The key to diagnosing TB is a high index of suspicion. The possibility of TB should be considered in all cases of subacute pulmonary disease as well as for patients with fevers of unknown origin or failure to thrive, suggesting occult neoplasm. 7 This is particularly true for patients with an increased risk of TB: the poor, minority group members, the elderly, the foreign-born, and substance abusers. Pulmonary TB continues to account for about 80% of TB infections, and radiographic characteristics will be discussed in subsequent articles. Direct microscopical examination of sputum will disclose acid-fast organisms in about 50% of cases; the tests in use have been described earlier in this article. They are less sensitive than cultures, requiring roughly 104 organisms/ mL to be observed compared with culture sensitivity of less than 10 organisms. Clinicians must assure that true sputum, not saliva, is provided to the laboratory; specimens lacking neutrophils and alveolar macrophages should be rejected. Patients unable to raise sputum spontaneously can have induction by the inhalation of heated hypertonic saline, and fiberoptic bronchoscopy with broncho-alveolar lavage and transbronchial biopsy should be reserved for cases where these methods fail. Gastric aspirates are rarely performed currently for diagnostic material and should never be stained, owing
105
to the number of nonpathogenic acid-fast organisms in normal mouth flora. Smear examination of urine, cerebrospinal fluid, and other body fluids is usually negative because of relatively low numbers of acid-fast bacilli (AFB) present. Cultures are necessary to confirm a diagnosis of TB and to identify the specific mycobacterium responsible. It takes 3 to 4 weeks for an initial isolate to grow to visible colonies. It takes several more weeks to confirm species; as noted, new techniques involving RNA probes and radiometric detection of growth promise to speed this process in the next few years. In areas of low TB incidence, mycobacteria isolated from sputum are more likely to be nontuberculous types such as Mkansasii, Mavium complex, and M gordonae than M tuberculosis. The extended time required for laboratory diagnosis underscores the fact that the initial diagnosis and therapy must antedate microbiological confirmation, and that laboratory data subsequently accrue to support, confirm, or refute this preliminary clinical diagnosis. Biopsy material from diseased tissue will usually demonstrate classical granuloma formation, with or without caseous necrosis. Acid-fast stains of tissue are negative in the majority of cases, owing to low numbers of organisms in tissue (as opposed to sputum). Cultures of infected tissue are more sensitive, yielding mycobacteria in from 40% to 80% of cases confirmed by other criteria. Other laboratory tests are nonspecific. Patients may have an anemia of chronic inflammation, neutropenia or neutrophilia, an elevated sedimentation rate, and/or hypoalbuminemia, especially in advanced disease; however, none of these may be present. Tuberculin skin testing has two uses. First, for patients suspected of active TB, it can indicate whether or not they have ever been infected with M tuberculosis. Any reaction of greater than 5mm induration at 48 to 72 hours is consistent with prior tuberculous infection, although not diagnostic because many people with insignificant prior infections with a nontuberculous mycobacterium or bacillus CalmetteGu6rin vaccination can have reactions in the 5 to 15mm range. A negative reaction, coupled with evidence of ability to react to other antigens such as candida, mumps, or tetanus toxoid,
106
ROB ROY MACGREGOR
strongly suggests that the host's immune system has never been exposed to tuberculoprotein, hence, that the patient's syndrome is not TB. A positive reaction, or a negative one coupled with anergy to all other test antigens, means that TB can still be the proper diagnosis. The second use of tuberculin testing is for discovering healthy individuals who have controlled primary TB and who could benefit from prophylactic treatment with INH to prevent reactivation. Six to 12 months of such treatment will reduce the risk of reactivation by 75% to 90% but because the drug can cause serious hepatitis, criteria for its administration vary according to the subject's relative risks of reactivation and of hepatitis. For people at increased risk of reactivation, it is proper to treat some reactions that may be secondary to nontuberculous infection, but for those with no additional risk factors, the hope is to avoid any unnecessary risk for hepatitis. The current Centers for Disease Control (CDC) recommendations9 use a 3-tiered approach, with 5mm, 10mm, or 15mm used as the threshold for treatment, depending on other clinical factors (see Table 2). Currently, there is great emphasis on discovering HIV-infected patients with positive tuberculin reactions because of the estimated 10% per year risk of reactivation of their TB infection.
Table 2. PPD Reactions Qualifying for Preventive INH Treatment Induration >_ 5ram:
Close contacts of patients with active TEl Persons with HIV infection Persons whose chest radiographs show fibrotic lesions indicating old, untreated TB Induration _> 10ram: Persons with medical risk factors that increase the change of TB Foreign-born persons from high-prevalence countries Low-income persons, including high-risk minorities Intravenous drug users Residents of long-term c a r e facilities such as prisons and nursing homes Other high-risk populations identified locally such as health care workers in some areas Induration _> 15ram: Persons with no additional riskfactors for TB Abbreviations: PPD, purified protein derivative.
THERAPY
A number of changes have evolved in the chemotherapy of TB over the last 20 years. 1~ In addition, drug resistance is becoming an increasing problem in patients who fail to take their medication properly, as well as for their contacts. Before considering specifics of TB treatment, several broad principles are important to remember: 1. Use of antibiotic combinations reduces the likelihood of developing drug resistance. 2. Patient compliance with therapy diminishes as a function of duration on treatment and improved sense of well-being. 3. Hence, the shorter the effective treatment regimen, the better. 4. Noncompliance is strongly associated with development of drug resistance and failure of treatment. 5. Noncompliance is also strongly associated with certain patient characteristics: poverty, substance abuse, social disorder. 6. The best way to assure compliance and successful completion of a therapeutic course is to give intermittent directly observed therapy. 7. Tuberculous organisms that are multiply drug-resistant (MDR stains) are still generally uncommon, but physicians must be alert for evidence that they are present in any patient under their care. 8. MDR stains occur in areas and among patients who are noncompliant with treatment, particularly in poverty areas of large cities, in prisons, and in health-care facilities. The evolution of current TB chemotherapy began in the 1970s with studies performed by the British Medical Research Council in East Africa demonstrating that the standard treatment of TB at that time, mainly 18 to 24 months of INH + ethambutol, could be shortened to 9 months by the use of multiple drug regimens containing INH and rifampin (rif). 1233 Further studies from Africa, Hong Kong, and finally the United States have shown that 9 months of INH + rif, or 6-month courses using INH/rif plus pyrazinamide (PZA) for the first 2 months, followed by INH/rif alone for the last four all produced 97% to 98% cure rates. Finally, stud-
TB: HISTORY AND MANAGEMENT
ies have proven that use of intermittent dosing to assure compliance does not reduce the effectiveness of these short course regimens. 14 Modern chemotherapy is based on these studies. In June 1992, the CDC of the United States Public Health Service made the following recommendation for initial treatment of TB in the United States15: For the first 8 weeks: INH/rif/PZA should be administered daily (plus ethambutol or streptomycin until susceptibility to INH and rifampin is demonstrated), followed by INH/rif daily or twice weekly for 16 more weeks. Treatment should continue for at least 6 months, and 3 months after the first negative culture. Alternatively, shorter daily regimens followed by intermittent regimens are also recommended as effective and helpful in assuring compliance with therapy (Table
3). When drug resistance is suspected or known, at least two new agents to which the patient has not been exposed must be added at once; addition of a single drug to the patient's regimen presents too great a risk of inducing additional resistance. Risk factors for resistance include previous treatment, prior noncompliance, and acquisition in an area of known drug resistance (eg, certain United States cities such as New York, Newark, and Miami, third-world countries, and institutions such as prisons and homeless shelters). Other treatment modalities to be remembered include rest, diet, surgery, and glucocorticoid drugs. The first two helped many patients to control their disease in the prechemotherapy era. Surgery is still a useful option for removing foci of resistant organisms, particularly if it can be accompanied by aggressive multidrug therapy to prevent development of sinus tracts. Table 3. CDC Options for the Initial Treatment of TB First 8 weeks:
INH/rif/PZA daily [+ EMB or SM until organism proven susceptible to INH/rif] Next 16 weeks: INH/rif daily or twice weekly OR First 2 weeks: INH/rif/PZA/EMB or SM daily Next 6 weeks: INH/rif/PZA/EMB or SM twice weekly Next 16 weeks: INH/rif twice weekly OR All 24 weeks: INH/rif/PZA/EMB or SM three times weekly All intermittent administration must be directly observed.
107
Finally, steroid therapy for 4 to 6 weeks in patients receiving chemotherapy to which their organism is susceptible can reduce the period of generalized malaise (caused by the antituberculous inflammatory reaction), resulting in more rapid clinical recovery without adverse effects on bacteriological cure. PATIENT MANAGEMENT AND DISEASE COURSE
Initially, patients should be placed in respiratory isolation on the basis of a clinical picture consistent with TB; waiting for confirmation of the diagnosis will expose health care workers and fellow patients to the risk of infection. When the presentation is highly suggestive of TB, it is prudent to initiate chemotherapy as well. Thereafter, if stains of sputum demonstrate AFB, treatment can continue with confidence; if strains are negative for AFB, the diagnosis of TB is not excluded, as up to 50% of patients with active disease can have a negative AFB smear. (Contrarily, a negative smear generally is viewed as indicating a lower concentration of organisms and thus a lower degree of infectiousness to others.) Patients on effective chemotherapy will usually respond within 1 to 2 weeks with a decrease in cough, a reduction in fever, an increased appetite, and an improved sense of well-being. The decision to discontinue respiratory isolation in a patient on therapy has become more complicated with the increase in drug resistance. Prior studies have shown that patients stop transmitting the organism within 1 to 2 weeks after starting effective therapy, 16-18and so most centers had adopted an arbitrary time such as 2 weeks on therapy to discontinue respiratory isolation. CDC now recommends that three criteria be met to remove a patient from respiratory isolation in a pressure-negative room: (1) administration of chemotherapy for 2 weeks; (2) clinical evidence of a therapeutic response, such as decreased cough, fever, or malaise; and (3) microbiological evidence of a response, specifically a decrease in the number of AFB seen on sputum smear. ~7 Outpatient management of patients on therapy consists of measurement of clinical improvement and tolerance of drugs. CDC recommends
108
ROB ROY MACGREGOR
visits for questioning and examination for signs and symptoms of drug toxicity and compliance twice monthly for the first 2 months, and then once monthly. 15 Sputum smears are examined and cultured twice monthly until negative and then at monthly intervals for the treatment course. Continued smear or culture positivity after 3 months is unusual and indicates need for further evaluation. Baseline hematology and liver chemistries should be measured in patients over 35 years of age, but then should be repeated only when symptoms suggest toxicity.
Serious hepatitis is uncommon, 2~ but patients should be warned to call the physician with suspicious symptoms and should also be warned to discontinue treatment if unable to consult. Chest radiographs change slowly during therapy. Hence, many consultants advise follow-up examination at 3-month intervals. Once the treatment course is completed without complication, patients may be discharged from care with instructions to return only if symptoms suggestive of relapse occur. Routine follow-up is not cost effective.
REFERENCES
1. US Department of Health, Education, and Welfare. Extrapulmonary Tuberculosis in the United States (HEW Publication No. [CDC] 78-8360). Atlanta, GA, US Government Printing Office, September 1978 2. American Thoracic Society: Control of tuberculosis in the United States. Official American Thoracic Society Statement. Am Rev Respir Dis 146:1623-1633, 1992 3. Centers for Disease Control: Tuberculosis Statistics in the United States, 1989 (HHS Publication No. [CDC] 91-8322). Atlanta, GA, Centers for Disease Control, Division of Tuberculosis Elimination, August 1991 4. Mangura BT, Reichman LB: Pulmonary tuberculosis, in Pennington JE (ed): Respiratory Infections: Diagnosis and Management, (ed 2). New York, NY, Raven Press, 1988 5. CurranJ: Public policy implications ofthe tuberculosis/ HIV epidemics. Presented at Session 64. Tuberculosis & HIV, Eighth International Conference on AIDS/Third STD World Congress, Amsterdam, Netherlands, July 21, 1992 6. FitzGerald JM, Grzybowski S, Allen EA: The impact of human immunodeficiency virus infection on tuberculosis and its control. Chest 100:191-200, 1991 7. MacGregor RR: A year's experience with tuberculosis in a private urban teaching hospital in the postsanitorium era. Am J Med 58:221-228, 1975 8. Shafer RW, Kim DS, Weiss JP, et al: Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine 70:384-397, 1991 9. American Thoracic Society/Centers for Disease Control: Diagnostic standards and classification of tuberculosis. Am Rev Respir Dis 142:725-735, 1990 10. Dutt AK, Stead WW: Chemotherapy of tuberculosis for the 1980s. Clin Chest Med 4:243-252, 1980
11. Davidson PT, Le HQ: Drug treatment of tuberculosis-1992. Drugs 43:651-673, 1992 12. Fox W, Mitchison DA: Short-course chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 111:325352, 1975 13. Fox W: Whither short-course chemotherapy? Brit J Dis Chest 75:331-357, 1981 14. Dutt AK, Jones L, Stead WW: Short-course chemotherapy for tuberculosis with largely twice-weekly isoniadizrifampin. Chest 75:441-447, 1979 15. Prevention and control of tuberculosis in migrant farm workers. MMWR 41:1-15, June 5, 1992 (suppl RR-10) 16. Riley RL, Mills CC, O'Grady F, et al: Infectiousness of air from a tuberculosis ward. Am Rev Respir Dis 85:511-525, 1962 17. Kamat SR, Dawson JJ, Devadatta S, et al: A controlled study of the influence of segregation of tuberculosis patients for 1 year on the attack rate of tuberculosis in a five-year period in close family contacts in South India. Bull WHO 34:517-532, 1966 18. Gunnels JJ, Bates JH, Swindall H: Infectivity of sputum-positive tuberculosis patients on chemotherapy. Am Rev Respir Dis 109:323-330, 1974 19. Guidelines for preventing the transmission of tuberculosis in health care settings, with special focus on HIVrelated issues. MMWR 39:1-29, 1990 (suppl RR-17) 20. Kopanoff DE, Snider DE, Caras GJ: Isoniazidrelated hepatitis. A US Public Health Service cooperative surveillance study. Am Rev Respir Dis 117:991-1001, 1978 21. Gangadharam PRJ: Isoniazid, rifampin, and hepatotoxicity. Am Rev Respir Dis 133:963-965, 1986