Tuberculosis in the immunosuppressed patient

Tuberculosis

in the Immunosuppressed Patient Wallace T. Miller

T

UBERCULOSIS is intimately involved with the immunologic defense mechanisms of the body and particularly with cell-mediated immunity. Consequently, in a discussion of tuberculosis and the immunosuppressed patient, it should be useful to review briefly the immune system. THE IMMUNE

SYSTEM

The immunologic response is divided into two types: immediate hypersensitivity and delayed hypersensitivity.4 With the skin as a target organ, immediate hypersensitivity is exemplified by the acute reaction that occurs 15 min after a small amount of ragweed antigen is injected intradermally into a person with hay fever. Delayed hypersensitivity is illustrated by the erythema and induration that occurs 24-48 hr after a tuberculin skin test. Experimentally, immediate hypersensitivity can be transferred to a previously unsensitized person by serum from a hypersensitive person.4 On the other hand, delayed hypersensitivity cannot be transferred with serum but only by lymphoid cells.’ For this reason, immediate hypersensitivity is considered the universe of antibody mediated (humoral) immunity, while delayed hypersensitivity is the universe of cellmediated (cellular) immunity. Both humoral and cell-mediated immunities are dependent upon their own distinct population of lymphocytes-B (for bursa) lymphocytes for humoral immunity and T (for thymus) lymphocytes for cellular immunity. B Cells

This population of lymphocytes was originally discovered in a juxtacloaca organ of birds called the bursa of Fabricius” and have therefore been designated B lymphocytes. The central lymphoid organ concerned with control of antibodysecreting lymphocytes in humans is probably the bone marrow.” The B lymphocytes reside primarily in the reticuloendothelial tissues of the immune organ system, and their lifespan is measured in days.” The function of the B lymphocyte is to make antibodies when stimulated by the appropriate Seminars in Roentgenology,

Vol. XIV, No. 3 (July). 1979

antigen. These small lymphocytes are coated with various immunoglobulins (IgG, IgA, IgM, IgE, or IgD) and contain specific antigen receptors on the surface that are triggered by antigen to produce antibodies.” This triggering is a complex response and is often aided by a complex antigen signal or by collaboration of T lymphocytes.4 T Cells

The second universe of immune response is cell-mediated immunity, which is mediated by the T lymphocytes, a special breed of lymphocytes derived from the thymus. Unlike the B lymphocytes, these cells are very long lived. Some have been shown to live for over 20 years.j The functions of the T lymphocyte are primarily to combat intracellular infection, to suppress malignancy, and to promote graft rejection. Immunity

and Infectious

Diseases

Infectious diseases in the human body can be combated by either T cells (ceil-mediated immunity) or B cells (humoral immunity). Humoral immunity protects against infection from most bacteria and from pneumocystis. Cellular immunity protects against infection by intracellular organisms, such as the mycoses, viruses (chickenpox, measles, and cytomegalovirus), and the subject of this discussion, Mycobacterium tuberculosis.6 Tuberculosis And Cellular Immunity The cell-mediated immune response achieves destruction of the tubercle bacillus in at least two ways. First, sensitized lymphocytes may directly attack and destroy the tuberculous organism. Secondly, contact between the tuberculous antigen and antigen-reactive lymphocytes may lead to the release of soluble factors called lymphokines. These lymphokines attract macroWallace T. Miller, M.D.: Professor of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pa. Reprint requests should be addressed to Dr. Wullace T. Miller, Professor of Radiology. Hospital of the University of Pennsylvania. 3400 Spruce St., Philadelphia. Pa. 19104. 0 1979 by Grune & Stratton, Inc. 0037-I 98X/79/1403-o008~02.00/0 249

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phages to the site of infection, increase their metabolic activity, and make them more aggressive in phagocytosis and in destruction of the tubercle bacillus.’ The manner in which the immune defense mechanism is involved in both primary tuberculosis and in the development of reactivation (postprimary tuberculosis) has been elaborated by Stead et al.” In the primary infection, the tubercle bacillus is spread by aerosol inhalation into a well-ventilated portion of the lung, usually a lower lobe. There the bacilli grow and, depending upon the initial host immune reaction, one of several possible clinical outcomes occur: (1) In the patient with excellent cell-mediated immunity the organisms are destroyed and no clinical findings are apparent other than a positive tuberculin skin test. (2) When cell-mediated immunity is not as good, the patient may develop tuberculous bacteremia with implantation of metastatic foci in areas of high oxygen tension, such as the apex of the lung or the cortex of the kidney. These lesions are then walled off by the activated immune system, and the organism may lie dormant intracellularly for many months or years. They may reactivate, probably as a result of inhibition of the host’s cell-mediated immune defense system. (3) In the patient with poor cell-mediated immunity, the primary infection may proceed directly into postprimary or reactivation tuberculosis with development of active pulmonary disease. (4) With complete failure of cell-mediated immunity, the patient may develop miliary tuberculosis. Tuberculosis may develop in several clinical situations when there is impaired cellular immunity. On the one hand, the patient who has a poor immune defense system, when challenged with a primary infection of tuberculosis, may develop active tuberculosis or even disseminated miliary tuberculosis. In a similar fashion, the patient who has previously had primary tuberculosis and harbors viable intracellular organisms that have been walled off by the body’s immune response may develop reactivation tuberculosis when the body’s immune defenses are compromised by some process that lowers cell-mediated immunity to the degree that it can no longer contain the viable tuberculous organism. One paradoxical situation in the immunologic response to M. tuberculosis is the inverse rela-

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tionship between tuberculin hypersensitivity and the immunologic protection against the development of pulmonary tuberculosis. Despite a positive skin test, patients may experience reactivation of their disease. This suggests that delayed hypersensitivity to tuberculin protein is disassociated from immunity to M. tuberculosis.’ TUBERCULOSIS IN THE PATIENT WITH DEPRESSED CELLULAR IMMUNITY

Certain stresses to the human organism can result in varying degrees of depression of the body’s cell-mediated immunity. Sometimes this depressed immunity may lead to the development of pulmonary tuberculosis. The radiographic appearance of tuberculosis in patients with severe depression of cellmediated immunity (ie, on immunosuppressive drugs) is essentially no different from that in patients with only mild immune depression (eg, aging), except that the former are much more likely to have rapidly progressive and far advanced disease or disseminated miliary disease.” Aging

Aging is probably the primary risk factor in the development of reactivation tuberculosis. There are some indications of depression in cellmediated immunity in the aging population. The elderly have a moderately reduced number of circulating T lymphocytes, and the ability of these lymphocytes to transform into blast cells is impaired.7 Also, aging is associated with the development of autoantibodies and autoimmune disease. Such defects in cell-mediated immunity may reflect a “rundown” in the number of thymocytesz7 Although other factors (starvation, chronic illness, etc.) may be at work in the increased incidence of tuberculosis in the aged population, the aging process alone certainly is a contributory factor. Starvation

Severe protein-calorie malnutrition is generally associated with a depression of cellmediated immunity. Starvation may lead to low numbers of circulating T lymphocytes with depression of lymphocyte transformation into blast cells. Gross lymphatic depletion of lymph

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nodes may be seen at autopsy.” Thus patients with severe malnutrition are particularly prone to develop intracellular types of infection. In children, there is a high incidence of fatal virus infections, particularly measles.6 Adults with severe malnutrition have a high incidence of tuberculosis.” Chronic Illness Many chronically ill patients, particularly those with advanced malignancy, suffer from some degree of malnutrition that may be responsible for depression of cell-mediated immunity. However, certain metabolic illnesses, in particular uremia (Fig. l), iron deficiency anemia, and diabetes mellitus, are consistently associated with defects in cell-mediated immunity. These diseases show defects in delayed hypersensitivity skin reactions and in vitro lymphocyte transformation.*’ A definite increase in incidence of tuberculosis in patients on dialysis has been demonstrated.‘” It is likely that diabetics and patients with iron deficiency anemia also have an increased susceptibility to tuberculosis. Alcoholism Alcoholics have a clearcut increased incidence of tuberculosis (Fig. 2).‘2.23 No recent studies have been made to explain their immunocompe-

Fig. 1. Tuberculosis and chronic illness. This 74y-old male with chronic renal disease and generalized organ failure was in the medical intensive care unit for several weeks with chronic right lower lobe infiltrate presumed to be aspiration pneumonia. At autopsy, right lower lobe tuberculosis was found.

Tuberculosis and alcoholism. 47-y-old male Fig. 2. with chronic right lower lobe infiltrate initially thought to represent aspiration. Sputum smear and culture showed M.

tuberculosis.

tence. However, it is likely that there is decreased cell-mediated immunity in this population, if for no other reason than malnutrition and other chronic illness. Cancer Considerable effort has been made to assess immunity factors in patients with early and advanced malignancy. Recent work clearly confirms that defects in cell-mediated immunity exist. Patients with many varieties of solid tumors exhibit depression of delayed hypersensitivity skin reaction and in vitro lymphocyte transformation.*’ Although many suspect an etiologic connection between cell-mediated immunity and malignancy, most studies have failed to clearly establish this connection. Nonetheless, defects in cell-mediated immunity do exist and clearly make patients with neoplastic disease more susceptible to intracellular types of infection, such as tuberculosis. Various clinical studies have established a significant increase in the incidence of tuberculosis in many neoplastic diseases.‘3S’4,‘8Kaplan et a1.,13in a review of patients with active tuberculosis at Memorial Hospital, showed an increased incidence of tuberculosis in carcinoma of the lung (Fig. 3), head and neck cancer, breast cancer, and gastric cancer, in gynecologic malignancies, and in Hodgkin and non-Hodgkin lymphoma and leukemia. These cases are complex, of course, because many of these

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Fig. 3. Tuberculosis and cancer of the lung. 62-yr-old male with a left hilar mass secondary to squamous cell carcinoma of the lung. On the same film, a right upper lobe lesion wes present that proved to be active pulmonary tuberculosis.

patients also had been treated with steroids, radiation, and immunosuppressive drugs. However, Stefani et a1.,26in a study of patients at M. D. Anderson Hospital, showed that defects in cell-mediated immunity existed in patients with head and neck cancer prior to the institution of therapy. Tuberculosis in the cancer patient is a particu-

Fig. 4. Miliery tuberculosis in lymphome patient on immunosuppressive drugs. This 44-yr-old female with nonHodgkin lymphoma involving the mediastinum and causing left pleural effusion also had unexplained fever. A fine nodular infiltrate noted throughout the lung fields proved to be miliary tuberculosis.

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larly difficult problem because the lesions may mimic those of the cancer itself (i.e., the adenopathy of primary tuberculosis may imitate that of metastatic neoplastic disease). Tuberculosis may produce severeand rapidly progressive pneumonia, particularly in the immunosuppressed patients with Hodgkin disease or nonHodgkin lymphoma (Fig. 4). It also may appear in disseminated form (miliary TB), which is frequently occult and particularly lethal.13 Another interesting problem with tuberculosis is that it may masquerade as leukemia, pancytopenia, or other hematologic disorders.’ Disseminated tuberculosis in particular may present with severe hematologic abnormality and be mistaken for aplastic anemia or leukemia. There is also a very significant increased incidence of tuberculosis in patients with lymphoproliferative disease. Glasser et al9 found that leukopenia, leukocytosis, monocytosis, and anemia may be secondary responses to tuberculosis. However, patients with a leukemic blood picture or pancytopenia invariably have a true hematologic disease. The mortality rate in patients with neoplastic disease and tuberculosis was extremely high in the series of Kaplan et aLI3 The overall mortality rate due to tuberculosis was 17% and was actually 48% in patients with lymphoproliferative disorders. Carcinoma of the lung not uncommonly pre-

THE IMMUNOSUPPRESSED

PATIENT

Fig. 5. Tuberculosis and ssrcoidosis. 23-y-old black male with diffuse pulmonary changes and lymphadenopathy secondary to sarcoidosis. Patchy infiltrates in the upper lobes were initially thought to be sarcoid as well. Smears and cultures showed M. tuberculosis. The upper lobe disease cleared on antituberculous therapy.

sents in conjunction with tuberculosis.” Some feel that carcinoma may be induced in old tuberculous scars.*’ Sarcoidosis

Patients with sarcoidosis have definite evidence of depressed cell-mediated immunity. Many are anergic, and various in vitro tests show diminution of T lymphocyte function.‘.*’ Various investigators have reported an increased incidence of tuberculosis in patients with known sarcoidosis (Fig. 5). Scadding” found an incidence of tuberculosis of 13% among 230 cases of sarcoidosis, and Mayock et al noted that 4.1% of patients with sarcoidosis developed active tuberculosis.‘6 Some investigators feel that sarcoidosis may actually represent an unusual manifestation of tuberculous involvement of the lung, possibly modified by uninhibited mycobacteriophage.‘5 This concept is not espoused by many; at present the relationship between sarcoidosis and M. tuberculosis is not known. Silicosis

and Coalworker’s

253

The immunologic problem in patients with silicosis appears to be secondary to inhibition of macrophages by sublethal doses of silica. M. tuberculosis has been shown to grow more rapidly, and macrophages exposed to sublethal doses of silica dust and bacilli are released more rapidly into the surrounding medium.’ Because the macrophage is the major effector cell (ie, the cell that is stimulated by the T lymphocyte to destroy the tubercle bacillus), the reason for increased susceptibility of silicotic patients to tuberculosis is apparent. In recent years the prevalence of tuberculosis among silicotics and coalworkers has fallen strikingly, presumably because of better tuberculosis control and hygiene. However, tuberculosis is still difficult to control when associated with pneumoconiosis. Pregnancy

Cell-mediated immunity, as assessed by delayed hypersensitivity skin reaction and in vitro transformation of mitogens, is depressed in pregnancy.*’ This may explain the high rates of tuberculosis that have been reported among pregnant women.2~22 Familial

Immune

Deficiency

Diseases

A number of familial immune deficiency diseases exist in which there is severe impairment of cellular immunity, often times associated with impaired humoral immunity. These include combined severe immunodeficiency, congenital absence of the thymus and parathyroids (DiGeorge syndrome), thymic dysplasia (Nezelof syndrome), ataxia-telangiectasia syndrome, Wiskott-Aldrich syndrome, and immunologic amnesia. These congenital diseases result in very severe immune deficiency that almost invariably leads to early death. Tuberculosis is certainly a theoretical problem in these patients but they are much more frequently infected by viral or fungal agents.

Pneumoconiosis

Many reports have been made of a very high incidence of tuberculosis among coalworkers and silicotics.‘0,24 The diagnosis of tuberculosis in these patients may be difficult because a conglomerate mass may simulate tuberculous infection, even undergoing cavitation.

Drug-induced

lmmunosuppression

Various drugs may produce mild to severe repression of cell-mediated immunity. Corticosteroids rapidly suppress cell-mediated immunity, probably by removing T lymphocytes from the circulation.*’ Although this is a transient

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phenomenon and is generally reversed within 24 hr after a single injection of cortisone, patients on long-term steroids do have an increased incidence of tuberculosis. Renal transplant patients on steroids show an increased incidence of both M. tuberculosis and atypical Mycobacteria infections.8 A high incidence of tuberculosis has not been reported in renal transplant patients, probably because most of the patients with a positive tuberculin skin test are routinely given prophylactic antituberculous drug therapy with their steroid therapy.3 Antilymphocyte serum is a powerful inhibitor of delayed hypersensitivity and of cellular immunity. It thus has wide effects in the field of organ transplantation and, theoretically at least, should make patients more susceptible to tuberculous infection. Similarly alkylating agents (cyclophosphamide), purine antagonists (6mercaptopurine), and folic acid analogs (methotrexate) are cytotoxic drugs that have a lethal effect on lymphocytes. As such, they too inhibit cellular immunity and theoretically should increase susceptibility to tuberculosis. However, so far a high incidence of tuberculosis in the host

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compromised by immunosuppressive drugs has not been reported.28 Radiation

Radiation also induces impaired cellular immunity, both locally and systemically.26 An increased incidence of tuberculosis has been reported in patients after radiation therapy.28 One would expect that the immunosuppressed patients most likely to develop tuberculosis would be those on immunosuppressive drugs, radiotherapy, or steroids. Interestingly, this does not appear to be the case. These patients are usually being cared for by physicians who are cognizant of the risk of tuberculosis and frequently use prophylactic antituberculous therapy (usually a single drug, such as isoniazid).3 Several studies indicate that the patients most likely to develop tuberculosis, particularly unusual patterns of tuberculosis, are the elderly, the debilitated, and those with chronic diseases or malignancy. These are the high risk patients and the ones in whom any chronic pulmonary infiltrate should be suspectedof being tuberculosis.

REFERENCES 1. Allison AC, Hart PD: Potentiation by silica of the growth of M. tuberculosis in macrophage cultures. Br J Exp Pathol49:465416, 1968 2. Bailey WE, Thompson DH, Greenberg HB: Indigent pregnant women of New Orleans require tuberculosis control measures. Health Serv Rep 87:737-741, 1973 3. Blank N, Castellino RA: The diagnosis of pulmonary infection in patients with altered immunity. Semin Roentgenol l&63-72,1975 4. Claman HN: Cellular immunology, in Guttman RD (ed): Immunology. Kalamazoo, Upjohn, pp 45-53, 1975 5. David JR: Cellular immunity and hypersensitivity, in Guttman RD (ed): immunology. Kalamazoo, Upjohn, pp 55-67,1975 6. Faulk WP, Greenwood BM: Infectious diseases, in Holborow ET, Reeves WG (eds): Immunology in Medicine. New York, Grune & Stratton, 1977, pp 433-472 7. Freedman SO, Kongshaven PL: Immunobiology and tuberculin hypersensitivity. Chest 68:470-474, 1975 8. Friedman H: Personal communication 9. Glasser RM, Walker RI, Herion JC: The significance of hematologic abnormalities in patients with tuberculosis. Arch Intern Med 125:691695, 1970 10. Gooding CG: Pneumoconiosis in South Wales anthracite miners. Lancet 2891-895, 1946 11. Gowan JL: Immunobiology of the small lymphocyte, in Good RA, Fish DW (eds): Immunobiology. Stanford, Sinauer, 1971, p 18

12. Hudolin V: Tuberculosis and alcoholism. Ann NY Acad Sci 252~353-364, 19’75 13. Kaplan MH, Armstrong D, Rosen P: Tuberculosis complicating ncoplastic diseases; A review of 201 cases. Cancer 33850-858, 1974 14. Lowther CP: Leukemia and tuberculosis. Ann Intern Med 5152-56, 1959 15. Mankewicz E, Beland J: The roles of Mycobacteriophages and of cortisone in experimental tuberculosis and sarcoidosis. Am Rev Resp Dis 89:707-720, 1964 16. Mayock RL, Bertrand P, Morrison CE, et al: Manifestations of sarcoidosis. Am Rev Resp Dis 35:67-89, 1963 17. McCreary CB: Tuberculous control in India. Dis Chest 53:699-708, 1968 18. McQuarrie DG, Nicoloff DM, VanNostrand D, et al: Tuberculosis and carcinoma of the lung. Chest 54:427432, 1968 19. Pradham RP, Katz LA, Nidus BD, et al: Tuberculosis in dialyzed patients. JAMA 229:798-800, 1974 20. Ripstein C: Scar carcinoma of the lung. J Thoracic Cardiovasc Surg 56:362-369, 1968 21. Scadding JG: Mycobacterium tuberculosis in the etiology of sarcoidosis. Br Med J 2: 1617, 1960 22. Schaeffer G, Zervoudakis IA, Fuchs FF, et al: Pregnancy and pulmonary tuberculosis. Obstet Gynecol 46:706715,1975 23. Smith JC, Demone HW Jr: Measurement of tubercu-

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losis in Massachusetts and steps to combat it. Am Rev Resp Dis 84:263-267, 1961 24. Snider DE: The relationship between tuberculosis and sihcosis. Am Rev Resp Dis 118:455-460, 1978 25. Stead WW, Kerby GR, Schleuter DP, et al: Clinical spectrum of primary tuberculosis in adults. Ann Intern Med 68:73lL735, 1968 26. Stefani S, Kerman R, Abbate J: Serial studies of

255 immunocompetence in head and neck patients undergoing radiation therapy. Am J Roentgen01 126:880-886. 1976 27. Webster ABD: Immunodeficiency, in Holborow EJ, Reeves WG (eds): Immunology in Medicine. New York, Grune & Stratton, 1977, pp 473-537 28. Williams DM, Krick JA, Remington JS: State of the art. Pulmonary infections in the compromised host. Part II. Am Rev Resp Dis I 14:593-627, 1976