State of the Art Pulmonary Infectious Complications of Human Immunodeficiency Virus Infection Part 11-3

JOHN F. MURRAY and JOHN MILLS Contents Introduction Diagnostic Approach History Physical Examination Laboratory Tests Chest Radiography Pulmonary Function Studies Radionuclide Imaging Sputum Examination Bronchoscopy Other Procedures Viral Infections Cytomegalovirus Infection Other Pulmonary Viral Infections Bacterial Infections Community-acquired Bacterial Pneumonias Nosocomial Bacterial Pneumonias Tuberculosis Mycobacterium avium Complex Other Mycobacterial Infections Fungal Infections Cryptococcosis Histoplasmosis Coccidioidomycosis Candidiasis Aspergillosis Other Fungal Infections Pneumocystis carinii Infection Taxonomy Epidemiology Pathology and Pathogenesis Clinical Features Diagnosis Treatment Adjunctive Measures Prevention Parasitic Infections Toxoplasmosis Cryptosporidiosis Strongyloidiasis Conclusion

Introduction

The first cases of what is now called the acquired immunodeficiency syndrome (AIDS) were reported by the Centers for Disease Control (CDC) as a new clinical 1356

entity in mid-1981 (1); more details about this and a second cluster of cases soon followed (2, 3). Since then, several important advances have occurred. Paramount among these was the discovery of the causative virus, the human immunodeficiency virus (HIV), formerly called the human T-Iymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by scientists at the Pasteur Institute (4) and the National Institutes of Health (5), and the development of accurate tests to demonstrate the presence of the virus in its human host (6). As new cases of AIDS werediagnosed, it quickly became evident that the disease was a worldwide problem, particularly in North and South America, Europe, and Central Africa, and that persons outside the originally described risk groups (male homosexuals and intravenous drug abusers) werealso afflicted (7). Moreover, the spectrum of AIDS-related diseases has increased considerably and now includes numerous opportunistic infections, certain specific neurologic syndromes, a constitutional (wasting) syndrome ("slim disease"), and a few other conditions (e.g., lymphocytic interstitial pneumonitis) (8). Of equal importance have been the acquisition of knowledge concerning the natural history of HIV infection itself and the recognition that AIDS is the last stage of advanced immune suppression due to prolonged viral infection and that certain other complications, such as thrush, hairy leukoplakia, pulmonary tuberculosis, and bacteremic pyogenic pneumonias, are clearly related to HIV infection. These complications, which occur when immunity is suppressed but not to the extreme degree found later on, indicate progression of the underlying HIV infection and serve as harbingers of impending AIDS. For diagnostic and therapeutic reasons, especially those concerning prevention

(9), it is far more useful to consider the entire continuum of HIV infection than only the last and invariably fatal stage that we call AIDS. The lungs are the principal target organ of the infectious complications of AIDS and are often involved in earlier HIV infection as well. Why the lungs are so commonly infected is not entirely evident. Undoubtedly, part of the explanation lies in the fact that the lungs are the portal of entry into the body of many infectious agents that either may cause acute illness or may cause latent infection that becomes the nidus for subsequent reactivation disease.The lungs may also be predisposed to infectious complications because their immunologic capabilities may be evenmore suppressed than those of other organs. It is well known that HIV infection can cause virtually every conceivable type of systemic immunologic deficiency (10). What is much less clear is whether the vulnerability of the lungs to infectious microorganisms is merely the regional manifestation of the systemic abnormality or whether additional HIV-induced factors affect the lungs' own complex system of

(This is Part I oftwo parts; the second will appear in the next issue of the Review) I From the Pulmonary and Infectious Disease Divisions, San Francisco General Hospital Medical Center, and the Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California. 2 Supported by Pulmonary Vascular Specialized Center of Research Grant No. HL-19155 from the National Heart, Lung, and Blood Institute and by Grant No. AI-27663, AI-25157, and AI-25329 from the National Institute of Allergy and Infectious Diseases. J Correspondence and requests for reprints should be addressed to John F. Murray, M.D., University of California, San Francisco, Campus Box 0841, San Francisco, CA 94143-0841.

AM REV RESPIR DIS 1990; 141:1356-1372

STATE OF THE ART: PULMONARY COMPLICATIONS OF HIV INFECTION

local defense mechanisms. The results of extensive studies of bronchoalveolar lavage fluid in patients with HIV infection support this notion but are inconclusive (ll). It seems likely that pulmonary host defenses are compromised by direct infection of alveolar macrophages with HIV (12) and decreased production of soluble factors by lymphocytes (13) and that these defects act in concert with systemic abnormalities to favor the development of pulmonary infections. The spectrum of pulmonary disorders associated with HIV infection includes both infectious and noninfectious diseases (table 1).In this report, we will discuss only major pulmonary infectious complications noted by us and by others (14-17). Case reports of other much less common or exotic HIV-associated infections can be found and more undoubtedly will occur. When working up a patient with known or suspected HIV infection, physicians must remember that the differential diagnosis of a suspected pulmonary infection includes several noninfectious HIV-related complications such as Kaposi's sarcoma (18, 19), nonHodgkin's lymphoma (20), lymphocytic interstitial pneumonitis (21), and nonspecific interstitial pneumonitis (22), which are the subjects of a recent extensive review (22a). It should be added, however, that the workup described in the next section emphasizes the diagnosis of pulmonary infections because, for the most part, these respond better to treatment than the malignancies, and many patients with interstitial pneumonia do not require treatment (22a). Diagnostic Approach

In viewof the many kinds of pulmonary disorders that may occur during the course of HIV infection (table 1), a specific diagnosis should be made each time a complication occurs. Empiric treatment is seldom justified, except while awaiting the results of diagnostic studies. The workup to be described here is guided by the importance of Pneumocystis carinii pneumonia, which is by far the most common HIV-related pulmonary infection in the United States. Similar approaches have been recommended before (14-17, 23), but other diagnostic algorithms may be warranted in countries where different pathogens predominate. Likewise, widespread use of chemoprophylaxis for P. carinii (or other organisms) will markedly affect the future relative incidence of the pulmonary complications of HIV infection.

1357 TABLE 1 PULMONARY COMPLICATIONS OF HIV INFECTION

Infections Viruses Cytomegalovirus Herpes simplex virus Varicella-zoster virus Epstein-Barr virus? Human immunodeficiency virus? Bacteria Pyogenic organisms (especially Streptococcus pneumoniae, Hemophilus influenzae) Mycobacterium tuberculosis Mycobacterium avium complex Other nontuberculous mycobacteria Fungi Histoplasma capsula tum Coccidioides immitis Cryptococcus neoformans Candida species Aspergillus species Parasites Pneumocystis carinii Toxoplasma gondii Cryptosporidia Strongyloides stercoralis Malignancies Kaposi's sarcoma Non-Hodgkin's lymphoma Interstitial pneumonias Lymphocytic interstitial pneumonitis Nonspecific interstitial pneumonitis Drug-induced reactions Other Adult respiratory distress syndrome Secondary alveolar proteinosis

History Upper respiratory tract viral infections, asthma, and chronic bronchitis seem to occur with the same frequency and with the same clinical features in patients with HIV infection as in those without. In contrast, HIV-seropositive persons are unusually susceptible to pyogenic bacterial pneumonias (see Bacterial Infections), particularly those caused by Streptococcus pneumoniae or Haemophilus influenzae (24). These infections present with the typical acute onset of fever, shortness of breath, pleuritic chest pain, and productive cough. Patients with Pneumocystis, mycobacterial, or fungal pneumonias usually complain of the gradual development of the systemic symptoms of fatigue, weight loss, and fever, as well as the respiratory symptoms of dyspnea and nonproductive cough. Nearly all patients who have HIV-related pulmonary Kaposi's sarcoma or nonHodgkin's lymphoma will already have had the diagnosis made because of extrapulmonary involvement (18-20). If the patient is not already known to have or to be at risk for HIV infection, a thorough history concerning the sensitive issues of previous sexually transmitted diseases, sexual lifestyle, and intra-

venous drug usage is essential. Knowledge about past pulmonary diseases, place of origin, and history of travel will aid in diagnosing certain HIV-associated infections. Physical Examination The physical examination may provide important information about the presence of HIV infection or one of its complications. For example, oral candidiasis (thrush) or hairy leukoplakiaare presumptive evidence of HIV infection and herald progression to AIDS. Skin lesions are common in HIV-infected patients (25). Lymphadenopathy and hepatosplenomegaly are often present and may indicate Kaposi's sarcoma, non-Hodgkin's lymphoma, or disseminated mycobacterial or fungal infection. Advanced lung disease is apt to be signaled by the presence of tachypnea and a dry cough, particularly if the cough is aggravatedby deep breathing (26). Breath sounds are often exaggerated, but frank signs of consolidation (e.g., bronchophony) and rales are unusual except in patients with bacterial pneumonia. Examination of the chest may be completely normal in patients with early or mild HIV-related lung disease.

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Laboratory Tests Several laboratory tests are useful in documenting the presence of HIV infection and the severity of its involvement. The diagnosis of infection with HIV itself is usually made by detecting specific antibodies to the virus using a screening assay (ELISA) and a confirmatory test such as immunofluorescence or immunob lot (western blot) (6). In many states, written consent from the patient is necessary before HIV serologic tests can be performed. Culture of peripheral blood lymphocytes for HIV is laborious and expensive and is usually performed for research purposes. Tests of circulating viral antigens, detected primarily as p24 viral core protein, have been used to identify patients who are infected with HIV but who have not yet developed antibodies to the virus (27) and in evaluating the response to therapeutic agents (28, 29). Recently, an extremely sensitive test, the polymerase chain reaction, which is capable of detecting single viral genomes in peripheral blood, has proved useful in discovering latent infection, clarifying confusing serologic profiles, and in predicting whether or not an infant born to a seropositive mother has been infected in utero (6). Of the laboratory tests that have been used to document the state of disease and the likely outcome of progressive HIV infection, the best are the determination of the absolute number or percentage of circulating CD4lymphocytes and the serum level of either neopterin or 13-2microglobulin (30); p24 antigenemia, IgA, and interlukin-2 receptors are less useful for staging HIV infection. Other markers are the hematocrit, erythrocyte sedimentation rate, and CD4/CD8 lymphocyte ratio. Skin tests with multiple antigens are useful in identifying the presence of anergy, and if the tuberculin skin test is positive, further evaluation and treatment are indicated (see Tuberculosis). The choice of other laboratory tests should be guided by standard clinical principles. Common abnormalities of routine chemistry tests are hypoalbuminemia, hyperglobulinemia, and hypocholesterolemia. An elevated lactate dehydrogenase (LDH) in patients with HIV infection is associated with lymphoreticular malignancy and P. carinii pneumonia (25). Blood cultures should be done in any patient with or suspected to have AIDS who is sufficiently ill to warrant hospitalization, especially if no clear cause for the illness is evident; an appreciable incidence of community-ac-

MURRAY AND MILLS

quired bacteremia has been reported in patients with AIDS, many of whom (57070) were afebrile on admission (31). Chest Radiography The evaluation of suspected lung disease in a patient who is or who might be infected with HIV begins with a plain posteroanterior and lateral chest radiograph. The presence and type of abnormalities provide clues to the cause of the disorder and help to direct subsequent workup (32-34). One of three radiographic patterns is customarily found, each of which has its own differential diagnosis: (1) diffuse, reticulonodular densities (figure 1); (2) focal airspace consolidation (figure 2); (3) normal lungs. Pleural effusion (figure 3) and intrathoracic adenopathy (figure 4) are less common but also suggest a certain differential diagnosis (table 2). Computed tomography (CT) has not been extensively used in patients with HIV infection, probably because the abnormalities on plain chest radiographs are sufficiently straightforward to direct the workup that leads to a diagnosis. CT may be valuable in HI V-infectedpatients with either mediastinal abnormalities or localized masses or fluid collections to define anatomic relationships and to provide a guide to biopsy or drainage procedures. It has been reported that up to 20070 of patients with P. carinii pneumonia have normal or nearly normal plain chest radiographs (34); although in our experience only about 8070 of patients with Pneumocystis pneumonia have normal chest films (33), the potential value of thin-section CT in this interesting group of patients has not been explored. Pulmonary Function Studies Given the extent and severity of most of the pulmonary infectious complications of HIV infection, it is not surprising that associated pulmonary function abnormalities are common. Furthermore, because the majority of AIDS-related pulmonary infections present as diffuse disease of the lung parenchyma, it is also not surprising that the resulting functional disturbances are similar and do not discriminate among the various causes of the abnormalities. Several groups of investigators have also made the interesting observation that subtle abnormalities of pulmonary function, particularly a low carbon monoxide diffusing capacity, may occur in patients with few or no respiratory symptoms and normal chest radiographs (22, 35, 36); the pathologic

correlate of the functional disturbance is not wellestablished, but available evidence points to a lymphocytic alveolitis or some type of interstitial pneumonitis (22, 37). Four types of functional disturbances have been identified: (1) a restrictive ventilatory defect characterized by a low vital capacity, which is occasionally extremely severe (38), and often with high expiratory flow rates (39); (2) an abnormality of oxygenation reflected in a low arterial P0 2 or widened alveolar-arterial P0 2 difference, which may be present at rest and is virtually always present in patients with P. carinii pneumonia during exercise (15, 35); (3) a low carbon monoxide diffusing capacity, which is caused, at least in P. carinii pneumonia, by a decreased diffusing capacity of the alveolarcapillary membrane and not, as is usual, by a decreased pulmonary capillary blood volume (40); (4) an obstructive ventilatory defect characterized by low expiratory flow rates, which has been associated with endobronchial Kaposi's sarcoma (18)but which may occur in the absence of detectable airways abnormalities (35, 41). Pulmonary function studies are not routinely indicated in the evaluation of patients with obvious HIV-related pulmonary complications. The major role of physiologic testing is to help select from among symptomatic patients with normal or nearly normal chest radiographs, those whose function is abnormal and who therefore require further diagnostic evaluation, often with invasive procedures; an algorithm for this purpose has been published (35). Radionuc/ide Imaging Two different radionuclides have been used to study the lungs of patients with HIV infection. One of these, gallium-67 citrate, has been used clinicallyas a means of detecting whether or not lung disease is present and as a guide to further diagnostic studies, and the other, technetium-99m diethylenetriamine pentaacetate C9mTc-DTPA ), has been used for research purposes to study the permeability characteristics of the lung parenchyma (42). The mechanisms leading to gallium accumulation in regions of inflammation are complex and not known with certainty (43). After intravenous injection, gallium is believed to bind to transferrin and to circulate in the bloodstream to areas of inflammation where local increases in permeability favor its extravasation and accumulation. A small amount

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STATE OF THE ART: PULMONARY COMPLICATIONS OF HIV INFECTION

Fig. 1 (left). Posteroanterior chest radiograph of a patient with newly diagnosed P. carinii pneumon ia shoWing a dif iuse bilateral reticulonodular infiltration, particularly in the lower lung zones. Fig. 2 (right). Posteroanterior chest radiograph of a patient with focal consol idation in the right midlung zone. Biopsy showed inflammation and a few trophozoites suggest ive of T. gond ii. The wires and clips are from previous coronary artery bypass surgery. Final diagnos is at authopsy was non-Hodgk in's lymphoma.

of gallium is taken up by inflammatory cells, but the majority remains extracellular where it may combine with high affinity binding sites on lactoferrin and bacterial siderophores. Several studies of gallium-67 lung imaging in patients with suspected pulmo-

nary complications of HIV infection have been reported (44-47). The results are consistent and show that gallium-67 scans have a high sensitivity for P. carinii pneumonia (> 950/0) but a low specificity. Not only has uptake been reported in a variety of other HIV-related pulmonary

infections but in (presumably) noninfectious lymphocytic and nonspecific interstitial pneumonitis as well (48, 49). Moreover, even though certain patterns (diffuse intrapulmonary, focal intrapulmonary, localized and corresponding to regional lymph nodes, or ill-defined peri-

Fig. 3 (left). Posteroanterior chest radiograph of a HIV seropositive patient showing a left-sided pleural effusion . Culture of the fluid revealed M. tuberculosis. Fig. 4 (right). Posteroanterior chest radiograph of an HIV seropositive patient showing mediastinal adenopathy. Culture of biopsy material revealed M. tuberculos is.

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TABLE 2 DIFFERENTIAL DIAGNOSIS OF COMMONLY OBSERVED CHEST RADIOGRAPHIC PATIERNS IN PATIENTS WITH HIV INFECTION Pattern

Diseases

Diffuse reticulonodular infiltration

Pneumocystis carinii pneumonia Disseminated tuberculosis Disseminated histoplasmosis Disseminated coccidioidomycosis Lymphocytic interstitial pneumonitis

Focal airspace consolidation

Bacterial pneumonia Kaposi's sarcoma Cryptococcosis

Normal

Pneumocystis carinii pneumonia Disseminated Mycobacterium avium complex Disseminated histoplasmosis

Adenopathy

Tuberculosis Kaposi's sarcoma Disseminated Mycobacterium avium complex Non-Hodgkin's lymphoma

Pleural effusion

Kaposi's sarcoma Tuberculosis Non-Hodgkin's lymphoma Pyogenic empyema

hilar) are associated with particular in- nonspecific because Meignan and fections or neoplasms (47), the specifici- colleagues (52) found increased 99mTc_ ty is too low to have diagnostic value. The DTPA clearance in seven persons with utility of gallium imaging lies in direct- lymphocytic alveolitis, a newly described ing the subsequent workup in symptom- pulmonary complication of asymptomatic patients with or at risk for HIV in- atic patients with HIV infection (37). fection whose chest radiographs are negaSputum Examination tive: (1) if the lung scan is negative, attention should be directed outside the Most patients with HIV-related pyogenthorax; (2) if there is parenchymal up- ic pneumonia have a cough productive take (diffuse or focal), sputum induction of purulent sputum. Examination of a or bronchoalveolar lavage (see Sputum Gram-stained specimen of this material Examination and Bronchoscopy) is in- is useful in selecting initial antimicrobidicated; (3) if there is hilar or mediasti- al therapy. Final diagnosis depends on nal node uptake, biopsy of lymph node, the results of cultures of sputum, blood, liver, or bone marrow is indicated. An or, when available, pleural fluid. algorithm with a recommended role Patients with P. carinii pneumonia and for gallium-67 scanning has been pub- other diffuse infections nearly always lished (47). complain of cough, but the cough is usuIn contrast to gallium-67 citrate, which ally nonproductive. In these patients, exis administered intravenously and then amination of sputum induced by inhalaccumulates in the lungs, 99mTc_DTPA is ing an aerosol of hypertonic saline (3 or delivered to the lungs as an aerosol, af- 5OJo) generated by an ultrasonic nebulizter which it diffuses through the respira- er has a high likelihood of revealing P. tory tract epithelium and neighboring en- carinii on direct examination of the dothelium and is cleared by the blood- stained specimen; the yield is not suffistream (50). Mason and coworkers (51) ciently high to warrant routine culture used this technique to study 12 patients of the specimen for mycobacteria and with P. carinii pneumonia; all had ac- fungi (53). Meticulous technique is recelerated clearances of 99mTc-DTPA and quired in collecting the specimen (42) as clearance values returned to or toward wellas in processing and examining it (54). normal in the seven patients who were The first reports of the results of spurestudied after successful treatment. Six tum induction in patients suspected of patients with AIDS or AIDS-related com- having P. carinii pneumonia had a simiplex without clinical evidence of Pneu- lar yield, 55% in one series (55) and 56% mocystis infection had normal or near in the other (56). Subsequently, it was normal clearances. However, the abnor- learned that mucolysis with dithiothreimalities in Pneumocystis pneumonia are tol and centrifugation increased the sen-

sitivity of the method considerably (57). In the largest series reported to date (404 episodes of pulmonary disease in 358 patients), the range of sensitivity for detecting P. carinii in induced sputum was 74 to 77%; the negative predictive value was 58 to 64% (53). In the study by Ng and associates (53), which was carried out under routine clinical practice conditions, the smears were stained with a rapid Giemsa-like stain (Diff-Quiks; American Scientific Products, Chicago, IL). An even higher yield was obtained with an indirect immunofluorescent stain using monoclonal antibodies directed against P. carinii (58). The sensitivity in detecting Pneumocystis was 42 of 49 (92%) for immunofluorescence; 37 of 49 (76%) for Diff-Quik'"; and 39 of 49 (80%) for toluidine blue. Recent results using the immunofluorescent method continue to demonstrate its higher sensitivity (80%) but a lower specificity (90%) compared with other staining methods (72 to 75% and 100%, respectively) (58a).

Bronchoscopy If sputum induction is not available or if the results of an induction are negative, fiberoptic bronchoscopy is indicated (14, 16, 59). In the first few years of the HIV epidemic, both bronchoalveolar lavage and transbronchial biopsy were usually performed during the initial bronchoscopy because it was shown that the yield from the two procedures was complementary in identifying respiratory tract pathogens (59, 60): bronchoalveolar lavage had a sensitivity of 86% and transbronchial biopsy of 87%. When the two procedures were combined, the yield was 98% for all pathogens and 100% for P. carinii (60). Transbronchial biopsy is contraindicated in patients with severe respiratory failure, including all who are being mechanically ventilated, and in patients with intractable coagulopathy. However, bronchoalveolar lavage may be safely performed in these patients. The hazards of transbronchial biopsy are occasional severe hemorrhage and an appreciable incidence of pneumothorax (9%), with half or more requiring tube thoracostomy to facilitate reexpansion of the lung (60). In HIV-infected patients with diffuse lung disease, it is not necessary to perform bronchoscopy with transbronchial biopsy under fluoroscopic guidance; the results of the large study from two institutions showed no difference in either diagnostic yield or complications between those who were and those who were not biopsied with the aid of fluoroscopy (61).

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Bronchial brushing has a relatively low yield and is not routinely carried out in most institutions. More recently, because the techniques and experience in identifying P. carinii have improved, physicians in some institutions have abandoned transbronchial biopsy and now perform only bronchoalveolar lavage during the initial bronchoscopy (42,62). The advantages of this approach are that bronchoalveolar lavage is faster and easier to perform than transbronchial biopsy, the major complication, pneumothorax, is virtually eliminated, and both diagnosis and treatment for P. carinii can be carried out completelyon an outpatient basis. But there is a possible disadvantage to this approach as well. As the diagnostic yield for P. carinii from sputum induction continues to increase and the use of chemoprophylaxis for P. cariniibecomes more widespread, a decreasing percentage of patients who come to bronchoscopy will have Pneumocystis pneumonia and an increasing percentage will have some other pulmonary complication. It has been shown that bronchoalveolar lavage alone is not as effective as bronchoalveolar lavage plus transbronchial biopsy in diagnosing coccidioidomycosis (63), and the same may be true for the remaining fungal, mycobacterial, and other pulmonary infections. It is clear that biopsy, not lavage, is needed to diagnose HIV-related lymphocytic interstitial pneumonitis and nonspecific interstitial pneumonitis (21, 22). Finally, judging from reports of the results of bronchoscopy of patients with AIDS and other causes of immunosuppression, lavage has a low yield in diagnosing malignanciesand drug toxicity (64). However, whether or not the addition of transbronchial biopsy to bronchoalveolar lavage will increase the yield of treatable pulmonary disorders and favorably affect the course of HIV infection is unknown and needs to be studied. In addition to its important role in diagnosis, much has been learned about pulmonary defense mechanisms in normal subjects and in patients with HIV infection from the study of the cellular and humoral constituents obtained from the lungs by bronchoalveolar lavage. Most studies of the composition of lavage fluid have been on patients with various HIV-related lung diseases (65-67); in general, the findings have been nonspecific and have included a consistent lymphocytosis, an increase in percentage of CD8 and a decrease in percentage of CD41ymphocytes (but not always in ab-

solute numbers), and an occasional increase in neutrophils (11). The reports of bronchoalveolar lavage findings in patients with HIV infection but without symptomatic or radiographic evidence of lung disease have also shown a lymphocytosis in as many as 70070 of persons and a decrease in the ratio of CD4/CD8Iymphocytes parallel to or exceeding that found in the blood (37, 68). The cause of the striking lymphocytosis that has been observed in a majority of asymptomatic persons with HIV infection is unknown, but it has been suggested by GuilIon and colleagues that an alveolar lymphocytosis of cytotoxic CD8 cells may account for some of the subtle abnormalities of pulmonary physiology and pathology that have been reported by other investigators (15, 22, 36).

Other Procedures Respiratory secretions may be obtained by direct aspiration of the airway, and special catheters have been designed for this purpose (69). Although simple to perform, this technique has not supplanted bronchoscopy with bronchoalveolar lavage. Percutaneous needle aspiration of the lungs has limited value in the diagnosis of diffuse infectious processes because the high diagnostic yield is more than offset by the substantial incidence (50%) of pneumothorax, which may often require chest tube placement (70). Fine needle aspiration does have a role in the diagnostic evaluation of focal mass lesions and adenopathy (71). An important unresolved question is what diagnostic procedure, if any, to do next in a patient who has symptomatic and radiographic evidence of progressive lung disease but in whom the results of sputum induction (if available) and bronchoscopy are negative. If the initial bronchoscopy included bronchoalveolar lavage only, unless contraindicated, most physicians would rebronchoscope the patient and perform both transbronchial biopsy and repeat lavage. A second bronchoscopy is probably also indicated in the patient who has already had the procedure with both biopsy and lavage, although the yield under these circumstances is low; only one of 21 patients in the series reported by Barrio and coworkers (72) had a treatable disease identified by a second bronchoscopy. Open lung biopsy, which is generally regarded as the ultimate diagnostic procedure for the evaluation of pulmonary disease of unknown etiology, has a limited role in HIV-infected patients who have had a satisfactory bronchoscopic study

with negative results. The results of open lung biopsy in 18 patients who had had a preceding nondiagnostic bronchoscopy that included both a transbronchial biopsy and bronchoalveolar lavage revealed treatable infections in five, malignancy in eight, interstitial fibrosis in three, and no diagnosis in two. A similar distribution of findings occurred in 11 other patients who had open lung biopsyafter a bronchoscopy that included only lavage (73). Although these data provide some support for open lung biopsy after a nondiagnostic bronchoscopy and others recommend it (74), it is likely that recent improvements in the technique of lavage and, particularly, in processing and examining the specimens will identify most treatable causes of pulmonary disease in patients with HIV infection. Thus, it is still arguable whether open lung biopsy is indicated to diagnose unusual cases of Kaposi's sarcoma or lymphoma localized to the lungs, or other rare HIV complications like secondary pulmonary alveolar proteinosis (75), all of which respond poorly to treatment. The debate over open lung biopsy extends to HIV-related lymphocytic interstitial pneumonitis, which is rare in adults and little is known about its natural history or response to therapy. At San Francisco General Hospital where we have diagnosed and treated several hundred HIVrelated pulmonary complications yearly for over five years, we seldom perform open lung biopsy (less than five per year) and when we do, the yield of treatable diseases has been low and the complication rate seems high. Nevertheless, there undoubtedly is a role for open lung biopsy in highly selected patients, and further studies are needed to define this population. Viral Infections

The role of viruses as discrete pulmonary pathogens in patients with HIV infection has been difficult to document, despite the frequent recovery or identification of several different viruses in clinical or postmortem specimens from the respiratory tract (76). This is somewhat surprising because of the facts (1) that certain viruses, particularly members of the herpesvirus family, are recognized as common causes of mild or asymptomatic infection in childhood, (2)that thereafter these viruses may persist in host tissues for the lifetime of the infected person, (3) that cell-mediated immunity is necessary for persistent containment of these latent infections, and (4) that severe viral pneumonias are recognized

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many virus-specific glycoproteins. It differs from herpes simplex, varicella zoster, and Epstein-Barr viruses in that the Cytomegalovirus Infection CMV genome does not appear to speciThe role of cytomegalovirus (CMV) in fy a thymidine kinase enzyme, necessary pulmonary disease in patients with HIV for the initial phosphorylation step reinfection remains controversial, although quired to activate the antiviral drug acythe authors believe the weight of the evi- clovir. Thus, CMV is markedly less susdence suggests that the majority of in- ceptible to acyclovir than the other hufections either are not associated with man herpes viruses. CMV is also a very disease or coexist with more serious HIV- fastidious pathogen, as it is readily inacrelated complications. In the latter cir- tivated by a variety of mild physical meacumstance, CMV infection appears to sures (heat, freezing, etc.)and it will replihave only a trivial effect on the clinical cate only in cells of human origin. Clinical features. CMV is a frequent course of the patient (78). Epidemiology. Infection with CMV cause of pneumonitis in other types of generally occurs by two distinct mecha- immunosuppressed patients, particularnisms at two periods of life. Infection in ly those who have received bone marrow childhood occurs through the sharing of transplants (83). However, CMV pneurespiratory secretions during close con- monitis in this population may well reptact, particularly in nurseries and day- resent a combination of CMV infection care centers. Depending on the social and with a graft-versus-host reaction (84). economic circumstances of the children, Evidence for this joint immunologic-infrom 25 to 90070 of children will be in- fectious mechanism comes from animal fected in early childhood. Transmission studies as well as from clinical observain adult life occurs predominantly via sex- tions in patients (84). Bone marrow transual intercourse, although some young plant recipients with CMV pneumonia adults will be infected from their chil- rarely respond well to treatment with andren. By 30 to 40 years of age, anywhere tiviral agents active against CMV, whereas from 50 to 95% of persons will be in- about half the patients given a combinafected with CMV, again depending on tion of an antiviral and an immunotheir socioeconomic status. Primary in- modulator (specifically, intravenous imfection with CMV is easily controlled by munoglobulin) will recover (85-87). Retinitis due to CMV occurs in over the immunologically normal host, and the infection becomes latent. Reactiva- 5% of patients with AIDS, and there is tion occurs spontaneously in healthy per- an abundance of data supporting a pathsons, although the level of infection re- ogenetic relationship, including response mains minimal and it is always asymp- to specific chemotherapy (88, 89). In adtomatic. CMV infection is present in over dition, CMV may cause gastrointestinal 99% of sexually active homosexual men disease in a small percentage of AIDS and is almost uniformly present in those patients, although the association bewith HIV infection (79). In contrast, oth- tween infection and illness is somewhat er population groups with HIV infection less clear in this instance (89). However, (hemophiliacs, intravenous drug users, the relation between CMV infection in etc.) have a prevalence of prior CMV in- the lung and pneumonia in patients with fection not markedly different from that AIDS still requires further study. Thirty found in the normal population, about to 40% of patients with AIDS and pneu50% (80). Reactivation of CMV infec- monia of diverse etiologies have CMV tion is common in patients during the present in bronchoalveolar lavage (14, later stages of HIV infection, with per- 60). In many of these cases, cells with haps 50 to 75% of patients shedding vi- typical cytomegalic inclusions in the nurus in the urine and a smaller percentage cleus and cytoplasm were also present eiwith viremia (79, 81, 82). ther in bronchoalveolar cellsor in the pulPathogenesis. CMV is a typical her- monary parenchyma, sampled by transpesvirus, closely related to the other six bronchial biopsy. The prevalence may be human herpesviruses, herpes simplex vi- even higher judging from postmortem rus types 1 and 2, varicella-zoster virus, studies, which revealed CMV in 69 to Epstein-Barr virus, and human herpes- 90% of cases with AIDS, with the lungs virus-6 and 7, as well as to the animal being the most common site of involveherpesviruses. Like other herpesviruses, ment (90-93). However, some of the paCMV has a large, double-stranded DNA tients in these reports had coexisting genome contained within a lipoprotein pathogens in their lungs, which would envelope, on the surface of which are have explained their pulmonary sympcomplications of other (non-HIV) immunosuppressive disorders (77).

MURRAY AND MILLS

toms and radiographic signs. In addition, the investigators of most large series of patients with AIDS and pneumonitis have noted that the clinical course of those who have had CMV in their lungs does not differ from those without CMV (94-97a). This lack of pathogenicity was recently reinforced by the results of a small study by Youle and associates (98), who randomized 20 patients with AIDS with CMV infection of the lung to receive a course of either intravenous foscarnet (an antiviral active against CMV infections at other sites) or placebo and who found no difference in outcome between the two groups of patients. Diagnosis. Nonetheless, there are occasional patients, such as those described by Masur and colleagues (99), who have definite CMV pneumonitis. The criteria for a tentative clinical diagnosis should include (1) CMV recovered on culture, (2) CMV inclusions in bronchoalveolar lavage cells or, preferably, transbronchial biopsy or, rarely, open lung biopsy specimens, (3) no other pathogen recovered or visualized, and (4) progressive pneumonitis (worsening radiographic or pulmonary function tests). A response to an antiviral active against CMV (ganciclovir and foscarnet) confirms the diagnosis. In our experience, such patients represent less than 1% of all patients with AIDS with pulmonary CMV infection. Although over 50 patients with "cytomegalovirus pneumonia" treated with ganciclovir have been reported, the diagnostic criteria employed in these cases were loose (78). Treatment. Treatment of the patient with suspected CMV pneumonitis is straightforward. The largest experience is with ganciclovir, a nucleoside analog prod rug similar to acyclovir but with much greater activity toward CMV. Treatment with ganciclovir arrests the progression of CMV retinitis in 80 to 95% of patients with AIDS (88, 89) and may have a beneficial effect on gastrointestinal disease as well (89). Only one case report unequivocally supports activity of ganciclovir in CMV pneumonitis in AIDS (99), although there is good reason to suppose it would be effective in other cases. As the diagnosis of CMV pneumonia may be delayed in comparison with CMV retinitis or gastrointestinal disease, treatment may accordingly be less effective. In contrast to the experience in treating CMV pneumonitis in bone marrow transplant recipients, there is no evidence that co-administration of CMV immune globulin has a beneficial effect

1363

STATE OF THE ART: PULMONARY COMPLICATIONS OF HIV INFECTION

on the course of the disease (86, 87, 100, 100a). Foscarnet has received more limited trials in CMV infection of the retina in patients with AIDS and appears to be about as effective as ganciclovir (100). It might, therefore, be considered in the patient with suspected CMV pneumonitis who had failed ganciclovir or who was intolerant to this drug. The usual dose for ganciclovir is 5 mg/kg every 12 h, given by intravenous injection during approximately 1 h. The initial treatment (socalled induction phase) is given for 10 to 14 days and is usually followed by a "maintenance" phase in which the drug is given at 5 to 7 mg/kg/day, once a day, 5 to 7 days per week. Foscarnet induetion dosage is 60 mg/kg every 8 hr, given intravenously during 1 h. The proper maintenance dosage has not been established but is probably 80 to 120 mg/kg/ day (M. Jacobson and colleagues, unpublished data).

Other Pulmonary Viral Infections Other herpesviruses (herpes simplex virus, varicella-zoster virus, Epstein-Barr virus) may cause pulmonary infections in patients with AIDS. Herpes simplex virus (HSV) is a recognized cause of pneumonia in other immunosuppressed patients (101)but has been reported only occasionally in patients with AIDS (14, 32, 102). As HSV is commonly recovered from oropharyngeal secretions of patients, particularly those who are immunosuppressed, it is also a frequent contaminant of lower respiratory secretions. Hence, recovery of HSV from bronchoalveolar lavage or induced sputum rarely indicates the presence of HSV pneumonia. The criteria that should be applied for diagnosis of HSV pneumonia are similar to those for CMV pneumonia: clinical evidence of progressive pneumonitis, histopathologic evidence of HSV infection of the lung accompanied by recovery of virus, and no other pathogen identified. In patients who have documented HSV infection, acyclovir (5 mg/kg intravenously every 8 h for 10 to 14 days) is the treatment of choice. Based on the experience with other patients, the clinical response should be good (103). Bear in mind, however, that severely immunosuppressed patients - such as those with AIDS - may develop acyclovir-resistant strains of HSV (104). Thus, in patients who previously have received acyclovir, failure to respond to acyclovir within a reasonable period of time (3 to 5 days) should be reason to suspect acyclovir-resistant virus. In this instance,

repeat cultures for susceptibility testing should be obtained, and an alternative antiviral such as foscarnet or vidarabine should be employed (105). Varicella zoster virus may cause pneumonia in normal adults (in the setting of chickenpox) as well as in the immunosuppressed patient. The diagnosis is usually easy, as pneumonitis occurs in the setting of widely disseminated, overt varicella-zoster infection. Varicella-zoster pneumonia appears to be an unusual complication in patients with AIDS, although 11 cases of disseminated infection were recently reported (106). Acyclovir, 10mg/kg every 8 h by intravenous injection, is the drug of choice (85). Acyclovir-resistantvaricella-zoster virus should be considered in patients who fail to respond to therapy (107, 107a). A role for Epstein-Barr virus in the pathogenesis of HIV-related lung disease was proposed by Andiman and colleagues (108) based on their finding of specific viral DNA in 8 of 10 lung biopsy specimens of infants and children with lymphocytic interstitial pneumonitis. However, HIV itself has been isolated from bronchoalveolar lavage fluid from a child with lymphocytic interstitial pneumonitis (109). More recently, highly sensitive in situ hybridization techniques have identified HIV RNA in the lung of another infant with lymphocytic interstitial pneumonitis (110). Accordingly, the investigators proposed that HIV may play a direct causal role in this form of pneumonitis, a suggestion that was later supported by the finding of both HIV antigen and specific IgG antibody in bronchoalveolar lavage fluid from two adults with lymphocytic interstitial pneumonitis (111). However, it is possible that both HIV and Epstein-Barr virus act in concert in view of the in vitro observation that Epstein-Barr virus-infected B cells are unusually susceptible to infection by HIV (112). Other viruses do not appear to be uniquely pathogenic in the setting of HIV-induced immunosuppression. Several cases of influenza have been reported in patients with AIDS or an AIDSrelated condition (ARC), and although the clinical picture was not unusually severe, symptoms appeared to be prolonged (113, 113a). Immunization with influenza vaccine will stimulate an antibody response in at least some HIV-infected patients and has been recommended for prevention of influenza (114-116). Respiratory syncytial virus and parainfluenza viruses have been reported to cause un-

usually severe or prolonged illness in other immunosuppressed populations and may do so in patients with AIDS as well (117-119). Adenoviruses have been recovered from the urine of ten patients (120) and the lungs of one patient with AIDS (91), but no association between virus recovery and disease has been made. Bacterial Infections

Bacterial pulmonary infections appear to occur at increasing frequency in patients with HIV infection, although epidemiologic data supporting this contention are scant. Stover and coworkers (15) studied 130 patients with AIDS admitted to one hospital and found that four of the admissions were due to bacterial pneumonia. A later study from the same institution reported that 4010 of patients with AIDS had bacterial pneumonia (24), similar to the 3 % incidence reported in the multi-institutional survey conducted by Murray and associates (14). In contrast, Witt and colleagues (121) reported a 31% incidence of bacterial pneumonia; however, this figure was derived from a review of the medical records of hospitalized patients at an inner-city institution that serves patients who were mainly intravenous drug users. Reports of autopsy studies indicate that bacterial pneumonia may occur in as many as one-third of the patients (74, 122), butthese results may overestimate the incidence of infection as terminal aspiration pneumonia unrelated to the disease process may be included in the cumulative total. On the other hand, the true incidence of bacterial pneumonia may be underestimated in cohort studies because of the use of co-trirnoxazole as chemoprophylaxis or empiric therapy for P. carinii infections because this antimicrobial combination is also active against H. influenzae and pneumococci. However, there have been no studies comparing the rates of bacterial pneumonia observed in patients with HIV infection with those of matched, non-HIV-infected control subjects.

Community-acquired BacrerialPneumonws Bacterial pneumonias in persons with HIV infection, as in other patient populations, can be divided into those acquired out of the hospital, so-called community-acquired pneumonias, and those resulting from nosocomial infection, or hospital-acquired pneumonias. The etiology and pathogenesis of these two

1364

types of bacterial pneumonia are quite different (123). Epidemiology. The pneumococcus and H. influenzae are the most common causes of community-acquired bacterial pneumonia in patients with HIV infection as they are in immunologically normal patients (24, 121, 124, 125). Infections due to pneumococci and H. influenzae frequently occur before an AIDSdefining diagnosis has occurred, at a time when the patient may have only lymphadenopathy or ARC (121,126). However, systematic studies of the stage of HIV infection, as measured by CD4lymphocyte numbers, for example, have not been performed in patients with bacterial pneumonia. Polsky and colleagues (24) estimated an annual attack rate of pneumococcal pneumonia for HIV-infected patients at nearly 18cases/l,000 patients, over fivetimes that observed in the general population. Moreover, patients commonly have one or two recurrences in the ensuing 6 to 12 months (24, 121). Occasional patients may have community-acquired pneumonias due to other bacteria (14, 24, 121, 123, 127); we have seen cases due to Staphylococcus aureus, Klebsiella pneumonia, Rhodococcus equi, and Legionella species in patients with HIV infection without other overt defects of host defenses (J. Mills and associates, unpublished data). Bordatella pertussis has been recovered from bronchoscopic specimens obtained from patients with AIDS, although the relationship to disease was not clear (128). Clinicalfeatures. The main clinical features of pneumococcal and H. influenzae pneumonia in patients with HIV infection are similar in many respects to those seen in patients without HIV infection (15, 24, 126). Important differences include an apparent increase in frequency of multilobar involvement and an increased incidence of bacteremia in HIVinfected patients compared to those with normal immune systems (15, 24, 121, 126). Patients with P. carinii pneumonia may have concurrent bacterial pneumonia, which complicates diagnosis and treatment (14, 129) (P. C. Hopewell and colleagues, unpublished data). In addition, the response of bacterial pneumonia to chemotherapy may be suboptimal in some patients (24), although the vast majority respond well to treatment. Treatment. Treatment of HI V-infected patients with pneumonia due to pneumococci or H. influenzae is the same as in non-HIV-infected patients. Pneumococcal infections are best treated with peni-

MURRAY AND MILLS

cillin; first-generation cephalosporins, clindamycin, and erythromycin should be reserved for penicillin-allergic patients. H. influenzae may be treated with ampicillin unless the organism is a beta-Iactamase producer, in which case a secondor third-generation cephalosporin or cotrimoxazole (at a dose of 10mg trimethoprim and 50 mg sulfamethoxazole/kg/ day) may be employed. All of the secondgeneration cephalosporins (e.g., cefuroxime, 0.75 to 1.5 g every 8 h) are active against both pneumococci and H. influenzae (including beta-lactamase-producing strains) and may be used as empiric therapy for patients in whom the etiology of community-acquired bacterial pneumonia is not yet clear. Prevention. No clear strategy has emerged for preventing community-acquired bacterial pneumonias in patients with HIV infection. Although vaccines against the common serotypes of pneumococci and H. influenzae are available, the humoral immune response of patients with HIV infection is blunted to both polysaccharide and protein immunogens, particularly in the later stages of infection (114, 115, 130). In addition, no studies have shown the vaccines to be effective in this patient population, and clearcut instances of vaccine failure have been reported (121, 131). Nevertheless, the CDC has recommended that pneumococcal vaccinebe givento all patients with HIV infection (116). From a practical viewpoint, however, most clinicians do nothing for the HIV-infected patient who has had a single episode of communityacquired bacterial pneumonia, although some will administer pneumococcal vaccine. In the patient who has had recurrent infections, particularly if they have been bacteremic, continuous chemoprophylaxis is often recommended, although not based on any clinical data. Co-trimoxazole should be employed in those patients who can tolerate the drug, as it will also prevent episodes of P. carinii pneumonia. No clear alternative is available for patients unable to tolerate cotrimoxazole, although ampicillin or amoxicillin (500 mg every 12 h) may be tried. In children with HIV infection, regular intravenous administration of immune globulin has been recommended and has been claimed to be beneficial (132). However, the efficacy of this form of preventive therapy is considered unproven, and a randomized, comparative trial is now under way under the auspices of the National Institutes of Health (NIH). Intravenous therapy with immune

globulin has been proposed for adults with recurrent bacterial infections, but antibiotic prophylaxis is simpler, much less expensive, and may be more effective.

Nosocomial Bacterial Pneumonias Nosocomial pneumonias in patients with HIV infection are usually due to staphylococci and aerobic gram-negative rods. The infections almost alwaysdevelop late in the course of HIV infection, generally after an AIDS index diagnosis has been made (15, 121). In addition, the majority of these patients have other risk factors for bacterial infection such as druginduced severe neutropenia or a central venous catheter. In many instances, pneumonia due to bacterial pathogens has been due to terminal aspiration in moribund patients. Thus, the morbidity and mortality of nosocomial bacterial pneumonias has been high, even when they are recognized early and treated appropriately. Legionella species also cause nosocomial as well as community-acquired pneumonia, although it is unusual (17). Other infrequent bacterial pathogens, such as Nocardia, Branhamella, Rhodococcus, group B streptococci, and Mycoplasma pneumoniae, have been reported occasionally as a cause of either community- or hospital-acquired pneumonia in patients with HIV infection (123). Tuberculosis Poverty, with its attendant overcrowding and poor hygiene, is believed to enhance the spread of Mycobacterium tuberculosis from one person to another, but the most important factor, by far, that determines whether latent infection with tubercle bacilli will progress to clinically significant disease is the adequacy of the host's immune response, especially cellmediated immunity. Youmans (133)says succinctly: "Progression of tuberculous disease can only take place in the presence of inadequate cellular immunity to infection." In keeping with this dictum, clinical tuberculosis has been linked to the cellular immune deficiencies associated with age, undernutrition, and possible racially determined genetic factors, and other as yet undetermined causes of immunologic abnormalities probably exist as well. Thus, it is not at all surprising that tuberculosis, a quintessential opportunistic infection, is becoming a major infectious pulmonary complication of HIV infection, particularly in developing countries. But tuberculosis differs from virtually all other HIV-related infections in ways that make it especially

STATE OF THE ART: PULMONARY COMPLICATIONS OF HIV INFECTION

important: it is transmissible, curable, and preventable (134). Epidemiology. From 1953, the year national reporting was started in the United States, to 1984, there was an average decline in the tuberculosis case rates in the United States of about 5070 per year. In 1985, the rate of decline lessened to 0.2%, and in 1986, for the first time in 33 years, there was an increase of 2.6% in the number of reported cases (135); in 1987, the number of reported cases was a little less than that reported in 1986 (figure 5). Thus, from 1985 through 1987, there have been 9,226 more cases of tuberculosis in the United States, the hatched area in the figure, than would have been expected if the prevailing secular trend had continued. Although not definitely proved, evidence from several sources, persuasively summarized by Pitchenik and coworkers (136), supports the hypothesis that coexisting HIV infection is responsible for the unprecedented increase in tuberculosis in the United States. Probably the most compelling evidence for an association between tuberculosis and HIV infection comes from a prospective study of 520 intravenous drug users enrolled in a methadone-maintenance program in New York City (137). In this investigation, 49 of 217 HIV-seropositive subjects (23%) and 62 of 303 HIV-seronegative subjects (20%) were found to have a positive tuberculin skin test reaction, data which indicate a high rate of latent tuberculous infection in this population. Active tuberculosis developed in eight seropositive subjects, seven of whom had a positive tuberculin test and one of whom was anergic, and in none of the seronegative subjects (p < 0.002). 30,000

TUBERCULOSIS IN USA 1981-1987

26,000

Reportee

Cases 22,000

(138-142).

In contrast to the low prevalence of tuberculous infection in the United States and other developed countries, most persons in sub-Saharan Africa are infected with tubercle bacilli before or during early adulthood. In urban centers of this region, 5 to 20% of the sexually active population are also infected with HIV (143). Predictably, high HlV-seroprevalence rates have been reported in patients with tuberculosis from several countries in Central Africa (144-146). It seems clear that HIV infection is having a profound effect on the already immense problem of tuberculosis in Africa and in other developing countries where there is a high prevalence of both infections (147, 148). Pathogenesis. Nearly all cases of tuberculosis are acquired via the lungs through the inhalation of an infectious aerosol composed of droplet nuclei containing viable M. tuberculosis. Acquisition of tubercle bacilli through the oropharynx or gastrointestinal tract by ingesting contaminated food or milk is uncommon. Direct inoculation of M. tuberculosis is rare. Newly inhaled tubercle bacilli may or may not cause infection in the lungs of a previously unexposed person. It is difficult to document how often this does or does not happen, but the prevalence of tuberculin reactivity among close contacts of infectious cases suggests that new infection occurs about 50% of the time (149).

lB'ooo~

.,

1

Evidence from this and other reports demonstrates that in the United States, where the prevalence of tuberculosis is low and, accordingly, new exposure in the community to M. tuberculosis is infrequent, most of today's cases of tuberculosis occur in patients with a high background prevalence of tuberculous infection and, thus, represent reactivation of remotely acquired tubercle bacilli (138140). Thus, the risk of developing HIVrelated tuberculosis is considerably increased among blacks, Hispanics, intravenous drug users, and immigrants from Haiti and other countries where the prevalence of tuberculosis is extremely high

l---.L.-...L-..-L-......I..---'------I

1981

1983

1965

1987

Year Fig. 5. Graph showing the number of reported cases of tuberculosis in the United States from 1981 to 1987. Those that are HIV-related are shown by the hatched area. (Reproduced from reference 148 with permission.)

About 10% of newly infected persons will develop clinically apparent tuberculosis during their lifetimes; half of these occur during the first few years after the onset of infection and the other half occurs many years, often decades, later (150). In the other 90%, host defenses are sufficient to prevent progression from infection to disease. Although M. tuberculosis infection stimulates both humoral and cellular immunologic systems, cell-

1365

mediated immunity is the major determinant of host resistance and controls the infection by killing many organisms and walling off the remainder within granulomata. The development of cellmediated immunity against M tuberculosis tremendously strengthens host defenses; the immunologically armed patient is not only much better able to thwart progression of infection already present in his body but to resist the implantation and development of sites of new infection by subsequently encountered tubercle bacilli (151). When immunity wanes, as by the effects of age, or is suppressed, as by drugs or diseases such as HIV infection, the potential exists (1) for the reactivation of previously acquired tuberculosis wherever endogenous sites of viable organisms remain or (2) for the development of newly acquired tuberculosis from recently inhaled bacilli from an exogenous source. Undoubtedly both circumstances occur, and the likelihood of one or the other will depend on the background prevalence of tuberculosis in the immunosuppressed host group and the chances of contacting infectious cases of tuberculosis in the community. Stead (152) has presented evidence that in the United States, endogenous reactivation is the more important, but his own data also suggest that exogenous infection may occur and, of course, this would be enhanced in sub-Saharan African and other developing countries where there are many patients in the community with transmissible tuberculosis. Because M tuberculosis is more virulent than most HIVrelated opportunistic pathogens causing latent infection, such as P. carinii or Toxoplasma gondii, tuberculosis is often the first endogenous infection to reactivate during progressive HIV-inducedimmunosuppression. Clinicalfeatures. There are two distinct clinical patterns of tuberculosis in HIVinfected patients that depend on when in the course of evolving HIV infection the tuberculosis develops (151, 153). Of the two, the one that has received the greater attention develops when tuberculosis complicates the late stages of HIV disease; in other words, just before or even after the onset of AIDS (139, 154, 155). In this circumstance, the clinical and radiographic features are likely to differ substantially from those in non-Hlv-infected patients with "ordinary" tuberculosis. Among the important differences that have been observed are (1) that patients with tuberculosis and HIV infec-

1366

tion often have a negative tuberculin skin test reaction; (2) that more than half will have extrapulmonary (especially lymph node) involvement; and (3) that upper lobe cavitary disease is infrequent and the chest radiographs are usuall y at ypical (156). These features often suggest a disease other than tuberculosis, thus delaying diagnosis and the institution of specific chemotherapy and increasing the likelihood of transmission. The diffuse lower lung field radiographic densities (figure 6), in particular, may mimic P. carinii pneumonia or other opportunistic pulmonary infections and create diagnostic confusion. It should be noted that hilar and mediastinal adenopathy are not part of the HIV-related generalized lymphadenopathy syndrome (157); intrathoracic lymph node enlargement in a patient with HIV infection usually indicates tuberculosis (figure 4), Mycobacterium avium complex infection (figure 7), Kaposi's sarcoma, or (less commonly) lymphoma (140). Endobronchial tuberculosis associated with HIV infection has been reported (158). In contrast to the atypical pattern of tuberculosis that is so striking in patients with late HIV infection manifested by AIDS (or soon-to-be AIDS), tuberculosis with features indistinguishable from "ordinary" disease has been found in pa-

MURRAY AND MILLS

tients with earlier HIV infection in San Francisco and Kinshasa (146, 159). Cutaneous reactivity to tuberculin is preserved, the usual upper lobe predominance of infiltrations that tend to cavitate is seen radiographically, and extrapulmonary disease occurs with the same frequency (15 to 200/0) as it does in non-HIV-infected persons. The difference in the two patterns of tuberculosis is explained by the degree to which cellular immunity is preserved . Patients with advanced HIV infection and virtual ab sence of cellular immunity cannot develop or maintain hypersensitivity to tuberculoprotein; this explains many of the unusual features of tuberculosis in this setting, including dissemination. In contrast, patients with less advanced HIV infection have relatively well-preserved cellular immunity, and the usual clinical-radiographic features are observed. Diagnosis. The diagnosis of tuberculosis depends on the isolation and identification of M. tuberculosis by culture. Finding acid-fast bacilli in secretions or tissue provides an indication for empiric antituberculous treatment but does not prove M. tuberculosis infection. Identifi- . cation by culture is mandatory in view of the increasing numbers of immunosuppressed patients in developed countries who prove to have nontuberculous mycobacterial disease (160); this

does not appear to be the case in developing countries (146). Specimens for examination for acid-fast bacilli and mycobacterial culture include sputum, bronchoalveolar lavage, transbronchial biopsy, bone marrow aspirate or biopsy, fine needle aspirate of lymph node or other lesion, and biopsy of other suspicious sites. Blood cultures using special techniques are occasionally positive but not nearly as often as in disseminated M avium complex disease (161). The results of drug susceptibility studies are useful in planning definitive treatment. Treatment. Because tuberculosis is treatable and communicable until treatment is begun and because nontuberculous mycobacterial disease responds poorly to medications, the CDC (162) has recommended that antituberculous chemotherapy be started whenever acid-fast bacilli are found in a specimen from a patient with known or suspected HIV infection and clinical evidence of mycobacterial disease. While awaiting the results of cultures to distinguish M. tuberculosis from M. avium complex and other Mycobacteria , it is important for individual and public health reasons to initiate treatment for tuberculosis with three or four drugs: isoniazid, 10to 15 mg/kg/ day up to 300 mg/day; rifampin, 10 to 15 mg/kg/day up to 600 mg/day; and pyrazinamide, 20 to 30 mg/kg/day dur-

Fig. 6 (left). Posteroanterior chest radiograph of a patient with HIV-related tuberculosis. Note widespread nodular infiltrat ion, part icularly in both lower lung zones and left hilar adenopathy. Fig. 7 (right) . Posteroanterior chest radiograph of a patient with AIDS and disseminated M. avium complex infection. Note bilateral hilar and right paratracheal adenopathy. Patchy infiltrations are evident in both lower lung zones and in the left apex.

STATE OF THE ART: PULMONARY COMPLICATIONS OF HIV INFECTION

ing the first two months of therapy. Occasionally, when drug resistance is suspected (because of previous antituberculosis therapy or residence in certain regions of the world) or extensivedisease is present, ethambutol, 25 mg/kg/day, is also administered until the results of drug susceptibility studies are available (163). Becausethe appropriate duration of therapy in HIV infection is unknown, both the CDC (162) and American Thoracic Society (ATS) (163) recommend that treatment be administered for a minimum of nine months and for at least six months after documented culture conversion. If isoniazid or rifampin is not included in the regimen, therapy should continue for a minimum of 18 months and for at least 12 months after culture conversion. It is worth pointing out, however, that although failures have been reported (164), standard four-drug, sixmonths therapy for otherwise uncomplicated HIV-related pulmonary tuberculosis has produced excellent results in San Francisco and Miami (138, 165). The results of one retrospective study indicated that patients with tuberculosis and HIV infection were more likely than non-HIV-infected persons to experience toxicity from antituberculous drugs (155). Prospective studies of HIV-related tuberculosis in Kinshasa revealed an increased incidence of side effects to thiacetazone, an antituberculous drug widely used in developing countries, including two cases of Stevens-Johnson syndrome (146). Toxicity of antituberculosis drugs in HIVinfected patients does not appear to be nearly as serious a problem as is toxicity from antipneumocystis drugs but needs to be kept in mind when evaluating new signs or symptoms in HIV-positive patients being treated for tuberculosis. Prevention. There is mounting evidence that prophylaxis with isoniazid, 300 mg/day for 12 months, in patients with HIV infection will prevent progression from latent tuberculous infection to clinical tuberculosis (137). Thus, all persons with evidence of HIV infection, usually a positive serology, should have a tuberculin skin test with 5 tuberculin units (TU). If there is more than 5 mm induration (note 5 not 10 mm as is customary), a chest X-ray should be obtained, and if abnormal, the patient should be evaluated for tuberculous disease. Even if evidence of tuberculosis is not found, the person should receive isoniazid chemoprophylaxis. Although it is not definitely proved that isoniazid prevents tuberculosis in HIV-infected per-

sons, the usually good response to standard prophylactic treatment in most tuberculin positive patients suggests that isoniazid preventivetherapy should be effective (163). The obvious advantage of preventing clinicaltuberculosis in persons with HIV infection is one of the reasons given for encouraging voluntary HIV testing in high risk groups who may also have tuberculous infection (9). Because of the high HIV seroprevalence rate among pregnant women and the increasing evidence of HIV infection among infants and children in parts of Africa and other regions of the world, concern has been raised about the safety and efficacy of bacillus Calmette-Guerin (BCG) and other immunizations in HIVinfected persons (166, 167). Local lymphadenitis (166) and disseminated disease (168-170) haveboth been described. However, fewstudies comparing the incidence and severity of BCG reactions in HIVseropositive and HI V-seronegative persons have been performed (147), and the limited data available suggest no significant difference between the two groups (171).

Accordingly, the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Diseases (IUATLD) continue to recommend widespread vaccination with BCG in developing countries where there is a high prevalence of HIV infection but state that BCG should not be given to any symptomatic HIV-infected children or adults (172). The ATScautions against the use of BCG and other live, attenuated vaccines in persons with HIV infection (163). Given the occasional severe infections due to BCG in patients with profoundly depressed cellular immunity, these cautions are appropriate. Prognosis. The prognosis of patients with HIV-related tuberculosis is poor but obviously depends on when in the course of evolving HIV infection the tuberculosis supervenes. Among the 27 Haitian patients with tuberculosis and HIV infection followed by Pitchenik and colleagues (154), tuberculosis usually preceded the diagnosis of AIDS by an average of six months (range, 1to 17months). In the cases followed in San Francisco, death occurred an average of 7.4 months after diagnosis of the tuberculosis and was caused by HIV-induced complications other than tuberculosis (155). Recent data from Zaire, however, indicate a significantly higher mortality during the first two months of treatment after the diagnosis of tuberculosis in patients

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who were HIV seropositive (25070) compared with those who were seronegative (9%), a difference probably attributable in part to other HIV-associated complications and in part to the tuberculosis itself (146). Mycobacterium avium Complex Twoclosely related nonchromogenic mycobacteria (Runyon's group III), M avium and Mycobacterium intracellulare, have been grouped together as Mycobacterium avium complex (MAC). In the United States and other developed countries, these organisms are isolated from patients with HIV infection much more often than are other mycobacteria,including the more virulent M. tuberculosis, although the reverseis true in Central African and other developing countries. Epidemiology. Before the AIDS epidemic, only 37 cases of disseminated MAC had been reported (173). However, once the epidemic began, disseminated MAC was soon recognized as a frequent and important opportunistic infection in patients with HIV infection (174, 175). From 1981 through 1987, 1,906 cases of disseminated MAC in patients with AIDS were reported to the CDC (176). Although the number of cases has risen steadily since 1981, the rate as a percentage of all cases of AIDS has remained stable at approximately 5%. Disseminated MAC is an infrequent index diagnosis of AIDS because this opportunistic infection tends to occur late in the course of the HIVinduced immunosuppression. MAC was cultured between the diagnosis of AIDS and death in 74 of 441 patients (17%) in one series (14) and in 50 of 366 patients (14%) in another series (177). The actual prevalence of infection is probably much higher than these figures indicate. Disseminated MAC wasdiagnosed at autopsy in 42 of 79 patients with AIDS (53%) at Memorial Sloan-Kettering (177) and 9 of 16 patients (56%) at the National Institutes of Health (178); in many of these patients, the presence of MAC infection had not been recognized during life. Pathogenesis. MAC is a ubiquitous microorganism found commonly in water and soil and known to cause disease in birds and several mammals, including humans (179). Infection in humans is believed to result from environmental sources, and the organism probably enters the body through either the lungs or the gastrointestinal tract (180), although homosexual intercourse has been proposed as a means of transmission (181).

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The declining prevalence of MAC with age reported by Horsburgh and Selik (176) suggests that younger persons are more frequently exposed to the organisms than older persons and that disease results from progressive recent infection rather than reactivation of latent infection, as occurs with many AIDS-related opportunistic infections. Studies of strains of MAC cultured from patients with AIDS revealed that a high proportion were serotypes 4, 6, and 8 (182) and that all contained plasmids (183), whereas environmental isolates lacked plasmids and were rarely serotype 4, 6, or 8. However, the implications of these findings, if any, with respect to possible sources of infection, modes of transmission, pathogenicity, or virulence have not been determined. Clinicalfeatures. MAC is a recognized cause of lung disease that resembles tuberculosis in apparently immunocompetent hosts, especially elderly persons with preexisting chronic lung disease (bronchiectasis, pneumoconiosis, emphysema-bronchitis, or chronic aspiration from esophageal disease). MAC is also a well-documented cause of localized cervicallymphadenitis in children (179). As stated, disseminated MAC is usually diagnosed late in the course of HIV infection, at a time when other AIDS-related complications are present; thus, it is difficult to identify specific clinical features attributable solely to this infection. MAC has been associated with (1) a wasting syndrome consisting of fever, weight loss, and cachexia; (2) chronic diarrhea and abdominal pain; (3) progressive anemia often requiring transfusion; (4) a chronic malabsorption syndrome resembling Whipple's disease; (5) extrabiliary obstructive jaundice (160). Respiratory symptoms are usually unimportant and the chest radiographs are typically normal, even when the organism can be cultured from respiratory tract secretions (160, 180). Diagnosis. MAC has been cultured from numerous sites in patients with HIV infection, including lungs, bone marrow, liver, spleen, lymph nodes, intestine, blood, urine, and feces. The organisms may be cultured initially from sputum or bronchoalveolar lavage fluid, but this finding does not necessarily indicate either invasive or disseminated disease and does not lead to the diagnosis of AIDS. Colonization, or perhaps local infection, has been substantiated at autopsy examinations in which MAC organisms have been cultured from lung tissue, but no acid-fast bacilli were seen on histologic

MURRAY AND MILLS

specimens from either the lungs or other organs (90). The pathologic findings of MAC infection are characteristic but not definitive. Acid-fast bacilli are remarkably plentiful and often found within foamy macrophages or histiocytes (71); granulomata are usually absent or poorly formed (122). Mycobacteremia is common in patients with disseminated MAC infection (161, 184), and quantitative methods (lysis centrifugation) are useful in monitoring response to treatment. When sufficient numbers of MAC organisms are present, the differentiation between MAC and M tuberculosis can be made quickly by nucleic acid hybridization using specific probes (185). The value of drug susceptibility studies in guiding the selection of drugs is controversial. There is no documented relationship between the results of in vitro susceptibility testing and successful treatment of MAC infection in patients with AIDS (186) as has been published for M. avium pulmonary disease in patients without AIDS (173). Treatment. Although there remains some doubt about the efficacy of chemotherapy for MAC-induced pulmonary disease in immunocompetent patients, successful results have been reported (187). Furthermore, the results of a recent study of serial minimal inhibitory concentrations during treatment, which mainly showed increasing values to a variety of antituberculous drugs, were interpreted as demonstrating a therapeutic response (188). Unfortunately, no treatment regimen has been found that consistently reduces mycobacteremia or improves survival in patients with disseminated MAC and AIDS, although some patients experience transient clinical improvement and/or a reduction in mycobacteria colony counts in their blood. Various combinations of drugs, including rifabutin, isoniazid, ethambutol, clofazimine, rifampin, amikacin, pyrazinamide, and cycloserine, have been tried, but none has produced sustained remission for the majority of patients (160). The most consistent antimycobacterial effects have been observed with the four-drug regimen of ciprofloxacin, rifampin, ethambutol, and amikacin; this has resulted in decreased blood colony counts, a decrease in systemic symptoms, and possibly decreased transfusion requirements. The reasons for the poor therapeutic response are unknown but may include the advanced stage of immunosuppression and the coexistence of other HIV-

related complications as well as lack of good drugs. Most strains of MAC show resistance to standard antituberculous drugs (except ethambutol) and only inhibition, not killing, to attainable plasma concentrations of other available agents. Bactericidal synergism of various combinations has been difficult to achieve but it has recently been demonstrated (189). Prognosis. For obvious reasons, the prognosis in patients with AIDS-related disseminated MAC is poor. Life-table analysis revealed that patients with AIDS and disseminated nontuberculous mycobacterial infection, which in nearly all instances was caused by MAC, had a shorter survival (median, 7.4 months) than did patients with AIDS and an index diagnosis of pneumocystosis (median, 13.3 months; p < 0.0001)(176). Given the poor prognosis of disseminated MAC as well as the costs and toxicity of the various medications used to treat the infection, many physicians caring for these patients believe that supportive care alone is the most appropriate treatment. Other physicians urge that treatment can be undertaken in carefully selected patients, particularly those who have symptoms attributable to MAC infection and not to another disease, who have reasonably intact renal and liver function and who are willing to cooperate in a course of treatment that involves potentially toxic medications (186).

Other Mycobacterial Infections Analysis of the 1,906 AIDS-related cases of disseminated nontuberculous mycobacterial infection reported to the CDC from 1981 through 1987 showed that nearly all (96070) were caused by MAC (176);other species of mycobacteria were distinctly uncommon (table 3). The reason(s) for this striking disparity, which contrasts with the frequency with which various mycobacteria cause dissemination in non-HIV-immunosuppressed patients, is unknown (173). Increased frequency of exposure or the presence of specific defects of host defenses might account for the predominance of MAC in patients with AIDS. In addition to the organisms identified in table 3, M. xenopi has caused disseminated disease in a patient with HIV infection (190), and three cases of disseminated M. bovis have been reported in patients with AIDS: one occurred in a 29- year-old man with Kaposi's sarcoma who was given BCG in an attempt to stimulate immunity (168);the second occurred in a 4-month-old infant who was

STATE OF THE ART: PULMONARY COMPLICATIONS OF HIV INFECTION

TABLE 3

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23. Hopewell PC, Luce 1M. Pulmonary involvement in the acquired immunodeficiency syndrome. Chest 1985; 87:104-12. 24. Polsky B, Gold lWM, Whimbey E, et 01. Bacterial pneumonia in patients with the acquired imSpecies Number Percentage munodeficiency syndrome. Ann Intern Med 1986; 104:38-41. Mycobacterium avium complex 1,906 96.1 25. Hollander H. Work-up of the HIV-infected Mycobacterium kansasii 57 2.9 patient. Practical approach. Infect Dis Clin North Mycobacterium gordonae 11 0.6 Am 1988; 2:353-8. Mycobacterium fortuitum 5 0.3 26. Clement Ml, Luce 1M, Hopewell PC. DiagMycobacterium chelonei 5 0.3 nosis of pulmonary diseases. In: White DA, Stover Total 1,984t 100.0 DE, eds. Pulmonary effects of AIDS. Clin Chest Med 1988; 9:497-505 . • Reprinted from Horsburgh and Selik (176) with permission. 27. Ranki A, ValleS-L, Krohn M, et at. Long latent An additional 285 isolates were reported without speciation. cy precedes overt seroconversion in sexually transmitted human-immunodeficiency virus infection. Lancet 1987; 2:589-93. vaccinated with BCG ten days after be- 9. Rhame FS, Maki lG. The case for wider use 28. Jackson GG, Paul DA, Falk LA, et at. Huing born to a mother with HIV infection of testing for HIV infection. N Engl J Med 1989; man immunodeficiency virus (HIV) antigenemia 320:1248-54. (p24) in the acquired immunodeficiency syndrome (170);the third occurred in a 22-year-old 10. Edelman AS, Zolla-Pazner S. AIDS: a syn- (AIDS) and the effect of treatment with zidovuman with persistent generalized lymph- drome of immune dysregulation, dysfunction and dine (AZT). Ann Intern Med 1988; 108:175-80. 29. Spector SA, Kennedy C, McCutchan JA, et adenopathy two months after inocula- deficiency. FASEB 1 1989; 3:22-30. II. Rankin lA, Collman R, Daniele RP. Acquired at. The antiviral effect of zidovudine and ribavirin tion with BCG (169). deficiency syndrome and the lung. Chest in clinical trials and the use of p24 antigen levels Localized mycobacterial disease has immune 1988; 94:155-64. as a virologic marker. J Infect Dis 1989;159:822-8. also been reported in patients with HIV 12. Salah uddin SZ, Rose RM, Groopman JE, 30. Fahey JL, Taylor JMG, Detels R, et 01. The infection. The species that have been iso- Markham PD, Gallo RC. Human T Iymphotro- prognostic value of cellular and serologic markers lated include M. scrofulaceum, M. szul- phic virus type III infection of human alveolar mac- in infection with the human immunodeficiency virus type I. N Engl J Med 1990; 322:166-72. gai, Mi flavescens, M. asiaticum, M mal- rophages. Blood 1986; 68:281-4. 13. Beck 1M, Shellito 1. Effects of human immu- 31. Krumholz H, Sande MA, Lo B. Communitymoense, and M. xenopi (136). nodeficiency virus on pulmonary host defenses. Se- acquired bacteremia in patients with acquired imGuidelines for treatment have not been min Respir Infect 1989; 4:75-84. munodeficiency: clinical presentation, bacterioloestablished. Recommended therapy for 14. Murray IF, Felton CP, Garay S, et at. Pulmo- gy and outcome. Am 1 Med 1989; 86:776-9. M. kansasii infection includes isoniazid, nary complications of the acquired immunodefi- 32. Cohen BA, Pomeranz S, Rabinowitz lG, et ciencysyndrome. Report of a National Heart, Lung, at. Pulmonary complications of AIDS: radiologic rifampin, and ethambutol for a mini- and Blood Institute Workshop. N Engl J Med 1984; features. A1R 1984; 143:115-22. mum of 18months and at least 15months 310:1682-8. 33. Goodman PC, Gamsu G. Pulmonary radioafter culture conversion (163). The prog- 15. Stover DE, White DA, Romano PA, Gellene graphic findings in the acquired immunodeficiennosis is not good, but occasional re- RA, Robeson WA.Spectrum of pulmonary diseases cy syndrome. Postgrad Radiol 1987; 7:3-15. associated with the acquired immune deficiencysyn- 34. Golden lA, Sollitto RA. The radiology of pulsponses have been observed (191). monary disease. Chest radiography, computed drome. Am J Med 1985; 78:429-37. 16. Talavera W, Mildvan D. Pulmonary infections tomography, and gallium scanning. In: White DA, in the acquired immunodeficiency syndrome. Se- Stover DE, eds. Pulmonary effects of AIDS. Clin References Chest Med 1988; 9:481-95. min Respir Infect 1986; 1:202-11. 17. Murray IF, Garay SM, Hopewell PC, Mills 35. Stover DE, Meduri cu Pulmonary function I. Gottlieb MS, Schanker H, Fan P, Saxon A, J, Snider GL, Stover DE. Pulmonary complica- tests. In: White DA, Stover DE, eds. Pulmonary Weisman JD. Pneumocystis pneumonia - Los Antions of the acquired immunodeficiency syndrome: effect of AIDS. Clin Chest Med 1988; 9:473-9. geles. MMWR 1981; 30:250-2. an update. Am Rev Respir Dis 1987; 135:504-9. 36. Shaw Rl, Roussak C, Forster SM, Harris lRW, 2. Gottlieb MS, Schroff R, Schanker HM, et at. 18. Meduri GU, Stover DE, Lee M, Myskowski Pinching AJ. Lung function abnormalities in paPneumocystis carinii pneumonia and mucosal candidiasis in previouslyhealthy homosexual men. Evi- PL, Caravelli IF, Zaman MB. Pulmonary Kaposi's tients infected with the human immunodeficiency sarcoma in the acquired immune deficiency syn- virus with and without overt pneumonitis. Thorax dence of a new acquired cellular immunodeficien1988; 43:436-40. drome. Clinical, radiographic and pathologic mancy. N Engl J Med 1981; 305:1425-31. 37. Guillen 1M, Autran B, Denis M, et at. Huifestations. Am J Med 1986; 81:11-8. 3. Masur H, Michelis MA, Green JB, et at. An outbreak of community-acquired Pneumocystis 19. Gill PS, Akil B, Colletti P, et at. Pulmonary man immunodeficiency virus related lymphocytic Kaposi's sarcoma: clinical findings and results of alveolitis. Chest 1988; 94:1264-70. cariniipneumonia. NEngll Med 1981; 305:1431-8. 38. Murphy PM, Fox C, TravisW, Koenig S, Fau4. Barre-Sinoussi F, Chermann lC, Rey F, et at. therapy. Am 1 Med 1989; 87:57-61. 20. Ziegler Jl., Beckslead JA, Volberding PA, et ci AS. Acquired immunodeficiency syndrome may Isolation of a T-Iymphotropic retrovirus from a papresent as severerestrictive lung disease. Am 1 Med tient at risk for acquired immune deficiency syn- at. Non-Hodgkin's lymphoma in 90 homosexual men. Relation to generalizedlymphadenopathy and 1989; 86:237-40. drome (AIDS). Science 1983; 220:868-71. 5. Popovic M, Sarngadharan MD, Read E, Gallo the acquired immunodeficiency syndrome. N Engl 39. Coleman DL, Dodek PM, Golden lA, et at. J Med 1984; 311:565-70. Correlation between serial pulmonary function tests RC. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III)from pa- 21. Oldham SAA, Castillo M, lacobson FL, and fiberoptic bronchoscopy in patients with Pneutients with AIDS and pre-AIDS. Science 1984; Mones JM, Saldana MJ. HIV-associated lympho- mocystis carinii pneumonia and the acquired imcytic interstitial pneumonia: radiologic manifesta- mune deficiency syndrome. Am Rev Respir Dis 224:497- 500. 6. Phair lP, Wolinsky S. Diagnosis of infection tions and pathologic correlation. Radiology 1989; 1984; 129:491-3. 170:83-7. 40. Sankary RM, Turner J, Lipavsky A, Howes with the human immunodeficiency virus. J Infect Dis 1989; 159:320-3. 22. Suffredini AF, Ognibene FP, Lack EE, et at. EL Jr, Murray JE Alveolar-capillary block in pa7. Curran JW, laffe HW, Hardy AM, Morgan Nonspecific interstitial pneumonitis: a common tients with AIDS and Pneumocystis carinii pneucause of pulmonary disease in the acquired immu- monia. Am Rev Respir Dis 1988; 137:443-9. WM, Selik RM, Dondero TJ. Epidemiology of HIV infection and AIDS in the United States. Science nodeficiency syndrome. Ann Intern Med 1987; 41. O'Donnell CR, Bader MB, Zibrak lD, Jensen WA, Rose RM. Abnormal airway function in indi107:7-13. 1988; 239:610-6. 8. Centers for Disease Control. Classification sys- 22a. White DA, Matthay RA. Noninfectious pul- viduals with the acquired immunodeficiency syntem for human immunodeficiency virus (HIV) in- monary complications of infection with the human drome. Chest 1988; 94:945-8. immunodeficiency virus. Am Rev Respir Dis 1989; 42. Luce JM, Clement MJ. Pulmonary diagnosfection in children under 13 years of age. MMWR tic evaluation in patients suspected of having an 1987; 36:225-36. 140:1763-87. MYCOBACTERIAL SPECIES CAUSING DISSEMINATED, NONTUBERCULOUS MYCOBACTERIAL INFECTION IN PATIENTS WITH AIDS REPORTED TO THE CENTERS FOR DISEASE CONTROL·

1370 HIV-related disease. Semin Respir Infect 1989; agnosis of lung disease in acquired immune deficiency syndrome: biopsy or cytology and implica4:93-101. tions for management. J Clin Pathol 1987; 40: 43. Tsau ME Mechanisms of gallium-67 accumulation in inflammatory lesions. J Nucl Med 1985; 1269-73. 60. Broaddus VC, Dake MD, Stulbarg MS, et at. 26:88-92. Bronchoalveolar lavage and trans bronchial biop44. Coleman DL, Hattner RS, Luce JM, Dodek sy for the diagnosis of pulmonary infections in the PM, Golden JA, Murray JE Correlation between gallium lung scans and fiberoptic bronchoscopy acquired immunodeficiency syndrome. Ann Intern in patients with suspected Pneumocystis carinii Med 1985; 102:747-52. pneumonia and the acquired immunodeficiency 61. Milligan SA, Luce JM, Golden J, Stulbarg M, Hopewell PC, Transbronchial biopsy without flusyndrome. Am Rev Respir Dis 1984; 130:1166-9. 45. Woolfenden JM, Carrasquillo JA, Larson SM, oroscopy in patients with diffuse roentgenographet at. Acquired immunodeficiency syndrome: Ga- ic infiltrates and the acquired immunodeficiency syndrome. Am Rev Respir Dis 1988; 137:486-8. 67 citrate imaging. Radiology 1987; 162:383-7. 62. Golden JA, Hollander H, Stulbarg MS, Gamsu 46. Bitran J, Bekerman C, Weinstein R, Bennett C, Ryo U, Pinsky S. Patterns of gallium-67 scintig- G. Bronchoalveolar lavage as the exclusive diagraphy in patients with acquired immunodeficiency nostic modality for Pneumocystiscariniipneumonia. Chest 1986; 90:18-22. syndrome and the AIDS-related complex. J Nucl 63. Graham AR, Sobonya RE, Bronnimann DA, Med 1987; 28:1103-6. Galgiani IN. Quantitative pathology of coccidi47. Kramer EL, Sanger JH, Garay SM, Grossman oidomycosis in acquired immunodeficiency synRJ, Tin S, Banner H. Diagnostic implications of Ga-67 chest-scan patterns in human immunodefi- drome. Hum Pathol 1988; 19:800-6. ciency virus-seropositive patients. Radiology 1989; 64. Stover DE, Zaman MB, Hajdu SI, Lange M, Gold J, Armstrong D. Bronchoalveolar lavage in 170:671-6. 48. Schiff RG, Kabat L, Kamani N. Gallium scan- the diagnosis of diffuse pulmonary infiltrates in ning in lymphoid interstitial pneumonitis of chil- the immunocompromised host. Ann Intern Med 1984; 101:1-7. dren with AIDS. J Nucl Med 1987; 28:1915-9. 65. Wallace JM, Barbers RG, Oishi JS, Prince H. 49. Ognibene FP, Masur H, Rogers P, et at. Nonspecific interstitial pneumonitis without evidence Cellular and T-Iymphocyte subpopulation profiles of Pneumocystis cariniiin asymptomatic patients in bronchoalveolar lavage fluid from patients with infectedwith human immunodeficiencyvirus (HIV). acquired immunodeficiency syndrome and pneumonitis. Am Rev Respir Dis 1984; 130:786-90. Ann Intern Med 1988; 109:874-9. 50. Effros RM, Mason GR. Measurement of pul- 66. Young RK Jr, Rankin JA, Naegel GP, Paul ES, Reynolds HY. Bronchoalveolar lavage cellsand monary epithelial permeability in animals and man. proteins in patients with the acquired immunodeAm Rev Respir Dis 1983; 127(Suppl:59-65). ficiency syndrome: an immunologic analysis. Ann 51. Mason GR, Duane GB, Mena I, Effros RM. Acceleratedsolute clearance in Pneumocystis carinii Intern Med 1985; 103:522-33. pneumonia. Am Rev Respir Dis 1987; 135:864-8. 67. Venet A, Clavel F, Israel-Biet D, et at. Lung 52. Meignan M, Denis M, Autran B, et at. In- in acquired immune deficiency syndrome: infeccreased alveolar permeability (A.P.) in HIV infect- tious and immunological status assessed by bronchoalveolar lavage. Bull Eur Physiopathol Respir ed patients with cytotoxic alveolitis (abstract). Am 1985; 21:535-43. Rev Respir Dis 1988; 137(Part 2:358). 53. Ng VL, Gartner I, Weymouth LA, Goodman 68. Fouret P, Touboul JL, Picard F, Mayaud C, CD, Hopewell PC, Hadley WK. The use of mucoRoland J. Apport de I'examen du liquide de lavage lysed induced sputum for the identification of pulbronchoalveolaire chez les patients atteints du synmonary pathogens associated with human immudrome d'immunodeficit acquis et des syndromes nodeficiency virus infection. Arch Pathol Lab Med associes, Ann Pathol 1986; 6:45-52. 1989; 113:488-93. 69. Caughey G, Wong H, Gamsu G, Golden J. 54. Hadley WK, Ng VL. Organization of microbi- Nonbronchoscopic bronchoalveolar lavage for the ology laboratory services for the diagnosis of puldiagnosis for Pneumocystis carinii pneumonia in monary infections in patients with human immuthe acquired immunodeficiency syndrome. Chest nodeficiency virus infection. Semin Respir Infect 1985; 88:659-62. 1989; 4:85-92. 70. Wallace JM, Batra P, Gong H Jr, Ovenfors 55. Pitchenik AE, Ganjei P, Torres A, Evans DA, CO. Percutaneous needle lung aspiration for diagRubin E, Baier H. Sputum examination for the di- nosing pneumonitis in the patient with acquired agnosis of Pneumocystiscariniipneumonia in the immunodeficiency syndrome (AIDS). Am Rev acquired immunodeficiency syndrome. Am Rev Respir Dis 1985; 131:389-92. 71. Bottles K, McPhaul LW, Volberding P. FineRespir Dis 1986; 133:226-9. needle aspiration in patients with the acquired im56. BigbyTD, Margolskee D, Curtis JL, et at. The usefulness of induced sputum in the diagnosis of munodeficiency syndrome (AIDS): experience in Pneumocystis carinii pneumonia" in patients with an outpatient clinic. Ann Intern Med 1988; 108: the acquired immunodeficiency syndrome. Am Rev 42-5. 72. Barrio Jl, Harcup C, Baier HJ, Pitchenik AE. Respir Dis 1986; 133:515-8. 57. Zaman MK, Wooten OJ, Suprahmanya B, Valueof repeat fiberoptic bronchoscopies and sigAnkobiah W, Finch PJP, Kamholz SL. Rapid nificance of nondiagnostic bronchoscopic results noninvasive diagnosis of Pneumocystis carinii from in patients with the acquired immunodeficiencysyninduced Iiquified sputum. Ann Intern Med 1988; drome. Am Rev Respir Dis 1987; 135:422-5. 109:7-10. 73. Fitzgerald W, Bevelaqua FA,Garay SM, Aran58. Kovacs JA, Ng VL, Masur H, et at. Diagnosis da CPo The role of open lung biopsy in patients of Pneumocystiscariniipneumonia: improved de- with the acquired immunodeficiency syndrome. tection in sputum with use of monoclonal antibod- Chest 1987; 91:659-61. 74. MarchevskyA, Rosen MJ, Chrystal G, Kleineries. N Engl J Med 1988; 318:589-93. 58a. Ng VL, YaikoDM, McPhaul LW, et at. Evalu- man J. Pulmonary complications of the acquired immunodeficiency syndrome: a clinicopathologic ation of an indirect fluorescent antibody stain for study of 70 cases. Hum Pathol 1985; 16:659-70. the detection of Pneumocystis cariniiin respirato75. Ruben FL, Talamo TS. Secondary pulmonary ry specimens. J Clin Microbiol 1990 (In Press). 59. Francis ND, Goldin RD, Forster SM, et at. Di- alveolar proteinosis occurring in two patients with

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acquired immune deficiency syndrome. Am J Med 1986; 80:1187-90. 76. Wallace JM. Pulmonary infection in human immunodeficiency disease: viral pulmonary infections. Semin Respir Infect 1989; 2:147-54. 77. Williams DM, Krick JA, Remington JS. State of the art. Pulmonary infections in the compromised host. Am Rev Respir Dis 1976; 114:359-94, 593-627. 78. Jacobson MA, Mills J. Cytomegalovirus infection. In: White DA, Stover DE, eds. Pulmonary effects of AIDS. Clin Chest Med 1988; 9:443-8. 79. Mintz L, Drew WL, Miner RC, BrafEH. Cytomegalovirus infections in homosexual men: an epidemiologic study. Ann Intern Med 1983; 98: 326-9. 80. Brodie HR, Drew WL, Maayan S. Prevalence of Kaposi'ssarcoma in AIDS patients reflectsdifferences in rates of cytomegalovirus infection in highrisk groups. AIDS Memo 1984; 1:12-5. 81. Quinnan GV Jr, Masur H, Rook AH, et at. Herpes virus infections in the acquired immunodeficiency syndrome. JAMA 1984; 252:72-7. 82. Collier AC, Meyers JD, Corey L, Murphy VL, Roberts PL, Handfield HH. Cytomegalovirus infection in homosexual men. Relationship to sexual practices antibody to human immunodeficiency virus and cell-mediated immunity. Am J Med 1987; 82:593-601. 83. Abdullah PS, Mark JBD, Merigan TC. Diagnosis of cytomegalovirus pneumonia in compromised hosts. Am J Med 1976; 61:326-32. 84. Grundy JE, Shanley JD, Griffiths PD. Is cytomegalovirus interstitial pneumonitis in transplant recipients an immunopathologic condition? Lancet 1987; 2:996-8. 85. Shepp DH, Dandliker DH, DeMiranda P, et at. Activity ofDHPG in the treatment of cytomegalovirus pneumonia. Ann Intern Med 1985; 103: 368-73. 86. Emanuel D, Cunningham I, Jules-Elysee K, Brockstein JA, Kernan NA, Laver J. Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann Intern Med 1988; 109:777-82. 87. Reed EC, Bowden RA, Dandliker PS, Lilleby KE, Meyers JD. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous immunoglobulin in patients with bone marrow transplants. Ann Intern Med 1988; 109:783-8. 88. Mills J, Jacobson M, O'Donnell J, Cederberg D, Holland G. Treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome. Rev Infect Dis 1988; 10:S522-31. 89. Jacobson MA, Mills J. Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS). Clinical findings, diagnosis and treatment. Ann Intern Med 1988; 108:585-94. 90. Reichert CM, O'leary TJ, Levens DL, Simrell CR, Macher AM. Autopsy pathology in the acquired immunodeficiency syndrome. Am J Pathol 1983; 112:357-82. 91. Wallace JM, Hannah JB. Pulmonary disease at autopsy in patients with the acquired immunodeficiency syndrome. West J Med 1988;149:167-71. 92. Hui AN, Koss MN, MeyerPRoNecropsy findings in acquired immunodeficiency syndrome: a comparison of premortem diagnoses with postmortem findings. Hum Pathol 1984; 15:670-6. 93. Welch K, Finkbeiner W, Alpers CE, et at. Autopsy findings in the acquired immune deficiency syndrome. JAMA 1984; 252:1152-9. 94. Brodie HR, Broaddus C, Blumenfeld W, Hopewell PC, Moss A, Mills J. Is cytomegalovirus a cause of lung disease in patients with AIDS (abstract)? Clin Res 1985; 33:396A.

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95. Miles PR, Linneman CC, Baughman RP. The significance of cytomegalovirus in the lung of patients with human immunodeficiency virus infection (abstract). Am Rev Respir Dis 1988; 137(Part 2:122). 96. Chan CK, Kasupski Gl, Stehle 1, et 0/. Significance of cytomegalovirus in the bronchoalveolar lavage of patients with acquired immunodeficiencysyndrome and allogeneicbone marrow transplant recipients (abstract). Am Rev Respir Dis 1989; 139(Part 2:AI50). 97. Arcia 1M, Bozzette SA, Bartok A, McCutchan lA, Richman DD, Spector S. Bronchoalveolar lavage (BAL) CMV culture positivity (CMV +) is associated with better outcome of Pneumocystis carinii pneumonia (PCP) in men with AIDS (abstract). Presented at the Fifth International Conference on AIDS, Montreal, Canada, 1989; 288. 97a. lacobson MA, Mills 1, Rush 1, et 0/. Morbidity and mortality of Pneumocystiscariniipneumonia in patients with AIDS is unaffected by concomitant pulmonary cytomegalovirusinfection. Am Rev Respir Dis 1990 (Submitted). 98. Youle M, Gazzard B, Chanas A, Lernstedt 1. Treatment with foscarnet of presumed CMV pneumonitis in patients with AIDS: a double-blind placebo-controlled study (abstract). Presented at the Fourth International Conference on AIDS, Stockholm, Sweden, 1988; 163. 99. Masur H, Lane HC, Palestine A, Smith PD, Manischewitz 1, Stevens G. Effect of DHPG on serious cytomegalovirus disease in eight immunosuppressed homosexual men. Ann Intern Med 1986; 104:41-4. 100. lacobsonMA, O'Donnell 11, Mills1. Foscarnet treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Antimicrob Agents Chemother 1989; 33: 736-41. l00a. 1acobson MA, O'Donnell 11, Rousell R, Dionian B, Mills 1. Failure of adjunctive cytmegalovirus intravenous immune globulin to improve efficacy of gancyclovir in patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis: a phase I study. Antimicrob Agents Chemother 1990, 34:176-8. 101. Ramsey PG, Fife KH, Hackman RC, Meyers lD, Corey L. Herpes simplex virus pneumonia. Clinical, virologic, and pathologic features in 20 patients. Ann Intern Med 1982; 97:813-20. 102. Suster B,Akerman M, Orenstein M, WaxMR. Pulmonary manifestations of AIDS: reviewof 106 episodes. Radiology 1986; 161:87-93. 103. Whitley Rl. Therapeutic approaches to herpes simplex encephalitis and neonatal herpes simplex virus infections. In: Mills 1, Corey L, eds. Antiviral chemotherapy. New York: Elsevier, 1986; 155-66. 104. Erlich K, Mills 1, Chatis P, et 0/. Acyclovirresistant herpes simplex virus type 2 infections in patients with acquired immunodeficiency syndrome. N Engl 1 Med 1989; 320:293-6. 105. Erlich K, lacobson M, Koehler 1, et 0/. Foscarnet therapy of severeacyclovir-resistant herpes simplexvirusinfections in patients with acquired immunoueficiency syndrome. Ann Intern Med 1989; 109:710-3. 106. Cohen PR, Beltrani VP, Grossman ME. Disseminated herpes zoster in patients with human immunodeficiency virus infection. Am 1 Med 1988; 84:1076-80. 107. Pahwa S, Biron K, Lim W, et 0/. Continuous varicella-zoster infection associated with acyclovir resistance in a child with AIDS. lAMA 1988; 290:2879-82. 107a. lacobson MA, Berger TO, Fikrig S, et 0/. Acyclovir-resistant varicella zoster virus infection

following chronic oral acyclovir therapy in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1990; 112:187-91. 108. Andiman WA, Martin K, Rubinstein A, et 0/. Opportunistic Iymphoproliferations associated with the Epstein-Barr viral DNA in infants and children with AIDS. Lancet 1985; 2:1390-3. 109. Ziza 1M, Brun-Vezinet :F, Venet A, et 0/. Lymphadenopathy-associated virus isolated from bronchoalveolar lavage fluid in AIDS-related complex with lymphoid interstitial pneumonitis (letter). N Engl 1 Med 1985; 313:183. 110. Chayt Kl, Harper ME, Marselle LM, et 0/. Detection of HTLV-III RNA in lungs of patients with AIDS and pulmonary involvement. lAMA 1986; 256:2356-9. Ill. Resnick L, Pitchenik AE, Fisher E, Croney R. Detection of HTLV-III/LAV-specific IgG and antigen in bronchoalveolar lavage fluid from two patients with lymphocytic interstitial pneumonitis associated with AIDS-related complex. Am 1 Med 1987; 82:553-6. 112. Montagnier L, Gruest 1, Charmaret S, Dauguet C, Axler C, Guetard D. Adaptation of lymphadenopathy associated virus (LAV) to replication in EBV-transformed B Iymphoblastoid cell lines. Science 1984; 225:63-6. 113. Cohen lP, Macauley C. Susceptibility to influenza A in HIV-positive patients (letter). lAMA 1989; 261:245. 113a. Safrin S, Rush lD, Mills 1. Influenza in patients with human immunodeficiency virus infection. Chest 1990 (In Press). 114. Huang BD, Ruben FL, Rinaldo CR, Kingsley L, Lyter DW, Ho M. Antibody response after influenza and pneumococcal immunization in HIVinfected homosexual men. lAMA 1989;261:245-9. 115. Nelson KE, Clements ML, Miotti P, Cohn S, Polk BF. The influence of human immunodeficiency virus (HIV) infection on antibody responses to influenza vaccines. Ann Intern Med 1988; 109: 383-8. 116. Centers for Disease Control. General recommendations on immunization. MMWR 1989; 38: 205-28 117. Bye MR, Bernstein L, Shah K, Ellaurie M, Rubenstein A. Diagnostic bronchoalveolar lavage in children with AIDS. Pediatr Pulmonol 1987; 3:425-8. 118. Wong VK, Ross LA. Branhamellacatarrhalis septicemia in an infant with AIDS. Scand 1 Infect Dis 1988; 20:559-60. 119. Ogra PL, PatelJ. Respiratory syncytial virus infection and the immunocompromised host. Pediatr Infect Dis 1 1988; 7:246-9. 120. Delong Pl, ValderramaG, Spigland I, Horwitz MS. Adenovirus isolates from urine of patients with acquired immunodeficiency syndrome. Lancet 1983; 1:1293-6. 121. Witt Dl, Craven DE, McCabe WR. Bacterial infections in adult patients with the acquired immunodeficiency syndrome (AIDS) and AIDSrelated complex. Am 1 Med 1987; 82:900-6. 122. Nash G, F1igiel S. Pathologic features of the lung in the acquired immune deficiency syndrome (AIDS): an autopsy study of seventeen homosexual males. Am 1 Clin Pathol 1984; 81:6-12. 123. Fels AOS. Bacterial and fungal pneumonias. In: White DA, Stover DE, eds. Pulmonary effects of AIDS. Clin Chest Med 1988; 9:449-57. 124. Gibson PG, Bryant DH, Harkness J, Munro VF,Penny R, Cooper DA. Pulmonary manifestations of the acquired immunodeficiency syndrome. Aust N Z 1 Med 1987; 17:551·-6. 125. KrasinskiK, BorkowskyW, Bonk S, Lawrence R, Chandwani S. Bacterial infections in human immunodeficiency virus infected children. Pediatr In-

1371

feet Dis 1 1988; 7:323-8. 126. Murata GH, Ault Ml, Meyer RD. Community-acquired bacterial pneumonias in homosexual men: presumptive evidence for a defect in host resistance. AIDS Res 1984-5; 1:379-93. 127. Khardori N, Haron E, Rolston K. Legione//0 micdadei pneumonia in the acquired immunodeficiency syndrome. Am 1 Med 1987; 83:600-1. 128. Ng VL, York M, Hadley WK. Unexpected isolation of Bordatella pertussisfrom patients with acquired immunodeficiency syndrome. 1 Clin Microbiol 1989; 27:337-8. 129. Smith lW, Bartlett MS. Laboratory diagnosis of Pneumocystis carinii infection. Clin Lab Med 1988; 2:393-401. 130. Ammann Al, Schiffman G, Abrams D, Volberding P, Ziegler 1, Conant M. B-cell immunodeficiency in acquired immunodeficiency syndrome. lAMA 1984; 251:1447-9. 131. Simberkoff MS, EI Sadr W, Schiffman G, Rahal 111 r. Streptococcuspneumoniae infections and bacteremia in patients with acquired immune deficiency syndrome, with report of a pneumococcal vaccine failure. Am Rev Respir Dis 1984; 130: 1174-6. 132. Calvelli TA, Rubenstein A. Intravenous gamma-globulin in infant acquired immunodeficiency syndrome. Pediatr Infect Dis 1 1986; 5(Suppl:S207-1O). 133. Youmans GP. Tuberculosis. Philadelphia: W. B. Saunders Co., 1979; 323. 134. Centers for DiseaseControl. Tuberculosisand human immunodeficiency virus infection: recommendations of the Advisory Committee for the elimination of tuberculosis (ACET). MMWR 1989; 39:236-50. 135. Centers for Disease Control. Tuberculosis, final data-United States, 1986. MMWR 1988; 36:817-20. 136. Pitchenik AE, Fertel D, Bloch AB. Mycobacterial disease: epidemiology, diagnosis, treatment and prevention. In: White DA, Stover DE, eds. Pulmonary effects of AIDS. Clin Chest Med 1988; 9:425-41. 137. Selwyn PA, Hartel D, Lewis VA, et 0/. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl 1 Med 1989; 320: 545-50. 138. Pitchenik AE, Burr 1, Suarez M, et 0/. Human T-cell lymphotropic virus-III (HTLV-III) seropositivity and related disease among 71 consecutive patients in whom tuberculosis was diagnosed. Am Rev Respir Dis 1987; 135:875-9. 139. Sunderam G, McDonald Rl, Maniatis T, OIeske 1, Kapila R, Reichman LB. Tuberculosis as a manifestation of the acquired immunodeficiency syndrome (AIDS). lAMA 1986; 256:362-6. 140. Hewlett D Jr, Duncanson FP, lagadha V,Lieberman 1, Lenox TH, Wormser GP. Lymphadenopathy in an inner-city population consisting principally of intravenous drug abusers with suspected acquired immunodeficiency syndrome. Am Rev Respir Dis 1988; 137:1275-9. 141. Handwerger S, Mildvan D, Senie R, McKinley FW. Tuberculosis and the acquired immunodeficiency syndrome at a New York City hospital: 1978- 1985. Chest 1987; 91:176-80. 142. Guarner 1, del Rio C, Slade B. Tuberculosis as a manifestation of the acquired immunodeficiency syndrome (letter). lAMA 1986; 256:3092. 143. Mann 1M, Chin 1, Piot P, Quinn T. The international epidemiology of AIDS. Sci Am 1988; 8:82-9. 144. Mann 1, Snider DE Jr, Francis H, et 0/. Association between HTLVIII/LAV infection and tuberculosis in Zaire (letter). lAMA 1986; 256:346.

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145. Slutkin G, Leowski J, Mann J. The effects ofthe AIDS epidemic on the tuberculosis problem and tuberculosis programmes. Bull Int Union Tuberc Lung Dis 1988; 63:21-4. 146. Colebunders RL, Ryder RW, Nzilambi N. HIV infection in patients with tuberculosis in Kinshasa, Zaire. Am Rev Respir Dis 1989; 139:1082-5. 147. Quinn Te. Interactions of the human immunodeficiency virus and tuberculosis and the implications for BCG vaccination. Rev Infect Dis 1989; l1(Suppl 2:S379-84). 148. Murray JE The J. Burns Amberson lecture. The white plague: down and out or up and coming? Am Rev Respir Dis 1989; 140:1788-95. 149. Rouillon A, Pedrizet S, Parrot R. Transmission of tubercle bacilli: the effects of chemotherapy. Tubercle 1976; 57:275-99. 150. Styblo K. Epidemiology of tuberculosis. Jena, GDR: Gustav Fischer Verlag, 1984; 1-161. 151. Hopewell PC. Tuberculosis and the human immunodeficiency virus infection. Semin Respir Infect 1989; 4:111-2. 152. Stead WW. Pathogenesis of a first episode of chronic pulmonary tuberculosis in man: recrudescence of residual of the primary infection or exogenous reinfection. Am Rev Respir Dis 1967; 95: 729-45. 153. Chaisson RE, Slutkin G. Tuberculosis and human immunodeficiency virus infection. J Infect Dis 1989; 159:96-100. 154. Pitchenik AE, Cole C, Russell BW, Fischl MA, Spira TJ, Snider DE Jr. Tuberculosis, atypical mycobacteriosis, and the acquired immunodeficiencysyndrome among Haitian and non-Haitian patients in South Florida. Ann Intern Med 1984; 101:641-5. 155. Chaisson RE, Schecter GR, Theuer CP, Rutherford GW, Echenberg DF, Hopewell PC, Tuberculosis in patients with the acquired immunodeficiency syndrome. Clinical features, response to therapy, and survival. Am Rev Respir Dis 1987; 136:570-4. 156. Pitchenik AE, Rubinson HA. The radiographic appearance of tuberculosis in patients with the acquired immune deficiency syndrome (AIDS) and pre-AIDS. Am Rev Respir Dis 1985;131:393-6. 157. Stern RG, Gamsu G, Golden JA, Hirji M, Webb WR, Abrams DI. Intrathoracic adenopathy: differential feature of AIDS and diffuse lymphadenopathy syndrome. AJR 1984; 142:689-92. 158. WasserLS, ShawGW, ThlaveraW. Endobronchial tuberculosis in the acquired immunodeficiency syndrome. Chest 1988; 94:1240-4. 159. Theuer CP, Chaisson RE, Schecter GF, Hopewell Pc. Human immunodeficiency virus infection in tuberculosis patients in San Francisco (abstract). Am Rev Respir Dis 1988; 137:121. 160. Jacobson MA. Mycobacterial diseases:tuberculosis and Mycobacterium avium complex. Infect Dis Clin North Am 1988; 2:465-74. 161. Wong B, Edwards FF, Kiehn TT. Continuous high grade Mycobacterium avium-intracellulare

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bacteremia in patients with acquired immunodeficiency syndrome. Am J Med 1985; 78:35-40. 162. Centers for Disease Control. Diagnosis and management of mycobacterial infection and disease in persons with human immunodeficiency virus infection. Ann Intern Med 1987; 106:254-6. 163. American Thoracic Society/Centers for Disease Control. Mycobacterioses and the acquired immunodeficiency syndrome. Am Rev Respir Dis 1987; 136:492-6. 164. Sunderam G, Mangura BT, Lombardo JM, Reichman LB. Failure of "optimal" four-drug shortcourse tuberculosis chemotherapy in a compliant patient with human immunodeficiency virus. Am Rev Respir Dis 1987; 136:1475-8. 165. Theuer CPo Tuberculosis in patients with human immunodeficiency virus infection. West J Med 1989; 150:700-4. 166. von Reyn CR, Clements CJ, Mann JM. Human immunodeficiency virus infection and routine childhood immunization. Lancet 1987; 2:669-72. 167. Halsey NA, Henderson DA. HIV infection and immunization against other agents. N Engl J Med 1987; 313:683-5. 168. Centers for Disease Control. Disseminated Mycobacterium infection from BCG vaccination of a patient with acquired immunodeficiency. MMWR 1985; 34:227-8. 169. Nousbaum JB, Garre M, Boles JM, Garo B, Larzul JJ. Deux manifestations inhabituelles d'une infection par Ie virus LAV-HTLV-III BGGite et varicelle pulmonaire. Rev Pneumol Clin 1986; 42:310-1. 170. Ninane J, Grymonprez A, Burtonboy G, Francois A, Cornu G. Disseminated BCG in HIV infection. Arch Dis Child 1988; 63:1268-9. 171. Colebunders RL, Izaley L, Musampo M, Pauwels P, Francis H, Ryder R. BCG vaccine abscesses are unrelated to HIV infection (letter). JAMA 1988; 259:352. 172. World Health Organization/IUATLD. Tuberculosis and AIDS. Statement on AIDS and tuberculosis, Geneva, March 1989.Bull Int Union Tuberc Lung Dis 1989; 64:8-11. 173. Horsburgh CR Jr, Mason UG, Farhi DC, Iseman MD. Disseminated infection with Mycobacterium avium-intracellulare. Medicine 1985; 64: 36-48. 174. Greene JB, Sidhu GS, Lewin S, et a'. Mycobacterium avium-intracellulare: a cause of disseminated life-threatening infection in homosexuals and drug abusers. Ann Intern Med 1982; 97:539-46. 175. Zakowski P, Fligiel S, Berlin GW, Johnson BL Jr. Disseminated Mycobacterium aviumintracellulare infection in homosexual men dying of acquired immunodeficiency. JAMA 1982; 248: 2980-2. 176. Horsburgh CR Jr, Selik RM. The epidemiology of disseminated nontuberculous mycobacterial infection in the acquired immunodeficiency syndrome (AIDS). Am Rev Respir Dis 1989; 139:4-7.

177. Hawkins CC, Gold JWM, Whimbey E, et al. Mycobacterium avium complex infections in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1986; 105:184-8. 178. Fauci AS, Macher AM, Longo DL, et al. Acquired immunodeficiency syndrome: epidemiologic, clinical, immunologic, and therapeutic considerations. Ann Intern Med 1984; 100:92-106. 179. Wolinsky E. Nontuberculous mycobacteria and associated diseases. Am Rev Respir Dis 1979; 119:107-59. 180. MacDonnell KB, Glassroth J. Mycobacterium avium complex and other nontuberculous mycobacteria in patients with HIV infection. Semin Respir Infect 1989; 4:123-32. 181. Damsker B, Bottone EJ. Mycobacterium avium-Mycobacterium intracellulare from the intestinal tracts of patients with the acquired immunodeficiency syndrome: concepts regarding acquisition and pathogenesis. J Infect Dis 1985; 151: 179-81. 182. Kiehn TE, Edward FF, Brannon P. Infections caused by Mycobacterium avium complex in immunocompromised patients: diagnosis by blood culture and fecal examination, antimicrobial susceptibility tests, and morphological and seroagglutination characteristics. J Clin Microbiol 1985; 21:168-73. 183. Crawford ST, Bates JH. Analysis of plasmids in Mycobacterium avium-intracellulare isolates from persons with acquired immunodeficiency syndrome. Am Rev Respir Dis 1986; 134:659-61. 184. Macher AM, Kovacs JA, Gill V, et al. Bacteremia due to Mycobacterium avium-intracellulare in the acquired immunodeficiency syndrome. Ann Intern Med 1983; 99:782-5. 185. Drake TA, Hindler JA, Berlin OGW, Bruckner DA. Rapid identification of Mycobacterium avium complex in culture using DNA probes. J Clin Microbiol 1987; 25:1442-5. 186. Young LS. Mycobacterium avium complex infection. J Infect Dis 1988; 157:863-7. 187. Davidson PT, Khanijo V, Goble M, Moulding TS. Treatment of disease due to Mycobacterium intracellulare. Rev Infect Dis 1981; 3:1052-9. 188. Tsukamura M. Evidence that antituberculous drugs are really effective in the treatment of pulmonary infection caused by Mycobacterium avium complex. Am Rev Respir Dis 1988; 137:144-8. 189. Heifets LB, Iseman MD, Linholm-Levy PJ. Combinations of rifampin or rifabutine plus ethambutol against Mycobacterium avium complex. Am Rev Respir Dis 1988; 137:711-5. 190. Tecson-TumangFT, Bright JL. Mycobacterium xenopi and the acquired immunodeficiency syndrome. Ann Intern Med 1984; 100:461-2. 191. Jacobson MA, Isenberg WM. Mycobacterium kansasii diffuse pulmonary infection in a patient with acquired immune deficiency syndrome. Am J Clin Pathol 1989; 91:236-8.

Pulmonary infectious complications of human immunodeficiency virus infection. Part I.

State of the Art Pulmonary Infectious Complications of Human Immunodeficiency Virus Infection Part 11-3 JOHN F. MURRAY and JOHN MILLS Contents Introd...
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