Dr. Aviram is a Specialist in Radiology Chest and Cardiovascular Imaging in the Department of Radiology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel; Dr. Fishman is an Assistant Professor of Radiology in the Department of Radiology, Jackson Memorial Hospital, University of Miami, Miami, FL; and Dr. Boiselle is t he Director of Thoracic Imaging and Co-Director of the Residency Program in the Department of Radiology, Beth Israel Deaconess Medical Center, and Assistant Professor of Radiology at Harvard Medical School, Boston, MA.

During the two decades since the emergence of the acquired immune deficiency syndrome (AIDS), many changes have been noted in the demographics, complications, and treatment of this epidemic. ^1,2 It is important to be aware that AIDS is no longer a disease confined to the homosexual male population. Indeed, in the past decade, there has been an increasing prevalence of AIDS among intravenous drug abusers and women. ³ The introduction of highly active antiretroviral therapy (HAART) has been associated with a dramatic reduction in human immunodeficiency virus (HIV)-associated morbidity and mortality. ^1-3 By effectively suppressing viral replication, HAART results in a decrease in viral load and a rise in the CD4 lymphocyte count, with an associated reduced prevalence of various opportunistic infections and certain neoplasms. Following dramatic reductions in the number of new AIDS cases and deaths in the United States in the mid-1990s, a plateau in morbidity and mortality was observed at the end of the last decade. ³ Importantly, the battle against AIDS looms largely on a global basis, with continued explosive growth of the epidemic in the setting of significant barriers to antiretroviral therapy.

Pulmonary disorders, particularly respiratory infections, remain an important cause of morbidity and mortality among HIV-infected individuals, even in the current era of potent antiretroviral therapy. Interestingly, demographic and therapy changes of HIV infection have been accompanied by changes in the frequency and nature of the pulmonary complications of AIDS and their imaging features. ⁴ In this article, we review the various pulmonary complications of AIDS, with a particular emphasis upon recent trends in imaging features of pulmonary disorders as shown on chest radiography and computed tomography (CT) examinations.

Approach to imaging diagnosis

Because the various pulmonary complications of HIV occur with different frequencies among patients with specific risk factors, different levels of immune compromise, and various prophylactic therapies, one should combine all these factors along with the clinical presentation and the recognized radiographic pattern in order to reach the most likely correct diagnosis. ⁵ Of these parameters, the patient's immune status, as reflected by the serum CD4 lymphocyte count, is considered the most important determinant for assessing the relative likelihood of various pulmonary complications (Table). ^4-7

Chest radiography is usually the first imaging test obtained for the assessment of an HIV-infected individual with respiratory symptoms. Despite atypical manifestations and overlapping features among several entities, the chest radiograph is fairly accurate for diagnosing common complications. ⁸ Even in asymptomatic HIV patients, an abnormal chest radiograph usually signifies an active process. ⁹ CT is considered as a second-line study for problems unresolved by chest radiography. CT, particularly using high resolution (HRCT), is more sensitive in detecting various opportunistic infections when the chest radiograph is normal. ⁷ CT is also very useful in assessing patients for complications of pneumonia, such as abscess and empyema; in detecting and characterizing enlarged intrathoracic lymph nodes; and in staging AIDS-related malignancies.

Infectious lung diseases in AIDS

Bacterial infections

Although mainly cell-mediated immunity is impaired in HIV infection, humoral immunity is also altered. ¹⁰ In particular, B-cell dysfunction is associated with high risk for frequent infections with encapsulated bacteria, such as Streptococcus pneumoniae . ^10,11 In recent years, bacterial infections, including infectious airways disease and pneumonia, have surpassed Pneumocystis carinii pneumonia (PCP) as the most common cause of pulmonary infection in HIV-positive patients. ¹⁰ Although bacterial pneumonia often occurs early in the course of HIV, the risk for this infection progressively increases with decreasing CD4 counts. ¹⁰ Most episodes of pneumonia occur secondary to S pneumoniae and Haemophilus influenzae , the same organisms that cause most community-acquired pneumonia in the general population. ¹¹ Pseudomonas aeruginosa has also recently been recognized as a cause of pulmonary infection in AIDS, especially among patients with a recent history of hospitalization, antibiotic use, or steroid therapy. ¹² AIDS patients are also at risk for infection with unusual zoonoses such as Rhodococcus equi , ¹¹ an organism that is more commonly encountered in horses, cattle, and swine, and Bartonella henselae and B quintana , the causative agents of bacillary angiomatosis. ¹³

Patients with bacterial pneumonia typically present with an acute onset of fever and productive cough. ¹⁴ In most cases, bacterial pneumonia presents radiographically as single or multiple sites of focal consolidation, in either a segmental or lobar distribution ^4,7,8 (Figure 1). Atypical patterns, including bilateral diffuse opacities, are not uncommon. ⁸ Importantly, complications, such as bacteremia and abscess, develop more often in HIV-infected individuals with bacterial pneumonia than in non-HIV patients. ^7,11

Pyogenic infectious airways diseases, including infectious bronchitis, bronchiolitis, and bronchiectasis, have been increasingly recognized in HIV-positive patients in recent years. ^4,15 Chest radiographs of patients with acute bacterial bronchitis are usually normal, but may show bronchial wall thickening. ¹⁶ In contrast, the high-resolution CT features of infectious bronchiolitis are characteristic and include small nodular and branching, Y- and V-shaped centrilobular opacities, which represent bronchioles that are impacted with inflammatory secretions. This pattern has been coined the tree-in-bud appearance. ¹⁶ Although pyogenic infections are the most common cause of proliferative small airways disease in AIDS patients, viral and mycobacterial infections may produce similar imaging findings.

Pneumocystis carinii pneumonia

P carinii pneumonia remains the most common serious AIDS-related opportunistic infection, despite a declining incidence secondary to HAART and prophylactic use of trimethoprim-sulfamethoxazole (TMP-SMZ). ^17-19 P carinii pneumonia usually occurs in persons not receiving medical care, ^20-22 and whose CD4 counts are <200 cells/mm ³ . ²⁰ Affected patients generally present with a hi tory of approximately 1 month of fever, dry cough, and dyspnea. ^20,21

The classic chest radiographic presentation of PCP is a bilateral perihilar or diffuse symmetric interstitial pattern, which may be finely granular, reticular, or ground-glass in appearance ^4,20 (Figure 2A). Importantly, the chest radiograph may be normal in approximately one-third of cases at the time of presentation. ²⁰ CT, particularly HRCT, is very helpful in detecting PCP in symptomatic patients with normal or equivocal radiographic findings. ^20,23 The classic HRCT finding in PCP is extensive ground-glass attenuation (Figure 2B). It is often distributed in a patchy or geographic fashion, with a predilection for the central, perihilar regions of the lungs. ²⁰ Cystic lung disease is observed in up to one-third of cases (Figure 3), and may be complicated by pneumothorax. ²⁰

Tuberculosis

As tuberculosis (TB) is both highly curable and contagious, prompt diagnosis and treatment are essential. ²⁴ The HIV-infected individuals at particularly high risk for TB include intravenous drug abusers and patients from areas where TB is endemic. ²⁴ Tuberculosis can occur at any stage of HIV infection. ²⁴ In fact, reactivation (postprimary) TB is often one of the initial manifestations of HIV infection. Presenting symptoms may include more than a week of cough, night sweats, and weight loss. ¹⁴ Typical imaging features include parenchymal opacities with associated cavitation, often located within the apical, posterior, and superior segments of the lungs. ^24-26 In patients with decreased CD4 counts (<200 cells/mm ³ ), one will observe findings typically associated with primary TB (regardless of the actual mechanism of infection), including consolidation and lymph-node enlargement. ^24-26 At advanced levels of immune suppression, a minority of patients may have normal chest radiographs, though CT will often show abnormalities such as small nodules and lymph node enlargement. ²⁵

The immune reconstitution syndrome (also known as reversal syndrome) refers to a newly described phenomenon that may be observed in AIDS patients who are being treated for tuberculosis infection and are also receiving antiretroviral therapy. ²⁷ In the setting of immune restoration, such patients may exhibit new or worsening lymph node enlargement, lung paren-chymal disease, and/or pleural effusions, accompanied by onset of fever (Figure 4). Such paradoxical reactions are thought to be immunologically mediated by a heightened immune response. ²⁷ The diagnosis requires exclusion of other important causes, including noncompliance with therapy, drug resistance, other superimposed disease process, and drug reaction. ^26,27

Atypical mycobacterial infections

Atypical mycobacterial infections in AIDS patients are usually secondary to Mycobacterium avium-intracellulare (MAI) and, less commonly, due to M kansasii . ^4,28,29 Because MAI is a less virulent organism than M tuberculosis , it is usually encountered in the setting of more advanced immunosuppression (CD4 <50/mm ³ ). ^4,28,29 Thoracic MAI involvement usually occurs in the setting of disseminated disease, with the gastrointestinal tract serving as the main entry site in most cases. Imaging findings in the lungs are variable and include multifocal patchy consolidation, ill-defined nodules, and cavities. ^4,28,29 Lymphadenopathy is frequently present, but is observed less frequently than it is in patients with TB.

Fungal infections

Fungal infections are a relatively uncommon cause of pulmonary infection in AIDS patients but are more prevalent in endemic areas. ^4,30 The most common fungal pathogen to involve the lungs in AIDS patients is Cryptococcus neoformans . ^4,30 Less common fungal infections include aspergillosis, histoplasmosis, blastomycosis, and coccidiomycosis. Fungal pulmonary infection usually occurs in the setting of advanced immunosuppression (CD4 <100/mm ³ ). Imaging findings include nodules, reticular or reticulonodular opacities, and foci of consolidation (Figure 5). ^4,30,31 Parenchymal abnormalities may be accompanied by lymph node enlargement and pleural effusion.

Although infection with Aspergillus is uncommonly encountered in AIDS, its incidence is increasing. ^30,32 This infection occurs almost exclusively in HIV-positive individuals with CD4 counts <50 cells/mm ³ and neutropenia. ^30,32 The most common imaging presentation is cavitary disease with an upper lobe predominance. ^4,33

Viral infections

Cytomegalovirus (CMV) is the most common viral agent identified in the lungs of AIDS patients. ³⁴ However, it is much more frequently a colonizer than an actual cause of pneumonia. Cytomegalovirus pneumonitis occurs in patients with advanced levels of immunosuppression (CD4 <100/mm ³ ) who almost always have documented extrathoracic CMV infection. ⁴ The most common imaging features of CMV pneumonitis are ground-glass opacities and alveolar consolidation, which may mimic PCP. ³⁴ Other imaging findings include nodules, masses, and small airways disease. ³⁴

Noninfectious lung diseases in AIDS

Kaposi's sarcoma

Early in the AIDS era, up to 40% of homosexual men presented at the time of their initial AIDS diagnosis with Kaposi's sarcoma (KS). ⁴ Subsequently, there has been a continuous decrease in the incidence of KS among HIV-infected people, from approximately 10% to 20% in the early 1990s to even lower levels at present. ³⁵ Kaposi's sarcoma is a multicentric disease that frequently involves the skin, lymph nodes, gastrointestinal tract, and lungs. Pulmonary KS in the absence of mucocutaneous involvement is uncommon. ³⁶ The CD4 cell count in patients with pulmonary KS is usually <100 cells/mm ³ . ³⁷

The most common presenting symptoms of pulmonary KS are dyspnea and cough; hemoptysis is less common. ³⁸ Characteristic findings on chest radiography include thickening along the peribronchovascular bundles, often in the perihilar regions. As the tumor grows, reticulonodular opacities may appear, mainly in the lower lobes. The interstitial and ill-defined nodular opacities may coalesce to form dense areas of alveolar consolidation. Thickened interlobular septae are commonly observed. ^4,37,39 Pleural effusions are also common; they may be unilateral or bilateral and may vary considerably in size. ⁴ CT of the chest offers additional benefits over conventional chest radiography by revealing mediastinal lymphadenopathy, which is present in 50% of cases, and improved characterization of the bronchovascular pattern of lung parenchymal opacities. ³⁹

Lymphoma

Non-Hodgkin's lymphoma (NHL) is the second most common malignancy in AIDS, occurring in 2% to 10% of HIV-infected individuals. ^35,40 The incidence of lymphomas in AIDS patients may be on the rise due to longer life expectancies in AIDS. ⁴¹ However, there is conflicting data regarding the relative incidence of NHL in the HAART era as compared with previously. ^19,42 The disease is twice as common in whites and males than in African Americans and women, respectively. ³⁵ AIDS-related NHL usually affects patients with CD4+ levels <100 cells/mm ³ . ⁴³ At presentation, 75% of the patients are at advanced stage (stage 3 or 4), and constitutional B-cell symptoms are commonly reported. Extranodal involvement of the central nervous system, gastrointestinal tract, and bone marrow are frequently observed. ³⁵

Pulmonary involvement is clinically diagnosed in only 6% to 10% of AIDS patients with NHL. ⁴⁴ The most common symptoms are cough, dyspnea, and pleuritic chest pain.

Intrathoracic NHL in AIDS is most often extranodal. ⁴ The most common radiologic findings consist of multiple pulmonary nodules, areas of consolidation, and pleural effusions. ^44,45 Reticular opacities and masses are also observed relatively frequently. ⁴⁴ With regard to lung nodules, they are usually well circumscribed and range in size from 0.5 to 5 cm in diameter; air bronchograms are frequently present, and a halo of ground-glass attenuation may be observed around the nodules on thin-slice CT. ⁴⁵ One distinctive form is primary pulmonary AIDS-related lymphoma, which is defined by exclusive lymphomatous parenchymal involvement with no other sites of involvement identified up to 3 months following diagnosis ⁴⁰ (Figure 6). CT shows mediastinal and hilar lymph-adenopathy in approximately half of patients imaged. ⁴⁴ AIDS-related NHL may occasionally present as a mediastinal mass in the absence of pulmonary parenchymal disease (Figure 7).

Lung cancer

Epidemiological surveys continue to debate a possible link between HIV infection and an increased risk for the development of bronchogenic carcinoma. ^41,46,47 It is generally accepted that patients with lung cancer and HIV infection are often younger, present at a more advanced stage, and have a more fulminant course of disease than the general population with lung cancer. ^48,49 Similar to the general population, lung cancer occurs in HIV in association with cigarette smoking, and adenocarcinoma is the most common cell type. ^44,49 Prognosis has historically been considered dismal, but a recent report suggests that the disease may be treatable in the short- or intermediate-term. ⁵⁰ The most frequent radiographic presentation, similar to HIV-negative individuals, is a central or peripheral mass (Figure 8). ^48,51 Ipsilateral hilar and variable mediastinal lymphadenopathy, postobstructive consolidation or atelectasis, and pleural effusion or pleural mass are also common. ^49,51

Lymphocytic interstitial pneumonia

Lymphocytic interstitial pneumonia (LIP) is characterized by interstitial lung infiltration by mature lymphocytes and plasma cells creating peribronchovascular nodules without airspace involvement. ^4,52 Lymphocytic interstitial pneumonia is seen in 30% to 40% of pediatric HIV-infected patients with pulmonary disease but less frequently in adults with AIDS. ⁵³ Patients may be asymptomatic or show an insidious onset of respiratory distress with cough and mild hypoxemia.

Characteristic findings on chest radiography consist of fine or coarse reticular and nodular opacities (Figure 9) with an occasional alveolar component. ⁵² CT reveals ill-defined 2- to4-mm nodules, often in peribronchovascular distribution and bilateral areas of ground-glass attenuation. ^54,55 On thin-section CT, poorly defined centrilobular nodules involving all lung zones can be identified. ⁵⁵ Thickening of bronchovascular bundles, thickened septal lines, small subpleural nodules, and cystic air spaces are also observed in a majority of patients. Mediastinal or hilar lymphadenopathy is frequently seen. ⁵⁵

Emphysema

Recently published reports suggest that there may be an increased susceptibility to pulmonary emphysema among HIV-positive smokers (Figure 10). ⁵⁶ A comparison between a cohort of HIV-positive patients without history of pulmonary complications and HIV-negative controls revealed an incidence of emphysema of 15% among the HIV patients and only 2% among the control subjects. ⁵⁶ It is possible that the pathogenesis of emphysema is accelerated by the attendant pulmonary infections.

Cardiovascular complications

As survivial of HIV patients increases due to HAART, cardiovascular complications are becoming more manifest in these patients. Some of these many entities include cardio-myopathy, pulmonary artery hypertension, and atherosclerosis, the latter possibly related to protease inhibitor therapies. ⁵⁷ It has also been suggested that venous thromboembolic disease (deep venous thrombosis and pulmonary embolism) is of increased incidence in HIV-positive patients (Figure 11). ⁵⁸ Possible links between cardiovascular diseases and HIV are the subject of ongoing investigation.

Conclusion

Even in the current era of potent antiretroviral therapy, pulmonary complications of AIDS remain an important cause of morbidity and mortality among HIV-infected individuals. Interpretation of imaging studies should integrate demographic, clinical, and laboratory information with radiographic pattern recognition. Although chest radiography remains the mainstay of thoracic imaging in HIV-infected patients, CT plays an in-creasingly important complementary role in establishing an accurate diagnosis when chest radiographic findings are equivocal or nonspecific.