In most developed countries, the incidence of tuberculosis steadily declined until 1985. After 1985, the incidence began to rise again, at least partly due to the advent of widespread HIV infection. In developed countries, the incidence again leveled off in the mid-1990s and began to slowly decline thereafter. The advent of ART has had a substantial effect on the incidence of tuberculosis in patients with access to therapy (see Box 6.2). ⁹ However, M. tuberculosis remains an important pathogen in the HIV/AIDS population in developed countries, and is still the major cause of death in AIDS patients in Africa (see Box 6.4). ⁴⁷ Latent tuberculosis is an important cofactor in development of IRIS (see below). ^17,18 The risk of tuberculous infection depends on the concentration of tubercle bacilli in the environment, which is heavily dependent on social conditions. The high rate of multidrug resistant tuberculosis in HIV-positive patients in cities such as New York is of great importance both to those with HIV infection and to the immunocompetent population. ⁴⁸ Patients with AIDS-related tuberculosis⁴⁹ are more likely to be nonwhite and also more likely to be heterosexual drug users than AIDS patients without tuberculosis. ⁵⁰

The diagnosis of tuberculosis in HIV-infected patients can be difficult. ^51,52 The various tuberculin tests, which rely on an intact cell-mediated response, are falsely negative in 50–70% of patients with advanced AIDS. Up to half of AIDS patients with culture proven tuberculosis have false-negative sputum and bronchoalveolar lavage samples for acid-fast bacilli. As many as 10% of patients with advanced AIDS and tuberculosis have normal chest radiographs. ^53,54 Prompt diagnosis and treatment therefore requires a high index of clinical suspicion.

The clinical and imaging manifestations of tuberculosis in HIV-infected patients very much depend upon the level of immunosuppression (see Box 6.3).^{55.56.57.58.59.60.61.62. and 63.} In individuals with only mild reductions in CD4+ lymphocyte counts, or in those receiving ART, disease is usually localized to the lung and is quite similar to tuberculosis in nonimmune-suppressed populations. ^{1,64.65. and 66.} With more advanced reductions in cell-mediated immunity, however, disease is more likely to manifest with atypical patterns and be disseminated. ^1,64,65 Up to 60% of AIDS patients with tuberculosis have at least one extrapulmonary site of disease, a much higher incidence than in patients who do not have AIDS. ⁵⁰

Thus, in HIV-infected patients with CD4+ lymphocyte counts above 200 cells/µL including those receiving ART, tuberculosis usually manifests on chest radiographs or CT with a postprimary pattern of disease: upper lobe linear and nodular opacities and cavitation (Fig. 6.5). ⁶⁴ With more advanced degrees of immune suppression (CD4+ <200 cells/µL), cavitation becomes less common and disease increasingly manifests with focal or multifocal lobar or segmental opacities (often in atypical locations), bronchial wall thickening and centrilobular nodules (endobronchial spread), miliary nodules, enlarged hilar or mediastinal lymph nodes, and/or pleural effusion (Fig. 6.6, Fig. 6.7 and Fig. 6.8).^{55.56.57.58. and 59.,67.68. and 69.} Lymphadenopathy may be the dominant imaging feature in some; mycobacterial infection is a common cause of isolated lymphadenopathy on chest radiographs in HIV-infected patients (Fig. 6.7). ⁶⁰ Tuberculous lymph nodes frequently contain low attenuation centers and show rim enhancement (Fig. 6.7).^{70.71.72. and 73.} CT has a limited role in the evaluation of HIV-infected patients with tuberculosis. CT can be used to: confirm the presence of parenchymal abnormalities suspected on chest radiographs; to further characterize abnormalities such as miliary or endobronchial spread of disease (Fig. 6.8); to identify cavitation or other complications of infection; and to evaluate suspected hilar or mediastinal lymphadenopathy (Fig. 6.7).

After diagnosis and institution of appropriate antituberculous therapy, serial radiographs usually demonstrate rapid clearing within months, with no evidence of residual disease. ⁷⁴ Transient worsening of imaging findings may occur after institution of ART (Fig. 6.9); ⁷⁵ improvement usually occurs within several weeks, however. If there is no clinical and radiographic improvement on appropriate treatment, concurrent opportunistic infection, tumor, or multidrug resistant tuberculosis should be considered. Noncompliance with antituberculous medications is also a problem in this population and is a further cause of treatment failure. Directly observed therapy may be required in this setting.^{76.77. and 78.}

Nontuberculous mycobacteria (NTM) are present worldwide, being found particularly in water and soil. ⁷⁹ Although much less common than tuberculosis, NTM infection in HIV-infected individuals remains an important cause of morbidity and mortality in patients with advanced degrees of immunosuppression. ⁸⁰ MAC and M. kansasii are the two most common pathogens in this setting (see Box 6.4). ^1,9,81 In immune-competent patients, NTM disease is usually confined to the chest; in AIDS patients, disease is more often extrathoracic, disseminated and commonly involves gut, liver, lymph nodes, and bone marrow. ¹ Infection confined to the thorax is rare in AIDS patients, but has been reported. ⁸² Infection due to MAC is thought to enter via the gastrointestinal tract causing systemic upset and chronic diarrhea; clinically significant pneumonia is uncommon in the AIDS population. ^83,84 Organisms may be found in bronchoalveolar lavage fluid or sputum, blood, bone marrow, stool, and urine cultures; culture of the organism does not always correlate with clinical disease, however.

The chest radiograph is normal in most AIDS patients with disseminated MAC disease, even when the organism is cultured from respiratory secretions. ⁸⁵ When radiographic findings are present (Figs 6.10 and 6.11), the predominant features are hilar and mediastinal lymphadenopathy and diffuse pulmonary opacities that often have upper lung predominance. ^83,86,87 Less frequent manifestations include intrapulmonary nodules and pleural effusions, ⁸⁶ endobronchial masses, possibly from erosion by hilar lymph nodes, and, rarely, cavitary upper lobe disease (Fig. 6.11). ⁸³ CT, particularly high-resolution CT (HRCT), may demonstrate ground-glass opacities and bronchial wall and interlobular septal thickening. ^87,88

The second most common atypical mycobacterium, M. kansasii, has a greater predilection for the lungs and causes disease that is clinically similar to infection with M. tuberculosis. A variety of radiographic appearances are found in AIDS patients with M. kansasii infection, including focal homogeneous segmental or lobar opacities (often in mid- and lower long zones) that may cavitate, focal or diffuse nodular or reticulonodular opacities, and thin-walled cavities.^{89.90. and 91.} Pleural effusions are uncommon. ⁸⁹ Intrathoracic lymphadenopathy is seen in 25% of patients and lymphadenopathy may be the only radiographic finding of infection in 12%.

The less common atypical mycobacteria, including M. gordonae, M. xenopi, M. fortuitum, M. chelonae and M. malmoense (Fig. 6.12) may also cause symptomatic pulmonary disease in HIV-infected patients. ^92,93 A variety of radiographic patterns have been described with these infections, including interstitial opacities, scattered peribronchial opacities, miliary nodules, and parenchymal consolidation. ^94,95

The organism that causes Pneumocystis pneumonia in humans, formerly known as P. carinii, was renamed P. jirovecii in order to better reflect its distinctiveness from the organism that infects animals. ⁹⁶ Further, although previously thought to be a protozoan, the organism is now regarded as a fungus. ⁹⁶ Because of the confusion attendant to this change in nomenclature, the abbreviation PCP is still commonly accepted for the pneumonia caused by P. jirovecii.

Prior to the widespread use of antibiotic prophylaxis and ART, P. jirovecii caused pneumonia in over half of all patients with AIDS at some point in the course of their disease. Many AIDS-related deaths were due to respiratory failure directly attributable to PCP. The overall incidence of symptomatic infection has declined due to effective prophylaxis and ART, earlier recognition and more effective therapy (see Box 6.2). ⁹⁷ PCP is now a less common cause of hospitalization and morbidity in HIV-infected individuals receiving ART than bacterial pneumonia, but remains an important cause of morbidity and mortality in underserved populations. ⁹ Nevertheless, PCP remains the most common opportunistic pneumonia in HIV-infected persons, even in developed countries where it may be the first presenting illness in patients with previously unrecognized HIV infection. ^1,98

On chest radiographs, PCP typically manifests with diffuse or perihilar fine reticular and ill-defined ground-glass opacities (Fig. 6.13). ⁹⁹ Untreated, these opacities may progress to diffuse homogeneous opacification in 3–4 days (Figs 6.14 and 6.15). Coarse reticular opacities may develop if infection persists (Fig. 6.16). ^{23,24,100,101} The chest radiograph is normal at presentation in up to 6% of symptomatic patients. ¹⁰² Hilar or mediastinal lymphadenopathy is rare, as is pleural fluid in the absence of extrapulmonary pneumocystosis.

Atypical radiographic features are seen in 5–18% of cases of PCP. ^{100,103.104.105. and 106.} Isolated segmental or lobar consolidation (Fig. 6.17) that can be mistaken for pyogenic pneumonia is occasionally seen. Focal nodular opacities with or without cavitation can occur (Fig. 6.18) and be confused with lung cancer (Fig. 6.19), lymphoma (Fig. 6.20), or metastases. ^105,107 Such nodules may show granulomatous inflammation on histopathologic examination. ^108,109

PCP may rarely manifest as miliary nodules, pleural effusion, ^103,104,110 endobronchial mass, or hilar and mediastinal lymphadenopathy, ^{100,103,104,106,111} which may be calcified.^{112.113. and 114.} Upper lobe disease mimicking tuberculosis (Fig. 6.21) can be seen^104,115 in patients using aerosolized pentamidine because of relative undertreatment of the lung apices. ^115,116 Extrapulmonary disease involving the abdominal viscera is occasionally encountered. ¹¹² Organizing pneumonia caused by P. jirovecii in the setting of IRIS has recently been described. ¹¹⁷

The CT and, in particular, the HRCT findings of PCP include scattered or diffuse ground-glass opacities, consolidation, and thickening of interlobular septa (Figs 6.13 and 6.14). ^118,119 The CT findings may reflect disease chronicity with ground-glass opacities predominating in the early stages of the disease and with linear opacities predominating in cases of more chronic, repetitive, or undertreated infection (Fig. 6.16). ¹⁰³ In practice, however, the disease affects both interstitium and airspaces in an unpredictable way; ^120,121 thickening of interlobular septa can be the sole CT manifestation of PCP. ¹²² CT is usually not necessary in symptomatic patients with classic findings on chest radiographs. However, CT, particularly HRCT, can be quite useful for evaluating patients with suspected PCP and a normal chest radiograph or patients who have atypical radiographic findings for PCP. In this setting, the CT may show typical ground-glass opacities and be used to direct invasive diagnostic procedures (Figs. 6.22 and 6.23). ^{118,122.123.124. and 125.} Conversely, a normal HRCT is good evidence that PCP is not the cause of symptoms. ^122,124 Gallium-67 and DTPA radionuclide scans are sensitive but nonspecific for diagnosing PCP.^{126.127. and 128.} Both are time consuming and expensive, may be poorly tolerated by debilitated patients, and are thus rarely used for this purpose.

Up to one-third of patients with PCP develop thin-walled air-containing cysts (pneumatoceles), in either the acute or postinfective period (Fig. 6.24, Fig. 6.25, Fig. 6.26 and Fig. 6.27). ^{100,104,110,129,130} The incidence in one series of patients examined by CT was 38%. ¹⁰³ The cysts are round, oval or crescent-shaped, and range in size from 1 cm to 8.5 cm; they are usually multiple but may be solitary. ^{109,129.130.131. and 132.} They may occur at any location, although there was a predilection for the upper lobes in several series, ^{103,129,131,133} especially in patients on prophylactic aerosolized pentamidine (Fig. 6.24). ^104,116 The etiology of Pneumocystis-related pneumatoceles is unclear, although a number of possible mechanisms have been suggested: ^{109,131,134,135}P. jirovecii infection may stimulate macrophages to release elastase, tissue necrosis factor and other toxins that cause cystic destruction of lung parenchyma; vascular invasion by P. jirovecii may cause tissue necrosis and cavitation; and obstruction of small airways may lead to a ball valve effect on distal lung. A history of intravenous drug use¹³⁶ and repeated prior infections are also likely to be associated with cystic change. The cysts usually resolve within 7 months of treatment, usually without sequelae. ¹³⁰ However, cysts that persist up to 3 years have been reported. ^137,138 Spontaneous pneumothorax due to cyst (Fig. 6.27) or subpleural bleb rupture may complicate the course of infected patients. ^{100,103,104,129,131,134,139.140. and 141.}

The yeast C. albicans is a normal commensal organism of the skin and mouth. In advanced cases of AIDS, it initially causes oral, then esophageal, candidiasis. ¹⁴² The incidence of candidal esophagitis does not seem to have decreased in the ART era. ¹⁴² Patients with esophageal candidiasis may present with severe, painful dysphagia. Barium swallow examination may show focal or diffuse irregular narrowing of the esophagus and diffuse ulceration. Although Candida is isolated from the airways or lungs of 2% of all patients with AIDS, ¹⁴³ pulmonary candidiasis is a late, often preterminal, manifestation of HIV infection. It usually occurs in the setting of widely disseminated disease¹⁴⁴ and nearly always occurs in AIDS patients who also have profound neutropenia. Histopathologic evidence of tissue invasion is required for definitive diagnosis of Candida pneumonia. In less severely immunocompromised patients, the organism may occasionally colonize preexisting tuberculous cavities or cystic spaces due to P. jirovecii infection. The imaging manifestations of pulmonary candidiasis are nonspecific and include diffuse heterogeneous or homogeneous pulmonary opacities. Nodules and thick-walled cavities are less common. ¹⁴⁵

C. neoformans (see Box 6.6) is a ubiquitous fungus that infects up to 2% of patients with HIV infection and a markedly reduced CD4+ lymphocyte count (<100 cells/µL). ¹⁴⁶ Cryptococcal infection in this population usually manifests with meningitis and disseminated disease. ¹ Most cases occur in conjunction with other opportunistic infections; cryptococcosis is the sole manifestation of AIDS in less than 4% of patients. ¹⁴³ Latent cryptococcal infection is believed to be an important cofactor for development of IRIS in patients receiving ART. ^9,147

The clinical presentation of cryptococcal meningitis is often nonspecific. Patients may complain of vague symptoms and have a prolonged prodrome lasting from 1 to 4 months. Typical features of bacterial meningitis are usually absent. Less than half of patients complain of nausea and vomiting and only a quarter complain of neck stiffness or photophobia at diagnosis. The organism must be isolated from body fluids or tissues for definitive diagnosis. ¹⁴³ The serologic test for cryptococcal capsular polysaccharide antigen is both sensitive and specific for invasive infection.

Cryptococcus accounts for 2–15% of all respiratory tract infections in patients with AIDS. ¹⁴⁶ A variety of imaging patterns are described for pulmonary cryptococcal infection (Fig. 6.28, Fig. 6.29 and Fig. 6.30).^{148.149.150.151. and 152.} Diffuse heterogeneous or reticulonodular opacities are common. ¹⁵³ Infection can also manifest as solitary or multiple nodules varying from several millimeters to centimeters in diameter, with or without cavitation. Miliary disease, indistinguishable from tuberculosis, has been reported. ¹⁵⁴ Intrathoracic lymphadenopathy is a common feature and may be the sole radiographic manifestation of disease. Pleural effusions are rare, occurring in less than 10% of cases in most series. Normal chest radiographs do not exclude the diagnosis. ¹⁵²

C. immitis (see Box 6.6) is endemic in the semiarid regions of North America. It is widely distributed by the wind and then inhaled. ¹⁴³ Symptoms are nonspecific and include night sweats, fatigue, and weight loss. Cough and dyspnea are reported in up to 50% of patients. Neurologic complications, typically meningoencephalitis or brain abscess, occur less commonly than in cases of cryptococcosis. When such complications occur, however, they are quite difficult to treat and have a very poor prognosis. Disseminated coccidioidomycosis usually occurs in the setting of low CD4+ lymphocyte counts (less than 200 cells/µL) and has very high mortality (up to 70%). ^143,155,156 More localized pulmonary disease occurs in patients receiving ART. ¹⁵⁶ Radiographs of affected patients show focal or diffuse homogeneous or heterogeneous pulmonary opacities. ¹⁵⁷ Less common findings include discrete nodules, hilar or mediastinal lymphadenopathy, cavitation, and bilateral pleural effusions (1%).

H. capsulatum (see Box 6.6) is found throughout the world, but histoplasmosis is rare except in North America and the Caribbean. In immunocompetent individuals, it may cause a flulike illness that resolves spontaneously in almost all cases. In patients with impaired T cell function, progressive extrapulmonary infection leads to a systemic, debilitating febrile illness known as progressive disseminated histoplasmosis. Infection occurs in 2–5% of AIDS patients in endemic areas. ¹⁵⁸ Affected patients complain of cough, dyspnea and weight loss, and 10% are frankly septic with lymphadenopathy and hepatosplenomegaly. ¹⁴³ It is not clear whether pulmonary disease in AIDS patients results from reactivation of latent infection or from new exposure. Like tuberculosis, the intradermal skin test is negative in advanced disease and a positive antibody or prick test does not establish active current infection. ¹⁴³ The highest diagnostic yields are from bronchoalveolar lavage samples or bone marrow aspiration and biopsy. ¹⁵⁹ Identification of Histoplasma capsular polysaccharide antigen in blood and urine specimens is a rapid and relatively sensitive and specific means for diagnosing disseminated infection and for following patients during treatment.^{158.159.160.161. and 162.} Latent disseminated histoplasmosis has been implicated as an important cofactor in development of IRIS in patients receiving ART. ^163,164

Up to half of AIDS patients with disseminated histoplasmosis have normal chest radiographs. ^165,166 Radiographs in the remainder may show diffuse small nodules (miliary pattern) (Fig. 6.31), linear opacities, and focal or diffuse homogeneous opacities. ¹⁶⁵ Small pleural effusions and septal thickening may also be seen. On HRCT, the disease usually manifests with perivascular, paraseptal, and subpleural nodules as well as intra- and interlobular septal thickening – findings that are indistinguishable from those of miliary tuberculosis. ¹⁶⁷ Mediastinal lymphadenopathy, which may be calcified, is noted in up to 13% of cases. ^165,166 After treatment, parenchymal findings usually resolve completely. ¹⁶⁵

B. dermatitidis is endemic in North America and disseminated infection in patients with AIDS produces clinical features indistinguishable from other fungal infections or tuberculosis: notably fever, weight loss, cough, and dyspnea. ¹⁶⁸ Typically, other concurrent AIDS-defining illnesses are present at the time of diagnosis and the CD4+ lymphocyte count is below 200 cells/µL. Disseminated blastomycosis is characterized by multiorgan involvement, including the central nervous system, and has high mortality (over 30%). Pulmonary involvement can lead to ARDS. There are very few reports regarding imaging manifestation of Blastomyces infection in AIDS patients. Pappas et al. ¹⁶⁸ reported the chest radiographic manifestations of blastomycosis in 15 AIDS patients. In that series, a diffuse reticulonodular or fine nodular (miliary) pattern was most common. However, chest radiographs were normal in 27% of AIDS patients with disseminated blastomycosis.

The incidence of Aspergillus infection (see Box 6.6) in HIV-infected patients remains fairly low in contrast to a high incidence (up to 41%) reported in patients with acute leukemia.^{169.170. and 171.} This difference is because the neutrophil is the primary effector cell against Aspergillus. Thus, patients with HIV infection are not particularly susceptible to Aspergillus infection until they become very severely immunocompromised. Aspergillus infection usually occurs only when the CD4+ count falls below 50 cells/µL^{170.171.172. and 173.} or when the patient becomes secondarily neutropenic due to use of bone-marrow suppressive drugs. Use of aerosolized pentamidine may be an independent risk factor. ¹⁷³ Hemoptysis is a common and often fatal complication. ¹⁷¹

The radiographic manifestations of pulmonary aspergillosis in AIDS patients are quite varied, with several types of infection often present in the same patient. The most common pattern seen in the AIDS population resembles the type of infection described as chronic necrotizing aspergillosis. In this form, Aspergillus infection manifests with progressive cavitary pneumonia, usually in the upper lobes (Fig. 6.32). Cavitary lesions are reported in 20–80% of patients with AIDS and aspergillosis. ^{170,171,173.174.175. and 176.} Intracavitary masses, due to either true mycetomas or infarcted lung, may develop. Noncavitating nodules, secondary to tissue invasion with or without infarction, have been reported in up to a third of cases (Fig. 6.33). ^{171,173,174,176} Invasive aspergillosis may also cause pulmonary consolidation and vascular invasion with infarction in AIDS patients. ^{170,171,173,175,176} Colonization of preexisting cavities or pneumatoceles may result in intracavitary aspergillomas. ^174,177 Other reported features of aspergillosis in AIDS patients include pleural effusion, ^173,174 pneumothorax, ^170,171 lymphadenopathy, ¹⁷³ cardiomegaly, ¹⁷⁶ pericardial effusion, ¹⁷⁶ and pericardial thickening. ¹⁷⁴

There are several reports of a distinctive form of airway infection in AIDS patients known as obstructing bronchopulmonary aspergillosis. ^171,175,178 In this unusual form of the disease, invasive airway infection leads to pseudomembranes and obstructing mucus plugs in the large airways. Chest radiographs of affected patients may be normal or show mucoid impaction, atelectasis, or obstructive pneumonia. ^171,175 CT may show circumferential airway wall thickening, intramural sinus tracts, and large mucus plugs (Fig. 6.34). ¹⁷⁸

The protozoan T. gondii is a frequent cause of focal neurologic abnormalities in patients with AIDS, but is an extremely rare cause of pulmonary infection. Nonspecific fever is the typical presenting manifestation when the thorax is affected. Occasionally, an acute disseminated form occurs that manifests with septic shock. ¹⁷⁹ Affected patients are typically severely immunosuppressed with a mean CD4+ lymphocyte count of 32 cells/µL. ¹⁸⁰ Diagnosis may be difficult because, in this setting, there may be no specific IgM Toxoplasma antibody response. Diagnosis is made by identifying the organism in bronchoalveolar lavage fluid or lung biopsy specimens. ¹⁸⁰

The radiographic findings of pulmonary toxoplasmosis^179,181 can be very similar to severe PCP but usually show a coarser nodular pattern. Small pleural effusions are occasionally encountered, but mediastinal or hilar adenopathy is not a feature.

The protozoan Cryptosporidium is an unusual pathogen in the immunocompetent patient, being limited to farm workers or to individuals drinking contaminated water. In patients with AIDS, Cryptosporidium infection causes severe protracted diarrhea that is resistant to therapy. The organism passes from the gut into the biliary system and causes a form of sclerosing cholangitis. Pulmonary infection is quite uncommon, and, when it occurs, is thought to be due to aspiration of trophozoites during episodes of vomiting. Radiographic manifestations of Cryptosporidium pneumonia are quite nonspecific and include focal or diffuse air-space opacities that cannot be differentiated from other causes of pneumonia.

Non-Hodgkin rather than Hodgkin lymphoma predominates in patients with AIDS (see Box 6.7), being invariably of high grade and usually of B cell or non-B–non-T cell origin. ²⁰⁶ The disease is typically extranodal and is in most cases associated with Epstein–Barr virus (EBV) infection. ²⁰⁷ EBV-driven polyclonal B cell proliferations, similar to those seen in organ transplant patients, and body cavity or primary effusion lymphomas associated with the human herpes virus type 8 (HHV-8) have also been reported in patients with HIV infection. ^12,208

The effect of ART on the incidence of AIDS-related lymphoma is controversial (see Box 6.2). ¹² Some early reports suggested a decreased incidence, while later reports have found no significant change in incidence or even an increase, attributed to longer patient survival. ^9,12 However, despite a relatively unchanged incidence, survival does appear to be improved in patients receiving ART. ¹²

Thoracic involvement is reported in up to 40% of patients with AIDS-related lymphoma. ^209,210 Extranodal pulmonary involvement in the setting of disseminated disease is the usual pattern, but primary pulmonary lymphoma has been reported. ^211,212 The presence of extranodal disease predicts a poor outcome, with most affected patients surviving less than 1 year. ²¹³ Parenchymal lymphoma usually manifests with solitary or multiple lung nodules or masses of varying size (Figs 6.37 and 6.38).^{209.210. and 211.,214,215} Cavitation is rare; one case of cavitation with an intracavitary mass resembling mycetoma has been reported. ²⁰⁹

Pleural fluid is also common in patients with thoracic AIDS-related lymphoma. Effusions may be unilateral or bilateral and are usually moderate to large in size.^{209.210. and 211.} The pleura is sometimes the only site of disease (Fig. 6.39). ²¹⁰ Unlike NHL that occurs in non-HIV-infected individuals, mediastinal or hilar lymphadenopathy is often a prominent imaging feature in AIDS-related lymphoma. Although reported in up to 45% of cases, adenopathy is usually not bulky or always multicompartmental. The nodes are often less than 1 cm in diameter and may therefore be seen only on CT.^{209.210. and 211.,216}

Prior to the advent of the AIDS epidemic, Kaposi sarcoma (see Box 6.7) was a rare neoplasm seen primarily in endemic form in sub-Saharan Africa, in elderly people in the Eastern Mediterranean and in heavily immunosuppressed patients. It had a relatively benign course and caused purple nodular lesions on the skin of the lower limbs; other forms of the disease were quite rare. ²¹⁷ In patients with AIDS, Kaposi sarcoma is a multifocal polyclonal neoplasm with distinct histopathologic features. It is composed of a proliferation of vascular or lymphatic endothelial cells with associated spindle cells and atypical mitotic nuclear figures. The tumor forms multiple slitlike spaces that trap erythrocytes, a feature that accounts for the purple coloration of the lesion.

Kaposi sarcoma in AIDS patients particularly affects homosexual or bisexual men and individuals from Africa. It is uncommon in patients who acquire HIV infection transplacentally, through needle sharing, or from blood products. The incidence has decreased since the disease was first described in AIDS patients; this reduction occurred at the same time as the increased practice of safe sex and is presumed to be due to a decrease in the sexually transmitted form of the disease. Also, the incidence of Kaposi sarcoma is unequivocally decreased in HIV-infected patients receiving ART. ¹² A close association has been documented between HHV-8 infection and Kaposi sarcoma. ²¹⁸ The great majority of affected AIDS patients have cutaneous disease and over half also have oropharyngeal lesions; ²¹⁹ a much smaller proportion have bronchopulmonary Kaposi sarcoma. ²²⁰ The clinical manifestations of pulmonary involvement are often nonspecific. Affected patients usually have advanced AIDS with a median CD4+ count of 34 cells/µL²¹⁹ and present with fever and recurrent pneumonia. In most cases, cutaneous findings of Kaposi sarcoma precede visceral involvement.

On chest radiographs and CT, focal Kaposi sarcoma may cause segmental, lobar-shaped, or masslike opacities due to the tumor itself (Fig. 6.40). Endobronchial disease may cause atelectasis or postobstructive pneumonia. ²²¹ Disseminated pulmonary disease is seen more frequently. This form of the disease is distinctly bronchocentric in distribution as the lesions spread via the bronchial mucosa. Chest radiographs typically show nodular or coalescent masslike opacities in a perihilar and distinctively peribronchovascular distribution (Fig. 6.41). ^220,222,223 On CT, ^{219,221,224.225. and 226.} lesions are usually nodular in shape with either well- or ill-defined borders (Fig. 6.41, Fig. 6.42 and Fig. 6.43). Such lesions are sometimes described as ‘flame-shaped’ (Fig. 6.42). The lesions vary in size from less than 1 cm to well over 2 cm in diameter. The larger masses may contain air bronchograms (Fig. 6.43) and may have a surrounding rim of ground-glass opacity. Smooth or nodular thickening of bronchovascular bundles is seen in two-thirds of cases. Thickened interlobular septa and nodularity along the fissures are also common. ²²⁵ Up to half of affected patients have either unilateral or bilateral pleural effusions, which may be quite large. Hilar and mediastinal lymph node enlargement is seen in a substantial proportion of patients. While any of these findings may be seen in isolation, multiple findings are present in the great majority of patients. ²²⁴

Magnetic resonance imaging (MRI) findings of Kaposi sarcoma were reported in a series of 10 cases. ²²⁷ The lesions were of high signal intensity on T1-weighted images and of low signal intensity on T2-weighted images. These findings were suggestive of hemorrhage within the lesions (Fig. 6.44). The masses also enhanced following intravenous administration of a gadolinium-based contrast agent.

Strictly speaking, either transbronchial or thoracoscopic lung biopsy is required for definitive diagnosis of pulmonary Kaposi sarcoma. Neither pleural fluid analysis nor pleural biopsy is diagnostic. In practice, however, the presence of typical imaging features (poorly defined nodules in a peribronchovascular distribution) and findings of endobronchial Kaposi sarcoma at bronchoscopy are regarded as evidence of pulmonary involvement.

Lymphocytic bronchiolitis, ²²⁸ lymphocytic alveolitis, ²²⁹ and LIP form a spectrum of atypical lymphoproliferative disorders encountered in patients with AIDS. Along with nonspecific interstitial pneumonia (see below), these are pulmonary complications of HIV infection that may occur in the absence of a detectable opportunistic infection or neoplasm. ²³⁰

LIP is an AIDS-defining illness in children less than 13 years of age. ²³¹ LIP frequently occurs as part of a widespread syndrome of lymphocytic infiltration of parotid glands, stomach, thymus, liver, kidneys, and spleen. This syndrome is thought, in many cases, to be a reactive immune response to EBV. ²⁰⁷ It responds well to ART and has a relatively good prognosis. Although the radiographic features of LIP may persist unchanged for a long while, they may also resolve as the level of immunosuppression worsens. ²³² Affected patients may be asymptomatic or present with subacute dyspnea and cough. Diagnosis in children rarely requires biopsy and is often based on the clinical and radiographic features alone. LIP in adults with AIDS is very uncommon and is thought to represent a specific pulmonary response to HIV infection. ²³³ Symptoms are nonspecific and include cough, dyspnea, and fever. ²³⁴ Histopathologic specimens show polyclonal proliferations of lymphocytes and micronodular lymphoid aggregates that diffusely infiltrate alveolar septa and bronchovascular bundles. ^233,234

The imaging features of LIP are similar to, and often indistinguishable from, those of other infectious and noninfectious conditions that occur in patients with AIDS. Reticulonodular opacities are the most common finding on chest radiographs; the nodules vary from 1 mm to 5 mm in size (Figs 6.45 and 6.46).^{233.234.235. and 236.} Lobar or segmental homogeneous opacities have also been described. ²³³ CT, especially HRCT, typically confirms the presence of small nodules in a diffuse distribution. Ground-glass opacities, bronchial wall thickening, and findings of bronchiolitis may also be seen. ²³⁵ Bronchiectasis, observed in children with LIP, ¹⁹² probably results from lymphocytic infiltration of the bronchioles leading to wall thickening, destruction, fibrosis, and dilatation. ²³⁷ CT may also demonstrate small, thin-walled air-filled cysts in cases of LIP. ²³⁸ The cysts may be related to partial obstruction of bronchioles from lymphocytic infiltration. Lymphadenopathy is seen in 25% of cases. ²³³ Gallium scanning may be positive, but is rarely performed. ²³⁹

Pulmonary nodules measuring approximately 5–6 mm in diameter are also seen in cases of bronchus-associated lymphoid tissue hyperplasia. ^235,240 Ground-glass opacities and bronchiectasis may also be seen in this condition. ²³⁵

Nonspecific interstitial pneumonia (NSIP), a noninfectious pneumonia that may be clinically indistinguishable from PCP, has been described in patients with AIDS. ^{230,241.242.243. and 244.} Affected patients present with cough, dyspnea, and pyrexia. Histopathologic specimens show diffuse alveolar damage, an increased number of alveolar macrophages, alveolar hemorrhage, interstitial inflammation, and fibrin deposition. No causative agent has been identified, although patients may have a recent history of PCP, Kaposi sarcoma, drug therapy, or drug misuse.

The reported incidence of NSIP in patients with AIDS varies. One group evaluated lung biopsy specimens from 351 HIV-positive patients with presumed PCP. ²⁴³ Of the 67 patients who did not have PCP, 16 (24%) had findings of NSIP. Clinical symptoms, physical examination findings, and blood gas values were similar in patients with NSIP and patients with PCP. Patients with NSIP tended to present earlier in the course of their disease and had higher CD4+ lymphocyte counts (492 cells/µL versus 57 cells/µL) than patients with PCP. These authors concluded that NSIP may be the most common entity that mimics PCP in AIDS patients. They also found that NSIP tended to improve during empiric therapy for PCP. Another group evaluated 23 consecutive HIV-positive patients with no pulmonary symptoms, normal chest radiographs, no history of PCP, and no prior treatment with anti-Pneumocystis prophylaxis. ²⁴⁴ None of the patients had evidence of P. jirovecii or other infectious pathogens by stains of bronchoalveolar lavage fluid and histopathologic examination of lung biopsy specimens. However, transbronchial lung biopsy specimens showed findings of NSIP in 11 of 23 (48%) patients. It would thus appear that NSIP can exactly mimic the clinical features of PCP or be found by transbronchial lung biopsy in asymptomatic AIDS patients with normal chest radiographs.

Over half of symptomatic AIDS patients with biopsy-proven NSIP have a normal chest radiograph. Diffuse reticular opacities are noted in the remainder. ²⁴¹ Radiographic findings vary in severity from minimal perihilar opacities to severe bilateral pulmonary consolidation, frequently associated with pleural effusion. Although the disease usually resolves without sequelae, repeated episodes may cause permanent lung injury and may contribute to long-term pulmonary dysfunction in patients with AIDS.

Persistent generalized lymphadenopathy is a feature of early but otherwise asymptomatic HIV infection. It characteristically affects the peripheral lymph nodes and, although documented in the nasopharyngeal lymphoid tissue, rarely causes important hilar or mediastinal lymph node enlargement.

Lung cancer (see Box 6.7) is a common neoplasm encountered in HIV-positive patients. ^{12,245.246.247.248.249. and 250.} Many, ^247,249,250 but not all, ²⁴⁸ investigators have reported an increased incidence of lung cancer in AIDS patients, especially among women. However, whether the incidence of lung cancer in patients with HIV infection is truly increased or not continues to be debated. ^{12,250.251. and 252.} The risk of cancer does not seem to correlate with CD4+ lymphocyte count. ⁹ ART has not yet seemed to affect incidence or prognosis; paradoxically, incidence may be increasing when compared with non-ART groups, perhaps because of longer survival. ^9,12

Patients with AIDS and lung cancer are typically smokers, with an average age at diagnosis of approximately 40 years. Lung cancer frequently occurs early in the course of disease, sometimes before seropositivity for HIV infection is known. Rapid progression of carcinoma is the rule and the prognosis is extremely poor, with an increased proportion of poorly differentiated and advanced stage carcinomas. ²⁵³ The lung cancers are predominantly found in the upper lobes^246,254 and have frequently spread to lymph nodes in the adjacent mediastinum or hilum (Fig. 6.47). ²⁵³ Extensive pleural disease from adenocarcinoma was present in 35% of HIV-positive patients with lung cancer in one study. ²⁴⁶

The ability of an individual to combat infections can be impaired in a variety of ways (see Box 6.10). The immunocompromised patient with fever and new pulmonary opacities is a very common clinical problem. Before the differential diagnosis is discussed in more detail, a few generalizations are applicable.^{259.260.261. and 262.}

The chest radiograph yields a specific diagnosis in a minority of cases. In most instances, all that can be expected is a reasonable differential diagnosis that must be correlated with clinical and laboratory findings. Table 6.2, Table 6.3 and Table 6.4 outline conditions that should be considered when chest radiographs show segmental or lobar disease, diffuse lung disease, and nodular or masslike opacities respectively.

Fever and new pulmonary opacities are commonly encountered problems in immunocompromised patients. Elucidation of their cause requires consideration of the following: cause of immune impairment; results of previous tuberculin testing; whether the infection was acquired in or out of hospital; whether there is any known potential source of infection; and the results of blood or sputum cultures and serologic testing.

Chest radiography is usually the first imaging study requested for these patients. Radiography is useful for detecting intrathoracic abnormalities, but is limited in its ability to delineate a precise etiology. In an autopsy study of patients with leukemia, chest radiography was deemed valuable for detecting pulmonary abnormalities, but, as noted, very limited in its ability to discriminate causes, with the exception of ARDS. ²⁶² However, most of the 45 patients in this series were critically ill with more than one infectious or noninfectious complication; only seven patients had a single complication (either ARDS or pulmonary hemorrhage). In a less critically ill group of non-AIDS patients with a wide range of causes of immune compromise, the correct diagnosis was made on the basis of the chest radiograph in 34% of cases, a figure that seems high. ²⁶⁰ Winer-Muram et al., ²⁶¹ in a study involving less critically ill patients with hematologic malignancies, had better results with chest radiography, particularly with fungal pneumonia and cryptogenic organizing pneumonia.

CT can play an important role in the evaluation of persistently febrile immune-suppressed patients. The two best-studied populations in this regard are patients with AIDS and severely neutropenic patients. As previously noted, CT, particularly HRCT, can be useful in AIDS patients with symptoms of pneumonia and a normal or equivocal chest radiograph. In this setting, CT can be useful for either diagnosing or excluding pulmonary complications such as PCP. ^{118,122.123.124. and 125.,167,182}

In the febrile patient with neutropenia, CT can be useful for showing findings of pneumonia when the chest radiograph is normal or equivocal, for better characterizing the nature of radiographically evident abnormalities, and for planning diagnostic procedures such as fiberoptic bronchoscopy or bronchoalveolar lavage. ^353,354 One group of investigators prospectively studied 87 patients with fever and neutropenia of more than 2 days’ duration despite empiric antibiotics. ³⁵⁵ Of the patients with a normal chest radiograph, almost half had findings suggestive of pneumonia on HRCT. In a separate study, the same group reported that CT showed findings of pneumonia in 60% of 112 persistently febrile neutropenic patients with normal chest radiographs. ³⁵⁶ In both studies, CT showed findings of pneumonia about 5 days earlier than did chest radiographs, leading the authors to conclude that all febrile neutropenic patients with normal chest radiographs should undergo CT. In another study of 33 febrile neutropenic patients, chest radiographs were interpreted as normal in one-third and as showing nonspecific findings in the remainder. ³⁵⁷ In this study, CT findings resulted in a change in clinical management in one-third of patients. Gulati et al. ³⁵⁸ assessed the utility of HRCT in 21 consecutive renal transplant recipients with suspected pulmonary infection. Compared with chest radiography, HRCT revealed additional findings suggestive of the correct diagnosis in 11 (50%) patients. CT has also been shown to be helpful for predicting the nature of pulmonary complications in febrile HSCT recipients. When CT shows nodular opacities, pulmonary fungal infection (usually aspergillosis) is usually the cause. ³⁵⁹ When CT is negative, bacteremia or nonpulmonary fungal infection is usually the cause. ³⁵⁹

Owing to the high incidence, morbidity, and mortality of invasive Aspergillus infection in neutropenic patients, many investigators have studied the use of CT for early diagnosis. ^275,282,284 One group showed that CT was better than a variety of novel serologic tests for early diagnosis of aspergillosis in HSCT recipients. ³⁶⁰ In that series, CT showed abnormalities at least a week before these tests became positive. In two separate studies, systematic use of CT allowed very early recognition of Aspergillus infection in at-risk patients. ^285,361 In one of the studies, mean time to diagnosis was reduced from 7 to 2 days. ³⁶¹ They also reported that earlier diagnosis and aggressive management could improve outcome. ^285,361 These findings have been reproduced by others. ^{275,282.283. and 284.} Galactomannan (an antigen released when Aspergillus hyphae invade host tissue) assays performed on either serum or bronchoalveolar lavage has proven useful for diagnosis of invasive Aspergillus infection. ^362,363 However, galactomannan positivity was found to lag, by at least several days, the development of characteristic CT findings in 107 patients with aspergillosis. ³⁶⁴ Galactomannan assays were also found less likely to be positive in cases of airway invasive aspergillosis (60%) than in cases of angioinvasive disease (80%). ³⁶⁵ CT and galactomannan assays are probably complementary diagnostic approaches and, when used appropriately, may facilitate early diagnosis and treatment of Aspergillus infection in immunocompromised hosts. ³⁶⁶

In summary, a wealth of data supports the role of CT for evaluation of febrile neutropenic patients who have normal or equivocal chest radiographs. In this setting, a normal CT suggests a nonpulmonary complication. An abnormal CT suggests a pulmonary complication, can suggest the nature of that complication, and can direct further invasive testing such as bronchoalveolar lavage or transbronchial biopsy. It should also be remembered that a host of noninfectious complications can cause pulmonary problems in immunocompromised patients. These include, but are not limited to, neoplastic involvement of the lung (see Chapter 13), drug or radiation-induced toxicity (see Chapter 9), transfusion reactions, pulmonary edema, and pulmonary hemorrhage. Transfusion reactions are usually acute and the temporal relationship to the transfusion of blood or blood products is clear. The reaction may simply be one of volume overload and pulmonary edema. More capricious are the agglutinin reactions resulting from an excess of antibodies in the donor serum directed against the recipient’s cells, particularly granulocytes. The result is the abrupt onset of fever, chills, tachypnea, and tachycardia coincident with the development of varying patterns of pulmonary edema (Fig. 6.70). The edema pattern may persist for 24–48 hours, and a response to corticosteroid therapy may occur. Leukemia may be associated with pulmonary hemorrhage. The clinical features may clearly indicate the bleeding tendency, and the abrupt appearance of scattered homogeneous opacities with hemoptysis and a fall in the hematocrit may allow confident diagnosis. The incidence of pulmonary hemorrhage in leukemia is difficult to ascertain, particularly because the coagulopathy may preclude biopsy. Pulmonary hemorrhage varying from microscopic to massive hemorrhage is seen in some three-quarters of leukemic patients at autopsy. ³⁶⁷ Pulmonary hemorrhage may be associated not only with a bleeding tendency, but also with infection or diffuse alveolar damage. ^367,368 Tenholder and Hooper³⁶⁹ suggest that the incidence of pulmonary hemorrhage as a sole cause of pulmonary opacities in leukemic patients may be as high as 40%. This seems a high figure, but it does serve to emphasize that pulmonary hemorrhage is probably underdiagnosed.

Exhaustive clinical investigation may fail to establish the etiology of pulmonary opacities in immunocompromised patients. Lung biopsy, either by video-assisted thoracoscopy or by fiberoptic bronchoscopy, may be required in the most problematic cases. In a considerable number of patients, however, histopathologic examination of affected lung only shows findings of diffuse alveolar damage, NSIP, or organizing pneumonia (OP); etiologic agents cannot be identified. NSIP is found in some 30–45% of biopsies in this clinical setting.^{370.371. and 372.} It is possible that lung injury in these patients is multifactorial and may be a manifestation of undiagnosed infection, pulmonary drug toxicity, radiation therapy, sepsis, etc. Organizing pneumonia is probably less commonly encountered in this setting than NSIP but responds well to corticosteroids and has a more favorable prognosis (Fig. 6.71). The radiographic and CT findings of organizing pneumonia are discussed in detail on page 575. Because the imaging findings of OP are quite similar to those of other pulmonary complications in immunocompromised patients, the diagnosis is typically made at biopsy.373.^{374.375. and 376.} Organizing pneumonia should be clearly distinguished from obliterative bronchiolitis, a distinct condition that results in irreversible airway occlusion in hematopoietic stem cell and lung transplant recipients. Transplant-related obliterative bronchiolitis generally has a very poor prognosis. ³⁷⁷

Many thousands of HSCTs (formerly called bone marrow transplants) are performed annually for a diverse range of malignant and nonmalignant conditions (see Box 6.15). ^378,379 Pulmonary complications are seen in 40–60% of HSCT recipients and many of the complications (see Box 6.16) carry significant mortality. ^380,381 In previous years, infection was the most common cause of pulmonary complications after HSCT. Now, because of advances in transplant protocols and procedures and more effective antimicrobial prophylaxis and treatment, noninfectious complications are the major cause of pulmonary morbidity and mortality after transplantation. ^382,383 Important risk factors for development of pulmonary complications after HSCT include the pretransplant conditioning regimen, the type of transplant, the duration of immune system dysfunction, and the presence of graft-versus-host disease (GVHD). ³⁸⁴

Most myeloablative stem cell transplant procedures involve infusion of progenitor stem cells into a patient whose bone marrow has been ablated by high-dose chemotherapy and total body irradiation (the conditioning regimen). Because the patient may receive radiation to the entire lungs and the chemotherapeutic doses used are often quite formidable, the conditioning regimen employed is a major factor contributing to pulmonary complications. In older patients or in those with poor cardiopulmonary reserve, ‘mini’ or nonmyeloablative transplant techniques that use more moderate conditioning regimens combined with posttransplant immunosuppression are sometimes employed. ³⁸⁴ Complications of these transplants are less severe than those of traditional myeloablative transplants, perhaps because of the more moderate pretransplant conditioning regimen. ³⁸⁵

Transplanted stem cells may be harvested from the patient prior to conditioning (autologous HSCT), from an identical twin (syngeneic HSCT), or from a human leukocyte antigen (HLA)-matched donor source (allogeneic HSCT). Common to all myeloablative transplant procedures is a 2–4-week period of profound bone marrow dysfunction between the time of stem cell infusion and engraftment. During this period, red blood cells and platelets can be supplied by transfusion, but the consequent neutropenia renders the patient susceptible to bacterial and fungal infection. Neutrophil production usually begins to accelerate after about 2 weeks and the period of severe neutropenia usually lasts only about 4 weeks. Neutropenia is only a part of the profound immune deficit in these patients, though. Lymphocytes, for example, are the most radiosensitive cellular element in the body and can also be depleted. Immune dysfunction is less severe and less prolonged in patients receiving autologous and nonmyeloablative transplants. Hence, their risk for opportunistic infection (especially CMV and fungal pneumonia) is reduced compared with patients receiving myeloablative allogeneic transplants. After the first month, there is a continuous recovery of immune function that is usually complete at about 1 year. Graft-versus-host disease (GVHD) results from transplantation of immunocompetent donor lymphocytes that attack the recipient’s tissues and can develop at any time after transplant. Recipients of autologous or syngeneic stem cells are, of course, not susceptible to GVHD. Both the development of, and treatment for, GVHD can predispose transplant recipients to further pulmonary complications, including infection.

The pulmonary complications of HSCT are customarily divided (see Fig. 6.72 and Box 6.17) into those that occur in the 30 days after transplant (neutropenic phase), those that occur between 30 and 100 days after transplant (early phase), and those that occur thereafter (late phase). The advantage of this temporal division is that certain complications, although their clinical and imaging manifestations may be similar, tend to occur during specific time periods after transplantation.