The granuloma is the earliest lesion of sarcoidosis. ¹⁰ Early loose granulomas evolve into mature ones that consist of a tightly packed central collection of epithelioid histiocytes and occasional multinucleate giant cells surrounded by lymphocytes (activated T cells), monocytes, and fibroblasts. ¹ Necrosis is rare and when it does occur is minimal and confined to the center of granulomas. ¹¹ Granulomas are predominantly interstitial and are distributed along lymphatic pathways, being characteristically found along bronchovascular bundles, interlobular septa, and pleura, ¹² with or without interstitial pneumonitis in the adjacent lung. Granulomas, once formed, may remain stable for months or years. They may resolve spontaneously or in response to treatment. In a minority of cases (perhaps 20%) the granulomas become obliterated by centripetal fibrosis that may develop into extensive interstitial fibrosis, with destruction and distortion of lung architecture and the eventual production of an end-stage lung.

A substantial range of disorders can cause granulomatous lung disease (Box 11.2). ¹³ Distinguishing features of granulomas due to sarcoid or beryllium include their tendency to conglomerate along lymphatic pathways, and the presence of surrounding dense eosinophilic lamellar collagen, which often contains granulomas. ¹⁴ They differ from infective granulomas because of the absence of caseous necrosis. The granulomas of hypersensitivity pneumonitis tend to be small, poorly defined, and bronchiolocentric. Intravenous talcosis is characterized by perivascular clusters of giant cells containing birefringent particles. The tendency of sarcoid granulomas to involve other organs is an important feature that distinguishes sarcoidosis from various lung-limited granulomatous disorders. ¹⁵ For example, chronic beryllium disease is generally confined to the lungs.

Incidence rates for sarcoidosis vary greatly from country to country and depend, among other factors, on race, the sophistication of medical care, and use of screening programs. Quoted figures for incidence of clinical disease are of the order of 1–10 cases per 100 000 population per year, but this is almost certainly an underestimate because many cases remain subclinical. ¹⁶ Studies performed using mass radiographic screening for tuberculosis have yielded a prevalence of 10–30 cases per 100 000; many of these cases were asymptomatic, and might never have been detected clinically.^{17. and 18.} The highest incidence of this condition is found in northern European countries (5–25 cases per 100 000).^{17. and 19.} In the USA, the annual incidence is about 3.5 times greater in African Americans than in white people. ²⁰ Sarcoidosis begins later in African Americans, and is more likely to be chronic and fatal. ²⁰ In individual cases, the ethnic origin of the patient is relatively unhelpful in determining the likelihood of sarcoidosis.

A number of conditions have been reported to show an association with sarcoidosis; the relationship is best established for tuberculosis. ²¹ In a series of 425 patients with sarcoidosis, tuberculosis immediately preceded sarcoidosis in 1.6% and sarcoidosis developed into overt tuberculosis in 1.9%. ²² More recently, a sarcoidlike syndrome has been shown to occur as part of an immune reconstitution syndrome in patients treated with highly active retroviral treatment for acquired immune deficiency syndrome (AIDS).^{23.24. and 25.} Sarcoidosis in these individuals may present up to 3 years after the commencement of treatment, and the clinicopathologic characteristics of sarcoidosis in human immunodeficiency virus (HIV)-infected patients are similar to those of sarcoidosis in HIV-uninfected patients. Sarcoidosis may be also related to treatment with interferon-α for chronic hepatitis C²⁶ or melanoma. ²⁷

Sarcoidlike reactions may occur in lung or other tissues adjacent to lymphoma, and lung cancer. ²⁸ Lymphoma (Hodgkin or non-Hodgkin) appears to be the most common associated neoplasm, but lung cancer may also be associated with sarcoidlike reactions. Other associated tumors may include testicular cancer, ²⁹ head and neck cancer, ³⁰ breast cancer, ³¹ and renal cancer. ³² The relative risk of malignancy in the decade following diagnosis of sarcoidosis is at least twice the expected value, and this is probably due at least in part to initial misdiagnosis of sarcoidosis. ²⁸ The radiologist should be alert for imaging features suggesting neoplasm in individuals with a diagnosis of sarcoidosis.

Sarcoidosis most commonly presents between 20 and 40 years of age,^{20.33. and 34.} but the range is wide, ranging from the first year of life³⁵ to the eighth decade. There is a slight female predominance. ⁶ The mode of presentation varies greatly among series, depending particularly on racial mix and the use of screening radiography. In studies with predominantly Caucasian populations, presentation as an incidental radiographic finding is common and may occur in 30–50% of cases. ³⁶ Low-grade fever, musculoskeletal symptoms, weight loss, and fatigue are also common. ³⁶ Respiratory illness (21%), erythema nodosum (16%), ocular symptoms (7%), and other skin lesions (4%) ³⁷ represent the other common presentations. In those of black racial origin, respiratory and systemic symptoms such as fatigue, malaise, weakness, weight loss, and fever are most common. ³⁸ A striking difference between black individuals and Caucasians at presentation is in the frequency of erythema nodosum. This finding is uncommon in African Americans but very common in Caucasians, particularly in the UK, where 30–40% of patients present with the condition^{37.39. and 40.} often as part of Löfgren syndrome (erythema nodosum, fever, and hilar adenopathy). ⁴¹ In general, sarcoidosis occurring in African Americans is later in onset, is more likely to involve peripheral nodes, skin, and eyes, and to become chronic and disseminated. Because of the lower incidence of the benign Löfgren syndrome and the higher incidence of chronic, disseminated disease, the prognosis of sarcoidosis is worse in African Americans than in white people. ⁶

Hematologic evaluation may show anemia, neutropenia, or lymphopenia. A significant blood eosinophilia has been reported in up to one-quarter of patients.^{15.42. and 43.} Sarcoidosis should therefore be considered in the differential diagnosis of pulmonary eosinophilia, though patients with sarcoidosis do not usually have eosinophilia of the lung parenchyma.

Disordered calcium homeostasis is caused by synthesis of 1,25-dihydroxyvitamin D₃ (calcitriol) by activated sarcoid macrophages⁴⁴ and is rapidly responsive to steroids. ⁴⁵ Hypercalciuria and hypercalcemia may become prominent features. ¹ Hypercalcemia can cause metastatic calcification and renal failure. ³³ Hypercalciuria is two to three times more common than hypercalcemia, ⁴⁶ occurring in about 11% of patients, ³⁷ and may lead to renal calculi.

Serum levels of angiotensin-converting enzyme (ACE), produced by activated macrophages, are raised in about 50–60% of patients.^{47.48. and 49.} Serum ACE levels correlate with the total body granuloma burden. ⁵⁰ However, measurement of these levels is not diagnostically helpful, as raised levels of serum ACE can also be present in other granulomatous conditions, and in Hodgkin lymphoma.^{40. and 51.} Other biochemical changes may include abnormal liver function (particularly alkaline phosphatase). ⁵⁰

Various immunologic derangements are seen with sarcoidosis. Cutaneous anergy is well recognized. About two-thirds of patients have a negative tuberculin test, and in many of the remainder it is only weakly positive.^{37. and 38.} Cutaneous anergy is probably related to the relative abundance of suppressor T cells (CD4 cells) in the peripheral blood following sequestration of helper T cells (CD8 cells) in active sarcoid lesions. Activated helper T cells stimulate nonspecific antibody production by B cells, ¹ producing a whole range of antibodies and resulting in hypergammaglobulinemia¹ in about 50% of patients, particularly in individuals of African races. ³⁷

In active sarcoidosis, bronchoalveolar lavage (BAL) shows T cell lymphocytosis with an increase in activated helper cells, manifest as an increase in the CD4/CD8 ratio^{38. and 52.} and to a lesser extent activated alveolar macrophages. Such lymphocytosis can even be seen in sarcoidosis without evidence of lung disease. ⁵² This ‘sarcoidosis’ pattern of BAL may also be seen with other conditions such as chronic beryllium disease and hypersensitivity pneumonitis. ⁵² Although a high CD4/CD8 ratio in BAL is associated with other measures of disease ‘activity’, its usefulness in predicting outcome and monitoring treatment is debatable¹ and most clinicians believe it has no role in routine management of the patient with sarcoidosis. ⁵³

Typical physiologic findings in patients with sarcoidosis are restrictive, with a decrease in total lung capacity, a reduced diffusing capacity, and reduced compliance.^{54. and 55.} However, airway obstruction may also be present, either as a manifestation of early disease with small airway involvement^{56.57. and 58.} or in later disease when there is reticular abnormality and bronchovascular distortion. ⁵⁹ A loose relationship exists between respiratory function tests and chest radiographic changes.^{55. and 60.} The mean values for respiratory function tests correlate with the radiographic stage, becoming worse from stage I to stage III. However, individual exceptions to this correlation are common. For example, several studies have shown that about 50% of patients in stage I have a diffusion defect.^{55. and 61.} Also, respiratory function tests can give results in the normal range in stage II and stage III disease. Discrepancies between radiographs and function are most likely to arise when patients are treated with steroids, which commonly improve function in the face of an unchanging chest radiograph. ⁵⁵

The diagnosis of sarcoidosis requires clinical and imaging features compatible with the diagnosis, and the identification of noncaseating granulomas in at least one organ. ⁶² In clinical practice the organs most commonly sampled are lymph nodes, liver, and lung. Transbronchial biopsy is usually the investigation of first choice, with a diagnostic yield of about 90%, provided that enough tissue samples are obtained.^{63.64.65.66. and 67.} Even in patients with hilar adenopathy who have normal lung parenchyma on chest radiographs, the yield from biopsy is over 80%. ⁶⁸ The high yield of transbronchial biopsy in this condition is due to the predominantly peribronchovascular distribution of the granulomas.

A large number of conditions can produce granulomatous lesions (Box 11.2), and if the diagnosis of sarcoidosis rests on histologic appearances, these other conditions must be excluded as far as possible by history, special histologic stains, and microbiologic culture. Establishing the widespread nature of the granulomatous process is also important, since local sarcoidlike reactions can be produced by a number of primary processes, including lymphoma and carcinoma.^{69. and 70.} In clinical practice, the diagnosis of sarcoidosis is sometimes accepted without biopsy, provided that clinical, laboratory, and imaging features are typical. In particular, biopsy is usually unnecessary when the patient presents with Löfgren syndrome (erythema nodosum, fever, and bilateral hilar adenopathy), and the resolution is rapid and spontaneous. ⁶² When the clinical diagnosis is less firmly based, histologic proof is essential. The Kveim test, in which skin biopsy is performed 4–6 weeks after intracutaneous injection of a saline suspension of human sarcoid tissue, ⁷¹ is now rarely used, largely because the injected material is poorly standardized and is not widely available. ⁶²

The term ‘activity’ is frequently used in relation to sarcoidosis but it is not exactly defined and its clinical relevance is unproven. Current understanding of the pathogenesis of sarcoidosis suggests that an initiating event (antigen exposure) sets in train a three-phase response: (1) T-lymphocyte/macrophage inflammation; (2) granuloma formation; (3) active fibrosis – any or all of which can be active, i.e. changing or evolving. ⁷² Different markers of activity reflect different elements of this process. A great variety of markers have been proposed, using clinical parameters, imaging tests (chest radiography, computed tomography [CT], gallium-67 scanning), serum levels (e.g. calcium, ACE), and BAL markers. Despite this great variety the consensus view is that the clinical activity of sarcoidosis is best assessed on the basis of the onset, worsening, or persistence of symptoms related to sarcoidosis. ⁶² In general, tests to stage activity can be limited to clinical investigation, chest radiography, and lung function testing. ⁷² The basic problem with all markers of disease ‘activity’ is that they do not necessarily predict outcome or the necessity to start corticosteroid therapy. ⁷²

Indications for treating chest disease are not firmly established but most patients with symptomatic or progressive stage II or stage III disease are treated. The clinician will usually base treatment decisions on the patient’s symptoms, physiologic impairment, or evidence of extrathoracic involvement rather than solely on the chest radiographic appearance. If treatment of sarcoidosis is indicated, then corticosteroids are the agents of first choice.^{10.53. and 73.} There is no doubting the short-term efficacy of steroids but their long-term value is less clear and a number of controlled studies have shown no long-term difference between treated and untreated patients⁷⁴ and symptoms will commonly recur when treatment is reduced or stopped. ⁶² Other agents have been tried in steroid-resistant sarcoidosis including immunosuppressive, cytotoxic, and antimalarial drugs. ⁵³

Lung transplantation has been successfully employed in end-stage sarcoidosis with survival rates at 1 year that are slightly less than in other forms of diffuse lung disease. ⁷⁵ Recurrence of sarcoidosis has been described in the transplanted lung^{76. and 77.} but is not usually associated with a significant clinical problem and can be controlled with augmented immunosuppression. In a multi-institutional study, sarcoidosis was found to have recurred in nine (35%) of 26 patients transplanted for this disease, and was the most common disease to recur in transplanted lungs. ⁷⁸ Recurrent sarcoidosis was identifiable on CT in only 3/9 cases identified histologically. In those with abnormal CT, recurrence was manifested by either miliary nodules (n = 2) or a solitary pulmonary nodule (n = 1). ⁷⁸

The majority of deaths from sarcoidosis are related to pulmonary, cardiac, or neurologic disease. In three series of 113 sarcoid-related deaths, 69 (61%) resulted from pulmonary involvement – overwhelming granulomatous disease, pulmonary fibrosis, cor pulmonale, hemorrhage, mycetoma formation, and respiratory failure.^{79.80. and 81.} Symptomatic cardiac involvement appears to have a particularly poor prognosis, with mortality up to 20% for symptomatic patients. ⁸² In several large series, overall mortality ranged between 2.2% and 7.6%.^{37.62. and 83.}

Sarcoidosis is commonly staged according to its appearance on the chest radiograph. A widely used classification is the following:^{34. and 84.}

Other classifications⁸⁵ use a three-stage system, with fibrotic and nonfibrotic opacities grouped together as stage III. The use of the term ‘stage’ should not be taken to mean that sarcoidosis always begins as stage 0, with orderly progression through the higher stages. Nevertheless, patients commonly pass sequentially from stage I to stage III. At the time of presentation the percentages of patients at each stage are:

The stage at presentation is generally considered to correlate with prognosis. Untreated patients with stage I disease experience resolution of symptoms and radiographic abnormalities in 50–90% of cases, compared with 30–70% for stage II, 10–20% with stage III, and 0% with stage IV. ⁵³

The frequency of detection of nodal calcification in sarcoidosis (Fig. 11.7) is related to the mode of detection and the duration of disease. ¹¹³ In short-term studies using chest radiography, nodal calcification is seen in about 1–3% of cases,^{33. and 84.} but in a longer term study of 111 patients observed for 10 years or more the prevalence was 20%, ¹¹⁴ leading to the suggestion that sarcoid is probably the most common cause of mediastinal nodal calcification in regions where the prevalence of tuberculosis or fungal infection is low.

The occurrence of calcification is unrelated to either hypercalcemia or coincident tuberculosis. Most descriptions are of paratracheal and hilar involvement, but any nodal group may be involved. ¹¹⁵ The morphology of the calcification on chest radiographs is variable and nonspecific. However, in a number of patients, peripheral, eggshell calcification develops (see Fig. 11.7).^{90.99.115.116. and 117.} This is of diagnostic value because its occurrence is largely limited to sarcoidosis and silicosis. ¹¹⁷ Spontaneous resolution of eggshell calcification has been reported. ²²

CT allows a more detailed analysis of the frequency and morphology of nodal calcification than the chest radiograph. The prevalence of nodal calcification detected by CT in patients with sarcoidosis is from 45%¹¹⁸ to 55%. ¹¹⁶ Gawne-Cain and Hansell¹¹⁶ compared findings in 28 patients with tuberculosis and those in 49 with sarcoidosis, selected on the basis that they had had mediastinal CT. In sarcoidosis, the number of calcified nodes is greater, the calcified nodes are larger, and hilar calcification when present is more commonly bilateral. Nine percent of sarcoid nodes showed an eggshell pattern and in 4% this was the predominant pattern. In other patients with sarcoidosis, a central, less dense, cloudlike or icing sugar pattern of nodal calcification is seen (Figs 11.5 and 11.8), differing from the punctate dense calcification typically seen in tuberculosis or fungal infection.

Large vessel involvement is rare in sarcoidosis¹⁹² and is usually the result of compression by large nodes, or bronchovascular distortion by conglomerate masses.^{193.194.195.196. and 197.} Typically the lobar divisions, particularly the upper lobe vessels, are involved, and pulmonary arterial hypertension is usually absent. Small vessel involvement by granulomas is common and is usually accompanied by widespread parenchymal disease.^{68. and 184.}

Pulmonary artery hypertension is found in 6–23% of patients with sarcoidosis at rest, and in up to 43% on exertion. ⁶ It is most commonly related to advanced lung disease with fibrosis and bullae¹⁹⁸ but about 30% of cases of pulmonary hypertension are not associated with radiographic evidence of lung fibrosis (Fig. 11.31). ¹⁹⁹ When pulmonary hypertension is not associated with lung fibrosis, it may respond to corticosteroid therapy.^{199. and 200.}

Occasionally, granulomatous involvement of large or small pulmonary veins causes venous obliteration and postcapillary pulmonary arterial hypertension.^{201. and 202.} Imaging features may include interlobular septal thickening (and resemble those of venoocclusive disease). ²⁰² Rarely, intraluminal filling defects may be seen in the pulmonary veins in patients with sarcoidosis. ²⁰¹

Although mediastinal adenopathy is often massive, it rarely causes compression of great veins with subsequent superior vena cava syndrome, a fact that has been ascribed to the lack of perinodal fibrosis in sarcoidosis. ¹¹³ A handful of cases of superior vena caval obstruction are described. ²⁰³ A single case of subclavian vein obstruction²⁰⁴and of innominate vein obstruction which produced a large exudative pleural effusion is recorded. ²⁰⁵ The rarity of superior vena cava syndrome with sarcoidosis is such that other causes of obstruction should be sought. ²⁰⁶

In sarcoidosis, granulomas may be found on both the visceral and parietal pleura. These pleural granulomas commonly cause no signs or symptoms. ²⁰⁷ On rare occasions, however, they may be associated with a dry pleurisy²⁰⁸ or a pleural effusion that is usually painless²⁰⁹ but may be painful. ²¹⁰ These effusions are classically lymphocyte-rich exudates that in nearly one-fifth of cases are sanguineous or serosanguineous. ²¹¹ Eosinophilic effusions are described. ²¹²

In 1870 cases of sarcoidosis taken from major series in the world literature, 55 had pleural effusions, giving a prevalence of 1.9%.^{15.33.90.92.93.148.213. and 214.} Effusions may be present initially, but more often they develop during the course of established disease, a few months to 16 years after onset. ²¹³ Sarcoid effusions are usually seen in the context of extensive pulmonary disease²¹⁴ or multisystem involvement. ²¹³ About one-third of the effusions are bilateral, ²¹³ and while they are usually small, large effusions have been described.^{211.215. and 216.} The effusions resolve spontaneously in weeks or months and are almost invariably gone by 6 months. ²¹ Resolution is usually complete, but about 20% of patients are left with residual pleural thickening.^{90. and 214.} In a CT-based study of 61 patients, pleural effusions were found in 9%, with pleural thickening in 30%. ²¹⁷

In general, pleural effusion is a relatively minor and incidental finding in the course of sarcoidosis. However, because it is an atypical feature, it may prove a diagnostic puzzle, and other entities such as tuberculosis²¹⁸ or chylothorax⁵³ must be excluded. ²¹⁹ Sarcoidosis is associated with a 2–3% prevalence of pneumothorax in several series, usually associated with advanced fibrocystic disease. ²²⁰ Uncommonly pneumothorax can be a presenting manifestation of sarcoidosis, associated with multiple pleural granulomata at thoracotomy or subpleural cavitary nodules and bullae at HRCT. ²²¹ Bilateral pneumothorax is also described. ²²²

Mycetoma formation (Fig. 11.32) is a well-recognized complication of stage IV cystic sarcoidosis.^{223. and 224.} Indeed, with the declining incidence of tuberculosis, sarcoid is probably now the commonest cause of mycetoma. This is particularly so in the USA, where the proportion of African Americans with sarcoidosis results in more cases of gross fibrobullous disease. ²²⁵ In a series of mycetomas reported from Philadelphia, 45% were in patients with sarcoidosis, ²²⁶ whereas in a series of 26 patients in the UK only 15% were in patients with sarcoidosis. ²²⁷ The frequency of mycetoma in sarcoidosis varies from series to series and ranges between 1% and 10% depending on racial mix of the patients and method of detection.^{33.90.148.224. and 228.} In the subset of sarcoid patients with stage IV fibrocystic disease, the proportion of patients harboring a mycetoma can be as high as 50%.^{90. and 224.}

The imaging features of mycetoma are discussed in Chapter 5. In sarcoidosis, mycetoma formation should be considered when new masslike lesions or pleural thickening develop in patients with stage IV sarcoidosis. ²²⁶ Mycetomas are confined virtually to the upper lobes and are commonly bilateral (Fig. 11.32), in 50% of cases in one series. ²²⁸ Serum precipitins against Aspergillus spp. are almost always strongly positive. CT is the most sensitive imaging technique.^{227. and 229.}

The role of CT in patients with known or suspected pulmonary sarcoidosis remains undefined. Recognition of the characteristic CT pattern of sarcoidosis may help to suggest the diagnosis, and may in some cases be sufficiently specific to obviate the need for biopsy. If a biopsy is desired, CT may provide a ‘road-map’, identifying high-yield areas for transbronchial biopsy. In patients with unilateral adenopathy, in whom there is concern for the presence of lymphoma or other abnormality, CT may help by identifying bilateral nodal enlargement, characteristic nodal calcification, and parenchymal abnormalities suggestive of sarcoidosis. However, CT adds little to the diagnostic evaluation of patients with typical clinical and chest radiographic findings of sarcoidosis.

A study by Mana et al. ²³⁰ of 100 patients with sarcoidosis found that CT scans added diagnostically useful information in only one of the 35 patients in whom they were performed. These authors concluded that CT may be helpful in patients with atypical chest radiographic findings, normal chest radiographs, hemoptysis, or suspicion of a second complicating disease, and in those who are lung transplant candidates. To these indications we would add suspected large or small airway disease, and those in whom a diagnosis is not made by transbronchial biopsy. Costabel et al. ³⁶ suggested the following indications for CT: atypical clinical and/or chest radiographic findings; high clinical suspicion of sarcoidosis without typical imaging findings; and suspected complications of lung disease including bronchiectasis, aspergilloma, traction emphysema, infection, or malignancy.

Follow-up CTs have been used to look at the change with time in opacities identified on CT,^{86.88.118.132.142.144. and 147.} giving further insight into the nature of the underlying pathology. Results are not entirely consistent but in general show that nodules, consolidation, ground-glass opacity, and septal lines are potentially reversible (see Figs 11.17 and 11.20) while irregular coarse lines, cysts, honeycombing, traction bronchiectasis, and distortion are permanent. However, a considerable proportion of ‘potentially reversible’ opacities do not improve with treatment; for example 57% and 39% of nodules did not change in two follow-up studies,^{118. and 142.} and ground-glass abnormality and consolidation evolved to a fibrotic pattern on long-term follow-up in another study. ¹³²

Identification of the extent and predominant pattern of abnormality on CT may be helpful in predicting the degree of physiologic impairment. Patients with focal alveolar abnormality or masses tend to have little or no physiologic impairment, while those with profuse nodules or architectural distortion tend to be significantly impaired. ¹⁶¹ As mentioned above, patients with air-trapping on expiratory imaging will usually have a component of airflow obstruction. However, the overall level of correlation between extent of CT findings and physiologic abnormality is relatively weak.

Gallium-67 is commonly taken up in sarcoid lesions; therefore, gallium-67 scintigraphy was previously used to assist in diagnosis of sarcoid, and in determination of disease ‘activity’. Characteristic scintigraphic patterns include uptake in bilateral mediastinal nodes, producing the ‘lambda’ sign, and symmetric uptake in salivary and lacrimal glands, producing the ‘Panda’ sign. ²³¹ However, the technique is now rarely used because of lack of specificity of the pulmonary findings, ²³² and because of the greater sensitivity of [¹⁸ F]2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)-CT scanning for detection of organ involvement, particularly extrathoracic involvement.^{233. and 234.}

PET scans with FDG may show increased metabolism in affected lung parenchyma²³⁵ and nodes²³⁶ (Fig. 11.33). In a study of 137 patients, evaluated with FDG-PET for cardiac involvement by sarcoidosis (n = 88) or for other reasons, extracardiac uptake was identified in 139 of 188 scans performed. ²³⁷ Mediastinal nodal uptake was the most common abnormality, identified in 54, extrathoracic nodal uptake in 30, and lung uptake in 24. In 20 patients (15%), FDG-PET scan findings indicated the presence of abnormality that was not detected by physical examination, chest radiograph, or CT, including uptake in the lung, mediastinal lymph nodes, peripheral lymph nodes, skin, muscle, and bone. In these 20 patients, the PET scan findings led to a diagnostic biopsy at different sites in five patients. Pulmonary uptake was visible in four of 14 patients with radiographic stage I disease, in 16 of 22 patients with stage II or III disease, but, interestingly, in only three of 22 patients with fibrotic, stage IV disease. On repeat scanning, 11 steroid-treated patients showed decreased standardized uptake values (SUVs) in the affected areas, but the paper does not indicate how many patients were unchanged. These findings suggest that FDG-PET may occasionally have a role in identifying appropriate biopsy sites, or in determining whether patients with fibrotic abnormality have residual active disease. Other studies have shown that FDG-PET commonly identifies occult bony or soft tissue sites of sarcoidosis, ²³⁸ and can also identify cardiac involvement. ²³⁹ Sequential scans may be helpful in monitoring response to treatment, particularly in atypical, complex, and multisystemic disease. ²³³ Kaira et al. ⁷⁹⁸ studied 24 patients with sarcoidosis and suspected malignancy using fluorine-18-alpha-methyltyrosine (18-FMT) and found that the 18-FMT scans were always negative, allowing distinction from a control group of patients with lung cancer, in whom the 18-FMT scans were abnormal in 88%.

MRI of the lung or mediastinum does not have a role in evaluation of sarcoidosis. However, magnetic resonance (MR) with delayed hyperenhancement has a well-established role in the diagnosis of cardiac involvement by sarcoidosis. ²⁴⁰

The eosinophilic pneumonias are classified on the basis of their severity and chronicity (Table 11.1). ²⁴⁴ However, it should be noted that substantial overlap exists among these entities, and specific categorization may sometimes be difficult. ²⁴⁵ Simple eosinophilic pneumonia (SEP) (Löffler syndrome) has classically been distinguished from chronic eosinophilic pneumonia (CEP), on the basis of duration of symptoms. ²⁴² SEP is defined as lasting less than 1 month, while CEP lasts more than 1 month. The 1-month dividing line is rather arbitrary and not universally applied, so that the distinction between the two types is not always clear, and this is particularly true now that the natural history is commonly modified by steroids. Nevertheless the division is useful clinically, as the majority of chronic, cryptogenic eosinophilic pneumonias (CEP) form a relatively homogeneous group. The more recently recognized acute eosinophilic pneumonia (AEP)^{246. and 247.} differs from SEP in that patients are highly symptomatic and in respiratory failure.

Allergic bronchopulmonary mycosis is almost certainly the most common cause of eosinophilic lung disease in developed countries. Allergic bronchopulmonary aspergillosis (ABPA) accounted for 78% of the patients with a diagnosis of pulmonary eosinophilia in a series of 143 in the UK who were admitted to a tertiary referral center. ²⁸⁷ First described in 1952, ²⁸⁸ the disease is characterized by asthma, radiographic pulmonary opacities, blood eosinophilia, and evidence of allergy to antigens of Aspergillus species. Its importance lies in the fact that recurrent acute episodes cause progressive bronchial damage that can be controlled by steroid administration. ²⁸⁹

Though it may be due to a wide variety of organisms, Aspergillus species are by far the most common causative agent, resulting in ABPA. In more than 90% of patients, the species involved is Aspergillus fumigatus, but occasionally other species are implicated, including Aspergillus flavus, Aspergillus niger, Aspergillus nidulans, ²⁹⁰Aspergillus terreus, ²⁹¹Aspergillus oryzae, ²⁹² and Aspergillus ochraceus. ²⁹³ In addition there are isolated case reports of an ABPA-like syndrome caused by fungi other than Aspergillus spp., including Candida albicans, Curvularia (see Fig. 11.41 below) and at least seven other genera.^{294. and 295.} These conditions may be more difficult to diagnose because Aspergillus precipitins may be absent.

In ABPA, a hypersensitivity reaction develops to Aspergillus spp. that grow as a mycelial plug in proximal airways, usually the second or third order bronchi. ²⁹⁶ Tissue invasion is either absent²⁹⁰ or very limited. ²⁹⁷ The factors that favor the initial airway colonization by Aspergillus are unclear, ²⁹⁰ but in part are probably related to the almost universal presence of asthma and atopy in affected patients. Other important factors are the size of the spores (2.5–3.0 µm), which favors inhalation and airway deposition, and their thermotolerance, which allows hyphal growth at body temperatures.^{294. and 298.} Certainly, once the fungus gets a foothold, local damage will promote further colonization.

The immunology and pathogenesis of ABPA is complex. CD4+Th-2 lymphocyte activation is thought to be important in releasing mediators that increase eosinophil production, and stimulate B cells to produce IgE and IgG production. ²⁹⁹ Because antigen production is localized to the mycelial plug in the proximal airway, tissue damage tends to be greatest in this region, giving rise to granulomatous airway inflammation that results in the characteristic proximal bronchiectasis. In addition, however, there appears to be a separate pathologic process centered on the lung parenchyma, giving an eosinophilic pneumonia which does not produce permanent damage. ²⁹⁴

Typically, ABPA occurs in patients with atopy and longstanding asthma. A few patients, particularly older ones, develop asthma concurrently with their first attack of ABPA. ²⁸⁷ Although unusual, the disease is well-recognized in nonasthmatic patients.^{287. and 300.} Overall there is a slight female preponderance.^{287.301. and 302.} It may occur at any age,^{302.303. and 304.} but typically presents between 20 and 40 years of age. The entity is familial in about 5% of cases. ³⁰⁵ There is an association with several HLA alleles. ³⁰⁶ The length of the interval between the onset of asthma and ABPA is inversely related to the age of onset of asthma. McCarthy and co-workers³⁰⁷ found that with asthma beginning before 10 years of age, there was an average gap of 24 years, but with late-onset asthma (30 years of age or more), the mean gap was only 3.5 years. Late-onset asthma was associated with more frequent attacks of ABPA and greater lung damage. ³⁰⁷ ABPA also occurs in patients with cystic fibrosis in whom there is an approximately 10% prevalence. ²⁶⁶

In about 10% of patients, allergic bronchopulmonary mycosis may be associated with allergic fungal sinusitis. ³⁰⁸ This condition is characterized by accumulation of mucin in the sinuses, associated with polyposis in the sinuses and nose. It is associated with a wider range of organisms than allergic bronchopulmonary mycosis, including Curvularia and Bipolaris spp.^{309.310.311. and 312.} On imaging, it is characterized by mucosal thickening and hyperattenuating sinus contents, often associated with bony erosions.^{313. and 314.}

ABPA runs a relapsing and remitting course and an acute attack may be indistinguishable from an uncomplicated exacerbation of asthma. ²⁹⁴ Patterson et al. ³¹⁵ described five clinical stages of ABPA: acute, remission, exacerbation, steroid-dependent asthma, and fibrosis. These must not be regarded as phases of disease, as patients need not pass from one stage to the next in orderly progression. Characteristic symptoms in the acute stage are wheeze, dyspnea, and a cough that is often productive and associated with minor hemoptysis. Systemic symptoms such as fever, malaise, and weight loss are common. About 50% of patients have pleuritic pain, and about the same percentage give a history of coughing up sputum plugs. ²⁸⁷ These contain fungal mycelia and are important pointers to the diagnosis. ²⁸⁷ Plugs are about l–2 cm long, firm, friable, and pelletlike. ²⁸⁷ An abnormal chest radiograph, blood eosinophilia, and an immediate skin ‘wheal and flare’ reaction to Aspergillus antigens are characteristic of the acute phase. Eosinophilia is usually mild to moderate, with 74% of patients having counts between l × 10⁹/L and 3 × 10⁹/L. ²⁸⁷ The eosinophil level may be depressed by steroid treatment. Serum precipitins against Aspergillus antigens are detected in about 90% of patients in the acute phase, particularly if the serum is concentrated.^{287.294.301. and 316.} It must be remembered, however, that this test is nonspecific in that 12–25% of patients with extrinsic asthma will have a positive precipitin test. ³¹⁷ Both nonspecific and Aspergillus antigen-specific IgE are greatly raised, perhaps 20 times normal. ³¹⁶ Smaller elevations may be found in simple asthma. As with the finding of positive precipitins, elevation of IgE per se is not diagnostic of ABPA. Nevertheless the IgE level is probably the single most useful laboratory test in ABPA since levels correlate with disease activity and a normal level virtually excludes the diagnosis.^{266. and 316.} Criteria for the diagnosis of ABPA have changed over time as knowledge about the disease has become more sophisticated; yet even now there are no universally accepted diagnostic criteria. Rosenberg and co-workers³¹⁶ have set out the following major and minor criteria and suggest that if the first six of the major criteria are satisfied, the diagnosis of ABPA can be made with reasonable certainty. The major criteria for ABPA are:

The minor criteria for ABPA are:

ABPA can be present without bronchiectasis,^{266.318. and 319.} and ABPA without bronchiectasis appears to carry a better prognosis, with fewer exacerbations.^{320. and 321.} In one study, 11 of 31 patients with serologically diagnosed ABPA did not have bronchiectasis; ³²¹ these patients had less severe disease than those with bronchiectasis, and did not subsequently develop bronchiectasis on follow-up over 2 years. ³²² The prevalence of bronchiectasis may decrease with increasing use of serology to screen for ABPA: in a more recent study of 155 patients with ABPA, 37 (24%) had a normal findings on CT. ³²³

In a prospective study of 255 patients with asthma, Eaton et al. ³²⁴ found that 47 patients had positive skin prick tests for A. fumigatus, of whom 35 underwent CT. Central bronchiectasis was found on CT in 12 of these patients, eight of whom met all of the criteria for ABPA. These investigators found that performing CT in patients with skin prick positivity who had histories of sputum plugs, eczema, or steroid dependency would identify all cases of ABPA with bronchiectasis. These authors proposed the following minimal criteria for ABPA: asthma, skin prick test positivity, and central bronchiectasis.

A great variety of imaging changes are found in ABPA, and may be related to the phase of the disease.^{301.302.304.307.325.326. and 327.} The imaging findings are best considered as acute and transient or chronic and permanent (Table 11.2). ³⁰⁷

The transient changes are listed in Table 11.2. Consolidation ranges from patchy subsegmental or smaller opacities (Fig. 11.40) to complete lobar or multisegmental opacity (Fig. 11.41). Areas of consolidation show little if any zonal predilection and are often multiple. The segmental configuration contrasts with the nonsegmental consolidation seen in other eosinophilic states. The pathologic basis of the consolidation is unclear: it might be related to airway obstruction or eosinophilia. Although consolidation is usually transient, it can last for 6 weeks or more. Phelan and Kerr³⁰² described some patients with apparently permanent consolidation, perhaps due to endobronchial obstruction. When consolidation clears, it often leaves residual bronchiectasis (Fig. 11.41). Consolidation may recur in 25–50% of cases, often in the same area. Radiographic consolidation may be asymptomatic in 20–30% of patients,289. ^{and 304.} and ABPA is one of those conditions in which gross radiographic changes may be accompanied by little in the way of symptoms. ³⁰⁷

The most common transient change is mucoid impaction (bronchocele). In this condition, an airway becomes obstructed and distended by retained secretions, but the subtended lung remains aerated by collateral air drift, allowing direct visualization of the impacted airway. Mucoid impaction is characterized by a sharply demarcated, bandlike opacity, sometimes branching (Fig. 11.42), which points to the hilum, usually about 2–3 cm long and some 5–8 mm wide. Rounded opacities are produced by linear bronchoceles seen end-on. Impacted airways are usually proximal. They are often inseparable from the hilum and may simulate lymphadenopathy³²⁷ or a mass. Another variant is produced by distal bronchiectatic airways which, when impacted, give a band shadow with a club-shaped end – the ‘gloved finger shadow’. Bronchoceles show a strong upper zone predilection (Figs 11.42 and 11.43). ³⁰⁴ They disappear once their contents have been coughed up, leaving dilated bronchi, manifested as ring or parallel line opacities (Fig. 11.43). Like consolidation in ABPA plugging may recur at the same site. Occasionally they persist for many months. On CT, the bronchoceles are seen as bandlike abnormalities in the expected position of the bronchi (Fig. 11.42). Their attenuation may be similar to that of water or soft tissue, or they may be hyperattenuating (Figs 11.41 and 11.42). ³²⁸ The hyperattenuation is presumed to be due to calcium³²⁹ or metallic ions within chronically inspissated mucus, and is found in 20–30% of cases.^{330. and 323.} Relapse of ABPA occurred in 23% of one series of 155 patients, and was more common in those with more severe bronchiectasis or with hyperattenuating mucus. ³²³ Another major transient manifestation of ABPA is atelectasis (Fig. 11.44), which ranges in frequency from 3%³⁰⁴ to 46%. ²⁹⁶ It may be subsegmental, segmental, lobar, or even affect a whole lung.^{302.326. and 331.} Like consolidation and mucoid impaction, collapse has a tendency to recur in the same area. On CT, mucus plugs may be seen within the areas of atelectasis if they are hyperattenuating or of water attenuation. There have been a few reports of pleural effusion.^{304. and 332.}

Permanent changes (Table 11.2) are of importance because, first, they indicate irreversible lung damage and, second, they may be the only clue that an asthmatic patient has ABPA when a patient is in remission. Bronchiectasis is responsible for most of the permanent radiographic changes. The characteristic finding (Box 11.9) is proximal bronchiectasis, usually affecting first and second order subsegmental bronchi (Figs 11.45 and 11.46). Beyond the proximal bronchiectasis, more distal airways remain normal and patent, though a tree-in-bud pattern of abnormality is common on CT. Proximal bronchiectasis has been considered highly specific for ABPA³¹⁶ and in a selected patient population of asthmatic patients, with skin tests positive for A. fumigatus, this is probably so. ³³³ However, central bronchiectasis may also be found in other conditions such as cartilage deficiency syndromes, primary ciliary dyskinesia, and idiopathic bronchiectasis. ³³⁴

Several papers have compared the CT features of ABPA with those of uncomplicated asthma.335.^{336. and 337.} The prevalence of bronchial dilatation in patients with severe or chronic asthma ranges from 17% to 30%, compared with 90% or more in ABPA.^{335. and 336.} However, the bronchial dilatation in asthma is usually mild, cylindric, and distal, in contrast to the more severe proximal varicose or cystic bronchiectasis of ABPA. ³³⁵ Other distinguishing features on CT include a higher prevalence of centrilobular nodules and mucoid impaction in ABPA.^{335. and 336.} The presence of bronchiectasis in three or more lobes is suggestive of ABPA. ³³⁶

Parenchymal scarring representing the fibrotic stage of ABPA commonly follows bronchiectasis, and is manifest by linear abnormality and lobar shrinkage (Figs 11.46 and 11.47). Mirroring the distribution of bronchiectasis, these features have a strong upper zone predilection, with 78% being so distributed in one series. ³⁰⁷ Such lobar shrinkage is accompanied by a variety of ring and linear opacities. Lower lobe shrinkage, though described, is very unusual. ³⁰² Although there is often chronic lobar shrinkage, the overall lung volume is frequently increased, reflecting airflow limitation, emphysema, and bulla formation. Between 30% and 40% of patients in one series showed overinflation. ³⁰² Pleural thickening is not a major feature, having a prevalence of 18% in the same series, though pleural thickening was seen on CT in 14 of 17 cases of ABPA in one series. ³³³

Mycetomas may form in the bronchiectatic cavities. In one series of 111 patients with ABPA, eight had mycetomas, predominantly mid-zonal. ³⁰⁷ Since mid-zone mycetomas are unusual in other conditions, it has been suggested that a mycetoma found in this position should raise the possibility of underlying ABPA. ³⁰⁷ It is of interest that an ABPA-type syndrome has been recorded as developing as a result of a mycetoma lodged in a tuberculous cavity. ³³⁸

A large number of drugs has been recorded as producing pulmonary opacities as part of a hypersensitivity response together with blood eosinophilia (see p 509). Patients generally develop symptoms within days or a few weeks of starting the drug and some develop an associated rash and pyrexia, which provide helpful clues as to the nature of the imaging opacity. A variety of chest radiographic patterns are produced:

A distinctive syndrome was described in association with l-tryptophan ingestion (l-tryptophan eosinophilia myalgia syndrome). Principal features include peripheral eosinophilia, myopathy, peripheral neuropathy, eosinophilic fasciitis, and respiratory disorder. This latter is characterized on imaging by bilateral, often basally predominant, opacity with mixed alveolar and interstitial features, and pleural effusions.^{346. and 347.} Pathologically there is chronic interstitial pneumonitis, tissue eosinophilia, and vasculitis. ³⁴⁶

This is a specific systemic disease caused by hypersensitivity to microfilariae – the early larval forms of various filarial nematodes, the most important being Brugia malayi and Wuchereria bancrofti.^{348. and 349.} Transmission is by mosquito. Tropical pulmonary eosinophilia (TPE) is found in all parts of the world where filariasis is endemic, particularly the Indian subcontinent, South East Asia, the South Pacific, North Africa, and South America. It occurs chiefly in the indigenous residents (particularly in the Indian subcontinent),^{350. and 351.} and is very uncommon in visitors unless they have resided in the area for many months. ³⁵² In nonendemic areas the disease is seen in immigrants and, because of persistence of the parasite in the host, may present as long as 3 years after returning from an endemic area. ³⁵³ Occurrence is extremely rare in Caucasians. ³⁵⁴

The disease is more common in males, in some series by as much as 4 : l, ³⁵⁵ but this is not a universal finding. ³⁵⁴ The usual age at presentation is between 5 and 40 years, ³⁵⁵ though the range can be larger; in one series of 350 it varied from l.5 to 74 years. ³⁵¹ The principal features of the illness are a systemic disturbance marked by fatigue, weight loss, and low-grade fever together with chronic cough, which is particularly troublesome at night. Even without treatment, symptoms tend to remit after several weeks or months only to recur later. ³⁵² Patients who have not had treatment or who have responded inadequately may go on to develop progressive dyspnea secondary to interstitial fibrosis. ³⁴⁹ There is a gross eosinophilia of more than 3 × 10⁹/L, characteristically between 5 × 10⁹/L and 60 × 10⁹/L, IgE levels are greatly elevated, usually more than 1000 units/mL, and there is a high titer of antifilarial antibody. BAL shows a high percentage of eosinophils, in the order of 50%.

Imaging findings in the chest^{351.354.356. and 357.} may be caused by active alveolitis and/or interstitial scarring. The chest radiograph has a normal appearance in 2–13% of cases. The most common abnormalities, seen in 30–60% of patients, are fine linear opacities distributed diffusely and symmetrically, accompanied by hilar haziness, and an accentuation or blurring of vessels. Some authors³⁵⁴ describe a basal preponderance, and others stress a diffuse ground-glass type of pattern. ³⁵¹ Small nodules are a slightly less common finding, seen in about 30–50% of patients. The nodules range in size from l mm to 5 mm and may occur alone or with the linear opacities described above. ³⁵⁴ Though generally bilateral and symmetric, nodules may be asymmetric or even unilateral. Other patterns are much less common and consist of areas of consolidation that are generally small and single. In a study of 10 patients with tropical pulmonary eosinophilia, ³⁵⁸ CT showed reticulonodular abnormality, bronchiectasis, and air-trapping, but the extent of CT abnormalities did not correlate with physiologic impairment.

Tropical pulmonary eosinophilia characteristically responds rapidly to diethylcarbamazine therapy and this is an important diagnostic criterion. However, 5% of patients, even early on in the natural history of the disease, fail to respond adequately and this figure rises to 20–40% in patients who have had longstanding symptoms. ³⁴⁹ A 5-year follow-up of a large series of patients showed a 20% relapse rate³⁴⁹ and a significant number of patients develop chronic, progressive dyspnea on the basis of interstitial fibrosis.

This uncommon form of pulmonary granulomatosis, first described by Liebow in 1973, ³⁶⁸ differs from other lung granulomatoses, such as Wegener granulomatosis, in that it is localized to the lung, and centered around airways (bronchocentric) rather than vessels (angiocentric). Pathologically, small airways and bronchioles are filled and replaced by cellular debris and necrotic granulomas surrounded by palisaded epithelioid cells. At least 30% of cases are related to asthma, and in these individuals is probably part of the spectrum of ABPA.^{369. and 370.} In asthmatic people, the major part of the cellular infiltrate is made up of eosinophils, whereas in nonasthmatic people the plasma cell is dominant. ³⁷¹ Large airways may show bronchocele formation, and distal lung is often consolidated by an eosinophilic or obstructive pneumonitis. Vasculitic changes appear to be minor and incidental.

Only four series of patients with bronchocentric granulomatosis have been recorded,^{371.372.373. and 374.} representing a total of 60 cases. However, there have been many additional case reports. Patients commonly present in their forties, but there is a wide age range (9–76 years) and a tendency for asthmatic patients to present at a younger age (mean age 22 years) than nonasthmatic patients (mean age 50 years). ³⁷¹ The incidence in both sexes is equal. Symptoms may be absent or minor and, when present, consist of fever, cough, chest pain, wheeze, and hemoptysis. About 50% of patients have had a blood eosinophilia, a finding that appears to be limited to asthmatic people.^{371. and 373.}

On imaging,^{371.372.373. and 375.} two major patterns are seen: consolidation and masslike lesions. Consolidation may be lobar or sublobar and may be accompanied by volume loss (Fig. 11.51). They are thought to represent either eosinophilic or obstructive pneumonitis. ³⁷¹ They tend to be more common in the upper zones,^{371. and 375.} and are unilateral in about 75% of patients. Sublobar consolidation was the commonest finding (16 out of 22) in one large series. ³⁷¹ Masslike lesions (Fig. 11.52) are commonly solitary, but can be multiple. They are considered to represent a mass of necrotic tissue with surrounding granulomatous or organizing pneumonia. They vary in size from 2 cm to 15 cm, ³⁷⁶ and are often not particularly well defined. They may be centered on an airway. Occasionally they cavitate.^{371.376. and 377.} Less common imaging patterns include mucoid impaction^{368.371.377. and 378.} and reticulonodular opacities. ³⁷⁷ On some occasions the reticulonodular abnormality has evolved from antecedent consolidation. Adenopathy and pleural disease are not features. ³⁷⁷ In a study of five patients with bronchocentric granulomatosis, ³⁷⁴ CT showed spiculated mass lesions in three cases and consolidation in two. Extensive mucoid impaction was seen in two patients. The imaging findings were felt to be due to granuloma formation with or without proximal airway obstruction.

Prognosis is good. Lesions may clear spontaneously or with steroids and generally do not recur following surgical removal. If this should happen, recurrences can usually be controlled with steroid treatment.

Hypereosinophilic syndrome is an uncommon heterogeneous group of disorders in which the eosinophilia may be neoplastic (such as an eosinophilic leukemia) or reactive, and in the latter instance some appear to be truly idiopathic in that a cause is not established even at death. ³⁷⁹ It is characterized by: (1) prolonged and marked eosinophilia (a blood count of more than 1.5 × 10⁹/L for more than 6 months); (2) no recognizable cause for the eosinophilia such as parasitic infestation or allergy; and (3) signs or symptoms of organ dysfunction (Box 11.11). ³⁸⁰ The sustained hypereosinophilia causes tissue damage, particularly cardiac, and this is a key element to the syndrome. The illness varies in severity from mild to fatal, involving in particular the cardiovascular and nervous systems. The cardiac abnormality consists primarily of endocardial thickening and fibrosis related to widespread tissue infiltration with mature eosinophils, ³⁸¹ leading to endocardial fibrosis, restrictive cardiomyopathy, and thrombosis. Several subtypes of hypereosinophilic syndrome have been described, including myeloproliferative, lymphocytic, and familial variants. ³⁸² A significant recent advance in understanding of this condition has been the recognition of FIP1L1-platelet-derived growth factor receptor-α fusion protein in up to 50% of individuals with this syndrome, and the recognition that these individuals may respond to treatment with the protein kinase inhibitor imatinib.^{245. and 382.} Other forms of this condition may respond to treatment with mepolizumab. ³⁸³

Almost all patients have been men, typically young or middle-aged adults who present with progressive cardiopulmonary symptoms, skin rash, or myalgia, together with systemic symptoms such as weight loss, weakness, fatigue, and fever. The peripheral blood shows a marked eosinophilia, often in the order of 30–70% of the total white blood cell count (10–50 × 10⁹/L), some of the eosinophils being degranulated and vacuolated. Some patients have a mild increase in IgE. The organ systems most commonly affected are the nervous and cardiovascular systems and the skin. Cardiovascular involvement is usually the dominant feature and is a major cause of morbidity, with signs of restrictive cardiomyopathy and pump failure, mitral and tricuspid regurgitation, and endocardial thrombosis. The last leads to systemic emboli in about 5% of patients³⁸⁴ or pulmonary emboli if the thrombus is right sided. ³⁸¹

Clinical pulmonary involvement has been recorded in about 40% of patients.^{380. and 381.} In most, these are findings related to heart failure, ³⁸⁵ and include pulmonary edema (Fig. 11.53) and pleural effusions. ³⁸⁰ Because the cardiomyopathy is restrictive in type, any accompanying cardiomegaly is often mild. ³⁸⁴ Pulmonary emboli were recorded in 9% of 57 patients reviewed from the literature. ³⁸⁰ Other less common pulmonary manifestations include transient consolidations, which are presumably eosinophilic pneumonias and diffuse interstitial fibrosis.^{380. and 384.} HRCT findings in five patients in whom chest radiographs were normal (3/5) or showed nonspecific focal opacities (2/5) consisted of scattered nodules (about 2–10 mm) with ground-glass halos (5/5) and focal areas of ground-glass attenuation (3/5) (Fig. 11.53). There was no pathologic correlation, but the authors considered that the lesions probably represented areas of eosinophilic infiltration. ³⁸⁶ In three patients studied by Johkoh et al., ²⁶² the common imaging features were ground-glass attenuation and nodules, with septal thickening and thickening of bronchovascular bundles. The challenge in these cases is to distinguish findings due to heart failure from those due to pulmonary involvement.

Before the use of steroids, cytotoxic drugs, and monoclonal antibodies, the prognosis of hypereosinophilic syndrome was poor, with a 25% 2-year survival rate, ³⁸⁰ but this figure has now improved considerably, and the 3-year mortality has reduced to 4%.^{383. and 387.}

There is often a mild to moderate eosinophilia in patients with asthma. ³⁸⁸ The radiology of asthma is discussed elsewhere (p 752). In addition, asthma is often a prominent symptom in a number of specific eosinophilic lung states such as ABPA and the Churg–Strauss syndrome. Other pulmonary conditions associated with blood eosinophilia, and often with tissue eosinophilia, are listed in Box 11.12. The degree of eosinophilia in these conditions is generally relatively slight (less than 1 × 10⁹/L). Box 11.12 emphasizes the importance of considering infection and neoplasm (Fig. 11.54) in patients presenting with eosinophilia and pulmonary parenchymal abnormalities.