Aetiology

Aetiologically, pulmonary eosinophilia may be classified as cryptogenic or of known cause, the latter including allergy to fungi, parasites or drugs (Box 9.1).

Allergic aspergillosis is a common cause of pulmonary eosinophilia in the UK whereas infestation by metazoan parasites is commoner in communities in which these parasites are prevalent (Box 9.2). In some parts of the world filariasis is the cause: this is tropical pulmonary eosinophilia, which can be readily diagnosed from the patient’s history of residence in the tropics, by the presence of extraordinarily high levels of both serum IgE and antifilarial antibodies, and by the dramatic therapeutic response to filaricides.^3–5 Pulmonary eosinophilia is also caused by a number of drugs, notably nitrofurantoin but occasionally sulphonamides and aspirin, amongst others (Box 9.3). Pulmonary eosinophilia may also be a manifestation of rheumatoid disaease.⁶

In other patients the cause of the pulmonary eosinophilia is not recognised: such cases are categorised as suffering from cryptogenic pulmonary eosinophilia.⁷ A majority of these patients are atopic, giving a history of rhinitis or asthma.⁸ There is a high level of activated helper T lymphocytes in their bronchoalveolar lavage fluid.⁹ They also show a transient increase in circulating immune complexes.¹⁰ The Churg–Strauss syndrome of allergic angiitis and granulomatosis may be regarded as a subset of cryptogenic pulmonary eosinophilia but the hypereosinophilic syndrome is quite distinct from all these reactive forms of eosinophilia and probably represents a leukoproliferative disorder.

Pathogenesis

The eosinophil leukocyte is central to the pathogenesis of all the diseases in this chapter. Eosinophil leukocytes are produced in the bone marrow under the control of cytokines secreted by type 2 helper lymphocytes, notably interleukin-5. Once released into the blood they normally remain there for 12–18 hours, maintaining a count of 50–250/µl. An absolute count is more meaningful than the percentage in a differential white blood cell count. They enter the tissues under the influence of chemotactic agents known as eotaxins,¹¹ of which three are now recognised. These agents are small proteins produced by a variety of cells, which in the lung include bronchial epithelial cells, smooth-muscle cells and fibroblasts, acting under the influence of interleukins derived from type 2 helper lymphocytes and mast cells (see Fig. 3.30, p. 115).^11–13

Tissue eosinophilia does not necessarily correlate with blood eosinophilia even though the two usually go together: blood counts may dip as eosinophils flood the lung and then rise as the infiltrate resolves due to a lag in bone marrow response. Sputum and bronchoalveolar lavage counts reflect lung tissue eosinophilia better than blood counts but, like neutrophils, eosinophils appear to be washed out of the lung more easily than macrophages so that raised lavage counts are encountered in diseases such as idiopathic pulmonary fibrosis that are seldom characterised by any appreciable degree of tissue eosinophilia. Bronchoalveolar lavage eosinophils are usually expressed as a percentage of total cells recovered from the lungs, the normal being less than 3%. Eosinophils in sputum are generally expressed only in broad qualitative terms (e.g. ‘small, moderate or large numbers’). When there is eosinophilic pneumonia, eosinophils are the predominant cell in both sputum and bronchoalveolar lavage fluid. They are represented at levels greatly in excess of those found in diseases such as idiopathic pulmonary fibrosis.

Biopsy is the only way to establish tissue eosinophilia with certainty but in practice a tissue diagnosis is often inferred from the clinical features coupled with sputum, blood and bronchoalveolar lavage findings. If a tissue diagnosis is deemed essential a transbronchial biopsy will generally suffice because most of the conditions causing pulmonary eosinophilia affect sufficiently large areas of the lung to be targeted successfully by the bronchoscopist. However, some forms of tissue eosinophilia are characterised by an associated vasculitis and it is unlikely that a transbronchial biopsy will identify this. Vasculitis is more likely to be revealed by thoracoscopic biopsy. Alternatively, it may be identified in more accessible tissue, such as skin or muscle.

Once in the tissues, eosinophils secrete a number of products, some of which counter the action of substances secreted by mast cells. Histaminase and aryl sulphatase, for example, respectively destroy histamine and the leukotriene complex formerly known as slow-reacting substance of anaphylaxis. Eosinophils also phagocytose immune complexes and mast cell granules, and tend to dampen reaginic hypersensitivity reactions. However, they also secrete substances such as reactive oxygen radicals, major basic protein and eosinophil cationic protein which, whilst helping to eliminate parasites, are also toxic to host cells (Fig. 9.1).^14–17 These eosinophil products are thought to be responsible for much of the tissue damage in the eosinophilic disorders about to be described. Activation of the cells involved in cryptogenic eosinophilic pneumonia is suggested by the demonstration that they express intercellular adhesion molecules, probably under the influence of the activated T lymphocytes referred to above.¹⁸ Electron microscopy shows that released eosinophil granules are closely associated with degenerate and necrotic alveolar tissue.¹⁹

Figure 9.1 Electron micrograph of an eosinophil. A bilobed nucleus is surrounded by granules, many of which have a bar-shaped electron-dense core. The granule core consists of a basic protein whilst the surrounding matrix contains cationic protein, both of which are highly toxic.¹⁴

(Courtesy of Miss A Dewar, Brompton, UK.)

Corticosteroids act on eosinophils in a variety of ways.²⁰ They cause rapid eosinophil sequestration in peripheral blood vessels and inhibit their production in the bone marrow. They also reduce eosinophil survival by blocking lymphokines that inhibit eosinophil apoptosis. Eosinophil adherence and chemotaxis are also diminished by corticosteroids. In view of these many actions it is not surprising that corticosteroids are effective in treating many diseases characterised by eosinophilia.

Simple pulmonary eosinophilia

The Swiss physician Löffler described two conditions that were characterised by blood eosinophilia. One is the hypereosinophilic syndrome, which is dealt with below. The other is one that later came to be known as simple pulmonary eosinophilia.²¹ Rarely a patient may display features of both conditions.²² The term ‘Löffler’s syndrome’ is confusingly applied to both and therefore best avoided.

Simple pulmonary eosinophilia is characterised by migratory pulmonary opacities accompanied by blood eosinophilia and minimal or no pulmonary symptoms. Ascariasis was prevalent in Switzerland in Löffler’s day and was probably the cause of the eosinophilia in his cases. Drug reactions are a more important cause today but many cases are unexplained. Löffler emphasised the benign transient nature of the condition. Corticosteroids are highly effective but are rarely required because the condition is usually self-limiting. However, an underlying cause such as parasitic infestation should always be considered. The lung is seldom biopsied but it may be presumed to show changes similar to those seen in chronic eosinophilic pneumonia.

Chronic eosinophilic pneumonia

Chronic eosinophilic pneumonia is a serious condition which generally requires treatment with corticosteroids.^8,20,23–26 These usually prove efficacious but may have to be continued for many months, or even indefinitely, to prevent relapse. The disease is occasionally life-threatening. The peak incidence is in the fifth decade and females preponderate 2:1. There is often a history of atopic illnesses such as rhinitis or asthma and the condition is regarded as having an allergic basis. Any of the aetiological agents outlined above may be responsible, drugs, fungi or parasites, or the cause may not be identified.

Clinical features

The onset is insidious, with gradually worsening cough, dyspnoea, fever and weight loss. There is blood and sputum eosinophilia. However, blood and tissue eosinophil levels are not always elevated contemporaneously, the raised blood counts often having abated whilst eosinophils are still evident in the lung tissue. Bronchoalveolar lavage cell counts correlate better with the tissue findings, eosinophils being the predominant cell in lavage fluid from an involved segment.¹³ The chest radiograph is distinctive, showing bilateral opacification that is peripheral and apical.²⁷ It has been likened to the plume of a volcano or the photographic negative of the perihilar shadowing of pulmonary oedema. This is mirrored by subpleural consolidation on high-resolution computed tomography.

Pathology

In the occasional case that comes to autopsy the lungs are found to be heavy and firm with irregular areas of pale consolidation (Fig. 9.2). Microscopically, eosinophils fill the alveoli and infiltrate the interstitium (Fig. 9.3).^8,23,28 The alveoli also contain a variable number of macrophages, some of which may be multinucleate (Fig. 9.4). The macrophages may outnumber the eosinophils to mimic the appearances of desquamative interstitial pneumonia (Fig. 9.5). Focal collections of eosinophils may undergo necrosis to form so-called eosinophil abscesses, which are sometimes attended by foreign-body-type giant cells engulfing eosinophilic debris (Fig. 9.6).⁸ Sparse sarcoid-like granulomas are occasionally seen, and in rare cases are unduly prominent.²⁹ The eosinophil infiltrate may involve small blood vessels but necrotising vasculitis is not encountered: its presence would suggest Churg–Strauss allergic granulomatosis, which is dealt with below. Knowledge of treatment is important as eosinophils diminish with corticosteroid administration. Healing, whether occurring spontaneously or in response to such treatment, usually results in complete resolution but may be by repair, this resulting in alveolar fibrosis that is indistinguishable from any other organising pneumonia.^10,30

Figure 9.2 Fatal cryptogenic eosinophilic pneumonia. Confluent areas of consolidation represent alveoli filled with eosinophils.

Figure 9.3 Eosinophilic pneumonia. The alveoli contain many eosinophil polymorphonuclear leukocytes.

Figure 9.4 Eosinophilic pneumonia in which the alveoli are filled by both eosinophils and macrophages.

(Courtesy of Dr T Jelihovsky, Sydney, Australia.)

Figure 9.5 Eosinophilic pneumonia. There is moderate eosinophil exudation but these cells are outnumbered by alveolar macrophages.

Figure 9.6 An eosinophilic ‘abscess’ consisting of agglutinated necrotic eosinophils attended by a giant cell granulomatous reaction.

Differential diagnosis

The location of the eosinophils in air spaces as well as in the interstitium helps to distinguish eosinophilic pneumonia from eosinophilic granuloma (Langerhans cell histiocytosis), as do the presence of eosinophils in the blood, sputum and bronchoalveolar lavage fluid and a lack of Langerhans cells aggregation. Pneumothorax may provoke a reactive eosinophilic infiltrate but this is limited to the alveoli immediately beneath the pleura.

Acute eosinophilic pneumonia

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