18.14.2 Eosinophilic pneumonia 4238 S.J. Bourke an

18.14.2 Eosinophilic pneumonia 4238 S.J. Bourke and G.P. Spickett

section 18  Respiratory disorders 4238 FURTHER READING Casian A, Jayne D (2011). Plasma exchange in the treatment of Wegener’s granulomatosis, microscopic polyangiitis, Churg–​ Strauss syndrome and renal limited vasculitis. Curr Opinion Rheumatol, 23, 12–​17. De Groot K, et  al. (2009). Pulse versus daily oral cyclophospha- mide for induction of remission in antineutrophil cytoplasmic antibody-​associated vasculitis: a randomized trial. Ann Int Med, 150, 670–​80. De Prost N, et al. (2012). Diffuse alveolar haemorrhage in immuno- competent patients: aetiologies and prognosis revisited. Resp Med, 106, 1021–​32. Ioachimescu OC, Sieber S, Kotch A (2004). Idiopathic pulmonary haemosiderosis revisited. Eur Respir J, 24, 162–​70. Keogh KA, et  al. (2006). Rituximab for refractory Wegener’s granulomatosis. Am J Respir Crit Care Med, 173, 180–​7. Kim D, et al. (2017). Clinical characteristics and outcomes of diffuse alveolar hemorrhage in patients with systemic lupus erythematosus. Semin Arthritis Rheum, 46, 782–7. Lazor R (2011). Alveolar haemorrhage syndromes. Eur Respir Mon, 54, 15–​31. Pedchenko V, et  al. (2010). Molecular architecture of the Goodpasture autoantigen in anti-​GBM nephritis. N Engl J Med, 363, 343–​54. Puchecco A, et  al. (1991). Long-​term clinical follow-​up of adult idiopathic pulmonary hemosiderosis and celiac disease. Chest, 99, 1525–​6. Saeed MM, et al. (1999). Prognosis in pediatric idiopathic pulmonary hemosiderosis. Chest, 116, 721–​5. 18.14.2  Eosinophilic pneumonia S. J. Bourke and G.P. Spickett ESSENTIALS Eosinophilic pneumonia is characterized by eosinophilic inflam- mation of the alveoli, usually with an accompanying eosinophilia of peripheral blood. The diagnosis should be considered when in- filtrates on a chest radiograph are associated with blood eosino- philia, and is confirmed by demonstrating an excess of eosinophils in bronchoalveolar lavage fluid. Aetiology—​before concluding that the cause is ‘idiopathic’, the fol- lowing must be considered: (1) parasitic infestation with blood-​borne parasites such as (in tropical eosinophilia) filarial worms; (2) adverse drug reaction; (3)  asthma; (4)  allergic bronchopulmonary mycosis; (5)  vasculitis, notably eosinophilic granulomatosis with polyangiitis (previously known as Churg–​Strauss syndrome); (6) hypereosinophilic syndrome, a rare haematological disorder; and (7)  other disorders known to be associated with eosinophilic pneumonia. Management—​causal factors need to be treated, but eosino- philic pneumonia otherwise often responds well to corticosteroid medication. Introduction Eosinophilic pneumonia is characterized by eosinophilic inflam- mation of the lung, usually in association with peripheral blood eo- sinophilia (>0.45 × 109/​litre) such that the presentation is often as pulmonary infiltrates on the chest radiograph with blood eosino- philia (PIE syndrome). Several descriptive terms are used to classify the diverse range of clinical syndromes, but there are often overlapping features (Table 18.14.2.1). The initial focus is on identifying any provoking factors and excluding other diseases. Particular attention should be paid as to whether the patient been in areas where parasitic dis- eases are endemic, has pre-​existing asthma or atopy, has recently started medications, has contact with pets, or has features of sys- temic disease or vasculitis. Important aspects of eosinophilic pneu- monia to consider are: • It may arise acutely and resolve quickly over a matter of days—​ acute eosinophilic pneumonia, Löffler’s syndrome, simple pul- monary eosinophilia. • It may arise gradually and persist for many months, leading some- times to pulmonary fibrosis or fixed airway obstruction—​chronic eosinophilic pneumonia. • It may be a consequence of allergy, particularly to blood-​borne parasites (tropical eosinophilia), inhaled moulds (allergic bronchopulmonary mycosis), or other common environmental allergens. • It is often due to drugs, including prescribed medications, over-​ the-​counter medications, and illicit substances. • It is often associated with asthma—​asthmatic eosinophilia. • It may be associated with pulmonary vasculitis—​ eosinophilic granulomatosis with polyangiitis. • It may be a component of the hypereosinophilic syndrome. • It may seem to be idiopathic. Since there is often overlap, there is limited benefit from using any classification system; the important issue is to identify potentially remediable causes, and to exclude infection or other causes before starting treatment with corticosteroids. Diagnosis In practice the finding of blood eosinophilia in association with pulmonary infiltrates on a chest radiograph provides a valuable Table 18.14.2.1  The spectrum of eosinophilic pneumonia Simple pulmonary eosinophilia Chronic eosinophilic pneumonia Acute eosinophilic pneumonia (Löffler’s syndrome) Drug-​induced pulmonary eosinophilia Tropical/​parasite-​induced eosinophilic pneumonia Allergic bronchopulmonary aspergillosis Eosinophilic granulomatosis with polyangiitis Hypereosinophilic syndrome Eosinophilic pneumonia encompasses a spectrum of conditions characterized by eosinophilic inflammation of the lung, often with blood eosinophilia. There are diverse provoking factors resulting in a confusing range of overlapping conditions.

18.14.2  Eosinophilic pneumonia 4239 clue that pneumonia of infectious origin may not be the diag- nosis. Once suspected, eosinophilic pneumonia is most conveni- ently confirmed by demonstrating an excess of eosinophils in bronchoalveolar lavage fluid in the absence of pathogenic micro- organisms. Sometimes sputum alone is sufficient, whether ex- pectorated spontaneously or induced. Alternatively, an excess of alveolar eosinophils is revealed in lung biopsy tissue. Not surpris- ingly, the use of CT scanning in subjects with confirmed eosino- philic pneumonia has shown that episodes of recurrent pulmonary infiltration occur more frequently than can be detected from plain chest radiographs. As different segments of lung become involved the infiltrates may characteristically ‘migrate’ from one to another. Once eosinophilic pneumonia is confirmed, a variety of possible causes should be considered before it is assumed to be idiopathic in origin and before empirical treatment with corticosteroids is admin- istered. Look for evidence of: • parasitic infestation • administration of drugs • inhaled tobacco smoke, cocaine, marijuana • asthma • allergic bronchopulmonary mycosis (particularly aspergillosis) • other manifestations of vasculitis • other manifestations of the hypereosinophilic syndrome • other disorders known to be associated with eosinophilic pneumonia Treatment Eosinophilic pneumonia is a very distinct type of interstitial lung disease in that the lung architecture is usually preserved such that there is often a complete response to treatment with corticoster- oids without any permanent lung damage. Treatment may need to be prolonged (6 months or more) in the chronic forms of the dis- order. The importance of identifying whether it is associated with the aforementioned causal factors listed lies with the additional need to treat these also, otherwise eosinophilic pneumonia may not re- spond adequately to steroid therapy and the associated diseases may produce other manifestations. Particular forms of eosinophilic pneumonia Acute eosinophilic pneumonia (Löffler’s syndrome, simple pulmonary eosinophilia) The essential features are transitory migratory pulmonary shadows associated with modest peripheral eosinophilia in patients with a mild self-​limiting illness. Some cases are asymptomatic and dis- covered incidentally. Most patients present with cough, sometimes with oddly yellowish sputum containing an abundance of eosino- phils, and a few have general malaise and a mild fever. The pul- monary shadows reflect fan-​shaped areas of consolidation, often peripheral and sometimes rather nodular, which last a few days only and appear haphazardly in various lobes, seldom following a truly segmental pattern. In some cases they are single and in others they are multiple. The peripheral eosinophilia is obvious but rarely gross; a differential of more than 20% in a modestly raised total white cell count is unusual and more often the absolute eosinophil count ranges between 1 × 109 and 2 × 109/​litre (normal <0.45 × 109/​litre). Patients are often atopic and may have other manifestations of an atopic diathesis, such as asthma, urticaria, and angio-​oedema. Allergic reactions to parasites or drugs are the best recognized forms, but sometimes no provoking factor is identified. Eosinophilic pneumonia may be an allergic reaction to blood-​borne parasites migrating through the lung, particularly larvae of Ascaris lumbri- coides and (occasionally) A.  suum. Ancylostoma, strongyloides, taenia, trichinella, and trichuris may also cause eosinophilic pneu- monia. Drugs form the second major aetiological group. Löffler’s syndrome is described after administration of aspirin, amiodarone, angiotensin converting enzyme inhibitors, β-​blockers, metho- trexate, nitrofurantoin, imipramine, penicillin, p-​aminosalicylic acid, sulphonamides, toxic smoke, and lymphangiography contrast medium. Successful management requires the eradication of any parasites or the cessation of relevant medication, as well as the administration (if necessary) of oral corticosteroids. Tropical eosinophilia Eosinophilic pneumonia in tropical climates is often a consequence of migrating larvae of the filarial worms Wuchereria bancrofti and Brugia malayi. The effects are fundamentally similar to those of Löffler’s syndrome, but tend to be more persistent and more ser- ious, are more often associated with asthma, and may be associated with systemic symptoms of weight loss, persistent fever, and lymph- adenopathy. The peripheral eosinophil count tends to be greater than in Löffler’s syndrome (>3 × 109/​litre), and the total serum IgE level is markedly elevated. With chronicity, pulmonary fibrosis may develop. A cure is to be expected with antifilariasis medication (e.g. diethylcarbamazine). Chronic eosinophilic pneumonia (prolonged pulmonary eosinophilia) Eosinophilic pneumonia persisting for more than a month is distin- guished from the more transitory Löffler’s syndrome, although its clinical characteristics are fundamentally similar. As with eosino- philic pneumonia associated with tropical filariasis, it tends to be more persistent and more serious than Löffler’s syndrome, and may be associated with systemic symptoms, such as fever, malaise, and fatigue. It can sometimes progress to pulmonary fibrosis. It may last for several months and be associated additionally with eosinophilic pleural effusion, focal skin lesions, atopic manifestations such as rhinitis, sinusitis, and angio-​oedema, hepatosplenomegaly, and even hepatic necrosis. The pulmonary disease is often extensive, and may cause hypoxaemia as well as dyspnoea. A curious peripheral radio- graphic distribution of infiltrates, dubbed a ‘negative photographic image of pulmonary oedema’, is particularly suggestive of chronic eosinophilic pneumonia but occurs in only a few cases. The radio- logical abnormalities tend to recur and last for weeks or months, and like the shadows of Löffler’s syndrome may vary in site during the course of the illness. Chronic eosinophilic pneumonia is more commonly idiopathic than Löffler’s syndrome, but may also be a consequence of para- site infestation (e.g. tropical filariasis) or drug hypersensitivity. Case reports have identified aminoglutethimide, BCG vaccin- ation, bicalutamide, captopril, chlorpropamide, clarithromycin, clomipramine, dapsone, ethambutol, ibuprofen, meloxicam, mesalazine, minocycline, nitrofurantoin, perindopril, progesterone, sertraline, sotalol, sulphonamides, trimethoprim, and venlafaxine as

section 18  Respiratory disorders 4240 possible causes. Peripheral blood eosinophilia is less consistent with chronic compared with acute forms of eosinophilic pneumonia, although is often of greater level (>1 × 109/​litre). When a definitive cause is identified, appropriate specific man- agement should follow, but often no cause is evident and oral cor- ticosteroid therapy should be given. Responses are often dramatic, but recurrences are common if treatment is discontinued within 6 to 12 months. There may be a persistent mixed obstructive and re- strictive loss of ventilatory function, and radiographic evidence of persistent pulmonary fibrosis. Eosinophilic pneumonia with asthma Eosinophilic pneumonia is commonly associated with asthma, even in the absence of parasite infestation or drug hypersensitivity. In a study of 53 cases, asthma preceded eosinophilic pneumonia in about half, and then worsened; in the remainder it arose by similar pro- portion either contemporaneously or within about 2 years. Two par- ticular associations with asthma are noteworthy. Allergic bronchopulmonary mycosis When fungal hypersensitivity develops in atopic subjects with asthma, additional manifestations may occur in the lung:  these include eosinophilic pneumonia, mucoid impaction, bronchiec- tasis, and pulmonary fibrosis. The ensuing syndrome of allergic bronchopulmonary mycosis occurs most commonly with Aspergillus fumigatus, though has been reported with other aspergillus, can- dida, curvularia, and helminthosporium species. It accounts for most cases of eosinophilic pneumonia with asthma in the United Kingdom and is best considered a complication of atopic asthma, appearing to result from airway colonization by the relevant mould. The mechanism, however, is clearly one of hypersensitivity, not in- fection or invasion, and both IgE and IgG antibodies are necessary to support its diagnosis. Allergic bronchopulmonary aspergillosis is also common in patients with cystic fibrosis lung disease. In acute phases there is patchy obstruction of bronchi with inspis- sated mucus that, if expectorated, appears as brown rubbery lumps in the sputum (plugs). Fungal hyphae may be recovered from them, indicating that fungal growth has occurred within the airway. This impaction of mucus in one or more bronchi leads to atelectasis of segments or lobes of the lung, and is often associated with eosino- philic pneumonia. The radiographic appearances are of fleeting pul- monary infiltrates (Fig. 18.14.2.1). The condition usually responds well to corticosteroids, a useful diagnostic feature being the expectoration of plugs during this period of resolution. In the medium term the involved bronchi (generally proximal) may become bronchiectatic, leading in turn to the char- acteristic features of bronchiectasis (productive cough, intermittent haemoptysis). In the longer term, pulmonary fibrosis may ensue, particularly in the upper lobes and apices, so that the radiographic appearances resemble tuberculosis. If mucoid impaction and/​or eo- sinophilic pneumonia become superimposed, the radiographic ap- pearances may simulate active tuberculosis very closely. Suspicion of tuberculosis in an individual with atopic asthma should always prompt consideration of allergic bronchopulmonary mycosis. Antifungal agents (itraconazole, voriconazole) decrease the antigen burden and the associated immune response, but need to be used in conjunction with corticosteroids. They are particularly useful in allowing a reduction in the dose of corticosteroids. Eosinophilic granulomatosis with polyangiitis A much rarer association of eosinophilic pneumonia with asthma is that involving eosinophilic granulomatosis with polyangiitis. This is a vasculitic and granulomatous disorder that commonly involves lungs, gut, peripheral nerves, skin, and kidneys, and occasionally heart. It is characterized typically by asthma, eo- sinophilic pneumonia, and very high numbers of circulating eo- sinophils (>5 × 109/​litre), but the pulmonary manifestations may additionally include haemorrhage and haemoptysis. Serological investigation may also demonstrate raised serum levels of IgE and eosinophil cationic protein, P-​ANCA (perinuclear antineutrophil cytoplasmic antibodies) with myeloperoxidase activity (in most cases), and C-​ANCA with proteinase-​3 specificity (in a few cases). Autoantibodies against eosinophil granule enzymes have also been described. Pathologically there is vasculitis of small arteries and veins with necrotizing extravascular granulomas. Biopsy of af- fected tissue may be needed to confirm the diagnosis, and may be diagnostic even in the prevasculitic phase if there is characteristic eosinophilic infiltration of involved tissue. See Chapter 19.11.7 for further discussion. Fig. 18.14.2.1  Allergic bronchopulmonary aspergillosis: two radiographs taken 6 months apart from a woman with asthma, peripheral eosinophilia, and high titres of IgE and precipitating IgG antibodies to Aspergillus fumigatus.