Asthmatic pulmonary eosinophilia: A review of 65 cases

Br.

ASTHMATIC W. G. MIDDLETON,

J. Dis.

Chest

(1977) 71, 115

PULMONARY EOSINOPHILIA: A REVIEW OF 65 CASES I. C. PATERSON, I. W. B. GRANT AND A. C. DOUGLAS

Department of Respiratory Diseases, City Respiratory Unit, Northern General

Hospital, Hospital,

Edinburgh, Edinburgh

and

Summary In a series of 65 patients with asthma with pulmonary eosinophilia 54 were adequately investigated for allergic aspergillosis and this was present in 32 (59%). Asthma with pulmonary eosinophilia was found to carry a relatively poor prognosis in terms of permanent symptoms, impairment of pulmonary function and residual radiographic abnormality. The prognosis was least favourable when allergic aspergillosis was associated with long-standing asthma. On the other hand there was a group of patients with asthma with pulmonary eosinophilia who had relatively little permanent disability. These were mainly women with asthma of recent onset, and in these evidence of allergy to Aspevgillus fumigatus was less apparent. Those patients who received long-term daily corticosteroid therapy were less likely to develop further radiographic opacities than those given intermittent corticosteroid therapy. To prevent recurrent pulmonary infiltrates it is probably necessary to give prednisolone in a daily dosage of at least 10 mg for an indefinite period. INTRODUCTION

The combination of pulmonary lesions and peripheral blood eosinophilia has been variously termed Loeffler’s syndrome (Loeffler 1936), pulmonary eosinophilia (Crofton et al. 1952), PIE (pulmonary infiltrates with eosinophilia) syndrome (Reader & Goodrick 1952) and eosinophilic pneumonia (Liebow & Carrington 1969). The recognition of allergic bronchopulmonary aspergillosis by Hinson et al. (1952) and subsequent study of its immunological basis (Pepys et al. 1959; Campbell & Clayton 1964; Longbottom & Pepys 1964; Pepys 1964; Golbert & Patterson 1970) have provided a better understanding of the syndrome of pulmonary eosinophilia seen in asthmatic patients. The present paper reports a study of asthmatic pulmonary eosinophilia with particular reference to the aetiological role of Aspergillus fumigatus, the clinical course and prognosis and the results of corticosteroid therapy.

Patients

and

Methods

An analysis was made of the case records of 65 asthmatic patients in whom there was documented evidence of pulmonary infiltration with an associated peripheral blood eosinophilia of greater than 0.5 x 10g/litre. Each patient’s history was reviewed in detail, with particular reference to age at onset of asthma

116

W. G. Middleton,

I. C. Paterson, I. W. B. Grant and A. C. Douglas

and at the first reported incident of pulmonary eosinophilia. was recorded if available at the time of presentation: 1. 2. 3. 4. 5.

In addition

the following

information

Initial clinical diagnosis. Forced expiratory volume in one second (FEV1). Nature and distribution of radiographic opacities. Presence or absence of eosinophil leucocytes in the sputum. Results of (a) Sputum culture for A. fumigatus. (b) Immediate and later type skin sensitivity tests with an extract of A. fumigatus (c) Serum precipitin test with an A. fumigatus antigen. (d) Skin (prick) tests with a group of common allergens (Bencard).

(Bencard).

The number and duration of subsequent radiographic opacities were noted and a complete record was made of the corticosteroid therapy received by each patient. As this was a retrospective review of patients under the care of a number of physicians not all patients received similar surveillance. Those with more severe symptoms, and hence usually those on corticosteroid therapy, were supervised more closely. An assessment of prognosis was made on the basis of symptoms, FEVr and residual radiographic abnormality at the time of the patient’s latest follow-up visit. The patients were observed during the period 1958-73 at respiratory units in the City Hospital and the Northern General Hospital, Edinburgh.

RESULTS Age and sex Age at the time of the first recorded episode of pulmonary eosinophilia ranged from 7.5 to 78 years with peaks in the 21-30 and 51-60 age groups (Fig. 1). The series included slightly more females (3.5) than males (30). Eosinophils The absolute blood eosinophil counts ranged from 0.62 to 21.4x lOs/litre. Of the 65 patients 57 had an eosinophilia exceeding 10% of the total white cell count and in

NUMBER OF PATIENTS

AGEINYEARS Fig. 1. Age at time of first recorded

episode of asthmatic

pulmonary

eosinophilia.

Asthmatic

Pulmonary

Eosinophilia

117

25 it was greater than 20%. In 48 patients the sputum was examined for eosinophils and these were present in 28 (58%). Radiographic

appearances

Fifty-five patients at some stage showed opacities which were anatomically classifiable as segmental or lobar. Eleven patients at some stage had radiographic opacities which were less clearly related to segmental anatomy, as they were often multiple and smaller in size than segments. There were two patients with more widespread opacities with a tendency to a peripheral distribution. Asthmatic history In 26 of the 65 patients asthma began before the age of 10 years, but in the remaining 39 the onset of asthma was recorded in almost equal numbers for each decade between 10 and 70. The first symptoms of asthma either preceded or were coincident with the first reported incident of pulmonary eosinophilia, with only one exception. The exception was a woman who did not develop asthma until two years after she presented with pulmonary eosinophilia. In 29 patients the first recorded episode of pulmonary eosinophilia occurred within two years of the onset of asthmatic symptoms. In 27 patients, however, there was an interval of 10 years or more (greater than 20 years in 19 patients) between the onset of asthma and the first recorded incident of pulmonary eosinophilia. Skin sensitivity tests were positive to a variety of common allergens in 25 patients, but in another 25 patients no positive reactions were recorded. Skin tests were not performed in the remaining 15. A. fumigatus

investigations

An immediate (Type I) skin reaction to A. fumigatus was positive in 30 of 53 patients tested (57%). A late (Type III) reaction was looked for in only seven patients and of these five were positive. Precipitating antibodies to A. fumigatus were present in 29 (60%) of the 48 patients tested. Mycological examination of sputum was undertaken in 56 patients and A. fumigatus was isolated in 25 (45%). It was considered that 32 patients had evidence of allergic aspergillosis. Fifteen of these 32 patients had serum precipitins, repeated positive sputum and a positive immediate skin reaction (Table I). The remaining 17 patients were included in the subgroup of allergic aspergillosis because they had two of the three tests positive (13 cases) or serum precipitins only (4 cases). Table II identifies a subgroup of 22 patients found to lack the full features of allergic aspergillosis. In eight all three tests were negative and in the remaining 14 at least two of the tests were negative. Thus 32 of 54 (59%) had positive evidence of allergic aspergillosis and 22 of 54 (41%) had no evidence of allergic aspergillosis. Eleven patients were not adequately investigated for Aspergillus hypersensitivity. One woman who had a history of asthma in childhood and pulmonary tuberculosis at the age of 50 years presented at the age of 62 years with pulmonary opacities, the features of allergic aspergillosis and the characteristic radiographic appearance of aspergilloma in the right upper lobe.

118

W. G. Middleton, Table

I.

I. C. Paterson, I. W. B. Grant and A. C. Douglas

32 Patients with asthmatic pulmonary features of allergic aspergillosis

No. of patients

Serum precipitins

15 5 5 3

Sputum culture for A. fumigatus

f -I-

+ +

+

-ve +

2 -ve

eosinophilia

and

Type I skin reaction

+ 4 -ve 1 not known + +

1 not known 4

Table

II.

f

-ve

1 -ve 3 not known

22 Patients with asthmatic pulmonary out features of allergic aspergillosis

No. of patients

Serum precipitins

Sputum culture for A. fumigatus

eosinophilia

but with-

skin

Type 1 reaction

not known

not known -

3 Sve 2 not known -

Clinical cowse and prognosis Adequate information was obtained on 62 of the 65 patients, with follow-up periods ranging from six months to 16 years and a mean follow-up period of 6.4 years. These 62 patients were arbitrarily divided into four grades (O-III) according to the symptoms, functional abnormality and radiographic abnormality noted at the time of their latest follow-up visit (Table III). Patients with no evidence of allergic aspergillosis tended to have a better follow-up grade (14 of 22 were graded 0 or I) than those with allergic aspergillosis (27 of 32 were graded II or III). These differences are statistically significant (P< 0.001). Long-term corticosteroid therapy was given in 56% of the aspergillosis-positive subgroup and in 5.5% of the aspergillosis-negative subgroup. Table IV compares those who did well (14 Grade 0 patients) with those who did badly (25 Grade III patients). The patients with Grade 0 follow-up assessments were predominantly women and differed from those with Grade III follow-up assessments in that they had developed asthma later in life, had a shorter history of asthma before pulmonary eosinophilia was reported and usually did not show the features characteristic of allergic aspergillosis. The better condition of patients with Grade 0 follow-up assessments was reflected in the smaller proportion requiring long-term corticosteroid therapy.

Asthmatic Table

111. Asthmatic pulmonary aspergillosis

Follow-up

Pulmonary

eosinophilia:

Relationship

Whole

grade

group

(65 patients)

0 (no symptomatic, functional or radiographic abnormality) I (only one of the above) II (two of the above) III (all three of the above or death) No follow-up

119

Eosinophilia between

prognosis

Aspergillosis-negative subgroup

Allergic

(22 patients)

14 8 15 25 3

;> 4 4 0

and

allergic

aspergillosis subgyoup

(32 patients) 3 1

14

“127 171 1 x2=14.73 P
Number given long-term corticosteroids

daily

34 (52%)

Guidance of allergy to A. fumigatus of the 65 patients.

Table

Follow-up grade

0 (14 patients) III (25 patients)

or of A. fumigatus

IV. Factors related to prognosis Mean age Sex

3M 11F 12M 13F

at onset of asthma

in the sputum

in pulmonary

Duration of asthma before jiivst episode of pulmonary eosinophilia

< 2 years

18 (56%)

12 (55%)

> 10 years

was sought in 54 (22 + 32)

eosinophilia

with asthma

Allergic” aspergillosis

Absent

Present

No. requiring long-term corticosteroids

42 years

13

1

8

3

6 (43%)

21 years

6

15

4

17

16 (64%)

x2=14.0 P
x2=8.0 P-CO.01 with Grade III assessments were

Influence of corticostevoid therapy on yecuwence of eosinophilic in$ltvates Long-term daily corticosteroid therapy was given to 34 patients, always for the control of symptoms of chronic asthma. In 12 of these (35%) 24 recurrences of radiographic opacity were recorded while regular corticosteroid therapy was being given. Twenty of these 24 incidents occurred while the patients were receiving their usual dose of prednisolone (5-10 mg daily) and four while dose reduction was being attempted. Fifteen (83%) of 18 patients whose asthma was controlled by intermittent courses of corticosteroids had further radiographic opacities during the period of observation. Ten patients did not receive corticosteroids and of these nine (90%) had further radiographic opacities. Most patients had symptoms (for example, cough and malaise) coincident with the appearance of further radiographic opacities, although this was not always accompanied by a worsening of their asthma. No patient receiving cortico-

120

W. G. Middleton,

I. C. Paterson, I. W. B. Grant and A. C. Douglas

steroids developed invasive pulmonary aspergillosis. Within recent months eight patients with pulmonary eosinophilia have been given corticosteroid aerosols for control of their asthma. Eleven patients received, at some stage, antifungal therapy (natamycin by inhalation) without lasting benefit. Bronchiectasis There was bronchographic evidence of bronchiectasis in all of eight patients in whom this investigation was carried out, and two patients were found to have bronchiectasis at autopsy. One of these had cylindrical bronchiectasis involving the segmental bronchi of both lower lobes although the subsegmental bronchi appeared normal (‘proximal’ bronchiectasis). The other had extensive bronchiectasis with multiple pulmonary abscesses. All 10 patients with bronchiectasis had clinical and immunological evidence of allergic aspergillosis. Deaths Six of the 65 patients with asthmatic pulmonary eosinophilia have died. Three of these deaths were due to unrelated disorders, namely bronchial carcinoma, pulmonary embolism and myocardial infarction. The remaining three died from respiratory failure due to bronchopneumonia. These three patients were women who presented in middle age, two with a history of asthma since childhood, and all three had severe, largely irreversible, airways obstruction at the time of presentation.

DISCUSSION The incidence of pulmonary eosinophilia in asthmatics is difficult to estimate. Ford (1966) studied 5702 consecutive asthmatics seen over five years and only 20 patients with pulmonary eosinophilia were identified. On the other hand, a more recent paper (McCarthy & Pepys 1971) re f ers to 143 patients seen over two years, but many of these were probably special referrals. It is generally considered that in Great Britain most cases of pulmonary eosinophilia are due to allergic bronchopulmonary aspergillosis (Pepys 1966; Scadding 1971). Allergic aspergillosis is said to be characterized by a dual Type III skin response to an antigen of A. fumigatus and by the presence of precipitating antibodies to A. fumigatus in the patient’s serum (Pepys 1964). Unfortunately, the late Type III skin reaction was looked for in only seven of the patients in the present review. Because of an immediate skin reaction, serum precipitins and sputum culture, 59% of patients with asthmatic pulmonary eosinophilia who were adequately investigated were considered to have evidence of allergic aspergillosis. Where evidence of allergic aspergillosis was lacking (Table II) no cause was obvious. The progression of allergic aspergillosis to irreversible airways obstruction and bronchiectasis has been documented by others (Scadding 1967; Henderson 1968; available on prognosis in McCarthy & Pepys 1971). Th ere is much less information patients with asthmatic pulmonary eosinophilia but without evidence of allergic aspergillosis. Our data indicate that the residual disability is, in fact, significantly greater where allergic aspergillosis is present and that those patients without evidence of allergic

Asthmatic

Pulmonary

Eosinophilia

121

aspergillosis have a relatively good prognosis. This difference in outcome does not appear to be related to oral corticosteroid therapy since almost the same percentage of patients in both subgroups were receiving this form of treatment. Another factor influencing prognosis is the duration of asthmatic symptoms at the time of presentation with pulmonary eosinophilia: in this series the outlook was more favourable in patients with asthma of more recent onset. Although pulmonary infiltrates usually resolve after corticosteroid therapy, there is still some doubt whether this treatment prevents further eosinophilic episodes (Leading Article, 1972). Safirstein et al. (1973), in a five-year follow-up of 50 patients with allergic aspergillosis, reported that 20% of patients on continuous corticosteroid therapy had further pulmonary infiltrates, as compared with 65% of those who did not receive corticosteroids. In the present series 35% of patients on long-term daily corticosteroid therapy had further eosinophilic episodes. Recurrences were noted in patients receiving 10 mg prednisolone daily or less, supporting the conclusion of McCarthy and Pepys (1971) that doses of more than 5 mg prednisolone daily are required to prevent recurrence. Our data also indicate that the risk of further episodes is much greater when asthmatic symptoms are controlled by intermittent courses of corticosteroid than by regular daily treatment. Experience with inhaled corticosteroids in this group of patients is limited. There is, however, reason to doubt their efficacy as a means of preventing eosinophilic episodes as Paterson et al. (1975) have reported three asthmatic patients in whom pulmonary eosinophilia occurred after the replacement of corticosteroid in tablets by beclomethasone dipropionate by inhalation. It seems reasonable to aim at preventing eosinophilic episodes, particularly when allergic aspergillosis is present, as each subsequent incident is likely to cause further bronchial damage (Scadding 1967). On present evidence this aim will only be achieved by prescribing prednisolone in a daily dosage of at least 10 mg and it would appear that treatment should be continued indefinitely. ACKNOWLEDGEMENTS

We thank Professor J. W. Crofton, Dr G. K. Crompton, Dr N. W. Horne, Dr D. C. F. Muir and Dr J. D. Ross for permission to study the case records of patients under their care. We are grateful to Miss Jane Williamson and Miss M. C. Drummond for secretarial assistance. REFERENCES CAMPBELL, M. J. & CLAYTON, Y. M. (1964) Bronchopulmonary aspergillosis. Am. Rev. resg. Dis. 89, 186. CROFTON, J. W., LIVINGSTONE, J. L., OSWALD, N. C. & ROBERTS, A. T. M. (1952) Pulmonary eosinophilia. Thorux 7, 1. FORD, R. M. (1966) Review of 20 cases of pulmonary eosinophilia in 5702 asthmatics. Am. Rev. resp. Dis. 93, 797. GOLBERT, T. M. & PATTERSON, R. (1970) Pulmonary allergic aspergillosis. Ann. intern. Med. 72, 395. HENDERSON, A. M. (1968) Allergic aspergillosis-Review of 32 cases. Thonzx 23, 501. HINSON, K. F. W., MOON, A. J. & PLUMMER, N. S. (1952) Bronchopulmonary aspergillosis. Thorax 7, 317.

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LEADING ARTICLE (1972) Corticosteroids in pulmonary aspergillosis. Br. med. J. 4, 567. LIEBOW, A. A. & CARRINGTON, C. B. (1969) Eosinophilic pneumonia. Medicine, Baltimore 48, 251. LOEFFLER, W. (1936) Die fluchtigen Lungeninfiltrate mit Eosinophilie. Schweiz. med. Wschr. 66, 1069. LONGBOTTOM, J. L. & PEPYS, J. (1964) P u 1monary aspergillosis : diagnostic and immunological significance of antigens and C substance in Aspergillus fumigatus. J. Path. Bact. 88, 141. MCCARTHY, D. S. & PEPYS, J. (1971) Allergic bronchopulmonary aspergillosis. Clin. Allergy 1, 261. PATERSON, I. C., COOKE, N. J., MURRAY, K., CROMPTON, G. K. & GRANT, I. W. B. (1975) Pulmonary eosinophilia after substitution of aerosol for oral corticosteroid therapy. Br. J. Dis. Chest 69, 217. PEPYS, J. (1964) Possible role of precipitins against Aspergillus fumigatus. Am. Rev. resp. Dis. 90, 465. PEPYS, J. (1966) Pulmonary hypersensitivity disease due to inhaled organic allergens. Postgrad. med. J., 42, 698. PEPYS, J., RIDDELL, R. W., CITRON, K. W., CLAYTON, Y. M. & SHORT, E. I. (1959) Clinical and immunological significance of Aspergillus fumigatus in the sputum. Am. Rev. Tesp. Dis. 80, 167. READER, W. H. & GOODRICK, B. E. (1952) Pulmonary infiltrates with eosinophilia (PIE syndrome). Ann. intern. Med. 36, 1217. SAFIRSTEIN, B. H., D’Souzo, M. F., SIMON, G., TAI, E. H.-C. & PEPYS, J. (1973) Five-year follow-up of allergic bronchopulmonary aspergillosis. Am. Rev. resp. Dis. 108, 450. SCADDING, J. G. (1967) The bronchi in allergic aspergillosis. &and. J. resp. Dis. 48, 372. SCADDING, J. G. (1971) Eosinophilic infiltrations of the lungs in asthmatics. PYOC. R. Sot. Med. 64, 381.