Thorax (1970), 25, 19.

Fever in aspergillus mycetoma

C. HILVERING, E. A. M. STEVENS, N. G. M. ORIE

University Hospital, Groningen, The Netherlands

Two patients with aspergillus mycetoma presenting with fever as a major sign are described.The clinical presentation is correlated with the results of experimental inhalation of Aspergillusfumigatus extract in patients with aspergillus mycetoma. A theory is put forward which tries toexplain fever and haemoptysis as belonging to a type III (Gell and Coombs, 1963) antigen-antibody reaction. Therapeutic implications are discussed.

Fever as a sign of growth of Aspergillus fumigatusin the lungs is known only in patients with allergicaspergillosis (Hinson, Moon, and Plummer, 1952;Pepys, Riddell, Citron, Clayton, and Short, 1959)and acute pulmonary aspergillosis (Hertzog, Smith,and Goblin, 1949; Delikat and Dyke, 1945; Strel-ling, Rhaney, Simmons, and Thomson, 1966).Fever and malaise as major signs in patients withaspergillus mycetoma have up till now beendescribed only by Dieulafoy (1920).

Here we describe two patients with aspergillusmycetoma in the lung, presenting with fever andmalaise as major signs, and suggest that the feveris the result of an aspergillus antigen-antibodyreaction. We base this view on the results of in-halation tests in patients with aspergillus myce-toma, presented by Stevens, Hilvering, and Orie,in a preceding paper in this issue (p. 11).

CASE REPORTS

PATIENT 1 This 44-year-old housewife had sclero-derma, poikiloderma, bilateral cataract, and slowlyprogressive neurological symptoms that have ulti-mately led to a Brown-S6quard syndrome. A diag-nosis of Werner's syndrome (Annotation, 1967) has beenconsidered. Probably secondary to fibrosis, an asper-gillus mycetoma developed in the left lung, as wasshown by radiographs (Fig. 1) and by the presenceof precipitating antibodies in the serum (Fig. 2).

During the first admission (13 April to 27 May 1966)her body temperature was subfebrile and the E.S.R.was 20 mm. after one hour. Only sporadically wassome haemorrhagic sputum produced. A month afterdischarge her condition worsened, and she startedcoughing, producing large amounts of purulent,haemorrhagic sputum. When she was admitted for

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the second time the patient appeared to be ill, shehad lost about 8 kg., the body temperature was febrile-between 38' and 40' C.-and the E.S.R. had risento 85 mm. On radiographic examination the mycetomahad increased in size (Fig. 3). A. fumigatus could nowbe cultured from the sputum. Other micro-organismscould not be demonstrated in blood, sputum, or urine.A course of amphotericin B was started but had to bestopped because of acute renal insufficiency. Eventu-ally we decided to remove her left lung. Treatmentwith prednisolone, 25 mg. daily, was started a weekbefore the operation. This caused a remarkableimprovement in her condition, and the body tem-perature became normal. A left pneumonectomy wasperformed on 14 December 1966. During the pro-cedure the wall of the mycetoma ruptured, resultingin spilling of its contents into the pleural cavity. Post-operatively, amphotericin B, 10 mg. daily, was injectedinto the pleural cavity for about 14 days. No com-plications occurred; the body temperature remainednormal though corticosteroid treatment was stopped.We saw her again in February and November 1967.

She had no pulmonary symptoms and the E.S.R. wasnormal.

PATENT 2 This 55-year-old housewife had chronicnon-specific obstructive lung disease and bilateralapical inactive tuberculous lesions. In 1963 A. fumi-gatus was cultured from the sputum and graduallythe apical lesions began to show the typical appear-ance of an aspergillus mycetoma (Fig. 4).

In 1965 her symptoms became worse. The dyspnoeaincreased and she started producing large amounts ofpurulent, haemorrhagic sputum. The body tempera-ture was febrile, between 38' and 39' C. In the serumprecipitating antibodies to A. fumigatus were demon-strated. On skin-testing an immediate type I reaction(Gell and Coombs, 1963) was seen. With the excep-tion of A. fumigatus in the sputum, no micro-organ-

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FIG. 2. Patient 1. Results of immunoelectrophoresis(upper part) and Ouchterlony double diffusion test (lowerpart). Patient serum in upper trough in the immunoelectro-phoresis and large well in the Ouchterlony. Aspergillusfumigatus extract in the small wells. The lower trough was

not filled.

FIG. 1. Patient 1. Chest radiograph takenduring the first admission (April 1966)showing a large aspergillus nmycetoma inthe left upper lobe.

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FIG. 3. Patient 1. Chest radio-graph taken during the secondadmission (September 1966) show-ing an increase in size of theaspergillus mycetoma in the leftupper lobe.

FIG. 4. Patient 2. Chestradiograph taken in 1963,showing aspergillus mycetomawith characteristic air-capsin right and left upper lobes.

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isms could be demonstrated in the blood, urine orsputum. Treatment with ampicillin and chlor-amphenicol did not result in any improvement.

Resection of the mycetoma was not possible becauseit was situated bilaterally and lung function wasseverely impaired. Again a course of amphotericin Bhad to be stopped because of acute renal failure. Onadministration of corticosteroids prednisolone 25 mg.daily-the body temperature became normal and hersymptoms improved. She was reasonably well forabout two years on this regime, but finally died inMarch 1969 of respiratory failure.

DISCUSSION

In the two patients presented, apart from the pre-sence of an aspergillus mycetoma, no other causefor the fever could be found. In the sera of bothpatients a high level of precipitins to A. fum.gatuscould be demonstrated. On radiographic examina-tion the picture was typical of an aspergillus myce-toma; transient infiltrations as in allergic aspergil-losis (Hinson et al., 1952; Pepys et al., 1959) werenot seen. In the first patient the rise in temperaturecoincided with an increase in size of the aspergil-loma, whereas the body temperature became nor-mal when the aspergilloma was removed. In bothpatients administration of corticosteroids causedthe temperature to drop to normal and an improve-ment of symptoms.

Stevens et al. (p. II in this issue) described alate febrile reaction in patients with aspergillusmycetoma on inhalation of A. fumigatus extract.The fever in the present patients could have beencaused by a similar probably allergic mechanism.In the opinion of Pepys et al. (1959), precipitatingas well as reaginic antibodies might play a role inthe causation of signs and symptoms in patientswith allergic aspergillosis. The fever and transientinfiltrations are attributed to a type III antigen-antibody reaction in lung tissue surrounding thefungus, the latter being present intrabronchially(Scadding, 1967). A type I reaction might be in-volved in the causation of eosinophilia and bron-chial obstruction.

If these types of reaction could exist indepen-dently in cases of hypersensitivity to A. fumigatus,theoretically, apart from the combined early andlate reactions, two other patterns of reactionmight be possible:

an early asthmatic reaction 'aspergillusasthma'-already described (Pepys et al., 1959);

a late reaction not yet identified as aseparate entity.Probably the two patients with aspergilloma and

fever represent examples of the latter type of

reaction. However, it is difficult to explain whyfever, a characteristic sign in patients with allergicaspergillosis, is rare in patients with an aspergillusmycetoma. Several factors might be responsible,such as the amount of precipitating antibody pre-sent in the serum, a relation between the earlytype I (Gell and Coombs, 1963) reaction and thelate febrile reaction in patients with allergic asper-gillosis or the amount of antigen available for re-action with circulating precipitins.

Precipitating antibodies are present more fre-quently and in higher concentration in the seraof patients with aspergilloma than in the sera ofpatients with allergic aspergillosis (Gernez-Rieux,Biguet, Voisin, Capron, and Tran van Ky, 1963;Longbottom, Pepys, and Temple Clive, 1964:Bronnestam and Hallberg, 1965).A type I (Gell and Coombs, 1963) bronchial re-

action preceding the late febrile reaction, as inpatients with allergic aspergillosis (Pepys et al..1959), is not a necessary condition for the occur-rence of a late febrile reaction on inhalation ofA. fumigatus extract (Stevens et al., p. 11 in thisissue).The amount of antigen available for reaction

with circulating precipitins depends on the sourceof the antigen and its accessibility to the circula-tion.The source of the antigen eliciting an attack in

patients with allergic aspergillosis might be thefungus present intrabronchially in varyingamounts, depending on the degree of bronchialobstruction, but might also be environmental, ashas been suggested by Henderson et al. (1968). Inthe patients presented here, the source of theantigen is probably not external because the feverpersisted for several months in both of them evenwhen the environment was changed. As was shownby Stevens et al., the late febrile reaction after oneinhalation of an A. fumigatus extract lasted only24 hours.The foregoing arguments lead to the conclusion

that the source of the antigen is the fungus presentin the mycetoma, and that the occurrence ofgeneral symptoms and signs-previously not pre-sent-depends only on a change, probably anincrease, in the amount of antigenic materialleaving the mycetoma, to react with circulatingantibody.

Contact between antigen and antibody cantheoretically occur (a) across the wall betweenmycetoma and surrounding lung tissue; or (b)across the alveolar membrane, when finely dis-persed antigenic material is distributed by way ofthe bronchial tree to alveoli in normal lung tissue.

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Fever in aspergillus mycetoma

In case (a) the amount of antigenic material enter-ing the circulation depends on the permeability ofthe wall for antigenic components of the fungus.Changes in this permeability may be caused byacute respiratory infections, causing an increasein blood flow in the surrounding lung tissue.Haemoptysis often occurs in patients withaspergillus mycetoma and bronchial infection.Haemoptysis, a characteristic symptom in patientswith aspergillus mycetoma, should probably alsobe regarded as belonging to a type III reactionwhich, apart from fever, is characterized byvascular damage leading to oedema and haemor-rhage (Cochrane, 1967).

In case (b), the amount of antigen reacting withcirculating antibody depends on the communica-tion between bronchus and mycetoma and thefineness of the antigenic particles leaving themycetoma. These particles might be mycelial frag-ments or spores. In the latter case, the relativerarity of general symptoms and signs in patientswith aspergillus mycetoma would be explained bythe rarity of sporulation (Orie, Vries, and Kikstra,1960). Though highly speculative, this mechanismmore or less agrees with the findings in patientswith aspergillus mycetoma after experimentalinhalation of A. fumigatus extract.

If most of the symptoms and signs in patientswith aspergillus mycetoma could be attributed toa type III reaction, the administration of cortico-steroids to some of these patients should be con-sidered, especially in those cases with fever,malaise, or frequent and severe haemoptysis, inwhom other methods of treatment have beenwithout results, considered to be too dangerous,or have had to be stopped because of complica-tions.The usual treatment-resection-is often impos-

sible because of the bilateral location of the asper-gilloma or severely impaired lung function. Theadministration of amphotericin B may also beconsidered. If given intravenously, the drug isextremely toxic (Utz, 1963 ; Utz, Bennett, Bran-driss, Butler, and Hill, 1964) and only moderatelyactive against A. fumigatus. However, goodresults have been reported after administrationdirectly into the aspergilloma cavity by way of atransthoracic puncture (Krakowka, Chodkowska,Halweg, and Pawlicka, 1963; Brouet, Liot,Demange, and Nevot, 1964; Migueres, Paczus-zynski, and Esteve, 1965).

Corticosteroid treatment of patients withallergic aspergillosis is often successful. However,in these patients corticosteroids might assist in

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evacuating the fungus from the bronchial lumenby reducing oedema and inflammation of thebronchial mucosa. The effect of corticosteroidtherapy would then not necessarily depend on adirect suppression of the type III reaction and thelikelihood of undesirable effects progression offungus growth-would be decreased.

In patients with aspergilloma, removal of fungusas a result of corticosteroid treatment will prob-ably not occur. Besides it has been shown thatcorticosteroids promote the growth of A. fumi-gatus in mice (Sidransky and Friedman, 1959;Hoer, 1964). Patients treated with high doses ofcorticosteroids for malignant haematologicaldiseases (Torack, 1957) or as part of immuno-suppressive therapy (Rifkind, Marchioro, Schneck,and Hill, 1967) show a high incidence of fungalinfections, often with a fatal outcome. Althoughthe dosages mentioned in these publications aremuch higher (equivalent to 60-100 mg. predni-solone daily) than those from which an effectmight be expected in patients with allergic aspergil-losis (20-30 mg. prednisolone daily), cortico-steroids should only be used with the utmostcaution in patients with aspergilloma.

In our opinion, there may be an indication forthe administration of corticosteroids in somepatients, since corticosteroids have been given topatients with an aspergillus mycetoma withouthaving any unfavourable effect on the mycetoma.

REFERENCESAnnotation (1967). Lancet, 2, 1293.Bronnestam, R., and Hallberg, T. (1965). Precipitins against an

antigen extract of aspergillus fumigatus in patients with asper-gillosis or other pulmonary diseases. Acta med. scand., 177, 385.

Brouet, G., Liot, F., Demange, J., and Nevot, P. (1964). Traitementlocal de l'aspergillome pulmonaire par injections transparietalesd'Amphotericine B. J. franC. Med. Chir. thor., 18, 789.

Cochrane, C. G. (1967). The Arthus phenomenon-A mechanism oftissue damage. Arth. and Rheum., 10, 392.

Delikat, E., and Dyke, S. C. (1945). Acute pulmonary mycosis.Lancet, 2, 370.

Dieulafoy, G. (1920). Manuel de Pathologie Interne, Vol. 1, 6th ed.,p. 430. Masson, Paris.

Gell, P. G. H., and Coombs, R. R. A., Ed. (1963). Clinical Aspects ofImmunology, 1st ed. Blackwell, Oxford.

Gernez-Rieux, C., Biguet, J., Voisin, C., Capron, A., and Tran vanKy, P. (1963). Diagnostic immunologique des aspergillomesbronchopulmonaires. Presse med., 71, 1541.

Henderson, A. H., English, M. P., and Vecht, R. J. (1968). Pulmonaryaspergillosis. Thorax, 23, 513.

Hertzog, A. J., Smith, T. S., and Goblin, M. (1949). Acute pulmonaryaspergillosis. Report of a case. Pediatrics, 4, 331.

Hinson, K. F. W., Moon, A. J., and Plummer, N. S. (1952). Broncho-pulmonary aspergillosis. Thorax, 7, 317.

Hoer, P. W. (1964). Die Preumonomycosis aspergillina im Tierversuchund beim Menschen: Beitrag zur Pathogenese der Lungen-mykosen. Ann. Univ. sarav. Med., 11, 363.

IKrakowka, P., Chodkowska. S., Halweg, H., and Pawlicka, L.(1963). Treatment of pulmonary aspergilloma. Proc. int. symp.Med. Mycol., p. 249, Warszawa.

Longbottom, J. L., Pepys, J., and Temple Clive, F. (1964). Diagnosticprecipitin tests in aspergillus pulmonary mycetoma. Lancet, 1,588.

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Migueres, J., Paczuszynski, H., and Esteve, R. (1965). Aspergillomepulmonaire en apparence primitif, traite avec succes par injec-tions trans-thoraciques d'Amphotericine B. J. franc. Med. Chir.thor., 19, 59.

Orie, N. G. M., Vries, G. A. de, and Kikstra, A. (1960). Growth ofAspergillus in human lung. Amer. Rev. resp. Dis., 82, 649.

Pepys, J., Riddell, R. W., Citron, K. M., Clayton, Y. M., and Short,E. I. (1959). Clinical and immunologic significance of Aspergillusfumigatus in the sputum. Ibid., 80, 167.

Rifkind, D., Marchioro, T. L., Schneck, S. A., and Hill, R. B. (1967).Systemic fungal infections complicating renal transplantationand immunosuppressive therapy. Amer. J. Med., 43, 28.

Scadding, J. G. (1967). The bronchi in allergic aspergillosis. Scand. J.resp. Dis., 48, 372.

Sidransky, H., and Friedman, L. (1959). The effect of cortisone andantibiotic agents on experimental pulmonary aspergillosis.Amer. J. Path., 35, 169.

Stevens, E. A. M., Hilvering, C., and Orie, N. G. M. (1970). Inhalationexperiments with extracts of Aspergillus fumigatus on patientswith allergic aspergillosis and aspergilloma. Thorax, 25, 11.

Strelling, M. K., Rhaney, K., Simmons, D. A. R., and Thomson, J.(1966). Fatal acute pulmonary aspergillosis in two children ofone family. Arch. Dis. Childh., 41, 34.

Torack, R. M. (1957). Fungus infections associated with antibioticand steroid therapy. Amer. J. Med., 22, 872.

Utz, J. P. (1963). Chemotherapeutic agents for the systemic mycoses.New Engl. J. Med., 268,938.

-Bennett, J. E., Brandriss, M. W., Butler, W. T., and Hill, G. J.(1964). Amphotericin-B toxicity. Combined clinical staff confer-ence. Ann. intern. Med., 61, 334.

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