Pulmonary Eosinophilia in Coccidioidal Infections

Pulmonary Eosinophilia in Coccidioidal Infections* Cha rles M. Lombard, M .D.;t Henry D. Tazelaar, M .D .;+' and David L. Krasne, M .D.§

Two cases of pulmonary eosinophilia associated with coccidioidal infections are reported. Pulmonary eosinophilia in these cases represents a hypersensitivity reaction to the fungus. Histologically, the pulmonary eosinophilia in these case s closely mimicked or appeared identical to idiopathic

chronic eosinophilic pneumonia. Coccidioides immitis organisms were rare or ab sent in the areas of pulmonary eosinophilia. Recognition of this phenomenon is important for proper care of the patient.

p eriPheral eosinophilia associated with coccirlioidnl infection is a well recognized phenomenon . Estimates of the incidence of peripheral eosinophilia in primary infections range as high as 88 percent. 1 Tissu e eosinophilic reactions were noted in early pathologic descriptions of coccidioidomycosis; however, there is only one detailed review ofthis subject. 2 We report two cases of pulmonary eosinophilia associated with coccidioidomycosis. In one , en dospo res and spherules characteristic of coccidioidomycosis were identified on th e open lung biopsy. In th e second case, no organisms were identified on op en lung biopsy. The patient was rea e WI 1 immunosuppressrve agents or a presumed hypersensitivity re action with severe cons equ ences . In this report we wish to stress the following points: Pulmonary eosinophilia may be associated infect ious agents including coccidioidomycosis which histologically may resemble or appear identical to idiopathic chronic eosinophilic pneumonia. The infectious organisms may not be identified histologically in th ese areas of pulmonary eosinophilia. Pulmonary eosinophilia in the cases we report represents a hypersensitivity reaction to coccidioidomycosis and not a primary host defense mechanism. There are clinical clues which may help to distinguish idiopathic chronic eo sinophilic pneumonia from pulmonary eosinophilia secondary to infectious agents. CASE REPORTS CASE

1

A 15-year-old whit e girl living in Arizona presented with exacerbation of her childhood asth ma. Ches t roentgenograms revealed hyperinHated lung fields with peribronchial cuffing consi stent with her known histor y of asthma and an ahscess cavity in th e right upper lobe of the lung . Sputum cultures grew Coccidioides immitis. Skin *From the Department of Path ology, Stanford Univer sit y Medi cal Ce nte r, Stanford. t Clinic.·11 1nstructor in Path ology. *Fc llow in Cardi ac and Pulmonary Pathology , §Rcsident in Path ology. Manu script received August 28; revision acc epte d November 19. lleprlnl requests: Dr. Taze/llor. Slemfo rd University Medical Center, Slonf m'd fH 305 734

CASE

2

A 58-year-old white woman presented with dyspnea, pleuritic che st pain , fever, and chills . Her cond ition progressed over seve ral days and her chest roentgen ogram revealed marked bibasilar alveolar interstitial infiltrates and a 3 em peripheral opacit y in the righ t midlung field (F ig 2). Lab oratory values were remarkable for a leukocytosis value of 19,600 with 10 percent eosinophils. Sputum cultures were negative. Tuberculin and fungal skin tests including coccidioidin antigen were nonr eactive. Circulating immune complexes were identifi ed by the conglutinin binding assay. Bron choscopic biopsy and cultures wer e nondiagnostic, and an open lun g biopsy was performed. Microscopic sections of th e ope n lung biop sy showed a single small nodul e, the central port ion of wh ich containe d a striking numb er of eosinophils admixed with lymphocytes, neutrophils, and macrophages (F ig 3). The surro unding interstitium cont ained a cellular infiltrate composed of an admixture of eosinophils and lymph ocytes. Th e alveoli contain ed a few small cluste rs of maerophag es, occasion ally associated with eosinophils. Results of special stains for the presence of fungi and acid-fast organisms were negative. Cultures were negative for bact erial , mycobacterial, and fungal organi sms. Th e impression was that th e biopsy represented a form of a Pulmonary Eosinophilia in Coccidioidal Infections (Lombard, Taze/aar, Krasne)

FI G UIII; 1. Open lung bi~PSY (case 1) with coccidioidal organisms {arrows} located in a necrotizing eosinophilic abscess. The surrou nding pulmonary pare nchyma contains prominent numbers or eosinephils, lymph ocytes. and histiocytes in II pattern characteristic or eosinophi lic pne umonia (hematoxylin and eosin , origina l magni fication X 200). hypersensitivity reaction. alth ough the etiology was unclear. Th e 3 em nodule seen roentgenogr aphically was not blopsied. The patient resp onded to intravenous steroid therapy and was discharged rece iving predni sone, 60 mg pe r day. After a week or clinical improvement, her shortness of breath recur red and was accompanie d by inter mitt ent fevers. Thi~ progressed for three to four wee ks until she was admitted to the hospit al with severe dyspn ea. Ch est rocntge nograms showed diffuse bilateral infiltrates. Cytoxan ~as added to her predni sone regimon and she was tra n sferred to th e Stanford University Medical Ce nte r. She suffered rapid det erioration in her respiratory status. Coccidioides irnrnitis was identified on endotrache al aspirate. Cytoxan was discontinued, stero ids were tapered, and amphotericin was started. However, the patient died two days later in respiratory failure . At autopsy, the pat ient had dissemin ated coccidioidomycosis with severe bilateral pul monar y involvement.

DISC USSIO N

Th e majority of cases of pulmonary coccidioidomycosis are diagnosed on the basis of history and physical

FIG UR E 2. Admission ches t x-ray film (case 2) shows bibasilar alveolar inter stitial infiltrates and a 3 ern peripher al opacity in the right mid -lun g field.

FIG UR E 3. Low power photomicrograph or the open lung biopsy (case 2) showing an ill-defined nodule with eenlral necrosis resembling an eosinophilic absce ss, The surroundlug inllllrale is cornposed or an adm ixtu re or eoslnop hils, histiocytes, and lymphocytes (hematoxyliu and eosin, originalmagnillcation X 40).

exam ina t io n with ap p rop r iate skin testing and serologic studies . Peripheral eosinophilia is common at th e tim e of initi al diagnosis. Pulmonary eosinophi lia has also been des crib ed , altho ugh most repor ts of the histopathologic findings of pulmonary coccidioidomycosis emphasize the granulomatous and suppurative reactions.v' On occasion, coccidioidomycosis will be diagnosed on an open lung biopsy and the associated pulmonar y eosinophilia seen in th e two cases presented here is importan t to recognize, as it may app ear indistinguishable from an idiopathic hyp ers ensitivit y reaction, Organisms may not be identifiable in th e tissue sections. In case 1, numerous organisms wer e present in a necrotic absc ess cavity. However, in the areas of eosinophilic pn eumonia, coccidioidomycosis organisms were rare, with most sections having no ide ntifiable fun gi. In case 2, no organism was demonstrable on multiple sections of a lung biopsy, and culture results were negative. Thus.ithe imp ortance of re cognizing th e po ssibility of having pulmonary eosinophilia secondary to coccidioidomycosis without identifying th e organism in th e tissu e sections is weli demonstrated. In our opinion, the pulmonary eosinophilia we have described represents a hypersensitivity reaction to coccidioidomycosis and does not represent a primary host defe nse me chanism . Th e following lines of evidence support this view: Fidh th er e is a marked histologic res emblance to oth er well docum ented hypersensitivity reactio ns including chronic eosinophilic pn eumonia, mucoid impaction , and bronehocentric granulomatosis, known manifestations of allergic bronchopulmonary aspergillosis . 5 Second, in most areas wh ere th ere is marked pulmonary eosinophilia, no organisms are identifi able . Furthermore, in case 2, cult ure of the lung biopsy failed to grow coccidioidomycosis. Thus, the pulmonary eosinophilia

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described, we feel these cases require careful scrutiny occurred at site remote from the primary infection. before accepting them as idiopathic hypersensitivity Third, the infrequency with which coccidioidal infecreactions. tions are associated with significant pulmonary Finally, in idiopathic chronic eosinophilic pneueosinophilia supports a hypersensitivity type reaction. monia, a prompt cliriical response to steroids is the In most cases of coccidioidomycosis the pathology is rule. However, as evidenced by our second case, an described as a mixture of tuberculosis-like granuinitial beneficial response to steroids does not ensure lomatous inflammation and necrosis with suppurative that the disease process is unrelated to an infectious neutrophilic inflammation. Eosinophils are usually riot organism. Furthermore, whereas relapse of the pula prominent component to these inflammatory reacmonary infiltrates during steroid tapering is a feature of tions.' It is important to recognize that these hypersenidiopathic chronic eosinophilic pneumonia, worsening sitivity type pulmonary eosinophilic reactions may of pulmonary infiltrates and clinical symptoms during occur in the presence of active infection and that a the course of steroid therapy is an ominous sign and an histologic diagnosis of chronic eosinophilic pneumonia indication for an aggressive clinical and laboratory or pulmonary eosinophilia suggestive of a hypersenworkup for an infectious etiology. In summary, we.present twopatients with coccidioi --.!'iU:~:~i!),_ X~il~ t!Qn ml~~t be int~!,preted ilUhe clinical setting in which it occurs . Pulmonary eosinophilia has domycosis and associated pulmonary eosinophilia. In been described in association with a variety of parasitic one, the organisms were identified in tissue sections diseases including infestations with members of the taken at open lung biopsy. In the other, no organisms ne~atode (roundworms), trematode (flukes), and were identified on open lung biopsy, and the patient cestode (tapeworms) families." The spectrum of was treated with immunosuppressive agents for a mucoid impaction-c-bronchocentric granulomatosispresumed hypersensitivity reaction. Following initial chronic eosinophilic pneumonia has been reported in improvement, she developed a rapidly fatal dissemiassociation with Aspergillus infection in patients with nated coccidioidomycosis infection. The pulmonary and without clinical asthma. in addition , similar eosinophilia in these cases represent a hypersensitivity changes have been seen with other more unusual reaction to coccidioidomycosis and distinguishing this from idiopathic hypersensitivity reactions is crucial for fungal infections. 7 Less frequently, eosinophilic pneu--------nrT1T....rom~.rnrel1 reported'tn , C, 011 \ I I""J~ II"'II':-,C;,C,..,I~U'"II'"S,---::==::-:~::-;~t~==.-proper care 0 t 1C pati ent. -~_--------------by brucellosis, B atypical Mycobacterium, " and CorREFERENCES ynebacterium pseudotuberculosis.10 Given these possibilities, we feel the following 1 Drutz DJ, Catanzaro A. Coccidioidomycosis: part 2 . Am Rev Respir Dis 1978; 727-71 points are useful in distinguishing these rare cases of 2 Echols RM , Palmer DL, Long CW. Tissue eosinophilia in human hypersensitivity type pulmonary eosinophilic reaccoccidioidomycosis. Rev Infect Dis 1982; 4:656-64 tions to infectious agents from idiopathic hypersen3 Fiese MJ. Coccidioidomycosis . Springfield, Ill : Charles C sitivity reactions. First, the patient may live in or have Thomas 1958:i04-26 visited an area where parasitic or fungal agents are 4 Huntington RW, Waldmann WJ, Sargent JA, O'Connell Ii, Wybel R, croli D. Pathologic and clinical observations on 142 endemic. Second, serologic studies and skin tests play cases offatal coccidioidomycosis with necropsy. In : Ajello L, cd . an important role in diagnosis of coccidioidomycosis as Coccidioidomycosis. Tucson: University of Arizona Press , 1967: well as other infections. In the second case, appropri143-67 ate serologic studies and skin testing could have led to 5 Katzenstein A. Liebow AA, Friedman PJ. Bronchocentric granuthe diagnosis of a coccidioidal infection. Third, belomatosis, mucoid impaction, and hypersensitivity reactions to fungi. Am Rev Respir Dis 1975; 111:497-537 cause of the frequency with which helminthic infec6 Spry Cj E Lung diseases associated with eo sinophils . In : Current tions are associated with eosinophilia, stool examinaperspectives in allergy. Edinburgh: Churchill Livingstone, 1982: tion for ova and parasites is important to include. 67-77 The chest roentgenogram offers valuable clues for 7 Glan cy J). Elder JL , McAleer R. Allergic bronchopulmonary this differential diagnosis. The roentgenographic apfungal disease without clinical asthma. Thorax 1981; 36:345-49 8 Elsom KA, Ingelfinger FJ. Eosinophilia and pneumonitis in pearance of classic idiopathic chronic eosinophilic chronic brucellosis : A report of two cases . Ann Intern Med 1942; pneumonia has been described as the photographic 16:995-1002 negative of pulmonary edema." This distribution of 9 Wright JL, Pare PD , Hammond M, Donevan RE . Eosinophilic infiltrates was not present in the two cases we present. pneumonia and atypical mycobacterial infection. Am Rev Respir It was also absent in the reported cases of eosinophilic Dis 1983; 127:497-99 10 Keslin MH, McCoy EL, McCusker JJ, Lutch JS. Corynebacpneumonia occurring in association with atypical Myterium pseudotuberculosis: a n ew cause of infectious and cobacterium, Corynebacterium pseudotuberculosis, eosinophilic pneumonia. Am J Med 1979; 67:228-302 and brucellosis . Although idiopathic eosinophilic 11 Caensler EA, Carrington CB. Peripheral opacities in chronic pneumonia has been reported to have roentgenoeosinophilic pneumonia: the photographic negative of pulmographic patterns of infiltrate other than that classically nary cdema. AJR 1977; 128:1-13 736

Pulmonary Eosinophilia in Coccidioidal Infections (Lombard, Taze/aar, Krasne)