coccidioides immitis: two cases of misidentified...

Can Respir J Vol 15 No 7 October 2008 377

Coccidioides immitis: Two cases of misidentified mycosis

Christine H Lee MD FRCPC1,2, Lindsay Wilcox ART2, Katherine Chorneyko MD FRCPC1,2, Andrew McIvor MD FRCPC3

1Department of Pathology and Molecular Medicine; 2Hamilton Regional Laboratory Medicine; 3Department of Medicine, McMaster University,Hamilton, Ontario

Correspondence: Dr Christine H Lee, Department of Pathology and Molecular Medicine, McMaster University, Hamilton Regional LaboratoryMedicine, St Joseph’s Healthcare, 50 Charlton Avenue East, 424 Luke Wing, Hamilton, Ontario L8N 4A6. Telephone 905-521-6021, fax 905-521-6083, e-mail [email protected]

CH Lee, L Wilcox, K Chorneyko, A McIvor. Coccidioides

immitis: Two cases of misidentified mycosis. Can Respir J

2008;15(7):377-379.

In the present report, two cases of pulmonary coccidioidomycosis that

caused a diagnostic confusion are presented. The first case was ini-

tially misdiagnosed as nonsmall cell carcinoma, and both cases were

initially misidentified as blastomycosis because of the presence of an

atypical morphological form of Coccidioides immitis.

Key Words: Coccidioides immitis; Pulmonary mycosis

Coccidioides immitis : Deux cas de mycose malidentifiés

On présente dans ce rapport deux cas de coccidioïdomycose pulmonaire

ayant prêté à une confusion diagnostique. Le premier cas a d’abord été

diagnostiqué à tort comme un cancer non à petites cellules et les deux cas

ont, à tort, été identifiés initialement comme une blastomycose en raison

de la morphologie atypique de Coccidioides immitis.

Coccidioides immitis exists in the semi-arid desert of thesouthwestern United States, northern Mexico, and

Central and South America. An estimated 100,000 new casesof C immitis infection occur in the United States annually, andmost commonly involve the lungs (1). Recognition of pul-monary infection is guided by an understanding of the epi-demiological factors associated with exposure, the use ofappropriate diagnostic tests and an awareness of the diversemanifestations of the pathogen (1,2).

C immitis is a dimorphic fungus that exhibits morphologi-cal variation in its mycelial and parasitic forms. It exists inthe desert soil as a mold. As the cells degenerate, barrel-shaped arthroconidia break off from the hyphae and becomeairborne. Arthroconidia undergo significant morphologicalchanges following inhalation into the lung. Within living tis-sue, it typically swells and develops into a large spherule con-taining numerous endospores. Endospores are released fromruptured spherules and develop additional spherules in theinfected host. Repeated cycles of endospore release andspherule formation in the lung lead to an area of pneumoni-tis; diagnosis is usually determined based on the presence ofthese endospores (1,3,4).

In rare cases, C immitis has been observed to have severereactive changes in bronchial epithelial cells as well as unchar-acteristic hyphae, which form arthroconidia in tissues or airspaces in the lung (2). Because of the presence of these unchar-acteristic hyphae, reactive bronchial epithelial cells in pul-monary coccidioidomycosis have been misdiagnosed ascarcinoma in cytological examinations (4,5). Finally, therehave also been reports of immature, atypical spherules ofC immitis, which have been confused with the budding cells ofBlastomyces dermatitidis (2). The presence of these unusualmorphological forms can lead to an incorrect diagnosis.

CASE PRESENTATIONSCase 1A 72-year-old man presented with a four-month history ofprogressive dyspnea, hemoptysis and weight loss. The patientwas a resident of southwestern Ontario and had been travel-ling to Arizona annually for six years. He had a significantsmoking history of 80 pack-years. Three years previously, hehad a left upper lobe cavitary lung lesion diagnosed as a poorlydifferentiated bronchogenic carcinoma with coexistent blas-tomycosis. For treatment, a left upper lobectomy was per-formed and itraconazole was given for six months. One yearbefore his current presentation, he had received an additional12-month course of itraconazole therapy for recurrent pul-monary blastomycosis.

The patient’s most recent chest x-ray showed left pleuralthickening, unchanged from three years previously. A pre-sumptive diagnosis of recurrent bronchogenic carcinomaand/or blastomycosis was made, and the patient underwentinvestigation with fibre optic bronchoscopy.

On bronchoscopy, abnormal tissue was found invading theleft lower lobe. Bronchoalveolar lavage (BAL), along withbrushings and a biopsy, was performed. The bronchial washingsmear showed atypical cells, interpreted as a poorly differenti-ated nonsmall cell carcinoma along with occasional organismsidentified as Blastomyces species. The biopsy specimen showedatypical squamous epithelium and fungal organisms compatiblewith Blastomyces species, but no malignant cells were detected.Direct microscopy of the tissue biopsy, which was performed inthe hospital microbiology laboratory using a calcofluor whitepreparation, showed the presence of a few spherules, suggestiveof C immitis. A culture of the specimen grew C immitis. Anucleic acid probe (AccuProbe, Gen-Probe Inc, USA) furtherconfirmed that the isolate was C immitis.

©2008 Pulsus Group Inc. All rights reserved

CASE REPORT

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In light of the alternative diagnosis, the microscopic slidesof the lung specimens obtained previously were re-examined.Periodic acid-Schiff and Gomori methenamine silver stainsshowed immature nonendosporulating cells and semi-maturespherules consistent with Coccidioides species (Figure 1).Typical mature spherules of C immitis were not present, butshowed individual, separately walled spherules adjacent to oneanother. There was no contiguity between adjacent cell walls,and no bud scars were present on the larger cells, as would befound with budding Blastomyces species (Figure 2).

Case 2A 51-year-old man presented with right-sided pleuritic chestpain and cough five days after returning from a camping tripto the Grand Canyon (Arizona, USA). He was treated withan oral antibiotic for community-acquired pneumonia, basedon his symptoms and an infiltrate on chest radiography. Atfollow-up, he complained of cough (only occasionally pro-ductive of clear sputum) and had no episodes of hemoptysis.He experienced intermittent fevers and chills, but no othersystemic complaints or weight loss. He was previously welland on no regular medications. Baseline blood work includ-ing complete blood counts, electrolytes, creatinine and liverenzymes were normal.

A repeat chest radiography and high-resolution computedtomography of the chest showed an opacity in the periphery ofthe right upper lobe. There were no calcifications or cavita-tions within the lesion. He underwent bronchoscopy, withBAL, mediastinoscopy and biopsy. The organisms seen on theBAL smear were interpreted by a pathologist to be consistentwith Blastomyces species. A culture of the specimen grewC immitis.

A three-month treatment with fluconazole 400 mg per daycompletely resolved the clinical symptoms and radiologicalfindings.

DISCUSSIONIn tissue specimens, detection of mature spherules containingendospores is pathognomonic of coccidioidomycosis and canbe identified with a variety of stains (4). Atypical forms ofC immitis in tissues from humans have been recognized in sev-eral studies (2). Immature nonendosporulating spherules can

resemble nonbudding forms of Blastomyces dermatitidis (2).Four distinct morphological forms (morula-like, broad-basedyeast-like, moniliform and true hyphae) of C immitis withoutthe typical endospores have been detected and confirmedusing fluorescent antibody reagents.

Occasionally, coccidioidomycosis has also been misdiag-nosed as carcinoma (4-6). Reactive atypia of pneumocytes isoften seen in cytological aspirates, and when spherules areundetected, the reactive atypia may be misidentified as carci-noma (6). Tissue biopsy is superior to cytological apirates fordirect visualization of the organism (6). The pitfalls of cytodi-agnosis have been highlighted in other reported cases of coc-cidioidomycosis misdiagnosed as carcinoma (5). Severelyreactive bronchial cells can be interpreted as malignant cellsbecause they have cytological features similar to nonsmall cellcarcinoma.

In our first patient, it is likely that chronic C immitis infec-tion contributed to chronic cough and dyspnea. Chronic pul-monary sequelae develop in approximately 5% of peopleinfected with C immitis, and may occur in individuals who aresymptomatic or asymptomatic at the time of primary infection(1). Occasionally, hemoptysis or low-grade fever may occur, asin the present report. Surgical therapy is indicated when thereis a rapidly expanding cavity, life-threatening hemoptysis, riskof rupture into the pleural space or recurrent superimposedbacterial infections. Otherwise, lifelong azole suppressive ther-apy should be administered for chronic pulmonary coccid-ioidomycosis (6).

CONCLUSIONOur first patient presented with pulmonary symptoms consistentwith pulmonary carcinoma. However, blastomycosis and coccid-ioidomycosis can present similarly and resemble each other clin-ically. During the first presentation, cultures for fungi were notperformed and the diagnosis was made based on microscopicmorphology. Coccidioidomycosis was diagnosed only after cul-ture was performed on lung tissue at follow-up. Because it is notuncommon for spherules to be absent, the morphological formspresent were confused with B dermatitidis. In such instances, anexamination of the specimen using fluorescent antibody ornucleic acid testing will be diagnostic in the absence of culturesor morphologically typical forms microscopically.

Lee et al

Can Respir J Vol 15 No 7 October 2008378

Figure 1) A bronchoalveolar lavage specimen stained with Gomorimethenamine silver

Figure 2) A lung tissue sample containing budding Blastomycesspecies stained with Gomori methenamine silver

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Our first patient may have had only chronic or recurrentcoccidioidomycosis and not carcinoma, or both diseases mayhave coexisted. The early, correct diagnosis of coccidioidomy-cosis is important to initiate appropriate therapy, and to pre-vent unnecessary diagnostic procedures and therapeuticmodalities such as lung resection or radiation.

Histopathologists should be aware of atypical forms ofCoccidioides species and be cautious in diagnosis of malignancyin the presence of this fungal infection.

CONFLICT OF INTEREST: There are no conflicts of interestfor any of the authors.

Coccidioides immitis: Two cases of misidentified mycosis

Can Respir J Vol 15 No 7 October 2008 379

REFERENCES 1. Goldman M, Johnson PC, Sarosi GA. Fungal pneumonias. The

endemic mycoses. Clin Chest Med 1999;20:507-19.2. Kaufman L, Valero G, Padhye AA. Misleading manifestations of

Coccidiodes immitis in vivo. J Clin Microbiol 1998;36:3721-3.3. Vaz A, Pineda-Roman M, Thomas AR, Carlson RW.

Coccidioidomycosis: An update. Hosp Pract (Minneap) 1998;33:105-8, 113-5, 119-20.

4. Stevens DA. Coccidioidomycosis. N Engl J Med 1995;332:1077-82.

5. Chen KT. Cytodiagnostic pitfalls in pulmonary coccidioidomycosis.Diagn Cytopathol 1995;12:177-80.

6. Case records of the Massachusetts General Hospital. Weeklyclinicopathological exercises. Case 35-1981. N Engl J Med1981;305:507-14.

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