Fusarium oxysporum pneumonia in an immunocompetent host.

Abstract: A case of symptomatic pulmonary infection caused by Fusarium oxysporum occurred in a woman after she had cleaned out bird droppings from a boat house. She was also a gardener who had mild, chronic obstructive lung disease, but who had no evidence of systemic immunosuppression. She was treated with oral voriconazole for four months and had marked clinical improvement and mycological cure. To the best of our knowledge, this is the first reported case of isolated pulmonary fusariosis in an apparently immunocompetent person. Oral voriconazole therapy was effective in this clinical setting.

Key Words: Fusarium oxysporum, pulmonary fusariosis, voriconazole

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Fusarium species occur in soil, water, and decaying organic debris, and they are effectively dispersed by airborne mechanisms, especially wind and rain. The genus Fusarium is the second most common mold-causing invasive infection in severely immunosuppressed patients and is especially common in patients with hematological malignancies or recipients of solid organ, stem cell or allogeneic bone marrow transplants. In immunocompetent patients, infections have been reported in patients with wounds or in the presence of foreign bodies that impair natural host defenses, such as central venous or peritoneal dialysis catheters. (1-3)

We report a case of pulmonary Fusarium oxysporum infection in a patient with a likely airborne exposure to a bioaerosol while cleaning out bird droppings from her boathouse. She carried a diagnosis of mild, chronic obstructive pulmonary disease without evidence of systemic immunocompromise.

Case Report

A 69-year-old Caucasian woman presented to the outpatient pulmonary clinic with a one month history of cough, mucopurulent sputum, low grade fevers, occasional night sweats, and weight loss of three to five pounds. She denied dyspnea, wheezing, chest pain, hemoptysis, rash, or sinus congestion.

The patient was diagnosed with mild, chronic obstructive pulmonary disease, hypertension, and osteoporosis. She had a 35 pack-year history of cigarette smoking but had stopped 10 years before. Two years earlier, she presented with a productive cough, night sweats, malaise, and pulmonary infiltrates. Mycobacterium avium complex (MAC) was diagnosed, and she was successfully treated with an 18-month course of ethambutol, rifabutin, and clarithromycin.

The patient denied any travel outside New England, enjoyed gardening, and had recently cleaned out bird droppings from a boathouse at her summer camp in Maine. On physical examination, she was thin, deeply tanned, and was breathing comfortably with a respiratory rate of 16 and an oxygen saturation of 100% on room air. Her temperature was 97.6[degrees]F, and she weighed 106 pounds. There was no lymphadenopathy. Breath sounds were generally diminished, but no crackles or wheezes were heard. Cardiac and abdominal examinations were unremarkable. No digital clubbing or edema was noted.

Laboratory data included a leukocyte count of 11.4 K/[micro]L with a normal differential, hemoglobin 12.8 g/dL, hematocrit 38, platelets 208 K/[micro]L, erythrocyte sedimentation rate 35 mm/h (normal 0-20), and a normal C-reactive protein (<5 mg/L).

Her chest x-ray showed bilateral, hazy, apical opacities with a nodular opacity in the right mid-lung zone. Computed tomography (CT) scan of the thorax showed multiple, small, right apical nodules; lingular and right middle lobe consolidation; right middle lobe bronchiectasis; and mediastinal lymphadenopathy (Fig. 1 and 2). These findings were new when compared with a CT scan from 13 months before.

On flexible fiberoptic bronchoscopy, there was diffuse, purulent bronchorrhea in the airways (Fig. 3). Septate hyphae and budding yeast cells were seen on direct examination of bronchial washings by Calcofluor white stain. Saccharomyces cerevisiae and [beta]-lactamase negative H influenzae grew, but the culture was overgrown by F oxysporum, which was confirmed at the fungal testing laboratory at the University of Texas Health Science Center at San Antonio. Susceptibility testing of the F oxysporum isolate defined minimum inhibitory concentrations (MICs) of amphotericin, itraconazole, and voriconazole as 2.0, >8.0, and 8 [micro]g/mL, respectively.

Additional laboratory investigations included negative fungal blood cultures, negative HIV antibody, and normal immunoglobulins. Flow cytometry showed normal peripheral CD4 and CD8 counts, and no population of abnormal lymphocytes. The CD4/CD8 ratio in the bronchoalveolar fluid was normal. Transbronchial needle aspiration of a right pretracheal lymph node showed numerous lymphocytes, a reactive process, and no tumor cells on cytological examination.

The patient was treated with levofloxacin 500 mg daily for one week without any improvement. Subsequently, after identification of F oxysporum infection, she was treated with voriconazole 200 mg orally twice daily, and her pulmonary symptoms completely resolved over the next few weeks. Following four months of voriconazole therapy, repeat lung imaging showed resolution of the radiographic abnormalities. She has remained free of disease for more than 16 months.

Discussion

Aspergillus spp., followed by Fusarium spp., are the leading cause of opportunistic mold infections and are associated with significant morbidity and mortality in immunosuppressed patients with hematologic malignancies, solid organ, bone marrow or stem cell transplants. (1-4) Fusarium spp. are ubiquitous fungi that are soil saprophytes and plant pathogens. Human infections are known to occur with F solani, F oxysporum, F moniliforme, F verticillioides, F dimerum, and F proliferatum, although F solani is the most common. (1-4) These organisms are responsible for a broad range of diseases in humans, ranging from localized, cutaneous involvement to disseminated infection. (1,3,4) Local infections typically include keratitis, ulcers, cellulitis, mycetomas, peritonitis, and onychomycosis. (2,3)

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Risk factors for disseminated infection include profound neutropenia, lymphopenia, graft-versus-host disease, severe burns, immunosuppressive or corticosteroid therapy, and indwelling venous catheters. (2,3) Disseminated infection in immunocompromised patients may be manifested by fever and involvement of any organ, but more commonly the skin, lungs, and sinuses. In life-threatening infections, the skin is frequently the primary source of infection. (5) Fungemia occurs in about 40 to 60% of these patients. (2,3) Disseminated fusariosis in immunocompromised patients carries a mortality of 50 to 80%. (3) Significant predictors of poor outcome include persistent neutropenia and corticosteroid therapy. (6) Resolution of neutropenia is the most important predictor of survival in immunocompromised patients. (1,3,6)

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Several cases of isolated pulmonary Fusarium infection have been reported, all in patients with documented, underlying immunocompromised states. The major portal of entry besides the skin appears to be inhalation of Fusarium micro-conidia from the environment. In one case, a lung transplant recipient, who spent considerable time gardening, developed a cavitary pneumonia due to F solani. (7) A case of F moniliforme pneumonia was reported in an immunocompromised child who participated in farming. (8) Pneumonia has been reported in 84% of cases of disseminated fusariosis. (5) Imaging of pulmonary fusarial infections may show nonspecific infiltrates and nodular or cavitary lesions. (4,6)

Two cases of primary sinus infection by Fusarium spp. were reported in immunocompetent, young male farmers. (9) Our patient, who had a history of COPD and opportunistic infection due to MAC, also engaged in gardening and frequently cleaned out organic debris, such as bird feces, from a boathouse without wearing respiratory protection. We postulate that these activities may have served as the source of her Fusarium infection.

Fusarium infections are difficult to treat and often refractory to established antifungal agents. Many of the in vivo data are from patients with refractory disease or those previously treated with other agents, thereby illustrating the limited activity of antifungals against Fusarium spp. Recently, the National Committee for Clinical Laboratory Standards (NCCLS) proposed the M38-A document for antifungal susceptibility testing of molds. However, standardized methodology for establishing MICs of antifungal drugs is not always utilized, and MICs may vary according to inoculum size and incubation time. Therefore, breakpoints are not available for any antifungal agent against molds. (10,11)

Voriconazole has been approved for the treatment of serious infections with Fusarium spp. A case of successful treatment of disseminated fusariosis with a combination of voriconazole and high-dose liposomal amphotericin B in a patient with severe aplastic anemia has been described. (12) Another case report describes a patient with acute myelogenous leukemia who was treated successfully with voriconazole after failure of treatment with amphotericin B and liposomal amphotericin B. (13) In a recent study by Perfect et al, 45% (5 of 11) of patients with refractory fusariosis treated with voriconazole had a satisfactory global response, and the proportion of subjects alive at 90 days was 0.71. (14)

Conclusion

To our knowledge, this case is the first documented case of primary pulmonary infection due to F oxysporum in an apparently immunocompetent individual. This case report is noteworthy for several other reasons, including the likely route of airborne infection and the documentation of pulmonary Fusarium infection in an immunocompetent host with a history of mild COPD and prior pulmonary MAC. Finally, data on the management of pulmonary fungal infections with oral voriconazole are limited, and our patient had an excellent clinical response to therapy with complete resolution of her symptoms and pulmonary infiltrates. She has remained asymptomatic for more than 16 months since the conclusion of antifungal therapy. She has been advised to refrain from cleaning bird droppings from her boathouse or to wear a mask if she continues to perform this task.

References

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2. Walsh TJ, Groll A, Hiemenz J, et al. Infections due to emerging and uncommon medically important fungal pathogens. Clin Microbiol Infect. 2004;10(Suppl. 1):48-66.

3. Dignani MC, Anaissie E. Human fusariosis. Clin Microbiol Infect. 2004;10(Suppl. 1):67-75

4. Fleming RV, Walsh TJ, Anaissie EJ. Emerging and less common fungal pathogens. Infect Dis Clin N Amer 2002;16:915-933.

5. Boutati EI, Anaissie EJ. Fusarium, a significant emerging pathogen in patients with hematologic malignancy: ten years' experience at a cancer center and implications for management. Blood 1997;90:999-1008.

6. Nucci M. Anaissie EJ, Queiroz-Telles F, et al. Outcome predictors of 84 patients with hematologic malignancies and Fusarium infection. Cancer 2003;98:315-319.

7. Arney KL, Tiernan R, Judson MA. Primary pulmonary involvement of Fusarium solani in a lung transplant recipient. Chest 1997;112:1128-1130.

8. Zach TL, Penn RG, Gnarra DJ, et al. Fusarium moniliforme pneumonia. Nebr Med J 1987;72:6-9.

9. Kurien M, Anandi V, Raman R, et al. Maxillary sinus fusariosis in immunocompetent hosts. J Laryngol Otol 1992;106:733-736.

10. Espinel-Ingroff A. Utility of mould susceptibility testing. Curr Opin Infect Dis 2003;16:527-532.

11. Paphitou NI, Ostrosky-Zeichner L, Paetznick VL, et al. In vitro activities of investigational triazoles against Fusarium species: effects of inoculum size and incubation time on broth microdilution susceptibility test results. Antimicrob Agents Chemother 2002;46:3298-3300.

12. Rodriguez CA, Lujan-Zilbermann J, Woodard P, et al. Successful treatment of disseminated fusariosis. Bone Marrow Transplant 2003;31:411-412.

13. Consigny S, Dhedin N, Datry A, et al. Successsful voriconazole treatment of disseminated fusarium infection in an immunocompromised patient. Clin Infect Dis 2003;37:311-313.

14. Perfect JR, Marr KA, Walsh TJ, et al. Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis 2003; 36:1122-1131.

Most people would succeed in small things if they were not troubled with
great ambitions.
--Henry Wadsworth Longfellow

Stephen R. Gorman, DO, MSC, Anna-Pelagia Magiorakos, MD, Sarah K. Zimmerman, MED, and Donald E. Craven, MD

From the Departments of Pulmonary and Critical Care Medicine, Mycobacteriology, Parasitology, and Mycology Laboratory, and Department of Infectious Diseases, Lahey Clinic Medical Center, Burlington, MA; Department of Infectious Diseases, New England Medical Center, Boston, MA; and Tufts University School of Medicine, Boston, MA.

Reprint requests to Stephen R. Gorman, DO, Department of Pulmonary and Critical Care Medicine, Lahey Clinic Medical Center, 41 Mall Road, Burlington, MA 01805. Email: [e-mail]

Disclosure: Dr. Gorman is on the speaker's bureau of Pfizer, Elan, and Wyeth. Dr. Craven is on the speaker's bureau for Pfizer, Elan, and Merck.

Accepted January 23, 2006.

RELATED ARTICLE: Key Points

* Isolated pulmonary Fusarium oxysporum infection has not been previously reported in immunocompetent patients.

* Fusariosis should be considered in immunocompetent patients exposed to bird feces, soil, and in those with chronic lung disease.

* Oral voriconazole appears to be effective in producing mycological cure in this setting.