Coccidioidomycosis pneumonia in a nonendemic area associated with infliximab.

Abstract: Tumor necrosis factor (TNF) inhibitors, such as infliximab, are highly effective in the management of rheumatoid arthritis; however, these agents are associated with an increased risk of infectious complications. Individuals developing coccidiomycosis pneumonia frequently acquire this while residing in endemic regions. We present a patient with rheumatoid arthritis treated with infliximab who developed acute respiratory distress syndrome (ARDS) from coccidiomycosis pneumonia while residing in a nonendemic region near the Texas-Louisiana border and was successfully treated with antifungal therapy. The source for coccidiomycosis was suspected to be from inhalation of pulverized rock dust imported from Arizona. Patients treated with TNF inhibitors may acquire coccidiomycosis infection through fomite dust exposure.

Key Words: infliximab, tumor necrosis factor inhibitor, coccidiomycosis, pneumonia, rheumatoid arthritis

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Pulmonary manifestations frequently occur in patients with severe rheumatoid arthritis (RA) and when present, may result from pleuropulmonary involvement, infectious or drug-related complications. (1) Effective treatment of RA has led to the use of tumor necrosis factor-[alpha] (TNF) inhibitors; however, these have been associated with an increased risk of bacterial, tuberculous and fungal infections. (2,3) We present a patient with RA treated with infliximab who developed coccidiomycosis pneumonia while residing in a nonendemic region. Moreover, exposure to fomites from an endemic area was the likely source for his coccidiomycosis pneumonia.

Case Report

A 50-year-old male presented with three weeks of progressive dyspnea, fatigue and productive cough. He was diagnosed with RA at age 20 and treated with prednisone, methotrexate, and infliximab (5 mg/kg) (Remicade; Centocor Inc.; Horsham, PA) for two years with a satisfactory clinical response. He was a nonsmoking, retired pipeline technician who had lived in California for several months as an adolescent. For 35 years, he lived in a town near Beaumont, Texas, 30 miles from the Louisiana border, and had not traveled outside southeast Texas for the past twenty-five years. For several months he was exposed to dust that covered his home and car which emanated from a nearby construction facility where rock and gravel imported by rail from Arizona was stored.

Initial physical examination revealed a nontoxic-appearing male with a blood pressure of 110/60 mm Hg, pulse 72 minute, (1) respiratory rate 18 minutes, (1) temperature 37[degrees]C and Sp[O.sub.2] 88% (ambient air). Physical examination revealed cervical neck stiffness and prominent deformities of the hands, feet and knees. Chest auscultation revealed bilateral rhonchi with no murmurs or rubs. Initial laboratory data revealed a leukocyte count of 5,400 cells [mm.sup.3], hemoglobin 12 g/dL, and a normal platelet count. Chest radiography demonstrated new nodular and linear opacities (Fig.). Chest CT revealed bilateral infiltrates with mediastinal adenopathy and bronchoscopy demonstrated a normal-appearing tracheobronchial tree. Bronchoalveolar lavage did not reveal an organism or neoplastic cells. A transbronchial fine needle aspirate of a subcarinal lymph node demonstrated lymphoid tissue with a granuloma and rare intracellular spherules subsequently identified as Coccidioidis immitis. Unfortunately, he was released before the initiation of antifungal therapy, but returned several weeks later with fever, diffuse radiographic infiltrates and respiratory failure. A lumbar puncture did not demonstrate evidence of CNS involvement, and he was initiated on amphotericin and itraconazole. Over several days his condition deteriorated, requiring mechanical ventilation for treatment of ARDS. Seven weeks later, mechanical ventilation was discontinued, and he was released to a skilled nursing facility on itraconazole. Six months after hospital discharge, he was ambulating, oxygen-free with an improved chest x-ray while on itraconazole, methotrexate and prednisone.

Discussion

Infliximab is a TNF antagonist which has been successfully used in the treatment of rheumatoid and psoriatic arthritis and inflammatory bowel disease. (2,3) However, infliximab and other TNF inhibitors have been associated with an increased risk of tuberculous and fungal infections. (4,5,6) A retrospective study of patients residing in California, Arizona and Nevada found that infliximab administration was associated with a greater risk for coccidioidomycosis compared with patients not receiving infliximab. In endemic areas, coccidioidomycosis commonly presents as cough, fever, and pleuritic chest pain and is a self-limited process in the majority of individuals. (7) After resolution of primary coccidioidal pneumonia, an asymptomatic nodule or thin-walled cavity is not uncommon and this gradually resolves. Immunocompromised individuals may present with fever, cough and respiratory failure with chest radiographic features of bilateral reticulonodular or miliary infiltrates. Diagnosis frequently requires sampling of lower respiratory secretions or biopsy of an involved organ. Unfortunately, respiratory failure in the immunocompromised carries a high mortality rate. (7) Sporadic cases of coccidioidomycosis occurring in nonendemic areas are frequently mistaken for other entities. One report described 23 patients developing coccidioidomycosis while living in nonendemic areas and noted that 20 patients had previously resided or traveled to endemic regions, one patient had exposure to fomites from an endemic area, and in two cases, the source was not identified. (8)

Our patient had no recent travel to an endemic area, but described exposure to dust from crushed rocks transported from Arizona. Whether he developed pneumonia due to reactivation of an infection acquired over 25 years previously, or from the dust exposure, is uncertain; however, we believe the latter was more likely since an earlier chest x-ray did not reveal nodules or cavities and his clinical course deteriorated after dust exposure. To our knowledge, this is the first published report of coccidioidomycosis pneumonia associated with infliximab therapy in a person residing in a nonendemic area.

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Clearly, patients treated with TNF inhibitors need to be screened for previous infections with simple measures such as a chest x-ray and Mantoux skin testing before initiation of biologic therapies. (9) We recommend a thorough history regarding prior residence in endemic areas be obtained before initiation of TNF inhibitor therapy and that a chest x-ray be obtained to screen for features indicative of past respiratory infections.

References

1. Triggiani M, Granata F, Giannattasio G, et al. Lung involvement in rheumatoid arthritis. Sarcoidosis Vasc Diffuse Lung Dis 2003;20:171-179.

2. Liang GC, Cordero M, Dyer A, et al. Current tumor necrosis factor-alpha inhibitor use is associated with a higher probability of remissions in patients with rheumatoid arthritis. J Rheumatol 2005;32:1662-1665.

3. Hamilton CD. Immunosuppression related to collagen-vascular disease or its treatment. Proc Am Thorac Soc 2005;2:456-460.

4. Hochberg MC, Lebwohl MG, Plevy SE, et al. The benefit/risk profile of TNF-blocking agents: findings of a consensus panel. Semin Arthritis Rheum 2005;34:819-836.

5. Wood KL, Hage CA, Knox KS, et al. Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. Am J Respir Crit Care Med 2003;167:1279-1282.

6. Bergstrom L, Yocum DE, Ampel NM, et al. Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor alpha antagonists. Arthritis Rheum 2004;50:1959-1966.

7. Chiller TM, Galgiani JN, Stevens DA. Coccidioidomycosis. Infect Dis Clin North Am 2003;17:41-57.

8. Desai SA, Minai OA, Gordon SM, et al. Coccidioidomycosis in nonendemic areas: a case series. Resp Med 2001;95:305-309.

9. Carmona L, Gomez-Reino JJ, Rodriguez-Valverde V, et al. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum 2005;52:1766-1772.

Mahmood Dweik, MD, Bruce A. Baethge, MD, and Alexander G. Duarte, MD

From the Division of Allergy, Pulmonary, Immunology, Critical Care and Sleep Medicine, and the Division of Rheumatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX.

Reprint requests to Alexander G. Duarte, MD, Associate Professor, Division of Allergy, Pulmonary, Immunology, Critical Care and Sleep Medicine, University of Texas Medical Branch, 301 University Boulevard Galveston, TX 77555. Email: [e-mail]

Drs. Duarte, Dweik and Baethge do not have financial interests in any of the products included in this report and do not have any information to disclose concerning personal or financial support regarding material presented in this report.

Accepted July 13, 2006.

RELATED ARTICLE: Key Points

* Patients receiving infliximab are prone to the development of infectious complications.

* Coccidiomycosis pneumonia is a fungal infection previously noted to occur in patients residing in endemic regions while receiving TNF inhibitor therapy.

* In the present case, fomite-dust exposure was the most likely source for coccidiomycosis pneumonia.

* Before initiation of biologic therapies, patients considered as candidates for TNF inhibitor treatment should be screened for respiratory infections with a chest x-ray and Mantoux skin testing.