Cryptococcosis

Many patients with rheumatoid arthritis are being treated with immunosuppressive regimens that include an agent directed at blocking tumor necrosis factor (TNF)-[alpha]. Although reportedly safe, tuberculosis and fungal infections have emerged as significant complications of therapy. We report a case of pulmonary cryptococcosis soon after the initiation of therapy with the anti-TNF-[alpha] antibody, infliximab. A diagnosis was made early in the disease course, and the patient responded quickly to antifungal therapy. This case should alert clinicians to the increased incidence of pulmonary mycoses in patients receiving anti-TNF-[alpha] therapy.

Key words: cryptococcosis; Cryptococcus neoformans; infliximab; tumor necrosis factor-[alpha]

Abbreviation: TNF = tumor necrosis factor

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Pulmonologists often participate in the care of immuno-compromised patients, as the majority of infections in this population involve the lungs. The immunosuppressive effects and infectious complications associated with the use of traditional cytotoxic agents are well known. The immunosuppressive effect of targeted anticytokine therapy, however, is just now being defined. Infliximab, a chimeric monoclonal antibody against tumor necrosis factor (TNF)-[alpha], has revolutionized the care of patients with rheumatoid arthritis. Interestingly, the spectrum of infectious disease associated with the use of anti-TNF-[alpha] therapy is similar to that in patients with AIDS and includes tuberculosis, (1) histoplasmosis, (2) and cryptococcosis. (3) This suggests that anti-TNF- [alpha] therapy produces a downstream defect ill the T-helper type 1 arm of immunity. We report a ease of pulmonary cryptococcosis after the initiation of infliximab. Symptoms resolved with discontinuation of infliximab and treatment with antifungal therapy.

CASE REPORT

A 61-year-old man with a 6-year history of advanced rheumatoid arthritis was admitted to the Veterans Affairs hospital for shortness of breath and anemia. His indications included prednisone, 10 mg/d; methotrexate, 25 mg/wk; and leflunomide, 20 mg/d. He was started on infliximab and received three doses at 3 mg/kg ideal body weight, the last dose being administered 3 weeks prior to presentation.

He denied fever, chills, night sweats, chest pain, and weight loss. He denied any sick contacts or recent travel outside Indiana. He lives in a trailer home surrounded by large trees. Physical examination revealed a temperature of 37.7[degrees]C, respiratory rate of 20 breaths/min, BP of 125/61 mm Hg, pulse rate of 85 beats/min, and room air oxygen saturation of 96%. Lungs were clear to auscultation. He had upper-extremity synovitis and rheumatoid skin nodules.

Admission blood work was remarkable for a normal cell count and differential, hemoglobin of 7.1 g/dL, and platelets of 640,000/ [micro] L. The biochemistry profile and liver enzyme findings were normal. Chest radiography showed a round opacity with adjacent airspace disease in the right lower lobe (Fig 1). Subsequent testing included a nonreactive tuberculin skin test, negative fungal serology results, negative serum cryptococcal antigen, and a negative HIV screen. A CT guided, fine-needle aspiration of the parenchymal lesion was performed. Direct smear showed "few fungal elements" and mixed inflammatory cells. Seventeen days later, fungal cultures grew Cryptococcocus neoformans, Infliximab therapy was discontinued, The patient was treated with amphotericin-B, followed by fluconazole maintenance therapy, with significant improvement of respiratory, symptoms.

[FIGURE 1 OMITTED]

DISCUSSION

The lung is the site of primary infection with C neoformans. Containment and effective control of this infection requires intact host defenses, Immunosuppression can lead to dissemination to the CNS and reticuloendothelial system. In the absence of effective antifungal therapy, immunocompromised patients with pulmonary cryptococcosis are at an increased risk of dissemination with significant morbidity and mortality. (4)

TNF-[alpha] plays a major role in the generation of cell-mediated immunity to cryptococcal infection in the lung. (5) In a murine model of cryptococcal pneumonia, pretreatment with anti TNF-[alpha] antibodies dramatically reduced the recruitment of inflammatory cells, hampered the development of cell-mediated immunity, and led to dissemination. (6) Moreover, TNF-[alpha] is essential in maintaining a T-helper type 1 immune response, (7,8) as it induces the production of interleukin-12 and interleukin-18, with sub sequent production of fungicidal interferon-[gamma]. (9)

TNF-[alpha] blockade has become a popular anti-inflammatory strategy in the treatment of rheumatoid arthritis and Crohn disease. Despite reported safety of these agents, infectious complications have been linked to the use of infliximab and etanercept, (1,2) the two anti-TNF- [alpha] regimens currently available in the United States. Since approval of these agents in 1998, through June 2001, the Adverse Event Reporting System of die US Food and Drug Administration has reported four cases of cryptococcosis related to the use of etanercept but none with infliximab. (10)

We describe a patient with pulmonary cryptococcosis that developed shortly after initiation of infliximab for severe rheumatoid arthritis. The diagnosis was made early, and appropriate therapy was initiated before evidence of dissemination. To date, three other patients (Table 1) with pulmonary cryptococcosis have been reported and linked to the use of infliximab, (3,11,12) The infection was limited to the respiratory tract in three of the four patients. Dissemination was evident in one patient when antifungal therapy was initiated later, after five doses of infliximab had been received. (3) These infections occurred early, likely within 2 months of initiating therapy give n current dosing regimens of infliximab, suggesting that infectious complications can occur quickly. New pulmonary infiltrates in a patient receiving anti-TNF-[alpha] therapy should be aggressively pursued, as infections are common and delay in diagnosis is likely to be associated with disseminated disease and significant morbidity. This case should alert clinicians to the increased incidence of pulmonary mycoses in patients receiving anti-TNF-[alpha] therapy.

REFERENCES

(1) Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor- [alpha] neutralizing agent. N Engl J Med 2001; 345:1098-1104

(2) 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

(3) True DG, Penmetcha M, Peekham sJ. Disseminated cryptococcal infection in rheumatoid arthritis treated with methotrexate and infliximab, J Rheumatol 2002; 29:1561-1563

(4) Kerkering TM, Duma RJ, Shadomy S. The evolution of pulmonary cryptococcosis: clinical implications from a study of 41 patients with and without compromising host factors. Ann Intern Med 1981; 94:611-616

(5) Bauman SK, Huffnagle GB, Murphy JW. Effects of tumor necrosis factor [alpha] on dendritic cell accumulation in lymph nodes draining the immunization site and the impact on the anticryptococcal cell-mediated immune response. Infect Immun 2003; 71:68-74

(6) Huffnagle G, Toews G, Burdick M, et al. Afferent phase production of TNF- [alpha] is required for the development of protective T cell immunity to Cryptococcus neoformans. j Immunol 1996; 157:4529-4536

(7) Herring AC, Lee J, McDonald RA, et al. Induction of interleukin-12 and [gamma] interferon requires tumor necrosis factor [alpha] for protective Tl-cell-mediated immunity to pulmonary Cryptococcus neoformans infection. Infect Immun 2002; 70:2959-2964

(8) Gardam MA, Keystone EC, Menzies R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 2003; 3:148-155

(9) Kawakami K, Qureshi MH, Koguchi Y, et at. Role of TNF- [alpha] in the induction of fungicidal activity of mouse peritoneal exudate cells against Cryptococcus neoformans by IL-12 and IL-18. Cell Immunol 1999; 193:9-16

(10) Adverse Event Reporting System (AERS). Center for Drug Evaluation and Research, US Food and Drug Administration. Available at: http://www.fda.gov/eder/aers/. Accessed November 6, 2003

(11) Starrett WG, Czachor J, Dallal M, et al. Cryptococcal pneumonia following treatment with infliximab for rheumatoid arthritis [abstract 374]. Presented at the 40th Annual Meeting of the Infectious Diseases Society of America, October 24-27, 2002; book of program mad abstracts, page 110

(12) Shrestha R, Stoller JK, Procop G, et al. Possible zoonotic transmission of Cryptococcus neoformans from a pet cockatiel to a patient associated with infliximab [abstract 376]. Presented at the 40th Annual Meeting of the infectious Diseases Society of America, October 24-27, 2002; book of program and abstracts, page 110

* From Pulmonary Critical Care (Drs. Hage, Wood, and Knox) and Infectious Diseases (Dr, Wilson), Department of Medicine (Dr. Sarosi), and the Department of Radiology (Dr. Winer-Muram), Indiana University School of Medicine, Indianapolis. IN. Funding was provided by grant K08 HL04545 to Dr. Knox. Manuscript received April 9, 2003; revision accepted June 12, 2003.

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Correspondence to: Kenneth S. Knox, MD, FCCP, Center for Sarcoidosis and Immunologic Lung Disease, Indiana University School of Medicine, 1001 West Tenth St. WD/OPW 425, Indianapolis, IN 46202; e-mail: kknoxl@iupui.edu

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