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Simultaneous Presentation of Cryptococcal Meningitis and Lupus Nephritis To the Editor: Infection is a significant cause of morbidity and mortality in systemic lupus erythematosus (SLE)1. Patients with lupus are known to be at heightened risk for common pathogens as well as opportunistic organisms1. Susceptibility to infection may be attributed to underlying immune dysregulation and to immunosuppressive therapy. Clinicians caring for these patients need to be familiar with the range of potential pathogens and maintain a high index of suspicion for infection whenever new symptoms or fevers occur. Indeed, severe life-threatening infection can not only mimic but can present simultaneously with new-onset lupus, based on our recent experience. A 30-year-old woman originally from Guatemala presented to the Johns Hopkins Hospital with acute renal failure. She was well until 2 months prior to admission, when she developed gradual onset of fatigue with intermittent diffuse abdominal discomfort and nausea. One week prior to admission, she developed diffuse myalgias and arthralgias involving the knees, hands, and wrists and pleuritic chest pain. Several days prior to admission she complained of a bitemporal headache without photophobia. Upon hospitalization, she was afebrile. She had no rash, oropharyngeal ulcers, or synovitis. Meningismus was absent; mental status and peripheral neurologic examination were unremarkable. Admission examinations included serum creatinine of 4.4 mg/dl and white blood cell (WBC) count of 2300 cells/mm3. Erythrocyte sedimentation rate was elevated at 102 mm/h. Profound hypocomplementemia was present, with C3 24 mg/dl and C4 3 mg/dl. Antinuclear antibody titer was 1:640. Anti-double-stranded DNA titer was markedly elevated at 1:640. Chest computer tomography scan revealed pleural and pericardial effusions. Renal histopathology showed WHO class IV glomerulonephritis with numerous crescents. Based on these findings she was diagnosed with SLE. The headache was initially attributed to lupus disease activity. Intravenous methylprednisolone was initiated at 1 gm/day for 3 consecutive days, followed by oral prednisone 60 mg/day. Given the severity of renal disease, intravenous cyclophosphamide was administered at 750 mg/m2. The day after cyclophosphamide infusion, she developed fever. She continued to have a mild intermittent headache and no abnormalities detected by neurologic or funduscopic examination. Lumbar puncture revealed normal cerebrospinal fluid (CSF) protein and glucose concentrations and only 12 WBC/mm3, but both CSF and blood cultures grew Cryptococcus neoformans. She was treated with a 14 day course of liposomal amphotericin, followed by a 42 day course of fluconazole, with prompt resolution of the fever and headache. Corticosteroids were gradually tapered. Subsequent blood and CSF cultures one month after diagnosis were negative for fungal growth. She did require hemodialysis at the time of discharge, but was not given additional cyclophosphamide during the hospitalization. A large variety of organisms have been reported in association with SLE including bacteria, mycobacteria, viruses, fungi, and protozoa2. Moreover, infections are reported to account for 14% of hospital admissions in affected persons3. Whether susceptibility to infection is due to immunosuppressive treatment only or to the underlying disease is uncertain. Glucocorticoid and cytotoxic drugs may suppress the immune system and heighten susceptibility to infection. Infection rates are reported to be 24 times higher in patients treated with compared to those treated without steroids4. Interestingly, there may be inherent immunologic abnormalities associated with lupus that also predispose to infection. Studies conducted prior to the widespread use of immunosuppressive therapies indicated an elevated risk of infection in lupus4. Further, deficiencies of complement components, which are known to predispose to development of lupus5, may also lead to impaired clearance of immune complexes and microbial pathogens6,7. Specifically, patients with lupus who possess deficient mannose-binding lectin are at higher risk for serious infection8. Cryptococcal meningitis is an uncommon complication of SLE. Most reports of cryptococcal disease in lupus describe patients who have been maintained on high levels and sustained durations of immunosuppressive therapy. Zimmermann, et al reported 2 new cases and reviewed the literature regarding 24 previous cases9. Mean duration of lupus at development of cryptococcal meningitis was 3.3 years. Twenty-four of these patients were treated with corticosteroids and 10 with azathioprine. The outcome without antifungal therapy was uniformly poor, and all 5 untreated patients died. In contrast, there were 8 deaths in the 20 patients treated with amphotericin. Further, there has been one previous report of a patient who developed cryptococcal meningitis concurrent with the diagnosis of SLE and prior to initiation of immunosuppressive therapy10. Our case represents the second report of a patient diagnosed with cryptococcal meningitis simultaneously with onset of SLE. We believe the unusual presentation suggests that underlying immune defects associated with lupus contributed to their infection, since both cases became clinically apparent before receipt of prolonged immunosuppression. K. KWASIND HUSTON, MD; ALLAN C. GELBER, MD, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Address reprint requests to Dr. A.C. Gelber, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Mason F. Lord Bldg. Center Tower, Suite 4100, Baltimore, MD 21224. E-mail: agelber@jhmi.edu REFERENCES 1. Hellmann DB, Petri M, Whiting-O'Keefe Q. Fatal infections in systemic lupus erythematosus: the role of opportunistic organisms. Medicine 1987;66:341-8. 2. Kang I, Park SH. Infectious complications in SLE after immunosuppressive therapies. Curr Opin Rheumatol 2003;15:528-34. 3. Petri M, Genovese M. Incidence of and risk factors for hospitalizations in systemic lupus erythematosus: a prospective study of the Hopkins lupus cohort. J Rheumatol 1992;19:1559-65. 4. Staples PJ, Gerding DN, Decker JL, Gordon RS. Incidence of infection in systemic lupus erythematosus. Arthritis Rheum 1974;17:1-10. 5. Walport MJ. Complement. Second of two parts. N Engl J Med 2001;344:1140-4. 6. Walport MJ. Complement. First of two parts. N Engl J Med 2001;344:1058-66. 7. Ross SC, Densen P. Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine 1984;63:243-73. 8. Garred P, Madsen HO, Halberg P, et al. Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus. Arthritis Rheum 1999:42:2145-52. 9. Zimmermann B, Spiegel M, Lally EV. Cryptococcal meningitis in systemic lupus erythematosus. Semin Arthritis Rheum 1992;22:18-24. 10. Mok CC, Lau CS, Yuen KY. Cryptococcal meningitis presenting concurrently with systemic lupus erythematosus. Clin Exp Rheumatol 1998;16:169-71.
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