Invasive Fungal Infections in Argentine Patients with Systemic Lupus Erythematosus

Introduction: Infections are the leading cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Invasive fungal infections (IFI) comprise a group of diseases caused by Cryptococcus, Histoplasma, Aspergillus and Candida. Few studies of IFI have been published in patients with SLE and associated factors have not been completely defined.

Objectives: The objectives of this paper are to estimate the frequency of IFI in admitted patients with SLE in our hospital, to determine the risk factors associated with IFI in our patients with SLE, and to compare IFI group with a control group (SLE without IFI).

Methods: The medical charts of patients with IFI (EORTC/MSG, 2008) and SLE (ACR, 1997) admitted to our hospital from June 2001 until June 2012 were reviewed. To identify factors associated with IFI, we developed a case-control study (SLE + IFI vs SLE alone) in a one to three ratio adjusted for sex and age and hospitalization for other reasons. Comparison was made of demographic characteristics, duration of disease and disease activity previous to IFI diagnosis, especially three months before fungal infection. We defined severe activity as SLEDAI ≥ 8. Infection by fungi of the genus Candida was considered only in its disseminated form.

Results: Ten cases of IFI were identified in 208 patients with SLE admitted between June 2001 and June 2012. We included 40 patients with SLE (10 with IFI and 30 controls). Of the SLE-IFI patients, eight were women and the average age was 27.5 years (range, 19-42 years). Fungal isolation: eight Cryptococcus neoformans, one Histoplasma capsulatum and one Candida albicans. Sites affected: five in peripheral blood, five in central nervous system (CNS), four in skin/soft tissue and one in pleura. Mortality was 40% (p = 0.002), with Cryptococcus neoformans being the most common fungus. The SLE disease activity was severe in 70% of infected patients and no significant difference with the control group was found (p = 0.195). We also found no association with leukopenia, lymphopenia, hypocomplementemia, hypogammaglobulinemia or anti-DNA positivity; neither with meprednisone doses >20 mg/day or intravenous methylprednisolone pulse therapy before fungal infection. The use of immunosuppressive therapy with azathioprine showed a significant association (p = 0.017). Cyclophosphamide (p = 0.100) or mycophenolate mofetil (p = 0.256) did not show similar results.

Conclusion: The frequency of IFI in hospitalized SLE patients in our hospital was 4.8%. Cryptococcus neoformans was the most common etiologic agent and was primarily responsible for the deaths in this cohort. These data are consistent with publications in East Asia rather than North America where Candida spp. is more common. Unlike other publications, previous immunosuppression with azathioprine was the only risk factor associated with the development of the infection. Invasive fungal infection should be suspected in hospitalized patients with SLE and immunosuppression with CNS or atypical cutaneous manifestation of SLE in order to start appropriate treatment early and obtain better outcome.