Invasive fungal disease in systemic lupus erythematosus: A systematic review of disease characteristics, risk factors, and prognosis

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Abstract

Objectives

Invasive fungal disease (IFD) is a life-threatening complication of systemic lupus erythematosus (SLE) and/or its treatment. We conducted a systematic review to characterize IFD in SLE and identify risk factors and outcomes.

Methods

MEDLINE, Embase, and Web of Science were searched up to June 2013 using MeSH terms and keywords pertaining to SLE and IFD. Two independent reviewers selected adult cohort studies and case series/reports on IFD in SLE based on the established classification criteria for both diseases.

Results

In total, 393 cases from 182 studies met the criteria for inclusion. Cryptococcus spp., Aspergillus spp., and Candida spp. were the most common fungal pathogens. Cohorts described IFD in 0.6–3.2% of SLE inpatients and 0.28% of SLE outpatients. IFD occurred at a median of 2 years of disease duration (IQR: 0.5–7.1), and 39% of cases occurred within the first year of SLE. Disease activity and corticosteroid dose >60 mg/day emerged as risk factors for IFD. IFD was associated with a mortality rate of 53% (161/316 cases), and worse in the absence of antifungal therapy (n = 43). Overall, 44 cases of IFD were only diagnosed on autopsy.

Conclusions

Our systematic review confirms the severe sequelae of IFD in SLE. Cases occurred in patients with active SLE, who were on high daily corticosteroids doses and at early stages of disease. This highlights the role of poor disease control and a high “net state of immunosuppression” in risk. IFD in SLE should be prospectively examined in the modern era.

Introduction

Infections constitute a major cause of mortality and morbidity in patients with systemic lupus erythematosus (SLE). An estimated 20–40% of all SLE deaths are attributable to infection [1], [2], [3], [4]. This greater susceptibility in SLE patients is hypothesized to be due to both the disease itself and the immunosuppressive agents used to treat it [5]. Although many infections in SLE are due to bacterial pathogens, there is emerging literature on invasive fungal diseases in SLE patients.

Typically occurring in hosts with human immunodeficiency virus (HIV) infection, or in patients immunosuppressed due to transplantation or chemotherapy [6], there is a substantial risk that invasive fungal infections in SLE are under-recognized by clinicians. In a case series, 3 of 10 cases of invasive fungal disease in SLE patients were only diagnosed post-mortem [7]. Furthermore, features of invasive fungal infection may overlap with findings of a SLE flare.

In contrast with superficial infections, such as oral thrush and vaginal candidiasis, which are far more common and readily treatable, invasive fungal diseases, such as Cryptococcal meningitis and Candidemia, are rare and life-threatening conditions. As invasive fungal infections are typically acquired from endogenous sources (such as from gastrointestinal flora or colonized skin through artificial lines) as well as environmental sources, a complex set of diagnostic criteria for invasive fungal disease must be used to distinguish these acute and devastating systemic infections from fungal colonization or superficial mucocutaneous infections. The recently revised consensus criteria for invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG 2008) provide case definitions for invasive fungal diseases to apply using rigorous mycological and clinical evidence [6].

In the absence of prospective population-based data describing the epidemiology of invasive fungal infections in SLE, we present a systematic review applying the EORTC/MSG 2008 criteria [6] to synthesize existing SLE literature, aiming to describe the epidemiologic patterns of infection frequency, risk factors for developing an invasive fungal infection, causative organisms for systemic infection, and clinical characteristics of the patients and their outcomes. This synthesis identifies characteristics of SLE patients who are most at risk of invasive fungal infections and highlights the possible clinical presentations of invasive fungal disease in SLE.

Section snippets

Search strategy

MEDLINE, Embase, and Web of Science were searched up to June 2013 using terms for the following 2 major themes: Systemic lupus erythematosus and Invasive fungal disease (search strategy shown in Appendix 1). These search terms were combined to create the initial list of abstracts for screening. Published English articles of adult cohorts, case series and reports, and autopsy studies documenting an invasive fungal infection in patients with SLE were included. Studies that met the American

Study characteristics

Of 3348 records returned from the search strategy, 182 studies from 35 countries were ultimately included (Fig.), detailing 393 total cases (252 females, 48 males, and 98 unreported sex), which met the SLE and the invasive fungal disease criteria for inclusion. Cases from historical and prospective cohorts, case reports, and case series were captured (Table 1). Of the 32 historical cohorts and 8 prospective cohorts, only 10 performed comparative analyses with a control group.

Prevalence of invasive fungal infections in cohort studies

Seven cohorts

Discussion

Our systematic review of the reported epidemiology, risk factors, clinical characteristics, and outcomes of invasive fungal infections in SLE reported in the medical literature, although not population-based and incorporating historical data, suggests that invasive fungal disease contributes between 0.64% and 3.24% of hospital admissions for SLE. Most commonly, invasive fungal infections presented early in the disease course of SLE, associated with high disease activity and corticosteroid use.

Conclusion

Clinicians should maintain a high index of suspicion for invasive fungal infections in SLE, especially in a patient with high disease activity at early stages of disease or with significant corticosteroid use (high “net state of immunosuppression”). It is often difficult to distinguish the presentation of invasive fungal infections from active SLE, resulting in increased immunosuppression rather than appropriate antifungal treatment. Our study was limited by the uncontrolled retrospective

Acknowledgments

We would like to thank Helen L. Robertson, medical librarian, University of Calgary, for her assistance in developing the search strategy. We would also like to thank M. Martínez-Martínez, C. Abud-Mendoza, G.L. Chen, and S. Ye for providing data for individual cases.

References (23)

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    Invasive fungal infections in patients with systemic lupus erythematosus

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    Linda Wang is supported by a Clinical Summer Studentship from the Canadian Rheumatology Association.

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    Dr. Barber is supported by a Clinical Research Fellowship from Alberta Innovates Health Solutions (AIHS) and by a research fellowship from The Arthritis Society and the Canadian Rheumatology Association (CRA-TAS-UCB research fellowship).

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