Epidemiology and risk of invasive fungal infections in systemic lupus erythematosus: a nationwide population-based cohort study

Abstract

Introduction: Infections are a leading cause of mortality in patients with systemic lupus erythematosus (SLE). Among various infections, invasive fungal infections (IFIs) have a particularly high mortality rate; however, studies examining IFIs in patients with SLE are limited. Methods: Patients diagnosed as having SLE between 1997 and 2012 were enrolled from Taiwan’s National Health Insurance Research Database along with age- and sex-matched non-SLE controls at a ratio of 1:10. IFIs were identified based on International Classification of Diseases, Ninth Revision, Clinical Modification codes and validated by the prescriptions of systemic antifungal agents. The incidence rate (IR), incidence rate ratio (IRR), and all-cause mortality rate of IFIs and its subtypes were analyzed. A Cox multivariate regression model with time-dependent covariates was applied to analyze independent risk factors for IFIs. Results: A total of 24,541 patients with SLE and 245,410 non-SLE controls were included. We observed 445 IFI episodes in the SLE cohort, with an all-cause mortality rate of 26.7%. Candida spp. (52.8%) was the most common pathogen, followed by Cryptococcus spp. (18.2%) and Aspergillus spp. (18.2%). The IR of IFIs in the SLE cohort was 20.83 per 10,000 person-years, with an IRR of 11.1 [95% confidence interval (CI): 9.8–12.6] relative to the non-SLE controls. Juvenile patients with SLE aged ⩽18 years had the highest IRR of 47.2 (95% CI: 26.9–86.8). Intravenous steroid therapy administered within 60 days (hazard ratio: 29.11, 95% CI: 23.30–36.37) was the most critical risk factor for overall IFIs and each of the three major fungal pathogens. Distinct risk factors were found among different IFI subtypes. Conclusion: Patients with SLE had a higher risk of IFIs, especially juvenile patients. Intravenous steroid therapy is the most critical risk factor for IFIs. This study provides crucial information for the risk stratification of IFIs in SLE. Plain Language Summaries Patients with systemic lupus erythematosus and physicians treating this patient group should be aware of the risk of invasive fungal infections. Invasive fungal infections (IFIs) are a severe complication with a high mortality rate among patients with systemic lupus erythematosus (SLE); however, studies on this topic are scant. We performed a nationwide population-based study in Taiwan to estimate the incidence and mortality of and risk factors for IFIs. We found an incidence rate of 20.83 per 10,000 person-years for IFIs, with a mortality rate of 26.7%. Juvenile patients aged ⩽18 years had the highest relative risk of IFIs. Although candidiasis was the most common IFI, cryptococcosis and aspergillosis should be concerned in juvenile patients as well. Intravenous steroid therapy was the most critical risk factor for all IFIs, and different immunosuppressive agents posed different risks in patients for acquiring certain fungal pathogens. Our findings provide pivotal epidemiological information and indicate risk factors for IFIs in patients with SLE. Age and exposure to specific immunosuppressants and steroids might help predict the risk of IFIs. Because the manifestation of these infections is sometimes indistinguishable from a lupus flare, physicians should be aware of this fatal complication, especially when patients are not responsive to immunosuppressive therapy. Early recognition, implication of diagnostic tools, and empirical antimicrobial agents can be the key to treating patients with IFIs. Additional studies are required to develop a risk management program for patients with SLE.

Factors Associated With Candidiasis in Systemic Lupus Erythematosus Patients in Cipto Mangunkusumo National General Hospital: A Single-Center Case-Control Study

“…This study also agrees with previous studies that suggest the use of high-dose corticosteroids is a predisposing factor to candidiasis [ 8 , 15 , 16 ]. There are several mechanisms proposed for how corticosteroid use can lead to candidiasis.…”

Risk factors for mortality in systemic lupus erythematosus patients: Analysis of adult and pediatric cohorts in Taiwan

“…Cumulative exposure of systemic glucocorticoids or recent high-dose glucocorticoid treatment has the risk of invasive fungal infections and is associated with an increased risk of mortality in SLE. 8,25,26 Furthermore, the present study revealed that the average daily dose of systemic glucocorticoids equivalent to >10 mg of prednisolone increases the mortality in adult SLE patients who ever received hospital admission. A higher average daily dose of steroid treatment is aimed to control disease activities in severe SLE patients, and the risk of sepsis usually increased according to our risk factor analysis.…”

Temporal trends in hospitalisation for opportunistic infections in lupus patients in Western Australia

“…Fungal infections are eleven times more frequent in lupus patients than healthy controls with an overall IR for fungal infections in Taiwan between 1997 and 2012 of 2.1/1000 person years 26 and Candidiasis the most frequent (>50%) fungal infection and IR for Cryptococcus three times higher than for Aspergillus. As Candida infection has been shown to have low validity (PPV 20%) in administrative data in contrast to Cryptococcus (PPV 100%) and Aspergillus (67%), 27 we excluded candida infections but found a similarly IR difference for Cryptococcus and Aspergillus (IR 2.72 vs 0.57 respectively).…”