Active Surveillance Program to Increase Awareness on Invasive Fungal Diseases: the French RESSIF Network (2012 to 2018)

Abstract

The French National Reference Center for Invasive Mycoses and Antifungals leads an active and sustained nationwide surveillance program on probable and proven invasive fungal diseases (IFDs) to determine their epidemiology in France. Between 2012 and 2018, a total of 10,886 IFDs were recorded. The incidence increased slightly over time (2.16 to 2.36/10,000 hospitalization days, P = 0.0562) in relation with an increase of fungemia incidence (1.03 to 1.19/10,000, P = 0.0023), while that of other IFDs remained stable. The proportion of ≥65-year-old patients increased from 38.4% to 45.3% (P < 0.0001). Yeast fungemia (n = 5,444) was due mainly to Candida albicans (55.6%) with stable proportions of species over time. Echinocandins became the main drug prescribed (46.7% to 61.8%), but global mortality rate remained unchanged (36.3% at 1 month). Pneumocystis jirovecii pneumonia (n = 2,106) was diagnosed mostly in HIV-negative patients (80.7%) with a significantly higher mortality than in HIV-positive patients (21.9% versus 5.4% at 1 month, P < 0.0001). Invasive aspergillosis (n = 1,661) and mucormycosis (n = 314) were diagnosed mostly in hematology (>60% of the cases) with a global mortality rate of 42.5% and 59.3%, respectively, at 3 months and significant changes in diagnosis procedure over time. More concurrent infections were also diagnosed over time (from 5.4% to 9.4% for mold IFDs, P = 0.0115). In conclusion, we observed an aging of patients with IFD with a significant increase in incidence only for yeast fungemia, a trend toward more concurrent infections, which raises diagnostic and therapeutic issues. Overall, global survival associated with IFDs has not improved despite updated guidelines and new diagnostic tools. IMPORTANCE The epidemiology of invasive fungal diseases (IFDs) is hard to delineate given the difficulties in ascertaining the diagnosis that is often based on the confrontation of clinical and microbiological criteria. The present report underlines the interest of active surveillance involving mycologists and clinicians to describe the global incidence and that of the main IFDs. Globally, although the incidence of Pneumocystis pneumonia, invasive aspergillosis, and mucormycosis remained stable over the study period (2012 to 2018), that of yeast fungemia increased slightly. We also show here that IFDs seem to affect older people more frequently. The most worrisome observation is the lack of improvement in the global survival rate associated with IFDs despite the increasing use of more sensitive diagnostic tools, the availability of new antifungal drugs very active in clinical trials, and a still low/marginal rate of acquired in vitro resistance in France. Therefore, other tracks of improvement should be investigated actively.

Keywords: aspergillosis; candidemia; epidemiology; invasive fungal infections; mucormycosis; pneumocytosis.

FIG 1

Invasive fungal diseases (IFDs) and related underlying conditions and their evolution (RESSIF network, France, 2012 to 2018). (A) Evolution of the incidence of the major IFDs/10,000 hospitalization days in the 21 centers participating sustainably to the RESSIF network between 2013 and 2018. A linear regression was performed for all IFDs (P = 0.0562), fungemia (P = 0.0023), pneumocystosis (PJP; P = 0.2274), invasive aspergillosis (IA; P = 0.1029), and mucormycosis (P = 0.1886). (B) Proportion of the major IFDs among the 10,886 episodes recorded through the RESSIF network (2012 to 2018). (C to F) Trends in the 21 centers participating sustainably to the RESSIF network between 2013 and 2018 (chi-squared test for trends). (C) Proportion of fungemia (P = 0.3022), PJP (P = 0.7649), mucormycosis (P = 0.3801), cryptococcosis (P = 0.6689), and IA (P = 0.0007) recorded. (D) Culture as a tool for the diagnosis of IA (P = 0.1524) and mucormycosis (P < 0.0001). (E) PCR-based methods as a tool for the diagnosis of PJP, IA, and mucormycosis (P < 0.0001). (F) Global mortality rate at 3 months for all and selected IFDs (not significant).

FIG 2

Underlying conditions associated with the diagnosis of invasive fungal diseases in 10,154 patients (RESSIF network, France, 2012 to 2018). (A) Proportion of the major exclusive underlying conditions in the 10,154 patients. (B) Trends in the evolution of the following major underlying conditions in the 21 centers participating sustainably to the RESSIF network between 2013 and 2018: malignancy (blue solid line; P = 0.1583), solid organ transplantation (gray line; P = 0.3496), recent surgery (orange line; P = 0.0017), HIV infection (yellow line; P = 0.0097), other risk factors (dotted pale-blue line; P = 0.0009), and no known risk factor (green line; P = 0.0720) (chi-squared test for trends). (C) Trends in the evolution of associated risk factors, as follows: diabetes (diamond; P = 0.0443), stay in intensive care unit (triangle; P = 0.0061), autoimmune disorders (square; P = 0.0055), and other risk factor (same dotted line shown in B) (chi-squared test for trends). (D) Histograms showing the evolution of age over time in the 5 age categories (80 years old and over, 65 to 79 years old, 45 to 64 years old, 15 to 44 years old, and <15 years old old) in a range of yellow getting darker with age. The figures correspond to the number of cases. The proportion of older patients increased significantly (from 8.1% to 10.6% for ≥80 years old, P = 0.0026; and from 30.3% to 34.7% for those between 65 and <80 years old, P = 0.0045) in the 21 centers participating sustainably to the RESSIF network between 2013 and 2018. (E) Histograms showing the relative distribution of the major IFDs, fungemia (blue), PJP (pale gray), IA (pale blue), mucormycosis (dark blue), and cryptococcosis (dark gray) in the 241 children <15 years old, 1,001 patients 15 to 44 years old, 2,687 patients 45 to 64 years old, 2,591 patients 65 to 79 years old, and 710 patients ≥80 years old. The figures correspond to the number of cases. (F) Evolution of the median age of the French population (gray line; data available online at https://www.insee.fr/fr/statistiques/2381476) and of the patients diagnosed with IFDs in the 21 centers (red line, linear regression; P = 0.0027).

FIG 3

Specific host and species patterns (RESSIF network, France, 2012 to 2018). (A) Distribution of the underlying conditions for the 845 patients for whom the diagnosis of proven or probable invasive aspergillosis was associated with culture of Aspergillus spp. belonging to various sections. (B) Distribution of pulmonary, rhino cerebral, and skin/bone infections according to the species of Mucorales identified after culture of the specimens.