Invasive fungal infections (IFI) are reportedly increasing in many countries, especially candidemia and invasive aspergillosis (IA) among immunocompromised patients ( 1 – 4 ). Conversely, a decline of AIDS-associated Pneumocystis jirovecii pneumonia (Pjp) and cryptococcosis has been observed in Western countries since the advent of highly active antiretroviral treatments ( 5 , 6 ). Many publications provide insight on a given IFI and its trends in specific risk groups, but the overall burden of illness associated with IFI and its trends at a country level have not been described ( 7 – 10 ). To describe the epidemiology and trends of IFIs and to better identify public health priorities (e.g., surveillance, research, prevention strategies), we analyzed the national hospital discharge database of France, Programme de Médicalisation du Système d’Information, spanning 2001–2010. Materials and Methods The national hospital database covers >95% of the country's hospitals ( 11 ). An anonymous subset of this database can be made available for epidemiologic studies without need for ethical approval or consent of patients, according to legislation by the government of France. A unique anonymous patient identifier enables distinction among first and subsequent hospital admissions. Information filed at discharge includes the major cause of admission and associated diseases, coded according to the International Classification of Diseases, Tenth Revision, the medical and surgical procedures performed, and the outcome including transfer, discharge, or death. Details on the data source, case definitions, and methods used are available in Technical Appendix 1. Records of all hospital stays for which an IFI was recorded as the principal cause of admission or as a related disease were extracted from the national database for the period of January 2001 through December 2010. Records of the 5 most frequent IFIs were retained for this analysis. To facilitate comparisons with published studies, we restricted the study of invasive candidiasis to candidemia (i.e., excluding Candida endocarditis and meningitis), and invasive aspergillosis (IA) included pulmonary and disseminated cases. All cryptococcosis cases were included. Gastrointestinal mucormycoses were excluded because results of a previous study showed that cases were mostly identified on the basis of false-positive test findings ( 12 ). Finally, codes corresponding to “pneumocystosis” or “HIV infection resulting in pneumocystosis” were designated as Pjp only if pneumonia was associated. We excluded rare IFIs ( 70%). The mean age was 54.7 years (range 0–107 years). Gender and age characteristics of case-patients and of those who died differed according to the IFI. Details are provided in online Technical Appendix 2, Table 1. Incidence and fatality rates of candidemia and IA were particularly high in patients ≥60 years of age, and male patients predominated in all age groups, except in those >80 years of age. Case-patients in extreme age groups included 185 neonates (mainly with candidemia: 174 cases, 61.5% male patients, specific incidence 2.2/100,000 population) and 3,030 adults >80 years of age (2,283 with candidemia: 50.5% male, incidence 8.1/105). Among case-patients with Pjp and cryptococcosis, the proportion of male case-patients was higher among HIV-infected persons than in non–HIV-infected persons (Pjp 74.0% vs. 62.2%; cryptococcosis 77.9% vs. 62.3%, respectively). Table 1 Cases of invasive fungal infection and attributable deaths in metropolitan France by disease, sex, and age, 2001–2010* Infections No. case-patients Male sex, % Age, y, median (IQR) Illness incidence (95% CI)† Fatality rate, % (95% CI) Candidemia Cases 15,559 58.8 64 (51–75) 2.5 (2.1–2.9) Deaths 6,217 60.0 69 (56–77) 40.0 (38.7–42.0) Pneumocystis pneumonia Cases 9,365 71.3 44 (37–55) 1.5 (1.2–1.9) Deaths 862 71.9 58 (43–70) 9.2 (7.6–12.4) Invasive aspergillosis‡ Cases 8,563 63.9 58 (45–68) 1.4 (1.2–1.6) Deaths 2,443 66.7 61 (49–71) 28.5 (26.9–30.5) Cryptococcosis‡ Cases 1,859 72.3 43 (36–55) 0.3 (0.2–0.4) Deaths 278 73.4 49 (39–65) 15.0 (13.2–17.9) Mucormycosis‡ Cases 530 57.7 58 (43–71) 0.09 (0.07–0.1) Deaths 89 62.9 57 (44–67) 16.8 (11.3–20.2) Total Cases 35,876 64.0 56 (42–70) 5.9 (5.5–6.3) Deaths 9,889 63.1 65 (53–75) 27.6 (25.3–29.7) *A total of 197 Candida-related endocarditis and 10 meningitis cases were excluded from analysis. IQR, interquartile range.
†Incidence expressed as number of cases per 100,000 population per year (averaged over 10 y)
‡Invasive aspergillosis includes 91.7% pulmonary and 8.3% disseminated cases. Cryptococcosis includes 63.8% cerebral or disseminated forms; 13.2% pulmonary, cutaneous, or bone localizations; and 23.0% unspecified; forms. Mucormycosis includes 50.9% pulmonary, rhinocerebral and disseminated forms; 16.9% cutaneous forms; and 32.1% unspecified forms. The highest incidences of Pjp and cryptococcosis were observed among persons 30–59 years of age with AIDS and among those ≥60 years of age who were not infected with HIV (p 55% each). The incidence of candidemia, IA, and mucormycosis in patients with HM (especially with neutropenia) increased significantly, as did the incidence of candidemia and IA in solid organ transplant recipients, and patients with solid tumors or chronic renal failure. The incidence of Pjp decreased in patients with HM and increased in patients with solid organ transplants, solid tumors, and chronic renal failure. IFI Trends in Specific Risk Groups, 2004–2010 We estimated trends from the annual proportion of risk factor–associated IFIs in the corresponding risk population. Only statistically significant trends are shown in Figure 2. In the general population, the number of patients with HM, solid organ transplantations, chronic renal failure, HIV/AIDS, and diabetes substantially increased over time, and the population of HSCT recipients remained unchanged. In patients with HM, there was a statistically significant increase of candidemia, IA, and mucormycosis, and a decrease of Pjp (Figure 2, panel A). In HSCT recipients, candidemia and IA increased (Figure 2, panel B). Figure 2 A) Invasive fungal infections in patients with hematologic malignancies (HM) in France, 2004–2010. The case count continuously increased (p 20 years of age who had candidemia and Pjp, and in those >70 years who had IA. HM represented a substantial risk factor for death in patients with candidemia, IA, mucormycosis, and in non-HIV cryptococcosis. Solid tumors were a substantial risk factor for death in patients with candidemia, IA, and Pjp, regardless of HIV status. Cirrhosis and acute renal failure were also substantial risk factors for death in patients with candidemia, IA, and non-HIV Pjp and cryptococcosis. Hospitalization in an intensive care unit was associated with a higher risk for death among patients with all IFIs except candidemia. Inversely, chronic renal failure decreased the risk for death among those with IA or Pjp, respiratory diseases decreased the risk in patients with IA, and surgical procedures decreased the risk for those with candidemia. Discussion This nationwide study provides evidence that ≈3,600 patients have IFI each year in France, of whom 28% die. The incidence of candidemia, IA, mucormycosis, and non-HIV Pjp has increased over the last decade, predicting a protracted trend over the coming years. Studies on the epidemiology of the 5 predominant IFIs have reached conflicting results, depending on the IFI studied (most studies focused on a single IFI), the study design, and source of data (active surveillance system, cohorts, multicentric or monocentric, laboratory-based diagnosis, hospital discharge data), the population of interest (neutropenic patients, HM, HSCT and solid organ transplant recipients), and the practices regarding antifungal agents use (prophylactic, empiric, preemptive, or curative therapy). Here, we analyzed the hospital dataset at a country level, covering all persons who were admitted to hospitals over a period of 10 years, regardless of age or underlying conditions. We included those with illness caused by IFIs that have straightforward diagnostic criteria (candidemia, cryptococcosis) or well-characterized clinical entities (pulmonary or disseminated IA, pulmonary Pjp), as well as mucormycosis, for which we previously validated the accuracy of diagnostic coding in the hospital national database ( 14 , 15 ). Despite potential bias in the precise classification of cases, particularly for mold infections, and other limitations of administrative datasets that have been previously discussed ( 12 , 14 , 16 ), several points validate the findings obtained through this large database. The predominance of candidemia and IA has been described in other studies of a variety of IFIs in the general population or in other groups ( 7 , 9 , 17 ). For candidemia, the incidence and trends we estimated are comparable to many other, although smaller scale, population-based studies from Europe and North America ( 18 – 22 ). For IA in France, we observed a lower incidence and higher mortality rate than were found by Dasbach et al. in their analysis of US hospital discharge data . ( 23 ). The differences may be explained by the researchers’ use of the International Classification of Diseases, Ninth Revision case definitions in that study, which would impair the comparison of invasive and noninvasive forms. The decreasing incidence of Pjp and cryptococcosis was expected after the advent of active antiretroviral therapy ( 5 , 6 , 24 , 25 ). However, we observed some noteworthy changes: Pjp incidence in non-HIV–infected patients has currently reached the levels observed in HIV-infected patients, as observed in the United Kingdom during the same period ( 26 ); incidence of cryptococcosis is also increasing in the seronegative population, and the mortality rate of both IFIs among non-HIV–infected patients is higher than among HIV-infected patients. Most risk factors described in this study are well known in clinical practice. The major risk factors for candidemia, IA, and mucormycosis, i.e., HM, HSCT, and solid tumors, are described in many studies, such as those by the Transplant Associated Infections Surveillance Network, known as TRANSNET, and Prospective Antifungal Therapy Alliance, known as PATH ( 3 , 27 – 29 ), albeit sometimes reported as differently distributed. The hierarchical ranking process used here may have influenced the risk factor distribution, underestimating some conditions. Most studies of risk factors are performed on the basis of cohorts of cases in referral centers where a large number of high-risk patients are recruited, whereas in our population-based approach, we used a national dataset covering all levels of care, thus selecting a wider range of underlying conditions, including those less commonly recognized as risk factors. As a result, we documented substantial increases of candidemia, IA, and Pjp in patients with chronic renal failure, suggesting that the increase is not uniquely caused by the growing number of persons at risk (Figure 2). The growing number and longer survival of patients with protracted immunosuppression beyond traditional hematology patients, transplant patients, and HIV/AIDS populations are major challenges. The fact that 2 IFIs that are frequently associated with health care settings (candidemia and IA) are still on the rise despite existing infection control recommendations is of specific concern ( 30 ). Hospital data are not collected for clinical research purposes. Thus, it is very hazardous to explain the trends on the basis of our limited observations. Specific analyses should be encouraged, aiming at better understanding the role of comorbid conditions in the occurrence of IFI (e.g., chronic renal failure) or the effect of the improved overall survival of patients, even those who are immunocompromised. Another noteworthy finding of this study is that the risk for death was altered by factors that were not frequently documented before. For instance, cirrhosis was found in 1.3% of all patients with IFIs but was an independent risk factor for death among all except those with mucormycosis, suggesting underrecognition of IFIs in such populations, possibly leading to delayed prevention or treatment. Similarly, patients with HM showed an increased risk for death when cryptococcosis was also diagnosed, as did those with cirrhosis and acute renal failure, which suggest that specific attention should be paid to patients with these conditions; this could modify their clinical management. This population-based study has limitations. The increase in IFIs observed parallels a better awareness of clinicians and microbiologists of the threat of IFIs in at-risk populations, improving the sensitivity of the hospital-based dataset. The availability of a broader antifungal drug armamentarium and efficient treatment could have the paradoxical effect of improving the prevention of IFI for selected groups of at-risk patients, thus lowering the population of infected patients. We report trends and risk factors for invasive mycosis in France. Hence, our findings may not apply to other countries with different endemic mycoses, population structures, and health care systems. Our observations are based on hospital discharge coding, which is subject to many biases, including misdiagnosis and incorrect coding. More notably, the advent of new diagnostic tools for the detection of many invasive mycoses may have affected our ability to diagnose these diseases over the study period, which may have had a substantial impact on the temporal trends observed. Nevertheless, this large-scale study provides benchmarking data on the current burden of illness of major IFIs and shows the effects of disease trends and death rates spanning a decade in a Western European country. The need for baseline data was recently highlighted ( 10 ). Our data provide complementary information to specific studies or investigations linked to outbreaks ( 31 , 32 ). IFIs in this study occurred among a broad spectrum of patients and the fatality rate was high; clinicians should be made aware of risk factors, signs, and symptoms. Beyond the specific issues addressed by our study, such as the identification and management of patients in potentially under-recognized risk groups, the expected consequences of the increasing incidence of IFIs should be anticipated in terms of hospital and laboratory workload, antifungal use, and need for new systemic antifungal drugs and strategies ( 33 ). The development of epidemiologic studies is also of specific concern to clarify the determinants of the trends and identify effective interventions that can reduce deaths and the general public health burden of illness. These questions should be addressed jointly by clinicians and public health authorities at national and international levels. Technical Appendix 1 Methods: the French hospital information system, data sources, case definitions, and risk factors for invasive fungal infections, France, 2001–2010. Technical Appendix 2 Incidence and mortality rates, risk factors and trends, demographics, and distribution of invasive fungal infections, France, 2001–2010.
