Abstract
Among 1107 cryptococcosis cases from the French surveillance network (2005–2020), the proportion of HIV-seronegative individuals has recently surpassed that of HIV-seropositive individuals. We observed marked differences in patient characteristics, disease presentations, cryptococcal antigen results, infecting species, and mortality according to HIV serostatus.
Keywords: cryptococcal meningitis, cryptococcosis, fungemia, human immunodeficiency virus
Graphical Abstract
Graphical Abstract.
Among 1,107 cryptococcosis cases from the French surveillance network (2005-2020), the proportion of HIV-seronegative individuals has recently surpassed that of HIV-seropositive individuals. We observed marked differences in patient characteristics, disease presentations, cryptococcal antigen results, infecting species, and mortality according to HIV serostatus.
Cryptococcosis is an opportunistic fungal infection that causes significant morbidity and mortality in immunocompromised hosts. Predisposing factors are T-cell immunodeficiencies mostly associated with advanced human immunodeficiency virus (HIV), but other risk groups such as solid-organ transplant recipients, patients with malignancy, and those receiving various immunosuppressive treatments or biologics constitute an increasing proportion of reported cases in North America and Europe [1–3] and up to 90% in Australia and New Zealand [4]. Differences in patient characteristics and outcomes have been reported among HIV-seropositive and HIV-seronegative individuals in population-based studies and single-center studies in North America [2, 5, 6], but precise multicenter data from Europe are lacking. We sought to describe the baseline characteristics, presentations, and outcomes of cryptococcosis according to HIV serostatus in France.
METHODS
We performed a cross-sectional study nested within a nationwide laboratory-based surveillance network for cryptococcosis in France (including overseas departments and territories) implemented in 1985 by the French National Reference Center for Invasive Mycoses and Antifungals (NRCMA, Institut Pasteur, Paris, France). All isolates received were identified to the species level [7], and clinical data were monitored and stored at the NRCMA.
We included patients with incident microbiologically confirmed cryptococcosis from 1 January 2005 to 31 December 2020, and excluded cases caused by Cryptococcus gattii species complex (n = 20), isolated cryptococcal antigenemia, and recurrent cases. Cases of cryptococcosis were defined as illness in an individual with culture yielding growth of Cryptococcus neoformans species complex from any site, or with a positive cryptococcal antigen result (CrAg) from cerebrospinal fluid (CSF). For CSF, positive culture and/or a positive CrAg defined meningitis, while positive blood culture defined fungemia. In the absence of cryptococcal meningitis (CM)/fungemia, including when a lumbar puncture and/or blood culture had not been performed, cases were defined as isolated extrameningeal infections.
We compared baseline characteristics, disease presentations, and 14- and 90-day case fatality ratios (CFR) according to HIV serostatus. We compared categorical variables between groups using the χ2 test or Kruskal-Wallis test and reported unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) using univariable logistic regression, taking into account only patients with available data. We used a multivariable logistic regression model to examine the association between HIV serostatus and 14- and 90-day mortality, adjusting for age (<50 and ≥50 years), sex, site of infection (CM/fungemia, isolated pulmonary infections, or other isolated extrameningeal infections), and induction treatment regimen (flucytosine-containing regimen, other treatment regimen, or no treatment). Analyses were performed using Stata version 17 software (StataCorp, College Station, Texas). NRCMA surveillance activities were approved by the Institut Pasteur Institutional Review Board 1 (2009–34/IRB) and the Commission Nationale de l’Informatique et des Libertés. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed.
RESULTS
We included 1107 incident cases of C neoformans–related infections from 132 centers throughout France. Over the study period, while the total annual number of cases remained stable, the proportion of HIV-seropositive individuals decreased and that of HIV-seronegative individuals increased, eventually surpassing that of HIV-seropositive individuals from 2010 onward (Figure 1).
Figure 1.
Number of cases reported to the NRCMA over time according to underlying HIV status, France.
The median age of patients was 51 years (interquartile range [IQR], 39–65), and 759 of 1107 (68.6%) were male (Table 1). The most common presentation was CM/fungemia (74.2% [821/1107]). Of 286 individuals considered to have isolated extrameningeal infections, 44.1% (126/286) had neither lumbar puncture nor blood culture results recorded. Of the 1107 individuals, 469 (42.4%) were HIV seropositive and 638 (57.6%) were HIV seronegative. The median CD4 T-cell count was 26 cells/µL (IQR, 8–60) for 442 of 469 HIV-seropositive individuals with available data. Of 638 patients considered to be HIV-seronegative, 631 (98.9%) had records of a negative HIV serological test result. Compared to HIV-seronegative individuals, HIV-seropositive individuals were younger (median, 42 years [IQR, 36–50] vs 62 years [IQR, 49–72]’ P < .0001), and more likely to be male (76.1% [357/469] vs 63% [402/638]; P < .001). HIV-seropositive individuals were more likely to present with CM/fungemia (88.9% [417/469] vs 63.5% [405/638]) and less likely to present with isolated pulmonary disease (9% [42/469] vs 24.9% [159/638]) or other isolated extrameningeal disease (2.1% [10/469] vs 11.6% [74/638]) (P < .001).
Table 1.
Baseline Characteristics and Outcomes According to Human Immunodeficiency Virus Serostatus Among 1107 Individuals With Cryptococcus neoformans–Related Infections in France, 2005–2020
| Variable | Total (N = 1107) | HIV Seropositive (n = 469) | HIV Seronegativea (n = 638) | P Value |
|---|---|---|---|---|
| Age, y, median (IQR) | 51 (39–65) | 42 (36–50) | 62 (49–72) | <.0001 |
| Male sex | 759/1107 (68.6) | 357/469 (76.1) | 402/638 (63) | <.001 |
| Site of infection | <.001 | |||
| Meningitis/fungemia | 821/1107 (74.2) | 417/469 (88.9) | 404/638 (63.3) | |
| Isolated pulmonary | 202/1107 (18.3) | 42/469 (9) | 160/638 (25.1) | |
| Other isolated site | 84/1107 (7.6) | 10/469 (2.1) | 74/638 (11.6) | |
| LP performed | 835/1107 (75.4) | 428/469 (91.3) | 407/638 (63.8) | <.001 |
| Positive LP | 623/1107 (56.3) | 346/469 (73.8) | 277/638 (43.4) | <.001 |
| Blood culture performed | 766/1107 (69.2) | 356/469 (75.9) | 410/638 (64.3) | <.001 |
| Positive blood culture | 480/1107 (43.4) | 261/469 (55.7) | 219/638 (34.3) | <.001 |
| Pulmonary specimen obtained | 442/1107 (39.9) | 182/469 (38.8) | 260/638 (40.8) | .54 |
| Positive pulmonary culture | 316/1107 (28.6) | 113/469 (24.1) | 203/638 (31.8) | .006 |
| Urine culture obtained | 433/1107 (39.1) | 179/469 (38.2) | 254/638 (39.8) | .62 |
| Positive urine culture | 137/1107 (12.4) | 64/469 (13.7) | 73/638 (11.4) | .31 |
| Skin specimen obtained | 104/1107 (9.4) | 29/469 (6.2) | 75/638 (11.8) | .002 |
| Positive skin culture | 85/1107 (7.7) | 17/469 (3.6) | 68/638 (10.7) | <.001 |
| Serum CrAg results | ||||
| Serum CrAg performed | 880/1035 (85) | 405/442 (91.6) | 475/593 (80.1) | <.001 |
| Positive CrAg | 722/880 (82.1) | 388/405 (95.8) | 334/475 (70.3) | <.001 |
| Positive CrAg (cases of meningitis/fungemia only) | 626/675 (92.7) | 352/362 (97.2) | 274/313 (87.5) | <.001 |
| Positive CrAg (cases of isolated extrameningeal infections only) | 96/205 (46.8) | 36/43 (83.7) | 60/162 (37) | <.001 |
| C neoformans complex serotype | <.001 | |||
| C neoformans (serotype A) | 734/1021 (71.9) | 336/435 (77.2) | 398/586 (67.9) | |
| C deneoformans (serotype D) | 169/1021 (16.6) | 39/435 (9) | 130/586 (22.2) | |
| Serotype AD hybrid | 118/1021 (11.6) | 60/435 (13.8) | 58/586 (9.9) | |
| Induction antifungal therapy | ||||
| Overall | <.001b | |||
| 5FC combination therapy | 618/1076 (57.4) | 322/457 (70.5) | 296/619 (48.0) | |
| Including a polyene | 598/1076 (55.6) | 316/457 (69.1) | 282/619 (45.6) | |
| AmB + 5FC | 274/1076 (25.5) | 170/457 (37.2) | 104/619 (16.8) | |
| L-AmB + 5FC | 324/1076 (30.1) | 146/457 (32) | 178/619 (28.8) | |
| Fluconazole + 5FC | 20/1076 (1.9) | 6/457 (1.3) | 14/619 (2.3) | |
| Other treatment regimen | 342/1076 (31.8) | 120/457 (26.3) | 222/619 (35.9) | |
| AmB monotherapy | 31/1076 (2.9) | 19/457 (4.2) | 12/619 (1.9) | |
| L-AmB monotherapy | 53/1076 (4.9) | 16/457 (3.5) | 37/619 (6) | |
| Fluconazole monotherapy | 235/1076 (21.8) | 74/457 (16.2) | 161/619 (26) | |
| AmB and fluconazole | 5/1076 (0.5) | 4/457 (0.9) | 1/619 (0.2) | |
| L-AmB and fluconazole | 6/1076 (0.6) | 5/457 (1.1) | 1/619 (0.2) | |
| Other | 12/1076 (1.1) | 2/457 (0.4) | 10/619 (1.6) | |
| No antifungals prescribed | 116/1076 (10.8) | 15/457 (3.3) | 101/619 (16.3) | |
| Recorded as postmortem diagnosis | 31/1076 (2.9) | 3/457 (0.7) | 28/619 (4.5) | |
| For cases of cryptococcal meningitis/fungemia only | <.001b | |||
| 5FC combination therapy | 571/790 (72.3) | 306/401 (76.3) | 265/389 (68.1) | |
| Including a polyene | 563/803 (70.1) | 305/407 (74.9) | 258/396 (65.2) | |
| AmB + 5FC | 262/803 (32.6) | 164/407 (40.3) | 98/396 (24.8) | |
| L-AmB + 5FC | 301/803 (37.5) | 141/407 (34.6) | 160/396 (40.4) | |
| Fluconazole + 5FC | 18/803 (2.2) | 5/407 (1.2) | 13/396 (3.3) | |
| Other treatment regimen | 160/790 (20.3) | 82/401 (20.5) | 78/389 (20.1) | |
| AmB monotherapy | 27/803 (3.4) | 18/407 (4.4) | 9/396 (2.3) | |
| L-AmB monotherapy | 32/803 (4) | 13/407 (3.2) | 19/396 (4.8) | |
| Fluconazole monotherapy | 43/803 (11.6) | 43/407 (10.6) | 50/396 (12.6) | |
| AmB and fluconazole | 4/803 (0.5) | 3/407 (0.7) | 1/396 (0.3) | |
| L-AmB and fluconazole | 5/803 (0.6) | 5/407 (1.2) | 0/396 (0) | |
| Other | 2/803 (0.3) | 2/407 (0.5) | 0/396 (0) | |
| AmB monotherapy | 27/803 (3.4) | 18/407 (4.4) | 9/396 (2.3) | |
| No antifungals prescribed | 59/790 (7.5) | 13/401 (3.2) | 46/389 (11.8) | |
| Recorded as postmortem diagnosis | 29/59 (49.2) | 3/13 (23.1) | 26/46 (56.5) | |
| 14-d CFR | 128/899 (14) | 33/380 (8.7) | 95/535 (17.8) | <.001 |
| 90-d CFR | 200/899 (22.3) | 54/369 (14.6) | 146/530 (27.6) | <.001 |
Data are presented as no./No. (%) unless otherwise indicated. Differences in denominators within each row reflect missing data.
5FC, flucytosine; AmB, amphotericin B; CFR, case fatality ratio; CrAg, cryptococcal antigen; HIV, human immunodeficiency virus; IQR, interquartile range; L-AmB, liposomal amphotericin B; LP, lumbar puncture.
aIncluding 130 solid organ transplant recipients, 206 individuals with malignancy, 203 with other immunocompromising conditions, and 99 with no identified underlying factor.
bComparison of 5FC combination therapy versus other treatment regimen versus no antifungals prescribed.
HIV-seropositive individuals were more likely to have infections caused by C neoformans (serotype A) (77.2% [336/435] vs 67.9% [398/586]) or serotype AD hybrids (13.8% [60/435] vs 9.9% [58/586]) and less likely to have infections caused by Cryptococcus deneoformans (serotype D) (9% [39/435] vs 22.2% [130/586]) (P < .001). Cryptococcus deneoformans infections remained more frequent among HIV-seronegative than among HIV-seropositive individuals when considering those with CM/fungemia (20.4% [76/372] vs 9.2% [36/393]; P < .001) or with extrameningeal infections (25.2% [54/214] vs 7.1% [3/42]; P = .006).
HIV-seropositive individuals were also more likely to have a positive serum CrAg result at diagnosis (95.8% [388/405] vs 70.3% [334/475]; P < .001). This stayed significant when considering only patients with CM/fungemia (97.2% [352/362] vs 87.5% [274/313]; P < .001) or those with isolated extrameningeal infections (85.7% [36/42] vs 37% [60/162]; P < .001).
Over the study period, the proportion of patients with CM/fungemia who were prescribed a flucytosine-containing regimen gradually increased for both HIV-positive individuals (2005–2009: 66.3% [110/166] vs 2010–2014: 80.5% [103/128] vs 2015–2020: 85.8% [97/113]; P < .001) and for HIV-seronegative individuals (2005–2009: 57.9% [62/107] vs 2010–2014: 64.4% [74/115] vs 2015–2020: 77.6% [135/174]; P < .001) (Supplementary Table). Among cases of CM/fungemia, HIV-seropositive individuals were nevertheless more likely to have received a flucytosine-containing treatment regimen than HIV-seronegative individuals (76.3% [306/401] vs 68.1% [265/389]) and less likely to have received no antifungals (3.2% [13/401] vs 11.8% [46/389]) (P < .001). In addition, the use of liposomal amphotericin B as opposed to conventional amphotericin B in association with flucytosine increased over time in HIV-seropositive individuals (2005–2009: 11.5% [19/166] vs 2010–2014: 33.6% [43/128] vs 2015–2020: 69.9% [79/113]) and in HIV-seronegative individuals (2005–2009: 16.8% [18/107] vs 2010–2014: 40% [46/115] vs 2015–2020: 55.2% [96/174]).
The crude 90-day CFR was 14.6% (95% CI, 11.2%–18.7%; 54/369) among HIV-seropositive individuals and 27.5% (95% CI, 23.8%–31.6%; 146/530) among HIV-seronegative individuals. For 899 individuals with available outcome data, the crude odds of death at 90 days among HIV-seronegative individuals were 2.22 times (OR, 2.22 [95% CI, 1.57–3.13]; P < .001) higher than among HIV-seropositive individuals. After adjustment, the odds of 14-day and 90-day mortality in HIV-seronegative patients were still respectively 1.70 times (adjusted OR, 1.70 [95% CI, .97–2.99]; P = .06) and 1.60 times (adjusted OR, 1.60 [95% CI, 1.03–2.49]; P = .038) higher compared to HIV-seropositive individuals.
DISCUSSION
In these data from a large nationwide surveillance program in France, HIV-seronegative individuals have currently surpassed HIV-seropositive individuals as the main underlying risk group among reported cases of C neoformans–related infections over 16 years. This is driven by a persistent decline in the annual number of cases reported among HIV-seropositive individuals since the mid-1990s, paralleling the declining incidence of AIDS (but not of HIV seropositivity) in France [8], and a steady increase in the number of cases reported among HIV-seronegative individuals. This shift in the epidemiology of cryptococcosis is consistent with previously reported trends from population-based studies in France and the United States [1, 2].
We found marked differences in patient characteristics and disease presentations among patients according to HIV serostatus. HIV-seropositive individuals were younger and more likely to be male than HIV-seronegative individuals [2, 5, 6, 9]. CM/fungemia accounted for 89% of reported cases among HIV-seropositive individuals, compared to only 64% for HIV-seronegative individuals, who more frequently presented with isolated pulmonary and other isolated infections. Similar differences were previously reported, albeit with different definitions of dissemination [10]. In addition, infecting C neoformans complex species varied according to HIV serostatus, with HIV-seropositive individuals more likely to have infections caused by C neoformans and serotype AD hybrid while HIV-seronegative individuals were more likely to have C deneoformans infections. These differences persisted when accounting for the fact that serotype D infections are more prevalent in primary cutaneous infections [9]. HIV-seropositive individuals were also more likely to have a positive serum CrAg test at baseline. Of note, 12.5% of HIV-seronegative patients with CM/fungemia had a negative serum CrAg compared to only 2.8% for HIV-seropositive individuals. This illustrates its poorer diagnostic contribution in HIV-seronegative populations, presumably reflecting a lower fungal burden among HIV-seronegative patients [9, 10]. Thus, it should be remembered that in clinical practice, a negative serum CrAg result does not exclude CM/fungemia among HIV-seronegative patients.
Of note, HIV-seronegative individuals experienced a 1.6 times higher mortality compared to HIV-seropositive individuals after adjustment. Differences in mortality rates can be attributed to (1) a delayed diagnosis linked to a lower index for suspicion in HIV-seronegative individuals, (2) decreased awareness of less typical disease presentations, (3) the prognosis of the underlying disease, and/or (4) the irreversibility of immunodepression among many HIV-seronegative individuals [2, 3].
Some limitations of our study are linked to the data collected at the NRCMA. For instance, we were not able to assess attributable mortality. In addition, important confounders of mortality, such as altered mental status and elevated opening pressure [11], were not routinely collected.
Our study nevertheless represents the first large cohort emphasizing that Cryptococcus neoformans is responsible for 2 different diseases according to HIV serostatus. It should serve as a reminder that the recent dramatic therapeutic improvements obtained in HIV-associated cryptococcal meningitis patients should not necessarily be extrapolated to HIV-seronegative individuals [12]. As HIV-seronegative individuals comprise a heterogenous group with a wide range of immunosuppressive backgrounds [3, 5, 6, 9, 10], there is a need for more in-depth research on cryptococcosis in this setting.
Supplementary Material
Contributor Information
Olivier Paccoud, Department of Infectious Diseases and Tropical Medicine, Université Paris Cité, Necker–Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, Institut Hospitalo-Universitaire Imagine, Paris, France.
Marie Desnos-Ollivier, National Reference Center for Invasive Mycoses and Antifungals, Mycology Department, Institut Pasteur, Université Paris Cité, Mycology Translational Research Group, Paris, France.
Sophie Cassaing, Department of Parasitology and Mycology, Toulouse University Hospital, Restore–FLAMES, Toulouse III University, Toulouse, France.
Karine Boukris-Sitbon, National Reference Center for Invasive Mycoses and Antifungals, Mycology Department, Institut Pasteur, Université Paris Cité, Mycology Translational Research Group, Paris, France.
Alexandre Alanio, National Reference Center for Invasive Mycoses and Antifungals, Mycology Department, Institut Pasteur, Université Paris Cité, Mycology Translational Research Group, Paris, France; Laboratoire de Parasitologie-Mycologie, Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France.
Anne-Pauline Bellanger, Centre Hospitalier Universitaire de Besançon, Laboratoire de Parasitologie-Mycologie, Unité Mixte de Recherche Chrono-Environnement/Centre national de la recherche scientifique 6249, Besançon, France.
Christine Bonnal, Laboratory of Parasitology-Mycology, Bichat-Claude Bernard University Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France.
Julie Bonhomme, Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire de Caen, Toxicologie de l’Environnement, Milieux Aériens et Cancers - Aliments Bioprocédés Toxicologie Environnements, Unicaen Université Normandie, Caen, France.
Françoise Botterel, Unité de Parasitologie-Mycologie, Département des agents infectieux, Assistance Publique–Hôpitaux de Paris, Dynamic Research Unit, Université Paris-Est Créteil, Paris, France.
Marie-Elisabeth Bougnoux, Unité de Parasitologie-Mycologie, Service de Microbiologie Clinique, Hôpital Necker-Enfants-Malades, Assistance Publique–Hôpitaux de Paris, Paris, France; Institut Pasteur, Université Paris Cité, Institut national de recherche pour l'agriculture, l'alimentation et l'environnement USC2019, Unité Biologie et Pathogénicité Fongiques, Paris, France.
Sophie Brun, Parasitology-Mycology Department, Avicenne Hospital, Assistance Publique–Hôpitaux de Paris, Bobigny, France.
Taieb Chouaki, Service de Parasitologie Mycologie Médicales, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France; Unité de Glycobiologie Structurale et Fonctionnelle, Inserm U1285, Université Lille, Centre national de la recherche scientifique, Unité Mixte de Recherche 8576, Lille, France.
Muriel Cornet, Service de Parasitologie-Mycologie, Université Grenoble Alpes, Centre national de la recherche scientifique, Unité Mixte de Recherche 5525, Centre Hospitalier Universitaire Grenoble Alpes, VetAgro Sup, Grenoble Institut National Polytechnique, Techniques de l'imagerie médicale et de la complexité, Grenoble, France.
Eric Dannaoui, National Reference Center for Invasive Mycoses and Antifungals, Mycology Department, Institut Pasteur, Université Paris Cité, Mycology Translational Research Group, Paris, France; Unité de Parasitologie-Mycologie, Service de Microbiologie Clinique, Hôpital Necker-Enfants-Malades, Assistance Publique–Hôpitaux de Paris, Paris, France.
Magalie Demar, Laboratoire Hospitalo-Universitaire de Parasito-Mycologie, Centre hospitalier de Cayenne Guyane, Cayenne, France.
Nicole Desbois-Nogard, Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire de Martinique, Fort-de-France, Martinique, France.
Marie-Fleur Durieux, Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire Dupuytren, Limoges, France.
Loïc Favennec, Laboratoire de Parasitologie, French National Cryptosporidiosis Reference Center, Centre Hospitalier Universitaire de Rouen, Rouen, France; Unité de Recherche Equipe d'Accueil 7510, Unité de Formation et de Recherche Santé, University of Rouen Normandy, Rouen, France.
Arnaud Fekkar, Assistance Publique–Hôpitaux de Paris, Groupe Hospitalier La Pitié-Salpêtrière, Parasitologie Mycologie, Paris, France; Centre d’Immunologie et des Maladies Infectieuses, Sorbonne Université, Inserm, Centre national de la recherche scientifique, Cimi-Paris, Paris, France.
Frederic Gabriel, Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
Jean-Pierre Gangneux, Unité Mixte de RechercheUMR_S 1085, Université de Rennes, Centre Hospitalier Universitaire Rennes, Inserm, École des hautes études en santé publique, Institut de recherche en santé, environnement et travail, Rennes, France; Laboratory of Parasitology and Medical Mycology, European Confederation of Medical Mycology Excellence Center, Centre National de Référence Aspergilloses Chroniques, Rennes Teaching Hospital, Rennes, France.
Juliette Guitard, Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, Centre de Recherche Scientifique Saint-Antoine, Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Antoine, Service de Parasitologie-Mycologie, Paris, France.
Lilia Hasseine, Service de Parasitologie-Mycologie, Hôpital de l’Archet, Centre Hospitalier Universitaire Nice, Nice, France.
Antoine Huguenin, Laboratoire de Parasitologie-Mycologie, Université de Reims Champagne Ardenne, ESCAPE EA7510, Pôle de Biologie Pathologie, Centre Hospitalier Universitaire de Reims, Rue du Général Koening, Reims, France.
Solène Le Gal, Centre Hospitalier Universitaire de Brest, Laboratoire de Parasitologie-Mycologie, Université Brest, Université Angers, Infections Respiratoires Fongiques, Brest, France.
Valérie Letscher-Bru, Laboratoire de Parasitologie et Mycologie Médicale, Les Hôpitaux Universitaires de Strasbourg, Institut de Parasitologie et Pathologie Tropicale, UR7292 Dynamique des interactions hôte pathogène, Fédération de Médecine Translationnelle, Université de Strasbourg, Strasbourg, France.
Caroline Mahinc, Service de Parasitologie Mycologie, Centre Hospitalier Universitaire de Saint Etienne, Saint Etienne, France.
Florent Morio, Service de Parasitologie Mycologie, Nantes Université, Centre Hospitalier Universitaire Nantes, Cibles et Médicaments des Infections et de l’Immunité, Nantes, France.
Muriel Nicolas, Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire de Guadeloupe, Pointe-à-Pitre, Guadeloupe, France.
Célia Rouges, Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
Estelle Cateau, Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire de Poitiers, Ecologie et Biologie des Interactions, Unité Mixte de Recherche, Centre national de la recherche scientifique, Poitiers, France.
Florence Persat, UR3738 Centre pour l’lnnovation en Cancérologie de Lyon, Team Inflammation and Immunity of the Respiratory Epithelium, Claude Bernard University-Lyon 1, Pierre Bénite, France; Department of Medical Mycology and Parasitology, Institute of Infectious Agents, Croix-Rousse Hospital, Hospices Civils de Lyon, Lyon, France.
Philippe Poirier, Service de Parasitologie-Mycologie, Université Clermont Auvergne, Inserm, 3IHP, Centre Hospitalier Universitaire Clermont-Ferrand, Clermont-Ferrand, France.
Stéphane Ranque, Aix-Marseille Université, Institut Hospitalo-Universitaire Méditerranée Infection, Assistance Publique des Hopitaux de Marseilles, Institut de Recherche pour le Développement, Service de Santé des Armées, Vecteurs – Infections Tropicales et Méditeranéennes, Marseille, France.
Gabrielle Roosen, Service de Microbiologie, Centre Hospitalier Tourcoing, Tourcoing, France.
Anne-Laure Roux, Laboratoire Infection et Inflammation, Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines, Inserm, Montigny-Le-Bretonneux, France; Microbiology Department, Assistance Publique–Hôpitaux de Paris, Groupe Hospitalo-Universitaire Paris Saclay, Hôpital Ambroise Paré, Boulogne-Billancourt, France.
Milène Sasso, Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire Nîmes and Université de Montpellier, Centre national de la recherche scientifique, Institut de Recherche pour le Développement, MiVEGEC, Montpellier, France.
Olivier Lortholary, Department of Infectious Diseases and Tropical Medicine, Université Paris Cité, Necker–Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, Institut Hospitalo-Universitaire Imagine, Paris, France; National Reference Center for Invasive Mycoses and Antifungals, Mycology Department, Institut Pasteur, Université Paris Cité, Mycology Translational Research Group, Paris, France.
Fanny Lanternier, Department of Infectious Diseases and Tropical Medicine, Université Paris Cité, Necker–Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, Institut Hospitalo-Universitaire Imagine, Paris, France; National Reference Center for Invasive Mycoses and Antifungals, Mycology Department, Institut Pasteur, Université Paris Cité, Mycology Translational Research Group, Paris, France.
for the French Mycoses Study Group:
N Brieu, C Durand, D Bertei, J P Bouchara, M Pihet, S Bland, J P Bru, M Pulik, F Le Turdu, H Lefrand, M Ferrand, M Larrouy, G Nevez, D Quinio, M N Bachelier, A Le Coustumier, F Carmagnol, B Rivière, B Podac, O Augereau, J P Emond, J L Bacri, G Berthelot, F Dalle, E Vallee, J Bizet, L Noussair, J L Herrmann, C Brocard, P Guiffault, A Layet, A Morel, P Penn, A Gigandon, B Sendid, M Cornu, N Prades, T Benoit-Cattin A Fiacre, S Levy, A Pitsch, M H Kiefer, A Debourgogne, O Moquet, J Colot, L Courtellemont, D Poisson, V Laurens, P Martres, N Godineau, S Picot, C Chassagne, N Djibo, R Devallière, A M Camin-Ravenne, F Bissuel, F Janvier, C Eloy, A Fur, L Rezzouk, E Mazars, O Eloy, E Chachaty, L Mihaila, S Dellion, O Patey, A Thouvenot, L Limousin, N Desplaces, G Raguin, and M Gits-Muselli
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Author contributions. Writing–original draft: O. P. Writing–review and editing: M. D.-O., A. A., O. L., and F. L. Methodology: O. P., M. D.-O., and F. L. Data curation: M. D.-O., K. B.-S., A. A., S. C., C. B., J. B., F. B., M.-E. B., S. B., T. C., M. C., E. D., M. D., N. D.-N., M.-F. D., L. F., A. F., F. G., J.-P. G., J. G., L. H., A. H., S. L., V. L. B., C. M., L. M., F. M., M. N., C. R., E. P., F. P., P. P., S. R., G. R., A.-L. R., and M. S. Conceptualization: O. P., O. L., and F. L.
Acknowledgments. The graphical abstract was created with Biorender.com. We would like to thank Professor Françoise Dromer for her tremendous input in the conceptualization of this study, and in particular for the expansion of the French cryptococcosis surveillance network and her continuous investment in its management over 30 years. The French Mycoses Study Group is composed of the following individuals who actively participated in the data collection (by alphabetical order of the cities): N. Brieu (Aix-en-Provence); C. Durand, D. Bertei (Ajaccio); J. P. Bouchara, M. Pihet (Angers); S. Bland, J. P. Bru (Annecy); M. Pulik, F. Le Turdu (Argenteuil); H. Lefrand (Avignon); M. Ferrand, M. Larrouy (Bayonne); G. Nevez, D. Quinio (Brest); M. N. Bachelier (Bourges); A. Le Coustumier (Cahors); F. Carmagnol (Cannes); B. Rivière (Castres); B. Podac (Chalon/Saône); O. Augereau (Colmar); J. P. Emond (Compiegne); J. L. Bacri, G. Berthelot (Dieppe); F. Dalle (Dijon); E. Vallee (Eaubonne); J. Bizet (Fresnes); L. Noussair, J. L. Herrmann (Garches); C. Brocard, P. Guiffault, A. Layet, A. Morel (Le Havre); P. Penn (Le Mans); A. Gigandon (Le-Plessis-Robinson); B. Sendid, M. Cornu (Lille); N. Prades (Lorient); T. Benoit-Cattin (Mayotte) A. Fiacre, S. Levy (Meaux); A. Pitsch (Melun); M. H. Kiefer (Mulhouse); A. Debourgogne (Nancy); O. Moquet (Nevers); J. Colot (Noumea); L. Courtellemont, D. Poisson (Orléans); V. Laurens (Perpignan); P. Martres (Pontoise); N. Godineau (Saint-Denis, Ile de France); S. Picot, C. Chassagne (Saint-Denis, La Réunion); N. Djibo (Saint-Lo); R. Devallière (Saint-Nazaire); A. M. Camin-Ravenne (Tarbes); F. Bissuel (Thonon); F. Janvier (Toulon); C. Eloy, A. Fur, L. Rezzouk (Troyes); E. Mazars (Valenciennes); O. Eloy (Versailles); E. Chachaty, L. Mihaila (Villejuif); S. Dellion, O. Patey (Villeneuve-St-Georges); A. Thouvenot (Villeurbanne); L. Limousin (Suresne); N. Desplaces, G. Raguin (Hôpital de La Croix-Saint-Simon, Paris); and M. Gits-Muselli (Hôpital Robert-Debré, Paris).
Disclaimer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Financial support. This research was supported by Institut Pasteur and Santé Publique France.
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