Cryptocococcosis is the most common life-threatening systemic fungal infection occurring in HIV-infected patients, and extrapulmonary cryptococcosis is an AIDS-defining illness. The most frequent clinical presentation is disseminated meningoencephalitis which is rapidly fatal in the absence of antifungal treatment [1–4].
Excellent reviews on the epidemiology of the infection were published in the early 1990s [5–7]. Up to 1996, the prevalence of cryptococcosis among HIV-patients varied from < 1 to 10% in Western countries [8–13] as opposed to almost a third of HIV-infected individuals in sub-Saharian Africa and Southeast Asia [14,15] where it is associated with high mortality [16,17].
Before 1996, the decline in the frequency of some opportunistic fungal infections was attributed to increased prophylactic usage of drugs active against various pathogens [12,18–20]. Since the introduction of highly active antiretroviral therapy (HAART), the nationwide AIDS surveillance programmes implemented in Western countries have reported sharp decreases in the incidences of AIDS cases and the estimated number of deaths among AIDS patients, while the number of persons living with AIDS has increased [21–24]. Concomitant decreases of the incidences of several opportunistic infections, especially Pneumocystis carinii pneumonia, Mycobacterium avium complex, cytomegalovirus and even Cryptococcus neoformans have been ascribed to the introduction of HAART in these countries [25–30].
Data collected by our national surveillance program enabled us to analyse the modifications of cryptococcosis epidemiology in France and to identify demographic factors associated with an increased risk of cryptococcosis in the post-HAART era.
Materials and methods
In 1985, the National Reference Center for Mycoses (NRCM)  instigated a nationwide survey on cryptococcosis in France through a passive system of data collection with the voluntary participation of clinicians and biologists comprising the French Cryptococcosis Study Group. We previously assessed the completeness of our data collection system by capture–recapture analysis . We have now analysed the cases diagnosed in France from 1 January 1985 to 31 December 2001 and sent to the NRCM before 30 June 2002 (without adjustment of reported cases for reporting delays).
Cases diagnosed by culture of C. neoformans from a specimen from any site, by antigen detection in cerebrospinal fluid (CSF) and/or serum samples, and/or by histopathological findings consistent with cryptococcosis were considered to be cryptococcosis. Recurrence was considered only if it occurred > 6 months after the previous episode or it was the first episode reported to the NRCM. The isolate had been identified as C. neoformans in each participating laboratory and was sent to the NRCM for serotyping .
Data collection and evaluation
Data were recorded on a standardized form by the treating clinician and/or the biologist and mailed to the NRCM. The one-page questionnaire, unchanged since 1990 , included demographic characteristics, and epidemiological and mycological data.
Our classification of HIV-infected patients was based on that established by the Centers for Disease Control and Prevention (CDC) in 1993  and on criteria used by the French Government Agency for Disease control and Prevention (Institut de Veille Sanitaire) . Thus, five exposure categories were established: homosexuality/bisexuality, injecting drug use, heterosexuality, contamination by blood or blood products, and others (including combinations of the previous categories, mother-to-child transmission, and unknown risk factors). Depending on the stage of HIV infection, extrapulmonary cryptococcosis was considered to be an AIDS-defining illness (sometimes revealing HIV infection) or not. Patients also were classified according to their continent of birth: Europe, Africa, or others (including North, Central and South America, Caribbean Islands, and Asia).
Cases were classified as cryptococcal meningitis (C. neoformans-positive CSF assessed by direct examination, antigen testing or culture) or as extrameningeal cryptococcosis.
Two periods were defined: pre-HAART (1985–1996) and post-HAART (1997–2001); HAART was introduced in France in mid-1996.
In accordance with French law, the NRCM database was approved by the National Commission on Informatics and Freedom (Commission Nationale de l'Informatique et des Libertés). All variables were coded. Epi-Info software (version 6.04c, 1997, CDC, Atlanta, Georgia, USA, and World Health Organization, Geneva, Switzerland) was used to record data. For the analyses of cryptococcosis, all reported cases were used, whereas only the first recorded episode was considered for the analysis of patients. Percentages were compared using chi-square or Fisher's exact tests. Means were compared with Student's t test or analysis of variance. A logistic regression was constructed for multivariate analysis. All variables that were clinically relevant or statistically significant in the univariate analysis (P < 0.25) were entered simultaneously into the full model . These results are reported as odds ratios (OR) and their 95% confidence intervals (CI). A negative binomial regression model was constructed to evaluate the evolution of the incidence of cryptococcosis among HIV-positive subjects after the introduction of HAART. Estimates of the total number of HIV-positive subjects per year in France were obtained from Angela Downs (EuroHIV, Institut de Veille Sanitaire; personal communication, 2003). Analyses were performed using Stata computer package version 7 (Stata Statistical Software, Stata Corporation, College Station, Texas, USA).
Trends in the occurrence of cryptococcosis in France
Among the 2125 cases recorded from 135 cities around the country, 1644 were diagnosed in HIV-infected individuals (including 184 cases recorded as recurrences of which 46 were a first notification). The total number of cases paralleled that recorded for HIV-positive patients with a steady rise until 1995, a sharp decrease in 1996 and 1997 and a plateau thereafter (Fig. 1). Using recent data from the Institut de Veille Sanitaire , we found that the annual percentage of cryptococcosis cases among the new AIDS cases was stable over time (mean, 3.5 ± 0.3%).
Cases of cryptococcosis were recorded throughout the country but mostly in three regions: Paris and its suburbs (54% of all cases), the Mediterranean area (15%) and the Southwest (11%), which correspond to the highest densities of HIV-positive individuals. No seasonal fluctuation was observed in the numbers of cases recorded.
Characteristics of the population diagnosed with cryptococcosis
HIV-infected patients were significantly younger and more often born in Africa than HIV-negative patients (Table 1). The percentage of males of all ages was significantly higher for HIV-positive than HIV-negative patients (male : female ratio, 6.8 versus 1.7; P < 0.001) and increased significantly with age among males. The sex ratio according to the HIV seropositivity or -negativity was similar for African patients (male : female ratio, 2.5) while it differed significantly for European patients (male : female ratio, 10 versus 1.7, P < 0.001). Females were significantly younger than males only in the HIV-infected population [median age in years (range), 33 (8–80) versus 36 (9–84); P < 0.001].
HIV-negative patients risk factors for cryptococcosis included solid organ transplantation (mostly kidney, 17.4%), haematological malignancies (lymphomas, chronic lymphoid leukaemia, myeloma and other dysglobulinaemias) and solid cancers (36.8%), miscellaneous underlying diseases (systemic inflammatory diseases, sarcoidosis, idiopathic CD4 lymphocytopenia, cirrhosis, diabetes mellitus, or pre-existing pulmonary diseases such as tuberculosis, asthma or cystic fibrosis; 20.4%), and no underlying disease (25.4%) but a clinical history compatible with primary cutaneous cryptococcosis for some patients .
Among the 19 children diagnosed with cryptococcosis (≤ 15 years old, 10 boys and nine girls) with a median age of 11 years [3–15], six were HIV-infected, four had malignancies (lymphomas, myeloid leukaemia), two had hyper-IgM syndrome. Five children including three with primary cutaneous cryptococcosis had no identified risk factor.
Characteristics of the fungal infection
Cryptococcal meningitis was diagnosed in 74% of the HIV-positive patients and the infection was disseminated in 46% of them [based on positive cultures of blood (31%), urine (17%), bronchoalveolar lavage (14%) or skin (2.5%) samples]. Among the HIV- negative patients, 51% had cryptococcal meningitis and the infection was disseminated in 41% of them [based on positive cultures of blood (22.5%), urine (15%), bronchoalveolar lavage (11%) or skin (7%) samples]. For patients with no positive CSF culture (i.e., negative culture or not done), blood, urine, broncholaveolar lavage and skin cultures were positive for respectively 29%, 14%, 32% and 5% of HIV-positive patients, and for 19.5%, 9%, 35% and 33.5% of HIV-negative patients. It should be noted however, that differences were observed in clinical practices (diagnostic procedures, extent of work-up) according to HIV status and the region of diagnosis (data not shown).
The isolates recovered from 1190 patients with cryptococcosis were available for serotyping. Rare isolates were identified as variety gattii serotype B (11 isolates including four from HIV-positive patients), 22.5% were serotype D and serotype A predominated (76.5%).
Influence of HAART introduction on the epidemiology of cryptococcosis in France
Demographic characteristics of HIV-infected patients diagnosed with cryptococcosis were analysed over time. We defined two periods according to the year of cryptococcosis diagnosis, i.e., the pre-HAART (n = 1352) and post-HAART (n = 292) eras (Table 2). The incidence of cryptococcosis among HIV-positive individuals decreased by 46% during the post-HAART period (P < 0.001).
The number of cases recorded for male homosexuals declined sharply and the diminution was somewhat less for male and female injecting drug users, while the number of cases recorded of persons exposed through heterosexual contacts remained stable (Fig. 2). Compared to the pre-HAART era, significantly higher post-HAART percentages were observed for African-born patients whose cryptococcosis revealed HIV infection (13% versus 30%; P < 0.001), patients with no previous AIDS-defining diagnosis (40.7% versus 58.5% for both sexes; P < 0.001), and heterosexual HIV transmission for both sexes (19.3% versus 47.6%; P < 0.001). The types of cryptococcal disease, the percentages of serotype D isolates and the median CD4 counts did not change over time. According to our multivariate analysis, African origin (OR, 2.07; 95% CI, 1.35–3.14; P = 0.001), ‘older’ age (35–45 years: OR, 2.04; 95% CI, 1.42–2.93; P < 0.001; and > 45 years-old: OR, 1.93; 95% CI, 1.23–3.03; P = 0.004), heterosexual HIV contamination (OR, 2.39; 95% CI, 1.64–3.47; P < 0.001), no previous HIV-infection diagnosis (OR, 1.6; 95% CI, 1.03–2.49; P = 0.035) or no previous AIDS-defining diagnosis (OR, 1.66; 95% CI, 1.14–2.42; P = 0.008) were variables independently associated with the post-HAART era.
Among patients with cryptococcosis whose HIV status was known, 14.6% were seronegative during the pre-HAART era as opposed to 26.1% during the post-HAART era (P < 0.001). However, none of the characteristics of the HIV-negative population (sex ratio, age, ethnic origin, risk factors, serotype of the isolate) changed over time (data not shown).
Because cryptococcosis is not a notifiable disease anywhere, only specific surveillance programs can provide accurate data on the trends in its epidemiology. The NRCM instigated such a program in 1985, at the beginning of the AIDS epidemic, when clinical advice was increasingly sought for this unusual fungal infection. Since then, clinicians and microbiologists have voluntarily reported their cases. Given that the system did not change since we assessed its exhaustivity at approximately 50% in 1996 , we assumed that the following years also provided accurate data.
Over the 17-year study, 2125 patients were diagnosed with cryptococcosis in France (population, 59 million). The number of cryptococcosis cases recorded for HIV-infected patients increased until 1995, declined abruptly over 1996 and 1997 and then levelled off, in parallel with the incidence of AIDS cases recorded in France . This evolution differs from that observed in four areas of the USA, where decreased incidences of cryptococcosis started in 1994, first attributed to the use of fluconazole  and later to HAART .
We observed that the characteristics of the HIV-infected patients with cryptococcosis changed after the introduction of HAART. The decreased incidence essentially occurred among European male homosexuals, leading to a significant increase of the relative percentages of African-born patients and patients contracting HIV through heterosexual contacts, a finding not elucidated in the recent American analysis made by Mirza et al. . In both the French and the American-AIDS surveillance programs however [21,22], the numbers of AIDS cases attributed to heterosexual transmission have stabilized or even increased in the recent years, while the other exposure groups (male homosexuals and intravenous drug users of both sexes) declined, and the number of patients with poorer access to care increased.
Other demographic characteristics of the patients also changed. The median age of the HIV-infected patients with cryptococcosis increased during the post-HAART era, a finding in agreement with what has been observed for the entire AIDS population in France. Cryptococcosis revealed the HIV infection for a higher percentage of patients diagnosed in France during the post-HAART era. Indeed, it was the AIDS-defining illness for 57% of the 221 males and 66% of the 53 females patients during the post-HAART era, values significantly higher than those observed during the pre-HAART era in France (39.5% of the 961 males and 49% of the 124 females) and during the 1992–2000 survey in the USA (39% of 179 patients) . The reason for the difference between the two countries is not clear but could reflect the divergence in the approaches to HIV infection management. In addition, various socio-demographic conditions account for an increased risk of developing cryptococcosis in these two countries. Thus, cryptococcosis continues to occur but primarily in patients availing themselves less to routine medical care and to HAART (i.e., African-born individuals and women in France), often because of reticence or ignorance, considering themselves not at risk for HIV infection, or in patients with poor access to care in the USA (i.e., African–American individuals) .
Although the HIV-infected population diagnosed with cryptococcosis changed over time, the HIV-negative population did not, thereby suggesting the absence of a new source of immunosuppression predisposing to cryptococcosis during the study period. Analysis of our data showed that diagnostic procedures differed according to the patient's HIV status and the region of diagnosis. Although this was never explicitly stated, it is probable that it represents a bias in all recent or earlier studies conducted for surveillance purposes and not therapeutic issues [8,16,20,29,30,37]. It is also likely that patient management is influenced by other events, such as local clinical trials, publications of multicenter trial results and practical guidelines [38–41]. Thus, the features that distinguish patients with cryptococcosis according to their HIV status can only be determined accurately in a specifically designed investigation, such as the CryptoA/D study currently under analysis .
In conclusion, cryptococcosis represents an important worldwide cause of morbidity and mortality for HIV-infected patients, which tends to decline in countries where HAART is available but remains high elsewhere. A surveillance system such as that implemented by the French Cryptococcosis Study Group provides important information on the evolution of this opportunistic fungal infection and the efficacy of antiretroviral therapies that pertinently complements findings obtained through other surveillance programs.
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The French Cryptococcosis Study Group includes clinicians and biologists from various hospitals in France. The following members actively participated in data collection for this study: H. Chardon (Aix- en-Provence), H. Greze (Albi), O. Chrétien (Alençon), B. Carme, M.P. Hayette, G. Nevez (Amiens), J.P. Bouchara, D. Chabasse (Angers), M. Martin (Angoulême), S. Blanc (Annecy), V. Blanc (Antibes), F. Leturdu, M. Pulik (Argenteuil), B. Hautefort (Arles), J. Fruit (Arras), I. Cahitte (Asnières), F. Giacomini, M.P. Le Pennec (Aulnay-sous-Bois), H. Lefrand (Avignon), M. Larrouy (Bayonne), X. Doat, J. Larfouilloux (Beaune), J.P. Faller (Belfort), T. Barale, R. Piarroux, G. Reboux (Besançon), A. Dayan (Blois), C. Bouges-Michel, O. Launay (Bobigny), G. Delzanig, I. Poilane (Bondy), C. Boisseau, B. Couprie, A. Texier, F.X. Weill (Bordeaux), M.E. Bougnoux (Boulogne-Billancourt), H. de Montclos (Bourg-en-Bresse), M. Gavignet (Bourges), O. Masure, E. Moalic, D. Quinio (Brest), G. Otterbein (Brie-sur-Marne), C. Lefort (Brives), C. Duhamel (Caen), C. Bidault (Chalon-sur-Saône), O. Rogeaux (Chambéry), M. Zaigel (Chartres), C. Allard (Cherbourg), E. Laurens (Cholet), Y. Guibert, V. Hervé, P. Soler (Clamart), M. Cambon (Clermont-Ferrand), R. Roué (Clichy), Y. Boussougant, G. Galeazzi, S. Lasry (Colombes), C. Malbrunot (Corbeil-Essonne), F. Cordier (Creil), S. Bretagne, G. Belkacem, M. Geslin, P. Lesprit, A. Marmorat-Khuong (Créteil), X. Lhoste (Dax), M. Berthelot, C. Bessin, J.P. Gaillard (Dieppe), A. Bonin, P. Camerlynck, J. Lopez (Dijon), G. Grise (Elboeuf), M. Gauthier (Evry), J.M. Chevalier, P. Lafay, X. Poullain (Flers), E. Counillon (Fréjus), I. Bouchard (Fresnes), C. Nauciel (Garches), F. Poujade (Gonesse), R. Grillot, B. Lebeau, A. Thomas (Grenoble), F. Botterel, P. Bourée, S. Romand (Kremlin-Bicêtre), A. Lagarde (Lagny), X. Gosset (Lannion), M. Auberger (Laval), M.A. Dessailly-Chanson (La Roche-sur-Yon), J. Vincent (La Rochelle), O. Eloy (Le Chesnay), M.L. Grillot (Le Havre), E. Boyer (Le Mans), A. Capbern (Libourne), B. Bouteille, M.L. Darde (Limoges), Y. Lermercier (Longjumeau), E. Dannaoui, M.A. Piens, M. Rabodnirina (Lyon), G. Janin (Macon), L. Berardi (Mantes-la-Jolie), A. Blancard, L. Collet, A. Michel-N'Guyen, A. Penaud (Marseille), M. Bietrix, M. Nezri (Martigues), A. Eme, A. Fiacre (Meaux), C. Chandesris (Montargis), M. Piquet (Montfermeil), P. Rispail (Montpellier), V. Gettler (Montreuil), M.F. Penner, A. Trévoux (Mulhouse), M.F. Biava, L. Kures (Nancy), O. Morin (Nantes), M. Felz, S. Kernbaum (Neuilly-sur-Seine), X. Lenon (Nevers), Y. Le Fichoux, M. Gari-Toussaint (Nice), A. Delage (Nîmes), X. Romaru (Niort), J.P. Barthez, D.M. Poisson (Orléans), X. Méion (Pau), Y. Giudicelli (Poissy), J.L. Jacquemin, C. Kauffmann-Lacroix (Poitiers), A. Blanchard, X. Thibault (Pontoise), F. Pateyron (Provins), J.M. Pinon, D. Toubas (Reims), S. Chevrier, C. Guigen (Rennes), P. Brasseur, L. Favenec (Rouen), J.M.P. Lafaye (Royan), G. Sirondelle (Rozoy-sur-Serre), M. Janvier (Saint-Cloud), N. Godineau, S. Hamane (Saint-Denis), G. Dorche, H. Raberin (Saint-Etienne), S. Fegueux (Saint-Germain-en-Laye), A. Gregory (Saint-Julien-en-Genevois), X. Cavallo, M.C. Debord, R. Roué (Saint-Mandé), M. Simoneau (Saint-Maurice), J.Y. Leberre (Saint-Nazaire), P. Malherbe (Saint-Quentin), S. Liebeau (Saumur), M. Gauthron (Sens), H. Koenig, J. Waller (Strasbourg), P. Cahen (Suresnes), L. Kures (Toul), Y. Muzellec (Toulon), M.T. Baixench, M.D. Linas, P. Luydlin, J.F. Magnaval, P. Recco, J.P. Seguela (Toulouse), C. Coignard, F. de Keyser, M. Vinocour (Tourcoing), F. Declosets, M. Ferly-Therizol, R. Lenoble (Tours), F. Moreau-Benaoudia (Troyes), J. Verger (Tulle), M.A. Piens (Valence), E. Mazars (Valenciennes), O. Eloy (Versailles), D. Fortineau, D. Matthieu, F. Salida (Villejuif), J. Breuil, S. Dellion, O. Patey (Villeneuve-Saint-Georges); and in Paris, C. Chochillon (Hôpital Bichat), V. Lavarde (Hôpital Broussais), C. Bizet, A. Buré, B. Pangon (Hôpital Claude-Bernard), M.T. Baixench, J. Dupouy-Camet, A. Paugham, F. Robert-Gangeux (Hôpital Cochin), N. Desplaces (Hôpital de la Croix-Saint-Simon), J. Prost, F. Raymond, M. Segonds (Hôpital des Diaconesses), M. Cornet, V. Lavarde (Hôpital Européen Georges Pompidou), D. Basset, M. Cornet, P. Lagrange (Hôpital de l'Hôtel-Dieu), M.C. Escande (Institut Curie), C. Lamer, Y. Pean (Institut Mutualiste Montsouris), N. Fortineau (Hôpital Laënnec), C. Dematons (Hôpital Lariboisière), S. Challier, C. Hennequin (Hôpital Necker), C. Aznar, J. Fleury (Hôpital Pasteur), I. Abeille, E. Bart-Delabesse, J. Carrière, A. Datry, M. Gentilini, V. Zeller (Hôpital La Pitié-Salpêtrière), A.M. Deluol (Hôpital Rothschild), G. Buot (Fondation Rothschild), J.L. Poirot (Hôpital Saint-Antoine), A. Marmorat (Hôpital Saint-Joseph), C. Lacroix, F. Derouin, M. Feuilhade-Chauvin, F. Traore (Hôpital Saint-Louis), J. de Recondo (Hôpital Sainte-Anne), G. Ponsot (Hôpital Saint-Vincent-de-Paul), P. Roux, G. Kac (Hôpital Tenon), X. Crozas (Hôpital Trousseau), M. Arborio (Hôpital du Val de Grâce).