Invasive Fungal Diseases in Patients with Autoimmune Diseases: Prospective Data from a Nationwide French Registry

Simon Galmiche¹, Benjamin Thoreau², Stéphane Bretagne³, Alexandre Alanio³, André Paugam⁴, Valérie Bru⁵, Sophie Cassaing⁶, Jean-Pierre Gangneux⁷, Hélène Guégan⁷, Loïc Favennec⁸, Alida Minoza⁹, Florent Morio¹⁰, Julie Bonhomme¹¹, Guillaume Desoubeaux¹², Odile Eloy¹³, Lilia Hasseine¹⁴, Milène Sasso¹⁵, Laurence Millon¹⁶, Anne-Pauline Bellanger¹⁶, Philippe Poirier¹⁷, Maxime Moniot¹⁷, Taieb Chouaki¹⁸, Antoine Huguenin¹⁹, Frédéric Dalle²⁰, Bernard Bouteille²¹, Muriel Nicolas²², Nicole Desbois-Nogard²³, Marie-Elisabeth Bougnoux²⁴, François Danion²⁵, Vincent Poindron²⁶, Antoine Néel²⁷, Karine Boukris-Sitbon²⁸, Fanny Lanternier²⁹ and Benjamin Terrier³⁰, ¹Institut Pasteur, Paris, France, ²AP-HP, Université Paris Cité, INSERM U1016, CNR UMR 8104, Paris, France, ³Institut Pasteur, Université Paris Cité, Centre National de Référence Mycoses Invasives et Antifongiques, UMR 2000, AP-HP, Paris, France, ⁴Parasitologie – Mycologie, Université Paris Cité, Cochin Hospital, AP-HP, Paris, France, ⁵Institut de parasitologie et de pathologie tropicale, Hôpitaux universitaires de Strasbourg, Université de Strasbourg, Strasbourg, France, ⁶Parasitologie - Mycologie, Université de Toulouse, CHU de Toulouse, Toulouse, France, ⁷Université de Rennes, CHU, INSERM, Irset: Institut de Recherche en Santé, Environnement et Travail, UMR_S 1085, Rennes, France, ⁸French National Cryptosporidiosis Reference Center, Rouen University Hospital, Rouen, France, ⁹Département des agents infectieux, Service de Mycologie-Parasitologie, CHU de Poitiers, Poitiers, France, ¹⁰Parasitologe – Mycologie, CHU de Nantes, Nantes, France, ¹¹Microbiologie, CHU de Caen, Caen, France, ¹²Parasitologie - Mycologie - Médecine tropicale, CHU de Tours, Tours, France, ¹³Microbiologie, Hôpital de Versailles, Le Chesnay, France, ¹⁴Parasitologie – Mycologie, hôpital de l'Archet, CHU Nice, Nice, France, ¹⁵Laboratoire de Parasitologie-Mycologie, CHU Nîmes, Université de Montpellier, CNRS, IRD, MiVEGEC, Nîmes, France, ¹⁶Laboratoire de Parasitologie – Mycologie, CHU Besançon, Besançon, France, ¹⁷Parasitologie – Mycologie, CHU de Clermont-Ferrand, Clermont-Ferrand, France, ¹⁸Mycologie – parasitologie, CHU d’Amiens, Amiens, France, ¹⁹Parasitologie – Mycologie, hôpital Maison-Blanche, CHU de Reims, Reims, France, ²⁰Parasitologie – Mycologie, Plateforme de Biologie Hospitalo-Universitaire Gérard Mack, Dijon, France, ²¹Parasitologie – Mycologie, Centre de Biologie et de Recherche en Santé, CHU Dupuytren, Limoges, France, ²²Mycologie – Parasitologie, CHU de Pointe-à-pitre/Abymes, Pointe-à-Pitre, France, ²³Parasitologie – Mycologie, CHU de la Martinique, Fort-de-France, France, ²⁴Institut Pasteur, Unité Biologie et Pathogénicité Fongiques, Département Mycologie, Laboratoire de Parasitologie – Mycologie, Service de Microbiologie, Necker-Enfants Malades University Hospital, AP-HP, Paris, France, ²⁵Maladies infectieuses et tropicales, Hôpitaux universitaires de Strasbourg, Strasbourg, France, ²⁶Immunologie clinique et médecine interne, Hôpitaux universitaires de Strasbourg, Strasbourg, France, ²⁷CHU de Nantes, Nantes, France, ²⁸Institut Pasteur, Université Paris Cité, CNRS, Mycologie Moléculaire, Centre National de Référence Mycoses Invasives et Antifongiques, UMR 2000, Paris, France, ²⁹Infectious Diseases Unit, Necker-Enfants Malades University Hospital, AP-HP, Institut Pasteur, Université Paris Cité, Centre National de Référence Mycoses Invasives et Antifongiques, CNRS UMR 2000, Paris, France, ³⁰National Referral Center for Rare Systemic Autoimmune Diseases, Cochin Hospital, Paris, France

Meeting: ACR Convergence 2022

Keywords: autoimmune diseases, Disease-Modifying Antirheumatic Drugs (Dmards), glucocorticoids, Infection

Session Information

Date: Monday, November 14, 2022

Title: Abstracts: Epidemiology and Public Health II: COVID, Infection and Pregnancy Outcomes

Session Type: Abstract Session

Session Time: 3:00PM-4:30PM

Background/Purpose: Patients with autoimmune diseases (AIDs) display a risk of invasive fungal diseases (IFDs), because of the underlying disease or treatments used. Our objective was to describe the characteristics of IFDs in patients with AID and factors associated with mortality.

Methods: We analysed IFD cases included into a prospective multicenter registry conducted by the French national reference center for invasive mycoses and antifungals. We performed clustering after multiple correspondence analysis and a multivariable Cox model for factors associated with mortality.

Results: From 2012 to 2018, 552 individuals with IFD and AID were included, mainly with Pneumocystis jirovecii pneumonia (PCP) (n=229, 41.5%), fungemia (n=168, 30.4%) and invasive aspergillosis (n=84, 15.2%) (other IFD: n=58; multiple IFD: n=13). Rheumatoid arthritis (RA) and systemic vasculitis were the most frequent underlying AIDs in patients with PCP (respectively n=55 and n=42) and invasive aspergillosis (n=15 and n=14). Inflammatory bowel diseases (IBD) were predominant in fungemia (n=36). At IFD diagnosis, 346 (62.7%) patients received glucocorticoids (GCs) and 321 (58.2%) received immunosuppressive agents, mainly methotrexate (n=113), azathioprine (n=38) and cyclophosphamide (n=27). Mortality at 90 days was 34.5% (174/504), and was higher in invasive aspergillosis (31/81, 38.3%) and fungemia (72/148, 48.7%) compared to PCP (54/207, 26.1%) (p< 0.001) (figure 1). Fungemia (hazard ratio 2.4, 95% confidence interval 1.6-3.5, compared with PCP), advanced age (HR 2.1, 95% CI 1.3-3.2, for age ≥70 years compared with age < 55), cirrhosis (HR 3.7, 95% CI 2.1-6.4), and use of high-dose GCs ( > 0.3 mg/kg/day for > 1 month at IFD diagnosis) (HR 1.7, 95% CI 1.2-2.3) were independently associated with higher mortality. Clustering analysis identified three clusters: Cluster 1 consisted mainly of patients with PCP, IFD occurred 1 year after AID diagnosis in median, and almost all received high doses of GCs. Cluster 2 included mostly patients with RA, less frequently receiving GCs, and IFD occurred long after AID diagnosis (median 6 years). Cluster 3 included almost exclusively fungemia, occurring long after AID diagnosis (median 8 years). Cluster 2 (24.4%) displayed a lower mortality than the other two (cluster 1: 39.5%; cluster 3: 40.5%; p = 0.002). PCP (n=239) mostly occurred early after AID diagnosis (median 2 years, interquartile range 0-11) except for cases with RA (9 years, IQR 3-18). CD4+ T cells were measured within 3 months of PCP diagnosis for 78 patients (32.6%): median level was 472.5/mm3 (IQR 198-858), 49.6% (IQR 36.8-65.3) and CD4/CD8 ratio 2.2 (IQR 1.3-4.3). Among cases of fungemia, patients with IBD had an improved survival (HR 0.19, 95% CI 0.07-0.52).

Conclusion: IFDs are associated with a high mortality in patients with AID. PCP is the main IFD in this population and occurs primarily in patients with RA. Fungemia (apart for patients with IBD), high-dose GCs, cirrhosis and older age are associated with poor survival. PCP occurs usually early after AID onset except in cases of RA. CD4 T cell lymphopenia, mostly absent in cases of PCP, poorly predicts the risk of PCP in patients with AID.

Figure 1: Kaplan-Meier analysis of survival in the 90 days following diagnosis of the invasive fungal disease (IFD) according to the type of IFD
Legend: patients with multiple IFDs were not included in the analysis; 23 participants (including 21 dead and 2 lost to follow-up) were censored before date of diagnosis and were not included in the analysis

Disclosures: S. Galmiche, None; B. Thoreau, None; S. Bretagne, None; A. Alanio, None; A. Paugam, None; V. Bru, None; S. Cassaing, None; J. Gangneux, None; H. Guégan, None; L. Favennec, None; A. Minoza, None; F. Morio, None; J. Bonhomme, None; G. Desoubeaux, None; O. Eloy, None; L. Hasseine, None; M. Sasso, None; L. Millon, None; A. Bellanger, None; P. Poirier, None; M. Moniot, None; T. Chouaki, None; A. Huguenin, None; F. Dalle, None; B. Bouteille, None; M. Nicolas, None; N. Desbois-Nogard, None; M. Bougnoux, None; F. Danion, None; V. Poindron, None; A. Néel, None; K. Boukris-Sitbon, None; F. Lanternier, None; B. Terrier, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb(BMS), Eli Lilly, LFB, Boehinger Ingelheim, Vifor Pharma, Pfizer, Roche.

To cite this abstract in AMA style:

Galmiche S, Thoreau B, Bretagne S, Alanio A, Paugam A, Bru V, Cassaing S, Gangneux J, Guégan H, Favennec L, Minoza A, Morio F, Bonhomme J, Desoubeaux G, Eloy O, Hasseine L, Sasso M, Millon L, Bellanger A, Poirier P, Moniot M, Chouaki T, Huguenin A, Dalle F, Bouteille B, Nicolas M, Desbois-Nogard N, Bougnoux M, Danion F, Poindron V, Néel A, Boukris-Sitbon K, Lanternier F, Terrier B. Invasive Fungal Diseases in Patients with Autoimmune Diseases: Prospective Data from a Nationwide French Registry [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/invasive-fungal-diseases-in-patients-with-autoimmune-diseases-prospective-data-from-a-nationwide-french-registry/. Accessed .

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