Invasive aspergillosis in adult patients with rheumatic diseases

Objective: to study risk factors for invasive aspergillosis (IA), its etiology, clinical manifestations, and treatment efficiency in patients with rheumatic diseases (RD).

Patients and methods. The first study of proven and probable IA (EORT/MSGERC, 2019) was conducted in 18 patients with RD, who accounted for 3% of all adult IA patients (n=699) included in the 1998–2020 registry of the Department of Clinical Mycology, Allergology, and Immunology, I.I. Mechnikov North-Western State Medical University (Group 1). This group comprised 56% women; the median age was 59 [21; 75] years. Group 2 (a comparison group) included 610 adult hematology patients with IA (median age, 45 [18; 79] years; 42% women). A prospective case-control study was conducted to identify risk factors for IA in patients with RD: 36 rheumatic patients without IA (median age, 58 (18–79) years; 61% women) (a control group).

Results and discussion. Patients with RD were found to often develop IA in the presence of anti-neutrophilic cytoplasmic antibody-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis) and systemic lupus erythematosus (50 and 16%, respectively). It was shown for the first time that the likelihood of IA in patients with RD increases with prolonged (median 14 days) lymphocytopenia during RD treatment (odds ratio 13.0; 95% confidence interval, 3.3–50.3). The main causative agents of IA were A. fumigatus (50%) and A. niger (29%). IA was more severe in Group 1 than in Group 2: in the resuscitation and intensive care units, there were 44 and 18%, respectively (p=0.01). Group 1 versus Group 2 more frequently had respiratory failure (61 and 37%, respectively; p=0.03), hemoptysis (28 and 7%; p=0.0001), chest pain (17 and 7%; p=0.04), and cardiac involvement (11 and 1%; p=0.0001), and less frequently had fever (67 and 85%; p=0.01). The common site of IA was the lung (83%); the characteristic feature detected by computed tomography (CT) is pulmonary cavitation (44%). Antifungal therapy was used in 89% of Group 1 patients; the overall 12-week survival was 69%.

Conclusion. In patients with RD, it is difficult to differentiate between the progression of the underlying disease, adverse drug reactions, infectious complications, or a combination of these disorders due to the similarity of their clinical manifestations. When RD patients with infectious syndrome and respiratory failure develop prolonged lymphocytopenia during combination therapy, AI should be suspected and lung CT, bronchoscopy, and mycological examination of the material obtained by bronchoalveolar lavage be done.

1. Taccone FS, van den Abeele AM, Bulpaet P, et al. Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes. Crit Care. 2015 Jan 12;19(1):7. doi: 10.1186/s13054-014-0722-7.

2. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008 Jun 15;46(12):1813-21. doi: 10.1086/588660.

3. Donnelly JP, Chen SC, Kauffman CA, et al. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2020 Sep 12;71(6):1367-76. doi: 10.1093/cid/ciz1008.

4. Ullmann AJ, Aguado JM, Arikan-Akdagli S, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018 May;24 Suppl 1: e1-e38. doi: 10.1016/j.cmi.2018.01.002. Epub 2018 Mar 12.

5. Montagna MT, Lovero G, Coretti C, et al. SIMIFF study: Italian fungal registry of mold infections in hematological and non-hematological patients. Infection. 2014 Feb;42(1): 141-51. doi: 10.1007/s15010-013-0539-3. Epub 2013 Oct 23.

6. Dabas Y, Mohan A, Xess I. Serum galactomannan antigen as a prognostic and diagnostic marker for invasive aspergillosis in heterogeneous medicine ICU patient population. PLoS One. 2018 Apr 23;13(4):e0196196. doi: 10.1371/journal.pone.0196196. eCollection 2018.

7. Di Franco M, Licchino B, Spaziante M, et al. Lung Infections in Systemic Rheumatic Disease: Focus on Opportunistic Infections. Int J Mol Sci. 2017 Jan 29;18(2):293. doi: 10.3390/ijms18020293.

8. Skattum L, van Deuren M, van der Poll T, et al. Complement deficiency states and associated infections. Mol Immunol. 2011 Aug; 48(14):1643-55. doi: 10.1016/j.molimm.2011.05.001. Epub 2011 May 31.

9. Ali T, Kaitha S, Mahmood S, et al. Clinical use of anti-TNF therapy and increased risk of infections. Drug Healthc Patient Saf. 2013; 5:79-99. doi: 10.2147/DHPS.S28801. Epub 2013 Mar 28.

10. Singh JA, Hossain A, Kotb A, Wells G. Risk of serious infections with immunosuppressive drugs and glucocorticoids for lupus nephritis: a systematic review and network meta-analysis. BMC Med. 2016 Sep 13;14(1): 137. doi: 10.1186/s12916-016-0673-8.

11. Lao M, Wang X, Ding M, et al. Invasive fungal disease in patients with systemic lupus erythematosus from Southern China: a retrospective study. Lupus. 2019 Jan;28(1):77-85. doi: 10.1177/0961203318817118. Epub 2018 Dec 8.

12. Davis MR, Thompson GR, Patterson TF. Fungal Infections Potentiated by Biologics. Infect Dis Clin North Am. 2020 Jun;34(2): 389-411. doi: 10.1016/j.idc.2020.02.010. Epub 2020 Apr 23.

13. Vallabhaneni S, Chiller TM. Fungal Infections and New Biologic Therapies. Curr Rheumatol Rep. 2016 May;18(5):29. doi: 10.1007/s11926-016-0572-1.

14. Gea-Banacloche JC. RituximabAssociated Infections. Semin Hematol. 2010 Apr;47(2):187-98. doi: 10.1053/j.seminhematol.2010.01.002.

15. Zhou W, Li H, Zhang Y, et al. Diagnostic Value of Galactomannan Antigen Test in Serum and Bronchoalveolar Lavage Fluid Samples from Patients with Nonneutropenic Invasive Pulmonary Aspergillosis. J Clin Microbiol. 2017 Jul;55(7):2153-61. doi: 10.1128/JCM.00345-17. Epub 2017 Apr 26.