Invasive fungal infections in children with rheumatic diseases

Introduction. In children with rheumatic diseases, severe fungal infections (invasive mycoses – IM) are not well understood.

Objectives. To analyze risk factors, disease course of IM in children with systemic rheumatic diseases.

Materials and methods. For diagnosis of IM were used criteria EORTC/MSGERC, 2019. We reviewed the literature over the past 15 years on IM in children with rheumatic diseases from the international databases Pubmed and Web of Science.

Results. In retrospective multicenter study were included 8 children with IM and systemic rheumatic diseases: ANCA-associated vasculitis (n=4), systemic lupus erythematosus (n=3), juvenile rheumatoid arthritis (n=1). Median age was 13,5 (8-17) y., boys – 67%. Invasive aspergillosis was diagnosed in 5 patients and invasive candidiasis – 3. The risk factors of invasive mycoses were high rheumatic disease activity (100%), corticosteroids (prednisolone ≥ 0,3 mg/kg/d) use for ≥21 d (87,5%), immunosuppressive therapy (87,5%), recent (≤ 2 weeks) pulse steroid therapy (75%), hemophagocytic lymphohistiocytosis (62,5%), prolonged (≥ 10 days) severe neutropenia (≤ 0,5х109/l) (62,5%), and prolonged (≥10 days lymphopenia (≤ 1,0х109/l) (37,5%). In patients with invasive aspergillosis the involved organ was the lung, in patients with invasive candidiasis a candidemia was diagnoses. All patients received antifungal therapy. The overall 30 days survival rate was 37,5%.

Сonclusions. Children with high rheumatic diseases activity and intensive treatment with immunosuppressive agents should be considered as patients with a high risk of invasive mycoses with a high mortality. 

1. Belov B.S., Bukhanova D.V., Tarasova G.M. Lower respiratory tract infections in rheumatic diseases // Modern Rheumatology Journal. - 2018 .- 12 (1). - P. 47–54. (in Russian)

2. Shadrivova O.V., Kozlova O.P., Desyatik E.A., Shagdileeva E.V., Borzova Yu.V., Bogomolova T.S., Ignatieva S.M., Trofimova O.A., Klimko N.N. A clinical case of invasive pulmonary aspergillosis against the background of the use of an inhibitor of tumor necrosis factor - alpha // Problems of medical mycology. - 2016. - T.18, No. 4. - S. 23-26. (in Russian)

3. Santamaría-Alza Y, Sánchez-Bautista J, Fajardo-Rivero JF, Figueroa CL Invasive fungal infections in Colombian patients with systemic lupus erythematosus // Lupus. – 2018. – 27(7). – P.1116-1122. doi: 10.1177/0961203318763743.

4. Wang LR, Barber CE, Johnson AS, Barnabe C S Invasive fungal disease in systemic lupus erythematosus: a systematic review of disease characteristics, risk factors, and prognosis // Arthritis Rheum. – 2014. – 44(3). – P.325-330. doi: 10.1016/j.semarthrit.2014.06.001.

5. Lao M, Wang X, Ding M, Yang Z, Chen H, Liang L, Zhan Z, Chen D Invasive fungal disease in patients with systemic lupus erythematosus from Southern China: a retrospective study // Lupus. – 2019. – 28(1). – P.77-85. doi: 10.1177/0961203318817118.

6. Wenjie Fang, Min Chen, Jia Liu, Ferry Hagen, Abdullah MS, Al-Hatmi, Peilian Zhang, Yun Guo, Teun Boekhout, Danqi Deng, Jianping Xu, Weihua Pan, Wanqing Liao Cryptococcal meningitis in systemic lupus erythematosus patients: pooled analysis and systematic review // Emerg Microbes Infect. – 2016. – 5(9) . – e95. doi: 10.1038/emi.2016.93.

7. Hung ML, Liao HT, Chen WS, Chen MH, Lai CC, Tsai CY, Chang DM. Invasive aspergillosis in patients with systemic lupus erythematosus: a retrospective study on clinical characteristics and risk factors for mortality //Lupus. – 2018. – 27(12). – 1944-1952. doi: 10.1177/0961203318796294.

8. Tragiannidis A, Kyriakidis I, Zündorf I, Groll AH. Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-α) inhibitors. // Mycoses. – 2017. – 60(4). – P.222-229. doi: 10.1111/myc.12576.

9. Donnelly P., Chen S., Kauffman C., Steinbach W., Baddley J., Verweij P., Clancy C., Wingard J., Lockhart S., Groll A., Sorrell T., Bassetti M., Akan H. 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, Clinical Infectious Diseases, 2019, ciz1008. https://doi. org/10.1093/cid/ciz1008

10. Silva MF, Ferriani MP, Terreri MT, Pereira RM, Magalhães CS, Bonfá E, Campos LM, Okuda EM, Appenzeller S, Ferriani VP, Barbosa CM, Ramos VC, Lotufo S, Silva CA. A Multicenter Study of Invasive Fungal Infections in Patients with Childhood-onset Systemic Lupus Erythematosus // J Rheumatol. – 2015.– 42(12). – P.2296-2303. doi: 10.3899/jrheum.150142.

11. Dixon WG, Suissa S, Hudson M. The association between systemic glucocorticoid therapy and the risk of infection in patients with rheumatoid arthritis: systematic review and meta-analyses // Arthritis Res Ther. – 2011. – 13(4). – R139. doi:10.1186/ar3453.

12. Kourbeti IS, Ziakas PD, Mylonakis E. Biologic therapies in rheumatoid arthritis and the risk of opportunistic infections: a meta-analysis // Clin Infect Dis. – 2014.– 58(12). – P.1649– 1657. doi:10.1093/cid/ciu185.

13. Kuchinskaya E.M., Kostik M.M., Chasnyk V.G. Modern foundations of a formalized description of the course of systemic lupus erythematosus in children // Pediatr. - 2017. - T. 8. - No. 2. - P. 68–80. doi: 10.17816/PED8268-80. (in Russian)

14. Chen HS, Tsai WP, Leu HS, Ho HH, Liou LB. Invasive fungal infection in systemic lupus erythematosus: An analysis of 15 cases and a literature review // Rheumatology. – 2007. – 46. – P.539–544.

15. Silva MF, Ribeiro AS, Fiorot FJ, Aikawa NE, Lotito AP, Campos LM, Invasive aspergillosis: a severe infection in juvenile systemic lupus erythematosus patients // Lupus 2012. – 21. – P.1011–1016.

16. Horneff G. Biologic-associated infections in pediatric rheumatology // Curr Rheumatol Rep. – 2015. – 17:66.

17. Seminerio JL, Loftus EV, Colombel JF, Thapa P, Sandborn WJ. Infliximab for Crohn’s disease: the first 500 patients followed up through 2009 // Dig Dis Sci. – 2013. – 58. – P.797–806.

18. Toussi SS, Pan N, Walters HM, Walsh TJ. Infections in children and adolescents with juvenile idiopathic arthritis and inflammatory bowel disease treated with tumor necrosis factorinhibitors: systematic review of the literature // Clin Infect Dis. – 2013. – 57. – P.1318–1330.

19. Veereman-Wauters G, de Ridder L, Veres G, et al. Risk of infection and prevention in pediatric patients with IBD: ESPGHAN IBD Porto Group commentary // J Pediatr Gastroenterol Nutr. – 2012. – 54. – P. 830–837.

20. Rumyantsev A.G., Maschan A.A., Maschan M.A., Novichkova G.A. Federal clinical guidelines for the diagnosis and treatment of hemophagocytic lymphohistiocytosis in children. - 2015. - M / GOST R 56034-2014. - 38 S. (in Russian)

21. Dhote R, Simon J, Papo T, Detournay B, Sailler L, Andre MH, Dupond JL, Larroche C, Piette AM, Mechenstock D, Ziza JM, Arlaud J, Labussiere AS, Desvaux A, Baty V, Blanche P, Schaeffer A, Piette JC, Guillevin L, Boissonnas A, Christoforov B. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review.Arthritis Rheum. 2003 Oct 15;49(5):633-639.