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DOI: 10.1055/s-0042-1759882
Clinical Relevance of Fungi in Cystic Fibrosis
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Abstract
In cystic fibrosis, a new era has started with the approval and use of highly effective cystic fibrosis transport regulator (CFTR) modulator therapy. As pulmonary function is increasing and exacerbation rate significantly decreases, the current meaning of fungal pulmonary diseases is questioned. During the past couple of decades, several studies have been conducted regarding fungal colonization and infection of the airways in people with cystic fibrosis. Although Aspergillus fumigatus for filamentous fungi and Candida albicans for yeasts remain by far the most common fungal species in patients with cystic fibrosis, the pattern of fungal species associated with cystic fibrosis has considerably diversified recently. Fungi such as Scedosporium apiospermum or Exophiala dermatitidis are recognized as pathogenic in cystic fibrosis and therefore need attention in clinical settings. In this article, current definitions are stated. Important diagnostic steps are described, and their usefulness discussed. Furthermore, clinical treatment strategies and recommendations are named and evaluated. In cystic fibrosis, fungal entities can be divided into different subgroups. Besides colonization, allergic bronchopulmonary aspergillosis, bronchitis, sensitization, pneumonia, and aspergilloma can occur as a fungal disease entity. For allergic bronchopulmonary aspergillosis, bronchitis, pneumonia, and aspergilloma, clear indications for therapy exist but this is not the case for sensitization or colonization. Different pulmonary fungal disease entities in people with cystic fibrosis will continue to occur also in an era of highly effective CFTR modulator therapy. Whether the percentage will decrease or not will be the task of future evaluations in studies and registry analysis. Using the established definition for different categories of fungal diseases is recommended and should be taken into account if patients are deteriorating without responding to antibiotic treatment. Drug–drug interactions, in particular when using azoles, should be recognized and therapies need to be adjusted accordingly.
Publication History
Article published online:
06 February 2023
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References
- 1 Jain R, Mall M, Drevine P. et al. Phase 3 efficacy and safety of the ELX/TEZ/IVA triple combination in people with CF and F508del/minimal function genotypes. Pediatr Pulmonol 2019; 54: 346-347
- 2 Middleton PG, Mall MA, Dřevínek P. et al; VX17-445-102 Study Group. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 2019; 381 (19) 1809-1819
- 3 Ridley K, Condren M. Elexacaftor-tezacaftor-ivacaftor: the first triple-combination cystic fibrosis transmembrane conductance regulator modulating therapy. J Pediatr Pharmacol Ther 2020; 25 (03) 192-197
- 4 Pihet M, Carrere J, Cimon B. et al. Occurrence and relevance of filamentous fungi in respiratory secretions of patients with cystic fibrosis – a review. Med Mycol 2009; 47 (04) 387-397
- 5 Düesberg U, Wosniok J, Naehrlich L, Eschenhagen P, Schwarz C. Risk factors for respiratory Aspergillus fumigatus in German cystic fibrosis patients and impact on lung function. Sci Rep 2020; 10 (01) 18999
- 6 Schwarz C, Bouchara J-P, Buzina W. et al. Organization of patient management and fungal epidemiology in cystic fibrosis. Mycopathologia 2018; 183 (01) 7-19
- 7 Singh A, Ralhan A, Schwarz C, Hartl D, Hector A. Fungal pathogens in CF airways: Leave or treat?. Mycopathologia 2018; 183 (01) 119-137
- 8 Bouchara J-P, Symoens F, Schwarz C, Chaturvedi V. Fungal respiratory infections in cystic fibrosis (CF): recent progress and future research agenda. Mycopathologia 2018; 183 (01) 1-5
- 9 Schwarz C, Vandeputte P, Rougeron A. et al; ECMM/ISHAM Working Group Fungal Respiratory Infections in Cystic Fibrosis (Fri-CF). Developing collaborative works for faster progress on fungal respiratory infections in cystic fibrosis. Med Mycol 2018; 56 (suppl 1): 42-59
- 10 Chotirmall SH, McElvaney NG. Fungi in the cystic fibrosis lung: bystanders or pathogens?. Int J Biochem Cell Biol 2014; 52: 161-173
- 11 Ramirez-Garcia A, Pellon A, Rementeria A. et al. Scedosporium and lomentospora: an updated overview of underrated opportunists. Med Mycol 2018; 56 (suppl 1): 102-125
- 12 Bouchara J-P, Hsieh HY, Croquefer S. et al. Development of an oligonucleotide array for direct detection of fungi in sputum samples from patients with cystic fibrosis. J Clin Microbiol 2009; 47 (01) 142-152
- 13 Middleton PG, Chen SCA, Meyer W. Fungal infections and treatment in cystic fibrosis. Curr Opin Pulm Med 2013; 19 (06) 670-675
- 14 Roehmel JF, Tintelnot K, Bernhardt A, Seibold M, Staab D, Schwarz C. Arxula adeninivorans causing invasive pulmonary mycosis and fungaemia in cystic fibrosis. Lancet 2015; 385 (9976): 1476
- 15 Zalar P, Novak M, de Hoog GS, Gunde-Cimerman N. Dishwashers – a man-made ecological niche accommodating human opportunistic fungal pathogens. Fungal Biol 2011; 115 (10) 997-1007
- 16 Kusenbach G, Skopnik H, Haase G, Friedrichs F, Döhmen H. Exophiala dermatitidis pneumonia in cystic fibrosis. Eur J Pediatr 1992; 151 (05) 344-346
- 17 Haase G, Skopnik H, Kusenbach G. Exophiala dermatitidis infection in cystic fibrosis. Lancet 1990; 336 (8708): 188-189
- 18 Hickey PW, Sutton DA, Fothergill AW. et al. Trichosporon mycotoxinivorans, a novel respiratory pathogen in patients with cystic fibrosis. J Clin Microbiol 2009; 47 (10) 3091-3097
- 19 Hirschi S, Letscher-Bru V, Pottecher J. et al. Disseminated Trichosporon mycotoxinivorans, Aspergillus fumigatus, and Scedosporium apiospermum coinfection after lung and liver transplantation in a cystic fibrosis patient. J Clin Microbiol 2012; 50 (12) 4168-4170 [Internet]
- 20 Jubin V, Ranque S, Stremler Le Bel N, Sarles J, Dubus JC. Risk factors for Aspergillus colonization and allergic bronchopulmonary aspergillosis in children with cystic fibrosis. Pediatr Pulmonol 2010; 45 (08) 764-771
- 21 Eschenhagen P, Grehn C, Schwarz C. Prospective evaluation of Aspergillus fumigatus-specific IgG in patients with cystic fibrosis. Front Cell Infect Microbiol 2021; 10: 602836
- 22 Geller DE, Kaplowitz H, Light MJ, Colin AA. Allergic bronchopulmonary aspergillosis in cystic fibrosis: reported prevalence, regional distribution, and patient characteristics. Scientific Advisory Group, Investigators, and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Chest 1999; 116 (03) 639-646
- 23 Baxter CG, Dunn G, Jones AM. et al. Novel immunologic classification of aspergillosis in adult cystic fibrosis. J Allergy Clin Immunol 2013; 132 (03) 560-566.e10
- 24 Brandt C, Roehmel J, Rickerts V, Melichar V, Niemann N, Schwarz C. Aspergillus bronchitis in patients with cystic fibrosis. Mycopathologia 2018; 183 (01) 61-69
- 25 European Cystic Fibrosis Society. Accessed November 25, 2022 at: https://www.ecfs.eu/projects/ecfs-patient-registry/annual-reports
- 26 Hong G, Desai S, Moss RB, Eschenhagen P, Quon BS, Schwarz C. Clinician variability in the diagnosis and treatment of Aspergillus fumigatus-related conditions in cystic fibrosis: an international survey. J Cyst Fibros 2022; 21 (01) 136-142
- 27 Shoseyov D, Brownlee KG, Conway SP, Kerem E. Aspergillus bronchitis in cystic fibrosis. Chest 2006; 130 (01) 222-226
- 28 Schwarz C, Brandt C, Whitaker P. et al. Invasive pulmonary fungal infections in cystic fibrosis. Mycopathologia 2018; 183 (01) 33-43
- 29 King J, Brunel SF, Warris A. Aspergillus infections in cystic fibrosis. J Infect 2016; 72 (suppl): S50-S55
- 30 Ryan PJ, Stableforth DE, Reynolds J, Muhdi KM. Treatment of pulmonary aspergilloma in cystic fibrosis by percutaneous instillation of amphotericin B via indwelling catheter. Thorax 1995; 50 (07) 809-810
- 31 Maguire CP, Hayes JP, Hayes M, Masterson J, FitzGerald MX. Three cases of pulmonary aspergilloma in adult patients with cystic fibrosis. Thorax 1995; 50 (07) 805-806
- 32 Logan M, McLoughlin R, Gibney RG. Aspergilloma complicating cystic fibrosis. AJR Am J Roentgenol 1993; 161 (03) 674-675
- 33 Cohen-Cymberknoh M. Fungal infection and ABPA in CF. Paediatr Respir Rev 2013; 14: S34-S35
- 34 Schwarz C, Hartl D, Eickmeier O. et al. Progress in definition, prevention and treatment of fungal infections in cystic fibrosis. Mycopathologia 2018; 183 (01) 21-32
- 35 Scheffold A, Schwarz C, Bacher P. Fungus-specific CD4 T cells as specific sensors for identification of pulmonary fungal infections. Mycopathologia 2018; 183 (01) 213-226
- 36 Bacher P, Steinbach A, Kniemeyer O. et al. Fungus-specific CD4(+) T cells for rapid identification of invasive pulmonary mold infection. Am J Respir Crit Care Med 2015; 191 (03) 348-352
- 37 Agarwal R, Chakrabarti A, Shah A. et al; ABPA Complicating Asthma ISHAM Working Group. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clin Exp Allergy 2013; 43 (08) 850-873
- 38 Mastella G, Rainisio M, Harms HK. et al; Epidemiologic Registry of Cystic Fibrosis. Allergic bronchopulmonary aspergillosis in cystic fibrosis. A European epidemiological study. Eur Respir J 2000; 16 (03) 464-471
- 39 Stevens DA, Moss RB, Kurup VP. et al; Participants in the Cystic Fibrosis Foundation Consensus Conference. Allergic bronchopulmonary aspergillosis in cystic fibrosis – state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis 2003; 37 (suppl 1): S225-S264
- 40 Nikolaizik WH, Weichel M, Blaser K, Crameri R. Intracutaneous tests with recombinant allergens in cystic fibrosis patients with allergic bronchopulmonary aspergillosis and Aspergillus allergy. Am J Respir Crit Care Med 2002; 165 (07) 916-921
- 41 Fricker-Hidalgo H, Coltey B, Llerena C. et al. Recombinant allergens combined with biological markers in the diagnosis of allergic bronchopulmonary aspergillosis in cystic fibrosis patients. Clin Vaccine Immunol 2010; 17 (09) 1330-1336
- 42 Li BCM, Huh SM, Prieto MD. et al. Biomarkers for the diagnosis of allergic bronchopulmonary aspergillosis in cystic fibrosis: a systematic review and meta-analysis. J Allergy Clin Immunol Pract 2021; 9 (05) 1909-1930.e4
- 43 Schwarz C, Brandt C, Melichar V. et al. Combined antifungal therapy is superior to monotherapy in pulmonary scedosporiosis in cystic fibrosis. J Cyst Fibros 2019; 18 (02) 227-232
- 44 Schwarz C, Eschenhagen P, Bouchara JP. Emerging fungal threats in cystic fibrosis. Mycopathologia 2021; 186 (05) 639-653
- 45 Marchiori E, Zanetti G, Hochhegger B, Irion KL, Carvalho ACP, Godoy MCB. Reversed halo sign on computed tomography: state-of-the-art review. Lung 2012; 190 (04) 389-394
- 46 Hussien A, Lin CT. CT findings of fungal pneumonia with emphasis on aspergillosis. Emerg Radiol 2018; 25 (06) 685-689
- 47 Bacher P, Scheffold A. Flow-cytometric analysis of rare antigen-specific T cells. Cytometry A 2013; 83 (08) 692-701
- 48 Bacher P, Schink C, Teutschbein J. et al. Antigen-reactive T cell enrichment for direct, high-resolution analysis of the human naive and memory Th cell repertoire. J Immunol 2013; 190 (08) 3967-3976
- 49 Jenks JD, Prattes J, Frank J. et al. Performance of the bronchoalveolar lavage fluid Aspergillus galactomannan lateral flow assay with cube reader for diagnosis of invasive pulmonary aspergillosis: a multicenter cohort study. Clin Infect Dis 2021; 73 (07) e1737-e1744
- 50 Hoenigl M, Egger M, Boyer J, Schulz E, Prattes J, Jenks JD. Serum lateral flow assay with digital reader for the diagnosis of invasive pulmonary aspergillosis: a two-centre mixed cohort study. Mycoses 2021; 64 (10) 1197-1202
- 51 Egger M, Penziner S, Dichtl K. et al. Performance of the Euroimmun Aspergillus antigen ELISA for the diagnosis of invasive pulmonary aspergillosis in bronchoalveolar lavage fluid. J Clin Microbiol 2022; 60 (04) e0021522
- 52 Williams C, Ranjendran R, Ramage G. Pathogenesis of fungal infections in cystic fibrosis. Curr Fungal Infect Rep 2016; 10 (04) 163-169
- 53 Kosmidis C, Denning DW. The clinical spectrum of pulmonary aspergillosis. Thorax 2015; 70 (03) 270-277
- 54 Grehn C, Eschenhagen P, Temming S, Düesberg U, Neumann K, Schwarz C. Frequent pet contact as risk factor for allergic bronchopulmonary aspergillosis in cystic fibrosis. Front Cell Infect Microbiol 2021; 10: 825
- 55 Thomson JM, Wesley A, Byrnes CA, Nixon GM. Pulse intravenous methylprednisolone for resistant allergic bronchopulmonary aspergillosis in cystic fibrosis. Pediatr Pulmonol 2006; 41 (02) 164-170
- 56 Fayon M, Corvol H, Chiron R, Bui S. le Groupe de Travail Inflammation de la Société Française de la Mucoviscidose. [National consensus regarding the prescription of inhaled corticosteroids in cystic fibrosis]. Arch Pediatr 2014; 21 (01) 88-94
- 57 Elphick HE, Southern KW. Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Cochrane Database Syst Rev 2016; 11 (11) CD002204
- 58 Hennig S, Waterhouse TH, Bell SC. et al. A d-optimal designed population pharmacokinetic study of oral itraconazole in adult cystic fibrosis patients. Br J Clin Pharmacol 2007; 63 (04) 438-450
- 59 Brüggemann RJ, Alffenaar JW, Blijlevens NM. et al; Clinical Relevance of the Pharmacokinetic Interactions of Azole Antifungal Drugs with Other Coadministered Agents. Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis 2009; 48 (10) 1441-1458
- 60 Tanou K, Zintzaras E, Kaditis AG. Omalizumab therapy for allergic bronchopulmonary aspergillosis in children with cystic fibrosis: a synthesis of published evidence. Pediatr Pulmonol 2014; 49 (05) 503-507
- 61 Jat KR, Walia DK, Khairwa A. Anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Cochrane Database Syst Rev 2021; 9 (09) CD010288
- 62 Jat KR, Walia DK, Khairwa A. Anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Cochrane Database Syst Rev 2018; 3 (03) CD010288
- 63 Schwarz C, Müller T, Lau S, Parasher K, Staab D, Wahn U. Mepolizumab-a novel option for the treatment of hypereosinophilic syndrome in childhood. Pediatr Allergy Immunol 2018; 29 (01) 28-33
- 64 McElvaney G. What role do fungi play in CF lung disease?. Pediatr Pulmonol 2013
- 65 Agache I, Rocha C, Beltran J. et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for severe allergic asthma: a systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma. Allergy 2020; 75 (05) 1043-1057
- 66 Agache I, Beltran J, Akdis C. et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma. Allergy 2020; 75 (05) 1023-1042
- 67 Bacher P, Hohnstein T, Beerbaum E. et al. Human anti-fungal Th17 immunity and pathology rely on cross-reactivity against Candida albicans . Cell 2019; 176 (06) 1340-1355.e15
- 68 Tsai A, Wu SP, Haseltine E. et al. Physiologically based pharmacokinetic modeling of CFTR modulation in people with cystic fibrosis transitioning from mono or dual regimens to triple-combination elexacaftor/tezacaftor/ivacaftor. Pulm Ther 2020; 6 (02) 275-286
- 69 Ruhnke M, Cornely OA, Schmidt-Hieber M. et al. Treatment of invasive fungal diseases in cancer patients - revised 2019 Recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Mycoses 2020; 63 (07) 653-682
- 70 Prigitano A, Esposto MC, Biffi A. et al. Triazole resistance in Aspergillus fumigatus isolates from patients with cystic fibrosis in Italy. J Cyst Fibros 2017; 16 (01) 64-69
- 71 Risum M, Hare RK, Gertsen JB. et al. Azole-resistant Aspergillus fumigatus among Danish cystic fibrosis patients: increasing prevalence and dominance of TR34/L98H. Front Microbiol 2020; 11: 1850
- 72 Hong G, White M, Lechtzin N. et al. Fatal disseminated Rasamsonia infection in cystic fibrosis post-lung transplantation. J Cyst Fibros 2017; 16 (02) e3-e7
- 73 Hamprecht A, Morio F, Bader O, Le Pape P, Steinmann J, Dannaoui E. Azole resistance in Aspergillus fumigatus in patients with cystic fibrosis: a matter of concern?. Mycopathologia 2018; 183 (01) 151-160
- 74 Bentley S, Davies JC, Carr SB, Balfour-Lynn IM. Combination antifungal therapy for Scedosporium species in cystic fibrosis. Pediatr Pulmonol 2020; 55 (08) 1993-1995
- 75 Cuenca-Estrella M, Alastruey-Izquierdo A, Alcazar-Fuoli L. et al. In vitro activities of 35 double combinations of antifungal agents against Scedosporium apiospermum and Scedosporium prolificans . Antimicrob Agents Chemother 2008; 52 (03) 1136-1139
- 76 Shah AV, McColley SA, Weil D, Zheng X. Trichosporon mycotoxinivorans infection in patients with cystic fibrosis. J Clin Microbiol 2014; 52 (06) 2242-2244
- 77 Kröner C, Kappler M, Grimmelt AC, Laniado G, Würstl B, Griese M. The basidiomycetous yeast Trichosporon may cause severe lung exacerbation in cystic fibrosis patients - clinical analysis of Trichosporon positive patients in a Munich cohort. BMC Pulm Med 2013; 13: 61
- 78 Yang YL, Liu YW, Chen HT, Tsai MS, Chu WL, Lo HJ. Genotype analysis based on intergenic spacer 1 sequences of Trichosporon asahii collected in Taiwan. Med Mycol 2013; 51 (08) 880-883
- 79 Navarro J, Rainisio M, Harms HK. et al; European Epidemiologic Registry of Cystic Fibrosis. Factors associated with poor pulmonary function: cross-sectional analysis of data from the ERCF. Eur Respir J 2001; 18 (02) 298-305
- 80 Chotirmall SH. Candida albicans in cystic fibrosis: “opening statements presented, let the trial begin”. Pediatr Pulmonol 2016; 51 (05) 445-446
- 81 Hector A, Kirn T, Ralhan A. et al. Microbial colonization and lung function in adolescents with cystic fibrosis. J Cyst Fibros 2016; 15 (03) 340-349
- 82 Meis JF, Chowdhary A, Rhodes JL, Fisher MC, Verweij PE. Clinical implications of globally emerging azole resistance in Aspergillus fumigatus . Philos Trans R Soc Lond B Biol Sci 2016; 371 (1709): 20150460
- 83 Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A. The global problem of antifungal resistance: prevalence, mechanisms, and management. Lancet Infect Dis 2017; 17 (12) e383-e392
- 84 Mourad A, Perfect JR. Tolerability profile of the current antifungal armoury. Accessed November 25, 2022 at: https://academic.oup.com/jac/article/73/suppl_1/i26/4769698
- 85 Rivosecchi RM, Samanta P, Demehin M, Nguyen MH. Pharmacokinetics of azole antifungals in cystic fibrosis. Mycopathologia 2018; 183 (01) 139-150
- 86 King JA, Nichols AL, Bentley S, Carr SB, Davies JC. An update on CFTR modulators as new therapies for cystic fibrosis. Paediatr Drugs 2022; 24 (04) 321-333
- 87 Hoenigl M, Sprute R, Egger M. et al. The antifungal pipeline: fosmanogepix, ibrexafungerp, olorofim, opelconazole, and rezafungin. Drugs 2021; 81 (15) 1703-1729