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Cystic Fibrosis pp 93–126Cite as

Fungal Infections and ABPA

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Part of the book series: Respiratory Medicine ((RM))

Abstract

An increased fungal presence in the cystic fibrosis (CF) airway is associated with immune and clinical consequences including sensitisation to fungal allergens, reduced lung function and allergic bronchopulmonary aspergillosis (ABPA). Key drivers of fungal colonisation in CF remain unclear and are related to impaired mucociliary clearance, aberrant innate immunity and a skewed Th2 airway hyperresponsiveness. The commonest fungal pathogen, Aspergillus fumigatus, represents the predominant species that chronically colonises the CF lung, perpetuating a spectrum of varied disease states that each pose scientific, diagnostic and therapeutic challenges to CF scientists and clinicians. Recent progress in this field has explored the emergence of other fungal genera including Candida, Scedosporium, Exophiala, Rasamsonia and Malassezia, in the setting of CF, while culture-independent studies including next-generation sequencing provide a new perspective on the diversity, complexity and resistance profile of the CF mycobiome. System-based analyses of microbial-host interaction have further uncovered novel paradigms in CF pathogenesis including inter-kingdom signalling and the gut-lung axis, where fungi play an emerging and critical role. Current treatment modalities against CF-associated fungal pathogens aim at targeting host inflammation (with steroids) and fungal presence (with antifungals), and the approaches are accompanied by a weak evidence base coupled to a dearth of randomised controlled clinical trials proving efficacy. More specifically, emerging immunotherapeutic approaches targeting Th2-mediated hyperresponsiveness, multi-omics technologies and fungal sequencing platforms represent promising areas for future work that require strong and sustained investment to improve our understanding of the complex host-microbe-immunological interaction that underpins CF-associated fungal diseases.

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References

  1. Lyczak JB, Cannon CL, Pier GB. Lung infections associated with cystic fibrosis. Clin Microbiol Rev. 2002;15(2):194–222.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Filkins LM, O’Toole GA. Cystic fibrosis lung infections: polymicrobial, complex, and hard to treat. PLoS Pathog. 2015;11(12):e1005258.

    PubMed  PubMed Central  Google Scholar 

  3. McIntyre K. Gender and survival in cystic fibrosis. Curr Opin Pulm Med. 2013;19(6):692–7.

    PubMed  Google Scholar 

  4. Goss CH, Burns JL. Exacerbations in cystic fibrosis center dot 1: epidemiology and pathogenesis. Thorax. 2007;62(4):360–7.

    PubMed  PubMed Central  Google Scholar 

  5. Corriveau S, Sykes J, Stephenson AL. Cystic fibrosis survival: the changing epidemiology. Curr Opin Pulm Med. 2018;24(6):574–8.

    PubMed  Google Scholar 

  6. Jackson AD, Goss CH. Epidemiology of CF: how registries can be used to advance our understanding of the CF population. J Cyst Fibros. 2018;17(3):297–305.

    PubMed  Google Scholar 

  7. Bosch B, Bilton D, Sosnay P, Raraigh KS, Mak DYF, Ishiguro H, et al. Ethnicity impacts the cystic fibrosis diagnosis: a note of caution. J Cyst Fibros. 2017;16(4):488–91.

    PubMed  Google Scholar 

  8. Taylor-Robinson DC, Schechter MS, Smyth RL. Comparing cystic fibrosis outcomes across the pond. Thorax. 2015;70(3):203–4.

    PubMed  Google Scholar 

  9. Vahedi L, Jabarpoor-Bonyadi M, Ghojazadeh M, Vahedi A, Rafeey M. Gender differences in clinical presentations of cystic fibrosis patients in Azeri Turkish population. Tuberc Respir Dis (Seoul). 2016;79(4):267–73.

    Google Scholar 

  10. Harness-Brumley CL, Elliott AC, Rosenbluth DB, Raghavan D, Jain R. Gender differences in outcomes of patients with cystic fibrosis. J Womens Health (Larchmt). 2014;23(12):1012–20.

    Google Scholar 

  11. Parkins MD, Floto RA. Emerging bacterial pathogens and changing concepts of bacterial pathogenesis in cystic fibrosis. J Cyst Fibros. 2015;14(3):293–304.

    CAS  PubMed  Google Scholar 

  12. Williams C, Ranjendran R, Ramage G. Pathogenesis of fungal infections in cystic fibrosis. Curr Fungal Infect Rep. 2016;10(4):163–9.

    PubMed  PubMed Central  Google Scholar 

  13. Janahi IA, Rehman A, Al-Naimi AR. Allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. Ann Thorac Med. 2017;12(2):74–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Armstead J, Morris J, Denning DW. Multi-country estimate of different manifestations of aspergillosis in cystic fibrosis. PLoS One. 2014;9(6):e98502.

    PubMed  PubMed Central  Google Scholar 

  15. Yii AC, Koh MS, Lapperre TS, Tan GL, Chotirmall SH. The emergence of Aspergillus species in chronic respiratory disease. Front Biosci (Schol Ed). 2017;9:127–38.

    Google Scholar 

  16. Maturu VN, Agarwal R. Prevalence of Aspergillus sensitization and allergic bronchopulmonary aspergillosis in cystic fibrosis: systematic review and meta-analysis. Clin Exp Allergy. 2015;45(12):1765–78.

    CAS  PubMed  Google Scholar 

  17. Latge JP. Aspergillus fumigatus and aspergillosis. Clin Microbiol Rev. 1999;12(2):310–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. van de Veerdonk FL, Gresnigt MS, Romani L, Netea MG, Latge JP. Aspergillus fumigatus morphology and dynamic host interactions. Nat Rev Microbiol. 2017;15(11):661–74.

    PubMed  Google Scholar 

  19. Chotirmall SH, Martin-Gomez MT. Aspergillus species in bronchiectasis: challenges in the cystic fibrosis and non-cystic fibrosis airways. Mycopathologia. 2018;183(1):45–59.

    CAS  PubMed  Google Scholar 

  20. de Vrankrijker AM, van der Ent CK, van Berkhout FT, Stellato RK, Willems RJ, Bonten MJ, et al. Aspergillus fumigatus colonization in cystic fibrosis: implications for lung function? Clin Microbiol Infect. 2011;17(9):1381–6.

    PubMed  Google Scholar 

  21. Kraemer R, Delosea N, Ballinari P, Gallati S, Crameri R. Effect of allergic bronchopulmonary aspergillosis on lung function in children with cystic fibrosis. Am J Respir Crit Care Med. 2006;174(11):1211–20.

    PubMed  Google Scholar 

  22. Kosmidis C, Denning DW. The clinical spectrum of pulmonary aspergillosis. Thorax. 2015;70(3):270–7.

    PubMed  Google Scholar 

  23. Slesiona S, Gressler M, Mihlan M, Zaehle C, Schaller M, Barz D, et al. Persistence versus escape: Aspergillus terreus and Aspergillus fumigatus employ different strategies during interactions with macrophages. PLoS One. 2012;7(2):e31223.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Sabino R, Ferreira JA, Moss RB, Valente J, Verissimo C, Carolino E, et al. Molecular epidemiology of Aspergillus collected from cystic fibrosis patients. J Cyst Fibros. 2015;14(4):474–81.

    CAS  PubMed  Google Scholar 

  25. Romani L. Immunity to fungal infections. Nat Rev Immunol. 2011;11(4):275–88.

    CAS  PubMed  Google Scholar 

  26. Braedel S, Radsak M, Einsele H, Latge JP, Michan A, Loeffler J, et al. Aspergillus fumigatus antigens activate innate immune cells via toll-like receptors 2 and 4. Br J Haematol. 2004;125(3):392–9.

    CAS  PubMed  Google Scholar 

  27. Werner JL, Metz AE, Horn D, Schoeb TR, Hewitt MM, Schwiebert LM, et al. Requisite role for the dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus. J Immunol. 2009;182(8):4938–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wasylnka JA, Moore MM. Aspergillus fumigatus conidia survive and germinate in acidic organelles of A549 epithelial cells. J Cell Sci. 2003;116(Pt 8):1579–87.

    CAS  PubMed  Google Scholar 

  29. de Luca A, Bozza S, Zelante T, Zagarella S, D'Angelo C, Perruccio K, et al. Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO. Cell Mol Immunol. 2010;7(6):459–70.

    PubMed  PubMed Central  Google Scholar 

  30. Allard JB, Poynter ME, Marr KA, Cohn L, Rincon M, Whittaker LA. Aspergillus fumigatus generates an enhanced Th2-biased immune response in mice with defective cystic fibrosis transmembrane conductance regulator. J Immunol. 2006;177(8):5186–94.

    CAS  PubMed  Google Scholar 

  31. Mueller C, Braag SA, Keeler A, Hodges C, Drumm M, Flotte TR. Lack of cystic fibrosis transmembrane conductance regulator in CD3+ lymphocytes leads to aberrant cytokine secretion and hyperinflammatory adaptive immune responses. Am J Respir Cell Mol Biol. 2011;44(6):922–9.

    CAS  PubMed  Google Scholar 

  32. Moss RB, Hsu YP, Olds L. Cytokine dysregulation in activated cystic fibrosis (CF) peripheral lymphocytes. Clin Exp Immunol. 2000;120(3):518–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Boucher RC. Evidence for airway surface dehydration as the initiating event in CF airway disease. J Intern Med. 2007;261(1):5–16.

    CAS  PubMed  Google Scholar 

  34. Cosgrove S, Chotirmall SH, Greene CM, McElvaney NG. Pulmonary proteases in the cystic fibrosis lung induce interleukin 8 expression from bronchial epithelial cells via a heme/meprin/epidermal growth factor receptor/Toll-like receptor pathway. J Biol Chem. 2011;286(9):7692–704.

    CAS  PubMed  Google Scholar 

  35. Hamon Y, Jaillon S, Person C, Ginies JL, Garo E, Bottazzi B, et al. Proteolytic cleavage of the long pentraxin PTX3 in the airways of cystic fibrosis patients. Innate Immun. 2013;19(6):611–22.

    PubMed  Google Scholar 

  36. Chotirmall SH, Mirkovic B, Lavelle GM, McElvaney NG. Immunoevasive Aspergillus virulence factors. Mycopathologia. 2014;178(5–6):363–70.

    CAS  PubMed  Google Scholar 

  37. Schlam D, Canton J, Carreno M, Kopinski H, Freeman SA, Grinstein S, et al. Gliotoxin suppresses macrophage immune function by subverting phosphatidylinositol 3,4,5-trisphosphate homeostasis. MBio. 2016;7(2):e02242.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Fallon JP, Reeves EP, Kavanagh K. Inhibition of neutrophil function following exposure to the Aspergillus fumigatus toxin fumagillin. J Med Microbiol. 2010;59(Pt 6):625–33.

    CAS  PubMed  Google Scholar 

  39. Lee MJ, Liu H, Barker BM, Snarr BD, Gravelat FN, Al Abdallah Q, et al. The fungal exopolysaccharide galactosaminogalactan mediates virulence by enhancing resistance to neutrophil extracellular traps. PLoS Pathog. 2015;11(10):e1005187.

    PubMed  PubMed Central  Google Scholar 

  40. Cohen TS, Prince A. Cystic fibrosis: a mucosal immunodeficiency syndrome. Nat Med. 2012;18(4):509–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Ratner D, Mueller C. Immune responses in cystic fibrosis: are they intrinsically defective? Am J Respir Cell Mol Biol. 2012;46(6):715–22.

    CAS  PubMed  Google Scholar 

  42. Coughlan CA, Chotirmall SH, Renwick J, Hassan T, Low TB, Bergsson G, et al. The effect of Aspergillus fumigatus infection on vitamin D receptor expression in cystic fibrosis. Am J Respir Crit Care Med. 2012;186(10):999–1007.

    CAS  PubMed  Google Scholar 

  43. Amin R, Dupuis A, Aaron SD, Ratjen F. The effect of chronic infection with Aspergillus fumigatus on lung function and hospitalization in patients with cystic fibrosis. Chest. 2010;137(1):171–6.

    PubMed  Google Scholar 

  44. McMahon MA, Chotirmall SH, McCullagh B, Branagan P, McElvaney NG, Logan PM. Radiological abnormalities associated with Aspergillus colonization in a cystic fibrosis population. Eur J Radiol. 2012;81(3):e197–202.

    PubMed  Google Scholar 

  45. Liu JC, Modha DE, Gaillard EA. What is the clinical significance of filamentous fungi positive sputum cultures in patients with cystic fibrosis? J Cyst Fibros. 2013;12(3):187–93.

    PubMed  Google Scholar 

  46. Aaron SD, Vandemheen KL, Freitag A, Pedder L, Cameron W, Lavoie A, et al. Treatment of Aspergillus fumigatus in patients with cystic fibrosis: a randomized, placebo-controlled pilot study. PLoS One. 2012;7(4):e36077.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Singh A, Ralhan A, Schwarz C, Hartl D, Hector A. Fungal pathogens in CF airways: leave or treat? Mycopathologia. 2018;183(1):119–37.

    CAS  PubMed  Google Scholar 

  48. Harun SN, Wainwright CE, Grimwood K, Hennig S, Australasian Cystic Fibrosis Bronchoalveolar Lavage study g. Aspergillus and progression of lung disease in children with cystic fibrosis. Thorax. 2019;74(2):125–31.

    PubMed  Google Scholar 

  49. Engel TGP, Slabbers L, de Jong C, Melchers WJG, Hagen F, Verweij PE, et al. Prevalence and diversity of filamentous fungi in the airways of cystic fibrosis patients – a Dutch, multicentre study. J Cyst Fibros. 2019;18(2):221–6.

    PubMed  Google Scholar 

  50. Agarwal R, Chakrabarti A, Shah A, Gupta D, Meis JF, Guleria R, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clin Exp Allergy. 2013;43(8):850–73.

    CAS  PubMed  Google Scholar 

  51. Hartl D. Immunological mechanisms behind the cystic fibrosis-ABPA link. Med Mycol. 2009;47(Suppl 1):S183–91.

    CAS  PubMed  Google Scholar 

  52. Stevens DA, Moss RB, Kurup VP, Knutsen AP, Greenberger P, Judson MA, et al. Allergic bronchopulmonary aspergillosis in cystic fibrosis – state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis. 2003;37(Suppl 3):S225–64.

    PubMed  Google Scholar 

  53. Svirshchevskaya E, Zubkov D, Mouyna I, Berkova N. Innate immunity and the role of epithelial barrier during Aspergillus fumigatus infection. Curr Immunol Rev. 2012;8(3):254–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Muthu V, Sehgal IS, Dhooria S, Aggarwal AN, Agarwal R. Utility of recombinant Aspergillus fumigatus antigens in the diagnosis of allergic bronchopulmonary aspergillosis: a systematic review and diagnostic test accuracy meta-analysis. Clin Exp Allergy. 2018;48(9):1107–36.

    PubMed  Google Scholar 

  55. Baxter CG, Dunn G, Jones AM, Webb K, Gore R, Richardson MD, et al. Novel immunologic classification of aspergillosis in adult cystic fibrosis. J Allergy Clin Immunol. 2013;132(3):560–6.e10.

    PubMed  Google Scholar 

  56. Baxter CG, Moore CB, Jones AM, Webb AK, Denning DW. IgE-mediated immune responses and airway detection of Aspergillus and Candida in adult cystic fibrosis. Chest. 2013;143(5):1351–7.

    CAS  PubMed  Google Scholar 

  57. Mac Aogain M, Chandrasekaran R, Lim AYH, Low TB, Tan GL, Hassan T, et al. Immunological corollary of the pulmonary mycobiome in bronchiectasis: the CAMEB study. Eur Respir J. 2018;52(1). pii: 1800766.

    Google Scholar 

  58. Mac Aogain M, Tiew PY, Lim AYH, Low TB, Tan GL, Hassan T, et al. Distinct ‘Immuno-allertypes’ of disease and high frequencies of sensitisation in non-cystic-fibrosis bronchiectasis. Am J Respir Crit Care Med. 2019;199(7):842–53.

    PubMed  Google Scholar 

  59. Agarwal R, Khan A, Aggarwal AN, Varma N, Garg M, Saikia B, et al. Clinical relevance of peripheral blood eosinophil count in allergic bronchopulmonary aspergillosis. J Infect Public Health. 2011;4(5–6):235–43.

    PubMed  Google Scholar 

  60. Chotirmall SH, Branagan P, Gunaratnam C, McElvaney NG. Aspergillus/allergic bronchopulmonary aspergillosis in an Irish cystic fibrosis population: a diagnostically challenging entity. Respir Care. 2008;53(8):1035–41.

    PubMed  Google Scholar 

  61. Slavin RG, Bedrossian CW, Hutcheson PS, Pittman S, Salinas-Madrigal L, Tsai CC, et al. A pathologic study of allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 1988;81(4):718–25.

    CAS  PubMed  Google Scholar 

  62. Gernez Y, Waters J, Mirkovic B, Lavelle GM, Dunn CE, Davies ZA, et al. Blood basophil activation is a reliable biomarker of allergic bronchopulmonary aspergillosis in cystic fibrosis. Eur Respir J. 2016;47(1):177–85.

    CAS  PubMed  Google Scholar 

  63. Mirkovic B, Lavelle GM, Azim AA, Helma K, Gargoum FS, Molloy K, et al. The basophil surface marker CD203c identifies Aspergillus species sensitization in patients with cystic fibrosis. J Allergy Clin Immunol. 2016;137(2):436–43.e9.

    CAS  PubMed  Google Scholar 

  64. Gernez Y, Dunn CE, Everson C, Mitsunaga E, Gudiputi L, Krasinska K, et al. Blood basophils from cystic fibrosis patients with allergic bronchopulmonary aspergillosis are primed and hyper-responsive to stimulation by aspergillus allergens. J Cyst Fibros. 2012;11(6):502–10.

    CAS  PubMed  Google Scholar 

  65. Cohen-Cymberknoh M, Blau H, Shoseyov D, Mei-Zahav M, Efrati O, Armoni S, et al. Intravenous monthly pulse methylprednisolone treatment for ABPA in patients with cystic fibrosis. J Cyst Fibros. 2009;8(4):253–7.

    CAS  PubMed  Google Scholar 

  66. Moss RB. Treating allergic bronchopulmonary aspergillosis: the way forward. Eur Respir J. 2016;47(2):385–7.

    CAS  PubMed  Google Scholar 

  67. Moreira AS, Silva D, Ferreira AR, Delgado L. Antifungal treatment in allergic bronchopulmonary aspergillosis with and without cystic fibrosis: a systematic review. Clin Exp Allergy. 2014;44(10):1210–27.

    CAS  PubMed  Google Scholar 

  68. Dunne K, Prior AR, Murphy K, Wall N, Leen G, Rogers TR, et al. Emergence of persistent Aspergillus terreus colonisation in a child with cystic fibrosis. Med Mycol Case Rep. 2015;9:26–30.

    PubMed  PubMed Central  Google Scholar 

  69. Ashkenazi M, Sity S, Sarouk I, Bar Aluma BE, Dagan A, Bezalel Y, et al. Omalizumab in allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. J Asthma Allergy. 2018;11:101–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Nove-Josserand R, Grard S, Auzou L, Reix P, Murris-Espin M, Bremont F, et al. Case series of omalizumab for allergic bronchopulmonary aspergillosis in cystic fibrosis patients. Pediatr Pulmonol. 2017;52(2):190–7.

    PubMed  Google Scholar 

  71. Perisson C, Destruys L, Grenet D, Bassinet L, Derelle J, Sermet-Gaudelus I, et al. Omalizumab treatment for allergic bronchopulmonary aspergillosis in young patients with cystic fibrosis. Respir Med. 2017;133:12–5.

    PubMed  Google Scholar 

  72. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Jordan CL, Noah TL, Henry MM. Therapeutic challenges posed by critical drug-drug interactions in cystic fibrosis. Pediatr Pulmonol. 2016;51(S44):S61–70.

    PubMed  Google Scholar 

  74. Harrison MJ, Ronan NJ, Khan KA, O'Callaghan G, Murphy DM, Plant BJ. Ivacaftor therapy in siblings with cystic fibrosis-the potential implications of Itraconazole in dosage and efficacy. Pulm Pharmacol Ther. 2015;31:49–50.

    CAS  PubMed  Google Scholar 

  75. Heltshe SL, Mayer-Hamblett N, Burns JL, Khan U, Baines A, Ramsey BW, et al. Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. Clin Infect Dis. 2015;60(5):703–12.

    CAS  PubMed  Google Scholar 

  76. Schwarz C, Bouchara JP, Buzina W, Chrenkova V, Dmenska H, de la Pedrosa EGG, et al. Organization of patient management and fungal epidemiology in cystic fibrosis. Mycopathologia. 2018;183(1):7–19.

    PubMed  Google Scholar 

  77. Maguire CP, Hayes JP, Hayes M, Masterson J, FitzGerald MX. Three cases of pulmonary aspergilloma in adult patients with cystic fibrosis. Thorax. 1995;50(7):805–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Luong ML, Chaparro C, Stephenson A, Rotstein C, Singer LG, Waters V, et al. Pretransplant Aspergillus colonization of cystic fibrosis patients and the incidence of post-lung transplant invasive aspergillosis. Transplantation. 2014;97(3):351–7.

    CAS  PubMed  Google Scholar 

  79. Denning DW, Cadranel J, Beigelman-Aubry C, Ader F, Chakrabarti A, Blot S, et al. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016;47(1):45–68.

    CAS  PubMed  Google Scholar 

  80. Chotirmall SH, Al-Alawi M, Mirkovic B, Lavelle G, Logan PM, Greene CM, et al. Aspergillus-associated airway disease, inflammation, and the innate immune response. Biomed Res Int. 2013;2013:723129.

    PubMed  PubMed Central  Google Scholar 

  81. Mosquera RA, Estrada L, Clements RM, Jon CK. Early diagnosis and treatment of invasive pulmonary aspergillosis in a patient with cystic fibrosis. BMJ Case Rep. 2013;2013. pii: bcr2013201360.

    Google Scholar 

  82. Warren TA, Yau Y, Ratjen F, Tullis E, Waters V. Serum galactomannan in cystic fibrosis patients colonized with Aspergillus species. Med Mycol. 2012;50(6):658–60.

    CAS  PubMed  Google Scholar 

  83. Kelly MT, MacCallum DM, Clancy SD, Odds FC, Brown AJ, Butler G. The Candida albicans CaACE2 gene affects morphogenesis, adherence and virulence. Mol Microbiol. 2004;53(3):969–83.

    CAS  PubMed  Google Scholar 

  84. Odds FC. Morphogenesis in Candida albicans. Crit Rev Microbiol. 1985;12(1):45–93.

    CAS  PubMed  Google Scholar 

  85. Blaschke-Hellmessen R. Habitats for Candida in medical and hygienic respects. Mycoses. 1999;42 Suppl 1:22–9.

    CAS  PubMed  Google Scholar 

  86. Chotirmall SH, Greene CM, McElvaney NG. Candida species in cystic fibrosis: a road less travelled. Med Mycol. 2010;48(Suppl 1):S114–24.

    PubMed  Google Scholar 

  87. Odds FC. Pathogenesis of Candida infections. J Am Acad Dermatol. 1994;31(3 Pt 2):S2–5.

    CAS  PubMed  Google Scholar 

  88. Kleinegger CL, Lockhart SR, Vargas K, Soll DR. Frequency, intensity, species, and strains of oral Candida vary as a function of host age. J Clin Microbiol. 1996;34(9):2246–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Chotirmall SH, McElvaney NG. Fungi in the cystic fibrosis lung: bystanders or pathogens? Int J Biochem Cell Biol. 2014;52:161–73.

    CAS  PubMed  Google Scholar 

  90. Valenza G, Tappe D, Turnwald D, Frosch M, Konig C, Hebestreit H, et al. Prevalence and antimicrobial susceptibility of microorganisms isolated from sputa of patients with cystic fibrosis. J Cyst Fibros. 2008;7(2):123–7.

    CAS  PubMed  Google Scholar 

  91. Guinea J. Global trends in the distribution of Candida species causing candidemia. Clin Microbiol Infect. 2014;20(Suppl 6):5–10.

    PubMed  Google Scholar 

  92. Yazici O, Cortuk M, Casim H, Cetinkaya E, Mert A, Benli AR. Candida glabrata pneumonia in a patient with chronic obstructive pulmonary disease. Case Rep Infect Dis. 2016;2016:4737321.

    PubMed  PubMed Central  Google Scholar 

  93. Shweihat Y, Perry J 3rd, Shah D. Isolated Candida infection of the lung. Respir Med Case Rep. 2015;16:18–9.

    PubMed  PubMed Central  Google Scholar 

  94. Muthig M, Hebestreit A, Ziegler U, Seidler M, Muller FM. Persistence of Candida species in the respiratory tract of cystic fibrosis patients. Med Mycol. 2010;48(1):56–63.

    CAS  PubMed  Google Scholar 

  95. Moyes DL, Runglall M, Murciano C, Shen C, Nayar D, Thavaraj S, et al. A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. Cell Host Microbe. 2010;8(3):225–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Wachtler B, Wilson D, Haedicke K, Dalle F, Hube B. From attachment to damage: defined genes of Candida albicans mediate adhesion, invasion and damage during interaction with oral epithelial cells. PLoS One. 2011;6(2):e17046.

    PubMed  PubMed Central  Google Scholar 

  97. Thompson DS, Carlisle PL, Kadosh D. Coevolution of morphology and virulence in Candida species. Eukaryot Cell. 2011;10(9):1173–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Mayer FL, Wilson D, Hube B. Candida albicans pathogenicity mechanisms. Virulence. 2013;4(2):119–28.

    PubMed  PubMed Central  Google Scholar 

  99. Wahab AA, Taj-Aldeen SJ, Kolecka A, ElGindi M, Finkel JS, Boekhout T. High prevalence of Candida dubliniensis in lower respiratory tract secretions from cystic fibrosis patients may be related to increased adherence properties. Int J Infect Dis. 2014;24:14–9.

    PubMed  Google Scholar 

  100. Hogan DA, Kolter R. Pseudomonas-Candida interactions: an ecological role for virulence factors. Science. 2002;296(5576):2229–32.

    CAS  PubMed  Google Scholar 

  101. Chotirmall SH. Candida albicans in cystic fibrosis: “opening statements presented, let the trial begin”. Pediatr Pulmonol. 2016;51(5):445–6.

    PubMed  Google Scholar 

  102. Hector A, Chotirmall SH, Lavelle GM, Mirkovic B, Horan D, Eichler L, et al. Chitinase activation in patients with fungus-associated cystic fibrosis lung disease. J Allergy Clin Immunol. 2016;138(4):1183–9. e4

    PubMed  Google Scholar 

  103. Seibold MA, Donnelly S, Solon M, Innes A, Woodruff PG, Boot RG, et al. Chitotriosidase is the primary active chitinase in the human lung and is modulated by genotype and smoking habit. J Allergy Clin Immunol. 2008;122(5):944–50. e3

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Leonardi S, Parisi GF, Capizzi A, Manti S, Cuppari C, Scuderi MG, et al. YKL-40 as marker of severe lung disease in cystic fibrosis patients. J Cyst Fibros. 2016;15(5):583–6.

    CAS  PubMed  Google Scholar 

  105. Reihill JA, Moore JE, Elborn JS, Ennis M. Effect of Aspergillus fumigatus and Candida albicans on pro-inflammatory response in cystic fibrosis epithelium. J Cyst Fibros. 2011;10(6):401–6.

    CAS  PubMed  Google Scholar 

  106. Chotirmall SH, O’Donoghue E, Bennett K, Gunaratnam C, O’Neill SJ, McElvaney NG. Sputum Candida albicans presages FEV(1) decline and hospital-treated exacerbations in cystic fibrosis. Chest. 2010;138(5):1186–95.

    PubMed  Google Scholar 

  107. AbdulWahab A, Salah H, Chandra P, Taj-Aldeen SJ. Persistence of Candida dubliniensis and lung function in patients with cystic fibrosis. BMC Res Notes. 2017;10(1):326.

    PubMed  PubMed Central  Google Scholar 

  108. Gileles-Hillel A, Shoseyov D, Polacheck I, Korem M, Kerem E, Cohen-Cymberknoh M. Association of chronic Candida albicans respiratory infection with a more severe lung disease in patients with cystic fibrosis. Pediatr Pulmonol. 2015;50(11):1082–9.

    PubMed  Google Scholar 

  109. Noni M, Katelari A, Kaditis A, Theochari I, Lympari I, Alexandrou-Athanassoulis H, et al. Candida albicans chronic colonisation in cystic fibrosis may be associated with inhaled antibiotics. Mycoses. 2015;58(7):416–21.

    CAS  PubMed  Google Scholar 

  110. Rougeron A, Giraud S, Alastruey-Izquierdo A, Cano-Lira J, Rainer J, Mouhajir A, et al. Ecology of Scedosporium species: present knowledge and future research. Mycopathologia. 2018;183(1):185–200.

    CAS  PubMed  Google Scholar 

  111. Tracy MC, Moss RB. The myriad challenges of respiratory fungal infection in cystic fibrosis. Pediatr Pulmonol. 2018;53(S3):S75–85.

    PubMed  Google Scholar 

  112. Schwarz C, Brandt C, Antweiler E, Krannich A, Staab D, Schmitt-Grohe S, et al. Prospective multicenter German study on pulmonary colonization with Scedosporium/Lomentospora species in cystic fibrosis: epidemiology and new association factors. PLoS One. 2017;12(2):e0171485.

    PubMed  PubMed Central  Google Scholar 

  113. Sedlacek L, Graf B, Schwarz C, Albert F, Peter S, Wurstl B, et al. Prevalence of Scedosporium species and Lomentospora prolificans in patients with cystic fibrosis in a multicenter trial by use of a selective medium. J Cyst Fibros. 2015;14(2):237–41.

    CAS  PubMed  Google Scholar 

  114. Lamaris GA, Chamilos G, Lewis RE, Safdar A, Raad II, Kontoyiannis DP. Scedosporium infection in a tertiary care cancer center: a review of 25 cases from 1989-2006. Clin Infect Dis. 2006;43(12):1580–4.

    PubMed  Google Scholar 

  115. Cimon B, Carrere J, Vinatier JF, Chazalette JP, Chabasse D, Bouchara JP. Clinical significance of Scedosporium apiospermum in patients with cystic fibrosis. Eur J Clin Microbiol Infect Dis. 2000;19(1):53–6.

    CAS  PubMed  Google Scholar 

  116. Kaur J, Duan SY, Vaas LA, Penesyan A, Meyer W, Paulsen IT, et al. Phenotypic profiling of Scedosporium aurantiacum, an opportunistic pathogen colonizing human lungs. PLoS One. 2015;10(3):e0122354.

    PubMed  PubMed Central  Google Scholar 

  117. Wine JJ. The genesis of cystic fibrosis lung disease. J Clin Invest. 1999;103(3):309–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Kondori N, Gilljam M, Lindblad A, Jonsson B, Moore ER, Wenneras C. High rate of Exophiala dermatitidis recovery in the airways of patients with cystic fibrosis is associated with pancreatic insufficiency. J Clin Microbiol. 2011;49(3):1004–9.

    PubMed  PubMed Central  Google Scholar 

  119. Ziesing S, Suerbaum S, Sedlacek L. Fungal epidemiology and diversity in cystic fibrosis patients over a 5-year period in a national reference center. Med Mycol. 2016;54(8):781–6.

    CAS  PubMed  Google Scholar 

  120. Sudhadham M, Prakitsin S, Sivichai S, Chaiyarat R, Dorrestein GM, Menken SB, et al. The neurotropic black yeast Exophiala dermatitidis has a possible origin in the tropical rain forest. Stud Mycol. 2008;61:145–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Lebecque P, Leonard A, Huang D, Reychler G, Boeras A, Leal T, et al. Exophiala (Wangiella) dermatitidis and cystic fibrosis – prevalence and risk factors. Med Mycol. 2010;48(Suppl 1):S4–9.

    PubMed  Google Scholar 

  122. Steinmann J, Giraud S, Schmidt D, Sedlacek L, Hamprecht A, Houbraken J, et al. Validation of a novel real-time PCR for detecting Rasamsonia argillacea species complex in respiratory secretions from cystic fibrosis patients. New Microbes New Infect. 2014;2(3):72–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Houbraken J, Spierenburg H, Frisvad JC. Rasamsonia, a new genus comprising thermotolerant and thermophilic Talaromyces and Geosmithia species. Antonie Van Leeuwenhoek. 2012;101(2):403–21.

    CAS  PubMed  Google Scholar 

  124. Giraud S, Favennec L, Bougnoux ME, Bouchara JP. Rasamsonia argillacea species complex: taxonomy, pathogenesis and clinical relevance. Future Microbiol. 2013;8(8):967–78.

    CAS  PubMed  Google Scholar 

  125. Nagano Y, Elborn JS, Millar BC, Walker JM, Goldsmith CE, Rendall J, et al. Comparison of techniques to examine the diversity of fungi in adult patients with cystic fibrosis. Med Mycol. 2010;48(1):166–76.e1.

    CAS  PubMed  Google Scholar 

  126. Leong C, Goh J, Irudayaswamy A, Dawson T. Geographical and ethnic differences in Malassezia species distribution on healthy skin. Med Mycol. 2018;56:S149-S.

    Google Scholar 

  127. Prohic A, Sadikovic TJ, Krupalija-Fazlic M, Kuskunovic-Vlahovljak S. Malassezia species in healthy skin and in dermatological conditions. Int J Dermatol. 2016;55(5):494–504.

    PubMed  Google Scholar 

  128. Velegraki A, Cafarchia C, Gaitanis G, Iatta R, Boekhout T. Malassezia infections in humans and animals: pathophysiology, detection, and treatment. PLoS Pathog. 2015;11(1):e1004523.

    PubMed  PubMed Central  Google Scholar 

  129. Vylkova S. Environmental pH modulation by pathogenic fungi as a strategy to conquer the host. PLoS Pathog. 2017;13(2).

    Google Scholar 

  130. Kale SD, Ayubi T, Chung D, Tubau-Juni N, Leber A, Dang HX, et al. Modulation of immune signaling and metabolism highlights host and fungal transcriptional responses in mouse models of invasive pulmonary aspergillosis. Sci Rep. 2017;7:17096.

    PubMed  PubMed Central  Google Scholar 

  131. Goncalves SM, Lagrou K, Duarte-Oliveira C, Maertens JA, Cunha C, Carvalho A. The microbiome-metabolome crosstalk in the pathogenesis of respiratory fungal diseases. Virulence. 2017;8(6):673–84.

    CAS  PubMed  Google Scholar 

  132. Kolwijck E, van de Veerdonk FL. The potential impact of the pulmonary microbiome on immunopathogenesis of Aspergillus-related lung disease. Eur J Immunol. 2014;44(11):3156–65.

    CAS  PubMed  Google Scholar 

  133. Dickson RP, Erb-Downward JR, Huffnagle GB. The role of the bacterial microbiome in lung disease. Expert Rev Respir Med. 2013;7(3):245–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Fujimura KE, Lynch SV. Microbiota in allergy and asthma and the emerging relationship with the gut microbiome. Cell Host Microbe. 2015;17(5):592–602.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Gensollen T, Blumberg RS. Correlation between early-life regulation of the immune system by microbiota and allergy development. J Allergy Clin Immunol. 2017;139(4):1084–91.

    PubMed  PubMed Central  Google Scholar 

  136. Hogan DA. Talking to themselves: autoregulation and quorum sensing in fungi. Eukaryot Cell. 2006;5(4):613–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Williams P. Quorum sensing, communication and cross-kingdom signalling in the bacterial world. Microbiology. 2007;153(Pt 12):3923–38.

    CAS  PubMed  Google Scholar 

  138. Cugini C, Calfee MW, Farrow JM 3rd, Morales DK, Pesci EC, Hogan DA. Farnesol, a common sesquiterpene, inhibits PQS production in Pseudomonas aeruginosa. Mol Microbiol. 2007;65(4):896–906.

    CAS  PubMed  Google Scholar 

  139. Hogan DA, Vik A, Kolter R. A Pseudomonas aeruginosa quorum-sensing molecule influences Candida albicans morphology. Mol Microbiol. 2004;54(5):1212–23.

    CAS  PubMed  Google Scholar 

  140. Cottier F, Muhlschlegel FA. Communication in fungi. Int J Microbiol. 2012;2012:351832.

    PubMed  Google Scholar 

  141. Tsatsaronis JA, Franch-Arroyo S, Resch U, Charpentier E. Extracellular vesicle RNA: a universal mediator of microbial communication? Trends Microbiol. 2018;26(5):401–10.

    CAS  PubMed  Google Scholar 

  142. Peres da Silva R, Puccia R, Rodrigues ML, Oliveira DL, Joffe LS, Cesar GV, et al. Extracellular vesicle-mediated export of fungal RNA. Sci Rep. 2015;5:7763.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Sjostrom AE, Sandblad L, Uhlin BE, Wai SN. Membrane vesicle-mediated release of bacterial RNA. Sci Rep. 2015;5:15329.

    PubMed  PubMed Central  Google Scholar 

  144. Stacy A, McNally L, Darch SE, Brown SP, Whiteley M. The biogeography of polymicrobial infection. Nat Rev Microbiol. 2016;14(2):93–105.

    CAS  PubMed  Google Scholar 

  145. Wolcott R, Costerton JW, Raoult D, Cutler SJ. The polymicrobial nature of biofilm infection. Clin Microbiol Infect. 2013;19(2):107–12.

    CAS  PubMed  Google Scholar 

  146. Sibley CD, Parkins MD, Rabin HR, Surette MG. The relevance of the polymicrobial nature of airway infection in the acute and chronic management of patients with cystic fibrosis. Curr Opin Investig Drugs. 2009;10(8):787–94.

    CAS  PubMed  Google Scholar 

  147. Kim YG, Udayanga KG, Totsuka N, Weinberg JB, Nunez G, Shibuya A. Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE(2). Cell Host Microbe. 2014;15(1):95–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Kozel TR, Wickes B. Fungal diagnostics. Cold Spring Harb Perspect Med. 2014;4(4):a019299.

    PubMed  PubMed Central  Google Scholar 

  149. Lipuma JJ. The changing microbial epidemiology in cystic fibrosis. Clin Microbiol Rev. 2010;23(2):299–323.

    PubMed  PubMed Central  Google Scholar 

  150. Chen SC, Meyer W, Pashley CH. Challenges in laboratory detection of fungal pathogens in the airways of cystic fibrosis patients. Mycopathologia. 2018;183(1):89–100.

    CAS  PubMed  Google Scholar 

  151. Delhaes L, Touati K, Faure-Cognet O, Cornet M, Botterel F, Dannaoui E, et al. Prevalence, geographic risk factor, and development of a standardized protocol for fungal isolation in cystic fibrosis: results from the international prospective study “MFIP”. J Cyst Fibros. 2019;18(2):212–20.

    Google Scholar 

  152. Botterel F, Angebault C, Cabaret O, Stressmann FA, Costa JM, Wallet F, et al. Fungal and bacterial diversity of airway microbiota in adults with cystic fibrosis: concordance between conventional methods and ultra-deep sequencing, and their practical use in the clinical laboratory. Mycopathologia. 2018;183(1):171–83.

    PubMed  Google Scholar 

  153. Rogers GB, Hart CA, Mason JR, Hughes M, Walshaw MJ, Bruce KD. Bacterial diversity in cases of lung infection in cystic fibrosis patients: 16S ribosomal DNA (rDNA) length heterogeneity PCR and 16S rDNA terminal restriction fragment length polymorphism profiling. J Clin Microbiol. 2003;41(8):3548–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Acosta N, Heirali A, Somayaji R, Surette MG, Workentine ML, Sibley CD, et al. Sputum microbiota is predictive of long-term clinical outcomes in young adults with cystic fibrosis. Thorax. 2018;73(11):1016–25.

    PubMed  Google Scholar 

  155. Heirali AA, Workentine ML, Acosta N, Poonja A, Storey DG, Somayaji R, et al. The effects of inhaled aztreonam on the cystic fibrosis lung microbiome. Microbiome. 2017;5(1):51.

    PubMed  PubMed Central  Google Scholar 

  156. Prevaes SM, de Steenhuijsen Piters WA, de Winter-de Groot KM, Janssens HM, Tramper-Stranders GA, Chu ML, et al. Concordance between upper and lower airway microbiota in infants with cystic fibrosis. Eur Respir J. 2017;49(3).

    Google Scholar 

  157. Whelan FJ, Heirali AA, Rossi L, Rabin HR, Parkins MD, Surette MG. Longitudinal sampling of the lung microbiota in individuals with cystic fibrosis. PLoS One. 2017;12(3):e0172811.

    PubMed  PubMed Central  Google Scholar 

  158. Feigelman R, Kahlert CR, Baty F, Rassouli F, Kleiner RL, Kohler P, et al. Sputum DNA sequencing in cystic fibrosis: non-invasive access to the lung microbiome and to pathogen details. Microbiome. 2017;5(1):20.

    PubMed  PubMed Central  Google Scholar 

  159. Carmody LA, Zhao J, Kalikin LM, LeBar W, Simon RH, Venkataraman A, et al. The daily dynamics of cystic fibrosis airway microbiota during clinical stability and at exacerbation. Microbiome. 2015;3:12.

    PubMed  PubMed Central  Google Scholar 

  160. Renwick J, McNally P, John B, DeSantis T, Linnane B, Murphy P, et al. The microbial community of the cystic fibrosis airway is disrupted in early life. PLoS One. 2014;9(12):e109798.

    PubMed  PubMed Central  Google Scholar 

  161. Zhao J, Schloss PD, Kalikin LM, Carmody LA, Foster BK, Petrosino JF, et al. Decade-long bacterial community dynamics in cystic fibrosis airways. Proc Natl Acad Sci U S A. 2012;109(15):5809–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Tipton L, Ghedin E, Morris A. The lung mycobiome in the next-generation sequencing era. Virulence. 2017;8(3):334–41.

    CAS  PubMed  Google Scholar 

  163. Bokulich NA, Mills DA. Improved selection of internal transcribed spacer-specific primers enables quantitative, ultra-high-throughput profiling of fungal communities. Appl Environ Microbiol. 2013;79(8):2519–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Nguyen LD, Viscogliosi E, Delhaes L. The lung mycobiome: an emerging field of the human respiratory microbiome. Front Microbiol. 2015;6:89.

    PubMed  PubMed Central  Google Scholar 

  165. Delhaes L, Monchy S, Frealle E, Hubans C, Salleron J, Leroy S, et al. The airway microbiota in cystic fibrosis: a complex fungal and bacterial community – implications for therapeutic management. PLoS One. 2012;7(4):e36313.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Mounier J, Gouello A, Keravec M, Le Gal S, Pacini G, Debaets S, et al. Use of denaturing high-performance liquid chromatography (DHPLC) to characterize the bacterial and fungal airway microbiota of cystic fibrosis patients. J Microbiol. 2014;52(4):307–14.

    CAS  PubMed  Google Scholar 

  167. Willger SD, Grim SL, Dolben EL, Shipunova A, Hampton TH, Morrison HG, et al. Characterization and quantification of the fungal microbiome in serial samples from individuals with cystic fibrosis. Microbiome. 2014;2:40.

    PubMed  PubMed Central  Google Scholar 

  168. Kim SH, Clark ST, Surendra A, Copeland JK, Wang PW, Ammar R, et al. Global analysis of the fungal microbiome in cystic fibrosis patients reveals loss of function of the transcriptional repressor Nrg1 as a mechanism of pathogen adaptation. PLoS Pathog. 2015;11(11):e1005308.

    PubMed  PubMed Central  Google Scholar 

  169. Kramer R, Sauer-Heilborn A, Welte T, Guzman CA, Abraham WR, Hofle MG. Cohort study of airway mycobiome in adult cystic fibrosis patients: differences in community structure between fungi and bacteria reveal predominance of transient fungal elements. J Clin Microbiol. 2015;53(9):2900–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Smith EE, Buckley DG, Wu Z, Saenphimmachak C, Hoffman LR, D'Argenio DA, et al. Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients. Proc Natl Acad Sci U S A. 2006;103(22):8487–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Chotirmall SH, Gellatly SL, Budden KF, Mac Aogain M, Shukla SD, Wood DL, et al. Microbiomes in respiratory health and disease: an Asia-Pacific perspective. Respirology. 2017;22(2):240–50.

    PubMed  Google Scholar 

  172. Chotirmall SH. The microbiological gender gap in cystic fibrosis. J Womens Health (Larchmt). 2014;23(12):995–6.

    Google Scholar 

  173. Nilsson RH, Anslan S, Bahram M, Wurzbacher C, Baldrian P, Tedersoo L. Mycobiome diversity: high-throughput sequencing and identification of fungi. Nat Rev Microbiol. 2019;17(2):95–109.

    Google Scholar 

  174. O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373(9678):1891–904.

    PubMed  Google Scholar 

  175. Schafer J, Griese M, Chandrasekaran R, Chotirmall SH, Hartl D. Pathogenesis, imaging and clinical characteristics of CF and non-CF bronchiectasis. BMC Pulm Med. 2018;18(1):79.

    PubMed  PubMed Central  Google Scholar 

  176. Moss RB. Fungi in cystic fibrosis and non-cystic fibrosis bronchiectasis. Semin Respir Crit Care Med. 2015;36(2):207–16.

    PubMed  Google Scholar 

  177. Khoury O, Barrios C, Ortega V, Atala A, Murphy SV. Immunomodulatory cell therapy to target cystic fibrosis inflammation. Am J Respir Cell Mol Biol. 2018;58(1):12–20.

    CAS  PubMed  Google Scholar 

  178. Mahdavinia M, Grammer LC. Management of allergic bronchopulmonary aspergillosis: a review and update. Ther Adv Respir Dis. 2012;6(3):173–87.

    CAS  PubMed  Google Scholar 

  179. Vaughan LM. Allergic bronchopulmonary aspergillosis. Clin Pharm. 1993;12(1):24–33.

    CAS  PubMed  Google Scholar 

  180. Agarwal R, Dhooria S, Singh Sehgal I, Aggarwal AN, Garg M, Saikia B, et al. A randomized trial of itraconazole vs prednisolone in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Chest. 2018;153(3):656–64.

    PubMed  Google Scholar 

  181. Singh Sehgal I, Agarwal R. Pulse methylprednisolone in allergic bronchopulmonary aspergillosis exacerbations. Eur Respir Rev. 2014;23(131):149–52.

    PubMed  Google Scholar 

  182. Chmiel JF, Konstan MW, Elborn JS. Antibiotic and anti-inflammatory therapies for cystic fibrosis. Cold Spring Harb Perspect Med. 2013;3(10).

    Google Scholar 

  183. Cheng K, Ashby D, Smyth RL. Oral steroids for long-term use in cystic fibrosis. Cochrane Database Syst Rev. 2015;12

    Google Scholar 

  184. Dinwiddie R. Anti-inflammatory therapy in cystic fibrosis. J Cyst Fibros. 2005;4(Suppl 2):45–8.

    CAS  PubMed  Google Scholar 

  185. Lai HC, FitzSimmons SC, Allen DB, Kosorok MR, Rosenstein BJ, Campbell PW, et al. Risk of persistent growth impairment after alternate-day prednisone treatment in children with cystic fibrosis. N Engl J Med. 2000;342(12):851–9.

    CAS  PubMed  Google Scholar 

  186. Balfour-Lynn IM, Welch K. Inhaled corticosteroids for cystic fibrosis. Cochrane Database Syst Rev. 2016;8

    Google Scholar 

  187. Agarwal R, Khan A, Aggarwal AN, Saikia B, Gupta D, Chakrabarti A. Role of inhaled corticosteroids in the management of serological allergic bronchopulmonary aspergillosis (ABPA). Intern Med. 2011;50(8):855–60.

    CAS  PubMed  Google Scholar 

  188. Moss RB. Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis. Eur Respir J. 2014;43(5):1487–500.

    CAS  PubMed  Google Scholar 

  189. Katelari A, Petrocheilou A, Doudounakis S. Is the combination of intravenous corticosteroid pulses and inhaled amphotericin a better treatment option than oral corticosteroids and inhaled amphotericin for ABPA? C108 pediatric cystic fibrosis and primary ciliary dyskinesia. American Thoracic Society International Conference Abstracts: American Thoracic Society; 2012. p. A5261-A.

    Google Scholar 

  190. Thomson JM, Wesley A, Byrnes CA, Nixon GM. Pulse intravenous methylprednisolone for resistant allergic bronchopulmonary aspergillosis in cystic fibrosis. Pediatr Pulmonol. 2006;41(2):164–70.

    PubMed  Google Scholar 

  191. Wark P. Pathogenesis of allergic bronchopulmonary aspergillosis and an evidence-based review of azoles in treatment. Respir Med. 2004;98(10):915–23.

    PubMed  Google Scholar 

  192. Wark PA, Gibson PG. Allergic bronchopulmonary aspergillosis: new concepts of pathogenesis and treatment. Respirology. 2001;6(1):1–7.

    CAS  PubMed  Google Scholar 

  193. Wark P, Wilson AW, Gibson PG. Azoles for allergic bronchopulmonary aspergillosis associated with asthma. Cochrane Database Syst Rev. 2001;4:CD001108.

    Google Scholar 

  194. Ashbee HR, Barnes RA, Johnson EM, Richardson MD, Gorton R, Hope WW. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother. 2014;69(5):1162–76.

    CAS  PubMed  Google Scholar 

  195. Markantonis SL, Katelari A, Pappa E, Doudounakis S. Voriconazole pharmacokinetics and photosensitivity in children with cystic fibrosis. J Cyst Fibros. 2012;11(3):246–52.

    CAS  PubMed  Google Scholar 

  196. Armstrong-James D, Brown GD, Netea MG, Zelante T, Gresnigt MS, van de Veerdonk FL, et al. Immunotherapeutic approaches to treatment of fungal diseases. Lancet Infect Dis. 2017;17(12):e393–402.

    CAS  PubMed  Google Scholar 

  197. Erratum: Omalizumab in allergic bronchopulmonary aspergillosis in patients with cystic fibrosis [Erratum]. J Asthma Allergy. 2018;11:245.

    Google Scholar 

  198. Beam KT, Coop CA. Steroid sparing effect of omalizumab in seropositive allergic bronchopulmonary aspergillosis. Allergy Rhinol. 2015;6(2):143–5.

    Google Scholar 

  199. Smith S, Rowbotham NJ, Charbek E. Inhaled antibiotics for pulmonary exacerbations in cystic fibrosis. Cochrane Database Syst Rev. 2018;10:CD008319.

    PubMed  Google Scholar 

  200. Campoy S, Adrio JL. Antifungals. Biochem Pharmacol. 2017;133:86–96.

    CAS  PubMed  Google Scholar 

  201. 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–e92.

    PubMed  Google Scholar 

  202. Denning DW, Bromley MJ. Infectious disease. How to bolster the antifungal pipeline. Science. 2015;347(6229):1414–6.

    CAS  PubMed  Google Scholar 

  203. Burgel PR, Baixench MT, Amsellem M, Audureau E, Chapron J, Kanaan R, et al. High prevalence of azole-resistant Aspergillus fumigatus in adults with cystic fibrosis exposed to itraconazole. Antimicrob Agents Chemother. 2012;56(2):869–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Fischer J, van Koningsbruggen-Rietschel S, Rietschel E, Vehreschild MJ, Wisplinghoff H, Kronke M, et al. Prevalence and molecular characterization of azole resistance in Aspergillus spp. isolates from German cystic fibrosis patients. J Antimicrob Chemother. 2014;69(6):1533–6.

    CAS  PubMed  Google Scholar 

  205. Prigitano A, Esposto MC, Biffi A, De Lorenzis G, Favuzzi V, Koncan R, et al. Triazole resistance in Aspergillus fumigatus isolates from patients with cystic fibrosis in Italy. J Cyst Fibros. 2017;16(1):64–9.

    CAS  PubMed  Google Scholar 

  206. 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(1):151–60.

    CAS  PubMed  Google Scholar 

  207. Casciaro R, Naselli A, Cresta F, Ros M, Castagnola E, Minicucci L. Role of nebulized amphotericin B in the management of allergic bronchopulmonary aspergillosis in cystic fibrosis: case report and review of literature. J Chemother. 2015;27(5):307–11.

    CAS  PubMed  Google Scholar 

  208. Mesa-Arango AC, Rueda C, Roman E, Quintin J, Terron MC, Luque D, et al. Cell wall changes in amphotericin B-resistant strains from Candida tropicalis and relationship with the immune responses elicited by the host. Antimicrob Agents Chemother. 2016;60(4):2326–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Garczewska B, Jarzynka S, Kus J, Skorupa W, Augustynowicz-Kopec E. Fungal infection of cystic fibrosis patients – single center experience. Pneumonol Alergol Pol. 2016;84(3):151–9.

    PubMed  Google Scholar 

  210. Mortensen KL, Johansen HK, Fuursted K, Knudsen JD, Gahrn-Hansen B, Jensen RH, et al. A prospective survey of Aspergillus spp. in respiratory tract samples: prevalence, clinical impact and antifungal susceptibility. Eur J Clin Microbiol Infect Dis. 2011;30(11):1355–63.

    CAS  PubMed  Google Scholar 

  211. Kordalewska M, Lee A, Park S, Berrio I, Chowdhary A, Zhao Y, et al. Understanding echinocandin resistance in the emerging pathogen Candida auris. Antimicrob Agents Chemother. 2018;62(6).

    Google Scholar 

  212. Gauvreau GM, Arm JP, Boulet LP, Leigh R, Cockcroft DW, Davis BE, et al. Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses. J Allergy Clin Immunol. 2016;138(4):1051–9.

    CAS  PubMed  Google Scholar 

  213. Liour SS, Tom A, Chan YH, Chang TW. Treating IgE-mediated diseases via targeting IgE-expressing B cells using an anti-CepsilonmX antibody. Pediatr Allergy Immunol. 2016;27(5):446–51.

    PubMed  Google Scholar 

  214. Chmiel JF, Aksamit TR, Chotirmall SH, Dasenbrook EC, Elborn JS, LiPuma JJ, et al. Antibiotic management of lung infections in cystic fibrosis. II. Nontuberculous mycobacteria, anaerobic bacteria, and fungi. Ann Am Thorac Soc. 2014;11(8):1298–306.

    PubMed  PubMed Central  Google Scholar 

  215. Chmiel JF, Aksamit TR, Chotirmall SH, Dasenbrook EC, Elborn JS, LiPuma JJ, et al. Antibiotic management of lung infections in cystic fibrosis. I. the microbiome, methicillin-resistant Staphylococcus aureus, gram-negative bacteria, and multiple infections. Ann Am Thorac Soc. 2014;11(7):1120–9.

    PubMed  PubMed Central  Google Scholar 

  216. 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(8):764–71.

    PubMed  Google Scholar 

  217. Chakrabarti A, Chatterjee SS, Shivaprakash MR. Overview of opportunistic fungal infections in India. Nippon Ishinkin Gakkai Zasshi. 2008;49(3):165–72.

    Google Scholar 

  218. Hong G, Psoter KJ, Jennings MT, Merlo CA, Boyle MP, Hadjiliadis D, et al. Risk factors for persistent Aspergillus respiratory isolation in cystic fibrosis. J Cyst Fibros. 2018;17(5):624–30.

    PubMed  PubMed Central  Google Scholar 

  219. Bird J, O’Brien C, Moss S. Risk factors for allergic bronchopulmonary aspergillosis in paediatric patients with cystic fibrosis. Arch Dis Child. 2010;95(Suppl 1):A60.

    Google Scholar 

  220. Sudfeld CR, Dasenbrook EC, Merz WG, Carroll KC, Boyle MP. Prevalence and risk factors for recovery of filamentous fungi in individuals with cystic fibrosis. J Cyst Fibros. 2010;9(2):110–6.

    PubMed  Google Scholar 

  221. Vardhan V, Mulajker DS. Allergic bronchopulmonary candidiasis. Med J Armed Forces India. 2012;68(4):395–7.

    PubMed  PubMed Central  Google Scholar 

  222. Bernhardt A, Sedlacek L, Wagner S, Schwarz C, Wurstl B, Tintelnot K. Multilocus sequence typing of Scedosporium apiospermum and Pseudallescheria boydii isolates from cystic fibrosis patients. J Cyst Fibros. 2013;12(6):592–8.

    CAS  PubMed  Google Scholar 

  223. Sahi H, Avery RK, Minai OA, Hall G, Mehta AC, Raina P, et al. Scedosporium apiospermum (Pseudoallescheria boydii) infection in lung transplant recipients. J Heart Lung Transplant. 2007;26(4):350–6.

    PubMed  Google Scholar 

  224. Kusenbach G, Skopnik H, Haase G, Friedrichs F, Dohmen H. Exophiala dermatitidis pneumonia in cystic fibrosis. Eur J Pediatr. 1992;151(5):344–6.

    CAS  PubMed  Google Scholar 

  225. Diemert D, Kunimoto D, Sand C, Rennie R. Sputum isolation of Wangiella dermatitidis in patients with cystic fibrosis. Scand J Infect Dis. 2001;33(10):777–9.

    CAS  PubMed  Google Scholar 

  226. Abdolrasouli A, Bercusson AC, Rhodes JL, Hagen F, Buil JB, Tang AYY, et al. Airway persistence by the emerging multi-azole-resistant Rasamsonia argillacea complex in cystic fibrosis. Mycoses. 2018;61(9):665–73.

    CAS  PubMed  Google Scholar 

  227. Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10020):760–9.

    CAS  PubMed  Google Scholar 

  228. Kullberg BJ, Viscoli C, Pappas PG, Vazquez J, Ostrosky-Zeichner L, Rotstein C, et al. Isavuconazole versus caspofungin in the treatment of candidemia and other invasive Candida infections: the ACTIVE trial. Clin Infect Dis. 2019;68(12):1981–89.

    Google Scholar 

  229. Katragkou A, McCarthy M, Meletiadis J, Hussain K, Moradi PW, Strauss GE, et al. In vitro combination therapy with isavuconazole against Candida spp. Med Mycol. 2017;55(8):859–68.

    CAS  PubMed  Google Scholar 

  230. Wiederhold NP, Najvar LK, Matsumoto S, Bocanegra RA, Herrera ML, Wickes BL, et al. Efficacy of the investigational echinocandin ASP9726 in a guinea pig model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2015;59(5):2875–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Lamoth F, Alexander BD. Antifungal activities of SCY-078 (MK-3118) and standard antifungal agents against clinical non-Aspergillus mold isolates. Antimicrob Agents Chemother. 2015;59(7):4308–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Shibata T, Takahashi T, Yamada E, Kimura A, Nishikawa H, Hayakawa H, et al. T-2307 causes collapse of mitochondrial membrane potential in yeast. Antimicrob Agents Chemother. 2012;56(11):5892–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Oliver JD, Sibley GEM, Beckmann N, Dobb KS, Slater MJ, McEntee L, et al. F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proc Natl Acad Sci U S A. 2016;113(45):12809–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Gebremariam T, Alkhazraji S, Alqarihi A, Jeon HH, Gu Y, Kapoor M, et al. APX001 is effective in the treatment of murine invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2018;63:e01713.

    Google Scholar 

  235. McCarthy MW, Kontoyiannis DP, Cornely OA, Perfect JR, Walsh TJ. Novel agents and drug targets to meet the challenges of resistant fungi. J Infect Dis. 2017;216(suppl_3):S474–S83.

    CAS  PubMed  Google Scholar 

  236. Arendrup MC, Jensen RH, Cuenca-Estrella M. In vitro activity of ASP2397 against Aspergillus isolates with or without acquired azole resistance mechanisms. Antimicrob Agents Chemother. 2016;60(1):532–6.

    CAS  PubMed  Google Scholar 

  237. Nyborg AC, Zacco A, Ettinger R, Jack Borrok M, Zhu J, Martin T, et al. Development of an antibody that neutralizes soluble IgE and eliminates IgE expressing B cells. Cell Mol Immunol. 2016;13(3):391–400.

    CAS  PubMed  Google Scholar 

  238. Harris JM, Maciuca R, Bradley MS, Cabanski CR, Scheerens H, Lim J, et al. A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma. Respir Res. 2016;17:29.

    PubMed  PubMed Central  Google Scholar 

  239. Mastella G, Rainisio M, Harms HK, Hodson ME, Koch C, Navarro J, et al. Allergic bronchopulmonary aspergillosis in cystic fibrosis. A European epidemiological study. Epidemiologic Registry of Cystic Fibrosis. Eur Respir J. 2000;16(3):464–71.

    CAS  PubMed  Google Scholar 

  240. Zhao Y, Garnaud C, Brenier-Pinchart MP, Thiebaut-Bertrand A, Saint-Raymond C, Camara B, et al. Direct molecular diagnosis of aspergillosis and CYP51A profiling from respiratory samples of French patients. Front Microbiol. 2016;7:1164.

    PubMed  PubMed Central  Google Scholar 

  241. 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(3):639–46.

    CAS  PubMed  Google Scholar 

  242. Sharma VK, Raj D, Xess I, Lodha R, Kabra SK. Prevalence and risk factors for allergic bronchopulmonary aspergillosis in Indian children with cystic fibrosis. Indian Pediatr. 2014;51(4):295–7.

    CAS  PubMed  Google Scholar 

  243. Skov M, McKay K, Koch C, Cooper PJ. Prevalence of allergic bronchopulmonary aspergillosis in cystic fibrosis in an area with a high frequency of atopy. Respir Med. 2005;99(7):887–93.

    PubMed  Google Scholar 

  244. Peetermans M, Goeminne P, De Boeck C, Dupont LJ. IgE sensitization to Aspergillus fumigatus is not a bystander phenomenon in cystic fibrosis lung disease. Chest. 2014;146(3):e99–e100.

    PubMed  Google Scholar 

  245. Fillaux J, Bremont F, Murris M, Cassaing S, Tetu L, Segonds C, et al. Aspergillus sensitization or carriage in cystic fibrosis patients. Pediatr Infect Dis J. 2014;33(7):680–6.

    PubMed  Google Scholar 

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Acknowledgements

This research is supported by the Singapore Ministry of Health’s National Medical Research Council under its Transition Award (NMRC/TA/0048/2016) and the Lee Kong Chian School of Medicine, Nanyang Technological University Start-Up Grant (both S.H.C). The authors would like to acknowledge The Academic Respiratory Initiative for Pulmonary Health (TARIPH) for collaboration support.

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  1. Translational Respiratory Research Laboratory, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

    Micheál Mac Aogáin, Céline Vidaillac & Sanjay H. Chotirmall

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  1. Micheál Mac Aogáin
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  2. Céline Vidaillac
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  3. Sanjay H. Chotirmall
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Correspondence to Sanjay H. Chotirmall .

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  1. The University of North Carolina at Chapel Hill, Department of Pediatrics, UNC Children’s Hospital, Chapel Hill, NC, USA

    Stephanie Duggins Davis

  2. Department of Pediatrics, University of Washington School of Medicine, Division of Pulmonary and Sleep Medicine, Seattle Children’s Hospital, Seattle, WA, USA

    Margaret Rosenfeld

  3. Department of Pediatrics, Indiana University School of Medicine, Division of Pediatric Pulmonology, Allergy and Sleep Medicine, Riley Hospital for Children at IU Health, Indianapolis, IN, USA

    James Chmiel

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Mac Aogáin, M., Vidaillac, C., Chotirmall, S.H. (2020). Fungal Infections and ABPA. In: Davis, S., Rosenfeld, M., Chmiel, J. (eds) Cystic Fibrosis. Respiratory Medicine. Humana, Cham. https://doi.org/10.1007/978-3-030-42382-7_6

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