, Volume 183, Issue 1, pp 119–137 | Cite as

Fungal Pathogens in CF Airways: Leave or Treat?

  • A. Singh
  • A. Ralhan
  • C. Schwarz
  • D. Hartl
  • A. HectorEmail author


Chronic airway infection plays an essential role in the progress of cystic fibrosis (CF) lung disease. In the past decades, mainly bacterial pathogens, such as Pseudomonas aeruginosa, have been the focus of researchers and clinicians. However, fungi are frequently detected in CF airways and there is an increasing body of evidence that fungal pathogens might play a role in CF lung disease. Several studies have shown an association of fungi, particularly Aspergillus fumigatus and Candida albicans, with the course of lung disease in CF patients. Mechanistically, in vitro and in vivo studies suggest that an impaired immune response to fungal pathogens in CF airways renders them more susceptible to fungi. However, it remains elusive whether fungi are actively involved in CF lung disease pathologies or whether they rather reflect a dysregulated airway colonization and act as microbial bystanders. A key issue for dissecting the role of fungi in CF lung disease is the distinction of dynamic fungal–host interaction entities, namely colonization, sensitization or infection. This review summarizes key findings on pathophysiological mechanisms and the clinical impact of fungi in CF lung disease.


Cystic fibrosis Fungal colonization Aspergillus fumigatus Candida albicans Pneumocystis jirovecii Exophiala dermatitidis 



This work was supported by the German Research Foundation (DFG to A.H.; DFG, SFB/CRC685 at Tübingen to D.H.), Christiane-Herzog-Stiftung (Christiane-Herzog-Award to A.H.) and funding of the University of Tübingen (Junior Research Group Program/IZKF to A.H.). We would like to thank Mr. Peter-Michael Weber for his excellent work on the illustration.


  1. 1.
    Hamutcu R, Rowland JM, Horn MV, et al. Clinical findings and lung pathology in children with cystic fibrosis. Am J Respir Crit Care Med. 2002;165:1172–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352:1992–2001.PubMedCrossRefGoogle Scholar
  3. 3.
    Sly PD, Gangell CL, Chen L, et al. Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med. 2013;368:1963–70.PubMedCrossRefGoogle Scholar
  4. 4.
    Wielputz MO, Puderbach M, Kopp-Schneider A, et al. Magnetic resonance imaging detects changes in structure and perfusion, and response to therapy in early cystic fibrosis lung disease. Am J Respir Crit Care Med. 2014;189:956–65.PubMedCrossRefGoogle Scholar
  5. 5.
    Ramsey KA, Ranganathan S, Park J, et al. Early respiratory infection is associated with reduced spirometry in children with cystic fibrosis. Am J Respir Crit Care Med. 2014;190:1111–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Jensen T, Pedersen SS, Garne S, et al. Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection. J Antimicrob Chemother. 1987;19:831–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999;340:23–30.PubMedCrossRefGoogle Scholar
  8. 8.
    Quittner AL, Buu A. Effects of tobramycin solution for inhalation on global ratings of quality of life in patients with cystic fibrosis and Pseudomonas aeruginosa infection. Pediatr Pulmonol. 2002;33:269–76.PubMedCrossRefGoogle Scholar
  9. 9.
    McCoy KS, Quittner AL, Oermann CM, et al. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med. 2008;178:921–8.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Retsch-Bogart GZ, Quittner AL, Gibson RL, et al. Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis. Chest. 2009;135:1223–32.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Konstan MW, Flume PA, Kappler M, et al. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: the EAGER trial. J Cyst Fibros. 2011;10:54–61.PubMedCrossRefGoogle Scholar
  12. 12.
    Schuster A, Haliburn C, Doring G, et al. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax. 2013;68:344–50.PubMedCrossRefGoogle Scholar
  13. 13.
    Conole D, Keating GM. Colistimethate sodium dry powder for inhalation: a review of its use in the treatment of chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis. Drugs. 2014;74:377–87.PubMedCrossRefGoogle Scholar
  14. 14.
    Elborn JS, Flume PA, Cohen F, et al. Safety and efficacy of prolonged levofloxacin inhalation solution (APT-1026) treatment for cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. J Cyst Fibros. 2016;15:634–40.PubMedCrossRefGoogle Scholar
  15. 15.
    Flume PA, VanDevanter DR, Morgan EE, et al. A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients. J Cyst Fibros. 2016;15:495–502.PubMedCrossRefGoogle Scholar
  16. 16.
    Lee TW, Brownlee KG, Denton M, et al. Reduction in prevalence of chronic Pseudomonas aeruginosa infection at a regional pediatric cystic fibrosis center. Pediatr Pulmonol. 2004;37:104–10.PubMedCrossRefGoogle Scholar
  17. 17.
    Hansen CR, Pressler T, Hoiby N. Early aggressive eradication therapy for intermittent Pseudomonas aeruginosa airway colonization in cystic fibrosis patients: 15 years experience. J Cyst Fibros. 2008;7:523–30.PubMedCrossRefGoogle Scholar
  18. 18.
    Crull MR, Ramos KJ, Caldwell E, et al. Change in Pseudomonas aeruginosa prevalence in cystic fibrosis adults over time. BMC Pulm Med. 2016;16:176.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Sudfeld CR, Dasenbrook EC, Merz WG, et al. Prevalence and risk factors for recovery of filamentous fungi in individuals with cystic fibrosis. J Cyst Fibros. 2010;9:110–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Nagano Y, Elborn JS, Millar BC, et al. Comparison of techniques to examine the diversity of fungi in adult patients with cystic fibrosis. Med Mycol. 2010;48(Suppl1):S166–76.CrossRefGoogle Scholar
  21. 21.
    Aaron SD, Vandemheen KL, Freitag A, et al. Treatment of Aspergillus fumigatus in patients with cystic fibrosis: a randomized, placebo-controlled pilot study. PLoS ONE. 2012;7:e36077.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Millar FA, Simmonds NJ, Hodson ME. Trends in pathogens colonising the respiratory tract of adult patients with cystic fibrosis, 1985–2005. J Cyst Fibros. 2009;8:386–91.PubMedCrossRefGoogle Scholar
  23. 23.
    Burns JL, Van Dalfsen JM, Shawar RM, et al. Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis. J Infect Dis. 1999;179:1190–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Bargon J, Dauletbaev N, Kohler B, et al. Prophylactic antibiotic therapy is associated with an increased prevalence of Aspergillus colonization in adult cystic fibrosis patients. Respir Med. 1999;93:835–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Hodson ME, Gallagher CG, Govan JR. A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J. 2002;20:658–64.PubMedCrossRefGoogle Scholar
  26. 26.
    de Vrankrijker AM, van der Ent CK, van Berkhout FT, et al. Aspergillus fumigatus colonization in cystic fibrosis: implications for lung function? Clin Microbiol Infect. 2011;17:1381–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Noni M, Katelari A, Kaditis A, et al. Candida albicans chronic colonisation in cystic fibrosis may be associated with inhaled antibiotics. Mycoses. 2015;58:416–21.PubMedCrossRefGoogle Scholar
  28. 28.
    Noni M, Katelari A, Dimopoulos G, et al. Inhaled corticosteroids and Aspergillus fumigatus isolation in cystic fibrosis. Med Mycol. 2014;52:715–22.PubMedCrossRefGoogle Scholar
  29. 29.
    Saunders RV, Modha DE, Claydon A, et al. Chronic Aspergillus fumigatus colonization of the pediatric cystic fibrosis airway is common and may be associated with a more rapid decline in lung function. Med Mycol. 2016;54:537–43.PubMedCrossRefGoogle Scholar
  30. 30.
    Bakare N, Rickerts V, Bargon J, et al. Prevalence of Aspergillus fumigatus and other fungal species in the sputum of adult patients with cystic fibrosis. Mycoses. 2003;46:19–23.PubMedCrossRefGoogle Scholar
  31. 31.
    Valenza G, Strasen J, Schafer F, et al. Evaluation of new colorimetric vitek 2 yeast identification card by use of different source media. J Clin Microbiol. 2008;46:3784–7.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Baumann K, Carnicer M, Dragosits M, et al. A multi-level study of recombinant Pichia pastoris in different oxygen conditions. BMC Syst Biol. 2010;4:141.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Paugam A, Baixench MT, Demazes-Dufeu N, et al. Characteristics and consequences of airway colonization by filamentous fungi in 201 adult patients with cystic fibrosis in France. Med Mycol. 2010;48(Suppl 1):S32–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Coughlan CA, Chotirmall SH, Renwick J, et al. The effect of Aspergillus fumigatus infection on vitamin D receptor expression in cystic fibrosis. Am J Respir Crit Care Med. 2012;186:999–1007.PubMedCrossRefGoogle Scholar
  35. 35.
    Lott TJ, Kuykendall RJ, Reiss E. Nucleotide sequence analysis of the 5.8S rDNA and adjacent ITS2 region of Candida albicans and related species. Yeast. 1993;9:1199–206.PubMedCrossRefGoogle Scholar
  36. 36.
    Bouchara JP, 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;47:142–52.PubMedCrossRefGoogle Scholar
  37. 37.
    Eickmeier O, Rieber N, Eckrich J, et al. Immune response, diagnosis and treatment of allergic bronchopulmonary aspergillosis in cystic fibrosis lung disease. Curr Pharm Des. 2013;19:3669–78.PubMedCrossRefGoogle Scholar
  38. 38.
    Tang AC, Turvey SE, Alves MP, et al. Current concepts: host–pathogen interactions in cystic fibrosis airways disease. Eur Respir Rev. 2014;23:320–32.PubMedCrossRefGoogle Scholar
  39. 39.
    Alekseeva L, Huet D, Femenia F, et al. Inducible expression of beta defensins by human respiratory epithelial cells exposed to Aspergillus fumigatus organisms. BMC Microbiol. 2009;9:33.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Hartl D. Immunological mechanisms behind the cystic fibrosis-ABPA link. Med Mycol. 2009;47(Suppl 1):S183–91.PubMedCrossRefGoogle Scholar
  41. 41.
    Balloy V, Chignard M. The innate immune response to Aspergillus fumigatus. Microbes Infect. 2009;11:919–27.PubMedCrossRefGoogle Scholar
  42. 42.
    Morton CO, Bouzani M, Loeffler J, et al. Direct interaction studies between Aspergillus fumigatus and human immune cells; what have we learned about pathogenicity and host immunity? Front Microbiol. 2012;3:413.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Chotirmall SH, Al-Alawi M, Mirkovic B, et al. Aspergillus-associated airway disease, inflammation, and the innate immune response. Biomed Res Int. 2013;2013:723129.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Chmiel JF, Davis PB. State of the art: why do the lungs of patients with cystic fibrosis become infected and why can’t they clear the infection? Respir Res. 2003;4:8.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Painter RG, Valentine VG, Lanson NA Jr, et al. CFTR Expression in human neutrophils and the phagolysosomal chlorination defect in cystic fibrosis. Biochemistry. 2006;45:10260–9.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Bonfield TL, Hodges CA, Cotton CU, et al. Absence of the cystic fibrosis transmembrane regulator (Cftr) from myeloid-derived cells slows resolution of inflammation and infection. J Leukoc Biol. 2012;92:1111–22.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Ng HP, Zhou Y, Song K, et al. Neutrophil-mediated phagocytic host defense defect in myeloid Cftr-inactivated mice. PLoS ONE. 2014;9:e106813.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Hartl D, Latzin P, Hordijk P, et al. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat Med. 2007;13:1423–30.PubMedCrossRefGoogle Scholar
  49. 49.
    Iannitti RG, Carvalho A, Cunha C, et al. Th17/Treg imbalance in murine cystic fibrosis is linked to indoleamine 2,3-dioxygenase deficiency but corrected by kynurenines. Am J Respir Crit Care Med. 2013;187:609–20.PubMedCrossRefGoogle Scholar
  50. 50.
    Hamon Y, Jaillon S, Person C, et al. Proteolytic cleavage of the long pentraxin PTX3 in the airways of cystic fibrosis patients. Innate Immun. 2013;19:611–22.PubMedCrossRefGoogle Scholar
  51. 51.
    Ralhan A, Laval J, Lelis F, et al. Current concepts and controversies in innate immunity of cystic fibrosis lung disease. J Innate Immun. 2016;8:531–40.PubMedCrossRefGoogle Scholar
  52. 52.
    Brouard J, Knauer N, Boelle PY, et al. Influence of interleukin-10 on Aspergillus fumigatus infection in patients with cystic fibrosis. J Infect Dis. 2005;191:1988–91.PubMedCrossRefGoogle Scholar
  53. 53.
    Iannitti RG, Napolioni V, Oikonomou V, et al. IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis. Nat Commun. 2016;7:10791.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Hector A, Chotirmall SH, Lavelle GM, et al. Chitinase activation in patients with fungus-associated cystic fibrosis lung disease. J Allergy Clin Immunol. 2016;138(1183–9):e4.Google Scholar
  55. 55.
    Noni M, Katelari A, Dimopoulos G, et al. Aspergillus fumigatus chronic colonization and lung function decline in cystic fibrosis may have a two-way relationship. Eur J Clin Microbiol Infect Dis. 2015;34:2235–41.PubMedCrossRefGoogle Scholar
  56. 56.
    Milla CE, Wielinski CL, Regelmann WE. Clinical significance of the recovery of Aspergillus species from the respiratory secretions of cystic fibrosis patients. Pediatr Pulmonol. 1996;21:6–10.PubMedCrossRefGoogle Scholar
  57. 57.
    Valenza G, Tappe D, Turnwald D, et al. Prevalence and antimicrobial susceptibility of microorganisms isolated from sputa of patients with cystic fibrosis. J Cyst Fibros. 2008;7:123–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Borman AM, Palmer MD, Delhaes L, et al. Lack of standardization in the procedures for mycological examination of sputum samples from CF patients: a possible cause for variations in the prevalence of filamentous fungi. Med Mycol. 2010;48(Suppl 1):S88–97.PubMedCrossRefGoogle Scholar
  59. 59.
    Amin R, Dupuis A, Aaron SD, et al. The effect of chronic infection with Aspergillus fumigatus on lung function and hospitalization in patients with cystic fibrosis. Chest. 2010;137:171–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Baxter CG, Moore CB, Jones AM, et al. IgE-mediated immune responses and airway detection of Aspergillus and Candida in adult cystic fibrosis. Chest. 2013;143:1351–7.PubMedCrossRefGoogle Scholar
  61. 61.
    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;54:781–6.PubMedCrossRefGoogle Scholar
  62. 62.
    Chotirmall SH, O’Donoghue E, Bennett K, et al. Sputum Candida albicans presages FEV(1) decline and hospital-treated exacerbations in cystic fibrosis. Chest. 2010;138:1186–95.PubMedCrossRefGoogle Scholar
  63. 63.
    Muthig M, Hebestreit A, Ziegler U, et al. Persistence of Candida species in the respiratory tract of cystic fibrosis patients. Med Mycol. 2010;48:56–63.PubMedCrossRefGoogle Scholar
  64. 64.
    Gileles-Hillel A, Shoseyov D, Polacheck I, et al. Association of chronic Candida albicans respiratory infection with a more severe lung disease in patients with cystic fibrosis. Pediatr Pulmonol. 2015;50:1082–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Cimon B, Carrère J, Vinatier JF, et al. Clinical significance of Scedosporium apiospermum in patients with cystic fibrosis. Eur J Clin Microbiol Infect Dis. 2000;19:53–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Williamson EC, Speers D, Arthur IH, et al. Molecular epidemiology of Scedosporium apiospermum infection determined by PCR amplification of ribosomal intergenic spacer sequences in patients with chronic lung disease. J Clin Microbiol. 2001;39:47–50.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Blyth CC, Middleton PG, Harun A, et al. Clinical associations and prevalence of Scedosporium spp. in Australian cystic fibrosis patients: identification of novel risk factors? Med Mycol. 2010;48(Suppl 1):S37–44.PubMedCrossRefGoogle Scholar
  68. 68.
    Sedlacek L, Graf B, Schwarz C, 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;14:237–41.PubMedCrossRefGoogle Scholar
  69. 69.
    Horré R, Schaal KP, Siekmeier R, et al. Isolation of fungi, especially Exophiala dermatitidis, in patients suffering from cystic fibrosis. A prospective study. Respiration. 2004;71:360–6.PubMedCrossRefGoogle Scholar
  70. 70.
    Kondori N, Lindblad A, Welinder-Olsson C, et al. Development of IgG antibodies to Exophiala dermatitidis is associated with inflammatory responses in patients with cystic fibrosis. J Cyst Fibros. 2014;13:391–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Kirchhoff L, Olsowski M, Zilmans K, et al. Biofilm formation of the black yeast-like fungus Exophiala dermatitidis and its susceptibility to antiinfective agents. Sci Rep. 2017;7:42886.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Sing A, Geiger AM, Hogardt M, et al. Pneumocystis carinii carriage among cystic fibrosis patients, as detected by nested PCR. J Clin Microbiol. 2001;39:2717–8.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Respaldiza N, Montes-Cano MA, Dapena FJ, et al. Prevalence of colonisation and genotypic characterisation of Pneumocystis jirovecii among cystic fibrosis patients in Spain. Clin Microbiol Infect. 2005;11:1012–5.PubMedCrossRefGoogle Scholar
  74. 74.
    Pederiva MA, Wissmann G, Friaza V, et al. High prevalence of Pneumocystis jirovecii colonization in Brazilian cystic fibrosis patients. Med Mycol. 2012;50:556–60.PubMedCrossRefGoogle Scholar
  75. 75.
    Hernandez-Hernandez F, Fréalle E, Caneiro P, et al. Prospective multicenter study of Pneumocystis jirovecii colonization among cystic fibrosis patients in France. J Clin Microbiol. 2012;50:4107–10.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Delhaes L, Monchy S, Fréalle E, et al. The airway microbiota in cystic fibrosis: a complex fungal and bacterial community-implications for therapeutic management. PLoS ONE. 2012;7:e36313.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Willger SD, Grim SL, Dolben EL, et al. Characterization and quantification of the fungal microbiome in serial samples from individuals with cystic fibrosis. Microbiome. 2014;2:40.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Kramer R, Sauer-Heilborn A, Welte T, et al. 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;53:2900–7.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Losada PM, Chouvarine P, Dorda M, et al. The cystic fibrosis lower airways microbial metagenome. ERJ Open Res. 2016;2:00096-2015.CrossRefGoogle Scholar
  80. 80.
    Nguyen LD, Viscogliosi E, Delhaes L. The lung mycobiome: an emerging field of the human respiratory microbiome. Front Microbiol. 2015;6:89.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Latgé JP. Aspergillus fumigatus and aspergillosis. Clin Microbiol Rev. 1999;12:310–50.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Chaudhary N, Datta K, Askin FB, et al. Cystic fibrosis transmembrane conductance regulator regulates epithelial cell response to Aspergillus and resultant pulmonary inflammation. Am J Respir Crit Care Med. 2012;185:301–10.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Navarro J, Rainisio M, Harms HK, et al. Factors associated with poor pulmonary function: cross-sectional analysis of data from the ERCF. European Epidemiologic Registry of Cystic Fibrosis. Eur Respir J. 2001;18:298–305.PubMedCrossRefGoogle Scholar
  84. 84.
    de Boer K, Vandemheen KL, Tullis E, et al. Exacerbation frequency and clinical outcomes in adult patients with cystic fibrosis. Thorax. 2011;66:680–5.PubMedCrossRefGoogle Scholar
  85. 85.
    Hector A, Kirn T, Ralhan A, et al. Microbial colonization and lung function in adolescents with cystic fibrosis. J Cyst Fibros. 2016;15:340–9.PubMedCrossRefGoogle Scholar
  86. 86.
    McMahon MA, Chotirmall SH, McCullagh B, et al. Radiological abnormalities associated with Aspergillus colonization in a cystic fibrosis population. Eur J Radiol. 2012;81:e197–202.PubMedCrossRefGoogle Scholar
  87. 87.
    Gangell C, Gard S, Douglas T, et al. Inflammatory responses to individual microorganisms in the lungs of children with cystic fibrosis. Clin Infect Dis. 2011;53:425–32.PubMedCrossRefGoogle Scholar
  88. 88.
    Cimon B, Zouhair R, Symoens F, et al. Aspergillus terreus in a cystic fibrosis clinic: environmental distribution and patient colonization pattern. J Hosp Infect. 2003;53:81–2.PubMedCrossRefGoogle Scholar
  89. 89.
    Rougeron A, Giraud S, Razafimandimby B, et al. Different colonization patterns of Aspergillus terreus in patients with cystic fibrosis. Clin Microbiol Infect. 2014;20:327–33.PubMedCrossRefGoogle Scholar
  90. 90.
    Gautier M, Normand AC, L’Ollivier C, et al. Aspergillus tubingensis: a major filamentous fungus found in the airways of patients with lung disease. Med Mycol. 2016;54:459–70.PubMedCrossRefGoogle Scholar
  91. 91.
    Shoseyov D, Brownlee KG, Conway SP, et al. Aspergillus bronchitis in cystic fibrosis. Chest. 2006;130:222–6.PubMedCrossRefGoogle Scholar
  92. 92.
    Baxter CG, Dunn G, Jones AM, et al. Novel immunologic classification of aspergillosis in adult cystic fibrosis. J Allergy Clin Immunol. 2013;132(560–6):e10.Google Scholar
  93. 93.
    Maturu VN, Agarwal R. Prevalence of Aspergillus sensitization and allergic bronchopulmonary aspergillosis in cystic fibrosis: systematic review and meta-analysis. Clin Exp Allergy. 2015;45:1765–78.PubMedCrossRefGoogle Scholar
  94. 94.
    Baxter CG, Rautemaa R, Jones AM, et al. Intravenous antibiotics reduce the presence of Aspergillus in adult cystic fibrosis sputum. Thorax. 2013;68:652–7.PubMedCrossRefGoogle Scholar
  95. 95.
    Nicolai T, Arleth S, Spaeth A, et al. Correlation of IgE antibody titer to Aspergillus fumigatus with decreased lung function in cystic fibrosis. Pediatr Pulmonol. 1990;8:12–5.PubMedCrossRefGoogle Scholar
  96. 96.
    Wojnarowski C, Eichler I, Gartner C, et al. Sensitization to Aspergillus fumigatus and lung function in children with cystic fibrosis. Am J Respir Crit Care Med. 1997;155:1902–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Kraemer R, Delosea N, Ballinari P, et al. Effect of allergic bronchopulmonary aspergillosis on lung function in children with cystic fibrosis. Am J Respir Crit Care Med. 2006;174:1211–20.PubMedCrossRefGoogle Scholar
  98. 98.
    Kanthan SK, Bush A, Kemp M, et al. Factors effecting impact of Aspergillus fumigatus sensitization in cystic fibrosis. Pediatr Pulmonol. 2007;42:785–93.PubMedCrossRefGoogle Scholar
  99. 99.
    Knutsen AP, Bellone C, Kauffman H. Immunopathogenesis of allergic bronchopulmonary aspergillosis in cystic fibrosis. J Cyst Fibros. 2002;1:76–89.PubMedCrossRefGoogle Scholar
  100. 100.
    Hartl D, Latzin P, Zissel G, et al. Chemokines indicate allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. Am J Respir Crit Care Med. 2006;173:1370–6.PubMedCrossRefGoogle Scholar
  101. 101.
    Felton IC, Simmonds NJ. Aspergillus and cystic fibrosis: old disease—new classifications. Curr Opin Pulm Med. 2014;20:632–8.PubMedCrossRefGoogle Scholar
  102. 102.
    Cockrill BA, Hales CA. Allergic bronchopulmonary aspergillosis. Ann Rev Med. 1999;50:303–16.PubMedCrossRefGoogle Scholar
  103. 103.
    Greenberger PA. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 2002;110:685–92.PubMedCrossRefGoogle Scholar
  104. 104.
    Cortese G, Malfitana V, Placido R, et al. Role of chest radiography in the diagnosis of allergic bronchopulmonary aspergillosis in adult patients with cystic fibrosis. Radiol Med. 2007;112:626–36.PubMedCrossRefGoogle Scholar
  105. 105.
    Chotirmall SH, Branagan P, Gunaratnam C, et al. Aspergillus/allergic bronchopulmonary aspergillosis in an Irish cystic fibrosis population: a diagnostically challenging entity. Respir Care. 2008;53:1035–41.PubMedGoogle Scholar
  106. 106.
    Cohen-Cymberknoh M, Blau H, Shoseyov D, et al. Intravenous monthly pulse methylprednisolone treatment for ABPA in patients with cystic fibrosis. J Cyst Fibros. 2009;8:253–7.PubMedCrossRefGoogle Scholar
  107. 107.
    Sequeiros IM, Jarad N. Factors associated with a shorter time until the next pulmonary exacerbation in adult patients with cystic fibrosis. Chron Respir Dis. 2012;9:9–16.PubMedCrossRefGoogle Scholar
  108. 108.
    Thronicke A, Heger N, Antweiler E, et al. Allergic bronchopulmonary aspergillosis is associated with pet ownership in cystic fibrosis. Pediatr Allergy Immunol. 2016;27:597–603.PubMedCrossRefGoogle Scholar
  109. 109.
    Barton RC, Hobson RP, Denton M, et al. Serologic diagnosis of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis through the detection of immunoglobulin G to Aspergillus fumigatus. Diagn Microbiol Infect Dis. 2008;62:287–91.PubMedCrossRefGoogle Scholar
  110. 110.
    Latzin P, Hartl D, Regamey N, et al. Comparison of serum markers for allergic bronchopulmonary aspergillosis in cystic fibrosis. Eur Respir J. 2008;31:36–42.PubMedCrossRefGoogle Scholar
  111. 111.
    Gernez Y, Dunn CE, Everson C, 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;11:502–10.PubMedCrossRefGoogle Scholar
  112. 112.
    Mirkovic B, Lavelle GM, Azim AA, et al. The basophil surface marker CD203c identifies Aspergillus species sensitization in patients with cystic fibrosis. J Allergy Clin Immunol. 2016;137(436–43):e9.Google Scholar
  113. 113.
    Katelari A, Tzanoudaki M, Noni M, et al. The role of basophil activation test in allergic bronchopulmonary aspergillosis and Aspergillus fumigatus sensitization in cystic fibrosis patients. J Cyst Fibros. 2016;15:587–96.PubMedCrossRefGoogle Scholar
  114. 114.
    Stevens DA, Moss RB, Kurup VP, 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.PubMedCrossRefGoogle Scholar
  115. 115.
    Accurso FJ. Update in cystic fibrosis 2006. Am J Respir Crit Care Med. 2007;175:754–7.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Guarro J, Kantarcioglu AS, Horré R, et al. Scedosporium apiospermum: changing clinical spectrum of a therapy-refractory opportunist. Med Mycol. 2006;44:295–327.PubMedCrossRefGoogle Scholar
  117. 117.
    Borghi E, Iatta R, Manca A, et al. Chronic airway colonization by Scedosporium apiospermum with a fatal outcome in a patient with cystic fibrosis. Med Mycol. 2010;48(Suppl 1):S108–13.PubMedCrossRefGoogle Scholar
  118. 118.
    Russell GK, Gadhok R, Simmonds NJ. The destructive combination of Scedosporium apiospermum lung disease and exuberant inflammation in cystic fibrosis. Paediatr Respir Rev. 2013;14(Suppl 1):22–5.PubMedCrossRefGoogle Scholar
  119. 119.
    Padoan R, Poli P, Colombrita D, et al. Acute Scedosporium apiospermum endobronchial infection in cystic fibrosis. Pediatr Infect Dis J. 2016;35:701–2.PubMedCrossRefGoogle Scholar
  120. 120.
    Schwarz C, Brandt C, Antweiler E, 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:e0171485.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Haase G, Skopnik H, Kusenbach G. Exophiala dermatitidis infection in cystic fibrosis. Lancet. 1990;336:188–9.PubMedCrossRefGoogle Scholar
  122. 122.
    Kusenbach G, Skopnik H, Haase G, et al. Exophiala dermatitidis pneumonia in cystic fibrosis. Eur J Pediatr. 1992;151:344–6.PubMedCrossRefGoogle Scholar
  123. 123.
    Kondori N, Gilljam M, Lindblad A, et al. High rate of Exophiala dermatitidis recovery in the airways of patients with cystic fibrosis is associated with pancreatic insufficiency. J Clin Microbiol. 2011;49:1004–9.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Pihet M, Carrère J, Cimon B, et al. Occurrence and relevance of filamentous fungi in respiratory secretions of patients with cystic fibrosis-a review. Med Mycol. 2009;47:387–97.PubMedCrossRefGoogle Scholar
  125. 125.
    Marguet C, Favennec L, Matray O, et al. Clinical and microbiological efficacy of micafungin on Geosmithia argillacea infection in a cystic fibrosis patient. Med Mycol Case Rep. 2012;1:79–81.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Hong G, White M, Lechtzin N, et al. Fatal disseminated Rasamsonia infection in cystic fibrosis post-lung transplantation. J Cyst Fibros. 2017;16:e3–7.PubMedCrossRefGoogle Scholar
  127. 127.
    Peltroche-Llacsahuanga H, Dohmen H, Haase G. Recovery of Candida dubliniensis from sputum of cystic fibrosis patients. Mycoses. 2002;45:15–8.PubMedCrossRefGoogle Scholar
  128. 128.
    Wahab AA, Taj-Aldeen SJ, Kolecka A, et al. 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.PubMedCrossRefGoogle Scholar
  129. 129.
    Sokulska M, Kicia M, Wesolowska M, et al. Pneumocystis jirovecii-from a commensal to pathogen: clinical and diagnostic review. Parasitol Res. 2015;114:3577–85.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Goto N, Futamura K, Okada M, et al. Management of Pneumocystis jirovecii pneumonia in kidney transplantation to prevent further outbreak. Clin Med Insights Circ Respir Pulm Med. 2015;9:81–90.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Kaur R, Katariya P, Dhakad MS, et al. An unusual case of cystic fibrosis associated Pneumocystis jirovecii pneumonia in an infant. Case Rep Infect Dis. 2016;2016:9206707.PubMedPubMedCentralGoogle Scholar
  132. 132.
    Green HD, Bright-Thomas RJ, Mutton KJ, et al. Increased prevalence of Pneumocystis jirovecii colonisation in acute pulmonary exacerbations of cystic fibrosis. J Infect. 2016;73:1–7.PubMedCrossRefGoogle Scholar
  133. 133.
    Morris A, Sciurba FC, Lebedeva IP, et al. Association of chronic obstructive pulmonary disease severity and Pneumocystis colonization. Am J Respir Crit Care Med. 2004;170:408–13.PubMedCrossRefGoogle Scholar
  134. 134.
    Calderon EJ, Rivero L, Respaldiza N, et al. Systemic inflammation in patients with chronic obstructive pulmonary disease who are colonized with Pneumocystis jirovecii. Clin Infect Dis. 2007;45:e17–9.PubMedCrossRefGoogle Scholar
  135. 135.
    Montes-Cano MA, de la Horra C, Dapena FJ, et al. Dynamic colonisation by different Pneumocystis jirovecii genotypes in cystic fibrosis patients. Clin Infect Dis. 2007;13:1008–11.CrossRefGoogle Scholar
  136. 136.
    van der Ent CK, Hoekstra H, Rijkers GT. Successful treatment of allergic bronchopulmonary aspergillosis with recombinant anti-IgE antibody. Thorax. 2007;62:276–7.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Zirbes JM, Milla CE. Steroid-sparing effect of omalizumab for allergic bronchopulmonary aspergillosis and cystic fibrosis. Pediatr Pulmonol. 2008;43:607–10.PubMedCrossRefGoogle Scholar
  138. 138.
    Kanu A, Patel K. Treatment of allergic bronchopulmonary aspergillosis (ABPA) in CF with anti-IgE antibody (omalizumab). Pediatr Pulmonol. 2008;43:1249–51.PubMedCrossRefGoogle Scholar
  139. 139.
    Lebecque P, Leonard A, Argaz M, et al. Omalizumab for exacerbations of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. BMJ Case Rep. 2009. doi: 10.1136/bcr07.2008.0379.
  140. 140.
    Brinkmann F, Schwerk N, Hansen G, et al. Steroid dependency despite omalizumab treatment of ABPA in cystic fibrosis. Allergy. 2010;65:134–5.PubMedCrossRefGoogle Scholar
  141. 141.
    Elmallah MK, Hendeles L, Hamilton RG, et al. Management of patients with cystic fibrosis and allergic bronchopulmonary aspergillosis using anti-immunoglobulin E therapy (omalizumab). J Pediatr Pharmacol Ther. 2012;17:88–92.PubMedPubMedCentralGoogle Scholar
  142. 142.
    Nathan N, Girodon E, Clement A, et al. A rare CFTR intronic mutation related to a mild CF disease in a 12-year-old girl. BMJ Case Rep. 2012. doi: 10.1136/bcr-2012-006918.PubMedPubMedCentralGoogle Scholar
  143. 143.
    Wong R, Wong M, Robinson PD, et al. Omalizumab in the management of steroid dependent allergic bronchopulmonary aspergillosis (ABPA) complicating cystic fibrosis. Paediatr Respir Rev. 2013;14:22–4.PubMedCrossRefGoogle Scholar
  144. 144.
    Zicari AM, Celani C, De Castro G, et al. Anti IgE antibody as treatment of allergic bronchopulmonary aspergillosis in a patient with cystic fibrosis. Eur Rev Med Pharmacol Sci. 2014;18:1839–41.PubMedGoogle Scholar
  145. 145.
    Lehmann S, Pfannenstiel C, Friedrichs F, et al. Omalizumab: a new treatment option for allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. Ther Adv Respir Dis. 2014;8:141–9.PubMedCrossRefGoogle Scholar
  146. 146.
    Emiralioglu N, Dogru D, Tugcu GD, et al. Omalizumab treatment for allergic bronchopulmonary aspergillosis in cystic fibrosis. Ann Pharmacother. 2016;50:188–93.PubMedCrossRefGoogle Scholar
  147. 147.
    Nove-Josserand R, Grard S, Auzou L, et al. Case series of omalizumab for allergic bronchopulmonary aspergillosis in cystic fibrosis patients. Pediatr Pulmonol. 2017;52:190–7.PubMedCrossRefGoogle Scholar
  148. 148.
    Jat KR, Walia DK, Khairwa A. Anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Cochrane Database Syst Rev. 2015;(11):CD010288.Google Scholar
  149. 149.
    Nguyen NL, Pilewski JM, Celedon JC, et al. Vitamin D supplementation decreases Aspergillus fumigatus specific Th2 responses in CF patients with Aspergillus sensitization: a phase one open-label study. Asthma Res Pract. 2015;1:3.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Hilliard T, Edwards S, Buchdahl R, et al. Voriconazole therapy in children with cystic fibrosis. J Cyst Fibros. 2005;4:215–20.PubMedCrossRefGoogle Scholar
  151. 151.
    Skov M, Hoiby N, Koch C. Itraconazole treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. Allergy. 2002;57:723–8.PubMedCrossRefGoogle Scholar
  152. 152.
    Proesmans M, Vermeulen F, Vreys M, et al. Use of nebulized amphotericin B in the treatment of allergic bronchopulmonary aspergillosis in cystic fibrosis. Int J Pediatr. 2010;2010:376287.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Hayes D Jr, Murphy BS, Lynch JE, et al. Aerosolized amphotericin for the treatment of allergic bronchopulmonary aspergillosis. Pediatr Pulmonol. 2010;45:1145–8.PubMedCrossRefGoogle Scholar
  154. 154.
    Holle J, Leichsenring M, Meissner PE. Nebulized voriconazole in infections with Scedosporium apiospermum—case report and review of the literature. J Cyst Fibros. 2014;13:400–2.PubMedCrossRefGoogle Scholar
  155. 155.
    Elphick HE, Southern KW. Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Cochrane Database Syst Rev. 2016;11:CD002204.PubMedGoogle Scholar
  156. 156.
    Bader O, Weig M, Reichard U, et al. cyp51A-based mechanisms of Aspergillus fumigatus azole drug resistance present in clinical samples from Germany. Antimicrob Agents Chemother. 2013;57:3513–7.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Morio F, Aubin GG, Danner-Boucher I, et al. High prevalence of triazole resistance in Aspergillus fumigatus, especially mediated by TR/L98H, in a French cohort of patients with cystic fibrosis. J Antimicrob Chemother. 2012;67:1870–3.PubMedCrossRefGoogle Scholar
  158. 158.
    Mortensen KL, Jensen RH, Johansen HK, et al. Aspergillus species and other molds in respiratory samples from patients with cystic fibrosis: a laboratory-based study with focus on Aspergillus fumigatus azole resistance. J Clin Microbiol. 2011;49:2243–51.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Burgel PR, Paugam A, Hubert D, et al. Aspergillus fumigatus in the cystic fibrosis lung: pros and cons of azole therapy. Infect Drug Resist. 2016;9:229–38.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Surette MG. The cystic fibrosis lung microbiome. Ann Am Thorac Soc. 2014;11:S61–5.PubMedCrossRefGoogle Scholar
  161. 161.
    Coburn B, Wang PW, Diaz Caballero J, et al. Lung microbiota across age and disease stage in cystic fibrosis. Sci Rep. 2015;5:10241.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Caverly LJ, Zhao J, LiPuma JJ. Cystic fibrosis lung microbiome: opportunities to reconsider management of airway infection. Pediatr Pulmonol. 2015;50:S31–8.PubMedCrossRefGoogle Scholar
  163. 163.
    Hogan DA, Vik A, Kolter R. A Pseudomonas aeruginosa quorum-sensing molecule influences Candida albicans morphology. Mol Microbiol. 2004;54:1212–23.PubMedCrossRefGoogle Scholar
  164. 164.
    Williams P, Cámara M. Quorum sensing and environmental adaptation in Pseudomonas aeruginosa: a tale of regulatory networks and multifunctional signal molecules. Curr Opin Microbiol. 2009;12:182–91.PubMedCrossRefGoogle Scholar
  165. 165.
    Hogan DA, Kolter R. PseudomonasCandida interactions: an ecological role for virulence factors. Science. 2002;296:2229–32.PubMedCrossRefGoogle Scholar
  166. 166.
    Chen AI, Dolben EF, Okegbe C, et al. Candida albicans ethanol stimulates Pseudomonas aeruginosa WspR-controlled biofilm formation as part of a cyclic relationship involving phenazines. PLoS Pathog. 2014;10:e1004480.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    McAlester G, O’Gara F, Morrissey JP. Signal-mediated interactions between Pseudomonas aeruginosa and Candida albicans. J Med Microbiol. 2008;57:563–9.PubMedCrossRefGoogle Scholar
  168. 168.
    Kim SH, Clark ST, Surendra A, 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:e100530.Google Scholar
  169. 169.
    Shirtliff ME, Peters BM, Jabra-Rizk MA. Cross-kingdom interactions: Candida albicans and bacteria. FEMS Microbiol Lett. 2009;299:1–8.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Carlson EC. Synergism of Candida albicans and delta toxin producing Staphylococcus aureus on mouse mortality and morbidity: protection by indomethacin. Zentralbl Bakteriol Mikrobiol Hyg A. 1988;269:377–86.PubMedGoogle Scholar
  171. 171.
    Jabra-Rizk MA, Meiller TF, James CE, et al. Effect of farnesol on Staphylococcus aureus biofilm formation and antimicrobial susceptibility. Antimicrob Agents Chemother. 2006;50:1463–9.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Kuroda M, Nagasaki S, Ito R, et al. Sesquiterpene farnesol as a competitive inhibitor of lipase activity of Staphylococcus aureus. FEMS Microbiol Lett. 2007;273:28–34.PubMedCrossRefGoogle Scholar
  173. 173.
    Briard B, Heddergott C, Latgé J-P. Volatile compounds emitted by Pseudomonas aeruginosa stimulate growth of the fungal pathogen Aspergillus fumigatus. mBio. 2016;7:e00219-16.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Mowat E, Rajendran R, Williams C, et al. Pseudomonas aeruginosa and their small diffusible extracellular molecules inhibit Aspergillus fumigatus biofilm formation. FEMS Microbiol Lett. 2010;313:96–102.PubMedCrossRefGoogle Scholar
  175. 175.
    Briard B, Bomme P, Lechner BE, et al. Pseudomonas aeruginosa manipulates redox and iron homeostasis of its microbiota partner Aspergillus fumigatus via phenazines. Sci Rep. 2015;5:8220.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Shirazi F, Ferreira JAG, Stevens DA, et al. Biofilm filtrates of Pseudomonas aeruginosa strains isolated from cystic fibrosis patients inhibit preformed Aspergillus fumigatus biofilms via apoptosis. PLoS ONE. 2016;11:e0150155.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Moree WJ, Phelan VV, Wu C-H, et al. Interkingdom metabolic transformations captured by microbial imaging mass spectrometry. Proc Natl Acad Sci USA. 2012;109:13811–6.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Penner JC, Ferreira JAG, Secor PR, et al. Pf4 bacteriophage produced by Pseudomonas aeruginosa inhibits Aspergillus fumigatus metabolism via iron sequestration. Microbiology. 2016;162:1583–94.PubMedCrossRefGoogle Scholar
  179. 179.
    Casaulta C, Schöni MH, Weichel M, et al. IL-10 controls Aspergillus fumigatus- and Pseudomonas aeruginosa-specific T-cell response in cystic fibrosis. Pediatr Res. 2003;53:313–9.PubMedGoogle Scholar
  180. 180.
    Kaur J, Pethani BP, Kumar S, et al. Pseudomonas aeruginosa inhibits the growth of Scedosporium aurantiacum, an opportunistic fungal pathogen isolated from the lungs of cystic fibrosis patients. Front Microbiol. 2015;6:866.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Erwig LP, Gow NAR. Interactions of fungal pathogens with phagocytes. Nat Rev Microbiol. 2016;14:163–76.PubMedCrossRefGoogle Scholar
  182. 182.
    Hardison SE, Brown GD. C-type lectin receptors orchestrate antifungal immunity. Nat Immunol. 2012;13:817–22.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Netea MG, Brown GD, Kullberg BJ, et al. An integrated model of the recognition of Candida albicans by the innate immune system. Nat Rev Microbiol. 2008;6:67–78.PubMedCrossRefGoogle Scholar
  184. 184.
    Romani L. Immunity to fungal infections. Nat Rev Immunol. 2011;11:275–88.PubMedCrossRefGoogle Scholar
  185. 185.
    Greene CM, Carroll TP, Smith SGJ, et al. TLR-induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells. J Immunol. 2005;174:1638–46.PubMedCrossRefGoogle Scholar
  186. 186.
    Muir A, Soong G, Sokol S, et al. Toll-like receptors in normal and cystic fibrosis airway epithelial cells. Am J Respir Cell Mol. 2004;30:777–83.CrossRefGoogle Scholar
  187. 187.
    Netea MG, Van De Veerdonk F, Verschueren I, et al. Role of TLR1 and TLR6 in the host defense against disseminated candidiasis. FEMS Immunol Med Microbiol. 2008;52:118–23.PubMedCrossRefGoogle Scholar
  188. 188.
    Nahum A, Dadi H, Bates A, et al. The biological significance of TLR3 variant, L412F, in conferring susceptibility to cutaneous candidiasis, CMV and autoimmunity. Autoimmun Rev. 2012;11:341–7.PubMedCrossRefGoogle Scholar
  189. 189.
    Melvin T-AN, Lane AP, Nguyen M-T, et al. Sinonasal epithelial cell expression of Toll-like receptor 9 is elevated in cystic fibrosis-associated chronic rhinosinusitis. Am J Rhinol Allergy. 2013;27:30–3.PubMedCrossRefGoogle Scholar
  190. 190.
    Wagener J, Malireddi RKS, Lenardon MD, et al. Fungal chitin dampens inflammation through IL-10 induction mediated by NOD2 and TLR9 activation. PLoS Pathog. 2014;10:e1004050.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Lowman DW, Greene RR, Bearden DW, et al. Novel structural features in Candida albicans hyphal glucan provide a basis for differential innate immune recognition of hyphae versus yeast. J Biol Chem. 2014;289:3432–43.PubMedCrossRefGoogle Scholar
  192. 192.
    Davis SE, Hopke A, Minkin SC, et al. Masking of (1–3)-glucan in the cell wall of Candida albicans from detection by innate immune cells depends on phosphatidylserine. Infect Immun. 2014;82:4405–13.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Kennedy AD, Willment JA, Dorward DW, et al. Dectin-1 promotes fungicidal activity of human neutrophils. Eur J Immunol. 2007;37:467–78.PubMedCrossRefGoogle Scholar
  194. 194.
    Marakalala MJ, Vautier S, Potrykus J, et al. Differential adaptation of Candida albicans in vivo modulates immune recognition by dectin-1. PLoS Pathog. 2013;9:15.CrossRefGoogle Scholar
  195. 195.
    Taylor PR, Tsoni SV, Willment JA, et al. Dectin-1 is required for β-glucan recognition and control of fungal infection. Nat Immunol. 2007;8:31–8.PubMedCrossRefGoogle Scholar
  196. 196.
    Saijo S, Fujikado N, Furuta T, et al. Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nat Immunol. 2007;8:39–46.PubMedCrossRefGoogle Scholar
  197. 197.
    Ferwerda B, Ferwerda G, Plantinga TS, et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med. 2009;361:1760–7.PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Saijo S, Ikeda S, Yamabe K, et al. Dectin-2 recognition of α-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. Immunity. 2010;32:681–91.PubMedCrossRefGoogle Scholar
  199. 199.
    Chai LYA, van de Veerdonk F, Marijnissen RJ, et al. Anti-Aspergillus human host defence relies on type 1 T helper (Th1), rather than type 17 T helper (Th17), cellular immunity. Immunology. 2010;130:46–54.PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Wells CA, Salvage-Jones JA, Li X, et al. The macrophage-inducible C-type lectin, mincle, is an essential component of the innate immune response to Candida albicans. J Immunol. 2008;180:7404–13.PubMedCrossRefGoogle Scholar
  201. 201.
    Chai LYA, Kullberg BJ, Vonk AG, et al. Modulation of Toll-like receptor 2 (TLR2) and TLR4 responses by Aspergillus fumigatus. Infect Immun. 2009;77:2184–92.PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Meier A, Kirschning CJ, Nikolaus T, et al. Toll-like receptor (TLR) 2 and TLR4 are essential for Aspergillus-induced activation of murine macrophages. Cell Microbiol. 2003;5:561–70.PubMedCrossRefGoogle Scholar
  203. 203.
    Flo TH, Ryan L, Latz E, et al. Involvement of toll-like receptor (TLR) 2 and TLR4 in cell activation by mannuronic acid polymers. J Biol Chem. 2002;277:35489–95.PubMedCrossRefGoogle Scholar
  204. 204.
    Chai LYA, Vonk AG, Kullberg BJ, et al. Aspergillus fumigatus cell wall components differentially modulate host TLR2 and TLR4 responses. Microbes Infect. 2011;13:151–9.PubMedCrossRefGoogle Scholar
  205. 205.
    de Luca A, Bozza S, Zelante T, et al. Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO. Cell Mol Immunol. 2010;7:459–70.PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Shin S-H, Lee Y-H. Airborne fungi induce nasal polyp epithelial cell activation and Toll-like receptor expression. Int Arch Allergy Immunol. 2010;153:46–52.PubMedCrossRefGoogle Scholar
  207. 207.
    Kasperkovitz PV, Cardenas ML, Vyas JM. TLR9 Is actively recruited to Aspergillus fumigatus phagosomes and requires the N-terminal proteolytic cleavage domain for proper intracellular trafficking. J Immunol. 2010;185:7614–22.PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Cohen TS, Prince A. Cystic fibrosis: a mucosal immunodeficiency syndrome. Nat Med. 2012;18:509–19.PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    John G, Yildirim AÖ, Rubin BK, et al. TLR-4-mediated innate immunity is reduced in cystic fibrosis airway cells. Am J Respir Cell Mol. 2010;42:424–31.CrossRefGoogle Scholar
  210. 210.
    Steele C, Rapaka RR, Metz A, et al. The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus. PLoS Pathog. 2005;1:e42.PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Sun WK, Lu X, Li X, et al. Dectin-1 is inducible and plays a crucial role in Aspergillus-induced innate immune responses in human bronchial epithelial cells. Eur J Clin Microbiol Infect Dis. 2012;31:2755–64.PubMedCrossRefGoogle Scholar
  212. 212.
    Gersuk GM, Underhill DM, Zhu L, et al. Dectin-1 and TLRs permit macrophages to distinguish between different Aspergillus fumigatus cellular states. J Immunol. 2006;176:3717–24.PubMedCrossRefGoogle Scholar
  213. 213.
    Liu Z-C, Wang M, Sun W-K, et al. Up-regulation of Dectin-1 in airway epithelial cells promotes mice defense against invasive pulmonary aspergillosis. Int J Clin Exp Med. 2015;8:17489–97.PubMedPubMedCentralGoogle Scholar
  214. 214.
    Werner JL, Metz AE, Horn D, et al. Requisite role for the dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus. J Immunol. 2009;182:4938–46.PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Yang J, Lu Q, Liu W, et al. Cyclophosphamide reduces dectin-1 expression in the lungs of naive and Aspergillus fumigatus-infected mice. Med Mycol. 2009;48:1–7.Google Scholar
  216. 216.
    Serrano-Gómez D, Leal JA, Corbí AL. DC-SIGN mediates the binding of Aspergillus fumigatus and keratinophylic fungi by human dendritic cells. Immunobiology. 2005;210:175–83.PubMedCrossRefGoogle Scholar
  217. 217.
    Loures FV, Röhm M, Lee CK, et al. Recognition of Aspergillus fumigatus hyphae by human plasmacytoid dendritic cells is mediated by dectin-2 and results in formation of extracellular traps. PLoS Pathog. 2015;11:e1004643.PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Chiarini M, Sabelli C, Melotti P, et al. PTX3 genetic variations affect the risk of Pseudomonas aeruginosa airway colonization in cystic fibrosis patients. Genes Immun. 2010;11:665–70.PubMedPubMedCentralCrossRefGoogle Scholar
  219. 219.
    Paroni M, Moalli F, Nebuloni M, et al. Response of CFTR-deficient mice to long-term chronic Pseudomonas aeruginosa infection and PTX3 therapy. J Infect Dis. 2013;208:130–8.PubMedCrossRefGoogle Scholar
  220. 220.
    Garlanda C, Hirsch E, Bozza S, et al. Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response. Nature. 2002;420:182–6.PubMedCrossRefGoogle Scholar
  221. 221.
    Bidula S, Sexton DW, Yates M, et al. H-ficolin binds Aspergillus fumigatus leading to activation of the lectin complement pathway and modulation of lung epithelial immune responses. Immunology. 2015;146:281–91.PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Chrdle A, Mustakim S, Bright-Thomas RJ, et al. Aspergillus bronchitis without significant immunocompromise. Ann N Y Acad Sci. 2012;1272:73–85.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  1. 1.Department of Pediatrics, Pediatric Infectiology, Immunology and Cystic Fibrosis, Children’s HospitalUniversity of TübingenTübingenGermany
  2. 2.Department of Pediatric Pneumology and ImmunologyCystic Fibrosis Center Berlin/Charité, University of BerlinBerlinGermany

Personalised recommendations