Advertisement

Fungal Infections with Ibrutinib and Other Small-Molecule Kinase Inhibitors

  • Marissa A. Zarakas
  • Jigar V. Desai
  • Georgios Chamilos
  • Michail S. LionakisEmail author
Fungal Genomics and Pathogenesis (S Shoham, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Fungal Genomics and Pathogenesis

Abstract

Purpose of Review

Small-molecule kinase inhibitors (SMKIs) have revolutionized the management of malignant and autoimmune disorders. Emerging clinical reports point towards an increased risk for invasive fungal infections (IFIs) in patients treated with certain SMKIs. In this mini-review, we highlight representative examples of SMKIs that have been associated with or are expected to give rise to IFIs.

Recent Findings

The clinical use of the Bruton’s tyrosine kinase inhibitor ibrutinib as well as other FDA-approved SMKIs has been associated with IFIs. The fungal infection susceptibility associated with the clinical use of certain SMKIs underscores their detrimental effects on innate and adaptive antifungal immune responses.

Summary

The unprecedented development and clinical use of SMKIs is expected to give rise to an expansion of iatrogenic immunosuppressive factors predisposing to IFIs (and other opportunistic infections). Beyond increased clinical surveillance, better understanding of the pathogenesis of SMKI-associated immune dysregulation should help in devising improved risk stratification and prophylaxis strategies in vulnerable patients.

Keywords

Invasive fungal infections Small-molecule kinase inhibitors Ibrutinib Aspergillosis Pneumocystis jirovecii pneumonia Cryptococcosis 

Notes

Funding Information

This work was supported by the Division of Intramural Research (DIR) of the NIAID, NIH.

Compliance With Ethical Standards

Conflict of Interest

Marissa Zarakas, Jigar Desai, Georgios Chamilos, and Michail Lionakis declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Skerratt LF, Berger L, Speare R, Cashins S, McDonald KR, Phillott AD, et al. Spread of chytridiomycosis has caused the rapid global decline and extinction of frogs. Ecohealth. 2007;4(2):125–34.  https://doi.org/10.1007/s10393-007-0093-5.CrossRefGoogle Scholar
  2. 2.
    Frick WF, Pollock JF, Hicks AC, Langwig KE, Reynolds DS, Turner GG, et al. An emerging disease causes regional population collapse of a common North American bat species. Science (New York, NY). 2010;329(5992):679–82.  https://doi.org/10.1126/science.1188594.CrossRefGoogle Scholar
  3. 3.
    Kohler JR, Hube B, Puccia R, Casadevall A, Perfect JR. Fungi that infect humans. Microbiol Spectrum. 2017;5(3).  https://doi.org/10.1128/microbiolspec.FUNK-0014-2016.
  4. 4.
    Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci Transl Med. 2012;4(165):165rv13.  https://doi.org/10.1126/scitranslmed.3004404.CrossRefPubMedGoogle Scholar
  5. 5.
    Havlickova B, Czaika VA, Friedrich M. Epidemiological trends in skin mycoses worldwide. Mycoses. 2008;51(Suppl 4):2–15.  https://doi.org/10.1111/j.1439-0507.2008.01606.x.CrossRefPubMedGoogle Scholar
  6. 6.
    • Benedict K, Jackson BR, Chiller T, Beer KD. Estimation of direct healthcare costs of fungal diseases in the United States. Clin Infect Dis. 2018.  https://doi.org/10.1093/cid/ciy776 Recent study using data from large insurance claims databases that sheds light on the profound burden that fungal diseases impose on the healthcare system of the USA.
  7. 7.
    Robert VA, Casadevall A. Vertebrate endothermy restricts most fungi as potential pathogens. J Infect Dis. 2009;200(10):1623–6.  https://doi.org/10.1086/644642.CrossRefPubMedGoogle Scholar
  8. 8.
    Lionakis MS, Levitz SM. Host control of fungal infections: lessons from basic studies and human cohorts. Annu Rev Immunol. 2018;36:157–91.  https://doi.org/10.1146/annurev-immunol-042617-053318.CrossRefPubMedGoogle Scholar
  9. 9.
    •• Chamilos G, Lionakis MS, Kontoyiannis DP. Call for action: invasive fungal infections associated with Ibrutinib and other small molecule kinase inhibitors targeting immune signaling pathways. Clin Infect Dis. 2018;66(1):140–8.  https://doi.org/10.1093/cid/cix687 A comprehensive review of SMKIs outlining their association with IFIs . CrossRefPubMedGoogle Scholar
  10. 10.
    •• Ghez D, Calleja A, Protin C, Baron M, Ledoux MP, Damaj G, et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood. 2018;131(17):1955–9.  https://doi.org/10.1182/blood-2017-11-818286 A retrospective study of patients treated with ibrutinib during the period 2013–2017, demostrating increased incidence of IFIs, particularly IA with frequent cerebral involvement.CrossRefPubMedGoogle Scholar
  11. 11.
    •• Varughese T, Taur Y, Cohen N, Palomba ML, Seo SK, Hohl TM, et al. Serious infections in patients receiving ibrutinib for treatment of lymphoid cancer. Clin Infect Dis. 2018;67(5):687–92.  https://doi.org/10.1093/cid/ciy175 A retrospective analysis of lymphoid cancer patients receiving ibrutinib during a 5-year period, indicating ibrutinib as a major risk factor for serious infections, including IFIs.CrossRefPubMedGoogle Scholar
  12. 12.
    •• Lionakis MS, Dunleavy K, Roschewski M, Widemann BC, Butman JA, Schmitz R, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell. 2017;31(6):833–43.e5.  https://doi.org/10.1093/cid/ciy175 Important paper showing promising results of a Phase Ib study of ibrutinib use for the treatment of PCNSL. The authors also highlighted the remarkable 39% incidence of Aspergillus infections associated with ibrutinib therapy . CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    • Rogers KA, Mousa L, Zhao Q, Bhat SA, Byrd JC, El Boghdadly Z, et al. Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies. Leukemia. 2019.  https://doi.org/10.1038/s41375-019-0481-1 A single institution retrospective study of opportunistic infections (OIs) in ibrutinib-treated patients, in which IFIs accounted for the majority of opportunistic infections.
  14. 14.
    Rogers KA, Luay M, Zhao QH, Wiczer T, Levine L, Zeinab E, et al. Incidence and type of opportunistic infections during Ibrutinib treatment at a single academic center. Blood. 2017;130.Google Scholar
  15. 15.
    • Barbosa CC, DeAngelis LM, Grommes C. Ibrutinib associated infections: a retrospective study. 2017;35(15_suppl):e19020-e.  https://doi.org/10.1200/JCO.2017.35.15_suppl.e19020 A retrospective analysis of patients treated with ibrutinib for various lymphomas between 4/2014–11/2016. The authors reported 7 cases of IFIs among 200 treated patients.
  16. 16.
    Sun K, Kasparian S, Iyer S, Pingali SR. Cryptococcal meningoencephalitis in patients with mantle cell lymphoma on ibrutinib. Ecancermedicalscience. 2018;12:836.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Swan CD, Gottlieb T. Cryptococcus neoformans empyema in a patient receiving ibrutinib for diffuse large B-cell lymphoma and a review of the literature. BMJ Case Rep. 2018;2018.  https://doi.org/10.3332/ecancer.2018.836.
  18. 18.
    Grossi O, Pineau S, Sadot-Lebouvier S, Hay B, Delaunay J, Miailhe AF, et al. Disseminated mucormycosis due to Lichtheimia corymbifera during ibrutinib treatment for relapsed chronic lymphocytic leukaemia: a case report. Clin Microbiol Infect. 2019;25(2):261–3.  https://doi.org/10.1016/j.cmi.2018.10.004.CrossRefPubMedGoogle Scholar
  19. 19.
    Nasir T, Lee C, Lawrence AS, Brown JS. Invasive aspergillosis complicating treatment with tyrosine kinase inhibitors. BMJ Case Rep. 2019;12(1):e226121.  https://doi.org/10.1136/bcr-2018-226121.CrossRefPubMedGoogle Scholar
  20. 20.
    Faisal MS, Shaikh H, Khattab A, Albrethsen M, Fazal S. Cerebral aspergillosis in a patient on ibrutinib therapy-a predisposition not to overlook. J Oncol Pharm Pract. 2018:1078155218788717.  https://doi.org/10.1177/1078155218788717.
  21. 21.
    Beresford R, Dolot V, Foo H. Cranial aspergillosis in a patient receiving ibrutinib for chronic lymphocytic leukemia. Med Mycol Case Rep. 2019;24:27–9.  https://doi.org/10.1016/j.mmcr.2019.02.005.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Stephens DM, Byrd JC. How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia. Blood. 2019;133(12):1298–307.  https://doi.org/10.1182/blood-2018-11-846808.CrossRefPubMedGoogle Scholar
  23. 23.
    McCarter SJ, Vijayvargiya P, Sidana S, Nault AM, Lane CE, Lehman JS, et al. A case of ibrutinib-associated aspergillosis presenting with central nervous system, myocardial, pulmonary, intramuscular, and subcutaneous abscesses. Leuk Lymphoma. 2019;60(2):559–61.  https://doi.org/10.1080/10428194.2018.1494271.CrossRefPubMedGoogle Scholar
  24. 24.
    Pouvaret A, Guery R, Montillet M, Molina TJ, Dureault A, Bougnoux ME, et al. Concurrent cerebral aspergillosis and abdominal mucormycosis during ibrutinib therapy for chronic lymphocytic leukaemia. Clin Microbiol Infect. 2019;25:771–3.  https://doi.org/10.1016/j.cmi.2019.01.016.CrossRefPubMedGoogle Scholar
  25. 25.
    Wilson PA, Melville K. Disseminated cryptococcal infection in a patient receiving acalabrutinib for chronic lymphocytic leukemia. 9000;Publish Ahead of Print.  https://doi.org/10.1097/IPC.0000000000000722, 2019.
  26. 26.
    Wysham NG, Sullivan DR, Allada G. An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor. Chest. 2013;143(5):1478–9.  https://doi.org/10.1378/chest.12-1604.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lee SC, Feenstra J, Georghiou PR. Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy. BMJ Case Rep. 2014;2014:bcr2014204950.  https://doi.org/10.1136/bcr-2014-204950.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Chan JF, Chan TS, Gill H, Lam FY, Trendell-Smith NJ, Sridhar S, et al. Disseminated infections with Talaromyces marneffei in non-AIDS patients given monoclonal antibodies against CD20 and kinase inhibitors. Emerg Infect Dis. 2015;21(7):1101–6.  https://doi.org/10.3201/eid2107.150138.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Chen CC, Chen YY, Huang CE. Cryptococcal meningoencephalitis associated with the long-term use of ruxolitinib. Ann Hematol. 2016;95(2):361–2.  https://doi.org/10.1007/s00277-015-2532-7.CrossRefPubMedGoogle Scholar
  30. 30.
    Hirano A, Yamasaki M, Saito N, Iwato K, Daido W, Funaishi K, et al. Pulmonary cryptococcosis in a ruxolitinib-treated patient with primary myelofibrosis. Respir Med Case Rep. 2017;22:87–90.  https://doi.org/10.1016/j.rmcr.2017.06.015.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Polverelli N, Breccia M, Benevolo G, Martino B, Tieghi A, Latagliata R, et al. Risk factors for infections in myelofibrosis: role of disease status and treatment. A multicenter study of 507 patients. Am J Hematol. 2017;92(1):37–41.  https://doi.org/10.1002/ajh.24572.CrossRefPubMedGoogle Scholar
  32. 32.
    Liu J, Mouhayar E, Tarrand JJ, Kontoyiannis DP. Fulminant Cryptococcus neoformans infection with fatal pericardial tamponade in a patient with chronic myelomonocytic leukaemia who was treated with ruxolitinib: case report and review of fungal pericarditis. Mycoses. 2018;61(4):245–55.  https://doi.org/10.1111/myc.12735.CrossRefPubMedGoogle Scholar
  33. 33.
    Moruno-Rodriguez A, Sanchez-Vicente JL, Rueda-Rueda T, Lechon-Caballero B, Munoz-Morales A, Lopez-Herrero F. Invasive aspergillosis manifesting as retinal necrosis in a patient treated with ruxolitinib. Arch Soc Esp Oftalmol. 2019;94(5):237–41.  https://doi.org/10.1016/j.oftal.2018.12.006.CrossRefPubMedGoogle Scholar
  34. 34.
    Dioverti MV, Abu Saleh OM, Tande AJ. Infectious complications in patients on treatment with ruxolitinib: case report and review of the literature. Infect Dis (London, Engl). 2018;50(5):381–7.  https://doi.org/10.1080/23744235.2017.1390248.CrossRefGoogle Scholar
  35. 35.
    Prakash K, Richman D. A case report of disseminated histoplasmosis and concurrent cryptococcal meningitis in a patient treated with ruxolitinib. BMC Infect Dis. 2019;19(1):287.  https://doi.org/10.1186/s12879-019-3922-6.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Chakrabarti A, Sood N. Cryptococcal meningitis in an immunocompetent patient with primary myelofibrosis on long-term ruxolitinib: report of a rare case and review of literature. memo – Mag Eur Med Oncol. 2018;11(4):348–50.  https://doi.org/10.1007/s12254-018-0435-8.CrossRefGoogle Scholar
  37. 37.
    • Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ, Berkun Y, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018;128(7):3041–52.  https://doi.org/10.1172/JCI98814 This study reported fungal infections in 4 out of 18 baricitinib-treated patients with interferonopathies . CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Locati LD, Perrone F, Cortelazzi B, Bergamini C, Bossi P, Civelli E, et al. A phase II study of sorafenib in recurrent and/or metastatic salivary gland carcinomas: translational analyses and clinical impact. Eur J Cancer (Oxford, Engl: 1990). 2016;69:158–65.  https://doi.org/10.1016/j.ejca.2016.09.022.CrossRefGoogle Scholar
  39. 39.
    Bazaz R, Denning DW. Subacute invasive aspergillosis associated with sorafenib therapy for hepatocellular carcinoma. Clin Infect Dis. 2018;67(1):156–7.  https://doi.org/10.1093/cid/ciy038.CrossRefPubMedGoogle Scholar
  40. 40.
    Kloos RT, Ringel MD, Knopp MV, Hall NC, King M, Stevens R, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol. 2009;27(10):1675–84.  https://doi.org/10.1200/JCO.2008.18.2717.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115(13):2578–85.  https://doi.org/10.1182/blood-2009-08-236471.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Al-Ameri A, Kantarjian H, Borthakur G, Bahceci E, Szatrowski T, Damokosh A, et al. Opportunistic infections are uncommon with dasatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP). Blood. 2009;114(22):1120.Google Scholar
  43. 43.
    Chang H, Hung YS, Chou WC. Pneumocystis jiroveci pneumonia in patients receiving dasatinib treatment. Int J Infect Dis. 2014;25:165–7.  https://doi.org/10.1016/j.ijid.2014.04.030.CrossRefPubMedGoogle Scholar
  44. 44.
    Su CX, Ren SX, Li XF, Hou LK, Zhou CC. Pseudo-progression in a patient with lung adenocarcinoma and ALK fusion who responded to crizotinib. Int J Clin Exp Med. 2016;9(6):12290–3.Google Scholar
  45. 45.
    Deiana L, Grisanti S, Ferrari V, Tironi A, Brugnoli G, Ferrari L, et al. Aspergillosis superinfection as a cause of death of crizotinib-induced interstitial lung disease successfully treated with high-dose corticosteroid therapy. Case Rep Oncol. 2015;8(1):169–73.  https://doi.org/10.1159/000381209.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017;18(8):1061–75.  https://doi.org/10.1016/S1470-2045(17)30416-3.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Crisan AM, Ghiaur A, Stancioaca MC, Bardas A, Ghita C, Manea CM, et al. Mucormycosis during imatinib treatment: case report. J Med Life. 2015;8(3):365–70.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390–7.  https://doi.org/10.1182/blood-2013-11-535047.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, et al. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015;126(6):746–56.  https://doi.org/10.1182/blood-2015-03-636548.CrossRefPubMedGoogle Scholar
  50. 50.
    Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132(4):393–404.  https://doi.org/10.1182/blood-2016-09-739086.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Visvardis EE, Gao F, Paes MN, Duprez O, Waxman J. Lung aspergillosis in renal cell carcinoma patient treated with sunitinib. QJM. 2012;105(7):689–92.  https://doi.org/10.1093/qjmed/hcr091.CrossRefPubMedGoogle Scholar
  52. 52.
    Kim YW, Lee HW, Cho J, Choi HS, Lee J, Park SS, et al. Conversion of aspergilloma to chronic necrotizing pulmonary aspergillosis following treatment with sunitinib: a case report. Oncol Lett. 2016;12(5):3472–4.  https://doi.org/10.3892/ol.2016.5052.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Bongomin F, Gago S, Oladele RO, Denning DW. Global and multi-national prevalence of fungal diseases-estimate precision. J Fungi (Basel). 2017;3(4).  https://doi.org/10.3390/jof3040057.
  54. 54.
    Pappas PG, Lionakis MS, Arendrup MC, Ostrosky-Zeichner L, Kullberg BJ. Invasive candidiasis. Nat Rev Dis Primers. 2018;4:18026.  https://doi.org/10.1038/nrdp.2018.26.CrossRefPubMedGoogle Scholar
  55. 55.
    Pagano L, Caira M, Candoni A, Offidani M, Fianchi L, Martino B, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91(8):1068–75.PubMedGoogle Scholar
  56. 56.
    Hohl TM. Immune responses to invasive aspergillosis: new understanding and therapeutic opportunities. Curr Opin Infect Dis. 2017;30(4):364–71.  https://doi.org/10.1097/QCO.0000000000000381.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Marciano BE, Spalding C, Fitzgerald A, Mann D, Brown T, Osgood S, et al. Common severe infections in chronic granulomatous disease. Clin Infect Dis. 2015;60(8):1176–83.  https://doi.org/10.1093/cid/ciu1154.CrossRefPubMedGoogle Scholar
  58. 58.
    Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM, et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis. 2017;17(8):873–81.  https://doi.org/10.1016/S1473-3099(17)30243-8.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Richardson M, Lass-Florl C. Changing epidemiology of systemic fungal infections. Clin Microbiol Infect. 2008;14(Suppl 4):5–24.  https://doi.org/10.1111/j.1469-0691.2008.01978.x.CrossRefPubMedGoogle Scholar
  60. 60.
    Maertens J, Vrebos M, Boogaerts M. Assessing risk factors for systemic fungal infections. Eur J Cancer Care. 2001;10(1):56–62.  https://doi.org/10.1046/j.1365-2354.2001.00241.x.CrossRefGoogle Scholar
  61. 61.
    Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130(21):2243–50.  https://doi.org/10.1182/blood-2017-07-793786.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Burger JA, Wiestner A. Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nat Rev Cancer. 2018;18(3):148–67.  https://doi.org/10.1038/nrc.2017.121.CrossRefPubMedGoogle Scholar
  63. 63.
    • Ahn IE, Jerussi T, Farooqui M, Tian X, Wiestner A, Gea-Banacloche J. Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib. Blood. 2016;128(15):1940–3.  https://doi.org/10.1182/blood-2016-06-722991 A study reporting incidence of PJP in 5% of patients on ibrutinib monotherapy for CLL.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, Maniar HS, et al. Expression of Bruton’s agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J Immunol (Baltimore, Md : 1950). 1994;152(2):557–65.Google Scholar
  65. 65.
    Kolls JK. An emerging role of B cell immunity in susceptibility to Pneumocystis pneumonia. Am J Respir Cell Mol Biol. 2017;56(3):279–80.  https://doi.org/10.1165/rcmb.2016-0360ED.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Hoving JC, Kolls JK. New advances in understanding the host immune response to Pneumocystis. Curr Opin Microbiol. 2017;40:65–71.  https://doi.org/10.1016/j.mib.2017.10.019.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Martin-Garrido I, Carmona EM, Specks U, Limper AH. Pneumocystis pneumonia in patients treated with rituximab. Chest. 2013;144(1):258–65.  https://doi.org/10.1378/chest.12-0477.CrossRefPubMedGoogle Scholar
  68. 68.
    Kelly MN, Shellito JE. Current understanding of Pneumocystis immunology. Future Microbiol. 2010;5(1):43–65.  https://doi.org/10.2217/fmb.09.116.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Hajjeh RA, Brandt ME, Pinner RW. Emergence of cryptococcal disease: epidemiologic perspectives 100 years after its discovery. Epidemiol Rev. 1995;17(2):303–20.  https://doi.org/10.1093/oxfordjournals.epirev.a036195.CrossRefPubMedGoogle Scholar
  70. 70.
    Sloan DJ, Parris V. Cryptococcal meningitis: epidemiology and therapeutic options. Clin Epidemiol. 2014;6:169–82.  https://doi.org/10.2147/CLEP.S38850.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Osterholzer JJ, Chen GH, Olszewski MA, Curtis JL, Huffnagle GB, Toews GB. Accumulation of CD11b+ lung dendritic cells in response to fungal infection results from the CCR2-mediated recruitment and differentiation of Ly-6Chigh monocytes. J Immunol (Baltimore, Md : 1950). 2009;183(12):8044–53.  https://doi.org/10.4049/jimmunol.0902823.CrossRefPubMedCentralGoogle Scholar
  72. 72.
    Osterholzer JJ, Chen GH, Olszewski MA, Zhang YM, Curtis JL, Huffnagle GB, et al. Chemokine receptor 2-mediated accumulation of fungicidal exudate macrophages in mice that clear cryptococcal lung infection. Am J Pathol. 2011;178(1):198–211.  https://doi.org/10.1016/j.ajpath.2010.11.006.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Osterholzer JJ, Curtis JL, Polak T, Ames T, Chen GH, McDonald R, et al. CCR2 mediates conventional dendritic cell recruitment and the formation of bronchovascular mononuclear cell infiltrates in the lungs of mice infected with Cryptococcus neoformans. J Immunol (Baltimore, Md : 1950). 2008;181(1):610–20.  https://doi.org/10.4049/jimmunol.181.1.610.CrossRefPubMedCentralGoogle Scholar
  74. 74.
    Lionakis MS, Netea MG, Holland SM. Mendelian genetics of human susceptibility to fungal infection. Cold Spring Harb Perspect Med. 2014;4(6).  https://doi.org/10.1101/cshperspect.a019638.
  75. 75.
    Szymczak WA, Davis MJ, Lundy SK, Dufaud C, Olszewski M, Pirofski LA. X-linked immunodeficient mice exhibit enhanced susceptibility to Cryptococcus neoformans infection. mBio. 2013;4(4).  https://doi.org/10.1128/mBio.00265-13.
  76. 76.
    Rohatgi S, Pirofski LA. Host immunity to Cryptococcus neoformans. Future Microbiol. 2015;10(4):565–81.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Lionakis MS, Iliev ID, Hohl TM. Immunity against fungi. JCI Insight. 2017;2(11):565–81.  https://doi.org/10.2217/fmb.14.132.CrossRefGoogle Scholar
  78. 78.
    •• Espinosa V, Dutta O, McElrath C, Du P, Chang YJ, Cicciarelli B, et al. Type III interferon is a critical regulator of innate antifungal immunity. Sci Immunol. 2017;2(16).  https://doi.org/10.1126/sciimmunol.aan5357. This study describes how neutrophil-intrinsic STAT1 activation via IFN-λ/IFNLR1 signaling leads to reactive oxygen species production for efficient Aspergillus clearance. Given the association of IFIs with ruxolitinib (JAK1/2 inhibitor) use, the findings from this study are highly relevant.
  79. 79.
    •• Bercusson A, Colley T, Shah A, Warris A, Armstrong-James D. Ibrutinib blocks Btk-dependent NF-kB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis. Blood. 2018;132(18):1985–8.  https://doi.org/10.1182/blood-2017-12-823393 This study demonstrates that ibrutinib-mediated blockade of BTK decreases A. fumigatus-induced NF-kB and NFAT activation in human macrophages.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    • Herbst S, Shah A, Mazon Moya M, Marzola V, Jensen B, Reed A, et al. Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus. EMBO Mol Med. 2015;7(3):240–58.  https://doi.org/10.15252/emmm.201404556 This study demonstrates that phagocytosis of A. fumigatus activates NFAT in BTK-dependent manner.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Zelante T, Wong AY, Mencarelli A, Foo S, Zolezzi F, Lee B, et al. Impaired calcineurin signaling in myeloid cells results in downregulation of pentraxin-3 and increased susceptibility to aspergillosis. Mucosal Immunol. 2017;10(2):470–80.  https://doi.org/10.1038/mi.2016.52.CrossRefPubMedGoogle Scholar
  82. 82.
    Kanegane H, Nakano T, Shimono Y, Zhao M, Miyawaki T. Pneumocystis jiroveci pneumonia as an atypical presentation of X-linked agammaglobulinemia. Int J Hematol. 2009;89(5):716–7.  https://doi.org/10.1007/s12185-009-0322-5.CrossRefPubMedGoogle Scholar
  83. 83.
    Nishi K, Kawai T, Kubota M, Ishiguro A, Onodera M. X-linked agammaglobulinemia complicated with pulmonary aspergillosis. Pediatr Int. 2018;60(1):90–2.  https://doi.org/10.1111/ped.13453.CrossRefPubMedGoogle Scholar
  84. 84.
    • Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J, et al. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-Cell diffuse large B-Cell lymphoma. J Clin Oncol. 2019:Jco1802403.  https://doi.org/10.1200/JCO.18.02403. A paper outlining the patient age as a possible determining factor for clinical outcomes in lymphoma patients treated with ibrutinib-based chemotherapy. Higher rates of infection and worse outcomes were demonstrated in patients 60 years or older. Interestingly, Aspergillus infections were only reported in this group of patients.
  85. 85.
    Raedler LA. Jakafi (Ruxolitinib): first FDA-approved medication for the treatment of patients with polycythemia vera. Am Health Drug Benefits. 2015;8(Spec Feature):75–9.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Tefferi A. Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91(12):1262–71.  https://doi.org/10.1002/ajh.24592.CrossRefPubMedGoogle Scholar
  87. 87.
    Gregory SA, Mesa RA, Hoffman R, Shammo JM. Clinical and laboratory features of myelofibrosis and limitations of current therapies. Clin Adv Hematol Oncol. 2011;9(9 Suppl 22):1–16.PubMedGoogle Scholar
  88. 88.
    Mughal TI, Vaddi K, Sarlis NJ, Verstovsek S. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med. 2014;7:89–101.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.  https://doi.org/10.1056/NEJMoa1110557.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–98.  https://doi.org/10.1056/NEJMoa1110556.CrossRefPubMedGoogle Scholar
  91. 91.
    Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117–27.  https://doi.org/10.1056/NEJMoa1002028.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Quintas-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115(15):3109–17.  https://doi.org/10.1182/blood-2009-04-214957.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Galli S, McLornan D, Harrison C. Safety evaluation of ruxolitinib for treating myelofibrosis. Expert Opin Drug Saf. 2014;13(7):967–76.  https://doi.org/10.1517/14740338.2014.916273.CrossRefPubMedGoogle Scholar
  94. 94.
    Vannucchi AM. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(17):1670–1.  https://doi.org/10.1056/NEJMc1502524.CrossRefPubMedGoogle Scholar
  95. 95.
    Mesa R, Vannucchi AM, Yacoub A, Zachee P, Garg M, Lyons R, et al. The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double-blind, double-dummy, symptom study (RELIEF). Br J Haematol. 2017;176(1):76–85.  https://doi.org/10.1111/bjh.14382.CrossRefPubMedGoogle Scholar
  96. 96.
    Passamonti F, Griesshammer M, Palandri F, Egyed M, Benevolo G, Devos T, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol. 2017;18(1):88–99.  https://doi.org/10.1016/S1470-2045(16)30558-7.CrossRefPubMedGoogle Scholar
  97. 97.
    Lussana F, Cattaneo M, Rambaldi A, Squizzato A. Ruxolitinib-associated infections: a systematic review and meta-analysis. Am J Hematol. 2018;93(3):339–47.  https://doi.org/10.1002/ajh.24976.CrossRefPubMedGoogle Scholar
  98. 98.
    Tong LX, Jackson J, Kerstetter J, Worswick SD. Reactivation of herpes simplex virus infection in a patient undergoing ruxolitinib treatment. J Am Acad Dermatol. 2014;70(3):e59–60.  https://doi.org/10.1016/j.jaad.2013.09.035.CrossRefPubMedGoogle Scholar
  99. 99.
    Caocci G, Murgia F, Podda L, Solinas A, Atzeni S, La Nasa G. Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis. Leukemia. 2014;28(1):225–7.  https://doi.org/10.1038/leu.2013.235.CrossRefPubMedGoogle Scholar
  100. 100.
    Tsukamoto Y, Kiyasu J, Tsuda M, Ikeda M, Shiratsuchi M, Ogawa Y, et al. Fatal disseminated tuberculosis during treatment with ruxolitinib plus prednisolone in a patient with primary myelofibrosis: a case report and review of the literature. Intern Med (Tokyo, Jpn). 2018;57(9):1297–300.  https://doi.org/10.2169/internalmedicine.9165-17.CrossRefGoogle Scholar
  101. 101.
    Palandri F, Tiribelli M, Benevolo G, Tieghi A, Cavazzini F, Breccia M, et al. Efficacy and safety of ruxolitinib in intermediate-1 IPSS risk myelofibrosis patients: results from an independent study. Hematol Oncol. 2018;36(1):285–90.  https://doi.org/10.1002/hon.2429.CrossRefPubMedGoogle Scholar
  102. 102.
    Polverelli N, Palumbo GA, Binotto G, Abruzzese E, Benevolo G, Bergamaschi M, et al. Epidemiology, outcome, and risk factors for infectious complications in myelofibrosis patients receiving ruxolitinib: a multicenter study on 446 patients. Hematol Oncol. 2018;36:561–9.  https://doi.org/10.1002/hon.2509.CrossRefGoogle Scholar
  103. 103.
    Lescuyer S, Ledoux MP, Gravier S, Natarajan-Ame S, Duval C, Maloisel F, et al. Tuberculosis and atypical mycobacterial infections in ruxolitinib-treated patients with primary or secondary myelofibrosis or polycythemia vera. Int J Infect Dis. 2019;80:134–6.  https://doi.org/10.1016/j.ijid.2019.01.002.CrossRefPubMedGoogle Scholar
  104. 104.
    McLornan DP, Khan AA, Harrison CN. Immunological consequences of JAK inhibition: friend or foe? Curr Hematol Malig Rep. 2015;10(4):370–9.CrossRefPubMedGoogle Scholar
  105. 105.
    Chen S, Yan H, Zhang L, Kong W, Sun Y, Zhang W, et al. Cryptococcus neoformans infection and immune cell regulation in human monocytes. Cell Physiol Biochem. 2015;37(2):537–47.  https://doi.org/10.1159/000430375.CrossRefPubMedGoogle Scholar
  106. 106.
    Moodley D, Yoshida H, Mostafavi S, Asinovski N, Ortiz-Lopez A, Symanowicz P, et al. Network pharmacology of JAK inhibitors. Proc Natl Acad Sci U S A. 2016;113(35):9852–7.  https://doi.org/10.1073/pnas.1610253113.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    • Villarino AV, Kanno Y, O’Shea JJ. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol. 2017;18(4):374–84.  https://doi.org/10.1038/ni.3691 Important review about the Jak-STAT pathway focusing on immune cell function, human disease, and therapeutic interventions of drugs targeting this pathway.CrossRefPubMedGoogle Scholar
  108. 108.
    Adnane L, Trail PA, Taylor I, Wilhelm SM. Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006;407:597–612.  https://doi.org/10.1016/S0076-6879(05)07047-3.CrossRefPubMedGoogle Scholar
  109. 109.
    Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006;5(10):835–44.  https://doi.org/10.1038/nrd2130.CrossRefPubMedGoogle Scholar
  110. 110.
    Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64(19):7099–109.  https://doi.org/10.1158/0008-5472.CAN-04-1443.CrossRefPubMedGoogle Scholar
  111. 111.
    Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66(24):11851–8.  https://doi.org/10.1158/0008-5472.CAN-06-1377.CrossRefPubMedGoogle Scholar
  112. 112.
    Watt TC, Cooper T. Sorafenib as treatment for relapsed or refractory pediatric acute myelogenous leukemia. Pediatr Blood Cancer. 2012;59(4):756–7.  https://doi.org/10.1002/pbc.23394.CrossRefPubMedGoogle Scholar
  113. 113.
    Sammons SL, Pratz KW, Smith BD, Karp JE, Emadi A. Sorafenib is tolerable and improves clinical outcomes in patients with FLT3-ITD acute myeloid leukemia prior to stem cell transplant and after relapse post-transplant. Am J Hematol. 2014;89(9):936–8.  https://doi.org/10.1002/ajh.23782.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Takeda H, Nishikawa H, Iguchi E, Matsuda F, Kita R, Kimura T, et al. Sorafenib-induced acute interstitial pneumonia in patients with advanced hepatocellular carcinoma: report of three cases. Clin J Gastroenterol. 2012;5(4):407–12.  https://doi.org/10.1007/s12328-012-0339-9.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Chen CB, Wu MY, Ng CY, Lu CW, Wu J, Kao PH, et al. Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies. Cancer Manag Res. 2018;10:1259–73.  https://doi.org/10.2147/CMAR.S163391.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Macdonald JB, Macdonald B, Golitz LE, LoRusso P, Sekulic A. Cutaneous adverse effects of targeted therapies: part I: inhibitors of the cellular membrane. J Am Acad Dermatol. 2015;72(2):203–18; quiz 19-20.  https://doi.org/10.1016/j.jaad.2014.07.032.CrossRefPubMedGoogle Scholar
  117. 117.
    Chen KH, Weng MT, Chou YH, Lu YF, Hsieh CH. Epigastric distress caused by esophageal candidiasis in 2 patients who received sorafenib plus radiotherapy for hepatocellular carcinoma: case report. Medicine. 2016;95(11):e3133.  https://doi.org/10.1097/MD.0000000000003133.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Coppola R, Zanframundo S, Rinati MV, Carbotti M, Graziano A, Galati G, et al. Rhodotorula mucilaginosa skin infection in a patient treated with sorafenib. J Eur Acad Dermatol Venereol. 2015;29(5):1028–9.  https://doi.org/10.1111/jdv.12455.CrossRefPubMedGoogle Scholar
  119. 119.
    Dubourdeau M, Athman R, Balloy V, Huerre M, Chignard M, Philpott DJ, et al. Aspergillus fumigatus induces innate immune responses in alveolar macrophages through the MAPK pathway independently of TLR2 and TLR4. J Immunol (Baltimore, Md : 1950). 2006;177(6):3994–4001.  https://doi.org/10.4049/jimmunol.177.6.3994.CrossRefGoogle Scholar
  120. 120.
    Jia XM, Tang B, Zhu LL, Liu YH, Zhao XQ, Gorjestani S, et al. CARD9 mediates Dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity. J Exp Med. 2014;211(11):2307–21.  https://doi.org/10.1084/jem.20132349.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Hipp MM, Hilf N, Walter S, Werth D, Brauer KM, Radsak MP, et al. Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood. 2008;111(12):5610–20.  https://doi.org/10.1182/blood-2007-02-075945.CrossRefPubMedGoogle Scholar
  122. 122.
    Martin del Campo SE, Levine KM, Mundy-Bosse BL, Grignol VP, Fairchild ET, Campbell AR, et al. The Raf kinase inhibitor sorafenib inhibits JAK-STAT signal transduction in human immune cells. J Immunol (Baltimore, Md : 1950). 2015;195(5):1995–2005.  https://doi.org/10.4049/jimmunol.1400084.CrossRefGoogle Scholar
  123. 123.
    Markham A. Fostamatinib: first global approval. Drugs. 2018;78(9):959–63.  https://doi.org/10.1007/s40265-018-0927-1.CrossRefPubMedGoogle Scholar
  124. 124.
    McKeage K, Lyseng-Williamson KA. Fostamatinib in chronic immune thrombocytopenia: a profile of its use in the USA. Drugs Ther Perspect. 2018;34(10):451–6.  https://doi.org/10.1007/s40267-018-0551-x.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    • Drummond RA, Franco LM, Lionakis MS. Human CARD9: a critical molecule of fungal immune surveillance. Front Immunol. 2018;9:1836.  https://doi.org/10.3389/fimmu.2018.01836 A review on the important adaptor signaling molecule CARD-9 and the critical role Syk-CARD-9 signaling in human antifungal host defense, underscoring the potentially detrimental effects of Syk inhibitors . CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    •• Drummond RA, Collar AL, Swamydas M, Rodriguez CA, Lim JK, Mendez LM, et al. CARD9-dependent neutrophil recruitment protects against fungal invasion of the central nervous system. PLoS Pathog. 2015;11(12):e1005293.  https://doi.org/10.1371/journal.ppat.1005293 This study described for the first time the protective role of CARD9 in orchestrating neutrophil recruitment to the Candida-infected brain. The conclusions drawn from this study are highly relevant in light of the clinical use of fostamatinib and other SMKIs that may block Syk-CARD9-dependent signaling . CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    •• Drummond RA, Swamydas M, Oikonomou V, Zhai B, Dambuza IM, Schaefer BC, et al. CARD9(+) microglia promote antifungal immunity via IL-1beta- and CXCL1-mediated neutrophil recruitment. Nat Immunol. 2019;20(5):559–70.  https://doi.org/10.1038/s41590-019-0377-2 This study provides novel mechanistic insight into how CARD9-signaling in brain-resident microglia regulates protective neutrophil recruitment to the Candida-infected brain.CrossRefPubMedGoogle Scholar
  128. 128.
    Drewniak A, Gazendam RP, Tool AT, van Houdt M, Jansen MH, van Hamme JL, et al. Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood. 2013;121(13):2385–92.  https://doi.org/10.1182/blood-2012-08-450551.CrossRefPubMedGoogle Scholar
  129. 129.
    • Rieber N, Gazendam RP, Freeman AF, Hsu AP, Collar AL, Sugui JA, et al. Extrapulmonary Aspergillus infection in patients with CARD9 deficiency. JCI Insight. 2016;1(17):e89890.  https://doi.org/10.1172/jci.insight.89890 This study describes CARD9-deficient patients developing extrapulmonary aspergillosis, associated with a defect in neutrophil accumulation in the infected tissue.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    LeibundGut-Landmann S, Gross O, Robinson MJ, Osorio F, Slack EC, Tsoni SV, et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol. 2007;8(6):630–8.  https://doi.org/10.1038/ni1460.CrossRefPubMedGoogle Scholar

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2019

Authors and Affiliations

  • Marissa A. Zarakas
    • 1
  • Jigar V. Desai
    • 1
  • Georgios Chamilos
    • 2
    • 3
  • Michail S. Lionakis
    • 1
    Email author
  1. 1.Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious DiseasesNational Institutes of HealthBethesdaUSA
  2. 2.Department of Clinical Microbiology and Microbial Pathogenesis, School of MedicineUniversity of CreteHeraklionGreece
  3. 3.Institute of Molecular Biology and BiotechnologyFoundation for Research and TechnologyHeraklionGreece

Personalised recommendations