New approaches for the detection of invasive fungal diseases in patients following liver transplantation—results of an observational clinical pilot study

Abstract

Purpose

Despite antifungal prophylaxis following liver transplantation (LTX), patients are at risk for the development of subsequent opportunistic infections, such as an invasive fungal disease (IFD). However, culture-based diagnostic procedures are associated with relevant weaknesses.

Methods

Culture and next-generation sequencing (NGS)-based fungal findings as well as corresponding plasma levels of ß-D-glucan (BDG), galactomannan (GM), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, -4, -6, -10, -17A and mid-regional proadrenomedullin (MR-proADM) were evaluated in 93 patients at 6 consecutive time points within 28 days following LTX.

Results

A NGS-based diagnostic approach was shown to be suitable for the early identification of fungal pathogens in patients following LTX. Moreover, MR-proADM and IL-17A in plasma proved suitable for the identification of patients with an IFD.

Conclusion

Plasma measurements of MR-proADM and IL-17A as well as a NGS-based diagnostic approach were shown to be attractive methodologies to attenuate the weaknesses of routinely used culture-based diagnostic procedures for the determination of an IFD in patients following LTX. However, an additional confirmation within a larger multicenter trial needs to be recommended.

Trial registration

German Clinical Trials Register: DRKS00005480.

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References

  1. 1.

    Trunecka P (2013) Immunosuppression after liver transplant, now and in future. Vnitr Lek 59(8):671–677

    CAS  PubMed  Google Scholar 

  2. 2.

    Reed A, Herndon JB, Ersoz N, Fujikawa T, Schain D, Lipori P, Hemming A, Li Q, Shenkman E, Vogel B (2007) Effect of prophylaxis on fungal infection and costs for high-risk liver transplant recipients. Liver Transpl 13(12):1743–1750. https://doi.org/10.1002/lt.21331

    Article  PubMed  Google Scholar 

  3. 3.

    Singh N (2003) Fungal infections in the recipients of solid organ transplantation. Infect Dis Clin N Am 17(1):113–134 viii

    Article  Google Scholar 

  4. 4.

    Neofytos D, Fishman JA, Horn D, Anaissie E, Chang CH, Olyaei A, Pfaller M, Steinbach WJ, Webster KM, Marr KA (2010) Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis 12(3):220–229. https://doi.org/10.1111/j.1399-3062.2010.00492.x

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, Anaissie EJ, Brumble LM, Herwaldt L, Ito J, Kontoyiannis DP, Lyon GM, Marr KA, Morrison VA, Park BJ, Patterson TF, Perl TM, Oster RA, Schuster MG, Walker R, Walsh TJ, Wannemuehler KA, Chiller TM (2010) Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis 50(8):1101–1111. https://doi.org/10.1086/651262

    Article  PubMed  Google Scholar 

  6. 6.

    Andes DR, Safdar N, Baddley JW, Alexander B, Brumble L, Freifeld A, Hadley S, Herwaldt L, Kauffman C, Lyon GM, Morrison V, Patterson T, Perl T, Walker R, Hess T, Chiller T, Pappas PG, Investigators T (2016) The epidemiology and outcomes of invasive Candida infections among organ transplant recipients in the United States: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Transpl Infect Dis 18(6):921–931. https://doi.org/10.1111/tid.12613

    Article  PubMed  Google Scholar 

  7. 7.

    Shah T, Lai WK, Gow P, Leeming J, Mutimer D (2005) Low-dose amphotericin for prevention of serious fungal infection following liver transplantation. Transpl Infect Dis 7(3–4):126–132. https://doi.org/10.1111/j.1399-3062.2005.00108.x

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Husain S, Tollemar J, Dominguez EA, Baumgarten K, Humar A, Paterson DL, Wagener MM, Kusne S, Singh N (2003) Changes in the spectrum and risk factors for invasive candidiasis in liver transplant recipients: prospective, multicenter, case-controlled study. Transplantation 75(12):2023–2029. https://doi.org/10.1097/01.TP.0000065178.93741.72

    Article  PubMed  Google Scholar 

  9. 9.

    Eschenauer GA, Kwak EJ, Humar A, Potoski BA, Clarke LG, Shields RK, Abdel-Massih R, Silveira FP, Vergidis P, Clancy CJ, Nguyen MH (2015) Targeted versus universal antifungal prophylaxis among liver transplant recipients. Am J Transplant 15(1):180–189. https://doi.org/10.1111/ajt.12993

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Fortun J, Martin-Davila P, Moreno S, Barcena R, de Vicente E, Honrubia A, Garcia M, Nuno J, Candela A, Uriarte M, Pintado V (2003) Prevention of invasive fungal infections in liver transplant recipients: the role of prophylaxis with lipid formulations of amphotericin B in high-risk patients. J Antimicrob Chemother 52(5):813–819. https://doi.org/10.1093/jac/dkg450

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Nagao M, Fujimoto Y, Yamamoto M, Matsumura Y, Kaido T, Takakura S, Uemoto S, Ichiyama S (2016) Epidemiology of invasive fungal infections after liver transplantation and the risk factors of late-onset invasive aspergillosis. J Infect Chemother 22(2):84–89. https://doi.org/10.1016/j.jiac.2015.11.005

    Article  PubMed  Google Scholar 

  12. 12.

    Barchiesi F, Mazzocato S, Mazzanti S, Gesuita R, Skrami E, Fiorentini A, Singh N (2015) Invasive aspergillosis in liver transplant recipients: epidemiology, clinical characteristics, treatment, and outcomes in 116 cases. Liver Transpl 21(2):204–212. https://doi.org/10.1002/lt.24032

    Article  PubMed  Google Scholar 

  13. 13.

    Silveira FP, Kusne S, Practice ASTIDCo (2013) Candida infections in solid organ transplantation. Am J Transplant 13(Suppl 4):220–227. https://doi.org/10.1111/ajt.12114

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Clancy CJ, Nguyen MH (2013) Finding the “missing 50%” of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care. Clin Infect Dis 56(9):1284–1292. https://doi.org/10.1093/cid/cit006

    Article  PubMed  Google Scholar 

  15. 15.

    Vazquez JA, Miceli MH, Alangaden G (2013) Invasive fungal infections in transplant recipients. Ther Adv Infect Dis 1(3):85–105. https://doi.org/10.1177/2049936113491936

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Pappas PG, Maertens J, Lortholary O, Kauffman CA, Denning DW, Patterson TF, Maschmeyer G, Bille J, Dismukes WE, Herbrecht R, Hope WW, Kibbler CC, Kullberg BJ, Marr KA, Munoz P, Odds FC, Perfect JR, Restrepo A, Ruhnke M, Segal BH, Sobel JD, Sorrell TC, Viscoli C, Wingard JR, Zaoutis T, Bennett JE, European Organization for R, Treatment of Cancer/Invasive Fungal Infections Cooperative G, National Institute of A, Infectious Diseases Mycoses Study Group Consensus G (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus group. Clin Infect Dis 46(12):1813–1821. https://doi.org/10.1086/588660

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Bassetti M, Scudeller L, Giacobbe DR, Lamoth F, Righi E, Zuccaro V, Grecchi C, Rebuffi C, Akova M, Alastruey-Izquierdo A, Arikan-Akdagli S, Azoulay E, Blot SI, Cornely OA, Lass-Florl C, Koehler P, Cuenca-Estrella M, de Lange DW, De Rosa FG, De Waele JJ, Dimopoulos G, Garnacho-Montero J, Hoenigl M, Kanj SS, Maertens J, Martin-Loeches I, Munoz P, Kullberg BJ, Agvald-Ohman C, Poulakou G, Rello J, Sanguinetti M, Taccone FS, Timsit JF, Torres A, Vazquez JA, Calandra T, from the Study Group for Infections in Critically Ill P, the Fungal Infection Study Group of the European Society of Clinical M, Infectious D, European Society of Intensive Care M, European Confederation of Medical M, Mycoses Study Group E, Research C (2018, 2019) Developing definitions for invasive fungal diseases in critically ill adult patients in intensive care units. Protocol of the FUNgal infections definitions in ICU patients (FUNDICU) project. Mycoses. https://doi.org/10.1111/myc.12869

  18. 18.

    Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach WJ, Stevens DA, Walsh TJ, Wingard JR, Young JA, Bennett JE (2016) Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 63(4):e1–e60. https://doi.org/10.1093/cid/ciw326

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Singh N, Husain S, Practice ASTIDCo (2013) Aspergillosis in solid organ transplantation. Am J Transplant 13(Suppl 4):228–241. https://doi.org/10.1111/ajt.12115

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Singh N, Winston DJ, Limaye AP, Pelletier S, Safdar N, Morris MI, Meneses K, Busuttil RW, Wagener MM, Wheat LJ (2015) Performance characteristics of galactomannan and beta-d-glucan in high-risk liver transplant recipients. Transplantation 99(12):2543–2550. https://doi.org/10.1097/TP.0000000000000763

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Leeflang MM, Debets-Ossenkopp YJ, Wang J, Visser CE, Scholten RJ, Hooft L, Bijlmer HA, Reitsma JB, Zhang M, Bossuyt PM, Vandenbroucke-Grauls CM (2015) Galactomannan detection for invasive aspergillosis in immunocompromised patients. Cochrane Database Syst Rev 12:CD007394. https://doi.org/10.1002/14651858.CD007394.pub2

    Article  Google Scholar 

  22. 22.

    Pfeiffer CD, Fine JP, Safdar N (2006) Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 42(10):1417–1427. https://doi.org/10.1086/503427

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Ljungman P (2001) Prophylaxis against herpesvirus infections in transplant recipients. Drugs 61(2):187–196

    CAS  Article  Google Scholar 

  24. 24.

    Slifkin M, Doron S, Snydman DR (2004) Viral prophylaxis in organ transplant patients. Drugs 64(24):2763–2792

    CAS  Article  Google Scholar 

  25. 25.

    Giannella M, Bartoletti M, Morelli M, Cristini F, Tedeschi S, Campoli C, Tumietto F, Bertuzzo V, Ercolani G, Faenza S, Pinna AD, Lewis RE, Viale P (2016) Antifungal prophylaxis in liver transplant recipients: one size does not fit all. Transpl Infect Dis 18(4):538–544. https://doi.org/10.1111/tid.12560

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Fortun J, Muriel A, Martin-Davila P, Montejo M, Len O, Torre-Cisneros J, Carratala J, Munoz P, Farinas C, Moreno A, Fresco G, Goikoetxea J, Gavalda J, Pozo JC, Bodro M, Vena A, Casafont F, Cervera C, Silva JT, Aguado JM, Grupo de Estudio de Infeccion en Pacientes Trasplantados-Grupo de Estudio de Micologia M, Red Espanola de Investigacion en Patologia I (2016) Caspofungin versus fluconazole as prophylaxis of invasive fungal infection in high-risk liver transplantation recipients: a propensity score analysis. Liver Transpl 22(4):427–435. https://doi.org/10.1002/lt.24391

    Article  PubMed  Google Scholar 

  27. 27.

    Decker SO, Sigl A, Grumaz C, Stevens P, Vainshtein Y, Zimmermann S, Weigand MA, Hofer S, Sohn K, Brenner T (2017) Immune-response patterns and next generation sequencing diagnostics for the detection of mycoses in patients with septic shock—results of a combined clinical and experimental investigation. Int J Mol Sci 18(8). https://doi.org/10.3390/ijms18081796

  28. 28.

    Hospital HU (2006) Heidelberger Manual der Lebertransplantation. (2.Auflage)

  29. 29.

    Grumaz S, Stevens P, Grumaz C, Decker SO, Weigand MA, Hofer S, Brenner T, von Haeseler A, Sohn K (2016) Next-generation sequencing diagnostics of bacteremia in septic patients. Genome Med 8(1):73. https://doi.org/10.1186/s13073-016-0326-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Salter SJ, Cox MJ, Turek EM, Calus ST, Cookson WO, Moffatt MF, Turner P, Parkhill J, Loman NJ, Walker AW (2014) Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol 12:87. https://doi.org/10.1186/s12915-014-0087-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Boonsarngsuk V, Niyompattama A, Teosirimongkol C, Sriwanichrak K (2010) False-positive serum and bronchoalveolar lavage Aspergillus galactomannan assays caused by different antibiotics. Scand J Infect Dis 42(6–7):461–468. https://doi.org/10.3109/00365541003602064

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Metan G (2013) The interaction between piperacillin-tazobactam and Aspergillus galactomannan antigenemia assay: is the story over? Infection 41(1):293–294. https://doi.org/10.1007/s15010-012-0327-5

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Morris PJ (2004) Transplantation—a medical miracle of the 20th century. N Engl J Med 351(26):2678–2680. https://doi.org/10.1056/NEJMp048256

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Sayegh MH, Carpenter CB (2004) Transplantation 50 years later—progress, challenges, and promises. N Engl J Med 351(26):2761–2766. https://doi.org/10.1056/NEJMon043418

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Li C, Wen TF, Mi K, Wang C, Yan LN, Li B (2012) Analysis of infections in the first 3-month after living donor liver transplantation. World J Gastroenterol 18(16):1975–1980. https://doi.org/10.3748/wjg.v18.i16.1975

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Kaltenborn A, Hartmann C, Salinas R, Ramackers W, Kleine M, Vondran FW, Barthold M, Lehner F, Klempnauer J, Schrem H (2015) Risk factors for short- and long-term mortality in liver transplant recipients with MELD score >/= 30. Ann Transplant 20:59–69. https://doi.org/10.12659/AOT.892322

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Sganga G, Bianco G, Frongillo F, Lirosi MC, Nure E, Agnes S (2014) Fungal infections after liver transplantation: incidence and outcome. Transplant Proc 46(7):2314–2318. https://doi.org/10.1016/j.transproceed.2014.07.056

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Smoter P, Nyckowski P, Grat M, Patkowski W, Zieniewicz K, Wronka K, Hinderer B, Morawski M (2014) Risk factors of acute renal failure after orthotopic liver transplantation: single-center experience. Transplant Proc 46(8):2786–2789. https://doi.org/10.1016/j.transproceed.2014.09.044

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Kawagishi N, Satoh K, Enomoto Y, Akamatsu Y, Sekiguchi S, Fujimori K, Satomi S (2006) Risk factors and impact of beta-D glucan on invasive fungal infection for the living donor liver transplant recipients. Tohoku J Exp Med 209(3):207–215

    CAS  Article  Google Scholar 

  40. 40.

    Fortun J, Martin-Davila P, Moreno S, De Vicente E, Nuno J, Candelas A, Barcena R, Garcia M (2002) Risk factors for invasive aspergillosis in liver transplant recipients. Liver Transpl 8(11):1065–1070. https://doi.org/10.1053/jlts.2002.36239

    Article  PubMed  Google Scholar 

  41. 41.

    Gladdy RA, Richardson SE, Davies HD, Superina RA (1999) Candida infection in pediatric liver transplant recipients. Liver Transpl Surg 5(1):16–24

    CAS  Article  Google Scholar 

  42. 42.

    Nieto-Rodriguez JA, Kusne S, Manez R, Irish W, Linden P, Magnone M, Wing EJ, Fung JJ, Starzl TE (1996) Factors associated with the development of candidemia and candidemia-related death among liver transplant recipients. Ann Surg 223(1):70–76

    CAS  Article  Google Scholar 

  43. 43.

    Cornely OA, Bassetti M, Calandra T, Garbino J, Kullberg BJ, Lortholary O, Meersseman W, Akova M, Arendrup MC, Arikan-Akdagli S, Bille J, Castagnola E, Cuenca-Estrella M, Donnelly JP, Groll AH, Herbrecht R, Hope WW, Jensen HE, Lass-Florl C, Petrikkos G, Richardson MD, Roilides E, Verweij PE, Viscoli C, Ullmann AJ, Group EFIS (2012) ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect 18(Suppl 7):19–37. https://doi.org/10.1111/1469-0691.12039

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Avni T, Leibovici L, Paul M (2011) PCR diagnosis of invasive candidiasis: systematic review and meta-analysis. J Clin Microbiol 49(2):665–670. https://doi.org/10.1128/JCM.01602-10

    Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Cummings LA, Kurosawa K, Hoogestraat DR, SenGupta DJ, Candra F, Doyle M, Thielges S, Land TA, Rosenthal CA, Hoffman NG, Salipante SJ, Cookson BT (2016) Clinical next generation sequencing outperforms standard microbiological culture for characterizing polymicrobial samples. Clin Chem 62(11):1465–1473. https://doi.org/10.1373/clinchem.2016.258806

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Long Y, Zhang Y, Gong Y, Sun R, Su L, Lin X, Shen A, Zhou J, Caiji Z, Wang X, Li D, Wu H, Tan H (2016) Diagnosis of sepsis with cell-free DNA by next-generation sequencing technology in ICU patients. Arch Med Res 47(5):365–371. https://doi.org/10.1016/j.arcmed.2016.08.004

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Grumaz C, Kirstahler P, Sohn K (2017) The molecular blueprint of a fungus by next-generation sequencing (NGS). Methods Mol Biol 1508:361–383. https://doi.org/10.1007/978-1-4939-6515-1_21

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Digby J, Kalbfleisch J, Glenn A, Larsen A, Browder W, Williams D (2003) Serum glucan levels are not specific for presence of fungal infections in intensive care unit patients. Clin Diagn Lab Immunol 10(5):882–885

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Marty FM, Lowry CM, Lempitski SJ, Kubiak DW, Finkelman MA, Baden LR (2006) Reactivity of (1-->3)-beta-d-glucan assay with commonly used intravenous antimicrobials. Antimicrob Agents Chemother 50(10):3450–3453. https://doi.org/10.1128/AAC.00658-06

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Prattes J, Schneditz D, Pruller F, Jaindl E, Sauseng N, Hoenigl M, Schilcher G, Krause R (2017) 1,3-ss-d-Glucan testing is highly specific in patients undergoing dialysis treatment. J Inf Secur 74(1):72–80. https://doi.org/10.1016/j.jinf.2016.09.005

    Article  Google Scholar 

  51. 51.

    Metan G, Koc AN, Kaynar LG, Atalay A, Ozturk A, Eser B, Cetin M (2013) What is the role of the (1-->3)-beta-D-glucan assay in the screening of patients undergoing autologous haematopoietic stem-cell transplantation? Mycoses 56(1):34–38. https://doi.org/10.1111/j.1439-0507.2012.02195.x

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Mikulska M, Furfaro E, Del Bono V, Raiola AM, Ratto S, Bacigalupo A, Viscoli C (2012) Piperacillin/tazobactam (Tazocin) seems to be no longer responsible for false-positive results of the galactomannan assay. J Antimicrob Chemother 67(7):1746–1748. https://doi.org/10.1093/jac/dks111

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Furfaro E, Mikulska M, Del Bono V, Guolo F, Minetto P, Gobbi M, Ghiso A, Bacigalupo A, Viscoli C (2014) Bloodstream infections are an improbable cause of positive serum (1,3)-beta-D-glucan in hematology patients. Clin Vaccine Immunol 21(9):1357–1359. https://doi.org/10.1128/CVI.00214-14

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Denning DW (1998) Invasive aspergillosis. Clin Infect Dis 26(4):781–803 quiz 804-785

    CAS  Article  Google Scholar 

  55. 55.

    Zedek DC, Miller MB (2006) Use of galactomannan enzyme immunoassay for diagnosis of invasive aspergillosis in a tertiary-care center over a 12-month period. J Clin Microbiol 44(4):1601. https://doi.org/10.1128/JCM.44.4.1601.2006

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Krause R, Zollner-Schwetz I, Salzer HJ, Valentin T, Rabensteiner J, Pruller F, Raggam R, Meinitzer A, Prattes J, Rinner B, Strohmaier H, Quehenberger F, Strunk D, Heidrich K, Buzina W, Hoenigl M (2015) Elevated levels of interleukin 17A and kynurenine in candidemic patients, compared with levels in noncandidemic patients in the intensive care unit and those in healthy controls. J Infect Dis 211(3):445–451. https://doi.org/10.1093/infdis/jiu468

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Cheng SC, van de Veerdonk F, Smeekens S, Joosten LA, van der Meer JW, Kullberg BJ, Netea MG (2010) Candida albicans dampens host defense by downregulating IL-17 production. J Immunol 185(4):2450–2457. https://doi.org/10.4049/jimmunol.1000756

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Kim N, Yoon YI, Yoo HJ, Tak E, Ahn CS, Song GW, Lee SG, Hwang S (2016) Combined detection of serum IL-10, IL-17, and CXCL10 predicts acute rejection following adult liver transplantation. Mol Cell 39(8):639–644. https://doi.org/10.14348/molcells.2016.0130

    CAS  Article  Google Scholar 

  59. 59.

    Hawkes JE, Yan BY, Chan TC, Krueger JG (2018) Discovery of the IL-23/IL-17 signaling pathway and the treatment of psoriasis. J Immunol 201(6):1605–1613. https://doi.org/10.4049/jimmunol.1800013

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Li Y, Wei C, Xu H, Jia J, Wei Z, Guo R, Jia Y, Wu Y, Li Y, Qi X, Li Z, Gao X (2018) The immunoregulation of Th17 in host against intracellular bacterial infection. Mediat Inflamm 2018(6587296):1–13. https://doi.org/10.1155/2018/6587296

    CAS  Article  Google Scholar 

  61. 61.

    Angeletti S, Battistoni F, Fioravanti M, Bernardini S, Dicuonzo G (2013) Procalcitonin and mid-regional pro-adrenomedullin test combination in sepsis diagnosis. Clin Chem Lab Med 51(5):1059–1067. https://doi.org/10.1515/cclm-2012-0595

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Miguel D, Prieto B, Alvarez FV (2013) Biological variation and prognosis usefulness of new biomarkers in liver transplantation. Clin Chem Lab Med 51(6):1241–1249. https://doi.org/10.1515/cclm-2012-0713

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Fabrega E, Crespo J, Casafont F, de La Pena J, Garcia-Unzueta MT, Amado JA, Pons-Romero F (1999) Adrenomedullin in liver transplantation and its relationship with vascular complications. Liver Transpl Surg 5(6):485–490

    CAS  Article  Google Scholar 

  64. 64.

    Geny B, Ellero B, Charloux A, Brandenberger G, Doutreleau S, Piquard F (2003) Circulating adrenomedullin is increased in relation with increased creatinine and atrial natriuretic peptide in liver-transplant recipients. Regul Pept 114(1):61–66

    CAS  Article  Google Scholar 

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Acknowledgements

We would like to thank Ute Krauser and Karolina Glanz for their excellent technical assistance.

Funding

The study was conducted with the financial support of the Department of Anesthesiology (Heidelberg University Hospital, Germany) and Fraunhofer IGB (Stuttgart, Germany). Furthermore, this study received financial grants from the B. Braun Foundation, Melsungen, as well as the Heidelberg Foundation of Surgery, and was supported by the European Union grant Fungitect. MR-proADM measurements were carried out by BRAHMS GmbH.

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SOD conceived the study, participated in its design and coordination, and helped in drafting the article. Furthermore, he performed data acquisition, carried out the measurements in the laboratory, and prepared the tables and figures. AK and HW performed data acquisition and were involved in critical revision of the article. FU, FCFS, AM, MM, KHW, MAW, and SH participated in the design of the study and were involved in revising the article. TBru participated in the design of the study and performed the statistical analysis. SZ performed all microbiological analyses and was involved in critical revision of the article. SG, YV, and KS were responsible for NGS-based diagnostics and revised the article critically. TBre conceived the study, participated in its design and coordination, and drafted the article. All authors read and approved the final manuscript.

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Correspondence to Kai Sohn or Thorsten Brenner.

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Decker, S.O., Krüger, A., Wilk, H. et al. New approaches for the detection of invasive fungal diseases in patients following liver transplantation—results of an observational clinical pilot study. Langenbecks Arch Surg 404, 309–325 (2019). https://doi.org/10.1007/s00423-019-01769-y

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Keywords

  • Candida spp.
  • Aspergillus spp.
  • Next-generation sequencing
  • Interleukin-17A
  • ß-D-glucan
  • Mid-regional proadrenomedullin