Skip to main content
Top
Published in: BMC Immunology 1/2019

Open Access 01-12-2019 | Stem Cell Transplantation | Research article

Low pre-transplant levels of mannose-binding lectin are associated with viral infections and mortality after haematopoietic allogeneic stem cell transplantation

Authors: M. Puente, C. Fariñas-Alvarez, A. Moreto, P. Sánchez-Velasco, J. G. Ocejo-Vinyals, M. C. Fariñas, on behalf of SCT team

Published in: BMC Immunology | Issue 1/2019

Login to get access

Abstract

Background

Mannose-binding lectin (MBL) is a key component of innate immunity. Low serum MBL levels, related to promoter polymorphism and structural variants, have been associated with an increased risk of infection. The aim of this work was to analyse the incidence and severity of infections and mortality in relation to the MBL2 genotype and MBL levels in patients underwent allogeneic haematopoietic stem cell transplantation (Allo-HSCT).

Results

This was a prospective cohort study of 72 consecutive patients underwent Allo-HSCT between January 2007 and June 2009 in a tertiary referral centre. Three periods were considered in the patients’ follow-up: the early period (0–30 days after Allo-HSCT), the intermediate period (30–100 days after Allo-HSCT) and the late period (> 100 days after Allo-HSCT). A commercial line probe assay for MBL2 genotyping and an ELISA Kit were used to measure MBL levels. A total of 220 episodes of infection were collected in the 72 patients. No association between donor or recipient MBL2 genotype and infection was found. The first episode of infection presented earlier in patients with pre-transplant MBL levels of < 1000 ng/ml (median 6d vs 8d, p = 0.036). MBL levels < 1000 ng/ml in the pre-transplant period (risk ratio (RR) 2.48, 95% CI 1.00–6.13), neutropenic period (0–30 days, RR 3.28, 95% CI 1.53–7.06) and intermediate period (30–100 days, RR 2.37, 95% CI 1.15–4.90) were associated with increased risk of virus infection. No association with bacterial or fungal disease was found. Mortality was associated with pre-transplant MBL levels < 1000 ng/ml (hazard ratio 5.55, 95% CI 1.17–26.30, p = 0.03) but not with MBL2 genotype.

Conclusions

Patients who underwent Allo-HSCT with low pre-transplant MBL levels presented the first episode of infection earlier and had an increased risk of viral infections and mortality in the first 6 months post-transplant. Thus, pre-transplant MBL levels would be important in predicting susceptibility to viral infections and mortality and might be considered a biomarker to be included in the pre-transplantation risk assessment.
Appendix
Available only for authorised users
Literature
1.
go back to reference Kim SH, Kee SY, Lee DG, Choi SM, Park SH, Kwon JC, et al. Infectious complications following allogeneic stem cell transplantation: reduced-intensity vs myeloablative conditioning regimens. Transpl Infect Dis. 2013;15:49–59.CrossRef Kim SH, Kee SY, Lee DG, Choi SM, Park SH, Kwon JC, et al. Infectious complications following allogeneic stem cell transplantation: reduced-intensity vs myeloablative conditioning regimens. Transpl Infect Dis. 2013;15:49–59.CrossRef
2.
go back to reference Frère P, Baron F, Bonnet C, Hafraoui K, Pereira M, Willems E, et al. Infections after allogeneic hematopoietic stem cell transplantation with a nonmyeloablative conditioning regimen. Bone Marrow Transplant. 2006;37:411–8.CrossRef Frère P, Baron F, Bonnet C, Hafraoui K, Pereira M, Willems E, et al. Infections after allogeneic hematopoietic stem cell transplantation with a nonmyeloablative conditioning regimen. Bone Marrow Transplant. 2006;37:411–8.CrossRef
3.
go back to reference Frère P, Hermanne JP, Debouge MH, de Mol P, Fillet G, Beguin Y. Bacteremia after hematopoietic stem cell transplantation: incidence and predictive value of surveillance cultures. Bone Marrow Transplant. 2004;33:745–9.CrossRef Frère P, Hermanne JP, Debouge MH, de Mol P, Fillet G, Beguin Y. Bacteremia after hematopoietic stem cell transplantation: incidence and predictive value of surveillance cultures. Bone Marrow Transplant. 2004;33:745–9.CrossRef
4.
go back to reference Ip WK, Takahashi K, Ezekowitz RA, Stuart LM. Mannose-binding lectin and innate immunity. Immunol Rev. 2009;230:9–21.CrossRef Ip WK, Takahashi K, Ezekowitz RA, Stuart LM. Mannose-binding lectin and innate immunity. Immunol Rev. 2009;230:9–21.CrossRef
5.
go back to reference Eisen DP, Minchinton RM. Impact of mannose-binding lectin on susceptibility to infectious diseases. Clin Infect Dis. 2003;37:1496–505.CrossRef Eisen DP, Minchinton RM. Impact of mannose-binding lectin on susceptibility to infectious diseases. Clin Infect Dis. 2003;37:1496–505.CrossRef
6.
go back to reference Thiel S, Kolev M, Degn S, Steffensen R, Hansen AG, Ruseva M, et al. Polymorphisms in mannan-binding lectin (MBL)-associated serine protease 2 affect stability, binding to MBL, and enzymatic activity. J Immunol. 2009;182:2939–47.CrossRef Thiel S, Kolev M, Degn S, Steffensen R, Hansen AG, Ruseva M, et al. Polymorphisms in mannan-binding lectin (MBL)-associated serine protease 2 affect stability, binding to MBL, and enzymatic activity. J Immunol. 2009;182:2939–47.CrossRef
7.
go back to reference Thiel S, Frederiksen PD, Jensenius JC. Clinical manifestations of mannan-binding lectin deficiency. Mol Immunol. 2006;43:86–96.CrossRef Thiel S, Frederiksen PD, Jensenius JC. Clinical manifestations of mannan-binding lectin deficiency. Mol Immunol. 2006;43:86–96.CrossRef
8.
go back to reference Schlapbach LJ, Aebi C, Otth M, Luethy AR, Leibundgut K, Hirt A, et al. Serum levels of mannose-binding lectin and the risk of fever in neutropenia pediatric cancer patients. Pediatr Blood Cancer. 2007;49:11–6.CrossRef Schlapbach LJ, Aebi C, Otth M, Luethy AR, Leibundgut K, Hirt A, et al. Serum levels of mannose-binding lectin and the risk of fever in neutropenia pediatric cancer patients. Pediatr Blood Cancer. 2007;49:11–6.CrossRef
9.
go back to reference Vekemans M, Robinson J, Georgala A, Heymans C, Muanza F, Paesmans M, et al. Low mannose-binding lectin concentration is associated with severe infection in patients with hematological cancer who are undergoing chemotherapy. Clin Infect Dis. 2007;44:1593–601.CrossRef Vekemans M, Robinson J, Georgala A, Heymans C, Muanza F, Paesmans M, et al. Low mannose-binding lectin concentration is associated with severe infection in patients with hematological cancer who are undergoing chemotherapy. Clin Infect Dis. 2007;44:1593–601.CrossRef
10.
go back to reference Bergmann OJ, Christiansen M, Laursen I, Bang P, Hansen NE, Ellegaard J, et al. Low levels of mannose-binding lectin do not affect occurrence of severe infections or duration of fever in acute myeloid leukaemia during remission induction therapy. Eur J Haematol. 2003;70:91–7.CrossRef Bergmann OJ, Christiansen M, Laursen I, Bang P, Hansen NE, Ellegaard J, et al. Low levels of mannose-binding lectin do not affect occurrence of severe infections or duration of fever in acute myeloid leukaemia during remission induction therapy. Eur J Haematol. 2003;70:91–7.CrossRef
11.
go back to reference Frakking FN, Israëls J, Kremer LC, Kuijpers TW, Caron HN, Van de Wetering MD. Mannose-binding lectin (MBL) and the risk for febrile neutropenia and infection in pediatric oncology patients with chemotherapy. Pediatr Blood Cancer. 2011;57:89–96.CrossRef Frakking FN, Israëls J, Kremer LC, Kuijpers TW, Caron HN, Van de Wetering MD. Mannose-binding lectin (MBL) and the risk for febrile neutropenia and infection in pediatric oncology patients with chemotherapy. Pediatr Blood Cancer. 2011;57:89–96.CrossRef
12.
go back to reference Lausen B, Schmiegelow K, Andreassen B, Madsen HO, Garred P. Infections during induction therapy of childhood acute lymphoblastic leukemia – no association to mannose-binding lectin deficiency. Eur J Haematol. 2006;76:481–7.CrossRef Lausen B, Schmiegelow K, Andreassen B, Madsen HO, Garred P. Infections during induction therapy of childhood acute lymphoblastic leukemia – no association to mannose-binding lectin deficiency. Eur J Haematol. 2006;76:481–7.CrossRef
13.
go back to reference Riwes MM, Leather H, Neal D, Bennett C, Sugrue M, Cline C, et al. Association of mannose-binding lectin levels and invasive fungal disease in hematologic malignancy patients receiving myelosuppressive chemotherapy or allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2016;51:1228–32.CrossRef Riwes MM, Leather H, Neal D, Bennett C, Sugrue M, Cline C, et al. Association of mannose-binding lectin levels and invasive fungal disease in hematologic malignancy patients receiving myelosuppressive chemotherapy or allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2016;51:1228–32.CrossRef
14.
go back to reference Eleutherakis-Papaiakovou E, Dimopoulos MA, Kastritis E, Christoulas D, Roussou M, Migkou M, Gavriatopoulou M, Fotiou D, Panagiotidis I, Ziogas DC, Kanellias N, Papadimitriou C, Terpos E. Low circulating mannan-binding lectin levels correlate with increased frequency and severity of febrile episodes in myeloma patients who undergo ASCT and do not receive antibiotic prophylaxis. Bone Marrow Transplant. 2017;52(11):1537–42.CrossRef Eleutherakis-Papaiakovou E, Dimopoulos MA, Kastritis E, Christoulas D, Roussou M, Migkou M, Gavriatopoulou M, Fotiou D, Panagiotidis I, Ziogas DC, Kanellias N, Papadimitriou C, Terpos E. Low circulating mannan-binding lectin levels correlate with increased frequency and severity of febrile episodes in myeloma patients who undergo ASCT and do not receive antibiotic prophylaxis. Bone Marrow Transplant. 2017;52(11):1537–42.CrossRef
15.
go back to reference Mølle I, Peterslund NA, Thiel S, Steffensen R. MBL2 polymorphism and risk of severe infections in multiple myeloma patients receiving high-dose melphalan and autologous stem cell transplantation. Bone Marrow Transplant. 2006;38:555–60.CrossRef Mølle I, Peterslund NA, Thiel S, Steffensen R. MBL2 polymorphism and risk of severe infections in multiple myeloma patients receiving high-dose melphalan and autologous stem cell transplantation. Bone Marrow Transplant. 2006;38:555–60.CrossRef
16.
go back to reference Horiuchi T, Gondo H, Miyagawa H, Otsuka J, Inaba S, Nagafuji K, et al. Association of MBL gene polymorphisms with major bacterial infection in patients treated with high-dose chemotherapy and autologous PBSCT. Genes Immun. 2005;6:162–6.CrossRef Horiuchi T, Gondo H, Miyagawa H, Otsuka J, Inaba S, Nagafuji K, et al. Association of MBL gene polymorphisms with major bacterial infection in patients treated with high-dose chemotherapy and autologous PBSCT. Genes Immun. 2005;6:162–6.CrossRef
17.
go back to reference Moreto A, Fariñas-Alvarez C, Puente M, Ocejo-Vinyals JG, Sánchez-Velasco P, Horcajada JP, et al. Mannose-binding lectin gene variants and infections in patients receiving autologous stem cell transplantation. BMC Immunol. 2014;15:17.CrossRef Moreto A, Fariñas-Alvarez C, Puente M, Ocejo-Vinyals JG, Sánchez-Velasco P, Horcajada JP, et al. Mannose-binding lectin gene variants and infections in patients receiving autologous stem cell transplantation. BMC Immunol. 2014;15:17.CrossRef
18.
go back to reference Mullighan CG, Heatley SL, Danner S, Dean MM, Doherty K, Hahn U, et al. Mannose-bindins lectin status is associated with risk of major infection following myeloablative sibling allogeneic hematopoietic stem cell transplantation. Blood. 2008;112:2120–8.CrossRef Mullighan CG, Heatley SL, Danner S, Dean MM, Doherty K, Hahn U, et al. Mannose-bindins lectin status is associated with risk of major infection following myeloablative sibling allogeneic hematopoietic stem cell transplantation. Blood. 2008;112:2120–8.CrossRef
19.
go back to reference Osthoff M, Rovó A, Stern M, Danner D, Gratwohl A, Tichelli A, et al. Mannose-binding lectin levels and major infections in a cohort of very long-term survivors after allogenic stem cell transplantation. Haematologica. 2010;95:1389–96.CrossRef Osthoff M, Rovó A, Stern M, Danner D, Gratwohl A, Tichelli A, et al. Mannose-binding lectin levels and major infections in a cohort of very long-term survivors after allogenic stem cell transplantation. Haematologica. 2010;95:1389–96.CrossRef
20.
go back to reference Chaudhry SH, Chaudhry S, Jansen-Hoogendijk AM, Jol van der Zijde CM, van Tol MJ, Roos A, et al. Mannose-binding lectin levels and infections in children after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2010;45:289–93.CrossRef Chaudhry SH, Chaudhry S, Jansen-Hoogendijk AM, Jol van der Zijde CM, van Tol MJ, Roos A, et al. Mannose-binding lectin levels and infections in children after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2010;45:289–93.CrossRef
21.
go back to reference Granell M, Urbano-Ispizua A, Suarez B, Rovira M, Fernández-Avilés F, Martínez C, et al. Mannan-binding lectin pathway deficiencies and invasive fungal infections following allogeneic stem cell transplantation. Exp Hematol. 2006;34:1435–341.CrossRef Granell M, Urbano-Ispizua A, Suarez B, Rovira M, Fernández-Avilés F, Martínez C, et al. Mannan-binding lectin pathway deficiencies and invasive fungal infections following allogeneic stem cell transplantation. Exp Hematol. 2006;34:1435–341.CrossRef
22.
go back to reference Rocha V, Franco RF, Porcher R, Bittencourt H, Silva WA Jr, Latouche A, et al. Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation. Blood. 2002;100:3908–18.CrossRef Rocha V, Franco RF, Porcher R, Bittencourt H, Silva WA Jr, Latouche A, et al. Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation. Blood. 2002;100:3908–18.CrossRef
23.
go back to reference Mullighan CG, Heatley S, Doherty K, Szabo F, Grigg A, Hughes TP, et al. Mannose-binding lectin gene polymorphisms are associated with major infection following allogeneic hemopoietic stem cell transplantation. Blood. 2002;99:3524–9.CrossRef Mullighan CG, Heatley S, Doherty K, Szabo F, Grigg A, Hughes TP, et al. Mannose-binding lectin gene polymorphisms are associated with major infection following allogeneic hemopoietic stem cell transplantation. Blood. 2002;99:3524–9.CrossRef
24.
go back to reference Neth OW, Bacher U, Das P, Zabelina T, Kabisch H, Kroeger N, et al. Influence of mannose-binding lectin genotypes and serostatus in Allo-SCT: analysis of 131 recipients and donors. Bone Marrow Transplant. 2010;45:13–9.CrossRef Neth OW, Bacher U, Das P, Zabelina T, Kabisch H, Kroeger N, et al. Influence of mannose-binding lectin genotypes and serostatus in Allo-SCT: analysis of 131 recipients and donors. Bone Marrow Transplant. 2010;45:13–9.CrossRef
25.
go back to reference Kilpatrick DC, Stewart K, Allan EK, McLintock LA, Holyoake TL, Turner ML. Successful haemopoietic stem cell transplantation does not correct mannan-binding lectin deficiency. Bone Marrow Transplant. 2005;35:179–81.CrossRef Kilpatrick DC, Stewart K, Allan EK, McLintock LA, Holyoake TL, Turner ML. Successful haemopoietic stem cell transplantation does not correct mannan-binding lectin deficiency. Bone Marrow Transplant. 2005;35:179–81.CrossRef
26.
go back to reference Kase T, Suzuki Y, Kawai T, Sakamoto T, Ohtani K, Eda S, et al. Human mannan-binding lectin inhibits the infection of influenza a virus without complement. Immunology. 1999;97:385–92.CrossRef Kase T, Suzuki Y, Kawai T, Sakamoto T, Ohtani K, Eda S, et al. Human mannan-binding lectin inhibits the infection of influenza a virus without complement. Immunology. 1999;97:385–92.CrossRef
27.
go back to reference Gadjeva M, Paludan SR, Thiel S, Slavov V, Ruseva M, Eriksson K, et al. Mannan-binding lectin modulates the response to HSV-2 infection. Clin Exp Immunol. 2004;138:304–11.CrossRef Gadjeva M, Paludan SR, Thiel S, Slavov V, Ruseva M, Eriksson K, et al. Mannan-binding lectin modulates the response to HSV-2 infection. Clin Exp Immunol. 2004;138:304–11.CrossRef
28.
go back to reference Manuel O, Pascual M, Trendelenburg M, Meylan PR. Association between mannose-binding lectin deficiency and cytomegalovirus infection after kidney transplantation. Transplantation. 2007;83:359–62.CrossRef Manuel O, Pascual M, Trendelenburg M, Meylan PR. Association between mannose-binding lectin deficiency and cytomegalovirus infection after kidney transplantation. Transplantation. 2007;83:359–62.CrossRef
29.
go back to reference Kwakkel-van Erp JM, Paantjens AW, van Kessel DA, Grutters JC, van den Bosch JM, van de Graaf EA, et al. Mannose-binding lectin deficiency linked to cytomegalovirus (CMV) reactivation and survival in lung transplantation. Clin Exp Immunol. 2011;165:410–6.CrossRef Kwakkel-van Erp JM, Paantjens AW, van Kessel DA, Grutters JC, van den Bosch JM, van de Graaf EA, et al. Mannose-binding lectin deficiency linked to cytomegalovirus (CMV) reactivation and survival in lung transplantation. Clin Exp Immunol. 2011;165:410–6.CrossRef
30.
go back to reference Hellemann D, Larsson A, Madsen HO, Bonde J, Jarløv JO, Wiis J, et al. Heterozygosity of mannose-binding lectin (MBL2) genotypes predicts advantage (heterosis) in relation to fatal outcome in intensive care patients. Hum Mol Genet. 2007;16:3071–80.CrossRef Hellemann D, Larsson A, Madsen HO, Bonde J, Jarløv JO, Wiis J, et al. Heterozygosity of mannose-binding lectin (MBL2) genotypes predicts advantage (heterosis) in relation to fatal outcome in intensive care patients. Hum Mol Genet. 2007;16:3071–80.CrossRef
31.
go back to reference Cervera C, Balderramo D, Suárez B, Prieto J, Fuster F, Linares L, et al. Donor mannose-binding lectin gene polymorphisms b influence the outcome of liver transplantation. Liver Transpl. 2009;15:1217–24.CrossRef Cervera C, Balderramo D, Suárez B, Prieto J, Fuster F, Linares L, et al. Donor mannose-binding lectin gene polymorphisms b influence the outcome of liver transplantation. Liver Transpl. 2009;15:1217–24.CrossRef
32.
go back to reference Ibernon M, Moreso F, O’Valle F, Grinyo JM, Moral RG, Seron D. Low serum mannose-binding lectin levels are associated with inflammation and apoptosis in early surveillance allograft biopsies. Transplant Immunol. 2014;31:152–6.CrossRef Ibernon M, Moreso F, O’Valle F, Grinyo JM, Moral RG, Seron D. Low serum mannose-binding lectin levels are associated with inflammation and apoptosis in early surveillance allograft biopsies. Transplant Immunol. 2014;31:152–6.CrossRef
33.
go back to reference Liu XH, Li Q, Zhang P, Su Y, Zhang XR, Sun Q. Serum mannose-binding lectin and C-reactive protein are potential biomarkers for patients with community-acquired pneumonia. Genet Test Mol Biomarkers. 2014;18:630–5.CrossRef Liu XH, Li Q, Zhang P, Su Y, Zhang XR, Sun Q. Serum mannose-binding lectin and C-reactive protein are potential biomarkers for patients with community-acquired pneumonia. Genet Test Mol Biomarkers. 2014;18:630–5.CrossRef
34.
go back to reference Eisen DP, Dean MM, Boermeester MA, Fidler KJ, Gordon AC, Kronborg G, et al. Low serum mannose-binding lectin level increases the risk of death due to pneumococcal infection. Clin Infect Dis. 2008;47:510–6.CrossRef Eisen DP, Dean MM, Boermeester MA, Fidler KJ, Gordon AC, Kronborg G, et al. Low serum mannose-binding lectin level increases the risk of death due to pneumococcal infection. Clin Infect Dis. 2008;47:510–6.CrossRef
35.
go back to reference Gao D-N, Zhang Y, Ren Y-B, Kang J, Jiang L, Feng Z, et al. Relationship of serum mannose-binding lectin levels with the development of sepsis: a meta-analysis. Inflammation. 2015;38:338–47.CrossRef Gao D-N, Zhang Y, Ren Y-B, Kang J, Jiang L, Feng Z, et al. Relationship of serum mannose-binding lectin levels with the development of sepsis: a meta-analysis. Inflammation. 2015;38:338–47.CrossRef
36.
go back to reference Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;34:730–51.CrossRef Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;34:730–51.CrossRef
37.
go back to reference Razonable RR, Paya CV, Smith TF. Role of the laboratory in diagnosis and management of cytomegalovirus infection in hematopoietic stem cell and solid-organ transplant recipients. J Clin Microbiol. 2002;40:746–52.CrossRef Razonable RR, Paya CV, Smith TF. Role of the laboratory in diagnosis and management of cytomegalovirus infection in hematopoietic stem cell and solid-organ transplant recipients. J Clin Microbiol. 2002;40:746–52.CrossRef
Metadata
Title
Low pre-transplant levels of mannose-binding lectin are associated with viral infections and mortality after haematopoietic allogeneic stem cell transplantation
Authors
M. Puente
C. Fariñas-Alvarez
A. Moreto
P. Sánchez-Velasco
J. G. Ocejo-Vinyals
M. C. Fariñas
on behalf of SCT team
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Immunology / Issue 1/2019
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/s12865-019-0318-8

Other articles of this Issue 1/2019

BMC Immunology 1/2019 Go to the issue