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Haematology (incl blood transfusion)
Protocol
Protocol for updating a systematic review of randomised controlled trials on the prophylactic use of intravenous immunoglobulin for patients undergoing haematopoietic stem cell transplantation
  1. Juthaporn Cowan1,
  2. D W Cameron1,2,
  3. Greg Knoll2,3,
  4. Jason Tay2,4
  1. 1Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  2. 2Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  3. 3Renal Transplantation, Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  4. 4Blood and Marrow Transplant Program, The Ottawa Hospital, Ottawa, Ontario, Canada
  1. Correspondence to Dr Juthaporn Cowan; jcowan{at}toh.on.ca

Abstract

Introduction Haematopoietic stem cell transplantation (HSCT) is commonly employed in the management of haematological malignancies. This intervention results in an increased risk of infectious and immune-related complications. Prophylactic immunoglobulin therapy has been used to prevent post-HSCT complications, including infections, with varying efficacy. We sought to update the current evidence supporting the use of immunoglobulins in the modern HSCT era.

Methods/analysis Using a structured search strategy, we will perform a systematic review of the literature from MEDLINE, EMBASE and all EBM Reviews databases. We will include randomised clinical trials investigating clinical outcomes of prophylactic polyvalent immunoglobulin or cytomegalovirus (CMV)-specific immunoglobulin or plasma in patients undergoing HSCT. Clinical outcomes will include overall survival, transplant-related mortality, CMV infection, CMV disease, graft-versus-host disease, interstitial pneumonitis/fibrosis and hepatic veno-occlusive disease. Studies that only reported the results of biochemical tests will be excluded. Data will be extracted by two investigators independently. Study quality assessment will be evaluated using a validated five-point system as proposed by Jadad. Trial quality will be further assessed by identifying whether there was adequate allocation concealment. Where appropriate, a meta-analysis will be performed where relative risk will be used as the primary summary measure with 95% CIs. Pooled measures will be calculated for randomised clinical trials using a random-effects model. The Cochrane Q/χ2 test and I2 statistic will also be calculated to evaluate heterogeneity. We will also use a visual inspection of a funnel plot to assess potential publication bias.

Discussion This systematic review aims to provide current evidence to justify the use of immunoglobulin prophylaxis in HSCT recipients. We will discuss whether current HSCT guidelines are supported by the current evidence, and whether further trials are needed, given the changing landscape of patients undergoing HSCT and the immunoglobulin manufacturing process.

Systematic review registration PROSPERO CRD42015016684.

  • Immunoglobulin
  • Prophylaxis
  • Hematopoietic stem cell transplantation
  • clinical outcomes

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/bmjopen-2015-008316

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    Strengths and limitations of this study

    • Rigorous study selection, data extraction, quality assessment and data synthesis.

    • Predefined a priori sensitivity analyses.

    • There may be a limited number of recent trials representing the haematopoietic stem cell transplantation population in the modern era.

    Introduction

    Haematopoietic stem cell transplantation (HSCT) is commonly employed in the management of a variety of malignancies.1 ,2 High-dose chemotherapy and/or radiotherapy are given to maximise the tumouricidal effects, followed by the timely infusion of stem cells to reconstitute the bone marrow and immune system. Pancytopaenia and immunodeficiency from therapy may cause potentially fatal bacterial, viral or fungal infections such as cytomegalovirus (CMV) and immune complications such as graft-versus-host disease,3–5 following transplantation.

    Intravenous immunoglobulin (IVIG) is a complex biological product with multiple potential mechanisms of action.6 IVIG is used in many HSCT centres to prevent infectious complication post-HSCT.7 ,8 For instance, at our centre, we have previously reported 31 and 13 doses of IVIG use during the first month post-HSCT in 77 autologous and 39 allogeneic transplant recipients.9 CMV-specific immunoglobulin and plasma preparations are also available, and have been reported to be superior to polyvalent IVIG in the management of CMV infections.10 ,11 However, a recent systematic review of immunoglobulin prophylaxis did not demonstrate a mortality benefit but, rather, showed an increased risk of a veno-occlusive side effect.12 Consequently, current societal guidelines do not recommend the routine use of immunoglobulin prophylaxis in recipients of HSCT.13 ,14 However, the clinical trials included in the previous systematic review were mostly published before the year 2000.12 Further, there are other limitations in this review that deserve mention. First, the review included non-randomised studies;15 second, some studies only looked at biochemical surrogates, which may not correlate with patient relevant ‘hard’ outcomes and, lastly, results from higher quality studies were not separately analysed, potentially introducing bias. Moreover, the landscape of patients receiving HSCT has evolved in the past decade. Patients undergoing HSCT are older and are more likely to be immunocompromised.16 Further, HSCT technology including conditioning and chemosuppressive measures has also evolved.2 ,17–19 Finally, the technology of immunoglobulin production has evolved, resulting in intact IgG preparations with normal half-life and effector functions, and with higher pathogen safety.20 Taken together, the prior available evidence may not be adequate to inform current HSCT practice.

    We seek to conduct a comprehensive systematic review of available evidence from prospective randomised controlled clinical trials assessing the use of immunoglobulins in HSCT that report clinically important end points.

    Aims and objectives

    Our overarching objective is to update, summarise and quantify the clinical effects of prophylactic immunoglobulins in the context of HSCT. Specifically, we seek to evaluate the utility of peri-HSCT use of IVIG on mortality, post-HSCT complications, infections and relapse post-HSCT.

    Methods/design

    Search strategy

    The systematic search strategy will include MEDLINE (1966 to February 2015), EMBASE (1980 to February 2015) and all EBM Reviews (December 2014). A Dickersin et al21 filter will be used to aid identification of randomised controlled trials (RCTs). A Google Scholar search will be performed in order to identify any grey literature. Studies relevant to animals but not to humans will be excluded. Publications, regardless of language, and regardless of whether they were published as conference proceedings, abstracts or journals, will be included in our review. Local HSCT physicians will also be approached to identify additional relevant studies/trials. References to selected articles will be examined by two reviewers (JT and JC) to identify relevant citations.

    Draft of search strategy

    Database: Embase Classic+Embase <1947 to 2015 February >, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) <1946 to Present>

    1. Hematopoietic Stem Cell Transplantation/

    2. h?ematopoietic stem cell transplant$.tw.

    3. (hsct or h?ematopoietic sct).tw.

    4. stem cell transplant$.tw.

    5. Peripheral Blood Stem Cell Transplantation/ or pbsct.tw.

    6. (peripheral blood cell transplant$ or peripheral blood stem cell transplant$ or peripheral stem cell transplant$).tw.

    7. Bone Marrow Transplantation/ or (bone marrow transplant$ or bmt).tw.

    8. blood transplant$.tw.

    9. ((autologous or allogeneic or allogenic) adj2 (transplant$ or graft$)).tw.

    10. or/1-9

    11. exp Immunoglobulins/ and (exp Immunization, Passive/ or exp Administration, Intravenous/ or exp Injections, Subcutaneous/ or exp Infusions, Subcutaneous/)

    12. Immunoglobulin$.tw.

    13. Immune Globulin$.tw.

    14. (ivig or (Intravenous adj5 IG) or (iv adj5 ig) or (iv adj5 igg)).tw.

    15. or/11-14

    16. 10 and 15

    17. randomized controlled trial.pt.

    18. controlled clinical trial.pt.

    19. random$.tw.

    20. placebo.ab.

    21. clinical trials as topic.sh.

    22. trial.ti.

    23. or/17-22

    24. animals/ not humans/

    25. 23 not 24

    26. 16 and 25

    27. guideline.pt.

    28. practice guideline.pt.

    29. guidelines as topic/ or practice guidelines as topic/

    30. guideline$.tw.

    31. 27 or 28 or 29 or 30

    32. 16 and 31

    33. 26 or 32

    34. 33 use prmz

    35. exp hematopoietic stem cell transplantation/

    36. h?ematopoietic stem cell transplant$.tw.

    37. (hsct or h?ematopoietic sct).tw.

    38. stem cell transplant$.tw.

    39. peripheral blood stem cell transplantation/

    40. pbsct.tw.

    41. (peripheral blood cell transplant$ or peripheral blood stem cell transplant$ or peripheral stem cell transplant$).tw.

    42. bone marrow transplantation/

    43. (bone marrow transplant$ or bmt).tw.

    44. blood transplant$.tw.

    45. ((autologous or allogeneic or allogenic) adj2 (transplant$ or graft$)).tw.

    46. or/35-45

    47. exp immunoglobulin/iv, sc [Intravenous Drug Administration, Subcutaneous Drug Administration]

    48. exp immunoglobulin/ and (intravenous drug administration/ or subcutaneous drug administration/ or passive immunization/)

    49. immunoglobulin$.tw.

    50. Immune Globulin$.tw.

    51. (ivig or (Intravenous adj5 IG) or (iv adj5 ig) or (iv adj5 igg)).tw.

    52. or/47–51

    53. 46 and 52

    54. random$.tw. or placebo$.mp. or double-blind$.tw.

    55. practice guideline/

    56. guideline$.tw.

    57. 54 or 55 or 56

    58. 53 and 57

    59. 58 use emczd

    60. 34 or 59

    61. remove duplicates from 60

    62. 61 use prmz Medline Search

    63. 61 use emczd Embase Search

    Inclusion and exclusion criteria

    Inclusion criteria will be prospective randomised controlled clinical trials, patients undergoing HSCT, patients receiving polyvalent IVIG or subcutaneous immunoglobulin, or CMV-specific immunoglobulin or plasma (CMVIG) prophylaxis, use of a comparator arm, studies reporting clinical outcomes of overall survival (primary outcome), transplant-related mortality, CMV infections, CMV diseases, non-CMV infections including bacterial, fungal, other viral infections, graft-versus-host disease, interstitial pneumonitis veno-occlusive disease and relapse of the underlying haematological condition. Studies that only reported the results of biochemical tests will be excluded from our review given the potential that it may not correlate with patient centred hard outcomes.

    Outcome measures

    Primary outcome: Overall survival is defined as survival with varying subsequent follow-up times as defined by the individual studies (at least 100 days).

    Secondary outcomes: (1) Transplant-related mortality; (2) CMV infection; (3) CMV disease; (4) non-CMV infection, which will be further stratified to bacterial, fungal and other viral infection; (5) hepatic veno-occlusive disease, broadly defined as weight gain or fluid accumulation, elevated bilirubin and abdominal pain; (6) graft-versus-host disease and interstitial pneumonitis/fibrosis, defined by the individual studies and (7) disease relapse.

    Definition

    • Transplant related mortality=death within 100–120 days of HSCT

    • CMV infection=recovery of the virus from the throat, urine or blood, seroconversion of a patient or significant increase in CMV viral copies in the absence of any clinical signs or symptoms of disease

    • CMV disease=symptomatic infection, recovery of virus from a visceral site or histological evidence of infection

    • Bacterial infection=reported infection due to microbiologically confirmed bacteria

    • Viral infection=reported infection due to microbiologically confirmed virus other than CMV

    • Fungal infection=reported infection due to microbiologically confirmed fungus

    Data extraction

    Two reviewers (JT and JC) will independently review the abstracts and apply our trial eligibility criteria. Any discrepancies will be documented, discussed and adjudicated by a third party (DWC). The two reviewers (JT and JC) will assess trial quality and extract the data using a standardised data abstraction form and data entry onto Microsoft Excel, to assist with data management. Similarly, discrepancies will be documented, discussed and adjudicated by a third party (DWC).

    Quality assessment

    The methodological quality of randomised studies will be evaluated by two reviewers (JT and JC) using a validated five-point system as proposed by Jadad.22 A quality score of 3 or greater will be considered high quality.22 Trial quality will be further assessed by identifying whether there was adequate allocation concealment.23 The quality of evidence across studies will be assessed for each outcome using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

    Risk of bias assessment

    The following domains of potential bias will be assessed by two reviewers (JT and JC) and any discrepancies will be discussed and adjudicated by DWC and GK: (1) selection bias (random sequence generation and allocation concealment); (2) performance bias (blinding of participants and personnel); and (3) detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data) and reporting bias (selective reporting).

    Data analysis/synthesis

    Relative risk will be used as the primary summary measure with 95% CIs. Pooled measures will be calculated for randomised clinical trials using a random-effects model. A relative risk of <1 would suggest a beneficial effect of IVIG, while a relative risk of >1 would suggest a harmful effect. Individual trial estimates and pooled estimates will be performed using Review Manager software (Cochrane Collaboration’s Information Management System).24 The Cochrane Q/χ2 test and I2 statistic will also be calculated to evaluate heterogeneity. We will use a visual inspection of a funnel plot to assess potential publication bias.25 ,26

    We will perform several a priori sensitivity analyses to understand the data and to identify any subpopulations that may benefit from the use of IVIG. These analyses include: type of HSCT (autologous or allogeneic), conditioning regimen, indication for transplant, type of IVIG used (IVIG or CMVIG), dose of IVIG used (≤2, >2, ≤5 and >5 g/kg), IgG levels (IgG <4 g/L and ≥4 g/L), methological quality of RCTs (Jadad scores ≥3 or <3), as well as year of publication of the study (before or after 2000).

    A systematic narrative synthesis will be provided with information presented in the text and tables to summarise and explain the characteristics and findings of the included studies. The narrative synthesis will explore the relationship and findings both within and between the included studies, in line with the guidance from the Centre for Reviews and Dissemination.

    Discussion

    A systematic review of immunoglobulin prophylaxis in HSCT published in 2009 analysed 30 studies.12 Some were not RCTs, or they only measured biochemical test results. Most studies (25/30) were published before the year 2000, when patients were less complex. The current guidelines14 recommended against use of prophylactic IVIG in HSCT, although IVIG prophylaxis may be considered in patients with severe hypogammaglobulinaemia (IgG <4 g/L). The latter statement was not supported by strong evidence.

    Our systematic review will update the current evidence on the use of immunoglobulin prophylaxis and may stimulate a re-evaluation of our current practice and practice guidelines. It is likely that the available data are outdated, and more current randomised trials are required to inform practice.

    References

    1. ↵
      1. Copelan EA
      . Hematopoietic stem-cell transplantation. N Engl J Med 2006;354:1813–26. doi:10.1056/NEJMra052638
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Petersdorf EW,
      2. Hansen JA
      . New advances in hematopoietic cell transplantation. Curr Opin Hematol 2008;15:549–54. doi:10.1097/MOH.0b013e328311891f
      OpenUrlCrossRefPubMed
    3. ↵
      1. Afessa B,
      2. Peters SG
      . Major complications following hematopoietic stem cell transplantation. Semin Respir Crit Care Med 2006;27:297–309. doi:10.1055/s-2006-945530
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      1. Weisdorf D
      . GVHD the nuts and bolts. Hematology Am Soc Hematol Educ Program 2007;62–7. doi:10.1182/asheducation-2007.1.62
    5. ↵
      1. Newman RG,
      2. Ross DB,
      3. Barreras H, et al
      . The allure and peril of hematopoietic stem cell transplantation: overcoming immune challenges to improve success. Immunol Res 2013;57:125–39. doi:10.1007/s12026-013-8450-7
      OpenUrlPubMed
    6. ↵
      1. Lemieux R,
      2. Bazin R,
      3. Neron S
      . Therapeutic intravenous immunoglobulins. Mol Immunol 2005;42:839–48. doi:10.1016/j.molimm.2004.07.046
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      1. Darabi K,
      2. Abdel-Wahab O,
      3. Dzik WH
      . Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature. Transfusion 2006;46:741–53. doi:10.1111/j.1537-2995.2006.00792.x
      OpenUrl
    8. ↵
      1. Lin MW,
      2. Kirkpatrick PE,
      3. Riminton DS
      . How intravenous immunoglobulin is used in clinical practice: audits of two Sydney teaching hospitals. Intern Med J 2007;37:308–14. doi:10.1111/j.1445-5994.2007.01336.x
      OpenUrlPubMed
    9. ↵
      1. Alsughayir A,
      2. Neurath D,
      3. Salloum D, et al
      . One year audit of transfusion support in bone marrow transplant patients at The Ottawa Hospital. Transfus Med 2009;19:285–6.
      OpenUrl
    10. ↵
      1. King SM
      . Immune globulin versus antivirals versus combination for prevention of cytomegalovirus disease in transplant recipients. Antiviral Res 1999;40:115–37. doi:10.1016/S0166-3542(98)00050-3
      OpenUrlPubMed
    11. ↵
      1. Messori A,
      2. Rampazzo R,
      3. Scroccaro G, et al
      . Efficacy of hyperimmune anti-cytomegalovirus immunoglobulins for the prevention of cytomegalovirus infection in recipients of allogeneic bone marrow transplantation: a meta-analysis. Bone Marrow Transplant 1994;13:163–7.
      OpenUrlPubMed
    12. ↵
      1. Raanani P,
      2. Gafter-Gvili A,
      3. Paul M, et al
      . Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: systematic review and meta-analysis. J Clin Oncol 2009;27:770–81. doi:10.1200/JCO.2008.16.8450
      OpenUrlAbstract/FREE Full Text
    13. ↵
      1. Kivity S,
      2. Katz U,
      3. Daniel N, et al
      . Evidence for the use of intravenous immunoglobulins—a Review of the literature. Clinic Rev Allerg Immunol 2010;38:201–69. doi:10.1007/s12016-009-8155-9
      OpenUrl
    14. ↵
      1. Tomblyn M,
      2. Chiller T,
      3. Einsele H, et al
      ., Center for International Blood and Marrow Research; National Marrow Donor program; European Blood and MarrowTransplant Group; American Society of Blood and Marrow Transplantation; Canadian Blood and Marrow Transplant Group; Infectious Diseases Society of America; Society for Healthcare Epidemiology of America; Association of Medical Microbiology and Infectious Disease Canada; Centers for Disease Control and Prevention. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 2009;15:1143–238. doi:10.1016/j.bbmt.2009.06.019
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Graham-Pole J,
      2. Camitta B,
      3. Casper J, et al
      . Intravenous immunoglobulin may lessen all forms of infection in patients receiving allogeneic bone marrow transplantation for acute lymphoblastic leukemia: a pediatric oncology group study. Bone Marrow Transplant 1988;3:559–66.
      OpenUrlPubMed
    16. ↵
      1. Pasquini MC,
      2. Wang Z
      . Current use and outcome of hematopoietic stem cell transplantaton: CIBMTR Summary Slides, 2013. http://www.cibmtr.org/referencecenter/slidesreports/summaryslides/pages/index.aspx (accessed Feb 2015).
    17. ↵
      1. Kekre N,
      2. Koreth J
      . Novel strategies to prevent relapse after allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia and myelodysplastic syndromes. Curr Opin Hematol 2015;22:116–22. doi:10.1097/MOH.0000000000000116
      OpenUrlPubMed
    18. ↵
      1. Gyurkocza B,
      2. Sandmaier BM
      . Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood 2014;124:344–53. doi:10.1182/blood-2014-02-514778
      OpenUrlAbstract/FREE Full Text
    19. ↵
      1. Kharfan-Dabaja M,
      2. Mhaskar R,
      3. Reljic T, et al
      . Mycophenolate mofetil versus methotrexate for prevention of graft-versus-host disease in people receiving allogeneic hematopoietic stem cell transplantation. Cochrane Database Syst Rev 2014;7:CD010280.doi:10.1002/14651858.CD010280.pub2
      OpenUrlPubMed
    20. ↵
      1. Radosevich M,
      2. Burnouf T
      . Intravenous immunoglobulin G: trends in production methods, quality control and quality assurance. Vox Sang 2010;98:12–28. doi:10.1111/j.1423-0410.2009.01226.x
      OpenUrlPubMed
    21. ↵
      1. Dickersin K,
      2. Scherer R,
      3. Lefebvre C
      . Identifying relevant studies for systematic reviews. BMJ 1994;309:1286–91. doi:10.1136/bmj.309.6964.1286
      OpenUrlAbstract/FREE Full Text
    22. ↵
      1. Jadad AR,
      2. Moore RA,
      3. Carroll D, et al
      . Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12. doi:10.1016/0197-2456(95)00134-4
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      1. Schulz KF,
      2. Grimes DA
      . Allocation concealment in randomised trials: defending against deciphering. Lancet 2002;359:614–18. doi:10.1016/S0140-6736(02)07750-4
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      Review Manager (RevMan). The Nordic Cochrane Centre. The Cochrane Collaboration, 2014. https://tech.cochrane.org/revman (accessed Feb 2015).
    25. ↵
      1. Soeken KL,
      2. Sripusanapan A
      . Assessing publication bias in meta-analysis. Nurs Res 2003;52:57–60. doi:10.1097/00006199-200301000-00009
      OpenUrlCrossRefPubMedWeb of Science
    26. ↵
      1. Sutton AJ,
      2. Duval SJ,
      3. Tweedie RL, et al
      . Empirical assessment of effect of publication bias on meta-analyses. BMJ 2000;320:1574–7. doi:10.1136/bmj.320.7249.1574
      OpenUrlAbstract/FREE Full Text

    Footnotes

    • Contributors JC drafted the protocol. JT critically reviewed and revised the protocol and the guarantor. JC and JT performed the data extraction, data interpretation and manuscript preparation. JT, DWC and GK were consulted for the interpretation of results and preparation of the manuscript. All the authors conceived and designed the review, and read and approved the final manuscript.

    • Funding This work was supported by Department of Medicine Developmental Research Grant, University of Ottawa.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement No additional data are available.