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Update on the use of immunoglobulin in human disease: A review of evidence

2016; Elsevier BV; Volume: 139; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2016.09.023

1097-6825

Elena Pérez, Jordan S. Orange, Francisco A. Bonilla, Javier Chinen, Iván K. Chinn, Morna J. Dorsey, Yehia El‐Gamal, Terry Harville, Elham Hossny, Bruce Mazer, Robert P. Nelson, Elizabeth Secord, Stanley C. Jordan, E. Richard Stiehm, Ashley Vo, Mark Ballow,

Platelet Disorders and Treatments

Human immunoglobulin preparations for intravenous or subcutaneous administration are the cornerstone of treatment in patients with primary immunodeficiency diseases affecting the humoral immune system. Intravenous preparations have a number of important uses in the treatment of other diseases in humans as well, some for which acceptable treatment alternatives do not exist. We provide an update of the evidence-based guideline on immunoglobulin therapy, last published in 2006. Given the potential risks and inherent scarcity of human immunoglobulin, careful consideration of its indications and administration is warranted. Human immunoglobulin preparations for intravenous or subcutaneous administration are the cornerstone of treatment in patients with primary immunodeficiency diseases affecting the humoral immune system. Intravenous preparations have a number of important uses in the treatment of other diseases in humans as well, some for which acceptable treatment alternatives do not exist. We provide an update of the evidence-based guideline on immunoglobulin therapy, last published in 2006. Given the potential risks and inherent scarcity of human immunoglobulin, careful consideration of its indications and administration is warranted. Immunoglobulin is increasingly recognized as a treatment of a variety of medical conditions, not only for its ability to fight infection as a replacement therapy but also for its anti-inflammatory and immunomodulating effects. The appropriate use of immunoglobulin can be life-saving. However, its administration can lead to numerous adverse events and potential additional adverse consequences.1Hefer D. Jaloudi M. Thromboembolic events as an emerging adverse effect during high-dose intravenous immunoglobulin therapy in elderly patients: a case report and discussion of the relevant literature.Ann Hematol. 2004; 83: 661-665Crossref PubMed Scopus (0) Google Scholar Due to finite supply, possible adverse events, and the need for further research in some applications of therapeutic immunoglobulin, it is important for clinicians prescribing immunoglobulin to be familiar with current clinical indications and levels of evidence in support of its use in these conditions. This document is intended as an update of the 2006 American Academy of Allergy, Asthma & Immunology guideline2Orange J.S. Hossny E.M. Weiler C.R. Ballow M. Berger M. Bonilla F.A. et al.Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma & Immunology.J Allergy Clin Immunol. 2006; 117: S525-S553Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and centers on the use of standard immunoglobulin preparations specifically manufactured for intravenous (IV) or subcutaneous (SC) administration. The SC route of administration has become more utilized in the United States, so we include an expanded section to cover practical considerations surrounding the administration of immunoglobulin subcutaneously. Clinical indications for which IV immunoglobulin (IVIG) have been licensed by the US Food and Drug Administration (FDA) include (Table I): (1) treatment of primary immunodeficiencies (PIs); (2) prevention of bacterial infections in patients with hypogammaglobulinemia and recurrent bacterial infection due to B-cell chronic lymphocytic leukemia (CLL); (3) prevention of coronary artery aneurysms in Kawasaki disease (KD); (4) prevention of infections, pneumonitis, and acute graft-versus-host disease (GVHD) following bone marrow transplantation; (5) reduction of serious bacterial infection in children infected with HIV; (6) increasing platelet count in idiopathic thrombocytopenic purpura to prevent or control bleeding; and (7) treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) and, more recently, multifocal motor neuropathy (MMN).3Hughes R. The role of IVIg in autoimmune neuropathies: the latest evidence.J Neurol. 2008; 255: 7-11Crossref PubMed Scopus (0) Google Scholar, 4European Federation of Neurological Societies and the Peripheral Nerve Society European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society—first revision.J Peripher Nerv Syst. 2010; 15: 295-301Crossref PubMed Scopus (97) Google Scholar Despite these indications, none of the original immunoglobulin products that were specifically licensed for use in pediatric HIV or post–bone marrow transplantation are still available in the US market. The only licensed indication of SC immunoglobulin (SCIG) to date is PI disease.Table IFDA-approved indications of IVIGDisease stateNo. of FDA-licensed products∗Refer to Table XIII for specific details regarding individual products.Indication†Note the indications listed represent a cumulative summary of the indications listed for the range of products that carry that indication. For the specific details relating to a given indication refer to the prescriber information for each individual product.PI disease, or primary humoral immunodeficiency15Indicated for the treatment of PI states, or for elevation of circulating antibody levels in PI, or for replacement therapy of PI states in which severe impairment of antibody forming capacity has been shownIdiopathic thrombocytopenic purpura7Indicated when a rapid rise in platelet count is needed to prevent and/or control bleeding in idiopathic thrombocytopenic purpura, or to allow a patient with idiopathic thrombocytopenic purpura to undergo surgeryB-cell CLL2Indicated for the prevention of bacterial infections in patients with hypogammaglobulinemia and/or recurrent bacterial infections associated with B-cell CLLCIDP2Indicated for the treatment of CIDP to improve neuromuscular disability and impairment and for maintenance therapy to prevent relapseKD2Indicated for the prevention of coronary artery aneurisms associated with Kawasaki diseaseMMN1Indicated as a maintenance therapy to improve muscle strength and disability in adult patients with MMNBone marrow transplantation0Indicated for bone marrow transplant patients ≥20 y of age to decrease the risk of septicemia and other infections, interstitial pneumonia of infectious or idiopathic etiologies and acute GVHD in the first 100 d after transplantationHIV infection0Indicated for pediatric patients with HIV infection to decrease the frequency of serious and minor bacterial infections and the frequency of hospitalization, and increase time free of serious bacterial infection∗ Refer to Table XIII for specific details regarding individual products.† Note the indications listed represent a cumulative summary of the indications listed for the range of products that carry that indication. For the specific details relating to a given indication refer to the prescriber information for each individual product. Open table in a new tab This document reviews the basis for the FDA-approved indications and discusses other disease states in which immunoglobulin therapy has been used. Some of these other conditions are extremely rare, making randomized controlled trials (RCTs) difficult. Others, however, are quite common, and rigorous scientific evaluation of immunoglobulin utility has been possible. Immunoglobulin holds great promise as a useful therapeutic agent in some of these diseases, whereas in others it is ineffectual and may actually increase risks to the patient. Thus, the evidence supporting the use of immunoglobulin in these conditions has been reviewed and categorized (Table II). Current recommendations for the appropriate use of immunoglobulin are outlined in this summary. There are relatively few studies looking at SCIG for indications other than PI; however, the SC route is emerging as an alternative for maintenance therapy in patients on IVIG for CIDP as well as other muscle and nerve disorders.5Dacci P. Riva N. Scarlato M. Andresen I. Schmidt D. Comi G. et al.Subcutaneous immunoglobulin therapy for the treatment of multifocal motor neuropathy: a case report.Neurol Sci. 2010; 31: 829-831Crossref PubMed Scopus (0) Google Scholar, 6Danieli M.G. Pettinari L. Moretti R. Logullo F. Gabrielli A. Subcutaneous immunoglobulin in polymyositis and dermatomyositis: a novel application.Autoimmun Rev. 2011; 10: 144-149Crossref PubMed Scopus (0) Google Scholar, 7Harbo T. Andersen H. Hess A. Hansen K. Sindrup S.H. Jakobsen J. Subcutaneous versus intravenous immunoglobulin in multifocal motor neuropathy: a randomized, single-blinded cross-over trial.Eur J Neurol. 2009; 16: 631-638Crossref PubMed Scopus (0) Google ScholarTable IICategorization of evidence and basis of recommendationNumberDefinitionEvidence category IaFrom meta-analysis of RCTs IbFrom at least one RCT IIaFrom at least one controlled trial without randomization IIbFrom at least one other type of quasi-experimental study IIIFrom non-experimental descriptive studies such as comparative, correlation or case-control studies IVFrom expert committee reports or opinions or clinical experience of respected authorities or bothStrength of recommendation ABased on category I evidence BBased on category II evidence or extrapolated from category I evidence CBased on category III evidence or extrapolated from category I or II evidence DBased on category IV evidence or extrapolated from category I, II or III evidence NRNot ratedOrdinal category∗Consider evidence category and strength of recommendation in clinical decision making regarding benefit of treatment with IVIG or SCIG. Definitely beneficial Probably beneficial May provide benefit Unlikely to provide benefit∗ Consider evidence category and strength of recommendation in clinical decision making regarding benefit of treatment with IVIG or SCIG. Open table in a new tab This updated summary is current through June 2015 and does not reflect clinical research or reports that have become available since that time. Although prior reviews of evidence were considered to have arrived at the conclusions contained in this document, primary literature for review on each subject was derived from searching the National Center for Biotechnology Information PubMed database using the key words IGIV, IVIG, intravenous immunoglobulin, intravenous immune globulin, subcutaneous immunoglobulin, and subcutaneous immune globulin, along with key words specific for each disease-related topic. The recommendations for appropriate use stated here were based on this literature review but will most certainly change over time as experience and understanding of these diseases increase. Immunoglobulin replacement therapy via the IV or SC route is required in patients with certain PI diseases characterized by absent or deficient antibody production and, in most cases, recurrent or unusually severe infection (Table III).8Ammann A.J. Ashman R.F. Buckley R.H. Hardie W.R. Krantmann H.J. Nelson J. et al.Use of intravenous gamma-globulin in antibody immunodeficiency: results of a multicenter controlled trial.Clin Immunol Immunopathol. 1982; 22: 60-67Crossref PubMed Scopus (0) Google Scholar, 9Buckley R.H. Schiff R.I. The use of intravenous immune globulin in immunodeficiency diseases.N Engl J Med. 1991; 325: 110-117Crossref PubMed Google ScholarTable IIIUses of immunoglobulin in primary and secondary immune deficienciesBenefitDiseaseEvidence categoryStrength of recommendationDefinitely beneficialPrimary immune defects with absent B cellsIIbBPrimary immune defects with hypogammaglobulinemia and impaired specific antibody productionIIbBDistinct genetically defined PIs with variable defects in antibody quality and quantity∗Hyper-IgE syndrome, dedicator of cytokinesis 8 (DOCK8), STAT-1, nuclear factor-κB essential modulator (NEMO) among others.IVDProbably beneficialCLL with reduced IgG and history of infectionsIbAPrevention of bacterial infection in HIV-infected childrenIbAPrimary immune defects with normal IgG and impaired specific antibody productionIIICMay provide benefitPrevention of neonatal sepsisIaATHI of infancyIIb-IIICOther immune mechanism driving recurrent infections that affect B-cell functionIVDSelective antibody deficiency “memory phenotype”IVDIsolated IgG subclass deficiency (IgG1, IgG2, IgG3) with recurrent infectionsIIICUnlikely to be beneficialIsolated IgE deficiencyIVDIsolated IgG4 deficiencyIVDSelective IgA deficiencyIVDIsolated IgM deficiencyIVD∗ Hyper-IgE syndrome, dedicator of cytokinesis 8 (DOCK8), STAT-1, nuclear factor-κB essential modulator (NEMO) among others. Open table in a new tab Replacement therapy for agammaglobulinemia and hypogammaglobulinemia in well-described immunodeficiencies such as X-linked agammaglobulinemia (XLA) or common variable immunodeficiency (CVID) is necessary and life-saving. Other more genetically complex PIs, however, may also involve defects in antibody function that contribute to an increased susceptibility to infections. Over 250 distinct PIs have been described to date, and with the advent of whole-exome sequencing, new PIs continue to be discovered at a rapid pace.10Al-Herz W. Bousfiha A. Casanova J.L. Chatila T. Conley M.E. Cunningham-Rundles C. et al.Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency.Front Immunol. 2014; 5: 162Crossref PubMed Scopus (222) Google Scholar The effects of these newly described gene defects on the humoral immune system may not be fully understood or qualified with currently commercially available tests of antibody level and function. Therefore, the indications of immunoglobulin therapy in various clinical presentations of immunodeficiency are likely to broaden as the disorders are better understood, considering that a majority of PI diseases involve antibody deficiency. A recent publication reviewed the controversies surrounding immunoglobulin therapy, including the need for better laboratory assays of functional antibody responses and better clinical and microbiological evaluation and characterization of the recurrent infections seen in antibody-deficient patients.11Gelfand E.W. Ochs H.D. Shearer W.T. Controversies in IgG replacement therapy in patients with antibody deficiency diseases.J Allergy Clin Immunol. 2013; 131: 1001-1005Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Here, we provide a framework of 6 distinct phenotypes of PI disease for which immunoglobulin replacement is or may be indicated12Stiehm E.R. Orange J.S. Ballow M. Lehman H. Therapeutic use of immunoglobulins.Adv Pediatr. 2010; 57: 185-218Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar: (1) agammaglobulinemia due to absence of B cells; (2) hypogammaglobulinemia with poor antibody function; (3) normal immunoglobulins with poor antibody function; (4) hypogammaglobulinemia with normal antibody function; (5) isolated IgG subclass deficiency with recurrent infections; and (6) recurrent infections due to a complex immune mechanism related to a genetically defined PI disease. These categories are briefly discussed subsequently (examples are not all-inclusive of the category described). Agammaglobulinemia due to the absence of B cells is the clearest indication of immunoglobulin replacement. Evaluation of IVIG usage in patients lacking immunoglobulin has demonstrated a clear benefit in terms of reducing both acute and chronic infections.8Ammann A.J. Ashman R.F. Buckley R.H. Hardie W.R. Krantmann H.J. Nelson J. et al.Use of intravenous gamma-globulin in antibody immunodeficiency: results of a multicenter controlled trial.Clin Immunol Immunopathol. 1982; 22: 60-67Crossref PubMed Scopus (0) Google Scholar, 13Lederman H.M. Winkelstein J.A. X-linked agammaglobulinemia: an analysis of 96 patients.Medicine (Baltimore). 1985; 64: 145-156Crossref PubMed Google Scholar, 14Quartier P. Debre M. De Blic J. de Sauverzac R. Sayegh N. Jabado N. et al.Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients.J Pediatr. 1999; 134: 589-596Abstract Full Text Full Text PDF PubMed Google Scholar Retrospective analyses of data from agammaglobulinemic children have revealed that the number and severity of infectious complications are inversely correlated with the dose of IVIG administered.14Quartier P. Debre M. De Blic J. de Sauverzac R. Sayegh N. Jabado N. et al.Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients.J Pediatr. 1999; 134: 589-596Abstract Full Text Full Text PDF PubMed Google Scholar, 15Liese J.G. Wintergerst U. Tympner K.D. Belohradsky B.H. High- vs low-dose immunoglobulin therapy in the long-term treatment of X-linked agammaglobulinemia.Am J Dis Child. 1992; 146: 335-339PubMed Google Scholar In particular, when IgG trough levels were maintained above 800 mg/dL, serious bacterial illness and enteroviral meningoencephalitis were prevented.14Quartier P. Debre M. De Blic J. de Sauverzac R. Sayegh N. Jabado N. et al.Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients.J Pediatr. 1999; 134: 589-596Abstract Full Text Full Text PDF PubMed Google Scholar A recent meta-analysis of data from studies in subjects with agammaglobulinemia described a decreased risk for pneumonia with increasing trough levels of up to 1000 mg/dL.16Orange J.S. Grossman W.J. Navickis R.J. Wilkes M.M. Impact of trough IgG on pneumonia incidence in primary immunodeficiency: A meta-analysis of clinical studies.Clin Immunol. 2010; 137: 21-30Crossref PubMed Scopus (0) Google Scholar Although agammaglobulinemia is rare, it provides insight into the value of immunoglobulin replacement in preventing disease due to defective humoral immunity that can be extrapolated to other antibody-deficient states. In severe combined immunodeficiency (SCID), the T-cell defect is often accompanied by an absence of B cells or B-cell function. Therefore, immunoglobulin replacement is warranted at diagnosis because transplacental maternal IgG wanes over time. In the setting of SCID, immunoglobulin replacement is also necessary in the post-transplantation period, during gene therapy or enzyme replacement (for adenosine deaminase deficiency), until B-cell function is restored.17Buckley R.H. B-cell function in severe combined immunodeficiency after stem cell or gene therapy: a review.J Allergy Clin Immunol. 2010; 125: 790-797Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 18Serana F. Sottini A. Chiarini M. Zanotti C. Ghidini C. Lanfranchi A. et al.The different extent of B and T cell immune reconstitution after hematopoietic stem cell transplantation and enzyme replacement therapies in SCID patients with adenosine deaminase deficiency.J Immunol. 2010; 185: 7713-7722Crossref PubMed Scopus (0) Google Scholar In some cases, B-cell function is never restored, and continual immunoglobulin replacement remains necessary. Deficient antibody production is characterized by decreased immunoglobulin concentrations and/or a significant inability to respond with IgG antibody on antigen challenge. In patients with recurrent bacterial infections, reduced levels of serum immunoglobulin, coupled with a lack of response to protein and/or polysaccharide vaccine challenge (ie, in patients who cannot make IgG antibody against diphtheria and tetanus toxoids and/or pneumococcal polysaccharide vaccine), are a clear indication of immunoglobulin replacement. The prototype of this category is CVID, the most commonly diagnosed and heterogeneous antibody-deficiency disorder. An early study of IVIG in patients in this setting showed that IVIG was associated with a reduced prevalence of infection compared with the infection rate prior to IVIG treatment.19Cunningham-Rundles C. Siegal F.P. Smithwick E.M. Lion-Boule A. Cunningham-Rundles S. O'Malley J. et al.Efficacy of intravenous immunoglobulin in primary humoral immunodeficiency disease.Ann Intern Med. 1984; 101: 435-439Crossref PubMed Google Scholar IVIG was also associated with lower infection rates compared with those with intramuscular immunoglobulin in patients in direct-comparison studies.20Nolte M.T. Pirofsky B. Gerritz G.A. Golding B. Intravenous immunoglobulin therapy for antibody deficiency.Clin Exp Immunol. 1979; 36: 237-243PubMed Google Scholar, 21Roifman C.M. Lederman H.M. Lavi S. Stein L.D. Levison H. Gelfand E.W. Benefit of intravenous IgG replacement in hypogammaglobulinemic patients with chronic sinopulmonary disease.Am J Med. 1985; 79: 171-174Abstract Full Text PDF PubMed Scopus (0) Google Scholar Because patients with CVID are at higher risk for chronic lung disease and pulmonary deterioration as a result of chronic or subclinical infection,22Cunningham-Rundles C. Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients.Clin Immunol. 1999; 92: 34-48Crossref PubMed Scopus (974) Google Scholar, 23Thickett K.M. Kumararatne D.S. Banerjee A.K. Dudley R. Stableforth D.E. Common variable immune deficiency: respiratory manifestations, pulmonary function and high-resolution CT scan findings.QJM. 2002; 95: 655-662Crossref PubMed Google Scholar early recognition of the diagnosis and initiation of IVIG therapy are crucial.23Thickett K.M. Kumararatne D.S. Banerjee A.K. Dudley R. Stableforth D.E. Common variable immune deficiency: respiratory manifestations, pulmonary function and high-resolution CT scan findings.QJM. 2002; 95: 655-662Crossref PubMed Google Scholar Adequate replacement of IgG has been associated with a reduced frequency of sinopulmonary infections, including pneumonia, which can lead to chronic lung inflammation and bronchiectasis.24Busse P.J. Razvi S. Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency.J Allergy Clin Immunol. 2002; 109: 1001-1004Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar Several publications have suggested that immunoglobulin replacement can decrease acute and chronic lung infections and may prevent or slow the progression of their sequelae in antibody-deficiency disorders, including XLA, CVID, and hyper-IgM.8Ammann A.J. Ashman R.F. Buckley R.H. Hardie W.R. Krantmann H.J. Nelson J. et al.Use of intravenous gamma-globulin in antibody immunodeficiency: results of a multicenter controlled trial.Clin Immunol Immunopathol. 1982; 22: 60-67Crossref PubMed Scopus (0) Google Scholar, 13Lederman H.M. Winkelstein J.A. X-linked agammaglobulinemia: an analysis of 96 patients.Medicine (Baltimore). 1985; 64: 145-156Crossref PubMed Google Scholar, 14Quartier P. Debre M. De Blic J. de Sauverzac R. Sayegh N. Jabado N. et al.Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients.J Pediatr. 1999; 134: 589-596Abstract Full Text Full Text PDF PubMed Google Scholar, 19Cunningham-Rundles C. Siegal F.P. Smithwick E.M. Lion-Boule A. Cunningham-Rundles S. O'Malley J. et al.Efficacy of intravenous immunoglobulin in primary humoral immunodeficiency disease.Ann Intern Med. 1984; 101: 435-439Crossref PubMed Google Scholar, 20Nolte M.T. Pirofsky B. Gerritz G.A. Golding B. Intravenous immunoglobulin therapy for antibody deficiency.Clin Exp Immunol. 1979; 36: 237-243PubMed Google Scholar, 21Roifman C.M. Lederman H.M. Lavi S. Stein L.D. Levison H. Gelfand E.W. Benefit of intravenous IgG replacement in hypogammaglobulinemic patients with chronic sinopulmonary disease.Am J Med. 1985; 79: 171-174Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 24Busse P.J. Razvi S. Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency.J Allergy Clin Immunol. 2002; 109: 1001-1004Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar, 25de Gracia J. Vendrell M. Alvarez A. Pallisa E. Rodrigo M.J. de la Rosa D. et al.Immunoglobulin therapy to control lung damage in patients with common variable immunodeficiency.Int Immunopharmacol. 2004; 4: 745-753Crossref PubMed Scopus (0) Google Scholar, 26Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar, 27Quartier P. Bustamante J. Sanal O. Plebani A. Debre M. Deville A. et al.Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to activation-induced cytidine deaminase deficiency.Clin Immunol. 2004; 110: 22-29Crossref PubMed Scopus (0) Google Scholar, 28Winkelstein J.A. Marino M.C. Lederman H.M. Jones S.M. Sullivan K. Burks A.W. et al.X-linked agammaglobulinemia: report on a United States registry of 201 patients.Medicine (Baltimore). 2006; 85: 193-202Crossref PubMed Scopus (236) Google Scholar, 29Winkelstein J.A. Marino M.C. Ochs H. Fuleihan R. Scholl P.R. Geha R. et al.The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.Medicine (Baltimore). 2003; 82: 373-384Crossref PubMed Scopus (257) Google Scholar The findings from a recent prospective study in 90 patients with CVID25de Gracia J. Vendrell M. Alvarez A. Pallisa E. Rodrigo M.J. de la Rosa D. et al.Immunoglobulin therapy to control lung damage in patients with common variable immunodeficiency.Int Immunopharmacol. 2004; 4: 745-753Crossref PubMed Scopus (0) Google Scholar and in a smaller group of patients with XLA, followed for up to 22 years, support individualizing doses and trough levels to attain infection-free outcomes rather than using a standardized dose in all patients by disease.30Lucas M. Lee M. Lortan J. Lopez-Granados E. Misbah S. Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years.J Allergy Clin Immunol. 2010; 125: 1354-1360.e4Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar Consensus among the Canadian expert panel of immunologists is to follow clinical outcomes to monitor the effectiveness of immunoglobulin, with an increase in the dose to improve clinical effectiveness and not merely to increase trough levels.31Shehata N. Palda V. Bowen T. Haddad E. Issekutz T.B. Mazer B. et al.The use of immunoglobulin therapy for patients with primary immune deficiency: an evidence-based practice guideline.Transfus Med Rev. 2010; 24: S28-S50Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Several reports have suggested that monitoring trough levels is insufficient because individuals may need doses >0.4-0.6 g/kg/month to prevent breakthrough infections.32Chapel H. Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions.Br J Haematol. 2009; 145: 709-727Crossref PubMed Scopus (163) Google Scholar Although double-blind, placebo-controlled studies demonstrating a benefit of immunoglobulin replacement in CVID and other antibody deficiencies are not available, the historical evidence and existing studies are compelling enough to indicate this therapy in these patients. A new diagnostic criterion of CVID was recently proposed. It emphasizes the importance of clinical symptoms as a sign of immune system impairment, and this criterion is required for diagnosis, along with the fulfillment of major criteria ( 4 years, absence of a secondary cause) plus either additional laboratory evidence or the presence of specific histologic markers of disease.33Ameratunga R. Woon S.T. Gillis D. Koopmans W. Steele R. New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin.Clin Exp Immunol. 2013; 174: 203-211PubMed Google Scholar The implications for clinical practice are that patients with hypogammaglobulinemia of unclear significance would be monitored closely over time and that immunoglobulin would be initiated only after the full criteria, including symptoms of immune system failure, were met. However, exceptions to this concept were also discussed and include: (1) that significant autoimmunity, hypogammaglobulinemia, and additional laboratory evidence supporting CVID or the presence of relatively specific histologic markers would be sufficient for diagnosis; and (2) asymptomatic patients with severe hypogammaglobulinemia whose risk for bacterial sepsis or severe viral infection is unknown. In the latter group, it is unknown whether a fatal infection may be the first presentation of disease; therefore, clinical judgement, counseling, and close follow-up are recommended as part of the decision to start immunoglobulin replacement.33Ameratunga R. Woon S.T. Gillis D. Koopmans W. Steele R. New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin.Clin Exp Immunol. 2013; 174: 203-211PubMed Google Scholar In contrast, the International Consensus Document on CVID,34Bonilla F.A. Barlan I. Chapel H. Costa-Carvalho B.T. Cunningham-Rundles C. de la Morena M.T. et al.International Consensus (ICON) document: Common variable immunodeficiency disorders.J Allergy Clin Immunol Pract. 2016; 4: 38-59Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar published in 2016 by an international coalition among the American Academy of Al