Controversies in IgG replacement therapy in patients with antibody deficiency diseases
2013; Elsevier BV; Volume: 131; Issue: 4 Linguagem: Inglês
10.1016/j.jaci.2013.02.028
ISSN1097-6825
AutoresErwin W. Gelfand, Hans D. Ochs, William T. Shearer,
Tópico(s)Blood disorders and treatments
ResumoThis Current perspectives article will review and highlight the importance of accurate diagnosis of patients who have failed to produce specific antibodies to naturally encountered foreign proteins or polysaccharides or after vaccination and the appropriate institution of immunoglobulin replacement therapy. The field of primary immunodeficiency disease (PIDD) has expanded remarkably since the early descriptions 6 decades ago. With greater recognition and advanced cellular and molecular diagnostic technology, new entities and single-gene defects in patients with PIDD are rapidly being defined. This, combined with treatment advances and newborn screening for severe combined immunodeficiency, has resulted in improved outcomes and survival and even permanent cures. Awareness of PIDD has also increased, but the guidelines for recognition remain to be validated. The zeal for registering and enrolling patients has potentially created a large body of "patients" treated with immunoglobulin replacement unnecessarily. The complexity, diversity, and availability of laboratory testing have brought awareness of PIDD to the forefront, but because of an absence of standardization of certain assays, concerns about the correct diagnosis and appropriate treatment have increased. We hope to refocus the discussion on identifying clear laboratory and clinical guidelines for the establishment of an accurate diagnosis of antibody deficiency, its rationale, and, where indicated, institution of safe treatment. This Current perspectives article will review and highlight the importance of accurate diagnosis of patients who have failed to produce specific antibodies to naturally encountered foreign proteins or polysaccharides or after vaccination and the appropriate institution of immunoglobulin replacement therapy. The field of primary immunodeficiency disease (PIDD) has expanded remarkably since the early descriptions 6 decades ago. With greater recognition and advanced cellular and molecular diagnostic technology, new entities and single-gene defects in patients with PIDD are rapidly being defined. This, combined with treatment advances and newborn screening for severe combined immunodeficiency, has resulted in improved outcomes and survival and even permanent cures. Awareness of PIDD has also increased, but the guidelines for recognition remain to be validated. The zeal for registering and enrolling patients has potentially created a large body of "patients" treated with immunoglobulin replacement unnecessarily. The complexity, diversity, and availability of laboratory testing have brought awareness of PIDD to the forefront, but because of an absence of standardization of certain assays, concerns about the correct diagnosis and appropriate treatment have increased. We hope to refocus the discussion on identifying clear laboratory and clinical guidelines for the establishment of an accurate diagnosis of antibody deficiency, its rationale, and, where indicated, institution of safe treatment. Major advances in the definition, delineation, diagnosis, and definitive treatment of primary immunodeficiency disease (PIDD) have provided the clinician with the ability to identify holes in the armor of host defense and even restore what nature did not provide.1Notarangelo L.D. Primary immunodeficiencies.J Allergy Clin Immunol. 2010; 125: S182-S194Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar Despite these satisfying developments, which include identification of defective genes in patients with PIDD2Al-Herz W. Bousfiha A. Casanova J.L. Chapel H. Conley M.E. 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Gene therapy for primary immunodeficiencies: Part 1.Curr Opin Immunol. 2012; 24: 580-584Crossref PubMed Scopus (71) Google Scholar there still remains a murky area of diagnosis and treatment in patients with the most common forms of PIDD: antibody deficiency disorders. These areas of concern center around the laboratory methods and interpretation of antibody test results,9Abraham R.S. Relevance of laboratory testing for the diagnosis of primary immunodeficiencies: a review of case-based examples of selected immunodeficiencies.Clin Mol Allergy. 2011; 9: 6Crossref PubMed Scopus (23) Google Scholar, 10Abraham R.S. Relevance of antibody testing in patients with recurrent infections.J Allergy Clin Immunol. 2012; 130: 558-559.e6Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 11Skoda-Smith S. Torgerson T.R. Ochs H.D. Subcutaneous immunoglobulin replacement therapy in the treatment of patients with primary immunodeficiency disease.Ther Clin Risk Manag. 2010; 6: 1-10Crossref PubMed Scopus (16) Google Scholar which often leads to inappropriate placement of individuals on lifelong immunoglobulin replacement therapy. Here we do not address those antibody deficiency diseases with established molecular and genetic lesions causing absent or nonfunctional cellular factors. Our concern is with the more common situation of patients given the presumptive diagnosis of antibody deficiency based on imperfect laboratory tests and nonvalidated interpretation of the results of such assays. Table I lists antibody deficiencies or combined cellular and antibody diagnoses, including proposed justifications for the use of immunoglobulin replacement therapy (A, established; F, not indicated). It is a very general approach that reflects, to a large degree, the opinion of the authors and is not meant to encompass all clinical situations. In several of the cellular and antibody deficiencies, immunoglobulin replacement has a limited effect because hematopoietic stem cell transplants are needed to restore T-cell numbers and function. We include this table to give readers a sense of the scope of immunoglobulin replacement in patients with PIDD and suggest where it might be considered effective therapy and where it is not.Table IIndication of immunoglobulin replacement for antibody deficiencyScorePIDD entityImmune defectExpected response to IVIG/SCIGA1Agammaglobulinemia (X-linked, AR)Lack of B cellsEffectiveHIgM caused by AID and UNG deficiencyAbnormal B-cell signaling resulting in defective CSR and SHMEffectiveA2HIgM caused by CD40L and CD40 deficiencyDefective T/B-cell interaction resulting in abnormal CSR and SHM; defective macrophage activationEffective, susceptibility to opportunistic infections not reducedA3CVID with normal T-cell function (including deficiencies of CD19, CD20, CD21, CD80, ICOS, TACI, or BAFF-R)Hypogammaglobulinemia, antibody deficiency, often with CSR defectEffectiveB1CVID with complications (splenomegaly, granuloma formation, autoimmunity, lymphoma)Hypogammaglobulinemia, antibody deficiency, CSR and SHM affected, often associated with a T-cell defect (abnormal CD40L expression, decreased CD4/CD8 ratio)Effective in reducing infections but not granuloma formation, autoimmunity or incidence of malignancyB2Thymoma with immune deficiency (Good syndrome)B- and T-cell defectsEffective in reducing infectionsB3XLP with EBV-induced loss of B cellsAntibody deficiency caused by reduced number of B cells; defective cytotoxic T cells, NK cellsEffective in reducing infections, no effect on EBV-related pathologyB4SCID after HSCT without B-cell engraftmentMixed chimera with donor T cells and host B cellsEffectiveC1Selective antibody deficiencyDefective CSR reported; anti-PPS antibodies measured by ELISA do not reflect functionalityAntibiotic prophylaxis might be equally effectiveC2Clinically and genetically well-described syndromes with variable antibody deficiency (WAS, DiGeorge syndrome, STAT3 deficiency, VODI, DKC, ICF, AT, Netherton syndrome)Abnormal antibody responses associated with other immune defects; characteristic syndromic defects might predominatePartially effective; other disease-specific strategies requiredD1CID (eg, mutations in PNP, ZAP70, and genes controlling MHC class I and II expression)Hypogammaglobulinemia; B- and T-cell defectsLimited benefit; HSCT should be consideredD2Hypomorphic mutations in RAG1/2, IL2RG, ADA, RMRP, Artemis, and DNA ligase IVHypogammaglobulinemia, combined immune deficiency, often normal (but oligoclonal) T-cell numbers, low B-cell numbers (Omenn syndrome)Limited benefit; HSCT indicatedD3SCIDSevere B- and T-cell deficiency, lymphopeniaLimited temporary benefit while waiting for and during HSCTE1Complement deficiencies (C3, C4, and C5-9), properdin deficiencyAbnormal antibody responses have been describedMight be beneficial; other prophylactic strategies include hyperimmunization, prophylactic antibioticsE2Transient hypogammaglobulinemia of infancy with severe recurrent infectionsHypogammaglobulinemia, generally normal antibody productionImmunoglobulin replacement not indicated except if antibody production is demonstrated to be temporarily defectiveE3IgG subclass deficiency≥1 IgG subclass affectedImmunoglobulin replacement only if a significant antibody deficiency is demonstratedFAsymptomatic hypogammaglobulinemia and normal antibody responses; selective immunoglobulin deficienciesNormal B- and T-cell numbers, normal antibody responses; selective IgM, IgA, and IgE deficiencyImmunoglobulin replacement not indicatedIVIG/SCIG is effective in entities scored A and in most that are scored B. Those entities scored C and D might obtain limited benefit, and those scored E and F are not expected to benefit from immunoglobulin replacement.ADA, Adenosine deaminase; AID, activation-induced cytokine deaminase; AR, autosomal recessive; AT, ataxia telangiectasia; BAFF-R, B cell–activating factor of the TNF family receptor; CD40L, CD40 ligand; CID, combined immunodeficiency; CSR, class-switch recombination; DKC, dyskeratosis congenita; HIgM, hyper-IgM syndrome; HSCT, hematopoietic stem cell transplantation; ICF, immunodeficiency with centromeric instability and facial anomalies; ICOS, inducible costimulator; IL2RG, IL-2 receptor γ; IVIG, intravenous immunoglobulin; NK, natural killer; PNP, purine nucleoside phosphorylase; PPS, pneumococcal polysaccharides; RAG, recombination-activating gene; RMRP, RnaseMRP RNA; SCID, severe combined immunodeficiency; SCIG, subcutaneous immunoglobulin; SHM, somatic hypermutation; STAT3, signal transducer and activator of transcription 3; TACI, transmembrane activator and calcium modulator and cyclophilin ligand; UNG, uracil-N-glycosylase; VODI, hepatic veno-occlusive disease with immunodeficiency; WAS, Wiskott-Aldrich syndrome; XLP, X-linked lymphoproliferative syndrome; ZAP70, ζ chain–associated protein of 70 kDa. Open table in a new tab IVIG/SCIG is effective in entities scored A and in most that are scored B. Those entities scored C and D might obtain limited benefit, and those scored E and F are not expected to benefit from immunoglobulin replacement. ADA, Adenosine deaminase; AID, activation-induced cytokine deaminase; AR, autosomal recessive; AT, ataxia telangiectasia; BAFF-R, B cell–activating factor of the TNF family receptor; CD40L, CD40 ligand; CID, combined immunodeficiency; CSR, class-switch recombination; DKC, dyskeratosis congenita; HIgM, hyper-IgM syndrome; HSCT, hematopoietic stem cell transplantation; ICF, immunodeficiency with centromeric instability and facial anomalies; ICOS, inducible costimulator; IL2RG, IL-2 receptor γ; IVIG, intravenous immunoglobulin; NK, natural killer; PNP, purine nucleoside phosphorylase; PPS, pneumococcal polysaccharides; RAG, recombination-activating gene; RMRP, RnaseMRP RNA; SCID, severe combined immunodeficiency; SCIG, subcutaneous immunoglobulin; SHM, somatic hypermutation; STAT3, signal transducer and activator of transcription 3; TACI, transmembrane activator and calcium modulator and cyclophilin ligand; UNG, uracil-N-glycosylase; VODI, hepatic veno-occlusive disease with immunodeficiency; WAS, Wiskott-Aldrich syndrome; XLP, X-linked lymphoproliferative syndrome; ZAP70, ζ chain–associated protein of 70 kDa. A majority of patients with proved PIDD have some impairment of humoral or antibody-mediated immunity.12Chinen J. Paul M.E. Shearer W.T. Approach to the evaluation of the immunodeficient patient.in: Rich R.R. Fleisher T.A. Shearer W.T. Schroeder H. Weyand C. Frew A. Clinical immunology: principles and practice. 4th ed. Elsevier, London2013: 381-390Google Scholar, 13Vale A.M. Schroeder Jr., H.W. Clinical consequences of defects in B-cell development.J Allergy Clin Immunol. 2010; 125: 778-787Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar There are currently a number of laboratory-based methods available for defining the extent of the antibody deficiency. With the advances in knowledge and technology, recognition of single-gene disorders has increased.3Parvaneh S. Cassanova J.L. Notarangelo L.D. Conley M.E. Primary immunodeficiencies: a rapidly evolving story.J Allergy Clin Immunol. 2013; 131: 314-323Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 14Alangari A. Alsultan A. Adly N. Massaad M.J. Kiani I.S. Aljebreen A. et al.LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency.J Allergy Clin Immunol. 2012; 130: 481-488.e2Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar Flow cytometry–based analyses of lymphocyte subpopulations, including B-cell phenotyping, have also become routine, together with quantitation of serum immunoglobulin levels. With a focus on the PIDDs that constitute predominantly antibody deficiencies, combining the 3 approaches of serum immunoglobulin quantitation, evaluation of circulating B-cell numbers and phenotypes, and molecular analyses has revealed important defects leading to arrests of B-cell differentiation at the pre–B-cell or B-cell stage.15Blessing J.J.H. Oliverira J.B. Assessment of functional immune responses.in: Rich R.R. Fleisher T.A. Shearer W.T. Schroeder Jr., H.W. Frew A.J. Weyand C. Clinical immunology: principles and practice. 4th ed. Elsevier, London2013: 1160-1182Google Scholar, 16Abraham R.S. Berridge D.R. Lanza I.R. Assessment of proteins of the immune system.in: Rich R.R. Fleisher T.A. Shearer W.T. Schroeder Jr., A.W. Frew A.J. Weyand C. Clinical immunology: principles and practice. 4th ed. Elsevier, London2012: 1145-1150Google Scholar, 17Oliveira J.B. Fleisher T.A. Laboratory evaluation of primary immunodeficiencies.J Allergy Clin Immunol. 2010; 125: S297-S305Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar These defects generally result in severe reductions in levels of all serum immunoglobulin isotypes with profoundly decreased or absent numbers of circulating B cells, severe reduction in at least 2 serum immunoglobulin isotypes with normal or low numbers of B cells, low serum IgG and IgA levels with normal to increased IgM levels and normal numbers of total circulating B cells but decreased numbers of memory and/or switched B cells, or rare light chain deficiencies with normal numbers of circulating B cells. Because these conditions are associated with a global failure of normal antibody production, immunoglobulin replacement is generally indicated. The present approach used to determine whether subjects with suspected antibody deficiency require immunoglobulin replacement therapy relies heavily on the performance of antibody tests to both protein and polysaccharide vaccines.18Orange J.S. Ballow M. Stiehm E.R. Ballas Z.K. Chinen J. De La Morena M. et al.Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology.J Allergy Clin Immunol. 2012; 130: S1-S24Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar A common belief is that these antibody responses to polysaccharide antigens are more meaningful than those to protein antigens, and the use of a 23-valent pneumococcal polysaccharide vaccine has been considered by some as the most informative. There are several problems with the interpretation of current laboratory measurements of antibody levels to the 23-valent pneumococcal vaccine: What constitutes a satisfactory increase in these antibody levels (is it a 2- or a 4-fold increase)? What defines a protective antibody concentration (currently 1.3 μg/mL)? The response to how many serotypes is considered normal? Finally, there is the lack of a functional assay. Importantly, these failures of response often are associated with a clinical picture that generally includes borderline immunoglobulin levels, a history of poorly documented pneumonias in which offending organisms are not defined, and a preponderance of chronic rhinosinusitis (often in atopic patients), and chronic fatigue is a common complaint. Because the decision to treat or not to treat such patients long-term with immunoglobulin replacement rests on nonfunctional laboratory assessments, subjects with normal B-cell immunity are often being treated unnecessarily. Moreover, these decisions to treat have been coupled with a trend toward use of larger and as yet nonvalidated doses of IgG (up to 800 mg/kg/mo) for immunoglobulin replacement, as reviewed in a meta-analysis of 12 open-label prospective clinical trials and 1 open-label retrospective clinical trial that included 482 patients with various forms of reported antibody deficiency.19Orange J.S. Belohradsky B.H. Berger M. Borte M. Hagan J. Jolles S. et al.Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement therapy.Clin Exp Immunol. 2012; 169: 172-181Crossref PubMed Scopus (104) Google Scholar Doses of up to 1.2 g/kg/mo have been given to patients with B-cell deficiency in a similar study of 151 patients.20Lucas 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: 1354-1360Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar Without the benefit of carefully controlled clinical trials with higher doses, this might result in significant and inappropriate expenditures. An important area of controversy is the use of immunoglobulin replacement therapy for subjects with IgG subclass deficiency with or without associated IgA deficiency.21Bonilla F.A. Antibody deficiency.in: Leung D.Y.M. Sampson H.A. Geha R. Szefler S.J. Pediatric allergy: principles and practice. 2nd ed. Elsevier, Saunders2010: 88-97Crossref Scopus (5) Google Scholar, 22Janzi M. Kull I. Sjoberg R. Wan J. Melen E. 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Immunoglobulin G subclass deficiency: fact or fancy?.Curr Allergy Asthma Rep. 2002; 2: 356-360Crossref PubMed Scopus (91) Google Scholar First, and perhaps most importantly, genetic deficiencies of any of the IgG subclasses were not associated with susceptibility to infection.26Lefranc M.P. Lefranc G. Rabbitts T.H. Inherited deletion of immunoglobulin heavy chain constant region genes in normal human individuals.Nature. 1982; 300: 760-762Crossref PubMed Scopus (135) Google Scholar Second, normal laboratory values are not well defined, especially in children, and therefore absolute values of a particular subclass are less meaningful than looking at percentage distribution. The latter provides a "check" on the laboratory by determining whether the sum of the 4 subclasses is similar to the "total" serum IgG value. If the difference is greater than 10%, it may be assumed there is an error. As a general rule, the subject IgG subclass distribution has been reported to be an IgG1 level of greater than 60%, an IgG2 level of greater than 10% to 15%, and an IgG3 level of greater than 5%; IgG4 might be absent in a significant number of subjects. Using the percentage range for assessing IgG subclass is preferable to judging quantitative immunoglobulin subclasses as abnormal in subjects with borderline total serum IgG. The third concern is that certain drugs, such as corticosteroids, lead to hypercatabolism of IgG, with perhaps the largest effect on IgG2 levels. Immunoglobulin replacement is not recommended in this latter group because antibody responses are usually normal.27Lack G. Ochs H.D. Gelfand E.W. Humoral immunity in steroid-dependent children with asthma and hypogammaglobulinemia.J Pediatr. 1996; 129: 898-903Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Perhaps the largest controversy revolves around the diagnosis of common variable immunodeficiency (CVID).28Chapel 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 (300) Google Scholar, 29Conley M.E. Dobbs A.K. Farmer D.M. Kilic S. Paris K. Grigoriadou S. et al.Primary B cell immunodeficiencies: comparisons and contrasts.Annu Rev Immunol. 2009; 27: 199-227Crossref PubMed Scopus (343) Google Scholar, 30Park M.A. Li J.T. Hagan J.B. Maddox D.E. Abraham R.S. Common variable immunodeficiency: a new look at an old disease.Lancet. 2008; 372: 489-502Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 31Salzer U. Bacchelli C. Buckridge S. Pan-Hammarstrom Q. Jennings S. Lougaris V. et al.Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes.Blood. 2009; 113: 1967-1976Crossref PubMed Scopus (207) Google Scholar, 32Yong P.F. Salzer U. Grimbacher B. The role of costimulation in antibody deficiencies: ICOS and common variable immunodeficiency.Immunol Rev. 2009; 229: 101-113Crossref PubMed Scopus (75) Google Scholar In a small percentage of cases, the diagnosis of CVID can be linked to a single-gene defect and thus should no longer be classified as CVID but rather as a specific form of antibody deficiency, such as mutations in inducible costimulator (ICOS), transmembrane activator and calcium modulator and cyclophilin ligand (TACI), B cell–activating factor of the TNF family receptor (BAFFR), CD19, CD20, and CD81 and immunoglobulin light and heavy chain deficiencies. The CVID phenotype is heterogeneous, complex, often associated with hepatosplenomegaly, granulomatous interstitial lung disease, autoimmunity, and increased incidence of cancer and lymphoma.33Cunningham-Rundles C. The many faces of common variable immunodeficiency.Hematology Am Soc Hematol Educ Program. 2012; 2012: 301-305PubMed Google Scholar To qualify as having CVID, patients have to present with hypogammaglobulinemia (significant reduction in ≥2 isotypes of serum immunoglobulin (less than 50% lower limit of normal) and not simply borderline values) and defective antibody production. In addition, flow cytometry analysis in CVID should show abnormalities in B cells, such as alterations in memory B cells or isotype switched B cells. Abnormal flow cytometry data are particularly important to confirm a questionable diagnosis.34Fleisher T.A. Oliveira J.B. Flow cytometry.in: Rich R.R. Fleisher T.A. Shearer W.T. Schroeder Jr., H.W. Frew A.J. Weyand C. Clinical immunology: principles and practice. 4th ed. Elsevier, London2013: 1162-1171Google Scholar The problem with the diagnosis of CVID lies not with the patients who exhibit these features (true CVID) but with those presenting with the more common presentation of "recurrent infections" that are often poorly defined, fatigue, and borderline IgG levels. The latter is often seen in older patients, although rare CVID with typical clinical features can occur in young children as well. In the absence of a genetic diagnosis and without the sentinel clinical features of CVID, overinterpretation of B-cell phenotyping and the findings of borderline IgG levels can prompt the diagnosis of CVID and initiation of immunoglobulin replacement therapy. As described above, the diagnosis has often been supported by the overinterpretation of responses to vaccination, particularly responses to pneumococcal polysaccharide vaccination, although responses to other protein antigens might be normal.32Yong P.F. Salzer U. Grimbacher B. The role of costimulation in antibody deficiencies: ICOS and common variable immunodeficiency.Immunol Rev. 2009; 229: 101-113Crossref PubMed Scopus (75) Google Scholar In fact, if there is an aspect directly related to the diagnosis and treatment of PIDD with predominantly antibody deficiency that requires the most in-depth re-evaluation, it is the laboratory assessment of the response to pneumococcal polysaccharide vaccination. We suggest that a significant number of subjects in the United States and elsewhere have been started on immunoglobulin replacement therapy erroneously based on the absence of a robust response to pneumococcal polysaccharide vaccine. 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