Javier Chinen

Practice parameter for the diagnosis and management of primary immunodeficiency

TABLE OF CONTENTS I. Preface S1 II. Executive Summary S2 III. Algorithms S7 IV. Summary Statements S14 V. General Considerations S20 VI. Humoral Immunodeficiencies S24 VII. Cellular Immunodeficiencies S30 VIII. Combined Immunodeficiencies S33 IX. Phagocytic Cell Disorders S40 X. Complement Deficiencies S43 XI. Acknowledgments S45 XII. References S45 XIII. Appendix S61

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.

A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research.

Transplantation immunology: solid organ and bone marrow.

Development of the field of organ and tissue transplantation has accelerated remarkably since the human MHC was discovered in 1967. Matching of donor and recipient for MHC antigens has been shown to have a significant positive effect on graft acceptance. The roles of the different components of the immune system involved in the tolerance or rejection of grafts and in graft-versus-host disease have been clarified. These components include antibodies, antigen-presenting cells, helper and cytotoxic T-cell subsets, immune cell-surface molecules, signaling mechanisms, and cytokines. The development of pharmacologic and biological agents that interfere with the alloimmune response has had a crucial role in the success of organ transplantation. Combinations of these agents work synergistically, leading to lower doses of immunosuppressive drugs and reduced toxicity. Reports of significant numbers of successful solid-organ transplantations include those of the kidneys, liver, heart, and lung. The use of bone marrow transplantation for hematologic diseases, particularly hematologic malignancies and primary immunodeficiencies, has become the treatment of choice in many of these conditions. Other sources of hematopoietic stem cells are also being used, and diverse immunosuppressive drug regimens of reduced intensity are being proposed to circumvent the mortality associated with the toxicity of these drugs. Gene therapy to correct inherited diseases by means of infusion of gene-modified autologous hematopoietic stem cells has shown efficacy in 2 forms of severe combined immunodeficiency, providing an alternative to allogeneic tissue transplantation.

Secondary immunodeficiencies, including HIV infection

Extrinsic factors can adversely affect immune responses, producing states of secondary immunodeficiency and consequent increased risk of infections. These immunodeficiencies, which can be encountered in routine clinical practice, arise from a number of conditions, such as treatment with glucocorticoids and immunomodulatory drugs, surgery and trauma, extreme environmental conditions, and chronic infections, such as those caused by HIV. The most common cause of immunodeficiency is malnutrition, affecting many communities around the world with restricted access to food resources. Protein-calorie deficiency and micronutrient deficiencies have been shown to alter immune responses; of note, recent progress has been made in the influence of vitamin D deficiency in causing failure of immune activation. Other categories of disease that might present with secondary immunodeficiency include metabolic diseases and genetic multisystemic syndromes. The immune defects observed in secondary immunodeficiency are usually heterogeneous in their clinical presentation, and their prognosis depends on the severity of the immune defect. Management of the primary condition often results in improvement of the immunodeficiency; however, this is sometimes not possible, and the risk of infections can be reduced with prompt antimicrobial treatment and prophylaxis.

Use of intravenous immunoglobulin and adjunctive therapies in the treatment of primary immunodeficiencies: A working group report of and study by the Primary Immunodeficiency Committee of the American Academy of Allergy Asthma and Immunology.

There are an expanding number of primary immunodeficiency diseases (PIDDs), each associated with unique diagnostic and therapeutic complexities. Limited data, however, exist supporting specific therapeutic interventions. Thus, a survey of PIDD management was administered to allergists/immunologists in the United States to identify current perspectives and practices. Among 405 respondents, the majority of key management practices identified were consistent with existing data and guidelines, including the provision of immunoglobulin therapy, immunoglobulin dosing and selective avoidance of live viral vaccines. Practices for which there are little specific data or evidence-based guidance were also examined, including evaluation of IgG trough levels for patients receiving immunoglobulin, use of prophylactic antibiotics and recommendations for complementary/alternative medicine. Here, variability applied to PIDD patients was identified. Differences between practitioners clinically focused upon PIDD and general allergists/immunologists were also identified. Thus, a need for expanded clinical research in PIDD to optimize management and potentially improve outcomes was defined.

Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency

The contribution of B cells to the pathology of Omenn syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination activity. In spite of a severe block at the pro–B cell stage and profound B cell lymphopenia, significant serum levels of immunoglobulin (Ig) G, IgM, IgA, and IgE and a high proportion of Ig-secreting cells were detected in mut/mut mice. Antibody responses to trinitrophenyl (TNP)-Ficoll and production of high-affinity antibodies to TNP–keyhole limpet hemocyanin were severely impaired, even after adoptive transfer of wild-type CD4+ T cells. Mut/mut mice produced high amounts of low-affinity self-reactive antibodies and showed significant lymphocytic infiltrates in peripheral tissues. Autoantibody production was associated with impaired receptor editing and increased serum B cell–activating factor (BAFF) concentrations. Autoantibodies and elevated BAFF levels were also identified in patients with Omenn syndrome and leaky SCID as a result of hypomorphic RAG mutations. These data indicate that the stochastic generation of an autoreactive B cell repertoire, which is associated with defects in central and peripheral checkpoints of B cell tolerance, is an important, previously unrecognized, aspect of immunodeficiencies associated with hypomorphic RAG mutations.

Basic and clinical immunology

The authors selected articles published in the literature from January 2004 through December 2004 that were relevant to the areas of basic and clinical immunology. Several articles explored the development of TH1 or TH2 response and the role of the monocyte-T cell interaction. Others were articles describing the action of drugs commonly used in asthma to inhibit cytokine responses and the anti-inflammatory role of nonimmune pulmonary cells present in the lung. Several reports show how dendritic cells are being developed as vehicles for DNA vaccines aimed at stimulating cellular responses, an advance of great importance for HIV researchers working on vaccines, who are concerned about the different ways HIV evades the immune response. Other publications described Toll-like receptors in diverse cells, including mast cells and CD4+ T cells, for the recognition of viruses and bacteria. In the area of clinical immunology, an updated classification for primary immunodeficiencies with more than 100 identified genes responsible for these diseases and the report on the second clinical trial of gene therapy for X-linked severe combined immunodeficiency syndrome were published. Significant advances included the clinical prognosis in common variable immunodeficiency for patients presenting with lung pathology, the safety of live vaccines in partial DiGeorge syndrome, the report of patients with complete DiGeorge syndrome with the presence of peripheral blood T cells, the clinical spectrum of patients with NF-kappaB essential modifier (NEMO) gene deficiency, the publication of a consensus algorithm for the management of hereditary angioedema, and the report of immune restoration syndrome in pediatric HIV infection.

Excellent survival after sibling or unrelated donor stem cell transplantation for chronic granulomatous disease.

BACKGROUND Matched related donor (MRD) hematopoietic stem cell transplantation (HSCT) is a successful treatment for chronic granulomatous disease (CGD), but the safety and efficacy of HSCT from unrelated donors is less certain. OBJECTIVE We evaluated the outcomes and overall survival in patients with CGD after HSCT. METHODS We report the outcomes for 11 children undergoing HSCT from an MRD (n = 4) or an HLA-matched unrelated donor (MUD) (n = 7); 9 children were boys, and the median age was 3.8 years (range, 1-13 years). We treated both X-linked (n = 9) and autosomal recessive (n = 2) disease. Nine children had serious clinical infections before transplantation. The conditioning regimens contained busulfan, cyclophosphamide, cytarabine, or fludarabine according to the donor used. All patients received alemtuzumab (anti-CD52 antibody). Additional graft-versus-host disease (GvHD) prophylaxis included cyclosporine and methotrexate for MUD recipients and cyclosporine and prednisone for MRD recipients. RESULTS Neutrophil recovery took a median of 16 days (range, 12-40 days) and 18 days (range, 13-24 days) for MRD and MUD recipients, respectively. Full donor neutrophil engraftment occurred in 9 patients, and 2 had stable mixed chimerism; all patients had sustained correction of neutrophil oxidative burst defect. Four patients had grade I skin acute GVHD responding to topical treatment. No patient had grade II to IV acute GvHD or chronic GvHD. All patients are alive between 1 and 8 years after HSCT. CONCLUSION For CGD, equivalent outcomes can be obtained with MRD or MUD stem cells, and HSCT should be considered an early treatment option.

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole‐exome screening methods to detect disease‐causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole‐exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome‐tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD‐causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high‐throughput genomic approach enabled detection of disease‐related variants in unexpected genes; permitted detection of low‐grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

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

&NA; 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.