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Autosomal recessive SOPH syndrome was first described in the Yakuts population of Asia by Maksimova et al. in 2010. It arises from biallelic pathogenic variants in the NBAS gene and is characterized by severe postnatal growth retardation, senile facial appearance, small hands and feet, optic atrophy with loss of visual acuity and color vision, and normal intelligence (OMIM #614800). The presence of Pelger-Huet anomaly in this disorder led to its name as an acronym for Short stature, Optic nerve atrophy, and Pelger-Huet anomaly. Recent publications have further contributed to the characterization of this syndrome through additional phenotype-genotype correlations. We review the clinical features described in these publications and report on a 27-year-old woman with dwarfism with osteolysis and multiple skeletal problems, minor anomalies, immunodeficiency, diabetes mellitus, and multiple secondary medical problems. Her condition was considered an unknown autosomal recessive disorder for many years until exome sequencing provided the diagnosis by revealing a founder disease-causing variant that was compound heterozygous with a novel pathogenic variant in NBAS. Based on the major clinical features of this individual and others reported earlier, a revision of the acronym is warranted to facilitate clinical recognition.

Specific antibody deficiency (SAD) is defined as the inability to mount an antibody response to purified Streptococcus pneumoniae capsular polysaccharide antigens in the presence of normal immunoglobulin concentrations and normal antibody responses to protein antigens. In this review, we discuss the difficulties in using presently available testing methods to adequately define SAD. The fact that there are different forms of SADs to pneumococcal surface polysaccharides is detailed. The diagnostic and therapeutic implications of recognizing that, in addition to SAD, there are other forms of SAD in the response to S. pneumoniae polysaccharides are described in detail. The conclusion of this review is that assessment of immunity and therapeutic actions to deal with SADs need to be based on clinical evidence rather than solely on arbitrarily defined antibody responses.

BackgroundImmunologists are increasingly being asked to assess patients with non-classical and secondary antibody deficiency to determine their potential need for immunoglobulin replacement therapy (IGRT). Immunoglobulin is a limited, expensive resource and no clear guidance exists for this broad patient group. The purpose of this survey is to establish what factors influence the decision to commence IGRT in adult patients, when diagnostic criteria for primary antibody deficiency are not fulfilled.MethodsUnder the auspices of the United Kingdom Primary Immunodeficiency Network (UKPIN), a study group was established which circulated an online questionnaire to the consultant body across the UK and Ireland. Results provided a snapshot of the current clinical practice of 71% of consultant immunologists, from 30 centers.ResultsIn order of importance, factors which influence the decision to commence IGRT include number of hospital admissions with infection, serum IgG level, bronchiectasis, radiologically proven pneumonia, number of positive sputum cultures, number of antibiotic courses, and results of immunization studies. The commonest test vaccine used was Pneumovax 23 with measurement of serotype-specific responses at 4 weeks, with a threshold of 0.35 μg/ml in 2/3 of serotypes measured. Eighty-six percent of patients are treated with a trial of prophylactic antibiotics prior to consideration of IGRT. Efficacy of IGRT trial is assessed at between 6 and 12 months.ConclusionsThere was consistency in clinical practice using a combination of clinical history, evidence of infections, and vaccination testing for diagnosis. However, there was some variation in the implementation of this practice, particularly in vaccine choice and assessment of response to vaccination.

BCG has been recommended because of its efficacy against disseminated and meningeal tuberculosis. The BCG vaccine has other mechanisms of action besides tuberculosis protection, with immunomodulatory properties that are now being discovered. Reports have shown a significant protective effect against leprosy. Randomized controlled trials suggest that BCG vaccine has beneficial heterologous (nonspecific) effects on mortality in some developing countries. BCG immunotherapy is considered the gold standard adjuvant treatment for non-muscle-invasive bladder cancer. BCG vaccine has also been tested as treatment for diabetes and multiple sclerosis. Erythema of the BCG site is recognized as a clinical clue in Kawasaki disease. BCG administration in the immunodeficient patient is associated with local BCG disease (BCGitis) or disseminated BCG disease (BCGosis) with fatal consequences. BCG administration has been associated with the development of autoimmunity. We present a brief review of the diverse facets of the vaccine, with the discovery of its new modes of action providing new perspectives on this old, multifaceted and controversial vaccine.

Las inmunodeficiencias primarias constituyen un grupo de más de 300 defectos innatos del sistema inmunitario, tanto en sus componentes hematopoyéticos como en los no-hematopoyéticos. Dichos defectos pueden presentarse con un amplio espectro de manifestaciones clínicas, ya sea con infecciones (comunes recurrentes, comunes graves, o raras y graves), autoinflamación, autoinmunidad, malignidad y/o alergia. Anteriormente clasificadas como “enfermedades raras”, las inmunodeficiencias primarias no son tan raras como se pensaba: hoy en día se estima que afectan a más de seis millones de personas alrededor del mundo, sin distinciones geográficas, de género o edad.

Primary immunodeficiencies (PID) are genetic diseases that affect the immune system and for the last 20 years, the Latin American Society for Immunodeficiencies (LASID) has been promoting initiatives in awareness, research, diagnosis, and treatment for the affected patients in Latin America. These initiatives have resulted in the development of programmes such as the LASID Registry (with 4900 patients registered as of January 2014), fellowships in basic and clinical research, PID summer schools, biannual meetings, and scientific reports, amongst others. These achievements highlight the critical role that LASID plays as a scientific organisation in promoting science, research and education in this field in Latin America. However, challenges remain in some of these areas and the Society must envision additional strategies to tackle them for the benefit of the patients. In June 2013, a group of experts in the field met to discuss the contributions of LASID to the initiatives of PID in Latin America, and this article summarises the current state and future perspectives of this society and its role in the advance of PIDs in Latin America. COL0012426

(59.4%), granulomata (49.3%), skin infections (42%), chronic diarrhea (41.9%), otitis (29%), sepsis (23.2%), abscesses (21.7%), recurrent urinary tract infection (20.3%), and osteomyelitis (15.9%). Adverse reactions to bacillus Calmette-Gu� (BCG) vaccination were identified in 30% of the studied Latin American CGD cases. The genetic diagnoses of the 71 patients revealed 53 patients from 47 families with heterogeneous mutations in the CYBB gene (five novel mutations:p.W361G,p.C282X,p.W483R,p.R226X,andp.Q93X),16 patientswith the commondeletionc.75_76 del.GTinexon2 ofNCF1 gene, and two patients with mutations in the CYBA gene. Conclusion. The majority of Latin American CGD patients carry a hemizygous mutation in the CYBB gene. They also presented a wide range of clinical manifestations most frequently bacterial and fungal infections of the respiratory tract, skin, and lymph nodes. Thirty percent of the Latin American CGD patients presented adverse reactions to BCG, indicating that this vaccine should be avoided in these patients. # 2015 Wiley Periodicals, Inc.

Antibodies are an essential component of the adaptative immune response and hold long-term memory of the immunological experiences throughout life. Antibody defects represent approximately half of the well-known primary immunodeficiencies requiring immunoglobulin replacement therapy. In this article, the authors review the current indications and therapeutic protocols in the Latin American environment. Immunoglobulin replacement therapy has been a safe procedure that induces dramatic positive changes in the clinical outcome of patients who carry antibody defects. COL0012426

A Chauveau, ML Dalphin, F Mauny; PASTURE Study Group. Allergy. 2017;72(9):1365–1373 To assess the agreement between skin prick testing (SPT) and specific immunoglobulin E (sIgE) and to correlate their association with childhood allergic diseases. A total of 529 children from a prospective birth cohort of children living in rural Europe underwent both SPT and sIgE testing at 10 years of age. Those with severe acute symptoms of asthma or rhinoconjunctivitis, eczema at SPT test site, or severe peanut allergy were excluded. SPT and sIgE testing were evaluated for 8 allergens, including dust mite ( Dermatophagoides pteronyssinus and D farinae) , cat, dog, birch, grass, Alternaria , and peanut. Agreement …

World Primary Immunodeficiency Week (WPIW) 2013 ran from 22 to 29th April (www.worldpiweek.org), providing an opportunity to reflect on progress made and the challenges that remain for the primary immunodeficiency diseases (PID) community. In this article, representatives from leading PID societies evaluate the situation and plans for further progress in their respective areas of the world. It is hoped that this situation analysis will prompt further focus and enhanced collaboration on the gaps that remain in the pursuit of promoting early diagnosis and treatment of PIDs.

In the last 5 years, several hundred articles have been published concerning the link between primary immunodeficiency disease (PID) and rheumatologic diseases. Although rheumatologic complications were originally thought to be at the opposite ends of the spectrum of immunopathologic manifestations, they are now all being considered secondary manifestations of a causative primary “immune derangement.” For the rheumatologist, it is important to be able to identify patients who may present with typical rheumatologic findings but who have an underlying PID. In a systematic manner, this overview addresses both the systemic and organ-based rheumatologic diseases which have known associations with primary immunodeficiencies, and explores how immunodeficiency may actually cause these clinical manifestations.

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.

ML Grant, J Crane, EA Mitchell. Allergy. 2016;71(9):1325–1334 To determine whether vitamin D supplementation during pregnancy and infancy prevents aeroallergen sensitization and respiratory illness identified by primary care providers. Two hundred and sixty women were recruited from an urban primary care maternity clinic in New Zealand from April 2010 to July 2011. The women were managed from 27 weeks’ gestation to delivery, and their infants were managed from birth to 18 months of age. Participants were not taking vitamin D supplementation before enrollment. This was a randomized, double-blind, placebo-controlled, parallel-group trial. The mother and infant pairs were randomly assigned …

Background Hypomorphic mutations in the nuclear factor–κB (NF-κB) essential modulator ( NEMO ) gene result in a variable syndrome of somatic and immunologic abnormalities. Clinically relevant genotype-phenotype associations are essential to understanding this complex disease. Objective To study 2 unrelated boys with novel NEMO mutations altering codon 223 for similarity in phenotype in consideration of potential genotype-phenotype associations. Methods Clinical and laboratory features, including cell counts, immunoglobulin quantity and quality, natural killer cell cytotoxicity, and Toll-like and tumor necrosis factor receptor signaling, were evaluated. Because both mutations affected NEMO codon 223 and were novel, consideration was given to new potential genotype-phenotype associations. Results Both patients were diagnosed as having hypohidrotic ectodermal dysplasia and had severe or recurrent infections. One had recurrent sinopulmonary infections and the other necrotizing soft tissue methicillin-resistant Staphylococcus aureus infection and Streptococcus anginosus subdural empyema with bacteremia. NEMO gene sequence demonstrated a 3-nucleotide deletion (c.667_669delGAG) in one patient and a substitution (667G>A) in the other. These findings predict either the deletion of NEMO glutamic acid 223 or it being replaced with lysine, respectively. Both patients had normal serum IgG levels but poor specific antibodies. Natural killer cell cytotoxicity and Toll-like and tumor necrosis factor receptor signaling were also impaired. Serious bacterial infection did not occur in both patients after immunoglobulin replacement therapy. Conclusions Two different novel mutations affecting NEMO glutamic acid 223 resulted in clinically relevant similar phenotypes, providing further evidence to support genotype-phenotype correlations in this disease. They suggest NEMO residue 223 is required for ectodermal development and immunity and is apparently dispensable for quantitative IgG production but may be required for specific antibody production.

Early diagnosis and appropriate therapy are essential for the best prognosis and quality of life in patients with primary immunodeficiency diseases (PIDDs). Experts from several Latin American countries have been meeting on a regular basis as part of an ongoing effort to improve the diagnosis and treatment of PIDD in this region. Three programmes are in development that will expand education and training and improve access to testing facilities throughout Latin America. These programmes are: an educational outreach programme (The L-Project); an immunology fellowship programme; and the establishment of a laboratory network to expand access to testing facilities. This report provides the status of these programmes based on the most recent discussions and describes the next steps toward full implementation of these programmes.

M Sorensen, C Klingenberg, M Wickman. Allergy. 2017;72(10):1548–1555 In the authors’ previous study (Tromso Study Fit Futures 2) an association was found between nasal Staphylococcus aureus carriage and allergic morbidity in adolescent patients. The authors sought to determine the relationship between S aureus enterotoxin (SE) sensitization with both allergic polysensitization and allergic disease. A total of 1208 high school students were invited to partake in the study, and 868 (71.9%) ultimately participated. Students had been previously recruited in 2010–2011 to the authors’ initial cohort and some had participated in the original …

Background The outcomes of gene therapy to correct congenital immunodeficiencies are unknown. We reviewed long-term outcomes after gene therapy in nine patients with X-linked severe combined immunodeficiency (SCID-X1), which is characterized by the absence of the cytokine receptor common γ chain. Methods The nine patients, who lacked an HLA-identical donor, underwent ex vivo retrovirus-mediated transfer of γ chain to autologous CD34+ bone marrow cells between 1999 and 2002. We assessed clinical events and immune function on long-term follow-up. Results Eight patients were alive after a median follow-up period of 9 years (range, 8 to 11). Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients. However, acute leukemia developed in four patients, and one died. Transduced T cells were detected for up to 10.7 years after gene therapy. Seven patients, including the three survivors of leukemia, had sustained immune reconstitution; three patients required immunoglobulin-replacement therapy. Sustained thymopoiesis was established by the persistent presence of naive T cells, even after chemotherapy in three patients. The T-cell−receptor repertoire was diverse in all patients. Transduced B cells were not detected. Correction of the immunodeficiency improved the patients’ health. Conclusions After nearly 10 years of follow-up, gene therapy was shown to have corrected the immunodeficiency associated with SCID-X1. Gene therapy may be an option for patients who do not have an HLA-identical donor for hematopoietic stem-cell transplantation and for whom the risks are deemed acceptable. This treatment is associated with a risk of acute leukemia. (Funded by INSERM and others.)

The nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc) is metabolically incorporated into human tissues from certain mammalian-derived foods, and this occurs in the face of an anti-Neu5Gc “xeno-autoantibody” response. Given evidence that this process contributes to chronic inflammation in some diseases, it is important to understand when and how these antibodies are generated in humans. We show here that human anti-Neu5Gc antibodies appear during infancy and correlate with weaning and exposure to dietary Neu5Gc. However, dietary Neu5Gc alone cannot elicit anti-Neu5Gc antibodies in mice with a humanlike Neu5Gc deficiency. Other postnatally appearing anti-carbohydrate antibodies are likely induced by bacteria expressing these epitopes; however, no microbe is known to synthesize Neu5Gc. Here, we show that trace exogenous Neu5Gc can be incorporated into cell surface lipooligosaccharides (LOS) of nontypeable Haemophilus influenzae (NTHi), a human-specific commensal/pathogen. Indeed, infant anti-Neu5Gc antibodies appear coincident with antibodies against NTHi. Furthermore, NTHi that express Neu5Gc-containing LOS induce anti-Neu5Gc antibodies in Neu5Gc-deficient mice, without added adjuvant. Finally, Neu5Gc from baby food is taken up and expressed by NTHi. As the flora residing in the nasopharynx of infants can be in contact with ingested food, we propose a novel model for how NTHi and dietary Neu5Gc cooperate to generate anti-Neu5Gc antibodies in humans.

The identification of the molecular bases of more than 130 primary immunodeficiency diseases has prompted the use of mutation analysis in the diagnostic approach to these patients. Here we discuss the importance of and the limitations associated with molecular diagnosis of these disorders and emphasize the need that mutation analysis be accompanied by appropriate evidence that the identified genetic defect has pathologic consequences on RNA/protein expression and function.

Mice carrying the recessive locus for peripheral T cell deficiency (Ptcd) have a block in thymic egress, but the mechanism responsible is undefined. Here we found that Ptcd T cells had an intrinsic migration defect, impaired lymphoid tissue trafficking and irregularly shaped protrusions. Characterization of the Ptcd locus showed a point substitution of lysine for glutamic acid at position 26 in the actin regulator coronin 1A that enhanced its inhibition of the actin regulator Arp2/3 and resulted in its mislocalization from the leading edge of migrating T cells. The discovery of another coronin 1A mutant during an N-ethyl-N-nitrosourea-mutagenesis screen for T cell-lymphopenic mice prompted us to evaluate a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles. Our findings establish a function for coronin 1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation and demonstrate that actin regulation is a biological process defective in human and mouse severe combined immunodeficiency.

Patients with specific antibody deficiency (SAD) have a deficient immunologic response to polysaccharide antigens. Such patients experience sinopulmonary infections with increased frequency, duration, or severity compared with the general population. SAD is definitively diagnosed by immunologic challenge with a pure polysaccharide vaccine in patients 2 years old and older who have otherwise intact immunity, using the 23-valent pneumococcal polysaccharide vaccine as the current gold standard. Specific antibody deficiencies comprise multiple immunologic phenotypes. Treatment must be tailored based on the severity of symptoms. Most patients have a good prognosis. The deficiency may resolve over time, especially in children.

Summary Intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) are effective in the treatment of patients with primary antibody deficiency disorders (PAD). The purpose of this study was to evaluate Streptococcus pneumoniae (Spn) antibody titres to 14 serotypes in patients receiving IVIG compared to SCIG and to correlate Spn antibody levels to clinical outcome. The doses of immunoglobulin (Ig)G/kg/month were similar in both IVIG and SCIG groups. In 11 patients treated with IVIG, Spn antibody titres were ≥ 1·3 μg/ml to 99·4 ± 2·1% of the 14 serotypes at peak IVIG but decreased to 66·9 ± 19·8% at trough IVIG. Loss of Spn titres ≥ 1·3 μg/ml was most frequent for Spn serotypes 1, 4, 9V and 23. This correlated with lower Spn antibody titres to these serotypes at peak IVIG compared to the other serotypes. In 13 patients treated with SCIG, Spn antibody titres were protective to 58·2 ± 23·3% of the serotypes 3–5 days after infusion, similar to trough IVIG. Similarly, the Spn serotypes with the least protective percentages were the same as the ones observed in trough IVIG. There were no annualized serious bacterial infections (aSBI) in either group. However, there were significantly decreased annualized other infections (aOI) in the SCIG group compared to the IVIG-treated group, 0·8 ± 0·7 versus 2·2 ± 1·2 infections/patient/year (P = 0·004). Breakthrough aOI did not correlate with protective or higher serum Spn antibody titres.

This is the second report on the continuing efforts of LAGID to increase the recognition and registration of patients with primary immunodeficiency diseases in 12 Latin American countries: Argentina, Brazil, Chile, Colombia, Costa Rica, Honduras, Mexico, Panama, Paraguay, Peru, Uruguay, and Venezuela. This report reveals that from a total of 3321 patients registered, the most common form of primary immunodeficiency disease was predominantly antibody deficiency (53.2%) with IgA deficiency reported as the most frequent phenotype. This category was followed by 22.6% other well-defined ID syndromes, 9.5% combined T- and B-cell inmunodeficiency, 8.6% phagocytic disorders, 3.3% diseases of immune dysregulation, and 2.8% complement deficiencies. All countries that participated in the first publication in 1998 reported an increase in registered primary immunodeficiency cases, ranging between 10 and 80%. A comparison of the estimated minimal incidence of X-linked agammaglobulinemia, chronic granulomatous disease, and severe combined immunodeficiency between the first report and the present one shows an increase in the reporting of these diseases in all countries. In this report, the estimated minimal incidence of chronic granulomatous disease was between 0.72 and 1.26 cases per 100,000 births in Argentina, Chile, Costa Rica, and Uruguay and the incidence of severe combined immunodeficiency was 1.28 and 3.79 per 100,000 births in Chile and Costa Rica, respectively. However, these diseases are underreported in other participating countries. In addition to a better diagnosis of primary immunodeficiency diseases, more work on improving the registration of patients by each participating country and by countries that have not yet joined LAGID is still needed.

The majority of children with Down syndrome (DS) tend to have frequent bacterial infections including recurrent respiratory infections. Our objective was to evaluate the production of antibodies to pneumococcal polysaccharide antigens after active immunization in DS subjects. IgG antibodies to pneumococcal serotypes (1, 3, 6B, 9V, and 14) were measured before and 6 weeks after immunization with a 23-valent pneumococcal vaccine (Pneumo23, Pasteur-Merrieux) in 6- to 13-year-old DS children (N = 17) and in aged-matched normal controls (N = 30). An adequate response was defined as a 4-fold increase over baseline or a post-immunization level of specific pneumococcal serotype antibodyor = 1.3 microg/mL. After immunization, all DS children had an increase in post-immunization levels against all serotypes analyzed. A 4-fold or more increase was observed in all DS children concerning serotypes 1 and 14, in 90% of subjects for serotypes 3 and 9V, and in 65% for serotype 6B. Regarding this increase, 8 of the 17 DS children had an adequate response to all serotypes analyzed, 8/17 patients to 4 serotypes and 1/17 to 3 serotypes. However, when we compared post-immunization levels between DS children and controls, we observed lower levels in the former group (P0.05) for all serotypes except serotype 3. We conclude that pneumococcal polysaccharide immunization could be beneficial for these DS children.

Angioedema and chronic diarrhea in patients taking immunosuppressants are not always because of side effects and could be a new onset of food allergy. Our aim is to discuss the pathogenesis and treatment of the post-transplant development of food allergies. The first patient was receiving tacrolimus subsequent to heart transplantation and developed angioedema after consumption of dairy products at 12 months after transplantation. He was found to be allergic to multiple foods by both RAST and ImmunoCAP tests. The second patient with argininosuccinic aciduria, post-liver transplant, also received tacrolimus and developed chronic non-mucoid/bloody diarrhea at seven months following transplantation. ImmunoCAP test was positive only for egg white and peanuts. Biopsy showed eosinophilic infiltration of the mucosa from the stomach to the rectum. Elimination diets in both patients resolved the symptoms. These cases suggest a direct relationship between tacrolimus and development of food allergy.

The aim of this study was to evaluate the effect of absorption with pneumococcal type 22F polysaccharide on antipneumococcal antibody titers in unimmunized Chilean pregnant women and on antibodies in their offspring at birth and 3, 6, and 12 months of age. Sera from 10 healthy pregnant women and from their offspring at birth and at 3, 6, and 12 months of age were studied. Immunoglobulin G antibodies against serotypes 1, 3, 4, 5, 6B, 9V, 14, 18, 19F, and 23F were measured by a standardized enzyme-linked immunosorbent assay method. All sera were absorbed with polysaccharide C, and aliquots of each serum were absorbed with polysaccharide 22F. Individual results were expressed in μg/ml based on the standard serum pool 89-SF. Absorption with polysaccharide 22F reduced antibody concentrations in all samples and to all 10 serotypes studied. Reduction was highest in maternal sera and in cord blood, but it was also present at 3, 6, and 12 months of age. The percent reduction ranged from 24% for serotype 14 to 50% for serotype 1 in maternal samples and from 20% for serotype 18C to 49% for serotype 4 in cord blood samples. The percentages of transplacental transmission were similar for nonabsorbed and absorbed maternal fetal pairs. Absorption with serotype 22F had a significant impact on antipneumococcal antibody concentrations in unimmunized pregnant women and in their offspring. Our results suggest that absorption with 22F polysaccharide needs to be performed in studies of transplacental transmission of antipneumococcal antibodies.

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

A novel method of large-scale chromatography has been developed to improve recovery and purity of immunoglobulin G (IgG) from pooled plasma. The current study compares safety, toxicity and efficacy of two intravenous immunoglobulin products: a novel formulation, IGIV caprylate/chromatography (IGIV-C; Gamunex™, 10%) and a licensed solvent/detergent-treated product, Gamimune®N, 10% (IGIV-SD). The study, a randomized, double-blind, parallel group, therapeutic equivalence trial, was conducted at 25 treatment centers in Canada and the United States. Patients (n=172) having confirmed chronic primary immunodeficiency (PID), aged 1–75 years, and receiving IGIV therapy were enrolled. For 9 months, patients were treated with IGIV-C or IGIV-SD in accordance with the patient's individualized treatment regimen utilized before study entry. The primary endpoint was the proportion of patients with ≥1 validated acute sinopulmonary infection during the treatment period. Secondary endpoints included the proportion of patients with all infections, time to first infection, annual infection rates, lung function parameters, infusion-related safety and viral safety. The annual validated infection rate in the IGIV-C group was 0.18 compared to 0.43 in the IGIV-SD group (p=0.023). Nine patients receiving IGIV-C experienced validated infections, compared to 17 patients in IGIV-SD group (p=0.06). Acute sinusitis (validated plus clinically defined) was less frequent in the IGIV-C group (p=0.012). Presence of bronchiectasis did not affect efficacy. Adverse reactions were similar in frequency and severity in both groups. No evidence of viral transmission was observed. IGIV-C appears to be superior to IGIV-SD in preventing validated sinopulmonary infections, especially acute sinusitis, in patients with PID.

X-linked severe combined immunodeficiency due to a mutation in the gene encoding the common gamma (gamma(c)) chain is a lethal condition that can be cured by allogeneic stem-cell transplantation. We investigated whether infusion of autologous hematopoietic stem cells that had been transduced in vitro with the gamma(c) gene can restore the immune system in patients with severe combined immunodeficiency.CD34+ bone marrow cells from five boys with X-linked severe combined immunodeficiency were transduced ex vivo with the use of a defective retroviral vector. Integration and expression of the gamma(c) transgene and development of lymphocyte subgroups and their functions were sequentially analyzed over a period of up to 2.5 years after gene transfer.No adverse effects resulted from the procedure. Transduced T cells and natural killer cells appeared in the blood of four of the five patients within four months. The numbers and phenotypes of T cells, the repertoire of T-cell receptors, and the in vitro proliferative responses of T cells to several antigens after immunization were nearly normal up to two years after treatment. Thymopoiesis was documented by the presence of naive T cells and T-cell antigen-receptor episomes and the development of a normal-sized thymus gland. The frequency of transduced B cells was low, but serum immunoglobulin levels and antibody production after immunization were sufficient to avoid the need for intravenous immunoglobulin. Correction of the immunodeficiency eradicated established infections and allowed patients to have a normal life.Ex vivo gene therapy with gamma(c) can safely correct the immune deficiency of patients with X-linked severe combined immunodeficiency.

S Giavi, YM Vissers, A Muraro. Allergy. 2016;71(11):1575–1584 Egg allergy is 1 of the most common food allergies in children. This study aims to investigate a method to desensitize egg-allergic patients so that they can develop long-lasting oral tolerance to egg proteins. Twenty-nine egg-allergic patients (ages 1–5.5 years) from 3 study sites in Europe (Greece, Switzerland, and Italy). These patients had positive testing to egg via either in vitro or …

The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) have jointly accepted responsibility for establishing the "Practice parameter for the diagnosis and management of primary immunodeficiency." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.

M Jones, H Jeal, JM Harris. Allergy. 2013;68(9):1143–1149 The goal of this study was to determine if maternal production of anti-HLA antibodies arising from mismatch between mother and fetus is associated with allergic outcomes at 8 years of age. Previous studies have suggested that the prevalence of atopy is lower in children of higher birth order. Higher numbers of pregnancies are associated with increased antibodies against paternal HLA antigens and maternal interferon-γ production (Th1) in response to fetal cells. The authors postulated that the raised levels of interferon-γ secondary to HLA mismatch may be another factor …

Clinical observations in patients with specific antibody deficiency treated for periods of time with IgG infusion have suggested that IgG may have a positive immunoregulatory effect on the production of specific antibodies against pneumococcal polysaccharides. We developed an in vitro model to test the effect of an IgIV preparation on the antibody production in response to a pneumococcal polysaccharide serotype and on the antibody and cytokine production in response to both a protein antigen and a pneumococcal polysaccharide antigen. We studied 37 consecutive patients referred to our clinics for evaluation of their recurrent respiratory infections. Subjects were divided into two groups: 22 patients without SAD and 15 patients with SAD. PBMCs were left unstimulated or were stimulated with tetanus toxoid or pneumococcal polysaccharide serotype 19, in the presence of human albumin or IgIV. IgG anti-Pn-19 antibody, IL-4 and IFN-γ concentrations in culture supernatants were determined by ELISA. An increase in IgG anti-Pn-19 antibodies, associated with an increase in IFN-γ and a decrease in IL-4 production was observed in cultures stimulated with pneumococcal polysaccharide in the presence of IgIV when patients were analyzed together. The enhancing effect of IgIV was more significant for both IgG anti-Pn19 antibodies and IFN-γ in patients without SAD. In contrast, IgIV caused a significant decrease in IL-4 secretion in patients with SAD, which was associated with an increase in IgG anti-Pn19 antibodies in 3 of 7 of these patients. These results suggest that IgIV has some immunomodulatory effect on the in vitro production of IgG anti-Pn19 antibodies and cytokine production in cell cultures stimulated with Pn-19 antigen and that this modulation may be associated with a Th1/Th2 regulatory mechanism. Further studies at a cellular and molecular level are in progress to examine if the differences in the in vitro modulatory response to IgIV in these two groups of patients may point to a functional defect in patients with SAD.

All clinical S. pneumoniae specimens isolated from patients with invasive or sterile-site infections admitted to one regional general hospital in southern Chile were collected during a 5-year period (February 1994 to September 1999). A total of 247 strains belonging to 50 serotypes were isolated in this survey: 69 in patients under 5 years of age, 129 in patients 5 to 64 years old, and 49 from patients 65 years and older. Eight serotypes were identified in all age groups, while all other serotypes were found exclusively in one age group or in patients over 4 years of age. Serotype 3 was never found in patients under 5 years old, and serotype 14 was not found in patients >64 years of age. There was no difference in the serotypes causing infection in each one of the 5 years of the survey. Our results suggest that both bacterial virulence factors and host factors play an important role in the selection of S. pneumoniae serotypes causing invasive infection. Possible host factors include age-related differences in the immune response. Comparative studies with other areas of the world may help to further understanding of our observations in southern Chile.

Antibodies have a crucial role in protecting against infections, and antibody deficiencies are the commonest primary and secondary immunodeficiencies. Antibody deficiencies may be the only abnormality present in a patient, or they may be present and aggravate the symptoms of various other conditions. Because the presence of an antibody deficiency is difficult to predict from clinical presentation, physicians should perform an evaluation of antibody-mediated immunity, even knowing that, in many cases, the results are normal. When immunizations are included as a part of the evaluation, many patients experience a benefit from enhanced immunity against common pathogens. Some alternative practical approaches to the evaluation of patients with recurrent infections are outlined in Figure 8. Referral to a clinical immunologist can be based on the presence of recurrent infections, a positive family history without prior evaluation by a pediatrician, or abnormal immunologic findings that require an advanced evaluation. In any case, a close collaboration between pediatrician and immunologist likely will result in an accurate diagnosis and better treatment of patients with antibody-deficiency syndromes and their families.

Foods are an important cause of severe acute hypersensitivity reactions including fatal anaphylaxis. Food allergy has been estimated to be the most frequent cause of anaphylaxis treated in emergency rooms. 69 Severe reactions to foods can occur at all ages, from infants receiving cow's milk or casein or whey hydrolysate formulas 21 , 57 to children, adolescents, and adults. 56 , 70 Although some reactions caused by formula proteins in infants may decrease in intensity with age, 7 the risk for severe reactions to other foods persists for long periods of time, even in absence of exposure. 8 The current management of patients with severe acute food reactions is based on avoidance of specific foods and on the availability of emergency medications to immediately treat an acute reaction. These severe reactions have been associated with fish, shellfish, nuts and seeds, legumes, celery, and to a lesser extent with grains, milk, and eggs. 7 , 8 , 70 It is clear from looking at this list that even the most careful patients may not be safe from an accidental or inadvertent exposure. In most instances, individuals experiencing a food-induced anaphylactic reaction have inadvertently ingested the food that caused the allergic reaction. 56 The unpredictability of accidental exposures and the long periods of time during which patients at risk may not come in contact with the offending foods makes it difficult to have acute treatment medications available at all times, which is necessary for the prevention of fatal food reactions. 56 , 70 The vast majority of the acute, severe reactions to food appear to be IgE-mediated, although non–IgE-mediated reactions can also account for some severe food reactions. 28 The presence of IgE antibodies as the likely cause for severe acute food reactions suggests the possibility of changing this allergic reactivity to a less noxious or even protective form of immune response through immunotherapy or by altering the ability of major food allergens to interact with IgE antibodies through molecular biology methods. Strategies for developing any potentially successful food allergy immunotherapy for patients with life-long sensitivities must satisfy several requirements. First, these methods must be safe and provide an optimal risk-to-benefit ratio for the patient. Procedures must be cost effective and relatively easy to perform so that patients can be treated on a routine basis. In the ensuing discussion, we explore the mucosal immune response as it relates to food allergy, potential treatments of food-allergic individuals through alteration of the host immune responses, use of mucosal vaccines, and traditional and novel approaches to immunotherapy. Finally, genetic engineering and its use to alter allergenic protein molecules to reduce or abolish their allergenicity is discussed.

Cell-mediated immunity that results in IL-12/IFN-γ production is essential to control infections by intracellular organisms. Studies in animal models revealed contrasting results in regard to the importance of CD40-CD40 ligand (CD40L) signaling for induction of a type 1 cytokine response against these pathogens. We demonstrate that CD40-CD40L interaction in humans is critical for generation of the IL-12/IFN-γ immune response against Toxoplasma gondii. Infection of monocytes with T. gondii resulted in up-regulation of CD40. CD40-CD40L signaling was required for optimal T cell production of IFN-γ in response to T. gondii. Moreover, patients with hyper IgM (HIGM) syndrome exhibited a defect in IFN-γ secretion in response to the parasite and evidence compatible with impaired in vivo T cell priming after T. gondii infection. Not only was IL-12 production in response to T. gondii dependent on CD40-CD40L signaling, but also, patients with HIGM syndrome exhibited deficient in vitro secretion of this cytokine in response to the parasite. Finally, in vitro incubation with agonistic soluble CD40L trimer enhanced T. gondii-triggered production of IFN-γ and, through induction of IL-12 secretion, corrected the defect in IFN-γ production observed in HIGM patients. Our results are likely to explain the susceptibility of patients with HIGM syndrome to infections by opportunistic pathogens.

Background: Infants born to atopic parents are at an increased risk of developing allergy during the first 2 years of life. Objective: To assess the effects of the early introduction of soy, extensively-hydrolyzed casein, or partially-hydrolyzed whey formulas in infants at risk for atopic diseases. Methods: This prospective, double-blind study compared allergic manifestations in 113 formula-fed and 17 breast-fed infants during the first year of life. The children were equally distributed among feeding groups by sex, birth IgE levels, and parental atopy. Study formulas were introduced in the newborn nursery. Gastrointestinal and dermatologic manifestations suggestive of allergy were evaluated at regular intervals during the first year of life. Results: The cumulative incidence of chronic or recurrent vomiting, diarrhea or atopic dermatitis in the first year of life was 18 %. Persistent symptoms led to a formula change in 18 (16 %) of the formula-fed infants (mean age of change: 2.3 months). Formula intolerance was confirmed by an open challenge with the first formula in 15 infants (13%), without significant differences in the number of children with formula changes and positive challenges across all feeding groups. Conclusions: There was no significant difference among the formula groups in the development of symptoms of food intolerance. However, introduction of hydrolyzed cow's milk or soy infant formulas at birth to infants at risk for developing allergy did not completely prevent the development of symptoms commonly attributed to food intolerance. Of the infants who developed intolerance to one of the study formulas 81% improved when changed to a second, randomly-assigned formula, suggesting that intolerance was formula specific.