NK cells in treated HIV-infected children display altered phenotype and function.

BACKGROUND: Chronic HIV infection is known to trigger a population redistribution and alteration in the functional capacity of natural killer (NK) cells. Because of improved antiretroviral treatments, there are rising numbers of adolescents and young adults worldwide who are living with HIV infection since birth. OBJECTIVE: We sought to determine how NK-cell phenotypic and functional subsets are altered in treated pediatric patients. METHODS: NK cells were contrasted among 29 HIV-unexposed and uninfected controls (5-19 years), 23 HIV-exposed but uninfected patients (3-19 years), and 25 HIV-infected patients (3-19 years) using multiparametric flow cytometry. RESULTS: Although most NK-cell markers did not differ, activating receptors such as NKp46, DNAX accessory molecule-1, and NKG2C and stimulatory receptors such as CD2 and CD11c were expressed by a higher frequency of NK cells in HIV-infected patients than in controls. Interestingly, there were less differences between HIV-infected and HIV-exposed but uninfected children. There was an inverse relationship between CD4/CD8 T-cell ratio (as a marker of disease progression) and CD11c and NKG2C frequency and CD69 upregulation on stimulation among HIV-infected patients. CONCLUSIONS: A chronic NK-cell activation phenotype persists in HIV-infected children receiving antiretroviral therapy and is associated with declining CD4/CD8 T-cell ratios. A lower CD4/CD8 T-cell ratio was associated with higher baseline granzyme B (P = .0068; R2 = 0.29) and degranulation potential (P = .022; R2 = 0.22) in stimulated NK cells. Thus, NK cells in HIV-infected children receiving treatment have reduced functional potential and an activated phenotype that distinguishes them from uninfected children.

Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patients with typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survival was 90%, but was 95% for those who were infection-free at HCT vs 81% for those with active infection (P = .009). Other factors, including the diagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, use of preparative chemotherapy, or the type of donor used, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell-replete graft, landmark analysis at day +100 post-HCT revealed that CD3 < 300 cells/µL, CD8 < 50 cells/µL, CD45RA < 10%, or a restricted Vß T-cell receptor repertoire (<13 of 24 families) were associated with the need for a second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although newborn screening has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. The trial was registered at www.clinicaltrials.gov as #NCT01186913.

High Incidence of Autoimmune Disease after Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease.

There is a lack of consensus regarding the role and method of hematopoietic stem cell transplantation (HSCT) on patients with chronic granulomatous disease (CGD). Long-term follow-up after HSCT in these patient population is essential to know its potential complications and decide who will benefit the most from HSCT. We report the outcome of HSCT and long-term follow-up in 24 patients with CGD, transplanted in our center from either related (n = 6) or unrelated (n = 18) donors, over a 12-year period (2003 to 2015), using high-dose alemtuzumab in the preparative regimen. We evaluated the incidence and timing of adverse events and potential risk factors. We described in detailed the novel finding of increased autoimmunity after HSCT in patients with CGD. At a median follow-up of 1460 days, 22 patients were full donor chimeras, and 2 patients had stable mixed chimerism. All assessable patients showed normalization of their neutrophil oxidative burst test. None of the patients developed grades II to IV acute graft-versus-host disease, and no patient had chronic graft-versus-host disease. Twelve of 24 patients developed 17 autoimmune diseases (ADs). Severe ADs (cytopenia and neuropathy) occurred exclusively in the unrelated donor setting and mainly in the first year after HSCT, whereas thyroid AD occurred in the related donor setting as well and more than 3 years after HSCT. Two patients died due to infectious complications after developing autoimmune cytopenias. One additional patient suffered severe brain injury. The remaining 21 patients have long-term Lansky scores ≥ 80. The outcome of HSCT from unrelated donors is comparable with related donors but might carry an increased risk of developing severe AD. A lower dose of alemtuzumab may reduce this risk and should be tested in further studies.

Long-term pulmonary complications in perinatally HIV-infected youth.

BACKGROUND: Increased incidence and prevalence of asthma have been documented for perinatally HIV-infected youth 10 to 21 years of age compared with HIV-exposed uninfected (HEU) youth. OBJECTIVE: We sought to perform objective pulmonary function tests (PFTs) in HIV-infected and HEU youth with and without diagnosed asthma. METHOD: Asthma was determined in 370 participants (218 HIV-infected and 152 HEU participants) by means of chart review and self-report at 13 sites. Interpretable PFTs (188 HIV-infected and 132 HEU participants) were classified as obstructive, restrictive, or normal, and reversibility was determined after bronchodilator inhalation. Values for HIV-1 RNA, CD4 and CD8 T cells, eosinophils, total IgE, allergen-specific IgE, and urinary cotinine were measured. Adjusted prevalence ratios (PRs) of asthma and PFT outcomes were determined for HIV-infected participants relative to HEU participants, controlling for age, race/ethnicity, and sex. RESULTS: Current asthma was identified in 75 (34%) of 218 HIV-infected participants and 38 (25%) of 152 HEU participants (adjusted PR, 1.33; P = .11). The prevalence of obstructive disease did not differ by HIV status. Reversibility was less likely in HIV-infected youth than in HEU youth (17/183 [9%] vs 21/126 [17%]; adjusted PR, 0.47; P = .020) overall and among just those with obstructive PFT results (adjusted PR, 0.46; P = .016). Among HIV-infected youth with current asthma, serum IgE levels were inversely correlated with CD8 T-cell counts and positively correlated with eosinophil counts and not associated with CD4 T-cell counts. HIV-infected youth had lower association of specific IgE levels to several inhalant and food allergens compared with HEU participants and significantly lower CD4/CD8 T-cell ratios (suggesting immune imbalance). CONCLUSION: Compared with HEU youth, HIV-infected youth demonstrated decreased reversibility of obstructive lung disease, which is atypical of asthma. This might indicate an early stage of chronic obstructive pulmonary disease. Follow-up into adulthood is warranted to further define their pulmonary outcomes.

Transplantation outcomes for severe combined immunodeficiency, 2000-2009.

BACKGROUND: The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. METHODS: We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). RESULTS: Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival. CONCLUSIONS: Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Advances in clinical immunology in 2015.

Advances in clinical immunology in the past year included the report of practice parameters for the diagnosis and management of primary immunodeficiencies to guide the clinician in the approach to these relatively uncommon disorders. We have learned of new gene defects causing immunodeficiency and of new phenotypes expanding the spectrum of conditions caused by genetic mutations such as a specific regulator of telomere elongation (RTEL1) mutation causing isolated natural killer cell deficiency and mutations in ras-associated RAB (RAB27) resulting in immunodeficiency without albinism. Advances in diagnosis included the increasing use of whole-exome sequencing to identify gene defects and the measurement of serum free light chains to identify secondary hypogammaglobulinemias. For several primary immunodeficiencies, improved outcomes have been reported after definitive therapy with hematopoietic stem cell transplantation and gene therapy.

Primary Immune Deficiency Treatment Consortium (PIDTC) update.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a collaboration of 41 North American centers studying therapy for rare primary immune deficiency diseases (PIDs), including severe combined immune deficiency (SCID), Wiskott-Aldrich syndrome (WAS), and chronic granulomatous disease (CGD). An additional 3 European centers have partnered with the PIDTC to study CGD. Natural history protocols of the PIDTC analyze outcomes of treatment for rare PIDs in multicenter longitudinal retrospective, prospective, and cross-sectional studies. Since 2009, participating centers have enrolled more than 800 subjects on PIDTC protocols for SCID, and enrollment in the studies on WAS and CGD is underway. Four pilot projects have been funded, and 12 junior investigators have received fellowship awards. Important publications of the consortium describe the outcomes of hematopoietic cell transplantation for SCID during 2000-2009, diagnostic criteria for SCID, and the pilot project of newborn screening for SCID in the Navajo Nation. The PIDTC Annual Scientific Workshops provide an opportunity to strengthen collaborations with junior investigators, patient advocacy groups, and international colleagues. Funded by the National Institute of Allergy and Infectious Diseases and the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, the PIDTC has recently received renewal for another 5 years. Here we review accomplishments of the group, projects underway, highlights of recent workshops, and challenges for the future.

Advances in basic and clinical immunology in 2014.

Genetic identification of immunodeficiency syndromes has become more efficient with the availability of whole-exome sequencing, expediting the identification of relevant genes and complementing traditional linkage analysis and homozygosity mapping. New genes defects causing immunodeficiency include phophoglucomutase 3 (PGM3), cytidine 5' triphosphate synthase 1 (CTPS1), nuclear factor κB-inducing kinase (NIK), cytotoxic T lymphocyte-associated antigen 4 (CTLA4), B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10), phosphoinositide-3 kinase regulatory subunit 1 (PIK3R1), IL21, and Jagunal homolog 1 (JAGN1). New case reports expanded the clinical spectrum of gene defects. For example, a specific recombination-activating gene 1 variant protein with partial recombinant activity might produce Omenn syndrome or a common variable immunodeficiency phenotype. Central and peripheral B-cell tolerance was investigated in patients with several primary immunodeficiencies, including common variable immunodeficiency and Wiskott-Aldrich syndrome, to explain the occurrence of autoimmunity and inflammatory disorders. The role of IL-12 and IL-15 in the enhancement of natural killer cell activity was reported. Newborn screening for T-cell deficiency is being implemented in more states and is achieving its goal of defining the true incidence of severe combined immunodeficiency and providing early treatment that offers the highest survival for these patients. Definitive treatment of severe immunodeficiency with both hematopoietic stem cell transplantation and gene therapy was reported to be successful, with increasing definition of conditions needed for optimal outcomes. Progress in HIV infection is directed toward the development of an effective vaccine and the eradication of hidden latent virus reservoirs.

Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome.

BACKGROUND: DiGeorge syndrome affects more than 3.5 million persons worldwide. Partial DiGeorge syndrome (pDGS), which is characterized by a number of gene deletions in chromosome 22, including the chicken tumor virus number 10 regulator of kinase (Crk)-like (CrkL) gene, is one of the most common genetic disorders in human subjects. To date, the role of natural killer (NK) cells in patients with pDGS remains unclear. OBJECTIVE: We sought to define the effect of pDGS-related Crk haploinsufficiency on NK cell activation and cytotoxic immunological synapse (IS) structure and function. METHODS: Inducible CrkL-silenced NK cells were used to recapitulate the pDGS, CrkL-haploinsufficient phenotype. Findings were validated by using NK cells from patients with actual pDGS. Ultimately, deficits in the function of NK cells from patients with pDGS were restored by lentiviral transduction of CrkL. RESULTS: Silencing of CrkL expression inhibits NK cell function. Specifically, pDGS haploinsufficiency of CrkL inhibits accumulation of activating receptors, polarization of cytolytic machinery and key signaling molecules, and activation of ß2-integrin at the IS. Reintroduction of CrkL protein restores NK cell cytotoxicity. CONCLUSION: CrkL haploinsufficiency causes functional NK deficits in patients with pDGS by disrupting both ß2-integrin activation and activating receptor accumulation at the IS. Our results suggest that NK cell IS quality can directly affect immune status, providing a potential target for diagnosis and therapeutic manipulation in patients with pDGS and in other patients with functional NK cell deficiencies.

Practice parameter for the diagnosis and management of primary immunodeficiency.

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.

Aggregate risk of cardiovascular disease among adolescents perinatally infected with the human immunodeficiency virus.

BACKGROUND: Perinatally HIV-infected adolescents may be susceptible to aggregate atherosclerotic cardiovascular disease risk, as measured by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary arteries and abdominal aorta risk scores, as a result of prolonged exposure to HIV and antiretroviral therapy. METHODS AND RESULTS: Coronary arteries and abdominal aorta PDAY scores were calculated for 165 perinatally HIV-infected adolescents, using a weighted combination of modifiable risk factors: dyslipidemia, cigarette smoking, hypertension, obesity, and hyperglycemia. Demographic and HIV-specific predictors of scores ≥1 were identified, and trends in scores over time were assessed. Forty-eight percent and 24% of the perinatally HIV-infected adolescents had coronary arteries and abdominal aorta scores ≥1, representing increased cardiovascular disease risk factor burden. Significant predictors of coronary arteries scores ≥1 included male sex, history of an AIDS-defining condition, longer duration of use of a ritonavir-boosted protease inhibitor, and no prior use of tenofovir. Significant predictors of abdominal aorta scores ≥1 included suppressed viral load, history of an AIDS-defining condition, and longer duration of boosted protease inhibitor use. No significant changes in coronary arteries and abdominal aorta risk scores were observed over the 4-year study period. CONCLUSIONS: A substantial proportion of perinatally HIV-infected youth have high PDAY scores, reflecting increased aggregate atherosclerotic cardiovascular disease risk factor burden. High scores were predicted by HIV disease severity and boosted protease inhibitor use. PDAY scores may be useful in identifying high-risk youth who may benefit from early lifestyle or clinical interventions.

Advances in basic and clinical immunology in 2013.

A significant number of contributions to our understanding of primary immunodeficiencies (PIDs) in pathogenesis, diagnosis, and treatment were published in the Journal in 2013. For example, deficiency of mast cell degranulation caused by signal transducer and activator of transcription 3 deficiency was demonstrated to contribute to the difference in the frequency of severe allergic reactions in patients with autosomal dominant hyper-IgE syndrome compared with that seen in atopic subjects with similar high IgE serum levels. High levels of nonglycosylated IgA were found in patients with Wiskott-Aldrich syndrome, and these abnormal antibodies might contribute to the nephropathy seen in these patients. New described genes causing immunodeficiency included caspase recruitment domain 11 (CARD11), mucosa-associated lymphoid tissue 1 (MALT1) for combined immunodeficiencies, and tetratricopeptide repeat domain 7A (TTC7A) for mutations associated with multiple atresia with combined immunodeficiency. Other observations expand the spectrum of clinical presentation of specific gene defects (eg, adult-onset idiopathic T-cell lymphopenia and early-onset autoimmunity might be due to hypomorphic mutations of the recombination-activating genes). Newborn screening in California established the incidence of severe combined immunodeficiency at 1 in 66,250 live births. The use of hematopoietic stem cell transplantation for PIDs was reviewed, with recommendations to give priority to research oriented to establish the best regimens to improve the safety and efficacy of bone marrow transplantation. These represent only a fraction of significant research done in patients with PIDs that has accelerated the quality of care of these patients. Genetic analysis of patients has demonstrated multiple phenotypic expressions of immune deficiency in patients with nearly identical genotypes, suggesting that additional genetic factors, possibly gene dosage, or environmental factors are responsible for this diversity.

Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience.

BACKGROUND: The approach to the diagnosis of severe combined immunodeficiency disease (SCID) and related disorders varies among institutions and countries. OBJECTIVES: The Primary Immune Deficiency Treatment Consortium attempted to develop a uniform set of criteria for diagnosing SCID and related disorders and has evaluated the results as part of a retrospective study of SCID in North America. METHODS: Clinical records from 2000 through 2009 at 27 centers in North America were collected on 332 children treated with hematopoietic stem cell transplantation (HCT), enzyme replacement therapy, or gene therapy for SCID and related disorders. Eligibility for inclusion in the study and classification into disease groups were established by using set criteria and applied by an expert review group. RESULTS: Two hundred eighty-five (86%) of the patients were determined to be eligible, and 47 (14%) were not eligible. Of the 285 eligible patients, 84% were classified as having typical SCID; 13% were classified as having leaky SCID, Omenn syndrome, or reticular dysgenesis; and 3% had a history of enzyme replacement or gene therapy. Detection of a genotype predicting an SCID phenotype was accepted for eligibility. Reasons for noneligibility were failure to demonstrate either impaired lymphocyte proliferation or maternal T-cell engraftment. Overall (n = 332) rates of testing were as follows: proliferation to PHA, 77%; maternal engraftment, 35%; and genotype, 79% (mutation identified in 62%). CONCLUSION: Lack of complete laboratory evaluation of patients before HCT presents a significant barrier to definitive diagnosis of SCID and related disorders and prevented inclusion of subjects in our observational HCT study. This lesson is critical for patient care, as well as the design of future prospective treatment studies for such children because a well-defined and consistent study population is important for precision in outcomes analysis.

Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts.

The present uncertainty of which live viral or bacterial vaccines can be given to immunodeficient patients and the growing neglect of societal adherence to routine immunizations has prompted the Medical Advisory Committee of the Immune Deficiency Foundation to issue recommendations based on published literature and the collective experience of the committee members. These recommendations address the concern for immunodeficient patients acquiring infections from healthy subjects who have not been immunized or who are shedding live vaccine-derived viral or bacterial organisms. Such transmission of infectious agents can occur within the hospital, clinic, or home or at any public gathering. Collectively, we define this type of transmission as close-contact spread of infectious disease that is particularly relevant in patients with impaired immunity who might have an infection when exposed to subjects carrying vaccine-preventable infectious diseases or who have recently received a live vaccine. Immunodeficient patients who have received therapeutic hematopoietic stem transplantation are also at risk during the time when immune reconstitution is incomplete or while they are receiving immunosuppressive agents to prevent or treat graft-versus-host disease. This review recommends the general education of what is known about vaccine-preventable or vaccine-derived diseases being spread to immunodeficient patients at risk for close-contact spread of infection and describes the relative risks for a child with severe immunodeficiency. The review also recommends a balance between the need to protect vulnerable subjects and their social needs to integrate into society, attend school, and benefit from peer education.

Primary Immune Deficiency Treatment Consortium (PIDTC) report.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.

HCT survival in ADA-SCID: what's the buzz?

In this issue of Blood, Hassan et al have turned the spotlight on hematopoietic stem cell transplantation (HCT) of adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID). They opened up the curtain of beliefs on this therapy that enables facts to be separated from fiction.

Association between lymphocyte and monocyte subsets and cognition in children with HIV.

BACKGROUND: This study assesses the relationships between lymphocyte and monocyte subsets and intelligence quotient (IQ) scores in antiretroviral therapy (ART)-naive, HIV-infected Thai children without advanced HIV disease. FINDINGS: Sixty-seven ART-naive Thai children with CD4 between 15-24% underwent cognitive testing by Weschler intelligence scale and had 13 cell subsets performed by flow cytometry including naive, memory and activated subsets of CD4+ and CD8+ T cells, activated and perivascular monocytes and B cells. Regression modelling with log10 cell count and cell percentage transformation was performed.Median age (IQR) was 9 (7-10) years, 33% were male, CDC stages N:A:B were 1:67:31%, median CD4% and count (IQR) were 21 (18-24)%, 597 (424-801) cells/mm3 and HIV RNA (IQR) was 4.6 (4.1-4.9) log10 copies/ml. Most (82%) lived at home, 45% had a biological parent as their primary caregiver, and 26 (49%) had low family income. The mean (SD) scores were 75 (13) for full scale IQ (FIQ), 73 (12) for verbal IQ (VIQ) and 80 (14) for performance IQ (PIQ). Adjusted multivariate regression analysis showed significant negative associations between B cell counts and FIQ, VIQ and PIQ (p < 0.01 for all); similar associations were found for B cell percentages (p < 0.05 for all). CONCLUSIONS: High B cell counts and percentages were strongly associated with poorer FIQ, VIQ and PIQ scores. Prospective, long-term assessment of cell subsets and determination of relevant B cell subpopulations could help further elucidate associations between lymphocyte subsets and neurocognitive development.

Advances in basic and clinical immunology in 2012.

Basic and clinical immunology articles published in the Journal in 2012 were mostly related to the expanding area of primary immunodeficiencies (PIDs). Novel forms of PID were identified by using whole-exome sequencing or after careful examination of flow cytometric data, as in the reports of lymphocyte-specific protein tyrosine kinase, CD27, and CD21 deficiencies. Absent IgG and IgA memory B cells were described in patients with hyper-IgE syndrome, which is consistent with defective antibody response and suggests a potential benefit of immunoglobulin replacement. Impaired production of antibodies to polysaccharide antigens by the human B-cell subset analog to murine B-1 cells was reported in a child with selective polysaccharide antibody deficiency. Increased production of inflammatory cytokines by monocyte-derived cells on Toll-like receptor activation was reported in patients with X-linked agammaglobulinemia, underscoring the important role of Bruton tyrosine kinase in modulation of inflammation. The mechanisms explaining susceptibility to yeast infections and development of chronic mucocutaneous candidiasis were extensively studied. Universal newborn screening for T-cell deficiencies is being implemented in several states, resulting in the diagnosis of a higher number of immunodeficient newborns than previously estimated. The use of laboratory testing to distinguish PIDs from HIV infection was clarified. In the management of PIDs, refinement of indication and strategies to hematopoietic stem cell transplantation resulted in improved outcomes. The use of anti-IL-6 mAbs showed promise as an alternative treatment in patients with Schnitzler syndrome.

Controversies in IgG replacement therapy in patients with antibody deficiency diseases.

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.