Rethinking Immunological Risk: A Retrospective Cohort Study of Severe SARS-Cov-2 Infections in Individuals With Congenital Immunodeficiencies.

BACKGROUND: Debates on the allocation of medical resources during the coronavirus disease 2019 (COVID-19) pandemic revealed the need for a better understanding of immunological risk. Studies highlighted variable clinical outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in individuals with defects in both adaptive and innate immunity, suggesting additional contributions from other factors. Notably, none of these studies controlled for variables linked with social determinants of health. OBJECTIVE: To determine the contributions of determinants of health to risk of hospitalization for SARS-CoV-2 infection among individuals with inborn errors of immunodeficiencies. METHODS: This is a retrospective, single-center cohort study of 166 individuals with inborn errors of immunity, aged 2 months through 69 years, who developed SARS-CoV-2 infections from March 1, 2020, through March 31, 2022. Risks of hospitalization were assessed using a multivariable logistic regression analysis. RESULTS: The risk of SARS-CoV-2-related hospitalization was associated with underrepresented racial and ethnic populations (odds ratio [OR] 4.50; 95% confidence interval [95% CI] 1.57-13.4), a diagnosis of any genetically defined immunodeficiency (OR 3.32; 95% CI 1.24-9.43), obesity (OR 4.24; 95% CI 1.38-13.3), and neurological disease (OR 4.47; 95% CI 1.44-14.3). The COVID-19 vaccination was associated with reduced hospitalization risk (OR 0.52; 95% CI 0.31-0.81). Defects in T cell and innate immune function, immune-mediated organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization after controlling for covariates. CONCLUSIONS: The associations between race, ethnicity, and obesity with increased risk of hospitalization for SARS-CoV-2 infection indicate the importance of variables linked with social determinants of health as immunological risk factors for individuals with inborn errors of immunity.

Rethinking immunologic risk: a retrospective cohort study of severe SARS-CoV-2 infections in individuals with congenital immunodeficiencies.

Background: Debates on the allocation of medical resources during the COVID-19 pandemic revealed the need for a better understanding of immunologic risk. Studies highlighted variable clinical outcomes of SARS-CoV-2 infections in individuals with defects in both adaptive and innate immunity, suggesting additional contributions from other factors. Notably, none of these studies controlled for variables linked with social determinants of health. Objective: To determine the contributions of determinants of health to risk of hospitalization for SARS-CoV-2 infection among individuals with inborn errors of immunodeficiencies. Methods: This is a retrospective, single-center cohort study of 166 individuals with inborn errors of immunity, aged two months through 69 years, who developed SARS-CoV-2 infections from March 1, 2020 through March 31, 2022. Risks of hospitalization was assessed using a multivariable logistic regression analysis. Results: The risk of SARS-CoV-2-related hospitalization was associated with underrepresented racial and ethnic populations (odds ratio [OR] 5.29; confidence interval [CI], 1.76-17.0), a diagnosis of any genetically-defined immunodeficiency (OR 4.62; CI, 1.60-14.8), use of B cell depleting therapy within one year of infection (OR 6.1; CI, 1.05-38.5), obesity (OR 3.74; CI, 1.17-12.5), and neurologic disease (OR 5.38; CI, 1.61-17.8). COVID-19 vaccination was associated with reduced hospitalization risk (OR 0.52; CI, 0.31-0.81). Defective T cell function, immune-mediated organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization after controlling for covariates. Conclusions: The associations between race, ethnicity, and obesity with increased risk of hospitalization for SARS-CoV-2 infection indicate the importance of variables linked with social determinants of health as immunologic risk factors for individuals with inborn errors of immunity. Highlights: What is already known about this topic? Outcomes of SARS-CoV-2 infections in individuals with inborn errors of immunity (IEI) are highly variable. Prior studies of patients with IEI have not controlled for race or social vulnerability. What does this article add to our knowledge ? For individuals with IEI, hospitalizations for SARS-CoV-2 were associated with race, ethnicity, obesity, and neurologic disease. Specific types of immunodeficiency, organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization. How does this study impact current management guidelines? Current guidelines for the management of IEIs focus on risk conferred by genetic and cellular mechanisms. This study highlights the importance of considering variables linked with social determinants of health and common comorbidities as immunologic risk factors.

Advances in basic and clinical immunology in 2016.

Advances in basic immunology in 2016 included studies that further characterized the role of different proteins in the differentiation of effector T and B cells, including cytokines and proteins involved in the actin cytoskeleton. Regulation of granule formation and secretion in cytotoxic cells was also further described by examining patients with familial hemophagocytic lymphohistiocytosis. The role of prenylation in patients with mevalonate kinase deficiency leading to inflammation has been established. We reviewed advances in clinical immunology, as well as new approaches of whole-genome sequencing and genes newly reported to be associated with immunodeficiency, such as linker of activation of T cells (LAT); B-cell CLL/lymphoma 11B (BCL11B); RGD, leucine-rich repeat, tropomodulin domain, and proline-rich domain-containing protein (RLTPR); moesin; and Janus kinase 1 (JAK1). Trials of hematopoietic stem cell transplantation and gene therapy for primary immunodeficiency have had relative success; the use of autologous virus-specific cytotoxic T cells has proved effective as well. New medications are being explored, such as pioglitazone, which is under study for its role in enhancing the oxidative burst in patients with chronic granulomatous disease. Development of vaccines for HIV infection continues to provide insight into the immune response against a virus with an extraordinary mutation rate.

Combined immunodeficiency with EBV positive B cell lymphoma and epidermodysplasia verruciformis due to a novel homozygous mutation in RASGRP1.

RASGRP1 is a guanine-nucleotide-exchange factor essential for MAP-kinase mediated signaling in lymphocytes. We report the second case of RASGRP1 deficiency in a patient with a homozygous nonsense mutation in the catalytic domain of the protein. The patient had epidermodysplasia verruciformis, suggesting a clinically important intrinsic T cell function defect. Like the previously described patient, our proband also presented with CD4+ T cell lymphopenia, impaired T cell proliferation to mitogens and antigens, reduced NK cell function, and EBV-associated lymphoma. The severity of the disease and the development of EBV lymphoma in both patients suggest that hematopoietic stem cell transplantation should be performed rapidly in patients with RASGRP1 deficiency.

Primary mast cell disorders in children.

Mastocytosis arises from clonal mast cell expansion and the resultant accumulation of mast cells in cutaneous and sometimes extracutaneous tissues. Recent studies have demonstrated that c-kit mutations seem to be more prevalent in pediatric mastocytosis than previously assumed, but what determines disease evolution and severity in the individual patient remains elusive. For the large majority of children, mastocytosis is a self-limited cutaneous disease that spontaneously regresses before they reach adult age. Rarely, children develop systemic disease progression that is the hallmark of adult-onset disease. Therefore, invasive diagnostic testing, including performing a bone marrow biopsy, is not routinely recommended and usually reserved for children that present with signs of systemic involvement and persistently elevated serum tryptase levels. Despite its often-transient nature and limited skin involvement, some children experience challenging disease-associated symptoms due to spontaneous or trigger-induced mast cell degranulation. Anticipation of and preparation for potential complications can in many instances avoid symptomatic exacerbations. Proper symptomatic treatment and supportive care can often improve the child's quality of life. Cytoreductive therapy is usually not indicated given the natural history of spontaneous disease resolution.

Correlation of pneumococcal antibody concentration and avidity with patient clinical and immunologic characteristics.

PURPOSE: The quality of an antibody response is determined by both the concentration and the strength of antigen-binding, or avidity, of the antibodies produced. Currently, only antibody concentration is routinely evaluated in the clinical assessment of humoral immunity. Here we studied correlations of avidities and concentrations of antibodies to pneumococcal polysaccharides with immunologic and clinical characteristics of patients with recurrent infections. METHODS: We measured concentration and avidity of antibodies to 12 pneumococcal serotypes in 78 children aged 0.6-18 years with recurrent bacterial respiratory infections, and in 80 individuals who were being tested for peanut allergy, ages 0.4-15 years, serving as a comparison group. Avidity was assessed by measuring antibody binding in the presence of thiocyanate. RESULTS: Antibody concentrations and avidities correlated positively for very few types contained in the conjugated pneumococcal vaccine (PCV7) in both patients and controls with some dependence on age; there were even fewer correlations for non-PCV7 types. Antibody concentrations and avidities negatively correlated with age for most of the PCV7 types. There was no consistent correlation of total IgG or IgG subclasses with either concentrations or avidities. Overall, antibody concentrations were higher and avidities were lower in patients compared to controls. Patients requiring chronic antibiotic use tended to have higher antibody concentrations and lower avidities for most serotypes than patients who did not. We identified several patients having many infections with apparent good antibody concentrations with low avidity for many types. CONCLUSION: Antibody concentration and avidity correlate with patient clinical characteristics and distinguish patients from controls. Measurement of antibody avidity may provide another dimension for the clinical assessment of pneumococcal polysaccharide antibody response.

Intronic SH2D1A mutation with impaired SAP expression and agammaglobulinemia.

X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency syndrome associated with the inability to control Epstein-Barr virus (EBV), lymphoma, and hypogammaglobulinemia. XLP is caused by mutations in the SH2D1A gene, which encodes the SLAM-associated protein (SAP), or in the BIRC4 gene, which encodes the X-linked inhibitor of apoptosis protein (XIAP). Here we report a patient with recurrent respiratory tract infections and early onset agammaglobulinemia who carried a unique disease-causing intronic loss-of-function mutation in SH2D1A. The intronic mutation affected SH2D1A gene transcription but not mRNA splicing, and led to markedly reduced level of SAP protein. Despite undetectable serum immunoglobulins, the patient's B cells replicated and differentiated into antibody producing cells normally in vitro.

Congenital pancytopenia and absence of B lymphocytes in a neonate with a mutation in the Ikaros gene.

BACKGROUND: Congenital pancytopenia is a rare and often lethal condition. Current knowledge of lymphoid and hematopoietic development in mice, as well as understanding regulators of human hematopoiesis, have led to the recent discovery of genetic causes of bone marrow failure disorders. However, in the absence of mutations of specific genes or a distinct clinical phenotype, many cases of aplastic anemia are labeled as idiopathic, while congenital immune deficiencies are described as combined immune deficiency. PROCEDURE: We describe the case of a 33-week gestation age male with severe polyhydramnios, hydrops, and ascites who was noted to be pancytopenic at birth. Bone marrow examination revealed a hypocellular marrow with absent myelopoiesis. An immune workup demonstrated profound B lymphopenia, near absent NK cells, and normal T cell number. Due to the similarity of the patient's phenotype with the IKAROS knockout mouse, studies were performed on bone marrow and peripheral blood to assess a potential pathogenic role of Ikaros. RESULTS: DNA studies revealed a point mutation in one allele of the IKAROS gene, resulting in an amino acid substitution in the DNA-binding zinc finger domain. Functional studies demonstrated that the observed mutation decreased Ikaros DNA-binding affinity, and immunofluorescence microscopy revealed aberrant Ikaros pericentromeric localization. CONCLUSIONS: Our report describes a novel case of congenital pancytopenia associated with mutation of the IKAROS gene. Furthermore, these data suggest a critical role of IKAROS in human hematopoiesis and immune development.

Anti-IgE in the treatment of allergic disorders in pediatrics.

PURPOSE OF REVIEW: Neutralization of IgE antibodies is a conceptually new approach for the treatment of allergic diseases. This article reviews current concepts of anti-IgE therapy, with a focus on recent studies that provide insights into underlying mechanisms. Findings of the most recent clinical trials of anti-IgE in the treatment of allergic disorders are discussed. RECENT FINDINGS: Anti-IgE therapy in allergic asthma has been evaluated mostly in adults, but some studies have documented potential clinical efficacy in children and adolescent patients with moderate to severe uncontrolled asthma despite maximal conventional therapy. Pilot investigations have revealed some promising results regarding the use of anti-IgE in the treatment of other atopic diseases and as an adjunctive therapy in conjunction with allergen-specific immunotherapy. Recent work has provided novel insights into the kinetics of cellular responses to anti-IgE treatment and has identified significant anti-IgE effects on both basophils and dendritic cells, suggesting significant roles for these cells as effectors of IgE-mediated disease. SUMMARY: Studies of anti-IgE therapy have significantly advanced our understanding of IgE-mediated disease mechanisms and have demonstrated clinical efficacy in the treatment of allergic asthma in adults and children. Further studies are needed in children to evaluate long-term safety and to better define its potential use in allergic diseases other than asthma.

Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections.

Primary antibody deficiencies are the most common primary immunodeficiency diseases. They are a heterogeneous group of disorders with various degrees of dysfunctional antibody production resulting from a disruption of B-cell differentiation at different stages. While there has been tremendous recent progress in the understanding of some of these disorders, the etiology remains unknown for the majority of patients. As there is a large spectrum of underlying defects, the age at presentation varies widely, and the clinical manifestations range from an almost complete absence of B cells and serum immunoglobulins to selectively impaired antibody responses to specific antigens with normal total serum immunoglobulin concentrations. However, all of these disorders share an increased susceptibility to infections, affecting predominantly the respiratory tract. A delay of appropriate treatment for some diseases can result in serious complications related to infections, while timely diagnosis and adequate therapy can significantly decrease morbidity and increase life expectancy and quality of life.