Clinical utility of measuring CD4+ T follicular cells in patients with immune dysregulation.

Mechanistic studies of autoimmune disorders have identified circulating T follicular helper (cTfh) cells as drivers of autoimmunity. However, the quantification of cTfh cells is not yet used in clinical practice due to the lack of age-stratified normal ranges and the unknown sensitivity and specificity of this test for autoimmunity. We enrolled 238 healthy participants and 130 patients with common and rare disorders of autoimmunity or autoinflammation. Patients with infections, active malignancy, or any history of transplantation were excluded. In 238 healthy controls, median cTfh percentages (range 4.8%-6.2%) were comparable among age groups, sexes, races, and ethnicities, apart from a significantly lower percentages in children less than 1 year of age (median 2.1%, CI: 0.4%-6.8, p < 0.0001). Among 130 patients with over 40 immune regulatory disorders, a cTfh percentage exceeding 12% had 88% sensitivity and 94% specificity for differentiating disorders with adaptive immune cell dysregulation from those with predominantly innate cell defects. This threshold had a sensitivity of 86% and specificity of 100% for active autoimmunity and normalized with effective treatment. cTfh percentages exceeding 12% distinguish autoimmunity from autoinflammation, thereby differentiating two endotypes of immune dysregulation with overlapping symptoms and different therapies.

Spontaneous resolution of severe idiopathic T cell lymphopenia.

Potential etiologies of T-B+NK+ SCID include both hematopoietic defects and thymic aplasia. The management of patients with this phenotype, identified by newborn screen, may be unclear in the absence of a genetic diagnosis. We report an infant with lymphocyte flow cytometry consistent with T-B+NK+ SCID and reduced proliferative response to phytohemagglutinin. The patient had no genetic diagnosis after targeted panel and exome sequencing. The decision to trend laboratory values rather than move immediately to hematopoietic cell transplant was made given the absence of a genetic defect and the finding of a normal thymus on ultrasound. During the course of evaluation for transplant, the patient unexpectedly had normalization of T cell number and function. This case demonstrates a role for mediastinal ultrasound and the utility of trending laboratory values in patients with severe T cell lymphopenia but no genetic diagnosis, given the small but important possibility of spontaneous resolution.

Immunoglobulins in the treatment of COVID-19 infection: Proceed with caution!

The COVID-19 pandemic is one of the greatest infectious challenges in recent history. Presently, few treatment options exist and the availability of effective vaccines is at least one year away. There is an urgent need to find currently available, effective therapies in the treatment of patients with COVID-19 infection. In this review, we compare and contrast the use of intravenous immunoglobulin and hyperimmune globulin in the treatment of COVID-19 infection.

Clinical utility of measuring CD4 + T follicular cells in patients with immune dysregulation.

Mechanistic studies of autoimmune disorders have identified circulating T follicular helper (cTfh) cells as drivers of autoimmunity. However, the quantification of cTfh cells is not yet used in clinical practice due to the lack of age-stratified normal ranges and the unknown sensitivity and specificity of this test for autoimmunity. We enrolled 238 healthy participants and 130 patients with common and rare disorders of autoimmunity or autoinflammation. Patients with infections, active malignancy, or any history of transplantation were excluded. In 238 healthy controls, median cTfh percentages (range 4.8% - 6.2%) were comparable among age groups, sexes, races, and ethnicities, apart from a significantly lower percentages in children less than 1 year of age (median 2.1%, CI: 0.4% - 6.8, p< 0.0001). Among 130 patients with over 40 immune regulatory disorders, a cTfh percentage exceeding 12% had 88% sensitivity and 94% specificity for differentiating disorders with adaptive immune cell dysregulation from those with predominantly innate cell defects. This threshold had a sensitivity of 86% and specificity of 100% for active autoimmunity and normalized with effective treatment. cTfh percentages exceeding 12% distinguish autoimmunity from autoinflammation, thereby differentiating two endotypes of immune dysregulation with overlapping symptoms and different therapies.

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.

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.