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.

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.

Advances in clinical outcomes: What we have learned during the COVID-19 pandemic.

Our understanding of risk factors and interventions influencing outcomes from coronavirus disease 2019 (COVID-19) has continued to evolve, revealing advances emerging from hypotheses formed at the start of the pandemic. Epidemiologic studies have shown that asthma control, rather than a diagnosis of asthma, is a determinant of COVID-19 severity. Clinical outcomes in patients with primary immunodeficiencies, even in those with impaired cellular immunity, are variable. IL-6 has emerged as a reliable biomarker of COVID-19 severity, and large clinical trials have shown the potential for improving outcomes through inhibition of IL-6 signaling in some patients. Studies of genetic risk factors for severe COVID-19 have also revealed the importance of interferon homeostasis in the defense against severe acute respiratory syndrome coronavirus 2. Because COVID-19 vaccines constitute the primary tool for ending this pandemic, strategies have been developed to address potential allergic and immune-mediated reactions. Here, we discuss advances in our understanding of COVID-19 risk factors and outcomes within the context of allergic and immunologic mechanisms.

Distinct clinical and immunological features of SARS-CoV-2-induced multisystem inflammatory syndrome in children.

BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.

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.

Incidence and outcomes of antenatally detected congenital hydronephrosis.

BACKGROUND AND OBJECTIVES: Antenatally detected urinary tract abnormalities (ADUTA) are increasingly recognized. Our aims were to determine the incidence and outcomes of antenatally diagnosed congenital hydronephrosis in a large cohort. DESIGN AND SETTINGS: We recorded the number of total deliveries over 4 years at King Abdulaziz University Hospital (KAUH) between January 2008 and December 2011 from the number of nursery and neonatal intensive care unit (NICU) admissions. PATIENTS AND METHODS: We reviewed the records of 18 853 deliveries between January 2008 and December 2011 at KAUH, Saudi Arabia. ADUTA were recorded, and their postnatal medical records were reviewed for demographic and radiological data. RESULTS: ADUTA were diagnosed in 327 fetuses (1.7%). The commonest pathology was congenital hydronephrosis (n=313, 95.7%). Cystic renal anomalies were reported in 4 babies (1.2%), and 10 children (3.1%) were reported to have other renal anomalies, including duplex kidneys or a single kidney. A total of 240 babies with congenital hydronephrosis were followed up. Hydronephrosis resolved in 99 children (41.2%) within 2 months of birth. A total of 29 subjects had underlying renal anomalies (12.1%), including vesicoureteral reflux (n=12, 5%), pelvi-ureteric junction obstruction (n=14, 5.8%), and posterior urethral valve (n=3, 1.3%). The best predictor for nonresolving congenital hydronephrosis and underlying anatomical abnormalities was the anteroposterior diameter on the first postnatal scan. A cut-off point of 5 mm was found to be 83% sensitive in predicting nonresolving hydronephrosis, while 7 mm was 88% sensitive and 10 mm was 94% sensitive. CONCLUSIONS: Congenital hydronephrosis is the commonest ADUTA. A large percentage resolved within 2 months of birth, but underlying anatomical abnormalities were found in 12.1%. All babies with antenatally detected hydronephrosis should be examined by ultrasound postnatally but further radiological investigations should only be performed for persistent significant AP dilatation >=10 mm.