COVID-19 Vaccination in Patients with Inborn Errors of Immunity Reduces Hospitalization and Critical Care Needs Related to COVID-19: a USIDNET Report.

BACKGROUND: The CDC and ACIP recommend COVID-19 vaccination for patients with inborn errors of immunity (IEI). Not much is known about vaccine safety in IEI, and whether vaccination attenuates infection severity in IEI. OBJECTIVE: To estimate COVID-19 vaccination safety and examine effect on outcomes in patients with IEI. METHODS: We built a secure registry database in conjunction with the US Immunodeficiency Network to examine vaccination frequency and indicators of safety and effectiveness in IEI patients. The registry opened on January 1, 2022, and closed on August 19, 2022. RESULTS: Physicians entered data on 1245 patients from 24 countries. The most common diagnoses were antibody deficiencies (63.7%). At least one COVID-19 vaccine was administered to 806 patients (64.7%), and 216 patients received vaccination prior to the development of COVID-19. The most common vaccines administered were mRNA-based (84.0%). Seventeen patients were reported to seek outpatient clinic or emergency room care for a vaccine-related complication, and one patient was hospitalized for symptomatic anemia. Eight hundred twenty-three patients (66.1%) experienced COVID-19 infection. Of these, 156 patients required hospitalization (19.0%), 47 required ICU care (5.7%), and 28 died (3.4%). Rates of hospitalization (9.3% versus 24.4%, p < 0.001), ICU admission (2.8% versus 7.6%, p = 0.013), and death (2.3% versus 4.3%, p = 0.202) in patients who had COVID-19 were lower in patients who received vaccination prior to infection. In adjusted logistic regression analysis, not having at least one COVID-19 vaccine significantly increased the odds of hospitalization and ICU admission. CONCLUSION: Vaccination for COVID-19 in the IEI population appears safe and attenuates COVID-19 severity.

Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation.

BACKGROUND: Forkhead box protein 3 (FOXP3) is the master transcription factor in CD4+CD25hiCD127lo regulatory T (Treg) cells. Mutations in FOXP3 result in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome. Clinical presentation of IPEX syndrome is broader than initially described, challenging the understanding of the disease, its evolution, and treatment choice. OBJECTIVE: We sought to study the type and extent of immunologic abnormalities that remain ill-defined in IPEX, across genetic and clinical heterogeneity. METHODS: We performed Treg-cell-specific epigenetic quantification and immunologic characterization of severe "typical" (n = 6) and "atypical" or asymptomatic (n = 9) patients with IPEX. RESULTS: Increased number of cells with Treg-cell-Specific Demethylated Region demethylation in FOXP3 is a consistent feature in patients with IPEX, with (1) highest values in those with typical IPEX, (2) increased values in subjects with pathogenic FOXP3 but still no symptoms, and (3) gradual increase over the course of disease progression. Large-scale profiling using Luminex identified plasma inflammatory signature of macrophage activation and TH2 polarization, with cytokines previously not associated with IPEX pathology, including CCL22, CCL17, CCL15, and IL-13, and the inflammatory markers TNF-α, IL-1A, IL-8, sFasL, and CXCL9. Similarly, both Treg-cell and Teff compartments, studied by Mass Cytometry by Time-Of-Flight, were skewed toward the TH2 compartment, especially in typical IPEX. CONCLUSIONS: Elevated TSDR-demethylated cells, combined with elevation of plasmatic and cellular markers of a polarized type 2 inflammatory immune response, extends our understanding of IPEX diagnosis and heterogeneity.

Multisystem inflammatory syndrome in children (MIS-C) and neonates (MIS-N) associated with COVID-19: optimizing definition and management.

During the SARS-CoV-2-associated infection (COVID-19), pandemic initial reports suggested relative sparing of children inversely related to their age. Children and neonates have a decreased incidence of SARS-CoV-2 infection, and if infected they manifested a less severe phenotype, in part due to enhanced innate immune response. However, a multisystem inflammatory syndrome in children (MIS-C) or paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 emerged involving coronary artery aneurysms, cardiac dysfunction, and multiorgan inflammatory manifestations. MIS-C has many similarities to Kawasaki disease and other inflammatory conditions and may fit within a spectrum of inflammatory conditions based on immunological results. More recently neonates born to mothers with SARS-CoV-2 infection during pregnancy demonstrated evidence of a multisystem inflammatory syndrome with raised inflammatory markers and multiorgan, especially cardiac dysfunction that has been described as multisystem inflammatory syndrome in neonates (MIS-N). However, there is a variation in definitions and management algorithms for MIS-C and MIS-N. Further understanding of baseline immunological responses to allow stratification of patient groups and accurate diagnosis will aid prognostication, and inform optimal immunomodulatory therapies. IMPACT: Multisystem inflammatory system in children and neonates (MIS-C and MIS-N) post COVID require an internationally recognized consensus definition and international datasets to improve management and plan future clinical trials. This review incorporates the latest review of pathophysiology, clinical information, and management of MIS-C and MIS-N. Further understanding of the pathophysiology of MIS-C and MIS-N will allow future targeted therapies to prevent and limit clinical sequelae.

When Screening for Severe Combined Immunodeficiency (SCID) with T Cell Receptor Excision Circles Is Not SCID: a Case-Based Review.

Newborn screening efforts focusing on the quantification of T cell receptor excision circles (TRECs), as a biomarker for abnormal thymic production of T cells, have allowed for the identification and definitive treatment of severe combined immunodeficiency (SCID) in asymptomatic neonates. With the adoption of TREC quantification in Guthrie cards across the USA and abroad, typical, and atypical SCID constitutes only ~ 10% of cases identified with abnormal TRECs associated with T cell lymphopenia. Several other non-SCID-related conditions may be identified by newborn screening in a term infant. Thus, it is important for physicians to recognize that other factors, such as prematurity, are often associated with low TRECs initially, but often improve with age. This paper focuses on a challenge that immunologists face: the diagnostic evaluation and management of cases in which abnormal TRECs are associated with variants of T cell lymphopenia in the absence of a genetically defined form of typical or atypical SCID. Various syndromes associated with T cell impairment, secondary forms of T cell lymphopenia, and idiopathic T cell lymphopenia are identified using this screening approach. Yet there is no consensus or guidelines to assist in the evaluation and management of these newborns, despite representing 90% of the patients identified, resulting in significant work for the clinical teams until a diagnosis is made. Using a case-based approach, we review pearls relevant to the evaluation of these newborns, as well as the management dilemmas for the families and team related to the resolution of genetic ambiguities.

Kawasaki disease: pathophysiology, clinical manifestations, and management.

Kawasaki Disease, a systemic vasculitis of unknown origin with specific predilection for the coronary arteries, is the most common cause of childhood-acquired heart disease in western countries. Despite its world-wide incidence, the pathophysiology of this enigmatic disease is still under investigation. Diagnosis is made on a clinical basis, with supportive laboratory evidence and imaging. Once identified, timely initiation of treatment is imperative in order to quell the inflammatory response and decrease the incidence of long-term sequelae, specifically coronary artery aneurysms. Finally, longitudinal follow-up should be implemented based on risk stratification and individualized to each patient.

Hypogammaglobulinemia in neonates: illustrative cases and review of the literature.

This article presents a review of causes of hypogammaglobulinemia in neonates utilizing illustrative cases to demonstrate commonly seen conditions. Overall, the causes of low immunoglobulin level can be divided into three main categories: decreased maternal transfer or production (due to physiological nadir, transient hypogammaglobulinemia of infancy, medication effects, or immunodeficiency), increased loss of immunoglobulins (from the gastrointestinal (GI) system, lymphatics, kidneys, skin disease, or blood loss) or destruction/suppression (from medication effects). Treatment of hypogammaglobulinemia is generally tailored to the underlying cause and condition of the patient. This can be through supportive care, prophylactic measures, or with immunoglobulin G (IgG) replacement at the recommendation of an immunologist.

Case report: Clinical course and treatment of SARS-CoV-2 in a pediatric CAR-T cell recipient with persistent hypogammaglobulinemia.

This report describes a pediatric patient who underwent chimeric antigen receptor (CAR) T-cell therapy for refractory B-cell acute lymphoblastic leukemia (B-ALL) four years prior, with resultant hypogammaglobulinemia for which he was receiving weekly subcutaneous immune globulin. He presented with persistent fever, dry cough, and a tingling sensation in his toes following a confirmed COVID-19 infection 3 weeks prior. His initial nasopharyngeal SARS-CoV-2 PCR was negative, leading to an extensive workup for other infections. He was ultimately diagnosed with persistent lower respiratory tract COVID-19 infection based on positive SARS-CoV-2 PCR from bronchoalveolar lavage (BAL) sampling. He was treated with a combination of remdesivir (antiviral) and casirivimab/imdevimab (combination monoclonal antibodies) with immediate improvement in fever, respiratory symptoms, and neurologic symptoms.

Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype.

Host defense and inflammation are regulated by the NF-κB essential modulator (NEMO), a scaffolding protein with a broad immune cell and tissue expression profile. Hypomorphic mutations in inhibitor of NF-κB kinase regulatory subunit gamma (IKBKG) encoding NEMO typically present with immunodeficiency. Here, we characterized a pediatric autoinflammatory syndrome in 3 unrelated male patients with distinct X-linked IKBKG germline mutations that led to overexpression of a NEMO protein isoform lacking the domain encoded by exon 5 (NEMO-Δex5). This isoform failed to associate with TANK binding kinase 1 (TBK1), and dermal fibroblasts from affected patients activated NF-κB in response to TNF but not TLR3 or RIG-I-like receptor (RLR) stimulation when isoform levels were high. By contrast, T cells, monocytes, and macrophages that expressed NEMO-Δex5 exhibited increased NF-κB activation and IFN production, and blood cells from these patients expressed a strong IFN and NF-κB transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi) that was stabilized by NEMO-Δex5, promoting type I IFN induction and antiviral responses. These data revealed how IKBKG mutations that lead to alternative splicing of skipping exon 5 cause a clinical phenotype we have named NEMO deleted exon 5 autoinflammatory syndrome (NDAS), distinct from the immune deficiency syndrome resulting from loss-of-function IKBKG mutations.

Case Report: Paradoxical Inflammatory Response Syndrome in a Previously Healthy, HIV-Negative, Pediatric Patient With Cryptococcus gatii Meningitis.

The immunological response of patients with cryptococcal meningitis (CM), particularly those not known to be immunocompromised, has generated an increased interest recently. Although CM is an infection with significant rates of morbidity and mortality, its sequelae may also include a post-infectious inflammatory response syndrome (PIIRS) in patients who have already achieved microbiological control. PIIRS can cause substantial immune-mediated damage to the central nervous system resulting in long-term neurological disability or even death. Steroids have been used successfully in the management of PIIRS in adults. In this report, we present the case of a previously healthy adolescent male with Cryptococcus gattii meningitis who experienced neurological deterioration due to PIIRS after the initiation of antifungal therapy. Immunological workup did not demonstrate any frank underlying immunodeficiencies, and genetic primary immunodeficiency screening was unremarkable. He was treated with steroids and recovered clinically; however, intermittent inflammatory episodes needed to be managed through several flares of symptoms. In the setting of the current literature, we discuss the management and monitoring of PIIRS in a pediatric patient, along with considerations of targeted future therapies.

At First Glance: Psoriatic Response to Transdermal Nicotine Patch Application.

Contact dermatitis and psoriasis are common skin disorders which represent two distinct pathologies. Skin disorders heavily rely on corresponding history for diagnosis; this case demonstrates the challenges of relying on history alone for final identification. A patient presented to clinic for evaluation of a new rash on his abdomen. Past medical history was notable for recent initiation of a smoking cessation program utilizing nicotine patches as well as a pharyngitis treated with antibiotics 1 week prior. Despite use of topical steroid and cessation of the patches, the well-demarcated rash became more generalized. Patch testing for the nicotine patch and chemical sensitizers was negative and an eventual biopsy was consistent with guttate psoriasis. Contact dermatitis relies heavily on clinical history for diagnosis. This case demonstrates that history can be misleading. In retrospect, it is likely that a preceding presumed streptococcal infection was the primary inducer of guttate psoriasis.

DOCK 8 Deficiency, EBV+ Lymphomatoid Granulomatosis, and Intrafamilial Variation in Presentation.

Dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive, combined immunodeficiency within the spectrum of hyper-IgE syndromes. Epstein-Barr virus-positive lymphomatoid granulomatosis (LYG) (EBV + LYG) is a rare diagnosis and a previously unreported presentation of DOCK8 deficiency. A 10-year-old girl was initially evaluated for mild eczema and recurrent sinopulmonary infections. She had normal immunoglobulins with elevated IgE, poor polysaccharide response with low switched memory B cells, low CD4 count, and normal mitogen and antigen responses. Despite clinical improvement following immunoglobulin replacement, a prolonged cough prompted a CT scan, which showed nodules. Biopsy identified a Grade 2 EBV + LYG. Due to an inadequate response with chemotherapy, further workup for primary immunodeficiency was performed. With her symptoms of eczema and IgE elevation, along with her brother's history of recurrent sinopulmonary infections and warts, targeted sequencing of DOCK8 was performed revealing compound heterozygous mutations for the two siblings. Both patients were successfully transplanted with resolution of the LYG and warts, respectively. This is the first reported case of LYG in DOCK8 deficiency. The EBV-driven lymphoproliferative disease along with the infection history in the brother led to the diagnosis of DOCK8 deficiency and curative hematopoietic stem cell transplants.

Neurosarcoidosis in Pediatric Patients: A Case Report and Review of Isolated and Systemic Neurosarcoidosis.

BACKGROUND: Neurosarcoidosis occurs in fewer than 5% of adults with systemic sarcoid. However, only 53 examples of neurosarcoidosis have been reported in the pediatric population, with nine of those cases being isolated neurosarcoidosis. We present the tenth case of a child with an initial presentation of isolated neurosarcoidosis and a review of the literature. METHODS: We searched the Ovid Medline database from 1946 to May 28, 2015. The Mesh terms "neurosarcoidosis," "pediatric," and "child" were exploded, and the Boolean "AND" was used to combine "neurosarcoidosis" with "pediatric" or "child." Articles that were not available in the English language were not included. RESULTS: A literature search revealed 53 children with neurosarcoidosis. The most common manifestations included cranial neuropathy (21%), papilledema or optic neuritis (15%), seizures (24.5%), and hypothalamic dysfunction (17%), with the latter two being more likely in younger children. Diagnosis is made by biopsy, but imaging and laboratory tests can aid in diagnosis. Treatment includes corticosteroids or other immunosuppressants. CONCLUSIONS: Neurosarcoidosis in children is rare, and our patient is only the tenth child with isolated neurosarcoidosis. These patients highlight the importance of considering a noninfectious diagnosis in the setting of clinical and radiographic findings suggestive of neurosarcoidosis.

Childhood sarcoidosis: Louisiana experience.

A retrospective chart review was conducted to detect patients with sarcoidosis seen by pediatric rheumatology service from the period of 1992 to 2013 at Children's hospital of New Orleans. Twenty-seven patients were identified. The average duration of symptoms before diagnosis was 5 (range 1-120) months. Five patients had onset before the age of 5 years and were diagnosed with early-onset sarcoidosis. The most common manifestations at presentation were constitutional symptoms (62 %) followed by ocular (38 %). During the course of illness, 19/27 (70 %) had multiorgan involvement. Common manifestations included uveitis/iritis (77 %), fever (50 %), hilar adenopathy (42 %), arthritis (31 %), peripheral lympadenopathy (31 %), hepatosplenomegaly (31 %), parenchymal lung disease (27 %), and skin rash (19 %). Unusual manifestations included granulomatous bone marrow disease (3 cases), hypertension (2), abdominal aortic aneurysm (large vessel vasculitis; 1), granulomatous hepatitis (1), nephrocalcinosis (1), membranous nephropathy (1), refractory granulomatous interstitial nephritis with recurrence in transplanted kidney (1), CNS involvement (2), parotid gland enlargement (1), and sensorineural hearing loss (1). Biopsy specimen was obtained in 21/27 (77 %) patients, and demonstration of noncaseating granuloma associated with negative stains for mycobacteria and fungi was seen in 18 patients. Elevated angiotensin-converting enzyme level was seen in 74 % of patients. Treatment with oral prednisone was initiated in symptomatic patients with significant clinical improvement. Low-dose methotrexate (MTX) 10-15 mg/m(2)/week orally, as steroid-sparing agent, was administered in 14 patients. Other immunomodulators included cyclophosphamide (2 patients), etanercept (2), infliximab (2), mycophenolate mofetil (1), and tacrolimus (1). Childhood sarcoidosis is prevalent in Louisiana. Most of the affected children present with a multisystem disease associated with manifestations similar to those of adult patients. Low-dose MTX seems to be effective, steroid sparing, and safe adjunct to treat sarcoidosis with multiorgan involvement. Early-onset disease is less common and associated with increased morbidity, flares, and poor prognosis.

Treating pediatric atopic dermatitis: current perspectives.

Atopic dermatitis (AD) is a chronic, inflammatory skin condition which affects millions of people worldwide. It is most commonly seen in children but may also progress into adulthood. Management of this complex disease requires a multi-pronged approach which can address the myriad of issues which underscore its development. Avoidance of triggering factors is imperative in establishing consistent control of skin irritation while daily moisturization can be very effective in skin barrier repair and maintenance. Judicious use of anti-inflammatory medications has been shown to make a significant impact on both treatment as well as prevention of disease. Unfortunately, pruritus, a key feature of AD, has proven much harder to control. Finally, awareness of the risks of colonization and infection in patients with AD should be incorporated into their surveillance and management plans. While our understanding has progressed greatly regarding this disease, further research is still needed regarding future directions for both treatment and prevention.

Specific Antibody Deficiencies.

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.