Juvenile idiopathic arthritis is a complex rheumatic disease that is influenced by environmental and genetic factors. Linkage and genome-wide association studies have identified genes that contribute to the risk of developing juvenile idiopathic arthritis but are limited in their ability to identify disease-risk variants of large effect. Penetrant, heritable risk variants can be detected in high-risk families, but such cases are uncommon due to the low prevalence of juvenile idiopathic arthritis. This study utilizes whole-genome sequencing of 23 multiplex families, the largest such cohort to date, to discover variants and genes relevant to JIA pathogenesis. Pathogenic variants in NOD2 associated with Blau syndrome, an ultra-rare Mendelian inflammatory disorder, are the most recurrent variants in the cohort, consistent with previous reports that milder presentations of Blau syndrome are oftentimes misdiagnosed as juvenile idiopathic arthritis. For the first time, however, rare variants in ACVR1 and SMAD6, integral components of the Bone Morphogenic Protein pathway, are found to be associated with juvenile idiopathic arthritis. Identified ACVR1 variants map to critical protein domains. AlphaFold modeling predicts that the ACVR1 interaction with its inhibitor OGT is disrupted by these variants, indicating that the patient-mutated protein has a gain-of-function phenotype. Drosophila melanogaster expressing either a wild-type or patient-mutated version of ACVR1 exhibit embryonic lethality, with the mutant exhibiting 1.4-fold greater lethality than wild-type. The combination of family-based cohorts for gene discovery, AI-based computational tools, and animal model studies for tests of variant function underscores shared disease pathogenesis between JIA and monogenic disorders of immunity and connective tissue.

Objective:To evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH) genes and systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS). Methods:Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in sJIA subjects from an established cohort. Sequence data from control subjects were obtained in silico (dbGaP:phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test (SKAT) package. Significance was defined as p<0.05 after 100,000 permutations. Results:Sequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 3000 controls. Quality control operations produced a set of 481 cases and 2924 ancestrally-matched control subjects. RVT of sJIA cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF]<0.01) of STXBP2 (p=0.020), and ultra-rare variants (MAF<0.001) of STXBP2 (p=0.007) and UNC13D (p=0.045). A subanalysis of 32 cases with known MAS and 90 without revealed significant association of rare UNC13D variants (p=0.0047). Additionally, sJIA patients more often carried ≥2 HLH variants than did controls (p=0.007), driven largely by digenic combinations involving LYST. Conclusion:We identified an enrichment of rare HLH variants in sJIA patients compared with healthy controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.

BACKGROUND:Patients with partial DiGeorge syndrome (pDGS) can present with immune dysregulation, the most common being autoimmune cytopenia (AIC). There is a lack of consensus on the approach to type, combination, and timing of therapies for AIC in pDGS. Recognition of immune dysregulation early in pDGS clinical course may help individualize treatment and prevent adverse outcomes from chronic immune dysregulation. OBJECTIVES:Objectives of this study were to characterize the natural history, immune phenotype, and biomarkers in pDGS with AIC. METHODS:Data on clinical presentation, disease severity, immunological phenotype, treatment selection, and response for patients with pDGS with AIC were collected via retrospective chart review. Flow cytometric analysis was done to assess T and B cell subsets, including biomarkers of immune dysregulation. RESULTS:Twenty-nine patients with the diagnosis of pDGS and AIC were identified from 5 international institutions. Nineteen (62%) patients developed Evan's syndrome (ES) during their clinical course and twenty (69%) had antibody deficiency syndrome. These patients demonstrated expansion in T follicular helper cells, CD19hiCD21lo B cells, and double negative cells and reduction in CD4 naïve T cells and regulatory T cells. First-line treatment for 17/29 (59%) included corticosteroids and/or high-dose immunoglobulin replacement therapy. Other overlapping therapies included eltrombopag, rituximab, and T cell immunomodulators. CONCLUSIONS:AIC in pDGS is often refractory to conventional AIC treatment paradigms. Biomarkers may have utility for correlation with disease state and potentially even response to therapy. Immunomodulating therapies could be initiated early based on early immune phenotyping and biomarkers before the disease develops or significantly worsens.

Objective The aim of this study was to report the interim 5-year safety and effectiveness of abatacept in patients with JIA in the PRINTO/PRCSG registry.Methods The Abatacept JIA Registry (NCT01357668) is an ongoing observational study of children with JIA receiving abatacept; enrolment started in January 2013. Clinical sites enrolled patients with JIA starting or currently receiving abatacept. Eligible patients were assessed for safety (primary end point) and effectiveness over 10 years. Effectiveness was measured by clinical 10-joint Juvenile Arthritis Disease Activity Score (cJADAS10) in patients with JIA over 5 years. As-observed analysis is presented according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.Results As of 31 March 2020, 587 patients were enrolled; 569 are included in this analysis (including 134 new users) with 1214.6 patient-years of safety data available. Over 5 years, the incidence rate (IR) per 100 patient-years of follow-up of serious adverse events was 5.52 (95% CI: 4.27, 7.01) and of events of special interest was 3.62 (95% CI: 2.63, 4.86), with 18 serious infections [IR 1.48 (95% CI: 0.88, 2.34)]. As early as month 3, 55.9% of patients achieved cJADAS10 low disease activity and inactive disease (20.3%, 72/354 and 35.6%, 126/354, respectively), sustained over 5 years. Disease activity measures improvement over 5 years across JIA categories.Conclusion Abatacept was well tolerated in patients with JIA, with no new safety signals identified and with well-controlled disease activity, including some patients achieving inactive disease or remission.Trial registration Clinicaltrials.gov, NCT01357668.

OBJECTIVES:We report the safety, tolerability and efficacy of tofacitinib in patients with juvenile idiopathic arthritis (JIA) in an ongoing long-term extension (LTE) study. METHODS:Patients (2-<18 years) with JIA who completed phase 1/3 index studies or discontinued for reasons excluding treatment-related serious adverse events (AEs) entered the LTE study and received tofacitinib 5 mg two times per day or equivalent weight-based doses. Safety outcomes included AEs, serious AEs and AEs of special interest. Efficacy outcomes included improvement since tofacitinib initiation per the JIA-American College of Rheumatology (ACR)70/90 criteria, JIA flare rate and disease activity measured by Juvenile Arthritis Disease Activity Score (JADAS)27, with inactive disease corresponding to JADAS ≤1.0. RESULTS:Of 225 patients with JIA (median (range) duration of treatment, 41.6 (1-103) months), 201 (89.3%) had AEs; 34 (15.1%) had serious AEs. 10 patients developed serious infections; three had herpes zoster. Two patients newly developed uveitis. Among patients with polyarticular course JIA, JIA-ACR70/90 response rates were 60.0% (78 of 130) and 33.6% (47 of 140), respectively, at month 1, and generally improved over time. JIA flare events generally occurred in <5% of patients through to month 48. Observed mean (SE) JADAS27 was 22.0 (0.6) at baseline, 6.2 (0.7) at month 1 and 2.8 (0.5) at month 48, with inactive disease in 28.8% (36 of 125) of patients at month 1 and 46.8% (29 of 82) at month 48. CONCLUSIONS:In this interim analysis of LTE study data in patients with JIA, safety findings were consistent with the known profile of tofacitinib, and efficacy was maintained up to month 48. TRIAL REGISTRATION NUMBER:NCT01500551.

Chronic anterior uveitis (CAU) carries a significant risk for eye complications and vision loss. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) introduced consensus treatment plans (CTPs) to standardize treatment for CAU and facilitate future comparative effectiveness studies. Two CTPs were developed to address: 1) initiation of methotrexate (MTX) in patients with CAU naïve to steroid-sparing therapy, and 2) initiation of a TNF inhibitor (TNFi) in patients with severe uveitis or uveitis refractory to MTX. We evaluated implementation of the uveitis CTPs using existing CARRA Registry infrastructure and assessed feasibility of the CTPs for comparative effectiveness research. This prospective observational cohort study was conducted at nine pilot sites between February 2020 and August 2022. Patients with JIA-associated CAU (JIA-U) were treated according to either the MTX or TNFi CTP. Uveitis activity and medication use were recorded at 0, 3, and 6 months. We assessed patient enrollment rates, CTP arm selection, uveitis control, and quality of data collection. We also evaluated CTP arm selection in a retrospective cohort of similar JIA-U patients enrolled in the CARRA Registry during the same study period. Seventeen patients were included in the pilot cohort. Eight were treated with the MTX CTP (4 oral MTX, 4 subcutaneous MTX), and 9 with the TNFi CTP (9 received standard-dose adalimumab, none selected high-dose adalimumab or infliximab). Uveitis was controlled in 13 of 17 patients by 6 months. Query of the CARRA-wide Registry identified 42 patients with JIA-U who were treated according to the MTX or TNFi CTPs. Among these, 26 were treated with MTX (8 oral, 18 subcutaneous) and 16 with TNFi (12 standard dose adalimumab, 2 high dose adalimumab, and 2 infliximab). Both the MTX and TNFi uveitis CTPs can practically be implemented in clinical settings and are currently being utilized across Registry sites. However, in patients starting TNFi therapy, all pilot study participants and most patients across the CARRA Registry were treated with a standard dose of adalimumab. This consensus on the treatment approach underscores its broad acceptance but also limits the applicability of the uveitis TNFi CTP for comparative effectiveness research.

Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease encompassing several clinically defined subtypes of varying severity. The etiology of JIA remains largely unknown, but genome-wide association studies (GWASs) have identified up to 22 genes associated with JIA susceptibility, including a well-established association with HLA-DRB1. Continued investigation of heritable risk factors has been hindered by disease heterogeneity and low disease prevalence. In this study, we utilized shared genomic segments (SGS) analysis on whole-genome sequencing of 40 cases from 12 multi-generational pedigrees significantly enriched for JIA. Subsets of cases are connected by a common ancestor in large extended pedigrees, increasing the power to identify disease-associated loci. SGS analysis identifies genomic segments shared among disease cases that are likely identical by descent and anchored by a disease locus. This approach revealed statistically significant signals for major histocompatibility complex (MHC) class I and class III alleles, particularly HLA-A∗02:01, which was observed at a high frequency among cases. Furthermore, we identified an additional risk locus at 12q23.2-23.3, containing genes primarily expressed by naive B cells, natural killer cells, and monocytes. The recognition of additional risk beyond HLA-DRB1 provides a new perspective on immune cell dynamics in JIA. These findings contribute to our understanding of JIA and may guide future research and therapeutic strategies.

Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. Conclusion: : STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome. (J Allergy Clin Immunol 2023;151:1081-95.)

RELA haploinsufficiency is a recently described autoinflammatory condition presenting with intermittent fevers and mucocutaneous ulcerations. The RELA gene encodes the p65 protein, one of five NF-κB family transcription factors. As RELA is an essential regulator of mucosal homeostasis, haploinsufficiency leads to decreased NF-κB signaling which promotes TNF-driven mucosal apoptosis with impaired epithelial recovery. Thus far, only eight cases have been reported in the literature. Here, we report four families with three novel and one previously described pathogenic variant in RELA. These four families included 23 affected individuals for which genetic testing was available in 16. Almost half of these patients had been previously diagnosed with more common rheumatologic entities (such as Behcet’s Disease; BD) prior to the discovery of their pathogenic RELA variants. The most common clinical features were orogenital ulcers, rash, joint inflammation, and fever. The least common were conjunctivitis and recurrent infections. Clinical variability was remarkable even among familial cases, and incomplete penetrance was observed. Patients in our series were treated with a variety of medications, and benefit was observed with glucocorticoids, colchicine, and TNF inhibitors. Altogether, our work adds to the current literature and doubles the number of reported cases with RELA-Associated Inflammatory Disease (RAID). It reaffirms the central importance of the NF-κB pathway in immunity and inflammation, as well as the important regulatory role of RELA in mucosal homeostasis. RELA associated inflammatory disease should be considered in all patients with BD, particularly those with early onset and/or with a strong family history.

Abstract Background The prevalence of Celiac Disease (CD) in Juvenile Idiopathic Arthritis (JIA) has been reported to be 0.1–7% in various small studies. As a result of the limited number of research and their inconclusive results there are no clear recommendations for routine CD screening in asymptomatic patients with JIA. Our aim is to estimate the prevalence of IgA deficiency and tissue transglutaminase (tTG) IgA in a cohort of JIA followed in two large academic medical centers. Methods Serum was collected and stored from all subjects and analyzed in a reference laboratory for total IgA (Quantitative Nephelometry) and tTG IgA antibody levels (Semi-Quantitative Enzyme-Linked Immunosorbent Assay). Fisher’s exact tests were performed for statistical significance. Risk estimates (odds ratios) with 95% confidence intervals were calculated. Results 808 JIA cases and 140 controls were analyzed. Majority were non-Hispanic whites (72% vs. 68% p = 0.309). A total of 1.2% of cases were IgA deficient compared to none of the controls (p = 0.373). After excluding IgA deficient subjects, 2% of cases had tTG IgA ≥ 4u/mL compared to 3.6% of controls (p = 0.216) (OR = 0.5; 95% C.I = 0.1–1.4); and 0.8% of cases had tTG IgA > 10u/mL compared to 1.4% of controls (p = 0.627) (OR = 0.5; 95%C.I = 0.1–2.9). Conclusions Using the largest JIA cohort to date to investigate prevalence of celiac antibodies, the prevalence of positive tTG IgA was 0.8% and of IgA deficiency was 1.2%. The results did not demonstrate a higher prevalence of abnormal tTG IgA in JIA. The study did not support the routine screening of asymptomatic JIA patients for CD.

Objective To describe the efficacy and safety data of children with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with abatacept (ABA) + methotrexate (MTX) or ABA monotherapy when prior MTX use was either ineffective or not tolerated. Methods Posthoc analysis of 2 phase III trials of subcutaneous (SC) and intravenous (IV) ABA over 2 years in patients with pcJIA (aged 2-17 years). Patients were stratified by treatment with ABA + MTX or ABA monotherapy and further by prior biologic use. Efficacy outcomes included JIA–American College of Rheumatology (JIA-ACR) responses, Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein (JADAS27-CRP), and safety. Descriptive pharmacokinetic analyses were also performed. Results Efficacy responses (JIA-ACR and JADAS27-CRP) were similar between patients receiving ABA + MTX (n = 310) or ABA monotherapy (n = 99) and persisted over 2 years. Clinical response rates were similar in biologic-naïve patients and prior biologic users; this was independent of MTX use. Across both studies, ABA + MTX and ABA monotherapy displayed similar safety profiles. Pharmacokinetic results revealed similar minimum steady-state trough ABA concentrations between studies. Further, baseline MTX did not influence ABA clearance and was not a significant predictor of JIA-ACR responses. Conclusion ABA monotherapy (SC and IV) was effective and well tolerated in children with pcJIA when prior MTX use was ineffective or not tolerated. Treatment effects of ABA appear to be independent of MTX coadministration. Consequently, ABA monotherapy can be considered for those with prior biologic therapy if MTX use is inappropriate. ( ClinicalTrials.gov : NCT01844518 and NCT00095173 )

Primary immunodeficiency diseases are associated with an increased tendency for noninfectious complications of autoimmunity and malignancy, particularly leukemia and lymphoma. The mechanisms of immune dysregulation have been linked to the combination of dysregulated immune cells and environmental factors such as infections. In particular, dysfunction in T-cell subsets and Epstein-Barr virus contributes to the development of autoimmunity and lymphoproliferative disease in primary immunodeficiency diseases. There are scant reports of patients with partial DiGeorge syndrome and Epstein-Barr virus-driven lymphoma. We report 1 patients with partial DiGeorge syndrome who developed lymphoma, and review reported cases in the literature.

An 11-year-old boy presented with 2 weeks of intermittent headache, right orbital pain, and constant diplopia. Brain MRI showed dural thickening and enhancement of the right lateral cavernous sinus, right orbital apex, and tentorium. Initial cerebral spinal fluid analysis showed only mild pleocytosis, and serum diagnostics were unrevealing. The working diagnosis was Tolosa-Hunt syndrome. His pain and sixth nerve palsy resolved with corticosteroids. Five months after initial presentation, he developed new numbness of the right cheek, complete right ophthalmoplegia, and weakness and numbness of his right hand and leg, all of which were responsive to steroids. Fifteen months later, he returned to the emergency department with 2 weeks of left-sided headaches and acute diplopia. On examination, he had a left cranial nerve 6 palsy. Dural biopsy showed diffuse mononuclear inflammatory cell reaction consisting mostly of lymphocytes with no signs of granuloma formation, nor any epithelioid or giant cells. His clinical course was consistent with an autoinflammatory condition of unknown etiology. Genetic testing with an immunodeficiency panel showed a risk allele in NOD2 (nucleotide-binding oligomerization domain 2) c.3019dup (p.Leu1007Prof*2) that is associated with an increased risk for Crohn disease. His clinical condition had similarities to central nervous system sarcoidosis. Because of the similarities between our patient's clinical, imaging, and genetic findings and neurosarcoidosis, he was switched to a more targeted therapy-infliximab. His condition has since been stable for nearly 2 years. In conclusion, genetic testing should be considered in patients with suspected occult autoimmunity.

In adults with COVID-19 (the disease caused by infection with severe acute respiratory syndrome coronavirus, SARS-CoV-2), the prevalence of acute neurologic symptoms (e.g., headaches, anosmia, seizure) and conditions (e.g., encephalopathy, stroke, delirium, encephalitis) ranges widely, from 4.4% to 100% of cases (1,2). Neurologic manifestations in children younger than 18 years with COVID-19 is also relatively common. For example, in the United States, of nearly 3,700 cases, 17% had nonspecific neurologic conditions such as headache, fatigue, and myalgia, and 1% presented with encephalopathy, seizures, and meningeal signs (3). Worldwide, a report of nearly 1,400 pediatric patients described similar prevalence of headache (4%), anosmia (2%), seizures (0.7%), and cerebrovascular stroke (0.7%) (4). The pathophysiology of acute and postacute neurologic manifestations of COVID-19 is likely multifactorial. Each of the following mechanistic pathways could interactively or independently cause disease: 1) direct viral invasion and replication in the CNS, 2) large vessel or microvascular insufficiency due to vasoconstriction and/or occlusion, 3) nonspecific effects of severe systemic COVID-19 illness or treatment, and 4) immune system dysregulation and autoimmunity. VIRAL INVASION OF THE NERVOUS SYSTEM Cellular invasion by the SARS-CoV-2 begins with binding of the viral spike protein to a transmembrane receptor, followed by viral membrane fusion with the cellular membrane after activation of the spike protein by cellular proteases. SARS-CoV-2 binds to the angiotensin-converting enzyme (ACE) 2 receptor, a protein coexpressed with the protease transmembrane serine protease 2 (TMPRSS2) in endothelial cells throughout the body. ACE2 is particularly abundant in the small intestine, kidney, lungs, and heart (5). ACE2 is also present in human adult and fetal brain, with highest expression in the pons and medulla oblongata (6). In mice, brain ACE2 protein is higher in the early postnatal period than in the adult, whereas ACE2 activity is similar (7). ACE2 is also expressed in components of the cerebral vasculature and blood-brain barrier (BBB): that is, the endothelium, pericytes, and contractile cells (8–10). Purkinje cells, cortical layer V neurons, astrocytes, and micrglia also express ACE2 and TMPRSS2 (10). SARS-CoV-2 may bind instead, or also, to the neuronal adhesion molecule neuropilin (1 and undergo activation by Furin, an ubiquitous protease, to allow entry into the host cell (11). Neuropilin 1 is a glycoprotein essential for normal nervous and cardiovascular system formation and function in vertebrates. It is expressed in immune (i.e., macrophages, microglia) and nonimmune cells (i.e., endothelia, neurons) (12,13). Neuropilin 1 has essential roles in axon guidance, dendrite formation, and cerebral vasculogenesis, among other processes. Indeed, mouse brain neuropilin 1 expression is two to three times higher in embryonic than adult tissues (14,15). Of note, the developing brain expresses the main receptors and proteins considered necessary for SARS-CoV-2 invasion into neural cells. Therefore, direct viral invasion of the CNS or peripheral nervous system is biologically plausible across the age spectrum, but evidence supporting this mechanism as the sole or predominant pathophysiologic process in patients is scarce (16). Direct viral invasion of the CNS would require either viremia and BBB disruption or transsynaptic viral passage along cranial nerves V, VII, IX, and X, using nasopharyngeal, respiratory, and/or gastrointestinal tracts as entry points (16,17). Figure 1A illustrates transsynaptic passage starting at the nasal neuroepithelium traveling via olfactory pathways to the brain stem and cortical areas. Viral entry via the respiratory system (Fig. 1B) leads to systemic inflammation and viremia, setting the stage for CNS invasion via BBB disruption (Figure 1, C and D).Figure 1.: Schematic of hypothesized neuropathology of COVID-19 neurologic manifestations. A, Expanded view of the neuroepithelium (arrow) showing olfactory neurons, neural stem cells, and sustentacular cells. Olfactory neurons are bipolar, projecting axons that traverse the cribriform plate apically and the nasal cavity basally. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binding to angiotensin-converting enzyme (ACE) 2 on sustentacular cell membranes enveloping basal dendrites may allow viral invasion into olfactory neurons followed by transsynaptic spread via cranial nerves and olfactory pathways to enter the brainstem, basal ganglia, and cortex. B, Inhaled viral particles easily bind to ACE2 on respiratory epithelium to replicate and enter the bloodstream. C, Shows a cross-section of the vasculature with a cartoon of viremia, the "cytokine storm" and the ACE2-expressing vascular endothelium. SARS-CoV-2 binding to endothelial ACE2 enhances viremia and multiple organ involvement. D, Schematically shows the blood-brain barrier and ACE2 expressing pericytes. ACE2 loss decreases flow in the cerebral microcirculation, in part by pericyte action on cerebral vessels. Finally, E shows cerebral microinfarcts from vascular plugging and vasoconstriction. IL = interleukin, TNFα = tumor necrosis factor-α.Transsynaptic entry into the brain via the nasal cavity is supported by data from human autopsy and biopsy tissues and by work using animal models (10,18,19). The nasal olfactory epithelium is a neuroepithelium containing neural stem cells, sustentacular (or supporting) cells and olfactory sensory neuronal dendrites in which ACE2 messenger RNA and protein are coexpressed with neuronal markers (19). Sustentacular cells express ACE2 messenger RNA and protein at levels similar to those found in the respiratory epithelium (18). Sustentacular cells wrap around the apical dendrites of olfactory sensory neurons, the bipolar neurons whose axons pierce the cribriform plate to synapse at the olfactory bulb. Whether or not sustentacular cells can transfer SARS-CoV-2 to these neurons, possibly via exosomes as noted in some herpesviruses, is unknown (10,18). SARS-CoV-2 could thus travel transsynaptically from the olfactory bulb to the olfactory tubercule and cortex and/or to the brainstem and medulla (17,19). The likely importance of the olfactory route as a pathway to the CNS is supported by reports of MRI confirmed involvement of the olfactory cortex and brainstem in both adults and children (20,21). However, reports of clinical encephalitis, meningitis, and intracranial ischemia/hemorrhage, in general, lack evidence of SARS-CoV-2 in the cerebrospinal fluid (CSF) (16,22). Polymerase chain reaction SARS-CoV-2 positivity in brain slices has been noted (23,24), but pathologic evidence of viral-specific injury in autopsy studies is lacking. THE PROTHROMBOTIC STATE AND THE CNS (IMPAIRED LARGE VESSEL OR MICROVASCULAR BLOOD FLOW) A feature that distinguishes neurologic disease associated with COVID-19 from that seen in most other respiratory viruses is the marked prothrombotic state and increased risk of stroke, particularly ischemic rather than hemorrhagic (16). Thrombotic and thromboembolic strokes have been reported in COVID-19 patients across the age spectrum, ranging from the elderly to those as young as 7 years (25,26) depicted schematically in Figure 1E. SARS-CoV-2 infection is associated with cerebral large vessel and microcirculatory occlusion or insufficiency in young adults and children (25,27,28). Case reports of thrombotic and hemorrhagic stroke in children with acute COVID-19 are growing (4,29–31). Loss of ACE2 activity secondary to SARS-CoV-2 infection is likely to play an important role in the cerebral vascular insufficiency, endotheliopathy, and neuropsychiatric manifestations of COVID-19. Microcirculatory insufficiency and endotheliopathy in the CNS of COVID-19 patients (32) are supported by the predominance of hypoxic injury and/or microvascular plugging (Fig. 1E) in brain autopsies from adults who died from COVID-19 even in those without systemic hypoxia or respiratory failure (24,26). As shown in Figure 2, SARS-CoV-2 bound to cell surface ACE2, followed by viral entry, depletes ACE2 (9). ACE2 loss has multiple effects. First, ACE2 normally counteracts angiotensin II, a potent vasoconstrictor, procoagulant, and inflammatory neuropeptide, via a number of pathways. ACE2 not only directly inactivates angiotensin II but it also produces angiotensin 1–7, an agonist at the Mas receptor (MasR) that counteracts the actions of angiotensin II by promoting anti-inflammatory, anticoagulant, vasodilatory, and antioxidant effects downstream of MasR. MasR agonists are protective against ischemia in vitro and in vivo (33). Hence, ACE2 depletion and subsequent renin-angiotensin system (RAS) disequilibrium could produce the endothelitis, inflammation, and prothrombotic state associated with COVID-19 (34,35). ACE2 acts on numerous other substrates in the brain, including the endogenous opioid neuropeptides known as dynorphins. (36) ACE2 loss leading to unopposed bradykinin, neurotensin, and dynorphin levels could help explain increased vascular permeability, delirium, and high sedative requirements in COVID-19 patients (37). Preclinical studies show that the ACE2/angiotensin 1–7/MasR-axis affects cognition, anxiety, depression, and other mood disorders. In support of the role of ACE2, high circulating angiotensin II levels are correlated with disease severity in critically ill COVID-19 patients (38). In summary, ACE2 loss could account for vascular and nonvascular neurologic manifestations associated with COVID-19.Figure 2.: Angiotensin-converting enzyme (ACE) 2 and Mas receptor (MasR) pathways. Renin, produced in the kidney, acts on circulating angiotensinogen to produce angiotensin I. Angiotensin I is the physiologically inactive precursor of angiotensin II. The conversion of angiotensin I to angiotensin II is catalyzed by ACE, a type I integral membrane protein found primarily in the vascular endothelium of the lungs and kidneys. Angiotensin II exerts vasoconstrictive procoagulant, proinflammatory, and prooxidant effects via the angiotensin receptor (AT1R). Angiotensin II may instead be inactivated by the ACE2, a homologous type I integral membrane protein expressed in the vascular endothelium, lungs, kidney, adrenal cortex, arterioles, and brain. ACE2 also converts angiotensin I and angiotensin II into angiotensin 1–9 and angiotensin 1–7, respectively. Angiotensin 1–7 activates the MasR to promote anti-inflammatory, anticoagulant, vasodilatory, and antioxidant effects. SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.SYSTEMIC FACTORS (CRITICAL ILLNESS AND THE CNS) Seizures, delirium, and encephalopathy observed in many critically ill patients with COVID-19 are likely related in whole or in part to hepatic and/or renal failure, medications, hypoxia, and hypotension. The pooled estimates of seizure and encephalopathy frequency in children with severe COVID-19 are 3.1% and 12.6% of cases, respectively (3). IMMUNE DYSREGULATION AND THE CNS Immune dysregulation resulting in "cytokine storm" and macrophage activation, possibly related to inefficient innate immunity and impaired viral clearance, could produce neurologic manifestations from systemic effects and/or BBB breakdown (39). Acute or late neurologic manifestations of COVID-19 in adults and children may also be triggered by autoimmunity. Immune profiling suggests that autoantibodies in multiystem inflammatory syndrome in children (MIS-C) (the COVID-19–associated MIS-C) play a role in organ dysfunction including the brain (40,41). Shared sequence similarity between SARS-CoV-2 and sialic acid residues on neural tissue as well as the postinfectious nature of MIS-C supports an autoimmune hypothesis in neurologic manifestations of COVID-19 in adults and children alike after resolution of the acute infection (22,40,42). Serum and CSF from a series of adult patients with severe COVID-19 infection contained high-affinity SARS-CoV-2–neutralizing antibodies that cross-react with mammalian self-antigens, including self-antigens found in the CNS (43). Postinfectious neurologic manifestations include Guillain-Barre syndrome and acute disseminated encephalomyelitis (3,44,45). In COVID-19, the presence of antiphospholipid antibodies in patients with severe thrombosis and the correlation between anti-interferon antibodies and severity of disease also support the possible role of autoimmunity (46,47). CONCLUDING REMARKS ABOUT THERAPIES Knowledge about mechanisms of neurologic disease and immunologic response to SARS-CoV-2 is scarce, but rapidly growing. Experimental and clinical data suggest a major role for inflammation in the genesis of neurologic complications of COVID-19 in adults and children, with potential pathophysiologic involvement of disequilibrium in the RAS. This growing knowledge about potential mechanisms as outlined in this PCCM Concise Clinical Science review supports the currently used clinical interventions such as steroids in COVID-19 and steroids and IV immunoglobulin in MIS-C. Future potential immunologic interventions include blocking agents (against interleukin-1 and -6, for example) and autoreactive cell and autoantibody depletion with plasmapheresis and/or anti-CD20 monoclonal antibodies to ameliorate neurologic complications of COVID-19. Other possible pharmacologic approaches include combatting RAS disequilibrium induced by ACE2 loss using MasR agonists. In this regard, a clinical trial (NCT04452435) of the MasR agonist C21 for treating nonneurologic complications of COVID-19 was recently completed (48). This group had previously demonstrated successful treatment of rodent stroke after nasal delivery of C21, suggesting the potential for future trials for treating or preventing neurologic complications of COVID-19 (49). There are also ongoing mechanistic studies of the cytokine storm in pediatric COVID-19, with or without MIS-C (NCT04538495; NCT04588363), which should yield highly valuable insights into systemic disease pathogenesis. However, studies using biosamples and imaging relevant to the CNS and peripheral nervous system are needed to gain further understanding of the mechanisms of neurologic disease in pediatric COVID-19.

Primary immunodeficiency diseases are associated with an increased tendency for noninfectious complications of autoimmunity and malignancy, particularly leukemia and lymphoma. The mechanisms of immune dysregulation have been linked to the combination of dysregulated immune cells and environmental factors such as infections. In particular, dysfunction in T-cell subsets and Epstein-Barr virus contributes to the development of autoimmunity and lymphoproliferative disease in primary immunodeficiency diseases. There are scant reports of patients with partial DiGeorge syndrome and Epstein-Barr virus-driven lymphoma. We report 1 patients with partial DiGeorge syndrome who developed lymphoma, and review reported cases in the literature.

Background The transition of health care from Pediatric to Adult providers for adolescents and young adults with chronic disease is associated with poor outcomes. Despite the importance of this transition, over 80% of these patients do not receive the services necessary to transition to Adult health care. In 2018, we initiated a transition clinic structure, integrating an Internal Medicine - Pediatrics trained Adult Rheumatologist in a Pediatric Rheumatology clinic to guide this transition. Our goal was to improve transition outcomes. We report the methods of this clinic and its preliminary outcomes. Methods For patients referred to the transition clinic, the Adult Rheumatologist assumed medical management and implemented a six-part modular transition curriculum. This curriculum included a Transition Policy, Transition Readiness Assessment, medication review and education, diagnosis review and education, and counseling on differences between Pediatric and Adult-oriented care. Eligible patients and their families were enrolled in a prospective observational outcomes research registry. Initial data from this transition clinic is reported including adherence with certain aspects of the transition curriculum and clinic utilization. Results The transition clinic Adult Rheumatologist saw 177 patients in 2 years, and 57 patients were eligible for, approached, and successfully enrolled in the registry. From this registry, all patients reviewed the Transition Policy with the Adult Rheumatologist and 45 (78.9%) completed at least one Transition Readiness Assessment. Of the 22 patients for whom transition was indicated, all were successfully transitioned to an Adult Rheumatologist. 17 (77.3%) continued care post-transition with the transition clinic Adult Rheumatologist, and 5 (22.7%) continued care post-transition with a different Adult Rheumatologist. The median time between the last transition clinic visit and first Adult clinic visit was 5.1 months. Conclusions Our experience demonstrated the success of our clinic model regarding participation in the transition curriculum and improved clinic utilization data. Our results are an improvement over transition rates reported elsewhere that did not implement our model. We believe that this structure could be applied to other primary care and subspecialty clinics. Trial registration This research was approved by the University of Utah Institutional Review Board (IRB) in January 2019 (IRB_00115964). Patients were retrospectively registered if involved prior to this date.