Majority of new patient referrals to a large pediatric rheumatology center result in non-rheumatic diagnosis.

OBJECTIVE: Pediatric rheumatology faces a looming supply-demand crisis. While strategies have been proposed to address the supply shortfall, investigation into the increased demand for pediatric rheumatic care has been limited. Herein, we analyze new patient visits to a large tertiary care pediatric rheumatology center to identify emerging trends in referrals and areas for potential intervention to meet this increased demand. METHODS: All patients referred to and seen by the University of Alabama at Birmingham Pediatric Rheumatology Division between January 2019 and December 2021 for a new patient evaluation were identified. Patient data was retrospectively abstracted, de-identified, and analyzed to develop trends in referrals and frequency of rheumatic disease, non-rheumatic disease, and specific diagnoses. RESULTS: During the study period, 2638 patients were referred to and seen in by the pediatric rheumatology division. Six hundred and ten patients (23.1%) were diagnosed with rheumatic disease. The most common rheumatic disease was juvenile idiopathic arthritis (JIA) at 45.6%, followed by primary Raynaud phenomenon (7.4%), recurrent fever syndromes (6.9%), vasculitides (6.7%), and inflammatory eye disease (6.2%). Of the 2028 patients (76.9%) diagnosed with a non-rheumatic condition, benign musculoskeletal pain was the most common (61.8%), followed by a combination of somatic conditions (11.6%), and non-inflammatory rash (7.7%). CONCLUSION: In this analysis of new patient referrals to a large pediatric rheumatology center, the majority of patients were diagnosed with a non-rheumatic condition. As a worsening supply-demand gap threatens the field of pediatric rheumatology, increased emphasis should be placed on reducing non-rheumatic disease referrals.

Cytokine Storm Syndrome Triggered by Extracorporeal Membrane Oxygenation in Pediatric Patients.

Cytokine storm syndrome (CSS) is a serious and potentially life-threatening condition caused by severe systemic inflammation, immune activation, and a positive feedback loop of cytokine release. Typically triggered by systemic infection, malignancy, monogenic or rheumatic disease, similar patterns of hyper-inflammation have been seen in patients undergoing cardiopulmonary bypass (CPB) and in patients treated with extracorporeal membrane oxygenation (ECMO). Typical treatments used for the prevention and treatment of CPB/ECMO-induced hyper-inflammation have not been shown to be substantially effective. Two patients suffering from ECMO-related CSS were identified by their severe hyper-inflammatory profile and life-threatening sequelae of vasodilatory shock and respiratory failure. Anakinra, an interleukin-1 receptor antagonist, was employed as specific cytokine-directed therapy for the treatment of CSS in these two patients to good effect, with significant improvement in hyper-inflammation and cardiorespiratory status. The use of cytokine-directed therapies in CPB/ECMO-related CSS has great potential to improve the treatment and outcomes of this serious condition.

DOCK2 Mutation and Recurrent Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome resulting from uncontrolled hyper-inflammation, excessive immune system activation, and elevated levels of inflammatory cytokines. HLH can be caused by the inability to downregulate activated macrophages by natural killer (NK) and CD8 cytotoxic T cells through a process reliant on perforin and granzyme B to initiate apoptosis. Homozygous genetic mutations in this process result in primary HLH (pHLH), a disorder that can lead to multi-system organ failure and death in infancy. Heterozygous, dominant-negative, or monoallelic hypomorphic mutations in these same genes can cause a similar syndrome in the presence of an immune trigger, leading to secondary HLH (sHLH). A genetic mutation in a potential novel HLH-associated gene, dedicator of cytokinesis 2 (DOCK2), was identified in a patient with recurrent episodes of sHLH and hyperinflammation in the setting of frequent central line infections. He required baseline immune suppression for the prevention of sHLH, with increased anti-cytokine therapies and corticosteroids in response to flares and infections. Using a foamy-virus approach, the patient's DOCK2 mutation and wild-type (WT) control DOCK2 cDNA were separately transduced into a human NK-92 cell line. The NK-cell populations were stimulated with NK-sensitive K562 erythroleukemia target cells in vitro and degranulation and cytolysis were measured using CD107a expression and live/dead fixable cell dead reagent, respectively. Compared to WT, the patient's DOCK2 mutation was found to cause significantly decreased NK cell function, degranulation, and cytotoxicity. This study speaks to the importance of DOCK2 and similar genes in the pathogenesis of sHLH, with implications for its diagnosis and treatment.

A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome.

BACKGROUND: Primary (familial) hemophagocytic lymphohistiocytosis (pHLH) is a potentially lethal syndrome of infancy, caused by genetic defects in natural killer (NK) cell and CD8 T cell cytotoxicity, leading to hyperinflammation, elevated cytokine levels, and a disorganized immune response resulting in multi-organ system failure and frequently death. Secondary HLH (sHLH) can be triggered in the setting of malignances, diseases of chronic immune system activation, or by infectious etiologies. While pHLH is usually a result of homozygous gene mutations, monoallelic hypomorphic and dominant-negative mutations in pHLH genes have been implicated in sHLH. Coronavirus disease 2019 (COVID-19) has been an omnipresent viral infection since its arrival, and severe cases can present with cytokine storm and have clinical features and laboratory findings consistent with sHLH. Herein, we report an adolescent with severe COVID-19, decreased NK cell function, and features of sHLH. Her genetic evaluation identified a monoallelic missense mutation in the pHLH gene STXBP2, and NK cell assays of her blood showed decreased cytolysis and degranulation ex vivo. METHODS: Patient data was extracted through an electronic medical record review. Using a lentiviral approach, the patient's STXBP2 mutation and wild-type (WT) STXBP2 were separately transduced into the NK-92 human NK cell line. The WT and mutant STXBP2 transduced NK-92 cells were stimulated with NK-sensitive K562 erythroleukemia target cells in vitro, and NK cell degranulation and cytolysis were measured via CD107a expression and Live/Dead near-IR dye, respectively. RESULTS: Compared to WT STXBP2, the patient's STXBP2 mutation caused significantly decreased NK cell cytolysis and associated degranulation in vitro. CONCLUSION: These findings add weight to the hypothesis that some severe cases of COVID-19 may be accompanied by sHLH and hyperinflammation, especially in the setting of heterozygous pHLH genetic mutations. This has implications both diagnostically and therapeutically for severe COVID-19.

Who Would Have Predicted Multisystem Inflammatory Syndrome in Children?

PURPOSE OF REVIEW: Multisystem inflammatory disease in children (MIS-C) is a novel post-infectious phenomenon following coronavirus disease-19 (COVID-19). Herein, we present an in-depth review of the latest MIS-C literature related to clinical findings, pathophysiology, imaging and laboratory studies, treatment algorithms, and disease outcomes. RECENT FINDINGS: With its non-specific presentation of fever, gastrointestinal symptoms, cardiovascular injury and shock, systemic inflammation, and Kawasaki disease (KD)-like features, MIS-C can be a diagnostic challenge, overlapping with KD and active COVID-19 infection. However, common laboratory features, imaging findings, and historical clues can lead to accurate diagnosis and allow for appropriate treatment with a variety of immunomodulatory therapies, including intravenous immunoglobulin (IVIG). Aggressive treatment of MIS-C leads to good outcomes. Longitudinal studies continue to illuminate long-term cardiac sequelae and recovery. MIS-C presents with fever, KD features, gastrointestinal symptoms, cardiac inflammation, and shock. Early recognition and prompt institution of IVIG and glucocorticoids provide for rapid improvement.

Timely Resolution of SARS-CoV-2-Related Multi-System Inflammatory Syndrome in Children.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe, postinfectious manifestation of coronavirus disease 2019 (COVID-19) in the pediatric population. The disease is manifested by hyperinflammation and can result in cardiac dysfunction, coronary changes, and end-organ damage. Adequate timely treatment can prevent poor outcomes in the short term, but long-term data is lacking. Methods: A large single center MIS-C cohort was followed longitudinally after treatment with intravenous immunoglobulin (IVIG) ± glucocorticoids to determine the natural history of the disease and to describe improvement in laboratory markers and cardiac outcomes. Patient were stratified by disease severity and compared. Results: 137 patients were identified with demographics similar to previously described cohorts. Regardless of disease severity, when adequately treated, initial lab abnormalities rapidly improved by the 6-8 month follow-up period, with some resolved in as little as 1-2 weeks. Similarly, cardiac abnormalities improved quickly after treatment; all abnormalities resolved in this cohort by 1-2 months post-hospitalization. Conclusions: Although MIS-C is a serious sequela of COVID-19, when identified quickly and treated aggressively, laboratory abnormalities, coronary dilatation, and systolic dysfunction rapidly improve with minimal long-term morbidity or mortality.

New onset ANCA-associated vasculitis in an adolescent during an acute COVID-19 infection: a case report.

BACKGROUND: SARS-CoV-2 has been found to be exquisitely adept at triggering autoimmunity and multiple new onset autoimmune diseases have been described as a post-infectious complication of COVID-19 infection in the adult population. Less has been described in the pediatric population, as infections are more likely to be asymptomatic and less severe. This case reports a previously healthy adolescent patient with new onset antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) diagnosed in the setting of acute COVID-19 infection. CASE PRESENTATION: A previously healthy adolescent male was diagnosed with COVID-19 pneumonia after presenting with infectious symptoms of fever, cough, congestion, and shortness of breath. After worsening of disease, he was found to have pulmonary nodules, atypical for COVID-19. Further imaging and laboratory workup showed elevated inflammatory markers, negative infectious testing, and positive antineutrophil cytoplasmic antibodies (ANCA) diagnostic for AAV. He was treated with pulse dose steroids followed by a prolonged taper and rituximab. Symptoms resolved and laboratory abnormalities improved over time. At six-month follow-up, lesions were much improved, laboratory markers were within normal limits, and patient remained asymptomatic off medications. CONCLUSIONS: This case is one of the first in the pediatric population to describe new onset AAV presenting with an acute, symptomatic COVID-19 infection. There is increasing evidence for COVID-19 induced autoimmunity in the pediatric population and pediatric care providers should be on high alert for new onset autoimmune disease in children afflicted by COVID-19.

Performance of Cytokine Storm Syndrome Scoring Systems in Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children.

OBJECTIVE: The objective of this study is to evaluate pediatric patients using existing macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) scoring systems to determine how these systems identify patients with cytokine storm syndrome (CSS) in the setting of a multisystem inflammatory syndrome in children (MIS-C) and active coronavirus disease 2019 (COVID-19) infection. METHODS: Hospitalized pediatric patients with MIS-C and active COVID-19 infection at a single institution were identified. Infectious data, clinical findings, and laboratory values were collected, and patients were stratified by disease severity. Eight historically used scoring systems for MAS, HLH, and CSS were examined in the cohort of patients with MIS-C and pediatric COVID-19. RESULTS: The HLH-2004 criteria and HScore did not identify any patients as having CSS on admission, with only one patient with COVID-19 meeting criteria at peak disease severity. The 2016 systemic juvenile idiopathic arthritis (sJIA)/MAS criteria, ferritin/erythrocyte sedimentation rate (ESR) ratio, and COVID-19 CSS Quick Score most frequently identified CSS in this population and distinguished between COVID-19 and MIS-C hyperinflammation. The 2019 MAS/sJIA (MS) score and the COVID-19-associated hyperinflammatory syndrome (cHIS) criteria were less likely to identify CSS, as the MS score overestimated CSS and the cHIS resulted in similar scores regardless of severity or disease type. The Caricchio COVID-Cytokine Storm (COVID-CS) criteria identified patients with COVID-19 frequently but was less useful in MIS-C because of its COVID-19-specific criteria. CONCLUSION: MIS-C and pediatric COVID-19 result in relatively unique CSSs and patterns of inflammation. Existing scoring systems for CSSs likely do not capture the full breadth of this disease process in MIS-C and pediatric COVID-19.

Distinguishing active pediatric COVID-19 pneumonia from MIS-C.

IMPORTANCE: Active pediatric COVID-19 pneumonia and MIS-C are two disease processes requiring rapid diagnosis and different treatment protocols. OBJECTIVE: To distinguish active pediatric COVID-19 pneumonia and MIS-C using presenting signs and symptoms, patient characteristics, and laboratory values. DESIGN: Patients diagnosed and hospitalized with active COVID-19 pneumonia or MIS-C at Children's of Alabama Hospital in Birmingham, AL from April 1 through September 1, 2020 were identified retrospectively. Active COVID-19 and MIS-C cases were defined using diagnostic codes and verified for accuracy using current US Centers for Disease Control case definitions. All clinical notes were reviewed for documentation of COVID-19 pneumonia or MIS-C, and clinical notes and electronic medical records were reviewed for patient demographics, presenting signs and symptoms, prior exposure to or testing for the SARS-CoV-2 virus, laboratory data, imaging, treatment modalities and response to treatment. FINDINGS: 111 patients were identified, with 74 classified as mild COVID-19, 8 patients as moderate COVID-19, 8 patients as severe COVID-19, 10 as mild MIS-C and 11 as severe MIS-C. All groups had a male predominance, with Black and Hispanic patients overrepresented as compared to the demographics of Alabama. Most MIS-C patients were healthy at baseline, with most COVID-19 patients having at least one underlying illness. Fever, rash, conjunctivitis, and gastrointestinal symptoms were predominant in the MIS-C population whereas COVID-19 patients presented with predominantly respiratory symptoms. The two groups were similar in duration of symptomatic prodrome and exposure history to the SARS-CoV-2 virus, but MIS-C patients had a longer duration between presentation and exposure history. COVID-19 patients were more likely to have a positive SAR-CoV-2 PCR and to require respiratory support on admission. MIS-C patients had lower sodium levels, higher levels of C-reactive protein, erythrocyte sedimentation rate, d-dimer and procalcitonin. COVID-19 patients had higher lactate dehydrogenase levels on admission. MIS-C patients had coronary artery changes on echocardiography more often than COVID-19 patients. CONCLUSIONS AND RELEVANCE: This study is one of the first to directly compare COVID-19 and MIS-C in the pediatric population. The significant differences found between symptoms at presentation, demographics, and laboratory findings will aide health-care providers in distinguishing the two disease entities.

Precision medicine in juvenile idiopathic arthritis-has the time arrived?

The introduction of disease-modifying anti-rheumatic drug therapies for treating children and adolescents with chronic arthritis (ie, juvenile idiopathic arthritis [JIA]) has revolutionised care and outcomes. The biologic revolution continues to expand, with ever-changing immunological targets coming to market after basic research and clinical trials. The first class of biologics that was beneficial for children with JIA was tumour necrosis factor (TNF) inhibitors. If used early and aggressively, TNF inhibitors are capable of inducing disease remission for most of the seven subtypes of JIA, with the exception of systemic JIA (which more frequently responds to interleukin [IL]-1 or IL-6 inhibition). Nevertheless, there are still subsets of patients with JIA with disease that is difficult to treat or who develop extra-articular features that require a different therapeutic approach. Although finding an effective biological therapy for individual children with JIA can be trial and error, ongoing research and clinical trials are providing insight into a more personalised approach to care. In addition, redefining the JIA classification, in part based on shared similarities with various adult arthritides, could allow for extrapolation of knowledge from studies in adults with chronic arthritis.

Pigmented Villonodular Synovitis Mimicking an Acute Septic Hip in an Eight-Year-Old Male.

Pigmented villonodular synovitis (PVNS) is a less common but known cause of joint pain in the adult population. PVNS in pediatric patients is even more rare, with only case reports of occurrence in persons under the age of 18 years. Presentation is typically that of more insidious pain and limited range of motion, and is primarily seen in the knee joint. Diagnosis can be suspected with imaging, but ultimately surgical intervention is needed for tissue confirmation. We present a case of PVNS in a pediatric patient with acute symptoms concerning for a septic joint. The patient's workup revealed a large effusion on hip ultrasound, with operative intervention pursued and further imaging deferred given the patient's symptom burden. A 4 × 1 × 1.5 cm intra-articular pigmented mass excised from the synovium in the operating room. The patient's symptoms improved after the procedure, with pathology showing sheets of plump mononuclear cells in a collagenized stroma with hemosiderin deposits, confirming the diagnosis. This case highlights the importance of keeping non-infectious etiologies in the differential diagnosis of acute onset joint pain.

Characteristics of coexisting localized scleroderma and inflammatory arthritis.

OBJECTIVE: Localized scleroderma (LS), including morphea and linear scleroderma, is an autoimmune disease where excessive subcutaneous collagen deposits lead to thickening, scarring, and fibrosis of the tissues. LS coexisting with inflammatory arthritis is less well-described but has been reported in as many as 20% of 53 LS patients in a recent cohort. Herein, we describe a cohort of 8 children with both LS and inflammatory arthritis. The objective of this study is to determine the characteristics of inflammatory arthritis in children with LS and their response to treatment regimens. METHODS: A retrospective chart review was completed on patients less than 19 years of age who were diagnosed with either morphea or linear scleroderma at the Children of Alabama center from 2004-2018. Patients were identified using ICD-9 and ICD-10 diagnostic codes. Records were reviewed for additional diagnostic codes, exams, and laboratory findings confirming coexisting inflammatory arthritis and LS. RESULTS: A total of 87 patients with a diagnosis of either morphea or linear scleroderma were identified. Eight (9%) had coexisting inflammatory arthritis according to the diagnostic codes with documented active arthritis. Median age of initial rheumatic disease diagnosis was 7.5 years. A majority of patients with both LS and inflammatory arthritis were female (62.5%). Half of the patients (n=4, 50%) had LS lesions over arthritic joints. All of the identified patients were diagnosed with a form of juvenile idiopathic arthritis (JIA). The JIA diagnoses varied widely in 3 (37.5%) patients with rheumatoid factor (RF) negative polyarticular JIA, 2 (25%) with oligoarticular JIA, 2 (25%) with psoriatic JIA, and 1 (12.5%) with enthesitis-related JIA. The timing of onset of LS and inflammatory arthritis varied widely. Three (37.5%) patients had LS lesions preceding clinical arthritis, and three (37.5%) had arthritis before the appearance of LS. Two (25%) patients had both LS and arthritis at the time of diagnosis. All patients received methotrexate (MTX) during their disease course with only 3 (37.5%) receiving systemic steroids during treatment. All 8 patients showed resolution of LS lesions. However, 6 of the 8 patients demonstrated active arthritis on combination MTX and TNFi therapy. CONCLUSION: In this cohort of pediatric LS, 9% of patients had coexisting inflammatory arthritis. The characteristics of this cohort varied widely. All patients received MTX initially and showed a resolution of LS lesions. However, in the majority of patients, the arthritis failed to respond to MTX and TNFi combination therapy. These results suggest that inflammatory arthritis coexisting with LS may be less likely to respond to traditional inflammatory arthritis or JIA therapies.

Vitamin D treatment modulates organic dust-induced cellular and airway inflammatory consequences.

Exposure to organic dusts elicits airway inflammatory diseases. Vitamin D recently has been associated with various airway inflammatory diseases, but its role in agricultural organic dust exposures is unknown. This study investigated whether vitamin D reduces organic dust-induced inflammatory outcomes in cell culture and animal models. Organic dust extracts obtained from swine confinement facilities induced neutrophil chemokine production (human IL-8, murine CXCL1/CXCL2). Neutrophil chemokine induction was reduced in human blood monocytes, human bronchial epithelial cells, and murine lung slices pretreated with 1,25-(OH)(2) D(3) . Intranasal inhalation of organic dust extract induced neutrophil influx, and CXCL1/CXCL2 release was also decreased in mice fed a relatively high vitamin D diet as compared to mice fed a low vitamin D diet. These findings were associated with reduced tracheal epithelial cell PKCα and PKCε activity and whole lung TLR2 and TLR4 gene expression. Collectively, vitamin D plays a role in modulating organic dust-induced airway inflammatory outcomes.