Understanding COVID-19 vaccine hesitancy in vasculitis patients.

Objective: To identify the factors that impact COVID-19 vaccine decision-making in vaccine-hesitant vasculitis patients, and compare their perceptions with other rheumatology patients, given existence of data suggesting rheumatology patients may have disease-specific factors that influence their COVID-19 vaccine decision-making. Methods: This cross-sectional study surveyed adult rheumatology patients from the Kaye Edmonton Clinic Rheumatology Clinic, in Canada, between June and August 2021, using an anonymous online questionnaire. Survey responses were analyzed for statistical differences using chi-square analysis. Results: The COVID-19 Vaccine Perceptions Survey had a response rate of 70.9%. Of the total 231 respondents, 103 patients were diagnosed with vasculitis. At the time of the survey, 10.6% of vasculitis patients refused to receive a COVID-19 vaccine compared to 6.3% for other rheumatology patients. Compared to other rheumatology patients, vaccine-hesitant vasculitis patients were significantly more concerned about almost every aspect of available COVID-19 vaccines [e.g., safety (p < 0.001), components (p < 0.001)], and feared that they could contract SARS-CoV-2 from a vaccine (p < 0.001). These vaccine-hesitant patients were also significantly less pleased with the government's pandemic response, less confident in healthcare team-provided information (p < 0.001), and more likely to report that healthcare providers had no role in their COVID-19 vaccine decision-making (p < 0.001). Conclusion: Vaccine-hesitant vasculitis patients may have multiple considerations influencing COVID-19 vaccine hesitancy, including vaccine and disease-specific concerns, along with unfavorable perceptions of the healthcare system (government and healthcare providers). Healthcare providers can address some of these concerns by initiating patient-centered discussions around immunizations to help support educated decision-making.

Evidence of a Novel Mitochondrial Signature in Systemic Sclerosis Patients with Chronic Fatigue Syndrome.

Symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are common in rheumatic diseases, but no studies report the frequency of these in early systemic sclerosis. There are no known biomarkers that can distinguish between patients with ME/CFS, although mitochondrial abnormalities are often demonstrated. We sought to assess the prevalence of ME/CFS in limited cutaneous SSc (lcSSc) patients early in their disease (<5 years from the onset of non-Raynaud's symptoms) and to determine if alterations in mitochondrial electron transport chain (ETC) transcripts and mitochondrial DNA (mtDNA) integrity could be used to distinguish between fatigued and non-fatigued patients. All SSc patients met ACR/EULAR classification criteria. ME/CFS-related symptoms were assessed through validated questionnaires, and the expression of ETC transcripts and mtDNA integrity were quantified via qPCR. SSc patients with ME/CFS could be distinguished from non-fatigued patients through ETC gene analysis; specifically, reduced expression of ND4 and CyB and increased expression of Cox7C. ND4 and CyB expression correlated with indicators of disease severity. Further prospective and functional studies are needed to determine if this altered signature can be further utilized to better identify ME/CFS in SSc patients, and whether ME/CFS in early SSc disease could predict more severe disease outcomes.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia: PR3-versus MPO-ANCA-associated vasculitis, an exploratory cross-sectional study.

Background: Persistent fatigue is a common complaint in ANCA-vasculitis (AAV) patients and has a profound impact on patient's quality of life. The symptoms associated with this fatigue mirror those found in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia. Etiologic and pathophysiologic differences exist between PR3- and MPO-ANCA disease, yet differences in their fatigue manifestations have not been well researched. We compared fatigue and its associations in healthy controls, AAV patients and fibromyalgia controls. Methods: The Canadian consensus criteria were used for ME/CFS diagnosis, and American College of Rheumatology criteria for fibromyalgia diagnosis. Factors such as cognitive failure, depression, anxiety, and sleep disturbances were assessed by patient reported questionnaires. Clinical factors such as BVAS, vasculitis damage index, CRP and BMI were also collected. Findings: Our AAV cohort comprised 52 patients, with a mean age of 44.7 (20-79), 57% (30/52) of the patients were female. We found 51.9% (27/52) of patients fulfilled the diagnostic criteria for ME/CFS, with 37% (10/27) of those having comorbid fibromyalgia. Rates of fatigue were higher in MPO-ANCA patients, than in PR3-ANCA patients, and their symptoms were more similar to the fibromyalgia controls. Fatigue in PR3-ANCA patients was related to inflammatory markers. These differences may be due to the varied pathophysiology of the PR3- and MPO-ANCA serotypes. Interpretation: A large proportion of AAV patients suffer from debilitating fatigue consequential enough to meet the diagnostic criteria for ME/CFS. Fatigue associations were not the same between PR3- and MPO-ANCA patients, suggesting that the underlying mechanisms may be different. Future studies should consider ANCA serotype, as further research may inform different clinical treatment strategies for AAV patients suffering from ME/CFS. Funding: This manuscript was funded by the Dutch Kidney Foundation (17PhD01).

COVID-19 Vaccination Perceptions in Patients With Rheumatic Disease: A Cross-Sectional Online Survey.

OBJECTIVE: To identify the factors that affect coronavirus disease 2019 (COVID-19) vaccine decision making among individuals diagnosed with a rheumatologic condition, given that previous international studies have demonstrated that a significant proportion of patients with rheumatic disease (RD) are vaccine hesitant. METHODS: This cross-sectional study involved an online survey with adult patients with RD from the Kaye Edmonton Clinic Rheumatology Clinic between June and August 2021. Quantitative results were descriptively analyzed, whereas qualitative thematic analysis was conducted for open-ended responses. RESULTS: The survey had a response rate of 70.9% (N = 231). Regarding COVID-19 vaccines, patients with RD were most concerned about the possible effect of vaccination on their rheumatic condition (45.2%) and about vaccine effectiveness (45.1%). Most patients had discussed COVID-19 vaccination (75.9%) and its risks and benefits (66.1%) with their medical team, and 83.6% of respondents were confident in the information provided. Patients' perceptions of the government's role in handling the COVID-19 pandemic varied: 33% reported that they found government-instituted public health measures effective. Surprisingly, 9.7% of patients with RD still reported concerns that they could develop COVID-19 from an approved COVID-19 vaccine. CONCLUSION: This study describes factors implicated in COVID-19 vaccine decision making among patients with RD. Three important themes included possible adverse effects of the vaccine on RD control, reduced vaccine efficacy because of RD/treatment, and risk of contracting SARS-CoV-2 from the COVID-19 vaccine. Knowledge from this study can assist healthcare providers in looking after patients with RD to initiate discussions with patients to share evidence-based vaccine information and assist with informed decision making.

Development of a predictive algorithm to identify pre-school children at risk for behavior changes associated with sleep-related breathing disorders.

STUDY OBJECTIVES: Children with late-onset (2-5 years) or persistent (3 months-5 years) sleep-related breathing disorder (SRBD) have an increased risk of behavior problems compared to children with no or early-onset SRBD. We sought to determine whether a combination of urine metabolites and sleep questionnaires could identify children at risk for SRBD-associated behavior problems. METHODS: Urine and data were analyzed from the Edmonton site of the CHILD birth cohort study. We measured urine metabolites (random, mid-stream) at age three-years among a sub-cohort of participants (n = 165). Random Forest with a Boruta wrapper was used to identify important metabolites (creatinine-corrected, z-scores) for late/persistent SRBD versus no/early SRBD (reference). An algorithm was subsequently generated to predict late/persistent SRBD in children with a history of snoring using a metabolite composite score (z-scores < or ≥ 0) plus the SDBeasy score defined as [age (yrs.) of most recent positive SRBD]2 - [age (yrs.) first reported ever snoring]2. RESULTS: Of the 165 children with SRBD data, 40 participants had late/persistent SRBD. Seven urinary metabolites in addition to the SDBeasy score were confirmed as important for late/persistent SRBD (AUC = 0.87). Among children with an ever-snoring history and a metabolite composite score ≥0, those with SDBeasy score ≥3 were over 13-fold more likely to have late/persistent SRBD (OR 13.7; 95%CI: 3.0, 62.1; p = 0.001). This algorithm has a Sensitivity of 69.6%, Specificity of 85.7% and a positive likelihood ratio (+LR) of 4.9. CONCLUSIONS: We developed a predictive algorithm using a combination of questionnaires and urine metabolites at age three-years to identify children with late/persistent SRBD by five-years of age.

Fatigue in ANCA-associated vasculitis (AAV) and systemic sclerosis (SSc): similarities with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A critical review of the literature.

INTRODUCTION: Persistent debilitating fatigue is a frequent complaint in patients with systemic autoimmune rheumatic diseases (SARDs). Fatigue is, however, frequently overlooked in the clinic, and patients who successfully achieve remission of their disease, often still have a lowered quality of life due to its persistence. How similar is this fatigue to Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), what is this fatigue associated with, and what tools/approaches (if any), have resulted in the improvement of fatigue in these patients is poorly defined. AREAS COVERED: Similarities between the pathophysiology of ME/CFS, systemic sclerosis (SSc) and primary systemic vasculitides (PSV) are discussed, followed by an in-depth review of the prevalence and correlates of fatigue in these diseases. The authors reviewed literature from MEDLINE, APA PsycInfo, Embase, and CINAHL. EXPERT OPINION: Persistent fatigue is a prominent feature in SARDs and may not be associated with components commonly associated with disease activity and/or progression. Immune and metabolic commonalities exist between ME/CFS, SSc, and PSVs - suggesting that common pathways inherent to the diseases and fatigue may be present. We suggest that patients with features of ME/CFS need to be identified by treating physicians, as they may require alternative approaches to therapy to improve their quality of life.

Nailfold Capillaroscopy Abnormalities Correlate With Disease Activity in Adult Dermatomyositis.

Objectives: The aim of this study was to determine the relationship between disease activity in adult patients with dermatomyositis (DM) and other biomarkers of disease activity such as C-reactive protein creatinine kinase and nailfold video capillaroscopy (NVC). Methods: We performed a prospective single center study of 15 adult patients with DM. Study participants underwent two assessments at least 9 months apart including clinical, laboratory and NVC evaluations. Patients received immunosuppressive medications for their dermatomyositis, and ongoing disease activity was measured by the Myositis Intention to Treat Index (MITAX). NVC evaluation included assessment of capillary density, capillary apical diameter (mm), and the number of microhemorrhages per digit. Results: Microvascular abnormalities were present in most DM patients. Of these, capillary density (4.71 vs. 6.84, p = 0.006) and mean apical diameter (56.09 vs. 27.79 µm, p = 0.003) significantly improved over the study period in concordance with improving disease control (MITAX 8.53 vs. 2.64, p = 0.002). Longitudinal analysis demonstrated that capillary density was independently associated with MITAX (ß = -1.49 [CI -2.49, -0.33], p = 0.013), but not other parameters such as C-reactive protein and creatinine kinase. Conclusions: Nailfold capillary density is a dynamic marker of global disease activity in adult DM. NVC may be utilized as a non-invasive point-of-care tool to monitor disease activity and inform treatment decisions in patients with DM.

Do COVID-19 Infections Result in a Different Form of Secondary Hemophagocytic Lymphohistiocytosis.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality across the world, with no current effective treatments available. Recent studies suggest the possibility of a cytokine storm associated with severe COVID-19, similar to the biochemical profile seen in hemophagocytic lymphohistiocytosis (HLH), raising the question of possible benefits that could be derived from targeted immunosuppression in severe COVID-19 patients. We reviewed the literature regarding the diagnosis and features of HLH, particularly secondary HLH, and aimed to identify gaps in the literature to truly clarify the existence of a COVID-19 associated HLH. Diagnostic criteria such as HScore or HLH-2004 may have suboptimal performance in identifying COVID-19 HLH-like presentations, and criteria such as soluble CD163, NK cell activity, or other novel biomarkers may be more useful in identifying this entity.

COVID-19, rheumatic diseases and immune dysregulation-a perspective.

The COVID-19 pandemic has resulted in widespread hospitalisations and deaths around the world. As patients with rheumatic diseases generally have increased risk of infections and complications, understandably, there is significant concern of the impact of SARS-CoV-2 on these patients. However, there is a paucity of data in rheumatic patients. We review mechanisms through which SARS-CoV-2 results in infection, including ACE2 receptor, and complications (including immune dysregulation, thrombosis and complement activation). We assess these pathways in patients with rheumatic disease and those on immune modulating therapy. Although data thus far does not appear to show worse outcomes in rheumatic patients as a whole, given alterations in the underlying immune pathways in certain diseases (such as systemic lupus erythematosus), we posit that the risk is not equal in all rheumatic patients. We also discuss the benefit of underlying disease control with respect to COVID-19 risk reduction and potential increased risk of disease flares following viral infection from an immune standpoint.

Development and Validation of SDBeasy Score as a Predictor of Behavioral Outcomes in Childhood.

Rationale: There are limited tools to identify which children are at greatest risk for developing sleep-disordered breathing (SDB)-associated behavioral morbidity.Objectives: To examine associations between age of onset and duration of parent-reported symptoms of SDB and behavioral problems at the age of 5 years.Methods: Data were collected and analyses were completed for participants in the CHILD (Canadian Healthy Infant Longitudinal Development) cohort at the Edmonton and Toronto sites. We generated an SDBeasy score on the basis of the age of onset and duration of SDB symptoms as reported by parents completing the Pediatric Sleep Questionnaire. Using CHILD-Edmonton data, we completed multivariate linear regression to determine whether the SDBeasy score was associated with behavioral problems at the age 5 years of age as assessed by using the Child Behavior Checklist (CBCL). We then validated the SDBeasy score using CHILD-Toronto data.Measurements and Main Results: At the 5-year visit, 581 of 716 (81%) CHILD-Edmonton participants still enrolled had CBCL data. Of the 581 children with data, 77% (446 of 581) had an SDBeasy score of 0 (never had SDB symptoms), whereas 20 of 581 children (3.4%) had persistent SDB symptoms from infancy through 5 years of age (SDBeasy score of 24). Children had a 0.35-point-higher CBCL total behavioral score at 5 years for each 1-point increase in their SDBeasy score (95% confidence interval, 0.24-0. 5; P < 0.01). We found consistent results among CHILD-Toronto participants; children had a 0.26-point-higher CBCL total behavioral score at 5 years for each 1-point increase in their SDBeasy score (95% confidence interval, 0.08-0.44; P = 0.005).Conclusions: The SDBeasy score, based on the Pediatric Sleep Questionnaire, enables identification of children with higher behavioral-problem scores.

Natural Killer Cell Dysfunction and Its Role in COVID-19.

When facing an acute viral infection, our immune systems need to function with finite precision to enable the elimination of the pathogen, whilst protecting our bodies from immune-related damage. In many instances however this "perfect balance" is not achieved, factors such as ageing, cancer, autoimmunity and cardiovascular disease all skew the immune response which is then further distorted by viral infection. In SARS-CoV-2, although the vast majority of COVID-19 cases are mild, as of 24 August 2020, over 800,000 people have died, many from the severe inflammatory cytokine release resulting in extreme clinical manifestations such as acute respiratory distress syndrome (ARDS) and hemophagocytic lymphohistiocytosis (HLH). Severe complications are more common in elderly patients and patients with cardiovascular diseases. Natural killer (NK) cells play a critical role in modulating the immune response and in both of these patient groups, NK cell effector functions are blunted. Preliminary studies in COVID-19 patients with severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells, and unchecked elevation of tissue-damaging inflammation markers. SARS-CoV-2 infection skews the immune response towards an overwhelmingly inflammatory phenotype. Restoration of NK cell effector functions has the potential to correct the delicate immune balance required to effectively overcome SARS-CoV-2 infection.

Shuni Virus in Wildlife and Nonequine Domestic Animals, South Africa.

We screened nonequine animals with unexplained neurologic signs or death in South Africa during 2010-2018 for Shuni virus (SHUV). SHUV was detected in 3.3% of wildlife, 1.1% of domestic, and 2.0% of avian species. Seropositivity was also demonstrated in wildlife. These results suggest a range of possible SHUV hosts in Africa.

The relationship between machine-learning-derived sleep parameters and behavior problems in 3- and 5-year-old children: results from the CHILD Cohort study.

STUDY OBJECTIVES: Machine learning (ML) may provide insights into the underlying sleep stages of accelerometer-assessed sleep duration. We examined associations between ML-sleep patterns and behavior problems among preschool children. METHODS: Children from the CHILD Cohort Edmonton site with actigraphy and behavior data at 3-years (n = 330) and 5-years (n = 304) were included. Parent-reported behavior problems were assessed by the Child Behavior Checklist. The Hidden Markov Model (HMM) classification method was used for ML analysis of the accelerometer sleep period. The average time each participant spent in each HMM-derived sleep state was expressed in hours per day. We analyzed associations between sleep and behavior problems stratified by children with and without sleep-disordered breathing (SDB). RESULTS: Four hidden sleep states were identified at 3 years and six hidden sleep states at 5 years using HMM. The first sleep state identified for both ages (HMM-0) had zero counts (no movement). The remaining hidden states were merged together (HMM-mov). Children spent an average of 8.2 ± 1.2 h/day in HMM-0 and 2.6 ± 0.8 h/day in HMM-mov at 3 years. At age 5, children spent an average of 8.2 ± 0.9 h/day in HMM-0 and 1.9 ± 0.7 h/day in HMM-mov. Among SDB children, each hour in HMM-0 was associated with 0.79-point reduced externalizing behavior problems (95% CI -1.4, -0.12; p < 0.05), and a 1.27-point lower internalizing behavior problems (95% CI -2.02, -0.53; p < 0.01). CONCLUSIONS: ML-sleep states were not associated with behavior problems in the general population of children. Children with SDB who had greater sleep duration without movement had lower behavioral problems. The ML-sleep states require validation with polysomnography.

V2-Directed Vaccine-like Antibodies from HIV-1 Infection Identify an Additional K169-Binding Light Chain Motif with Broad ADCC Activity.

Antibodies that bind residue K169 in the V2 region of the HIV-1 envelope correlated with reduced risk of infection in the RV144 vaccine trial but were restricted to two ED-motif-encoding light chain genes. Here, we identify an HIV-infected donor with high-titer V2 peptide-binding antibodies and isolate two antibody lineages (CAP228-16H/19F and CAP228-3D) that mediate potent antibody-dependent cell-mediated cytotoxicity (ADCC). Both lineages use the IGHV5-51 heavy chain germline gene, similar to the RV144 antibody CH58, but one lineage (CAP228-16H/19F) uses a light chain without the ED motif. A cocrystal structure of CAP228-16H bound to a V2 peptide identified a IGLV3-21 gene-encoded DDxD motif that is used to bind K169, with a mechanism that allows CAP228-16H to recognize more globally relevant V2 immunotypes. Overall, these data further our understanding of the development of cross-reactive, V2-binding, antiviral antibodies and effectively expand the human light chain repertoire able to respond to RV144-like immunogens.

Genomic and phylogenetic characterization of Shuni virus.

Shuni virus (SHUV), a member of the genus Orthobunyavirus, has in a recent study been associated with neurological disease in horses in South Africa. After its first isolation in 1966 from an asymptomatic bovine, very little attention was given to the genetic characterisation of SHUV. The association of SHUV with severe neurological disease in several horses in South Africa prompted us to determine the full genome sequence of a horse neurovirulent isolate to compare it to other members of the genus Orthobunyavirus, as well as the partially sequenced genome of the prototype SHUV strain. The availability of a full genome sequence will facilitate the development of a reverse genetics system to study SHUV molecular biology and pathogenesis.

Shuni virus as cause of neurologic disease in horses.

To determine which agents cause neurologic disease in horses, we conducted reverse transcription PCR on isolates from of a horse with encephalitis and 111 other horses with acute disease. Shuni virus was found in 7 horses, 5 of which had neurologic signs. Testing for lesser known viruses should be considered for horses with unexplained illness.