Current Evidence on Vaccinations in Pediatric and Adult Patients with Systemic Autoinflammatory Diseases.

Systemic autoinflammatory diseases (SAIDs) are defined by recurrent febrile attacks associated with protean manifestations involving joints, the gastrointestinal tract, skin, and the central nervous system, combined with elevated inflammatory markers, and are caused by a dysregulation of the innate immune system. From a clinical standpoint, the most known SAIDs are familial Mediterranean fever (FMF); cryopyrin-associated periodic syndrome (CAPS); mevalonate kinase deficiency (MKD); and periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome. Current guidelines recommend the regular sequential administration of vaccines for all individuals with SAIDs. However, these patients have a much lower vaccination coverage rates in 'real-world' epidemiological studies than the general population. The main purpose of this review was to evaluate the scientific evidence available on both the efficacy and safety of vaccines in patients with SAIDs. From this analysis, neither serious adverse effects nor poorer antibody responses have been observed after vaccination in patients with SAIDs on treatment with biologic agents. More specifically, no new-onset immune-mediated complications have been observed following immunizations. Post-vaccination acute flares were significantly less frequent in FMF patients treated with colchicine alone than in those treated with both colchicine and canakinumab. Conversely, a decreased risk of SARS-CoV-2 infection has been proved for patients with FMF after vaccination with the mRNA-based BNT162b2 vaccine. Canakinumab did not appear to affect the ability to produce antibodies against non-live vaccines in patients with CAPS, especially if administered with a time lag from the vaccination. On the other hand, our analysis has shown that immunization against Streptococcus pneumoniae, specifically with the pneumococcal polysaccharide vaccine, was associated with a higher incidence of adverse reactions in CAPS patients. In addition, disease flares might be elicited by vaccinations in children with MKD, though no adverse events have been noted despite concurrent treatment with either anakinra or canakinumab. PFAPA patients seem to be less responsive to measles, mumps, and rubella-vaccine, but have shown higher antibody response than healthy controls following vaccination against hepatitis A. In consideration of the clinical frailty of both children and adults with SAIDs, all vaccinations remain 'highly' recommended in this category of patients despite the paucity of data available.

Increased Referrals for New PFAPA (Aphthous Stomatitis, Pharyngitis, Adenitis) Diagnosis during the COVID-19 Pandemic

Background. COVID-19 pandemic caused by SARS-CoV-2 resulted in a global health crisis in 2020. Quarantining, wearing masks and physical distancing- key infection prevention strategies implemented to stop the spread of COVID-19, also led to dramatic decreases in rates of common respiratory viral infection seen in young children. Due to lack of school and daycare exposure, we evaluated a larger than usual number of patients with periodic fevers without any known infectious contacts. Based on this observation, we conducted an analysis of all suspected cases of periodic fevers seen at our institution during the COVID-19 lockdown compared to prior seasons. Methods. The clinical charts were queried for all patients presenting to any Lurie Children's Hospital outpatient specialty clinic or laboratory with ICD diagnosis code of MO4.1 and MO4.8 (all recurrent and periodic fever syndromes) from June 1, 2020 through September 30, 2020, and compared to similar months the previous 2 years (2018 and 2019). Each patient chart was reviewed by the lead investigator to verify all new diagnoses of PFAPA. The number of new patients with PFAPA diagnosis were tallied and analyzed. Statistical comparisons were made using Kruskal-Wallis tests for monthly distributions in different years. Results. We noted a significant increase in patients with new PFAPA diagnosis between June through August 2020 compared to similar months in 2018 and 2019 (Figure1). Experienced pediatric infectious disease physicians and rheumatologists diagnosed majority of the cases. During these months, a monthly median (IQR) of 13 (11.5, 14.5) patients were diagnosed among different Lurie specialty clinics, which is more than 2.5 folds increase in new PFAPA patients from the previous two years which were about 5 (3.5, 6) (Figure 2). Conclusion. We observed a significant increase in PFAPA patients referred to our institution soon after introduction of public health measures to slow spread of COVID-19. Given that most children were not in daycare, schools, or camps, we suspect that parents and pediatricians were able to recognize patterns of periodic fevers in children much quicker than preceding years, when fevers would typically be attributed to an infectious process.

Emotional distress as a trigger for PFAPA attacks

Introduction: There is scarce information regarding potential triggers for PFAPA attacks. Objectives: To examine whether an emotional stress serves as a trigger for these attacks. Methods: Active PFAPA Patients aged 3-12 years from two Israeli centers were enrolled. Patients parents were reached via phone call and asked about the occurrence of PFAPA attacks in the preceding 2 weeks of a 'stressful period' which was assumed to be (and later validated by an emotional distress scale questionnaire) within two weeks of returning to school after the first Israeli COVID-19 lockdown. Each patient served as its own control and parents were re-reached two weeks during summer break where COVID-19 outbreak was in remission (i.e. un-stressful period). The difference between occurrences of attacks during these 2 periods was recorded Results: One hundred and six pediatric patient were enrolled in the study. Mean age was 7.37± 2.9. The mean emotional distress questionnaire was higher in the first period compared to the second period (35.6± 8.1 versus 32.1± 7.7, respectively, P = 0.047). In the 'Stressful period' 41 (38.7%) reported at least 1 attack during the preceding 2 weeks compared to 24 (22.6%) in the 'unstresfull period' (p = 0.017). Conclusion: Here we provide first evidence that emotional stress may induce PFAPA attack.

Recurrent fever: An epidemic in a pandemic

Introduction: Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome is the most common periodic fever syndrome in children. It is a benign self-limiting multifactorial disorder with an estimated incidence of 2.3/10000 children up to 5 years of age. Year 2020 was dramatically affected by the Covid-19 pandemic, with a yet undefined impact on several aspects of child health. Objectives: To describe the demographic and clinical features of pediatric patients with recurrent febrile episodes referred to a single centre, with a focus on cases with onset in 2020. Methods: Patients referred to the Pediatric Immunology and Pediatric Rheumatology departments between 01/01/2015 and 01/ 05/2021 for recurrent fever without an infectious cause were included in the study. Demographic, clinical and laboratory features were retrospectively reviewed and compared between patients with fever onset before and after January 1st, 2020. For the classification of PFAPA, both the modified Marshall criteria and the Eurofever/ PRINTO criteria were used. Resolution of PFAPA was defined in presence of a 3-month fever-free interval. For statistical analysis, Mann-Whitney U test and Fisher's exact test were used as appropriate. Results: 84 patients were included;33 were female, 82 were white. Median age at onset was 3.7 years (IQR 2-4.6, range 0.3- 12.9). Median length of follow-up was 1.3 years (IQR 1.1-2.3, range 0.5-6.4 years). 57/84 (68%) patients met the modified Marshall criteria, 72/82 (88%) patients met the Eurofever/ PRINTO criteria for PFAPA. Thirty-nine patients had disease onset between 01/2015 and 12/19, while 45 patients in 2020. One patient with onset in 2015 and resolution in 2018, restarted presenting recurrent fever in January 2020. In 29 patients recurrent fever resolved during the follow-up, 39 in the 2015-2019 cohort and 10 in the 2020 cohort. Median follow-up since onset was 2.4 years in the 2015-2019 group and 1.1 years in the 2020 group. While median age at onset was not significantly different in the two groups (3.2 vs 3.8 years), in patients with onset in 2020 median time to referral was shorter (14.3 vs 7.5 months, p<0.0001) and recurrent fever episodes tended to resolve faster (median 2.3 vs 0.9 years, p<0.0001). Aphtous stomatitis and lymphadenitis appeared more common in patients with onset before 2020 (64% vs 32%, p=0.0062 and 84% vs 58, p=0.0322 respectively). Duration of fever episodes and intercritic interval, periodicity, prevalence of pharyngitis, abdominal pain and arthralgia were not significantly different between the two cohorts. (Table Presented) Conclusion: We observed an increase in referrals for recurrent fever with onset during 2020. Demographic and clinical features did not significantly differ between patients with onset in 2015-2019 and patients with onset in 2020, with the exception reduced occurrence of aphtous stomatitis and lymphadenitis, and faster referral and resolution for the latter. Whether an increase in parental attention and concern for fever episodes, or environmental factors, including SARSCoV- 2, contributed to the increase of referrals for recurrent fever still needs to be clarified.

Impact of the COVID-19 pandemic on the frequency of the pediatric rheumatic diseases

Introduction: Coronavirus disease (COVID-19) has brought many changes in our daily lives such as wearing masks, social distancing, and curfews. These implemented measures and restrictions have probably prevented some other infections. The impact of the COVID-19 pandemic, and implemented measures/ restrictions on the frequency of the pediatric rheumatic diseases remain unknown. Objectives: We aim to investigate the effect of COVID-19 on the frequency of the pediatric rheumatic diseases in our practice. Methods: We retrospectively reviewed the medical records of patients admitted to the pediatric rheumatology unit between February 2016 and March 2021. Patients were divided into five groups according to the year of diagnosis (February 2016 to February 2017;March 2017 to February 2018;March 2018 to February 2019;March 2019 to February 2020;and March 2020 to March 2021). The distribution of the patients who were newly diagnosed with a rheumatic disease in the pre-COVID- 19 period (February 2016-March 2020) and during the COVID-19 pandemic (March 2020-March 2021) was compared. Results: A total of 32,333 patients visited the pediatric rheumatology department between 2016 and 2021. The mean annual number of patients decreased by 42% during the COVID-19 pandemic (7060 patients/ year vs. 4090 patients/ year). 25,156 out of 32,333 admissions (77.8%) were recurrent visits. Among the 7177 patients who remained after the exclusion of repeated visits, 2728 patients got 2813 new diagnoses of rheumatic diseases. In the pre-pandemic period, the most frequently diagnosed rheumatic disease was familial Mediterranean fever (FMF) (n=695, 28.3%), whereas multisystem inflammatory syndrome in children (MIS-C) (n=68, 18.6%) was the most common diagnosis in the pandemic period. There were significant differences in the numbers of newly diagnosed cases with FMF, Behçet's disease, and IgA vasculitis (IgAV), chronic non-bacterial osteomyelitis (CNO), cutaneous vasculitis, primary central nervous system (CNS) vasculitis, and idiopathic orbital myositis. When we compared the frequencies during the 2019-2020 period with those in the pandemic period (2020-2021), there were significant decreases in the numbers of newly diagnosed patients with FMF (p=0.043), IgAV (p=0.001), primary CNS vasculitis (p=0.035), and idiopathic uveitis (p=0.015);while the number of newly diagnosed cases with CNO increased (p<0.001). Also, the numbers of newly diagnosed patients with juvenile idiopathic arthritis, PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) syndrome, acute rheumatic fever, and Kawasaki disease decreased remarkably in the pandemic period although these differences were not statistically significant. Conclusion: This study highlighted the decreased prevalence of some rheumatic diseases in the COVID-19 period. The potential decrease in infectious diseases due to pandemic restrictions could be affecting the diagnostic rates in pediatric rheumatology since infection is a trigger for some rheumatic diseases such as IgAV. Another reason could be the decrease in clinical visits of patients during the pandemic.

Familial mediterranean fever and COVID-19: A monocentric Italian study

Introduction: The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19). Its rapid spreading all over the world has caused a pandemia that has a deleterious impact on public health worldwide. The COVID-19 is associated with cytokines dysregulation, increased IL-1β tumor necrosis factor (TNF) and IL-6 release with hyperinflammation and risk of cytokine storm syndrome. Autoinflammatory diseases (AID) are rare, potentially life-threatening conditions caused by pathogenic gene variants encoding for inflammasomes leading to excessive production of pro-inflammatory cytokines. The innate immune system that plays a critical role in the pathogenesis of Familiar Mediterranean Fever (FMF) is also essential in antiviral defense. Colchicine is the main drug therapy for FMF and fulfills its role with the inhibition of microtubule polymerization and pyrin inflammasome. Colchicine effects on COVID-19 have not yet been evaluated in trials, but some studies on COVID-19 patients under colchicine treatment for FMF arouse interest. Anti-SARS-COV-2 vaccination is of key role for COVID-19 eradication worldwide, few data are available for AID patients. Objectives: This study aims to describe the COVID-19 impact on patients under regular treatment for AID and their outcome after anti- SARS-COV-2 vaccination. Methods: An observational monocentric study has been conduct on a cohort of Italian AID patients who were under regular follow up for their disorders. Data have been collected both retrospectively and prospectively. Results: Seventy-eight adult AID patients (65 FMF, 5 PFAPA, 3 FCAS, 2 TRAPS, 2 Behcet Disease, 1 SAPHO,) followed at Center for Primary Immunodeficiency and Autoinflammatory disorders have been considered. Among FMF patients, eight communicated to the center when they got COVID-19 and were followed by regular phone calls. The mean age was 36.9 years, (range 27-60) and they had no other comorbidities. All the patients were on regular colchicine therapy and were on complete remission before COVID-19. They were started with azithromycin (with precaution for colchicine interference) and four were treated also with low-weight heparin prophylaxis. None of the patients need oxygen or hospitalization. Two sisters (MEFV genotype M694V/V726A) had FMF attack relapsing during COVID-19 disease, despite regular colchicine therapy. All the cases recovered from COVID-19 without complications. None of the other AID patients declared to have COVID-19, and all the swabs, that they did when they had symptoms suspected for, were negative. Genetics of FMF patients' with COVID-19 - 2 M694V/V726A - 2 M694V Pediatric Rheumatology 2021, 19(Suppl 1):155 Page 205 of 229 - 1 M694V/M694V - 1 M680IGC/E148Q - 1 R761H/E148Q - 1 -/- Till now 31 AID patients have been vaccinated (22 FMF, 4 PFAPA, 3 FCAS, 2 Behcet disease). No adverse reactions were observed. All the patients who had COVID-19 have been vaccinated (Pfizer/ Biontech or Moderna), two had FMF attack. Two patients with PFAPA had a mild attack. Post-vaccination titre was checked after 4 week since 2nd dose for those patients who were under anti-IL inhibitors (n=5) or anti-TNF (n=1). Conclusion: In this study, the FMF patients who had COVID-19 under chronic colchicine treatment had a mild/moderate disease and recovered without consequences. According to other studies, FMF under colchicine treatment seems not to be a risk factor for severe COVID-19 and colchicine anti-inflammatory effect worths to be considered for treatment in COVID-19. Anti-SARS-COV-2 vaccination in AID patients of this study has been observed to be safe and effective.