Changes in Kawasaki disease incidence and phenotype during the COVID-19 pandemic

INTRODUCTION. The aetiology of Kawasaki disease (KD) remains unknown. Changes in infectious exposure during the COVID-19 pandemic owing to infection prevention measures may have affected the incidence of KD, supporting the pathogenic role of an infectious trigger. The purpose of this study was to evaluate the incidence, phenotype and outcome of KD before and during the COVID-19 pandemic in Denmark. METHODS. This was a retrospective cohort study based on patients diagnosed with KD at a Danish paediatric tertiary referral centre from 1 January 2008 to 1 September 2021. RESULTS. A total of 74 patients met the KD criteria of whom ten were observed during the COVID-19 pandemic in Denmark. Alof these patients were negative for SARS-CoV-2 DNA and antibodies. A high KD incidence was observed during the first six months of the pandemic, but no patients were diagnosed during the following 12 months. Clinical KD criteria were equally met in both groups. The fraction of intravenous immunoglobulin (IVIG) non-responders was higher in the pandemic group (60%) than in the in the pre-pandemic group (28.3%), although the rate of timely administered IVIG treatment was the same in both groups (>= 80%). Coronary artery dilation was observed in 21.9% in the pre-pandemic group compared with 0% in KD patients diagnosed during the pandemic. CONCLUSION. Changes in KD incidence and phenotype were seen during the COVID-19 pandemic. Patients diagnosed with KD during the pandemic had complete KD, higher liver transaminases and significant IVIG resistance but no coronary artery involvement.Copyright © 2023, Almindelige Danske Laegeforening. All rights reserved.

PPP1R13L-Related Cardiomyopathy Stability Following IL1 Inhibition

Introduction: Variants in PPP1R13L are associated with severe childhood-onset cardiomyopathy resulting in rapid progression to death or cardiac transplantation. PPP1R13L is proposed to encode a protein that limits the transcriptional activity of the NFkappaB pathway leading to elevated IL-1, IL-6, and TNF-alpha production in murine models. Optimal medical management for PPP1R13L-related cardiomyopathy is unknown. Here we report usage of a targeted anti-IL-1 immuno-modulatory therapy resulting in cardiac stabilization in a pediatric patient with congenital cardiomyopathy secondary to PPP1R13L variants. Case Report: A 4-year-old boy presented acutely with fever in the setting of persistent abdominal pain, vomiting, fatigue, and decreased appetite for two months following a mild COVID-19 related illness. Echocardiogram revealed severely depressed biventricular systolic function with an ejection fraction of 30%. Due to acute decompensated heart failure symptoms with hemodynamic instability, he was intubated and placed on continuous inotropic infusions with aggressive diuresis. Cardiac MRI demonstrated extensive subepicardial to near transmural fibrosis by late gadolinium enhancement in right and left ventricles. An implantable cardioverter-defibrillator (ICD) was placed due to frequent runs of polymorphic non-sustained ventricular tachycardia. Testing for viral pathogens was positive for rhino/enterovirus. Initial genetic testing was non-diagnostic (82-gene cardiomyopathy panel) but given the patient's significant presentation whole genome sequencing was pursued that showed two separate PPP1R13L variants in trans (c.2167A>C,p.T723P and c.2179_2183del,p. G727Hfs*25, NM_006663.4). Patient serum cytokine testing revealed elevations in IL-10 (4.7 pg/mL) and IL-1beta (20.9 pg/mL). Given the patient's tenuous circumstances and concern for continued progression of his cardiac disease, a trial of IL-1 inhibition via anakinra dosed at 3 mg/kg or 45 mg daily was initiated following hospital discharge. With approximately 6 months of therapy, the patient's cardiac function is stable with normalization of IL-10 and IL-1beta serum levels. Notably, the ventricular arrhythmia decreased after initiation of anakinra with no ICD shocks given. Therapy overall has been well tolerated without infectious concerns. Conclusion(s): In patients with PPP1R13L-related cardiomyopathy, immuno-modulatory therapies should be considered in an attempt to slow cardiac disease progression.Copyright © 2023 Elsevier Inc.

Tocilizumab versus anakinra in COVID-19: results from propensity score matching.

Background: Tocilizumab and anakinra are anti-interleukin drugs to treat severe coronavirus disease 2019 (COVID-19) refractory to corticosteroids. However, no studies compared the efficacy of tocilizumab versus anakinra to guide the choice of the therapy in clinical practice. We aimed to compare the outcomes of COVID-19 patients treated with tocilizumab or anakinra. Methods: Our retrospective study was conducted in three French university hospitals between February 2021 and February 2022 and included all the consecutive hospitalized patients with a laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection assessed by RT-PCR who were treated with tocilizumab or anakinra. A propensity score matching was performed to minimize confounding effects due to the non-random allocation. Results: Among 235 patients (mean age, 72 years; 60.9% of male patients), the 28-day mortality (29.4% vs. 31.2%, p = 0.76), the in-hospital mortality (31.7% vs. 33.0%, p = 0.83), the high-flow oxygen requirement (17.5% vs. 18.3%, p = 0.86), the intensive care unit admission rate (30.8% vs. 22.2%, p = 0.30), and the mechanical ventilation rate (15.4% vs. 11.1%, p = 0.50) were similar in patients receiving tocilizumab and those receiving anakinra. After propensity score matching, the 28-day mortality (29.1% vs. 30.4%, p = 1) and the rate of high-flow oxygen requirement (10.1% vs. 21.5%, p = 0.081) did not differ between patients receiving tocilizumab or anakinra. Secondary infection rates were similar between the tocilizumab and anakinra groups (6.3% vs. 9.2%, p = 0.44). Conclusion: Our study showed comparable efficacy and safety profiles of tocilizumab and anakinra to treat severe COVID-19.

An Evaluation of the Causes and Outcomes of Haemophagocytic Lymphohistiocytosis in Sheffield Teaching Hospitals: 2016 to 2021

Background/Aims Haemophagocytic lymphiohistiocytosis (HLH) is a rare, underrecognised hyperinflammatory syndrome, characterised by immune dysregulation. Without treatment, the ensuing cytokine storm leads to high mortality. Secondary HLH (sHLH) is triggered by malignancy, infection, autoimmunity and medicines;treatment with immunosuppression is consensus- rather than evidence-based and extrapolated from primary HLH. Sheffield hosts a mature HLH multidisciplinary advisory group (MDAG). Here we evaluate the cause, treatment, requirement for critical care and mortality of people with HLH managed through the MDAG in a period including the coronavirus pandemic but prior to NHS England approval of anakinra (IL-1 antagonist) for HLH. Methods This retrospective evaluation (approved locally STH 10850) identified patients from MDAG records 1st October 2016 to 30th September 2021. Data from electronic/paper records was analysed using Microsoft Excel. Results HLH triggers were infection (viral 34%, bacterial 10%), haematological (35%), rheumatological (13%) and other (8%). Rheumatological causes were Still's disease (n=5);antiphospholipid syndrome (n=2);JO1 dermatomyositis (n=1);SLE (n=1);and rheumatoid arthritis (n=1). Other causes included unknown (n=3);combined systemic JIA and sickle cell crisis (n=1);medication (alemtuzumab) (n=1);and primary HLH (n=1). Overall mortality was 53% and highest in HLH with a haematological malignancy trigger (82%) Prior to the COVID19 pandemic (pre-March 2020), the commonest trigger of HLH was haematological malignancy (47%);after March 2020, the commonest trigger was infection (64%);COVID-19 explained 42% of cases. Mortality fell from 72% to 31%. Conclusion In this real-world series of people with HLH, mortality and critical care requirement was high. HLH triggers reflect published evidence as does poor prognosis in haematological malignancy-associated HLH. No-HLH associated with non-haematological malignancy was identified;we may need to improve MDAG reach into oncology. Seeming reduction in mortality following the COVID-19 pandemic may reflect increased recognition of COVID-19 induced hyperinflammation along with locallyagreed access to anakinra for COVID-19-induced HLH. The increase in infection related HLH cases since March 2020 is explained largely by COVID-19 cases. This has led to a relative reduction in cases related to haematological malignancy. HLH requires multidisciplinary management and better research to improve treatment. (Table Presented).

Clinical efficacy and safety of interleukin-1 blockade in the treatment of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: This study evaluated the clinical efficacy and safety of interleukin-1 (IL-1) blockade for patients with COVID-19. METHODS: The PubMed, Web of Science, Ovid Medline, Embase and Cochrane Library databases were searched for relevant articles from their inception to 25 September 2022. Only randomized clinical trials (RCTs) that assessed the clinical efficacy and safety of IL-1 blockade in the treatment of patients with COVID-19 were included. RESULTS: This meta-analysis included seven RCTs. No significant difference in the all-cause mortality rate of patients with COVID-19 was observed between the IL-1 blockade and control groups (7.7 vs. 10.5%, odds ratio [OR] = 0.83, 95% confidence interval [CI] 0.57-1.22; I2 = 18%). However, the study group was at significantly lower risk of requiring mechanical ventilation (MV) compared with the control group (OR = 0.53, 95% CI 0.32-0.86; I2 = 24%). Finally, the risk of adverse events was similar between the two groups. CONCLUSIONS: IL-1 blockade does not provide increased survival benefits in hospitalized patients with COVID-19, but it may reduce the need for MV. Furthermore, it is a safe agent for use in the treatment of COVID-19.>.

This systematic review and meta-analysis of randomized clinical trials (RCTs) evaluated the clinical efficacy and safety of interleukin-1 (IL-1) blockade for patients with COVID-19.Based on the analysis of six RCTs, no significant difference in the all-cause mortality rate of patients with COVID-19 was observed between the IL-1 blockade and control groups.The study group using IL1 was associated with a significantly lower risk of requiring mechanical ventilation compared with the control group.The risk of adverse events was similar between the study and the control groups.

High Dose Ivig in Multisystem Inflammatory Syndrome in Children and Response to Treatment

Purpose of Study: In February 2022, the American College of Rheumatology (ACR) updated its guidance for multisystem inflammatory syndrome in children (MIS-C). The treatment recommendation is to use intravenous immunoglobulin (IVIG) at 2 grams/kg with a maximum dose of 100 grams based on a moderate level of consensus among the task force members. To date, there are no studies comparing the response to doses of more than 100 grams in MIS-C. Methods Used: A retrospective review was conducted of patients admitted to Loma Linda University Children's Hospital for MIS-C from May 2020 to March 2021. Demographic, symptom, laboratory, and treatment data were systematically collected from the electronic medical record. The PRISM III score was calculated for all patients admitted to the PICU and used to control for severity of illness. Patients were designated non-responders if anakinra, or a second IVIG dose was given. A binomial logistic regression was used to model response to the IVIG dose in univariate and multivariate analysis with and without the PRISM III score and PICU length of stay. A Fisher's exact test was used to compare categorical variables. Summary of Results: There were 77 children treated for MIS-C. The median age was 118.5 months with a range of 3 to 254 months. There was a total of 30 patients who initially received at least 100 grams of IVIG of which 20 were in the PICU. All patients given at least 100 grams of IVIG received steroids concurrently. A univariate binomial regression using IVIG dose for patients admitted to the PICU showed an odds ratio of non-response was 0.98 (CI 0.94 - 1.02). The analysis is the same for all patients who received greater than 100 grams of IVIG. In a multivariate binomial regression, which included the PRISM III score, length of PICU stay and days of symptoms prior to admission, the odds ratio of non-response to IVIG was 0.98 (CI 0.92 - 1.03). Of the 10 patients who were not admitted to the PICU, only 1 failed to respond to IVIG and required anakinra. None of the patients who received more than 100 grams of IVIG were tested for hemolytic anemia but only 1 patient who received more than 1 dose of IVIG had a decline in hemoglobin. There was a median decline of 2.75 g/dL (range 1.6 - 6.7 g/dL) in all patients who had a decline in hemoglobin and received more than 100 grams of IVIG. Conclusion(s): In this single center cohort of patients who were admitted to the PICU for MIS-C who received more than 100 grams of IVIG initially, there was no relationship between higher doses of IVIG and halting inflammation. This study agrees with the ACR guidance regarding the dose of IVIG in MIS-C and adds evidence to give no more than 100 grams of IVIG.

Complications Of A Severe Case Of Multisystem Inflammatory Syndrome In Children

Case Presentation: A 10 year old male with prior COVID-19 exposure presented with 7 days of fever, rash, cough, vomiting, and hypotension. Laboratory evaluation was notable for SARS-CoV2 antibodies, elevated cardiac enzymes, BNP, and inflammatory markers. Initial echocardiogram showed normal cardiac function and a small LAD coronary aneurysm. He was diagnosed with Multisystemic Inflammatory Syndrome in Children (MIS-C) and given methylprednisolone and IVIG. Within 24 hours, he developed severe LV dysfunction and progressive cardiorespiratory failure requiring VA-ECMO cannulation and anticoagulation with bivalirudin. Cardiac biopsy demonstrated lymphocytic infiltration consistent with myocarditis. On VA-ECMO, he had transient periods of complete AV block. With immunomodulator treatment (anakinra, infliximab) and 5 days of plasmapheresis, inflammatory symptoms and cardiac function improved. He weaned off ECMO, and anticoagulation was transitioned to enoxaparin. He had left sided weakness 5 days later, and brain MRI revealed an MCA infarct. Ten days later, he had focal right sided weakness and repeat MRI showed multiple hemorrhagic cortical lesions, thought to be thromboembolic with hemorrhagic conversion secondary to an exaggerated inflammatory response to an MSSA bacteremia in the setting of MIS-C. Enoxaparin was discontinued. After continued recovery and a slow anakinra and steroid wean, he has normal coronary arteries, cardiac function, and baseline ECG but requires ongoing neurorehabilitation. Discussion(s): COVID-19 infection in children is often mild, but MIS-C is an evolving entity that can present with a wide range of features and severity. This case highlights two concepts. While first degree AV block is often reported in MIS-C, there is potential for progression to advanced AV block. Close telemetry monitoring is critical, especially if there is evidence of myocarditis. MIS-C shares features with Kawasaki disease, with a notable difference being a higher likelihood of shock and cardiac dysfunction in MIS-C. In MIS-C patients with cardiovascular collapse requiring ECMO, there is a risk for stroke. There should be a low threshold for neuroimaging and multidisciplinary effort to guide anticoagulation in these complex cases.

A new score to predict severe respiratory failure and guide anakinra treatment in COVID-19 pneumonia: analysis of the randomized SAVE-MORE trial

Introduction: Anakinra treatment is approved for the treatment of COVID-19 pneumonia in hospitalized adults in need of oxygen and at risk for progression into severe respiratory failure (SRF) defined as circulating concentrations of the biomarker suPAR (soluble urokinase plasminogen activator receptor) >= 6 ng/mL by the EMA and has been authorized for emergency use by FDA under an EUA [1]. This is based on the results of the randomized SAVE-MORE trial where suPAR >= 6 ng/ mL was used to select patients at risk for SRF [2]. The suPAR test is not commercially available in the USA and an alternative method of patient selection was needed. Method(s): In collaboration with the US FDA, an alternative method to select patients most likely to have suPAR >= 6 ng/mL based on commonly measured patient characteristics was developed. Patients with at least 3 of the following criteria are considered likely to have suPAR >= 6 ng/ ml: age >= 75 years, severe pneumonia by WHO criteria, current/previous smoking status, Sequential Organ Failure Assessment score >= 3, neutrophil-to-lymphocyte ratio >= 7, hemoglobin <= 10.5 g/dl, history of ischemic stroke, blood urea >= 50 mg/dl and/or history of renal disease. Result(s): The positive predictive value of this new score was 95.4% in SAVE-MORE population. However, a lower sensitivity meant a small proportion of patients with suPAR >= 6 ng/ml will not be identified by the new score. The adjusted hazard ratio for survival at 60 days for patients meeting this score and who receive anakinra is 0.45 (Fig. 1). Conclusion(s): The developed score predicts accurately patients with suPAR levels >= 6 ng/mL and may be used as an alternative to guide anakinra treatment in patients with COVID-19 pneumonia. Based on these subgroup results, patients in SAVE-MORE who met the new score appeared to show beneficial efficacy results with treatment of anakinra consistent with the overall studied population.

Epidemiologic Characteristics of Multisystem Inflammatory Syndrome in Children (Mis-C) with a Focus on Outcomes

Purpose of Study Treatment outcomes of children diagnosed with MIS-C are unclear and warrant investigation. The purpose of this study is to investigate the characteristics of pediatric patients diagnosed with MIS-C and their treatment outcomes with an emphasis on fatalities associated with MISC. Methods Used A literature review using Google Scholar and Pubmed using keywords such as 'Multisystem Inflammatory Syndrome in Children', 'Pediatric Inflammatory Multisystem Syndrome', and 'Coronavirus Disease 2019' was conducted. We included studies of hospitalized MIS-C patients with a sample size of more than 15. Summary of Results Of ten studies published before August 2020, five reported hospitalized MIS-C cases in the United States and five in Europe. A total of 514 hospitalized patients were reported with a sample size of 15 to 186 in various studies. Of 514 patients, 431 (84%) tested positive for SARS-CoV-2 via RT-PCR or serology. In different studies, 50% to 100% of MIS-C patients required PICU admission, 10% to 54% were intubated, and up to 80% required vasopressors. In studies that reported echocardiogram results, coronary artery dilations or aneurysm were noted in up to 93%, and depressed cardiac function was reported in 51- 100% of MIS-C patients. Treatment of MIS-C patients included intravenous immunoglobulins (IVIG) 388/514 (75%) plus steroids 288/514 (56%), along with anticoagulants and Anakinra 26/514 (5%). In total, 23 patients were put on ECMO, and of those, 16 (70%) survived. The larger studies reported fatality rate of 2% to 3% in hospitalized MIS-C patients. A total of 10 deaths were reported. Of the fatality causes that were described, 3 were associated with cerebral infarction after ECMO, 2 had not received IVIG, systemic glucocorticoids, or immunomodulators, and another 2 had co-morbidities. Conclusions Our review suggests that children with MIS-C who are hospitalized typically have a severe disease course. The outcome in vast majority of patients is favorable but death can occur, most likely as a result of cardiac dysfunction or cerebral infarction. Larger studies are needed to identify clinical features as well as laboratory and diagnostic parameters that predict disease severity and outcome.

A Multicenter Study of Covid-19 Infection in Pediatric Intensive Care Units in the Us

Background: To describe characteristics of COVID-19 infection among patients requiring admission to pediatric intensive care units (PICU) in the USA. Method(s): Observational surveillance study of COVID-19 infected patients admitted to PICUs in 27 US states between April 1, 2020 - May 1, 2021. Result(s): Four hundred fifty-three patients were included;the majority were from institutions in the South and Midwest regions (40% and 34%). The population was mainly male (57%) and Hispanic (36%), with a median age of 10 years (IQR 4-15). 76% had 1 or more comorbidity. Patient's or caregiver's reported sources for COVID-19 infection were household and community contacts (31% and 24%). One hundred sixty-seven (40%) individuals were diagnosed with the multisystem inflammatory syndrome in children (MISC) within 7 days of PICU admission. Compared to COVID-19 cases without MISC, gastrointestinal, mucocutaneous, and neurological signs and symptoms were more frequent at PICU admission. Nasal cannula (20%) and high-flow oxygen (12.4%) were the most common respiratory support strategies at day 1 of admission, and mechanical ventilation by day 7. Overall, 104 (23%) and 8 (1.8%) individuals were placed on mechanical ventilation and extracorporeal membrane oxygenation (ECMO) within the interval of observation. Steroids and remdesivir were the most delivered COVID-19 targeted therapies (60% and 33%), and only 3% of the patients received convalescent plasma;IVIG (86.8%) and anakinra (61%) were commonly used among individuals with MISC. The overall mortality proportion (MP) was 2.65 (n= 12), and mortality was more frequent among individuals > 2 years old. Of the 167 children with MISC, only 1 died, MP (0.6). Conclusion(s): Mortality associated with pediatric COVID-19 infection is less frequent than in critically ill COVID-19-infected adults. Among pediatric/ adolescent patients, children > 2 years are the most vulnerable to adverse COVID-19-associated outcomes. MISC cases were frequent, yet mortality was low.

Atrio-Ventricular Conduction Abnormalities in Multisystem Inflammatory Syndrome in Children

Purpose of study Since mid-April 2020 in Europe and North America, clusters of pediatric cases with a newly described severe systemic inflammatory response with shock have appeared. Patients had persistent fevers >38.5 C, hypotension, features of myocardial dysfunction, coagulopathy, gastrointestinal symptoms, rash, and elevated inflammatory markers without other causes of infection. The World Health Organization, Centers for Disease Control, and Royal College of Paediatrics associated these symptoms with SARS-CoV-2 as multisystem inflammatory syndrome in children (MIS-C). Cardiac manifestations include coronary artery aneurysms, left ventricular systolic dysfunction evidenced by elevation of troponin-T (TnT) and pro-B-type naturietic peptide (proBNP), and electrocardiogram (ECG) abnormalities. We report the clinical course of three children with MIS-C while focusing on the unique atrioventricular (AV) conduction abnormalities. Case #1:19-year-old previously healthy Hispanic male presented with abdominal pain, fever, and non-bloody diarrhea for three days. He was febrile and hypotensive (80/47 mmHg) requiring fluid resuscitation. Symptoms, lab findings, and a positive COVID-19 antibody test were consistent with MIS-C. Methylprednisolone, intravenous immunoglobulin (IVIG), and enoxaparin were started. He required epinephrine for shock and high flow nasal cannula for respiratory distress. Initial echocardiogram demonstrated a left ventricular ejection fraction (LVEF) of 40% with normal appearing coronaries. Troponin and proBNP were 0.41 ng/mL and proBNP 15,301 pg/mL respectively. ECG showed an incomplete right bundle branch block. He eventually became bradycardic to the 30s-50s and cardiac tracing revealed a complete AV block (figure 1a). Isoproterenol, a B1 receptor agonist, supported the severe bradycardia until the patient progressed to a type 2 second degree AV block (figure 1b). A second dose of IVIG was administered improving the rhythm to a type 1 second degree AV block. An IL-6 inhibitor, tocilizumab was given as the rhythm would not improve, and the patient soon converted to a first-degree AV block. Cardiac magnetic resonance imaging showed septal predominant left ventricular hypertrophy and subepicardial enhancement along the basal inferior/anteroseptal walls typical for myocarditis. Case #2: 9-year-old previously healthy Hispanic male presented after three days of daily fevers, headaches, myalgias, diffuse abdominal pain, and ageusia. He was febrile, tachycardic, and hypotensive (68/39 mmHg). Hypotension of 50s/20s mmHg required 3 normal saline boluses of 20 ml/kg and initiation of an epinephrine drip. Severe hypoxia required endotracheal intubation. After the MIS-C diagnosis was made, he was treated with IVIG, mehtylprednisolone, enoxaparin, aspirin, and ceftriaxone. Due to elevated inflammatory markers by day 4 and patient's illness severity, a 7-day course of anakinra was initiated. Initial echocardiogram showed mild tricuspid and mitral regurgitation with a LVEF of 35-40%. Despite anti-inflammatory therapy, troponin and proBNP were 0.33 ng/mL and BNP of 25,335 pg/mL. A second echocardiogram confirmed poor function so milrinone was started. Only, after two doses of anakinra, LVEF soon normalized. Despite that, he progressively became bradycardic to the 50's. QTc was prolonged to 545 ms and worsened to a max of 592 ms. The aforementioned therapies were continued, and the bradycardia and QTc improved to 405 ms. Patient #3: 9-year-old African American male presented with four days of right sided abdominal pain, constipation, and non-bilious non-bloody emesis. He had a negative COVID test and unremarkable ultrasound of the appendix days prior. His history, elevated inflammatory markers, and positive COVID- 19 antibody were indicative of MIS-C. He was started on the appropriate medication regimen. Initial ECG showed sinus rhythm with normal intervals and echocardiogram was unremarkable. Repeat imaging by day three showed a decreased LVEF of 50%. ECG had since changed to a right bundle branch block. Anakinra as started and steroid dosing was increased. By day 5, he became bradycardic to the 50s and progressed to a junctional cardiac rhythm. Cardiac function normalized by day 7, and anakinra was subsequently stopped. Thereafter, heart rates ranged from 38-48 bpm requiring transfer to the pediatric cardiac intensive care unit for better monitoring and potential isoproterenol infusion. He remained well perfused, with continued medical management, heart rates improved. Methods used Retrospective Chart Review. Summary of results Non-specific T-wave, ST segment changes, and premature atrial or ventricular beats are the most often noted ECG anomalies. All patients initially had normal ECGs but developed bradycardia followed by either PR prolongation or QTc elongation. Two had mild LVEF dysfunction prior to developing third degree heart block and/or a junctional escape rhythm;one had moderate LVEF dysfunction that normalized before developing a prolonged QTc. Inflammatory and cardiac markers along with coagulation factors were the highest early in disease course, peak BNP occurred at approximately hospital day 3-4, and patient's typically had their lowest LVEF at day 5-6. Initial ECGs were benign with PR intervals below 200 milliseconds (ms). Collectively the length of time from initial symptom presentation till when ECG abnormalities began tended to be at day 8-9. Patients similarly developed increased QTc intervals later in the hospitalization. When comparing with the CRP and BNP trends, it appeared that the ECG changes (including PR and QTc elongation) occurred after the initial hyperinflammatory response. Conclusions Although the mechanism for COVID-19 induced heart block continues to be studied, it is suspected to be secondary to inflammation and edema of the conduction tissue. Insufficiency of the coronary arterial supply to the AV node and rest of the conduction system also seems to play a role. Although our patients had normal ECG findings, two developed bundle branch blocks prior to more complex rhythms near the peak of inflammatory marker values. Based on the premise that MIS-C is a hyperinflammatory response likely affecting conduction tissue, our group was treated with different regimens of IVIG, steroids, anakinra, and/or tocilizumab. Anakinra, being an IL-1 inhibitor, has been reported to dampen inflammation in viral myocarditis and tocilizumab has improved LVEF in rheumatoid arthritis patients. Based on our small case series, patient's with MISC can have AV nodal conduction abnormalities. The usual cocktail of IVIG and steroids helps;however, when there are more serious cases of cardiac inflammation, adjuvant immunosuppresants like anakinra and toculizumab can be beneficial. (Figure Presented).

Evaluation of the effects of anakinra treatment on clinic and laboratory results in patients with COVID-19.

OBJECTIVE: Some anti-cytokine treatments are being used to control the hyperinflammatory condition defined as cytokine storm that develops during COVID-19 infection. In this study, we aim to investigate the effects of anakinra, an IL-1 antagonist, on the clinical status and laboratory values of hospitalized patients with the COVID-19 infection. The aim of the study was to investigate the effects of anakinra, an IL-1 antagonist, on the clinical and laboratory results of hospitalized patients with COVID-19 infection. METHODS: This study was planned as a retrospective study. The age, gender, and current comorbidities of a total of 66 patients who were treated with anakinra for COVID-19 infection from November 2020 to January 2021 were analyzed. The amount of oxygen demand (L/s), the type of oxygen supplementation, oxygen saturation, radiological findings, WBC count, lymphocyte count, neutrophil count, C-reactive protein, LDH, ferritin, fibrinogen, D-dimer levels were monitored before the treatment, and after the anakinra treatment, newly gathered results were compared. Patients' hospitalization period, oxygen need, and their clinical status at discharge were evaluated. The effects of early anakinra treatment (9 days before and after the onset of symptoms) on the prognosis were evaluated. SPSS version 21.0 provided by IBM Company in the USA, Chicago, IL was used for statistical analysis and p<0.05 was considered significant. RESULTS: Sixty-six patients were included in the study. There was no significant gender difference in the prognosis of the patients. There was a significant difference in the statistical deterioration in patients with comorbidities (p=0.004). Patients who started the anakinra treatment at an early stage developed less need for intensive care and low mortality ratios (p=0.019). There were significant improvements on the levels of WBC (p=0.045), neutrophils (p=0.016), lymphocyte (p=0.001), LDH (p=0.005), ferritin (p=0.02), and fibrinogen (p=0.01) after the administration of anakinra therapy. CONCLUSION: We found that earlier and appropriate use of anakinra therapy in COVID-19 patients with the signs of macrophage activation syndrome reduces the need for oxygen support in patients and contributes to improvement in laboratory results and radiological findings, and most importantly reduces the need for intensive care.

Anakinra as a potential treatment for COVID-19.

On November 8, 2022, the United States Food and Drug Administration (FDA) issued an emergency use authorization for the interleukin-1 (IL-1) inhibitor anakinra for the treatment of patients with COVID-19 pneumonia. The authorization was specifically intended for patients requiring supplemental oxygen who are at risk of progression to respiratory failure and are likely to have an elevated plasma soluble urokinase plasminogen activator receptor. Anakinra is a modified, recombinant human IL-1 receptor antagonist used to treat rheumatoid arthritis, neonatal-onset multisystem inflammatory disease and other inflammatory diseases. This manuscript examines what is known about the role of IL-1 receptor antagonism in the treatment of patients with COVID-19 and examines how anakinra may be used in the future to address the SARS-CoV-2 infection pandemic.

The Role of Monoclonal Antibodies in Contrasting Cases of Norse

1. A 42-year-old female developed status ten days following admission for alcohol-related liver disease. MRI brain showed symmetrical medial temporal high signal. No cause was identified. Though the convulsive seizures settled, focal seizures persisted. A second MRI showed extensive multi-lobar signal change, presumed inflammatory in nature. Pulsed methylprednisolone and plasma exchange were ineffective. Tocilizumab was administered ten weeks following onset of seizures. Sequential MRIs showed resolution of inflammatory changes. The patient was discharged to rehabilitation-Modified Rankin Score 3. 2. A 79-year-old female presented with convulsive NORSE, 24hours after first dose of Pfizer COVID vaccine. She had a background of vascular dementia. The patient never recovered her GCS. Convulsive seizures were replaced by epilepsy partialis continua. Sequential MRIs showed diffuse left parietal cortical high signal. An inflammatory aetiology was presumed, pulsed methylprednisolone and the ketogenic diet (3 months) were ineffective. Anakinra was administered on week twelve. Subsequent MRIs showed progression of confluent white matter disease, now bi-hemispheric. She remains symptomatic, a year post presentation. We hypothesise that both patients had NORSE arising from an unidentified inflammatory aetiology. Age and premorbid function are known to influence recovery. Early use of monoclonal antibodies may be beneficial, including in those with systemic disease.

Immunological examination of patients with rheumatological involvement after Covid-19 infection

Background: The emergence of autoinflammatory/autoimmune disorders in COVID-19 patients has necessitated the development of new strategies for the management of these phenomena. Several viruses have been shown to cause autoimmunity by boosting the production of autoreactive lymphocytes, resulting in a lack of tolerance in the host's immune response. The SARS-CoV- 2 virus and/or its proteins can cause autoimmunity by molecular mimicry, superantigen activity, and disruption of type I IFN production. Method(s): The data of three patients who applied to the outpatient clinics of pediatric immunology and rheumatology at Uludag University Hospital between March 2020 and December 2021 and were followed up with autoimmune/autoinflammatory disease following CCovid-19- 19 infection were analyzed retrospectively. Result(s): All patients were female and aged between 2-17 years. They had SARS-COV- 2 infection which was mild a few months ago. Before the Covid-19 infection, all of the patients were in good health. The patients had no history of frequent infections or familial predisposition to rheumatic diseases. Following the Covid-19- infection, all of our patients showed fever, rash, joint discomfort, and muscle soreness. Despite the fact that myalgia affects the whole body, arthralgia was present on the wrists and knees of patients. CRP, sedimentation rate, and acute phase reactants increased in all of them. According to the American College of Rheumatology's diagnostic criteria, our first patient was diagnosed with systemic lupus erythematosus (SLE) and was treated with hydroxychloroquine, intravenous immunoglobulin treatment and anakinra. Two of three were diagnosed with systemic juvenile idiopathic arthritis (sJIA) according to the League of Associations for Rheumatology (ILAR) criteria. Only one patient had low IgG and IgA levels (Table 1). Two patients showed a decrease in CD19+ naive cells percent and numbers. Conclusion(s): Following SARS-CoV- 2 infection, autoimmune and autoinflammatory disorders such as rheumatoid arthritis, psoriatic arthritis, type 1 diabetes and Still disease have been documented in adult cases. There are limited pediatric cases on this issue. It has been suggested that the persistence of the latent immune response after COVID-19 infection happens by sensitizing the immune system to viral particles long after they have been eliminated from organisms. Is the autoimmune process the effect of a viral infection or mis-targeted immune system? These questions need deep research and discussion.

A Prospective Cohort Study of COVID-19: Evaluation of the Early Role of IL-1 and IL-6 Antagonists in Improving the Outcome of the Illness and Reduction in the Risk of Death.

The COVID-19 pandemic had a profound impact on global health, economies, and social systems. The crucial factor that determines the success of COVID-19 treatments is preventing the need for mechanical ventilation and intensive care admission. In the context of COVID-19, several treatments have been found to play a role in the disease's progression and severity. Interleukins (ILs) have been identified as key mediators of the cytokine storm that can occur in severe cases of COVID-19, leading to respiratory failure and other complications. For instance, IL-1 antagonist (anakinra) and IL-6 antagonist (tocilizumab) are supposed to be promising treatments as well as cortisones for COVID-19. This prospective study aims to evaluate the effectiveness of anakinra or tocilizumab in addition to cortisone in preventing the progression of mild to moderate COVID-19 cases to severe intensive care admission. Biochemical and hematological parameters, such as D-dimer, ferritin, LDH, CRP, and white blood cells (WBCs), were measured after treatment with either anakinra or tocilizumab in addition to cortisone or cortisone alone. The study also recorded the number of deaths and patients admitted to intensive care. The results indicate that anakinra significantly improved outcomes and decreased the number of intensive care admissions compared to tocilizumab or cortisone alone. Therefore, anakinra may play a vital role in controlling the progression of COVID-19, and its use in mild to moderate cases may prevent the worsening of the disease to severe stages.

The Role of Inflammatory Cytokines (Interleukin-1 and Interleukin-6) as a Potential Biomarker in the Different Stages of COVID-19 (Mild, Severe, and Critical).

Cytokine storm refers to the overproduction of immune and inflammatory cells and their proteins (cytokines) [interleukin (IL)-1 and IL-6] causing acute respiratory distress syndrome in COVID-19. COVID-19 causes inflammatory reactions, and patients with COVID-19 had categorized as mild, severe, and critical after reviewing previous studies. Then, it is crucial to find immune-inflammatory indicators that might predict the disorder severity and the prognosis primarily for guiding medical therapy in the face of this unexpectedly developing unique infectious disease. Higher levels of IL-6 and IL-1 levels might be seen in patients with COVID-19 at each stage. In addition, IL-1-induced IL-6 assists in the synthesis of liver C-reactive protein (CRP) in acute phase responses. Recent studies suggested that IL-6 levels are an independent predictor of COVID-19 illness because they were significantly higher in patients with severe than with mild COVID-19 symptoms. Anakinra and tocilizumab (TCZ) are beneficial in lowing mortality in COVID-19 patients; however, information on their safety and efficacy is scarce. The aim of this study was to investigate the role of inflammatory cytokines (IL-1 and IL-6) as potential biomarkers in the different stages (mild, severe, and critical) of COVID-19. A systematic search during the years 2021-2022 using the keywords SARS-CoV-2, COVID-19, IL-6, IL-1, CRP, mild stage, severe stage, critical stage, cytokine storm, tocilizumab, and anakinra was performed in PubMed and Google Scholar databases. This study reviews studies that have investigated the role of high levels of these cytokines in the severity of the disease in patients with COVID-19 and the inhibitory function of TCZ and anakinra in preventing mechanical ventilation and patient mortality. According to the result, studies suggest that decreased innate immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in association with the production of inflammatory cytokines is the determining and driving function of COVID-19.

Anti-inflammatory therapy in patients with severe COVID-19 pneumonia: A single-center observational study Hyperinflammation treatment in COVID-19

Aim: In our study, the effects of methylprednisolone and anakinra drugs in the treatment of hyperinflammation in severe COVID-19 patients were investigated. Material(s) and Method(s): In this single-center retrospective study, severe COVID-19 patients followed up with signs of hyperinflammation were examined. The patients were examined in the Sequential Treatment Group receiving high-dose methylprednisolone followed by Anakinra, and the concomitant treatment group receiving both at the same time. Inflammatory parameters, imaging findings, and way of leaving the intensive care unit of the patients were compared. Result(s): A total of 87 patients were included in the present study. In both treatment groups, an increase in lymphocyte levels and a decrease in CRP, lactate dehydrogenase (LDH) and ferritin levels were detected at the end of treatment values compared to the initial treatment values. (p<0.001 and p<0.001). Also, LDH values after the treatment were significantly lower in the concomitant treatment group than in the sequential treatment group (p=0.049). In the present study, 53 of the patients were discharged with good recovery and 34 died. The mortality rate was 31% in the concomitant treatment group and 43% in the sequential treatment group. In terms of mortality, numerical findings in favor of the concurrent treatment group were determined. Discussion(s): In addition to the studies in the literature, it was found that the concomitant use of Methylprednisolone and Anakinra can be an effective treatment option that reduces mortality and improves inflammatory parameters.Copyright © 2022, Derman Medical Publishing. All rights reserved.

Effect of 2 Different High-Dose Methylprednisolone Treatments on Clinical Outcomes in Severe COVID-19 Patients

OBJECTIVE: The present study aimed to evaluate and compare the use of 2 different high-dose methylprednisolone posology in treat-ing severe coronavirus disease 2019 pneumonia regarding mortality and recovery time between themselves and against steroidal/ non-steroidal treatment. MATERIAL AND METHODS: Severe coronavirus disease 2019 patients followed up between March 2020 and January 2021 were included. The steroid-free treatment protocol was applied before August 2020 (non-pulse group) and a treatment algorithm containing normal and high doses of methylprednisolone was applied after August 2020 (pulse group). Patients with clinical deterioration under the normal dose of methylprednisolone were administered 250 mg or 1000 mg of methylprednisolone for 3 days. We compared the pulse and non-pulse groups, in addition to pulse subgroups with each other, for clinical outcomes. RESULT(S): A total of 138 patients were included, including 36 patients in the non-pulse group and 102 in the pulse group. In the pulse group, 70 patients received 1000 mg/day and 32 received 250 mg/day of high-dose methylprednisolone therapy. In the comparison of pulse and non-pulse patient groups, mortality rate was lower in the pulse group (P <.001), and the time to discharge without oxygen support was shorter. Although the patients in the 250 mg subgroup were older, there was no difference between the 250 mg and 1000 mg subgroups in terms of end of oxygen requirement, discharge with oxygen support, and mortality. In addition, the required time to reach the oxygen-free period in patients discharged without oxygen support was similar in the 2 subgroups, and the majority of patients in both subgroups reached the oxygen-free period on the 20th day after initiating methylprednisolone. CONCLUSION(S): Since there was no difference in clinical improvement between the use of 250 mg or 1000 mg methylprednisolone in patients with severe coronavirus disease 2019 infection, 1000 mg methylprednisolone was not required.Copyright © 2023, AVES. All rights reserved.

Modulation of thromboinflammation in hospitalized COVID-19 patients with aprotinin, low molecular weight heparin, and anakinra: the DAwn- AntiCo study

Background/Introduction: Thromboinflammation in severe COVID-19 is associated with disease severity and outcome. The kallikrein pathway is suggested to mediate thromboinflammation in COVID-19 by activating inflammatory pathways and contactmediated coagulation. Purpose(s): The DAWn-antico study investigates if a multitarget modulation of the thromboinflammatory response improves outcomes in hospitalized patients with severe COVID-19. Method(s): In this multicenter open-label randomized clinical trial (EudraCT 2020-001739-28), patients hospitalized with COVID- 19 were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention. The intervention consisted of aprotinin (2,000,000 IE IV four times daily) combined with low-molecular-weight heparin (LMWH;SC 50 IU/kg twice daily at the ward, 75 IU/kg twice daily at intensive care). Additionally, patients with predefined hyperinflammation received the interleukin-1- receptor antagonist anakinra (100mg IV four times daily). The primary outcome was time to a sustained 2-point improvement on the 7-point WHO ordinal scale for clinical status, or discharge. The trial was funded by Life Sciences Research Partners, Research Foundation Flanders (G0G4720N), and KU Leuven COVID-19 fund. Result(s): Between 24 June 2020 and 01 February 2021, 105 patients were randomized, and 102 patients were included in the full analysis set (intervention N=67 vs. SOC N=35). Twenty-five patients from the intervention group (37%) received anakinra. The intervention did not affect the primary outcome (HR 0.77 [CI 0.50;1.19], p=0.24) or mortality (intervention n=3 (4.6%) vs. SOC n=2 (5.7%), HR 0.82, [CI 0.14;4.94], p=0.83). There was one treatment-related adverse event in the intervention group (hematuria, 1.49%). There was one thrombotic event in the intervention group (1.49%) and one in the SOC group (2.86%), but no major bleedings. Conclusion(s): In hospitalized COVID-19 patients, modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra did not improve outcome in patients with moderate to severe COVID-19. (Disclosure: this RCT was presented at ISTH 2022 in London and will be published in Research and Practise in Thrombosis and Haemostasis).