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.

A Case of a Relapsing Remitting Macrophage Activating Syndrome After Covid-19 Vaccine In a Teenager with UNC13D Heterozygous Variant of Uncertain Significance

Introduction: Macrophage activation syndrome (MAS) is a severe hyper inflammatory condition caused by the over-activation and proliferation of T cells, NK cells and macrophages. It is often associated with complications of rheumatic/immune diseases. We present a case of a 15-year-old female who experiences recurrent episodes of MAS without any known definitive underlying etiology. Case Presentation: A 15-year-old previously healthy female developed fatigue, fevers, myalgia, chest pain, splenomegaly and lymphadenopathy 10 days after receiving her first Pfizer COVID-19 vaccine. Her symptoms recurred 10 days after receiving the second dose. Her myocarditis, MIS-C, and infectious work up was negative except for positive EBV IgG. Laboratory studies revealed anemia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. She initially responded to decadron;however, her symptoms recurred with steroid taper. Bone marrow biopsy revealed hemophagocytosis. Whole exome sequencing (WES) revealed a heterozygous variant of uncertain significance in UNC13D c.962C>A (p.Thr321Asn). She had multiple re-admissions with significantly elevated inflammatory markers, including extremely high IL2-R, IL-18 and CXCL9. Each episode was complicated by an acute viral infection. She responds to high dose steroids, anti-IL-1, and JAK inhibitors. Nonetheless, it has been difficult to wean decadron without triggering a flare. She continues to require increasing doses of baricitinib. Discussion(s): MAS may be seen as a complication of rheumatic diseases, as well as inborn errors of immunity. However, none of these conditions have been diagnosed in this patient despite extensive testing, including WES. The degree of her immune dysregulation has been very severe making her disease process unpredictable and extremely difficult to control. She has frequent flares precipitated by viral infections or attempts at adjusting her immunomodulators. Weaning her medications has been challenging as she continues to require increasing doses of baricitinib and corticosteroids. The UNC13D gene is associated with autosomal recessive familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Our patient is heterozygous for an UNC13D variant of uncertain significance. Additional genetic inquiries with whole genome sequencing to help elucidate the underlying etiology of her severe condition is being conducted. We hypothesize she developed MAS due to a combination of genetic predisposition, prior EBV infection, and immune stress associated with the COVID-19 vaccine. [Formula presented] [Formula presented] [Formula presented]Copyright © 2023 Elsevier Inc.

Oncolytic virus TG6002 safety and activity after intrahepatic artery administration in patients with liverdominant metastatic colorectal cancer

The TG6002.03 trial is a dose-escalation phase 1 clinical trial of TG6002 infusion via the hepatic artery in patients with liver-dominant colorectal cancer metastases. TG6002 is an engineered Copenhagen strain oncolytic Vaccinia virus, deleted of thymidine kinase and ribonucleotide reductase to enhance tumor selective viral replication and expressing FCU1, an enzyme converting the non-cytotoxic prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). In this trial, patients with advanced unresectable liver-dominant metastatic colorectal cancer who had failed previous oxaliplatin and irinotecan-based chemotherapy were treated with up to 2 cycles of TG6002 infusion 6 weeks apart via the hepatic artery on day 1 combined with oral 5-FC on days 5 to 14 (where day 1 = TG6002 infusion). TG6002 infusion was performed over 30 minutes via selective catheterization of the hepatic artery proper. 5-FC oral dosing was 50mg/kg x4 daily. Blood was sampled for TG6002 pharmacokinetics and 5-FC and 5-FU measurements. Sampling of liver metastases was performed at screening and on day 4 or day 8 for virus detection and 5-FC and 5-FU quantification. In total, 15 patients (median age 61 years, range 37-78) were treated in 1 UK centre and 2 centres in France and received a dose of TG6002 of 1 x 106 (n=3), 1 x 107 (n=3), 1 x 108 (n=3), or 1 x 109 pfu (n=6). Fourteen of the 15 patients received a single cycle of treatment, including one patient who did not received 5-FC, and one patient received two cycles. TG6002 was transiently detected in plasma following administration, suggesting a strong tissue selectivity for viral replication. In the highest dose cohort, a virus rebound was observed on day 8, concordant with replication time of the virus. In serum samples, 5-FU was present on day 8 in all patients with a high variability ranging from 0.8 to 1072 ng/mL and was measurable over several days after initiation of therapy. Seven of the 9 patients evaluable showed the biodistribution of the virus in liver lesions by PCR testing on day 4 or day 8. Translational blood samples showed evidence for T-cell activation and immune checkpoint receptor-ligand expression. At 1 x 109 pfu, there was evidence for T-cell proliferation and activation against tumour-associated antigens by ELISpot and for immunogenic cell death. In terms of safety, a total of 34 TG6002-related adverse events were reported, of which 32 were grade 1-2 and 2 were grade 3. The maximum tolerated dose was not reached, and a single dose-limiting toxicity was observed consisting of a myocardial infarction in a context of recent Covid-19 infection in a 78-year-old patient. These results indicate that TG6002 infused via the hepatic artery in combination with oral 5-FC was well tolerated, effectively localized and replicated in the tumor tissues, expressed its therapeutic payload and showed anti-tumoral immunological activity.

Development of warm autoimmune hemolytic anemia after initiation of Ruxolitinib in a patient with STAT1 gain-of-function mutation

Introduction: STAT1 gain-of-function (GOF) disease is associated with chronic mucocutaneous candidiasis (CMC) and a broad spectrum of infectious, inflammatory, and vascular manifestations. The Janus Kinase inhibitor ruxolitinib has been used successfully for CMC and autoimmune phenomena. We describe a case of warm autoimmune hemolytic anemia (WAIHA) in a patient with STAT1 GOF disease after initiating ruxolitinib. Case report: A 36-year-old man with STAT1 c.850G>A (p.Glu284Lys) mutation presented with CMC as well as recurrent viral and bacterial infections, lymphadenopathy, enteritis, nodular regenerative hyperplasia (NRH) and splenomegaly. Immune workup confirmed a combined immunodeficiency with hypogammaglobulinemia and T-cell lymphopenia. Ruxolitinib was initiated at 5 mg twice daily (due to pre-existing thrombocytopenia) with up titration over 3 months to 20 mg twice daily. He improved with weight gain, increased energy, resolution of chronic anemia, and improved lymphadenopathy and splenomegaly on imaging. Serum CXCL9 only minimally decreased from 4660 pg/ml to 3990 pg/ml. Soon after reaching ruxolitinib 20 mg twice daily, he developed JC viremia, prompting dose reduction to 15 mg BID. Within two weeks, he developed a non-COVID upper respiratory tract infection followed by fatigue, shortness of breath with ambulation, and dark urine. Emergency evaluation revealed warm antibody positive hemolytic anemia with a hemoglobin of 5 g/dL, and worsened thrombocytopenia. He was treated with blood transfusions, pulse steroids, and high-dose IVIG with stabilization but continued hemolysis. Due to the JC viremia, there was concern to give rituximab with increased PML risk. Bone marrow showed trilineage hematopoiesis, a mild increase in megakaryocytes and RBC precursors, and a loss of B-cell progenitors with retention of mature B cells. His B and T lymphocyte numbers had increased since prior to ruxolitinib, with a predominance of Tfh1-cells (58.7% of total Tfh-cells). He was started on sirolimus with a slow taper of prednisone with continued stable hemoglobin and platelets, and resolution of hemolysis after 3 months. Conclusion(s): To our knowledge, this is the first case of a STAT1 GOF patient developing WAIHA while receiving ruxolitinib therapy. Treatment choices were complicated by the risks of PML. Sirolimus combined with ruxolitinib allowed wean of corticosteroid and subsequent resolution of hemolysis.Copyright © 2023 Elsevier Inc.

ID: 212302 Prevalence of False Negative Results for Morphine in Oral Fluid Toxicology Compared With Urine Toxicology

Introduction: Urine drug testing has been the standard for monitoring opioid compliance in chronic pain patients. The COVID-19 pandemic created a dilemma for opioid monitoring by severely limiting in-person testing due to safety concerns. Oral fluid toxicology emerged as a feasible, alternative test due to its ability for remote sample collection under virtual supervision while minimizing infringements on patient privacy. However, the efficacy of these two tests for reliably detecting opioids should be explored prior to transitioning to testing only with oral fluids. Method(s): In this study, we compared morphine levels in oral fluid and urine toxicology studies from 5 randomly selected patients from a Chronic Pain Center who were regularly taking high doses (>=90 mEq) of extended-release morphine. Charts from the start of the COVID-19 pandemic until July 2022 were reviewed for urine and oral fluid testing results and medication regimens. All oral fluid and urine test results and collection methods were validated by a nationally recognized toxicology lab. Prescription Monitoring Program (PMP) reports were reviewed for each patient to observe pre-testing prescription trends. Result(s): We found that the overwhelming majority of patients had at least 1 false negative oral fluid test result. The remainder of the oral fluid results were below threshold (10 ng/mL) or ranged from 11.3 to 54 ng/mL of morphine. 80% of patients (n = 5) had at least one negative or positive-but-below-threshold (10 ng/mL) result in their oral fluid sample analyses. In contrast, none of the urine studies had negative results. Urine studies for all patients were positive for morphine and well-above primary cutoff values (100 ng/mL) with levels >6000 ng/mL. PMP reports did not reveal any aberrant drug taking behavior in any of the patients. No unprescribed medications or illicit substances were detected in any of the oral or urine samples. Conclusion(s): The prevalence of false negative results for the detection of morphine metabolites in oral fluid toxicology may be higher than clinicians are currently aware of. Physicians and other providers monitoring opioid compliance in chronic pain patients should keep this possibility in mind when selecting toxicology tests and making conclusions about aberrant drug-taking behavior. Larger scale studies are needed to compare oral fluid and urine levels of morphine with extension to other commonly prescribed opioids. Disclosure: Evan Chung, MD: None, Joseph Valenza, MD: NoneCopyright © 2023

High-Dose Steroids in COVID-19 Related Acute Respiratory Distress Syndrome: A Proposed Protocol

Introduction: The introduction of dexamethasone in the treatment of COVID-19 began in late 2020 after evidence emerged demonstrating that treatment with corticosteroids reduced mortality in those infected with severe COVID-19.1 Current guidelines suggest the use of Dexamethasone 6mg OD for 7-10 days for those requiring oxygen. A small proportion of patients in the intensive care unit do not respond to the usual dosing of dexamethasone. A treatment often advocated following discussion with the regional ECMO centre was high-dose steroid therapy.2-3 No guidance existed regarding the use of high-dose steroids in ARDS secondary to COVID-19. We believed there was inconsistency in patient selection, screening, dosing and monitoring. A protocol was needed to simplify this process. Objective(s): To develop a simple protocol for the use of high-dose steroids in COVID-19 related ARDS that provided the user with information on: 1. When to consider high-dose steroids 2. The precautions that should be taken to exclude infection prior to commencing high-dose steroids 3. The monitoring required while receiving high-dose steroids 4. A proposed treatment regimen Methodology and Results: A literature review of treatment regimens for high-dose steroids in COVID-19 ARDS was undertaken. We also included trials involving non-COVID-19 ARDS.3-4 A local evidence-based protocol for the use of high-dose steroids in COVID-19 related ARDS was designed. Following peer review by the wider MDT the protocol was first trialled, reviewed, and then adopted. An extended guideline with scientific context together with a quick reference bedside poster were launched. Conclusion(s): The protocol provided a user-friendly summary of the information required to safely use high-dose steroids for the treatment of COVID-19 related ARDS. The algorithm has now been adopted in several units and has been submitted for consideration as a network wide resource. Feedback from users has been positive and we will seek to review and update this guidance as further evidence emerges in this evolving condition.

A baby girl with TBX1 haploinsufficiency who died after elective cardiac repair surgery due to suspected enteroviral meningitis

Introduction: TBX1 haploinsufficiency is an inborn error of immunity with the phenotype of DiGeorge Syndrome. DiGeorge Syndrome has variable immunodeficiency associated with grade of thymic hypoplasia ranging from mild with no infections to severe requiring thymus implant. Enterovirus is an example of an opportunistic infection that can be fatal in these patients. Case Presentation: A 1 year old girl with TBX1 haploinsufficiency complicated by Tetralogy of Fallot, pulmonary atresia, high arched palate, and vesicovaginal fistula presented for elective cardiac repair surgery from another country due to failure to thrive and cyanosis. She had no prior infectious history but was on sulfamethoxazole-trimethoprim for prophylaxis. She was asymptomatic with a negative COVID test but no other infectious studies performed. Immediately postoperatively, she was febrile and nasal respiratory viral panel was positive for rhinovirus/enterovirus with increased procalcitonin and leukocytosis with left shift. She decompensated with multi-organ failure and cardiac arrest on postoperative day two. She was cannulated to veno-arterial extracorporeal membrane oxygenation (ECMO). Pre-operatively, she had a normal absolute lymphocyte count. No thymus tissue was observed in surgery. She had profound CD3 lymphopenia to 130 cells/cmm when critically ill. Enteroviral meningitis was suspected as no infectious, cardiac, or other pathology could be identified causing decompensation. Enteroviral serum polymerase chain reaction (PCR) test was negative while lumbar puncture deferred due to clinical status. She was treated with immunoglobulin. Offlabel investigational drug pocapavir was considered but deferred to patient's irreversible neurological status. The patient was disconnected from ECMO and expired. Discussion(s): Though we cannot confirm that this patient had enteroviral meningitis, invasive enteroviral infections are associated with elevated transaminases, coagulopathy, and seizures all present in our patient. There has also been reported negative serum enteroviral PCR but positive CSF enteroviral PCR in an immunodeficient patient. Additionally, this case highlights the importance of immunologic evaluation in patients with DiGeorge Syndrome and questions if asymptomatic viral screening for viruses like enterovirus should be considered pre-operatively in patients with inborn errors of immunity. This case highlights potential treatment options for invasive enteroviral infections in patients with inborn errors of immunity: high dose immunoglobulin, fluoxetine, and pocapavir.Copyright © 2023 Elsevier Inc.

A Review of Intra-Articular Corticosteroid Injection Safety and Clinical Effectiveness during Covid-19

Background/Aims Intraarticular corticosteroid injections (CSI) are used as a short-term treatment for inflammatory arthritis and osteoarthritis. At the outset of the COVID-19 pandemic there was concern regarding the immunosuppressive effect of steroids and the potential risk of COVID-19 infection in patients treated with CSI. There is no universal evidencebased consensus on the optimum dosing of CSI. Nationally there was a mixed response to CSI use during the COVID- 19 pandemic. Early during the pandemic, our Trust advised using only the lowest BNF indicated steroid dose to minimize any potential side effects. Large joints (knees and shoulders) were injected with 40mg of Kenalog compared to 80mg pre pandemic. No previous survey has reported the incidence of covid infection post CSI. The primary aim of this project was to address this gap. A secondary aim was to review the clinical effectiveness of a 'larger' versus 'smaller' steroid dose in CSI. Methods Retrospective data collection was carried out for 107 patients who received CSI during the pandemic. All patients who received CSI within the Trust rheumatology department were followed up with a sixweek phone call. During this consultation the effectiveness of the CSI was considered by asking them to score the effectiveness of the CSI out of 10 (10 being maximum improvement). The incidence of COVID- 19 infection was also recorded. This data was compared to the same data from a group of patients injected with a larger dose of CSI pre-pandemic (n=114). Results The patient reported incidence of COVID-19 infection within 6 weeks of CSI was 1.87%. Patient reported outcomes showed a mean improvement in joint symptoms of 6.97 using 80mg of kenalog, versus 5.02 improvement using the smaller 40mg dose at six week follow up. Interestingly 56% of people injected with a larger dose reported a minimum 8/10 improvement compared to 22% of patients injected with a smaller dose. Conclusion The low incidence of COVID-19 infections following CSI indicates that there is no significant correlation with increased in risk of contracting COVID-19. This study did not collect any data on outcomes of infection but at the time of the phone calls no patients had been hospitalized or died. The incidence of COVID-19 infection was below the national average. Some of the Rheumatology patients injected may have been advised to shield which may have contributed to the lower-than-expected figure. The significantly increased benefit consistently reported by patients supports the use of a higher dose steroid (Kenalog 80mg) versus lower dose (40mg) when injecting large joints in patients with arthritis. It is important to weight up the risks and benefits of CSI but this suggests that we should use the higher dose in clinical practice.

Outcomes and Impact of Covid-19 on Disease Activity in Patients with Systemic Vasculitides: Data from the Reuma-Cov Brazil Register

Objectives: To assess the impact of COVID-19 on disease activity and severity outcomes in patients with systemic vasculitis. Method(s): The Reuma-CoV Brazil is a longitudinal, multi-stage cohort study, designed to monitor patients with immune-mediated rheumatologic disease (IMRD) during the SARS-CoV-2 pandemic. Systemic vasculitis patients with COVID-19 were compared with those without COVID-19. Vasculitis activity was evaluated by the patient global assessment (PGA) and Birmingham Vasculitis Activity Score 3 (BVAS 3). The prognosis was assessed by the Five-Factor Score (FFS). Result(s): Between May 2020 and January 2021, 53 patients with vasculitis were included and followed for six months, 32 (60.3%) with COVID-19 and 21 (39.6%) in the control group. In total, 79.5% were female with a mean age (SD) of 49 (16.5) years. Both groups were homogeneous regarding sex, age, and comorbidities. Thirty-eight (71.8%) patients had at least one comorbidity. Thirty-two patients were classified as small vessels vasculitis (SVV), 10 as large vessels (LVV) and 11 as vasculitis of variable caliber. There was no difference in PGA, BVAS and FFS when comparing before and after SARSCoV-2 infection (Table 1). In the group of patients with LVV, two had clinical or laboratory worsening post infection. Compared to controls, patients with vasculitis and COVID-19 were at higher risk of intensive care unit (ICU) hospitalization [OR (IC95%) = 7.98 (3.78 - 16.8), p alpha 0.001], mechanical ventilation [OR (IC95%) = 7.45 (3.16 - 17.5), p = alpha0,001] and death [OR (IC95%) = 9.69 (3.87 - 24.3), p alpha 0,001]. Of the 7 patients who died, 40%were using high-dose prednisone (>20 mg/d) and 38.8% were using rituximab. Conclusion(s): In this sample of patients with systemic vasculitis, there was no worsening of disease activity after COVID-19, but there was a higher risk of poor outcomes, possibly related to immunosuppression.

A Rare Case of Isolated Renal Mucormycosis in an Immunocompetent Individual: Post Covid-19 Infection

Intro: Mucormycosis is known to effect patients with immunocompromised status from a variety of causes such as diabetes mellitus, hematologic malignancy, and HIV infection. Most common form of presentation is rhinocerebral infection. However, isolated presentation of renal mucormycosis is rare. With the ongoing COVID-19 pandemic and use of high-dose steroids and antibiotics, there have been increasing reports of bacterial and fungal coinfections in COVID-19 positive patients. We report a rare case of isolated renal mucormycosis, post COVID-19 infection, in a healthy individual presenting as unilateral right non-functioning pyonephrotic kidney. Method(s): A conscious, well oriented, afebrile 37 years old female patient presented with the complaints of right flank pain for one month. Patient was diagnosed as a case of post COVID-19 renal infarct with perinephric collection, right non-functioning pyonephrotic kidney. She had no previous comorbidities. Routine investigations, chest X-ray and CT scan were done. Finding(s): CT scan findings reveal a large right perinephric hyperdense collection inseparable from right kidney involving the internal oblique, psoas and quadratus lumborum muscles. Right simple nephrectomy was done and specimen was sent for histopathology and fungal culture. Histopathology report showed necrotizing granulomatous inflammation with broad, aseptate, irregularly branched fungal hyphae morphologically resembling Mucor species and fungal culture also confirmed Mucor species.Copyright © 2023

INTERIM RESULTS OF THE PML-16, PML-19 PROTOCOLS FOR PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA THERAPY

Introduction. Primary mediastinal lymphoma (PML) is an aggressive lymphoid tumor treatment success of which is determined by induction therapy. To date, none of the standard chemotherapy regimens (CT) have demonstrated an advantage in efficacy. Intensive therapy programs are associated with high toxicity. Aim - to evaluate the efficacy and toxicity of two pilot prospective treatment protocols PML-16 and PML-19 as well as the possibility of using the analysis of freely circulating tumor DNA (ctDNA) to assess MRD in patients with PML. Materials and methods. From January 2016 to January 2022, 34 previously untreated PML patients were included in the study;average age - 32;stage > I - in 60 %;extramediastinal lesions - in 14.7 %;bulky disease - in 73.5 % of patients. Positron emission tomography combined with computed tomography (PET-CT) was performed;ctDNA was determined to assess the completeness of remission. Results. Eighteen patients received treatment according to the PML-16 protocol (6 courses of chemotherapy;2 blocks of RmNHL-BFM-90 + 4 courses of R-EPOCH). After the end of therapy, all 18 patients achieved PET-negative remission. The next 16 patients received treatment according to the PML-19 protocol (4 courses of chemotherapy;2 blocks of R-mNHL-BFM-90 + 2 courses of R-EPOCH) in combination with lenalidomide. After the end of therapy, 9 (56 %) patients achieved PET-negative remission;7 (44 %) retained pathological activity (D4-5 points). After 3 and 6 months 15 (94 %) patients achieved normalization of metabolic activity. Considering the high frequency of false-positive results in patients with PML, a ctDNA study was performed to determine the depth of remission in 15 patients. After the end of therapy, all 15 patients had complete elimination of ctDNA. Of these, 5 (33 %) remained PET-positive at the end of treatment. During further observation, after 3-6 months, in 4 patients the level of metabolic activity decreased to physiological without the use of consolidating therapy. After the end of therapy, one patient suffered the new coronavirus infection, COVID-19. A month later, residual formation of SUVmax 14.2 remained in the mediastinum. The patient is currently under observation. With a median follow-up of 36 months (9 to 76 months) all 34 patients are in remission. Conclusion. The effectiveness of PML-16 made it possible to abandon the consolidation therapy and refuted the idea of the need for 6 courses of CT. The combination of programs based on the application of the principle of high-dose short-pulse induction of remission (R-mNHL-BFM-90) in combination with the prolonged administration of medium doses (R-EPOCH) was crucial in achieving a successful result. The inclusion of lenalidomide in the "PML-19" program made it possible to achieve complete remission in 100 % of cases after 4 courses. The possibility of using DNA analysis to assess MRD in patients with PML was shown.Copyright © 2022 Izdatel'stvo Meditsina. All rights reserved.

Safety and Immunogenicity of Coronavac and Chadox1 Vaccines against Sars-Cov-2 in Patients with Rheumatoid Arthritis: Brazilian Multicentric Study

Objectives: To evaluate the safety and immunogenicity of CoronaVac and ChAdOx1 vaccines against SARS-CoV-2 in patients with Rheumatoid Arthritis (RA). Method(s): These data are from the 'SAFER (Safety and Efficacy on COVID-19 Vaccine in Rheumatic Diseases)' study, a Brazilian multicentric longitudinal phase IV study to evaluate COVID-19 vaccine in immunomediated rheumatic diseases (IMRDs). Adverse events (AEs) in patients with RA were assessed after two doses of ChAdOx1 or CoronaVac. Stratification of postvaccination AEs was performed using a diary, filled out daily. The titers of neutralizing antibodies against the receptor-biding domain of SARS-CoV-2 (anti-RBD) were measured by chemilumine scence test after each dose of immunizers. Proportions between groups were compared using the Chi-square and Fisher's exact tests for categorical variables. Clinical Disease Activity Index (CDAI) before and after vaccination was assessed using the McNemar test. Result(s): A total of 188 patients with RA were included in the study, most of them were female. CoronaVac was used in 109 patients and ChAdOx1 in 79. Only mild AEs were observed. The more common AEs after the first dose were pain at injection site (46,7%), headache (39,4%), arthralgia (39,4%) and myalgia (30,5%), and ChAdOx1 had a higher frequency of pain at the injection site (66% vs 32 %, p alpha 0.001) arthralgia (62% vs 22%, p alpha 0.001) and myalgia (45% vs 20%, p alpha 0.001) compared to CoronaVac. The more common AEs after the second dose were pain at the injection site (37%), arthralgia (31%), myalgia (23%) and headache (21%). Arthralgia (41,42 % vs 25 %, p = 0.02) and pain at injection site (51,43% vs 27%, p = 0.001) were more common with ChAdOx1. No patients had a flare after vaccination. The titers of anti-RBDafter two doses of ChAdOx1 were higher compared to two doses of CoronaVac (6,03 BAU/mL vs 4,67 BAU/mL, p alpha 0,001). Conclusion(s): The frequency of local adverse effects, particularly pain at injection site, was high. AEs were more frequent with ChAdOx1, especially after the first dose. The use of the immunizers dis not change the degree of inflammatory activity of the disease. In patients with RA, ChAdOx1 was more immunogenic than CoronaVac. .

Humoral Immune Response to Sars-Cov-2 Third Vaccine in Patients with Autoimmune Rheumatic Diseases without Seroconversion after the Initial 2-Dose Regimen

Objectives: To evaluate the humoral immune response to the third dose (booster) of vaccine against SARS-CoV-2 in patients with autoimmune rheumatic diseases who were seronegative after a two-dose regimen. Method(s): Observational study. Patients with autoimmune rheumatic diseases who had not achieved seroconversion after a two-dose vaccine schedule against SARS-CoV-2 were included. To assess the humoral immune response, anti-RBD IgG (S protein receptor binding domain) neutralizing antibody titers were determined by ELISA (cutoff titer 200). The determination was made between 30 to 45 days after the third dose. Result(s): From 66 patients who received SARS-CoV-2 vaccination, 18 patients (29.5%) were seronegative after a two-dose schedule. 61% had SLE, 77% had comorbidities (61% with hypertension, p = 0.03). Patients were on treatment: 10 with prednisone (8 with doses greater than 10 mg/d, p = 0.01), 10 with hydroxychloroquine, one with methotrexate, one with leflunomide, four with azathioprine, five with my cophenolatemofetil and five with rituximab (they are the total number of non-responders on biological treatment, p = 0.03). Regarding the primary vaccination regimen, 11 received BBIBP-CorV (p = 0.01), 5 AZD1222, 1 Gam-COVID-Vac and 1 mRNA1273/Gam-COVID-Vac heterologous scheme. Of these 18 non-responders, 14 received a third dose;nine patients (62%) presented anti-RBD IgG detectable. Of the five patients who did not respond to the booster vaccination, three had received BBIBP-CorV as the initial schedule and the vaccines applied as a third dose were Ad5-nCoV (1), BNT162b2 (1), AZD 1222 (2) and Gam-COVID-Vac (1). They were being treated with: rituximab (2), azathioprine (2) and mycophenolate mofetil (1). Treatment with higher doses of prednisone was the only factor associated with non-seroconversion to the third dose (8 +/- 4.5;p 0.02). Conclusion(s): The third dose of SARS-CoV-2 vaccine allowed to improve the serological response to vaccination, achieving a seroconversion of 62% in this group of patients.

Clinical Features, Laboratory Findings Outcomes in Multisystem Inflammatory Syndrome (Mis-C) Following Covid-19 Infection - a Multicenter, Observational, Ambidirectional Cohort Study in Rio De Janeiro State, Brazil

Objectives: As of March 5th, 2022, around 1.585 cases of MIS-C and 98 deaths (6,4%) were reported in Brazil. The state of Rio de Janeiro State (RJ) having 94 cases (5,9%) and 4 deaths (4,2%)1.Our aim was to evaluate clinical and laboratory features, and management of MIS-C in seven pediatric hospitals in RJ, Brazil. Method(s): Multicenter, observational, ambidirectional cohort study in seven tertiary hospitals in RJ(Brazil), assessing medical charts of pediatric inpatients (0-18 years) diagnosed with MIS-C according to WHO/CDC criteria, from August, 2020 to February, 2022. Descriptive statistics were used to analyze distributions of continuous variables, frequencies, and proportions. Result(s): A total of 112 cases of MIS-C were enrolled. The mean age was 4.2 years and thre was male predominance (59,8%). All cases had a SARS-CoV-2 contact (29.5% close contact;31.3%:positive PCR;serology:43.8%).Only 12.5% had comorbidities. Length of stay (LOS) was 7 days.Median duration of fever was 8 days. Most common symptoms were: rash(67%);gastrointestinal (67%);conjunctivitis (42%);neurological(39.6%);cardiovascular(37.5%);cervical lymphadenopathy (36.6%), and shock/hypotension(28.6%).Co-infection occurred in 3 patients. Forty-four patients fulfilled criteria for Kawasaki disease. Most patients were admitted to PICU(12;62,5%) for amedian of 2 days. Respiratory distress was seen in 18,7%;hypotension:28,6%, and shock in 23,2%. Main laboratory findings were: high C-reactive protein in 95%;D-dimer:77%, anemia:77%, thrombocytosis:63%;transaminitis:43.8%, lymphopenia:38%;hypoalbuminemia:34%;thrombocytopenia: 29%;hypertriglyceridemia:28%, and high pro-BNP in 27%. Echocardiogram was performed in 91/112 patients;abnormal in 70,3%;exhibiting myocardial dysfunction( 25%);pericardial effusion(21%);coronary dilation/aneurysms(11%) and, valvulitis (14.5%). IVIG+corticosteroids (CTC) were administered in 59.8%(67/ 112);18.6%(18/112) IVIG only;10.7%(12/112) CTC only;3.4%(4/112)biologics, and 15(13.3%) received no treatment. ASA low dose in 77.7% (87/112) and moderate/high dose in 34.8%. Oxygen support was needed in 27,7%;vasoactive amines:18,7%;dialysis:5,3%, and transfusion:18,7%.One patient died from a cytokine storm syndrome. Conclusion(s): Our study reports a higher number of MIS-C cases in RJ than the number reported to Brazilian authorities, highlighting underreporting. Our patients were younger, had fewer comorbidities, cardiovascular/gastrointestinal/renal involvement, shortest LOS in ICU, and a higher frequency of myopericarditis.

Ndegree39 - Fulminant life-threatening myopathy of the genetic origin

Objectives: Acute myopathy are seen in critically ill patients, in severe SARS-CoV2 pneumonia requiring mechanical ventilation, and other infection illness, toxin and drug-induced complications, or systemic inflammation. Periodic paralysis or carnitine disorders are known genetic causes of acute muscular weakness, besides genetically determined muscle diseases rarely have an acute clinical course. Content: Case presentation: 61-years old, healthy woman, after a one-time vaccination against Covid-19 about 2 weeks earlier, was admitted to the Neurological Department due to symptoms lasting for 2 days. On the first day of the disease she complained of vertigo and double vision, on the following day dysarthia and dysphagia appeared, she stopped walking. On the second day of hospitalization, the patient required mechanical ventilation. The initial diagnosis of Guillaine-Barre syndrome was not confirmed in the electrophysiological and laboratory (CSF) studies. Myopathic pattern with polyphasic potentials of short duration and low amplitude was observed in EMG, without spontaneous activity. In the electron microscope numerous fat drops between bundles of myofibrils in most muscle fibers were seen. She received intravenous immunoglobulins, and steroid therapy, together with high doses of vitamin B2 with very good motor improvement. Multiple acyl-CoA dehydrogenase deficiency (MADD) was suspected, and the Whole Exome Sequencing (WES) was performed. Conclusion(s): The authors note the possibility of acute, life-threatening myopathy, which may be caused by a genetic defect. MADD is a very rare genetic entity which can manifest for the first time very suddenly, especially in the presence of triggers, including but not limited to after vaccinations. Keywords: Acute myopathy;Multiple acyl-CoA dehydrogenase deficiency;Vitamin B2.Copyright © 2023

Management of patients with liver derangement during the COVID-19 pandemic

COVID-19 pandemic has been affecting the whole world for more than 3 years since late 2019. It is often to encounter COVID-19 patients with abnormal liver function, either in the form of hepatitis, cholestasis or both. The clinical implication of such liver derangement may be variable in different clinical scenarios. With the growing evidence of the clinical significance of such liver derangement, it would be clinically helpful to provide practice recommendations to various common clinical scenarios of liver derangement during COVID-19 pandemic. The Asia-Pacific Working Group for Liver Derangement during the COVID-19 Pandemic was formed to systematically review the literature on specified domains of interest, with special focus on clinical management of patients who have been or are at risk of developing liver derangement during COVID-19 pandemic. This Asia-Pacific position statement reports an in-depth review and a position statement on liver derangement during COVID- 19 pandemic. Ten clinical scenarios covering the use of pharmacological treatment for COVID-19 in case of liver derangement, assessment and management of patients with chronic hepatitis B or C, nonalcoholic fatty liver disease (NAFLD), liver cirrhosis, liver transplantation are discussed. Specifically, some treatments target the patient's dysregulated inflammatory response during COVID-19 infection and may cause hepatitis B reactivation (HBVr) in patients with current or past hepatitis B virus (HBV) infection. Current evidence suggests that current or past HBV infection is not associated with an increased risk of liver injury and severe disease in COVID-19 patients. Among patients who received high-dose corticosteroids, various immunosuppressive monoclonal antibodies and inhibitors of Janus kinase, the risk of HBVr exists, especially among those without antiviral prophylaxis.

Analysis of Antibody Response to Sars-Cov-2 Vaccination and Natural Infection in a Tertiary Centre Cohort of Lupus Nephritis Patients

Background/Aims The immune response to SARS-CoV-2 is known to be reduced in the immunocompromised. However, extent to which immunity is affected by immunosuppression in specific disease cohorts remains poorly characterised. Furthermore, implications of the ongoing vaccination booster programme require further study. Individuals with lupus nephritis (LN) require prolonged high-dose immunosuppression in order to maintain disease control, rendering them important to study in this context. We evaluated SARS-CoV-2 nucleocapsid and spike antibody response in this cohort during the Spring/Summer 2022 booster vaccine campaign. Nucleocapsid antibody indicates previous infection whilst spike antibody indicates previous infection and/or vaccination response. Titre of spike antibody to prevent infection is not known, but presence of antibodies is likely to protect against severe disease. Methods SARS-CoV-2 spike and nucleocapsid antibody were measured in adult patients with LN attending a tertiary centre rheumatology clinic. Data was collected retrospectively on disease, immunosuppression, vaccine status and history of natural exposure. Results 35 cases of LN were investigated, of which LN III, IV and V were predominant biopsy diagnoses. Regarding immunosuppressants, the Eurolupus Cyclophosphamide protocol had been used in the majority of patients to achieve initial control, with 3/35 patients still receiving pulsed courses at data collection. 18/35 were on Mycophenolate Mofetil;a further 13/35 had previously received this. 31/35 took at least 5mg Prednisolone daily;25/35 took Hydroxychloroquine;7/35 took Azathioprine;7/35 had previously been on Methotrexate, 3/35 took Tacrolimus;1/35 took Ciclosporin. Regarding B-cell depleting monoclonal antibody therapy, 13/35 had received Rituximab and 8/35 were receiving Belimumab. Antibody levels were measured between 4 weeks and 13 months after last dose of vaccination;mean duration was 6 months. 11/35 had confirmed COVID-19 infection;a further 8/35 reported a possible history. Of the 35, 32 (91%) had mounted detectable SARS-CoV-2 spike antibody above the bottom 10% of assay detection, indicating some immunity to vaccination or natural exposure. 20 (57%) had detectable nucleocapsid antibody, suggesting natural infection with antibody response. Only 2 (6%) had not mounted any antibody response. Of note, neither were fully vaccinated: one had 1 vaccination with blood test 8 months subsequent;one had 2 vaccinations with blood test 7 months subsequent. The latter was also notably on haemodialysis. All who received 3+ vaccinations had detectable spike antibody responses, as well as 75% of those who had received 2 vaccinations. Conclusion Our study is the first analysis, to our knowledge, of SARS-CoV-2 antibody response in a LN cohort. Whilst neutralising capacity and level of antibody providing protection remains under research, these findings provide at least some reassurance that individuals with LN on immunosuppression are capable of mounting an immune response against SARS-CoV-2. Further work is required to establish extent and duration of protection with serial vaccinations in this cohort.

Clinical Nutrition in Covid-19 Patients-A Systematic Review

Introduction There is currently a lack of evidence on clinical nutrition in Covid-19. Aim of the work: Systematic overview of clinical nutrition in Covid-19. Material and methods A systematic literature search: 2 meta-analyses, 12 systematic reviews and meta-analyses, 9 prospective randomized controlled trials, 3 prospective observational studies, 7 retrospective studies, 25 narrative reviews. Results a) Obese patients have an increased risk of a severe course of the disease, b) there is a connection between obesity and an increased risk of death, c) Covid-19 mortality increases from a BMI>27 kg/m2, in all BMI classes 1,6% per 1 kg/m2 in the event of weight gain, in the case of severe obesity (> 40-45 BMI) by a factor of 1,5 to 2 and per 5 kg/m2, d) the risk of a severe course of Covid-19 increases also with increased visceral fat tissue percentage, total body fat mass and upper abdominal circumference, e) the mortality rate can be 10 times higher in malnourished Covid-19 patients, f) serum albumin provides evidence of a poor course of the disease, g) enteral omega-3 fatty acid intake could stabilize kidney function and improve the outcome, h) foods with a low glycemic index should be preferred, i) vitamin D deficiency should be avoided, daily vitamin D and zinc supplementation can be beneficial, j) one-time high dose vitamin D and enteral vitamin C provide no benefit, but the risk of thrombosis could be reduced and the antibody response enhanced with zinc, k) nutritional intervention reduces mortality. Conclusion Screening and assessment of nutritional status are important in Covid-19 patients. Overall, there are insufficient clinical results on specific nutritional therapy.Copyright © 2022 Georg Thieme Verlag. All rights reserved.

Anca-Associated but Not Vasculitis

Background/Aims A 72-year-old lady presented in primary care with complaints of generalised body aches, bilateral leg weakness and constitutional symptoms following a first dose of COVID-19 vaccine. Blood tests showed slightly raised inflammatory markers. She was initially diagnosed with polymyalgia rheumatica and was started on 40mg prednisolone with minimal improvement. Methods The examination in the rheumatology clinic was unremarkable. Investigations revealed raised white cell count, consistent with high dose steroid treatment, and elevated monocytes. There was mild improvement in inflammatory markers. The working diagnosis was of self-limiting viral illness. Further testing discovered strongly positive MPO ANCA (115 IU/ml), and the patient received three pulses of 500mg methylprednisolone for suspected vasculitis arranged by the medical team. There was no evidence of renal involvement. The diagnosis made at this point was autoimmune inflammatory disorder with unclear aetiology. At the subsequent clinic visit she reported mild shortness of breath, but no other symptoms suggestive of either vasculitis or connective tissue disease. Repeat ANCA showed significant reduction in MPO titre following pulse steroid treatment. CT of chest, abdomen and pelvis demonstrated a localised lobular/ nodular deformity of the liver. Viral hepatitis screen was negative. CA19-9 was raised at 100 U/ml. Liver biopsy was reported as poorly differentiated carcinoma without specific localising immunohistochemical features. Results The patient underwent hemi-hepatectomy for histologically confirmed pT2pNXM0R0 liver cholangiocarcinoma in a tertiary centre followed by adjuvant chemotherapy with capecitabine. With treatment, her MPO ANCA and CA19-9 levels declined. An interval CT scan of chest, abdomen and pelvis performed ten months after the surgery, showed no recurrence of malignancy. Given the fact that the patient's MPO ANCA fell following the treatment of cholangiocarcinoma, it is likely that positive MPO ANCA is associated with underlying malignancy rather than an active vasculitis. Conclusion This unusual case describes an evolution of the diagnostic process guided by non-specific symptoms and ANCA positivity, arriving at an unexpected diagnosis of malignancy. Although ANCA is a sensitive and specific marker of vasculitides, it can be positive in other conditions particularly hepatitis B, inflammatory bowel disease and autoimmune liver disorders. Malignancy can also be associated with ANCA in the absence of vasculitis. In one study, of 118 ANCA positive patients without ANCA-associated vasculitis, four were found to have malignancy. In a study of 1024 patients who had ANCA tested, 61 patients were found to have malignancy, predominantly haematological and lung cancers. However, after adjustment for sex, age and time of blood draw, no association was found between ANCA status and incidence of cancer. Interestingly, paraneoplastic vasculitis such as polyarteritis nodosa (PAN) has been described in the context of underlying cholangiocarcinoma, and is associated with ANCA rise. Moreover, patients with raised ANCA and PAN also have raised CA 19- 9.

Acute Fibrinous Organizing Pneumonia in a COVID-19 Patient: A Case Report

Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has varied clinical and radiographic manifestations. Severe initial viral infection, cytokine release, opportunistic infection and post-viral inflammation may all contribute to progressive symptoms and severe lung injury. Acute fibrinous and organizing pneumonitis (AFOP), a rare pattern of acute lung injury characterized by intra-alveolar fibrin ball, has so far been reported associated with infections, connective tissue diseases, drugs and toxins, hematologic malignancy, altered immune status and inhalation injury. Case Report: The authors report a case of 26-year-old man with severe COVID-19 pneumonia that clinical and radiographic imaging worsened after episode of cytokine storm. The diagnosis of AFOP was confirmed by transbronchial biopsy, and the patient was successfully treated with high-dose corticosteroids. Conclusion(s): AFOP can be found in severe COVID-19 patients especially when clinical deterioration occurs later in disease course. Clinical suspicion is needed for prompt diagnosis and treatment. High-dose corticosteroid is an effective medication.Copyright © 2023 JOURNAL OF THE MEDICAL ASSOCIATION OF THAILAND.