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.

Scientific rationale of Indian AYUSH Ministry advisory for COVID-19 prevention, prophylaxis, and immunomodulation

The current outbreak of COVID-19 is caused by the SARS-CoV-2 virus that has affected > 210 countries. Various steps are taken by different countries to tackle the current war-like health situation. In India, the Ministry of AYUSH released a self-care advisory for immunomodulation measures during the COVID-19 and this review article discusses the detailed scientific rationale associated with this advisory. Authors have spotted and presented in-depth insight of advisory in terms of immunomodulatory, antiviral, antibacterial, co-morbidity associated actions, and their probable mechanism of action. Immunomodulatory actions of advised herbs with no significant adverse drug reaction/toxicity strongly support the extension of advisory for COVID-19 prevention, prophylaxis, mitigations, and rehabilitation capacities. This advisory also emphasized Dhyana (meditation) and Yogasanas as a holistic approach in enhancing immunity, mental health, and quality of life. The present review may open-up new meadows for research and can provide better conceptual leads for future researches in immunomodulation, antiviral-development, psychoneuroimmunology, especially for COVID-19.Copyright © 2021, Institute of Korean Medicine, Kyung Hee University.

Reactivation of Parvovirus B19 Infection: An Uncommon Trigger of Macrophage Activation Syndrome in Adult-Onset Still's Disease.

A 40-year-old woman presented with four weeks of intermittent high-grade fever, cough, and joint pain, and two weeks of a generalized rash. She was found to have adult-onset Still's disease (AOSD) and rapidly developed macrophage activation syndrome (MAS) on the second day of admission. Among infectious etiologies, Epstein-Barr virus and members of the herpes virus family are common triggers of MAS. However, our patient was found to have reactivation/recurrence of parvovirus B19 infection as the cause; this is an uncommon trigger reported infrequently in the medical literature. Despite intensive treatment, the patient passed away.

Incidence and Clinical Outcomes of Newonset Autoimmune Connective Tissue Diseases after Covid-19 Infection- a Systematic Literature Review

Background/Aims Cases of new autoimmune and autoinflammatory conditions have been reported among COVID-19 survivors. A literature review on newonset autoimmune connective tissue diseases (ACTDs) following infection with COVID-19 is lacking.This systematic literature review aimed to evaluate the potential association between COVID-19 infection and the development of new-onset ACTDs in adults. Methods Articles published until September 2022, investigating the association between COVID-19 infection and new-onset ACTDs were included. The ''population'' searched was patients with disease terms for autoimmune connective tissue diseases, including (but not limited to) systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis (SSc), any idiopathic inflammatory myositis (IIM), antisynthetase syndrome, mixed CTD and undifferentiated CTD (and related MeSH terms), with ''intervention'' as COVID-19 and related terms. For terms for COVID-19, a dedicated search strategy developed by the National Institute for Clinical Excellence was used.Medline, Embase, and Cochrane databases were searched, restricted to English-language articles only. Eligible articles were: case reports and series (of any sample size), observational studies, qualitative studies and randomised controlled trials. Patients developing ACTDs without prior COVID-19 or reporting flares of existing ACTDs were excluded. Information was extracted on patient demographics, new ACTDs' onset time, clinical characteristics, COVID-19 and ACTD treatment, and COVID-19 and ACTDs outcomes. The protocol was registered in PROSPERO (CRD42022358750). Results After deduplication, 2239 articles were identified. After screening title and , 2196 papers were excluded, with 43 proceeding to fulltext screening. Ultimately, 28 articles (all single case reports) were included. Of the 28 included patients, 64.3% were female. The mean age was 51.1 years (range 20-89 years). The USA reported the most cases (9/28). ACTD diagnoses comprised: 11 (39.3%) IIM (including 4 cases of dermatomyositis);7 (25%) SLE;4 (14.3%) anti-synthetase syndrome;4 (14.3%) SSc;2 (7.1%) other ACTD (one diagnosed with lupus/MCTD overlap). Of eight, four (14.3%) patients (including that with lupus/MCTD) were diagnosed with lupus nephritis. The average onset time from COVID-19 infection to ACTD diagnosis was 23.7days. A third of the patients were admitted to critical care, one for ACTD treatment for SLE with haemophagocytic lymphohistiocytosis (14 sessions of plasmapheresis, rituximab and intravenous corticosteroids) and nine due to COVID-19. The majority (80%) of patients went into remission of ACTD following treatment, while two (10%) patients died- one due to macrophage activation syndrome associated with anti-synthetase syndrome and two from unreported causes. Conclusion Our results suggest a potential association between COVID-19 infection and new-onset ACTDs, predominantly in young females, reflective of wider CTD epidemiology. The aetiology and mechanisms by which ACTDs arise following COVID-19 infection remain unknown and require more robust epidemiological data.

CBD Treatment Improves Fatal Inflammatory Response Exhibited in SEB-Induced ARDS

The novel SARS-CoV-2 virus known to cause the COVID-19 outbreak has resulted in a global healthcare crisis that has persisted the past 3 years. Thus, understanding the mechanisms underlying this disease are vital at this time. While there are issues of research infrastructure to handle the virus and because of the refractoriness of rodents to this disease, the availability of these tools is still limited. The cytokine storm and fatality presented in patients with severe COVID-19 can be mimicked with Staphylococcal enterotoxin B (SEB)-induced Acute Respiratory Distress Syndrome (ARDS). Within ~7 days, the survival rate drops to 0% for C3H/HeJ mice exposed to a dual dose of SEB. In this study, we administered cannabidiol (CBD) intraperitoneally for 3 days pre- and post-SEB dosing and found that the clinical outcomes improved significantly. Initial evaluation of scRNASeq data from lungs comparing naive to SEB-induced ARDS mice illustrated an increase in infiltrating immune cells, and a loss in pulmonary epithelial cells in the latter group. When evaluating the effect of CBD treatment on SEB-induced ARDS, we were able to demonstrate that CBD reduced the macrophage population. To characterize the mechanism by which CBD treatment ameliorated the inflammatory response, we found that CBD treated mice had significant reduction in infiltrating immune cells and alveolar thickening. This same histology and infiltration is presented in ARDS. MicroRNA expression analysis showed a significant increase in the expression mmu-miR-298-5p and mmu-miR- 566 with CBD treatment. Ingenuity Pathway Analysis (IPA) indicated that the dysregulated miRNAs were also implicated in pathways associated with macrophage activation, respiratory disease and inflammation, interferon stimulated genes, as well as genes which have been upregulated in the disease state of this model. These targets include but are not limited to Cebpb, Efhd2, Stat3, Socs3, Cxcl5, Gbp2, and Birc3. This finding offers insights for the development of preventive and therapeutic strategies in the treatment of ARDS, including that induced in COVID-19. Supported by NIH grants P01AT003961, P20GM103641, R01ES003961, R01AI129788, R01AI123947, R01AI160896 to MN and PSN and K99GM147910 to KW.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

Inflammatory Pathways Associated with Covid-19 Severity Differ Based on Obesity Status

Background: Severe COVID-19 and obesity are characterized by higher inflammation. We aimed to examine early inflammatory patterns in people with (Ob) and without (NOb) obesity and COVID-19 and how they relate to COVID-19 disease severity Methods: Ob (BMI >30 Kg/m2) and NOb with COVID-19 matched for age, sex and WHO disease severity provided blood early after diagnosis. Immunoassays measured 57 plasma biomarkers reflecting innate immune and endothelial activation, systemic inflammation, coagulation, metabolism and microbial translocation (Fig 1). Between-group differences were assessed by Mann- Whitney. Associations between subsequent maximal COVID-19 severity (mild vs moderate/severe/critical) and biomarkers were explored by logistic regression adjusted for age, sex, hypertension (HTN) and diabetes (DM). Data are median pg/mL [IQR] or n [%] unless stated Results: Of 100 subjects (50 Ob and 50 Nob) presenting between April 2020 and March 2021, characteristics (Ob vs Nob) included: age 65 [23-91] vs 65 [21-95];female sex 27 (48%) vs 28 (56%);BMI 33.7 [30.0-71.8] vs 23.3 [15.3-25.9];disease severity mild 22 [48%] vs 23 [46%], moderate 15 [30%] vs 13 [26%], severe 6 [12%] vs 7 [14%];HTN 30 (60%) vs 17 (34%);DM 19 [38%] vs 6 [12%];days from symptom onset 7 [2-17] vs 8 [1-15];vaccinated 3 (6%) vs 0 (0%). Compared to NOb, Ob had higher IFN-alpha (1.8 [0.6;11] vs 0.9 [0.1;4.7]), CRP (10 mAU/mL [9.6;10.2] vs 9.7 [7.2;10]), IL-1RA (197 [122;399] vs 138 [88;253]), IL-4 (288 AU/mL [161;424] vs 205 [82;333]), vWF (252 [166;383] vs 163 [96;318]), Zonulin (114 ng/mL [77;131] vs 57 [18;106]), Resistin (956 [569;1153] vs 727 [712;1525]), Leptin (3482 [1513;5738] vs 848 [249;2114]), and lower Adiponectin (1.12 mg/L [0.09;1.5] vs 1.5 [1.18;1.93]), all p< 0.05. In both groups higher, proinflammatory IL-18 and lower levels of antiinflammatory CCL22 and IL-5 were associated with higher odds of disease severity, and lower E-selectin with higher disease severity only in Ob. However, in NOb higher type 3 interferons (IL-28A), macrophage activation (sCD163, CCL3) and vascular inflammation markers (ICAM-1, VCAM-1), along with higher S100B, GM-CSF and leptin were also associated with disease severity, a pattern not observed in Ob (Fig 1) Conclusion(s): Although Ob had higher overall levels of inflammation than NOb, few biomarkers predicted subsequent COVID-19 severity in Ob. These differential inflammatory patterns suggest dysregulated immune responses in Ob with COVID-19. (Figure Presented).

Activated CD8 T-cell hepatitis in children: a single institution experience

Background: Pediatric acute liver failure is a rare and serious life-threatening situation, principally for the 30 to 50% of children in whom the etiology of their liver failure is unclear or indeterminate. Treating these patients is challenging, requiring constant assessment over time with regular evaluation for possible liver transplantation. Children with pediatric acute liver failure of undetermined etiology have lower spontaneous survival and higher rates of transplantation and death than other diagnostic groups. Emerging evidence suggests that a subgroup of patients with indeterminate pediatric acute liver failure have clinical, laboratory, and liver biopsy features of immune dysregulation with a dense infiltration of CD8 T cells. Method(s): In 2022, we received percutaneous liver biopsies from three children with acute hepatic dysfunction that showed an increased number of lymphocytes including CD8 T cells. For each case, routine H&E stains with levels, special stains and immunostains were performed. The first biopsy was from an 18-month-old male who presented with COVID infection, pancytopenia, elevated transaminases, and synthetic liver dysfunction (elevated INR). The second was from a 9-year-old female with a history of elevated liver enzymes with no clear cause. The third case was from a 2-year-old male with elevated liver enzymes, coagulopathy, and cholestasis. Result(s): The three cases showed similar histopathologic findings;an acute liver injury pattern with lobular architectural disarray, giant cell formation, reactive changes, single cell necrosis, cholestasis and marked mixed lymphocytic infiltrates. The infiltrates were predominantly composed of CD8-positive T-lymphocytes with scattered neutrophils, eosinophils and rare plasma cells. Portal areas were mildly expanded with mild bile ductular proliferation and mild to moderate lymphocytic infiltrates. Immunostains for CD8 demonstrated that the infiltrates were predominantly composed of CD8-positive T-lymphocytes. All three patients received steroids and responded to treatment evidenced by normalization of liver enzymes and function. Conclusion(s): Dense hepatic CD8 T-cell infiltration is a major finding inactivated CD8 T-cell hepatitis. However, the percentage distribution of lymphocyte subtypes in the setting of hepatitis is not well established, and CD8 T-cell infiltration has also been described in cases of drug-induced hypersensitivity reactions, viral hepatitis, hemophagocytic lymphohistiocytosis, and macrophage activation syndrome, as well as autoimmune hepatitis. Further investigation is needed to better understand the diagnostic criteria in this disease.

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.

Case report: Multisystem inflammatory syndrome in children associated with COVID-19, macrophage activation syndrome, and incomplete Kawasaki disease.

Background: Multisystem inflammatory syndrome in children (MIS-C), is a severe complication of coronavirus disease 2019 (COVID-19), characterized by persistent fever, systemic inflammatory response, and organ failure. MIS-C with a history of COVID-19 may share clinical features with other well-defined syndromes such as macrophage activation syndrome, Kawasaki disease, hemophagocytic syndrome and toxic shock syndrome. Case 1: An 11-year-old male with a history of hypothyroidism and precocious puberty with positive antibody test for COVID-19 was admitted for fever, poor general condition, severe respiratory distress, refractory shock, and multiple organ failure. His laboratory examination showed elevated inflammatory parameters, and bone marrow aspirate showed hemophagocytosis. Case 2: A 13-year-old male with a history of attention deficit hyperactivity disorder and cognitive delay presented clinical manifestations of Kawasaki disease, fever, conjunctival congestion, exanthema, and hyperemia in oral mucosa, tongue, and genitals, with refractory shock and multiple organ failure. Reverse transcriptase polymerase chain reaction (RT-PCR) and antibodies for COVID-19 were negative, inflammation parameters were elevated, and bone marrow aspirate showed hemophagocytosis. Patients required intensive care with invasive mechanical ventilation, vasopressor support, intravenous gamma globulin, systemic corticosteroids, low molecular weight heparin, antibiotics, and monoclonal antibodies and, patient 2 required renal replacement therapy. Conclusions: Multisystemic inflammatory syndrome in children can have atypical manifestations, and identifying them early is very important for the timely treatment and prognosis of patients.

Cytokine Storm Syndromes in Pediatric Patients.

Cytokine storm syndromes (CSS) represent a diverse group of disorders characterized by severe overactivation of the immune system. In the majority of patients, CSS arise from a combination of host factors, including genetic risk and predisposing conditions, and acute triggers such as infections. CSS present differently in adults than in children, who are more likely to present with monogenic forms of these disorders. Individual CSS are rare, but in aggregate represent an important cause of severe illness in both children and adults. We present 3 rare, illustrative cases of CSS in pediatric patients that describe the spectrum of CSS.

Solid organ graft-versus-host disease in a recipient of a COVID-19 positive liver graft

A 66-year-old male with end-stage liver disease (ESLD) secondary to non-alcoholic fatty liver disease (NAFLD), complicated by hepatocellular carcinoma (HCC), underwent deceased donor liver transplantation from a Coronavirus disease 2019 (COVID-19) positive donor. He presented a month later with fever, diarrhea and pancytopenia which led to hospitalization. The hospital course was notable for respiratory failure, attributed to invasive aspergillosis, as well as a diffuse rash. A bone marrow biopsy revealed hypocellular marrow without specific findings. In the following days, laboratory parameters raised concern for secondary hemophagocytic lymphohistiocytosis (HLH). Clinical concern also grew for solid organ transplant graft-versus-host-disease (SOT-GVHD) based on repeat marrow biopsy with elevated donor-derived CD3+ T cells on chimerism. After, a multidisciplinary discussion, the patient was started on ruxolitinib, in addition to high dose steroids, to address both SOT-GVHD and secondary HLH. Patient developed symptoms concerning for hemorrhagic stroke and was transitioned to comfort care. Although GVHD has been studied extensively in hematopoietic stem cell transplant (HSCT) patients, it is a rare entity in SOT with a lack of guidelines for management. Additionally, whether COVID-19 may play a role in development of SOT-GVDH has not been explored.Copyright © 2023 The Authors

Could Metrnl be a New Biomarker to Predict the Development of Macrophage Activation Syndrome in COVID-19 Patients?

Introduction: Failure to maintain the inflammatory and anti-inflammatory balance during COVID-19 treatment may result in a severe clinical course. In our study, we aimed to determine the relationship between the meteorin-like protein (metrnl), which plays a role in the anti-inflammatory balance, and the clinical course. Material(s) and Method(s): Between October 2021 and December 2021, 160 patients who were hospitalized in our hospital and whose delta variant COVID-19 infection was confirmed and 80 healthy controls, were enrolled in the study. Patients were divided into two groups according to the severity degree of COVID-19 (Group 1: Moderate COVID-19, Group 2: Severe COVID-19 MAS). Result(s): When comparing the metrnl levels of the groups, it was observed that the metrnl level was statistically significantly lower in Group 2 patients (p< 0.001). While no statistically significant difference was observed between the healthy control group and Group 1, it was observed that the metrnl level of Group 2 patients was statistically significantly lower than the healthy control group (p= 0.77, <0.001 respectively). In the ROC curve analysis of Metrnl level performed in Group 1 and 2 patients, the cut-off value was taken as 17.54 ng/mL, its sensitivity was observed as 80% and the specificity was observed as 60% in predicting the development of severe COVID-19 in patients whose levels were below this value. Conclusion(s): The low level of metrnl, which is thought to play a key role in anti-inflammatory balance, contributes to the development of macrophage activation syndrome, which leads to the severe clinical course in COVID-19 patients.Copyright © 2023 Bilimsel Tip Yayinevi. All rights reserved.

The clinical utility of CD163 in viral diseases.

Macrophage activation and hypercytokinemia are notable presentations in certain viral infections leading to severe disease and poor prognosis. Viral infections can cause macrophage polarization into the pro-inflammatory M1 or anti-inflammatory M2 phenotype. Activated M1 macrophages usually restrict viral replication whereas activated M2 macrophages suppress inflammation and promote tissue repair. In response to inflammatory stimuli, macrophages polarize to the M2 phenotype expressing hemoglobin scavenger CD163 surface receptor. The CD163 receptor is shed as the soluble form, sCD163, into plasma or tissue fluids. sCD163 causes detoxification of pro-oxidative hemoglobin which produces anti-inflammatory metabolites that promote the resolution of inflammation. Hence, increased CD163 expression in tissues and elevated circulatory levels of sCD163 have been associated with acute and chronic inflammatory diseases. CD163 and other macrophage activation markers have been commonly included in the investigation of disease pathogenesis and progression. This review provides an overview of the involvement of CD163 in viral diseases. The clinical utility of CD163 in viral disease diagnosis, progression, prognosis and treatment evaluation is discussed.

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.

Effects of Various Mrna-Lnp Vaccine Doses on Neuroinflammation in Balb/C Mice

It has been proven that mRNA vaccines are highly effective against the COVID-19 outbreak, and low prevalence of side effects has been shown. However, there are still many gaps in our understanding of the biology and biosafety of nucleic acids as components of lipid nanoparticles (LNPs) most often used as a system for inctracellular delivery of mRNA-based vaccines. It is known that LNPs cause severe injection site inflammation, have broad biodistribution profiles, and are found in multiple tissues of the body, including the brain, after administration. The role of new medications with such pharmacokinetics in inflammation developing in inaccessible organs is poorly understood. The study was aimed to assess the effects of various doses of mRNA-LNP expressing the reporter protein (0, 5, 10, and 20 microg of mRNA encoding the firefly luciferase) on the expression of neuroinflammation markers (Tnfalpha, Il1beta, Gfap, Aif1) in the prefrontal cortex and hypothalamus of laboratory animals 4, 8, and 30 h after the intramuscular injection of LNP nanoemulsion. It was shown that mRNA-LNP vaccines in a dose of 10-20 microg of mRNA could enhance Aif1 expression in the hypothalamus 8 h after vaccination, however, no such differences were observed after 30 h. It was found that the Gfap, l11beta, Tnfalpha expression levels in the hypothalamus observed at different times in the experimental groups were different. According to the results, mRNA-LNPs administered by the parenteral route can stimulate temporary activation of microglia in certain time intervals in the dose-dependent and site specific manner.Copyright © 2022 Pirogov Russian National Research Medical University. All rights reserved.

Kawasaki Disease in Children and Pediatric Multisystem Inflammatory Syndrome Associated with SARS-CoV-2 During the Pandemic (Clinical Lecture).

The article presents modern data about Kawasaki disease, which is a genetically determined systemic vasculitis with damage to the coronary arteries and multisystem manifestations. The etiology is not fully understood, but there is considered a possible role of viruses in the initiation of the aggravated immune response with possible development of macrophage activation syndromes and shock, which can lead to death. There are difficulties in diagnosing Kawasaki disease due to a variety of symptoms that are typical for a lot of infectious and autoimmune diseases (scarlet fever, measles, yersiniosis, systemic juvenile idiopathic arthritis). Early diagnosis and treatment (in the first 10 days of illness) using high doses of intravenous immunoglobulin and aspirin are associated with a low risk of development of coronary aneurysms and other complications. The authors also presented the data on the characteristics of severe Kawasaki-like diseases, which were recorded in several countries of Europe and America at the peak of the COVID-19 pandemic, and diagnostic criteria for the pediatric multisystem inflammatory syndrome associated with SARS-CoV-2, proposed by the Royal College of Pediatrics and Children Health (UK).Copyright © 2020, Professionalnye Izdaniya. All rights reserved.

Kawasaki Disease in Children and Pediatric Multisystem Inflammatory Syndrome Associated with SARS-CoV-2 During the Pandemic (Clinical Lecture).

The article presents modern data about Kawasaki disease, which is a genetically determined systemic vasculitis with damage to the coronary arteries and multisystem manifestations. The etiology is not fully understood, but there is considered a possible role of viruses in the initiation of the aggravated immune response with possible development of macrophage activation syndromes and shock, which can lead to death. There are difficulties in diagnosing Kawasaki disease due to a variety of symptoms that are typical for a lot of infectious and autoimmune diseases (scarlet fever, measles, yersiniosis, systemic juvenile idiopathic arthritis). Early diagnosis and treatment (in the first 10 days of illness) using high doses of intravenous immunoglobulin and aspirin are associated with a low risk of development of coronary aneurysms and other complications. The authors also presented the data on the characteristics of severe Kawasaki-like diseases, which were recorded in several countries of Europe and America at the peak of the COVID-19 pandemic, and diagnostic criteria for the pediatric multisystem inflammatory syndrome associated with SARS-CoV-2, proposed by the Royal College of Pediatrics and Children Health (UK).Copyright © 2020, Professionalnye Izdaniya. All rights reserved.

Assessment and management of the SARS-CoV-2 infection: A secondary center experience: Approach to COVID-19 infection

Aim: The aim of the study was to evaluate the management and outcomes of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a secondary hospital. Material(s) and Method(s): This study included 699 hospitalized patients who had positive rRT-PCR for SARS-CoV-2 and/or typical findings of COVID-19 on chest computed tomography (CT). Demographics, comorbidities, initial laboratory tests on admission, treatment modalities, complications and outcomes were evaluated retrospectively. Result(s): The mean age was 57.0+/-15.6 (range:16-94 years), and male to female ratio was 1.24;58.7% of the patients had at least one underlying comorbidity, the most common was hypertension;18.1% of the patients had lymphopenia, 35.7% hyperferritinemia, 58.3% had increased lactate dehydrogenase, and 58.5% had increased D-dimer. Chest CT revealed moderate and severe stages in 57.9% of the patients. Hydroxychloroquine was given to 37.2% and favipiravir to 67.1% of the patients. No significant difference was observed between treatment groups in terms of mortality (P=0.487);5.8% of the patients were transferred to the ICU, 75.6% of whom needed non-invasive and 36.5% invasive mechanical ventilation. The overall case-fatality rate was 0.9. Discussion(s): Older age, male gender, low lymphocyte count, CT findings, including bilateral involvement and severe stage were significantly associated with poor prognosis and mortality.Copyright © 2022, Derman Medical Publishing. All rights reserved.

Diagnostic Criteria for COVID-19 Pneumonia in Broncho-Alveolar Lavage Specimens

Introduction: Acute respiratory distress syndrome develops in up to 30% of COVID-19 pneumonia patients. Characterizations of cytologic criteria in bronchoalveolar lavage (BAL) specimens are not well-established. This study evaluates the value of applying several cytologic criteria for the diagnosis of COVID-19 infection in BAL samples. Material(s) and Method(s): We performed a retrospective review of 64 BAL samples collected 6/2020 - 8/2021, divided into two groups: COVID-19 positive group (n=30) and negative group (n=34). Median time from COVID-19 diagnosis to BAL collection was 23 days (range;9-208). The type of inflammation and the cytologic features of alveolar macrophages and respiratory epithelial cells were enumerated. The most common features in COVID-19 positive patients were defined as major diagnostic criteria. Blinded review by a second cytopathologist was performed to predict COVID-19 diagnosis using the defined criteria. Result(s): COVID-19 positive group showed more mixedtype (acute and chronic) inflammation (67% vs 21%;P=0.002), fewer pigment-laden macrophages (22% vs 62%;P=0.001), more enlarged macrophages (85% vs 32%;P<0.001), multi-nucleated macrophages (67% vs 21%;P=0.002) and multi-vacuolated cytoplasm of the macrophages (78% vs 29%;P=0.003) [Figures 1&2]. There was insignificant difference for reactive respiratory epithelial Acta Cytologica 2022;66(suppl 1):1-150 DOI: 10.1159/000527858 12 Exfoliative - Fluids (CSF, Pleural, Peritoneal, etc.) cells (37% vs 24%;P=0.4) and macrophages abundance (63% vs 44%;P=0.5). Identification of diagnostic criteria by a second cytopathologist in COVID-19 positive group, predicted COVID- 19 disease in 27% (>3 major criteria present). After exclusion of cases with remote COVID-19 infection (n=4), the mean interval in days between COVID-19 infection and BAL collection was significantly higher in cases with positive disease prediction (30.5 vs 20.7, P=0.04). Conclusion(s): Features associated with macrophage activation (enlarged and multinucleated macrophages with multi-vacuolated cytoplasm) are prominent in COVID-19 BAL samples. These features may become more recognizable with longer time intervals after infection. Observation of these findings suggest consideration of COVID-19 as the etiology of an individual's pneumonia. (Figure Presented).

Multimodal Identification by Transcriptomics and Multiscale Bioassays of Active Components in Xuanfeibaidu Formula to Suppress Macrophage-Mediated Immune Response.

Xuanfeibaidu Formula (XFBD) is a Chinese medicine used in the clinical treatment of coronavirus disease 2019 (COVID-19) patients. Although XFBD has exhibited significant therapeutic efficacy in clinical practice, its underlying pharmacological mechanism remains unclear. Here, we combine a comprehensive research approach that includes network pharmacology, transcriptomics, and bioassays in multiple model systems to investigate the pharmacological mechanism of XFBD and its bioactive substances. High-resolution mass spectrometry was combined with molecular networking to profile the major active substances in XFBD. A total of 154 compounds were identified or tentatively characterized, including flavonoids, terpenes, carboxylic acids, and other types of constituents. Based on the chemical composition of XFBD, a network pharmacology-based analysis identified inflammation-related pathways as primary targets. Thus, we examined the anti-inflammation activity of XFBD in a lipopolysaccharide-induced acute inflammation mice model. XFBD significantly alleviated pulmonary inflammation and decreased the level of serum proinflammatory cytokines. Transcriptomic profiling suggested that genes related to macrophage function were differently expressed after XFBD treatment. Consequently, the effects of XFBD on macrophage activation and mobilization were investigated in a macrophage cell line and a zebrafish wounding model. XFBD exerts strong inhibitory effects on both macrophage activation and migration. Moreover, through multimodal screening, we further identified the major components and compounds from the different herbs of XFBD that mediate its anti-inflammation function. Active components from XFBD, including Polygoni cuspidati Rhizoma, Phragmitis Rhizoma, and Citri grandis Exocarpium rubrum, were then found to strongly downregulate macrophage activation, and polydatin, isoliquiritin, and acteoside were identified as active compounds. Components of Artemisiae annuae Herba and Ephedrae Herba were found to substantially inhibit endogenous macrophage migration, while the presence of ephedrine, atractylenolide, and kaempferol was attributed to these effects. In summary, our study explores the pharmacological mechanism and effective components of XFBD in inflammation regulation via multimodal approaches, and thereby provides a biological illustration of the clinical efficacy of XFBD.