The Impact of the Sars-Cov-2 Pandemic (COVID-19) on the Incidence of Newly Diagnosed Multiple Myeloma Patients Using a Federated Network of Real-World Evidence in US and Germany

Objectives: COVID-19 had an impact on health care, including diagnostics. Early diagnosis of MM is a critical factor for prognosis. We examined the impact of COVID-19 on incidence of NDMM patients and on characteristics in NDMM patients in US and in Germany. Method(s): 44,164 NDMM patients were identified in TriNetX federated network across 55 healthcare organizations in US between January 2018 and December 2021. A bivariate analysis examined changes in patient characteristics in two cohorts before (Cohort 1;n=25513) and after (Cohort 2;n=18.651) the start of the COVID-19 pandemic in March 2020. 4172 NDMM patients were identified in the German database in a sample of across >100 healthcare organizations in the same time period. Similarly, bivariate analysis examined changes in patient characteristics before (Cohort 1;n=2252) and after (Cohort 2;n=1920) the start of pandemic. Result(s): Analysis of US data showed a significant decrease in incidence of NDMM. Bivariate analysis revealed that NDMM patients in Cohort 2 have a significantly higher risk profile compared with patients in Cohort 1, higher incidence of renal failure (13.5% v. 15.43%), heart failure (10.3% v 11.26%), bone lesions (12.6% v. 13.05%) and anemia (26.8% v. 29.75%). The German data indicated an increased risk profile in Cohort 2, with higher reporting of renal impairment (12.3% v. 15.5%) and cardiac impairment (8.3% v. 10.9%). The higher risk profile was reflected in a significant increase of all SLiM-CRAB criteria, notably hypercalcemia (24.1 % v. 36.9%), bone marrow plasma cell infiltration (28.1% v. 36.8%) and free light chain involvement (27.3% v. 41.3%). Conclusion(s): The results provide real-world evidence of a change in risk profile for patients with NDMM during COVID-19. This higher risk profile is observed in both the US and Germany, and may negatively impact outcomes such as progression-free and five-year overall survival.Copyright © 2023

The immunopathology of COVID-19 placentitis: A multi-omic spatial approach

Problem: COVID-19 placentitis is a rare complication of maternal SARS-CoV-2 respiratory infection associated with serious adverse obstetric outcomes, including intra-uterine death. The precise role of SARS-CoV-2 in COVID-19 placentitis is uncertain, as trophoblast infection is only observed in around one-half of the affected placenta. Method of Study: Through multi-omic spatial profiling, including Nanostring GeoMX digital spatial profiling and Lunaphore COMET multiplex IHC, we provide a deep characterization of the immunopathology of placentitis from obstetrically complicated maternal COVID-19 infection. Result(s):We show that SARS-CoV-2 infection of placental trophoblasts is associated with a distinct innate and adaptive immune cell infiltrate, florid cytokine expression and upregulation of viral restriction factors. Quantitative spatial analyses reveal a unique microenvironment surrounding virus-infected trophoblasts characterizedd by multiple immune evasion mechanisms, including immune checkpoint expression, cytotoxic T-cell exclusion, and interferon blunting. Placental viral loads inversely correlated with the duration of maternal infection consistent with progressive virus clearance, potentially explaining the absence of virus in some cases. Conclusion(s): Our results demonstrate a central role for placental SARS-CoV-2 infection in driving the unique immunopathology of COVID-19 placentitis.

Exploration of potential mechanism of SARS-CoV-2 induced immune inflammatory response leading to progression of atherosclerosis and prediction of traditional Chinese medicine for preventing and treating based on bioinformatics.

Objective To explore the core targets and important pathways of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induced atherosclerosis (AS) progression from the perspective of immune inflammation, so as to predict the potential prevention and treatment of traditional Chinese medicine (TCM). Methods Microarray data were obtained from the Gene Expression Omnibus (GEO) database for coronavirus disease 2019 (COVID-19) patients and AS patients, and the "limmar" and "Venn" packages were used to screen out the common differentially expressed genes (DEGs) genes in both diseases. The gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses were performed on the common DEGs to annotate their functions and important pathways. The two gene sets were scored for immune cells and immune function to assess the level of immune cell infiltration. The protein-protein interaction (PPI) network was constructed by STRING database, and the CytoHubba plug-in of Cytoscape was used to identify the hub genes. Two external validation datasets were introduced to validate the hub genes and obtain the core genes. Immuno-infiltration analysis and gene set enrichment analysis (GSEA) were performed on the core genes respectively. Finally the potential TCM regulating the core genes were predicted by Coremine Medical database. Results A total of 7898 genes related to COVID-19, 471 genes related to AS progression;And 51 common DEGs, including 32 highly expressed genes and 19 low expressed genes were obtained. GO and KEGG analysis showed that common DEGs, which were mainly localized in cypermethrin-encapsulated vesicles, platelet alpha particles, phagocytic vesicle membranes and vesicles, were involved in many biological processes such as myeloid differentiation factor 88 (MyD88)-dependent Toll-like receptor signaling pathway transduction, interleukin-8 (IL-8) production and positive regulation, IL-6 production and positive regulation to play a role in regulating nicotinamide adenine dinucleotide phosphate oxidase activity, Toll-like receptor binding and lipopeptide and glycosaminoglycan binding through many biological pathways, including Toll-like receptor signaling pathways, neutrophil extracellular trap formation, complement and coagulation cascade reactions. The results of immune infiltration analysis demonstrated the state of immune microenvironment of COVID-19 and AS. A total of 5 hub genes were obtained after screening, among which Toll-like receptor 2 (TLR2), cluster of differentiation 163 (CD163) and complement C1q subcomponent subunit B (C1QB) genes passed external validation as core genes. The core genes showed strong correlation with immune process and inflammatory response in both immune infiltration analysis and GSEA enrichment analysis. A total of 35 TCMs, including Chuanxiong (Chuanxiong Rhizoma), Taoren (Persicae Semen), Danggui (Angelicae Sinensis Radix), Huangqin (Scutellariae Radix), Pugongying (Taraxaci Herba), Taizishen (Pseudostellariae Radix), Huangjing (Polygonati Rhizoma), could be used as potential therapeutic agents. Conclusion TLR2, CD163 and C1QB were the core molecules of SARS-CoV-2-mediated immune inflammatory response promoting AS progression, and targeting predicted herbs were potential drugs to slow down AS progression in COVID-19 patients.Copyright © 2023 Editorial Office of Chinese Traditional and Herbal Drugs. All rights reserved.

Extracorporeal cytokine hemadsorption in severe COVID-19 respiratory failure

Background: At least 20% of coronavirus disease 2019 (COVID-19) patients develop acute hypoxemic respiratory failure requiring admission to intensive care unit in 5-32% of the cases. Hyper-inflammatory activation characterized by immune cell infiltration and elevated levels of cytokines was reported as the main mechanism leading to critical illness and severe acute respiratory distress syndrome (ARDS). CytoSorb is currently used for all the conditions where elevated levels of cytokines are present. Along with the beneficial effect on systemic inflammation, CytoSorb can be easily integrated with all extracorporeal circulation systems. Case Presentation: Here, we present the laboratory and clinical outcomes of 11 patients with microbiological confirmed SARS-CoV-2 infection. These patients were treated with CytoSorb to remove the excess of cytokine. All patients were male, overweight and only 3 (27%) were over 70 years old. Median age was 62 years and median body mass index was 28. Best supportive care was provided according to hospital guidelines of that moment and included antibiotic therapy, antiretroviral therapy and protective ventilation. Result(s): Cytokines levels were evaluated before and after treatment. A significant reduction of IL-6, IL-8, IL-10 and IL-1beta was observed. A significant drop of C-reactive protein (CRP) median levels was observed starting from 48 hours after treatment start levels. The decrease in the inflammatory status was associated with a progressive improvement in the respiratory function, with a significant increase in P/F from the first day after the end of the therapy. A similar trend was observed for procalcitonin. Conclusion(s): CytoSorb therapy proved to be safe in COVID-19 patients. A clinical improvement was observed in most of the treated patients despite the severity of the disease. In this study CytoSorb was used empirically for 24- 48 hours based on previous experience in septic shock. The persistence of significant levels of IL-6 and CRP after CytoSorb treatment may suggest that a prolonged treatment can improve the efficacy in controlling COVID-19 hyperinflammatory status.

Multifactorial Effects of Covid-19: A Review of Published Autopsy Reports

Introduction: SARS-CoV-2 is responsible for the current global pandemic. SARS-CoV-2 infection underlies the novel viral condition coronavirus disease 2019 (COVID-19). COVID-19 causes significant pulmonary sequelae contributing to serious morbidities. The pathogenesis of COVID-19 is complex with a multitude of factors leading to varying levels of injury numerous extrapulmonary organs. This review of 124 published articles documenting COVID- 19 autopsies included 1,142 patients. Method(s): A PubMed search was conducted for COVID-19 autopsy reports published before March 2021 utilizing the query COVID-19 Autopsy. There was no restriction regarding age, sex, or ethnicity of the patients. Duplicate cases were excluded. Findings were listed by organ system from articles that met selection criteria. Result(s): Pulmonary pathology (72% of articles;866/1142 patients): diffuse alveolar damage (563/866), alveolar edema (251/866), hyaline membrane formation (234/866), type II pneumocyte hyperplasia (165/866), alveolar hemorrhage (164/866), and lymphocytic infiltrate (87/866). Vascular pathology (41% of articles;771/1142 patients): vascular thrombi (439/771)-microvascular predominance (294/439)-and inflammatory cell infiltrates (116/771). Cardiac pathology (41% of articles;502/1142 patients): cardiac inflammation (186/502), fibrosis (131/502), cardiomegaly (100/502), hypertrophy (100/502), and dilation (35/502). Hepatic pathology (33% of articles;407/1142 patients): steatosis (106/402) and congestion (102/402). Renal pathology (30% of articles;427/1142 patients): renal arteries arteriosclerosis (111/427), sepsis-associated acute kidney injury (81/427) and acute tubular necrosis (77/427). Conclusion(s): This review revealed anticipated pulmonary pathology, along with significant extrapulmonary involvement secondary to COVID-19, indicating widespread viral tropism throughout the human body. These diverse effects require additional comprehensive longitudinal studies to characterize short-term and long-term COVID-19 sequelae and inform COVID-19 treatment.

Evaluation of Efficacy of the Amino Acid-Peptide Complex Administered Intragastrically to Golden Hamsters Experimentally Infected with Sars-Cov-2

The development of coronavirus infection outbreak into a pandemic, coupled with the lack of effective COVID-19 therapies, is a challenge for the entire pharmaceutical industry. This study aimed to assess the treatment and preventive efficacy of the amino acid-peptide complex (APC) in male Syrian hamsters infected with SARSCoV-2 (intranasal administration of 26 mul of the virus culture, titer of 4 x 104 TCD50/ml). In a modeled COVID-19 case, APC administered for treatment and preventive purposes reduced lung damage. Compared to the positive control group, test group had the lung weight factor 15.2% smaller (trend), which indicates a less pronounced edema. Microscopic examination revealed no alveolar edema, atypical hypertrophied forms of type II alveolocytes, pulmonary parenchyma fibrinization. The macrophage reaction intensified, which is probably a result of the APC-induced activation of regenerative processes in the lung tissues. Spleens of the animals that received APC for therapeutic and preventive purposes were less engorged and had fewer hemorrhages. The decrease of body weight of the test animals that received APC for treatment and prevention was insignificant (p < 0.05), which indicates a less severe course of COVID-19. Administered following a purely therapeutic protocol, APC proved ineffective against SARS-CoV-2 post-infection. Thus, APC-based drug used as a therapeutic and preventive agent reduces pulmonary edema and makes morphological signs of lung tissue damage less pronounced in male Syrian hamsters infected with SARS-CoV-2.Copyright © Extreme Medicine.All right reserved.

Rare Case of Immune-Mediated Necrotizing Myopathy With Isolated Dysphagia as Presenting Symptom

Introduction: Immune mediated necrotizing myopathy (IMNM) is a rare, but progressive disease that accounts for about 19% of all inflammatory myopathies. Dysphagia occurs in 20-30% of IMNM patients. It often follows proximal muscle weakness and ensues in the later stages of the disease. We report a rare case of IMNM, presenting with dysphagia as the initial symptom, followed by proximal muscle weakness. Case Description/Methods: A 74-year-old male with a past medical history of coronary artery disease, hypertension, and hyperlipidemia presented to the ED with 2-3 weeks of intractable nausea, vomiting, and dysphagia for solids and liquids. Vital signs were stable, and initial labs displayed an AST of 188 U/L and ALT of 64 U/L with a normal bilirubin. Computed tomogram of the chest, abdomen, and pelvis were negative. An esophagram showed moderate to severe tertiary contraction, no mass or stricture, and a 13 mm barium tablet passed without difficulty. Esophagogastroduodenoscopy exhibited a spastic lower esophageal sphincter. Botox injections provided no significant relief. He then developed symmetrical proximal motor weakness and repeat labs demonstrated an elevated creatine kinase (CK) level of 6,357 U/L and aldolase of 43.4 U/L. Serology revealed positive PL-7 autoxantibodies, but negative JO-1, PL-12, KU, MI-2, EJ, SRP, anti-smooth muscle, and anti-mitochondrial antibodies. Muscle biopsy did not unveil endomysial inflammation or MHC-1 sarcolemmal upregulation. The diagnosis of IMNM was suspected. A percutaneous endoscopic gastrostomy feeding tube was placed as a mean of an alternative route of nutrition. He was started on steroids and recommended to follow up with outpatient rheumatology. He expired a month later after complications from an unrelated COVID-19 infection. Discussion(s): The typical presentation of IMNM includes painful proximal muscle weakness, elevated CK, presence of myositis-associated autoantibodies, and necrotic muscle fibers without mononuclear cell infiltrates on histology. Dysphagia occurs due to immune-mediated inflammation occurring in the skeletal muscle of the esophagus, resulting in incoordination of swallowing. Immunotherapy and intravenous immunoglobulin are often the mainstay of treatment. Our patient was unique in presentation with dysphagia as an initial presenting symptom of IMNM, as well as elevated enzymes from muscle breakdown. It is critical as clinicians to have a high degree of suspicion for IMNM due to the aggressive nature of the disease and refractoriness to treatment.

A CLINICAL CASE OF SARS-CoV-2 INFECTION COMPLICATED BY NEPHROGENIC PULMONARY EDEMA AND COVID-ASSOCIATED PNEUMONITIS, ALVEOLITIS.

COVID-19 is a highly transmissible disease with severe course especially in patients with nephrogenic hypertensive disease and chronic kidney disease due to a higher incidence of all-type infections than in the general population. The aim of the study is to describe a clinical case of SARS-CoV-2 infection complicated by nephrogenic pulmonary edema and COVID-associated pneumonitis, alveolitis. Description of the case. Patient K.S., born in 1975, was hospitalized 24 hours after symptom onset at emergency hospital due to complaints of increased blood pressure up to 180-200/110-120 mm Hg, temperature up to 38.7degreeC, dry cough, feeling of heaviness in the chest, change in urine color. PCR smear for SARS-CoV-2 was positive. Computed tomography revealed a pattern of bilateral COVID-associated pneumonitis, alveolitis, with 75% involvement. The electrocardiogram revealed signs of left ventricular myocardial hypertrophy. Ultrasound examination showed numerous cysts in the kidneys. Urinalysis at admission: leukocytes - 499, erythrocytes - 386. Glomerular filtration rate (CKD-EPI: 29 ml/min/1.73 m2) and corresponds to stage IV of chronic kidney disease. Coagulogram: fibrinogen: 32.3 (1.6-4.0) g/l, D-dimer: 663 (0-250). Despite the treatment, the patient's condition worsened, the phenomena of cardiopulmonary and renal insufficiency increased, which led to a fatal outcome. During a virological study of sectional material: SARS-CoV-2 coronavirus RNA was found in the lung and kidneys. Signs of bilateral COVID-associated pneumonitis, alveolitis with diffuse cellular infiltrates in combination with changes in the alveolar apparatus, signs of pulmonary edema were revealed. Heart-related signs - swelling of the interstitium, fragmented muscle fibers, some of them hypertrophied, a wave-like deformation of cardiomyocytes, blurring of the transverse striation. Arteries with thickened sclerosed walls. In the kidneys - diffuse damage to the proximal tubules of the nephron with areas of cortical and proximal necronephrosis, areas of fibrinoid swelling. Conclusion. The cause of death of a 45-year-old patient was a severe course of bilateral COVID-associated pneumonitis, alveolitis, which contributed to the development of renal medullary hypoxia and type 1 cardiorenal syndrome, which led to early nephrogenic pulmonary edema.Copyright © 2023 Saint Petersburg Pasteur Institute. All rights reserved.

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.

Characterization of the Immune Reaction to Covid-19 Treatment with Dexamethasone: A Narrative Review

Purpose of Study: The spread of SARS-CoV-2 and the resulting Coronavirus Disease 2019 (COVID-19) continues to manifest in individuals in varying severity with limited treatment options available. Despite research efforts put forth in developing therapeutic options for treatment of COVID-19 disease, effective and well understood mechanisms remain limited. Corticosteroid treatment with dexamethasone was shown to be beneficial for those with severe illness early in the pandemic with little understanding of its beneficial mechanism. This narrative review describes the current findings regarding the mechanism of action of dexamethasone treatment in the setting of SARS-CoV-2 infection. Methods Used: A comprehensive search of Embase and PubMed was conducted in consultation with a health sciences librarian. Search terms included (1) COVID-19 (2) dexamethasone (3) animal model and (4) immune response. No limits were used on the search and other reviews were excluded. Search results were screened based on titles and s before being selected for full text review. Outcomes recorded included characterization of the microenvironment of lung tissue following SARS-CoV-2 through cytokine measurement, histopathological staining and analysis of lung tissue, and clinical outcomes such as survival time. Summary of Results: The search resulted in 100 articles. Of these, 8 articles were identified that met the inclusion criteria. Three conducted experiments with Syrian hamsters, two with mice, two with alveolar macrophages, and one study was conducted with human subjects. Dexamethasone treatment was found to diminish inflammatory cytokine levels and preserve the integrity of lung tissue in several animal models and in vitro experiments in the setting of SARS-CoV-2 infection. Dexamethasone treatment was also found to reduce inflammatory cell infiltration of lung tissue infected with SARS-CoV-2. In humans, combination therapy of low dose dexamethasone with spironolactone proved more effective at lowering inflammatory markers than high dose dexamethasone alone. Conclusion(s): Collectively, the articles included in this review support the use of dexamethasone treatment in SARS-CoV-2 infection. Protective effects exhibited with dexamethasone treatment suggest that its action may be linked to the inflammatory nature of COVID-19 disease. Macrophage regulation and diminished inflammatory cytokine levels were hypothesized as possible mechanistic features of dexamethasone action but lacked exact characterization. Further exploration of combination treatment with dexamethasone and its mechanism of action is needed to identify specific and effective therapeutic strategies in the future.

Sars-Cov-2 Associated Myopathy

An association between SARS-CoV-2 infection and myopathy was suspected early in the pandemic: patients with severe COVID-19 showed increased levels of creatine kinase that could not be solely explained by cardiac affection. On the other hand, myalgia and muscle weakness are frequent symptoms in patients with mild or moderate COVID-19 - as with many other viral infections -and subsets of infected patients report persistent muscular weakness and fatigue even months after the initial infection. We performed a case-control autopsy comparing patients with severe COVID-19 to patients with other critical illnesses and assessed inflammation of skeletal muscle tissue by quantification of immune cell infiltrates, expression of major histocompatibility complex (MHC) class I and class II antigens on the sarcolemma. Relevant expression of MHC class I antigens on the sarcolemma was present in 23 of 42 specimens from patients with COVID-19 (55%) and upregulation of MHC class II antigens in 7 of 42 specimens from patients with COVID-19 (17%), but neither were found in any of the controls. In a subset of patients, MHC class I and MHC class II expression showed a clear perifascicular pattern. Signs of degenerating and necrotic fibers could also be found, however there was no statistically significant difference in the frequency of occurrence when compared to non-COVID-19 critically ill patients. We interpreted this as non-specific signs of muscular damage in critically ill patients. Numbers of macrophages, lymphocytes and natural killer cells were found to be increased in muscles from patients with COVID-19. Interestingly, no relevant expression of MxA on myofibers could be found by immunohistochemistry, but in some cases, expression of MxA was found on capillaries. Ultrastructural analysis of selected muscles with perifascicular MHC-expression did not show tubuloreticular inclusions. However, capillaries of the analyzed samples showed basement membrane alterations and signs of ongoing regenerative processes. In addition, we evaluated inflammation of cardiac muscles by quantification of immune cell infiltrates in the same patients, and found that skeletal muscles showed more inflammatory features than cardiac muscles. Moreover, inflammation was most pronounced in patients with COVID-19 with chronic courses. In some muscle specimens, SARS-CoV-2 RNA was detected by reverse transcription-polymerase chain reaction, but no evidence for a direct viral infection of myofibers was found by immunohistochemistry or electron microscopy. This suggests that SARS-CoV-2 may be associated with a postinfectious, immune-mediated myopathy.

Enhanced TLR7 immunity drives innate protection against SARS-CoV-2 with chilblains as collateral damage

Outbreaks of chilblains, a hallmark sign of type I interferonopathies, have been reported during the COVID-19 pandemic. These cases occurred mostly in patients who were asymptomatic and showed negative results from PCR and serology tests for SARS-CoV-2. We hypothesized that chilblain patients are predisposed to mount a robust innate immunity against the virus, which clinically manifests as chilblains and promotes early viral clearance, thereby preventing pulmonary disease and precluding adaptive responses. By profiling skin lesions in the early stage following chilblain onset, we uncover a transient IRF7-dependent type I interferon (IFN) signature that is driven by the acral infiltration of systemically activated plasmacytoid dendritic cells (pDCs). Patients' peripheral blood mononuclear cells (PBMCs) demonstrate increased production of IFNalpha when exposed to SARS-CoV-2 and influenza A, but not herpes simplex virus 1 (HSV-1), indicating a heightened ability to detect RNA -but not DNA- viruses. Further investigations revealed enhanced responsiveness of pDCs in chilblain patients to the RNA sensor TLR7, but not the DNA sensor TLR9. Collectively, our study establishes a two-step model for the immunopathology of SARS-CoV-2-related chilblains: enhanced TLR7 immunity in pDCs, likely triggered by SARS-CoV-2 exposure at the mucosal site, leads to prompt viral clearance, which explains the lack of infection markers in most cases. Subsequently, systemic spread of activated pDCs and infiltration of the toes in response to mechanical stress or acral coldness, may result in IFN-mediated tissue damage with development of chilblains.Copyright © 2023

Unusual Myositis of the Temporalis Muscle Occurring with Acute Covid-19

Background. SARS-CoV-2 infection can be accompanied by neuromuscular disorders. Rhabdomyolysis and Guillain-Barre syndrome have been described repeatedly. There are case reports of inflammatory myopathies manifesting during COVID-19, presenting as dermatomyositis, polymyositis or immune-mediated necrotizing myopathy, with dermatomyositis-like presentations most commonly reported. Larger cases series are from postmortem examinations of COVID-19 patients, where variable inflammatory pathology of the skeletal muscle has been found frequently but without local detection of the actual virus. Thus, autoimmune mechanisms or the systemic interferon response are discussed as causes. We report a case of focal inflammatory myopathy with perimysial pathology of the temporalis muscle occurring with acute, but mild COVID-19. Methods. Case report of clinical observations, cranial MRI, histopathological, and laboratory findings. 3T cranial MRI was performed with gadolinium contrast. Open temporalis muscle biopsy was performed. The sample underwent standard cryohistological studies as well as immunohistochemistry with antibodies against MHC-I and II, CD3, CD4, CD19, CD68, anti-MAC, p62 and MxA. Testing for auto-antibodies was based on immunoblots or ELISA. RT-PCR for SARS-CoV-2 was run with RNA extracted from cryopreserved muscle. Results. A Caucasian woman in her 60s with no history of autoimmune or muscle complaints developed swelling and pain of the right jaw musculature five days after testing positive for SARS-CoV-2 due to respiratory tract symptoms. In addition, she experienced trismus, but no further neuromuscular complaints. The course of respiratory tract symptoms stayed mild. She had been vaccinated previously with single shot SARS-CoV-2 vector vaccine. Due to persistent swelling and complaints, giant cells arteritis was excluded by unresponsiveness to five days oral steroids and sonography of the temporal artery. Cranial MRI was performed nearly four weeks after the SARS-CoV-2 infection and showed marked swelling and oedema of the temporalis muscle. Its biopsy showed numerous CD68 and acid phosphatase positive cells infiltrating from perimysial perivascular foci towards the endomysium with perimysial damage but little damage of adjacent, perifascicular muscle fibres. Muscle fibres did not react with anti-MHC-II, anti-MAC or -MxA. Capillaries did not react with anti-MAC or -MxA. SARS-CoV-2 RNA was not detected in muscle tissue. Serum creatine kinase was not elevated in the subacute phase. Slightly elevated ANA titre led to detection of autoantibodies against proliferating cell nuclear antigen (PCNA). No pathological results for other autoantibodies, including myositis-specific antibodies and anti-ds-DNA, were found in blood. Neither were antibodies against hepatitis C and B viruses. Retesting 15 weeks after infection, anti-PCNA immunoblot was still positive, but ELISA did not indicate a pathologic titre. The swelling, myalgia and trismus regressed spontaneously a month after onset, yet the latter still persists at the time of reporting. Conclusion. Our case diverges from the majority of COVID-19 associated my-ositis reports in the unusual location of the focal myositis and the histopathological pattern of predominantly perimysial damage and histiocytic infiltration. It concurs with the literature as no SARS-CoV2 RNA could be detected in the muscle. Anti-PCNA is associated very rarely with myositis. Other associated disorder (systemic lupus erythematosus, chronic viral hepatitis B or C) were not found. Increased levels of autoantibodies are reported in COVID-19 and mostly attributed to loss of self-tolerance during the acute disease phase. Interestingly, the structural protein M of SARS-CoV-2 appears to interact notably with PCNA in infected cells. Still, the causal connection between the myositis and COVID-19 in this case is based on the close temporal association in the absence of alternative, competing explanations from the medical history and findings.

A review of fibroblast-like synoviocytes in the pathogenesis of Rheumatoid arthritis: Their activation and the inhibition of their apoptosis

Rheumatoid Arthritis (RA) is a systemic, autoimmune, inflammatory disease characterized by synovial hyperplasia, inflammatory cell infiltration in the synovial tissues, and progressive destruction of cartilage and bones. This disease often leads to chronic disability. More recently, activation of synovial fibroblasts (SFs) has been linked to innate immune responses and several cellular signalingpathways that ultimately result in the aggressive and invasive stages of RA. SFs are the major sources of pro-inflammatory cytokines in RA synovium. They participate in maintaining the inflammatory state that leads to synovial hyperplasia and angiogenesis in the inflamed synovium. The altered apoptotic response of synovial and inflammatory cells has been connected to these alterations of inflamed synovium. RA synovial fibroblasts (RASFs) have the ability to inhibit several apoptotic proteins that cause their abnormal proliferation. This proliferation leads to synovial hyperplasia. Apoptotic pathway proteins have thus been identified as possible targets for modifying the pathophysiology of RA. This review summarizes current knowledge of SF activation and its roles in the inhibition of apoptosis in the synovium, which is involved in joint damage during the effector phase of RA development.Copyright © 2022 Biomedpress.

Jing Si Herbal Drink as a prospective adjunctive therapy for COVID-19 treatment: Molecular evidence and mechanisms

Background: SARS-CoV-2 has led to a sharp increase in the number of hospitalizations and deaths from pneumonia and multiorgan disease worldwide;therefore, SARS-CoV-2 has become a global health problem. Supportive therapies remain the mainstay treatments against COVID-19, such as oxygen inhalation, antiviral drugs, and antibiotics. Traditional Chinese medicine (TCM) has been shown clinically to relieve the symptoms of COVID-19 infection, and TCMs can affect the pathogenesis of SARS-CoV-2 infection in vitro. Jing Si Herbal Drink (JSHD), an eight herb formula jointly developed by Tzu Chi University and Tzu Chi Hospital, has shown potential as an adjuvant treatment for COVID-19 infection. A randomized controlled trial (RCT) of JSHD as an adjuvant treatment in patients with COVID-19 infection is underway Objectives: This article aims to explore the efficacy of the herbs in JSHD against COVID-19 infection from a mechanistic standpoint and provide a reference for the rational utilization of JSHD in the treatment of COVID-19. Method(s): We compiled evidence of the herbs in JSHD to treat COVID-19 in vivo and in vitro. Result(s): We described the efficacy and mechanism of action of the active ingredients in JSHD to treat COVID-19 based on experimental evidence. JSHD includes 5 antiviral herbs, 7 antioxidant herbs, and 7 anti-inflammatory herbs. In addition, 2 herbs inhibit the overactive immune system, 1 herb reduces cell apoptosis, and 1 herb possesses antithrombotic ability. Conclusion(s): Although experimental data have confirmed that the ingredients in JSHD are effective against COVID-19, more rigorously designed studies are required to confirm the efficacy and safety of JSHD as a COVID-19 treatment.Copyright © 2021

Eosinophilic fasciitis triggered by intensive exercise

A 59-year-old white female who was previously fit and well, developed gradual tightening and thickening of the skin on her forearms progressing to the abdomen, chest and lower legs associated with restricted movement. She also noticed bruise-like patches on her trunk. There were no systemic symptoms and no history of Raynaud syndrome. Since the beginning of the COVID-19 lockdown, the patient had engaged in increasing amounts of exercise compared with normal;this included yoga once weekly for 75 min, high-intensity interval training for 20 min on alternate days, running three times weekly for 45 min, lifting 2.5 kg weights for the arms every day and regular long walks. Examination showed a 'groove' sign on her forearms and a peau d'orange appearance of the skin with a woody induration and hardness on palpation. Symmetrical and circumferential involvement on the forearms and lower legs and bruise-like indurated patches on the abdomen were noted. Differential diagnoses included eosinophilic fasciitis (EF), morphoea, EF/morphoea overlap, scleroderma, scleromyxoedema and nephrogenic systemic fibrosis. Blood investigations showed an eosinophilia of 1.2 x 109 cells L-1, erythrocyte sedimentation rate of 31 mm h-1, a C-reactive protein of 20 mg L-1 and negative autoimmune and viral serology. She underwent two incisional biopsies down to fascia. The first was taken from the back, which showed an interstitial inflammatory cell infiltrate composed of lymphocytes, plasma cells and very occasional eosinophils. The subcutaneous septa were minimally thickened. The second biopsy taken from the left forearm showed striking thickening of the subcutaneous septa, with an associated inflammatory cell infiltrate, composed predominantly of lymphocytes and plasma cells. This process was deeper and more established than that seen in the biopsy from the trunk. The appearances were clearly those of a sclerosing process of the dermis and subcutis and consistent with eosinophilic fasciitis. Our diagnosis was EF with morphoea overlap and she was treated with oral methotrexate 15 mg weekly and oral prednisolone 50 mg once daily (weight 60 kg), reducing the dose by 5 mg every 2 weeks. An 80% improvement was seen in functionality within 3 months, but the skin remained tight and thickened and therefore the patient was referred for phototherapy [ultraviolet A 1 (UVA1)] as combination therapy. We present a rare case of EF, which appears to have been triggered by intensive exercise. Other causes include insect bites, radiation, infections (Mycoplasma and Borrelia) and paraneoplastic. Haematological associations have been seen, including aplastic anaemia and lymphoma. Treatment options for EF include prednisolone, UVA1/psoralen + UVA, immunosuppressive systemic agents (including ciclosporin and methotrexate), biological agents (including infliximab and rituximab) and physiotherapy.