Study on potential common action and mechanism of Reduning Injection against SARS, MERS and COVID-19 based on network pharmacology and molecular docking technology.

Objective To explore the potential common mechanism and active ingredients of Reduning Injection against SARS, MERS and COVID-19 through network pharmacology and molecular docking technology. Methods The TCMSP database was used to retrieve the chemical components and targets of Artemisiae Annuae Herba, Lonicerae Japonicae Flos and Gardeniae Fructus in Reduning Injection. The gene corresponding to the target was searched by UniProt database, and Cytoscape 3.8.2 was used to build a medicinal material-compound-target (gene) network. Three coronavirus-related targets were collected in the Gene Cards database with the key words of "SARS""MERS" and "COVID-19", and common target of three coronavirus infection diseases were screened out through Venny 2.1.0 database. The common targets of SARS, MERS and COVID-19 were intersected with the targets of Reduning Injection, and the common targets were selected as research targets. Protein-protein interaction (PPI) network map were constructed by Cytoscape3.8.2 software after importing the common targets into the STRING database to obtain data. R language was used to carry out GO biological function enrichment analysis and KEGG signaling pathway enrichment analysis, histograms and bubble charts were drew, and component-target-pathway network diagrams was constructed. The key compounds in the component-target-pathway network were selected for molecular docking with important target proteins, novel coronavirus (SARS-CoV-2) 3CL hydrolase, and angiotensin-converting enzyme II (ACE2). Results 31 active compounds and 207 corresponding targets were obtained from Reduning Injection. 2 453 SARS-related targets, 805 MERS-related targets, 2 571 COVID-19-related targets, and 786 targets for the three diseases. 11 common targets with Reduning Injection: HSPA5, CRP, MAPK1, HMOX1, TGFB1, HSP90AA1, TP53, DPP4, CXCL10, PLAT, PRKACA. GO function enrichment analysis revealed 995 biological processes (BP), 71 molecular functions (MF), and 31 cellular components (CC). KEGG pathway enrichment analysis screened 99 signal pathways (P < 0.05), mainly related to prostate cancer, fluid shear stress and atherosclerosis, hepatocellular carcinoma, proteoglycans in cancer, lipid and atherosclerosis, human T-cell leukemia virus 1 infection, MAPK signaling pathway, etc. The molecular docking results showed that the three core active flavonoids of quercetin, luteolin, and kaempferol in Reduning Injection had good affinity with key targets MAPK1, PRKACA, and HSP90AA1, and the combination of the three active compounds with SARS-CoV-2 3CL hydrolase and ACE2 was less than the recommended chemical drugs. Conclusion Reduning Injection has potential common effects on the three diseases of SARS, MERS and COVID-19. This effect may be related to those active compounds such as quercetin, luteolin, and kaempferol acting on targets such as MAPK1, PRKACA, HSP90AA1 to regulate multiple signal pathways and exert anti-virus, suppression of inflammatory storm, and regulation of immune function.Copyright © 2022 Drug Evaluation Research. All rights reserved.

A Literature Review on the Antiviral Mechanism of Luteolin

Background: Viral infections pose some of the most serious human health concerns worldwide. The infections caused by several viruses, including coronavirus, hepatitis virus, and human immunodeficiency virus, are difficult to treat. Method(s): This review details the findings of a literature search performed on the antiviral properties of luteolin. The keywords engaged in the search are "virus" along with "luteolin." Results: Luteolin possesses antiviral properties, which is the basis for the current review. It is an important natural flavonoid with numerous important biological properties, including anti-inflammatory, immune regulatory, and antitumor effects, and is found in vegetables, fruits, and several medicinal plants. Recent studies have revealed that many traditional Chinese medicines that contain luteolin inhibit the replication of coronaviruses. Conclusion(s): Luteolin effectively inhibits the replication of coronavirus, influenza virus, enterovirus, rotavirus, herpes virus, and respiratory syncytial virus, among others. In particular, it prevents viral infection by improving the body's nonspecific immunity and antioxidation capacity and inhibiting many pathways related to virus infection and replication, such as MAPK, PI3K-AKT, TLR4/8, NF-kappaB, Nrf-2/hemeoxygenase-1, and others. It also regulates the expression of some receptors and factors, including hepatocyte nuclear factor 4alpha, p53, NLRP3, TNF-alpha, and interleukins, thereby interfering with the replication of viruses in cells. Luteolin also promotes the repair of damaged cells induced by proinflammatory factors by regulating the expression of inflammatory molecules. The overall effect of these processes is the reduction in viral replication and, consequently, the viral load. This review summarizes the antiviral effect of luteolin and the mechanism underlying this property.Copyright © The Author(s) 2023.

A review of bioinformatics studies on the function of structural and nonstructural proteins and the level of glycoprotein inhibiting heme metabolism by SARS-CoV-2 virus

Coronavirus disease 2019 (COVID-19) is an acute respiratory infection. Its virus called SARS-COV-2 which is an RNA virus with high homology to the bat coronavirus. In this review study, first the molecular and cellular characteristics and the proliferation and replication of SARS-COV-2 are investigated. Then, by reviewing bioinformatics studies regarding protected domain analysis, homology modeling, and molecular docking, the biological role of some specific SARS-COV-2 proteins are examined. The results showed that the open reading frame 8 (ORF8) and surface glycoprotein could bind to porphyrin. At the same time, ORF1ab, ORF10, and ORF3a can attack the heme part of hemoglobin to dissociate iron and form porphyrin. This attack reduces hemoglobin ability to carry oxygen and carbon dioxide. As a result, lung cells become severely inflamed due to their inability to exchange carbon dioxide and oxygen, which leads to large ground-glass opacities on CT scan images. Based on the bioinformatics results, chloroquine can prevent ORF1ab, ORF3a, and ORF10 from attacking hemoglobin to form porphyrin and avoid the binding of ORF8 and surface glycoprotein to porphyrin, which effectively relieves the symptoms of acute respiratory syndrome. In the current pandemic, bioinformatics studies are of great importance for preventing the spread of COVID-19, developing drugs and vaccines, and clinical practice.

Efficient De Novo Biosynthesis of Heme by Membrane Engineering in Escherichia coli.

Heme is of great significance in food nutrition and food coloring, and the successful launch of artificial meat has greatly improved the application of heme in meat products. The precursor of heme, 5-aminolevulinic acid (ALA), has a wide range of applications in the agricultural and medical fields, including in the treatment of corona virus disease 2019 (COVID-19). In this study, E. coli recombinants capable of heme production were developed by metabolic engineering and membrane engineering. Firstly, by optimizing the key genes of the heme synthesis pathway and the screening of hosts and plasmids, the recombinant strain EJM-pCD-AL produced 4.34 ± 0.02 mg/L heme. Then, the transport genes of heme precursors CysG, hemX and CyoE were knocked out, and the extracellular transport pathways of heme Dpp and Ccm were strengthened, obtaining the strain EJM-ΔCyoE-pCD-AL that produced 9.43 ± 0.03 mg/L heme. Finally, fed-batch fermentation was performed in a 3-L fermenter and reached 28.20 ± 0.77 mg/L heme and 303 ± 1.21 mg/L ALA. This study indicates that E. coli recombinant strains show a promising future in the field of heme and ALA production.

Glutamine Deficiency Promotes Immune and Endothelial Cell Dysfunction in COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has caused the death of almost 7 million people worldwide. While vaccinations and new antiviral drugs have greatly reduced the number of COVID-19 cases, there remains a need for additional therapeutic strategies to combat this deadly disease. Accumulating clinical data have discovered a deficiency of circulating glutamine in patients with COVID-19 that associates with disease severity. Glutamine is a semi-essential amino acid that is metabolized to a plethora of metabolites that serve as central modulators of immune and endothelial cell function. A majority of glutamine is metabolized to glutamate and ammonia by the mitochondrial enzyme glutaminase (GLS). Notably, GLS activity is upregulated in COVID-19, favoring the catabolism of glutamine. This disturbance in glutamine metabolism may provoke immune and endothelial cell dysfunction that contributes to the development of severe infection, inflammation, oxidative stress, vasospasm, and coagulopathy, which leads to vascular occlusion, multi-organ failure, and death. Strategies that restore the plasma concentration of glutamine, its metabolites, and/or its downstream effectors, in conjunction with antiviral drugs, represent a promising therapeutic approach that may restore immune and endothelial cell function and prevent the development of occlusive vascular disease in patients stricken with COVID-19.

Acute Intermittent Porphyria Attack Triggered by COVID-19 Infection.

A 45-year-old male patient who was diagnosed with acute intermittent porphyria (AIP) four years ago and had his last episode two years prior presented to our clinic with an AIP attack complicated with rhabdomyolysis triggered by coronavirus disease 2019 (COVID-19) infection. Although there are well-known factors that might trigger an AIP attack, some studies also showed an association of COVID-19 with porphyria. These studies suggest that the accumulation of by-products in the heme synthesis pathway during COVID-19 infection may cause attacks mimicking acute intermittent porphyria. In respect to that, in the early phases of the pandemic, hypotheses emerged arguing the treatment of severe COVID-19 infections with hemin as the treatment of an AIP attack. In our instance, after a two-year period during which there had not been an episode, there was no evident cause other than COVID-19 infection. We believe that patients with porphyria are particularly prone to exacerbations during a COVID-19 infection and should be monitored carefully.

Features of management of anemia in pregnant women who have recovered from COVID-19

The article provides the definition of iron deficiency anemia (IDA), discusses the mechanisms of influence of iron deficiency during pregnancy, as well as the main reasons for the development of IDA in the practice of an obstetrician-gynecologist, accompanied by a significant increase in the physiological need for iron. Methods for the correction and prevention of iron deficiency are described, and differences in the absorption of heme and non-heme iron are indicated. Also, this article reveals the advantages of prevention and dietary correction of iron deficiency states using a combination of heme iron and ferrous sulfate-Richter FerroBio. © 2021, Publishing House Professional-Event. All rights reserved.

Landscape Analysis of Quercetin: A Potential Candidate Against SARS-CoV-2

Fruit, vegetables, and green tea contain quercetin (a flavonoid). Some of the diet's most signifi-cant sources of quercetin are apples, onions, tomatoes, broccoli, and green tea. Antioxidant, anticancer, anti-inflammatory, antimicrobial, antibacterial, and anti-viral effects have been studied of quercetin. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, ribonucleic acid (RNA) polymer-ase, and other essential viral life-cycle enzymes are all prevented from entering the body by quercetin. Despite extensive in vitro and in vivo investigations on the immune-modulating effects of quercetin and vitamin C treatment. 3-methyl-quercetin has been shown to bind to essential proteins necessary to convert minus-strand RNA into positive-strand RNAs, preventing the replication of viral RNA in the cytoplasm. Quercetin has been identified as a potential SARS-CoV-2 3C-like protease (3CLpro) suppressor in recent molecular docking studies and in silico assessment of herbal medicines. It has been demonstrated that quercetin increases the expression of heme oxygenase-1 through the nuclear factor erythroid-related factor 2 (Nrf2) signal network. Inhibition of heme oxygenase-1 may increase bilirubin synthesis, an endoge-nous antioxidant that defends cells. When human gingival fibroblast (HGF) cells were exposed to lipo-polysaccharide (LPS), inflammatory cytokine production was inhibited. The magnesium (Mg+2) cation complexation improves quercetin free radical scavenging capacity, preventing oxidant loss and cell death. The main objective of this paper is to provide an overview of the pharmacological effects of quercetin, its protective role against SARS-CoV-2 infection, and any potential molecular processes.Copyright © 2022 Bentham Science Publishers.

D155Y substitution of SARS-CoV-2 ORF3a weakens binding with Caveolin-1.

The clinical manifestation of the recent pandemic COVID-19, caused by the novel SARS-CoV-2 virus, varies from mild to severe respiratory illness. Although environmental, demographic and co-morbidity factors have an impact on the severity of the disease, contribution of the mutations in each of the viral genes towards the degree of severity needs a deeper understanding for designing a better therapeutic approach against COVID-19. Open Reading Frame-3a (ORF3a) protein has been found to be mutated at several positions. In this work, we have studied the effect of one of the most frequently occurring mutants, D155Y of ORF3a protein, found in Indian COVID-19 patients. Using computational simulations we demonstrated that the substitution at 155th changed the amino acids involved in salt bridge formation, hydrogen-bond occupancy, interactome clusters, and the stability of the protein compared with the other substitutions found in Indian patients. Protein-protein docking using HADDOCK analysis revealed that substitution D155Y weakened the binding affinity of ORF3a with caveolin-1 compared with the other substitutions, suggesting its importance in the overall stability of ORF3a-caveolin-1 complex, which may modulate the virulence property of SARS-CoV-2.

Association of heme-oxygenase 1, hemopexin, and heme levels with markers of disease severity in COVID-19.

Heme-oxygenase 1 (HO-1) is an enzyme with well-known anti-inflammatory and antioxidant properties, whose levels have been previously associated with disease severity in the context of sterile and infectious diseases. Moreover, the heme/HO-1 pathway has been associated with prothrombotic changes in other diseases. Accordingly, the potential of modulating HO-1 levels for the treatment of COVID-19 was extensively speculated during the COVID-19 pandemic, but very few actual data were generated. The aim of our study was to explore the association of HO-1, heme, and hemopexin (HPX) levels with COVID-19 severity and with markers of inflammation and coagulation activation. The study was conducted in 30 consecutive patients with COVID-19 admitted due to hypoxemia, and 30 healthy volunteers matched by sex, age, and geographic region. HO-1 and HPX levels were measured by enzyme immunoassay (ELISA) and heme levels were measured by a colorimetric method. A comprehensive panel of coagulation and fibrinolysis activation was also used. Patients with COVID-19 presented increased levels of HO-1 when compared to controls (5741 ± 2696 vs 1953 ± 612 pg/mL, respectively, P < 0.0001), as well as a trend toward increased levels of HPX (3.724 ± 0.880 vs 3.254 ± 1.022 mg/mL, respectively; P = 0.06). In addition, HO-1 and HPX levels reduced from admission to day + 4. HO-1 levels were associated with duration of intensive care unit stay and with several markers of coagulation activation. In conclusion, modulation of HO-1 could be associated with the prothrombotic state observed in COVID-19, and HO-1 could also represent a relevant biomarker for COVID-19. New independent studies are warranted to explore and expand these findings.

Association between heme oxygenase one and sepsis development in patients with moderate-to-critical COVID-19: a single-center, retrospective observational study.

BACKGROUND: Heme oxygenase one (HO-1) is considered a poor prognostic factor for survival in patients with severe-to-critical coronavirus disease (COVID-19), but the clinical correlation between heme catabolism biomarkers and COVID-19-related sepsis is unknown. The etiopathogenetic hypothesis of HO-1 response during sepsis in patients with poor prognosis should be clarified. This study aimed to investigate sepsis development within 48 h following moderate-to-critical COVID-19 and examined heme/HO-1 catabolism biomarkers associated with sepsis. We also studied the HO-1 and traditional prognostic factors for predicting survival in patients with COVID-19. METHODS: This retrospective observational study included patients unvaccinated for COVID-19 with moderate-to-critical COVID-19 (n = 156) who had been admitted to Taipei Tzu Chi Hospital in 2021. All COVID-19 patients were diagnosed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase polymerase chain reaction. For analysis of heme catabolism in SARS-CoV-2-induced sepsis, we excluded patients with co-infection and severe anemia. Heme catabolism biomarkers were compared between groups of patients with COVID-19 and sepsis (sepsis) and those with COVID-19 without sepsis (no sepsis), and a control group comprising 100 healthy individuals. All clinical and laboratory data were collected retrospectively and blood specimens were collected from Biobank. Multivariable logistic regression analysis was used to compare all variables between the sepsis and no-sepsis groups. Cox regression analysis was used to determine predictors of survival in patients with COVID-19. RESULTS: There were 71 and 85 patients with and without sepsis, respectively. Heme and HO-1 levels differed significantly between the sepsis, no sepsis, and control groups. In multivariate analysis, confusion, blood urea nitrogen, respiration, blood pressure in patients aged > 65 years (CURB-65) (adjusted odds ratio [aOR] 5.331, 95% confidence interval [CI] 2.587-10.987; p < 0.001), albumin (aOR 0.139, 95% CI 0.003-0.636; p = 0.01), D-dimer (aOR 1.001, 95% CI 1.000-1.002; p = 0.032), and HO-1 (aOR 1.116, 95% CI 1.055-1.180; p < 0.001) were significantly associated with 48-h sepsis episodes after adjusting for other confounding factors. HO-1 levels were also significantly associated with 48-h Sequential Organ Failure Assessment Score (SOFA) scores. However, HO-1 did not significantly increase the hazard of in-hospital mortality in moderate-to-critical COVID-19 by Cox regression analysis. CONCLUSIONS: HO-1 levels increased with sepsis development within 48 h of admission for COVID-19 after adjusting for other risk factors, but no significant association was observed between HO-1 and COVID-19 mortality. We suppose that HO-1 may have protective effect in early sepsis, but further clinical multicenter prospective studies are needed.

Identification of herbal teas and their compounds eliciting antiviral activity against SARS-CoV-2 in vitro.

BACKGROUND: The SARS-CoV-2/COVID-19 pandemic has inflicted medical and socioeconomic havoc, and despite the current availability of vaccines and broad implementation of vaccination programs, more easily accessible and cost-effective acute treatment options preventing morbidity and mortality are urgently needed. Herbal teas have historically and recurrently been applied as self-medication for prophylaxis, therapy, and symptom alleviation in diverse diseases, including those caused by respiratory viruses, and have provided sources of natural products as basis for the development of therapeutic agents. To identify affordable, ubiquitously available, and effective treatments, we tested herbs consumed worldwide as herbal teas regarding their antiviral activity against SARS-CoV-2. RESULTS: Aqueous infusions prepared by boiling leaves of the Lamiaceae perilla and sage elicit potent and sustained antiviral activity against SARS-CoV-2 when applied after infection as well as prior to infection of cells. The herbal infusions exerted in vitro antiviral effects comparable to interferon-ß and remdesivir but outperformed convalescent sera and interferon-α2 upon short-term treatment early after infection. Based on protein fractionation analyses, we identified caffeic acid, perilla aldehyde, and perillyl alcohol as antiviral compounds. Global mass spectrometry (MS) analyses performed comparatively in two different cell culture infection models revealed changes of the proteome upon treatment with herbal infusions and provided insights into the mode of action. As inferred by the MS data, induction of heme oxygenase 1 (HMOX-1) was confirmed as effector mechanism by the antiviral activity of the HMOX-1-inducing compounds sulforaphane and fraxetin. CONCLUSIONS: In conclusion, herbal teas based on perilla and sage exhibit antiviral activity against SARS-CoV-2 including variants of concern such as Alpha, Beta, Delta, and Omicron, and we identified HMOX-1 as potential therapeutic target. Given that perilla and sage have been suggested as treatment options for various diseases, our dataset may constitute a valuable resource also for future research beyond virology.

The Relationship between Nrf2 and HO-1 with the Severity of COVID-19 Disease.

Nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) have significant roles in the development of a hyperinflammatory state in infectious diseases. We aimed to investigate the association of the serum concentrations of Nrf2 and HO-1 with the severity of COVID-19 disease. The study included 40 subjects with mild and moderately severe forms of the disease (MEWS scoring system ≤2). Twenty of the subjects had MEWS scores of 3 or 4, which indicate a severe form of the disease, and twenty subjects had a MEWS score of ≥5, which indicates a critical form of the disease. HO-1 and Nrf2 were measured using the commercially available Enzyme-Linked Immunosorbent Assay (ELISA). Subjects with the most severe form of COVID-19 (critically ill) had a lower concentration of Nrf2 that negatively correlated with the markers of hyperinflammatory response (CRP, IL-6, ferritin). This observation was not made for HO-1, and the correlation between Nrf2 and HO-1 values was not established. In the mild/moderate form of COVID-19 disease, Nrf2 was associated with an increased 1,25 dihydroxy vitamin D concentration. The results of this study show that Nrf2 has a role in the body's anti-inflammatory response to COVID-19 disease, which makes it a potential therapeutic target.

Oxidant- induced preconditioning: A pharmacologic approach for triggering renal 'self defense'.

Acute kidney injury (AKI) is a common event, occurring in ~5% and ~35% of hospitalized and ICU patients, respectively. The development of AKI portends an increased risk of morbidity, mortality, prolonged hospitalization, and subsequent development of chronic kidney disease (CKD). Given these facts, a multitude of experimental studies have addressed potential methods for inducing AKI prevention in high-risk patients. However, successful clinical translation of promising experimental data has remained elusive. Over the past decade, our laboratory has focused on developing a method for safely triggering AKI protection by inducing "kidney preconditioning" in mice by the intravenous administration of a combination of Fe sucrose (FeS) + tin protoporphyrin (SnPP). These agents induce mild, but short lived, 'oxidant stress' which synergistically activate a number of kidney 'self-defense' pathways (e.g., Nrf2, ferritin, IL-10). Within 18-24 h of Fe/SnPP administration, marked protection against diverse forms of experimental toxic and ischemic AKI results. FeS/SnPP-mediated reductions in kidney injury can also indirectly decrease injury in other organs by mitigating the so called "organ cross talk" phenomenon. Given these promising experimental data, three phase 1b clinical trials were undertaken in healthy subjects and patients with stage 3 or 4 CKD. These studies demonstrated that FeS/SnPP were well tolerated and that they up-regulated the cytoprotective Nrf2, ferritin, and IL-10 pathways. Two subsequent phase 2 trials, conducted in patients undergoing 'on-pump' cardiovascular surgery or in patients hospitalized with COVID 19, confirmed FeS/SnPP safety. Furthermore, interim data analyses revealed statistically significant improvements in several clinical parameters. The goals of this review are to: (i) briefly discuss the historical background of renal "preconditioning"; (ii) present the experimental data that support the concept of FeS/SnPP- induced organ protection; and (iii) discuss the initial results of clinical trials that suggest the potential clinical utility of an 'oxidant preconditioning' strategy.

REFRACTORY HYPOXEMIA: A CASE OF DAPSONE-INDUCED METHEMOGLOBINEMIA IN A PATIENT WITH COVID-19

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Methemoglobinemia is an increase in methemoglobin (mHb) level characterized by functional anemia and tissue hypoxia. It can be caused by congenital enzymes deficiencies, but it is usually acquired. Dapsone, an oxidizing agent, is a medication commonly associated with acquired methemoglobinemia (1). We describe the diagnosis and management of a COVID-19 patient with acquired methemoglobinemia due to Dapsone. CASE PRESENTATION: 84-year-old female with history of MPO-ANCA vasculitis with renal involvement, CKD4 and anemia of chronic disease presented with shortness of breath, lethargy and weakness. Initially, the patient was saturating (SpO2) 80% on room air and was placed on 4L nasal cannula (NC) with improvement to 92%. CT of the chest showed b/l GGOs consistent with atypical pneumonia and patient tested positive for COVID-19. About 4 months prior, she had received 2 doses of Rituximab and on high steroid therapy that was tapered to 5mg of prednisone daily. She has been on Trimethoprim/Sulfamethoxazole for PJP prophylaxis, but due to hyperkalemia the medication was stopped. After confirming no G6PD deficiency, she was started on Dapsone 100mg daily. During hospitalization, she was given dexamethasone 6 mg daily and Dapsone was continued. On hospital stay day 6, a rapid response was called after oxygen dropped to 78% while walking on 6L NC. She was placed on high flow NC 100% and SpO2 went up to 90%. An arterial blood gas (ABG) was then obtained showing pO2 of 334, oxyhemoglobin (oxyHb) of 83 and mHb of 17.4. The SpO2-PaO2 gap and elevated mHb lead to the diagnosis of Dapsone-induced methemoglobinemia. Dapsone was discontinued. Patient received a one-time dose of 1mg/kg IV of methylene blue. One hour later her dyspnea had improved and was on 3L NC. Repeat ABG showed improvement of oxyHb (98) and decreased mHb (2.2). DISCUSSION: Physiologically, mHb is less than 1% of total Hb (1) and occurs when the iron in the porphyrin group of heme is oxidized from ferrous to the ferric form (2). Ferric heme binds oxygen irreversibly causing a left shift of the oxygen-hemoglobin dissociation curve. Clinical presentation tends to correlate with mHb levels, and it varies from being asymptomatic to fatigue, dyspnea, confusion, seizure, cyanosis resistant to oxygen therapy (mHb > 15%) and death. Methylene blue is safe and can be consider when mHb level is greater than 10 to 20% (2). Methylene blue was administer to our patient given the presence of COVID (leaving patient more susceptible to medication-induced methemoglobinemia (3)) and chronic anemia which made her less likely to tolerate state of reduced oxygen delivery. CONCLUSIONS: The diagnosis of methemoglobinemia is a rare cause of hypoxemia that is often overlooked. In patients with risk factors (COVID, medication exposure) a high index of suspicion is needed when interpreting an ABG (SpO2-PaO2 gap) for correct diagnosis and appropriate treatment. Reference #1: Toker, Ibrahim, et al. "Methemoglobinemia Caused by Dapsone Overdose: Which Treatment Is Best?” Turkish Journal of Emergency Medicine, vol. 15, no. 4, Dec. 2015, pp. 182–184, 10.1016/j.tjem.2014.09.002. Accessed 31 Aug. 2020. Reference #2: Cortazzo JA, Lichtman AD. Methemoglobinemia: a review and recommendations for management. J Cardiothorac Vasc Anesth. 2014 Aug;28(4):1043-7. doi: 10.1053/j.jvca.2013.02.005. Epub 2013 Aug 13. PMID: 23953868. Reference #3: Naymagon, Leonard, et al. "The Emergence of Methemoglobinemia amidst the COVID -19 Pandemic.” American Journal of Hematology, vol. 95, no. 8, 3 June 2020, 10.1002/ajh.25868. Accessed 3 Mar. 2021. DISCLOSURES: No relevant relationships by Mileydis Alonso No relevant relationships by Samantha Gillenwater No relevant relationships by Christine Girard No relevant relationships by Sikandar Khan No relevant relationships by Jose Rivera No relevant relationships by Frederick Ross

IDIOPATHIC MULTICENTRIC CASTLEMAN DISEASE (IMCD) AS A MANIFESTATION OF POST-COVID-19 INFLAMMATORY SYNDROME

SESSION TITLE: Pulmonary Manifestations of Infections SESSION TYPE: Case Reports PRESENTED ON: 10/17/2022 03:15 pm - 04:15 pm INTRODUCTION: Post-acute COVID-19 inflammatory syndrome is defined as persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms of original infection (1). These can manifest in various ways, but pulmonary, cardiac, and renal complications are the most common (1), with IL-6 thought to be an important mediator (2). We report what we believe to be the first case of Idiopathic Multicentric Castleman's Disease (iMCD) as a manifestation of post-acute COVID-19 inflammatory syndrome. CASE PRESENTATION: A 36-year old male with history of hypertension and childhood asthma (not on current therapy), and recently resolved COVID-19 from 4 weeks prior, is admitted to the hospital with progressive shortness of breath, cough, fevers and significant fatigue. Prior COVID-19 symptoms included fevers, cough, and shortness of breath, which improved after 2 weeks without treatment. Symptoms returned 2 weeks later and worsened. On admission, he was tachycardic to 108 with temp of 37.8C, and otherwise stable vitals. Pertinent labs included WBC 17 (neutrophil predominant), Hgb 11.6, Cr 2.52, Na 126 and albumin 2.7 (normal baselines). SARS-CoV2 PCR was negative. CT chest with PE protocol showed no PE but moderate bilateral pleural effusions and extensive mediastinal lymphadenopathy. 1.2L clear fluid (transudative with lymphocyte predominance) was removed via thoracentesis. Microbiology, flow cytometry and cytology were unremarkable. Renal and mediastinal lymph node biopsies were taken. Lymph node sampling was non-diagnostic x2, but renal biopsy showed acute microangiopathy without thrombi, concerning for acute glomerulonephritis. Serologic vasculitis and CTD workup were entirely negative. He was treated with a course of prednisone and improved, however as outpatient, had recurrence of all these issues. Repeat thoracentesis x3 was unrevealing. He was again admitted and had an excisional inguinal node biopsy, showing findings consistent with hyaline vascular Castleman Disease. Further heme/onc evaluation and discussion showed diagnosis meeting criteria for iMCD. DISCUSSION: Multicentric Castleman's Disease is most often associated with HHV-8 infection in the setting of HIV. If HHV-8 is negative, the disease is termed idiopathic (iMCD). In these cases, disease is mediated predominantly by IL-6, but the direct cause is unknown, though existing theories include non-specific viral infections, malignancy and autoimmune diseases (3). Our patient had no evidence of malignancy or autoimmune phenomena. Thus COVID-19 illness was the most plausible explanation, especially given known IL-6 activity in COVID-19 inflammatory syndromes. CONCLUSIONS: Post-acute COVID-19 inflammatory syndromes are extensive and can affect any organ system. iMCD is another possible manifestation, and must be diagnosed with excisional lymph node biopsy. High index of suspicion should be maintained to make this diagnosis. Reference #1: Nalbandian, Ani et al. "Post-acute COVID-19 syndrome." Nature medicine vol. 27,4 (2021): 601-615. Reference #2: Phetsouphanh, Chansavath et al. "Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection.” Nature immunology vol. 23,2 (2022): 210-216. Reference #3: Dispenzieri, Angela, and David C Fajgenbaum. "Overview of Castleman disease." Blood vol. 135,16 (2020): 1353-1364. DISCLOSURES: No relevant relationships by Kyle Halligan No relevant relationships by Chris Yan

Host and viral proteins involved in SARS-CoV-2 infection differentially bind heme.

In most severe cases, SARS-CoV-2-induced autoimmune reactions have been associated with hemolytic complications. Hemolysis-derived heme from ruptured red blood cells has been shown to trigger a variety of fatal proinflammatory and procoagulant effects, which might deteriorate the progression of COVID-19. In addition, the virus itself can induce proinflammatory signals via the accessory protein 7a. Direct heme binding to the SARS-CoV-2 protein 7a ectodomain and other COVID-19-related proteins has been suggested earlier. Here, we report the experimental analysis of heme binding to the viral proteins spike glycoprotein, protein 7a as well as the host protein ACE2. Thus, protein 7a chemical synthesis was established, including an in-depth analysis of the three different disulfide-bonded isomers. Surface plasmon resonance spectroscopy and in silico studies confirm a transient, biphasic binding behavior, and heme-binding affinities in the nano- to low micromolar range. These results confirm the presence of the earlier identified heme-binding motifs and emphasize the relevance for consideration of labile heme in preexisting or SARS-CoV-2-induced hemolytic conditions in COVID-19 patients.

PULMONARY MUCORMYCOSIS AS A COMPLICATION OF SARS COV-2 PNEUMONIA - CASE REPORT AND REVIEW OF LITERATURE

CASE: A 31-year-old woman G4P2204 was admitted with respiratory failure. Her hemoglobin was 9.7 g/dl, D-dimer 1349 ng/mL feu, procalcitonin 0.44 ng/ mL, CRP 91.4 mg/L, normal white count and nasal RT-PCR positive for COVID-19. Chest x-ray showed bilateral patchy airspace opacities. She underwent emergent C-section, was intubated and placed on mechanical ventilation, received Remdesivir, dexamethasone, vancomycin and piperacillintazobactam. On day 11, she developed bilateral pneumothorces and had chest tubes placed. She had new elevation in white blood count (16,000/ul) and inflammatory markers. She was put on extracorporeal membrane oxygenation (ECMO). Computed Tomography ( CT) chest on day 15 showed large multiloculated cavity. She underwent bronchoscopy with bronchoalveolar lavage cultures positive for Mucorales. She had CT abdomen-pelvis, CT head and nasal endoscopy without evidence of invasive disease. She was started on amphotericin B and posaconazole. She had tracheostomy on day 21 and underwent successful ECMO weaning and decannulation on day 35. Chest tubes were removed. Amphotericin B was discontinued. She was discharged on nasal cannula and oral posaconazole and continued to improve. IMPACT/DISCUSSION: There are 6 other cases reported in literature with isolated pulmonary mucormycosis associated with SARS-CoV-2. All of these patients had clinical improvement before deteriorating again with SARS Cov-2 treatment. The timeline of new imaging findings like cavities, changing opacities, pleural effusions or bronchopleural fistula was usually 2 to 3 weeks from diagnosis of SARS-CoV-2 pneumonia. On analysis 5/7 of these patients were not diabetic, 6/7 received steroids, 3/7 received Tocilizumab and 4/7 received Remdesivir. 2 patients received surgical intervention with medical management although it did not change the outcome. Unfortunately despite aggressive medical and surgical treatment, there were poor outcomes. 4/7 patients died, 1/7 was permanently ventilator dependent and 2/7 survived. The diagnosis of isolated pulmonary mucormycosis is challenging. This might be secondary to hesitance of invasive diagnostic tests like bronchoscopy, lack of rapid diagnostic tests and fewer autopsies. Amphotericin B, posaconazole and isavuconazole remain the main treatment options along with surgical debridement of necrotic tissue. The pathology of mucormycosis in COVID-19 has been attributed to impaired T-cell function, impaired phagocytosis and more availability of fungal heme oxygenase which facilitates iron uptake for its metabolism. Glucocorticoids, IL-6 inhibitors and monoclonal antibodies further increase the risk of secondary infections. CONCLUSION: Mucormycosis is a lifethreatening disease with high morbidity and mortality. Based on our case and literature review, it is important to have high index of suspicion for pulmonary mucormycosis in patients who are recently treated with immunosuppressants for SARS-CoV-2 pneumonia and suddenly deteriorate after treatment.

A comprehensive in silico exploration of the impacts of missense variants on two different conformations of human pirin protein.

Background: Pirin, a member of the cupin superfamily, is an iron-binding non-heme protein. It acts as a coregulator of several transcription factors, especially the members of NFκB transcription factor family. Based on the redox state of its iron cofactor, it can assume two different conformations and thereby act as a redox sensor inside the nucleus. Previous studies suggested that pirin may be associated with cancer, inflammatory diseases as well as COVID-19 severities. Hence, it is important to explore the pathogenicity of its missense variants. In this study, we used a number of in silico tools to investigate the effects of missense variants of pirin on its structure, stability, metal cofactor binding affinity and interactions with partner proteins. In addition, we used protein dynamics simulation to elucidate the effects of selected variants on its dynamics. Furthermore, we calculated the frequencies of haplotypes containing pirin missense variants across five major super-populations (African, Admixed American, East Asian, European and South Asian). Results: Among a total of 153 missense variants of pirin, 45 were uniformly predicted to be pathogenic. Of these, seven variants can be considered for further experimental studies. Variants R59P and L116P were predicted to significantly destabilize and damage pirin structure, substantially reduce its affinity to its binding partners and alter pirin residue fluctuation profile via changing the flexibility of several key residues. Additionally, variants R59Q, F78V, G98D, V151D and L220P were found to impact pirin structure and function in multiple ways. As no haplotype was identified to be harboring more than one missense variant, further interrogation of the individual effects of these seven missense variants is highly recommended. Conclusions: Pirin is involved in the transcriptional regulation of several genes and can play an important role in inflammatory responses. The variants predicted to be pathogenic in this study may thus contribute to a better understanding of the underlying molecular mechanisms of various inflammatory diseases. Future studies should be focused on clarifying if any of these variants can be used as disease biomarkers. Supplementary Information: The online version contains supplementary material available at 10.1186/s42269-022-00917-7.

Progress on the protective effect of heme oxygenase-1 in viral infection

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that catalyzes the conversion of heme to CO, biliverdin, and iron, which together protect cells from oxidative and inflammatory damage and play an important role in maintaining cell homeostasis. In recent years, HO-1 has also been found to have antiviral biological effects, and the induced expression of HO-1 inhibits the replication of various viruses such as hepatitis C virus, hepatitis B virus, human immunodeficiency virus, dengue virus, ebolavirus, influenza A virus, Zika virus, severe acute respiratory syndrome coronavirus 2, human respiratory syncytial virus, hepatitis A virus and enterovirus 71. The inhibitory effect of HO-1 on these viruses involves three mechanisms, including direct inhibition of virus replication by HO-1 and its downstream products, enhancement of type I interferon responses in host cell, and attenuation of inflammatory damage caused by viral infection. This review focuses on the recent advances in the antiviral effect of HO-1 and its mechanism, which is expected to provide evidence for HO-1 as a potential target for antiviral therapy.