scholarly journals Rapid Recovery in Six Patients with COVID-19 Respiratory Failure after Treatment with Vasoactive Intestinal Peptide

2020 ◽  
Author(s):  
Jonathan Javitt ◽  
Jihad Youssef
Keyword(s):  
Respiratory Failure ◽  
Vasoactive Intestinal Peptide ◽  
Inflammatory Markers ◽  
General Medicine ◽  
Blood Oxygenation ◽  
Ordinal Scale ◽  
Alveolar Type ◽  
Term Survival ◽  
Radiographic Appearance

Background: Vasoactive Intestinal Peptide (VIP) is known to bind to and protect the Alveolar Type II cell by blocking replication of the SARS-CoV-2 virus, upregulating surfactant production, blocking apoptosis, and blocking cytokine effects. RLF-100 (Aviptadil), a synthetic form of Vasoactive Intestinal Peptide (VIP) has been granted Fast Track Designation and is currently in phase 2/3 placebo-controlled trials. FDA has granted Emergency Use IND and Expanded Access Protocol approval for the use of RLF-100 in patients whose comorbidities render them ineligible for inclusion in the ongoing pivotal trial. Methods: This report describes the first 6 patients with Acute Respiratory Failure in Critical COVID-19, enrolled under Emergency Use IND were treated with three successive 12-hour infusions of intravenous Aviptadil at 50/100/150 pmol/kg/hr, while continuing to receive maximal ICU care. Results: Median patient follow-up time is 14 days. So far, all treated patients have survived. Improved radiographic appearance of typical “ground glass” COVID-19 features to varying degrees is seen in all patients within 72 hours. Improvement in blood oxygenation is seen in all patients, with complete remission from respiratory failure in 4 of 6 patients. An average 56% reduction in inflammatory markers was seen, together with a median 4 point reduction in the NIAID Ordinal Scale. 2/6 patients were discharged from the hospital and 1 patient was downgraded to the general medicine floor. Comment: The short term survival of 6/6 patients with respiratory failure in the setting of COVID-19 and major comorbidity is the most dramatic response ever seen with an antiviral agent. Improvement in radiographic appearance, oxygenation requirement, and inflammatory markers is consistent with in vitro evidence of direct anti-viral effect.

scholarly journals Rapid Recovery from Critical COVID-19 Respiratory Failure after treatment with VIP

2020 ◽  
Author(s):  
J. Georges Youssef ◽  
Jonathan Javitt ◽  
Mukhtar Al-Saadi ◽  
Faisal Zahiruddin ◽  
Sarah Beshay ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Protein A ◽  
Case Series ◽  
Fold Increase ◽  
Ordinal Scale ◽  
Term Outcome ◽  
Radiographic Appearance ◽  
Reactive Protein ◽  
Point Reduction

Abstract Background: Vasoactive Intestinal Peptide (VIP) blocks replication of the SARS-CoV-2 virus, inhibits cytokine synthesis, prevents cytopathy, and upregulates surfactant production in human pulmonary cells. RLF-100™ (aviptadil), is currently in phase 2/3 trials with FDA Fast Track designation for treating Critical COVID-19 with Respiratory Failure. Methods: Case series of 21 consecutive with Critical COVID-19 and multiple co-morbidities, treated with intravenous aviptadil (synthetic VIP). Sixteen patients were treated with ventilation alone and five with extracorporeal membrane oxygenation (ECMO). Results: So far, 19 of 21 patients have survived. Improved radiographic appearance was seen in both lungs of 17 patients and in one lung of 2 patients. A mean 2.5-fold increase in PaO2:FiO2 ratio was seen (P<0.0001) with complete remission from respiratory failure in 9 patients and ongoing improvement in 10. Seven patients were discharged from the hospital, 7 sent to intermediate care, and 5 remain in the ICU. Four of 5 patients on ECMO have been decannulated, and thus far three have been discharged. A 75% (95% CI±3%: P<.001) reduction in IL-6 was seen with corresponding decrease in C-reactive protein. A median 3 point reduction (mean 2.7; P<0.001) in the WHO Ordinal Scale was observed (P<.001). Comment: The short term outcome in these 21 patients represent a dramatic response in patients whose comorbidities precluded their randomization in all other trials of COVID therapeutics and who were previously treated with remdesivir, tocilizumab, or convalescent plasma. Improvement in radiographic appearance, oxygenation requirement, and inflammatory markers is consistent with in vitro evidence of direct anti-viral effect

scholarly journals Clonal Hematopoiesis of Indeterminate Potential Is Associated with Increased Age-Independent Morbidity and Mortality in Patients with COVID-19- the Beyond DNA COVID-19 Project

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2164-2164
Author(s):  
Marissa Li ◽  
Terra Lasho ◽  
Moritz Binder ◽  
Wazim Mohammed Ismail ◽  
Susan M. Geyer ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Inflammatory Markers ◽  
Research Funding ◽  
Ordinal Scale ◽  
Mortality And Morbidity ◽  
Clonal Hematopoiesis ◽  
Oncology Research ◽  
Age And Sex ◽  
Age Independent

Abstract Background: SARS-Cov-2 infections are associated with increased mortality and morbidity, largely due to inflammatory cascades and cytokine release syndrome (CRS). Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence and subsequent expansion of somatic, leukemia-associated driver mutations in apparently healthy individuals with normal blood counts. CHIP has been associated with increased inflammation, with cytokines such as IL1-b, IL6 and TNF-a being elevated at baseline in affected individuals. We hypothesized that the presence of CHIP in patients with COVID-19 would result in excessive inflammation-related mortality and morbidity. Methods: We used the Mayo Clinic COVID-19 database to identify patients with COVID-19 on whom peripheral blood mononuclear cells (PBMC) were available for research use (IRB approved). We carried out target-capture next generation sequencing for 220 CH related genes, by previously described methods (1000 x coverage, variant allele fraction/VAF detection limit &gt;0.5%; Kusne Y et al AJH 2021). CHIP was defined by the presence of a CH mutation with a VAF&gt;1% in an individual with normal baseline blood counts. Demographics, blood counts, and inflammatory markers (CRP and cytokine levels- ELISA assay) at COVID-19 diagnosis and during follow-up (as clinically indicated) were collected. COVID-19 disease severity was classified based on the presence and severity of CRS, graded using the Penn Grading Scale (Porter et. al., 2018), and the WHO ordinal scale (WHO Blueprint, 2020). We used Fisher's exact test and the Wilcoxon rank sum test to compare categorical and continuous variables. Survival analysis was performed using the Kaplan-Meier method. We accounted for differences in age and sex using multivariable-adjusted proportional hazards regression models. Results: Seventy-two CHIP mutations were detected in 56 (25%) of the 227 patients with COVID-19 that had PBMC available; median age 69 years (range; 42-99 years), 61% male. Fifteen (26%) patients had 2 CHIP mutations, while 1 patient had 3 CHIP mutations. Common mutations encountered included DNMT3A (32%) , TET2 (19%) , SF3B1 (8%) , ASXL1 (6%) , MPL (5%) , and TP53 (5%; Figure 1A). COVID-19 patients with CHIP were older in age (median 69 vs 57 years; p&lt;0.0001) and had higher baseline MCP-1 (p=0.04) levels. However, there were no differences in sex, comorbidities, blood counts, IL1-b, IL6 and TNF-a levels between the two groups. The median follow-up for the entire cohort was 9 months. The relative change from baseline in blood counts and inflammatory markers (CRP and cytokines) during follow-up was similar in CHIP and non-CHIP patients, with the exception that COVID-19-onset neutropenia was more common in CHIP patients (8% vs 1%; p=0.017) compared to those without CHIP. At last follow up neutropenia had resolved in all patients. Both groups had comparable number of patients with CRS (61% CHIP vs 53% non-CHIP patients, p=0.354, Figure 1B), however, CHIP patients had more severe CRS (median Penn Grade 3 versus 2 in non-CHIP, p=0.018, Figure 1C). Based on the WHO ordinal scale, CHIP patients were more likely to experience hospitalization with severe disease and death (61% versus 45% in non-CHIP, p = 0.049). Moreover, COVID-19 CHIP patients experienced worse overall survival in comparison to patients without CHIP (median 13.1 months vs not reached, p&lt;0.001, Figure 1D). This association remained consistent after adjusting for age and sex at the time of COVID-19 diagnosis (HR 3.15, 95% 1.32 - 7.55, p = 0.010). At last follow-up, 22 deaths were documented: 13 (23%) in patients with CHIP and 9 (5%) in the non-CHIP group (p=0.02), with the primary cause for mortality being hypoxic respiratory failure (62% in CHIP vs 44% non-CHIP, p=0.04). Conclusions: In this study, we observe an age-independent impact of CHIP on COVID-19 associated inflammatory morbidity (CRS) and mortality (hypoxemic respiratory failure). We are currently carrying out detailed single cell (ssDNA, RNA and ATAC-seq) and proteomic studies (O-link PEA assays) to better elucidate this pathophysiology. Figure 1 Figure 1. Disclosures Patnaik: Kura Oncology: Research Funding; StemLine: Research Funding.

Human thymic epithelial cells maintain long-term survival of clonogenic myeloid and erythroid progenitor cells in vitro

2000 ◽  
Vol 111 (1) ◽  
pp. 363-370 ◽  
Author(s):  
Katsuto Takenaka ◽  
Mine Harada ◽  
Tomoaki Fujisaki ◽  
Koji Nagafuji ◽  
Shinichi Mizuno ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Progenitor Cells ◽  
Thymic Epithelial Cells ◽  
Erythroid Progenitor ◽  
Term Survival ◽  
Long Term Survival ◽  
Erythroid Progenitor Cells

scholarly journals Direct antivirals working against the novel coronavirus: azithromycin (DAWn-AZITHRO), a randomized, multicenter, open-label, adaptive, proof-of-concept clinical trial of new antivirals working against SARS-CoV-2—azithromycin trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Iwein Gyselinck ◽  
◽  
Laurens Liesenborghs ◽  
Ewout Landeloos ◽  
Ann Belmans ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Standard Of Care ◽  
Ordinal Scale ◽  
Cytokine Signaling ◽  
Nasopharyngeal Swab ◽  
The Novel ◽  
Proof Of Concept ◽  
Open Label ◽  
Novel Coronavirus

Abstract Background The rapid emergence and the high disease burden of the novel coronavirus SARS-CoV-2 have created a medical need for readily available drugs that can decrease viral replication or blunt the hyperinflammatory state leading to severe COVID-19 disease. Azithromycin is a macrolide antibiotic, known for its immunomodulatory properties. It has shown antiviral effect specifically against SARS-CoV-2 in vitro and acts on cytokine signaling pathways that have been implicated in COVID-19. Methods DAWn-AZITHRO is a randomized, open-label, phase 2 proof-of-concept, multicenter clinical trial, evaluating the safety and efficacy of azithromycin for treating hospitalized patients with COVID-19. It is part of a series of trials testing promising interventions for COVID-19, running in parallel and grouped under the name DAWn-studies. Patients hospitalized on dedicated COVID wards are eligible for study inclusion when they are symptomatic (i.e., clinical or radiological signs) and have been diagnosed with COVID-19 within the last 72 h through PCR (nasopharyngeal swab or bronchoalveolar lavage) or chest CT scan showing typical features of COVID-19 and without alternate diagnosis. Patients are block-randomized (9 patients) with a 2:1 allocation to receive azithromycin plus standard of care versus standard of care alone. Standard of care is mostly supportive, but may comprise hydroxychloroquine, up to the treating physician’s discretion and depending on local policy and national health regulations. The treatment group receives azithromycin qd 500 mg during the first 5 consecutive days after inclusion. The trial will include 284 patients and recruits from 15 centers across Belgium. The primary outcome is time from admission (day 0) to life discharge or to sustained clinical improvement, defined as an improvement of two points on the WHO 7-category ordinal scale sustained for at least 3 days. Discussion The trial investigates the urgent and still unmet global need for drugs that may impact the disease course of COVID-19. It will either provide support or else justify the discouragement of the current widespread, uncontrolled use of azithromycin in patients with COVID-19. The analogous design of other parallel trials of the DAWN consortium will amplify the chance of identifying successful treatment strategies and allow comparison of treatment effects within an identical clinical context. Trial registration EU Clinical trials register EudraCT Nb 2020-001614-38. Registered on 22 April 2020

scholarly journals OP0244 A PRECLINICAL TESTING TOOL: THE IN VITRO 3D FRACTURE GAP MODEL

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 154.1-154
Author(s):  
M. Pfeiffenberger ◽  
A. Damerau ◽  
P. Hoff ◽  
A. Lang ◽  
F. Buttgereit ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Bone Healing ◽  
Inflammatory Markers ◽  
Initial Phase ◽  
Gap Model ◽  
Osteogenic Markers ◽  
Immunosuppressed Patients ◽  
The Impact

Background:Approximately 10% of fractures lead to significant fracture healing disorders, with a tendency to further increase due to the aging population. Of note, especially immunosuppressed patients with ongoing inflammation show difficulties in the correct course of fracture healing leading to fracture healing disorders. Most notably, invading immune cells and secreted cytokines are considered to provide an inflammatory microenvironment within the fracture gap, primarily during the initial phase of fracture healing. Current research has the focus on small animal models, facing the problem of translation towards the human system. In order to improve the therapy of fracture healing disorders, we have developed a human cell-basedin vitromodel to mimic the initial phase of fracture healing adequately. This model will be used for the development of new therapeutic strategies.Objectives:Our aim is to develop anin vitro3D fracture gap model (FG model) which mimics thein vivosituation in order to provide a reliable preclinical test system for fracture healing disorders.Methods:To assemble our FG model, we co-cultivated coagulated peripheral blood and primary human mesenchymal stromal cells (MSCs) mimicking the fracture hematoma (FH model) together with a scaffold-free bone-like construct mimicking the bony part of the fracture gap for 48 h under hypoxic conditions (n=3), in order to reflect thein vivosituation after fracture most adequately. To analyze the impact of the bone-like construct on thein vitroFH model with regard to its osteogenic induction capacity, we cultivated the fracture gap models in either medium with or without osteogenic supplements. To analyze the impact of Deferoxamine (DFO, known to foster fracture healing) on the FG model, we further treated our FG models with either 250 µmol DFO or left them untreated. After incubation and subsequent preparation of the fracture hematomas, we evaluated gene expression of osteogenic (RUNX2,SPP1), angiogenic (VEGF,IL8), inflammatory markers (IL6,IL8) and markers for the adaptation towards hypoxia (LDHA,PGK1) as well as secretion of cytokines/chemokines using quantitative PCR and multiplex suspension assay, respectively.Results:We found via histology that both the fracture hematoma model and the bone-like construct had close contact during the incubation, allowing the cells to interact with each other through direct cell-cell contact, signal molecules or metabolites. Additionally, we could show that the bone-like constructs induced the upregulation of osteogenic markers (RUNX2, SPP1) within the FH models irrespective of the supplementation of osteogenic supplements. Furthermore, we observed an upregulation of hypoxia-related, angiogenic and osteogenic markers (RUNX2,SPP1) under the influence of DFO, and the downregulation of inflammatory markers (IL6,IL8) as compared to the untreated control. The latter was also confirmed on protein level (e.g. IL-6 and IL-8). Within the bone-like constructs, we observed an upregulation of angiogenic markers (RNA-expression ofVEGF,IL8), even more pronounced under the treatment of DFO.Conclusion:In summary, our findings demonstrate that our establishedin vitroFG model provides all osteogenic cues to induce the initial bone healing process, which could be enhanced by the fracture-healing promoting substance DFO. Therefore, we conclude that our model is indeed able to mimic correctly the human fracture gap situation and is therefore suitable to study the influence and efficacy of potential therapeutics for the treatment of bone healing disorders in immunosuppressed patients with ongoing inflammation.Disclosure of Interests:Moritz Pfeiffenberger: None declared, Alexandra Damerau: None declared, Paula Hoff: None declared, Annemarie Lang: None declared, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi., Timo Gaber: None declared

scholarly journals In vitro evidence for the involvement of H2S pathway in the effect of clodronate during inflammatory response

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rosangela Montanaro ◽  
Alessio D’Addona ◽  
Andrea Izzo ◽  
Carlo Ruosi ◽  
Vincenzo Brancaleone
Keyword(s):  
Inflammatory Markers ◽  
In Vitro Study ◽  
Inos Expression ◽  
Beneficial Effects ◽  
Tnf Α ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Underlying Mechanisms ◽  
Inflammatory Effect

AbstractClodronate is a bisphosphonate agent commonly used as anti-osteoporotic drug. Throughout its use, additional anti-inflammatory and analgesic properties have been reported, although the benefits described in the literature could not solely relate to their inhibition of bone resorption. Thus, the purpose of our in vitro study is to investigate whether there are underlying mechanisms explaining the anti-inflammatory effect of clodronate and possibly involving hydrogen sulphide (H2S). Immortalised fibroblast-like synoviocyte cells (K4IM) were cultured and treated with clodronate in presence of TNF-α. Clodronate significantly modulated iNOS expression elicited by TNF-α. Inflammatory markers induced by TNF-α, including IL-1, IL-6, MCP-1 and RANTES, were also suppressed following administration of clodronate. Furthermore, the reduction in enzymatic biosynthesis of CSE-derived H2S, together with the reduction in CSE expression associated with TNF-α treatment, was reverted by clodronate, thus rescuing endogenous H2S pathway activity. Clodronate displays antinflammatory properties through the modulation of H2S pathway and cytokines levels, thus assuring the control of the inflammatory state. Although further investigation is needed to stress out how clodronate exerts its control on H2S pathway, here we showed for the first the involvement of H2S in the additive beneficial effects observed following clodronate therapy.

scholarly journals The Value of Interleukin-6 among Several Inflammatory Markers as a Predictor of Respiratory Failure in COVID-19 Patients

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1327
Author(s):  
Mitsuhiro Fujino ◽  
Michiyo Ishii ◽  
Takuya Taniguchi ◽  
Hiroya Chiba ◽  
Masaki Kimata ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Interleukin 6 ◽  
Inflammatory Markers ◽  
Characteristic Curve ◽  
Respiratory Illness ◽  
Reactive Protein ◽  
Short Period ◽  
Blood Marker ◽  
Fraction Of Inspired Oxygen ◽  
Reliable Marker

Patients with coronavirus disease 2019 (COVID-19) develop severe respiratory failure within a short period during the clinical course. It is essential to predict respiratory deterioration in the short term. We investigated the use of inflammatory markers to predict respiratory distress within three days from their analysis in COVID-19 patients. This retrospective observational study included 81 patients admitted with COVID-19. Patients were divided into two groups according to whether the maximum fraction of inspired oxygen (FiO2) for three days from the blood marker measurements was ≥0.4 (high FiO2 group; HFG) or <0.4 (low FiO2 group; LFG). Interleukin-6 (IL-6), C-reactive protein (CRP), lactate dehydrogenase (LDH), white blood cell, D-dimer, and creatinine levels were compared between the two groups. The levels of all markers were significantly higher in HFG patients. Areas under the receiver operating characteristic curve of IL-6, CRP, and LDH had high values of 0.85, 0.82, and 0.81, respectively. The odds ratio of IL-6 which was crude and adjusted for dexamethasone administration initiated before laboratory measurement, showed the high value of 29.1 (5.6–295.6) and 53.9 (4.5–3242.8), respectively. IL-6 can be used as a reliable marker for predicting respiratory illness within three days after assessment.

Cellular and immunological basis of the host-parasite relationship during infection withNeospora caninum

Parasitology ◽  
2006 ◽  
Vol 133 (3) ◽  
pp. 261-278 ◽  
Author(s):  
A. HEMPHILL ◽  
N. VONLAUFEN ◽  
A. NAGULESWARAN
Keyword(s):  
Host Cell ◽  
Cell Biology ◽  
Neospora Caninum ◽  
Host Cells ◽  
Term Survival ◽  
Prevention Of Infection ◽  
Parasite Relationship ◽  
Potential Applications

Neospora caninumis an apicomplexan parasite that is closely related toToxoplasma gondii, the causative agent of toxoplasmosis in humans and domestic animals. However, in contrast toT. gondii, N. caninumrepresents a major cause of abortion in cattle, pointing towards distinct differences in the biology of these two species. There are 3 distinct key features that represent potential targets for prevention of infection or intervention against disease caused byN. caninum. Firstly, tachyzoites are capable of infecting a large variety of host cellsin vitroandin vivo. Secondly, the parasite exploits its ability to respond to alterations in living conditions by converting into another stage (tachyzoite-to-bradyzoite orvice versa). Thirdly, by analogy withT. gondii, this parasite has evolved mechanisms that modulate its host cells according to its own requirements, and these must, especially in the case of the bradyzoite stage, involve mechanisms that ensure long-term survival of not only the parasite but also of the host cell. In order to elucidate the molecular and cellular bases of these important features ofN. caninum, cell culture-based approaches and laboratory animal models are being exploited. In this review, we will summarize the current achievements related to host cell and parasite cell biology, and will discuss potential applications for prevention of infection and/or disease by reviewing corresponding work performed in murine laboratory infection models and in cattle.

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