Exploring COVID-19 Therapies: An Extraordinary Global Challenge

Mohta, Srikant; Agarwal, Ashish; Makharia, Govind

doi:10.1055/s-0040-1712598

Cited by 3 publications

(6 citation statements)

References 14 publications

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“…There had been many theories to identify the cause that seemed to be epidemic only in the Indian subcontinent. Use of high doses of steroids, oxygen, use of immunomodulator drugs, such as Tocilizumab, and others was also on the list of a possible cause, but none have been proved yet.6,8,9 The destruction of the pancreatic cells has been linked to the delta variant of the virus, along with the use of a high dose of steroids to protect from the cytokine surge has made the host suffer from ill-controlled diabetic status and a very high serum Ferritin values, making them highly susceptible to ROCM [ 10 , 11 ]. The COVID infection had destroyed the nasal mucosa, the protective cilia with a layer of mucus that acted as a conveyor belt to wash off the allergen, and inhaled pathogens were lost to a varied extent.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the site involved the clinical features develop. Thus, an immunologically 'compromised', damaged nasal cavity mucosa along with an ill-controlled diabetic state makes a deadly combination for the mucor to colonize, invade and spread, within a few minutes to a few hours [ 10 – 16 ]. Mucor is angio-invasive, it causes thrombi, thus making the drug delivery to the affected area almost impossible as intravascular drugs cannot reach those sites.…”

Section: Discussionmentioning

confidence: 99%

“…MRI with contrast should be undertaken before surgery to access orbital involvement to decide whether to do a debridement or exenteration. Loss of contrast enhancement in extraocular muscle if mild or moderate, debridement can be done, and if severe exenteration should be undertaken [ 8 , 9 , 11 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…Thus an effective way of orbital disease control is prudent to control the progression of Mucormycosis. Winning over the fungi after it enters the intracranial cavity is almost impossible, with literature evidence of up to 100% mortality in Cerebral Mucormycosis [ 4 , 7 – 9 , 20 – 22 ].…”

Section: Discussionmentioning

confidence: 99%

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Is mucormycosis the end? A comprehensive management of orbit in COVID associated rhino-orbital–cerebral mucormycosis: preserving the salvageable

Keshri

Mathialagan

Aishwarya

et al. 2022

Eur Arch Otorhinolaryngol

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Background Rhino-orbital–cerebral mucor mycosis (ROCM) is a relatively rare opportunistic infection caused by the Mucorales species. While ROCM suggests involvement of the paranasal sinuses, orbit and brain ROM (rhino-orbital-Mucormycosis) stands for the fungal invasion in sinuses and orbit sans cerebral involvement. In India with the outbreak of the second COVID wave and the delta variant of the virus, there has been a steep increase in this opportunistic fulminant fungal infection, named COVID-associated Mucor mycosis (CAM). The most critical question in orbital management is when to go ahead with an exenteration. Our study aims to design a pertinent minimal invasive surgical protocol for surgeons to manage such cases based on our surgical experience and mitigate the need for exenteration and save the eyes wherever possible. Methods The study is a retrospective analysis of patients of ROM with and without brain involvement, who underwent minimal surgical management between March 2021 to March 2022 along with their follow-up. Results There were 184 eyes of 148 patients diagnosed with CAM. The mean age was 51.7 years with a male predominance of 103 (70%). All patients developed ROM following the COVID-19 infection and the duration between diagnosis of COVID-19 and ROM was 36 ± 23 days. 18 cases (12%) were bilateral. 76 eyes (41%) had no vision at the presentation. Imaging revealed paranasal sinus involvement (100%), orbital apex involvement (61%), cavernous sinus involvement (53%), and central nervous system (CNS) involvement (47%). All the patients (100%) were treated with systemic Liposomal amphotericin-B and sinus debridement. Endoscopic debridement of the orbital disease was performed in 45 (30.4%) cases, 15(8.1%) eyes underwent exenteration and were later rehabilitated with a customized ocular prosthesis, 103 (56%) eyes underwent transcutaneous retrobulbar amphotericin-B. At a mean follow-up of 13.1 months; the complete resolution was seen in 25 (17%) cases, the residual stable lesion was seen in 77(52%) of the cases and new lesions were developed in 13(9%) of the cases. Mortality was seen in 33 (22%) patients and all of them had CNS involvement. Conclusions Systemic and protocol-based management can save the life and salvage the eyes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Is mucormycosis the end? A comprehensive management of orbit in COVID associated rhino-orbital–cerebral mucormycosis: preserving the salvageable

Keshri

Mathialagan

Aishwarya

et al. 2022

Eur Arch Otorhinolaryngol

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“…In silico approaches (Mercurio et al, 2020) driven potential drug candidates (Balkrishna, 2020), non-human primate model for COVID-19 pathogenesis (Lu et al, 2020), and nutritional supplements (lactoferrin) (Chang et al, 2020), are other research guided strategies that are being actively investigated. However, exploring COVID-19 treatment still remains a global challenge (Mohta et al, 2020), and accelerating drug development through repurposed FDA approved drugs is encouraged for COVID-19 treatment, which involves employing pathogen-or hostdirected approaches that may potentiate anti-viral immune response by interfering with host cell factors or dampening pro-inflammatory cytokine storm (Gordy et Further, the emerging studies indicate that COVID-19 is commonly complicated with coagulopathy (Gris J-Christophe et al, 2020; Connors and Levy, 2020), marked by higher platelet count, and elevated D-dimer (Yin et al, 2020;. Continuous efforts to find potential treatments and understand the molecular determinants of disease mechanism are underway (Wang et.…”

Section: Introductionmentioning

confidence: 99%

Proteomic Profiling of Protease-Primed Virus-Permissive Caco-2 Cells Display Abortive-Interferon Pathway and Deregulated Thromboinflammatory SERPINS

Sharma¹,

Panda²

2020

Preprint

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Emerging paradigms in interferon (IFN) biology suggest a dynamic INF induced interactome that extends through broader Interferon Stimulated Gene (ISG)- induction, which implicates interferon- ISG coordinated cross-talk with mRNA processing, post-translational modification and metabolic processes that underlie pathological (viral, autoimmune and tumor biology) and physiological (stem cell regenerative pathways) processes. INF immune responses can also be triggered by endogenous host-derived molecules that are generated in response to cellular stress or hemostasis imbalance to establish tissue repair and regeneration in first place, however, overactivation or lack of countermeasures can result in host tissue damage. The proteases are integral to viral and tumor pathology, and importantly serine proteases TMPRSS2 and trypsin have been identified as important molecular determinants underlying COVID-19 pathology, and emergence of coronaviruses cultured in vitro, respectively. We propose that pathogen associated proteases can act as novel stress-inducers to facilitate viral- competent immunomodulation. We term it as Protease Induced Transcriptomic/ epi-Transcriptomic Reshaping (PITTR) of host cells to counter cellular stress. We present a novel experimental model and our preliminary findings of trypsin- primed Caco-2 cells (CPT) that result in translational halt comparable to cells grown under serum-starvation conditions (CSS). CPT at escalating trypsin concentration (CPT- EC) induce upregulation of selective proteins that majorly map to ribosomal, RNA transport, and spliceosome ribonucleoproteins (RNPs). The inclusion of proinflammatory IL1-b to CPT (CPT- IL) resulted in global overexpression of proteins comparable to Caco-2 cells cultured in growth-factor rich serum conditions (CFBS), indicating a likely de-repression of trypsin- induced translational halt. Caco-2 cells display abortive interferon proteome under differential trypsin conditions (CPT, CPT-EC and CPT-IL), which is marked by complete lack of INF generation despite induction of intermediate ISGs, suggestive of protease (trypsin)- dependent regulation of INF response. Viruses regulate the proteome of stress granules (SGs) that are induced to cope transient translational halt as a central adaptive response to pathogen induced cellular stress. The integral components of SGs include non-translating mRNA, ribonucleoproteins (RNPs) and RNA binding proteins (RBPs), which together form biological condensates through a biophysical process involving weak electrostatic interactions through intrinsically disordered regions in RBPs resulting in liquid- liquid phase separation. We compared the CPT- EC proteome to the Mammalian Stress Granules Proteome (MSGP) database to explore potential RBPs that could possibly regulate INF response (and could act as potential anti-viral targets). Notably, differentially upregulated RNPs and potential RBPs from ISG family including ADAR and PRKRA, and RNA helicases implicated in viral pathogenesis were found to be upregulated in the CPT- EC proteome further strengthening the role of proteases (trypsin) in regulating INF pathways independent of the pathogen. We propose that the supplementation of viable SARS-CoV-2 viral loads to trypsin- primed host cells could recapitulate an infectious disease model, which may closely phenocopy pathogen- driven inflammation and signaling events. Based on the global downregulation of seven SERPINS (serine protease inhibitors) linked to thromboinflammation in our LCMS profiling data, we support the candidature of serine protease inhibitors for protease mediated viral pathologies. COVID-19 is increasingly linked to coagulopathy and resemblance to Neutrophil Extracellular Trap (NET) related thromboinflammatory features; SERPIN A1AT (alpha 1 antitrypsin) being a potent neutrophil- elastase inhibitor and a negative regulator of coagulation complement pathway may be a promising candidate for establishing hemostasis rebalancing in COVID-19 pathology.

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Mesenchymal stromal cells as treatment for acute respiratory distress syndrome. Case Reports following hematopoietic cell transplantation and a review

et al. 2022

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Acute respiratory distress syndrome (ARDS) is a life-threatening lung disease. It may occur during the pancytopenia phase following allogeneic hematopoietic cell transplantation (HCT). ARDS is rare following HCT. Mesenchymal stromal cells (MSCs) have strong anti-inflammatory effect and first home to the lung following intravenous infusion. MSCs are safe to infuse and have almost no side effects. During the Covid-19 pandemic many patients died from ARDS. Subsequently MSCs were evaluated as a therapy for Covid-19 induced ARDS. We report three patients, who were treated with MSCs for ARDS following HCT. Two were treated with MSCs derived from the bone marrow (BM). The third patient was treated with MSCs obtained from the placenta, so-called decidua stromal cells (DSCs). In the first patient, the pulmonary infiltrates cleared after infusion of BM-MSCs, but he died from multiorgan failure. The second patient treated with BM-MSCs died of aspergillus infection. The patient treated with DSCs had a dramatic response and survived. He is alive after 7 years with a Karnofsky score of 100%. We also reviewed experimental and clinical studies using MSCs or DSCs for ARDS. Several positive reports are using MSCs for sepsis and ARDS in experimental animals. In man, two prospective randomized placebo-controlled studies used adipose and BM-MSCs, respectively. No difference in outcome was seen compared to placebo. Some pilot studies used MSCs for Covid-19 ARDS. Positive results were achieved using umbilical cord and DSCs however, optimal source of MSCs remains to be elucidated using randomized trials.

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Exploring COVID-19 Therapies: An Extraordinary Global Challenge

Cited by 3 publications

References 14 publications

Is mucormycosis the end? A comprehensive management of orbit in COVID associated rhino-orbital–cerebral mucormycosis: preserving the salvageable

Is mucormycosis the end? A comprehensive management of orbit in COVID associated rhino-orbital–cerebral mucormycosis: preserving the salvageable

Proteomic Profiling of Protease-Primed Virus-Permissive Caco-2 Cells Display Abortive-Interferon Pathway and Deregulated Thromboinflammatory SERPINS

Mesenchymal stromal cells as treatment for acute respiratory distress syndrome. Case Reports following hematopoietic cell transplantation and a review

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