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Long-Term Expanding Porcine Airway Organoids Provide Insights into the Pathogenesis and Innate Immunity of Porcine Respiratory Coronavirus Infection. J Virol 2022; 96:e0073822. [PMID: 35762755 PMCID: PMC9327677 DOI: 10.1128/jvi.00738-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Respiratory coronaviruses cause serious health threats to humans and animals. Porcine respiratory coronavirus (PRCoV), a natural transmissible gastroenteritis virus (TGEV) mutant with partial spike deletion, causes mild respiratory disease and is an interesting animal respiratory coronavirus model for human respiratory coronaviruses. However, the absence of robust ex vivo models of porcine airway epithelium hinders an understanding of the pathogenesis of PRCoV infection. Here, we generated long-term porcine airway organoids (AOs) derived from basal epithelial cells, which recapitulate the in vivo airway complicated epithelial cellularity. Both 3D and 2D AOs are permissive for PRCoV infection. Unlike TGEV, which established successful infection in both AOs and intestinal organoids, PRCoV was strongly amplified only in AOs, not intestinal organoids. Furthermore, PRCoV infection in AOs mounted vigorous early type I and III interferon (IFN) responses and upregulated the expression of overzealous inflammatory genes, including pattern recognition receptors (PRRs) and proinflammatory cytokines. Collectively, these data demonstrate that stem-derived porcine AOs can serve as a promising disease model for PRCoV infection and provide a valuable tool to study porcine respiratory infection. IMPORTANCE Porcine respiratory CoV (PRCoV), a natural mutant of TGEV, shows striking pathogenetic similarities to human respiratory CoV infection and provides an interesting animal model for human respiratory CoVs, including SARS-CoV-2. The lack of an in vitro model recapitulating the complicated cellularity and structure of the porcine respiratory tract is a major roadblock for the study of PRCoV infection. Here, we developed long-term 3D airway organoids (AOs) and further established 2D AO monolayer cultures. The resultant 3D and 2D AOs are permissive for PRCoV infection. Notably, PRCoV mediated pronounced IFN and inflammatory responses in AOs, which recapitulated the inflammatory responses associated with PRCoV in vivo infection. Therefore, porcine AOs can be utilized to characterize the pathogenesis of PRCoV and, more broadly, can serve as a universal platform for porcine respiratory infection.
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Systematic review of animal-based indicators to measure thermal, social, and immune-related stress in pigs. PLoS One 2022; 17:e0266524. [PMID: 35511825 PMCID: PMC9070874 DOI: 10.1371/journal.pone.0266524] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 03/22/2022] [Indexed: 11/19/2022] Open
Abstract
The intense nature of pig production has increased the animals’ exposure to stressful conditions, which may be detrimental to their welfare and productivity. Some of the most common sources of stress in pigs are extreme thermal conditions (thermal stress), density and mixing during housing (social stress), or exposure to pathogens and other microorganisms that may challenge their immune system (immune-related stress). The stress response can be monitored based on the animals’ coping mechanisms, as a result of specific environmental, social, and health conditions. These animal-based indicators may support decision making to maintain animal welfare and productivity. The present study aimed to systematically review animal-based indicators of social, thermal, and immune-related stresses in farmed pigs, and the methods used to monitor them. Peer-reviewed scientific literature related to pig production was collected using three online search engines: ScienceDirect, Scopus, and PubMed. The manuscripts selected were grouped based on the indicators measured during the study. According to our results, body temperature measured with a rectal thermometer was the most commonly utilized method for the evaluation of thermal stress in pigs (87.62%), as described in 144 studies. Of the 197 studies that evaluated social stress, aggressive behavior was the most frequently-used indicator (81.81%). Of the 535 publications examined regarding immune-related stress, cytokine concentration in blood samples was the most widely used indicator (80.1%). Information about the methods used to measure animal-based indicators is discussed in terms of validity, reliability, and feasibility. Additionally, the introduction and wide spreading of alternative, less invasive methods with which to measure animal-based indicators, such as cortisol in saliva, skin temperature and respiratory rate via infrared thermography, and various animal welfare threats via vocalization analysis are highlighted. The information reviewed was used to discuss the feasible and most reliable methods with which to monitor the impact of relevant stressors commonly presented by intense production systems on the welfare of farmed pigs.
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Razzuoli E, Armando F, De Paolis L, Ciurkiewicz M, Amadori M. The Swine IFN System in Viral Infections: Major Advances and Translational Prospects. Pathogens 2022; 11:175. [PMID: 35215119 PMCID: PMC8875149 DOI: 10.3390/pathogens11020175] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 02/01/2023] Open
Abstract
Interferons (IFNs) are a family of cytokines that play a pivotal role in orchestrating the innate immune response during viral infections, thus representing the first line of defense in the host. After binding to their respective receptors, they are able to elicit a plethora of biological activities, by initiating signaling cascades which lead to the transcription of genes involved in antiviral, anti-inflammatory, immunomodulatory and antitumoral effector mechanisms. In hindsight, it is not surprising that viruses have evolved multiple IFN escape strategies toward efficient replication in the host. Hence, in order to achieve insight into preventive and treatment strategies, it is essential to explore the mechanisms underlying the IFN response to viral infections and the constraints thereof. Accordingly, this review is focused on three RNA and three DNA viruses of major importance in the swine farming sector, aiming to provide essential data as to how the IFN system modulates the antiviral immune response, and is affected by diverse, virus-driven, immune escape mechanisms.
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Affiliation(s)
- Elisabetta Razzuoli
- National Reference Center of Veterinary and Comparative Oncology (CEROVEC), Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D’Aosta, Piazza Borgo Pila 39/24, 16129 Genoa, Italy;
| | - Federico Armando
- Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany; (F.A.); (M.C.)
| | - Livia De Paolis
- National Reference Center of Veterinary and Comparative Oncology (CEROVEC), Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D’Aosta, Piazza Borgo Pila 39/24, 16129 Genoa, Italy;
| | - Malgorzata Ciurkiewicz
- Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany; (F.A.); (M.C.)
| | - Massimo Amadori
- National Network of Veterinary Immunology (RNIV), Via Istria 3, 25125 Brescia, Italy;
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Kuchi Bhotla H, Balasubramanian B, Meyyazhagan A, Pushparaj K, Easwaran M, Pappusamy M, Alwin Robert A, Arumugam VA, Tsibizova V, Msaad Alfalih A, Aljowaie RM, Saravanan M, Di Renzo GC. Opportunistic mycoses in COVID-19 patients/survivors: Epidemic inside a pandemic. J Infect Public Health 2021; 14:1720-1726. [PMID: 34700291 PMCID: PMC8518133 DOI: 10.1016/j.jiph.2021.10.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/06/2021] [Accepted: 10/10/2021] [Indexed: 12/30/2022] Open
Abstract
Being considered minor vexations, fungal infections hinder the life of about 15% of the world population superficially, with rare threats to life in case of invasive sepsis. A significant rise in the intrusive mycoses due to machiavellian fungal species is observed over the years due to increased pathology and fatality in people battling life-threatening diseases. Individuals undergoing therapy with immune suppressive drugs plus recovering from viral infections have shown to develop fungal sepsis as secondary infections while recovering or after. Currently, the whole world is fighting against the fright of Coronavirus disease (COVID-19), and corticosteroids being the primitive therapeutic to combat the COVID-19 inflammation, leads to an immune-compromised state, thereby allowing the not so harmful fungi to violate the immune barrier and flourish in the host. A wide range of fungal co-infection is observed in the survivors and patients of COVID-19. Fungal species of Candida, Aspergillus and Mucorales, are burdening the lives of COVID-19 patients/survivors in the form of Yellow/Green, White and Black fungus. This is the first article of its kind to assemble note on fungal infections seen in the current human health scenario till date and provides a strong message to the clinicians, researchers and physicians around the world "non-pathological fungus should not be dismissed as contaminants, they can quell immunocompromised hosts".
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Affiliation(s)
- Haripriya Kuchi Bhotla
- Department of Life Sciences, CHRIST (Deemed to be University), Bengaluru, 560029 Karnataka, India
| | | | - Arun Meyyazhagan
- Department of Life Sciences, CHRIST (Deemed to be University), Bengaluru, 560029 Karnataka, India; Department of Obstetrics and Gynecology, Centre for Perinatal and Reproductive Medicine, University of Perugia, Perugia, Italy.
| | - Karthika Pushparaj
- Department of Zoology, School of Biosciences, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, 641 043, Tamil Nadu, India
| | - Murugesh Easwaran
- Computational Biology Lab, Department of Bioinformatics, Bharathiar University, Coimbatore, Tamil Nadu 641 046, India
| | - Manikantan Pappusamy
- Department of Life Sciences, CHRIST (Deemed to be University), Bengaluru, 560029 Karnataka, India
| | - Asirvatham Alwin Robert
- Department of Endocrinology and Diabetes, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Vijaya Anand Arumugam
- Medical Genetics and Epigenetics Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, 641046, Tamil Nadu, India
| | - Valentina Tsibizova
- Institute of Perinatology and Pediatrics, Almazov National Medical Research Centre, Saint-Petersburg, Russian Federation
| | - Abdullah Msaad Alfalih
- Department of Botany and Microbiology, College of Science, King Saud University, P.O Box 24552, 11495, Riyadh, Saudi Arabia
| | - Reem M Aljowaie
- Department of Botany and Microbiology, College of Science, King Saud University, P.O Box 24552, 11495, Riyadh, Saudi Arabia
| | - Muthupandian Saravanan
- Department of Microbiology and Immunology, Division of Biomedical Sciences, School of Medicine, College of Health Science, Mekelle University, Mekelle, 1871, Ethiopia; Department of Pharmacology, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha Dental College, 600077, Chennai, Tamil Nadu, India.
| | - Gian Carlo Di Renzo
- Department of Obstetrics and Gynecology, Centre for Perinatal and Reproductive Medicine, University of Perugia, Perugia, Italy.
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Peng JY, Shin DL, Li G, Wu NH, Herrler G. Time-dependent viral interference between influenza virus and coronavirus in the infection of differentiated porcine airway epithelial cells. Virulence 2021; 12:1111-1121. [PMID: 34034617 PMCID: PMC8162253 DOI: 10.1080/21505594.2021.1911148] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Coronaviruses and influenza viruses are circulating in humans and animals all over the world. Co-infection with these two viruses may aggravate clinical signs. However, the molecular mechanisms of co-infections by these two viruses are incompletely understood. In this study, we applied air-liquid interface (ALI) cultures of well-differentiated porcine tracheal epithelial cells (PTECs) to analyze the co-infection by a swine influenza virus (SIV, H3N2 subtype) and porcine respiratory coronavirus (PRCoV) at different time intervals. Our results revealed that in short-term intervals, prior infection by influenza virus caused complete inhibition of coronavirus infection, while in long-term intervals, some coronavirus replication was detectable. The influenza virus infection resulted in (i) an upregulation of porcine aminopeptidase N, the cellular receptor for PRCoV and (ii) in the induction of an innate immune response which was responsible for the inhibition of PRCoV replication. By contrast, prior infection by coronavirus only caused a slight inhibition of influenza virus replication. Taken together, the timing and the order of virus infection are important determinants in co-infections. This study is the first to show the impact of SIV and PRCoV co- and super-infection on the cellular level. Our results have implications also for human viruses, including potential co-infections by SARS-CoV-2 and seasonal influenza viruses.
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Affiliation(s)
- Ju-Yi Peng
- Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Dai-Lun Shin
- Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Guangxing Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Nai-Huei Wu
- Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany.,Department of Veterinary Medicine, National Taiwan University, Taipei, Taiwan
| | - Georg Herrler
- Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany
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Creeden JF, Imami AS, Eby HM, Gillman C, Becker KN, Reigle J, Andari E, Pan ZK, O'Donovan SM, McCullumsmith RE, McCullumsmith CB. Fluoxetine as an anti-inflammatory therapy in SARS-CoV-2 infection. Biomed Pharmacother 2021; 138:111437. [PMID: 33691249 PMCID: PMC7904450 DOI: 10.1016/j.biopha.2021.111437] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 01/27/2023] Open
Abstract
Hyperinflammatory response caused by infections such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) increases organ failure, intensive care unit admission, and mortality. Cytokine storm in patients with Coronavirus Disease 2019 (COVID-19) drives this pattern of poor clinical outcomes and is dependent upon the activity of the transcription factor complex nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and its downstream target gene interleukin 6 (IL6) which interacts with IL6 receptor (IL6R) and the IL6 signal transduction protein (IL6ST or gp130) to regulate intracellular inflammatory pathways. In this study, we compare transcriptomic signatures from a variety of drug-treated or genetically suppressed (i.e. knockdown) cell lines in order to identify a mechanism by which antidepressants such as fluoxetine demonstrate non-serotonergic, anti-inflammatory effects. Our results demonstrate a critical role for IL6ST and NF-kappaB Subunit 1 (NFKB1) in fluoxetine's ability to act as a potential therapy for hyperinflammatory states such as asthma, sepsis, and COVID-19.
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Affiliation(s)
- Justin Fortune Creeden
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; Department of Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.
| | - Ali Sajid Imami
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Hunter M Eby
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Cassidy Gillman
- Department of Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
| | - Kathryn N Becker
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Jim Reigle
- Department of Biomedical Informatics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Elissar Andari
- Department of Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
| | - Zhixing K Pan
- Department of Medical Microbiology and Immunology, University of Toledo Medical Center, Toledo, OH, USA
| | - Sinead M O'Donovan
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Robert E McCullumsmith
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; Neurosciences Institute, ProMedica, Toledo, OH 43606, USA
| | - Cheryl B McCullumsmith
- Department of Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
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Oz M, Lorke DE, Kabbani N. A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor. Pharmacol Ther 2021; 221:107750. [PMID: 33275999 PMCID: PMC7854082 DOI: 10.1016/j.pharmthera.2020.107750] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 02/06/2023]
Abstract
The recent emergence of coronavirus disease-2019 (COVID-19) as a global pandemic has prompted scientists to address an urgent need for defining mechanisms of disease pathology and treatment. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, employs angiotensin converting enzyme 2 (ACE2) as its primary target for cell surface attachment and likely entry into the host cell. Thus, understanding factors that may regulate the expression and function of ACE2 in the healthy and diseased body is critical for clinical intervention. Over 66% of all adults in the United States are currently using a prescription drug and while earlier findings have focused on possible upregulation of ACE2 expression through the use of renin angiotensin system (RAS) inhibitors, mounting evidence suggests that various other widely administered drugs used in the treatment of hypertension, heart failure, diabetes mellitus, hyperlipidemias, coagulation disorders, and pulmonary disease may also present a varied risk for COVID-19. Specifically, we summarize mechanisms on how heparin, statins, steroids and phytochemicals, besides their established therapeutic effects, may also interfere with SARS-CoV-2 viral entry into cells. We also describe evidence on the effect of several vitamins, phytochemicals, and naturally occurring compounds on ACE2 expression and activity in various tissues and disease models. This comprehensive review aims to provide a timely compendium on the potential impact of commonly prescribed drugs and pharmacologically active compounds on COVID-19 pathology and risk through regulation of ACE2 and RAS signaling.
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Key Words
- adam17, a disintegrin and metalloprotease 17
- ace, angiotensin i converting enzyme
- ace-inh., angiotensin i converting enzyme inhibitor
- ampk, amp-activated protein kinase
- ang-ii, angiotensin ii
- arb, angiotensin ii type 1-receptor blocker
- ards, acute respiratory distress syndrome
- at1-r, angiotensin ii type 1-receptor
- βarb, β-adrenergic receptor blockers
- bk, bradykinin
- ccb, calcium channel blockers
- ch25h, cholesterol-25-hydroxylase
- copd, chronic obstructive lung disease
- cox, cyclooxygenase
- covid-19, coronavirus disease-2019
- dabk, [des-arg9]-bradykinin
- erk, extracellular signal-regulated kinase
- 25hc, 25-hydroxycholesterol
- hs, heparan sulfate
- hspg, heparan sulfate proteoglycan
- ibd, inflammatory bowel disease
- map, mitogen-activated protein
- mers, middle east respiratory syndrome
- mrb, mineralocorticoid receptor blocker
- nos, nitric oxide synthase
- nsaid, non-steroid anti-inflammatory drug
- ras, renin-angiotensin system
- sars-cov, severe acute respiratory syndrome coronavirus
- sh, spontaneously hypertensive
- s protein, spike protein
- sirt1, sirtuin 1
- t2dm, type 2 diabetes mellitus
- tcm, traditional chinese medicine
- tmprss2, transmembrane protease, serine 2
- tnf, tumor necrosis factor
- ufh, unfractionated heparin
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Affiliation(s)
- Murat Oz
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait.
| | - Dietrich Ernst Lorke
- Department of Anatomy and Cellular Biology, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates; Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Nadine Kabbani
- School of Systems Biology, George Mason University, Fairfax, VA 22030, USA
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Espinosa-Solano M, Gonzalez-Vergara D, Ferrer-Galvan M, Asensio-Cruz MI, Lomas JM, Roca-Oporto C, Navarro-Amuedo MD, Paniagua-Garcia M, Sotomayor C, Espinosa N, Garcia-Gutierrez M, Molina Gil-Bermejo J, Aguilar-Guisado M, Poyato M, Praena-Segovia J, Palomo A, Borrero-Rodriguez M, Cordero E, Caballero-Eraso C, Jara-Palomares L, CortiCOVID-19 Team. Repeated Pulses of Methyl-Prednisolone in Adults Hospitalized With COVID-19 Pneumonia and Acute Respiratory Distress Syndrome: A Preliminary Before-After Study (CortiCOVID Study). OPEN RESPIRATORY ARCHIVES 2021; 3:100086. [PMID: 38620829 PMCID: PMC7977067 DOI: 10.1016/j.opresp.2021.100086] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 02/11/2021] [Indexed: 12/22/2022] Open
Abstract
Introduction The use of systemic corticosteroids in severely ill patients with coronavirus disease 2019 (COVID-19) is controversial. We aimed to evaluate the efficacy and safety of corticosteroid pulses in patients with COVID-19 pneumonia. Methods A quasi-experimental study, before and after, was performed in a tertiary referral hospital, including admitted patients showing COVID-19-associated pneumonia. The standard treatment protocol included targeted COVID-19 antiviral therapy from 23rd March 2020, and additionally pulses of methylprednisolone from 30th March 2020. The primary outcome was a composite endpoint combining oro-tracheal intubation (OTI) and death within 7 days. Results A total of 24 patients were included. Standard of care (SOC) (before intervention) was prescribed in 14 patients, while 10 received SOC plus pulses of methylprednisolone (after intervention). The median age of patients was 64.5 years and 83.3% of the patients were men. The primary composite endpoint occurred in 13 patients (92.9%) who received SOC vs. 2 patients (20%) that received pulses of methylprednisolone (odds ratio, 0.02; 95% confidence interval, 0.001 to 0.25; p = 0.019). Length of hospitalization in survivors was shorter in the corticosteroids group (median, 14.5 [8.5-21.8] days vs. 29 [23-31] days, p = 0.003). There were no differences in the development of infections between both groups. There were 3 deaths, none of them in the corticosteroids group. Conclusions In patients with severe pneumonia due to COVID-19, the administration of methylprednisolone pulses was associated with a lower rate of OTI and/or death and a shorter hospitalization episode.
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Affiliation(s)
| | | | | | - Maria Isabel Asensio-Cruz
- Respiratory Department, Virgen del Rocio Hospital, Sevilla, Spain
- Instituto de Biomedicina, Sevilla; CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
| | - Jose M. Lomas
- Departments of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocio-Institute of Biomedicine of Seville, Sevilla, Spain
| | - Cristina Roca-Oporto
- Departments of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocio-Institute of Biomedicine of Seville, Sevilla, Spain
| | - Maria Dolores Navarro-Amuedo
- Departments of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocio-Institute of Biomedicine of Seville, Sevilla, Spain
| | - Maria Paniagua-Garcia
- Departments of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocio-Institute of Biomedicine of Seville, Sevilla, Spain
| | - Cesar Sotomayor
- Departments of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocio-Institute of Biomedicine of Seville, Sevilla, Spain
| | - Nuria Espinosa
- Departments of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocio-Institute of Biomedicine of Seville, Sevilla, Spain
| | - Manuel Garcia-Gutierrez
- Departments of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocio-Institute of Biomedicine of Seville, Sevilla, Spain
| | - Jose Molina Gil-Bermejo
- Departments of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocio-Institute of Biomedicine of Seville, Sevilla, Spain
| | - Manuela Aguilar-Guisado
- Departments of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocio-Institute of Biomedicine of Seville, Sevilla, Spain
| | - Manuel Poyato
- Departments of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocio-Institute of Biomedicine of Seville, Sevilla, Spain
| | - Julia Praena-Segovia
- Departments of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocio-Institute of Biomedicine of Seville, Sevilla, Spain
| | | | | | - Elisa Cordero
- Departments of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocio-Institute of Biomedicine of Seville, Sevilla, Spain
| | - Candela Caballero-Eraso
- Respiratory Department, Virgen del Rocio Hospital, Sevilla, Spain
- Instituto de Biomedicina, Sevilla; CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
| | - Luis Jara-Palomares
- Respiratory Department, Virgen del Rocio Hospital, Sevilla, Spain
- Instituto de Biomedicina, Sevilla; CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
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9
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Hamouche W, Bisserier M, Brojakowska A, Eskandari A, Fish K, Goukassian DA, Hadri L. Pathophysiology and pharmacological management of pulmonary and cardiovascular features of COVID-19. J Mol Cell Cardiol 2021; 153:72-85. [PMID: 33373644 PMCID: PMC7833205 DOI: 10.1016/j.yjmcc.2020.12.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/25/2020] [Accepted: 12/13/2020] [Indexed: 02/06/2023]
Abstract
The first confirmed case of novel Coronavirus Disease 2019 (COVID-19) in the United States was reported on January 20, 2020. As of November 24, 2020, close to 12.2 million cases of COVID-19 was confirmed in the US, with over 255,958 deaths. The rapid transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), its unusual and divergent presentation has strengthened the status of COVID-19 as a major public health threat. In this review, we aim to 1- discuss the epidemiological data from various COVID-19 patient cohorts around the world and the USA as well the associated risk factors; 2- summarize the pathophysiology of SARS-CoV-2 infection and the underlying molecular mechanisms for the respiratory and cardiovascular manifestations; 3- highlight the potential treatments and vaccines as well as current clinical trials for COVID-19.
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Affiliation(s)
- Walid Hamouche
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Internal Medicine Department, Brookdale University Hospital Medical Center, Brooklyn, NY, USA
| | - Malik Bisserier
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Agnieszka Brojakowska
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Abrisham Eskandari
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kenneth Fish
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - David A Goukassian
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Lahouaria Hadri
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Vlasova AN, Saif LJ. Bovine Coronavirus and the Associated Diseases. Front Vet Sci 2021; 8:643220. [PMID: 33869323 PMCID: PMC8044316 DOI: 10.3389/fvets.2021.643220] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 03/08/2021] [Indexed: 12/17/2022] Open
Abstract
Coronaviruses (CoVs) possess the largest and most complex RNA genome (up to 32 kb) that encodes for 16 non-structural proteins regulating RNA synthesis and modification. Coronaviruses are known to infect a wide range of mammalian and avian species causing remarkably diverse disease syndromes. Variable tissue tropism and the ability to easily cross interspecies barriers are the well-known characteristics of certain CoVs. The 21st century epidemics of severe acute respiratory CoV (SARS-CoV), Middle East respiratory CoV and the ongoing SARS-CoV-2 pandemic further highlight these characteristics and emphasize the relevance of CoVs to the global public health. Bovine CoVs (BCoVs) are betacoronaviruses associated with neonatal calf diarrhea, and with winter dysentery and shipping fever in older cattle. Of interest, no distinct genetic or antigenic markers have been identified in BCoVs associated with these distinct clinical syndromes. In contrast, like other CoVs, BCoVs exist as quasispecies. Besides cattle, BCoVs and bovine-like CoVs were identified in various domestic and wild ruminant species (water buffalo, sheep, goat, dromedary camel, llama, alpaca, deer, wild cattle, antelopes, giraffes, and wild goats), dogs and humans. Surprisingly, bovine-like CoVs also cannot be reliably distinguished from BCoVs using comparative genomics. Additionally, there are historical examples of zoonotic transmission of BCoVs. This article will discuss BCoV pathogenesis, epidemiology, interspecies transmission, immune responses, vaccines, and diagnostics.
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Affiliation(s)
- Anastasia N Vlasova
- Center for Food Animal Health Research, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
| | - Linda J Saif
- Center for Food Animal Health Research, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
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11
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Ghosh S, Malik YS. Drawing Comparisons between SARS-CoV-2 and the Animal Coronaviruses. Microorganisms 2020; 8:E1840. [PMID: 33238451 PMCID: PMC7700164 DOI: 10.3390/microorganisms8111840] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 11/01/2020] [Accepted: 11/19/2020] [Indexed: 12/19/2022] Open
Abstract
The COVID-19 pandemic, caused by a novel zoonotic coronavirus (CoV), SARS-CoV-2, has infected 46,182 million people, resulting in 1,197,026 deaths (as of 1 November 2020), with devastating and far-reaching impacts on economies and societies worldwide. The complex origin, extended human-to-human transmission, pathogenesis, host immune responses, and various clinical presentations of SARS-CoV-2 have presented serious challenges in understanding and combating the pandemic situation. Human CoVs gained attention only after the SARS-CoV outbreak of 2002-2003. On the other hand, animal CoVs have been studied extensively for many decades, providing a plethora of important information on their genetic diversity, transmission, tissue tropism and pathology, host immunity, and therapeutic and prophylactic strategies, some of which have striking resemblance to those seen with SARS-CoV-2. Moreover, the evolution of human CoVs, including SARS-CoV-2, is intermingled with those of animal CoVs. In this comprehensive review, attempts have been made to compare the current knowledge on evolution, transmission, pathogenesis, immunopathology, therapeutics, and prophylaxis of SARS-CoV-2 with those of various animal CoVs. Information on animal CoVs might enhance our understanding of SARS-CoV-2, and accordingly, benefit the development of effective control and prevention strategies against COVID-19.
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Affiliation(s)
- Souvik Ghosh
- Department of Biomedical Sciences, Ross University School of Veterinary Medicine, Basseterre 334, Saint Kitts and Nevis
| | - Yashpal S. Malik
- College of Animal Biotechnology, Guru Angad Dev Veterinary and Animal Science University, Ludhiana 141004, India;
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12
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Yang YC, Chou CL, Kao CL. Exercise, nutrition, and medication considerations in the light of the COVID pandemic, with specific focus on geriatric population: A literature review. J Chin Med Assoc 2020; 83:977-980. [PMID: 32675738 PMCID: PMC7434014 DOI: 10.1097/jcma.0000000000000393] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The pandemic of severe acute respiratory syndrome coronavirus 2 has spread across the world, causing causalities and inflicting chronic complications in those who survive the infection. Disruptions in the immune system and lowered physical levels caused by quarantine protocols are the major causes of chronic dysfunction and impaired life independency, especially in elderly patients. Multiple exercise suggestions and novel program delivery methods, including telerehabilitation/tele-exercise programs, home-gym strategies, and exergames, have emerged. Patients with underlying obesity, diabetes mellitus, malnutrition, or binge-eating problems are at a high risk of serious infection and sequela. Adequate education and coping strategies can lessen the potential infection complications and improve the quality of life. Acknowledging the possible benefits and risks of nonsteroidal anti-inflammatory drug usage in chronic pain patients, and the supplementation of vitamin D may also aid in treating post-infected patients.
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Affiliation(s)
- Yi-Chiang Yang
- Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Cheng-Liang Chou
- Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Physical Medicine & Rehabilitation, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Chung-Lan Kao
- Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Physical Medicine & Rehabilitation, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Address correspondence. Dr. Chung-Lan Kao, Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, 201, Section 2, Shi-Pai Road, Taipei 112, Taiwan, ROC. E-mail address: (C.-L. Kao)
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13
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Kumar R, Srivastava JK, Singh R, Siddiqui MH, Mansouri RA, Abdulhakim JA, Bin-Jumah MN, Alkahtani S, Abdel-Daim MM, Uddin MS. Available Compounds With Therapeutic Potential Against COVID-19: Antimicrobial Therapies, Supportive Care, and Probable Vaccines. Front Pharmacol 2020; 11:582025. [PMID: 33123014 PMCID: PMC7573470 DOI: 10.3389/fphar.2020.582025] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 09/15/2020] [Indexed: 12/15/2022] Open
Abstract
The recent outbreak of the COVID-2019 (coronavirus disease 2019) due to the infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has realized the requirement of alternative therapeutics to mitigate and alleviate this lethal infection. These alternative therapies are effective when they are started at the initial stage of the infection. Some drugs that were used in previous other related infections SARS-CoV-2003 and Middle East respiratory syndrome coronavirus (MERS-CoV)-2012 could be potentially active against currently emerging SARS-CoV-2. This fact imparts some rationale of current interventions, in the absence of any specific therapeutics for SARS-CoV-2. It is imperative to focus on the available antimicrobial and adjunct therapies during the current emergency state and overcome the challenges associated with the absence of robust controlled studies. There is no established set of drugs to manage SARS-CoV-2 infected patients. However, closely following patients’ conditions and responding with the dosage guidelines of available drugs may significantly impact our ability to slow down the infection. Of note, it depends upon the condition of the patients and associated comorbid; therefore, the health workers need to choose the drug combinations judiciously until COVID-19 specific drug or vaccine is developed with the collective scientific rigor. In this article, we reviewed the available antimicrobial drug, supportive therapies, and probable high importance vaccines for the COVID-19 treatment.
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Affiliation(s)
- Rajnish Kumar
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Lucknow, India
| | | | - Rachana Singh
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Lucknow, India
| | | | - Rasha A Mansouri
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jawaher A Abdulhakim
- Department of Medical Laboratory, Faculty of Applied Medical Sciences, Taibah University, Yanbu, Saudi Arabia
| | - May N Bin-Jumah
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Saad Alkahtani
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Mohamed M Abdel-Daim
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia.,Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
| | - Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh.,Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
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14
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Heegaard PMH, Sturek M, Alloosh M, Belsham GJ. Animal Models for COVID-19: More to the Picture Than ACE2, Rodents, Ferrets, and Non-human Primates. A Case for Porcine Respiratory Coronavirus and the Obese Ossabaw Pig. Front Microbiol 2020; 11:573756. [PMID: 33101246 PMCID: PMC7545904 DOI: 10.3389/fmicb.2020.573756] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 08/31/2020] [Indexed: 12/31/2022] Open
Abstract
The ongoing COVID-19 pandemic caused by infection with SARS-CoV-2 has created an urgent need for animal models to enable study of basic infection and disease mechanisms and for development of vaccines, therapeutics, and diagnostics. Most research on animal models for COVID-19 has been directed toward rodents, transgenic rodents, and non-human primates. The primary focus has been on the angiotensin-converting enzyme 2 (ACE2), which is a host cell receptor for SARS-CoV-2. Among investigated species, irrespective of ACE2 spike protein binding, only mild (or no) disease has occurred following infection with SARS-CoV-2, suggesting that ACE2 may be necessary for infection but is not sufficient to determine the outcome of infection. The common trait of all species investigated as COVID models is their healthy status prior to virus challenge. In contrast, the vast majority of severe COVID-19 cases occur in people with chronic comorbidities such as diabetes, obesity, and/or cardiovascular disease. Healthy pigs express ACE2 protein that binds the viral spike protein but they are not susceptible to infection with SARS-CoV-2. However, certain pig breeds, such as the Ossabaw pig, can reproducibly be made obese and show most aspects of the metabolic syndrome, thus resembling the more than 80% of the critically ill COVID-19 patients admitted to hospitals. We urge considering infection with porcine respiratory coronavirus of metabolic syndrome pigs, such as the obese Ossabaw pig, as a highly relevant animal model of severe COVID-19.
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Affiliation(s)
- Peter M H Heegaard
- Department of Health Technology, Technical University of Denmark (DTU), Lyngby, Denmark
| | - Michael Sturek
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Mouhamad Alloosh
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Graham J Belsham
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
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15
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Fu HY, Luo Y, Gao JP, Wang L, Li HJ, Li X, Xue L, Tang XQ, Li HW, Du YR. Effects of Short-Term Low-Dose Glucocorticoids for Patients with Mild COVID-19. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2854186. [PMID: 33015160 PMCID: PMC7519460 DOI: 10.1155/2020/2854186] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/27/2020] [Accepted: 08/24/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVES To evaluate the role of short-term low-dose glucocorticoids in mild COVID-19 patients. METHODS We conducted a retrospective, cross-sectional, single-center study in Kunming, China. A total of 33 mild COVID-19 cases were divided into two treatment groups (with and without glucocorticoids, methylprednisolone, were used in this setting), and the absolute value of peripheral blood lymphocyte count; CD3+, CD4+, and CD8+ T cell counts; and the time to achieve negative transformation of a nucleic acid pharyngeal swab were recorded. Peripheral blood lymphocyte and T cell counts were compared between the treatment group and 25 healthy individuals. At the point of time when there was a 50% accumulation conversion rate (positive to negative nucleic acid on pharyngeal swab), and the nucleic acid turned negative in half of the patients in two groups, the peripheral blood lymphocyte and T cell counts were compared between treatment groups. RESULTS The mean cumulative time for the 50% negative conversion rate of the nucleic acid in the pharyngeal swab was 17.7 ± 5.1 days and 13.9 ± 5.4 days in the glucocorticoid group and the nonglucocorticoid group, respectively. The absolute peripheral blood lymphocyte count and the T cell subset count in the glucocorticoid group were lower than those in the nonglucocorticoid group. When the nucleic acid turned negative in half of the patients, the absolute value of peripheral blood lymphocyte count and CD4+ T cells of the glucocorticoid group and the nonglucocorticoid group was not significantly different; the CD3+ and CD8+ T cells in the glucocorticoid group were lower than those in the nonglucocorticoid group. The absolute peripheral blood lymphocyte count, CD3+ T cells, and CD4+ T cells in the glucocorticoid group were lower than those of the healthy group during the whole disease period, and CD8+ T cells returned to normal at 19-21 days of the disease period. There was no significant difference between the nonglucocorticoid group and the healthy group for absolute peripheral blood lymphocyte and CD8+ T cells; moreover, CD3+ T cells and CD4+ T cells were lower in the nonglucocorticoid group than those in the healthy group from the day of admission to the 18th day and returned to normal at the period of 19-21 days. The absolute peripheral lymphocyte count (P = 0.048, effect size d = 0.727) and T cell subset count (CD3: P = 0.042, effect size d = 0.655; CD4: P < 0.01, effect size d = 0.599; and CD8: P = 0.034, effect size d = 0.550) in the nonglucocorticoid group were higher than those in the glucocorticoid group, and the difference between the groups was statistically significant. CONCLUSIONS This study found that the use of short-term, low-dose glucocorticoids does not negatively influence the clinical outcome, without affecting the final clearance of viral nucleic acid in mild COVID-19 patients.
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Affiliation(s)
- Hai-Yan Fu
- Department of Palliative Care, The Sixth Affiliated Hospital of Dali University, The Third People's Hospital of Kunming, China
| | - Yu Luo
- Department of Palliative Care, The Sixth Affiliated Hospital of Dali University, The Third People's Hospital of Kunming, China
| | - Jian-Peng Gao
- Department of Palliative Care, The Sixth Affiliated Hospital of Dali University, The Third People's Hospital of Kunming, China
| | - Lin Wang
- Department of Clinical Laboratory, The Sixth Affiliated Hospital of Dali University, The Third People's Hospital of Kunming, China
| | - Hong-Juan Li
- Department of Palliative Care, The Sixth Affiliated Hospital of Dali University, The Third People's Hospital of Kunming, China
| | - Xiang Li
- Department of Radiology, The Sixth Affiliated Hospital of Dali University, The Third People's Hospital of Kunming, China
| | - Lian Xue
- Department of Palliative Care, The Sixth Affiliated Hospital of Dali University, The Third People's Hospital of Kunming, China
| | - Xiao-Qing Tang
- Department of Palliative Care, The Sixth Affiliated Hospital of Dali University, The Third People's Hospital of Kunming, China
| | - Hai-wen Li
- Department of Palliative Care, The Sixth Affiliated Hospital of Dali University, The Third People's Hospital of Kunming, China
| | - Ying-Rong Du
- Department of Palliative Care, The Sixth Affiliated Hospital of Dali University, The Third People's Hospital of Kunming, China
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16
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Imam A, Tzukert K, Merhav H, Imam R, Abu-Gazala S, Abel R, Elhalel MD, Khalaileh A. Practical recommendations for kidney transplantation in the COVID-19 pandemic. World J Transplant 2020; 10:223-229. [PMID: 32995318 PMCID: PMC7504192 DOI: 10.5500/wjt.v10.i9.223] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 05/23/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Kidney transplantation at the time of a global viral pandemic has become challenging in many aspects. Firstly, we must reassess deceased donor safety (for the recipient) especially in communities with a relatively high incidence of coronavirus disease 19 (COVID-19). With respect to elective live donors, if one decides to do them at all, similar considerations must be made that may impose undue hardship on the donor. Recipient selection is also problematic since there is clear evidence of a much higher morbidity and mortality from COVID-19 for patients older than 60 and those with comorbidities such as hypertension, diabetes, obesity and lung disease. Unfortunately, many, if not most of dialysis patients fit that mold. We may and indeed must reassess our allocation policies, but this must be done based on data rather than conjecture. Follow-up routines must be re-engineered to minimize patient travel and exposure. Reliance on technology and telemedicine is paramount. Making this technology available to patients is extremely important. Modifying or changing immunosuppression protocols is controversial and not based on clinical studies. Nevertheless, we should reassess the need for induction therapy across the board for ordinary patients and the more liberal use of mammalian target of rapamycin inhibitors in transplant patients with proven infection.
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Affiliation(s)
- Ashraf Imam
- Transplantation Unit, Department of Surgery, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Keren Tzukert
- Department of Nephrology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Hadar Merhav
- Transplantation Unit, Department of Surgery, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Riham Imam
- Transplantation Unit, Department of Surgery, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Samir Abu-Gazala
- Transplantation Unit, Department of Surgery, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Roy Abel
- Department of Nephrology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | | | - Abed Khalaileh
- Transplantation Unit, Department of Surgery, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
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Abstract
Concerns regarding infection with the novel coronavirus SARS-CoV-2 leading to COVID-19 are particularly marked for pregnant women with autoimmune diseases such as multiple sclerosis (MS). There is currently a relative paucity of information to guide advice given to and the clinical management of these individuals. Much of the limited available data around COVID-19 and pregnancy derives from the obstetric literature, and as such, neurologists may not be familiar with the general principles underlying current advice. In this article, we discuss the impact of potential infection on the pregnant woman, the impact on her baby, the impact of the current pandemic on antenatal care, and the interaction between COVID-19, MS and pregnancy. This review provides a framework for neurologists to use to guide the individualised advice given to both pregnant women with MS, and those women with MS who are considering pregnancy. This includes evidence derived from previous novel coronavirus infections, and emerging evidence from the current pandemic.
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Affiliation(s)
- Charmaine Yam
- Department of Neurology, Royal Free Hospital NHS Trust, London, UK
| | - Vilija Jokubaitis
- Department of Neuroscience, Monash University, Melbourne, VIC, Australia
| | - Kerstin Hellwig
- Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Ruth Dobson
- Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK/Department of Neurology, Royal London Hospital, Barts Health NHS Trust, London, UK
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Abstract
Coronavirus disease-2019 (COVID-19) has caused a pandemic that has affected millions of people worldwide. COVID-19 is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and is spread by close contact and by respiratory droplets. It has also impacted different aspects of caring for people with kidney disease, including those with acute kidney injury (AKI), chronic kidney disease (CKD), those requiring kidney replacement therapy (KRT), and those with a kidney transplant. All of these patients are considered high risk. The lessons learned from the COVID-19 pandemic will hopefully serve to protect patients with kidney disease in a similar situation in the future.
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Arca KN, Smith JH, Chiang C, Starling AJ, Robertson CE, Halker Singh RB, Schwedt TJ, Kissoon NR, Garza I, Rozen TD, Boes CJ, Whealy MA, VanderPluym JH. COVID-19 and Headache Medicine: A Narrative Review of Non-Steroidal Anti-Inflammatory Drug (NSAID) and Corticosteroid Use. Headache 2020; 60:1558-1568. [PMID: 32648592 PMCID: PMC7404408 DOI: 10.1111/head.13903] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/18/2020] [Accepted: 06/18/2020] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To summarize the current literature on non-steroidal anti-inflammatory drug and corticosteroid use during the coronavirus disease 2019 (COVID-19) pandemic, recognizing that these are commonly used treatments in the field of headache medicine. BACKGROUND The use of non-steroidal anti-inflammatory drugs and corticosteroids in patients during the COVID-19 pandemic has been a controversial topic within the medical community and international and national health organizations. Lay press and social media outlets have circulated opinions on this topic despite the fact that the evidence for or against the use of these medications is sparse. In the field of headache medicine, these medications are used commonly and both patients and clinicians may have questions or hesitations pertaining to their use during the COVID-19 pandemic. METHODS A detailed search of the scientific and popular literature was performed. RESULTS There is limited literature pertaining to the safety of non-steroidal anti-inflammatory drugs and corticosteroids during the COVID-19 pandemic. To date, there are no clear scientific data that preclude the use of non-steroidal anti-inflammatory drugs in the general population who may acquire COVID-19 or in those acutely infected with the virus. Several health organizations have concluded that treatment with corticosteroids during active infection should be avoided due to concerns of prolonged viral shedding in the respiratory tract and the lack of survival benefit based on the data from past coronaviruses and influenza virus; specific exceptions exist including treatment for underlying asthma or chronic obstructive pulmonary disease, septic shock, and acute respiratory distress syndrome. CONCLUSION Scientific information regarding the COVID-19 pandemic is constantly evolving, and limited or contradictory information can lead to confusion for both patients and clinicians. It is recommended that prior to prescribing non-steroidal anti-inflammatory drugs and steroids for the treatment of headache, clinicians have open discussions with their patients about the potential risks and benefits of using these medications during the COVID-19 pandemic. This manuscript summarizes the currently available evidence and understanding about these risks and benefits to help clinicians navigate such discussions.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Ivan Garza
- Department of NeurologyMayo ClinicRochesterMNUSA
| | - Todd D. Rozen
- Department of NeurologyMayo Clinic FloridaJacksonvilleFLUSA
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20
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Ma Y, Zeng H, Zhan Z, Lu H, Zeng Z, He C, Liu X, Chen C, Qin Q, He J, Zhou Z, Huang P, Jiang M, Deng D, Liao X, Xiang Z, Huang X, Chen Y, Chen P. Corticosteroid Use in the Treatment of COVID-19: A Multicenter Retrospective Study in Hunan, China. Front Pharmacol 2020; 11:1198. [PMID: 32903363 PMCID: PMC7434865 DOI: 10.3389/fphar.2020.01198] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 07/23/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) has developed into a worldwide pandemic. This study aimed to retrospectively describe the use of corticosteroids in treating COVID-19. METHODS For this multicenter retrospective study, medical records from 488 symptomatic COVID-19 patients were reviewed. Patients were divided into severe and nonsevere groups. Baseline characteristics, signs and symptoms, laboratory findings, treatments, and disease outcomes were compared. Specific data for corticosteroid treatment were further analyzed. RESULTS Four hundred fifty COVID-19 patients were included in this study, including 82 severe patients and 368 nonsevere cases. Out of the 450 patients, 126 (28.0%) received corticosteroid treatment. In the 126 patients treated with corticosteroids, the median daily dose of corticosteroid therapy was 56.6 [interquartile range (IQR): 40.0-78.4] mg and median corticosteroid therapy duration was 5.0 (IQR: 3.0-7.0) days. Among nonsevere cases, patients treated with corticosteroids were significantly older in comparison with patients who did not receive corticosteroid treatment (p<0.01); the proportion of patients receiving antibiotic therapy in the corticosteroid group was significantly higher than that in the noncorticosteroid group (p<0.001); hospitalization length and duration of viral shedding were significantly longer in patients in the corticosteroid group than in the noncorticosteroid group after adjusting for age, sex, and comorbidities (p<0.05). In severe cases, patients treated with corticosteroids were significantly older and comorbidities at admission were significantly more common in patients receiving corticosteroid treatment (p<0.05); the proportion of patients receiving antibiotic therapy in the corticosteroid group was significantly higher than that in the noncorticosteroid group (p<0.001); no significant difference in hospitalization length or viral shedding duration was found between two groups after adjusting for age, sex, and comorbidities (p>0.05). CONCLUSION Our study indicates that corticosteroids are regarded as one of treatments in the general clinical practice of COVID-19. However, corticosteroid use may be accompanied by increased use of antibiotics, longer hospitalization, and prolonged viral shedding.
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Affiliation(s)
- Yiming Ma
- Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Huihui Zeng
- Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Zijie Zhan
- Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Huanhuan Lu
- Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Zihang Zeng
- Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Chenjie He
- Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiangming Liu
- Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Chen Chen
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qingwu Qin
- Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jia He
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Zhiguo Zhou
- Department of Respiratory Medicine, The First Hospital of Changsha, Changsha, China
| | - Peng Huang
- Department of Respiratory Medicine, Zhuzhou Central Hospital, Zhuzhou, China
| | - Mingyan Jiang
- Department of Respiratory and Critical Medicine, Xiangtan Central Hospital, Xiangtan, China
| | - Dingding Deng
- Department of Respiratory Medicine, The First Affiliated Hospital of Shaoyang University, Shaoyang, China
| | - Xin Liao
- Department of Respiratory Medicine, The Central Hospital of Shaoyang, Shaoyang, China
| | - Zhi Xiang
- Department of Respiratory Medicine, Huaihua First People’s Hospital, Huaihua, China
| | - Xiaoying Huang
- Department of Respiratory Medicine, Loudi Central Hospital, Loudi, China
| | - Yan Chen
- Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ping Chen
- Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
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21
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Lin HY. The severe COVID-19: A sepsis induced by viral infection? And its immunomodulatory therapy. Chin J Traumatol 2020; 23:190-195. [PMID: 32690231 PMCID: PMC7451584 DOI: 10.1016/j.cjtee.2020.06.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/24/2020] [Accepted: 05/30/2020] [Indexed: 02/06/2023] Open
Abstract
COVID-19 is known for its magical infectivity, fast transmission and high death toll based on the large number of infected people. From the perspective of the clinical manifestation, autopsy examination and pathophysiology, the essence of COVID-19 should be viewed as a sepsis induced by viral infection, and has the essential characteristics as sepsis induced by other pathogens. Therefore, in addition to etiological and supportive treatment, immunomodulatory therapy is also appropriate to severe COVID-19. Although there is still a lack of consensus on immunotherapy for sepsis so far, relatively rich experiences have been accumulated in the past decades, which will help us in the treatment of severe COVID-19. This article will elaborate immunotherapy of sepsis, though it may not be consistent.
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Affiliation(s)
- Hong-Yuan Lin
- Forth Medical Center, General Hospital of PLA, Beijing, China.
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22
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Ali MJ, Hanif M, Haider MA, Ahmed MU, Sundas FNU, Hirani A, Khan IA, Anis K, Karim AH. Treatment Options for COVID-19: A Review. Front Med (Lausanne) 2020; 7:480. [PMID: 32850922 PMCID: PMC7412857 DOI: 10.3389/fmed.2020.00480] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 07/15/2020] [Indexed: 12/17/2022] Open
Abstract
Background: The recent COVID-19 pandemic sweeping the globe has caused great concern worldwide. Due to the limited evidence available on the dynamics of the virus and effective treatment options available, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a huge impact in terms of morbidity and mortality. The economic impact is still to be assessed. Aims: The purpose of this article is to review the evidence for the multiple treatment options available, to consider the future of this global pandemic, and to identify some potential options that could revolutionize the treatment of COVID-19. Moreover, this article underscores the sheer importance of repurposing some of the available antiviral and antimicrobial agents that have long been in use so as to have an effective and expeditious response to this widespread pandemic and the need to conduct a multicenter global randomized controlled trial to find an effective single antiviral agent or a cocktail of available antimicrobial agents. Method: We thoroughly searched and reviewed various case reports, retrospective analyses, and in vitro studies published in PubMed, EMBASE, and Google Scholar regarding the treatment options used for SARS-CoV, MERS-CoV, and SARS-CoV-2 since its outbreak in an attempt to highlight treatments with the most promising results. Conclusion: We are currently facing one of the worst pandemics in history. Although SARS-CoV-2 is associated with a lower mortality rate than are SARS-CoV and MERS-CoV, its higher infectivity is making it a far more serious threat. Unfortunately, no vaccine against SARS-CoV-2 or effective drug regimen for COVID-19 currently exists. Drug repurposing of available antiviral agents may provide a respite; moreover, a cocktail of antiviral agents may be helpful in treating this disease. Here, we have highlighted a few available antimicrobial agents that could be very effective in treating COVID-19; indeed, a number of trials are underway to detect and confirm the efficacy of these agents.
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Affiliation(s)
- Mukarram Jamat Ali
- Department of Medicine, King Edward Medical University, Lahore, Pakistan
| | - Muhammad Hanif
- Department of Medicine, Khyber Medical College, Peshawar, Pakistan
| | | | | | - FNU Sundas
- Department of Medicine, Khyber Medical College, Peshawar, Pakistan
| | - Arham Hirani
- Department of Medicine, Ziauddin University, Karachi, Pakistan
| | - Izhan Ali Khan
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Khurram Anis
- Department of Gastroenterology, Pakistan Kidney and Liver Institute, Lahore, Pakistan
| | - Amin H. Karim
- Department of Cardiology, Baylor College of Medicine, Houston, TX, United States
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Comparative Pathogenesis of Bovine and Porcine Respiratory Coronaviruses in the Animal Host Species and SARS-CoV-2 in Humans. J Clin Microbiol 2020; 58:JCM.01355-20. [PMID: 32522830 PMCID: PMC7383540 DOI: 10.1128/jcm.01355-20] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Discovery of bats with severe acute respiratory syndrome (SARS)-related coronaviruses (CoVs) raised the specter of potential future outbreaks of zoonotic SARS-CoV-like disease in humans, which largely went unheeded. Nevertheless, the novel SARS-CoV-2 of bat ancestral origin emerged to infect humans in Wuhan, China, in late 2019 and then became a global pandemic. Less than 5 months after its emergence, millions of people worldwide have been infected asymptomatically or symptomatically and at least 360,000 have died. Coronavirus disease 2019 (COVID-19) in severely affected patients includes atypical pneumonia characterized by a dry cough, persistent fever, and progressive dyspnea and hypoxia, sometimes accompanied by diarrhea and often followed by multiple organ failure, especially of the respiratory and cardiovascular systems. In this minireview, we focus on two endemic respiratory CoV infections of livestock: bovine coronavirus (BCoV) and porcine respiratory coronavirus (PRCV). Both animal respiratory CoVs share some common features with SARS-CoV and SARS-CoV-2. BCoV has a broad host range including wild ruminants and a zoonotic potential. BCoV also has a dual tropism for the respiratory and gastrointestinal tracts. These aspects, their interspecies transmission, and certain factors that impact disease severity in cattle parallel related facets of SARS-CoV or SARS-CoV-2 in humans. PRCV has a tissue tropism for the upper and lower respiratory tracts and a cellular tropism for type 1 and 2 pneumocytes in lung but is generally a mild infection unless complicated by other exacerbating factors, such as bacterial or viral coinfections and immunosuppression (corticosteroids).
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Drożdżal S, Rosik J, Lechowicz K, Machaj F, Szostak B, Majewski P, Rotter I, Kotfis K. COVID-19: Pain Management in Patients with SARS-CoV-2 Infection-Molecular Mechanisms, Challenges, and Perspectives. Brain Sci 2020; 10:E465. [PMID: 32698378 PMCID: PMC7407489 DOI: 10.3390/brainsci10070465] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/15/2020] [Accepted: 07/17/2020] [Indexed: 12/20/2022] Open
Abstract
Since the end of 2019, the whole world has been struggling with the pandemic of the new Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Available evidence suggests that pain is a common symptom during Coronavirus Disease 2019 (COVID-19). According to the World Health Organization, many patients suffer from muscle pain (myalgia) and/or joint pain (arthralgia), sore throat and headache. The exact mechanisms of headache and myalgia during viral infection are still unknown. Moreover, many patients with respiratory failure get admitted to the intensive care unit (ICU) for ventilatory support. Pain in ICU patients can be associated with viral disease itself (myalgia, arthralgia, peripheral neuropathies), may be caused by continuous pain and discomfort associated with ICU treatment, intermittent procedural pain and chronic pain present before admission to the ICU. Undertreatment of pain, especially when sedation and neuromuscular blocking agents are used, prone positioning during mechanical ventilation or extracorporeal membrane oxygenation (ECMO) may trigger delirium and cause peripheral neuropathies. This narrative review summarizes current knowledge regarding challenges associated with pain assessment and management in COVID-19 patients. A structured prospective evaluation should be undertaken to analyze the probability, severity, sources and adequate treatment of pain in patients with COVID-19 infection.
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Affiliation(s)
- Sylwester Drożdżal
- Department of Pharmacokinetics and Monitored Therapy, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland;
| | - Jakub Rosik
- Department of Physiology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (J.R.); (F.M.); (B.S.)
| | - Kacper Lechowicz
- Department of Anesthesiology, Intensive Therapy and Acute Intoxications, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland;
| | - Filip Machaj
- Department of Physiology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (J.R.); (F.M.); (B.S.)
| | - Bartosz Szostak
- Department of Physiology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (J.R.); (F.M.); (B.S.)
| | - Paweł Majewski
- Department of Anesthesiology and Intensive Therapy, Regional Specialist Hospital, 72-300 Gryfice, Department of Cardiac Surgery, Ceynowa Hospital, 84-200 Wejherowo, Poland;
| | - Iwona Rotter
- Department of Medical Rehabilitation and Clinical Physiotherapy, Pomeranian Medical University in Szczecin, 71-210 Szczecin, Poland;
| | - Katarzyna Kotfis
- Department of Anesthesiology, Intensive Therapy and Acute Intoxications, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland;
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Mishra S, Biswas S, Bhatnagar S. Palliative Care Delivery in Cancer Patients in the Era of Covid-19 Outbreak: Unique Needs, Barriers, and Tools for Solutions. Indian J Palliat Care 2020; 26:S130-S141. [PMID: 33088103 PMCID: PMC7535008 DOI: 10.4103/ijpc.ijpc_194_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 06/01/2020] [Indexed: 12/19/2022] Open
Abstract
World is facing a pandemic recently due to the outbreak of COVID-19 infection. Cancer has been identified as one of the major comorbidities which cause more severe disease due to COVID-19 infection. Moreover, there are several resource limitations and restrictions to avail the standard oncological health facilities due to robust measures taken for infection control. In this situation, palliative care in cancer patients deserves special attention. Their symptom management, psychological, social, cultural needs tremendously increase during the epidemic. Thus, we need to recognize the unique palliative care needs of cancer patients during pandemic and formulate the plan to maintain continuity of services. Triaging systems are essential tools for proper resource allocation during a pandemic. Therefore, we suggest triaging tools for emergency in hospital palliative care services: community-based palliative care and end of life care for cancer patients. Incorporation of newer technologies and identifying the potential resources are the other key components of the preparedness strategy.
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Affiliation(s)
- Seema Mishra
- Department of Onco-Anaesthesia and Palliative Medicine, Dr. Bhimrao Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Swagata Biswas
- Department of Onco-Anaesthesia and Palliative Medicine, Dr. Bhimrao Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Sushma Bhatnagar
- Department of Onco-Anaesthesia and Palliative Medicine, Dr. Bhimrao Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
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Abstract
The novel coronavirus, SARS-CoV-2, is causing a pandemic of unknown precedent, with huge healthcare challenges and worldwide disruptions to economic and social life. Lung transplant recipients and other solid organ transplant (SOT) recipients are immunosuppressed, and therefore are generally considered at an increased risk for severe infections. Given the current gap in knowledge and evidence regarding the best management of these patients, we conducted a systematic review of studies on SARS-CoV-2 infections and Coronavirus Disease 2019 (COVID-19) in SOT recipients, to evaluate the association between immunosuppression in these patients, SARS-CoV-2 infection and COVID-19 outcomes. The focus was the severity of the disease, the need for mechanical ventilation and intensive care unit (ICU) admissions, and rate of death. The literature search was conducted repeatedly between 16 March and 8 April 2020. We searched original papers, observational studies, case reports, and meta-analyses published between 2019 and 2020 using two databases (PubMed, Google Scholar) with the search terms: [transplant OR immunosuppression] AND [COVID-19 OR SARS-CoV-2]. Further inclusion criteria were publications in English, French, German and Italian, and reference to humans. We also searched the reference lists of the studies encountered. From an initial search of PubMed and Google Scholar, 19 potential articles were retrieved, of which 14 were excluded after full-text screening (not being case reports or case series), leaving 5 studies for inclusion. No further studies were identified from the bibliographies of retrieved articles. Based on the limited research, no firm conclusions can be made concerning SOT recipients, but the current evidence suggests that immunosuppression is most likely associated with a better outcome of SARS-CoV-2 infection and COVID-19 because it prevents hyperinflammation (cytokine storm) in this particular population. There is a need for further research that would allow results to be adjusted for other factors potentially impacting COVID-19 severity and outcome.
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Russell B, Moss C, Rigg A, Van Hemelrijck M. COVID-19 and treatment with NSAIDs and corticosteroids: should we be limiting their use in the clinical setting? Ecancermedicalscience 2020; 14:1023. [PMID: 32256706 PMCID: PMC7105332 DOI: 10.3332/ecancer.2020.1023] [Citation(s) in RCA: 195] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Indexed: 12/16/2022] Open
Abstract
Given the current SARS-CoV-2 (COVID-19) pandemic, the availability of reliable information for clinicians and patients is paramount. There have been a number of reports stating that non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids may exacerbate symptoms in COVID-19 patients. Therefore, this review aimed to collate information available in published articles to identify any evidence behind these claims with the aim of advising clinicians on how best to treat patients. This review found no published evidence for or against the use of NSAIDs in COVID-19 patients. Meanwhile, there appeared to be some evidence that corticosteroids may be beneficial if utilised in the early acute phase of infection, however, conflicting evidence from the World Health Organisation surrounding corticosteroid use in certain viral infections means this evidence is not conclusive. Given the current availability of literature, caution should be exercised until further evidence emerges surrounding the use of NSAIDs and corticosteroids in COVID-19 patients.
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Affiliation(s)
- Beth Russell
- Translational Oncology and Urology Research, School of Cancer and Pharmaceutical Sciences, King’s College London, London SE1 9RT, UK
- Denotes joint first authorship
| | - Charlotte Moss
- Translational Oncology and Urology Research, School of Cancer and Pharmaceutical Sciences, King’s College London, London SE1 9RT, UK
- Denotes joint first authorship
| | - Anne Rigg
- Guy’s Cancer Centre, Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK
| | - Mieke Van Hemelrijck
- Translational Oncology and Urology Research, School of Cancer and Pharmaceutical Sciences, King’s College London, London SE1 9RT, UK
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Russell B, Moss C, George G, Santaolalla A, Cope A, Papa S, Van Hemelrijck M. Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence. Ecancermedicalscience 2020; 14:1022. [PMID: 32256705 PMCID: PMC7105343 DOI: 10.3332/ecancer.2020.1022] [Citation(s) in RCA: 311] [Impact Index Per Article: 62.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Indexed: 12/12/2022] Open
Abstract
Background Cancer and transplant patients with COVID-19 have a higher risk of developing severe and even fatal respiratory diseases, especially as they may be treated with immune-suppressive or immune-stimulating drugs. This review focuses on the effects of these drugs on host immunity against COVID-19. Methods Using Ovid MEDLINE, we reviewed current evidence for immune-suppressing or -stimulating drugs: cytotoxic chemotherapy, low-dose steroids, tumour necrosis factorα (TNFα) blockers, interlukin-6 (IL-6) blockade, Janus kinase (JAK) inhibitors, IL-1 blockade, mycophenolate, tacrolimus, anti-CD20 and CTLA4-Ig. Results 89 studies were included. Cytotoxic chemotherapy has been shown to be a specific inhibitor for severe acute respiratory syndrome coronavirus in in vitro studies, but no specific studies exist as of yet for COVID-19. No conclusive evidence for or against the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of COVID-19 patients is available, nor is there evidence indicating that TNFα blockade is harmful to patients in the context of COVID-19. COVID-19 has been observed to induce a pro-inflammatory cytokine generation and secretion of cytokines, such as IL-6, but there is no evidence of the beneficial impact of IL-6 inhibitors on the modulation of COVID-19. Although there are potential targets in the JAK-STAT pathway that can be manipulated in treatment for coronaviruses and it is evident that IL-1 is elevated in patients with a coronavirus, there is currently no evidence for a role of these drugs in treatment of COVID-19. Conclusion The COVID-19 pandemic has led to challenging decision-making about treatment of critically unwell patients. Low-dose prednisolone and tacrolimus may have beneficial impacts on COVID-19. The mycophenolate mofetil picture is less clear, with conflicting data from pre-clinical studies. There is no definitive evidence that specific cytotoxic drugs, low-dose methotrexate for auto-immune disease, NSAIDs, JAK kinase inhibitors or anti-TNFα agents are contraindicated. There is clear evidence that IL-6 peak levels are associated with severity of pulmonary complications.
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Affiliation(s)
- Beth Russell
- Translational Oncology and Urology Research, King's College London, London, UK.,All authors contributed equally
| | - Charlotte Moss
- Translational Oncology and Urology Research, King's College London, London, UK.,All authors contributed equally
| | - Gincy George
- Translational Oncology and Urology Research, King's College London, London, UK.,All authors contributed equally
| | - Aida Santaolalla
- Translational Oncology and Urology Research, King's College London, London, UK.,All authors contributed equally
| | - Andrew Cope
- Guy's and St. Thomas NHS Foundation Trust, London, UK.,Centre for Rheumatic Diseases, King's College London, London, UK
| | - Sophie Papa
- Guy's and St. Thomas NHS Foundation Trust, London, UK.,School of Cancer and Pharmaceutical Sciences, King's College London, London, UK.,Both senior authors contributed equally
| | - Mieke Van Hemelrijck
- Translational Oncology and Urology Research, King's College London, London, UK.,Both senior authors contributed equally
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Rabaan AA, Alahmed SH, Bazzi AM, Alhani HM. A review of candidate therapies for Middle East respiratory syndrome from a molecular perspective. J Med Microbiol 2017; 66:1261-1274. [PMID: 28855003 PMCID: PMC7079582 DOI: 10.1099/jmm.0.000565] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
There have been 2040 laboratory-confirmed cases of Middle East respiratory syndrome coronavirus (MERS-CoV) in 27 countries, with a mortality rate of 34.9 %. There is no specific therapy. The current therapies have mainly been adapted from severe acute respiratory syndrome (SARS-CoV) treatments, including broad-spectrum antibiotics, corticosteroids, interferons, ribavirin, lopinavir–ritonavir or mycophenolate mofetil, and have not been subject to well-organized clinical trials. The development of specific therapies and vaccines is therefore urgently required. We examine existing and potential therapies and vaccines from a molecular perspective. These include viral S protein targeting; inhibitors of host proteases, including TMPRSS2, cathepsin L and furin protease, and of viral M(pro) and the PL(pro) proteases; convalescent plasma; and vaccine candidates. The Medline database was searched using combinations and variations of terms, including ‘Middle East respiratory syndrome coronavirus’, ‘MERS-CoV’, ‘SARS’, ‘therapy’, ‘molecular’, ‘vaccine’, ‘prophylactic’, ‘S protein’, ‘DPP4’, ‘heptad repeat’, ‘protease’, ‘inhibitor’, ‘anti-viral’, ‘broad-spectrum’, ‘interferon’, ‘convalescent plasma’, ‘lopinavir ritonavir’, ‘antibodies’, ‘antiviral peptides’ and ‘live attenuated viruses’. There are many options for the development of MERS-CoV-specific therapies. Currently, MERS-CoV is not considered to have pandemic potential. However, the high mortality rate and potential for mutations that could increase transmissibility give urgency to the search for direct, effective therapies. Well-designed and controlled clinical trials are needed, both for existing therapies and for prospective direct therapies.
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Affiliation(s)
- Ali A Rabaan
- Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran 31311, Saudi Arabia
| | - Shamsah H Alahmed
- Specialty Paediatric Medicine, Qatif Central Hospital, Qatif 32654, Saudi Arabia
| | - Ali M Bazzi
- Microbiology Laboratory, Johns Hopkins Aramco Healthcare, Dhahran 31311, Saudi Arabia
| | - Hatem M Alhani
- Maternity and Children Hospital, and Directorate of Infection Control at Eastern Province, Ministry of Health, Dammam, Saudi Arabia
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Diseases of the Alimentary Tract. Vet Med (Auckl) 2017. [PMCID: PMC7167529 DOI: 10.1016/b978-0-7020-5246-0.00007-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Mo Y, Fisher D. A review of treatment modalities for Middle East Respiratory Syndrome. J Antimicrob Chemother 2016; 71:3340-3350. [PMID: 27585965 PMCID: PMC7109760 DOI: 10.1093/jac/dkw338] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The Middle East Respiratory Syndrome coronavirus (MERS-CoV) has been a focus of international attention since its identification in 2012. Epidemiologically it is characterized by sporadic community cases, which are amplified by hospital-based outbreaks. Healthcare facilities in 27 countries from most continents have experienced imported cases, with the most significant outbreak involving 186 cases in Korea. The mortality internationally is 36% and guidance for clinical management has yet to be developed. Most facilities and healthcare providers outside of the Middle East receiving patients have no or little experience in the clinical management of MERS. When a case does occur there is likely little time for a critical appraisal of the literature and putative pharmacological options. We identified published literature on the management of both MERS-CoV and the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) through searches of PubMed and WHO and the US CDC websites up to 30 April 2016. A total of 101 publications were retrieved for critical appraisal. Most published literature on therapeutics for MERS are in vitro experiments, animal studies and case reports. Current treatment options for MERS can be categorized as: immunotherapy with virus-specific antibodies in convalescent plasma; polyclonal and monoclonal antibodies produced in vitro or in genetically modified animals; and antiviral agents. The use of any therapeutics in MERS-CoV remains investigational. The therapeutic agents with potential benefits and warranting further investigation include convalescent plasma, interferon-β/ribavirin combination therapy and lopinavir. Corticosteroids, ribavirin monotherapy and mycophenolic acid likely have toxicities that exceed potential benefits.
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Affiliation(s)
- Yin Mo
- Ministry of Health Holdings, Singapore.,Division of Infectious Diseases, University Medicine Cluster, National University Health System, Singapore
| | - Dale Fisher
- Division of Infectious Diseases, University Medicine Cluster, National University Health System, Singapore .,Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Renukaradhya GJ, Alekseev K, Jung K, Fang Y, Saif LJ. Porcine reproductive and respiratory syndrome virus-induced immunosuppression exacerbates the inflammatory response to porcine respiratory coronavirus in pigs. Viral Immunol 2011; 23:457-66. [PMID: 20883160 DOI: 10.1089/vim.2010.0051] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
We performed a comprehensive analysis of innate and adaptive immune responses in dual-virus infected pigs to understand whether a pre-existing immunomodulatory respiratory viral infection affects the overall immunity to a subsequent porcine respiratory coronavirus (PRCV) infection in pigs. Pigs were either mock-infected or infected with porcine reproductive and respiratory syndrome virus (PRRSV), a virus known to cause immunosuppressive respiratory disease, and then pigs were co-infected with PRCV, which normally causes subclinical respiratory infection. We collected samples for six independent experiments from 178 pigs that were also used for pathological studies. We detected a significant reduction in innate NK-cell-mediated cytotoxic function in PRRSV-infected pigs, which was synergistically further decreased in pigs co-infected with PRCV. Subsequently, in association with clinical signs we observed elevated levels of proinflammatory (IL-6), Th-1 (IL-12), and regulatory (IL-10 and TGF-β) cytokines. Increased frequencies of CD4CD8 double-positive T lymphocytes and myeloid cells, in addition to the elevated Th-1 and proinflammatory cytokines in dual-infected pigs, contributed to the severity of lung disease in pigs. The results of our study clarify how each virus modulates the host innate and adaptive immune responses, leading to inflammatory reactions and lung pathology. Thus measurements of cytokines and frequencies of immune cells may serve as indicators of the progression of respiratory viral co-infections, and provide more definitive approaches for treatment.
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Affiliation(s)
- Gourapura J Renukaradhya
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, Ohio 44691, USA.
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Jung K, Gurnani A, Renukaradhya GJ, Saif LJ. Nitric oxide is elicited and inhibits viral replication in pigs infected with porcine respiratory coronavirus but not porcine reproductive and respiratory syndrome virus. Vet Immunol Immunopathol 2010; 136:335-9. [PMID: 20409593 PMCID: PMC2902704 DOI: 10.1016/j.vetimm.2010.03.022] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2009] [Revised: 03/23/2010] [Accepted: 03/25/2010] [Indexed: 11/25/2022]
Abstract
There is little information on the role of nitric oxide (NO) in innate immunity to respiratory coronavirus (CoV) infections. We examined NO levels by Greiss assay in bronchoalveolar lavage (BAL) of pigs infected with either porcine respiratory coronavirus (PRCV) or porcine reproductive and respiratory syndrome virus (PRRSV), a member of Nidovirales, like CoV. The antiviral effects of NO on these two viruses were tested in an in vitro system using a NO donor, S-nitroso-N-acetylpenicillamine (SNAP). We detected a large increase in NO levels in BAL fluids of PRCV-infected pigs, but not in PRRSV-infected pigs. Pulmonary epithelial cell necrosis induced by PRCV coincided with increased NO. Moreover, NO levels in cell culture medium of PRRSV-infected alveolar macrophages (AMs) did not differ from that of mock-infected AMs. Antiviral assays showed that NO significantly inhibited PRCV replication in swine testicular (ST) cells, whereas PRRSV was not susceptible to NO based on the conditions tested. Our study suggests that unlike PRRSV which induces apoptosis in AMs, respiratory CoVs such as PRCV that infect pulmonary epithelial cells and cause cytolysis, induce NO production in the respiratory tract. Thus, NO may play a role in innate immunity to respiratory CoV infections by inhibiting viral replication.
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Affiliation(s)
| | | | | | - Linda J. Saif
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, 1680 Madison Ave., Wooster, OH 44691, USA
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Jung K, Renukaradhya GJ, Alekseev KP, Fang Y, Tang Y, Saif LJ. Porcine reproductive and respiratory syndrome virus modifies innate immunity and alters disease outcome in pigs subsequently infected with porcine respiratory coronavirus: implications for respiratory viral co-infections. J Gen Virol 2009; 90:2713-2723. [PMID: 19656969 PMCID: PMC2862479 DOI: 10.1099/vir.0.014001-0] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2009] [Accepted: 07/30/2009] [Indexed: 12/22/2022] Open
Abstract
The innate immune response is critical for host defence against respiratory coronaviruses (CoVs). This study demonstrated that an ongoing respiratory virus infection compromises innate immune responses and affects the pathogenesis of a respiratory CoV co-infection. An innate immunosuppressive respiratory virus infection was established by infecting weaned pigs with porcine reproductive and respiratory syndrome virus (PRRSV); 10 days later, the pigs were exposed to porcine respiratory coronavirus (PRCV). The PRRSV/PRCV dual-infected pigs had reduced weight gains, a higher incidence of fever and more severe pneumonia compared with either single infection. Significant suppression of innate immune responses [reduced alpha interferon (IFN-alpha) levels in the lungs and reduced blood natural killer cell cytotoxicity] by the ongoing PRRSV infection was observed in dual-infected pigs, which coincided with exacerbated pneumonia during early PRCV infection. The subsequent PRCV infection led to enhanced PRRSV replication in the lungs and a trend towards increased serum T-helper type 1 (Th1) (IFN-gamma) but decreased Th2 [interleukin (IL)-4] responses, further exacerbating PRRSV pneumonia. Following PRCV infection, more severe PRRSV-related pulmonary alveolar macrophage (PAM) apoptosis occurred, as determined by an in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling assay, suggesting increased PRRSV replication in PAMs. Collectively, these observations suggest interactive effects between PRCV and PRRSV via early innate (IFN-alpha) and later adaptive Th1 (IFN-gamma) and Th2 (IL-4) immune responses. These findings imply that an existing immunomodulating respiratory viral co-infection may be a contributing factor to more severe pneumonia in respiratory CoV disease. This study provides new insights into host-pathogen interactions related to co-infection by CoVs and other respiratory viruses.
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Affiliation(s)
- Kwonil Jung
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, OH 44691, USA
| | - Gourapura J. Renukaradhya
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, OH 44691, USA
| | - Konstantin P. Alekseev
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, OH 44691, USA
| | - Ying Fang
- Veterinary Science Department, South Dakota State University, Brookings, SD, USA
| | - Yuxin Tang
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, OH 44691, USA
| | - Linda J. Saif
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, OH 44691, USA
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Li H, Du S, Yang L, Chen Y, Huang W, Zhang R, Cui Y, Yang J, Chen D, Li Y, Zhang S, Zhou J, Wei Z, Yao Z. Rapid pulmonary fibrosis induced by acute lung injury via a lipopolysaccharide three-hit regimen. Innate Immun 2009; 15:143-54. [PMID: 19474208 DOI: 10.1177/1753425908101509] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Based on the common characteristic of severe acute respiratory syndrome (SARS) and highly pathogenic avian influenza and the mechanism of inflammation and fibrosis, it is speculated that there should exist a fundamental pathological rule that severe acute lung injury (ALI)-induced rapid pulmonary fibrosis is caused by various etiological factors, such as SARS coronavirus, H5N1-virus, or other unknown factors, and also by lipopolysaccharide (LPS), the most common etiological factor. The investigation employed intratracheally, and intraperitoneally and intratracheally applied LPS three-hit regimen, compared with bleomycin-induced chronic pulmonary fibrosis. Inflammatory damage and fibrosis were evaluated, and the molecular mechanism was analyzed according to Th1/Th2 balance, Sma- and MAD-related proteins (Smads) and signal transducer and activator of transcriptions (STATs) expression. The results suggested that rapid pulmonary fibrosis could be induced by ALI via LPS three-hits. The period from 3-7 days in the LPS group was the first rapid pulmonary fibrosis stage, whereas the second fast fibrosis stage occurred on days 14-21. Th2 cell polarization, Smad4 and Smad7 should be the crucial molecular mechanism of ALI-induced rapid fibrosis. The investigation was not only performed to establish a new rapid pulmonary fibrosis model, but also to provide the elicitation for mechanism of ALI changed into the rapid pulmonary fibrosis.
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Affiliation(s)
- Hui Li
- Department of Anatomy, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
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Borghetti P, Saleri R, Mocchegiani E, Corradi A, Martelli P. Infection, immunity and the neuroendocrine response. Vet Immunol Immunopathol 2009; 130:141-62. [PMID: 19261335 PMCID: PMC7112574 DOI: 10.1016/j.vetimm.2009.01.013] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2008] [Revised: 01/17/2009] [Accepted: 01/27/2009] [Indexed: 12/11/2022]
Abstract
The Central Nervous (CNS) and Immune Systems (IS) are the two major adaptive systems which respond rapidly to numerous challenges that are able to compromise health. The defensive response strictly linking innate to acquired immunity, works continuously to limit pathogen invasion and damage. The efficiency of the innate response is crucial for survival and for an optimum priming of acquired immunity. During infection, the immune response is modulated by an integrated neuro-immune network which potentiates innate immunity, controls potential harmful effects and also addresses metabolic and nutritional modifications supporting immune function. In the last decade much knowledge has been gained on the molecular signals that orchestrate this integrated adaptive response, with focus on the systemic mediators which have a crucial role in driving and controlling an efficient protective response. These mediators are also able to signal alterations and control pathway dysfunctions which may be involved in the persistence and/or overexpression of inflammation that may lead to tissue damage and to a negative metabolic impact, causing retarded growth. This review aims to describe some important signalling pathways which drive bidirectional communication between the Immune and Nervous Systems during infection. Particular emphasis is placed on pro-inflammatory cytokines, immunomodulator hormones such as Glucocorticoids (GCs), Growth hormone (GH), Insulin-like Growth Factor-1 (IGF-1), and Leptin, as well as nutritional factors such as Zinc (Zn). Finally, the review includes up-to-date information on this neuroimmune cross-talk in domestic animals. Data in domestic animal species are still limited, but there are several exciting areas of research, like the potential interaction pathways between mediators (i.e. cytokine-HPA regulation, IL-6-GCS-Zn, cytokines-GH/IGF-1, IL-6-GH-Leptin and thymus activity) that are or could be promising topics of future research in veterinary medicine.
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Contribution of Bordetella bronchiseptica filamentous hemagglutinin and pertactin to respiratory disease in swine. Infect Immun 2009; 77:2136-46. [PMID: 19237531 DOI: 10.1128/iai.01379-08] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Bordetella bronchiseptica is pervasive in swine populations and plays multiple roles in respiratory disease. Most studies addressing virulence factors of B. bronchiseptica are based on isolates derived from hosts other than pigs. Two well-studied virulence factors implicated in the adhesion process are filamentous hemagglutinin (FHA) and pertactin (PRN). We hypothesized that both FHA and PRN would serve critical roles in the adhesion process and be necessary for colonization of the swine respiratory tract. To investigate the role of FHA and PRN in Bordetella pathogenesis in swine, we constructed mutants containing an in-frame deletion of the FHA or the PRN structural gene in a virulent B. bronchiseptica swine isolate. Both mutants were compared to the wild-type swine isolate for their ability to colonize and cause disease in swine. Colonization of the FHA mutant was lower than that of the wild type at all respiratory tract sites and time points examined and caused limited to no disease. In contrast, the PRN mutant caused similar disease severity relative to the wild type; however, colonization of the PRN mutant was reduced relative to the wild type during early and late infection and induced higher anti-Bordetella antibody titers. Together, our results indicate that despite inducing different pathologies and antibody responses, both FHA and PRN are necessary for optimal colonization of the swine respiratory tract.
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