IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
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IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
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Designed to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
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After a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
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Our innovative Book Series format brings you:
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Topic Focused Publications - Each topic showcases high impact subject areas
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Renowned Editorial Expertise - Series Editors, Topic Editors, and a team of international Board Members that permanently support each Book Series
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Fast Publishing - quick turnaround which is unique for book publishing
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The benefit of ISSN and ISBN for increased citation and indexing possibilities
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IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\n
IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
We invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
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Note: Edited in October 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"5682",leadTitle:null,fullTitle:"Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy",title:"Physiologic and Pathologic Angiogenesis",subtitle:"Signaling Mechanisms and Targeted Therapy",reviewType:"peer-reviewed",abstract:"The purpose of this book is to highlight novel advances in the field and to incentivize scientists from a variety of fields to pursue angiogenesis as a research avenue. Blood vessel formation and maturation to capillaries, arteries, or veins is a fascinating area which can appeal to multiple scientists, students, and professors alike. Angiogenesis is relevant to medicine, engineering, pharmacology, and pathology and to the many patients suffering from blood vessel diseases and cancer, among others. We are hoping that this book will become a source of inspiration and novel ideas for all.",isbn:"978-953-51-3024-6",printIsbn:"978-953-51-3023-9",pdfIsbn:"978-953-51-4101-3",doi:"10.5772/64121",price:139,priceEur:155,priceUsd:179,slug:"physiologic-and-pathologic-angiogenesis-signaling-mechanisms-and-targeted-therapy",numberOfPages:464,isOpenForSubmission:!1,isInWos:1,isInBkci:!0,hash:"847efcb8c059798ea2a963d9578de2f5",bookSignature:"Dan Simionescu and Agneta Simionescu",publishedDate:"April 5th 2017",coverURL:"https://cdn.intechopen.com/books/images_new/5682.jpg",numberOfDownloads:35533,numberOfWosCitations:67,numberOfCrossrefCitations:32,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:83,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:182,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 24th 2016",dateEndSecondStepPublish:"June 14th 2016",dateEndThirdStepPublish:"September 10th 2016",dateEndFourthStepPublish:"December 9th 2016",dateEndFifthStepPublish:"February 7th 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,8",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"66196",title:"Dr.",name:"Dan",middleName:"T.",surname:"Simionescu",slug:"dan-simionescu",fullName:"Dan Simionescu",profilePictureURL:"https://mts.intechopen.com/storage/users/66196/images/system/66196.jpg",biography:"Dr. Dan Simionescu is the Harriet and Jerry Dempsey Professor of Bioengineering and Director of the Biocompatibility and Tissue Regeneration Laboratories at the Clemson University, Clemson, SC. He has published more than 95 peer-reviewed papers in highly ranked journals such as Circulation, Cardiovascular Pathology, American Journal of Pathology, Tissue Engineering, and Biomaterials and has more than 180 peer-reviewed conference proceedings presented worldwide. Dr. Simionescu’s general research interests include cardiovascular biology, pathology, and regeneration using scaffolds, stem cells and bioreactors. His current interest is preclinical validation of translational tissue engineering approaches and is being generously funded by the NIH and the biomedical industry for his efforts in the field of cardiovascular biology, pathology, and regenerative medicine.",institutionString:"Clemson University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Clemson University",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"191041",title:"Dr.",name:"Agneta",middleName:null,surname:"Simionescu",slug:"agneta-simionescu",fullName:"Agneta Simionescu",profilePictureURL:"https://mts.intechopen.com/storage/users/191041/images/5341_n.jpg",biography:"Dr. Agneta Simionescu received her PhD degree in Biochemistry/Cell Biology for the study of matrix remodeling in cardiac diseases. Agneta has research interests in translational tissue engineering, angiogenesis, remodeling, and mechanotransduction. She was the first to show that matrix metalloproteinases (MMPs) are involved in degeneration of implanted cardiovascular biomaterials and that matrix-derived degradation products (matrikines) induce pathologic osteogenic activation of cardiovascular cells. She has also shown that stabilization of biomaterials and scaffolds with mild and reversible cross-linking agents might counteract these effects. In recent years, she has developed a passion for investigating the effects of diabetes on cardiovascular tissue engineering, including diabetes-related alterations of biomaterials and scaffolds, stem cell differentiation, matrix remodeling, and microvascular network formation in vitro and in vivo models of diabetes.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"985",title:"Cardiogeriatrics",slug:"cardiogeriatrics"}],chapters:[{id:"53316",title:"TGF-β Activation and Signaling in Angiogenesis",doi:"10.5772/66405",slug:"tgf-activation-and-signaling-in-angiogenesis",totalDownloads:2472,totalCrossrefCites:13,totalDimensionsCites:25,hasAltmetrics:0,abstract:"The transforming growth factor-β (TGF-β) signaling pathway regulates various cellular processes during tissue and organ development and homeostasis. Deregulation of the expression and/or functions of TGF-β ligands, receptors or their intracellular signaling components leads to multiple diseases including vascular pathologies, autoimmune disorders, fibrosis and cancer. In vascular development, physiology and disease TGF-β signaling can have angiogenic and angiostatic properties, depending on expression levels and the tissue context. The objective of this chapter is to analyze the mechanisms that contribute to the activation and signaling of TGF-β in developmental, physiological and pathological angiogenesis, with a particular emphasis on the importance of TGF-β signaling in the mammalian central nervous system (CNS).",signatures:"Paola A. Guerrero and Joseph H. McCarty",downloadPdfUrl:"/chapter/pdf-download/53316",previewPdfUrl:"/chapter/pdf-preview/53316",authors:[{id:"193482",title:"Dr.",name:"Paola",surname:"Guerrero",slug:"paola-guerrero",fullName:"Paola Guerrero"},{id:"195670",title:"Dr.",name:"Joseph",surname:"McCarty",slug:"joseph-mccarty",fullName:"Joseph McCarty"}],corrections:null},{id:"53457",title:"Role of Notch, SDF-1 and Mononuclear Cells Recruitment in Angiogenesis",doi:"10.5772/66761",slug:"role-of-notch-sdf-1-and-mononuclear-cells-recruitment-in-angiogenesis",totalDownloads:1524,totalCrossrefCites:1,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Intussusceptive angiogenesis (IA) known also as splitting angiogenesis is a recently described mechanism of vascular growth alternative to sprouting. It plays an essential role in the vascular remodeling and adaptation of vessels during normal and pathological angiogenesis. It is an “escape” mechanism during and after irradiation and anti-VEGF therapy, both inducing angiogenic switch from sprouting to IA by formation of multiple transluminal tissue pillars. Our recently published data revealed the significant induction of IA after inhibition of Notch signaling associated with an increased capillary density by more than 50%. The induced IA was accompanied by detachment of pericytes from basement membrane, increased vessel permeability and recruitment of mononuclear cells toward the pillars; the process was dramatically enhanced after injection of bone marrow-derived mononuclear cells. The extravasation of mononuclear cells with eventual bone marrow origin was associated with upregulation of chemotaxis factors SDF-1 and CXCR4. In addition, SDF-1 expression was upregulated in the endothelium of liver sinusoids in Notch1 knockout mouse, together with vascular remodeling by intussusception. In this chapter, we discuss this important mechanism of angiogenesis, as well as the role of Notch signaling, SDF-1 signaling and mononuclear cells in the complex process of angiogenesis.",signatures:"Ivanka Dimova and Valentin Djonov",downloadPdfUrl:"/chapter/pdf-download/53457",previewPdfUrl:"/chapter/pdf-preview/53457",authors:[{id:"193572",title:"Prof.",name:"Ivanka",surname:"Dimova",slug:"ivanka-dimova",fullName:"Ivanka Dimova"},{id:"195601",title:"Prof.",name:"Valentin",surname:"Djonov",slug:"valentin-djonov",fullName:"Valentin Djonov"}],corrections:null},{id:"53381",title:"Angiogenesis Meets Skeletogenesis: The Cross-Talk between Two Dynamic Systems",doi:"10.5772/66497",slug:"angiogenesis-meets-skeletogenesis-the-cross-talk-between-two-dynamic-systems",totalDownloads:1397,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In this chapter, we describe the complex relationship between angiogenesis and skeletogenesis. While much is known about the interactions of these two dynamic systems for bones that ossify via a cartilage template, comparatively little is known about directly ossifying bones. Most of the bones of the head develop from osteogenic condensations and undergo intramembranous (direct) ossification during development. Our understanding of the relationship between osteogenic cell condensations (in particular) and angiogenesis is currently inadequate and prevents a comprehensive understanding of vertebrate head development. This chapter highlights our understanding of both direct and indirectly ossifying bones shedding light on where there are important gaps in our understanding.",signatures:"Tamara A. Franz-Odendaal, Daniel Andrews and Shruti Kumar",downloadPdfUrl:"/chapter/pdf-download/53381",previewPdfUrl:"/chapter/pdf-preview/53381",authors:[{id:"192854",title:"Dr.",name:"Tamara",surname:"Franz-Odendaal",slug:"tamara-franz-odendaal",fullName:"Tamara Franz-Odendaal"},{id:"197559",title:"Mr.",name:"Daniel",surname:"Andrews",slug:"daniel-andrews",fullName:"Daniel Andrews"},{id:"197560",title:"Ms.",name:"Shruti",surname:"Kumar",slug:"shruti-kumar",fullName:"Shruti Kumar"}],corrections:null},{id:"53374",title:"Corneal Angiogenesis: Etiologies, Complications, and Management",doi:"10.5772/66713",slug:"corneal-angiogenesis-etiologies-complications-and-management",totalDownloads:1838,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"A large subset of corneal pathologies involves the formation of new blood vessels, leading to compromised visual acuity. Additionally, neovascularization of the cornea worsens the prognosis of subsequent penetrating keratoplasty, keeping the patient in a vicious circle of poor prognosis. Ocular angiogenesis results from the upregulation of proangiogenic and downregulation of antiangiogenic factors. There is a tremendous need for developing effective measures to prevent and/or treat corneal neovascularization. Topical steroid medication, cautery, argon and yellow dye laser, and fine needle diathermy have all been advocated with varying degrees of success. The process of corneal neovascularization is primarily mediated by the vascular endothelial growth factor family of proteins, and current therapies are aimed at disrupting the various steps in this pathway. This article aims to review the clinical causes and presentations of corneal neovascularization caused by different etiologies. Moreover, this chapter reviews different complications caused by corneal neovascularization and summarizes the most relevant treatments available so far.",signatures:"Sepehr Feizi",downloadPdfUrl:"/chapter/pdf-download/53374",previewPdfUrl:"/chapter/pdf-preview/53374",authors:[{id:"37619",title:"Dr.",name:"Sepehr",surname:"Feizi",slug:"sepehr-feizi",fullName:"Sepehr Feizi"}],corrections:null},{id:"53142",title:"Angiogenesis-Related Factors in Early Pregnancy Loss",doi:"10.5772/66410",slug:"angiogenesis-related-factors-in-early-pregnancy-loss",totalDownloads:1529,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The habitual loss of early pregnancy is one of the major problems of obstetrics nowadays, provided that the cause of more than 50% of all early pregnancy losses is unknown. Adequate angiogenesis is one of the main indicators of proper formation of placental system, making the basis of fetal life support. The objective description of angiogenesis in physiological development of pregnancy and in pathological conditions is complicated by the difficulties in obtaining and characterizing placental tissue in early pregnancy. Thus, angiogenesis‐related factors are promising indicators to characterize angiogenesis in pregnancy. This chapter draws attention to alteration in angiogenesis‐related factors in peripheral blood of patients with habitual early pregnancy losses. Investigation of factors (vascular endothelial growth factor (VEGF), sFlt‐1, sKDR, metalloproteinase (MMP)‐2, MMP‐9, tissue inhibitor (TIMP)‐1, TIMP‐2 and placental growth factor (PLGF)), which specifically and nonspecifically regulate angiogenesis in pregnancy, was performed in the most significant terms for placentogenesis: 6 weeks, 7–8 weeks and 11–14 weeks of pregnancy. It was found that in a missed abortion there was a significant imbalance of angiogenesis‐related factors compared with normal pregnancy. These results reflect a disturbance of angiogenesis in a missed abortion and point to the importance of the studied factors in the pathogenesis of early pregnancy losses.",signatures:"Marina M. Ziganshina, Lyubov V. Krechetova, Lyudmila V. Vanko,\nZulfiya S. Khodzhaeva, Ekaterina L. Yarotskaya and Gennady T.\nSukhikh",downloadPdfUrl:"/chapter/pdf-download/53142",previewPdfUrl:"/chapter/pdf-preview/53142",authors:[{id:"193025",title:"Ph.D.",name:"Marina",surname:"Ziganshina",slug:"marina-ziganshina",fullName:"Marina Ziganshina"},{id:"196923",title:"Dr.",name:"Lyubov V.",surname:"Krechetova",slug:"lyubov-v.-krechetova",fullName:"Lyubov V. Krechetova"},{id:"196924",title:"Prof.",name:"Lyudmila V.",surname:"Vanko",slug:"lyudmila-v.-vanko",fullName:"Lyudmila V. Vanko"},{id:"196925",title:"Prof.",name:"Zulfiya S.",surname:"Khodzhaeva",slug:"zulfiya-s.-khodzhaeva",fullName:"Zulfiya S. Khodzhaeva"},{id:"196926",title:"Dr.",name:"Ekaterina L.",surname:"Yarotskaya",slug:"ekaterina-l.-yarotskaya",fullName:"Ekaterina L. Yarotskaya"},{id:"196927",title:"Prof.",name:"Gennady T.",surname:"Sukhikh",slug:"gennady-t.-sukhikh",fullName:"Gennady T. Sukhikh"}],corrections:null},{id:"53441",title:"Pathogenic Angiogenic Mechanisms in Alzheimer's Disease",doi:"10.5772/66403",slug:"pathogenic-angiogenic-mechanisms-in-alzheimer-s-disease",totalDownloads:1305,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Vascular dysfunction is a crucial pathological hallmark of Alzheimer's disease (AD). Studies have reported that beta amyloid (Aβ) causes increased blood vessel growth in the brains of AD mouse models, a phenomenon that is also seen in AD patients. This has given way to an alternative angiogenesis hypothesis according to which, increased leakiness in the blood vessels disrupts the blood‐brain barrier (BBB) and allows unwanted blood products to enter the brain causing progression of disease pathology, promoting amyloid clumping and aggregation along with impaired cerebral blood flow. Furthermore, the expression of melanotransferrin in AD model and patients may contribute to angiogenesis. The objective of this chapter is to attempt to establish a link between the vascular damage and AD pathology. Curbing the vascular changes and resulting damage seen in the brains of AD model mice and improving their cognition by treating with FDA‐approved anti‐angiogenic drugs may expedite the translational potential of this research into clinical trials in human patients. This direction into targeting angiogenesis will facilitate new preventive and therapeutic interventions for AD and related vascular diseases.",signatures:"Chaahat Singh, Cheryl G. Pfeifer and Wilfred A. Jefferies",downloadPdfUrl:"/chapter/pdf-download/53441",previewPdfUrl:"/chapter/pdf-preview/53441",authors:[{id:"193311",title:"Prof.",name:"Wilfred",surname:"Jefferies",slug:"wilfred-jefferies",fullName:"Wilfred Jefferies"},{id:"196143",title:"Dr.",name:"Singh",surname:"Chaahat",slug:"singh-chaahat",fullName:"Singh Chaahat"},{id:"196144",title:"Dr.",name:"Cheryl G",surname:"Pfeifer",slug:"cheryl-g-pfeifer",fullName:"Cheryl G Pfeifer"}],corrections:null},{id:"53523",title:"Hypoxia, Angiogenesis and Atherogenesis",doi:"10.5772/66714",slug:"hypoxia-angiogenesis-and-atherogenesis",totalDownloads:1855,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:1,abstract:"The balance between vascular oxygen supply and metabolic demand for oxygen within the vasculature is tightly regulated. An imbalance leads to hypoxia and a consequential cascade of cellular signals that attempt to offset the effects of hypoxia. Hypoxia is invariably associated with atherosclerosis, wound repair, inflammation and vascular disease. There is now substantial evidence that hypoxia plays an essential role in angiogenesis as well as plaque angiogenesis. It controls the metabolism, and responses of many of the cell types found within the developing plaque and whether the plaque will evolve into a stable or unstable phenotype. Hypoxia is characterized in molecular terms by the stabilization of hypoxia-inducible factor (HIF)-1α, a subunit of the heterodimeric nuclear transcriptional factor HIF-1 and a master regulator of oxygen homeostasis. The expression of HIF-1 is localized to perivascular tissues, inflammatory macrophages and smooth muscle cells where it regulates several genes that are important to vascular function including vascular endothelial growth factor, nitric oxide synthase, endothelin-1 and erythropoietin. This chapter summarizes the effects of hypoxia on the functions of cells involved in angiogenesis as well as atherogenesis (plaque angiogenesis) and the evidence for its potential importance from experimental models and clinical studies.",signatures:"Lamia Heikal and Gordon Ferns",downloadPdfUrl:"/chapter/pdf-download/53523",previewPdfUrl:"/chapter/pdf-preview/53523",authors:[{id:"195461",title:"Dr.",name:"Lamia",surname:"Heikal",slug:"lamia-heikal",fullName:"Lamia Heikal"},{id:"199995",title:"Prof.",name:"Gordon",surname:"Ferns",slug:"gordon-ferns",fullName:"Gordon Ferns"}],corrections:[{id:"79243",title:"Corrigendum to: Hypoxia, Angiogenesis and Atherogenesis",doi:null,slug:"corrigendum-to-hypoxia-angiogenesis-and-atherogenesis",totalDownloads:null,totalCrossrefCites:null,correctionPdfUrl:null}]},{id:"54134",title:"Coronary Collateral Growth: Clinical Perspectives and Recent Insights",doi:"10.5772/67164",slug:"coronary-collateral-growth-clinical-perspectives-and-recent-insights",totalDownloads:1497,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter summarizes recent research on the coronary collateral circulation. The chapter is focused on clinical perspectives and importance of a well-developed coronary collateral circulation, the mechanisms of growth induced by chemical factors and a role for stem cells in the process. Some discussion is devoted to the role of shear stress and mechanical signaling, but because this topic has been reviewed so extensively in the recent past, there is only small mention of its role in the growth of the coronary collateral circulation.",signatures:"Bhamini Patel, Peter Hopmann, Mansee Desai, Kanithra Sekaran,\nKathleen Graham, Liya Yin and William Chilian",downloadPdfUrl:"/chapter/pdf-download/54134",previewPdfUrl:"/chapter/pdf-preview/54134",authors:[{id:"192680",title:"Dr.",name:"Wiliam M.",surname:"Chilian",slug:"wiliam-m.-chilian",fullName:"Wiliam M. Chilian"},{id:"203403",title:"Dr.",name:"Liya",surname:"Yin",slug:"liya-yin",fullName:"Liya Yin"},{id:"203404",title:"Dr.",name:"Peter",surname:"Hopmann",slug:"peter-hopmann",fullName:"Peter Hopmann"},{id:"203405",title:"Dr.",name:"Kathleen",surname:"Graham",slug:"kathleen-graham",fullName:"Kathleen Graham"},{id:"203406",title:"Dr.",name:"Bhamini",surname:"Patel",slug:"bhamini-patel",fullName:"Bhamini Patel"},{id:"203407",title:"Dr.",name:"Kanithra",surname:"Sekaran",slug:"kanithra-sekaran",fullName:"Kanithra Sekaran"},{id:"203408",title:"Dr.",name:"Mansee",surname:"Desai",slug:"mansee-desai",fullName:"Mansee Desai"}],corrections:null},{id:"53407",title:"Angiogenesis and Cardiovascular Diseases: The Emerging Role of HDACs",doi:"10.5772/66409",slug:"angiogenesis-and-cardiovascular-diseases-the-emerging-role-of-hdacs",totalDownloads:1979,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Cardiovascular diseases (CVD) continue to be the leading cause of death in the world despite recent therapeutic advances. Although many CVDs remain incurable, enormous efforts have been placed in harnessing angiogenesis as therapeutics for these diseases. Epigenetics, the modification of gene expression post-transcriptionally and post-translationally, are important in regulating many biological processes. One of the main post-translational epigenetic modifications, modification of chromatin structure by the acetylation of histone tails within the chromatin by either histone deacetylases (HDACs) or histone acetyltransferases (HATs), is important in modulating gene transcription and has emerged as an important regulatory player from pathogenesis to therapeutics in CVDs. Particularly, HDACs, which are largely involved in promoting chromatin compaction and hence inhibitions of gene transcription, have been implicated in the pathogenic signalling underlying many aspects of CVDs. Recently, histone modifications have been demonstrated to play important roles in the angiogenesis process. Pharmacological inhibitions of HDACs have displayed promising therapeutic potentials in several pre-clinical models of CVDs where angiogenesis is of paramount importance. There are many evidences proving that pro- and anti-angiogenic therapies—and the impact of epigenetics in these processes—can help to artificially reconstruct the vasculature in patients with cardiovascular diseases. Conversely, utilising knowledge of HDACs in angiogenesis might help to develop anti-angiogenic therapies in tackling diseases that are characterised with excessive pathological angiogenesis, including cancer and age-related macular degeneration. Understanding the molecular mechanisms underlying HDACs in modulating angiogenesis will undoubtedly benefit future therapeutics development. This chapter focuses on the emerging role of HDACs in angiogenesis and discuss their potentials and challenges in utilising HDAC inhibitors as therapeutics in several major cardiovascular diseases.",signatures:"Ana Moraga, Ka Hou Lao and Lingfang Zeng",downloadPdfUrl:"/chapter/pdf-download/53407",previewPdfUrl:"/chapter/pdf-preview/53407",authors:[{id:"192735",title:"Dr.",name:"Lingfang",surname:"Zeng",slug:"lingfang-zeng",fullName:"Lingfang Zeng"},{id:"193673",title:"Dr.",name:"Ana",surname:"Moraga",slug:"ana-moraga",fullName:"Ana Moraga"},{id:"196605",title:"Dr.",name:"Ka Hou",surname:"Lao",slug:"ka-hou-lao",fullName:"Ka Hou Lao"}],corrections:null},{id:"53248",title:"Unique Phenotypes of Endothelial Cells in Developing Arteries: A Lesson from the Ductus Arteriosus",doi:"10.5772/66501",slug:"unique-phenotypes-of-endothelial-cells-in-developing-arteries-a-lesson-from-the-ductus-arteriosus",totalDownloads:1287,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Endothelial cells (ECs) play a critical role in regulating vascular pathophysiology. Various growth factors and relaxation factors such as vascular endothelial growth factor (VEGF) and nitric oxide (NO), which are derived from ECs, are known to maintain homeostasis and regulate vessel remodeling. Although the inner lumens of all types of vessels are covered by an EC monolayer, the characteristics of ECs differ in each tissue and developing stage of a vessel. Previously, we identified the heterogeneity of ECs of the ductus arteriosus (DA) by analyzing its gene profiles. The DA is a fetal artery that closes immediately after birth due to the changes in concentrations of oxygen and vasoactive factors such as NO and prostaglandin E. Studying the unique gene profile of ECs in the DA can therefore uncover the novel key genes involved in developing vascular function and morphology such as O2 sensitivity and physiological vascular remodeling. A comprehensive gene analysis identified a number of genes related to morphogenesis and development in the DA. In this chapter, we discuss the heterogeneity of vascular ECs in the developing vessel in the DA.",signatures:"Norika Mengchia Liu and Susumu Minamisawa",downloadPdfUrl:"/chapter/pdf-download/53248",previewPdfUrl:"/chapter/pdf-preview/53248",authors:[{id:"160350",title:"Prof.",name:"Susumu",surname:"Minamisawa",slug:"susumu-minamisawa",fullName:"Susumu Minamisawa"},{id:"192875",title:"MSc.",name:"Norika",surname:"Liu",slug:"norika-liu",fullName:"Norika Liu"}],corrections:null},{id:"54438",title:"Vascular Repair and Remodeling: A Review",doi:"10.5772/67485",slug:"vascular-repair-and-remodeling-a-review",totalDownloads:1752,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Vascular remodeling is alterations in the structure of resistance vessels contributing to elevated systemic vascular resistance in hypertension. In this review, physiopathology of vascular remodeling is discussed, and the impact of antihypertensive drug treatment on remodeling is described, emphasizing on human data, fundamentally as an independent predictor of cardiovascular risk in hypertensive patients. Then we discussed a vascular repair by endothelial progenitor cells (EPCs) that play important roles in the regeneration of the vascular endothelial cells (ECs). The normal arterial vessel wall is mostly composed of ECs, vascular smooth muscle cells (VSMCs), and macrophages. Endothelial impairment is a major contributor to atherosclerosis and restenosis after percutaneous coronary intervention (PCI). Reendothelialization can effectively inhibit VSMC migration and proliferation and decrease neointimal thickening.",signatures:"Nicolás F. Renna, Rodrigo Garcia, Jesica Ramirez and Roberto M.\nMiatello",downloadPdfUrl:"/chapter/pdf-download/54438",previewPdfUrl:"/chapter/pdf-preview/54438",authors:[{id:"192616",title:"Dr.",name:"Nicolás",surname:"Renna",slug:"nicolas-renna",fullName:"Nicolás Renna"},{id:"202536",title:"Dr.",name:"Rodrigo",surname:"García",slug:"rodrigo-garcia",fullName:"Rodrigo García"},{id:"202537",title:"Dr.",name:"Jesica",surname:"Ramirez",slug:"jesica-ramirez",fullName:"Jesica Ramirez"},{id:"202539",title:"Dr.",name:"Roberto M.",surname:"Miatello",slug:"roberto-m.-miatello",fullName:"Roberto M. Miatello"}],corrections:[{id:"79244",title:"Corrigendum to: Vascular Repair and Remodeling: A Review",doi:null,slug:"corrigendum-to-vascular-repair-and-remodeling-a-review",totalDownloads:null,totalCrossrefCites:null,correctionPdfUrl:null}]},{id:"53018",title:"Tumor Angiogenesis: A Focus on the Role of Cancer Stem Cells",doi:"10.5772/66402",slug:"tumor-angiogenesis-a-focus-on-the-role-of-cancer-stem-cells",totalDownloads:1783,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:1,abstract:"Angiogenesis is the process of growth of new blood vessels. Tumor angiogenesis plays pivotal roles in tumor development, progression, and metastasis. The conventional notion of tumor vasculature is that new tumor blood vessels sprout from preexisting vasculature near the tumor; hence, tumor endothelial cells are derived from normal endothelial cells. However, recent evidence suggests that CD133‐positive cancer stem cells (CSCs) in glioblastomas generate tumor endothelial progenitor cells, which further differentiate into tumor endothelial cells. This chapter offers an overview of current knowledge on the role of CSCs in tumor angiogenesis. Furthermore, we discuss our recent discoveries related to human hepatoblastoma stem cells. Future efforts to elucidate the characteristics of tumor angiogenesis should enable the development of effective new anti‐angiogenic therapies.",signatures:"Keiko Fujita and Masumi Akita",downloadPdfUrl:"/chapter/pdf-download/53018",previewPdfUrl:"/chapter/pdf-preview/53018",authors:[{id:"26281",title:"Prof.",name:"Masumi",surname:"Akita",slug:"masumi-akita",fullName:"Masumi Akita"},{id:"192582",title:"Dr.",name:"Keiko",surname:"Fujita",slug:"keiko-fujita",fullName:"Keiko Fujita"}],corrections:null},{id:"53461",title:"VEGF-Mediated Signal Transduction in Tumor Angiogenesis",doi:"10.5772/66764",slug:"vegf-mediated-signal-transduction-in-tumor-angiogenesis",totalDownloads:1736,totalCrossrefCites:2,totalDimensionsCites:8,hasAltmetrics:0,abstract:"The vascular endothelial growth factor-A (VEGF) plays a crucial role in tumor angiogenesis. Through its primary receptor VEGFR-2, VEGF exerts the activity of a multitasking cytokine, which is able to stimulate endothelial cell survival, invasion and migration into surrounding tissues, proliferation, as well as vascular permeability and inflammation. The core components of VEGF signaling delineate well-defined intracellular routes. However, the whole scenario is complicated by the fact that cascades of signals converge and branch at many points in VEGF signaling, thus depicting a complex signal transduction network that is also finely regulated by different mechanisms. In this chapter, we present a careful collection of the best-characterized VEGF-induced signal transduction pathways, attempting to offer an overview of the complexity of VEGF signaling in the context of tumor angiogenesis.",signatures:"Lucia Napione, Maria Alvaro and Federico Bussolino",downloadPdfUrl:"/chapter/pdf-download/53461",previewPdfUrl:"/chapter/pdf-preview/53461",authors:[{id:"193680",title:"Ph.D.",name:"Lucia",surname:"Napione",slug:"lucia-napione",fullName:"Lucia Napione"},{id:"196917",title:"Dr.",name:"Maria",surname:"Alvaro",slug:"maria-alvaro",fullName:"Maria Alvaro"},{id:"196992",title:"Prof.",name:"Federico",surname:"Bussolino",slug:"federico-bussolino",fullName:"Federico Bussolino"}],corrections:null},{id:"54103",title:"Noncoding RNAs in Lung Cancer Angiogenesis",doi:"10.5772/66529",slug:"noncoding-rnas-in-lung-cancer-angiogenesis",totalDownloads:1714,totalCrossrefCites:3,totalDimensionsCites:8,hasAltmetrics:1,abstract:"Lung cancer is the major death-related cancer in both men and women, due to late diagnostic and limited treatment efficacy. The angiogenic process that is responsible for the support of tumor progression and metastasis represents one of the main hallmarks of cancer. The role of VEGF signaling in angiogenesis is well‐established, and we summarize the role of semaphorins and their related receptors or hypoxia‐related factors role as prone of tumor microenvironment in angiogenic mechanisms. Newly, noncoding RNA transcripts (ncRNA) were identified to have vital functions in miscellaneous biological processes, including lung cancer angiogenesis. Therefore, due to their capacity to regulate almost all molecular pathways related with altered key genes, including those involved in angiogenesis and its microenvironment, ncRNAs can serve as diagnosis and prognosis markers or therapeutic targets. We intend to summarize the latest progress in the field of ncRNAs in lung cancer and their relation with hypoxia‐related factors and angiogenic genes, with a particular focus on ncRNAs relation to semaphorins.",signatures:"Ioana Berindan-Neagoe, Cornelia Braicu, Diana Gulei, Ciprian\nTomuleasa and George Adrian Calin",downloadPdfUrl:"/chapter/pdf-download/54103",previewPdfUrl:"/chapter/pdf-preview/54103",authors:[{id:"193102",title:"Dr.",name:"Ioana",surname:"Berindan-Neagoe",slug:"ioana-berindan-neagoe",fullName:"Ioana Berindan-Neagoe"},{id:"193316",title:"Dr.",name:"Cornelia",surname:"Braicu",slug:"cornelia-braicu",fullName:"Cornelia Braicu"},{id:"193317",title:"Dr.",name:"Ciprian",surname:"Tomuleasa",slug:"ciprian-tomuleasa",fullName:"Ciprian Tomuleasa"},{id:"193318",title:"BSc.",name:"Diana",surname:"Gulei",slug:"diana-gulei",fullName:"Diana Gulei"},{id:"193319",title:"Prof.",name:"George Adrian",surname:"Calin",slug:"george-adrian-calin",fullName:"George Adrian Calin"}],corrections:null},{id:"53402",title:"Recent Advances in Angiogenesis Assessment Methods and their Clinical Applications",doi:"10.5772/66504",slug:"recent-advances-in-angiogenesis-assessment-methods-and-their-clinical-applications",totalDownloads:1826,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Angiogenesis, a natural phenomenon of developing new blood vessels, is an integral part of normal developmental processes as well as numerous pathological states in humans. The angiogenic assays are reliable predictors of certain pathologies in particular tumor growth, metastasis, inflammation, wound healing, tissue regeneration, ischemia, cardiovascular, and ocular diseases. The angiogenic inducer and inhibitor studies rely on both in vivo and in vitro angiogenesis methods, and various animal models are also standardized to assess qualitative and quantitative angiogenesis. Analogously, the discovery and development of anti-angiogenic agents are also based on the choice of suitable angiogenic assays and potential drug targeted sites within the angiogenic process. Similarly, the selection of cell types and compatible experimental conditions resembling the angiogenic disease being studied are also potential challenging tasks in recent angiogenesis studies. The imaging analysis systems for data acquisition from in vivo, in vitro, and in ova angiogenesis assay to preclinic, and clinical research also requires novel but easy-to-use tools and well-established protocols. The proposition of this pragmatic book chapter overviews the recent advances in angiogenesis assessment methods and discusses their applications in numerous disease pathogenesis.",signatures:"Imran Shahid, Waleed H. AlMalki, Mohammed W. AlRabia,\nMuhammad Ahmed, Mohammad T. Imam, Muhammed K. Saifullah\nand Muhammad H. Hafeez",downloadPdfUrl:"/chapter/pdf-download/53402",previewPdfUrl:"/chapter/pdf-preview/53402",authors:[{id:"188219",title:"Prof.",name:"Imran",surname:"Shahid",slug:"imran-shahid",fullName:"Imran Shahid"},{id:"191256",title:"Prof.",name:"Waleed",surname:"Almalki",slug:"waleed-almalki",fullName:"Waleed Almalki"},{id:"191259",title:"Dr.",name:"Muhammad",surname:"Hassan Hafeez",slug:"muhammad-hassan-hafeez",fullName:"Muhammad Hassan Hafeez"},{id:"195198",title:"Prof.",name:"Muhammad",surname:"Ahmed",slug:"muhammad-ahmed",fullName:"Muhammad Ahmed"},{id:"195199",title:"MSc.",name:"Muhammed",surname:"Saifullah",slug:"muhammed-saifullah",fullName:"Muhammed Saifullah"},{id:"195200",title:"Prof.",name:"Mohammad",surname:"Imam",slug:"mohammad-imam",fullName:"Mohammad Imam"},{id:"195201",title:"Prof.",name:"Mohammed",surname:"Al Rabia",slug:"mohammed-al-rabia",fullName:"Mohammed Al Rabia"}],corrections:null},{id:"53313",title:"Novel Methods to Study Angiogenesis Using Tissue Explants",doi:"10.5772/66400",slug:"novel-methods-to-study-angiogenesis-using-tissue-explants",totalDownloads:1537,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Tissue explants of skeletal muscles, brain, kidney, liver and spleen from mice were cultured using collagen gel. Electron microscopic observation revealed that formation of capillary tubes with pericyte-like cells occurred only from the tissue explant of skeletal muscles. The capillary tubes formed in the collagen gel were positive for tomato lectin and platelet/endothelial cell adhesion molecule (PCAM)-1 antibody. Formation of capillary tubes in the rat was more predominant than in the mouse. Plasmalemmal vesicles were clearly observed in the capillary tubes from rat tissue explant. Muscle fiber-type differences were also observed. In the soleus muscle, the formation of capillary tubes was predominant than the tibialis anterior muscle. Using this culture model from the rat soleus muscle, effects of α-isoproterenol (β-adrenergic receptor agonist) and low-frequency electrical stimulation were examined on the formation of capillary tubes and fine structures of skeletal muscle explant. The formation of capillary tubes was promoted by α-isoproterenol administration. At low-frequency electrical stimulation, the formation of capillary tubes was inhibited. Both α-isoproterenol and electrical stimulation reduced the degeneration of skeletal muscles. This culture method of skeletal muscles may provide a useful model that can examine the effects of various drugs and physical stimulations.",signatures:"Tomoko Takahashi, Keiko Fujita and Masumi Akita",downloadPdfUrl:"/chapter/pdf-download/53313",previewPdfUrl:"/chapter/pdf-preview/53313",authors:[{id:"26281",title:"Prof.",name:"Masumi",surname:"Akita",slug:"masumi-akita",fullName:"Masumi Akita"},{id:"192582",title:"Dr.",name:"Keiko",surname:"Fujita",slug:"keiko-fujita",fullName:"Keiko Fujita"},{id:"192585",title:"MSc.",name:"Tomoko",surname:"Takahashi",slug:"tomoko-takahashi",fullName:"Tomoko Takahashi"}],corrections:null},{id:"53219",title:"Therapeutic Angiogenesis: Foundations and Practical Application",doi:"10.5772/66411",slug:"therapeutic-angiogenesis-foundations-and-practical-application",totalDownloads:1432,totalCrossrefCites:2,totalDimensionsCites:6,hasAltmetrics:0,abstract:"Angiogenesis as therapeutic target has emerged since early works by Judah Folkman, yet his “holy grail” was inhibiting vascular growth to block tumor nutrition. However, in modern biomedicine, “therapeutic angiogenesis” became a large field focusing on stimulation of blood vessel growth for ischemia relief to reduce its detrimental effects in the tissues. In this review, we introduce basic principles of tissue vascularization in response to ischemia exploited in this field. An overview of recent status in therapeutic angiogenesis is given with introduction to emerging technologies, including gene therapy, genetic modification of cells ex vivo and tissue engineering.",signatures:"Pavel Igorevich Makarevich and Yelena Viktorovna Parfyonova",downloadPdfUrl:"/chapter/pdf-download/53219",previewPdfUrl:"/chapter/pdf-preview/53219",authors:[{id:"75221",title:"Prof.",name:"Yelena",surname:"Parfyonova",slug:"yelena-parfyonova",fullName:"Yelena Parfyonova"},{id:"192434",title:"Dr.",name:"Pavel",surname:"Makarevich",slug:"pavel-makarevich",fullName:"Pavel Makarevich"}],corrections:null},{id:"53828",title:"Platelet Lysate to Promote Angiogenic Cell Therapies",doi:"10.5772/66934",slug:"platelet-lysate-to-promote-angiogenic-cell-therapies",totalDownloads:1414,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Cellular therapies for patients with ischemic muscle have been limited by poor cell retention and survivability. Platelets are a robust source of growth factors and structural proteins, and extracts from this peripheral blood component may be manipulated to improve both cell retention and survivability in percutaneous delivery methods. Human platelet lysate is generated from pooled human platelets and contains a growth factor milieu that promotes robust human mesenchymal stem cell (MSC) proliferation without risk of xenogenic contamination. As such, platelet lysate is a practical alternative to animal serum for MSC culture and, with minor adjustments to the production process, can also be used as a scaffold for cell delivery. Human platelet lysate is a promising substrate that can provide nutritive delivery both in vitro and during cell implantation, potentially improving retention and survivability of MSCs that may improve angiogenic function for cell therapy in treatment of ischemic tissues.",signatures:"Scott T. Robinson and Luke P. Brewster",downloadPdfUrl:"/chapter/pdf-download/53828",previewPdfUrl:"/chapter/pdf-preview/53828",authors:[{id:"193297",title:"Dr.",name:"Luke",surname:"Brewster",slug:"luke-brewster",fullName:"Luke Brewster"},{id:"193532",title:"Dr.",name:"Scott",surname:"Robinson",slug:"scott-robinson",fullName:"Scott Robinson"}],corrections:null},{id:"53483",title:"Anti-VEGF Therapy in Cancer: A Double-Edged Sword",doi:"10.5772/66763",slug:"anti-vegf-therapy-in-cancer-a-double-edged-sword",totalDownloads:2472,totalCrossrefCites:5,totalDimensionsCites:12,hasAltmetrics:0,abstract:"Vascular endothelial growth factor (VEGF) is a mitogen that plays a crucial role in angiogenesis and lymphangiogenesis. It is involved in tumor survival through inducing tumor angiogenesis and by increasing chemoresistance through autocrine signaling. Because of its importance in tumor formation and survival, several medications have been developed to inhibit VEGF and reduce blood vessel formation in cancer. Although these medications have proven to be effective for late-stage and metastatic cancers, they have been shown to cause side effects such as hypertension, artery clots, complications in wound healing, and, more rarely, gastrointestinal perforation and fistulas. Current research in using anti-VEGF medication as a part of cancer treatments is focusing on elucidating the mechanisms of tumor resistance to VEGF medication, developing predictive biomarkers that assess whether a patient will respond to VEGF therapy and creating novel treatments and techniques that increase the efficacy of antiangiogenic medication. This chapter aims to review the role of VEGF in tumor angiogenesis and metastasis, the structure and function of VEGF and its receptors, and VEGF’s role in cancer are discussed. Furthermore, tumor therapies targeting VEGF along with their side effects are presented and, finally, new directions in anti-VEGF therapy are considered along with the challenges.",signatures:"Victor Gardner, Chikezie O. Madu and Yi Lu",downloadPdfUrl:"/chapter/pdf-download/53483",previewPdfUrl:"/chapter/pdf-preview/53483",authors:[{id:"40915",title:"Dr.",name:"Yi",surname:"Lu",slug:"yi-lu",fullName:"Yi Lu"},{id:"195224",title:"Mr.",name:"Victor",surname:"Gardner",slug:"victor-gardner",fullName:"Victor Gardner"},{id:"195226",title:"Dr.",name:"Chikezie",surname:"Madu",slug:"chikezie-madu",fullName:"Chikezie Madu"}],corrections:null},{id:"53575",title:"Antiangiogenic Therapy for Hepatocellular Carcinoma",doi:"10.5772/66503",slug:"antiangiogenic-therapy-for-hepatocellular-carcinoma",totalDownloads:1640,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Angiogenesis plays a pivotal role in many pathological processes, including hepatocellular carcinoma (HCC). This indicates that antiangiogenic agents could be promising candidates for chemoprevention against HCC. Several inhibitors targeting receptor tyrosine kinases (RTKs) for the regulation of tumoral vascularization have been developed and employed in clinical practice, including sorafenib. However, there seem to be several issues for the long-term use of this agent as some patients have experienced adverse effects while taking sorafenib. Therefore, it is desirable for patients with chronic liver diseases to be administered sorafenib as little as possible by combining other safe-to-use antiangiogenic compounds. Various factors, such as renin-angiotensin-aldosterone system (RAAS) and insulin resistance (IR), reciprocally contribute to the promotion of angiogenesis. A blockade of RAAS with an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin-II (AT-II) receptor blocker (ARB) markedly attenuates HCC in conjunction with the suppression of angiogenesis. Moreover, the IR status has demonstrated direct acceleration in the progression of HCC via the augmentation of tumoral neovascularization. These findings suggest that a combination therapy involving a lower dose of sorafenib with other clinically used agents [e.g., RAAS blockers, insulin sensitizer agents, and branched-chain amino acids (BCAA)] may reduce the adverse effects of sorafenib without attenuating the inhibitory effect against HCC in comparison to a high-dose administration.",signatures:"Kosuke Kaji and Hitoshi Yoshiji",downloadPdfUrl:"/chapter/pdf-download/53575",previewPdfUrl:"/chapter/pdf-preview/53575",authors:[{id:"192883",title:"Dr.",name:"Kosuke",surname:"Kaji",slug:"kosuke-kaji",fullName:"Kosuke Kaji"},{id:"195636",title:"Prof.",name:"Hitoshi",surname:"Yoshiji",slug:"hitoshi-yoshiji",fullName:"Hitoshi Yoshiji"}],corrections:null},{id:"53335",title:"MCAM and its Isoforms as Novel Targets in Angiogenesis Research and Therapy",doi:"10.5772/66765",slug:"mcam-and-its-isoforms-as-novel-targets-in-angiogenesis-research-and-therapy",totalDownloads:1548,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Melanoma cell adhesion molecule (MCAM) (CD146) is a membrane glycoprotein of the mucin family. It is one of the numerous proteins composing the junction of the vascular endothelium, and it is expressed in other cell types such as cancer cells, smooth muscle cells, and pericytes. Some recent works were designed to highlight its structural features, its location in the endothelium, and its role in angiogenesis, vascular permeability, and monocyte transmigration, but also in the maintenance of endothelial junctions and tumor development. MCAM exists in different splice variants and is shedded from the vascular membrane by metalloproteases. Studies about MCAM spliced and cleaved variant on human angiogenic physiological and pathological models permit a better understanding on the roles initially described for this protein. Furthermore, this knowledge will help in the future to develop therapeutic and diagnostic tools targeting specifically the different MCAM variant. Recent advances in research on angiogenesis and in the implication of MCAM in this process are discussed in this chapter.",signatures:"Jimmy Stalin, Lucie Vivancos, Nathalie Bardin, Françoise Dignat-\nGeorge and Marcel Blot-Chabaud",downloadPdfUrl:"/chapter/pdf-download/53335",previewPdfUrl:"/chapter/pdf-preview/53335",authors:[{id:"192897",title:"Dr.",name:"Jimmy",surname:"Stalin",slug:"jimmy-stalin",fullName:"Jimmy Stalin"},{id:"195979",title:"Ms.",name:"Lucie",surname:"Vivancos",slug:"lucie-vivancos",fullName:"Lucie Vivancos"},{id:"195980",title:"Prof.",name:"Nathalie",surname:"Bardin",slug:"nathalie-bardin",fullName:"Nathalie Bardin"},{id:"195981",title:"Prof.",name:"Francoise",surname:"Dignat-George",slug:"francoise-dignat-george",fullName:"Francoise Dignat-George"},{id:"195982",title:"Dr.",name:"Marcel",surname:"Blot-Chabaud",slug:"marcel-blot-chabaud",fullName:"Marcel Blot-Chabaud"}],corrections:[{id:"79245",title:"Corrigendum to: MCAM and its isoforms as novel targets in angiogenesis research and therapy",doi:null,slug:"corrigendum-to-mcam-and-its-isoforms-as-novel-targets-in-angiogenesis-research-and-therapy",totalDownloads:null,totalCrossrefCites:null,correctionPdfUrl:null}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:[{id:"65",label:"highly cited contributor"}]},relatedBooks:[{type:"book",id:"830",title:"Vasculogenesis and Angiogenesis",subtitle:"from Embryonic Development to Regenerative Medicine",isOpenForSubmission:!1,hash:"1c8f85e5c4786ba9d585dfcdef77aa2e",slug:"vasculogenesis-and-angiogenesis-from-embryonic-development-to-regenerative-medicine",bookSignature:"Dan T. 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\r\n\tClustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated (Cas) protein is a system originated from bacteria that confer resistance to plasmids or phages and provides an adaptive immunity for the host. CRISPR RNAs (crRNAs) are transcribed from CRISPR locuses. Transactivating crRNA (tracrRNA) is partially complementary to and pairs with a pre-crRNA to form an RNA duplex cleaved by RNase III and a crRNA/tracrRNA hybrid acts as a guide for the endonuclease Cas, which cleaves the invading DNA. Currently, it has been successfully used in genome editing such as silencing, enhancing, or modification of specific genes. Plasmids are constructed to express crRNA and tracrRNA together as single-guide RNAs (sgRNA). By the Cas proteins and a specifically designed sgRNA, the organism’s genome can be cleaved at most locations with the only limitation being the availability of an NGG protospacer adjacent motif (PAM) sequence in the targeting site. Efficient genome engineering has been performed in human cells, bacteria, yeasts, zebrafish, nematodes, plants, animals, etc. These findings and their implications may be discussed in the broadest context possible. Future research directions may also be highlighted. In this book, we will explore the development of CRISPR-Cas encoding and its application in basic research.
",isbn:"978-1-80356-816-4",printIsbn:"978-1-80356-815-7",pdfIsbn:"978-1-80356-817-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"4051570f538bd3315e051267180abe37",bookSignature:"Dr. Yuan-Chuan Chen",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11804.jpg",keywords:"crRNA, tracr RNA, sgRNA, PAM sequence, Encoding, Silencing, Enhancing, Modification, Genetic Engineering, Animal Model, Delivery Tool, CRISPR",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 30th 2022",dateEndSecondStepPublish:"June 10th 2022",dateEndThirdStepPublish:"August 9th 2022",dateEndFourthStepPublish:"October 28th 2022",dateEndFifthStepPublish:"December 27th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Yuan-Chuan Chen completed his Ph.D. in Comparative Biochemistry at the University of California, Berkeley (UCB), USA. His studies are focusing on the discovery, production, application of biopharmaceuticals. Additionally, he is interested in basic research and human therapeutics using CRISPR/Cas9.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"185559",title:"Dr.",name:"Yuan-Chuan",middleName:null,surname:"Chen",slug:"yuan-chuan-chen",fullName:"Yuan-Chuan Chen",profilePictureURL:"https://mts.intechopen.com/storage/users/185559/images/system/185559.jpg",biography:"Yuan-Chuan Chen completed his PhD in Comparative Biochemistry at the University of California, Berkeley (UCB), USA and had postdoctoral studies at the Taiwan Food and Drug Administration (TFDA). His research interests include Pharmacy/Pharmacology, Biochemistry, Microbiology/Virology, Cell/Molecule Biology, Biotechnology/Nanotechnology, Cell/Gene therapy and Policy/Regulation. He has participated in publishing many co-authored articles in peer-reviewed journals and book chapters in the fields of basic science, biomedicine, and related policy/regulation. He is now an assistant professor in Jenteh Junior College of Medicine, Nursing and Management, Taiwan. He is also an adjunct member in the biopharmaceutical division of Chinese Pharmacopoeia (Taiwan) Revising Committee (9th edition) and has reviewed many materials for Pharmacopoeia revising. His research is focusing on the discovery, production, application, perspectives and challenges of biopharmaceuticals. He is interested in basic research, the development of agricultural/industrial products and human therapeutics using the CRISPR/Cas9 system. 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1. Introduction to corticosteroids
Corticosteroids are steroid hormones produced by the adrenal gland. Adrenal glands constitute the endocrine system of the body and are a pair of pyramidal shaped glands located just above the kidneys on either side of the body. Because of their location, they are also known as suprarenal glands and are perfused by suprarenal arteries, which arise on either side from renal arteries [1]. These endocrine glands are important as they secrete a number of hormones into the blood, which play a vital role in maintaining homeostasis. With respect to the structure of the adrenal glands, they consist of an outer cortex and inner medulla. The adrenal medulla secretes catecholamines (epinephrine and norepinephrine), which are stress hormones and are mediators of the sympathetic autonomic nervous system [2]. The adrenal cortex itself comprises of three layers viz. zona glomerulosa, zona fasciculata and zona reticularis. These three layers are responsible for secreting mineralocorticoids, glucocorticoids, and adrenal androgens (sex hormones) respectively [3]. As the name suggests, mineralocorticoids are responsible for maintenance of fluid and mineral (electrolyte) balance; the chief mineralocorticoid is aldosterone. Glucocorticoids are involved in regulating glucose metabolism (glycolysis and gluconeogenesis) and storage (glycogenesis and glycogenolysis); the prototype glucocorticoid is cortisol. The primary adrenal androgen is dehydroepiandrosterone and possesses virilizing properties. Cortisol and other related hormones (such as 11-deoxycortisol and corticosterone) are collectively referred to as corticosteroids [4].
2. Physiologic effects
Corticosteroids play important physiologic roles in the human body and are referred to as “stress hormones” as they prepare the body during periods of physiologic stress. One of the most important actions of corticosteroids is their ability to up-regulate glucose synthesis [5]. Glycogen is the principal storage form of glucose in humans and is stored in various organs of the body, especially the liver. Glycogen is a multibranched polysaccharide and its structure consists of a core protein (glycogenin), which gives off multiple branches composed of glucose monomers [6]. Glycogen is produced by a biochemical pathway known as glycogenesis, which occurs chiefly in the liver. Glycogen is broken down during periods of fasting to provide a supply of glucose monomers. Glucose monomers can be utilized by all cells of the body through the processes of glycolysis. Pyruvate produced during glycolysis can then produce acetyl-CoA which can enter the Krebs cycle. Oxidation of glucose (in conjunction with the electron transport chain) produces adenosine 1,4,5-triphosphate (ATP), which is the energy currency of the cell. Stress hormones (such as catecholamines) generally up-regulate gluconeogenesis and glycogenolysis to induce hyperglycemia, which helps in fulfilling energy demands of various cells of the body [7]. Corticosteroids also induce fasting hyperglycemia by up-regulating gluconeogenesis; this is achieved by increasing expression of several key enzymes involved in gluconeogenesis including phosphoenol pyruvate-carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase [8]. Cortisol and other corticosteroids are unique in that they up-regulate gluconeogenesis while inhibiting glycogenolysis. This seemingly contradictory effect of corticosteroids is important in intrauterine life when release of cortisol from the fetal adrenal gland helps in building glycogen stores in the fetal liver to prepare for delivery.
Protein metabolism is also affected by corticosteroids. Increased catabolism of proteins to amino acids provides a supply of alanine, which can be converted to glucose by the process of gluconeogenesis. Cahill cycle (glucose-alanine cycle) refers to a series of chemical reactions in which amino groups and carbon skeletons from muscles are transported to the liver in the form of alanine, which are subsequently converted to glucose [9]. An essential enzyme for Cahill cycle is alanine aminotransferase (ALT), which is present in both muscles and liver. Alanine aminotransferase (also known as serum glutamate-pyruvate transaminase [SGPT]) is responsible for transferring an amino group from alanine to α-ketoglutarate, which results in the production of pyruvate and glutamate [10]. Pyridoxal phosphate is a co-factor for this reaction and is formed from pyridoxine (vitamin B6). As corticosteroids up-regulate protein catabolism, they induce a state of negative nitrogen balance in the body, which is important during periods of starvation.
Corticosteroids have important effects on bone turnover and affect bone mass. Bone is a type of connective tissue composed of osteocytes, osteoblasts and osteoclasts [11]. Osteoclasts are derivatives of the reticuloendothelial system and are responsible for bone resorption. Osteoblasts are mesenchymal origin cells and are responsible for giving rise to osteocytes—the mature cells that make up bones. Osteoclasts and their progenitors express a receptor on their surface for nuclear factor-κB (NFκB) commonly referred to as RANK. Ligand for RANK (known as RANKL) is expressed on the surface of osteoblasts and RANK–RANKL interaction is necessary for the differentiation and formation of osteoclasts [12]. Osteoprotegerin (OPG) is a cytokine receptor that is secreted by stromal cells and osteoblasts, which acts as a decoy receptor for RANKL. Secretion of OPG is one of the mechanisms by which the body prevents excessive resorption of bones. Due to this reason, OPG is sometimes also referred to as “osteoclastogenesis inhibitory factor.” Corticosteroids can affect bone turnover by inhibiting the secretion of OPG and increasing RANK–RANKL interaction, which leads to enhanced formation of osteoclasts. By tipping the balance in favor of osteoclasts, corticosteroids favor bone resorption and loss of mineral bone mass [13]. Calcium homeostasis in the body is tightly regulated by a number of hormones including parathyroid hormone (PTH), calcitonin and other hormones. Under physiologic conditions, serum calcium level is not drastically affected by corticosteroids. However, in pathologic states including Cushing’s syndrome and Addison’s disease, hypocalcemia and hypercalcemia (respectively) may be occasionally seen.
Vascular tone is also affected by corticosteroids, which has important implications during states of physiologic stress. Under resting conditions, cortisol and other corticosteroids are not necessary for maintaining vascular tone. However, during periods of stress, corticosteroids have a “permissive effect” for catecholamines and help in maintaining the vascular tone [14]. In patients with severe deficiency of glucocorticoids (such as Addison’s disease), catecholamines are ineffective in increasing the blood pressure; this may manifest clinically as overt or orthostatic hypotension. This is especially important for patients with severe sepsis (or septic shock), myxedema coma, pituitary apoplexy and other diseases. Presence of stress hormones (including thyroid hormones and corticosteroids) is necessary for the optimal action of catecholamines, which helps in the maintenance of vascular tone and blood pressure [15]. This in turn maintains adequate perfusion of vital organs and allows the body to cope with physiologic stress.
Fluid status of the body is principally controlled by steroid hormones. Mineralocorticoids (such as aldosterone) are primarily responsible for maintaining the fluid and salt balance in the body. Renin is a hormone secreted by the juxtaglomerular apparatus of nephrons, which is responsible for cleaving angiotensinogen to angiotensin I. Angiotensinogen is produced in the liver and is a precursor to angiotensin I, which is produced in the circulation by action of renin. Angiotensin I is then converted to angiotensin II in the pulmonary microvasculature through the action of dipeptidyl peptidase (commonly referred to as angiotensin converting enzyme [ACE]) [16]. Angiotensin II has at least four important effects in the body: (a) stimulation of aldosterone synthesis and secretion; (b) increasing thirst; (c) vasoconstriction; and (d) enhancing activity of sodium (Na+)-hydrogen (H+) exchanger in the proximal convoluted tubule of nephrons. The overall impact of angiotensin II is to retain salt and water with expansion of the effective circulating volume [17]. Aldosterone leads to further expansion of the extracellular fluid by increasing reabsorption of sodium (Na+) and chloride (Cl−) in the distal convoluted tubule of nephrons. At the same time, aldosterone increases tubular secretion of potassium (K+) and loss of hydrogen (H+) ions in the urine, which can potentially induce hypokalemia and metabolic alkalosis respectively. The overall effect of the renin–angiotensin–aldosterone system (RAAS) is to retain salt and water, thereby expanding the effective circulating volume and blood pressure. Although corticosteroids possess mainly glucocorticoid effects, they do have weak mineralocorticoid effects at physiologic concentrations. In disease states, and when used therapeutically, corticosteroids can have substantial mineralocorticoid activity with clinically significant effects on the body [18].
A number of other effects are also possessed by corticosteroids, which are not evident in physiologic states; however, in disease states, these actions can result in protean manifestations. Corticosteroids are necessary for optimal functioning of the body and excess or deficiency of these hormones can manifest as Cushing’s syndrome or Addison’s disease respectively. Cushing syndrome is most commonly iatrogenic and results from exogenous use of steroids, although it can also result from cortisol or adrenocorticotrophic hormone (ACTH)-secreting tumors (such as pituitary adenoma, adrenal adenoma or carcinoma, small cell carcinoma of lung, etc.) [19]. Common features of this disease include obesity, buffalo lump (lipodystrophy), moon facies, purple abdominal striae, easy bruising, depression, psychosis, cataracts, glaucoma, hypertension, hypokalemia and hypocalcemia. On the other hand, Addison’s disease can be caused by auto-immune destruction of the adrenal gland (in developed countries) or infiltration of the adrenal gland by infections such as tuberculosis (in developing countries). Hypocortisolism manifests as weakness, fatigue, weight loss, hyperpigmentation of skin (due to increased release of ACTH from the pituitary gland), hyponatremia, hyperkalemia, orthostatic or resting hypotension, hypercalcemia, basophilia and/or eosinophilia [20]. Treatment of these diseases is directed at restoring the balance of steroid hormones back to normal. In the case of Cushing syndrome, the underlying cause is addressed (e.g. removal of primary tumor); rarely, bilateral adrenalectomy with exogenous replacement of steroids may be required. In Addison’s disease, replacement of steroid hormones is generally needed for life. These two diseases exemplify the importance of corticosteroids and the deleterious consequences of their excess or deficiency on the human body.
3. Mechanism of action
From a therapeutic standpoint, corticosteroids have been exploited most for their anti-inflammatory and immunosuppressive effects [21]. While these properties of corticosteroids are not evident during physiologic states, they are clinically important in the treatment of numerous diseases including auto-immune diseases, neoplastic diseases, inflammatory disorders, rheumatologic conditions and infectious diseases (in conjunction with other drugs).
Inflammation is the response of the body to any noxious stimulus with an aim to eliminate the noxious stimulus and start the process of tissue repair. Inflammatory response of the body involves leukocytes, chemical mediators and vascular changes. Acute inflammation begins with a series of vascular changes that increases blood flow to the inflamed tissue. Chemical mediators of inflammation, such as histamine and serotonin, cause arteriolar vasodilation and venous vasoconstriction. This in turn promotes the exudation of fluid from the intravascular compartment to the interstitial space [22]. Leukocytes are then recruited to the area of inflammation through the expression of selectins on endothelium and integrins on leukocytes. Selectins are responsible for weak binding of leukocytes to the endothelium, which results in “rolling” of leukocytes along the endothelium. On the other hand, integrins are responsible for high-affinity binding of leukocytes (“adhesion”) to the endothelium with pavementing of the endothelium with leukocytes. Through the interaction of various cell surface molecules, such as platelet–endothelial cell adhesion molecule-1 (PECAM-1), leukocytes migrate through the microvasculature into the interstitium [23]. Neutrophils, monocytes and macrophages can phagocytose microbes and other offending agents by binding to their pathogen-associated molecular patterns (PAMPs) using pattern recognition receptors (PRRs). Following phagocytosis, microbes are trapped inside vacuoles called “phagosomes,” which are then fused with lysosomes to form phagolysosomes. Microbes and dead cells are thus degraded through the action of hydrolytic enzymes present inside lysosomes. Neutrophils and macrophages can also generate free radicals through the action of enzymes, which can damage different micro-organisms and offending agents [24].
A number of chemical mediators play a crucial role in the process of inflammation. These include biogenic amines, prostaglandins, leukotrienes, lipoxins, cytokines, chemokines, complement proteins, bradykinin, nitric oxide and other molecules [25]. Histamine and serotonin are biogenic amines and mediate vascular changes implicated in acute inflammation; histamine also causes bronchoconstriction. Prostaglandins are eicosanoids and have a variety of actions in the body. PGE2 is the mediator of pain, PGF2α causes increased vascular permeability, PGI2 (prostacyclin) causes vasodilation and thromboxane A2 causes platelet aggregation and vasoconstriction. Leukotrienes are derivatives of arachidonic acid and mediate bronchoconstriction. Lipoxins are lipid-derived autacoids that have a modulatory effect on the overall process of inflammation [26]. Bradykinin is a product of the kinin cascade and is derived by the action of kallikrein on high-molecular weight kininogen. This molecule irritates bronchiolar smooth muscle and mediates cough and vasodilation. Nitric oxide is released from endothelium and causes vasodilation. Complement cascade plays an important role in inflammation and is a part of the humoral immune system. Some complement proteins act as opsonins and anaphylatoxins. C5a, a complement protein, also causes chemotaxis of leukocytes to the area of inflammation. Cytokines are a group of small protein molecules that play various roles in the body including chemotaxis of leukocytes (chemokines), communication between leukocytes (interleukins), mounting fever (pyrogens) and so on [27]. All these chemical mediators play a crucial role in mounting an inflammatory response and pharmacologic interruption of their actions can blunt or modulate the inflammatory response.
Phospholipase A2 is an enzyme that is responsible for the synthesis of arachidonic acid from phospholipids present in cell membranes of various cells. Arachidonic acid is an important lipophilic compound that serves as the precursor for the synthesis of prostaglandins, thromboxane A2, leukotrienes and lipoxins (Figure 1). Cyclooxygenase is an enzyme that is responsible for the formation of prostaglandins from arachidonic acid. Non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen exert their anti-inflammatory effects by inhibiting cyclooxygenase and preventing formation of prostaglandins and thromboxane [28]. Arachidonic acid can also be acted upon by 12-lipoxygenase that results in the formation of lipoxins A4 and B4, both of which modulate inflammation by inhibiting neutrophil adhesion and chemotaxis. Another enzyme, 5-lipoxygenase, is involved in the synthesis of leukotrienes from arachidonic acid. Leukotrienes C4, D4 and E4 induce bronchospasm, vasoconstriction and increased vascular permeability. Synthesis of arachidonic acid is inhibited by corticosteroids and this effect of corticosteroids is exploited therapeutically for treating inflammatory disorders [29].
Figure 1.
Arachidonic acid metabolism with cyclooxygenase and lipoxygenase pathways. HPETE = hydroperoxyeicosatetraenoic acid.
The anti-inflammatory effects of corticosteroids are chiefly achieved by altering the synthesis of chemical mediators of inflammation. When commercially available corticosteroids are administered therapeutically, these molecules are readily absorbed and penetrate into various cells of the body due to their highly lipophilic nature. Glucocorticoids enter the cytosol of cells and bind to the glucocorticoid receptor. The glucocorticoid–receptor complex can repress the expression of pro-inflammatory genes by preventing translocation of certain transcription factors (especially NFκB) from the cytosol into the nucleus [30]. Moreover, the glucocorticoid–receptor complex can translocate into the nucleus and up-regulate transcription of anti-inflammatory genes by binding to “zing fingers” of glucocorticoid-response elements (GRE). Glucocorticoids inhibit translocation of NFκB by inducing the expression of IκBα inhibitory protein, which sequesters NFκB in the cytosol and prevents transcription of pro-inflammatory genes [31]. This is in turn inhibits the expression of pro-inflammatory genes and results in a blunted inflammatory response.
One of the most important effects of glucocorticoids is the modulation of gene expression of enzymes involved in the metabolism of arachidonic acid. Most notably, glucocorticoids reduce the expression of the enzyme phospholipase A2, which is responsible for the formation of arachidonic acid [32]. By inhibiting the formation of arachidonic acid, synthesis of prostaglandins, lipoxins, leukotrienes and thromboxane is inhibited. Since arachidonic acid metabolites mediate several key steps in the process of inflammation, their inhibition results in a blunted inflammatory response. Consequently, margination, chemotaxis and phagocytosis by phagocytes are inhibited by corticosteroids, which manifests as an overall anti-inflammatory effect. Additionally, through inhibition of the NFκB pathway, inflammatory cells begin to produce anti-inflammatory cytokines, which down-regulate the overall immune and inflammatory response. This has important therapeutic implications for the treatment of many diseases in which chronic inflammation lies at the core of their pathogenesis [33].
4. Formulations
Different formulations of corticosteroids are commercially available and have been used in a variety of diseases. Tablets, intravenous formulations and intramuscular preparations are available for systemic use. Systemic formulations are generally more efficacious as compared to other formulations (such as inhaled or topical steroids). However, this greater efficacy comes at the cost of increased adverse effects, which may be substantial in some cases [34]. Oral formulations are available for various corticosteroids with the most popular ones being prednisolone, methylprednisolone, hydrocortisone, and dexamethasone. Given the lipophilic nature of steroids, adequate absorption of steroids is achieved in most patients as they readily cross cell membranes of enterocytes [35]. Oral formulations are convenient for patients who require chronic use of steroids, such as lung transplant recipients. Tablets are the most commonly used oral formulation of corticosteroids. Prednisone syrup and dexamethasone oral solution or elixirs are also available, which may be useful for pediatric patients and those with feeding tubes. Conversion from one systemic steroid to another requires knowledge of equipotent dosages, which are provided in Table 1. Frequency of dosage is determined by the half-life and duration of action for individual corticosteroids; for instance, hydrocortisone lasts for 8–12 hours whereas dexamethasone may last for 36–72 hours [36].
Comparison of equivalent doses of various steroids.
Fludrocortisone has no glucocorticoid effect, while dexamethasone and methylprednisolone have negligible mineralocorticoid effects
Parenteral systemic formulations of steroids are also available and have a number of important uses. Intramuscular preparations of steroids, such as methylprednisolone or triamcinolone acetonide, are often used to provide a delayed release of steroids over a prolonged period of time with a relatively steady plasma concentration. Intravenous methylprednisolone and hydrocortisone are often used in patients with life-threatening or organ-threatening inflammatory conditions. Very high doses of steroids can be given intravenously (termed ‘pulse therapy’), which have been postulated to have physicochemical effects on plasmalemma of various cells, which may modulate the function of transmembrane proteins [37]. Steroid therapy has also been employed via many other parenteral routes of administration. Intralesional triamcinolone acetonide injections have been used for the treatment of several dermatologic disorders, such as keloids, alopecia areata, granuloma annulare, lichen planus and psoriasis. Gout and other inflammatory joint disorders have been treated with intra-articular injections of steroids. In the field of oncology, intrathecal administration of hydrocortisone along with chemotherapeutic drugs has been used for the treatment of leukemia [38].
Inhaled preparations of corticosteroids come in the form of nebulizer solutions, metered-dose inhalers or dry powder inhalers. Inhaled formulations are useful for the treatment of various airway disorders as these preparations exert their maximal effects locally with minimal systemic absorption. Consequently, the risk of systemic adverse effects is reduced, although oral thrush, dysphonia and systemic adverse effects can still occur with long-term use [39]. Most notably, children may have deceleration of growth velocity with the long-term use of corticosteroids [40]. In adults, long-term use of inhaled corticosteroids (ICS) may lead to accelerated loss of bone mass and possible ophthalmic side-effects (such as increased intraocular pressure and/or cataracts) [41]. The most commonly used inhaled steroids include beclomethasone, fluticasone, budesonide and mometasone. Nebulized delivery of respiratory solutions provides the best delivery of medications to the lower airways when compared with metered-dose inhalers or dry powder inhalers. Proper inhaler technique with or without the use of spacer devices may provide equivalent effects with powder/inhaled forms of steroids as compared to nebulizer administrations [42].
Topical formulations of steroids are available for use and have been utilized therapeutically for a wide variety of dermatologic conditions. Like inhaled forms, topical use of steroids provides local effects on the skin with some systemic absorption. Consequently, local effects of steroids are maximized, while systemic side-effects are minimized. However, use of a large amount of topical steroids, especially if continued over a long period of time, can result in significant systemic side-effects (as is the case with inhaled steroids) [43]. A number of vehicles are available for the topical delivery of steroids including ointments, creams, lotions, gels, foams and wet dressings. Topical steroids have been classified on the basis of their potency into 7 categories viz. least potent, low potency, lower-mid potency, medium potency, high potency, very high potency, and super-high potency. Using the correct vehicle and potency of topical steroids is of utmost importance as inadvertent use of a weak steroid preparation may lead to treatment failure, while use of a very potent topical preparation can lead to thinning and atrophy of the skin [44]. It is important to bear in mind that the potency of topical steroids is determined not only by the dermatologic diagnosis, but also by the area and extent of the skin that is affected. For instance, genital skin or intertriginous areas are exquisitely sensitive to topical steroids, which make them suitable candidates for lower potency topical steroids. On the other hand, skin of palms and soles have thick stratum corneum (the uppermost layer of epidermis), which necessitates the use of more potent topical steroids.
5. Therapeutic use in respiratory disorders
Steroids have been approved for the use of various respiratory diseases for both pediatric and adult populations. Both systemic and inhaled formulations of steroids have been utilized for the treatment of various respiratory disorders. In most disorders, steroids exert a therapeutic effect through their anti-inflammatory or immunosuppressive effects [21]. In many diseases, steroids can be given in the form of short intermittent courses; examples include hypersensitivity pneumonitis, eosinophilic pneumonitis, allergic bronchopulmonary aspergillosis (ABPA), etc. In some diseases, such as bronchial asthma or chronic obstructive pulmonary disease (COPD), inhaled steroids are continued on a long-term basis as a maintenance therapy. Systemic steroid therapy may also be required on a long-term basis in patients with systemic disorders or diseases refractory to other therapies, for instance sarcoidosis or collagen vascular diseases. In many diseases requiring long-term immunosuppression, steroid-sparing agents (such as azathioprine, mycophenolate, cyclosporine, tacrolimus, etc.) can be introduced to taper off steroids and mitigate their long-term side-effects [45].
In the following lines, we discuss the use of corticosteroids in the management of various respiratory disorders. A general overview of each of these diseases is provided and along with a holistic view of how steroid therapy works in conjunction with other components of management.
5.1. Asthma
Bronchial asthma is a chronic inflammatory disorder of bronchi and bronchioles that results in intermittent and reversible bronchospasm [46]. Clinical features of the disorder include recurrent episodes of chest tightness, wheezing and shortness of breath. Most patients have a diurnal variation in their symptoms with worsening shortness of breath and cough towards the end of the day. Over time, patients tend to develop bronchial smooth muscle hypertrophy, goblet cell hyperplasia with hypersecretion of mucus, recruitment of eosinophils and a state of chronic inflammation within the airways. Genetic predisposition to type I hypersensitivity has been demonstrated in most patients with asthma, although environmental factors also play a central role in triggering attacks of asthma [47]. Asthma has been classified into multiple subtypes depending on the type of triggers that precipitate attacks of asthma viz. atopic asthma, non-atopic asthma, drug-induced asthma, occupational asthma, and exercise-induced asthma. Atopic asthma is characterized by a personal or family history of atopy, allergic rhinitis, eczema and hypersensitivity to allergens, such as pollens or dust mites [48]. In non-atopic asthma, patients do not have hypersensitivity responses to allergens; instead, attacks of asthma are precipitated by factors such as viral infections, cold temperature, inhaled gases (e.g. sulfur dioxide), etc. Drug-induced asthma is precipitated by drugs such as NSAIDs or aspirin, which tip the balance towards increased synthesis of leukotrienes with consequent bronchospasm. Likewise, occupational asthma is reportedly precipitated by exposure to chemicals (e.g. anhydrides, isocyanates, acids) in various industries, such as paints, varnishes, adhesives and resins. Exercise-induced asthma is precipitated by exercise and diagnostic testing at rest may be normal in such cases [49]. Irrespective of the type of asthma, the core pathogenesis underlying all these types of asthma is similar.
The pathogenesis of asthma entails an inflammatory response affecting the bronchi and bronchioles, which is chiefly driven by a type 2 helper T (TH2) lymphocytes. When an environmental allergen is inhaled, antigen-presenting cells (APCs) engulf the allergen and present it to T lymphocytes. As a consequence of this, a TH2 cell-mediated inflammatory response is mounted. TH2 cells produce an array of cytokines including interleukin (IL)-2, IL-4, IL-5 and IL-13. IL-2 acts upon other T lymphocytes to differentiate them into TH2 cells and promote an amplified response [50]. IL-4 activates B lymphocytes and promotes immunoglobulin class switching to immunoglobulin E (IgE) production. IL-5 acts on bone marrow to increase differentiation and proliferation of eosinophils. Eotaxin is another cytokine produced by airway epithelial cells and serves to recruit eosinophils. IL-13 is believed to stimulate mucus production from mucus glands and goblet cells. Through these cytokines, TH2 promote a humoral immune response that results in production of high circulating levels of allergen-specific IgE. IgE binds to mast cells and cross-linking of mast cell-bound IgE results in degranulation of mast cells with release of histamine, tryptase and heparin sulfate. Histamine is a potent bronchoconstrictor and is the chief mediator of bronchoconstrictor in atopic asthma. Repeated exposure to the same allergen results in stronger activation of TH2 lymphocytes. A state of chronic inflammation persists within the bronchioles and results in airway remodeling, which is a histopathological hallmark of chronic asthma [51].
Numerous pharmacologic and non-pharmacologic modalities are used in the management of patients with asthma. Non-pharmacologic approaches include avoidance of allergens by removing carpets from houses, avoiding exposure to animal dander, using personal protective equipment while at work (in cases of occupational asthma), maintaining a clean environment (reducing exposure to dust mites), and so on. Pharmacologic treatment options include short-acting β2-adrenoceptor agonists (SABA), short-acting muscarinic antagonists (SAMA), long-acting β2-adrenoceptor agonists (LABA), ICS, phosphodiesterase (PDE) inhibitors (such as theophylline), anti-leukotrienes (such as montelukast), systemic corticosteroids, and immunotherapy (such as omalizumab and mepolizumab) [52]. SABA causes bronchodilation by stimulating β2-adrenergic receptors on the smooth muscle layer of bronchioles. As β2-adrenoceptors are G-protein coupled receptors (GPCRs), their stimulation (Gs) results in activation of adenylyl cyclase and increased levels of cyclic adenosine monophosphate (cAMP) inside smooth muscle cells. This in turn activates protein kinase A and results in phosphorylation of myosin light chain kinase, which essentially deactivates this enzyme. Consequently, dephosphorylation of myosin light chain occurs via the unregulated action of myosin light chain phosphatase, which causes smooth muscle relaxation and bronchodilation. PDE inhibitors (such as theophylline and aminophylline) act in a similar manner by inhibiting degradation of cAMP (caused by PDE), which results in increased level of cAMP in smooth muscle cells [53]. This results in bronchodilation in the same manner as SABA, except that the β2-adrenoceptor and adenylyl cyclase are not involved in this pathway. SAMA causes bronchodilation by blocking muscarinic receptors and preventing vagal stimulation. Moreover, SAMA also blocks muscarinic M3 receptors present on smooth muscle cells of bronchioles and prevent bronchoconstriction in response to a variety of stimuli. Anti-leukotrienes effectively block bronchoconstriction in response to leukotrienes C4, D4 and E4 by either blocking their target receptors (montelukast) or reducing their synthesis (zileuton). Omalizumab is a humanized monoclonal antibody directed against free circulating IgE and reduces levels of IgE, thereby reducing sensitivity to allergens [54]. Mepolizumab is an antibody that binds IL-5 and blocks the signaling pathways activated by IL-5 [55]. While mepolizumab reduces activation and recruitment of eosinophils, its exact mechanism of action in the treatment of asthma remains unclear.
Corticosteroids act through multiple pathways in controlling asthma and are useful in the treatment of acute exacerbations of asthma as well as long-term maintenance therapy [56]. Systemic and ICS act in a similar manner and their chief effect is reduction of airway inflammation by blocking the NFκB pathway. Corticosteroids reduce the expression of the enzyme phospholipase A2, which results in decreased synthesis of arachidonic acid and its metabolites [21]. Reduced levels of leukotrienes promote bronchodilation and relieve airway obstruction. Anti-inflammatory activity of corticosteroid over a long period of time can retard airway remodeling, thereby reducing smooth muscle cell hypertrophy, thickening of the basement membrane, and goblet cell hyperplasia [56]. Corticosteroids also have immunosuppressive properties, which enable them to reduce levels of IgE and inhibit proliferation of TH2 and B lymphocytes [31]. By reducing transcription of IL-4 and IL-5, corticosteroids also inhibit eosinophil recruitment and activation. Furthermore, by blocking the synthesis of IL-13, mucus secretion is reduced, which can further relieve airway obstruction.
Corticosteroids form a cornerstone of the management of asthma. Management of acute exacerbation of asthma requires accurate assessment of the severity of the exacerbation and appropriate triage [57]. Airway, breathing and circulation need to be secured as in any other emergency condition. Inhaled oxygen and SABA therapy are the first and foremost in the management of acute exacerbations. Intravenous terbutaline (β2-agonist) may also be used. Systemic corticosteroids should also be administered to all patients with a moderate to severe acute exacerbation of asthma, although their onset of action is after several hours. If patients do not respond to acute SABA therapy, intravenous magnesium sulfate and/or aminophylline infusion may also be considered. Patients with signs of fatigue (such as mental status changes or normalization of arterial carbon dioxide levels) may require endotracheal intubation and mechanical ventilation. In patients with long-standing asthma, a stepwise approach to therapy has been proposed [58]. Again, accurate assessment of asthma control is essential to tailor therapy to individual patients. The first step of therapy consists of non-pharmacologic measures and rescue medication (inhaled SABA) as needed. The second step is to add a low-dose ICS (controlled medication) along with a rescue medication (inhaled SABA) as needed. The third step is to either add LABA along with ICS or to increase the dose of ICS to medium dose. The fourth step is to use LABA along with medium-dose ICS therapy, or to add another agent (such as an anti-leukotriene or a PDE inhibitor). The fifth step is to use high-dose ICS therapy along with LABA with or without other agents mentioned in step 4. The sixth step is the use of systemic corticosteroids and/or immunotherapy along with other therapies as mentioned in steps 1–4. Generally, refer to an asthma specialist should be considered for patients who persistently require step 4 or higher therapies [59].
5.2. Chronic obstructive pulmonary disease
COPD refers to a group of obstructive lung diseases which are characterized by progressive and irreversible limitation to airflow in the setting of a chronic inflammatory state of the airways and/or lung parenchyma. Generally, emphysema and chronic bronchitis are two entities included under the heading of COPD, although these entities are not mutually exclusive and may co-exist in a patient. Emphysema is characterized by destruction of the wall and interstitium of the lung parenchyma leading to irreversible dilatation and enlargement of acini, thereby leading to air trapping within the lungs [60]. Depending on the etiology of emphysema, it can affect either whole of the respiratory acinus (pan-acinar emphysema) or portions of it (centriacinar, distal acinar or irregular emphysema). Clinically, patients with emphysema have been referred to as ‘pink puffers’ as they tend to have a lean built, breath with pursed lips, are often tachypneic, and appear pink due to hypercapnia (carbon dioxide retention). In contrast, chronic bronchitis is characterized by the presence of a productive cough for ≥3 consecutive months over a period of at least 2 years [61]. Interestingly, chronic bronchitis has a ‘clinical’ definition as opposed to emphysema, which is defined on the basis of morphologic and histopathological features. Patients with chronic bronchitis often have pathology affecting the larger airways (i.e. bronchi) as opposed to the air-space (parenchymal) disease seen in patients with emphysema. ‘Blue bloaters’ is a term used to refer to patients with chronic bronchitis as they often have resting cyanosis due to hypoxemia and polycythemia, and fluid retention due to right-sided heart failure (‘cor pulmonale’). All patients with COPD do have a number of features in common. All patients have a demonstrable obstructive defect on pulmonary function testing, which differentiates them from those with restrictive lung diseases. Moreover, patients with COPD generally have a progressive, irreversible obstructive process, which differentiates them from the intermittent, reversible obstruction seen in patients with asthma [62]. From a physiologic standpoint, all patients with COPD have a higher than normal lung compliance, which increases the tendency for alveoli to collapse, and makes expiration difficult. Air trapping results in elevated residual volume and increased total lung capacity, but a reduced forced vital capacity. Consequently, patients have an elevated functional residual capacity at rest. Moreover, as the disease process progresses, patients with emphysema develop a defect in diffusion of gases and impaired gas exchange. All these processes increase the work of breathing and impair oxygenation and ventilation [63].
Cigarette smoking has been implicated as the main etiologic factor in the pathogenesis of COPD [64]. Exposure to inhaled pollutants and toxins leads to production of free radicals and oxidant stress that can damage the airway epithelial lining. On-going exposure to such inhaled pollutants leads to accumulation of inflammatory cells (such as neutrophils, macrophages and lymphocytes) with release of proteolytic enzymes and a cascade of pro-inflammatory cytokines. This process of active chronic inflammation leads to destruction of elastin contained in the pulmonary interstitium, which leads to dilatation of acini — the hallmark feature of emphysema. Cigarette smoke in particular has been shown to inhibit α1-antitrypsin — an enzyme that inhibits neutrophilic elastase and prevents destruction of elastin. Inhibition of α1-antitrypsin by cigarette smoking leads to unregulated activity of neutrophilic elastase and consequent destruction of acini. Similarly, in patients with congenital deficiency of α1-antitrypsin, pan-acinar emphysema sets in early in life, in the absence of any history of cigarette smoking [65]. In patients with chronic bronchitis, cigarette smoking leads to hyperplasia of mucus-secreting glands in the larger airways; this is an adaptive response of the body to the irritants contained in cigarette smoke. Accumulation of mucus plugs, co-existent emphysema and bronchiolitis results in airflow obstruction in patients with clinical features of chronic bronchitis [63]. In cases of both emphysema and chronic bronchitis, the core feature of pathogenesis is on-going exposure to inhaled toxins and a state of chronic inflammation within the smaller airways [60]. This explains why smoking cessation is the most important therapeutic intervention in patients with COPD and reduces overall mortality in such patients.
Corticosteroids have an important role in the overall management of patients with COPD. As is the case with asthma, corticosteroids provide a therapeutic effect in patients with COPD by inhibiting bronchoconstriction, promoting bronchodilation, suppressing the immune response, and having an overall anti-inflammatory effect [66]. In patients with acute exacerbation of COPD, SABA and SAMA are the first-line therapeutic agents. The use of non-invasive positive pressure ventilation (NIPPV) can reduce the need for endotracheal intubation and reduces overall mortality in such patients. Systemic corticosteroids and antibiotics also have an important role in the treatment of acute exacerbation of COPD, although the onset of their action is delayed. Nebulized corticosteroids (such as budesonide) may also be added along with other therapies. In patients with refractory respiratory failure or contraindications to NIPPV, endotracheal intubation and mechanical ventilation may become necessary. In the management of patients with stable COPD, ICS are a cornerstone of therapy. The optimal therapy for such patients is based on their degree of airflow limitation (quantified by the forced expiratory volume in first second of expiration [FEV1]) and clinical symptoms (quantified by the COPD assessment test [CAT] and/or modified Medical Research Council [mMRC] scores) [67]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifies patients into one of four stages (I–IV) depending on their degree of airflow limitation (FEV1 ≥ 80%, FEV1 50–79%, FEV1 30–49% and FEV1 < 30% respectively). In patients with GOLD stage III–IV COPD, ICS should be used in conjunction with other therapies [68]. As in patients with asthma, SABA or SAMA are used as rescue medications as needed. LAMA alone or LABA combined with ICS may be combined with ICS depending on the degree of airflow limitation and clinical symptoms in individual patients. Roflumilast, a PDE inhibitor, may also be used in patients with COPD who have frequent exacerbations despite other treatment modalities [69]. In patients with advanced COPD, lung volume reduction surgery or lung transplant may be needed to improve quality of life [70]. In patients with advanced COPD who have a limited life expectancy and/or contraindications to lung transplant, hospice care may be the best strategy to improve patients’ symptoms.
5.3. Pneumonia
Pneumonia is a term often used to indicate an infection affecting the pulmonary parenchyma. Pneumonitis is a term that specifically refers to any inflammatory process affecting the pulmonary parenchyma, whether infective in origin or otherwise. However, in different publications, the two terms are often used interchangeably. For the purpose of this chapter, we use the term ‘pneumonia’ to refer specifically to infections affecting the pulmonary parenchyma.
Pneumonia is an extremely common illness affecting approximately 450 million people a year and is also a leading cause of death among all parts of the world and across all age groups [71]. In the United States, pneumonia alone accounts for almost one-sixth of all deaths. These figures seem plausible as the epithelial lining of the lungs are continuously exposed to the atmosphere which contains a high burden of pollutants and microbes. Impairment in host immunity, mucociliary apparatus and/or cough reflex can predispose people to the development of pneumonia. Acute bacterial pneumonias tend to have an acute onset of a lobar pneumonia with exudation of fibropurulent material in the alveoli and hepatization (consolidation) of lungs. Intracellular microbes cause an atypical pneumonia with a subacute presentation and mononuclear interstitial infiltrates. Chronic pneumonia is usually secondary to fastidious mycobacteria or fungal infections, which lead to granulomatous inflammation and possible cavitation of lung parenchyma. A variety of microbial pathogens can cause pneumonia and the predisposition to infection with a particular organism is determined by several factors, such as age, co-morbidities, vaccination status, use of immunosuppressive drugs, exposure to animals, presence of microbial reservoirs, hospitalization status, presence of endotracheal or tracheostomy tube, alcoholism, smoking, malnutrition, and so on and so forth [72]. Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Legionella pneumophila, Chlamydia pneumoniae, Mycoplasma pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Mycobacterium tuberculosis and Pneumocystis jiroveci are some of the well-known causative organisms of pneumonia. While the aforementioned list is by no means exhaustive, a causative organism cannot be isolated in most cases of community acquired pneumonia (CAP) [73]. A number of explanations have been proposed to explain this phenomenon with the most likely explanation being that a significant proportion of patients have pneumonia secondary to viruses, which cannot be isolated by routine microbiological methods.
Corticosteroids are not routinely used in all cases of pneumonia. From a theoretical perspective, the use of corticosteroids in patients with pneumonia would seem counterintuitive. Pneumonia is an infection of the pulmonary parenchyma and use of antimicrobials seems to be the prime management. Corticosteroids have been avoided in most cases of pneumonia due to concerns that their immunosuppressive effects may actually worsen the underlying infection. However, corticosteroids do have a role to play in selected patients with pneumonia. The most well-established use of corticosteroids is in patients with severe Pneumocystis jiroveci pneumonia as defined by a resting arterial partial pressure of oxygen (PaO2) of less than 70 mm Hg or an alveolar–arterial (A–a) gradient of PaO2 of 35 mm Hg or more (both on room air) [74]. In such patients, corticosteroids have been shown to provide a clear benefit in terms of overall mortality and reduction in respiratory failure. Apart from this, there have been several studies that have assessed the use of steroids in patients with severe pneumonia in general. A randomized placebo-controlled trial by Torres et al. demonstrated that the use of a short course of methylprednisolone among patients with severe CAP reduced treatment failure [75]. A meta-analysis of 12 randomized clinical trials published in 2015 concluded that the use of systemic corticosteroids in adults hospitalized with CAP may reduce overall mortality by 3%, decrease hospital stay by 1 day and cut need for mechanical ventilation by 5% [76]. Clinical guidelines generally recommend that steroids be considered for all patients with CAP requiring hospitalization, especially those requiring admission to the intensive care unit, although the benefits and harms should be weighed on a case-by-case basis.
5.4. Allergic bronchopulmonary aspergillosis
ABPA is a pulmonary disorder characterized by a hypersensitivity reaction to the allergens of the fungus Aspergillus fumigatus, which occurs in patients with a history of bronchial asthma or cystic fibrosis (CF). [77] ABPA has been reported to occur in 1–3% of patients with asthma, while in patients with CF, its prevalence may be as high as 10% [78]. A. fumigatus is a spore-forming mold that occurs ubiquitously in nature. This fungus is medically important because it has been implicated in a number of diseases viz. ABPA, aspergilloma, invasive pulmonary aspergillosis, allergic fungal rhinosinusitis and bronchial asthma. In patients with long-standing asthma or CF, A. fumigatus spores can grow within the lumen of airways and lead to the formation of hyphae (molds). These fungal hyphae can trigger an IgE-mediated hypersensitivity which results in bronchial inflammation and airway destruction. Clinically, ABPA manifests as a worsening of asthma or CF with patients complaining of wheezing and cough. Laboratory investigations may reveal eosinophilia and elevated levels of total IgE. Skin prick tests to Aspergillus and precipitins to A. fumigatus are positive. Radiologic studies may reveal fleeting pulmonary opacities in the acute stage and signs of central bronchiectasis in longstanding cases. Mucus plugging within the larger airways may be visible on roentgenograms and computed tomograms may lead to a characteristic “finger-in-glove” appearance [77]. A diagnosis of ABPA should be suspected in patients with a history of previously controlled asthma or CF, who develop unexplained worsening of their disease. Diagnostic criteria have been published in the literature in order to enable clinicians to vouchsafe a diagnosis of ABPA with certainty [79].
Management of ABPA entails the achievement of two separate goals: (a) attenuating the hypersensitivity response to A. fumigatus; and (b) decreasing the overall burden of A. fumigatus allergens. Systemic corticosteroid therapy is useful to achieve the former goal, while anti-fungal therapy (typically itraconazole) is required for the latter [77]. Prednisone in a dose of 0.5–2.0 mg/kg/day (or an equivalent) is often employed as first-line therapy. This dosage is maintained for a period of 1–2 weeks, beyond which the dosage can be modified to an alternate day regimen. Depending on the patient’s response, dose of steroids can be reduced slowly and gradually weaned off over a period of 2–3 months. In patients who relapse when the dose of corticosteroids is reduced, itraconazole therapy can be especially useful [80]. As discussed previously for asthma and COPD, steroids afford a therapeutic effect in ABPA owing to their anti-inflammatory, immunosuppressive and bronchodilator effects. Recent studies have explored the role of omalizumab in the management of ABPA [81]. Small-scale studies suggest that omalizumab may be useful as a steroid-sparing agent in patients with either asthma or CF who develop chronic ABPA [82].
5.5. Sarcoidosis
Sarcoidosis is a multisystem disorder of unknown etiology characterized by the formation of non-caseating epithelioid cell granuloma. This disorder occurs 10 times more frequently among African Americans as compared to Caucasians and the incidence is higher among young and middle-aged women. Interestingly, this disease affects non-smokers more often than people who smoke. Most commonly, the disease may be discovered incidentally when a chest radiograph reveals bilateral hilar lymphadenopathy. Patients may also present with a variety of clinical features including uveitis, xerophthalmia, parotidomegaly, xerostomia, lupus pernio, skin nodules, erythema nodosum, hypercalcemia, cardiac conduction system abnormalities, hepatomegaly and pulmonary infiltration. Given the undetermined etiology of sarcoidosis, it is a histopathological diagnosis of exclusion [83]. Nevertheless, two clinical variants of sarcoidosis are well-recognized and may suggest a diagnosis of sarcoidosis in the absence of histopathological evidence. Heerfordt-Waldenström syndrome refers to a constellation of clinical findings viz. fever, uveitis, parotidomegaly and facial palsy. Uveoparotid fever is another term used to refer to this syndrome and, in the appropriate setting, may obviate the need for a biopsy [84]. Another variant of sarcoidosis, Löffgren’s syndrome, has been classically described in the literature, although it may be somewhat less specific as compared to uveoparotid fever. Löffgren’s syndrome refers to a triad of erythema nodosum, arthralgia (or arthritis) and bilateral hilar lymphadenopathy [85]. Generally, women who present with Löffgren’s syndrome tend to have a better prognosis compared to others. The diagnosis of sarcoidosis requires histopathological evaluation and is one of exclusion since its etiology is unknown. The hallmark feature on biopsies is the presence of non-caseating granuloma in different organs and tissues of the body without an alternative explanation. Laboratory investigations may also reveal elevated levels of ACE, although this is a non-specific finding. The differential diagnosis includes all granulomatous diseases, such as tuberculosis, histoplasmosis, berylliosis, silicosis and cat-scratch disease [83].
Management of sarcoidosis is dependent upon the severity and extent of the disease at the time of diagnosis. Pulmonary sarcoidosis has been traditionally described to have four stages [86]. Stage I refers to the presence of hilar lymphadenopathy and/or mediastinal lymphadenopathy in the absence of any lung infiltration. Stage II refers to the presence of pulmonary reticular opacities (predominantly in upper lung zones) along with hilar and/or mediastinal lymphadenopathy. Stage III refers to the presence of pulmonary fibrosis and/or reticular infiltrates with resolution of hilar and/or mediastinal lymphadenopathy. Stage IV refers to an advanced stage of “burnt out” disease in which diffuse pulmonary fibrosis with volume loss and bronchiectasis is evident in the absence of any lymphadenopathy. Fortunately, a substantial proportion of patients with pulmonary sarcoidosis do not require treatment as most of them have asymptomatic, non-progressive disease. Treatment is necessary for patients who have severe disease at the time of presentation, those who report bothersome symptoms, or those who demonstrate evidence of progressive disease upon follow-up [87]. Likewise, in patients with extra-pulmonary disease, treatment is generally indicated to prevent end-organ damage. First-line treatment is to begin prednisone at a dose of approximately 40 mg/day (0.6 mg/kg) and continue for about 4–6 weeks. If there is no clinical and/or radiographic improvement, this dose of prednisone (or an equivalent steroid) can be continued for another 4 weeks. Once the patient shows evidence of clinical improvement, reduction in dosage of steroids can be started. There is no evidence available to support a particular steroid tapering schedule. Most clinicians would gradually reduce the dose of prednisone to 10–15 mg/day (approximately 0.2 mg/kg); this maintenance dose of prednisone (or an equivalent steroid) would then be continued for a period of approximately 6 months with frequent monitoring of pulmonary function tests (PFTs) and radiologic studies. The usual duration of treatment with prednisone (or equivalent steroid) is almost 1 year. In cases where patients have disease refractory to steroids, patients experience relapses when steroids are tapered, or patients develop serious adverse effects related to steroids, steroid-sparing immunosuppressive agents (methotrexate, azathioprine or biologic agents) can be tried [88]. For patients who are at risk of steroid-induced adverse effects and have stage I-II pulmonary disease (or evidence of slowly progressive disease), inhaled corticosteroid therapy may be a feasible alternative to systemic corticosteroids [89]. Budesonide 800–1600 mcg inhaled twice daily has been most studied in this context. Fluticasone propionate 500–1000 mcg inhaled twice daily is also a possible alternative option.
5.6. Collagen vascular diseases
Collagen vascular diseases comprise of a group of disorders characterized by auto-immunity to antigens contained within blood vessels and extracellular matrix of various organs. A large number of diseases affecting connective tissue of the body are included under this heading. A substantial proportion of rheumatologic diseases and auto-immune vasculitides are included in this category with the most notable ones being systemic sclerosis (SSc), polymyositis (PM), dermatomyositis (DM), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA), Goodpasture syndrome (GPS) and relapsing polychondritis (RPC). Sometimes, vascular diseases are also included in this category irrespective of whether auto-immunity is implicated in pathogenesis or not.
Nearly all collagen vascular diseases can affect the lung in a variety of ways. This is not surprising since the lungs are rich in both connective tissue and blood vessels. Abundant pulmonary vasculature is necessary for gaseous exchange, while abundant collagen and elastin fibers in the interstitium are necessary to support the dynamic chest wall–lung breathing system [90]. In the following lines, we briefly discuss the spectrum of pulmonary pathologies seen in various collagen vascular diseases and the role of steroids in their management.
SSc is a disorder characterized by progressive fibrosis affecting multiple organs of the body including the skin, kidneys, lungs and other organs [91]. Within the pulmonary system, SSc can lead to the development of ground-glass opacities, which can slowly progress to fibrosis of the lung parenchyma. The most common pattern of pulmonary fibrosis seen in SSc is similar to that of usual interstitial pneumonitis (UIP) and may be histologically indistinguishable from rheumatoid lung or idiopathic pulmonary fibrosis (IPF). In some cases, SSc may involve the lung in a pattern similar to that of idiopathic non-specific interstitial pneumonitis (NSIP). Progressive pulmonary impairment in SSc is a sign of worse prognosis and mandates aggressive treatment [92]. The decision to start treatment with immunosuppressive agents is based on clear evidence of progressive pulmonary damage as demonstrated by radiologic worsening or decline in pulmonary function as measured by PFTs. Two pharmacologic agents have been studied for the treatment of SSc-related interstitial lung disease (ILD): mycophenolate and cyclophosphamide [93]. Mycophenolate is often prescribed as monotherapy and the usual duration of immunosuppressive therapy is approximately 2 years. Cyclophosphamide therapy can be given as intravenous injections or oral therapy and it is generally combined with corticosteroid therapy. Oral cyclophosphamide is given daily and necessitates a higher cumulative dosage of the drug; on the other hand, intravenous cyclophosphamide is given once monthly and allows a lower cumulative dosage with a lower incidence of adverse effects. Cyclophosphamide therapy is continued for a few months and thereafter, it is transitioned to an alternative immunosuppressive agent (such as azathioprine or mycophenolate). Most clinicians prefer a daily oral dosage of low-dose prednisone (7.5–10 mg) along with cyclophosphamide as it is associated with a lower incidence of scleroderma renal crisis. However, some small studies have also reported the use of pulse-dose methylprednisolone along with cyclophosphamide [94]. Generally, pulse steroid therapy should be reserved for patients with SSc who have another organ-threatening manifestation necessitating their use.
PM and DM are auto-immune diseases that primarily affect muscles and skin, but in severe cases, involvement of other organ systems (including the respiratory system) can occur. The pathogenesis of PM entails a primary injury to skeletal muscles that is mediated by T lymphocytes, while in DM, immune complex deposition occurs in blood vessels and skin followed by complement activation that leads to injury and inflammation of the skin and muscles [95]. Pulmonary manifestations may be due to aspiration pneumonitis (a consequence of bulbar muscle weakness), respiratory failure (secondary to diaphragmatic involvement or chest wall muscle weakness) and/or acute alveolitis. ILD associated with PM or DM has been associated with the presence of antibodies against aminoacyl-transfer ribonucleic acid (tRNA)–synthetase and can occur as part of the antisynthetase syndrome [96]. The spectrum of ILD associated with PM/DM ranges from a chronic, slowly progressive UIP to an acute interstitial pneumonitis with diffuse alveolar damage (DAD); NSIP or bronchiolitis obliterans organizing pneumonitis (BOOP) can also occur [97]. Depending on the severity of the disease, glucocorticoid therapy alone or in association with other immunosuppressive agents may be required. Since most patients with PM/DM require systemic glucocorticoid therapy, such corticosteroid therapy may suffice for the pulmonary manifestations as well in many cases. In patients with severe disease at baseline or rapidly progressive ILD, pulse-dose methylprednisolone therapy followed by systemic glucocorticoid therapy (such as prednisone 1 mg/kg/day) along with cyclophosphamide (or other immunosuppressive agents) may be required. Intravenous immunoglobulin (IVIG) and/or rituximab have also been used in severe cases [98]. In most patients who receive glucocorticoid therapy, another immunosuppressive agent (usually azathioprine or mycophenolate) is also started at the same time and continued for a prolonged period of time (as glucocorticoids are tapered off).
SLE is a systemic auto-immune disease with protean manifestations that can affect nearly every organ-system of the body, but, occurs more frequently in women. Diagnosis is based on exclusion of alternative diagnoses and by applying the classification criteria proposed by the American College of Rheumatology (1997) or Systemic Lupus International Collaborating Clinics (2012) [99]. Pulmonary manifestations of SLE include pleuritis or pleural effusions, pulmonary hypertension, diffuse alveolar hemorrhage (DAH), acute interstitial pneumonitis, ILD and/or shrinking lung syndrome (SLS) [100]. ILD associated with SLE can take one of several histologic forms including NSIP, UIP, BOOP, lymphocytic interstitial pneumonitis (LIP), follicular bronchitis and/or nodular lymphoid hyperplasia. The general approach to the management of these pulmonary manifestations is similar to that for PM/DM associated ILD. Aggressive immunosuppressive therapy (i.e. pulse steroid therapy along with cyclophosphamide, rituximab or IVIG) is used for patients with acute interstitial pneumonitis or DAH. Plasmapheresis may also be employed for the management of patients with DAH. NSAID therapy (if not contraindicated) is used for patients with pleuritis [101]. Long-term immunosuppressive therapy may be required for patients with ILD or SLS.
RA is an auto-immune disorder that results in chronic, symmetric, progressive, erosive polyarthritis which can affect any synovial joint of the body. Extra-articular manifestations of this disease are common and occur in 20–40% of affected patients. Pulmonary manifestations may include arthritis of the cricoarytenoid joints, vasculitis affecting the recurrent laryngeal nerve, bronchiolitis obliterans, pleuritis with pleural effusions, pulmonary nodules, pulmonary hypertension and/or UIP [102]. Management of RA is with disease modifying anti-rheumatoid drugs and/or biologic agents [103]. NSAIDs may be used for management of pain. Short courses of systemic corticosteroids are used to manage acute exacerbations of RA. Systemic corticosteroid therapy is also useful for patients who develop rheumatoid vasculitis or bronchiolitis obliterans. ILD associated with RA is treated in a similar fashion as that due to SLE or PM/DM [104].
GPA, EGPA and MPA are small-vessel vasculitides associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). GPA is a necrotizing, granulomatous vasculitis that frequently affects the nose, paranasal sinuses, upper airways, lungs and kidneys [105]. EGPA is a granulomatous vasculitis that is often associated with a history of asthma and eosinophilia, but can involve multiple organ-systems of the body [106]. MPA is another ANCA-related small-vessel vasculitis that is non-granulomatous and can affect multiple organ-systems of the body, although it usually spares the paranasal sinuses and upper airways [107]. GPS is an auto-immune disorder characterized by the formation of auto-antibodies against type IV collagen present in basement membrane. This disease principally affects the alveolar and glomerular basement membranes resulting in DAH and rapidly progressive glomerulonephritis respectively [108]. DAH and/or DAD can also occur in GPA, EGPA or MPA. Treatment of these disorders entails aggressive immunosuppression; pulse steroid therapy is combined with either rituximab or cyclophosphamide therapy. IVIG and/or plasmapheresis are also used in conjunction with immunosuppression. Patients who receive cyclophosphamide therapy are usually switched over to an alternative immunosuppressive agent, such as azathioprine or methotrexate. Patients who received rituximab initially may be maintained on the same agent or switched over to azathioprine or methotrexate [109].
RPC is a rare auto-immune disease that leads to inflammation and destruction of cartilaginous structures of the body. Auricular chondritis (sparing the earlobe), nasal chondritis (may lead to saddle-nose deformity), scleritis (or episcleritis), orbital pseudotumor, non-erosive arthritis, laryngeal inflammation, tracheal stricture, bronchial obstruction with post-obstructive pneumonia, and/or mitral or aortic regurgitation are some of the prominent clinical features of this disease [110]. Approximately one-third of cases occur in association with other rheumatologic diseases or malignancy. Patients with auricular or nasal chondritis and/or arthritis in the absence of other organ involvement can be treated with NSAIDs alone. Systemic corticosteroid therapy is used in patients with life or organ-threatening disease [111]. Dapsone or other immunosuppressive agents may be used in combination with, or in place of, corticosteroids; evidence does not support the use of any particular immunosuppressive agent over others. Surgical treatment or airway stenting may be required in patients who develop laryngeal or tracheal disease [112].
5.7. Eosinophilic pneumonitis
Eosinophilic pneumonitis may present either as an acute eosinophilic pneumonia or a more indolent chronic eosinophilic pneumonia. Patients with acute idiopathic eosinophilic pneumonia generally present with an acute febrile illness and progressive respiratory failure [113]. Most patients have a history of new onset or resumption of cigarette smoking, although heavy inhalational exposure to fine sand and dust may also precipitate this illness. Peripheral eosinophilia is generally absent at presentation, although it may develop later in the disease. Computed tomography usually shows bilateral patchy ground-glass opacities or reticular infiltrates. Bronchoalveolar lavage (BAL) may reveal a preponderance of eosinophils. Lung biopsies usually show marked eosinophilic infiltration of the interstitium and alveolar spaces with DAD and absence of hemorrhage or granuloma [114]. Treatment is with systemic corticosteroid therapy (usually prednisone 1 mg/kg) continued for a period of 2 weeks followed by a gradual taper over the next 4 weeks. Most patients respond dramatically to steroids within 24–72 hours and respiratory failure resolves rapidly [115].
Chronic eosinophilic pneumonia is an idiopathic disorder that presents with cough, fever, dyspnea and wheezing that progress over a period of several weeks to months. Radiologic findings of this disorder have been classically described as the “photographic negative of pulmonary edema” i.e. bilateral peripheral pleural-based opacities [116]. BAL reveals a predominance of eosinophils with the eosinophil count often exceeding 25% of leukocyte count. BAL and/or lung biopsy are also useful in excluding alternative causes, such as drug-induced or infectious causes. Treatment of chronic eosinophilic pneumonia is similar to that for acute eosinophilic pneumonia, although systemic corticosteroid therapy is generally tapered slowly over a period of 6 months (or more) [117].
5.8. Lymphocytic interstitial pneumonitis
LIP is characterized by benign polyclonal proliferation of lymphocytes with infiltration of pulmonary interstitium and alveolar spaces with lymphocytes and plasma cells. This disorder often occurs in association with rheumatologic diseases or human immunodeficiency virus (HIV) infection [118]. Patients may be asymptomatic or they may present with cough, dyspnea and/or constitutional symptoms. Radiologic studies may reveal ground-glass opacities, centrilobular nodules (or masses), septal thickening and/or lung cysts. Thoracoscopic or open lung biopsies are necessary in most cases to confirm the diagnosis and exclude alternative diseases [119]. Treatment of patients with asymptomatic disease may be watchful waiting with frequent monitoring. For patients with symptomatic disease, systemic corticosteroid therapy (usually prednisone 0.5 mg/kg/day) is used and gradually tapered over a period of 6–12 months. For patients who do not respond to steroids or relapse during taper, other immunosuppressive agents (azathioprine, cyclosporine, cyclophosphamide or rituximab) may be used [120]. For patients with HIV infection, highly active antiretroviral therapy is used as first-line treatment (instead of corticosteroid therapy). However, corticosteroid therapy will be needed for patients with HIV infection who continue to experience worsening LIP despite antiretroviral therapy [121]. Infrequently, LIP may undergo malignant transformation and evolve into a pulmonary lymphoma.
5.9. Hypersensitivity pneumonitis
Hypersensitivity pneumonitis (also known as extrinsic allergic alveolitis) refers to a group of diseases that develop secondary to numerous agricultural dusts, microorganisms, bioaerosols and/or reactive chemical species. Prompt diagnosis of hypersensitivity pneumonitis is important as the disease is reversible in its early stages. Correct diagnosis is usually based on a compatible exposure history, clinical assessment, radiographic findings and response to avoidance of the suspected etiologic agent [122]. Acute hypersensitivity pneumonitis often occurs following heavy exposure to an inciting agent and is usually confused with CAP. Patients present with fever, chest pain, cough and dyspnea about 6 hours following exposure. In most cases, symptoms improve within a few days after cessation of exposure to inciting agent, although radiographic resolution requires several weeks. Skin testing to allergens is not useful and serum precipitins may have a high false negative rate. Bronchoscopy with BAL shows lymphocytosis exceeding 20% (often >50%) and the BAL CD4+/CD8+ ratio is usually decreased to less than 1.0 [123]. Characteristic radiographic findings on computed tomography include mid-to-upper zone predominance of centrilobular ground-glass or nodular opacities with signs of air-trapping. Histopathological findings may reveal poorly formed granulomas and/or a patchy mononuclear infiltration near the alveolar walls [124]. Subacute hypersensitivity pneumonitis presents with productive cough, dyspnea, fatigue, anorexia, and weight loss. Most patients have mixed obstructive and restrictive abnormalities on PFTs with a reduction in diffusion capacity. Radiographic findings may include diffuse micronodules, ground-glass opacities, or mild fibrotic changes predominantly involving the middle to upper lung zones. Bronchoscopy with BAL may reveal lymphocytosis and negative cultures. Lung biopsy may reveal poorly formed, noncaseating granulomas in the pulmonary interstitium with fibrosis and bronchiolitis [125]. Removal of the inciting agent results in complete resolution of findings over a longer period of time (weeks to months) and most patients require systemic glucocorticoid therapy. In the chronic progressive form of hypersensitivity pneumonitis, patients present with cough, dyspnea, fatigue, and weight loss. Physical examination may reveal digital clubbing and hypoxemia. Radiographic studies will show widespread pulmonary fibrosis; BAL may reveal lymphocytosis. Lung biopsy is necessary to demonstrate granulomatous pneumonitis, diffuse interstitial pneumonitis, bronchiolitis obliterans and distal destruction of alveoli (honey-combing) with densely fibrotic zones [126]. At this stage, removal of exposure to the inciting agent will only lead to partial improvement. Corticosteroid therapy (usually 0.5–1 mg/kg/day of prednisone) should be prescribed to all symptomatic patients with hypersensitivity pneumonitis. Gradual tapering of steroid dosage can be started after 2 weeks and tapered over the ensuing 2–4 weeks in most patients [127]. In patients with chronic hypersensitivity pneumonitis and extensive pulmonary fibrosis, lung transplantation may be a viable treatment option.
5.10. Idiopathic interstitial pneumonitis
IIP refer to a group of idiopathic ILDs that are characterized by infiltration of the pulmonary interstitium with inflammatory cells and consequently result in progressive fibrosis. IIP is a broad umbrella category that includes a number of different disease entities with distinct histologic patterns, natural course and prognosis [128]. The American Thoracic Society (ATS) and European Respiratory Society (ERS) classification [129] has recognized 6 major IIPs: (i) idiopathic pulmonary fibrosis (IPF); (ii) idiopathic NSIP; (iii) cryptogenic organizing pneumonitis (COP); (iv) respiratory bronchiolitis (RB) associated ILD; (v) acute interstitial pneumonitis (AIP); and (vi) desquamative interstitial pneumonitis (DIP). Two other ILDs are also included in the ATS/ERS classification as rare IIP viz. idiopathic LIP and idiopathic pleuroparenchymal fibroelastosis (PPFE). A category of unclassifiable IIP is also included in the ATS/ERS classification which is reserved for those IIPs which do not fit the criteria for any specific category of IIP.
IPF and idiopathic NSIP are both ILDs that run a chronic course with most patients experiencing symptoms for many months prior to diagnosis. IPF usually presents in the sixth to seventh decades of life. Typical radiologic findings include bibasilar subpleural fibrosis with traction bronchiectasis and honeycombing in the later stages. IPF is characterized histologically by a UIP pattern with a temporal and geographical heterogeneity, patchy involvement of the lung parenchyma, presence of architectural distortion and fibroblast foci and absence of features suggesting an alternative pattern [130]. Two novel tyrosine kinase inhibitors—pirfenidone and nintedanib—have been approved for the treatment of IPF [131]. Despite this, the overall prognosis for IPF remains poor. Systemic corticosteroid therapy is often employed for patients who develop acute infective exacerbation of IPF, although high quality evidence in support of this practice is lacking [132]. Idiopathic NSIP is a distinct clinical entity and tends to have a subacute presentation and a better prognosis as compared to IPF. Histologically, NSIP is characterized by temporal and geographical homogeneity with uniform involvement of the lung parenchyma, mononuclear cell infiltration of the interstitium and relative preservation of lung architecture [133]. The term “non-specific” is used because the histologic appearance of NSIP lacks the characteristic features of UIP, DIP, RB-ILD or AIP. Radiologic findings include bibasilar subpleural reticular shadowing with traction bronchiectasis, ground-glass opacities and absence of honeycombing. Alternative causes of NSIP, such as collagen vascular diseases, drugs and infections, need to be excluded. Treatment of NSIP is with systemic corticosteroid therapy, usually prednisone 1 mg/kg, gradually tapered over 6–12 months [134]. Pulse-dose methylprednisolone therapy has also been used in those with severe disease on presentation. In patients who relapse or remain refractory despite systemic corticosteroid therapy, a second immunosuppressive agent is added to prednisone.
Cigarette smokers tend to have a number of subclinical pulmonary interstitial abnormalities identifiable on histopathology [135]. These subclinical abnormalities do not meet the criteria for any particular ILD or IIP. Smoking-related ILD include RB-ILD, DIP and Langerhans cell histiocytosis. Langerhans cell histiocytosis is a separate disease entity and is generally not included under the heading of IIP. Both DIP and RB-ILD occur in smokers, usually with a smoking history of over 30 pack-years, most often in the third to fourth decades of life; men are more commonly affected [136]. In DIP, radiologic studies reveal bilateral ground-glass opacities without the peripheral reticular shadowing typical of UIP. In RB-ILD, radiologic findings may include scattered ground-glass opacities along with bronchial wall thickening. Lung biopsy in DIP shows uniform histopathological findings and lacks the patchy nature typical of IPF. Honeycombing is characteristically absent and a striking feature is the presence of numerous “smokers’ macrophages” within the distal airspaces [137]. DIP is actually a misnomer as these macrophages were originally believed to be desquamated pneumocytes. A smoker macrophage is a macrophage that contains fine brown pigment flecked with tiny blackish particles; these cytoplasmic particles stain well with Prussian blue (iron content) and periodic acid Schiff (polysaccharides) stains. RB-ILD has a histopathological appearance somewhat similar to DIP in that numerous smoker macrophages are noted; however, these pigmented macrophages are abundant within the lumen of respiratory bronchioles [138]. Moreover, the histopathological findings seen in RB-ILD have a bronchiolocentric distribution, whereas DIP tends to affect the lung in a rather uniform and diffuse manner. The management of DIP and RB-ILD is similar; smoking cessation is the first line of management [139]. For patients who continue to experience symptoms and have worsening PFTs, systemic corticosteroid therapy is used. Rarely, other immunosuppressive agents may be used if patients do not improve, although evidence in this regard is scarce. Given the considerable overlap between RB-ILD and DIP, some researchers have suggested that the two categories may be merged together into a single group [140].
COP is the term applied to the idiopathic form of BOOP. This clinical disorder is characterized by an inflammatory pneumonitis and a proliferative bronchiolitis that results in excessive proliferation of granulation tissue within the smaller airways [141]. COP often presents with an acute or subacute clinical picture and mimics CAP with a lack of response to antibiotics. Patients are most often in their fifth or sixth decades of life and both sexes are affected equally. In many cases, a flu-like illness may precede the onset of COP. As is the case with other IIP, secondary causes of organizing pneumonia (such as drugs, collagen vascular diseases and infections) need to be excluded. PFTs reveal a restrictive defect with impairment of gaseous exchange (diffusion capacity). Radiologic studies show multiple patchy ground-glass opacities or peripheral consolidations [142]. Bronchoscopy with BAL is often performed to exclude other diagnoses such as infections, drug-induced pneumonitis, hypersensitivity pneumonitis, chronic eosinophilic pneumonitis and malignancy. In COP itself, BAL typically reveals a “mixed pattern” of increased cellularity (i.e. smaller proportion of macrophages and higher proportions of lymphocytes, neutrophils and eosinophils). Although transbronchial lung biopsy may be performed at the time of bronchoscopy, most patients suspected of having COP or other ILD require a thoracoscopic or open lung biopsy (i.e. via thoracotomy) to yield adequate specimens for histopathological evaluation [143]. Systemic corticosteroid therapy is the mainstay of treatment. Prednisone 1 mg/kg/day is usually started, unless the patient has severe symptoms or frank respiratory failure in which cases, IV methylprednisolone 500–1000 mg/day for 5 days may be used initially. Patients usually respond clinically to corticosteroids within a few days to a few weeks. Corticosteroid therapy is generally tapered over a period of 6–12 months. Other immunosuppressive agents may be used in patients who have COP refractory to steroids, or those who relapse frequently despite moderate doses of corticosteroids [144].
AIP (also known as Hamman-Rich syndrome) has a much more aggressive and acute disease course as compared to other ILD and it is similar to acute respiratory distress syndrome (ARDS) in terms of its worse prognosis. In fact, AIP differs from ARDS only in that it has no identifiable triggering event (i.e. it is idiopathic); otherwise, the histological pattern of AIP is identical to that for ARDS (DAD) [145]. Clinically, it presents with acute onset of rapidly worsening respiratory failure with diffuse airspace shadowing on plain radiographs. Computed tomography reveals bilateral diffuse ground glass opacities and/or consolidations with lobular sparing. The histologic hallmark of AIP is DAD as characterized by diffuse airspace organization with or without the formation of hyaline membranes and alveolar septal thickening (due to diffuse organizing fibrosis) with a geographic and temporal homogeneity [146]. As for other IIP, cultures should be negative and granulomas, viral inclusions or eosinophils should be absent on histopathology. AIP requires aggressive treatment with high doses of glucocorticoids—typically methylprednisolone 1–2 g/day in divided doses for 3–5 days, followed by systemic glucocorticoid therapy for several weeks to months [147]. The mortality of AIP is almost 50%, and even in patients who survive the acute illness, recurrence of AIP or progression to a chronic ILD frequently occurs [148].
5.11. Laryngotracheitis (croup)
Laryngotracheitis (also known as croup) is a viral infection caused by parainfluenza viruses (most commonly, type 1) and often affects children in the first 3 years of life with a slight predisposition for boys. Clinical symptoms include low-grade fever, dyspnea, inspiratory stridor and a characteristic barking cough. In older children, hoarseness may also be noticeable. In some cases, inflammation may extend to the lower airways and result in laryngotracheobronchitis or even superimposed bacterial laryngotracheobronchopneumonitis [149]. While croup is typically caused by parainfluenza viruses, other viruses may also cause croup in certain cases; these include respiratory syncytial virus, influenza virus, rhinoviruses and human metapneumoviruses [150]. Plain chest radiographs may show narrowing of the subglottic area, frequently referred to as the steeple sign—owing to its resemblance to the steeple of a church). It should be noted here that croup is different from bacterial tracheitis, acute epiglottitis and viral bronchiolitis. Bacterial tracheitis is a bacterial infection of the trachea that results in a thick purulent exudate in the trachea, frequently with involvement of the lower airways (tracheobronchopneumonitis) [151]. Acute epiglottitis is an infection that was frequently caused by Haemophilus influenzae prior to the widespread use of the “Hib” vaccine. Most cases in vaccinated children and adults are caused by streptococcal or staphylococcal infections. Epiglottitis generally has a more rapid onset and aggressive course than croup and children tend to have high-grade fever and a toxic appearance [152]. Airway obstruction may be precipitated by physical examination or manipulative procedures, such as laryngoscopy. Viral bronchiolitis is an infection that usually occurs in infants and children below the age of 2 years. Most infections are caused by respiratory syncytial virus and present with fever, cough, dyspnea and wheezing [153]. Bronchiolitis is treated with supportive care only and corticosteroids have no role in management.
Treatment of croup involves supportive care with humidified oxygen therapy and anti-pyretics, adequate hydration, corticosteroids and nebulized epinephrine [154]. A strong body of evidence suggests that the use of either nebulized budesonide or single-dose dexamethasone provides benefits in terms of reducing length of hospital stay and decreasing visits to the emergency department [155]. The Westley croup score can be used to grade the severity of croup [156]. Patients with mild croup may be managed at home with a single dose of oral dexamethasone 0.6 mg/kg. Patients with moderate croup may be admitted to the hospital and administered an intramuscular or intravenous dose of dexamethasone along with repeated nebulizations of epinephrine [157]. In patients with severe croup and impending respiratory failure, admission to the intensive care unit may be necessary with a plan for endotracheal intubation in the presence of anesthesiologist and/or otorhinolaryngologist.
5.12. Exacerbation of cystic fibrosis
CF is an autosomal recessive disorder that results from genetic mutations in the cystic fibrosis transmembrane conductance regular (CFTR) chloride channel. CF is the most common lethal genetic disorder in the European population with an incidence of about 1 in 2500 live births [158]. The most common genetic mutation responsible for CF worldwide is the ∆F508 mutation which results in deletion of a phenylalanine residue at the 508′ position of the CFTR channel. This mutation has a prevalence of about 70% in patients with CF. Interestingly, of the 2000 mutations described in CFTR, only 4 of the remaining mutations have a prevalence of greater than 1% [159]. In some parts of the world, mutations other than the ΔF508 mutation are relatively common; for instance, the G551D mutation is common in the Middle East region [160, 161, 162, 163, 164]. Despite the development of novel targeted therapies for CF patients [165], the median survival for CF patients remains at 37 years—although it has been consistently improving over the past few decades [166]. In patients with CF, defective functioning of the CFTR gene results in protean manifestations, such as sinonasal polyposis, bronchiectasis, chronic pancreatitis with pancreatic insufficiency, CF-related diabetes mellitus, gut pathologies (meconium ileus, meconium ileus equivalent and intestinal atresia), osteoporosis, malnutrition, infertility and delayed puberty [159]. However, the most disabling of these manifestations is lung disease; defective mucociliary clearance leads to recurrent and persistent infections with virulent organisms, resulting in progressive and cumulative lung damage and development of bronchiectasis and end-stage lung disease [166].
Patients with CF frequently present with recurrent and disabling infective exacerbations of their lung disease. The microbiologic agents implicated in pneumonia and lower respiratory tract infections among patients with CF are distinct from that of the general population [167, 168, 169, 170]. The management of pulmonary disease in patients with CF is best carried out in dedicated CF centers with a multidisciplinary team that is experienced in the care of such patients [171]. In patients presenting with acute infective exacerbations of CF, good evidence is available to substantiate the role of antibiotics, pulmonary toilet, bronchodilators, ventilatory support and mucolytics [172]. The use of corticosteroids in the management of patients with CF is controversial. Systematic reviews of randomized controlled trials suggest that the use of inhaled or systemic corticosteroid on a chronic basis in patients with CF without evidence of asthma or ABPA causes more harm than meaningful benefits [173, 174]. However, in patients with CF who present with an acute infective exacerbation, some data suggest that short-term corticosteroid therapy may be beneficial. In a randomized controlled trial, Tepper and colleagues demonstrated that use of a short course of intravenous hydrocortisone in patients with acute infective exacerbation of CF provided a greater and sustained improvement in pulmonary function [175]. However, guidelines from the CF Foundation conclude that larger studies would be needed to further evaluate the efficacy of corticosteroids in acute exacerbations of CF vis-à-vis their safety [176].
5.13. Acute respiratory distress syndrome
ARDS is the development of acute hypoxic respiratory failure in response to an identifiable inciting event, which is characterized pathologically by a diffuse inflammatory process involving the lung that leads to increased vascular permeability, generalized alveolar edema, loss of aerated tissue and markedly decreased lung compliance [177]. ARDS can occur in response to a wide range of etiologies including sepsis, acute pancreatitis, trauma, drowning, burns, aspiration, transfusion-related acute lung injury, and so on; however, all these clinical entities are grouped together under the heading of ARDS as their clinical management is similar [178]. Clinically, ARDS presents with worsening hypoxemia and respiratory failure that develops within 24–72 hours of an inciting event. Patients typically have severe tachypnea and hypoxemia with accessory muscle use and respiratory distress on examination; chest auscultation may reveal bilateral diffuse crackles. Plain radiographs reveal bilateral airspace shadowing, which may be patchy in the initial stages, and coalesce later to a more homogeneous pattern in later stages. Arterial blood gas analysis will typically show respiratory alkalosis with hypoxemia and an elevated A–a gradient. The degree of hypoxemia can be quantified by the ratio of PaO2 to the fraction of inspired oxygen (FiO2) [179]. Computed tomography reveals widespread airspace opacities that may coalesce and are more prominent in the dependent parts of the lung. Histopathologically, the hallmark feature of ARDS is DAD (similar to AIP) with or without the presence of focal alveolar hemorrhage and hyaline membranes [180]. As per the Berlin definition, ARDS can be diagnosed if a patient has impairment in oxygenation (as measured by a PaO2/FiO2 ratio of ≤300 mm Hg) with bilateral airspace opacities on chest radiographs (not fully explained by lung collapse, pulmonary nodules or pleural effusions) that started within a week of a known clinical insult and are not secondary to cardiac failure or fluid overload as assessed by an objective assessment method (such as echocardiography) [181]. The PaO2/FiO2 ratio can be used to quantify the oxygenation impairment and stratify the severity of ARDS into severe (PaO2/FiO2 ≤ 100 mm Hg), moderate (PaO2/FiO2 101–200 mm Hg) or mild (PaO2/FiO2 201–300 mm Hg) [182].
Management of ARDS is centered on mechanically ventilating patients with lung protective strategies. Low tidal volume ventilation is the mainstay of management while tolerating permissive hypercapnia and using high PEEP to maximize alveolar recruitment and prevent atelectasis [183]. In patients with very severe ARDS, prone positioning techniques and extra-corporeal membrane oxygenation may be necessary to support life [184]. The use of corticosteroids in patients with ARDS is controversial and remains contentious to date. There is good evidence to suggest that corticosteroids should not be used >14 days after onset of ARDS as there is no demonstrable benefit and clear evidence of harm [185]. Moreover, in patients who develop ARDS due to a steroid-responsive etiology, corticosteroids should be used early in the course of the disease [186]. In patients with severe ARDS secondary to a disease process that is not treated with corticosteroids, initiation of systemic corticosteroids early (<14 days) in the course of the disease may offer some benefit. Several meta-analyses have been published to evaluate the impact of steroids on mortality in ARDS and their results have been conflicting. Three meta-analyses suggest that there is no benefit of steroids in terms of overall mortality, but, they help to improve gas oxygenation, reduce duration of mechanical ventilation and decrease overall stay in the ICU [187, 188, 189]. Two other meta-analyses reported that use of systemic corticosteroids provided a reduction in overall mortality and reduced the duration of mechanical ventilation [190, 191]. In the light of such conflicting evidence, use of systemic corticosteroids in patients with severe ARDS remains at the discretion of the treating clinician. Critical care physicians should assess each case individually and decide whether to administer corticosteroids or not based on their perceived benefits and possible adverse effects.
5.14. Lung transplantation and transplant-related complications
Lung transplant is used as a treatment modality for a wide variety of disorders that lead to end-stage lung disease with the most common ones being COPD, IPF, CF, α1-antitrypsin deficiency and idiopathic pulmonary arterial hypertension [192]. Both single-lung and double-lung transplantation procedures are increasingly being performed; however, the availability of donor lungs is the main limiting factor to the number of procedures that can be performed. The basic selection criteria for lung transplantation include: (a) the presence of severe lung disease for which medical therapy is unavailable or ineffective and mortality without transplantation is estimated to be >50% within 2 years; (b) satisfactory psychosocial support system; (c) likelihood to withstand lung transplant surgery is >80%; and (d) absence of other comorbidities that would limit life expectancy in the first 5 years post-transplantation [193]. Absolute contraindications to lung transplant include psychosocial problems or non-adherence to medical therapy, cigarette smoking, alcohol dependency, substance abuse, uncontrolled or untreatable infection, malignancy in the last 2 years, uncorrectable bleeding diathesis, significant coronary artery disease that is not amenable to revascularization, significant dysfunction of other vital organs, severe obesity (body mass index ≥35 kg/m2), active infection with Mycobacterium tuberculosis, or significant deformity of the chest wall or spine that would be expected to cause a severe restrictive defect post-transplant [194]. Apart from these absolute contraindications, there are a number of other diseases or conditions that are considered relative contraindications to lung transplant. Interestingly, use of systemic corticosteroids perioperatively was prohibited in the past due to concerns of poor healing of the newly formed anastomosis [195]. However, most evidence has shown that use of prednisone in doses of up to 0.3 mg/kg pre-transplantation does not increase the risk of complications [196].
Corticosteroids are an important part of immunosuppressive therapy for patients undergoing lung transplantation. At the time of the surgical procedure, an initial dose of 500–1000 mg of methylprednisolone is administered intravenously as soon as the donor allograft’s vasculature and bronchus are anastomosed to the recipient’s respective structures, and allograft reperfusion is established. Corticosteroid therapy is then continued at a dose of 0.5–1 mg/kg/day of prednisone (or equivalent) and gradually tapered down to a goal of 5–10 mg/day of prednisone (or equivalent) over a period of 6 months [197]. Depending on the transplant center’s protocols and characteristics of the recipient (age, primary lung disease, panel reactive antibodies, etc.), induction therapy may or may not be administered post-transplantation. For induction therapy, the most commonly used agents are basiliximab, alemtuzumab or anti-thymocyte globulin [198]. Pre-medication with acetaminophen, diphenhydramine and corticosteroids (methylprednisolone 125 mg IV once) is required prior to infusion of alemtuzumab or anti-thymocyte globulin. Maintenance immunosuppression is then employed with a combination regimen consisting of a glucocorticoid (usually prednisone), a calcineurin inhibitor (usually tacrolimus or cyclosporine) and an anti-metabolite (usually mycophenolate or azathioprine) [199]. Occasionally, an mTOR (mechanistic target of rapamycin) inhibitor, such as sirolimus or everolimus, may also be used be as part of the maintenance immunosuppressive regimen; however, mTOR inhibitors should not be used in the first 3 months post-lung transplant as they may lead to fatal bronchial dehiscence [200].
Transplant rejections represent a significant problem in the world of transplantology. Corticosteroid therapy forms an integral component of the management of both acute and chronic graft rejections. In general terms, a graft rejection is the immune response of the recipient to the donor’s graft, which results in dysfunction and failure of the transplanted organ. From a pathological perspective, graft rejection can be cell-mediated or humoral graft rejection depending on whether cytotoxic T lymphocytes or antibodies are implicated in immunopathogenesis respectively. In chronologic terms, rejection is classified into hyperacute, acute or chronic rejection based on temporality [201].
Hyperacute rejection occurs within 24 hours of transplantation (usually in the first few minutes to hours) and results in severe hypoxemia and other signs of graft failure. Such a graft rejection occurs due to preformed circulating antibodies in the recipient that are directed against antigens of the donor. Treatment involves therapeutic plasma exchange (to remove preformed antibodies), IVIG (to bind circulating antibodies & prevent them from interacting with transplanted tissues) and rituximab (to deplete B lymphocytes and prevent further formation of antibodies) [202]. All patients who develop hyper-acute rejection are already on high-dose steroids as part of their usual post-transplant care. Additional therapies, such as bortezomib (proteasome inhibitor) or eculizumab (monoclonal antibody to C5 complement protein), are also employed in most cases. While the outcome of hyperacute rejection is dismal in most cases, HLA typing and “virtual cross-match” of donor and recipient have made it a rare occurrence [203].
Acute lung allograft rejection usually occurs within the first 6–12 months of transplantation and it is cell-mediated in most cases. In acute cellular lung graft rejection, treatment is with pulse-dose methylprednisolone along with intensification of the maintenance immunosuppressive regimen [204]. Patients with persistent graft rejection may be treated with repeated courses of pulse-dose methylprednisolone along with other therapies, such as anti-thymocyte globulin, alemtuzumab and/or mTOR inhibitors (sirolimus or everolimus). Cases of acute humoral lung graft rejection developing weeks to months after transplantation are less common. Such cases are managed with a combination of therapeutic modalities including pulse-dose methylprednisolone, therapeutic plasma exchange, IVIG, rituximab and/or intensification of maintenance immunosuppression [205]. Empiric antibiotics are often initiated in patients with acute lung graft rejection until results of microbiologic and histopathological studies are available.
Chronic lung transplant rejection remains a major source of late morbidity and mortality for lung transplant recipients [206]. Chronic lung allograft rejection may manifest as either bronchiolitis obliterans or a restrictive allograft syndrome. Bronchiolitis obliterans is the predominant subtype of chronic lung graft rejection and has a worse prognosis [207]. It is usually detected as an obstructive defect on PFTs. Histopathologically, fibrosis in the lower airways (bronchioles) with formation of dense scar tissue is typical [208]. In some patients, an unexplained obstructive defect on PFTs is noted in the absence of definitive histopathological evidence of bronchiolitis obliterans; such patients are termed to have bronchiolitis obliterans syndrome. In restrictive allograft syndrome, patients have a demonstrable restrictive defect on PFTs and evidence of fibrotic changes involving the upper lung lobes [209]. In most cases, chronic lung allograft rejection is irreversible and most patients eventually require retransplantation [210]. However, several therapeutic options may be tried in such patients (depending on the transplant center’s preferences) including intensification of the immunosuppressive regimen, addition of azithromycin, use of montelukast, use of mTOR inhibitors, trial of anti-thymocyte globulin, total lymphoid irradiation or extracorporeal photophoresis [211].
6. Adverse effects
The adverse effects of corticosteroid therapy are significant and, in most circumstances, these effects are a compelling reason to limit the dose and/or duration of their use [18]. In many of the chronic diseases discussed in this chapter, toxicities of steroid therapy are a major source of morbidity. Additionally, most patients with such chronic diseases are often on immunosuppressive therapy or other toxic medications that may lead to cumulative toxicity. While systemic glucocorticoid therapy is associated with the most number of adverse effects, inhaled glucocorticoid therapy can also have some adverse effects, although they tend to be generally less severe [40, 41, 42]. Moreover, some of the adverse effects of corticosteroids do not manifest until complications develop. For instance, loss of bone mineral density may go on unchecked until a patient develops vertebral collapse [212]. Luckily, most of the adverse effects of steroids are potentially reversible with time once corticosteroids are discontinued.
Side effects of systemic corticosteroids pertain to almost all systems of the body. Long-term corticosteroid therapy can cause skin thinning, dermal atrophy and purpura, especially on the dorsum of hand and forearm [213]. Dermal atrophy is a consequence of reduced collagen synthesis due to inhibition of protein synthesis. Purpura is a combined consequence of dermal atrophy and increased fragility of vessels, which predisposes to bleed in response to minor stress. In a case–control study, Karagas and co-workers reported that the risk of non-melanoma skin cancer was increased among patients who used corticosteroids [214]. Cushingoid striae occur due to overstretching of the skin with rupture of vessels within the skin. Steroid-induced acne is also a well-known dermatologic adverse effect of steroids [215]. Ophthalmic adverse effects of corticosteroids include cataracts, increased intraocular pressure and development of glaucoma [216]. Cataracts most commonly occur in a posterior subcapsular location and are often bilateral [41]. Central serous chorioretinopathy is another rare ophthalmic side effect of corticosteroids [217]. Redistribution of body fat with truncal obesity, buffalo hump and moon facies (Cushingoid features) develop when corticosteroids are used over a long period of time in high doses [218]. Prolonged periods of hyperglycemia predispose patients to the development of diabetes mellitus and central adiposity, which in turn leads to increasing insulin resistance. Insulin resistance and hyperinsulinemia lead to increased synthesis of very low-density lipoproteins and increase triglyceride levels and adipose tissue in the body [219]. Moreover, since many pharmacologically used corticosteroids have weak mineralocorticoid properties, they can lead to fluid retention, hypertension, hypokalemia and mild metabolic alkalosis. All these effects can culminate in accelerated atherosclerosis and increased incidence of cerebrovascular events and coronary artery disease [220]. Moreover, fluid retention and hypertension can worsen cardiac failure. Fluid retention can also be problematic in patients with pre-existing renal disease. In the gastrointestinal system, corticosteroids can lead to a number of adverse effects including gastritis and gastrointestinal bleeding [221]. Corticosteroids may also impair healing of peptic ulcers and mask signs of gastrointestinal perforation; however, in patients taking glucocorticoids alone, routine use of proton pump inhibitors is not recommended [222]. Proton pump inhibitors should be given to patients who are taking corticosteroids along with either aspirin or other NSAIDs [223]. Fatty liver is another adverse consequence of prolonged corticosteroid use. In the musculoskeletal system, glucocorticoids lead to accelerated bone loss due to decreased osteogenesis and increased osteolysis [224]. Corticosteroid use can lead to osteoporotic fractures; interestingly, vertebral fractures have been reported in patients treated with glucocorticoids, even with a normal bone mineral density [225]. Avascular necrosis, especially of the head of femur, is a serious adverse effect of glucocorticoid therapy [226]. In children, prolonged use of corticosteroids can lead to slowed growth or even, permanent growth impairment [227]. Corticosteroids can also lead to myopathy, which manifests as proximal muscle weakness, although muscle enzymes (serum creatine kinase) are within normal limits [228]. With respect to the reproductive system, corticosteroid use may lead to menstrual irregularities and decreased fertility in both sexes [229]. Moreover, use of high doses of corticosteroids during the first trimester of pregnancy may elevate the risk of cleft palate slightly [230]. The risk of fetal intrauterine growth restriction is also elevated in women who take corticosteroids throughout pregnancy [231]. Corticosteroids have also been shown to have a number of adverse effects on the central nervous system, especially when used in high doses [232]. Neuropsychiatric effects may include feeling of euphoria, anxiety, depression, mania, delirium or even psychosis. In a study by Shin et al. [233], patients with RA who were treated with oral glucocorticoids had a higher risk of having cognitive impairment. In another study by Keenan and colleagues [234], use of corticosteroids was associated with an adverse outcome on explicit memory at a period of 1 year. Last, but not the least, the immune system is also adversely affected by glucocorticoid therapy and immunosuppression leads to an increased risk of infections, decreased response to vaccines, poor wound healing and lymphopenia [235, 236]. Neutrophilia seen with corticosteroid therapy is a mere consequence of demargination of the neutrophil pool.
Close monitoring of such patients for the development of adverse effects is essential [237]. Routine monitoring should include blood pressure charting, weight charting, regular physical examination, lipid profile and fasting plasma glucose. Determination of bone mineral density and monitoring of intraocular pressure should be considered for patients who are receiving high doses of corticosteroids for a prolonged duration [238]. Specifically, patients with pre-existing co-morbid conditions, such as diabetes mellitus, hypertension, dyslipidemia, heart failure, peptic ulcer disease and osteoporosis, are at a much higher risk of developing adverse effects and must be monitored vigilantly [239].
In summary, corticosteroid therapy is a double-edged sword in patients with chronic diseases who are dependent on steroids. Adverse effects pertaining to nearly every system of the body can occur with the use of corticosteroids, which mandates that patients be treated with the lowest possible dose of corticosteroids for the minimum duration possible. Inhaled corticosteroid therapy can provide a therapeutic effect in many airway disorders, while reducing the risk of many steroid-induced adverse effects at the same time. Thus inhaled therapy for airway disorders should be preferred over systemic corticosteroid therapy, whenever possible.
Conflict of interest
The authors have no conflict of interests to disclose. The authors have no conflict of interests to disclose.
forced expiratory volume in first second of expiration
FiO2
fraction of inspired oxygen
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GPA
granulomatosis with polyangiitis
GPCR
G-protein coupled receptor
GPS
Goodpasture syndrome
GRE
glucocorticoid-response elements
HIV
human immunodeficiency virus
ICS
inhaled corticosteroids
IgE
immunoglobulin E
IL
interleukin
ILD
interstitial lung disease
IPF
idiopathic pulmonary fibrosis
IVIG
intravenous immunoglobulin
LABA
long-acting β2-adrenoceptor agonist
LAMA
long-acting muscarinic antagonists
LIP
lymphocytic interstitial pneumonitis
mMRC
modified Medical Research Council scale
MPA
microscopic polyangiitis
mTOR
mechanistic target of rapamycin
NFκB
nuclear factor-κB
NIPPV
non-invasive positive pressure ventilation
NSAID
non-steroidal anti-inflammatory drug
NSIP
non-specific interstitial pneumonitis
OPG
osteoprotegerin
PAMPs
pathogen-associated molecular patterns
PDE
phosphodiesterase
PECAM-1
platelet–endothelial cell adhesion molecule-1
PFT
pulmonary function test
PM
polymyositis
PPFE
pleuroparenchymal fibroelastosis
PRR
pattern recognition receptor
PTH
parathyroid hormone
RA
rheumatoid arthritis
RAAS
renin–angiotensin–aldosterone system
RANK
receptor activator for nuclear factor-κB
RANKL
receptor activator for nuclear factor-κB ligand
RB
respiratory bronchiolitis
RPC
relapsing polychondritis
SABA
short-acting β2-adrenoceptor agonist
SAMA
short-acting muscarinic antagonists
SGPT
serum glutamate-pyruvate transaminase
SLE
systemic lupus erythematosus
SLS
shrinking lung syndrome
SSc
systemic sclerosis
TH1
type 1 helper T
TH2
type 2 helper T
tRNA
transfer ribonucleic acid
UIP
usual interstitial pneumonitis
\n',keywords:"corticosteroids, glucocorticoids, respiratory diseases, airway disorders, asthma, chronic obstructive pulmonary disease, pneumonia, sarcoidosis",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/57931.pdf",chapterXML:"https://mts.intechopen.com/source/xml/57931.xml",downloadPdfUrl:"/chapter/pdf-download/57931",previewPdfUrl:"/chapter/pdf-preview/57931",totalDownloads:2288,totalViews:249,totalCrossrefCites:6,totalDimensionsCites:9,totalAltmetricsMentions:10,introChapter:null,impactScore:6,impactScorePercentile:95,impactScoreQuartile:4,hasAltmetrics:1,dateSubmitted:"May 29th 2017",dateReviewed:"November 2nd 2017",datePrePublished:"December 20th 2017",datePublished:"May 23rd 2018",dateFinished:"November 30th 2017",readingETA:"0",abstract:"Corticosteroids are adrenal hormones that play important physiologic roles including modulation of glucose metabolism, protein catabolism, alteration of calcium metabolism, regulation of bone turnover, suppression of immune system, and down-regulation of the inflammatory cascade. Because of their diverse effects, corticosteroids have been used therapeutically for treating a wide variety of auto-immune, rheumatologic, inflammatory, neoplastic and infectious diseases. In the field of pulmonology, corticosteroids have been used for the treatment of reactive airway diseases (such as asthma and allergic bronchopulmonary aspergillosis), chronic obstructive pulmonary disease, sarcoidosis, collagen vascular diseases (such as vasculitic disorders), eosinophilic pneumonitis, idiopathic interstitial pneumonias and infectious disorders (such as laryngotracheobronchitis). Different formulations of corticosteroids are commercially available including tablets, intravenous injections, intramuscular formulations and inhaled preparations. Long-term use of corticosteroids is often limited by their adverse effects, which include abnormal fat deposition, weight gain, diabetes mellitus, cataracts, glaucoma, osteoporosis, osteonecrosis, elevated risk of fractures, increased susceptibility to infections, proximal myopathy, depression, psychosis, adrenal atrophy with risk of Addisonian crisis, abdominal striae, acne vulgaris, delayed wound healing, easy bruising, electrolyte abnormalities and increased risk of peptic ulcer disease. As our understanding of corticosteroids advances, we may be able to identify individuals at higher risk of experiencing adverse effects.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/57931",risUrl:"/chapter/ris/57931",book:{id:"6146",slug:"corticosteroids"},signatures:"Ibrahim A. Janahi, Abdul Rehman and Noor Ul-Ain Baloch",authors:[{id:"191897",title:"Prof.",name:"Ibrahim",middleName:null,surname:"Janahi",fullName:"Ibrahim Janahi",slug:"ibrahim-janahi",email:"ijanahi@hamad.qa",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Qatar University",institutionURL:null,country:{name:"Qatar"}}},{id:"212576",title:"Dr.",name:"Abdul",middleName:null,surname:"Rehman",fullName:"Abdul Rehman",slug:"abdul-rehman",email:"jsmawais@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Qatar University",institutionURL:null,country:{name:"Qatar"}}},{id:"212577",title:"Dr.",name:"Noor",middleName:null,surname:"Baloch",fullName:"Noor Baloch",slug:"noor-baloch",email:"noor2000_2004@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction to corticosteroids",level:"1"},{id:"sec_2",title:"2. Physiologic effects",level:"1"},{id:"sec_3",title:"3. Mechanism of action",level:"1"},{id:"sec_4",title:"4. Formulations",level:"1"},{id:"sec_5",title:"5. Therapeutic use in respiratory disorders",level:"1"},{id:"sec_5_2",title:"5.1. Asthma",level:"2"},{id:"sec_6_2",title:"5.2. Chronic obstructive pulmonary disease",level:"2"},{id:"sec_7_2",title:"5.3. Pneumonia",level:"2"},{id:"sec_8_2",title:"5.4. Allergic bronchopulmonary aspergillosis",level:"2"},{id:"sec_9_2",title:"5.5. Sarcoidosis",level:"2"},{id:"sec_10_2",title:"5.6. Collagen vascular diseases",level:"2"},{id:"sec_11_2",title:"5.7. Eosinophilic pneumonitis",level:"2"},{id:"sec_12_2",title:"5.8. Lymphocytic interstitial pneumonitis",level:"2"},{id:"sec_13_2",title:"5.9. Hypersensitivity pneumonitis",level:"2"},{id:"sec_14_2",title:"5.10. Idiopathic interstitial pneumonitis",level:"2"},{id:"sec_15_2",title:"5.11. Laryngotracheitis (croup)",level:"2"},{id:"sec_16_2",title:"5.12. Exacerbation of cystic fibrosis",level:"2"},{id:"sec_17_2",title:"5.13. Acute respiratory distress syndrome",level:"2"},{id:"sec_18_2",title:"5.14. Lung transplantation and transplant-related complications",level:"2"},{id:"sec_20",title:"6. Adverse effects",level:"1"},{id:"sec_24",title:"Conflict of interest",level:"1"},{id:"sec_23",title:"Abbreviations",level:"1"}],chapterReferences:[{id:"B1",body:'Barwick TD, Malhotra A, Webb JA, Savage MO, Reznek RH. Embryology of the adrenal glands and its relevance to diagnostic imaging. Clinical Radiology. 2005;60(9):953-959'},{id:"B2",body:'De Diego AM, Gandia L, Garcia AG. A physiological view of the central and peripheral mechanisms that regulate the release of catecholamines at the adrenal medulla. Acta Physiologica. 2008;192(2):287-301'},{id:"B3",body:'Burchard K. A review of the adrenal cortex and severe inflammation: Quest of the “eucorticoid” state. 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Annals of the Rheumatic Diseases. 2010;69(11):1913-1919'},{id:"B238",body:'Sholter DE, Armstrong PW. Adverse effects of corticosteroids on the cardiovascular system. Canadian Journal of Cardiology. 2000;16(4):505-511'},{id:"B239",body:'Duru N, van der Goes MC, Jacobs JW, Andrews T, Boers M, Buttgereit F, Caeyers N, Cutolo M, Halliday S, Da Silva JA, Kirwan JR. EULAR evidence-based and consensus-based recommendations on the management of medium to high-dose glucocorticoid therapy in rheumatic diseases. Annals of the Rheumatic Diseases. 2013;72(12):1905-1913'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ibrahim A. Janahi",address:"ijanahi@hamad.qa",affiliation:'
Clinical Pediatrics, Weill-Cornell Medical College, Qatar
Pediatric Pulmonology, Department of Pediatrics, Hamad General Hospital, Qatar
Medical Research Center, Hamad Medical Corporation, Qatar
Department of Internal Medicine, Rutgers-New Jersey Medical School, University Hospital, United States
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1. Introduction
Since the end of 2019, when the first cases were documented in Wuhan (China), the corona virus disease 2019 (COVID-19), a zoonotic infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly and rampantly, raising major concerns regarding public health, while applying an unprecedented, continuous strain, on the global medical infrastructure. COVID-19 was officially declared a pandemic by the World Health Organization on 11 March 2020 [1], and since then it has affected over 400 million people worldwide, with a cumulative mortality rate of under 2% [2] and recent alleviation of clinical outcomes due to the development and widespread implementation of efficient vaccination. Taking into account the extreme polymorphism of clinical presentations, ranging from asymptomatic to severe systemic effects, mainly involving the respiratory and cardiovascular systems, and fatal, rapidly progressing, acute respiratory distress syndrome (ARDS), the containment of transmission, at least in the pre-vaccination era, and the therapeutic management of COVID-19 and its systemic complications, has proven to be quite a challenge for clinicians, especially in the case of high-risk patients [3].
A novel member of the β-coronavirus genus, group 2, the enveloped, positive-sense RNA single-stranded SARS-CoV-2, has established itself as the third emerging, highly pathogenic coronavirus, to infect humans and cause a large-scale outbreak since the early 2000s, after severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) [4]. Even though mortality rates are lower for SARS-CoV2 than for previous related coronavirus outbreaks (>35% for MERS-CoV and > 10% for SARS-CoV), contagiousness is much higher (MERS-CoV and SARS-CoV had only 10000 cumulative cases between them), as transmission is mainly airborne (via respiratory droplets), with multiple alternative mechanisms being reported (aerosols, direct contact with contaminated surfaces, and fecal-oral transmission [4]).
From a genomic viewpoint, SARS-CoV-2 shares ~80% sequence identity with SARS-CoV and ~ 50% with MERS-CoV, encoding 16 nonstructural proteins (that make up the replicase complex), 9 accessory proteins, and 4 structural proteins – spike (S), envelope (E), membrane (M), and nucleocapsid (N). The SARS-CoV-2 life cycle revolves around the envelope S protein. Direct contact between the Spike receptor-binding domain and the innate cellular receptor (angiotensin-converting enzyme 2 – ACE2), if provided adequate cleavage of the viral Spike S1/S2 polybasic cleavage site by host-cell proteolytic enzymes, will ensure Spike activation in endosomes and virus-cell membrane fusion (cell surface and endosomal compartments), allowing viral RNA to be released into the host-cell cytosol. Viral replication ensues, with subsequent expulsion into the intercellular space [4]. In fact, the S gene of SARS-CoV-2 represents the distinguishing genomic feature from SARS-CoV, sharing <75% nucleotide identity [4].
The main tissue tropism of SARS-CoV-2 is pulmonary, targeting high ACE2 expression cells (airway/alveolar epithelial cells, vascular endothelial cells, and alveolar macrophages) [5]. Even so, higher levels of ACE2 messenger RNA expression can be found in many extra-pulmonary tissues as well and nearly undetectable amounts of ACE2 still support viral host-cell entry. Therefore, additional, underappreciated, cell-intrinsic factors must also be involved in host-cell entry [4]. Noteworthy, a subpopulation of human type II alveolar cells has been documented, which manifest abundant ACE2 expression, and concomitant high levels of messenger RNA, specific to certain cellular proviral genes (coding elements of the, SARS-CoV-2 cell entry facilitating, and endosomal transport system) [6]. Also, ACE2 expression regulation must be considered, as, during viral infection, ACE2 gene expression in human airway epithelial cells is upregulated by type I and II interferons [5].
Considering the multitude of the medical literature written on the topic of multisystem impairment occurred during the infection with the SARS-CoV-2 virus, the purpose of our research was to summarize the opinions of experts concerning the cardiovascular alterations associated with COVID-19, and for this aim we reviewed the most significant articles published on PubMed, Medline, and Research gate on these topics and provided individualized summaries of expert opinions.
2. Effects of the SARS-CoV-2 virus on the cardiovascular system
The COVID-19 pandemic greatly challenged clinicians, both due to the sheer number of patients, but also because of the lack of therapeutic consensus and incomplete understanding of disease pathogenesis. Most fatal cases of COVID-19 relate to a severe atypical pneumonia, accompanied by a sudden systemic deterioration, despite therapeutic intervention in the hospital setting.
The infection with the SARS-CoV-2 virus primarily affects the respiratory structures, but the involvement of the cardiovascular system is also frequent. Cardiovascular complications in addition to respiratory disease may develop in all phases of COVID-19, which can start with the dramatic picture of acute heart failure (ACF), acute coronary syndrome (ACS), pulmonary venous thromboembolism (VTE), or even sudden cardiac death, as shown in Figure 1. The pathophysiological mechanisms underlying these disproportionate effects of the SARS-CoV-2 infection on patients with cardiovascular comorbidities, however, remain incompletely understood [7]. Thromboembolic events, usually accompanied by violent, pulmonary, and/or systemic complications, have been described from early on, since the beginning of the pandemic, with infectious inflammatory response patterns rapidly shifting into a typical systemic inflammatory response syndrome (SIRS) or ARDS, which could potentially induce multi-organ failure (MOF) and, subsequently, death. As we enter the third year of the pandemic, COVID-19 pathophysiology is slowly unraveling as we begin to better comprehend the complex interplay between the direct cytotoxic effects of SARS-CoV-2 on pneumocytes and endothelial cells, the emerging local and systemic inflammatory response, and the ways in which these responses interact with hemostatic homeostasis, a mechanism which has been deemed as central and, at least to this extent, unprecedented [8].
Figure 1.
Main COVID-19-associated cardiovascular complications and underlying pathophysiological mechanisms.
2.1 Cardiac tissue damage
COVID-19 was initially considered to be solely a respiratory disease, yet clinical outcomes quickly revealed that, undeniably, this infection implies multi-organ involvement. Perhaps most notably, the heart has been shown to represents a target organ for SARS-CoV-2-related pathogenesis, with a high prevalence of cardiac injury following COVID-19, often diagnosed only through biomarker evaluation. Beyond subclinical myocardial damage, SARS-CoV-2 infection may also cause more aggressive, clinically apparent modifications, such as myocarditis, accompanied by a subsequent diastolic dysfunction or severe reduction of left ventricle ejection fraction, not to mention the fact that heart failure may represent a short−/long-term consequence of COVID-19-related inflammatory cardiomyopathy, with dramatic consequences regarding prognosis [9].
Regarding myocardial damage in COVID-19, although the full pathophysiology is still incompletely understood, multiple mechanisms are most likely incriminated (see Figure 2), which, globally, can be divided into two main groups: direct, specific modifications, related to the cytopathic effects of SARS-CoV-2 infection, and indirect, general modifications, commonly seen in other severe infections, as well [10].
Figure 2.
Pathophysiology of COVID-19-related myocardial injury [15, 16].
2.1.1 Direct cytopathic myocardial injury
The aforementioned ACE2, a type I transmembrane protein, highly expressed in different organs (heart, lungs, gut, and kidneys), mediates SARS-CoV-2 entry into the host cells, with different clinical implications, depending on the targeted organ, and represents the key molecular entity involved in the direct cytopathic effects of SARS-CoV-2 infection within the cardiac tissue. After entering the host cell through the host ACE2 receptor, SARS-CoV-2 utilizes the host’s RNA-dependent RNA polymerase to replicate its own structural proteins, which are then assembled, and the newly formed virions are released from the infected cells, perpetuating the viral life cycle. Theoretically, as a consequence of this process, infected cells may become damaged/destroyed [11].
This idea is supported by a recent autopsy study, analyzing cardiac tissue from 39 consecutive patients who died as a consequence of COVID-19, which found viral genome in the myocardial tissue, yet in situ hybridization showed that the most likely localization of SARS-CoV-2 not to be in the cardiomyocytes, but rather in interstitial cells or macrophages invading the myocardial tissue [12]. Even so, in engineered heart tissue models of COVID-19 myocardial pathology, SARS-CoV-2 demonstrated the ability to directly infect cardiomyocytes through ACE2, resulting in contractile deficits, cytokine production, sarcomere disassembly, and cell death [9].
Furthermore, ACE2 must not be viewed as a mere bystander in the pathophysiology of COVID-19 myocardial injury, seeing as, besides being the host cell receptor of SARS-CoV-2, ACE2 is an enzyme involved in the renin-angiotensin-aldosterone system (RAAS). Specifically, ACE2 cleaves angiotensin II, a very potent vasoconstrictor, into angiotensin 1–7, which manifests vasodilator and anti-inflammatory effects. ACE2 also demonstrates a weak affinity for angiotensin I (or proangiotensin, formed by the action of renin on angiotensinogen), competitively limiting angiotensin II synthesis by ACE. Angiotensin I is converted by ACE2 into the nonapeptide angiotensin 1–9, which will manifest vasodilator effects through subsequent angiotensin type 2 (AT2) receptor stimulation. Therefore, ACE2 can counteract the undesirable effects of angiotensin II, demonstrating vasodilator, antioxidant, and anti-fibrotic effects [13]. In the context of SARS-CoV-2 infection, after S protein binding is complete, the virus attaches ACE2 through membrane fusion and invagination, causing a downregulation of ACE2 enzymatic activity [13]. Additionally, ACE2 also demonstrates immunomodulatory properties, both directly, via its interactions with macrophages, and indirectly, as it reduces expression of angiotensin II, which stimulates inflammation [14]. Thus, ACE2 downregulation in the context of SARS-CoV-2 infection may increase angiotensin II levels, favoring AT1 receptor activity, with a subsequent vasoconstriction, fibrotic, proliferative, and pro-inflammatory effects [10].
2.1.2 Indirect mechanisms of myocardial injury
As is the case with all severe respiratory infections, COVID-19 has a general deleterious effect on the cardiovascular system, with fever and sympathetic activation causing tachycardia and implicitly increasing myocardial oxygen consumption [9, 10], while prolonged bed rest and systemic inflammation will favor coagulation disorders, as supported by clinical findings – both venous and atypical arterial thromboembolic events have been documented in COVID-19 patients (see subchapter 3.4. Thromboembolic events and bleeding risk). Hypoxemia, another hallmark of COVID-19, will determine enhanced oxidative stress and increased production of reactive oxygen species, with subsequent intracellular acidosis, mitochondrial damage, and cell death [7, 9].
Moreover, another series of indirect mechanisms for COVID-19-related myocardial damage appears as a result of the abnormal inflammatory response which may be elicited by SARS-CoV-2 infection (i.e. a pro-inflammatory surge, the so-called “cytokine storm,” which may occur as early as 1 week after the initial exposure and infection) [15].
Indeed, individual immune response is the cardinal element behind SARS-CoV-2 infection progression. Upon viral genome expulsion into the host cytosol, SARS-CoV-2 viral replication begins, with aberrant RNA sequences, byproducts of replication, being, in turn, detected by intracellular receptors, which activate the cellular antiviral response, involving enhanced leukocyte chemotaxis and transcriptional induction of type I and III interferons (IFN-I/-III), followed by under-regulation of IFN-stimulated genes [16]. Lung cell damage incurred during replication will also activate the local immune response, resulting in monocyte/macrophage recruitment [16], while chemokines will induce specific leukocyte subset recruitment and coordination [16]. Circulating immune cell relocation in the pulmonary tissue will determine additional cytokine/chemokine production, while also creating multiple imbalances in immune cell populations – increased leukocyte count and neutrophil-lymphocyte ratio, with decreased lymphocytes (especially T cells [17]), thus setting the scene for immune response dysregulation [3].
In fact, the relationship between SARS-CoV-2 infection and extensive activation of inflammation signaling pathways has been well documented, representing the main immunopathological mechanism through which severe forms occur, in susceptible individuals. During the acute phase of the infection, a disproportionate response occurs between T helper cell populations (types 1 and 2), characterized by high circulating levels of interleukin (IL)-1β, IL-1RA, IL-2, IL-6, IL-7, IL-8, IL-9 IL-10, interferon gamma-induced protein-10 (CXCL10), monocyte chemoattractant protein-1 (CCL2), macrophage inflammatory protein 1α (CCL3) and 1β (CCL4), granulocyte colony-stimulating factor, vascular endothelial growth factor (VEGF), and tumor necrosis factor (TNF) α [16, 18, 19], which mediate widespread lung inflammation, in an attempt to eradicate the pathogen [3]. The resulting hyper-inflammatory status, as well as the individual excessive levels of certain circulating cytokine species, have been independently associated with an unfavorable evolution and increased mortality [20]. This hyper-inflammatory state seems, at least intuitively, to be pivotal in the development of cardiac injury, seeing as positive correlations have been established between the increase in inflammatory markers and myocardial damage in COVID-19 [21, 22]. Indeed, this idea is additionally supported by previous studies, in other septic conditions, evidencing that the release of pro-inflammatory cytokines such as TNFα and IL-1β, were responsible for myocardial cells depression through modulation of calcium channel activity and nitric oxide production [23].
It may also be the case that the cytokine storm following SARS-CoV-2 infection determines the AHF, recurrently seen in severe COVID-19, as the inflammatory activation and oxidative stress background are similarly expressed generally in heart failure, predisposing to a more severe clinical course [24].
Lastly, the aforementioned marked inflammatory changes will also take place in the endothelium, as shown in postmortem histological studies, evidencing lymphocytic endotheliitis with apoptotic bodies and viral inclusion in multiple organs [7, 25]. Endotheliitis can lead to disseminated intravascular coagulation, with small or large vessels thrombosis and infarction, and will determine significant new vessel growth through a mechanism of intussusceptive angiogenesis [25].
2.2 Coagulation disturbances
After becoming infected, roughly 20% of COVID-19 patients will be incapable of controlling/halting viral replication through their initial immune response, which may be aberrant/insufficient or overwhelmed by a high initial viral load, or both [26]. This subgroup of patients will thus progress to a more severe disease phenotype, with aggravating symptomatology secondary to uncontrolled viral replication, leading to host pneumocyte and endothelial cell apoptosis, which in turn will activate platelets, induce procoagulant factor expression (fibrinogen, factors V, VII, VIII, X, and von Willebrand), and increase inflammatory response, as the body tries and fails to keep the infection localized to the lungs [27]. This sequence of host responses will additionally damage the pulmonary parenchyma (through further destruction of pneumocytes, microangiopathy, and inflammatory microthrombi), causing even more severe symptoms and hindering oxygenation, thus imposing the need for an additional oxygen supply. Even so, at this point, a relative balance between procoagulant and anticoagulant (but also pro-inflammatory/anti-inflammatory) factors is still maintained. In only approximately 5% of symptomatic patients, the pro-inflammatory processes involved in the immune response to SARS-CoV-2 infection will derail into the so-called “cytokine storm,” which will fuel pro-inflammatory and pro-coagulatory processes even further, resulting in systemic endotheliitis and capillary leakage, cellular dysfunction, organ dysfunction (including ARDS), and overt activation of the (systemic) coagulation cascade resulting in the need for critical organ support [28]. In fact, SARS-CoV-2 infection may trigger endothelial dysfunction not only through the direct cytopathic effect of invasion on vascular endothelial cells but also through indirect mechanisms, such as hypoxia and the induced inflammatory response [27]. Moreover, some patients have also manifested antiphospholipid antibodies [28].
Therefore, all factors of the classic Virchow triad are influenced during the course of COVID-19, and they contribute synergically to the risk of thromboembolic events: hemodynamic changes (increased blood viscosity due to elevated fibrinogen, but also venous stasis due to hospitalization and disease-related immobilization); hypercoagulability (due to an overwhelming inflammatory state, occurring early after infection); and endothelial injury/dysfunction (ACE2 receptor expression on endothelial cells allows viral entry and cytopathic effects – endotheliitis) [3].
3. Acute cardiovascular complications of COVID-19
3.1 Myocarditis/pericarditis
It is generally accepted that viral infections, and corona viruses even more, are a common cause of myocarditis, frequently associated with congestive heart failure (CHF), and an increased risk to sudden death due to ventricular arrhythmias [29]. Emerging data suggest an increased association between myocarditis and COVID-19, observed more frequently in hospitalized patients, associated with an increased risk of adverse outcome, including higher mortality rates [30].
According to Dallas criteria, acute myocarditis is defined as “inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical for the ischemic damage associated with coronary artery disease.” Proposed pathophysiological pathways are myocardial injury due to the direct action of the virus, mediated via ACE2 receptors, and an intense, prolonged inflammatory response resulting in the release of high amounts of cytokines [29, 31, 32] together with additional factors such as hypoxia, increased metabolic demands, and physiological stress. At biopsy, myocyte and interstitial cells necrosis and mononuclear cell infiltrates were detected.
The real prevalence of acute myocarditis in patients infected with the SARS-CoV-2 virus is difficult to establish. In the medical literature, in these patients, the estimated incidence of acute myocarditis ranges from 12–17% or even 22–31% in ICU patients [33]. The symptoms vary from mild, nonspecific ones: palpitations, breathlessness, chest pain, common in influenza, to the dramatic picture of AHF with dyspnea, arrhythmias, or even sudden cardiac death. On the electrocardiogram (ECG), there are nonspecific ST, PR, and T-wave abnormalities, but signs mimicking an ACS, tachyarrhythmias, and conduction disturbances associated or not with left ventricular echocardiographic alterations and elevated levels of high sensitive troponins are also frequently seen [31, 33]. Another aspect is that the main diagnostic criteria require endomyocardial biopsy and cardiac magnetic resonance imaging (MRI), which are sometimes difficult or even impossible to access in COVID-19 patients due to the increased risk of contamination [33, 34]. It has been discussed that the prevalence of myocarditis rose parallel with the evolving strains of the SARS-CoV-2 virus being higher in patients infected in 2021 than in 2020 [30].
The incidence of pericarditis in COVID-19 patients ranges from 3% to 4.8% [35, 36]. It is often associated with myocarditis in COVID-19 patients with pneumonia and elevated inflammatory markers, as demonstrated by Diaz et al. in a meta-analysis performed on 33 studies, mainly case reports. The principal mechanism seems to be an autoreactive, inflammatory response [36].
Pericarditis manifests itself with a variety of symptoms, such as chest pain, fever, and dyspnea [36]. Pericardial friction rub is seldom encountered (9.3%) [36]. The predominant characteristic of this type of pericarditis is pericardial thickening observed at transthoracic echocardiography (TTE) persisting several weeks during recovery [37]. Over 50% of patients have pericardial effusion, mostly small to moderate in size, with 34% having large pericardial effusion, and even pericardial tamponade developed in about half of this last subset of patients [36]. On the ECG, 60% of patients present the typical four-stage evolution: diffuse ST elevation with depression of the PR segment, normalization of ST elevation, diffuse T-wave inversion, and in the end, normalization of the ECG [66]. Some patients presented unspecific signs, such as diffuse ST elevation, PR depression, and focal T-wave inversion [36].
The treatment of acute pericarditis consists in high doses of nonsteroidal anti-inflammatory drugs (NSAIDs) such as Ibuprofen, Indomethacin, or Naproxen recommended until symptom relief is achieved, and in addition, colchicine is recommended to be used for 3 to 6 months. Aspirin may be an alternative to NSAIDs [36]. Although low to moderate doses of steroids could be recommended in patients with SARS-CoV-2 infection, in most cases, this therapy is started sooner because of the associated viral myocarditis [36]. Furthermore, steroids can also be added to NSAIDs and colchicine as triple therapy for patients with an incomplete response. In the case of cardiac tamponade, pericardial drainage represents the standard of care [36]. Usually, the evolution of pericarditis associated with COVID-19 is benign.
3.2 Acute coronary syndrome
An increased incidence of ACS has been reported in several viral infections such as influenza, SARS, and MERS, being associated with a 3- to 10-fold increased risk, but in COVID-19 exact data are lacking [31, 32]. As principal potential pathophysiological pathways are considered: destabilization of atherosclerotic plaques due to systemic inflammation with an increased release of pro-inflammatory cytokines, the “cytokine storm,” associated microangiopathy, activation of prothrombotic factors, as well as other specific changes of immune cell polarization toward more unstable phenotypes. Contributing factors also are myocardial oxygen supply/demand mismatch in the context of increased metabolic demands due to tachycardia/arrhythmias, fever, and hypoxia. These factors probably represent also the best explanation for the increased troponin levels observed in many patients with acute COVID-19 in the absence of typical cardiovascular manifestations (chest pain, specific ischemic electrocardiographic modification, and parietal hypokinesia at TTE) [31, 32], the more so as some other complications such as myopericarditis may have similar symptoms, and often patients with COVID-19 may not have typical angina symptoms.
Patients already suffering with coronary artery disease and heart failure may be exposed in a greater extent to ACS as a consequence of coronary plaque rupture or stent thrombosis in the context of systemic inflammation [31, 32]. For this reason, it is strongly recommended that in patients with a previous history of coronary artery disease and especially in those with coronary interventions, antiplatelet therapy should be continued, eventually even intensified, together with other plaque stabilizing agents such as statins, beta-blockers, and angiotensin-converting enzyme inhibitors [27, 30, 38, 39].
In this global health systems crisis, an adequate diagnosis and management of ACS is complicate and health care institutions worldwide have reexamined their protocols considering the increased risk of contamination of healthcare personal and the high requirements for protective equipment [34, 40, 41]. However, risk stratification is difficult due to limited bedside approach for an accurate ECG and TTE examination [31, 42]. The treatment of acute myocardial infarction (AMI) in COVID-19 patients is even more controversial. While in patients diagnosed with non-ST elevation myocardial infarction (non-STEMI), the result of a PCR testing could be expected prior to cardiac catheterization, in cases with ST elevation myocardial infarction (STEMI), the American College of Cardiology (ACC) recommends reconsidering fibrinolysis in patients with “low-risk STEMI” such as inferior without right ventricular extension, or lateral STEMI without altered hemodynamic. Thus percutaneous coronary intervention (PCI) remains the most indicated therapy, remaining the best option also in non-STEMI patients who are hemodynamically unstable [34, 42, 43].
In a large meta-analysis, DeLuca et al. concluded that COVID-19 pandemic has significantly impacted the therapy of patients with STEMI, with a 19% reduction in PCI procedures leading to increased morbidity and mortality, aspects evidenced also in other studies [34, 40, 43].
3.3 Increased risk of arrhythmias
Arrhythmias were observed precociously in COVID-19 patients worldwide, several centers reporting a large spectrum of electrocardiographic abnormalities [31, 32]. In most cases, sinus tachycardia due to multiple, concomitant causes (hypoperfusion, fever, hypoxia, and anxiety) was observed, but also atrial tachycardia and fibrillation (AF), and less frequently atrioventricular block (AVB) and polymorphic ventricular tachycardia (VT), significantly increasing the morbidity and mortality, and explaining at least in part, the increased number of cardiac arrests noticed in out-of-hospital patients [44, 45]. It was considered that underlying mechanisms are myocardial injury, inflammation, coexisting hypoxia, electrolytic (especially hypokalemia) and acid–base imbalances, and activation of the sympathetic nervous system, which is contributing the medication used to treat this disease such as hydroxychloroquine, azithromycin, and antivirals that prolong the QT interval [46, 47].
Perhaps the most comprehensive study written on this topic is the one of Coromilas et al. who analyzed data collected from over 4000 patients with COVID-19 and arrhythmias, from 4 continents and 12 countries, and concluded that the majority of them (81.8%) developed supraventricular arrhythmias including AF and atrial flutter, 21% of subjects had ventricular arrhythmias, and 22.6% developed bradyarrhythmias [47]. They also observed that arrhythmias were more frequent in patients over 60 years old, male gender prevailed, and frequently systemic hypertension and diabetes mellitus were associated comorbidities [33, 46, 47].
Treatment of arrhythmias should follow the standard guidelines for the management of arrhythmias focusing on the underlying pathophysiological mechanisms, and addressing as much as possible the reversible causes, especially electrolyte abnormalities. In the case of recurrent, uncontrolled ventricular arrhythmias not responding to antiarrhythmic therapy, implantable cardioverter defibrillators may be recommended, and for persistent high-degree AVB transvenous pacemaker insertion [48].
3.4 Thromboembolic events and bleeding risk
As the pandemic unravels, medical literature has provided robust insight into the unique mechanisms of and specific propensity for COVID-19 thrombogenicity, identified as considerably different from other severe infectious and non-infectious diseases. The relationship between SARS-CoV-2 infection and subsequent dysregulation of coagulation homeostasis is reflected in the various rates of occurrence of major venous and arterial thromboembolic/thrombotic events, which, in more extreme cases, have been documented to occur concomitantly. A recent comparative study, which retrospectively evaluated thromboembolic risk in large patient cohorts of COVID-19 and Influenza, found that COVID-19 was independently associated with a higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared to Influenza, with secondary analysis showing a similar risk for ischemic stroke and myocardial infarction, and a higher risk for deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with COVID-19 [49].
In spite of early thromboprophylaxis, most frequently, VTE negatively impacts clinical outcomes in COVID-19 hospitalized patients, and the risk seems to be greatest in the intensive care unit (ICU) setting, among the critically ill [50]. Major arterial thrombotic events and VTE have been reported at a higher frequency, in COVID-19 ICU patients, as compared to non-ICU patients, over a 30-day period, despite a thromboprophylaxis rate of 85–90% [51]. Moreover, a recent meta-analysis of 12 studies, in which all patients were under thromboprophylaxis, with either low molecular weight or unfractionated heparin, still showed a 31% pooled prevalence of VTE for ICU admissions [52]. Very recently, an overall incidence of 17.3% for VTE among hospitalized COVID-19 has been reported (~2/3 DVT), with significant discrepancies between pooled incidences of VTE for ICU admissions as compared to general ward patients (27.9% vs. 7.1%, respectively), while including catheter-associated thromboembolism, isolated distal DVT, and isolated pulmonary emboli reached the highest incidence rates. Even so, VTE incidence was higher when assessed within a screening strategy (33.1% vs. 9.8% by clinical diagnosis), meaning that, in clinical practice, it is very likely that many COVID-19 patients with subclinical VTE remain undiagnosed [53]. Moreover, VTE prevalence in COVID-19 patients varies widely depending on the subpopulation evaluated, seemingly correlating well with disease severity and preexisting metabolic and cardiovascular comorbidities, a statement reflected by the variability of occurrence rates reported: <3% in non-ICU patient [51], >30% for ICU cases, with DVT and subsequent PE representing the most common thrombotic complication in the ICU setting [54], while autopsy findings of COVID-19 fatalities suggest it may reach nearly 60% [55].
Interestingly, amounting data suggest that the majority of so-called PE diagnoses occur without a recognizable source of venous embolism and may be better defined as primary in situ pulmonary arterial thrombosis, a direct consequence of the SARS-CoV-2 pulmonary disease, entailing thrombotic occlusion of small−/mid-sized pulmonary arteries, which will result in the infarction of afferent lung parenchyma [56]. This may explain why PE is the most prevalent thrombotic event seen in COVID-19 patients [54] and why screening yielded a higher incidence of VTE than clinical evaluation of asymptomatic patients. In a recent investigation, duplex ultrasound was performed for clinical suspicion of DVT, reporting 41.58% confirmed DVT, 6.93% superficial thrombophlebitis and, surprisingly, 23.76% PE (mostly involving distal pulmonary vessels), yet only 7.92% had PE and concomitant, associated DVT, meaning that 2/3 of PE occurred in the absence of a recognizable DVT, suggesting a causal mechanism of primary thrombosis rather than embolism [56]. Additionally, postmortem analyses of COVID-19 fatalities have frequently documented thrombosis of small- and mid-sized pulmonary arteries, a lesion capable of causing hemorrhagic necrosis, fibrosis, disruption of pulmonary circulation, acute pulmonary hypertension (PH), and ultimately death [55]. Other severe morphopathological modifications of pulmonary tissue architecture have also been frequently reported in COVID-19 autopsy reports, such as severe endothelial injury, with disruption of cell membranes, rampant vascular thrombosis, and significant angiogenesis [25], while other organs also showed microthrombotic lesions on autopsy, but at a lower rate (cardiac thrombi, epicardial coronary artery thrombi and microthrombi in myocardial capillaries, arterioles, and small muscular arteries) [55].
An aforementioned study, analyzing 184 COVID-19 ICU cases, all receiving thromboprophylaxis, demonstrated a 31% cumulative incidence of the defined vascular complication composite outcome (PE, DVT, ischemic stroke, ACS, or systemic arterial embolism). The main independent predictors of thrombotic complications identified were age, with an adjusted hazard ratio (aHR) of 1.05/per year, and coagulopathy [54]. Conversely, regarding VTE, an extensive meta-analysis (44 studies/14,866 hospitalized COVID-19 patients), on the topic acute complications and mortality, reported a much lower prevalence of 15% for VTE, than previously reported. This value may be influenced not only by cohort size but also by other factors such as heterogeneous reporting between the studies evaluated and increased risk of bias, resulting in very low-quality evidence [57].
On the other hand, as seen in the above-mentioned studies, VTE can still occur in noncritically ill COVID-19 patients; therefore, rigorous elaboration of adequate screening and risk stratification protocols for VTE, especially for mild and moderate COVID-19 phenotypes, will be essential, as these patients are much less likely to undergo tromboprophylaxis.
Regarding arterial thromboembolism (ATE), incidence rates among COVID-19 diagnosed patients have consistently been reported as being much lower than for VTE, since the early days of the pandemic (3.7%) to date [54]. Unsettlingly, large-vessel strokes in young and generally healthy people, which became infected with SARS-CoV-2, have been consistently reported [25, 55]. Early retrospective studies, seemingly corroborated these findings, claiming that acute, new-onset, cerebrovascular disease was not uncommon in COVID-19 patients – out 219 consecutive COVID-19 patients, 10 (4.6%) developed acute ischemic stroke and 1 (0.5%) had intracerebral hemorrhage [58] –,and that SARS-CoV-2 infection carried an increased risk of ACS, especially via coronary stent thromboses [59]. Nevertheless, investigations involving a much larger sample size showed that the actual incidence of ATE (thrombotic/embolic) is, in fact, much lower than initially reported in earlier studies [51, 60]. A large cohort retrospective study, evaluating 1114 COVID-19 patients with independently adjudicated thrombotic/embolic events, found stroke and ACS incidence were 0.1% (1/1114) and 1.3% (14/1114), respectively [51]. Most authors agree that thrombotic events occur early in the evolution of COVID-19, and in order to combat the hypercoagulable and prothrombotic state, administration of anticoagulants is recommended to reduce this risk [27].
Of great importance is the fact that, due to several factors such as thrombocytopenia, hyperfibrinolytic state, consumption of coagulation factors, which initiate their action later on, after 1 to 3 weeks, COVID-19 patients may also become prone to bleeding. This must be taken into account, especially in severe COVID-19 cases, where concomitant administration of anticoagulants as thromboprophylaxis is very likely to occur [61]. Additionally, critically ill COVID-19 patients have an even more increased bleeding risk, due to thrombocytopenia/platelet dysfunction or coagulation factor deficiencies, or both [62], which are frequent occurrences in this clinical population. Thus, it has become increasingly difficult to establish an adequate, integrative, anticoagulant prophylaxis strategy for COVID-19.
As opposed to the numerous investigations debating over thromboembolic events, there are much fewer articles focusing on major bleedings and just a few case reports on hematomas in COVID-19. Al-Shamkary et al. reported an overall incidence of 4.8–8% referring to bleeding events, and of 3.5% for major bleedings [62], being mostly associated with advanced age, comorbidities and apparently, more frequent in males.
All in all, thromboembolic events are a frequent morbidity encountered in COVID-19 patients, especially in those with severe forms and comorbidities. For their prophylaxis/treatment anticoagulant therapy is recommended, thus increasing the risk of bleedings. Both thromboembolic events and hemorrhagic complications aggravate the evolution of these patients, representing significant negative prognostic factors and increasing the morbidity and mortality associated with COVID-19.
4. Subacute and long-term cardiovascular sequels following the infection with the SARS-CoV-2 virus
The important contribution of COVID-19 in the pathogenesis of acute cardiovascular involvements is now well established, but because this pandemic is a new disease, long-term data on post-COVID-19 complications were not available [63, 64]. However, more and more studies revealed that the infection with the SARS-CoV-2 virus also causes chronic cardiac complications, even when the viral load is normalized [63, 64], explaining the persistence of symptoms during recovery observed in an increasing number of individuals [65]. In some patients, myocarditis, subacute pericarditis, persisting arrhythmias, pulmonary hypertension, or heart failure have been observed raising serious concerns and indicating that in symptomatic patients, a comprehensive evaluation and a regular long-term follow-up are needed for effective therapeutic regime and to prevent a worse evolution of these cardiovascular complications.
4.1 Pulmonary hypertension
It is well known that pulmonary hypertension (PH) may occur during the acute phase of the SARS-CoV-2 infection as a consequence of extensive lung injury and of altered pulmonary circulation, frequently leading to right heart failure (RHF), shearing common pathophysiological mechanisms with other complications encountered in this illness, and significantly increasing the mortality [66, 67].
In COVID-19 patients, the prevalence of PH varies wildly, depending on the studied population, ranging from 7.69% to 12–13,4% or even 22% in severe COVID-19 cases [67, 68]. While this topic was largely debated in the medical literature, information over its outcome is less available. It has been observed that some patients are predisposed to develop interstitial lung disease (ILD) frequently associated with persisting PH and explaining, at least partially, the persisting symptoms observed in patients with subacute and long COVID-19 [69, 70]. The backgrounds of this disease are complex and multifactorial, including a large variety of pathophysiological types, ranging from arterial PH (group 1), PH of group 3 – due to ILD, to chronic thromboembolism (group 4 PH) or even of group 2 PH (secondary left heart disease) [70, 71]. In their study, Suzuki et al., observed a unique hystopathological finding identified only at the autopsy of COVID-19 patients, namely thickened pulmonary vascular walls, considered an important hallmark of arterial PH [71]. This finding suggests that COVID-19, depending on the severity of the lung injury and the inflammatory responses, could favor the development of PH, and some of these patients may develop in the future signs and symptoms of PH and RHF [71].
The diagnosis of PH is difficult and implies right heart catheterization, which is limited during the pandemic considering the risk of contamination and shortness of personal and resources. In patients infected with SARS-CoV-2, TTE allows an accurate estimation of the systolic pressure in the pulmonary artery, being the most utilized method for the diagnostic and follow-up of these patients. A specific therapy for this type of PH has not been described, and future studies are needed to clarify its management.
4.2 Heart failure
AHF may appear precocious in the evolution of the SARS-CoV-2 infection, in some cases being even the first manifestations. Since COVID-19 and AHF/worsening of CHF shear similar symptoms, distinguishing these two pathologies is challenging, the more so as these two conditions may coexist. Some studies describe an increased prevalence of ACH (23% or even 33%) in patients hospitalized for COVID-19 being associated with an increased risk of mortality [63]. In many cases, it is difficult to establish if AHF is the consequence of a new myocarditis/cardiomyopathy or it represents the exacerbation of previously undiagnosed CHF. Responsible pathophysiological mechanisms of AHF in COVID-19 may include acute myocardial injury due to inflammation (myocarditis), tachyarrhythmia or ischemia, or to acute respiratory failure, acute kidney injury, and hypervolemia [9, 29, 31]. Importantly, RHF may also be present especially in patients with severe pulmonary injury and PE contributing to the increased mortality of these patients [37].
Diagnosis may be difficult, but clinical presentation, history of preexisting cardiovascular comorbidities, evidence of cardiomegaly, and/or bilateral pleural effusion on chest radiography are suggestive. Increased levels of B-type natriuretic peptide (BNP)/N-terminal B-type natriuretic peptide (NT-proBNP) could be an important clue for AHF/worsened CHF, although elevated BNP/NT-proBNP values were also found in COVID-19 patients in the absence of AHF. An important contribution offers TTE demonstrating enlarged cardiac cavities, impaired systolic performance, and other important signs [34, 49, 72].
Therapy of AHF in COVID-19 patients should be performed according to guidelines [63] based on the same recommendation as in subjects without COVID-19, with special attention to early detection and treatment of complications, especially hypoxia, thrombotic/bleeding events, and cardiac arrhythmias. It is important to consider AHF/CHF when administering intravenous fluids avoiding excessive fluid replacement and to be conscious on the cardiac adverse effects of medications used in the treatment of COVID-19 [9, 31, 64].
Referring to patients already diagnosed with CHF, it is well known that they are predisposed to develop more severe forms of COVID-19, being predisposed to a higher mortality. The SARS-CoV-2 infection may also unmask a latent CHF, particularly heart failure with preserved ejection fraction (HFpEF) which is common among elderly overweight, hypertensive patients. In addition, as a consequence of myocardial injury, cardiac fibrosis may occur, explaining the increased frequency of diastolic dysfunction identified on TTE. The risk to develop overt CHF is present both during the acute phase of COVID-19 and during the recovery from the acute illness in survivors [31, 33, 72, 73].
Another aspect is that the COVID-19 pandemic negatively impacted the outcome of patients with CHF who avoided or delayed hospital controls or admissions due to fear of contamination. They presented themselves to the hospital only when their condition was severe, which lead to an increased mortality worldwide [9, 74].
4.3 New onset or aggravation of systemic hypertension
The relationship between the infection with the SARS-CoV-2 virus and systemic hypertension is very complicated and difficult to establish. While it is generally accepted that COVID-19 patients with a history of cardiovascular diseases, especially systemic hypertension, have a worse outcome and increased mortality [29, 75], it is very difficult to establish if there is a new onset or a worsening of a chronic hypertension in the context of this illness, since a previous comprehensive evaluation is not available in the majority of cases. A meta-analysis of Lippi et al. evidenced a nearly 2.5-fold increase of severity and mortality of severe COVID-19 in patients with associated systemic hypertension, especially in those older than 60 years with other comorbidities [75].
Other large meta-analyses focused on the impact of hypertension’s severity and its control and the outcomes but failed to document significant connections [76]. It was concluded that hypertension is associated with endothelial dysfunction strongly impacted in COVID-19, and patients with more severe forms have more advanced atherosclerosis and consecutive complications, thus increasing the morbidity and mortality. As the concerns regarding therapy with ACE inhibitors were not found to be justified, treatment should be given according to guidelines to optimize blood pressure values [77].
4.4 Postural orthostatic tachycardiac syndrome
The postural tachycardia syndrome (POTS) is the result of an autonomic dysregulation which determines increased vasoconstriction when standing, resulting in blood pooling within the splanchnic vasculature and limbs, with reduced venous return to the heart. An excessive compensatory tachycardia and increased plasma noradrenaline levels contribute to symptoms, the commonest of which are fatigue, palpitations, light-headedness, headache, and nausea symptoms reported by many of patients with long-COVID (between 15% and 50% according to some studies) [78]. Although orthostatic intolerance is common among patients recovering from a COVID-19 infection, not all have POTS, some of them have only orthostatic hypotension [78].
The exact pathophysiological mechanism of POTS is not fully clarified, and there are several mechanisms involved, including hypovolemia, autonomic denervation, hyperadrenergic stimulation, and autoimmune pathology. It is not well established whether the same recognized pathophysiology of POTS is also present in patients with long COVID further studies being necessary [78].
4.5 Aggravation of preexisting cardiovascular pathologies
From the early stages of the infection with the SARS-CoV-2 virus, it became evident that underlying cardiovascular diseases, obesity, diabetes mellitus, and more advanced age are associated with a higher risk for severe COVID-19 infection [34]. Individuals already suffering from cardiovascular diseases were more likely to be infected with the virus, and the virus infection was likely to determine the deterioration of basic heart disease [79]. Apparently, among COVID-19 patients, there were almost 50% diagnosed with chronic diseases, 40% of them with cardiovascular and cerebrovascular disorders, chronic kidney failure, and chronic obstructive pulmonary disease, having an increased risk of morbidity or even death related to this infection. A large study from the USA reported that the most common comorbidities among patients with COVID-19 were systemic hypertension (56.6%), obesity (41.7%), diabetes (33.8%), coronary artery disease (11.1%), and CHF (6.9%) [33], and a retrospective cohort study in China conducted on patients with cardiovascular comorbidities evidenced a fivefold higher mortality risk (10.5%). Based on these results, hypertension and cardiovascular comorbidities can be considered as risk factors for persons with severe symptoms of the disease.
In COVID-19 cases, it is important to recognize the clinical characteristics of infected persons to identify and effectively treat the associated comorbidities and the newly developed cardiovascular complications as well to reduce patients’ morbidity and mortality. Since many antiviral drugs may determine cardiac insufficiency, arrhythmia or other cardiovascular disorders, therefore, during the therapy of this illness, especially with antiviral therapy, the risk of cardiac toxicity needs to be closely monitored [79].
Another aspect is that of the long-term outcome of patients who suffered from a SARS-CoV-2 infection. In a recent and comprehensive study realized on over 150000 individuals recovering from COVID-19 [80], Xie et al. highlighted that beyond the first month after infection, people with COVID-19 experienced at 12 months an increased morbidity risks and burdens of cardiovascular diseases, including cerebrovascular disorders, dysrhythmias, inflammatory heart disease, ischemic heart disease, heart failure, thromboembolic disease, and other cardiac disorders [80]. These risks were obvious regardless of age, race, gender, and associated cardiovascular risk factors, including obesity, hypertension, diabetes, chronic kidney disease, and hyperlipidemia, being evident even in individuals without history of cardiovascular pathology before the SARS-CoV-2 virus infection, raising concerns that these risks might be present even in people at low risk of cardiovascular disease [80]. These risks and associated burdens increased parallel to the severity of the acute phase of COVID-19: from non-hospitalized individuals – who were the majority – to hospitalized patients, especially to those admitted to the intensive care units [80].
4.6 Cardiovascular effects of medication used to treat COVID-19
It has been observed that many of the medications used for the treatment of COVID-19 strongly interfere with other medications used in the therapy of cardiovascular diseases, such as anticoagulants, antiplatelets, statins, antihypertensives, and especially antiarrhythmics favoring the occurrence of arrhythmias [31]. Some antibiotics (azithromycin), corticosteroids, antimalarials (chloroquine, hydroxychloroquine), newly developed therapies, still under study such as antivirals (remdesivir, ribavirin, lopinavir/ritonavir, and favipiravir), and biologics (tocilizumab) determine cardiotoxicity, interact with electrolyte metabolism, and many of them, especially Lopinavir/ritonavir, may cause QT and PR prolongation favoring the occurrence of arrhythmias or conduction disturbances, mainly in patients already treated with drugs prolonging the QT interval. Data over the mechanism of action and potential effects of main medication used in the treatment of COVID-19 is presented in Table 1 [31].
Medication
Mechanism of action
Cardiovascular effects and drug interactions
Azithromycin
Interacts with the synthesis of proteins and binds to 50s ribosome
Interferes with statins, anticoagulants, and antiarrhythmics, prolonging QT interval and favoring arrhythmias (torsades de pointes).
Chloroquine and Hydroxychloroquine
Alterations in the pH of endosomal/organelle
May induce direct myocardial toxicity worsening myocarditis and cardiomyopathy.
Alter intracardiac conduction resulting in bundle branch block, AV block.
Interact with antiarrhythmics favoring ventricular arrhythmias, torsades de pointes.
Methylprednisolone
Anti-inflammatory
Determines fluid retention, hypertension, and dyselectrolytemia.
Interacts with anticoagulants.
Remdesivir
Inhibitor of RNA polymerases
May cause hypotension and arrhythmias.
Ribavirin
Inhibits RNA and DNA virus replication
Interacts with anticoagulants.
May cause severe hemolytic anemia.
Lopinavir/Ritonavir
Lopinavir inhibits protease and Ritonavir inhibits CYP3A metabolism
Interacts with anticoagulants, antiplatelets, statins, and antiarrhythmics.
May determine prolonged QT interval, AV blocks, and torsades de pointes.
Favipiravir
Inhibits RNA-dependent RNA polymerases
Interacts with anticoagulants, statins, and antiarrhythmics.
May interfere with some medication metabolism such as statins.
May determine hypertension.
Table 1.
Interactions of medications used in the treatment of COVID-19.
4.7 Cardiovascular effects related to vaccination
After the introduction of mRNA COVID-19 vaccines a higher incidence of myocarditis in vaccine recipients. A study performed on the data basis from an Israeli national database concluded that the incidence of myocarditis after two doses of the BNT162b2 mRNA vaccine was reduced (risk ratio = 3.24), significantly lower than after COVID-19 (risk ratio = 18.28), but higher than in unvaccinated individuals. The risk of myocarditis was higher after the second dose of vaccine and in young male recipients [81].
Similar results were also reported by other researcher, with an elevated risk of myocarditis, pericarditis, and myopericarditis observed particularly among young males with 39–47 expected cases of per million second mRNA COVID-19 vaccine doses administered [82]. They reported an increased risk of myocarditis after the first dose of ChAdOx1 and BNT162b2 vaccines and the first and second doses of the mRNA-1273 vaccine [82].
5. Conclusions
The impairment of the cardiovascular system in COVID-19 comprises a wide spectrum of dysfunctions, ranging from mild to severe, or even life-threatening forms, often having an acute onset, sometimes continuing during recovery or even resulting in chronic pathologies. Individuals are affected regardless of age, race, gender, and associated cardiovascular risk factors, but those with a history of cardiovascular pathology prior to the SARS-CoV-2 virus infection have a worse outcome. Therefore, a comprehensive cardiologic evaluation, including TTE, is justified to assess the involvement of the cardiovascular system, for initiating a proper therapy as soon as possible and to schedule a follow-up program particularly in patients at high risk.
\n',keywords:"COVID-19, inflammation, cytokine storm, myocardial injury, heart failure, thromboembolic events, arrhythmias",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81733.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81733.xml",downloadPdfUrl:"/chapter/pdf-download/81733",previewPdfUrl:"/chapter/pdf-preview/81733",totalDownloads:13,totalViews:0,totalCrossrefCites:0,dateSubmitted:"February 12th 2022",dateReviewed:"February 27th 2022",datePrePublished:"May 13th 2022",datePublished:null,dateFinished:"May 13th 2022",readingETA:"0",abstract:"Although the infection with the severe acute respiratory syndrome (SARS-CoV-2) virus affects primarily the respiratory system, it became evident from the very beginning that the coronavirus disease 2019 (COVID-19) is frequently associated with a large spectrum of cardiovascular involvements such as myocarditis/pericarditis, acute coronary syndrome, arrhythmias, or thromboembolic events, explained by a multitude of pathophysiological mechanisms. Individuals already suffering of significant cardiovascular diseases were more likely to be infected with the virus, had a worse evolution during COVID-19, with further deterioration of their basal condition and increased morbidity and mortality, but significant cardiac dysfunctions were diagnosed even in individuals without a history of heart diseases or being at low risk to develop such a pathology. Cardiovascular complications may occur anytime during the course of COVID-19, persisting even during recovery and, potentially, explaining many of the persisting symptoms included now in terms as subacute or long-COVID-19. It is now well accepted that in COVID-19, the occurrence of cardiovascular impairment represents a significant negative prognostic factor, immensely rising the burden of cardiovascular pathologies.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81733",risUrl:"/chapter/ris/81733",signatures:"Cristina Tudoran, Mariana Tudoran, Voichita Elena Lazureanu, Adelina Raluca Marinescu, Dorin Novacescu and Talida Georgiana Cut",book:{id:"11369",type:"book",title:"RNA Viruses Infection",subtitle:null,fullTitle:"RNA Viruses Infection",slug:null,publishedDate:null,bookSignature:"Ph.D. Yogendra Shah",coverURL:"https://cdn.intechopen.com/books/images_new/11369.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-667-3",printIsbn:"978-1-80355-666-6",pdfIsbn:"978-1-80355-668-0",isAvailableForWebshopOrdering:!0,editors:[{id:"278914",title:"Ph.D.",name:"Yogendra",middleName:null,surname:"Shah",slug:"yogendra-shah",fullName:"Yogendra Shah"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Effects of the SARS-CoV-2 virus on the cardiovascular system",level:"1"},{id:"sec_2_2",title:"2.1 Cardiac tissue damage",level:"2"},{id:"sec_2_3",title:"2.1.1 Direct cytopathic myocardial injury",level:"3"},{id:"sec_3_3",title:"2.1.2 Indirect mechanisms of myocardial injury",level:"3"},{id:"sec_5_2",title:"2.2 Coagulation disturbances",level:"2"},{id:"sec_7",title:"3. Acute cardiovascular complications of COVID-19",level:"1"},{id:"sec_7_2",title:"3.1 Myocarditis/pericarditis",level:"2"},{id:"sec_8_2",title:"3.2 Acute coronary syndrome",level:"2"},{id:"sec_9_2",title:"3.3 Increased risk of arrhythmias",level:"2"},{id:"sec_10_2",title:"3.4 Thromboembolic events and bleeding risk",level:"2"},{id:"sec_12",title:"4. Subacute and long-term cardiovascular sequels following the infection with the SARS-CoV-2 virus",level:"1"},{id:"sec_12_2",title:"4.1 Pulmonary hypertension",level:"2"},{id:"sec_13_2",title:"4.2 Heart failure",level:"2"},{id:"sec_14_2",title:"4.3 New onset or aggravation of systemic hypertension",level:"2"},{id:"sec_15_2",title:"4.4 Postural orthostatic tachycardiac syndrome",level:"2"},{id:"sec_16_2",title:"4.5 Aggravation of preexisting cardiovascular pathologies",level:"2"},{id:"sec_17_2",title:"4.6 Cardiovascular effects of medication used to treat COVID-19",level:"2"},{id:"sec_18_2",title:"4.7 Cardiovascular effects related to vaccination",level:"2"},{id:"sec_20",title:"5. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'WHO Director-General’s Opening Remarks at the Media Briefing on COVID-19-11 March 2020. [cited April 27, 2021]. 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Obesity Medicine. 2021;22:100323'},{id:"B80",body:'Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nature Medicine. 2022'},{id:"B81",body:'Mevorach D, Anis E, Cedar N, Bromberg M, Haas EJ, Nadir E, et al. Myocarditis after BNT162b2 mRNA vaccine against Covid-19 in Israel. The New England Journal of Medicine. 2021;385(23):2140-2149'},{id:"B82",body:'Patone M, Mei XW, Handunnetthi L, Dixon S, Zaccardi F, Shankar-Hari M, et al. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nature Medicine. 2021'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Cristina Tudoran",address:"tudoran.mariana@umft.ro",affiliation:'
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UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)
Wellcome Trust (Funding available only to Wellcome-funded researchers/grantees)
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Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"243698",title:"Dr.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. 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Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. 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