Comparison of equivalent doses of various steroids.
\r\n\t
",isbn:"978-1-80356-678-8",printIsbn:"978-1-80356-677-1",pdfIsbn:"978-1-80356-679-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"6dcb071a2e978694b6b1cb9c20afc1a3",bookSignature:"Prof. Hai-Zhi Song",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11494.jpg",keywords:"Electric Field Effect, Nano-Materials, Electric Field Design, Antenna, Microelectronics, Optoelectronics, Electric Field Stimulation, Brain and Nerve, Electric Field Imaging, Atomic Electric Field, Space Science, Climate",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 22nd 2022",dateEndSecondStepPublish:"May 26th 2022",dateEndThirdStepPublish:"July 25th 2022",dateEndFourthStepPublish:"October 13th 2022",dateEndFifthStepPublish:"December 12th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in the fields of new materials, optoelectronic devices, and quantum information processing, appointed vice director of the Science and Technology Committee of SWITP, author/co-author of more than 170 research papers, and holder of 40 patents.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"196114",title:"Prof.",name:"Hai-Zhi",middleName:null,surname:"Song",slug:"hai-zhi-song",fullName:"Hai-Zhi Song",profilePictureURL:"https://mts.intechopen.com/storage/users/196114/images/system/196114.jpg",biography:"Curriculum Vitae\n\nName: Hai-Zhi Song \nGender: male\nDate of Birth: Oct. 20, 1968\nPlace of Birth: Shanxi, China\nAffiliation and Address: \nSouthwest Institute of Technical Physics\nNo.7, Section 4, Renminnan Road, Chengdu 610041, China\nAnd\nInstitute of Fundamental and Frontier Sciences,\nUniversity of Electronic Science and Technology of China,\nNo. 4, Section 2, Jianshebei Road, Chengdu 610054, China\n\nWork Phone: +86-28-68180751, +86-28-83208728\nMobile Phone: +86-158-28239155\nFax: +86-28-83201896\nE-mail: hzsong1296@163.com, hzsong@uestc.edu.cn\n \nEducation \nSept, 1990 – July, 1995:Peking University, PhD, Thesis “Visible luminescence of porous silicon and its mechanism”, Researches on hydrogen-influenced Schottky diodes and silicon-based light-emitting materials. \nSept, 1986 – July, 1990:Nanjing University, Bachelor of Science, Thesis “Study of refractory metal silicides”, Research on Ohmic contact of semiconductors.\n\nWork Experience \nJuly, 1995 – Sept. 1997: Nanjing University, Nanjing, China, Postdoctoral Researcher, Research on silicon-based light-emitting materials. \nOct, 1997 – Sept. 1998: Catholic University Leuven, Leuven, Belgium, Visiting free Researcher, Research on amorphous semiconductors. \nOct, 1998 – Sept. 2001: Tsukuba University, Tsukuba, Japan, Assistant Professor, Research on semiconductor quantum dots. \nOct, 2001 – March 2012: Fujitsu Lab. Ltd., Atsugi, Japan, Researcher/Senior Researcher, Researches on Semiconductor Quantum Dots for Quantum Information, Semiconductor Optoelectronic Materials and Devices. \nApril, 2012 – March 2014: University of Tokyo, Tokyo, Japan, Senior Researcher, Researches on Quantum Information Processing Devices. \nApril, 2014 – now: Southwest Institute of Technical Physics, Chengdu, China, Professor, Researches on Semiconductor Optoelectronic Materials and Devices. \nJune, 2015 – now: University of Electronic Science and Technology, Chengdu, China, Professor, Researches on Nanoscaled Semiconductors and Quantum Information Processing Devices.\n \nAchievements\nSystematically studied the property of porous silicon materials and verified their mechanism; found green and ultraviolet luminescence, and clarified the multiple luminescence mechanisms of nanocrystalline-silicon embedded in SiO2, which is valuable to silicon-based optoelectronic integration; realized enhanced hole mobility in amorphous silicon, verified the existence of deep trap states in amorphous selenium, providing ways to improve amorphous optoelectronic materials. \nDiscovered lateral coupling between self-assembled quantum dots (QDs) and their tuning effect to 2D electron gas; illustrated and deeply explained the metal-insulator transition in 2D ordered QD arrays, all of which are worth in optoelectronic application of semiconductor QDs. \nDeveloped Sb-free technique to double the InAs/GaAs QD density and suppress the atomic interdiffusion, helped producing 1.3 um QD lasers, which won Japanese national prizes and had been merchandized; developed 1.06 um quantum-well lasers, which have been used to produce pure-green lasers robust against high temperature. \nFound a way to access buried QDs by scanning tunneling microscope; achieved a way to prepare diluted QDs by post-annealing and clarified its mechanisms; invented a technique to control the size and site of QDs by atomic-force microscopy lithography, and an apparatus to detect single electron spin states by optically-detected magnetic resonance; designed a few types of micropillar cavities applicable to realize 1.55 um highly-efficient, even coherent (strongly coupled) InAs/InP QD single photon sources; produced fiber-integrated photon-entangled sources, all of which are very useful to the applications of QDs in quantum information processing. \nDeveloped focal-plane single-photon avalanche detectors, providing central devices for 3D laser detecting and ranging system; explored antimonide middle- and long-wavelength infrared detectors and the surface plasmon enhancement effect in such detectors; advanced the acetone-sensing function of Eu-doped SnO2 nano-belt; found Nickle Phosphide serving as a good catalyst in hydrogen-producing. Realized a series of optoelectronic quantum devices for quantum information processing, such as fiber-integrated photon-pair-entangler, chiplet heralded single photon emitter, fiber quantum memories, quantum number generator, etc.\n\nHonor and Group Memberships \nSelected Scholar of the Recruitment Program of Global Experts, China\nEditorial member of “Laser Technology”\nEditorial member of “Journal of Electronic Science and Technology”\nEditorial member of “Internal J. Mat. Sci. Appl”\nMember of APS (American Physics Society)\nMember of OSA (Optical Society of America)\nPermanent Member of China Physical Science and Technology\nPermanent Member of the Chinese Optical Society\nTechnical committee member of PIERS, organizing a series of “quantum information processing and devices” sessions\nTechnical committee member of ICICM",institutionString:"Southwest University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Southwest University",institutionURL:null,country:{name:"China"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"20",title:"Physics",slug:"physics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453623",firstName:"Silvia",lastName:"Sabo",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/453623/images/20396_n.jpg",email:"silvia@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"8356",title:"Metastable, Spintronics Materials and Mechanics of Deformable Bodies",subtitle:"Recent Progress",isOpenForSubmission:!1,hash:"1550f1986ce9bcc0db87d407a8b47078",slug:"solid-state-physics-metastable-spintronics-materials-and-mechanics-of-deformable-bodies-recent-progress",bookSignature:"Subbarayan Sivasankaran, Pramoda Kumar Nayak and Ezgi Günay",coverURL:"https://cdn.intechopen.com/books/images_new/8356.jpg",editedByType:"Edited by",editors:[{id:"190989",title:"Dr.",name:"Subbarayan",surname:"Sivasankaran",slug:"subbarayan-sivasankaran",fullName:"Subbarayan Sivasankaran"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"57931",title:"Corticosteroids and Their Use in Respiratory Disorders",doi:"10.5772/intechopen.72147",slug:"corticosteroids-and-their-use-in-respiratory-disorders",body:'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].
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.
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].
Arachidonic acid metabolism with cyclooxygenase and lipoxygenase pathways.
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].
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].
Steroids | Dexamethasone | Methylprednisolone | Prednisone | Hydrocortisone | Fludrocortisone |
---|---|---|---|---|---|
0.75 mg | 4 mg | 5 mg | 20 mg | - | |
- | - | 50 mg | 20 mg | 100 mcg | |
36–72 hours (long) | 12–36 hours (intermediate) | 12–36 hours (intermediate) | 8–12 hours (short) | 12–36 hours (intermediate) |
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.
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.
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
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].
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.
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
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
ABPA is a pulmonary disorder characterized by a hypersensitivity reaction to the allergens of the fungus
Management of ABPA entails the achievement of two separate goals: (a) attenuating the hypersensitivity response to
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.
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].
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].
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.
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.
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
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].
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
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
CF is an autosomal recessive disorder that results from genetic mutations in the cystic fibrosis transmembrane conductance regular (
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].
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
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
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].
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.
The authors have no conflict of interests to disclose. The authors have no conflict of interests to disclose.
A–a | alveolar–arterial |
ABPA | allergic bronchopulmonary aspergillosis |
ACE | angiotensin converting enzyme |
ACTH | adrenocorticotrophic hormone |
AIP | acute interstitial pneumonitis |
ALT | alanine aminotransferase |
ANCA | antineutrophil cytoplasmic antibody |
APC | antigen presenting cell |
ARDS | acute respiratory distress syndrome |
ATP | adenosine 1,4,5-triphosphate |
ATS | American Thoracic Society |
BAL | bronchoalveolar lavage |
BOOP | bronchiolitis obliterans organizing pneumonitis |
cAMP | cyclic adenosine monophosphate |
CAP | community acquired pneumonia |
CAT | COPD assessment test |
CF | cystic fibrosis |
CFTR | cystic fibrosis transmembrane conductance regulator |
COP | cryptogenic organizing pneumonitis |
COPD | chronic obstructive pulmonary disease |
DAD | diffuse alveolar damage |
DAH | diffuse alveolar hemorrhage |
DIP | desquamative interstitial pneumonitis |
DM | dermatomyositis |
EGPA | eosinophilic granulomatosis with polyangiitis |
ERS | European Respiratory Society |
FEV1 | 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 |
Moyamoya disease [MMD] is a form of chronic cerebrovascular occlusion characterized by occlusion of terminal internal carotid artery [ICA] along with a network of collateral vessels at the base of the brain. The disease was first brought to light by Takeuchi and Shimizu, where they described a young man with bilateral occlusion of ICA which was found to be due to congenital hypoplasia rather than atherosclerotic lesion [1]. Similar cases have been described in Japanese literature. After that, the condition came to be known by various names and the term ‘spontaneous occlusion of the circle of Willis’ by Kudo gained popularity [2]. The disease was finally coined ‘
This cerebral angiopathy is broadly termed ‘moyamoya phenomenon’ comprising of two nosological entities. The cerebrovascular syndrome is called ‘Moyamoya syndrome’ [MMS] when it is associated with neurological and extra neurological diseases like Neurofibromatosis 1 [NF1], Down syndrome, thyroid disease, cranial irradiation, sickle cell anemia, among other pathological conditions [4]. The Guidelines of the Research Committee on the Pathology and Treatment of Spontaneous Occlusion of Circle of Willis defined isolated moyamoya angiopathy as being idiopathic and called it ‘Moyamoya disease’ [5].
MMD is more common in Asian ethnicities as compared to the Western population [6]. The increased prevalence in Japan, Korea and other East Asian countries raised genetic predisposition to this condition. Subsequently, Kamada
A literature search was conducted using PubMed. The keywords used were Moyamoya disease, Moyamoya syndrome, ‘puff of smoke’, Suzuki classification, angiography, revascularization procedures etc. Relevant articles were reviewed in detail. The search was filtered to include as many recent publications as possible. An effort was made to compile and highlight the key differences in the disease’s clinical profile from East to West.
For a very long time, Moyamoya disease was thought to be a disease of Asian lineage, but now it has been observed to be prevalent across the world in people with many ethnic backgrounds. MMD has been most extensively studied in Japan, where it is the most common pediatric cerebrovascular disease [8]. It shows a prominent East–West gradient, with a in East Asian countries ten times higher than the Western countries [9]. MMD is most frequently seen in Japan, with an incidence of 0.35–1.13/1,00,000/year and a prevalence of 3.16–10.5/1,00,000 [10]. In a study done in Hokkaido, Japan, 267 new cases were diagnosed between 2002–2006 [8]. The incidence and prevalence were also found to be high in other Asian countries like Korea, China and Taiwan [11]. The incidence in all these countries is found to be increasing over the years, most likely due to advancements in diagnostic modalities and a better understanding of the genetic factors linked to the disease [12]. Studies from outside Asia are very few. The incidence in Washington state and California was 0.086/1,00,000, but in them the incidence in Asian Americans was 4.6 times that of White [9]. In Europe, the incidence of MMD was 1/10th of that in Japan. North America’s incidence was as low as 0.09/1,00,000 individuals, although an increasing trend is now being noted [13].
A similar bimodal age distribution is seen across the world, with the first peak occurring at 5–14 years in the pediatric population and around 4th decade in adulthood [5]. In Japan, family history is present in 10–15% of cases, and the risk of the disease in a family member is about 30–40 times higher than the general population. A familial predisposition was less commonly seen in European countries. In most countries, the disease was more frequently seen in females, with male to female ratio ranging from 1:1.8 to 1:2.2 [10, 14]. These epidemiological parameters remained constant from East to West as evident in the literature review from across the world by Kim et al. [6].
The pathological features have been described based on autopsy findings of cases of MMD. The most common lesion is intracranial hemorrhage, which occurs in basal ganglia, thalamus, hypothalamus and brain stem. The intracranial hemorrhage may show intraventricular extension. Other findings are subarachnoid hemorrhage and small infarcts in the capsule- ganglionic area [14]. The main pathological findings according to the vessels involved are mentioned below.
Thus, the pathology of the disease can be viewed as ICA [Internal carotid artery] to ECA [External carotid artery] prism, where the contribution of ICA to cerebral blood supply gradually decreases, and the compensatory vascular network is formed which is predominantly fed by ECA.
The mechanisms leading to the above-mentioned pathology are not entirely known. It is not clear what leads to migration and proliferation of smooth muscle cells in the intima and leads to its thickening. Moreover, why this thickening happens only in the circle of Willis is unknown. Many features of the disease point towards a hereditary predisposition- high incidence in Japanese people, familial occurrence, association with other congenital disorders like sickle cell anemia, neurofibromatosis, Down syndrome, etc. A multifactorial mode of inheritance has been suggested. A possible linkage of the disease with markers located on chromosome 6, chromosome 17, chromosome 8q23 has been suggested [18, 19, 20]. Recently, a genetic locus in the Ring Finger Protein [RNF] 213 gene was also associated with MMD [7]. A higher carrier rate in Eastern Asia probably explains the higher prevalence of the disorder in Japan and other eastern Asian countries as compared to the Western world [21].
Moyamoya angiopathy has been identified with many genetic disorders like Neurofibromatosis 1, Noonan syndrome, Costello syndrome, Sickle cell disease, GUCY1A3 mutations, BRCC3/MTCP1 gene mutation, Down syndrome, Turner syndrome, etc. [19] Moyamoya disease associated with other familial or acquired conditions has also been termed as ‘quasi-MMD’. It was noted that unilateral presentation was more common than bilateral and hemorrhagic manifestations were less common in quasi- MMD [21].
Although genetic predisposition to the disease exists, the majority of cases are sporadic. Certain acquired factors have been suggested for disease progression. These include vasculitis [3], infections [20], cranial trauma [22], post-irradiation state [23] to name a few.
The pathological changes in cerebral arteries lead to cerebrovascular events in Moyamoya disease. Two peaks have been identified, at around ten years and 30–40 years. The peak occurs later in women than in men [24].
The symptoms can be classified in the following four main heads (Figure 1) [13].
Clinical symptoms of Moyamoya disease.
Transient ischemic attacks [TIA] and infarct may present as a variety of symptoms- motor paresis, sensory disturbance, speech disturbances, alteration of consciousness [25]. Whereas these symptoms present acutely, mental decline, dyskinesias tend to progress over the years. Dilated collateral vessels in basal ganglia have been implicated in the development of choreiform movements [26]. Bilateral disease is associated with cognitive deficits. Hemorrhagic type is more common in adults >40 years of age and most commonly present with impaired consciousness. Irrespective of the primary pathology [ischemic/hemorrhagic], the symptoms tend to be recurrent and usually a single pathology predominates in each individual. Headache is another common symptom generally seen in children <14 years old [27]. Dilated transdural collaterals stimulate dural nociceptors precipitating migraine-like headaches. Headache may also be a manifestation of chronic hypoxemia.
The symptoms are triggered by hyperventilation, such as blowing/crying due to decreased cerebral blood flow secondary to CO2 washout. Worsening is also seen with infection of the upper respiratory tract. Hypertension and aging often contribute to hemorrhage, which may occur at repetitive intervals. Massive bleeding may even lead to death. Epilepsy, as a manifestation of the disease, is usually seen in children less than ten years of age [28].
The clinical features also tend to vary from East to West. The ischemic manifestations are more predominant in the US [United States] than in other eastern countries. The rate of hemorrhagic disease in adults in Asian countries is higher [42%] than in those of Asian descent residing in the US [29]. The disorder’s overall spectrum remains constant worldwide, with ischemic manifestations as the main presenting feature in children and both ischemia and hemorrhage in adults.
Angiography is the gold standard for diagnosis and assessing disease progression. The hallmark findings of cerebral angiography are occlusion of intracranial internal carotid arteries (Figure 2) and abnormal smog-like arteriolar network [moyamoya vessels] at the base of the brain (Figure 3). The Circle of Willis and its main branches, leptomeningeal vessels and transdural anastomosis between ophthalmic artery, external carotid artery and vertebral artery are frequently seen. Involvement of posterior circulation is less commonly observed.
Neuroimaging of a 40 years old lady who presented with ICH. Non-contrast CT axial sections of brain (a, b, c) show intraventricular hemorrhage involving bilateral lateral ventricles (L > R), third and fourth ventricle. Angiographic images (d, e) show occlusion of the supraclinoid segment of the left internal carotid artery and attenuation on the right side with lenticulostriate collaterals showing a “puff of smoke” appearance (f).
Neuroimaging of a young boy of 6 years of age who presented with recurrent ischemic strokes. MRI brain axial sections show altered signal intensity areas hypointense on T1 (a) and hyperintense on T2 (b, c)) in bilateral frontoparietal cortex involving the MCA territory. Angiographic images show multiple tortuous collaterals involving both anterior (d) and posterior circulation (d, e, f) giving the typical
Suzuki et al. staged the disease progression into the following stages based on the angiographic findings [3, 22, 27].
Narrowing of the carotid forks
Initiation of moyamoya[dilated major cerebral artery and a slight network of collaterals]
Intensification of moyamoya with the disappearance of middle and anterior cerebral arteries
Minimization of moyamoya [disappearance of posterior cerebral artery and narrowing of individual moyamoya vessels]
Reduction of moyamoya [disappearance of main cerebral arteries, further minimization of moyamoya, increase in collaterals from external carotid arteries]
Disappearance of moyamoya [complete disappearance of moyamoya with blood flow derived only from the external carotid artery and vertebrobasilar system]
Apart from these changes, aneurysm formation can also be seen in angiography. A revised version of Suzuki staging system was given by Mugikura et al. (Table 1), where staging is done based on angiographic severity of stenosis of the middle cerebral artery and anterior cerebral artery [30].
ICA Stage | Angiographic findings |
---|---|
I | Mild to moderate stenosis around carotid bifurcation, absent/slightly developed moyamoya, ACA/MCA branches opacified in anterograde fashion |
II | Severe stenosis around carotid bifurcation, well developed moyamoya, several of ACA/MCA branches opacified in anterograde fashion |
III | Occlusion of proximal ACA/MCA, well developed moyamoya, only a few of ACA/MCA branches are faintly opacified in anterograde fashion through the mesh work of ICA moyamoya |
IV | Complete occlusion of proximal ACA and MCA, small amount of moyamoya, no opacification of either ACA/MCA branches in anterograde fashion |
The angiographic ICA staging system modified by Mugikura et al.
ACA- anterior cerebral artery, MCA- middle cerebral artery, ICA- internal cerebral artery.
Both the staging systems highlight that with the progression of the disease, the contribution of blood supply from ICA decreases and an intricate collateral network is formed which derives its blood flow from vessels outside the cerebral circulation.
CT scan shows hyperdensities in basal ganglia, thalamus, ventricular system and subarachnoid spaces in the hemorrhagic type of MMD. In the ischemic type of the disease, lacunar infarcts can be seen as the areas of hypodensities. When contrast-enhanced, tortuous and curvilinear vessels in basal ganglia can be visualized which represent the moyamoya vessels.
Magnetic Resonance Imaging and Angiography [MRI and MRA].
MRI and MRA provide visualization of the arterial tree without being invasive as conventional angiography. In addition to this, MRI also helps demonstrate small subcortical lesions that are difficult to identify on the CT scan. MRA helps to identify the stenotic distal end of the internal carotid artery, small moyamoya vessels and dural anastomosis between external carotid arteries and vessels of the posterior circulation.
The classification and scoring based on the MRA findings are given above in Tables 2 and 3. This MRA scoring system also finds its place in the 2012 Guidelines for the Diagnosis and Treatment of MMD in Japan [5].
Score for each artery | MRA finding |
---|---|
0 | Normal |
1 | Stenosis of C1 |
2 | Discontinuity of the C1 signal |
3 | Invisible |
0 | Normal |
1 | Stenosis of M1 |
2 | Discontinuity of the M1 signal |
3 | Invisible |
0 | Normal A2 and blood vessels distal to A2 |
1 | Signal decrease A2 and its distal blood vessels |
2 | Invisible |
0 | Normal P2 and blood vessels distal to P2 |
1 | Signal decrease P2 and its distal blood vessels |
2 | Invisible |
The classification and scoring based on the MRA findings- Score of each artery.
MRA total score | MRA stage |
---|---|
0–1 | 1 |
2–4 | 2 |
5–7 | 3 |
8–10 | 4 |
The classification and scoring based on the MRA findings – MRA total Score.
MRA: Magnetic Resonance Imaging.
In patients with moyamoya disease, the involvement of many extracranial arteries like external carotid arteries, aorta, pulmonary artery, celiac artery, and renal artery has been described. Characteristic signs like ‘ champagne bottleneck sign’ seen due to reduction in the diameter of proximal ICA and ‘diamond reversal sign’ due to smaller ICA diameter compared to external carotid artery have been demonstrated [31].
Though all the diagnostic modalities contribute to identifying and staging abnormal vasculature, angiography remains the mainstay of diagnosis. It is also helpful in documenting the postoperative resolution of moyamoya.
Electroencephalography [EEG].
The following EEG findings have been seen in moyamoya disease [32]:
Diffuse, bilateral, low voltage, slow spike and wave
‘Buildup’ phenomenon- a diffuse pattern of slow waves
‘Rebuildup’ phenomenon- diffuse slow waves during hyperventilation. This rebuild up phenomenon is seen due to decreased pCO2 on hyperventilation leading to cerebral ischemia and vasoconstriction.
The advancements in various diagnostic modalities lead to the formulation of diagnostic guidelines for Moyamoya disease shown in Table 4 [5].
A. Cerebral angiography should present at least the following findings: |
1. Stenosis/occlusion at the terminal portion of ICA and/or at the proximal portion of ACA and/or MCA |
2. Abnormal vascular network in the vicinity of stenotic/occluded vessels |
3. Bilateral findings |
B. Conventional angiogram not required when MRI/MRA demonstrate following findings:1. |
1. Stenosis/occlusion at the terminal portion of ICA and/or at the proximal portion of ACA and/or MCA on MRA |
2. Abnormal vascular network in the basal ganglia on MRA[>2 flow voids in basal ganglia in MRI]. |
3. Bilateral findings |
C. Absence of arteriosclerosis, autoimmune disease, meningitis, brain neoplasm, down syndrome, Recklinghausen’s disease, head trauma, irradiation to head, others. |
D. Pathological findings: |
1. Stenosis/occlusion due to intimal thickening at the terminal ICA, usually on both sides |
2. Arteries of Circle of Willis show varying degree of stenosis/occlusion of intima, attenuation of media and waving of internal elastic lamina |
3. Numerous small vascular channels around the Circle of Willis |
4. Reticular conglomerates of small vessels in pia matter. |
Definitive case: A/B + C[In children, a case that fulfills A1 and A2 or B1 and B2 on one side and remarkable stenosis of terminal ICA on opposite side is also included.] |
Probable case: A1 and A2 [or B1 and B2] and C [unilateral] |
Diagnostic guidelines for Moyamoya disease.
Moyamoya disease is a chronic progressive disease described earlier, leading to recurrent strokes due to internal carotid artery occlusion and ischemia due to narrow, low caliber collaterals. The illness’s mainstay is revascularization surgery to increase the intracranial blood flow using extracerebral blood vessels by direct bypass or pialsynangiosis. The decision for surgical intervention is based on the patient’s age, symptomatic/asymptomatic disease, ischemic/hemorrhagic manifestations, presence/absence of aneurysm and risk of recurrence.
The indication of surgery can be briefly summarized as follows in Figure 4 [33].
Overview of the management of Moyamoya disease.
Moyamoya disease is known to progress over the years. The disease progression rate was reported to be approximately 20% over six years in those managed conservatively [34]. The risk factors of disease progression and subsequent ischemic stroke were identified as follows:
Female gender
Graves’ disease
RNF213 variant
Family history positive [35]
Posterior circulation was also recognized as a decisive risk factor for ischemic stroke [36].
Moyamoya disease is a progressive disease, and symptomatic progression is seen in approximately two-thirds of patients [29]. In a large meta-analysis, where 1,156 people were studied, it was seen that 87% of those who underwent surgical revascularization showed partial or complete resolution of symptomatic cerebral ischemia [37].
A careful choice of treatment, that is, conservative vs. surgical should thus be made keeping in mind the above-mentioned risk factors.
The predominant manifestation of MMD is ischemic stroke. However, antiplatelet therapy is ineffective to prevent recurrent cerebral infarction in ischemic MMD. The ischemic insult in MMD patients is a consequence of hemodynamic instability. There is no evidence of endothelial dysfunction at the site of internal carotid artery bifurcation. Therefore, increased platelet adhesion is not seen in MMD. Hence, theoretically, antiplatelet drugs are ineffective for preventing ischemic stroke in MMD. Moreover, increased risk of hemorrhage remains with antiplatelets in patients with MMD [38]. The annual stroke rate in patients managed conservatively is between 3.2%–15% [35].
Surgical revascularization is done to increase the cerebral blood flow and restore reserve capacity. The increase in cerebral blood flow prevents recurrent cerebral infarction. The indications for surgical revascularization are:
Recurrent clinical symptoms due to cerebral ischemia
Pediatric MMD because pediatric MMD is more progressive than adult MMD. Early diagnosis and intervention are of paramount importance to prevent irreversible damage. In a recent study, Rosi et al. confirmed a high benefit/risk ratio, with better postoperative functional status and low rates for the need of surgical retreatment in the pediatric population undergoing surgical revascularization [39].
Role of revascularization surgery in asymptomatic MMD with stable hemodynamics is not well established but preferred by neurosurgeons given the disease being a progressive disorder. Risk–benefit ratio determines the feasibility of the surgical intervention in such patients.
Role of revascularization surgery in hemorrhagic stroke is controversial.
With increased understanding of MMD being familial in at least some of the world’s regions, it is being suggested that asymptomatic siblings and family members should be screened for moyamoya pathology. Whenever such a condition is detected, it should be managed surgically, keeping in mind the illness’s progressive nature.
Anastomosis is formed between the superficial temporal artery and cortical branches of middle cerebral arteries in this procedure. For posterior circulation, the occipital artery is used as a donor for nteroposterior cerebral arteries’ cortical branches. The transdural or transcalvarial collateral channels should be preserved during the surgery.
The advantage of this procedure is an immediate improvement in the cerebral blood flow after surgery. However, the successful restoration of cerebral blood flow is operator dependant as it is challenging to perform. Moreover, postoperative hyperperfusion syndrome may develop after surgery leading to neurological deterioration. Patency and amount of bypass flow may be assessed postoperatively by digital subtraction angiography or quantitative magnetic resonance angiography.
The annual stroke rate after direct revascularization was reportedly 0–1.6% [40].
The various surgical procedures are
Encephalomyosynangiosis[EMS] where deep temporal artery supplying the temporalis muscle is the vessel for neovascularization
Encephalo-duro-arteriosynangiosis[EDAS]: Here, superficial temporal artery[STA] is harvested with surrounding galea and periosteum; STA flap is placed with a galea cuff. The dura and galea are then sutured to cover the brain with arterial flap.
Encephalo-myo-arteriosynangiosis[EDAMS]
Encephalo-galeo-synangiosis[EGS]
Omental flap surgery
Multiple burr hole surgery
The last two surgeries are performed as primary or after failed revascularization by other techniques.
Indirect revascularization is relatively easier to perform than direct surgeries, and the incidence of hyperperfusion is also less. However, the improvement in cerebral revascularization takes longer than the direct surgeries where the effect is immediate.
After indirect revascularization, patients experienced 0–14.3% postoperative annual stroke rate [41].
Thus either of the indirect and direct revascularization procedures can be performed to rectify the underlying pathology, but the risk of recurrence is much less with the direct revascularization surgeries without any delay to the benefit.
The following complications have been noted in the peri/postoperative period in MMD:
The risk of postoperative stroke has been estimated to be 1.6%- 16% [42].
The risk of perioperative ischemic complications is more in patients with unstable hemodynamics and advanced Suzuki stage with a lower cerebral blood flow.
Hemorrhagic stroke develops in 0.7%–8% [42].
Hyperperfusion syndrome- due to the chronic changes in cerebral blood vessels, the auto-regulatory function is lost, and the vascular reserve is decreased. The excessive blood flow immediately after the surgery is sometimes not well tolerated, leading to cerebral hemorrhage. Another factor that may predispose to intracranial hemorrhage is increased vascular permeability secondary to chronic ischemia.
Epidural hematoma mainly in the pediatric population.
Skin problems due to scalp ischemia after revascularization.
Moyamoya disease is a chronic progressive vasculopathy seen in children and adults, characterized by occlusion/stenosis at the terminal portions of the internal carotid artery and abnormal collateral network formation at the base of the brain. It is predominantly seen in Asian countries. It may be idiopathic [moyamoya disease] or associated with other disorders when it is called moyamoya syndrome. Various angiographic and magnetic resonance angiographic findings have been described which form the basis of the diagnostic guidelines for MMD. It may present as an ischemic/hemorrhagic stroke. It is generally managed with direct/indirect revascularization surgical techniques that aim to restore the cerebral blood flow and prevent strokes that restore the cerebral blood flow and prevent strokes’ recurrence.
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\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
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\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. 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Research suggests that physical activity levels of individuals with autism spectrum disorder (ASD) are lower than typically developing and developed peers. Despite evidence for PA decreasing negative behaviors and promoting positive behaviors, individuals with ASD may be less motivated and less likely to participate. Individuals with ASD may be more likely to be overweight or obese than their typically developing counterparts as a result of decreased activity levels. Conflicting findings regarding PA levels in individuals with ASD have been reported. Given mixed evidence, further inquiry is warranted. The present chapter provides a review of literature pertaining to PA in individuals with ASD. Four databases were searched. Predetermined search terms and inclusion/exclusion criteria were clearly outlined to identify relevant articles which were then critically appraised. This research provides a greater understanding of the status of PA participation of individuals with ASD.",book:{id:"5498",slug:"autism-paradigms-recent-research-and-clinical-applications",title:"Autism",fullTitle:"Autism - Paradigms, Recent Research and Clinical Applications"},signatures:"Sara M. Scharoun, Kristen T. Wright, Jennifer E. Robertson-Wilson,\nPaula C. Fletcher and Pamela J. Bryden",authors:[{id:"190972",title:"Dr.",name:"Pamela",middleName:null,surname:"Bryden",slug:"pamela-bryden",fullName:"Pamela Bryden"}]},{id:"52787",doi:"10.5772/65906",title:"The Clinical Gestalts of Autism: Over 40 years of Clinical Experience with Autism",slug:"the-clinical-gestalts-of-autism-over-40-years-of-clinical-experience-with-autism",totalDownloads:1731,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"The clinical gestalts of autism are very broad and much more heterogeneous than people realise. DSM V [1] gives a more narrow and condensed description of what autism is in the twentieth century. DSM focuses on problems with socioemotional reciprocity, non-verbal communication and difficult interpersonal relationships, restricted, repetitive patterns of behaviour, early onset and functional impairment. First, I want to flesh out the autism spectrum disorder gestalts as it presents to experienced clinical practitioners. It is the opposite of the “tick box” approach to diagnosis so common today. It focuses on the phenomena as they would have been focused on in the late nineteenth and early twentieth century, an approach that has faded into the background in the late twentieth and early twenty-first century. It is critical at this point of the twenty-first century that we re-engage with phenomenology and with the clinical gestalt of psychiatric conditions which show a great deal of overlap with much mixed phenomenology. We will start by examining social relations in autism spectrum disorders. Clearly, this is central to autism.",book:{id:"5498",slug:"autism-paradigms-recent-research-and-clinical-applications",title:"Autism",fullTitle:"Autism - Paradigms, Recent Research and Clinical Applications"},signatures:"Michael Fitzgerald",authors:[{id:"191313",title:"Dr.",name:"Michael",middleName:null,surname:"Fitzgerald",slug:"michael-fitzgerald",fullName:"Michael Fitzgerald"}]},{id:"52976",doi:"10.5772/66201",title:"Family Quality of Life in Autism Spectrum Disorders (ASD)",slug:"family-quality-of-life-in-autism-spectrum-disorders-asd-",totalDownloads:1804,totalCrossrefCites:3,totalDimensionsCites:7,abstract:"In latest years the concept of quality of life (QoL) has been acknowledged as an important outcome in psychiatric pathology fields. Most researchers consider that social indicators and the perception of personal wellbeing also, should be considered when measuring the quality of life. Our purpose was to investigate the QoLof the families of children with autism spectrum disorders (ASD) and to determine whether in this population, the potential mediators (irrational cognitions, negative automatic thoughts, coping strategies) relate significantly with the emotional distress reported. We also aimed to assess the parents’ irrational cognitions and negative automatic thoughts as mediators in the relationship between the overall assessment of family QoLand their emotional distress. We found significant correlations between the emotional distress reported by the parents and their automatic negative thoughts, irrational cognitions, and different coping strategies. The relationship between the overall assessment of family QoLand the parents’ emotional distress was partially explained by their negative automatic thoughts and irrational cognitions. In this view, the specialised services should include also interventions for the parents of children with developmental disorders (ASD, ADHD) in order to improve their overall assessment of familyQoL.",book:{id:"5498",slug:"autism-paradigms-recent-research-and-clinical-applications",title:"Autism",fullTitle:"Autism - Paradigms, Recent Research and Clinical Applications"},signatures:"Elena Predescu and Roxana Şipoş",authors:[{id:"191660",title:"Dr.",name:"Elena",middleName:null,surname:"Predescu",slug:"elena-predescu",fullName:"Elena Predescu"},{id:"191661",title:"Dr.",name:"Roxana",middleName:null,surname:"Sipos",slug:"roxana-sipos",fullName:"Roxana Sipos"}]},{id:"54644",doi:"10.5772/67624",title:"Impact of Infant Feeding Methods on the Development of Autism Spectrum Disorder",slug:"impact-of-infant-feeding-methods-on-the-development-of-autism-spectrum-disorder",totalDownloads:2111,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"There is strong and convincing evidence that infant’s sensory stimulation, which is associated with breastfeeding, contributes significantly to the infant’s neurodevelopment. Our study compared the prevalence of autism spectrum disorder (ASD) in children who were breastfed, given breast milk through a bottle (breast-milk fed), or formula-fed. We reported significant association of ASD in children who were formula-fed from birth or weaned early from the breast. The statistical data revealed that increasing the duration of breastfeeding resulted in a decrease in prevalence of ASD. The odds ratio of a child not having autism was 0.27, 0.93, and 6.67 for breastfeeding for less than 6, 6–12, or longer than 12 months, respectively. There is significant evidence that this association is mediated by the ingredients of the breast milk and infant’s endogenous oxytocin. Oxytocin is a neurotransmitter and neuromodulator and we postulate that oxytocin may increase neuroplasticity, synaptic connections, and alter ASD genes’ expression. Animal experiments and imaging studies demonstrate the central role of oxytocin in maternal love and bonding. Currently, there are no specific treatments for patients diagnosed with autism; therefore, it is imperative to identify the risk factors that contribute to the development of ASD. In this communication, we demonstrate that lack of breastfeeding is highly associated with ASD development in children with genetic susceptibility.",book:{id:"5498",slug:"autism-paradigms-recent-research-and-clinical-applications",title:"Autism",fullTitle:"Autism - Paradigms, Recent Research and Clinical Applications"},signatures:"Touraj Shafai, Monika Mustafa, Jeffrey Mulari and Antonio Curtis",authors:[{id:"192429",title:"M.D.",name:"Touraj",middleName:null,surname:"Shafai",slug:"touraj-shafai",fullName:"Touraj Shafai"}]},{id:"52521",doi:"10.5772/65409",title:"A Different Point of View: The Neurodiversity Approach to Autism and Work",slug:"a-different-point-of-view-the-neurodiversity-approach-to-autism-and-work",totalDownloads:2066,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"With this chapter, we want to open up the debate whether neurodiversity might be the next step of diversity. The term neurodiversity was first established in the online autism community in the 1990s and has since spread both off‐ and online. It describes the idea that, throughout the human population, different brain developments and structures exist. Neuronal variances such as Autism are therefore not to be seen as disorders but as variations different from the neurotypical brain. Instead of being considered ill and cure‐worthy, neurodiverse people should be included and integrated into society. In our current research, we follow the neurodiversity approach and focus on the subject of autism in the work context. We found that certain strengths and abilities are most prominent in autistic people (such as logical reasoning, visual perception) and that autistic people are able to find different effective solutions to overcome the barriers detaining them from entering the job market. Furthermore, while many autistic individuals are employed in regular competitive jobs, more focus on autism‐specific job environments is needed. These findings lead us to the conclusion that autistic individuals have potential that is beneficial for society.",book:{id:"5498",slug:"autism-paradigms-recent-research-and-clinical-applications",title:"Autism",fullTitle:"Autism - Paradigms, Recent Research and Clinical Applications"},signatures:"Timo Lorenz, Nomi Reznik and Kathrin Heinitz",authors:[{id:"190954",title:"Dr.",name:"Timo",middleName:null,surname:"Lorenz",slug:"timo-lorenz",fullName:"Timo Lorenz"},{id:"195124",title:"Ms.",name:"Nomi",middleName:null,surname:"Reznik",slug:"nomi-reznik",fullName:"Nomi Reznik"},{id:"195125",title:"Prof.",name:"Kathrin",middleName:null,surname:"Heinitz",slug:"kathrin-heinitz",fullName:"Kathrin Heinitz"}]}],mostDownloadedChaptersLast30Days:[{id:"52480",title:"Mindfulness and Autism Spectrum Disorder",slug:"mindfulness-and-autism-spectrum-disorder",totalDownloads:2404,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"The use of mindfulness interventions for individuals with autism spectrum disorder (ASD) is a relatively new research area, which has followed a more established body of research investigating the efficacy of mindfulness interventions for parents of children with ASD. Given the chronic stress levels experienced by parents and high anxiety and stress levels in individuals with ASD, such research is well justified. The utility of mindfulness in clinical practice for individuals with ASD and their parents will be discussed. This chapter aims to evaluate the research literature, identify important limitations, and propose crucial directions for future research. Acknowledgment of the impact of attitudes, social bias, and a generational shift that may be accelerating the salience of mindfulness is discussed. The author aims to emphasize the importance of high-quality future research with robust methodological designs to clearly identify the potential role for mindfulness in this population. Despite having a solid foundation of preliminary findings, it is important that researchers refine current procedures and evaluation of mindfulness interventions for individuals with ASD and their parents while carefully selecting measures that are not solely self-report or parent report.",book:{id:"5498",slug:"autism-paradigms-recent-research-and-clinical-applications",title:"Autism",fullTitle:"Autism - Paradigms, Recent Research and Clinical Applications"},signatures:"Renee L. Cachia",authors:[{id:"190422",title:"Ph.D. Student",name:"Renee",middleName:null,surname:"Cachia",slug:"renee-cachia",fullName:"Renee Cachia"}]},{id:"53550",title:"Physical Activity in Individuals with Autism Spectrum Disorders (ASD): A Review",slug:"physical-activity-in-individuals-with-autism-spectrum-disorders-asd-a-review",totalDownloads:2222,totalCrossrefCites:8,totalDimensionsCites:14,abstract:"Current recommendations indicate that children and youth ages 5–17 should participate in 60 min and adults in 150 min of moderate-to-vigorous physical activity daily. Research suggests that physical activity levels of individuals with autism spectrum disorder (ASD) are lower than typically developing and developed peers. Despite evidence for PA decreasing negative behaviors and promoting positive behaviors, individuals with ASD may be less motivated and less likely to participate. Individuals with ASD may be more likely to be overweight or obese than their typically developing counterparts as a result of decreased activity levels. Conflicting findings regarding PA levels in individuals with ASD have been reported. Given mixed evidence, further inquiry is warranted. The present chapter provides a review of literature pertaining to PA in individuals with ASD. Four databases were searched. Predetermined search terms and inclusion/exclusion criteria were clearly outlined to identify relevant articles which were then critically appraised. This research provides a greater understanding of the status of PA participation of individuals with ASD.",book:{id:"5498",slug:"autism-paradigms-recent-research-and-clinical-applications",title:"Autism",fullTitle:"Autism - Paradigms, Recent Research and Clinical Applications"},signatures:"Sara M. Scharoun, Kristen T. Wright, Jennifer E. Robertson-Wilson,\nPaula C. Fletcher and Pamela J. Bryden",authors:[{id:"190972",title:"Dr.",name:"Pamela",middleName:null,surname:"Bryden",slug:"pamela-bryden",fullName:"Pamela Bryden"}]},{id:"53617",title:"The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications",slug:"the-genetic-and-epigenetic-basis-involved-in-the-pathophysiology-of-asd-therapeutic-implications",totalDownloads:1802,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"The prevalence of autism has increased in an exponential way in the past few years. Many monogenetic mutations as well as copy number variants and single nucleotide polymorphisms have been associated with autism spectrum disorders (ASD), a large proportion of which occur in genes associated with synaptogenesis and synaptic function. However, the increase in appearance of genetic alterations does not explain the etiology of an elevated number of ASD cases. Recent research is now focusing on the role of environmental/epigenetic factors, which by themselves and/or in combination with classical genetic factors, may be the root cause of a large number of ASDs. In this chapter we review the current literature regarding the epigenetic changes involved in ASD, including their possible mechanisms of action such as oxidative stress, altered fatty acid metabolism, mitochondrial dysfunction, DNA methylation and histone methylation (via the one‐carbon metabolism cycle), histone variants, and ATP‐dependent chromatin remodeling. We discuss possible new biochemical markers related to autism as well as new lines of research for therapeutic targets.",book:{id:"5498",slug:"autism-paradigms-recent-research-and-clinical-applications",title:"Autism",fullTitle:"Autism - Paradigms, Recent Research and Clinical Applications"},signatures:"Maria Carmen Carrascosa-Romero and Carlos De Cabo-De La Vega",authors:[{id:"61718",title:"Dr.",name:"María Carmen",middleName:null,surname:"Carrascosa-Romero",slug:"maria-carmen-carrascosa-romero",fullName:"María Carmen Carrascosa-Romero"},{id:"61719",title:"Dr.",name:"Carlos",middleName:null,surname:"De Cabo De La Vega",slug:"carlos-de-cabo-de-la-vega",fullName:"Carlos De Cabo De La Vega"}]},{id:"54098",title:"Sex Bias in Autism",slug:"sex-bias-in-autism",totalDownloads:1430,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Autism is a neurodevelopmental disorder with unknown exact etiology. Interestingly, it affects males more than females in a striking ratio (4:1), respectively. This biased ratio served as a clue to search about the factors that are sex linked and hence sex hormones and X chromosomes were good candidates. Although understanding the basic sex dimorphism in male and female brains is essential to understand autism pathology. Theories regarding the biased sex ratio in autism have been raised, and some have been supported by evidence from human studies. Furthermore, sex-linked genetic dysregulation has also been reported in autism. In this chapter, an overview of what is known about sex bias in autism is reviewed, emphasizing the importance of carrying on in uncoding the sex bias in autism.",book:{id:"5498",slug:"autism-paradigms-recent-research-and-clinical-applications",title:"Autism",fullTitle:"Autism - Paradigms, Recent Research and Clinical Applications"},signatures:"Felwah S. Al-Zaid",authors:[{id:"191157",title:"Dr.",name:"Felwah",middleName:null,surname:"Al-Zaid",slug:"felwah-al-zaid",fullName:"Felwah Al-Zaid"}]},{id:"52453",title:"Constructing Healthy Experiences through Human-Animal Interactions for Autistic Children and Their Families: Implications for Research and Education",slug:"constructing-healthy-experiences-through-human-animal-interactions-for-autistic-children-and-their-f",totalDownloads:1504,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"A significant body of research in the field of animal assistance in autism spectrum disorder (ASD) therapy indicates that positive human-animal interactions (HAIs), such as playing with therapy dogs or dogs presence while reading Social Stories, improve the social interactions and the level of the behavioral indicators of positive moods (smiling, laughing) in autistic children. In this chapter, we aim to present a series of evidence-based modalities of including animal-assisted activities in standard therapeutic settings but also in the home environment (e.g., interactions with family animals), targeting the socio-emotional development of autistic children and their optimal communication with the family members, including the companion animals. The studies presented here are discussed from the perspective of potential mechanisms, such as oxytocin system, and several attachment-related views. Our studies point toward the valorization of companion animals in the process of development and optimizing the interpersonal communication abilities of ASD children in a positive and engaging manner for both humans and animals.",book:{id:"5498",slug:"autism-paradigms-recent-research-and-clinical-applications",title:"Autism",fullTitle:"Autism - Paradigms, Recent Research and Clinical Applications"},signatures:"Alina S. Rusu",authors:[{id:"191006",title:"Dr.",name:"Alina",middleName:"Simona",surname:"Rusu",slug:"alina-rusu",fullName:"Alina Rusu"}]}],onlineFirstChaptersFilter:{topicId:"1055",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. 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. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:36,paginationItems:[{id:"82195",title:"Endoplasmic Reticulum: A Hub in Lipid Homeostasis",doi:"10.5772/intechopen.105450",signatures:"Raúl Ventura and María Isabel Hernández-Alvarez",slug:"endoplasmic-reticulum-a-hub-in-lipid-homeostasis",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82409",title:"Purinergic Signaling in Covid-19 Disease",doi:"10.5772/intechopen.105008",signatures:"Hailian Shen",slug:"purinergic-signaling-in-covid-19-disease",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82374",title:"The Potential of the Purinergic System as a Therapeutic Target of Natural Compounds in Cutaneous Melanoma",doi:"10.5772/intechopen.105457",signatures:"Gilnei Bruno da Silva, Daiane Manica, Marcelo Moreno and Margarete Dulce Bagatini",slug:"the-potential-of-the-purinergic-system-as-a-therapeutic-target-of-natural-compounds-in-cutaneous-mel",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}}]},overviewPagePublishedBooks:{paginationCount:32,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:null}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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Dr. Şentürk currently works as an professor of Biochemistry in the Department of Basic Pharmacy Sciences, Faculty of Pharmacy, Ağri Ibrahim Cecen University, Turkey. \nDr. Şentürk published over 120 scientific papers, reviews, and book chapters and presented several conferences to scientists. \nHis research interests span enzyme inhibitor or activator, protein expression, purification and characterization, drug design and synthesis, toxicology, and pharmacology. \nHis research work has focused on neurodegenerative diseases and cancer treatment. 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He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,series:{id:"11",title:"Biochemistry"}}},seriesLanding:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:4,numberOfPublishedChapters:318,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},subseries:[{id:"14",title:"Cell and Molecular Biology",keywords:"Omics (Transcriptomics; Proteomics; Metabolomics), Molecular Biology, Cell Biology, Signal Transduction and Regulation, Cell Growth and Differentiation, Apoptosis, Necroptosis, Ferroptosis, Autophagy, Cell Cycle, Macromolecules and Complexes, Gene Expression",scope:"The Cell and Molecular Biology topic within the IntechOpen Biochemistry Series aims to rapidly publish contributions on all aspects of cell and molecular biology, including aspects related to biochemical and genetic research (not only in humans but all living beings). We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",annualVolume:11410,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},{id:"15",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. 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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://mts.intechopen.com/storage/users/81926/images/system/81926.png",institutionString:"Suez Canal University",institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"bookSubject",path:"/subjects/1055",hash:"",query:{},params:{id:"1055"},fullPath:"/subjects/1055",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()