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Sleep Disorders Medicine Basic Science Technical Considerations and Clinical Aspects Chokroverty
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Preface
The idea for this textbook arose during the implementation of our interdisciplinary allergy/sleep disorders clinic at the Ann & Robert H. Lurie Children’s Hospital of Chicago. In this clinic, we identify many children with allergic diseases, such as allergic rhinitis, asthma, atopic dermatitis, and other immunologically related problems that also have principal sleep-related complaints. In managing both allergic and sleep disorders, we gained insight into the impact these disciplines have upon each other. Comprehensive management requires attention to the underlying allergic disorder as well as identification and management of sleep-related problems. On the other hand, many children presenting to the Pediatric Sleep Medicine Center at Lurie Children’s Hospital have comorbid allergic symptomatology. Treatment only of the sleep-related difficulties does not result in optimal control of symptoms. Only after treatment of both the sleep-related difficulties and allergic pathology can treatment be personalized and optimized. This does not imply broad allergy testing in sleep patients but rather a symptom-directed approach.
In diagnosing and managing both sleep and allergic disorders, the practitioner must recognize important relationships. First, primary sleep-related abnormalities may affect daytime functioning caused by pathologic processes during sleep or may exacerbate existing primary medical disorders. Through diagnosis and treatment of sleep-related abnormalities, adverse health outcomes might be avoided or treatment of the primary medical problem more effective. Second, sleep-related pathology can exist concomitantly with an allergic disorder. This requires therapeutic approaches to comorbid conditions in order to obtain an optimal outcome. Finally, the presence of sleep-related abnormalities occurring as a result of allergic disorders not only impacts the health and well-being of the affected individual but can have more widespread effects on the entire family, particularly in pediatrics. A child’s nocturnal sleep disruption can cause sleeplessness, daytime fatigue, and significant diurnal performance difficulties.
Although our training is in pediatrics, authors of this book are experts in pediatric and adult disease and provide an overview of disease assessment and treatment approaches throughout the life-span. Chapter authors reflect the multidisciplinary practitioners required to assess and treat allergy and sleep disorders – allergists, sleep medicine physicians, otolaryngologists, dermatologists, primary care physicians, pharmacists, psychologists, dentists, and other researchers.
The book structure reflects our overall approach to comprehensive allergy and sleep care. First, in Part I, we provide a primer on the science of sleep, allergy, immunology, circadian rhythms, and circadian immunology. In Part II, the clinical science is addressed first by presenting symptoms in a case-based approach. Next, we address assessment and treatment by specific, common allergic diseases. Finally, disease, sleep, and circadian specific therapeutics are reviewed.
Researching the association of allergy and sleep-related disorders led us to a paucity of literature. It is clear from clinical practice that children and adults with allergic disorders sleep poorly. In our sleep medicine center, it is common to see children with sleep disorders also suffer from allergy. When choosing topics for chapters to include in this text, there were many with abundant literature from which to draw. Still other topics revealed minimal evidence. It was decided to still include these chapters to begin discussion of the topic and overlap. It was not to provide answers but to stimulate questions for discussion and future research.
It is hoped this textbook will provide insight into cause and effect as well as an understanding of the complex interactions healthcare practitioners face in order to provide optimal care to their patients and families.
Chicago, IL, USA
Chicago, IL, USA
Anna Fishbein
Stephen H. Sheldon
Laurie A. Manka and Richard J. Martin
Rui Guan and Roneil G. Malkani
Natalia M. Jasiak-Panek, Kevin T. Le, Thomas Moran, and Sukhraj Mudahar 29 Alternative/Integrative Medical Approaches
Xiu-Min Li, Henry Ehrlich, Paul Ehrlich, Anne Maitland, Erin Thanik, Julia A. Wisniewski, and Danna Chung
30 Assessment and Therapies for Sleep and Sleep-Related Breathing Disorders Associated with Atopic Disease in Children: A Dental Perspective
Kevin L. Boyd
Matthew Purkey, Chris Gouveia, and Bruce Tan
Contributors
Sabra M. Abbott, MD, PhD Department of Neurology, Northwestern University, Chicago, IL, USA
Andrew M. Abreo, MD Division of Allergy, Pulmonary, and Critical Care, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Hrayr Attarian, MD Department of Neurology, Sleep Medicine, Northwestern Medicine, Feinberg School of Medicine, Chicago, IL, USA
Fuad M. Baroody, MD, FACS Department of Surgery, Section of OtolaryngologyHead and Neck Surgery and Department of Pediatrics, The University of Chicago Medicine and The Comer Children’s Hospital, Chicago, IL, USA
Katalina Bertran, MD Department of Pediatric Cardiology and Pulmonology, Division of Pediatrics and Sleep Medicine Center, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Kevin L. Boyd, DDS, MSc Dentistry for Children and Families, Chicago, IL, USA
Ann & Robert H. Lurie, Children’s Hospital of Chicago, Chicago, IL, USA
Pablo E. Brockmann, MD, PhD Department of Pediatric Cardiology and Pulmonology, Division of Pediatrics and Sleep Medicine Center, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Daniel Cerrone, MD Division of Pulmonology and Sleep Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA
Danna Chung, MD Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Christopher Cielo, DO, MS Sleep Center, Department of Pulmonary Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Camil Correia, MD Department of Surgery, Section of Otolaryngology-Head and Neck Surgery, The University of Chicago, Chicago, IL, USA
Maria Teresa Coutinho, PhD Child and Family Psychiatry & Pediatrics, Brown Medical School, Bradley/Hasbro Children’s Research Center, Providence, RI, USA
Linda Cox, MD Department of Medicine, University of Miami at Holy Cross Hospital, Fort Lauderdale, FL, USA
Innessa Donskoy, MD, FAAP Department of Pediatric Sleep Medicine, Advocate Children’s Hospital, Park Ridge, IL, USA
Henry Ehrlich, BA Pediatric Allergy and Immunology, Jaffe Food Allergy Institute, Center for Integrative Medicine for Immunology and Wellness, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Paul Ehrlich, MD Department of Pediatrics, New York University Langone Medical Center, New York, NY, USA
Anna Fishbein, MD, MSci Division of Allergy & Immunology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Kourtney G. Gardner, MD Division of Allergy, Pulmonary, and Critical Care, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Emily Gillett, MD, PhD Division of Pulmonology and Sleep Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA
Chris Gouveia, MD Department of Otolaryngology, Head & Neck Surgery, Northwestern Memorial Hospital, Chicago, IL, USA
David Gozal, MD, MBA Department of Child Health, University of Missouri School of Medicine, Columbia, MO, USA
Rui Guan, MD Institute of Neurological Sciences, Prince of Wales Hospital, University of New South Wales, Sydney, NSW, Australia
Jonathan A. Hemler, MD Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
Namita Jain, MD, MPH Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Natalia M. Jasiak-Panek, PharmD, BCPS Department of Pharmacy, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Anjeni Keswani, MD, MSCI Division of Allergy/Immunology, Department of Medicine, GW School of Medicine and Health Sciences, Washington, DC, USA
Fatima S. Khan, MD Department of Allergy and Immunology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Leila Kheirandish-Gozal, MD, MSc Department of Child Health Research Institute, University of Missouri School of Medicine, Columbia, MO, USA
Sofia Konstantinopoulou, MD Division of Pulmonary Medicine, Department of Pediatrics, Sheikh Khalyfa Medical City, Tibbiyya, Abu Dhabi, United Arab Emirates
Sanjeev V. Kothare, MD Pediatric Sleep Program, Department of Neurology, NYU Langone Medical Center, New York, NY, USA
Lacey L. Kruse, MD Departments of Pediatrics and Dermatology, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Kevin T. Le, PharmD, BCPS Department of Pharmacy, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Xiu-Min Li, MD Department of Pediatrics, Pediatric Allergy and Immunology, Jaffe Food Allergy Institute, Center for Integrative Medicine for Immunology and Wellness, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Mahboobeh Mahdavinia, MD, PhD Allergy and Immunology Division, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA
Anne Maitland, MD Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Roneil G. Malkani, MD, MSCI Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Laurie A. Manka, MD Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, USA
Richard J. Martin, MD Department of Medicine, National Jewish Health, Denver, CO, USA
Daphne Koinis Mitchell, PhD Child and Family Psychiatry & Pediatrics, Brown Medical School, Bradley/Hasbro Children’s Research Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
Thomas Moran, PharmD, BCPS Department of Pharmacy, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Anne Marie Morse, DO Department of Child Neurology, Sleep Medicine, Geisinger Medical Center, Janet Weis Children’s Hospital, Danville, PA, USA
Sukhraj Mudahar, PharmD, BCPS Department of Pharmacy, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Tanvi H. Mukundan, MD Department of Sleep Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
Luis E. Ortiz, MD Sleep Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Nurcicek Padem, MD Division of Allergy & Immunology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, Chicago, IL, USA
Rafael Pelayo, MD Department of Psychiatry and Behavioral Sciences, Stanford Center for Sleep Sciences and Medicine, Stanford Sleep Medicine Center, Redwood City, CA, USA
Barry J. Pelz, MD Division of Asthma, Allergy, and Clinical Immunology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
Matthew Purkey, MD Department of Otolaryngology, Head & Neck Surgery, Northwestern Memorial Hospital, Chicago, IL, USA
Oriana Sanchez, MD Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Trinidad Sánchez, MD Department of Pediatric Cardiology and Pulmonology, Division of Pediatrics and Sleep Medicine Center, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
James W. Schroeder Jr., MD Department of Surgery, Division of Otorhinolaryngology, Head and Neck Surgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Department of Otorhinolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Sophie Shay, MD Division of Otolaryngology-Head and Neck Surgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern McGaw Medical Center, Chicago, IL, USA
Stephen H. Sheldon, DO, FAAP Departments of Pediatrics & Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Sleep Medicine Center, Division of Pulmonary and Sleep Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
Vinaya Soundararajan, MD Department of Dermatology, Northwestern University, Chicago, IL, USA
Bruce Tan, MD Department of Otolaryngology, Head & Neck Surgery, Northwestern Memorial Hospital, Chicago, IL, USA
Hui-Leng Tan, MBBChir, MD Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK
Ignacio E. Tapia, MD, MS Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Sleep Center, Division of Pulmonary Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Erin Thanik, MD, MPH Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Irina Trosman, MD Sleep Medicine Center, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Samuel J. Trosman, MD Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Charlie Tyack, DClinPsy Sleep Medicine Department, Evelina London Children’s Hospital, Guy’s & St Thomas’ NHS Foundation Trust, London, UK
Sally Ward, MD Division of Pulmonology and Sleep Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA
Joshua B. Wechsler, MD Division of Gastroenterology, Hepatology & Nutrition, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Julia A. Wisniewski, MD Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Manisha Witmans, MD, FRCPC, FAASM Division of Pediatric Pulmonology, Department of Pediatrics, The Stollery Children’s Hospital & University of Alberta Hospitals, Edmonton, AB, Canada
Duri Yun, MD, MPH Departments of Pediatrics and Dermatology, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Phyllis C. Zee, MD, PhD Department of Neurology, Northwestern Medicine Feinberg School of Medicine, Chicago, IL, USA
Part I
Science of Sleep
Sleep, Sleep Disorders, and Immune Function
Hui-Leng Tan, Leila Kheirandish-Gozal, and David Gozal
In this introductory chapter, our aim is not to provide comprehensive coverage of the topic, but rather highlight tantalizing snippets of interesting information regarding the paradigm of the busy cross talk between sleep, sleep disorders, and immune function, in the hope that it will pique the interest of the reader and stimulate further reading.
Sleep and Immune Function
Immunological processes are regulated by sleep and circadian rhythms [1]. During sleep, downregulation of the hypothalamus–pituitary-adrenal (HPA) axis and reduced activity of the sympathetic nervous system (SNS) occur. Levels of cortisol, epinephrine, and norepinephrine decrease, whereas levels of growth hormone (GH), leptin, and prolactin increase. All of these hormones and many others support immune cell activation, proliferation, and differentiation and the production of proinflammatory cytokines such as IL-1, IL-12, TNF-α, and IFN-γ. Immune rhythms are also regulated by intrinsic cellular clocks which arise from conserved transcription-translation feedback oscillator loops driven by a set of dedicated clock proteins. These circadian clocks regulate the rhythms of inflammatory processes by H.-L. Tan
Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK e-mail: H.Tan@rbht.nhs.uk
L. Kheirandish-Gozal (*)
Department of Child Health Research Institute, University of Missouri School of Medicine, Columbia, MO, USA
D. Gozal
Department of Child Health, University of Missouri School of Medicine, Columbia, MO, USA
A. Fishbein, S. H. Sheldon (eds.), Allergy and Sleep, https://doi.org/10.1007/978-3-030-14738-9_1
selectively intruding into immune pathways and orchestrate the phenotype and specific activity of multiple cells including macrophages, lymphocytes, and natural killer cells.
In accordance with such circadian-immune interactions, differentiated immune cells such as cytotoxic NK cells and terminally differentiated cytotoxic T lymphocytes increase their presence and activity during the day with increased prolonged wake periods. Since their activation can occur as a rapid response pattern and very quickly, this unique setup allows for the efficient and speedy combat of intruding antigens and organisms that are more likely to occur during the active waking phase. In contrast, undifferentiated or less differentiated immune cells, such as naïve and central memory T cells, peak during the night, when the more slowly evolving adaptive immune responses are initiated and propagated. Sleep, particularly slow-wave sleep, i.e., the predominant stage of sleep during the first half of the night, promotes the release of GH and prolactin, while cortisol and catecholamines are at trough levels. These conditions support not only the shift of the Th1/ Th2 cytokine balance toward that of Th1 but also enable the enhanced production of IL-12 by antigen-presenting cells, a process that is essential for the activation of T helper cells and an increase in T helper cell proliferation. Herein lies an important facet of the role of sleep in the formation and maintenance of immunological memory [2]. By the time one reaches the end of a night’s sleep in the early hours of the morning, Th2 activity predominates [3]. From such observations, it follows that perturbation to sleep integrity, cycling, or duration is likely to alter this finely regulated and coordinated set of immune interactions, leading to disruption of the immune homeostatic processes.
Interestingly, the relationship between the immune system and sleep is bidirectional, such that the immune response can reciprocally impact on sleep. For example, many infectious processes, particularly during the acute phase of the immune response, result in an increase in the duration of NREM sleep and concomitant decrease in REM sleep and wakefulness [4]. Cytokines such as IL-1β and TNF-α are produced as part of the acute phase immune response and can induce symptoms of fatigue and sleepiness and also promote non-rapid eye movement sleep [5]. This is postulated to be a mechanism by which organisms divert energy resources toward mounting a robust response against the infective challenge, and as such increased sleep activity is likely to improve the specific antimicrobial immune function response.
Sleep Deprivation and Its Impact on Immune Function
A substantial portion of our understanding on the relationship between sleep and the immune system has been derived from experiments which curtail the duration of sleep in experimental subjects. The impact of acute sleep deprivation differs from that of chronic sleep restriction or deprivation. Prolonged sleep curtailment invokes the non-specific persistent production of pro-inflammatory cytokines, resulting in a H.-L.
state of chronic low-grade systemic inflammation, while concomitantly impairing host defense mechanisms, both of which have significant detrimental effects on health. Low-grade systemic inflammation is one of the common themes that will be pervasively invoked throughout this chapter and is a risk factor for cognitive, cardiovascular, and metabolic morbidity, especially when present in conjunction with obesity, another common condition in which low-grade systemic inflammation is frequently detected.
It is a commonly held lay view that inadequate sleep makes one more prone to catching colds. This supposedly “old wives’ tale” is actually supported by experimental models. Prather et al. recruited 164 healthy adult volunteers, objectively assessed their sleep duration for a week, then quarantined them, and administered nasal drops containing rhinovirus [6]. Participants who had shorter sleep duration (<6 h) prior to inoculation had an increased likelihood of developing clinical cold symptoms. This work supported similar findings from a prior study by Cohen and collaborators, based on self-reported sleep duration [7]. Consistent with these experimental findings, analysis of data from National Health and Nutrition Examination Surveys (NHANES) in US adults revealed that self-reported short sleep duration, a physician’s diagnosis of a sleep disorder, or reported trouble with sleeping were all associated with a greater likelihood of a common cold, infection, or both in the 30 days prior to the survey [8].
To return to the previously alluded topic of immunological memory, sleep has been shown to have an impact on vaccine responses. Restricting sleep for a week prior to administration of the influenza vaccine significantly reduced the effectiveness of the vaccine response and the generation of neutralizing antibodies to the antigen epitopes of the vaccine [9]. Similarly, subjects who had regular sleep after hepatitis A vaccination (HAV) displayed a nearly twofold higher HAV antibody titer after 4 weeks when compared to subjects who were kept awake on the night prior to the administration of the vaccine [10]. Under real-life conditions, shorter sleep duration predicted a decreased likelihood of being clinically protected from hepatitis B at the conclusion of the three doses of hepatitis B vaccination series [11].
Shift Work and the Immune System
A growing number of epidemiological studies have linked night shift work to increased risk of cancer, presumably secondary to circadian disruption. Night shift work has been shown to be associated with epigenetic modifications of key circadian genes, some of which can act as transcriptional regulators, altering the expression of cancer-related susceptibility genes and gene networks regulating cell division and DNA repair [12]. It has also been postulated that the suppression of melatonin from nighttime light exposure further contributes to the environmental milieu favoring tumorigenesis, as melatonin can be oncostatic. Indeed, as far back as 2007, the WHO recognized this epidemiologic evidence and classified night shift work as a probable carcinogen.
Poor Sleep Quality and Telomeres
Prather et al. hypothesized that accelerated cellular aging, as indicated by telomere attrition in immune cells, may explain the association between poor sleep quality with increased incidence and progression of a number of chronic health conditions, particularly in obese individuals [13]. They showed that in obese adults, poorer global sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI), was associated with shorter telomere length in T lymphocytes.
Obstructive Sleep Apnea
Here we will take advantage of a rather extensive body of work in a highly prevalent sleep disorder, namely, obstructive sleep apnea (OSA), to illustrate some of the concepts briefly discussed above and to further explore a few of the themes in greater detail. OSA is now recognized as one of the most common sleep disorders in childhood as well in adulthood. Estimates of prevalence in pediatric populations vary depending on the country or ethnic groups evaluated as well as on the stringency of the diagnostic criteria used but typically range between 1% and 5% and can be appreciably higher in certain high-risk groups. It is defined as partial or complete obstruction of the upper airway during sleep, potentially resulting in oxygen desaturations and hypercapnia, increased respiratory effort with intrathoracic pressure swings and sleep fragmentation. The various relationships between pediatric OSA and immune function are closely entwined (for more details see chapter on Sleep-Related Breathing Disorders and Inflammation).
Firstly, immune cells play an important role in the etiology of pediatric OSA. OSA etiology is typically multifactorial, and pathophysiological factors are often empirically divided into anatomical factors that effectively reduce airway caliber and factors which increase upper airway collapsibility. Immune cells potentially contribute to both. One of the commonest etiological factors in pediatric OSA is adenotonsillar hypertrophy. The exact mechanisms underlying follicular lymphoid proliferation and hyperplasia of the tonsils and adenoids remain poorly understood. However, when tonsillar tissues from children with OSA are cultured in vitro, the proliferative rates of the associated cluster of differentiation (CD)3, CD4, and CD8 cells were higher compared with tonsillar tissues from children with recurrent tonsillitis. Proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1α were also more highly expressed in the OSA-derived tonsils. It has been postulated that respiratory viruses and possibly recurrent vibration of the upper airway wall from snoring may promote localized inflammation and perpetuate specific immune memory mechanisms that are more likely to be activated in the context of recurring viral stimuli prompting the accelerated proliferation and enlargement of the adenoids and tonsils and thereby facilitating upper airway obstructions during sleep. Inflammatory conditions affecting the upper airways, such as allergic rhinitis and asthma, can also contribute to increased upper airway collapsibility.
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Medical therapy for OSA, particularly when mild, is therefore centered around immune modulators, namely, leukotriene-receptor antagonists (such as montelukast) and intranasal corticosteroids. There is increased expression of cysteinyl leukotriene receptors in tonsils from children with OSA compared with children with recurrent tonsillitis [14]. These leukotriene receptors have been shown to be expressed by tonsillar T cell lymphocytes [15]. Application of leukotriene antagonist to an in vitro tonsillar cell culture system (obtained from children with OSA) elicited dose-dependent reductions in cell proliferation and reductions in the secretion of the cytokines TNF-α, IL-6, and IL-12 [16]. These results suggest that leukotriene pathways mediate intrinsic proliferative and inflammatory signaling pathways in adenotonsillar tissues from children with OSA, and targeted pharmacologic disruption of these pathways serves as a viable treatment option. Indeed, studies where children with mild OSA received a treatment course of montelukast have resulted in significant reductions in adenoidal size and improvement of their OSA severity [17, 18].
Similarly, the addition of corticosteroids in vitro to the tonsillar cell culture system resulted in decreased proliferative rates and increased apoptosis and reduction in the secretion of the pro-inflammatory cytokines IL-6, IL-8, and TNF-α [19]. A randomized crossover trial of 6-week treatment with intranasal budesonide for mild OSA showed reductions in the severity of OSA as well as in the size of adenoidal tissues. Importantly, discontinuation of therapy for 8 weeks did not result in the occurrence of rebound symptoms [20].
Obstructive Sleep Apnea and Inflammation
OSA can promote the activation and propagation of systemic inflammatory responses [21]. Microarray analyses of mRNA from peripheral leukocytes isolated from children with OSA has revealed the coordinated recruitment of gene clusters involved in the regulation and propagation of inflammatory pathways [22]. Studies have demonstrated the elevation of plasma levels of pro-inflammatory cytokines such as IL-6, IFN-γ, and TNF-α in children with OSA, while levels of the antiinflammatory cytokine IL-10 are reduced, thereby shifting the balance even further toward a pro-inflammatory state [23–26]. One potential mechanism of such findings may reside in the occurrence of epigenetic modifications within regulatory T lymphocyte (Tregs) subsets. The promoter region of the FOXP3 gene, which controls the transcriptional fate and differentiation of lymphocytes into Tregs, exhibits OSA severity-dependent increases in methylation in affected children [27]. Such epigenetic alterations have subsequently been linked to the presence of reduced Treg counts in the peripheral blood of children with OSA [28]. Considering the significant role Tregs play in the suppression of inflammation, it is postulated that differentially orchestrated responses of various tissues to OSA-induced perturbations may interact with environmental and intrinsic genetic factors to elicit a spectrum of inflammatory phenotypes linked to end-organ morbidities [29].
OSA and Asthma
The prevalence of children snoring and scoring positive for sleep-disordered breathing in the pediatric sleep questionnaire is higher in asthmatic children than in nonasthmatic children and increased with increasing asthma severity [30].
Kheirandish-Gozal et al. demonstrated that prevalence of polysomnographically proven OSA is indeed higher in children with poorly controlled asthma. Furthermore, asthma control was improved following effective treatment of OSA [31].
Bhattacharjee et al. took this a step further and studied asthma control of 13,506 asthmatic children in the USA who underwent adenotonsillectomy via electronic database analysis, comparing their asthma control the year prior to surgery with the year following the surgical procedure [32]. The authors found a 30% reduction in asthma exacerbations, a 25% decrease in the number of asthma-related emergency room visits, and a 36% reduction in asthma-related hospital admissions after adenotonsillectomy. In contrast, there was just a 2% reduction in asthma exacerbations seen in the 27,012 age-, sex-, and geography-matched control children with asthma who did not undergo adenotonsillectomy. A systematic review of the literature also found clinically significant reductions in markers of asthma severity after adenotonsillectomy, i.e., when the two conditions coexist, treatment of the OSA can be associated with improved asthma control [33]. When adult patients with asthma who had moderate/severe OSA were treated with CPAP, their asthma control, quality of life, and lung function were markedly improved [34]. These findings have prompted many respiratory centers to start screening for OSA in their difficult asthma programs. Of note, asthma has also been identified as one of the risk factors for residual OSA post adenotonsillectomy [35].
It is worth highlighting that there was a high proportion of obese children in the abovementioned study cohorts. Obesity is an important risk factor for OSA, and both are conditions where there is low-grade systemic inflammation [36]. When OSA was successfully treated in obese children with OSA, IL-6, IL-18, PAI-1, MCP-1, MMP-9, adropin, and leptin plasma levels decreased, whereas adiponectin levels increased [37]. These improvements were not seen in the 30 children in whom there was residual OSA. This study would suggest that in obese children, not only does OSA amplify the underlying systemic inflammatory pathways that have been a priori been activated by obesity, but more importantly, effective treatment of the OSA results in improvement in the overall inflammatory status. An epidemiological link has also been described between obesity and asthma, thereby suggesting an interplay between the three conditions [38].
The mechanisms underlying the link between OSA and asthma are still poorly understood. The united airway hypothesis [39] postulates that inflammation of the upper airway from OSA may exacerbate inflammation in the lower airways, with resultant deterioration in asthma control. Conversely, exhaled breath condensate containing inflammatory cytokines originating from the lower airways in poorly controlled asthmatics may initiate or contribute to the proliferation of upper airway lymphoid tissues and also promote upper airway collapsibility, and thus OSA.
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Intermittent
Allergic rhinitis
Chronic rhinosinusitis
Other atopic diseases
The relationship between OSA and other atopic diseases such as allergic rhinitis and atopic dermatitis is covered in greater detail in the rest of this book and will thus only be briefly alluded to in this chapter (Fig. 1.1). In 2015, members of the Work Group on Rhinitis and Sleep-Disordered Breathing conducted a webbased survey to members of the American Academy of Allergy, Asthma & Immunology [40]. Eighty-two percent of respondents treated were both adults and children, while 9% treated just children. While taking into account the low response rate of just 7% to the survey with the ensuing possibility that responders may have self-selected on the basis of their level of interest in this clinical topic, it is still illuminating to see that the majority of respondents routinely asked about sleep problems, believed that sleep-disordered breathing was a problem for at least a substantial minority (10–30%) of their patients, and believed that medical therapy for upper airway inflammatory conditions could potentially help ameliorate sleep-related complaints. Of the respondents evaluating children with suspected OSA and adenotonsillar hypertrophy, 60% used anti-inflammatory medication as initial therapy, although most managed cases in collaboration with an otolaryngologist.
Asthma
Atopic dermatitis
Fig. 1.1 Schematic of the reciprocal interactions between sleep and various atopic conditions that are covered in this book
Obstructive Sleep Apnea and Autoimmune Disorders
It has been hypothesized that OSA leads to the development and worsening of autoimmune disorders via the pathways of intermittent hypoxia during sleep and sleep disruption per se as evidence by the increased arousals from sleep required to facilitate upper airway opening. The aforementioned factors lead to a chronic systemic inflammatory state and immunological changes which are postulated to contribute to the pathophysiology of these autoimmune diseases. Examples include the relationships between OSA and psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.
OSA and Rheumatoid Arthritis
A bidirectional relationship exists between rheumatoid arthritis (RA) and OSA. A recent nationwide cohort study has revealed that patients with sleep disorders exhibited a 1.49-fold greater risk of developing RA compared with the comparison cohort when adjusted for covariates [41]. Conversely, a large population-based retrospective cohort study of 33,418 patients newly diagnosed with RA compared with 33,418 randomly selected controls showed an overall incidence rate of OSA that was 75% greater in the RA cohort than in the non-RA cohort, with an adjusted hazard ratio of 1.75 [42]. The pathophysiology by which RA can contribute to the development of OSA is better understood – RA can cause anatomical changes which result in OSA. For example, when RA affects the temporomandibular joint, destruction of this joint can lead to adult onset micrognathia or retrognathia, and the resultant anatomical narrowing of the oropharynx can result in OSA [43, 44]. Similarly, cervical spine instability secondary to RA can result in OSA: a study of RA patients with occipitocervical lesions showed that 79% had significant OSA and that a smaller atlantodental interval and shorter cervical lengths was associated with OSA [45]. Immobility due to painful arthritic hip or knee joints may predispose to weight gain which is another risk factor for OSA. Sleep problems such as poor sleep quality and sleep fragmentation are often reported in RA patients [46]. Sleep disturbances can exacerbate pain, and both are associated with poorer quality of life in these patients [47].
OSA and SLE
A large retrospective cohort study demonstrated that sleep disorders increased the risk of developing SLE with an overall adjusted hazard ratio of 2.20 [48]. SLE patients have been shown to have poorer sleep efficiency with increased arousals and decreased stage 3 and 4 sleep [49]. Poor sleep quality is common in patients with SLE and adversely affects their quality of life [50]. Contributing factors besides disease activity also include depression, SLE medications such as prednisolone, and fibromyalgia [50, 51].
OSA and Psoriasis
A large retrospective cohort study has shown that OSA is associated with an increased risk of developing psoriasis with a hazard ratio of 2.30 [52]. Psoriasis may also contribute to sleeping difficulties from associated depression or nighttime itching [53].
OSA and Cancer
Epidemiological studies have highlighted the association between OSA and cancer. The Wisconsin Sleep Cohort study showed that compared with control subjects, the adjusted relative hazard ratios of cancer mortality were 1.1 for mild SDB, 2.0 for moderate SDB, and 4.8 for severe SDB [54]. Similar findings were reported by a large multicenter Spanish cohort, though the difference was more significant in younger patients aged <65 years [55]. When overall cancer incidence was examined in the Spanish cohort, the severity of OSA as indicated by the number of respiratory events per hour of sleep was not associated per se with cancer incidence in the adjusted analyses, except for patients younger than 65 years. However, increasing severity of nocturnal hypoxia was associated with increased cancer incidence [56]. Of note, a database analysis in 1.7 million patients with OSA matched with 1.7 million of age-, gender-, co-morbidities, and local of residence controls also revealed that specific cancers were more likely in OSA, namely, pancreas, melanoma, lung, and kidney malignancies [57]. Intriguingly, in a pilot study of 18 patients with severe OSA, whole-genome expression of peripheral blood leucocytes was performed, and gene set enrichment analysis at baseline compared with post effective treatment with CPAP revealed a number of enriched gene sets, some of which were involved in neoplastic processes and were downregulated posttreatment [58].
In animal tumor models, mice exposed to sleep fragmentation (SF) had significantly larger and more invasive tumors than controls [59]. More tumor-associated macrophages (TAMs) were present in tumors from mice exposed to SF, and their distribution was closer to the tumor capsule as opposed to the tumor core as seen in the control mice. TAMs release growth factors, cytokines, inflammatory mediators, and proteolytic enzymes implicated in tumor growth and invasion and thus play a critical role in determining the tumor microenvironment. M1 macrophages exert antitumor properties, while M2 macrophages support tumor proliferation and invasion. The TAMs in the SF mice were predominantly M2 macrophages while expressing higher levels of TLR4. The more aggressive tumor phenotype was abrogated in TLR4 knockout mice, suggesting TLR4 signaling mediates SF-induced tumor progression. Further research is required to elucidate the role of OSA in this immunological context. Interestingly, reduced NADPH oxidase activity has been demonstrated within the solid tumor microenvironment of these mice, which may explain in part the increased tumor aggressiveness under SF conditions [60].
Animal tumor models exposed to intermittent hypoxia (IH) have also demonstrated increased tumor growth, invasiveness, and metastasis [61]. Similar to SF, IH appears to induce alterations in the host immune response such as a shift in macrophage polarity from M1 to M2, which results in the tumor’s more aggressive phenotype [62]. IH may induce an imbalance in oxidation/reduction processes, resulting in the generation of excessive reactive oxygen species. It can also trigger an inflammatory response and modulate transcriptional factors such as hypoxia-inducible factors (HIFs) and NF-κB [63]. Increased tumor vascularization has been observed in IH mice which could be mediated by the upregulation of vascular endothelial
growth factor (VEGF) via HIFs. This increased vascularization could facilitate tumor cell migration into the circulation and thus metastasis.
SF and IH can both result in surges in sympathetic outflow and corresponding changes in systemic and local tissue catecholamine levels. β-Adrenergic signaling has been shown to increase macrophage infiltration into primary tumor parenchyma and their shift toward M2 macrophage differentiation [64]. It can also induce a metastatogenic tumor cell type by directly regulating gene expression and increasing migratory activity of tumor cells [65].
Severe OSA patients (adults) have been shown to have significantly reduced levels of circulating invariant natural killer T (iNKT) cells compared with patients with mild/moderate OSA and controls [66]. These levels increased following 12-month treatment of OSA with CPAP therapy. In vitro experiments on iNKT cell lines demonstrated increased apoptosis and impaired cytotoxicity when the cells were exposed to a 24 h period of hypoxia. As iNKT cells are another immune cell type which plays an important role in cancer immunity, these observations may be another contributing factor to the increased cancer risk reported in patients with OSA.
Conclusions
Sleep and the immune system are intricately linked. Many immune disorders may affect sleep, and reciprocally, sleep characteristics may affect the clinical course of these diseases via interactions with the immune system. Taking a thorough sleep history, addressing sleep hygiene and having systems in place to screen for and treat common sleep disorders such as OSA should be a prerequisite in the overall holistic care of patients. Certainly, the emerging evidence would suggest that greater awareness and improved management of sleep disorders in patients with associated diseases may improve disease outcomes.
And now, “to sleep, perchance to dream”…
Financial Support LKG and DG are supported by National Institutes of Health grant HL130984. DG is also supported by the Herbert T. Abelson Chair in Pediatrics.
References
1. Irwin MR. Why sleep is important for health: a psychoneuroimmunology perspective. Annu Rev Psychol. 2015;66:143–72.
2. Besedovsky L, Lange T, Born J. Sleep and immune function. Pflugers Arch. 2012;463(1): 121–37.
3. Dimitrov S, Lange T, Tieken S, Fehm HL, Born J. Sleep associated regulation of T helper 1/T helper 2 cytokine balance in humans. Brain Behav Immun. 2004;18(4):341–8.
4. Ibarra-Coronado EG, Pantaleon-Martinez AM, Velazquez-Moctezuma J, Prospero-Garcia O, Mendez-Diaz M, Perez-Tapia M, et al. The bidirectional relationship between sleep and immunity against infections. J Immunol Res. 2015;2015:678164.
5. Clinton JM, Davis CJ, Zielinski MR, Jewett KA, Krueger JM. Biochemical regulation of sleep and sleep biomarkers. J Clin Sleep Med. 2011;7(5 Suppl):S38–42.
H.-L. Tan et al.
1 Sleep, Sleep Disorders, and Immune Function
6. Prather AA, Janicki-Deverts D, Hall MH, Cohen S. Behaviorally assessed sleep and susceptibility to the common cold. Sleep. 2015;38(9):1353–9.
7. Cohen S, Doyle WJ, Alper CM, Janicki-Deverts D, Turner RB. Sleep habits and susceptibility to the common cold. Arch Intern Med. 2009;169(1):62–7.
8. Prather AA, Leung CW. Association of insufficient sleep with respiratory infection among adults in the United States. JAMA Intern Med. 2016;176(6):850–2.
9. Spiegel K, Sheridan JF, Van Cauter E. Effect of sleep deprivation on response to immunization. JAMA. 2002;288(12):1471–2.
10. Lange T, Perras B, Fehm HL, Born J. Sleep enhances the human antibody response to hepatitis A vaccination. Psychosom Med. 2003;65(5):831–5.
11. Prather AA, Hall M, Fury JM, Ross DC, Muldoon MF, Cohen S, et al. Sleep and antibody response to hepatitis B vaccination. Sleep. 2012;35(8):1063–9.
12. Haus EL, Smolensky MH. Shift work and cancer risk: potential mechanistic roles of circadian disruption, light at night, and sleep deprivation. Sleep Med Rev. 2013;17(4):273–84.
13. Prather AA, Gurfein B, Moran P, Daubenmier J, Acree M, Bacchetti P, et al. Tired telomeres: poor global sleep quality, perceived stress, and telomere length in immune cell subsets in obese men and women. Brain Behav Immun. 2015;47:155–62.
14. Goldbart AD, Goldman JL, Li RC, Brittian KR, Tauman R, Gozal D. Differential expression of cysteinyl leukotriene receptors 1 and 2 in tonsils of children with obstructive sleep apnea syndrome or recurrent infection. Chest. 2004;126(1):13–8.
15. Kaditis AG, Ioannou MG, Chaidas K, Alexopoulos EI, Apostolidou M, Apostolidis T, et al. Cysteinyl leukotriene receptors are expressed by tonsillar T cells of children with obstructive sleep apnea. Chest. 2008;134(2):324–31.
16. Dayyat E, Serpero LD, Kheirandish-Gozal L, Goldman JL, Snow A, Bhattacharjee R, et al. Leukotriene pathways and in vitro adenotonsillar cell proliferation in children with obstructive sleep apnea. Chest. 2009;135(5):1142–9.
17. Goldbart AD, Goldman JL, Veling MC, Gozal D. Leukotriene modifier therapy for mild sleepdisordered breathing in children. Am J Respir Crit Care Med. 2005;172(3):364–70.
18. Goldbart AD, Greenberg-Dotan S, Tal A. Montelukast for children with obstructive sleep apnea: a double-blind, placebo-controlled study. Pediatrics. 2012;130(3):e575–80.
19. Kheirandish-Gozal L, Serpero LD, Dayyat E, Kim J, Goldman JL, Snow A, et al. Corticosteroids suppress in vitro tonsillar proliferation in children with obstructive sleep apnoea. Eur Respir J. 2009;33(5):1077–84.
20. Kheirandish-Gozal L, Gozal D. Intranasal budesonide treatment for children with mild obstructive sleep apnea syndrome. Pediatrics. 2008;122(1):e149–55.
21. Gozal D. Sleep, sleep disorders and inflammation in children. Sleep Med. 2009;10(Suppl 1):S12–6.
22. Khalyfa A, Capdevila OS, Buazza MO, Serpero LD, Kheirandish-Gozal L, Gozal D. Genomewide gene expression profiling in children with non-obese obstructive sleep apnea. Sleep Med. 2009;10(1):75–86.
23. Gozal D, Serpero LD, Kheirandish-Gozal L, Capdevila OS, Khalyfa A, Tauman R. Sleep measures and morning plasma TNF-alpha levels in children with sleep-disordered breathing. Sleep. 2010;33(3):319–25.
24. Tauman R, O’Brien LM, Gozal D. Hypoxemia and obesity modulate plasma C-reactive protein and interleukin-6 levels in sleep-disordered breathing. Sleep Breath. 2007;11(2):77–84.
25. Gozal D, Serpero LD, Sans Capdevila O, Kheirandish-Gozal L. Systemic inflammation in non-obese children with obstructive sleep apnea. Sleep Med. 2008;9(3):254–9.
26. Tam CS, Wong M, McBain R, Bailey S, Waters KA. Inflammatory measures in children with obstructive sleep apnoea. J Paediatr Child Health. 2006;42(5):277–82.
27. Kim J, Bhattacharjee R, Khalyfa A, Kheirandish-Gozal L, Capdevila OS, Wang Y, et al. DNA methylation in inflammatory genes among children with obstructive sleep apnea. Am J Respir Crit Care Med. 2012;185(3):330–8.
28. Tan HL, Gozal D, Wang Y, Bandla HP, Bhattacharjee R, Kulkarni R, et al. Alterations in circulating T-cell lymphocyte populations in children with obstructive sleep apnea. Sleep. 2013;36(6):913–22.
29. Kheirandish-Gozal L, Gozal D. Genotype-phenotype interactions in pediatric obstructive sleep apnea. Respir Physiol Neurobiol. 2013;189(2):338–43.
30. Goldstein NA, Aronin C, Kantrowitz B, Hershcopf R, Fishkin S, Lee H, et al. The prevalence of sleep-disordered breathing in children with asthma and its behavioral effects. Pediatr Pulmonol. 2015;50(11):1128–36.
31. Kheirandish-Gozal L, Dayyat EA, Eid NS, Morton RL, Gozal D. Obstructive sleep apnea in poorly controlled asthmatic children: effect of adenotonsillectomy. Pediatr Pulmonol. 2011;46(9):913–8.
32. Bhattacharjee R, Choi BH, Gozal D, Mokhlesi B. Association of adenotonsillectomy with asthma outcomes in children: a longitudinal database analysis. PLoS Med. 2014;11(11):e1001753.
33. Kohli N, DeCarlo D, Goldstein NA, Silverman J. Asthma outcomes after adenotonsillectomy: a systematic review. Int J Pediatr Otorhinolaryngol. 2016;90:107–12.
34. Serrano-Pariente J, Plaza V, Soriano JB, Mayos M, Lopez-Vina A, Picado C, et al. Asthma outcomes improve with continuous positive airway pressure for obstructive sleep apnea. Allergy. 2017;72(5):802–12.
35. Bhattacharjee R, Kheirandish-Gozal L, Spruyt K, Mitchell RB, Promchiarak J, Simakajornboon N, et al. Adenotonsillectomy outcomes in treatment of obstructive sleep apnea in children: a multicenter retrospective study. Am J Respir Crit Care Med. 2010;182(5):676–83.
36. Bhattacharjee R, Kim J, Kheirandish-Gozal L, Gozal D. Obesity and obstructive sleep apnea syndrome in children: a tale of inflammatory cascades. Pediatr Pulmonol. 2011;46(4):313–23.
37. Kheirandish-Gozal L, Gileles-Hillel A, Alonso-Alvarez ML, Peris E, Bhattacharjee R, TeranSantos J, et al. Effects of adenotonsillectomy on plasma inflammatory biomarkers in obese children with obstructive sleep apnea: a community-based study. Int J Obes. 2015;39(7):1094–100.
38. Kheirandish-Gozal L, Gozal D. Obesity, asthma, and sleep-disordered breathing. J Pediatr. 2012;160(5):713–4.
39. Gozal D. Pediatric OSA: a case for “United We Stand” in the way of a breath. Pediatr Pulmonol. 2010;45(12):1151–2.
40. Shusterman D, Baroody FM, Craig T, Friedlander S, Nsouli T, Silverman B, et al. Role of the allergist-immunologist and upper airway allergy in sleep-disordered breathing. J Allergy Clin Immunol Pract. 2017;5(3):628–39.
41. Chung WS, Lin CL. Sleep disorders associated with risk of rheumatoid arthritis. Sleep Breath. 2018;22:1083–91. https://doi.org/10.1007/s11325-018-1639-1
42. Shen TC, Hang LW, Liang SJ, Huang CC, Lin CL, Tu CY, et al. Risk of obstructive sleep apnoea in patients with rheumatoid arthritis: a nationwide population-based retrospective cohort study. BMJ Open. 2016;6(11):e013151.
43. Sugahara T, Mori Y, Kawamoto T, Sakuda M. Obstructive sleep apnea associated with temporomandibular joint destruction by rheumatoid arthritis: report of case. J Oral Maxillofac Surg. 1994;52(8):876–80.
44. Alamoudi OS. Sleep-disordered breathing in patients with acquired retrognathia secondary to rheumatoid arthritis. Med Sci Monit. 2006;12(12):CR530–4.
45. Shoda N, Seichi A, Takeshita K, Chikuda H, Ono T, Oka H, et al. Sleep apnea in rheumatoid arthritis patients with occipitocervical lesions: the prevalence and associated radiographic features. Eur Spine J. 2009;18(6):905–10.
46. Abad VC, Sarinas PS, Guilleminault C. Sleep and rheumatologic disorders. Sleep Med Rev. 2008;12(3):211–28.
47. Purabdollah M, Lakdizaji S, Rahmani A, Hajalilu M, Ansarin K. Relationship between sleep disorders, pain and quality of life in patients with rheumatoid arthritis. J Caring Sci. 2015;4(3):233–41.
48. Chung WS, Lin CL, Kao CH. Association of systemic lupus erythematosus and sleep disorders: a nationwide population-based cohort study. Lupus. 2016;25(4):382–8.
49. Iaboni A, Ibanez D, Gladman DD, Urowitz MB, Moldofsky H. Fatigue in systemic lupus erythematosus: contributions of disordered sleep, sleepiness, and depression. J Rheumatol. 2006;33(12):2453–7.
H.-L.
50. Mirbagher L, Gholamrezaei A, Hosseini N, Sayed Bonakdar Z. Sleep quality in women with systemic lupus erythematosus: contributing factors and effects on health-related quality of life. Int J Rheum Dis. 2016;19(3):305–11.
51. Da Costa D, Bernatsky S, Dritsa M, Clarke AE, Dasgupta K, Keshani A, et al. Determinants of sleep quality in women with systemic lupus erythematosus. Arthritis Rheum. 2005;53(2):272–8.
52. Yang YW, Kang JH, Lin HC. Increased risk of psoriasis following obstructive sleep apnea: a longitudinal population-based study. Sleep Med. 2012;13(3):285–9.
53. Hirotsu C, Nogueira H, Albuquerque RG, Tomimori J, Tufik S, Andersen ML. The bidirectional interactions between psoriasis and obstructive sleep apnea. Int J Dermatol. 2015;54(12):1352–8.
54. Nieto FJ, Peppard PE, Young T, Finn L, Hla KM, Farre R. Sleep-disordered breathing and cancer mortality: results from the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med. 2012;186(2):190–4.
55. Martinez-Garcia MA, Campos-Rodriguez F, Duran-Cantolla J, de la Pena M, Masdeu MJ, Gonzalez M, et al. Obstructive sleep apnea is associated with cancer mortality in younger patients. Sleep Med. 2014;15(7):742–8.
56. Campos-Rodriguez F, Martinez-Garcia MA, Martinez M, Duran-Cantolla J, Pena Mde L, Masdeu MJ, et al. Association between obstructive sleep apnea and cancer incidence in a large multicenter Spanish cohort. Am J Respir Crit Care Med. 2013;187(1):99–105.
57. Gozal D, Ham SA, Mokhlesi B. Sleep apnea and cancer: analysis of a nationwide population sample. Sleep. 2016;39(8):1493–500.
58. Gharib SA, Seiger AN, Hayes AL, Mehra R, Patel SR. Treatment of obstructive sleep apnea alters cancer-associated transcriptional signatures in circulating leukocytes. Sleep. 2014;37(4):709–14, 14A-14T
59. Hakim F, Wang Y, Zhang SX, Zheng J, Yolcu ES, Carreras A, et al. Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling. Cancer Res. 2014;74(5):1329–37.
60. Zheng J, Almendros I, Wang Y, Zhang SX, Carreras A, Qiao Z, et al. Reduced NADPH oxidase type 2 activity mediates sleep fragmentation-induced effects on TC1 tumors in mice. Oncoimmunology. 2015;4(2):e976057.
61. Almendros I, Gozal D. Intermittent hypoxia and cancer: undesirable bed partners? Respir Physiol Neurobiol. 2018;256:79–86. https://doi.org/10.1016/j.resp.2017.08.008. Epub 14 Aug 2017
62. Almendros I, Wang Y, Becker L, Lennon FE, Zheng J, Coats BR, et al. Intermittent hypoxiainduced changes in tumor-associated macrophages and tumor malignancy in a mouse model of sleep apnea. Am J Respir Crit Care Med. 2014;189(5):593–601.
63. Gozal D, Farre R, Nieto FJ. Obstructive sleep apnea and cancer: epidemiologic links and theoretical biological constructs. Sleep Med Rev. 2016;27:43–55.
64. Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 2010;70(18):7042–52.
65. Lang K, Drell TL, Lindecke A, Niggemann B, Kaltschmidt C, Zaenker KS, et al. Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int J Cancer. 2004;112(2):231–8.
66. Gaoatswe G, Kent BD, Corrigan MA, Nolan G, Hogan AE, McNicholas WT, et al. Invariant natural killer T cell deficiency and functional impairment in sleep apnea: links to cancer comorbidity. Sleep. 2015;38(10):1629–34.
Overview of Basic Immunology
Barry J. Pelz and Joshua B. Wechsler
Every day, humans are exposed to environmental challenges from potential pathogens such as bacteria, viruses, and fungi. This exposure occurs in several sites throughout the body including the airway, skin, and gastrointestinal tract, as these are continuously interacting with the environment. Yet exposure often does not lead to infection or illness.
The immune system has evolved at multiple levels to defend against unwanted invaders. Although the human immune system is quite adept at these defenses, it can become dysfunctional and inappropriately respond to presumably harmless stimuli (e.g., atopic disease, celiac disease, or inflammatory bowel disease) or pathologically lose the ability to regulate cell proliferation (e.g., cancer). An intricate interplay of various specialized immune cells including T and B cells, regulatory cells, mast cells, basophils, neutrophils, natural killer cells, dendritic cells, macrophages, and structural cells underlies innate and adaptive immunity. While the innate immune system functions as an initial barrier to foreign agents, it also communicates with the adaptive immune system to develop a focused response to eliminate a pathogen and repair the tissue. Along with mucosal sites of immunity, specialized secondary lymphoid sites exist such as the draining lymph nodes, thymus, and spleen which coordinate adaptive immune function. An understanding of the basic components and function of the immune system is critical to understanding the development of chronic diseases of immune dysfunction. In this chapter, a basic overview of the functional components of the immune system is presented.
B. J. Pelz (*)
Division of Asthma, Allergy, and Clinical Immunology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA e-mail: bpelz@mcw.edu
J. B. Wechsler
Division of Gastroenterology, Hepatology & Nutrition, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
A. Fishbein, S. H. Sheldon (eds.), Allergy and Sleep, https://doi.org/10.1007/978-3-030-14738-9_2
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THE TEMPLE OF KARNAK.
AMELIA B. EDWARDS.
WE now left the village behind, and rode out across a wide plain, barren and hillocky in some parts; overgrown in others with coarse halfeh grass; and dotted here and there with clumps of palms. The Nile lay low and out of sight, so that the valley seemed to stretch away uninterruptedly to the mountains on both sides. Now leaving to the left a Sheykh’s tomb, topped by a little cupola and shaded by a group of tamarisks; now following the bed of a dry watercourse; now skirting shapeless mounds that indicated the site of ruins unexplored, the road, uneven but direct, led straight to Karnak. At every rise in the ground we saw the huge propylons towering higher above the palms. Once, but for only a few moments, there came into sight a confused and wide-spread mass of ruins, as extensive, apparently, as the ruins of a large town. Then our way dipped into a sandy groove bordered by mud-walls and plantations of dwarfpalms. All at once this groove widened, became a stately avenue guarded by a double file of shattered sphinxes, and led towards a lofty pylon standing up alone against the sky.
Close beside this grand gateway, as if growing there on purpose, rose a thicket of sycamores and palms; while beyond it were seen the twin pylons of a Temple. The sphinxes were colossal, and measured about ten feet in length. One or two were ram-headed. Of the rest—some forty or fifty in number—all were headless, some split asunder, some overturned, others so mutilated that they looked like torrent-worn boulders. This avenue once reached from Luxor to Karnak. Taking into account the distance (which is just two miles from Temple to Temple) and the short intervals at which the sphinxes are placed, there cannot originally have been fewer than five
hundred of them; that is to say, two hundred and fifty on each side of the road.
Dismounting for a few minutes, we went into the Temple; glanced round the open courtyard with its colonnade of pillars; peeped hurriedly into some ruinous side-chambers; and then rode on. Our books told us that we had seen the small Temple of Rameses the Third. It would have been called large anywhere but at Karnak.
I seem to remember the rest as if it had all happened in a dream. Leaving the small Temple, we turned towards the river, skirted the mud-walls of the native village, and approached the Great Temple by way of its main entrance. Here we entered upon what had once been another great avenue of sphinxes, ram-headed, couchant on plinths deep cut with hieroglyphic legends, and leading up from some grand landing-place beside the Nile.
And now the towers that we had first seen as we sailed by in the morning rose straight before us, magnificent in ruin, glittering to the sun, and relieved in creamy light against blue depths of sky. One was nearly perfect; the other, shattered as if by the shock of an earthquake, was still so lofty that an Arab clambering from block to block midway of its vast height looked no bigger than a squirrel.
THE TEMPLE OF
On the threshold of this tremendous portal we again dismounted. Shapeless crude-brick mounds, marking the limits of the ancient wall of circuit, reached far away on either side. An immense perspective of pillars and pylons leading up to a very great obelisk opened out
KARNAK
before us. We went in, the great walls towering up like cliffs above our heads, and entered the First Court. Here, in the midst of a large quadrangle open to the sky stands a solitary column, the last of a central avenue of twelve, some of which, disjointed by the shock, lie just as they fell, like skeletons of vertebrate monsters left stranded by the Flood.
Crossing this Court in the glowing sunlight, we came to a mighty doorway between two more propylons—the doorway splendid with coloured bas-reliefs; the propylons mere cataracts of fallen blocks piled up to right and left in grand confusion. The cornice of the doorway is gone. Only a jutting fragment of the lintel stone remains. That stone, when perfect, measured forty feet and ten inches across. The doorway must have been full a hundred feet in height.
We went on. Leaving to the right a mutilated colossus engraven on arm and breast with the cartouche of Rameses II., we crossed the shade upon the threshold, and passed into the famous Hypostyle Hall of Seti the First.
It is a place that has been much written about and often painted; but of which no writing and no art can convey more than a dwarfed and pallid impression. To describe it, in the sense of building up a recognisable image by means of words, is impossible. The scale is too vast; the effect too tremendous; the sense of one’s own dumbness, and littleness, and incapacity, too complete and crushing. It is a place that strikes you into silence; that empties you, as it were, not only of words but of ideas. Nor is this a first effect only. Later in the year, when we came back down the river and moored close by, and spent long days among the ruins, I found I never had a word to say in the Great Hall. Others might measure the girth of those tremendous columns; others might climb hither and thither, and find out points of view, and test the accuracy of Wilkinson and Mariette; but I could only look, and be silent.
Yet to look is something, if one can but succeed in remembering; and the Great Hall of Karnak is photographed in some dark corner of my brain for as long as I have memory. I shut my eyes, and see it as if I were there—not all at once, as in a picture; but bit by bit, as the
eye takes note of large objects and travels over an extended field of vision. I stand once more among those mighty columns, which radiate into avenues from whatever point one takes them. I see them swathed in coiled shadows and broad bands of light. I see them sculptured and painted with shapes of Gods and Kings, with blazonings of royal names, with sacrificial altars, and forms of sacred beasts, and emblems of wisdom and truth. The shafts of these columns are enormous. I stand at the foot of one—or of what seems to be the foot; for the original pavement lies buried seven feet below. Six men standing with extended arms, finger-tip to finger-tip, could barely span it round. It casts a shadow twelve feet in breadth—such a shadow as might be cast by a tower. The capital that juts out so high above my head looks as if it might have been placed there to support the heavens. It is carved in the semblance of a full-blown lotus, and glows with undying colours—colours that are still fresh, though laid on by hands that have been dust these three thousand years and more. It would take not six men, but a dozen to measure round the curved lip of that stupendous lily.
Such are the twelve central columns. The rest (one hundred and twenty-two in number) are gigantic too; but smaller. Of the roof they once supported, only the beams remain. Those beams are stone— huge monoliths carved and painted, bridging the space from pillar to pillar, and patterning the trodden soil with bands of shadow.
Looking up and down the central avenue, we see at the one end a flame-like obelisk; at the other, a solitary palm against a background of glowing mountain. To right, to left, showing transversely through long files of columns, we catch glimpses of colossal bas-reliefs lining the roofless walls in every direction. The King, as usual, figures in every group, and performs the customary acts of worship. The Gods receive and approve him. Half in light, half in shadow, these slender, fantastic forms stand out sharp, and clear, and colourless; each figure some eighteen or twenty feet in height. They could scarcely have looked more weird when the great roof was in its place and perpetual twilight reigned. But it is difficult to imagine the roof on, and the sky shut out. It all looks right as it is;
and one feels, somehow, that such columns should have nothing between them and the infinite blue depths of heaven....
It may be that the traveller who finds himself for the first time in the midst of a grove of Wellingtonia gigantea feels something of the same overwhelming sense of awe and wonder; but the great trees, though they have taken three thousand years to grow, lack the pathos and the mystery that comes of human labour. They do not strike their roots through six thousand years of history. They have not been watered with the blood and tears of millions.8 Their leaves know no sounds less musical than the singing of the birds, or the moaning of the night-wind as it sweeps over the highlands of Calaveros. But every breath that wanders down the painted aisles of Karnak seems to echo back the sighs of those who perished in the quarry, at the oar, and under the chariot-wheels of the conqueror.
A Thousand Miles up the Nile (London, 2d ed., 1889).
SANTA MARIA DEL FIORE.
CHARLES YRIARTE.
THE document by which the council of the municipality of Florence decided the erection of her Cathedral, in 1294, is an historic monument in which is reflected the generous spirit of the Florentines.
“Considering that all the acts and works of a people who boast of an illustrious origin should bear the character of grandeur and wisdom, we order Arnolfo, director of the works of our commune, to make the model, or a design of the building, which shall replace the church of Santa Reparata. It shall display such magnificence that no industry nor human power shall surpass it.... A government should undertake nothing unless in response to the desire of a heart more than generous, which expresses in its beatings the heart of all its citizens united in one common wish: it is from this point of view that the architect charged with the building of our cathedral must be regarded.”
It must be admitted that it would be difficult to express a more noble idea and a more elevated sentiment than this.
The name of the Cathedral is evidently an allusion to the lily, the heraldic emblem of Florence. The ceremony of laying the first stone took place on September 8th, 1298; Pope Boniface VIII. was represented by his legate, Cardinal Pietro Valeriano. Arnolfo’s plan was a Latin cross with three naves, each nave divided into four arcades with sharp pointed arches. In the centre of the cross, under the vault of the dome, was reserved a space enclosed by a ringhiera, having open sides, with an altar in its axis, and in each of its little arms five rectangular chapels were placed. The walls were naked,
and the architecture alone served for decoration; the effect, however, was altogether imposing.
Arnolfo did not finish his work; he died about 1230, leaving the church completed only as far as the capitals destined to support the arches. In 1332 Giotto was nominated to succeed him, and for about two hundred years the work was continued without interruption, under the direction of the most worthy men.
It is to Giotto that we owe that extraordinary annex to the Duomo, so celebrated throughout the world under the name of Campanile; its foundation was laid in 1334, after the little church of San Zanobio was razed. It is 85 metres high; Giotto, however, had calculated 94 metres in his plan and intended to finish the square column with a pyramid, like the Campanile of Saint Mark’s in Venice; but he was unable to complete his work, and his successor, Taddeo Gaddi, suppressed this appendix. The Campanile has six divisions; the first and the second, which are easily examined, are ornamented with sculpture executed by Andrea Pisano, after Giotto’s designs....
Even at the risk of banality, the saying attributed to Charles V. when he entered Florence after the siege should be mentioned here; he paused before the Campanile, contemplated it for a long while, and then exclaimed: “They should make a case for the Campanile and exhibit it as a jewel.”
FAÇADE OF SANTA MARIA DEL FIORE
Mounting to the top of the tower, we can count, one by one, the domes, the towers, and the monuments, and gaze upon the beautiful landscape which surrounds the city of flowers. There are in this tower seven bells, the largest of which, cast in 1705 to replace the one that had been broken, does not weigh less than 15,860 pounds.
Among the architects who succeeded Giotto, we must count the master of masters, who was, perhaps, the most incontestably illustrious of the Fifteenth Century architects—Filippo Brunelleschi. It was in 1421 that he began the superb dome which crowns the Cathedral. This was his masterpiece, surpassing in audacity and harmony all the monuments of modern art. Everyone knows that this dome is double: the interior casing is spherical, and between it and the exterior dome are placed the stairways, chains, counter-weights, and all the accessories of construction which render it enduring. It was only fifteen years after the death of the great Philippo that this dome was finished (1461). It inspired Michael Angelo for Saint Peter’s in Rome, and Leon Battista Alberti took it for his model in building the famous temple of Rimini which he left unfinished. Andrea del Verocchio, the beautiful sculptor of the Enfant au dauphin and the Tomb of the Medicis in the old sacristy, designed and executed the ball, and Giovanni di Bartolo completed the node on which the Cross stands.
The church contains several tombs, among others those of Giotto, commissioned to Benedetto da Maiano by Lorenzo the Magnificent, and that of the famous organist, Antonio Squarcialupi, a favourite of Lorenzo to whom “The Magnificent” wrote an epitaph. It is thought that the Poggio rests in Santa Maria del Fiore. The sarcophagus of Aldobrandino Ottobuoni is near the door of the Servi.
I have said that the walls are naked, that is to say that architecture does not play a great part on them, but the building contains a number of works of the highest order by Donatello, Michelozzo, Ghiberti, della Robbia, Sansovino, Bandinelli, and Andrea del Castagno. It was by the door of the Servi that Dominico di Michelino on January 30, 1465, painted Dante, a tribute paid tardily to the memory of the prince of poets by the society of Florentines, who were none other than the workmen employed in the
construction of the Cathedral. Under these arches where Boccaccio made his passionate words resound to the memory of the author of the Divina Comedia, Michelino painted Dante clothed in a red toga and crowned with laurel, holding in one hand a poem and with the other pointing to the symbolical circles. The inscription states that the execution of this fresco is due to one of Dante’s commentators, Maestro Antonio, of the order of the Franciscans.
Florence: l’histoire—Les Medicis—Les humanistes—Les lettres—Les arts (Paris, 1881).
GIOTTO’S CAMPANILE.
MRS. OLIPHANT.
OF all the beautiful things with which Giotto adorned his city, not one speaks so powerfully to the foreign visitor—the forestiere whom he and his fellows never took into account, though we occupy so large a space among the admirers of his genius nowadays—as the lovely Campanile which stands by the great Cathedral like the white royal lily beside the Mary of the Annunciation, slender and strong and everlasting in its delicate grace. It is not often that a man takes up a new trade when he is approaching sixty, or even goes into a new path out of his familiar routine. But Giotto seems to have turned without a moment’s hesitation from his paints and panels to the less easily-wrought materials of the builder and sculptor, without either faltering from the great enterprise or doubting his own power to do it. His frescoes and altar-pieces and crucifixes, the work he had been so long accustomed to, and which he could execute pleasantly in his own workshop, or on the cool new walls of church or convent, with his trained school of younger artists round to aid him, were as different as possible from the elaborate calculations and measurements by which alone the lofty tower, straight and lightsome as a lily, could have sprung so high and stood so lightly against that Italian sky. No longer mere pencil or brush, but compasses and quaint mathematical tools, figures not of art by arithmetic, elaborate weighing of proportions and calculations of quantity and balance, must have changed the character of those preliminary studies in which every artist must engage before he begins a great work. Like the poet or the romancist when he turns from the flowery ways of fiction and invention, where he is unincumbered by any restrictions save those of artistic keeping and personal will, to the grave and beaten path of history—the painter must have felt when he too
turned from the freedom and poetry of art to this first scientific undertaking. The Cathedral was so far finished by this time, its front not scarred and bare as at present, but adorned with statues according to old Arnolfo’s plan, who was dead more than thirty years before; but there was no belfry, no companion peal of peace and sweetness to balance the hoarse old vacca with its voice of iron. Giotto seems to have thrown himself into the work not only without reluctance but with enthusiasm. The foundation-stone of the building was laid in July of that year, with all the greatness of Florence looking on; and the painter entered upon his work at once, working out the most poetic effort of his life in marble and stone, among masons’ chippings and the dust and blaze of the public street. At the same time he designed, though it does not seem sure whether he lived long enough to execute, a new façade for the Cathedral, replacing Arnolfo’s old statues by something better, and raising over the doorway the delicate tabernacle work which we see in Pocetti’s picture of St. Antonino’s consecration as bishop of St. Mark’s. It would be pleasant to believe that while the foundations of the Campanile were being laid and the ruder mason-work progressing, the painter began immediately upon the more congenial labour, and made the face of the Duomo fair with carvings, with soft shades of those toned marbles which fit so tenderly into each other, and elaborate canopies as delicate as foam; but of this there seems no certainty. Of the Campanile itself it is difficult to speak in ordinary words. The enrichments of the surface, which is covered by beautiful groups set in a graceful framework of marble, with scarcely a flat or unadorned spot from top to bottom, has been ever since the admiration of artists and of the world. But we confess, for our own part, that it is the structure itself that affords us that soft ecstasy of contemplation, sense of a perfection before which the mind stops short, silenced and filled with the completeness of beauty unbroken, which Art so seldom gives, though Nature often attains it by the simplest means, through the exquisite perfection of a flower or a stretch of summer sky. Just as we have looked at a sunset, we look at Giotto’s tower, poised far above in the blue air, in all the wonderful dawns and moonlights of Italy, swift darkness shadowing its white glory at the tinkle of the Ave Mary, and a golden glow of sunbeams
accompanying the midday Angelus. Between the solemn antiquity of the old Baptistery and the historical gloom of the great Cathedral, it stands like the lily—if not, rather, like the great Angel himself hailing her who was blessed among women, and keeping up that lovely salutation, musical and sweet as its own beauty, for century after century, day after day.
The Makers of Florence (London, 1876).
THE CAMPANILE OF FLORENCE
GIOTTO’S CAMPANILE.
JOHN RUSKIN.
IN its first appeal to the stranger’s eye there is something unpleasing; a mingling, as it seems to him, of over severity with over minuteness. But let him give it time, as he should to all other consummate art. I remember well how, when a boy, I used to despise that Campanile, and think it meanly smooth and finished. But I have since lived beside it many a day, and looked out upon it from my windows by sunlight and moonlight, and I shall not soon forget how profound and gloomy appeared to me the savageness of the Northern Gothic, when I afterwards stood, for the first time, beneath the front of Salisbury. The contrast is indeed strange, if it could be quickly felt, between the rising of those grey walls out of their quiet swarded space, like dark and barren rocks out of a green lake, with their rude, mouldering, rough-grained shafts, and triple lights, without tracery or other ornament than the martins’ nests in the height of them, and that bright, smooth, sunny surface of glowing jasper, those spiral shafts and fairy traceries, so white, so faint, so crystalline, that their slight shapes are hardly traced in darkness on the pallor of the Eastern sky, that serene height of mountain alabaster, coloured like a morning cloud, and chased like a sea shell. And if this be, as I believe it, the model and mirror of perfect architecture, is there not something to be learned by looking back to the early life of him who raised it? I said that the Power of human mind had its growth in the Wilderness; much more must the love and the conception of that beauty, whose every line and hue we have seen to be, at the best, a faded image of God’s daily work, and an arrested ray of some star of creation, be given chiefly in the places which He has gladdened by planting there the fir-tree and the pine. Not within the walls of Florence, but among the far away fields of her
lilies, was the child trained who was to raise that head-stone of Beauty above the towers of watch and war. Remember all that he became; count the sacred thoughts with which he filled Italy; ask those who followed him what they learned at his feet; and when you have numbered his labours, and received their testimony, if it seem to you that God had verily poured out upon this His servant no common nor restrained portion of His Spirit, and that he was indeed a king among the children of men, remember also that the legend upon his crown was that of David’s:—“I took thee from the sheepcote, and from following the sheep.”
The Seven Lamps of Architecture (London, 1849).
THE HOUSE OF JACQUES CŒUR IN BOURGES.
AD. BERTY.
CERTAINLY Jacques Cœur, that citizen of humble birth, who, by his merit reached the highest dignity of state at an epoch when aristocracy reigned supreme, this man of genius, who, while creating a maritime commerce for France, amassed so great a fortune for himself that he was able to help towards the deliverance of his own country in supporting at his own expense four armies at the same time, was not one of the least important figures of the Fifteenth Century. Posterity has not always been just to this illustrious upstart: he should be ranked immediately after Jeanne d’Arc, for the sword of the Maid of Domrémy would, perhaps, have been powerless to chase the enemy from the soil (which a cowardly king did not think of repulsing), without the wise economy and the generous sacrifices of him, who, at a later period, was abandoned by the king to the rapacity of his courtiers with that same ignoble ingratitude which he had shown to the sainte libertrice of the great nation over which he was so unworthy to rule.
Jacques Cœur was the son of a furrier, or according to some authorities, a goldsmith of Bourges. He was probably following his father’s business when his intelligence and talents brought him into the notice of Charles VII., who had been forced to take refuge in the capital of Berry on account of the English conquests. The king appointed him to the mint, then made him master of this branch of administration, and, finally, argentier, a title equivalent to superintendent of finance. Cœur, in his new and brilliant position, did not abandon commerce to which he owed his fortune; his ships continued to furrow the seas, and three hundred clerks aided him in
bartering European products for the silks and spices of the East and in realizing a fortune. Always fortunate in his enterprises, ennobled9 by the king in 1440, and charged by him with many important political missions, he probably did not know how to resist the vertigo which always seizes those of mean origin who attain great eminence. He exhibited an extraordinary luxury, whose splendours humiliated the pride of the noble courtiers, excited their hatred and envy, and contributed to his ruin. With little regard for the great services which he had rendered to the country, such as, for example, the gift of 200,000 crowns in gold at the time of the expedition of Normandy, the nobles only saw in the magnificent argentier an unworthy gambler, who should be deprived of his immense wealth10 for their profit. For this purpose they organized a cabal. Cœur was charged with a multitude of crimes: he was accused of having poisoned Agnès Sorel, who had made him her testamentary executor, of having altered money, and of various other peculations; he was also reproached for having extorted money for various purposes in the name of the king....
The sentence of Jacques Cœur was not entirely executed; he was not banished, but, on the contrary, was imprisoned in the Convent des Cordeliers de Beaucaire. Aided by one of his clerks, Jean de Village, who had married his niece, he made his escape and went to Rome, where Pope Calixtus III., at that moment preparing an expedition against the Turks, gave him command of a flotilla. Cœur then departed, but, falling ill on the way, he disembarked at Chio, where he died in 1461. His body was buried in the church of the Cordeliers in that island.
Of the different houses which Jacques Cœur possessed, the one considered among the most beautiful in all France, exists almost intact, and is still known under the name of the Maison de Jacques Cœur, although it now serves for a hall of justice and mayoralty. This house, or rather this hôtel, was built between the years 1443 and 1453, and cost a sum equal to 215,000 francs of our money. For its construction, Cœur, having bought one of the towers of the ramparts of Bourges, commonly called Tour de la chaussée, from the fief of
this name, built on a level with it another and more beautiful tower, and these two towers served as a beginning for the manoir, which was called, in consequence, the Hôtel de la chaussée. In building it they used stones taken from the old Roman walls of the town, which were on the site of the new hôtel, and which had already been pulled down by virtue of a charter given by Louis VIII. in 1224, by which, permission had been granted for building upon the ramparts and fortifications. At the time of the revision of the law-suit of Jacques Cœur under Louis XI. the hôtel was given back to his heirs, who in 1552 sold it to Claude de l’Aubespine, secretary of state. By a descendant of the latter it was ceded to Colbert in 1679; Colbert sold it again to the town of Bourges on January 30, 1682, for the sum of 33,000 livres. Jacques Cœur’s house was therefore destined to become a hôtel-de-ville, and, as we have said, still exists to-day.
