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",isbn:"978-1-83969-234-5",printIsbn:"978-1-83969-233-8",pdfIsbn:"978-1-83969-235-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"a5f5277a1c0616ce6b35f4b44a4cac7a",bookSignature:"Dr. Basel I. Ismail",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10013.jpg",keywords:"Thermodynamics, Heat Transfer Analyses, Geothermal Power Generation, Economics, Geothermal Systems, Geothermal Heat Pump, Green Energy Buildings, Exploration Methods, Geologic Fundamentals, Geotechnical, Geothermal System Materials, Sustainability",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 29th 2020",dateEndSecondStepPublish:"November 26th 2020",dateEndThirdStepPublish:"January 25th 2021",dateEndFourthStepPublish:"April 15th 2021",dateEndFifthStepPublish:"June 14th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Leading research investigator in a collaborative project (2007-2010) with Goldcorp-Musselwhite Canada Ltd. and Engineering of Lakehead University, owner of a Ph.D. degree in Mechanical Engineering from McMaster University, Hamilton, Ontario, Canada and postdoctoral researcher (2004 to 2005) at McMaster University.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"62122",title:"Dr.",name:"Basel",middleName:"I.",surname:"Ismail",slug:"basel-ismail",fullName:"Basel Ismail",profilePictureURL:"https://mts.intechopen.com/storage/users/62122/images/system/62122.jpg",biography:"Dr. B. Ismail is currently an Associate Professor and Chairman of the Department of Mechanical Engineering, Lakehead University, Thunder Bay, Ontario, Canada. In 2004, Prof. Ismail earned his Ph.D. degree in Mechanical Engineering from McMaster University, Hamilton, Ontario, Canada. From 2004 to 2005, he worked as a Postdoctoral researcher at McMaster University. His specialty is in engineering heat transfer, engineering thermodynamics, and energy conversion and storage engineering. Dr. Ismail’s research activities are theoretical and applied in nature. Currently, his research areas of interest are focused on green engineering technologies related to alternative and renewable energy systems for power generation, heating and cooling. Dr. Ismail was the leading research investigator in a collaborative project (2007-2010) with Goldcorp-Musselwhite Canada Ltd. and Engineering of Lakehead University. This innovative project was state-of-the-art in geothermal heat pump technology applied in Northwestern Ontario, Canada. Dr. Ismail has published many technical reports and articles related to his research areas in reputable International Journals and Conferences. During his research activities, Dr. Ismail has supervised and trained many graduate students and senior undergraduate students in Mechanical Engineering with projects and theses related to innovative renewable and alternative energy engineering, and technologies.",institutionString:"Lakehead University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Lakehead University",institutionURL:null,country:{name:"Canada"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"184402",firstName:"Romina",lastName:"Rovan",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/184402/images/4747_n.jpg",email:"romina.r@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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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"}}]},chapter:{item:{type:"chapter",id:"39807",title:"Pattern of Clinical Presentations in Immunocompromised Patient",doi:"10.5772/51519",slug:"pattern-of-clinical-presentations-in-immunocompromised-patient",body:'Immunodeficiency (or immune deficiency) is a state in which the immune system\'s ability to fight infectious disease is compromised or entirely absent. Most cases of immunodeficiency are acquired (secondary) but some people are born with defects in their immune system (Primary) immunodeficiency.
The following conditions and diseases that are associated with primary immunodeficiency disorder include, Combined variable immunodeficiency disease, Ataxia-telangiectasia, Chediak-Higashi syndrome, Complement deficiencies, DiGeorge syndrome, Hypogammaglobulinemia, Job syndrome, Leukocyte adhesion defects, Bruton disease, Congenital agammaglobulinemia, Selective deficiency of IgA, Wiscott-Aldrich syndrome etc
As for acquired immunodeficiency, in 2006, UNAIDS and the World Health Organization estimated that approximately 39.5 million people were living with HIV. That year alone, there were 4.3 million new infections, with the majority occurring in sub-Saharan Africa. HIV targets T cells, and in particular, T helper cells, which are critical to fighting infections caused by fungi and parasites. This is why people with advanced, untreated AIDS develop unusual infections such as Pneumocystis carinii pneumonia and Toxoplasmosis gondii.
Since transplanted organs such as kidneys, hearts, livers, and lungs are foreign bodies, recipients\' immune systems must be permanently suppressed to prevent them from attacking and destroying the organs. More than 19,000 transplants are performed in the United States each year. Each month, approximately 3,700 people are added to the U.S. national transplant waiting list, and each day, 77 people receive organ transplants. The breakthrough in transplant technology occurred in 1983 when cyclosporine, a powerful immunosuppressive drug, became licensed. However, even with cyclosporine, transplanted organs typically only last around 10 years before needing to be replaced. Research efforts to induce bodies to tolerate transplanted organs without using immunosuppressive drugs are ongoing. But until a breakthrough in understanding immunologic tolerance or a way to grow replacement organs occurs, newly immunocompromised organ-transplant recipients will occur each year.
In addition, cancer chemotherapies typically cause immunosuppression. Since cancer cells are cells that multiply uncontrollably, the goal of cancer therapy is to kill them without killing too many normal cells. Unfortunately, the cells involved in immunity are frequently adversely affected by chemotherapy, thus rendering the patient vulnerable to infections.
Autoimmune disorders are typically treated with immunosuppressive drugs such as corticosteroids, 6-mercaptopurine, and azathioprine to keep the immune system from attacking the body. For example, Crohn\'s disease is an autoimmune disease in which the immune system attacks the body\'s gastrointestinal system, causing intense pain, bleeding, and obstructions. Another treatment is infliximab, which stops the body’s inflammatory response. But these treatments only alleviate pain and suffering, they don\'t cure the underlying immune disorder.
Also splenectomy, diabetes mellitus, cancer, increasing age, chronic diseases and strenuous exercise had been associated with various degrees of impairment in immune functions
The immune System`s primary function is to fight off infection. When the immune system is suppressed or dysfunctional the ability to combat infection is reduced. A person who has an immunodeficiency of any kind is said to be immunocompromised. These immunocompromised patients are more vulnerable to infections including infection with organisms that don’t normally cause disease. In addition, they are more likely to develop severe and sometimes life-threatening illness following infection.
Many patients admitted into the Medical Unit especially Intensive Care Unit (ICU) have varying degrees of immunosuppression. In some, immunosuppression is easily apparent, especially when caused directly by underlying disease (such as haematological malignancy) or treatment (such as drugs used to prevent organ rejection or as a side effect of cancer chemotherapy). In others, immunosuppression is less apparent and is induced by the underlying disease, for example following traumatic injury or sepsis, or as a response to therapies provided during intensive care such as steroids.
Immunosuppression itself does not cause pathology but does leave the patient prone to infection and other disease conditions. There is no good clinical test to measure the degree of immunosuppression; the clinician must simply maintain a high index of suspicion. The consequences of immune suppression in most patients highlight the importance of infection prevention and control, as well as surveillance measures to ensure that appropriate treatment is implemented safely and quickly. Thus there is need to understand the pattern of clinical presentations of patients with immune dysfunction to avoid delay in making diagnosis and hence intervention.
Immunocompromised patients are prone to various infectious and non infectious disorders. The infectious disease is the commonest presentations of these patients because of the weakening of the patient’s immune state. The severity of the infection depends on the degree of the immunosuppression. Some organs like respiratory pathways are more liable to infections in these patients for obvious anatomical reasons; however all organs are at risk of developing infection.
Also there are various non infectious manifestation in patients with immunosuppression. These may be directly or indirectly related to the degree of immune suppression in the patient. Patients have presented with various degrees of impaired kidney function, liver disease, cardiorespiratory dysfunction, psychosocial, dermatological and neurological disorders that are not directly related to infections.
Immunocompromised patients also can present with features not directly related to immunosupression. For example obesity in patients on steroid therapy, and hepatic disease associated with severe combined immunodeffiency disease.
Clinical presentations in immunocompromised differs among patients. The presentations are determined by the severity of the immunosupression, the severity of the infection and other comorbid condition. Furthermore the organ involved and the type of the associated clinical state play important role in determining the presentation of the patient. There are many uncommon presentations that have been reported in these patients. However poor response to treatment of infection, incomplete recovery from illness, certain types of infections and malignancies are common presentations seen in immunocompromised patients.
The clinical setting is extremely important in recognizing immunosuppression. Immune dysfunction induced by therapeutic intervention will be evident from the history, but immune impairment due to underlying disease may be more difficult to recognize. Inherited immune deficiencies often have characteristic patterns of disease distribution and may be associated with other clinical abnormalities (such as cardiac anomalies).
The various organs/systems in the body have differing impact by the resultant effect of immunosuppression. This results from either the direct impact of the immunosupression or diseases resulting from the immunosupression.
These manifestations will be discussed according to the impact on various systems and organs..
The primary function of the gastrointestinal tract is digestive, absorption and assimilation of nutrients. It has the largest surface area among all organs. With such large surface area and its close proximity to the external environment it necessitates that it evolved a large compliment of both innate and acquired immune mechanism. The gastrointestinal associated lymphoid tissue constitutes the largest immune compartment in the body. It is estimated that the GIT contains about 60% of the total body lymphocyte. The immune cells in the GIT are organized into distinct anatomic and functional sub compartments..
The gastrointestinal tract associated lymphoid tissue, can be divided into three sectors. The first is represented by the pharyngeal tonsils, the appendix, and the large aggregates of nodules known as Peyer patches located at intervals throughout the small intestine. The second sector includes the lymphocytes and plasma cells that populate the basement membrane (lamina propria) of the small intestine, the area of loose connective tissue above the supporting tissue of the mucosal lining extending into the villi. The third sector comprises lymphocytes that lie between the epithelial cells in the mucosa. The interaction between these cells of the lymphatic system and the threatening agent is the basis of defense in the gastrointestinal tract. The gastrointestinal tract also posses other protective measures which include tight epithelial junctions, the digestive enzymes, the acidic gastric fluid, the lysozyme and the high flow of the gastrointestinal fluid.
However the gastrointestinal tract is particularly at risk of infectious and non infectious injuries because of the following reasons – because of their close proximity to the external environment and continuous exposure to myriad of food and other infectious and non infectious antigens, the mucosa is maintained in physiologic inflammatory state characterized by presence of proinflammatory cytokines, marked expression of CCR5 and CXCR4 chemokine receptor that promotes HIV entry into the mucosa cells.
In immunocompromised patients the normal defenses are disrupted, leading to a wide range of clinical and pathogenic consequences. This usually leads to various disease conditions that can be classified into one of several general categories: infections, mucosal injury and ulceration, biliary tract diseases, diverticular disease, pancreatitis, and malignancy
The infections may be bacterial, viral, fungal, or parasitic and may infect one or more gut segments between the mouth and anus. The viral infections that had been reported in these patients include cytomegalovirus, herpes simplex, human papilloma virus, ebstein barr virus and rota virus. The bacterial infections include cloctridium dificile, salmonella spp, shigella spp, H. pylori, eiserichia coli, campylobacter spp, Yersinia enterocolitica, mycobacterium tuberculosis, mycobacterium avium intracellurale complex. The parasitic infections include cryptosporidium, microsporidium, entamoeba histolytica, giardia lamblia, Strongyloides stercoralis. The fungal infections include histoplasma capsulatum, candida albicans, candida tropicalis, mucormyces spp. The gastrointestinal infections have varying presentations but the commonest presentation is diarrhea.\n\t\t\t
Mucosal injuries and ulceration of the gastrointestinal tract has been reported in patients with immunodeficiency. Many factors had been associated with ulcer formation and propagation in these patients. Some of these factors include stress, impairment of native cytoprotection of the gastrointestinal mucosa, drugs and infections especially helicobacter pylori. Complications that had resulted from gastrointestinal mucosa injury and ulceration include perforation, penetration, peritonitis and gastrointestinal bleeding.
Diverticular disease had been reported in immunocompromised patients especially in post transplant patients on immunosuppressive therapy. The clinical presentation varies from asymptomatic to peritonitis. Complicated diverticulitis which was reported in 1.1% of renal transplant patients can presents as intestinal perforation, abscess, phlegmon or fistula.
Acute pancreatitis in immunocompromised patients are not common. It has been associated with alcohol ingestion, billiary stones, malignancy, hepatitis B and cytomegalovirus infection. Acute pancreatitis markedly increase the morbidity and mortality associated with immunodeficiency. The clinical presentation is usually atypical.
There is increase in prevalence of both common and uncommon gastrointestinal malignancies in patients with immune deficiency. Decreased immune surveillance, continuous mucosa inflammation, gastrointestinal infections, ingestion of carcinogens including medications are some of the factors suspected to be responsible for the heightened prevalence of malignancy in these patients. Also cigarette smoking, sclerosing cholangitis, crohns syndrome and splenectomy had been reported as risk factor for the development of gastrointestinal malignancy in these patients. The gastrointestinal malignancies that have been associated with immunosuppression include Kaposi sarcoma, colorectal carcinoma, post transplant lymphoproliferative lymphoma, gastric mucosa associated lymphoma. The malignancies are initially asymptomatic however acute abdomen from perforation or obstruction and gastrointestinal bleeding are the usual though late presentations.
The commonly experienced gastrointestinal (digestive) complications; include oral lesions, esophageal lesions, diarrhea, and anorectal diseases (disease that affects the anus and/or rectum). The oral lesions are aphthous ulcer, oral thrush (candidiasis), oral wart, oral hairy leukoplakia, Kaposi sarcoma.
The oesophageal lesions include oesophageal candidiasis, oesopheal herpes simplex, cytomegalovirus, aphthous ulcer, malignancy, and reflux oesophagitis manifesting as dysphagia, odynophagia, and sensation of food sticking in the throat.
The anorectal lesions which are usually seen in immunocompromised patients with AIDS include herpes simplex infection, gonorhoea, syphilis, anal wart(condylomata) and Chlamydia.
Diarhoea is a common clinical presentation in immunocompromised patients independent of the cause. This has been attributed to gastrointestinal infections, malabsorption, medications etc.
The hepatobilliary system is usually considered part of the digestive system however they have both digestive and non digestive functions. The liver acts as a detoxifier by processing potentially harmful agents into safe chemicals. It is also responsible for metabolism of glucose, fat and protein. It manufactures and controls the release of bile.
The bile plays an important role in breaking down of fats, the source of cellular energy. It is necessary for the absorption of many vitamins and other fat related substances. It also participates in the excretion of many product of metabolism including bilirubin, bile acid and medications.
The hepatobilliary system receives dual blood supply, from the portal and systemic circulation. Hence in immunocompromised patient the hepatobilliary system is exposed to many infectious and non infectious antigens. This predisposes the patient to many disease conditions relating/affecting the system.
Immunodeficiency states resulting from AIDS, cytotoxic chemotherapy, radiation, organ transplantation and common variable immunodeficiency disorders have been associated with hepatobilliary disease. These disorders that have been reported in immunocompromised patients include infectious hepatitis, granulomatous hepatitis, alcoholic liver disease, cholangiopathy, hepatocellular carcinoma, schistosomiasis, haemangioma and hepatic adenoma. Nodular regenerative hyperplasia of the liver has also been reported in patients with combined variable immunodeficiency syndrome.
There are various clinical manifestations relating to this system in these patients. In a study of patients with common variable immunodeficiency syndrome with nodular regenerative hyperplasia 39% of the patients were asymptomatic but had deranged liver functions, 46% had jaundice, 46% had hepatomegaly, 23% had pruritus, 15% had ascitis, 15% had oesophageal varices. Also jaundice and hepatomegaly is a common presentation in immunocompromised patients resulting from opportunistic and conventional infections of either hepatobilliary or other systems. Other manifestations include portal hypertension, cirrhosis, primary and secondary malignancies of the liver and billiary tree, and hepatic failure.
The immune system in the airways consists of both innate and specific immunity. Innate immunity consists of mechanical defenses, antimicrobial molecules generated in the airways, and phagocytic defenses provided by the resident alveolar macrophages and the polymorphonuclear leukocytes (PMNs) that are recruited into the lung in response to infection. The specific immunity are usually initiated by the dendritic cell that act as the antigen presenting cell. They migrate to the regional lymphoid tissue to initiate the primary response with generation of memory B and T cells.
This sophisticated immune defense system effectively protects the host from infections and other immunodeficiency related diseases of the respiratory tract. However this function is impaired in immunocompromised individuals thus exposing them to many diseases of the airways.
Patients with compromised immune function suffer from a wide variety of infectious and non infectious lung insults. Infections are the most common cause of both acute and chronic lung diseases in immunocompromised patients however noninfectious diseases are not uncommon.
Pulmonary infections decisively contribute to morbidity and mortality in immunocompromised patients. The prevalence of both the common infections implicated in community acquired pneumonia and some uncommon infections including opportunistic infections are increased in immunocompromised patients. Among the infections encountered are streptococcus pneumoniae, klebsiella pneumonia, haemophilus influenza, pseudomonas aeruginosa, actinobacter spp, fusobacterium nucleatum, bacteroids melaninogenicus, bacteroids fragilis, mycobacterium tuberculi, mycobacterium avium intracellurale, pneumocystis carinii (jirovecii), norcadia spp, coccidomyces spp, aspergilus spp, Rhodococcus equi etc. The infections usually present as pneumonia, suppurative lung disease, interstitial lung disease and obstructive lung diseases
The spectrum of noninfectious lung injury and response in the immunosuppressed host includes interstitial edema, interstitial fibrosis, diffuse idiopathic pneumonia, acute respiratory distress syndrome, obliterative bronchiolitis, alveolar hemorrhage, pulmonary embolism, radiation pneumonitis, drug toxicity, progression or recurrence of neoplastic disorders, chemotherapy, transfusion and transplant related lung injuries. The clinical manifestations of various non infectious complications in immunocompromised patients are non specific and may mimic infections.
Clinical approach to respiratory tract diseases in immunocompromised patients are classified into five categories. The first situation is defined by a slow progression of the disease, the absence of fever (or mild fever), and diffuse opacities. Pulmonary oedema, pulmonary localisation of the underlying disease, or toxic treatment induced pneumonitis are usually the cause. Non-specific pneumonitis may also be responsible, particularly in bone marrow transplant recipients.
The second situation, defined by a rapid progression of the condition, fever, and diffuse opacities, usually indicates an opportunistic pneumonia but, in a few cases, a hypersensitivity drug induced pneumonitis (for example, to methotrexate) or a localisation of the underlying disease—for example, in cases of vasculitis or collagen vascular disease—may be the cause. In the absence of new extrapulmonary symptoms, Pneumocystis carinii must be considered. In contrast, the presence of new extrapulmonary symptoms or signs suggests an association or another opportunistic infection such as cytomegalovirosis, cryptococcosis, toxoplasmosis, or tuberculosis.
In the third situation the clinical feature is that of bacterial pneumonia or sepsis with ARDS. The pathogens responsible are usuallyStreptococcus pneumoniae or Haemophilus influenzae and, to a lesser degree, Legionella spp.
The fourth situation with rapid to moderate progression of the condition, fever, nodules or round infiltrates evolving towards dissemination and/or cavitation is highly suggestive of fungal pneumonia. However, legionellosis, tuberculosis and even pulmonary infarction or specific localisation of vasculitis may also result in similar manifestations.
The last situation is certainly the most complex. The clinician is confronted with focal pulmonary infiltrates which do not respond to antibiotics. Opportunistic agents such as Mycobacteria spp, Nocardia spp, or Rhodococcus equi, organising pneumonia or tumour may be the cause.
Skin, once thought to be an inert structure, plays a vital role in protecting the individual from the external environment. The epidermis impedes penetration of microbial organisms, chemical irritation, and toxins, absorbs and blocks solar and ionized radiation, and inhibits water loss.
The stratum corneum, the outermost layer of the epidermis that results from the terminal differentiation of the keratinocytes, forms the primary layer of protection from the external environment. This layer of anucleated keratinocytes is composed of highly cross-linked proteinaceous cellular envelopes with extracellular lipid lamellae consisting of ceramides, free fatty acids, and cholesterol. The free fatty acids create an acidic environment that inhibits colonization by certain bacteria such as Staphylococcus aureus, providing further protection.
Apart from the physical barriers the skin also contain other innate immunomodulating substances and cells. This include cathelicidins, cytokines. neuropeptides, eicosanoids, reactive oxygen species and langhern cell which has phagocytic properties, and act as antigen presenting cell. The skin is consistently exposed to host of injuries because of their size and exposure to the environment. These coordinated protective barriers, cells and substances maintain the integrity of the skin.
In immunodeficiency state there is alteration in this innate immune state in the skin. This thus predisposes the skin to many injuries – infectious and non infectious. Dermatological manifestations are important healthcare concerns in patients with immunodeficiency state. About 25% of patients with immunodeficiency had been reported with dermatological injuries.
Subsequent invasion of the skin by various bacterial, viral, fungal, and parasitic agents spur infectious skin lesions, whereas non-infectious skin conditions mainly emerge from adverse drug reactions or certain inflammatory or malignant aetiologies. Thus microbial infections, inflammatory conditions, and neoplasms are the three main causes for the development of dermatological findings in immunocompromised patients.
There have been several reports detailing the high frequency of dermatological manifestations in HIV infected patients, 96% in India, 70% in Taiwan, 65.3% in France, 65.3% in Tanzania, 34% in Thailand, 32.6% in Iran. The dermatological manifestations in these patients may be as a result of primary dermatological infection, metastastic infection with primary in another organ or systemic infection.
There are many organisms that are associated with infection of or manifestations in the skin in patients with immunodeficiency. The infections could be as a result of conventional or opportunistic infection. These infections include viral, bacterial, fungal and parasitic. The organisms that have been associated with dermatological infections or manifestation in immunocompromised patients are herpes simplex virus, varicella zoster virus, cytomegalovirus and pappiloma virus, staphylococcus spp, streptococcus spp, pseudomonas spp, atypical mycobacterium spp, the fungal infections including malasezia furfur, candidiasis, norcadia spp, Cryptococcus neoformans, Aspergillus species, Paecilomyces, Rhizopus species, Candida tropicalis, and scabies.
The commonly reported dermatological lesions in immunocompromised patients include dermatitis, seborrheic dermatitis, folliculitis, dermatophytes including pityriasis versicolor, wart, Kaposi sarcoma, herpes zoster, acne vulgaris, urticaria, pruritus, psoriasis, malasma and erythema multiforme. Other Skin lesions including pustules, gangrenous cellulitis, erythematous subcutaneous nodules, hemorrhagic bullae, petechiae, ecchymoses, and ecthyma gangrenosum had also been reported in immunocompromised patients.
Cutaneous manifestations often are accompanied by fever, defined as an isolated temperature of 38.3°C (101°F), that cannot be attributed to exogenous causes, such as blood products, or a temperature above 38°C (100.4°F) that persists for more than 1 hour.
Immune responses in the CNS are common, despite its perception as a site of immune privilege. These responses can be mediated by resident microglia and astrocytes, which are innate immune cells without direct counterparts in the periphery. Furthermore, CNS immune reactions often take place in virtual isolation from the innate/adaptive immune interplay that characterizes peripheral immunity. However, microglia and astrocytes also engage in significant cross-talk with CNS-infiltrating T cells and other components of the innate immune system.
Microglia are key players of the immune response in the central nervous system (CNS) and being the resident innate immune cells, they are responsible for the early control of infections and for the recruitment of cells of the adaptive immune system required for pathogen clearance. The innate and adaptive immune responses triggered by microglia include the release of proinflammatory mediators. Although an efficient immune response is required for the defense against invading pathogens, an inflammatory response in the CNS may also lead to tissue injury and neurodegeneration. Engagement of Toll-like receptors (TLRs), a major family of pattern recognition receptors that mediate innate immunity but also link with the adaptive immune response, provides an important mechanism by which microglia are able to sense both pathogen and host derived ligands within the CNS.
Patients with immunodeficiency are at risk of a wide range of neurologic diseases including infections, neoplasms, and drug-related complications of therapy
CNS infections caused by infective agents are rare in immunocompetent host, but more frequent in immunocompromised patients. The spectrum of causative organisms may vary greatly, depending on the underlying malignancy, its treatment and various other factors. Infections that had been reported to cause neurological diseases in immunocompromised patients are as detailed below;
Viral – herpes simplex virus, JC virus, cytomegalovirus, varicella zoster virus.
Bacterial – staphylococcus spp, pneumococcus, haemophilus spp, mycobacterium tuberculosis, mycobacterium Avium/ Intracellulare Complex, Listeria spp, norcadia spp.
fungal – Cryptococcus neoformans, Aspergillus fumigatus, Zygomycetes (Mucor and Rhizopus), Candida albicans, Coccidioides spp
Parasitic - toxoplasmosis, strongyloides.
Development of neurologic manifestations depends on a variety of factors, including therapy with drugs like antiretroviral drugs and the patient’s overall degree of immunosuppression. Heavily immunocompromised patients like those after allogeneic stem cell transplantation (SCT) or previous T cell depleting treatment regimens (e.g. with fludarabine or alemtuzumab) are at highest risk for cerebral infections.. The infections can cause global or focal cerebral dysfunction, subhemispheric impairment, spinal cord injury and occasionally, peripheral nerve injury.
Thus, in the immunosuppressed patient with neurological involvement there are three inter-related areas to consider. First, has whatever caused the immunosuppression either directly or indirectly affected the nervous system? Second, are such problems due to an infection of the nervous system? And last, are there any medical complications that might produce a neurological disturbance? In assessing immunosuppressed patients, the clinician must remember that more than one of these factors may be involved in the neurological presentation.
Clinical presentations in these patients may include headache, signs and symptoms of increased intracranial pressure, and lateralizing signs appropriate to the area(s) of involvement. These symptoms can include behavioral, cognitive, and personality changes. Focal symptoms include hemiparesis, aphasia, and visual field defects. Ataxia, seizures, and cranial nerve palsies can also occur but are not as common.
Meningoencephalitis is a common presentation however the classical symptoms and signs may be absent in these patients. Also cerebral toxoplasmosis, cerebral lymphoma and cerebral vascular accident in immunocompromised patients may have similarities in their clinical presentations. The nature of neurological manifestation in patients with impaired immune state also varies with the cause and the degree of the immunosuppression. There is need for high index of suspicion to avoid delay or misdiagnosis that may lead to delay in intervention.
The immune cells and mediators had been implicated in some musculoskeletal diseases. The bone marrow is the source of various haematological cells including the primordial immune cells. The bone marrow also harbours matured and maturing immune cells. However the physiological activities of both innate and acquired immunity in the musculoskeletal system are poorly documented.
There is increased prevalence of musculoskeletal diseases especially infections in immunocompromised patients. Musculoskeletal syndromes that occur in HIV-infected patients include manifestations of drug toxicity, reactive arthritis, Reiter\'s syndrome, infectious arthritis, and myositis. Post transplant patients have developed myopathies and various bony and joint disorders. Myopathy and myositis have been reported in patients with diabetes mellitus and some primary immune deficiency disorders.
Some other musculoskeletal disorders in patients with immunodeficiency include some syndromes with arthritis or myositis as one of the components eg Reiters syndrome, Dermatomyositis, Sjogrens syndrome, Polyomyositis and Psoriasis.
The hallmark of the presentation is pain in the muscle, swelling of muscle, occasionally associated with fever and muscle atrophy. Arthralgia, swelling of the joint and when intervention is delayed distortion of the joint. Patient may develop cellulitis with or without abscess formation and osteomyelitis. There is need for prompt diagnosis and intervention as delay may lead to rapid spread of the infection in these patients.
The urogenital tract contain both cellular and non cellular innate immune components. This ensure the sterility of the urinary tract and part of the genital tract. In immunodeficiency state the urogenital tract are exposed to higher prevalence of both common and rare infections. The urogenital diseases that have been reported in immunocompromised patients include urinary tract infection, epididymitis, prostatitis, extensive condylomata of the urethra, renal abscess and other renal related diseases.
The occurrence of urinary tract infection and its clinical impact is determined, as with any infectious disease, by the interaction between the virulence of the infecting organism and the host defense mechanisms that can be mobilized. In the case of urinary tract infections, an anatomically and functionally intact kidney and urinary tract are the primary host defenses, with phagocytic function and immune mechanisms coming into play to limit the consequences of those infections.
Defects in the immune system determine the clinical manifestations and severity of urinary tract infections (UTI) and the rates of complication. However they only have an indirect role in influencing susceptibility to infection. Of all the categories of immunocompromised hosts, the renal transplant patient is the one most susceptible to the direct and indirect consequences of urinary tract infections. The rates of UTI in diabetics, renal transplant, recipients, neutropenic patients, and patients with AIDS are primarily determined by the degree and duration of urinary tract manipulation, and the higher perineal prevalence of potential pathogens that result from frequent hospitalization and antimicrobial use.
Urogenital tract infection has a different clinicoradiological presentation in immunocompromised patients, with predominance of systemic symptoms, multiple parenchymatous renal foci, and lower frequency of lesions of the collecting system. In the context of immunosuppression, Urogenital tract infection behaves as a severe bacterial infection, with bacteremia and visceral metastatic foci.
Many patients are asymptomatic. Symptoms that may occur include dysuria, urinary frequency and incontinence, flank pain, and fever. Confusion and delirium are often attributed to UTI, although without high fever or sepsis. Uncomplicated UTI is unlikely to cause serious central nervous dysfunction. The clinical signs and follow up of these infections were straight forward in half of the cases. However, in some patients, the infection is fulminant with progression to an abscess despite the use of antibiotics or is unusual because of the pathogens isolated.
Mycobacterial agents causing UTIs are less frequent in immunocompetent individuals; they are more common and severe in immunocompromised individuals. Extra pulmonary tuberculosis (EPTB) represents a progressively greater proportion of new cases and the genitourinary tract is the most common site of EPTB. The most common causative organism of kidney and urinary tract tuberculosis is the Mycobacterium tuberculosis, and occasionally Mycobacterium bovis can also be responsible. Mycobacterium tuberculosis (MTB) has an important impact on kidney transplant recipients, particularly during the first year after surgery. Tuberculosis of the urinary tract is easily overlooked. Symptoms that sometimes occur include back, flank and suprapubic pain, hematuria, frequency, and nocturia. These might also suggest conventional bacterial urinary tract infection. Symptoms such as fever, weight loss, and night sweats also are not unusual.
A variety of renal syndromes have been reported in patients with immunosupression. These can be either acute or chronic kidney disease including electrolyte abnormalities. Renal impairment from opportunistic infections and drugs used in these patients has also been reported. A broad spectrum of renal diseases affecting glomerular, tubular and interstitial tissues had been documented in immunocompromised patients especially HIV infected patients. Most of the renal manifestations represent complications of concurrent infections in a severely immunocompromised host, or side effects of the plethora of treatments required to manage these patients. The renal related presentations except for hypertension and oedema are consistent with clinical presentations in renal disease in immunocompetent patients, however severity varies with the degree of immunosuppression. Hypertension and oedema were reported as not common in immunocompromised patients. The renal disease in these patients deteriorates faster without intervention thus the need for early diagnosis and prompt intervention.
Immunocompromised patients are predisposed to a variety of clinical syndromes. The manifestations depend on the cause of immunosuppression, the degree of immunosupression, the endemic infections, the system or organ with predominant injury, and other associated diseases like Malignancies and infiltrative diseases. It is noteworthy that these patients may have atypical presentations. Thus there is need for surveillance and high index of suspicion of injuries/diseases in these patients to ensure early diagnosis and intervention.
Serotonin or 5-hydroxytryptamine (5-HT) is a well-established monoamine neurotransmitter in the central nervous system (CNS). The discovery of 5-HT dates as far back as 1868 and can be traced to its presence in the blood and in the gastrointestinal tract [1]. Its well-known biological functions include modulating cognition, sleep, emotion, learning, memory, and numerous physiological processes. 5-HT is primarily found in the enteric nervous system located in the gastrointestinal tract [2], where it regulates intestinal movements [2], and the remainder is synthesized in the serotonergic neurons of the CNS, where it has various functions such as the regulation of mood, appetite, and sleep. Modulation of 5-HT at synapses is thought to be a major action of several classes of pharmacological antidepressants. Among these, selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine and citalopram, are the most important class of antidepressant in the treatment of major depressive disorder (MDD) and anxiety disorders [3]. The exact mechanism of action of SSRIs is not fully revealed. SSRIs are able to increase the extracellular level of the neurotransmitter 5-HT by inhibiting its reuptake into the presynaptic terminal, increasing the level of 5-HT in the synaptic cleft available to bind to the postsynaptic 5-HT receptor (as shown in Figure 1). SSRIs have different degrees of selectivity for the other monoamine transporters, and the most selective SSRI has weak affinity for the norepinephrine and dopamine transporters. They are the most widely prescribed antidepressants in many countries, and their efficacy in mild or moderate cases of depression has been disputed [4] and may be outweighed by side effects [3]. I have been involved in 5-HT research for two decades. This chapter summarized my research on 5-HT-related projects from measuring 5-HT concentration, attempting to discover a new generation of SSRIs to investigate 5-HT-regulated post-receptor signaling transduction. This chapter also discusses some perspectives research that is important for SSRI and depression treatment.
Model explaining PLA2 activation in response to serotonergic drugs. Under normal conditions, the 5-HT that is released from presynaptic vesicles into the synaptic cleft binds to postsynaptic 5-HT receptors coupled via a G-protein to PLA2, thus hydrolyzing arachidonic acid (AA) from membrane phospholipids (PL). Administration serotonergic drugs activate PLA and increase incorporation of AA by different routes. (1) 5-HT2A/2C agonist, DOI directly binds to 5-HT2 receptors to activate this signal; (2) fluoxetine (SSRI) inhibits 5-HT uptake, thus increasing 5-HT in the synaptic cleft so as to increase PLA activation and AA release. This figure adapted from [23].
In the early 1990s, liquid chromatography (LC) with an electrochemical detector (ED) had been widely used for the measurement of neurochemicals [5]. The first 5-HT project that I worked with was to develop a method for measuring 5-HT concentration in chicken brain tissue [6]. An isocratic LC-ED for the determination of L-3,4-dihydroxyphenylalanine, dopamine, norepinephrine, epinephrine, 5-HT, and their major metabolites, 3,4-dihydroxyphenylacetic acid, 4-hydroxy-3-methoxyphenylacetic acid, and 5-hydroxyindole-3-acetic acid in chicken brain tissue was developed in our lab. The method was applied to study the influence of food restriction on the concentration of 5-HT and other monoamine neurotransmitters in different brain areas, known to be involved in the feeding and reproductive behavior of female broiler chickens. In the experiment, two to six micropunches from 20 different brain areas on 300 μm cryostat brain section were punched out and expelled into Eppendorf for homogenization and extraction. Supernatant was injected onto LC-ED, and over 1000 micro-punched tissue samples from ad libitum fed and food-restricted female broiler chickens were analyzed. Tissue pellets were dissolved in PBS buffer for protein content determination to express the results as pg monoamine/μg protein. Although the concentration of monoamines in the brain is not high, multiple tissue micropunches made enough amount of monoamine and 5-HT to match the sensitivity of the assay. Our results provided a possible role for catecholamines and indolamines in the altered feeding and reproductive behavior of the broiler chicken [6]. To finish my Ph.D. thesis, I modified this method to measure 5-HT and other monoamine neurotransmitters in cat visual cortex [7]. The role of monoaminergic neuromodulators in the reorganization of cortical topography following limited sensory deprivation in the adult cat was investigated in this study [8]. The total concentrations of dopamine, noradrenaline, 5-HT, and their major metabolites were measured in the visual cortex of both control and experimental animals using this microbore LC-ED method. The sensory deprivation cats were subjected to a binocular retinal lesion corresponding to the central 10 degrees of vision and sacrificed 2 weeks post-lesion. The deprivation was confirmed in area 17 by measuring immediate-early gene if-268 messenger RNA expression. The total concentration of 5-HT was significantly lower in the deprived cortex, and the metabolite of 5-HT, 5-hydroxyindole-3-acetic acid, was significantly higher in the nondeprived cortex than in deprived cortex and normal cortex. The levels of noradrenaline and dopamine were significantly higher in the nondeprived cortex of retinal lesion cats than in the deprived cortex of retinal lesion cats and the cortex of normal animals. This pattern follows the release of the excitatory neurotransmitter glutamate under the same conditions. These results suggest that the modulation of 5-HT, noradrenaline, and dopamine is regulated by visual afferent activity [8].
To switch my scientific career to the pharmaceutical industry, I joined the CNS drug discovery team for making a new generation dual function SSRI [9] for depression treatment. Fluoxetine (Prozac) [10] is the first SSRI and widely used for the treatment of depression which was used as reference compounds for new SSRI discovery. Fluoxetine exerts its behavioral and clinical therapeutic effect by blocking the transport of 5-HT at the serotonin reuptake transporter (SERT), thereby increasing extracellular level of 5-HT in the serotonergic synaptic cleft of many brain regions as shown in Figure 1. In vivo microdialysis has been extensively used to document the changes of extracellular level of 5-HT in the rat brain after administration of fluoxetine [11]. Therefore, we designed a 21-hour in vivo microdialysis experiment and the effect of acute systemic administration of fluoxetine (3 and 10 mg/kg s.c.) on extracellular level of 5-HT in the frontal cortex of freely moving rats was analyzed by LC with ESA CoulArray coulometric detector (an electrochemical detector) [9, 12]. In this experiment, the guide cannula was implanted on rats’ brain by surgery and secured in place with skull screws and dental cement. Animals were allowed at least 3 days to recover from surgery prior to experimentation. Dialysis probes were perfused with artificial cerebral spinal fluid (aCSF, 47 mM NaCl, 4 mM KCl, 0.85 mM MgCl2, 2.3 mM CaCl2, pH 7.4) at a flow rate of 1 μL/min. Samples were collected every 60 min. Microdialysates were analyzed by LC-ED. Separation was performed on a C18 column. All values for microdialysis studies were calculated as percentage change at each time point compared with the average of three baseline values. Due to the limitation of low recovery of microdialysis probe (less than 20% in average) and low concentration of 5-HT in the frontal cortex of rat brain (about 100 fg/μL in this microdialysates), high sensitivity analytical tool is required. LC-ED was the most popular method to measure 5-HT. In recent years, liquid chromatography with tandem mass spectrometry (LC-MS/MS) was also used for this purpose [13].
Pharmacokinetic (PK) characterization and in vivo pharmacological properties of new chemical entities are important components during lead compound selection and optimization in the drug discovery process. Accordingly, reliable techniques are needed that can generate the requisite pharmacokinetic/pharmacodynamic (PK/PD) information for an increased number of compounds. When dealing with compounds targeting the central nervous system (CNS), biophase PK may differ significantly from plasma PK, because blood-brain barrier (BBB) transport and brain distribution often do not occur instantaneously and to a full extent. In vivo microdialysis technique can be used to collect not only the extracellular endogenous substances but also the extracellular free drug in the same local interstitial environment, which may reflect the amount of drug available at the pharmacological target. However, the application of this technique was highly limited by the lack of the proper sensitive analytical methods to determine the endogenous substance and exogenous drug. LC-MS/MS technique improvement provides a direct, structural-specific measurement of individual components with very high sensitivity. The mass spectrometer has minimal baseline drift and can be equilibrated very rapidly. For this purpose, we have developed a series of LC-MS/MS methods, which enable us to monitor drug, citalopram, and 5-HT in the same microdialysis samples [13]. These applications demonstrated in vivo microdialysis coupled with LC-MS/MS is a very important tool to evaluate the PK/PD relationship by comparing the time course of free drug versus biomarker. LC-MS/MS method measuring 5-HT concentration in the brain is possible, but not widely applied [13].
The World Health Organization (WHO) estimates that more than 300 million individuals of all ages suffer from depression [14]. SSRIs have been the drugs for depression treatment. These drugs increase 5-HT levels in the synaptic cleft by inhibiting its reuptake into the presynaptic neuron through blockade of the SERT. Although many patients experience relief after treatment with one of the many marketed SSRIs, efficacy is noticeable only after weeks of treatment. Many physicians are reported to co-prescribe stimulants with SSRI to provide subjective relief during the beginning weeks of antidepressant therapy [15]. Most of these stimulants are increased dopamine release and produced robust behavioral activation, which had the risk of allowing patients to act on their suicidal ideation. It is very important to choose other classes of molecules that have been shown to produce wakefulness in animals without releasing dopamine or producing behavioral activation. Wake-promoting agents such as modafinil are used in the clinic as adjuncts to antidepressant therapy in order to alleviate lethargy. Histamine H3 receptor antagonist has been demonstrated having the wake-promoting action in numerous animal studies and may therefore be a viable strategy for use as an antidepressant therapy in conjunction with SSRIs. Therefore, some potential antidepressant molecules were created, which combined the wake-promoting effect of a histamine H3 receptor antagonist with 5-HT reuptake blockage effects of SERT inhibitor [9]. The synthetic approach and structure-activity relationships associated with this effort have been studied [16, 17, 18]. In vivo microdialysis experiments were used to examine whether a compound was capable of inducing a robust and persistent increase in 5-HT level over baseline. One of these molecules, JNJ-28583867 (2-methyl-4-(4-methylsulfanyl-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline), is a selective and potent histamine H3 receptor antagonist (Ki = 10.6 nM) and inhibitor of the SERT (Ki = 3.7 nM), with 30-fold selectivity for SERT over the dopamine and norepinephrine transporters [9]. After subcutaneous administration, JNJ-28583867 significantly increased cortical extracellular levels of 5-HT as shown in Figure 2A. Baseline measurements of 5-HT levels were performed for 4 h prior to administration of JNJ-28583867. At all doses, 5-HT levels remained elevated for the duration of the experiment up to 18 h after dosing. JNJ-28583867 was also tested in a classical test of antidepressant activity, the mouse tail suspension model. As was expected based on the neurochemical profile of JNJ-28583867, an increase in struggling time was observed. Some PK characterization of JNJ-28583867 was carried out in the rat. The behavioral experiments had indicated good oral bioavailability and this was confirmed. The half-life correlates well with the observation that effects could be observed up to 24 h after a single oral dose, as was the case in the head twitch test. The plasma and brain levels of JNJ-28583867 are sustained and correlated reasonably well with efficacy for an extended period of time as shown in Figure 2B [9]. Similar PK/PD profiles were observed from norfluoxetine, which is the metabolite of reference SSRI, fluoxetine [12]. Norfluoxetine is the most important active metabolite of the widely used antidepressant fluoxetine. Following subcutaneous administration of fluoxetine in rats, plasma, and brain PK of fluoxetine and norfluoxetine were monitored, respectively, by LC-MS/MS. The extracellular level of 5-HT in the frontal cortex was measured by microdialysis as a PD endpoint. Norfluoxetine when directly administrated to rats caused a significant increase in the extracellular level of 5-HT in the frontal cortex and maintained for 18 hours as shown in Figure 2C. This result is correlated well with higher plasma and brain concentration and longer plasma and brain retention time of norfluoxetine (as shown in Figure 2D) [12]. In summary, these studies have shown that the combination of histamine H3 receptor antagonism with SSRI activity in a single molecule results in a pharmacology consistent with the combination of either class of molecule alone. JNJ-28583867 can be a prototype of such a compound to improve current SSRI efficacy and safety profiles [9].
(A). Effect of JNJ-28583867, administered s.c., on extracellular 5-HT levels in the frontal cortex of male Sprague-Dawley rats. Microdialysis time course. Results are expressed as the average ± S.E.M. of n = 3–6 rats per group. (B). Plasma levels of JNJ-28583867 after oral (10 mg/kg, square), intravenous (1 mg/kg, triangle), and subcutaneous (10 mg/kg, circle) administration to the rat. Results are shown as the average ± S.D. of n = 2–3 samples. (C). Effect of norfluoxetine on the extracellular level of 5-HT in the frontal cortex of free moving rat. Values are mean ± S.E.M. of extracellular 5-HT levels and expressed as a percentage of the average of three baseline samples (defined as 100%). Two-way ANOVA-post-hoc Duncan’s multiple range tests were used for comparison. Control (n = 5), 3 mg/kg (n = 6), and 10 mg/kg (n = 6) norfluoxetine were subcutaneously administrated. Asterisks indicate significance of overall effect of drug treatment versus vehicle, P < 0.01. (D). Time course of plasma concentrations of fluoxetine and norfluoxetine. Plasma concentrations (mean ± S.E., n = 10) of norfluoxetine were measured following subcutaneous administration of 3 or 10 mg/kg fluoxetine. Figure 4A and B was adapted from [9]; Figure 4C and D was adapted from [12].
Although antidepressants are generally effective in the treatment of MDD, side effects still exist. Serotonin syndrome is a potentially life-threatening adverse drug reaction that results from therapeutic drug use and a predictable consequence of excess serotonergic agonism of CNS and peripheral serotonergic receptors [19]. In 2002, the Toxic Exposure Surveillance System, which receives case descriptions from office-based practices, inpatients settings, and emergency department, reported 26,733 incidences of exposure to SSRIs that caused significant toxic effects in 7349 persons and resulted in 93 deaths [19, 20]. The development mechanism of serotonin syndrome is unknown. It is hypothesized that the level of 5-HT elevation in blood plasma has to be 10–15% above the baseline levels to result in 5-HT toxicity [21]. Several lines of evidence converge to suggest that agonism of 5-HT2A receptors contributes substantially to the condition [22].
To address this question, we studied 5-HT-mediated post-receptor signaling transduction [23]. The 5-HT2 receptor is G protein-coupled receptor and is recognized to be coupled to the phospholipase A2 (PLA2) signaling pathway, stimulating the release of the second messenger, arachidonic acid (AA). This signaling pathway is illustrated in Figure 1. PLA2 activation can be initiated by serotonergic 5-HT2 receptors via a G-protein. The in vivo fatty acid methods were developed in our lab to measure regional brain incorporation of a radiolabeled fatty acid, including [5,6,8,9,11,12,14,15-3H] arachidonic acid (3H-AA) in conscious rats. Tracer incorporation, represented as the incorporation coefficient k*, reflects PLA2-mediated AA release. Activation of PLA2 in the brain is revealed as increments in k* in different receptors or to change serotonergic neurotransmission (Figure 1). The fatty acid method can be used to evaluate serotonergic neurotransmission mediated by PLA2 in awake rats. It can quantify and localize brain PLA2 signaling in response to different drugs administered acutely or chronically.
In rats, 2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), which is a 5-HT2A/2C receptor agonist, provokes head twitches, skin jerks, and forepaw tapping, behaviors that are considered part of a “5-HT syndrome” [24]. The responses usually appear at a dose of 1.0 mg/kg and peak at 2.5 mg/kg. In one of our studies, DOI, when administered to unanesthetized rats, produced widespread and significant increases, of the order of 60%, in k* for arachidonate, particularly in neocortical brain regions reported to have high densities of 5-HT2A receptors [25]. The increases could be entirely blocked by chronic pretreatment with mianserin, a 5-HT2 receptor antagonist, which is an atypical antidepressant [25]. The results suggest that the 5-HT2 syndrome involves widespread brain activation of PLA2 via 5-HT2A receptors, leading to the release of the second messenger, arachidonic acid. Chronic mianserin, a 5-HT2 antagonist, prevents this activation [25]. In another study, brain PLA2-mediated signal transduction in response to acute fluoxetine administration in unanesthetized rats had been imaged [26]. By inhibiting presynaptic 5-HT reuptake, fluoxetine is thought to act by increasing 5-HT in the synaptic cleft, thus 5-HT binding to postsynaptic 5-HT2A/2C receptors, activates PLA2 pathway, and releases the second messenger AA from synaptic membrane phospholipids. To image this activation, fluoxetine (10 mg/kg) or saline vehicle was administered i.p. to unanesthetized rats, and regional brain incorporation coefficients k* of intravenously injected radiolabeled AA were measured after 30 min. Compared with vehicle, fluoxetine significantly increased k* in prefrontal, motor, somatosensory, and olfactory cortex, as well as in the basal ganglia, hippocampus, and thalamus. Many of these regions demonstrate high densities of the SERT and of 5-HT2A/2C receptors. The brain stem, spinal cord, and cerebellum, which showed no significant response to fluoxetine, have low densities of the transporters and receptors. The results show that it is possible to image quantitatively PLA2-mediated signal transduction in vivo in response to fluoxetine [26]. Fluoxetine’s therapeutic action when chronically administered has been ascribed to desensitization of pre-synaptic 5-HT1A and 5-HT1B auto-receptors, further augmenting extracellular 5-HT [27]. We thereby conducted a study to see if this signaling process in rat brain would be altered by chronic administration of fluoxetine followed by 3 days of washout of this SSRI [28]. [3H] AA was intravenously injected in unanesthetized rats and used quantitative autoradiography to determine the incorporation coefficient k* for AA (regional brain radioactivity/integrated plasma radioactivity), a marker of PLA2 activation, in each of 86 brain regions. k* was measured following acute i.p. saline or DOI (1.0 mg/kg i.p.), in rats injected for 21 days with 10 mg/kg i.p. fluoxetine or saline daily, followed by 3 days without injection. As shown in Figure 3, acute DOI produced statistically significant increments in k* in brain regions with high densities of 5-HT2A/2C receptors, but the increments did not differ significantly between the chronic fluoxetine- and saline-treated rats. Additionally, chronic fluoxetine is compared with saline widely and significantly increased baseline values of k*. These results suggest that 5-HT2A/2C receptor-initiated AA signaling is unaffected by chronic fluoxetine plus 3 days of washout in the rat, but that baseline AA signaling is nevertheless upregulated. This upregulation likely occurs because of significant active drug in the brain, considering the long brain half-lives of its metabolite, norfluoxetine [12]. To further understand SERT regulate brain serotonergic transmission and its mediated signaling transduction, we measured PLA2 activation in SERT knockout mice (SERT−/−) and their littermate controls (SERT+/+). Following administration of 1.5 mg/kg s.c. DOI to unanesthetized mice injected intravenously with radiolabeled AA, PLA2 activation, represented as the regional incorporation coefficient k* of AA, was determined with quantitative autoradiography in each of 71 brain regions. As shown in Figure 4, in SERT+/+ mice, DOI significantly increased k* in 27 regions known to have 5-HT2A/2C receptors, including the frontal, motor, somatosensory, pyriform and cingulate cortex, white matter, nucleus accumbens, caudate putamen, septum, CA1 of the hippocampus, thalamus, and hypothalamus. In contrast, DOI did not increase k* significantly in any brain region of SERT−/− mice. Head twitches following DOI, which also were measured, were robust in SERT+/+ mice but were markedly attenuated in SERT−/− mice. These results show that a lifelong elevation of the synaptic 5-HT concentration in SERT−/− mice leads to downregulation of 5-HT2A/2C receptor-mediated PLA2 signaling via AA and of head twitches, in response to DOI. Compared with wild-type mice, DOI-induced k* increments were reduced in SERT knock out mice [29], but there was no significant effect of 3 weeks of fluoxetine plus washout on DOI-induced k* increments in compared with baseline of chronic fluoxetine treated rats. The difference suggests that a life-long, but not a 3-week, elevation of synaptic 5-HT will downregulate 5-HT2A/2C receptor signaling involving PLA2.
Coronal autoradiographs demonstrating arachidonic acid incorporation coefficients k. Brain of (A) control rat given acute saline 3 days after receiving i.p. saline for 21 days; (B) control rat given acute DOI (1.0 mg/kg i.p.), 3 days after receiving i.p. saline for 21 days; (C) rat given fluoxetine (10 mg/kg i.p. daily) for 21 days, followed by 3 day washout, and then i.p. Saline on day 24; (D) rat given fluoxetine (10 mg/kg i.p. daily) for 21 days, followed by 3 day washout, and then acute DOI (1.0 mg/kg i.p.). k is color-coded. Abbreviations: Fr (IV), frontal cortex, layer IV; FrPaM (IV), frontal motor (layer IV); Soms, somatosensory cortex; IPC, interpeduncular nucleus; CPU, caudate putamen; CA1, CA2, CA3, DG, regions of the hippocampus; Pir, pyriform cortex; PO, olfactory cortex; GrCbG, granular layer, cerebellar gray; CbW, cerebellar white; DR, dorsal raphe; MVe, medial vestibular nucleus; Abc, nucleus accumbens. This figure adapted from [28].
Coronal autoradiographs demonstrating incorporation coefficients k* for arachidonic acid, from brain of SERT+/+ mouse given saline s.c.; SERT +/+ mouse given DOI (1.5 mg/kg s.c.); SERT−/− mouse given saline; SERT+/+ mouse given DOI. k* is color coded. This figure adapted from [29].
In summary, these studies suggest that labeled AA can be used to examine in vivo brain PLA2 signaling initiated by a serotonergic drug. Eventually, brain 5-HT2A/2C-mediated signaling coupled to PLA2 might be imaged in such subjects with positron emission tomography [30].
Depression is among the most prevalent psychiatric disorders with a highly variable treatment response and up to one-third of patients not achieving response [31]. SSRIs are the most commonly prescribed antidepressants and the best overall treatments for depression patients. However, therapeutic outcomes of SSRIs are often far from satisfactory for both patients and prescribing physicians [32]. Therefore, after having focused clinical research on the development of new drugs, growing evidence suggests that an improved application of available drug may still bring substantial benefit to patients [33, 34]. Moreover, there is a gap between the available pharmacological knowledge and its utilization in health care. The newest initiative to bridge this gap is “Precision Medicine.” It considers individual variability to build the evidence base needed to guide clinical practice [35]. Therapeutic drug monitoring (TDM) is a patient management tool for precision medicine [36]. It enables tailoring the dosage of the medications to the individual patient by combining the quantification of drug concentration in blood, information on drug properties, and patient characteristics [37]. Because patients differ in their ability to absorb, distribute, metabolize, and excrete drug due to concurrent disease, age, concomitant medication or genetic abnormalities, the drug’s steady-state concentration in the body may have a more than 20-fold interindividual variation when the same dose of drug is administrated [38, 39]. TDM quantifies the drug’s concentration in plasma or serum to adjust the dosage of individual patients, which increases probability of response and decreases risk of adverse drug reactions/toxicity [40, 41]. Moreover, TDM has the potential to enhance the cost-effectiveness of antidepressant therapy [42, 43, 44]. The benefits of TDM for optimization of pharmacotherapy, however, can only be obtained when the method is adequately integrated into the clinical treatment process. Current TDM use in depression care is often suboptimal as demonstrated by systematic studies [45, 46, 47]. The suboptimal use of TDM wastes laboratory resources and bears the risk of misleading results that will adversely influence clinical decision making. Studies on TDM for antidepressant will further specify the information on the imperfect use of TDM [48].
Among SSRIs, citalopram is the most SSRI [13], and some studies reported that it is more effective and better tolerated than other drugs for depression but has been associated with suicidality and worsening depression especially in adolescents and young adults [49]. Citalopram is strongly recommended for TDM by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AFNP) guidelines and was recently upgraded into the level 1 recommendation drug [37, 50]. Its reported therapeutic reference ranges (50–110 ng/mL) are established and have been quantified. Controlled clinical trials have known beneficial effects of TDM, reports on decreased tolerability or intoxications [50]. Fluoxetine strongly inhibits 5-HT uptake with minimal effects on other neurotransmitter uptake system [51]. Norfluoxetine, an active metabolite of fluoxetine, contributes to the long elimination half-life (3-15 days) and overall clinical effect of fluoxetine [12]. TDM of fluoxetine is listed as “useful” AFNP guidelines [37, 50]. The therapeutic reference range of 120–500 ng/mL includes the quantification of fluoxetine and its long-lasting active metabolite, norfluoxetine. The total concentration of fluoxetine and norfluoxetine in plasma is needed to be determined. Thus, there is a clinical demand for the detection of fluoxetine and norfluoxetine when patients are receiving fluoxetine. The clinical service for TDM of antidepressants needs to be established.
The authors gratefully acknowledge Victoria Li, Xiao Li, and Curt Becker for proofreading the draft of this chapter.
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\n\nCreative Commons licenses – enable licensors to retain copyright while allowing others to use their Works in an appropriate way.
\n\nWith the purpose of protecting Authors' copyright and the transparent reuse of OA (Open Access) content, IntechOpen has developed Rules of Attribution of Works licensed under Creative Commons licenses.
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\n\nAll rights to Books and other compilations published on the IntechOpen platform and in print are reserved by IntechOpen. The Copyright to Books and other compilations is subject to a separate Copyright from any that exists in the included Works.
\n\nA Book in its entirety or a significant part of a Book cannot be translated freely without specific written consent by the publisher. Further information can be obtained at permissions@intechopen.com.
\n\nIn instances where permission is obtained from the publisher for reusing or republishing the Book, or significant parts of the Book, all of the following conditions apply:
\n\nEvery single Work that is used has to be attributed in the way described. If you are unsure about proper attribution, please write to permissions@intechopen.com.
\n\nIndividual Works originally published in IntechOpen books are licensed under Creative Commons licenses and can be freely used under terms of the respective CC license, if properly attributed. In order to properly attribute the Work you must respect all the conditions outlined below:
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\n\nIn the event that you use more than one of IntechOpen's Works published in one or more books (but not a significant part of the book that is under separate Copyright), each of these have to be properly attributed in the way described.
\n\nIntechOpen does not have any claims on newly created copyrighted Works, but the Works originally published by IntechOpen must be properly attributed.
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