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By: Dr. Ahmadreza Mobaien MD-MPH Fever

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Core temperature is regulated by a series of independent feedback loops (symbolized here by two loops with arrows). Sensors in the periphery and core are triggered according to changes in temperature. Signals are sent via the spinal cord and brainstem to the preoptic area in the hypothalamus, where signals are integrated with core sensors in the brain. These, in turn, activate efferent pathways in the hypo-thalamus, brainstem, spinal cord, and sympathetic system, which instigate physiologic changes that regulate temperature. BAT, brown adipose tissue

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B ODY T EMPERATURE Core Temperature Aortic blood temperature Esophageal temperature Tympanic membrane temperature

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H YPERTHERMIA Excessive heat production (e.g. vigorous exercise, a reaction to some anesthetics) Decreased dissipation (e.g. dehydration) loss of regulation (injury to the hypothalamic regulatory center)

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CAUSES OF HYPERTHERMIA SYNDROMES

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Fever vs. Hyperthermia Fever Hypothalamic setpoint increased by cytokines Peripheral mechanisms generate and conserve heat Response to antipyretics Hyperthermia Hypothalamic setpoint is normal Peripheral mechanisms fail to match setpoint No response to antipyretics

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Hypothetical model for the febrile response OVLT, organum vasculosum of the lamina terminalis

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The letters inside the cells indicate a warm-sensitive (w) neuron and a cold-sensitive (c) neuron. With increases in Th, warm- sensitive neurons raise their FRs and heat production decreases. Pyrogens inhibit () the FRs of warm-sensitive neurons, thereby resulting in accelerated FRs of cold- sensitive neurons and increased heat production. The plots show FR and heat production responses during normal conditions in the absence of pyrogens (N) and in the presence of low concentrations (P 1 ) and high concentrations (P 2 ) of pyrogens firing rate (FR)

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Pathophysiology Pathophysiology The body temperature is under control of the preoptic area of the anterior hypothalamus( Thermostat ) It receives input from both central receptors and peripheral receptors Elevation of body Temperature shivering thermogenesis and dermal vasoconstriction Cooling mechanism sweating and dermal vasodilation mixture of sympathetic and parasympathetic pathways

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Fever Normal body temperature: 37 o C (set point) Circadian variation oral T 0. 5 o C > axillary T

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Pathogenesis of fever Pyrogens Substances that can cause fever Either exogenous or endogenous exogenous Most of them are with high molecule weight Could not penetrate blood-brain barrier Stimulating monocytes and macrophages to induce the formation of endogenous pyrogen

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Hypothetical model for the febrile response

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Exogenous Pyrogens Majority are microorganism, their products or toxins Gram - : endotoxin (lipopolysaccaride, LPS) Gram + : lipoteichoic acid peptidoglycan exotoxins and enterotoxins Others complement products steroid hormone metabolites Ag-Ab complex with complement

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Endogenous Pyrogen In response to invasive stimuli: exogenous pyrogen chemical agents (amphotericin B and other drug) Produced by cells of immune system of the host (macrophages, lymphocytes) Proteins designated monokines and lymphokines cytokines

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Endogenous Pyrogen Cytokines IL-1 IL-1 TNF TNF IFN IL-6 Phagocytes and lymphocytes: major source of pyrogenic cytokines

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Interleukin1 (alpha*, beta) Interleukin6 Interleukin11 Tumor necrosis factor (alpha) Interferon (alpha, beta, gamma) ProstaglandinE 2 Platelet activating factor Ciliary neurotropic factor (CNTF) Oncostatin M Cardiotropin1 Leukemic inhibitory factor (LIF)

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Monocytes, tissue macrophages Keratinocytes Gingival epithelium Corneal epithelium Renal mesangial cells Brain astrocytes Vascular endothelium Vascular smooth muscle NK cells Fibroblasts

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Fever and Host Defense Enhancement Neutrophil function Enhanced migration Enhanced superoxide production Mononuclear function Enhanced IFN production Enhanced interferon tumor and viral activity Tcell proliferation

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Bacteria provoke release of IL-1 Viral proteins stimulate IFN Combined production of several cytokines cause fever Pyrogenic cytokines bind receptors present on vascular endothelial cells that lie within the hypothalamus Resetting the hypothalamic thermoregulatory center by increased prostaglandin (PGE) and cAMP

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Infective fever Metabolites from organism cause fever Most common causes of fever (50%~60%) Bacteria pyrogens: common cause of infective fever (43%) Viral pyrogens: (6%)

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Non-infective fever Absorption of necrotic substances: injury - ischemic necrosis -cell necrosis Allergy antibiotics (penicillin-based) Endocrine and metabolic disturbances: hyperthyroidism -dehydration Decreased elimination of heat from skin: heat failure

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The grade of fever Low grade fever: 37.3~38 o C Moderate fever: 38.1~39 o C High fever: 39.1~41 o C Hyperthermia fever: >41 o C

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Fever of unknown origin (FUO)

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FUO defined by Petersdorf and Beeson (1961) Fevers higher than 38.3 o C on several occasions A duration of more than 3 weeks Failure to reach a diagnosis after 1 week of inpatient investigation 70%~90% of the cases can be diagnosed

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Four Proposed Categories of FUO Based on potential etiology of FUO All require temperature > 38.3C Categorization be especially helpful in organizing an approach to patient evaluation Classic Health careassociated Immune-deficient (neutropenic) HIV-related

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Summary of Definitions and Major Features of the Four Subtypes of Fever of UnknownOrigin (FUO)

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Classical FUO

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Health careassociated FUO

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Immune-Deficient FUO

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HIV-Related FUO

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Distinctive fever patterns. A, Malaria. B,Typhoid fever C, Hodgkins disease (Pel- Ebstein pattern) D, Borreliosis (relapsing fever pattern)

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Final Diagnosis in Elderly Compared with Younger Patients with Fever of Unknown Origin

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History Travel Exposures to toxins, sick persons, animals Immunosuppression Localizing symptoms Look for subtle findings: eg. Jaw claudication, nocturia with prostatitis Degree of fever, nature of fever curve, apparent toxicity, and response to antipyretics not specific enough to guide management

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Repeated examination may be needed Careful attention to skin, mucous membranes, lymph and abdominal system Ask pts to record and measure temperature daily Yield from history and physical examination unknown

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General Diagnostic Evaluation of Patients with Fever of Unknown Origin

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*Includes tuberculosis, histoplasmosis, coccidioidomycosis, sarcoidosis, and syphilis Examples of Subtle Physical Findings Having Special Significance in Patients with Fever of Unknown Origin

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Somatostatin Melanocytestimulating factor Vasopressin CRH>ACTH>GC Thyroliberin GIP Neuropeptide Y Bombesin IL1ra, soluble TNF receptor

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Cyclooxygenase (COX) Inhibitors Acetaminophen Poor peripheral activity 0.02% as active as indomethacin In CNS oxidized by p450 to potent inhibitor of PGE2 synthesis 10% as active as indomethacin Acetylsalacyclic acid (ASA) Other NSAIDs Corticosteroids Inhibit phospholipase A 2 > PGE2 synthesis Block mRNA transcription of pyrogenic cytokines Phenothiazines Block peripheral vasoconstriction

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Mechanisms of Drug Fever Hypersensitivity Reactions Drug as hapten, tissue binding, cell mediated Idiosyncratic Mechanisms Malignant hyperthermia, neuroleptic malignant syndrome Altered Thermoregulatory Mechanisms Thyroxine, sympathomimetics, anticholinergics, MAOI Cytolysis JarischHerxheimer reaction Cancer chemotherapy G6PD induced hemolysis Administration Related Fever Endotoxin in drug/vaccine Amphotericin B, bleomycin Phlebitis, IM induced abscess

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SELECTED AGENTS ASSOCIATED WITH DRUGINDUCED FEVER

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Ref Harrison 18 th ed Chapter 16. Fever and Hyperthermia Chapter 18. Fever of Unknown Origin Mandell 8 th ed. Principles and Practice of INFECTIOUS DISEASES Chapter 55. Temperature Regulation and the Pathogenesis of Fever Chapter 56. Fever of Unknown Origin

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