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
Slide 3
B ODY T EMPERATURE Core Temperature Aortic blood temperature
Esophageal temperature Tympanic membrane temperature
Slide 4
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)
Slide 5
CAUSES OF HYPERTHERMIA SYNDROMES
Slide 6
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
Slide 7
Hypothetical model for the febrile response OVLT, organum
vasculosum of the lamina terminalis
Slide 8
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)
Slide 9
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
Slide 10
Slide 11
Slide 12
Fever Normal body temperature: 37 o C (set point) Circadian
variation oral T 0. 5 o C > axillary T
Slide 13
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
Slide 14
Hypothetical model for the febrile response
Slide 15
Slide 16
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
Slide 17
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
Slide 18
Endogenous Pyrogen Cytokines IL-1 IL-1 TNF TNF IFN IL-6
Phagocytes and lymphocytes: major source of pyrogenic
cytokines
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
Slide 22
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
Slide 23
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%)
Slide 24
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
Slide 25
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
Slide 26
Fever of unknown origin (FUO)
Slide 27
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
Slide 28
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
Slide 29
Summary of Definitions and Major Features of the Four Subtypes
of Fever of UnknownOrigin (FUO)
Final Diagnosis in Elderly Compared with Younger Patients with
Fever of Unknown Origin
Slide 38
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
Slide 39
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
Slide 40
General Diagnostic Evaluation of Patients with Fever of Unknown
Origin
Slide 41
*Includes tuberculosis, histoplasmosis, coccidioidomycosis,
sarcoidosis, and syphilis Examples of Subtle Physical Findings
Having Special Significance in Patients with Fever of Unknown
Origin
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
Slide 44
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
Slide 45
SELECTED AGENTS ASSOCIATED WITH DRUGINDUCED FEVER
Slide 46
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