‫بنام خدا‬
Fever
By:
Dr. Ahmadreza Mobaien
MD-MPH
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
BODY TEMPERATURE

“Core Temperature”
Aortic blood temperature
 Esophageal temperature
 Tympanic membrane temperature

HYPERTHERMIA
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)
CAUSES OF
HYPERTHERMIA
SYNDROMES
Fever vs. Hyperthermia
 Fever
 Hypothalamic set–point increased by cytokines
 Peripheral mechanisms generate and conserve heat
 Response to antipyretics
 Hyperthermia
 Hypothalamic set–point is normal
 Peripheral mechanisms fail to match set–point
 No response to antipyretics
Hypothetical model for the febrile response
OVLT,
organum vasculosum of
the lamina terminalis
firing rate (FR)
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 coldsensitive 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
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
Fever



Normal body temperature:
37oC (set point)
Circadian variation <1o C ：36.3 - 37.2oC
◦ lowest: 4 a.m;

peak: 6~10 p.m
Definition of fever:
◦ An elevation of core body temperature above the normal range

rectal T 0.5oC > oral T 0. 5oC > axillary T
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
Hypothetical model for
the febrile response
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
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
Endogenous Pyrogen
Cytokines
IL-1
TNF
Phagocytes
IL-1
IFN
TNF
IL-6
and lymphocytes: major source of
pyrogenic cytokines
ENDOGENOUS
PYROGEN











Interleukin–1 (alpha*, beta)
Interleukin–6
Interleukin–11
Tumor necrosis factor (alpha)
Interferon (alpha, beta, gamma)
Prostaglandin–E2
Platelet activating factor
Ciliary neurotropic factor (CNTF)
Oncostatin M
Cardiotropin–1
Leukemic inhibitory factor (LIF)
PYROGENIC CYTOKINE PRODUCING
CELLS










Monocytes, tissue macrophages
Keratinocytes
Gingival epithelium
Corneal epithelium
Renal mesangial cells
Brain astrocytes
Vascular endothelium
Vascular smooth muscle
NK cells
Fibroblasts
Fever and Host Defense Enhancement
 Neutrophil function


Enhanced migration
Enhanced superoxide production
 Mononuclear function

Enhanced IFN production


Enhanced interferon tumor and viral
activity
T–cell proliferation





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

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%)
Non-infective fever

Absorption of necrotic substances:
◦ injury - ischemic necrosis

Allergy
◦

antibiotics (penicillin-based)
Endocrine and metabolic disturbances:
◦

-cell necrosis
hyperthyroidism -dehydration
Decreased elimination of heat from skin:
◦
heat failure
The grade of fever•
Low grade fever:
37.3~38oC
Moderate fever:
38.1~39oC
High fever:
39.1~41oC
Hyperthermia fever: >41oC
Fever of unknown origin
(FUO)
Fever of unknown origin (FUO)
FUO defined by Petersdorf and Beeson (1961)
 Fevers higher than 38.3oC 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
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 care–associated
◦ Immune-deficient (neutropenic)
◦ HIV-related

Summary of Definitions and Major Features of the
Four Subtypes of Fever of UnknownOrigin (FUO)
Classical FUO
Health care–associated
FUO
Immune-Deficient
FUO
HIV-Related FUO
Distinctive fever patterns.
A, Malaria.
B,Typhoid fever
C, Hodgkin’s disease (PelEbstein pattern)
D, Borreliosis (relapsing
fever pattern)
Final Diagnosis in Elderly Compared with Younger
Patients with Fever of Unknown Origin


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




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
General Diagnostic Evaluation of
Patients with Fever of Unknown Origin
Examples of Subtle Physical Findings Having Special
Significance in Patients with Fever of
Unknown Origin
*Includes tuberculosis, histoplasmosis, coccidioidomycosis, sarcoidosis, and syphilis
 Somatostatin
 Melanocyte–stimulating
factor
 Vasopressin
 CRH–>ACTH–>GC
 Thyroliberin
 GIP
 Neuropeptide
Y
 Bombesin
 IL–1ra,
soluble TNF receptor

Cyclo–oxygenase (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 A2 –> ↓PGE2 synthesis
◦ Block mRNA transcription of pyrogenic cytokines
Phenothiazines
◦ Block peripheral vasoconstriction
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
– Jarisch–Herxheimer reaction
– Cancer chemotherapy
– G6PD induced hemolysis
• Administration Related Fever
– Endotoxin in drug/vaccine
– Amphotericin B, bleomycin
– Phlebitis, IM induced abscess
SELECTED AGENTS ASSOCIATED WITH
DRUGINDUCED FEVER
Ref
 Harrison 18th ed
 Chapter 16. Fever and Hyperthermia
 Chapter 18. Fever of Unknown Origin
 Mandell 8th ed. Principles and Practice of INFECTIOUS
DISEASES
 Chapter 55. Temperature Regulation and the
Pathogenesis of Fever
 Chapter 56. Fever of Unknown Origin