Approach to fever

Presentation by: Asma Zeydan

 Outlin
 Definition of fever
 Pathophysiology of fever
 Etiology of fever
 Classification of fever.
e
 Case Scenario
 Approach to fever
 Objectives
• Discuss about Temperature regulation
• Recognize the causes and mechanisms of fever
• Distinguish between fever and hyperthermia
• Understand the to Approach a Febrile Patient
What is fever?
• Fever is an elevation of body temperature that exceeds the normal
daily variation and occurs in conjunction with an increase in the
hypothalamic set point (e.g., from 37°C to 39°C).

• A.M. temperature of >37.2°C (>98.9°F) or a P.M. temperature of

>37.7°C (>99.9°F) would define a fever.
NORMAL BODY TEMPERATURE
• Range of normal temperature — Normal body temperature ranges
from approximately 35.3 to 37.7°C (95.5 to 99.9°F), with an average of
36.7°C (98.0°F) when measured orally

• Individual daily variation — Normal body temperature varies over

the course of the day, controlled in the thermoregulatory center
located in the anterior hypothalamus.
Methods of measurement
• Peripheral methods
 Tympanic membrane
 Temporal artery
 Axillary
 Oral thermometry

• Central methods
 Pulmonary artery catheter
 Urinary bladder
 Esophageal
 Rectal thermometry
Cont’d
• Peripheral methods of monitoring temperature are not as accurate as
central methods but central methods are less practical than
peripheral methods.
• Rectal temperatures are generally 0.6°C (1.0°F) higher than oral
readings.
• Tympanic membrane temperature readings are close to core
temperature.
Physiology of temperature

regulation
• Body temperature is controlled by the hypothalamus.

• Neurons in both the preoptic anterior hypothalamus and the posterior

hypothalamus receive two kinds of signals
 From peripheral nerves that transmit information from
warmth/cold receptors in the skin
 The temperature of the blood bathing the region.
Hypothalmic response to cold temperature

• Shivering

• Non-shivering thermogenesis by brown adipose tissue (mainly in

neonates)

• Vasoconstriction

• Behavioral changes.
Hypothalmic response to hot
temperature
• Sweating (diaphoresis)

• Vasodilation

• Behavioral changes
Fever vs Hyperpyrexia vs

Hyperthermia
• Hyperpyrexia: is the term for an extraordinarily
high fever (>41.5°C), which can be observed in
patients with severe infections but can also occur
in patients with central nervous system (CNS)
hemorrhages.

• Hyperthermia: body temperature increases in an

uncontrolled fashion and overrides the ability to lose heat.
Exogenous heat exposure and endogenous heat production are two
mechanisms by which hyperthermia can result in dangerously high
internal temperatures
PATHOGENESIS OF FEVER
PYROGENS
• The term pyrogen is used to describe any substance that causes fever.
• Pyrogens are either
 Exogenous
 Endogenous.
Exogenous pyrogens
• Are derived from outside the patient
• Most are microbial products, microbial toxins, or whole
microorganisms (including viruses).
• The classic example of an exogenous pyrogen is the
lipopolysaccharide (endotoxin) produced by all gram-negative
bacteria.
Exogenous pyrogens
 Pyrogenic products of gram-positive
 Staphylococcus aureus - enterotoxins, The toxic shock
syndrome toxin (TSST-1)
 Groups A and B streptococcal toxins, also called superantigens
PYROGENIC CYTOKINES

• Cytokines are small proteins that regulate immune,

inflammatory, and hematopoietic processes.
• Fever-producing cytokines,formerly called Endogenous
pyrogens
• The pyrogenic cytokines include IL-1, IL-6, tumor necrosis
factor (TNF),

and ciliary neurotropic factor, a member of the IL-6 family.

• A wide spectrum of exogenous pyrogens induces the synthesis and
release of pyrogenic cytokines via activation of the TLRs.

• Most exogenous pyrogenic substances are from bacterial or fungal

sources. Viruses induce pyrogenic cytokines by infecting cells

• The cellular sources of pyrogenic cytokines are primarily monocytes,

neutrophils, and lymphocytes, although many different cells can
synthesize these molecules when stimulated.
ELEVATION OF THE HYPOTHALAMIC SET POINT
BY CYTOKINES

• During fever, levels of prostaglandin E2 (PGE2) are

elevated in hypothalamic tissue and the third
cerebral ventricle.
• The concentrations of PGE2 are highest near the
networks of enlarged capillaries surrounding the
hypothalamic regulatory centers( circumventricular
vascular organs
Chronology of events required for the induction of fever. AMP, adenosine
5′-monophosphate; IFN, interferon; IL, interleukin; PGE2, prostaglandin
E2; TNF, tumor necrosis factor.
• Cytokines can also be produced in the CNS, accounting for hyperpyrexia

in CNS hemorrhages, trauma, or infections.

• They do so by raising hypothalamic set-point, bypassing

circumventricular organs.

• Typically caused by viral infections that induce microglial and possibly

neuronal production of IL-1, TNF, and IL-6.

Classification of

fever
Based on duration:
• Acute (less than 7 days)
Example: malaria, viral URTIs

• Chronic (more than 14 days)

Example: TB, HIV, Cancers such as lymphomas.

Acute febrile illness: a fever of 38 C or higher, of less

than a week duration with no identified source.
A nonspecific term for an illness of sudden onset
accompanied by fever
Based on severity

• Low-grade: 37.3 to 38.0 C

• Moderate-grade: 38.1 to 39.0 C
• High-grade: 39.1 to 41.5 C
• Hyperpyrexia: Greater than 41.5 C
Based on pattern

• Continuous or sustained fever: defined as fever that does not fluctuate more than
about 1 °C (1.5 °F) during 24 h, but at no time touches normal.
Eg. Pneumonia, early stage typhoid and UTIs.
• Intermittent fever: This fever has a fluctuating baseline between normal
temperatures and fever levels over the course of the day.
Eg. Malaria, TB, leptosporiosis
 cont’
• d may come and go, and the temperature
Remittent fever: ——This type of fever

fluctuates, but though it falls, it never falls all the way back to normal. Eg.

Typhoid, endocarditis, lesihmaniasis, bruceliosis

• Relapsing fever: Fevers with periods during which patients are afebrile for one

or more days between febrile episodes . Mainly caused by Boriella spp.

• Quotidian fever- periodicity of 24 hours- P.falciparum or P.knowlesi.
• Tertian fever- 48 hour periodicity -P.vivax ,p.ovale,
• Quartan fever- 72 hour periodicity -P.malariae.

• The Pel-Epstein's fever is an intermittent low grade fever

characterised by 3–10 days of fever with subsequent a febrile periods
of 3–10 days. Mainly associated with Hodgkin’s lymphoma.
• Hectic fever
Either an intermittent or a remittent fever is considered hectic if the
temperature range swings widely throughout the day, with a difference of
at least 1.4 degrees Celsius between the highest and lowest temperatures.
 Fever of unknown

origin
—FUO is now defined as follows:
1. Fever ≥38.3°C (≥101°F) on at least two
occasions.
2. Illness duration of ≥3 weeks
3.No known immunocompromised state .
4. Diagnosis that remains uncertain after a
thorough history-taking, physical examination,
and the different obligatory investigations:
 Case
A 45 MaleConstruction Worker reported that his symptoms began gradually
with a low-grade intermittent fever that progressed to high-grade fever,
especially at night. He also experienced significant weight loss (approximately 5
kg in the past month) and fatigue. His cough was initially dry but later became
productive with yellowish sputum. He denied any hemoptysis (coughing up
blood).
He appeared ill and fatigued. He had a fever of 38.5°C (101.3°F).

Respiratory: On auscultation, there were crackles (rales) heard in the upper

lobes of both lungs. There was also dullness to percussion over the same areas.
Other systems: No significant findings.
CBC revealed elevated white blood cell count with lymphocyte predominance.
Sputum Smear was Positive for acid-fast bacilli (AFB)
Approach to patient with

fever
History
• Fever : character, pattern, duration, timing, severity - interfere with
sleep , interfere with usual activity, relieving and aggravating factors
• Treatment received or/and outcome
• Associated symptoms – cough, pain and location, frequency and
burning during urination, bone pain, body discharge
• Host factors & comorbid conditions
• Travel hx & endemicity
• Foreign bodies (barrier contraceptives, tampons, prosthetic)
cont’d
• Past medical hx
• Recent surgical hx – post-op complications
• Medication use
• Sexual hx
• Animal(including arthropod) bites
• Recent dietary intake
• Contact with ill individuals
• Review of systems
• Focal pain or tenderness
• Rashes or skin lesions
• Neurologic symptoms & sensorium alterations
• RS,GI,GU
Physical examination
General Appearance
Vital Signs - Temperature rise and change in other vitals
HEENT – Pale Conjuctiva, Icteric sclera, Ear discharge…
LGS – palpable lymph node, breast tenderness or discharge, enlarged
thyroid or nodular thyroid.
• Respiratory system: Tactile fremitus change, chest lag, dullness, crackles
• CVS - Finger clubbing. Heart murmurs and gallops
• GIT - Signs of liver disease such as ascites, hepatosplenomegaly, rigidity,
guarding tenderness or palpable mass.
• GUS - CVA and suprapubic tenderness.
• IS- Skin rash, nodules, ulcer, or wounds. Spooning or clubbing of nails, pale
nail-beds.
 Cont’

d
• MSS - Bone or joint tenderness and swelling,

Edema

• —NS- level of consciousness, focal neurological

findings, meningeal irritation signs.

Investigations
Blood tests
• CBC
• Blood smear
• ESR and CRP
• BUN
• Creatinine
• Serum glucose
• LFT
• Serum electrolytes
• Serology
• Culture
 cont’
• Stool examination
d
• Urinalysis
• CXR
• CSF
• Echocardiography
• CT
• MRI
• Special tests depending on most anticipated etiology. Eg. Culture, PCR and AFB
for TB.
TREATMENT OF FEVER AND

HYPERPYREXIA
• In deciding whether to treat fever, it is important to remember that fever
itself is not an illness: it is an ordinary response to a perturbation of normal
host physiology.
• Most fevers are associated with self-limited infections, such as common
viral diseases.

• In short, treatment of fever and its symptoms with routine antipyretics does
no harm and does not slow the resolution of common viral and bacterial
infections.
• We suggest treating fever in adults to reduce symptoms of headache,
myalgia, and arthralgias, or in individuals with underlying cardiac or
pulmonary disease.

• We suggest treating hyperpyrexia in individuals with advanced age, heart

or pulmonary disease, or chemotherapy or checkpoint inhibitor therapy;
we also treat hyperpyrexia due to CNS disease (eg, intracerebral
hemorrhage) to reduce adverse effects of high temperature on the brain
 Anticytokine therapy to reduce fever in
Autoimmune and Autoinflammatory diseases

• Although fever can be a manifestation of autoimmune diseases,

recurrent fevers are characteristic of autoinflammatory diseases.

• The fevers associated with many of these illnesses are dramatically

reduced by blocking of IL-1 activity with anakinra or canakinumab
Mechanism of

antipyretics
 The reduction of fever by lowering of the elevated hypothalamic set
point is a direct function of reduction of the PGE2 level in the
thermoregulatory center.
 The synthesis of PGE2 depends on the constitutively expressed enzyme
cyclooxygenase.

 The substrate for cyclooxygenase is arachidonic acid released from the

cell membrane, and this release is the rate-limiting step in the
synthesis of PGE2.

 Therefore, inhibitors of cyclooxygenase are potent

antipyretics.
Regimens for the treatment of fever
• The objectives in treating fever are first to reduce the elevated
hypothalamic set point and second to facilitate heat loss.
• Oral aspirin and NSAIDs effectively reduce fever but can adversely
affect platelets and the gastrointestinal tract. Therefore,
acetaminophen is preferred as an antipyretic
• In children, acetaminophen or oral ibuprofen must be used because
aspirin increases the risk of Reye’s syndrome.
• In hyperpyrexia, the use of cooling blankets facilitates the
reduction of temperature; however, cooling blankets
should not be used without oral antipyretics

• In hyperpyretic patients with CNS disease or trauma

(CNS bleeding), reducing core temperature mitigates
the detrimental effects of high temperature on the
brain
References

• Harrison’s principles of internal medicine 21th

edition

• UpToDate