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PRAUD 2019 - SURABAYA

Management of Adult Patients with Fever

Musofa Rusli
Dep/SMF Ilmu Penyakit Dalam – Divisi Tropik - Infeksi
FKUA – RSUD Dr. Soetomo Surabaya

TOPICS

oDefinition
oPathophysiology of fever
oManagement of fever
oFever of unknown origin
oDrug fever

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Definition
Fever oFever:
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., above 37.2°C].
Heat conservation (vasoconstriction) and heat production (shivering, fat
tissue thermogenesis)
Anatomic variations: rectal > oral > axillar  rectal 0.4 oC higher than
oral

oNormal daily oral temperature:

36.8 + 0.4 oC
Low levels at 6 AM and higher levels at 4 – 6 PM
Thus, 37.2 oC in the morning  fever 3

Normal Body Temperature

oFor healthy individuals 18 to 40 years of age, the mean

oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F)
oLow levels occur at 6 A.M. and higher levels at 4 to 6
P.M.
oThe maximum normal oral temperature is 37.2°C at 6
A.M. and 37.7°C at 4 P.M.
oThese values define the 99th percentile for healthy
individuals.

Mackowiak, et al., JAMA 1992;268:1578

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Wunderlich’s Maxim

oAfter analyzing >1 million axillary temperatures from ~25,000

patients, Wunderlich identified 37.0° C (36.2-37.5) as the mean
temperature in healthy adults.
oTemperature readings >38.0° C were deemed as
“suspicious/probably febrile.”

1Wunderlich C. Das Verhalten der Eiaenwarme in Krankenheiten.

Leipzig, Germany: Otto Wigard;1868.

2Mackowiak, et al., JAMA 1992;268:1578

Normal Body Temperature Caveats

oRectal temperatures are generally 0.4°C higher than

oral readings.
oTympanic membrane (TM) values are 0.8°C lower
than rectal temperatures

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Definition
Pyrogens
Pyrogens  any substance that causes fever
oEndogenous
class of biologically active proteins called cytokines  pyrogenic cytokines
related to activation of TLR
E.g.: IL-1, IL-6, TNF-α, IFN-γ

oExogenous
derived from outside the host
mainly microbes or their products: toxins

Definition
Elevated body temperature
oHyperthermia:
An uncontrolled increase in body temperature that
exceeds the body's ability to lose heat 
thermoregulatory center is unchanged
Does not involve pyrogenic molecules
Exogenous heat exposure and endogenous heat
production
oHyperpyrexia:
an extraordinarily high fever (>41.5ºC)
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Elevated body temperature

Fever Hyperthermia Hyperpyrexia
Infectious diseases Heat stroke Most commonly
Autoimmune disease Neuroleptic Malignant Synd occurs in patients
Malignancy drug-induced hyperthermia with CNS
serotonin syndrome hemorrhages
malignant hyperthermia
Thyrotoxicosis
Pheochromocytoma
cerebral hemorrhage
status epilepticus
hypothalamic injury

PATHOGENESIS OF FEVER

Heat conservation
Heat production

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TREATING FEVER

Antimicrobial Acetaminophen
drugs Corticosteroids NSAIDs

Anti-cytokines Antimicrobial
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drugs drugs

Definition
Temperature-pulse relationship

oThe temperature-pulse relationship is linear with an

increase in heart rate of 4.4 beats/ minute for each 1ºC
oTemperature-pulse dissociation (relative bradycardia) 
typhoid fever, brucellosis, leptospirosis, some drug-
induced fevers and factitious fever
oFever may not be present during infection in newborns,
the elderly, patients with chronic renal failure, and in
patients taking corticosteroids
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Pattern of temperature changes

The pattern of temperature changes may occasionally hint at the diagnosis

Patterns:
o Continuous fever: Temperature remains above normal throughout the day and does not
fluctuate more than 1 °C in 24 hours
o Intermittent fever: The temperature elevation is present only for a certain period, later
cycling back to normal
o Remittent fever: Temperature remains above normal throughout the day and fluctuates
more than 1 °C in 24 hours

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Fever Onset
< 1 week Within 1-3 weeks > 3 weeks
Dengue Typhoid fever Tuberculosis
Chikungunya Typhus HIV
Leptospirosis Leptospirosis CMV
JEV Ebola Autoimmune disease
SARS CMV Malignancies
Ebola Rabies
Hepatitis A Acute HIV

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Acute Fever Requiring Hospitalization

oTyphoid fever
oDengue fever/ DHF
oRickettsiosis
oLeptospirosis
oChikungunya fever
oHantavirus

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Of Course… the Differential is VERY Broad:

Infection (TB, Endocarditis, Abscess, Line Infection, Sinusitis, Meningitis,

Arthritis Osteomyelitis/Wound, Infectious Diarrhea/c. Diff)

Inflammatory (Rheumatic Disorders, Vasculitis, Neoplasms)

Drug Fever (Beta-Lactam antibiotics, Ampho B, Chemo, Drug Interactions)

Thrombotic (DVT/PE/MI)

Neurologic (Hypothalamic disorder, Spinal Cord Injuries, ICH)

Endocrine (Thyrotoxicosis, Adrenal Insufficiency, Subacute Thyroiditis)

Gastrointestinal (IBD, Pancreatitis)

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Treatment of Fever
oAntipyretics:
Acetaminophen
NSAIDs  side effects !
oCorticosteroids  side effects !!!
oCool damp sponges
oSubmersion should be avoided

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Benefit and complication of fever

Benefit:
o fever is associated with release of endogenous pyrogens, which activate the T
cells and thus enhance the host defence mechanism.
o Some febrile diseases have characteristic patterns  diagnostic benefit

Complications:
o a state of catabolism  detrimental to body
o fluid and electrolyte imbalance - due to sweating and loss of minerals
o high grade fevers can lead to convulsions, brain damage, circulatory overload
and arrhythmia
o increase oxygen consumption  COPD, CHD

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Drug Fever
Definition (Mackowiak & LeMaistre, 1987):
o a disorder characterized by fever coinciding with administration of a drug and disappearing after the
discontinuation of the drug
o no other cause for the fever is evident after a careful physical examination and laboratory investigation
o usually a diagnosis of exclusion

Important drugs related to drug fever:

o Antimicrobials: beta-lactams, sulfonamides and nitrofurantoin
o Anticonvulsant
o Minocycline
o Allopurinol
o Sympathomimetic drugs: amphetamines, cocaine

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SELECTED AGENTS ASSOCIATED WITH

DRUG-INDUCED FEVER

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Fever of Unknown Origin

Definition (Petersdorf & Beeson, 1961):
o Fever higher than 38.3ºC on several occasions
o Duration of fever for at least three weeks
o Uncertain diagnosis after one week of study in the hospital
o Classic, nosocomial, neutropenic and HIV-associated FUO (Durrack & Street, 1990)

“Classic”etiology:
o Infections: tuberculosis, infectious mononucleosis
o Malignancies
o Noninfectious inflammatory diseases (eg, vasculitis, systemic lupus erythematosus, polymyalgia
rheumatica)
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o Connective tissue diseases (eg, vasculitis, rheumatoid arthritis)

Time matters: the spectrum evolves

Mourad et al. Arch Int Med

2003;163:545

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1. Infections:
 Endocarditis
 Tuberculosis
 Abdominal abscesses FUO: most common causes
 EBV/CMV infections

2. Malignancies:
 Lymphoma
 Leukemia

3. Non-infectious inflammatory disorders

 Systemic lupus erythematosus
 Polymyalgia rheumatica – giant cell arteritis
 Crohn disease

4. Miscellaneous disorders
 Habitual hyperthermia
 Drug fever Vanderschueren S. et al. From prolonged febrile illness to
Fever of Unknown Origin: The challenge continues. Arch
 Subacute thyroiditis Intern Med 2003;163:1033.

Key Points
oHistory taking  finding source/ site of infection
oPhysical examination
oImaging
oLaboratory tests:
CBC, urinalisys, BUN/ SC, SGOT/ SGPT, LED, [CRP, lactate,
procalcitonine]
Blood/ urine/ body fluid culture
Serology, antigen-based test
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o PCT improves the management of patients with lower respiratory tract infections and
critically ill sepsis patients, as well as patients with UTIs, postoperative infections,
meningitis, and acute heart failure with possible superinfection (i.e., pneumonia)
o PCT-guided protocol shortened length of antibiotic treatment
o PCT is far from being a perfect marker and levels must be evaluated in the context of a
careful clinical and microbiological patient assessment 26

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Evidences in favor of PCT

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Procalcitonin (PCT) algorithm in patients with respiratory tract

infections in the emergency department

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Procalcitonin (PCT) algorithm in patients with sepsis in the

intensive care unit (ICU)

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THANK YOU

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