Medicine JC095: Fever Flashcards
Normal body temperature
Varies at different site of measurement:
- Oral: 33.2-38.2 (vary with food intake)
- Rectal (most resemblance to core body temp): 34.4-37.8 (less variation)
- Tympanic: 35.4-37.8
- Axillary: 35.5-37.0 (less variation)
—> peripheral temperature need to do adjustment: ∵ affected by circulation (e.g. vasoconstriction, hypotension, shock —> not necessarily mean patient has hypothermia)
Normal temperature also depends on:
1. Age (elderly has lower normal temperature ∵ lower metabolic rate)
2. ***Sex (female: ↑ after ovulation)
3. Time of measurement (↓ in midnight, ↑ in afternoon —> +/- 0.5oC from mean temp)
4. Activity level
Etc.
Physiology of Temperature regulation
2 main components:
1. **Hypothalamus (Temperature regulating centre: Thermostat)
2. **Peripheral regulatory mechanism
—> Very important to distinguish between Fever vs Hyperthermia
↑ Body temp
—> detected by Thermostat
—> ↓ Heat production + ↑ Cooling effect + Voluntary response
↓ Heat production:
- ↓ SNS —> ↓ Basal metabolic rate
↑ Cooling effect:
- ↓ SNS —> Vasodilation
- ↑ PNS —> Sweating
Voluntary response:
- ↓ Activity
- Exposing body to cold environment
- Cold drinks
- Loose clothing
↓ Body temp
—> detected by Thermostat
—> ↑ Heat production + ↓ Cooling effect + Voluntary response
↑ Heat production:
- ↑ Thyroid hormone —> ↑ Basal metabolic rate
- ↑ SNS —> ↑ Basal metabolic rate
- Shivering
↓ Cooling effect:
- ↑ SNS —> Vasoconstriction
- ↑ SNS —> Piloerection
Voluntary response:
- ↑ Muscle activity
- Seek heat source
- Eat
- Warm clothing
***Mechanism of Fever
Definition of Fever:
- Thermostat reset at Hypothalamus
LPS from Gram -ve bacteria / Infections
—> Monocyte activation
—> **Pyrogenic cytokines (IL1, TNFα, IL6)
—> Stimulate *Endothelium of Hypothalamus (LPS can also directly stimulate it)
—> ***PGE2 production (main mediator to adjust thermostat)
—> Neurotransmitter, cAMP
—> ↑ Set point in Hypothalamus
—> Peripheral heat response (↑ Heat production, ↓ Cooling effect)
—> Fever (result of readjusting set point in Hypothalamus)
End result:
1. Vasoconstriction —> Chills
2. Shivering —> Rigor (not necessarily depend on how high the thermostat adjusted, if little elevation of set point —> other mechanism enough to generate enough heat)
—> above usually occur ***before onset of fever (high body temperature)
Definition of Fever
Oral: 37.8
Rectal: 38
Tympanic: 38
Axillary: 37.2
Hyper-pyrexia:
- ***Core temperature (NOT peripheral) >40
- indicate serious underlying condition
- may lead to permanent brain damage
***Fever patterns
Varies with different causes of Fever
- NOT 100% sensitive / specific
- Continuous fever:
- Temp NOT fluctuate >1oC
- Causes: ***Pyrogenic infections, Dengue fever, Fungal infections - Remittent fever:
- Temp **remains above normal + fluctuate >1oC
- Causes: **IE, Brucellosis, Typhoid fever - Intermittent fever:
- Elevation of temp only present for a certain period (e.g. 1-2 hours), in between body temp is **normal
- Causes: **Malaria, TB, Lyme disease, Borreliosis, EBV
***Fever vs Hyperthermia
Fever:
- **Change in Hypothalamic set point
- Heat production / Cooling mechanisms intact (e.g. cool limbs during fever)
- Involves **Pyrogenic cytokines (IL1, TNFα, IL6, IFN)
- Diurnal variation usually ***preserved
Hyperthermia:
- **Failure in thermoregulation (imbalance between heat production / cooling mechanisms) (e.g. unable to sweat during exercise if severe dehydration)
- Thermostat / Hypothalamic set point is **normal
- Diurnal variation lost
- e.g. **Heatstroke, Malignant neuroleptic syndrome, Serotonin syndrome, **Thyroid storm
***Causes of Fever
Infections:
- Virus
- Bacteria
- Fungus
- Parasite
Autoimmune disease (activate monocytes / pyrogenic cytokine production):
- SLE
- Sarcoidosis
- Adult Still’s disease
- Giant cell arteritis
Malignancies:
- Lymphoma
- Leukaemia
- RCC (most classic example of ***solid organ tumour causing fever)
Tissue destruction:
- Massive infarction
- Massive haemolysis
- Rhabdomyolysis
Metabolic disorders:
- Gout
- Porphyria
Drugs:
- Antibiotics
- Anticonvulsants (technically cause hyperthermia due to SE to thermoregulation / muscle contraction)
***Pyrexia of unknown origin
Old definition (vague):
- Fever **>38.3 on several occasions
- Duration **>3 weeks
- Unable to reach a diagnosis despite ***1 week of inpatient investigation
Current definition (more widely accepted):
- Prolonged fever without an obvious identifiable cause
Proportion of fever:
- PUO > CT disease > Infection > Malignancies > Miscellaneous
Rmb:
- Most fever that persist beyond a period are caused by common conditions presenting **uncommonly
- Many conditions can cause PUO
- **Infection a significant cause (∵ ↑ global travel + use of immunomodulating drugs e.g. immunosuppressants, chemotherapy) —> need to **exclude Infection first!
- Most PUO in developed world caused by **Non-infectious inflammatory disorders (malignancy a much smaller percentage)
- PUO DDx depend on:
—> time
—> regional factors
—> exposures
—> available diagnostic tools
- Significant % of PUO are caused by miscellaneous conditions
- ***No standard algorithm for evaluating PUO
***Etiologies of PUO
Infection:
- **Endocarditis (need echo) > **Mycobacterial (esp. extrapulmonary) > Abdominal abscess (now easier to diagnose by advances in imaging)
Malignancies:
- ***Lymphoma > Solid organ tumour
Autoimmune diseases:
1. **SLE
2. **Systemic vasculitis
3. ***Adult Still’s disease
(- RA, Psoriatic arthritis, Spondyloarthritis usually not present with high fever —> low grade fever only)
Drug fever:
1. **Hypersensitivity reaction (∵ pyrogenic cytokine production)
- **Type 3 (Immune complex-mediated (Ag-Ab complex) —> Complement activation —> Attract Neutrophil —> Cytokines) (e.g. Serum sickness syndrome by drug —> GN, Arthritis, Rash, Fever)
2. Altered thermoregulatory mechanisms
3. Reactions that are direct extensions of pharmacological action of drug
4. Other Idiosyncratic reaction
Drug fever: 2. Altered thermoregulatory mechanisms
- Exogenous ***thyroid hormone
- Drugs with ***Anticholinergic activities (∵ ↓ sweating, urinary retention)
- ***Sympathomimetic agents (∵ ↑ SNS, e.g. recreational drugs: ecstasy, amphetamine —> agitation, twitching, cold extremities due to vasoconstriction, ↑ HR, mydriasis, sweating but less prominent than heat production mechanisms)
Differentiating Anticholinergic vs Sympathomimetics:
- Dry skin vs Sweaty skin
Drug fever: 4. Idiosyncratic reactions
Idiosyncratic: not based on primary pharmacological effect of medications, SE unpredictable
- **Malignant hyperthermia (esp. after **antipsychotic)
- ***Neuroleptic malignant syndrome
- Serotonin syndrome (SSRI, ***Tramadol)
***Diagnostic approach to PUO
History
1. Localising symptoms (e.g. chills, rigor)
2. **Intake of drugs (drugs that cause fever, drugs that alter immunity)
3. Travel
4. Animal exposure
5. **Risk of immunosuppression
P/E
1. **Organomegaly (malignancy)
2. CT disease
- Rash
- Arthritis
- Vasculitis
—> **small vessels (e.g. **ANCA-associated vasculitis —> Renal involvement: Proteinuria, Haematuria; Lung involvement)
—> **large vessels (e.g. **Temporal arteritis in elderly, **Takayasu’s arteritis)
Laboratory tests
1. ESR
- RBC stacked together (Rouleaux: one of major determinants of ESR)
—> promoted by **APR, **Ig (↑ during acute inflammation)
—> decreased by **Albumin (↓ during acute inflammation)
- less specific: also ↑ by ↑ age, female sex
- **↑: infection, TB, multiple myeloma, hypergammaglobulinaemia, pregnancy, anaemia, renal disease, ↑ age, female sex (RBC stick together —> sink more rapidly)
- ↓: RBC abnormalities, extreme leukocytosis, hyperviscosity (i.e. a lot of other components prevent sinking of RBC)
- CRP
- IL6, IL1β —> ↑ CRP synthesis by ***liver
- false negative: IL6, IL1β blockers -
**Procalcitonin
- Calcitonin: ONLY produced by Thyroid C-cells normally
- Procalcitonin: during **Bacterial infection
—> Bacterial infection —> IL1β, TNFα, LPS —> ↑ gene transcription of Procalcitonin in **ALL organs
(—> Viral infection —> IFNγ —> ↓ gene transcription of Procalcitonin)
- Rise and drops significantly **within 3 days —> also helpful to monitor treatment response
Imaging
1. CT
2. MRI
3. Gallium scan
4. ***PET-CT (more specific than Gallium scan)
