Fever is one of the most common presenting complaint that a patient has when he or she visits the hospital, this makes it necessary for us to know the exact mechanism behind the pathogenesis of fever, types of fever and the causes behind it. Here we are with this article to make sure we get the basics right.
What’s normal?
The human body is maintained at a temperature range of 36.5 – 37.8C (97.7 – 99.5 F) by the hypothalamus. The anterior and the posterior regions of the hypothalamus are responsible for the heat loss and heat conservation processes respectively. Any rise in temperature of the body sets off mechanisms that begin the process of heat loss – sweating, vasodilation, increased respiratory rate.
On the other hand a drop in the temperature of the body triggers the heat conservation mechanisms – peripheral vasoconstriction, shivering and non shivering heat generation by adipose tissue.
What is fever?
Fever is a condition where there is an elevation in the body temperature ( > 99.8 F) more than the normal diurnal variation in temperature due to increase in the set point of the thermostat in the hypothalamus.
This leads to the body being fooled to think that it’s body temperature is lower than the normal (because of increase in set point of temperature) setting off mechanisms to conserve and produce heat – peripheral vasoconstriction and shivering (Chills and rigor).
Now it’s absolutely essential for us to know the difference between hyperthermia and fever.
Hyperthermia is an increase in the body temperature without ever raising the hypothalamic thermoregulatory set point. There is no role of pyrogens in the setting of hyperthermia. Various causes for hyperthermia include exercising in a hot environment leading to failure of the body mechanism to loose enough heat and cool the body, malignant hyperthermia etc.
It is essential to distinguish between hyperthermia and fever because hyperthermia can be rapidly fatal and won’t respond to antipyretic therapy.
Now again here’s a term that might confuse you – hyperpyrexia , lets not allow this confuse us anymore. Hyperpyrexia is a fever where the body’s temperature is > 41.5C (106.7F).
Pathogenesis of fever:
The body’s temperature is chemically controlled by molecules called as pyrogens.
Pyrogens can be endogenous and exogenous.
Endogenous pyrogens – these are substances produced by our body and found in us. This includes interleukins ( IL-1 & IL-6 ), Tumour necrosis factor (TNF) and interferon alpha.
Exogenous pyrogens – Substances that when introduced into the body causes fever. This includes the microbial products, toxins and the organism itself. The classic example of the endotoxins (lipopolysaccharides) produced by gram negative bacteria.
Mechanism
Let’s take the case of a gram negative bacterial invasion:
• The endotoxins of the bacteria enters the body and activated the immune system to fight against it. The inflammatory cells produce a variety molecules in response to the foreign microbe and its products this includes cytokines IL-1, IL-6 and tumour necrosis factor TNF.
• The cytokines enter the circulation and reach the brain’s circumventricular area (organum vasculosum of lamina terminalis). They interact with the endothelium of the capillaries present there and causes production of PGE2 (Prostaglandin).
• PGE2 produced here as well as the PGE2 produced in capillaries elsewhere in the body which escape degradation in lungs reach the hypothalamus. This interacts with PGE2 type 3 receptor and increases cyclic AMP levels in the hypothalamus.
• There are distinct receptors like toll like receptors (TLR) for recognising bacterial products directly on the endothelium of the hypothalamus. This again leads to events which result in production of PGE2. (Cyclooxygenase pathway)
• Increase in the cAMP levels leads to elevation in thermoregulatory set point of hypothalamus.
• Increase in the thermoregulatory set point makes the body think that it’s core temperature is below normal. This triggers the mechanisms of heat conservation and heat production leading to an increase in the body’s core temperature.
Types of fever:
Now that we know the mechanism behind fever let’s jump in to know the types of fever and it’s various causes.
1. Continuous / sustained fever:
In this type of fever there is a sustained raise in temperature with minimal diurnal variation (<1C).
Common causes – urinary tract infections, pneumonia, meningitis etc.
2. Relapsing fever:
There are episodes of rise in temperature separated by intervals normal temperature.
Common causes – Malaria, tuberculosis, borellia infections etc.
This is further divided into many subtypes based on the fever free interval:
• Quotidian fever: daily febrile episodes with fever free interval. Seen in P. falciparum infection.
• Double quotidian fever: if there are two spikes of fever with a fever free interval in a day it’s called as double quotidian fever. Commonly seen in milliary TB (spike in morning and night).
• Tertian fever: spike of fever followed by 48 hours of fever free interval (i.e fever every two days). Seen in P. falciparum, P. ovale and P. vivax infections.
• Quartan fever: there is a spike of fever after every 72 hours of fever free interval. Seen in P. malariae infections.
3. Intermittent fever
Variation of more than 2 degree Celsius is seen with the temperature touching the baseline. This can be seen as an exaggeration of the diurnal temperature variation.
Commonly seen in abscess, kala-Azar and malignancies.
4. Remittent fever:
The temperature varies by more than two degree Celsius and never touches the baseline.
Commonly seen in Tuberculosis, viral infections etc.
5. Step ladder fever:
There is a sustained fever with gradual increase in temperature with every spike.
Seen in dengue, typhoid fever etc.
6. Night sweats:
Here there is an increase in the body temperature in the evenings and the patient wakes up from sleep due to sweating. This is usually due to a mild rise in temperature being added to the normal diurnal evening increase of temperature.
Seen in cases of tuberculosis, leukaemia etc.
Treating fever:
There’s always been a question on whether we should treat a fever or not. Fever is a defensive mechanism by our body against the foreign organisms, there is no clinical evidence that treating fever with antipyretic agents will delay the resolution of infection.
But withholding antipyretic drugs will allow the physician to note the fever pattern as in malaria infection, or allow to note specific signs like relative bradycardia during febrile interval in typhoid fever.
Mechanism of action of antipyretic drugs:
Antipyretic drugs are agents that inhibit the cyclooxygenase pathway (COX pathway), in turn inhibiting the production of PGE2.
Examples of antipyretic drugs- Paracetamol (acetaminophen), NSAIDs etc.
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