Embrace your fever!

Updated: May 22, 2019



The exclamation point in the title is a literal translation of my feelings and what I would always like to say to my near and dear ones. It took me more than just reading medical books to understand this phenomenon. So folks! It might be a little technical but I assure you that by the time you finish reading this; Fever will be your friend for life.






Paracetamol (generic name acetaminophen) is one of the top grossing products of pharmaceutical companies with sales reaching $6.12 billion in 2011 (1). This, individually or in association with aspirin, is most commonly used for treating fever (Antipyretics are a class of drugs that reduce inflammation related fever). Over the counter prescription (and hardcore advertising by the pharma companies) have led to years of overuse and misuse of this drug (which could be life saving in rare exceptions).

Did you know that fever is one of the oldest physiological phenomenon which has been conserved through years of evolution?

Mammals, reptiles, amphibians, fish and several invertebrate (those lacking spinal cord) species have been shown to manifest fever response (2). This should make you think that fever is special because only beneficial traits are passed on through evolution and the rest simply disappear (which has happened with many useless traits).

Before we go any further, you need to know that there are 2 kinds of immunity:


innate and acquired (3).

Innate immunity is that we are born with and consists of natural killer cells (NK), macrophages and Dendritic cells (DC) which non-specifically eat up all foreign body (phagocytosis) and present a partially digested mass to the acquired immune cells. This is important to keep the infection at bay till the specific immunity kicks in to kill that particular invading organism (acquired immunity) by producing specific antibodies.

Fever is one of the first steps in the inflammatory reaction cascade that follows invasion of any antigen (substance that the immune system recognizes as foreign). Here is a brief explanation for those interested but the rest can skip it and scroll further!

The innate cell receptor attaches to the invading antigen and this complex activates various factors (IL-1, IL-6, TNF) which produce prostaglandin E2 (PGE2) in the presence of COX-2 enzyme (Paracetamol inhibits this enzyme thus inhibiting the cascade). PGE2 further activates the hypothalamus (a small region in the base of the brain) releasing Nor-adrenaline and Acetylcholine which increases body temperature.

Why is fever good?

The natural febrile range (37ºC-41ºC or 98ºF-104ºF) has shown, in numerous studies, to augment almost every step of this inflammatory cascade leading to stronger immune response (4). Some of the changes are:

  • Increase in temperatures, as less as by 1 degree, has shown to improve bacterial clearance and increase digestive activity (phagocytosis) by the Dendritic cells.

  • It also activates the kupffer cells of the liver to stimulate production of IL-1, IL-6 and TNF which further enhances immune response.

  • Another very important step is the production of Heat Shock Protein (HSP) which prevents the denaturing of existing proteins (enzymes etc.) at such high temperatures.

  • It increases neutrophil (type of white blood cell)mobility and lymphatic drainage.

  • Children with chicken pox, who were treated with acetaminophen, have longer disease duration (till total crusting of the lesions) (5). So basically, fever reduces the duration of illness in chicken pox.

  • Adults infected with rhinovirus (common cold virus) exhibit more nasal shedding of the virus when treated with aspirin than the placebo group (6).

  • Another study has shown that treatment of acetaminophen in rhinovirus infection is also associated with suppression of antibody response and increased nasal symptoms (7).

  • In mice, increasing body temperature artificially has been shown to enhance resistance to herpes simplex virus, polio virus, rabies virus, coxsackie virus, rabies virus and Cryptococcus neoformans.2

  • In animal studies, treating fever in influenza cases has been shown to have increased mortality (8 ).Such evidences should motivate researchers to do similar studies on humans as well.

  • Another study in critically ill patients admitted to the intensive care units showed that aggressive fever treatment was associated with increased mortality. (9).

Though this list is not exhaustive, they do show strong circumstantial evidence that fever is an adaptive response in most situations!

Now the doctors argue that fever causes local damage to the tissue due to inflammatory products and hence the use of antipyretics. But what they fail to mention is that fever also has a negative feedback on itself wherein excessive heat dampens the inflammatory response that protect the tissue from excessive damage by cutting short the immune response (4). Thus, you can understand that fever is much more than a simple rise in temperature. It starts a series of inter-connected reactions that help the body fight better.

Fever after vaccinations

Vaccine is considered as “foreign” by the body (Ofcourse! It is a cocktail of dead viruses, bacterial material, adjuvants and additives) and generates a febrile response. However, most of physicians recommend use of paracetamol as a preventive/ curative for fever after vaccination.

In one survey, paracetamol use after MMR vaccination was associated with autistic disorders (10). There is a two-fold insult here caused by paracetamol. Firstly, it depresses the immune system and secondly, it depletes the liver’s detoxifying agents (11). Another study showed that paracetamol administration after DTP vaccine had no effect on febrile episodes (thankfully body is strong enough to fight it out anyway!) (12). Another study showed that preventive use of paracetamol after hepatitis B vaccination was associated with reduced antibody response (13).

Febrile Seizures?

A common argument given by doctors in favour of antipyretics use in children is febrile seizures. Fever can cause seizures so suppress it! Now let’s see the evidence for that shall we?

There is an ongoing debate about the cause of febrile seizures and some believe that seizures might be the first sign of a fever (so the temperature rise is sometimes secondary to the seizure so antipyretics have no use here) (14).

Febrile seizures have been associated with various risk factors like history of afebrile seizures, day care attendance, developmental delay, certain viral infections (herpes, metapneumovirus), DTP vaccination and MMR vaccination (4 fold increase in febrile seizures). So basically none of these risk factors is fever!

Though seizures occurring during the course of febrile illness are called febrile seizures, there is no direct evidence linking fever to the seizures (14). Also, a meta-analysis study (study that combines many studies) showed that antipyretics were inefficient in reducing recurrence of febrile seizures (15). And finally, there is no evidence that febrile seizure (<10 minutes) cause any brain damage, epilepsy, mental retardation or learning disabilities (14).

Antipyretics are definitely useful in septic shock!? NO

Another point of concern is septic shock where the invading antigen produces an overwhelming response such that it slowly leads to systemic shut down. Even in such cases, there is no evidence supporting routine treatment of septic shock patients with antipyretics. In fact, it is not recommended because it does more harm than good (16)

So let’s summarize what we learnt so far:

  • Fever is preserved though millions of years of evolution.

  • Fever helps stimulating immune cells production, transportation and its phagocytic (eating up) activities. In addition, it is self regulated to minimize tissue damage.

  • Febrile seizures, if they occur, have no association with fever itself and show no response to antipyretics.

  • Except for rare, life threatening occasions (fever above 105°F or 41.5°C) or other complications, routine treatment for fever seems unwarranted.

  • Though I might not have covered every scenario here, there is no concrete evidence to show that benefits of fever treatment outweigh the risks.

  • So finally the question; why treat something that is a blessing to our immunity?

  • (coming up next: Supporting the body naturally through fever)

References:

1 http://www.fiercepharma.com/special-report/top-20-generic-molecules-worldwide

2 Mackowiak PA. Physiological rationale for suppressing fever. Clinical Infectious Diseases (2000);31(Suppl 5):S185–9.

3 https://en.wikipedia.org/wiki/Immune_system

4 Evans SS et al. Fever and thermal regulation of immunity: The immune system feels the heat. Nature reviews: Immunology (2015); 15: 335-349.

5 Dorn TF et al. Acetaminophen: more harm than good for chicken pox? Journal of Paediatrics (1989); 114:1045-8.

6 Stanley ED et al. Increased viral shedding with aspirin treatment of rhinovirus infection. JAMA (1975); 231:1248-51.

7 Graham MH, Burrell CJ, Douglas RM, et al. Adverse effects of aspirin, acetaminophen, and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. Journal of infectious diseases (1990); 162:1277-82.

8 Sally Eyers et al. The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis. J R Soc Med (2010); 103(10): 403–411.

9 Schulman CI et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt). (2005); 6(4):369-75.

10 Schultz ST et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism (2008);12(3):293-307.

11 http://www.altmedrev.com/publications/14/4/364.pdf

12 Yalçin SS et al. Prophylactic use of acetaminophen in children vaccinated with diphtheria-tetanus-pertussis. World J Pediatr. (2008);4(2):127-9.

13 Doedée AM et al. Effects of prophylactic and therapeutic paracetamol treatment during vaccination on hepatitis B antibody levels in adults: two open-label, randomized controlled trials. PLoS One. (2014);9(6):e98175.

14 Jones T and Jacobson SJ. Childhood febrile seizures: Overview and implications. International Journal of Medical Sciences (2007); 4: 110-114.

15 Rosenbloom E et al. Do antipyretics prevent the recurrence of febrile seizures in children? A systematic review of randomized controlled trials and meta-analysis. Eur J Paediatr Neurol. (2013);17(6):585-8.

16

Drewry AM and Hotchkiss RS. Counterpoint: Should Antipyretic Therapy Be Given Routinely to Febrile Patients in Septic Shock? No. Chest (2013); 144: 1098-1101.

#Wellness #Health #fever