Don’t take paracetamol (acetaminophen) if you have a fever

Fever is highly effective in clearing infections

Many people use fever reducing drugs - antipyretics - when they have a fever. But I learned about 40 years ago from a specialist in infectious diseases that this is a bad idea because the body’s immune defense becomes ten times more effective if the body temperature goes up just a couple of degrees Celsius, which is a dramatic increase in efficiency. I am pretty sure he talked about white blood cells.

When I wrote my 2019 book, Survival in an overmedicated world: Find the evidence yourself, I decided to look it up. I played around with a few search strategies on Google like leucocytes fever, leucocytes activity temperature, and immune response temperature, and it didn’t take long before I found a useful article.

It was a very broad review, but already after having read the first sentence in the abstract, I realised how important it must be not to lower the body temperature: “Fever is a cardinal response to infection that has been conserved in warm-blooded and cold-blooded vertebrates for more than 600 million years of evolution.”

A mechanism that has survived for so long, in many animal species, must be essential for our survival.

The increase of 1-4°C in core body temperature that occurs during fever is associated with improved survival and resolution of many infections. For example, the use of antipyretic drugs to lower the fever is correlated with a 5% increase in mortality in human populations infected with influenza virus and negatively affects patient outcomes in the intensive care unit.

Preclinical studies in rabbits infected with rinderpest virus found an increase in mortality when fever was inhibited with acetylsalicylic acid (aspirin); 70% of aspirin treated animals died as compared with only 16% of the control animals.

The review article argued that fever may not always be beneficial. For example, it mentioned that in cases of extreme inflammation, lowering, rather than raising body temperature has evolved as a protective mechanism. It also noted that uncontrolled fever is associated with worse outcomes in patients with sepsis or neurological injuries, and that treatments that induce hypothermia (low temperature) can have a clinical benefit.

However, when I looked up the references to these statements, I got disappointed. These postulated effects had not been derived from randomised trials in humans or animals but were, for example, observations in rat experiments or hypothetical ideas not very well substantiated but discussed in review articles.

Cold-blooded vertebrates, which last shared a common ancestor with mammals over 600 million years ago, provide a sort of natural experiment in which to examine how animals behave when they have an infection. Reptiles and fish raise their core temperature during infection through behavioural regulation, which leads to their seeking warmer environments despite the risk of being eaten by predators. The survival of the desert iguana Dipsosaurus dorsalis is reduced by 75% if prevented from behaviourally raising its core temperature by approximately 2°C after infection with the Gram-negative bacterium Aeromonas hydrophila.

Insects also raise their temperature, and bees raise the local temperature of the hive through increased physical activity.

It is also of interest to study the protective mechanisms by which fever wards off attacks by invading pathogens. One such mechanism involves direct effects of febrile temperatures on the infectious potential of the pathogens. High temperatures (40-41°C) cause a greater than 200-fold reduction in the replication rate of poliovirus in mammalian cells and increase the susceptibility of Gram-negative bacteria to serum-induced lysis.

In the body, fever-range temperatures stimulate almost every step involved in the immune response, promoting both innate and adaptive immunity. Innate immune cells are the “first responders,” which arrive within hours to directly destroy pathogens via phagocytic or cytotoxic activities. These activities limit infection until a peak adaptive immune response is generated, normally around one week later.

The review is very technical but this is about what we need to know. My wife is a clinical microbiologist and I have worked as a doctor at the department of infectious and tropical diseases at the same hospital. We have never taken antipyretics like aspirin or paracetamol when we had a fever, and we have not given such drugs to our children. We assumed it would not be a good idea because fever is such a universal response to infection although we had not looked up the evidence.

You will not be helped if you look up textbooks, package inserts, or information on the Internet to be guided about if you should take antipyretics or not. You might be told that they lower the body temperature, which you already knew, and have small benefits like reducing the severity of headaches, which you also knew.

But these are not important outcomes. When we have an infection, the most important thing is to survive, and the second most important thing is to cure the infection and avoid sequelae.

When I tried to find systematic reviews of randomised trials that had looked at disease outcomes, I didn’t get any wiser. One review located only five studies examining the duration of symptoms associated with the illness studied and they did not seem to have been particularly useful. Another review concluded that high-quality evidence from trials was lacking.

Evidence-based medicine is about using the best scientific evidence we have when making decisions. I therefore find it prudent for patients to ignore the usual nonsense, which is standard in the nauseating TV ads for drugs in the United States: “Ask your doctor whether acetaminophen is right for you.” Your doctor would be unable to answer and would likely tell you to take the drug because this is what the drug industry has told your doctor. Remember: The drug industry doesn’t sell drugs, it sells lies about drugs. This is where the money is, as the gangster John Dillinger said when he was asked in court why he robbed banks. He was shot to death in 1934 by FBI agents when he left a cinema and tried to escape the planned arrest.

It is not right for anyone to take paracetamol for infectious fever, not even for a reptile or an insect unless in very special and rare cases, e.g. if the temperature is so high that there is a risk of brain damage, or if a child is prone to have febrile convulsions even if the temperature is not excessively high.