Fever-pitching!

fever 2One fine day, the mistress of evolution sat seaming in her courtyard. In her tinker-some best, she wondered what today. A fragrant breeze, the rustle of leaves, and that congenial stroke of inspiration, she conceived fever! With a grand flourish of her wand she had the next living moving thing to spike a modest rise in temperature as when any infection took seat. Little did she know then that that little whim would be such a hit in the ages to come. 600 million years have passed since, and the fashion is still in vogue. Come any infection, be it human, animal or plant, the organism spikes fever!

It was in 1st century AD that Celsus, a Roman scholar, despite being surrounded by Roman soldiers who wore sexy skirts and ambled around distracting gentle folks with that display of rippled manly thighs, had the focus of mind to notice beyond and club fever with three other signs, local redness, swelling and pain. These are the four cardinal signs of inflammation, the body’s response to any infection or trauma. With an addition of loss of function as the fifth sign, and the unfortunate restriction of man-skirts to Scotland, the firm association between fever and infection still holds today.

Evolution while a tinkerer, hates to hoard. Each organism is an essential minima. It doesn’t carry as baggage attributes that don’t benefit it in this struggle for existence. Anatomical features, physiological aspects, psychological quirks, all have a meaningful purpose in enabling the organism and the species to reproduce and survive. Enter man and he wonders, if so, then what good does fever do that evolution did not lose it despite the 600 million years of relationship it has had. Well, could it be that the rise in body temperature on infection helps the organism ward off the infecting agent, kill that irksome interfering microbes, be it bacteria, virus, protozoa or fungus?

fever 3Julius Wagner-Jauregg, other than having the misfortune of having been a life-long friend of Sigmund Freud, and an anti-Semite, the order of misfortunes with-standing, bagged the Nobel for medicine on 10th December, 1927, a decade right after he treated nine patients with neurosyphilis. Now neurosyphilis is a vintage disease, a relic of pre-antibiotic era, wherein tiny wriggly bacteria called Treponema pallidum pitch camp in one’s brain and go hiking; though this little adventure doesn’t bode well to the patient. There was no treatment to cure or stall this malady. Julius thought better and gave them malaria. Yes, you read that right. He infected them with malaria. Lo and behold, of the nine patients in his first trial in 1917, six got better. No kidding!

Julius Wagner was no run-of-the-mill mad scientist who just got lucky. There was a rationale to this radical trial. Malaria causes fever. Many including himself suspected whether this fever, the little whim of our evolutionary seamstress, could have the role in the clearance of infections. And as the story stands today, Shanon S.Evans of Rosewell Park Cancer Institute, Buffalo published in Nature Review in July, 2015 that Immune system feels the heat. Fever affects every aspect of the body’s intricate immune defence, and in almost every case, improving its robustness. It’s so useful that lizards, which can’t raise their body temperature (courtesy being cold-blooded), spike it to fever range by behaviourally seeking warm-shelter upon infection. And MJ Kluger found that if you don’t let these lizards do so by artificially restraining them, or giving them aspirin which curiously makes them not seek hot spots (suggesting the mechanism for physiological and behavioural fever induction is the same), the lizards perish to the infection.

Now if that were the case, why on earth do we have paracetamol, aspirin, ibuprofen and the likes prescribed for fever? If fever fights infection, why do we relieve one of fever? Shouldn’t we let it wage on! But before that, what’s fever? Is any rise in body temperature fever, or there’s more to the mix? And how does the body rig up this association between infection and fever?

Before we answer them, it would do well to dwell about my bathroom. It has white pristine tiles, a mirror that reflects my handsome British-ish visage, and a geyser with a thermostat. Akin to the geyser, our body has one thermostat as well. Right inside our brain, close to its centre, in a structure called the hypothalamus. For the nerdy folks, the median pre-optic nucleus of the hypothalamus. And as when the geyser thermostat is dialed to a higher temperature, the coil heats the water within, like-wise when the hypothalamic thermostat is dialed up, we burn calories in our liver, work our muscles to a shiver, shunt bloods from the peripheral more-exposed blood vessels, and the more fortunate ones, cozy into a blanket. The converse, dial it down, we sweat, and lose the blanket.

We humans are made up of lots of stuffs, proteins and things, that work well within a narrow range of temperature, usually 36.5-37.5 degrees on fever 4the Celsius scale. Taking into account the circadian (24 hourly) variation in body temperature, fever is defined as a core body temperature of above 37.2 in AM and 37.7 in PM. It’s akin to say if your body temperature is 37.3 degrees at 8 AM, you got fever, but a similar value at 8 PM is not, by definition fever. Humans! But this range covers 99th centile of the human folks, so it’s there to stay.

On infections, that is to say, you scrape your knee while at play and some bacteria makes abode there, the body’s immune defence will be pulled into action. The task force applied to the policing, the macrophages and neutrophils, release a cascase of chemicals called cytokines. Of these, the one’s carrying the name-tag IL-1, IL-6 and TNFalpha do the hardwork of dialing up the hypothalamic thermostat. The process has a few middle men, one important fellow named PGE2, prostaglandin E2. And once set to higher value, we produce more heat, cut down on heat loss, and rise our core body temperature. In plain simple English, have fever.

So fever is a bodily response to inflammation, of which infection is a prime cause. And as it happens, fever boosts immune defence. And a more robust immune defence defeats the invader, that being the infecting organism. But why then do we treat fever? That’s because there is a little grey here. Biology is an involved science. There are lots of if’s and but’s. The more robust immune response is, more the bitter blood bath against the bacteria, and thus more the collateral damage to the normal human cells in and around. Now this might not be entirely good to the welfare of the organism. And I assure this, this collateral damage is by no means ‘little’.

fever 5Now this might be a good spot to pitch forth the huge breach that lies between basic research and clinical research. We can launch rockets and bring them back. We can smash sub-atomic particles at velocities that make light photons wary of their speed. We can label neurons that encode a particular memory. More so, we can post selfies on facebook, open fake accounts, and write cheesy comments upon. But we still don’t know if to treat fever or not! Seriously.

The current undertone in the medical community is to treat fever. Its hewn firm as a dogma. And quite justifiably so. The purpose as proposed is to cause symptomatic relief and lower the metabolic burden on the already sick individual. It’s of note that a 1 degree Celsius rise in temperature requires the organism to raise its metabolic rate by 10-12.5%. That’s a considerable burden. Also evidence from a significant number of human trials has nothing to suggest that treating fever is of detriment to the host. True that absence of evidence is not evidence of absence. But absence of evidence sure is evidence of absent evidence! And medicine being a science needs evidence to inform its guidelines.

But since recent, there is mounting evidence to the otherwise. One study found that symptomatic relief in the infected increases the transmission rates in the population, for the sick person feels better and moves-and-mingles around despite harboring active infection. And there is also robust data from basic research on how fever enhances immune attack on the intruder. In the viewpoint Fever and sickness behavior: Friend or foe? published in the journal Brain, Behaviour and Immunity on July 2015, the Baby Expressionsauthors did an analysis of nearly all published literature on how treating fever in an organism harboring infection affects its clinical outcome as against in one where you let fever be. Their conclusion was though quite dismal. The common lament from the meta-analysis carried to answer the friend or foe conundrum was ‘the final result was equivocal: it could not be determined whether fever control is harmful or beneficial’.

It’s not a laughing matter. One needs to realize that to formulate guideline along the lines of ‘one should not treat fever in patients infected with…’ there has to be a research that concludes that ‘not treating fever in patients suffering from this particular infection improves the clinical outcome as when compared with the treated cohort’. This is clinical research. An evidence along the lines of ‘fever improves immune defence and host clearance of this particular microbe’ is basic research, and while a pre-sentiment to the former conclusion, is not the same. Not by a long shot. And as till that is to occur, heed your doctor and take your anti-fever meds. (Note that host clearance of microbes is a different end point from clinical outcome of illness. The patient could have a scarred lung as because of the immune damage though with complete bacterial clearance on treatment with fever for a particular microbe.)

fever 8As an after-note, the framework of medicine is rooted in biology and subject to continuous scrutiny and informed revisions. The science of it makes sense. And near-every aspect of it is backed by randomized controlled trials. This move towards Evidence-based medicine (EBM) is wrought large in the heart of medical science, and is what makes it credible. It does well to trust such a system and adhere with compliance to what the doc says. And hope all’s well with good health, hale and happy, on the good planet of ours.

P.S.- If you are wondering about Julius and his Nobel, he proved fever could cure (one particular infection). He didn’t prove controlling fever would cause detriment. That’s the charm in biology. Every subtle nuance makes it a different case!

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