Growing up in the Eastern part of India, I was subject to a most peculiar cultural phenomenon known as “ThanDa lege jaabe” (ঠাণ্ডা লেগে যাবে in the vernacular, translated as: You’ll catch a cold). This odd concept, most beloved of the mothers in that region and handed down generations after generations, would teach them that any vagary of the sub-tropical weather — sun, rain, autumnal zephyrs, wet and foggy riparian winters, and everything in between — was liable to cause acute upper respiratory tract infections (uRTIs), characterized by runny nose, cough and sneeze, perhaps even progressing to pharyngitis, laryngitis or tracheobronchitis. And the most feared symptom was elevated body temperature, or fever.

fever; image credit: Memo Angeles/Shutterstock

image credit: Memo Angeles/Shutterstock

The vernacular literature from my part of the world is replete with references to fever as a serious condition requiring urgent medical attention. And not all of it is perhaps unjustified. After all, the rural and semi-urban areas of this region were historically well-known for typhoid, malaria, leishmaniasis (“Kala-azar“), meningo-encephalitis, as well as tuberculosis — the appearance of high fever being the common clinical observation to all of these.

To compound the situation re fever, it is known that the most common culprit in upper respiratory symptoms, the Influenza viruses, thrive in tropical and subtropical climates (as in the Indian subcontinent) throughout the year, with increased resurgence in the monsoon (rainy season) as well as during wintertime — for which several seasonal, environmental, and behavioral factors have been considered. But a significant role is played by these viruses which appear to be transmitted with increased efficiency in colder temperatures and under both low and high relative humidity conditions. And, of course, infection by sundry rhinoviruses (responsible for common cold) or influenza orthomyxoviruses both may create an internal hyper-inflammatory condition in the sufferer, and fever (or feeling of feverishness) is one of the common outcomes.

So, that traditional concept from my childhood may not have been so odd after all, thanks mom! — that is, even if nobody, for all the fear of “catching a cold”, really had any clue about flu-epidemiology and transmission patterns and so forth.

Because of the historical and traditional burden associated with it, fever naturally inspires fear, which in turn prompts medical care- and/or medicine-seeking behavior. Unfortunately, in the absence of responsible antibiotic stewardship in developing nations such as India, antibiotics are often inappropriately prescribed, even in RTIs of viral origin, in part because of importunate patient demand in presence of fever. And with RTIs in particular, the decision-making is made difficult for the physicians, because the macrolide antibiotics commonly prescribed in these situations (an example is azithromycin) have significant anti-inflammatory activity, which often helps quell the fever (because the hyperthermia, or elevated temperature, is often a consequence of inflammatory chemicals — cytokines, chemokines, prostaglandin E2 — being released by the immune system preparing to fight the infection or deal with a pyrogen, i.e. substance causing fever).

But this knee-jerk response to fever is not restricted to the subcontinent by any means; there is evidence that in many places, antipyretic treatment (to reduce any and all kinds of rise in body temperature) remains commonplace amongst healthcare professionals, as well as lay public, who continue to view all fevers (including ordinary, non-life threatening ones) as detrimental — even though evidence-based, best-practice clinical recommendations for such treatment are rather selective, based upon specific pathologies, appraisal and consideration of the patient’s overall condition, including magnitude of the fever.

In an interesting, recent PLOS Pathogens “Pearls” essay, Professor Arturo Casadevall, currently Chair of Molecular Microbiology and Immunology of the Johns Hopkins School of Public Health, reviewed the current state of knowledge of this matter — especially the lack of scientific consensus on (a) the exact nature of fever’s role in health and disease – beneficial vs. detrimental; as well as (b) the best way to approach common fevers in healthcare. [Conflict of Interest Note: I know Arturo personally; have worked closely with his former lab within the same department, and have long admired his ability to bring a multidisciplinary approach to scientific investigations; and consider him nothing short of AWESOME as a physician-scientist of eminence.]

A few relevant points from the essay:

  • Fever as a host physiological response to microbial infection has been observed in diverse members of the animal kingdom such as vertebrates, arthropods (insects, spiders, centipedes, and crustaceans), as well as annelids (segmented worms, such as earthworms).
  • For organisms who rely on the external environment to regulate their body temperature (a.k.a. ectotherms), the core body temperature may rise (fever) above normal with increased metabolism and/or exposure to sources of heat (such as sunlight); in these ectotherms, fever appears to be highly beneficial against microbial infection.
  • For mammals (who can regulate their internal body temperature and maintain it at a favorable level for biochemical reactions to work), fever is associated with an increase in the metabolic rate; fever temperature 2°C above normal (afebrile state) reflects increased metabolism by 20%. However, there is some dispute over whether this increase is beneficial to the host over the associated risks (not the least of which is physical discomfort).
  • Some observations appear to support a beneficial role for fever; others consider it to be detrimental. The debate continues.

What about experimental approaches to demonstrate once and for all the effect of fever? As it turns out, reducing fever to an empirical model is conceptually very difficult, which Casadevall points out by indicating that “Any change in host temperature will simultaneously affect several variables“: (I’ve reorganized the concepts into points for easier understanding.)

  • The immune system and the microbes are differently affected by elevated temperatures; in addition, the features of host–microbe interactions may differ at different temperatures.
  • Mammals are good at maintaining their temperatures; therefore, experimental approaches involve, by necessity, artificial induction of fever (by using certain pyrogens, for example), which can have several non-physiological effects.
  • Antipyretics (fever-reducing agents), conversely, have a different problem; in abrogating the physiological response of fever, they interact/interfere with other biochemical processes, making it difficult to isolate the effects of temperature alone.

As Casadevall explains: the fact that it is not possible to isolate one variable, vary it, and measure an outcome means that the problem of the contribution of fever to host defense is innately resistant to reductionist experimental approaches […] there is a large body of evidence correlating fever with enhanced resistance to microbial diseases, but what is missing, at least in mammals, is an unambiguous demonstration that this relationship is causative.

That caveat said (and understood), the interesting concept that remains is how the fever response may be making the inside of a host unwelcoming to microbial pathogens, all of whom have an upper limit of temperature beyond which they cannot live and/or reproduce. Do read the Casadevall essay to understand a historical perspective of how this principle was exploited to use core temperature elevation as a therapy of certain infectious diseases. Casadevall visualizes fever as an adaptive response that creates a ‘thermal restriction’ zone which makes the host system unfavorable for many microbes to thrive and go about their business. An excellent example is provided by the ubiquitous environmental yeast-like fungal pathogen, Cryptococcus neoformans, which may cause life-threatening diseases in people and animals with suppressed immunity. Rabbits, in Casadevall’s example, are highly resistant to experimental cryptococcal infections, a peculiarity which may be predicated upon their elevated basal body temperatures of 39–40°C; similarly, pigeons and several other flighted birds may carry C. neoformans in their gut without themselves getting ill, by virtue of their elevated temperatures (around 42°C) at which avian innate immune cells can successfully keep the fungus in check.

Given the human mind’s reliance on tradition, it is natural that we might want to reach for the aspirin, the acetaminophen or the ibuprofen the moment we face the discomfort of feeling feverish or having a fever. But perhaps it is time to rethink our antipyretic strategy on a more global level, and reconsider our current reflexive approach to fever treatment. Heck, if push comes to shove, I’m going to go with “Feed the fever”. Food is good.