Do temperatures associated with infections track diurnal variations of body temperatures? 

A trip back to the 1800s

Sometimes searching for images is a good way of finding things.   One such image search led us to an article in a journal called the History of Science[1]. The authors described a group of physicians turning their clinics into a laboratory.  The physicians recorded the temperature of typhoid fever patients twice a day.  Note that in Figure 19, the patient that died with a fever over 43^oC, 109.4^oF.  Also note that the other patients had daily high and low temperatures.

This publication seems to have inspired a Russian language account of the same phenomenon.  We do not know if this is the abdominal variety, but the temperature curve sure presents that way.

In this particular typhoid patient, the temperature went from 38.7^oC to 36^oC to 38.5^oC on day 19-20.  This translates to  101.7^oF, 96.8^oF 101.3^oF.  Did this patient experience feeling hot, followed by “the chills” to feeling hot again as some Covid-19 patients report?   It is easier to find “fever curves” for typhoid fever 150 years ago than to find “fever curves” for  Covid-19.  Covid-19 patients who are not too “out of it” can be turned into citizen scientists by recording their temperatures .

Some undated Wikipedia Commons images for Antipyretic activities

Arsacetin is an arsenic containing compound that was formerly used to treat syphilis and trypanosomiasis.

These patients started out with temperatures of 39.5^oC or about 103^oF .  The patients were given arsacetin  Their temperatures dropped to an average of about 36^oC or about 96.8^oF.  These patients had 12 hr stretches in which their temperatures hovered in the low normal  range of  36.5^oC.  We do not know if all 104 cases were given arsacetin at the same time each day.  The subsequent daily highs were 37.5^oC or about 99.5^oF  and 37^oC or about 98.6^oF .

Continuing wih the Wikicommons image search, here we have an old image of a relapsing fever.  All we know that there were 30 patients treated with something.

In this case there was a linear decline of peak daily body temperatures of 40^oC, 39.5^oC, 39^oC and 38.5^oC.  . . ..  or about 104 ^oF, 103^oF, 102 ^oF, and 101^oF.  If we did not continue to monitor the body temperature of this group for several days, we may easily have concluded that the treatment cured the fever in a few hours.  Ironically, some of the anti-pyretic clinical trials on clinicaltrials.gov do not take into account diurnal variations in temperatures.

Absent from the fever curve in figure 4 is the placebo.  The savvy reader might  ask, “how do we know the the fever wouldn’t just go away as the patients recover from the infection?”   This is something we are doing right in this modern age.  A placebo is an inactive substance thought to have no biological activity.  If a patient believes that taking some pill is going to cure them, the fever might go away faster because their stress level is reduced.

Diurnal temperature variations and melatonin

This particular temperature curve for a malarial fever seems to track diurnal temperatures.  The nice thing about this image is that the physician recorded more than just the high and low temperature of the patient for several days.

 Reference [2] does a really nice job of summarizing the role of light in melatonin secretion and sleep.  Note that just because melatonin is going down as body temperature is going up,  one is causing the other.

Anderson and Reitner [3] make a strong argument for the role of melatonin and switching immune cells from inefficient glycolytic metabolism to more efficient mitochodrial oxidative phosphorylation.  Melatonin induces the circadian gene, Bmal1, which disinhibits the pyruvate dehydrogenase complex (PDC).   PDC drives mitochondrial conversion of pyruvate to acetyl‐coenzyme A (acetyl‐CoA).  Acetyl CoA feeds into the  tricarboxylic acid cycle that generates reducing equivalents for the electron transport chain.  The electron transport chain is the primary souce of ATP in metabolically active cells.  Anderson and Reitner [3] discuss the Covid-19 cytokine storm turning off the pineal gland production of melatonin.  We seen diurnal temperature variations in two of the three examples of typhoid fever curves [1].  These variations were turned off in the patient that died [1],  see Fig 1.

Is melatonin production turned off in severe Covid-19 but not in mild cases?  Unfortunately, “fever curves” are not as popular in 2020 as they were in the mid to late 1800s.

Time of day matters in fighting an infection

In bacterial septic shock, temperatures may go above or below average.  Circulatory collapse due to hypo-tension is another aspect of this killer.  Bacterial lipo polysaccaride (LPS) is what sets things off.  Mitochondria are important thermo controllers.  Does the time of day that a mouse sees LPS predict it’s outcome.  A group of scientists from Aires, Argentina tested this hypothesis [4].  In the experiments conducted under LD conditions, animals were injected with LPS at

• ZT11 …. Melatonin has been high for a while.
• ZT19…. Melatonin has been low for a while.

(ZT: zeitgeber time; ZT0: time of lights on; ZT12: time of lights off)  Note that the authors did not mention melatonin in their publication.

• After eight days, 80% of the mice injected with LPS as they were settling into sleep  (ZT11) were alive.  Fig 6A
• After eight days, two thirds of the mice injected with LPS in the morning were dead.  Fig 6A.
• Mice injected with the solvent used to dissolve the LPS maintain a constant body temperature regardless of the time of day of the injection, Fig 6B
• TNF-α in serum are higher in those mice inoculated at ZT11 compared to ZT19 (not shown)

Pineal Gland Pathways

Light entering the eye evokes a signal n the retina that is transmitted to the supra chiasmic nucleus (SCN) to the paraventricular nucleus (PVN), to the
intermediolateral column (IML) and then the cells from the superior cervical ganglion (SCG).  These cells  secrete norepinepthrin (also noradrenaline).  Reference [5] describes how norepinephrine controls the translation of melatonin synthesis gens into proteins.  This process may be blocked by agents involved in infections, see figure 7.

The role of the locus ceruleus in temperature control

When we exercise at night or during the day, we experience vasodilation and sweating to cool ourselves down.  Machado and coworkers measured rat tail vein vasodilation in response to intense exercise [8].  They found the absolute threshold for vasodilation was higher in the dark-phase:  39.3 ± 0.02°C vs. 38.5 ± 0.02°C in the light-phase. [7]

Fig 8 is a fusion of an image in reference [8] and Fig 7 to make the point that far more goes into controlling body temperature than just melatonin.  Chemically destroying the locus ceruleus blunts the fever response to lipopolysaccharide (LPS).  [9]  Kaneko and coworkers followed up on a previous study that showed an increase in NE in the locus ceruleus of mice injected with LPS at time points of two and four hours.  [10]  As a followup these authors examined gene expression of TNFα and IL-1β.  LPS into the abdominal cavity of rats. [10]  TNFα and IL-1β mRNA peaked at 2 and 4 hours then decreased to control levels. [10]  TNFα is produced by microglia, not the neurons of the locus ceruleus that secrete NE.  Kaneko and coworkers isolated microglia from neonatal mouse brains.  Cultured microglia were treated with LPS ± 1 µM NE.  NE down regulates TNFα on both the mRNA and protein level.The results point to an anti-inflammatory role of NE.

Conclusions

• We’ve know for over 150 years that diurnal temperature variations often persist with infections that cause fevers.
• Both the pineal gland (melatonin) and the locus ceruleus (norepinephrine) respond to light/dark cycles via the supra chiasmic nucleus (SCN).  We cannot blame a fever getting better or worse at normal diurnal highs on either the pineal gland and/or the locus ceruleus.
• LPS, the mediator of bacterial inflammation, interacts with both the pineal gland and the locus ceruleus.
• Even after 150 years, it still feels like we know little about the diurnal variation of fevers that are associated with infections.

Bored and quarantined at home with a fever, the citizen scientist can help out by simply recording their oral temperature throughout the day.  The more points, the better.  Just two points at 6AM and 6 PM is a good start.  This post describes how fever curves have been used in clinical trials.

References

1. Hess V, Berlin C, Mendelsohn JA(2010) Case and Series: Medical Knowledge and Paper Technology, 1600–1900  History of Science  [CrossRef]
2. Lack LC, Wright HR (2007) Chronobiology of sleep in humans.  Cell. Mol. Life Sci. 64 1205 – 1215 [Cross Ref]
3. Anderson G, Reiter RJ. (2020) Melatonin: Roles in influenza, Covid-19, and other viral infections. Rev Med Virol. 30(3):e2109. [PubMed free article]
4. Mul Fedele Malena Lis, Aiello Ignacio, Caldart Carlos Sebastián, Golombek Diego Andrés, Marpegan Luciano, Paladino Natalia (2020) Differential Thermoregulatory and Inflammatory Patterns in the Circadian Response to LPS-Induced Septic Shock Frontiers in Cellular and Infection Microbiology 10 [Cross Ref]
5. Markus RP, Fernandes PA, Kinker GS, da Silveira Cruz-Machado S, Marçola M. (2018) Immune-pineal axis – acute inflammatory responses coordinate melatonin synthesis by pinealocytes and phagocytes. Br J Pharmacol. 175(16):3239-3250.[PMC free article]

6. Almeida MC, Steiner AA, Coimbra NC, Branco LG(2004)Thermoeffector neuronal pathways in fever: a study in rats showing a new role of the locus coeruleus.J Physiol. 558(Pt 1):283-94. [PMC free article]

7. Machado FS, Fóscolo DR, Poletini MO, Coimbra CC.(2016) Influence of Time-of-Day on Maximal Exercise Capacity Is Related to Daily Thermal Balance but Not to Induced Neuronal Activity in Rats. Front Physiol. 2016 Oct 14;7:464.[PMC free article]
8. Atzori M, Cuevas-Olguin R, Esquivel-Rendon E, Garcia-Oscos F, Salgado-Delgado RC, Saderi N, Miranda-Morales M, Treviño M, Pineda JC, Salgado H. (2016) Locus Ceruleus Norepinephrine Release: A Central Regulator of CNS Spatio-Temporal Activation? Front Synaptic Neurosci. 2016 Aug 26;8:25. [Cross Ref]
9. Almeida MC, Steiner AA, Coimbra NC, Branco LG(2004)Thermoeffector neuronal pathways in fever: a study in rats showing a new role of the locus coeruleus.J Physiol. 558(Pt 1):283-94. [PMC free article]

10. Kaneko YS, Mori K, Nakashima A, Sawada M, Nagatsu I, Ota A(2005)Peripheral Injection of Lipopolysaccharide Enhances Expression of Inflammatory Cytokines in Murine Locus Coeruleus: Possible Role of Increased Norepinephrine Turnover 94(2):393-404. [Cross Ref]