A relationship between temperature, oxygen dissolved in blood and viral infections

An investigation is made on the environmental factors that may determine the seasonal cycle of respiratory affections. The driving role of temperature is examined, for its inverse synergism with the dissolution of oxygen in human plasma. Two best-fit equations are discussed to interpolate the experimental data about the oxygen solubility and the saturation levels reached at various temperatures, referring to the value of the basic alveolar temperature. A vulnerable condition is when the airways temperature is lowered, e.g. breathing cold air, or increasing the breathing frequency. In winter, the upper airways reach lower temperatures and greater oxygen concentrations; the opposite occurs in summer. As low temperatures increase the dissolution of oxygen in plasma, and blood oxidation favours viral activity, an explanation is given to the seasonality of infections affecting the respiratory system.

Oxygen dissolution constitutes the input of the complex system that distributes oxygen to all parts of the body.
Oxygen delivery in the human respiratory system depends on several factors including the partial pressure of oxygen, the efficiency of gas exchange, the concentration and affinity of haemoglobin to oxygen and cardiac output [Law and Bukwirwa, 1999]. The highest oxygen concentration is typically found in the respiratory tract, from where it is distributed throughout the body.
The oxygen content of arterial blood is the sum of the oxygen bound to haemoglobin and oxygen dissolved in plasma [Dunn et al., 2016]. The solubility of oxygen in an aqueous solution is regulated by the Henry's Law [Pauling, 1947] that states that, at a constant temperature, the concentration of oxygen in the aqueous phase is proportional to the partial pressure of oxygen in the gaseous phase in equilibrium with the liquid. However, the coefficient of proportionality is an inverse function of temperature, i.e. decreasing when temperature increases and may be represented with a single or a combination of exponential functions. This has been established for pure water, ponds, aquacultures, marine environments [Millero et al., 2002;Geng and Duan, 2010;Karbowiak et al., 2010;Valderrama et al., 2016;Eze and Ajmal, 2020], but also for physiological aqueous solutions of NaCl and human plasma [Christoforides et al., 1969;Christmas and Bassingthwaighte, 2017]. Christoforides et al. [1969] measured the concentration of oxygen X O2 [mL(gas)/L(fluid)] dissolved in human plasma at different temperatures T (°C) in the interval from 10 to 60° C, at standard atmospheric pressure. The observed data may be interpolated with two best-fit equations ( Figure 1).
The logarithmic best-fit is ₂ = -9.401 ln( ) +55.684 (1a) with excellent determination coefficient R 2 = 0.997 and, over the whole range, the observed values depart less than 1 [mL(gas)/L(fluid)] from the logarithmic best-fit. The exponential best-fit is ₂ = 36.616 exp(-0.014 ) with slightly smaller R 2 , i.e. R 2 = 0.971. The exponential approximation is equally good within the 20-40°C interval 3 Temperature, oxygen and viral infections but, externally to it, the observed values depart from the best-fit, reaching 2 [mL(gas)/L(fluid)] at the lower extreme (i.e. 10° C), and a similarly at the upper one (i.e. 60° C). However, in the 20-40° C interval, that is the most relevant for the human body, both approximations are satisfactory.

Uneven distribution of temperature in the respiratory system
The temperature of the body of a healthy person has an uneven distribution. Under normal conditions, the internal organs benefit of thermoregulation and keep a fairly constant temperature, i.e. 37°C that is the basic situation for the blood oxygenation in the lung alveoli [D'Amato et al., 2018]. As opposed, the temperature of the peripheral areas of the body, the skin and the upper airways may be variable. This temperature is determined by complex exchanges of heat and moisture (i.e. sensible heat and latent heat) between the body and the environment.
The environmental factors that should be considered for this complex heat balance are: air temperature, infrared radiation and, secondarily, relative humidity and ventilation [Fanger, 1982;ISO-7730, 2005]. The airways represent an internal interface between the body and the environment. The epidermis is the external interface and constitutes a very small secondary respiratory system, i.e. 5% of the total. Over the year, the various parts of the body undergo a temperature cycle whose relevance is determined by their position and function.
The exhaled breath temperature can be easily measured [Popov et al., 2012]. However, with the use of catheters with thermistors, fiberoptic bronchoscopes and other devices, also the temperature inside the respiratory ways has been monitored. It has been found to be determined by ambient temperature and ventilation, i.e. exchanged air volume [Afonso et al., 1962;McFadden et al., 1985]. In winter, when cold air is inhaled, the upper airways from nose to trachea are severely affected by cooling and the cooling decreases progressing in the lower airway inside lungs.
The expiration too is affected: the greater the cooling during inspiration, the lower the temperature during expiration. For instance, experiments made with very cold air (i.e. -18.6° C) at various ventilations (VE) per minute shown that during inspiration the glottis temperature falls from 28° C at VE = 15 min -1 to 20.5° C at VE =100 min -1 and during expiration from 29.5° C at VE 15 min -1 to 22.5° C at VE=100 min -1 [McFadden et al., 1985]. Each cold inhalation is followed by a milder, humid exhalation, determining a sinusoidal trend in which the solubility of oxygen is favoured during the colder inhalation phase.
In winter, under normal conditions, each breath brings in cold, dry air, that exchanges sensible and latent heat at a frequency of 12 to 20 inhalations per minute [Flenady et al., 2017]. When cold air is inhaled, the airway tissues are cooled and dried, with negative effects on the lungs for people with respiratory diseases and in particular asthma [D'Amato et al., 2018].

Consequences of the different saturation levels reached by oxygen in blood
The studies concerning the gas solubility in plasma and the temperature changes of the respiratory airways may be combined to explain some respiratory morbidity related to the seasonal climate cycle. This means to calculate how the dissolved concentration of oxygen in blood changes in relations to the reference value X O2 = 21.4 [mL(gas)/L(fluid)] found by Christoforides et al. [1969] at normal lung temperature, i.e. 37° C, and at standard atmospheric pressure.
In this paper, the amount of oxygen dissolved in the human plasma has been calculated for temperatures from 20 to 45° C and the result has been expressed in percent (%) of the typical saturation value at 37° C, assumed to be 100%. (Figure 2). The result is a comparison between the various oxygen saturation levels (SL O2 ); the percent representation is similar to the output of a saturimeter, also called oximeter, i.e. the medical instrument to monitor the blood oxygenation level. The selected range is representative of the upper airways [McFadden et al., 1985].
This variable has been calculated with the equation In the 20 to 45°C range, the logarithmic and the exponential interpolations  Table 1. The first row includes the headings with selected temperatures. The next two rows report the percentage difference compared to the normal alveoli temperature assumed to be 100%. The table shows the example that, if the temperature drops to 30° C or 20° C, the oxygen saturation level will increase by +11% or +29% respectively, compared to the reference value at 37° C. Conversely, it decreases if the temperature rises. In particular, in the interval around the normal alveolar temperature, the change rate is 1.4 %/° C.
In winter, the respiratory system lowers its temperature, oxygenation increases efficiency and tends to hyperoxemia, like the effect of higher ventilation. Airborne viruses find more oxygenated cells that constitute the very first hosting site and determine the prerequisite for their development and harmfulness. Generally, viruses that naturally infect well-oxygenated organs (i.e. in the cold season) are less able to infect cells under hypoxic conditions (i.e. in the warm season) and vice-versa [Gan and Ooi, 2020]. Some viral affections, typical of the cold season, take advantage from the higher oxygen concentration in blood. This suggests that the greatest vulnerability is in winter, when one enters a crowded building, because the temperature of the upper airways is lower, the oxygenation level higher, and the virus transmission easier.
As opposed, any temperature increase, such as the febrile response, would decrease the oxygen dissolution and increase the resistance to viruses [Ogoina, 2011]. Fever generates a temporary increase in body temperature to fight infections, reducing the availability of oxygen and reproduces the mechanism determined by the warm season.
In this respect, besides to filter air, protective face masks provide, although to the minimum extent, another unexpected advantage. They reduce the free exchange of air and the CO 2 dissipation, which implies fewer airways cooling and lower oxygenation rate and both these factors contribute to reduce viral infections.
The inhalation of hot summer air raises the airway temperature and oxygenation will decrease tending to hypoxemia, with an effect similar to lower ventilation. It is known that summer heat waves may lead to hypoxia, as it has been observed in human communities, animals and marine environments [Frölicher and Laufkötter, 2018;Stillman, 2019;McArley et al., 2020]. It is also known that cardiovascular affections dramatically increase in hot days [Petralli et al., 2012;Grasso et al., 2017] and in urban heat islands [Paravantis et al., 2017] for the effort of combining thermoregulation with intense heart activity needed to compensate for the lower oxygen concentration.
Last but not least, if high summer temperatures represent an adverse situation for viruses living in cold environments, rooms overcooled with air conditioning systems may break the physiological protective cycle that the warm season offers to the upper airways, altering the degree of oxygenation with not easily predictable implications for respiratory morbidity.
The saturation level of peripheral oxygen, as well as the respiratory frequency, are considered the first and second most sensitive vital signs, used as predictors of in-hospital mortality [Barfod et al., 2012].

Conclusions
This paper has considered that the ambient air temperature, its influence on the upper airways, the dissolution of oxygen in blood and the viral activity generate a sequential mechanism and each step of it is in accordance with findings reported in the literature. This mechanism may offer the key to understanding some relationships between environmental and physiological factors, including the seasonality of viral infections. Of course, this study does not include the contribution of human factors and transmission opportunities. The applications to human health are of potential interest but need a thorough multidisciplinary analysis and verification before being applied.