Turning up the heat on COVID-19: heat as a therapeutic intervention.

Enveloped viruses such as SAR-CoV-2 are sensitive to heat and are destroyed by temperatures tolerable to humans. All mammals use fever to deal with infections and heat has been used throughout human history in the form of hot springs, saunas, hammams, steam-rooms, sweat-lodges, steam inhalations, hot mud and poultices to prevent and treat respiratory infections and enhance health and wellbeing. This paper reviews the evidence for using heat to treat and prevent viral infections and discusses potential cellular, physiological and psychological mechanisms of action. In the initial phase of infection, heat applied to the upper airways can support the immune system's first line of defence by supporting muco-ciliary clearance and inhibiting or deactivating virions where they first lodge. This may be further enhanced by the inhalation of steam containing essential oils with anti-viral, mucolytic and anxiolytic properties. Heat applied to the whole body can further support the immune system's second line of defence by mimicking fever and activating innate and acquired immune defences and building physiological resilience. Heat-based treatments also offer psychological benefits and enhanced mental wellness by focusing attention on positive action, enhancing relaxation and sleep, inducing 'forced-mindfulness', and invoking the power of positive thinking and 'remembered wellness'. Heat is a cheap, convenient and widely accessible therapeutic modality and while no clinical protocols exist for using heat to treat COVID-19, protocols that draw from traditional practices and consider contraindications, adverse effects and infection control measures could be developed and implemented rapidly and inexpensively on a wide scale. While there are significant challenges in implementing heat-based therapies during the current pandemic, these therapies present an opportunity to integrate natural medicine, conventional medicine and traditional wellness practices, and support the wellbeing of both patients and medical staff, while building community resilience and reducing the likelihood and impact of future pandemics. Copyright:

Heat in viruses and mammals

Life exists within a narrowly defined temperature range, yet viruses, which are not technically alive, can remain biologically active in a wide range of environments. Enveloped viruses, such as rhinoviruses and coronaviruses, are most active in cool dry conditions, which are associated with increased occurrence of respiratory tract infections ( Mäkinen ), including infections with SARS-CoV ( Chan ) and SAR-CoV-2 ( Sajadi ; Wang ). While enveloped viruses can remain active for long periods in cold conditions, their lipid envelopes are destroyed by temperatures tolerable to humans. The heat sensitivity of viruses is used routinely to deactivate viruses within vaccines, and temperatures of 55 to 65°C for 15 to 30 minutes are reported to deactivate a range of enveloped viruses, including coronaviruses ( Darnell ; Duan ; Hu ; Kampf ; Lelie ; WHO Report, 2003).

The first line of defence against respiratory viruses is the nasal cavity and sinuses, which maintains a protective mucosal barrier that allows viruses to be trapped, identified by the immune system and swept away, as well as serving an important thermoregulatory role. The nasal cavity and sinuses in humans constantly exchanging heat with inhaled air through convection, conduction and evaporation, which serves to cool inhaled air in summer and warm and humidify air in winter ( Soni & Nayak, 2019). The upper airways also serve as the first line of defence against respiratory viruses by maintaining a protective mucosal barrier that filters and traps foreign particles and pathogens in a layer of watery mucus, and enables them to be identified by the immune system. This mucus is then moved by cilia towards the pharynx, where it is either swallowed or expelled by coughing, sneezing and nose blowing. A moist mobile mucosal barrier is vital in the defence against respiratory infections and this barrier is enhanced by warm humid conditions and impaired by cigarette smoke and particulate pollution ( Fahy & Dickey, 2010).

In winter when sunlight is restricted and the air is cold and dry, the nasal cavity becomes the coldest part of the body and if the airways dry out and the mucous becomes thicker and more difficult to clear, conditions become more favourable for viral penetration and replication. The ability of cool, dry conditions to enhance viral infection has been demonstrated in mice, with humidity of around 20% being shown to slow muco-ciliary clearance, impair innate antiviral defence, and reduce tissue repair function, leading to more rapid and severe illness compared with humidity of 50% ( Kudo ).

If respiratory viruses get past the first line of defence, fever is produced as part of the acute phase response, which forms the immune system’s second line of defence. Fever is a cardinal response to infection that has been conserved within vertebrates for more than 600 million years. Ectotherms as diverse as reptiles, fish, and insects raise their core temperature during infection through behavioural regulation, and all mammals have evolved sophisticated mechanisms to create and disperse heat and manage the oxidative stress associated with operating at higher temperatures ( Evans ).

Heat as medicine

The use of heat for cleansing and healing is a conscious extension of mammals’ use of heat that has been practiced throughout human history. Hot springs, saunas, hammams, steam rooms, sweat lodges, steam inhalations, baths, hot mud and poultices have been used traditionally in cold, dry climates to prevent and treat respiratory infections and to enhance overall health and wellbeing. Heat-based therapies are not widely used in mainstream medicine, other than the local application of hot packs for symptomatic relief, or the use of novel technologies such as microwaves, radiofrequency energy, ultrasound, infrared radiators, ferromagnetic seeds, nanoparticles and resistive implants that apply heat to treat various cancers ( Chicheł ). Heat-based treatments however, are standard offerings in wellness establishments, such as hot springs, bathing facilities, gymnasiums, fitness centers, hotels and resorts, where they are used for both therapy and recreation ( Clark-Kennedy & Cohen, 2017).

There are multiple lines of evidence to support the use of heat and humidity for the prevention and treatment of viral respiratory infections. Historical and emerging evidence suggests regular sauna bathing enhances cardiovascular, respiratory and immune function as well as improving mood and quality of life ( Hussain & Cohen, 2018)( Laukkanen ). Finnish sauna bathing, which involves brief exposures to high environmental temperature (80°C-100°C) has been shown to reduce the risk of all-cause mortality, sudden cardiac death, cardiovascular disease and vascular diseases such as high blood pressure and stroke, along with the risk of neurocognitive diseases, skin conditions and painful conditions such as rheumatic diseases and headache ( Laukkanen ; Laukkanen ; Laukkanen & Kunutsor, 2019). Epidemiological evidence further suggests that frequent sauna bathing is associated with a reduced risk of pneumonia and viral infection ( Kunutsor ) ( Kunutsor ; Kunutsor ), and randomised controlled trial evidence suggests that regular saunas can halve the incidence of respiratory viral infections ( Ernst ). Randomised controlled trials further suggest hot air can treat respiratory infections with humidified air at temperatures above 43°C for 20 to 30 minutes being found to reduce viral shedding, provide immediate relief of symptoms and improve the course of the common cold ( Tyrrell, 1988; Tyrrell ).

Mechanisms of action

The mechanisms by which heat overcomes viral infections depends on the setting, source, temperature, humidity, location and time course of applied heat. Whether internally generated or externally applied, heat has a profound influence on host defences and physiological resilience, as well as on viral load and virulence, and engages adaptive thermoregulatory mechanisms that can increase or decrease body temperature in order to restore homeostasis ( Schieber & Ayres, 2016).

Hyperthermia and heat stress have multiple actions that may help mitigate viral infections. These include direct inhibition of pathogens, stimulation of both the innate and adaptive arms of the immune system and activation of regulatory processes that dampen inflammatory responses and prevent excessive tissue damage ( Evans ). Inhalation of hot air supports the immune system’s first line of defence by direct inhibition or deactivation of virions in the upper airways where they first lodge. Inhalation of hot humid air also supports muco-ciliary clearance, which can be further enhanced by inhalation of steam ( Gujrathi ). Heat applied to the whole body further supports the immune system’s second line of defence by inducing heat-stress that mimics the effects of fever ( Schieber & Ayres, 2016).

Febrile temperatures activate multiple cellular responses that include complex reciprocal regulation between immune system activation, inflammation and the heat shock response pathway ( Singh & Hasday, 2013). While the mechanisms by which heat-stress modulates immune function are not fully understood, higher temperatures have been shown to activate immune cells by making their cell membranes more fluid, which increases cell differentiation and activation by viral antigens and enables a faster and more effective response to viral threats ( Mace ).

Acute heat stress has been shown to increase the TNF-alpha response of monocytes ( Zellner ), enhance interleukin-2 induced activity of Natural Killer (NK) cells ( Kappel ), and cause a 10-fold increase in interferon-γ production by T-lymphocytes ( Downing ) while regular heat-stress has been shown to reduce adrenaline and cortisol, increase the cytotoxicity of NK cells, and enhance the proliferative response of B cells ( Tomiyama ). Heat-stress also stimulates the release of Heat Shock Proteins (HSPs), ( Iguchi ) which play an important role in antigen presentation and cross-presentation, activation of macrophages and lymphocytes, and activation and maturation of dendritic cells ( Tsan & Gao, 2009) as well as serving a chaperone function and protecting immune cells and proteins from heat-induced damage ( Singh & Hasday, 2013). The immunostimulatory effects of heat stress on the innate immune system may be further enhanced by alternating heat exposure with exposure to cold ( Heinonen & Laukkanen, 2018), which leads to leukocytosis, granulocytosis, an increase in NK cell count and activity, and an elevation in circulating levels of IL-6 ( Brenner ).

In addition to enhancing cellular responses, heat-stress induces a hormetic stress response that builds physiological resilience and confers tolerance to subsequent stress in a similar way to exercise ( Gálvez ). Heat stress improves respiratory function by reducing pulmonary congestion and increasing tidal volume, vital capacity, ventilation, and forced expiratory volume of the lungs ( Laitinen ), and improves cardiovascular function by modulating the autonomic nervous system, reducing inflammation, oxidative stress and blood pressure, increasing cardiac output, plasma volume and peripheral blood flow, and improving endothelial function, lipid profile and arterial compliance ( Heinonen & Laukkanen 2018; Kunutsor ; Laukkanen ; Laukkanen & Kunutsor, 2019).

Heat stress also aids in detoxification via sweating ( Crinnion, 2011) through which some toxic elements are preferentially excreted ( Genuis ). Furthermore, when heat stress is followed by cold exposure, blood is shunted to the internal organs, which induces a diuresis ( Epstein, 1978), and further aids in detoxification ( Cochrane, 2004). Heat-stress may offer a further advantage against respiratory viral infections by altering blood pH through hyperthermia-induced hyperventilation and subsequent respiratory alkalosis ( Tsuji ), which creates alkaline conditions that may be more favourable to host defenses. The ability of a transient alkaline environment to inhibit viral replication and reduce infectivity has been demonstrated with human coronavirus 229E, which has maximal infectivity in acid conditions ( Lamarre & Talbot, 1989), and with coronavirus MHV-A59, which undergoes conformational changes in the spike glycoprotein at a pH of 8 at 37°C degrees and leads to rapid and irreversible inactivation and loss of infectivity ( Sturman ).

In addition to offering physiological advantages in the battle against viral infection such as COVID-19, heat-based treatments can support mental wellness and confer many psychological benefits. Sauna bathing and other forms of heat therapy require time and effort devoted towards active relaxation that can help divert attention from anxiety-producing news and/or relieve boredom associated with social confinement. Sauna bathing also enhances sleep ( Hussain ), which further supports immune function ( Irwin & Opp, 2017). Engaging in an activity with an intended positive outcome can also impart feelings of control that may otherwise be lacking, and doing something that feels good and having positive expectations elicits the power of positive thought and the placebo effect or ‘remembered wellness’ ( Benson & Friedman, 1996). Furthermore, the exploration of heat-tolerance induces a 'forced-mindfulness' and a focus on the breath, which has additional physical and psychological benefits ( Black & Slavich, 2016). In a time of social distancing, saunas can also provide a way for close family members to come together in ways that have supported family cohesion for generations in Finland and other Nordic countries ( Mather & Kaups, 1963).

Clinical applications and implications

There are a range of heat-based interventions that can be used alongside other personal hygiene measures to aid in overcoming COVID-19. For example, warming and humidifying indoor environments can prevent drying of the nasal mucosa, increase muco-ciliary clearance and nasal patency, and provide symptomatic relief ( Ophir & Elad, 1987). The direct application of heat to the upper airways, routinely or at the first signs of infection, may further serve to inhibit or deactivate virions in the place where they first lodge. This has been demonstrated in vitro with temperatures of 45°C for 20 minutes activating immune cells, releasing HSPs and suppressing rhinovirus multiplication by more than 90% ( Conti ). The inhalation of steam with added essential oils with anti-viral, decongestant, anxiolytic and other properties, may further assist in facilitating muco-ciliary clearance and reducing viral load as well as providing physical and psychological relief ( Ali ; Lee ).

Inducing mild heat-stress through the use of hot springs (balneotherapy), hot baths, saunas, steam-rooms and application of hot mud (pelotherapy), can be used to mimic fever and activate immune defenses. Enhanced immunity has been demonstrated with hyperthermia induced by traditional Finnish saunas ( Pilch ), far-infrared saunas ( Sobajima ), heated nano-mist ( Tomiyama ), hot baths ( Downing ; Kappel ; Tsuchiya ; Zellner ) and geothermal mineral water ( Uzunoglu ). The beneficial effects of heat-stress may be further potentiated by the traditional practice of alternating heat with exposure to cold, which may translate into greater resistance to viral infections as evidenced by a randomised controlled trial that found regular hot and cold showers reduced work absenteeism during an influenza outbreak ( Buijze ).

In recent years far-infrared (FIR) saunas have been used as an alternative to the traditional Finnish saunas. These saunas use infrared emitters without water or added humidity and generally run at lower temperatures than Finnish saunas. While the use of FIR saunas to treat viral infection has not been studied, FIR radiation is reported to deactivate single-strand RNA viruses ( Huang & Li, 2020) and FIR saunas have been shown to raise body temperature, induce hormetic stress responses and support host defenses ( Shemilt ). FIR saunas, along with other heat-based technologies may therefore also prove useful in treating patients with COVID-19.

There are currently no clinical protocols for using heat in the treatment of COVID-19, yet heat has a long history of traditional use, and traditional practices such as alternating hot and cold immersions, post-heat relaxation and use of essential oils can inform their development. While sauna bathing is generally well tolerated, heat-based clinical protocols are needed to design future studies and inform clinical practice in order to minimise the risk of cross-infection and reduce the incidence of adverse effects, which can range from burns, cramps, dizziness and fainting, to heat exhaustion, heat stroke and death. Such protocols must therefore consider contra-indications such as unstable angina, severe infection or high fever ( Hannuksela & Ellahham, 2001) along with factors such as age, weight, fitness, hydration status, co-morbidities and the use of alcohol or prescription drugs ( Leyk ). Hydro-therapy treatment plans also need to consider timing, temperature and humidity, as water is 25 times more conductive than air, making steam rooms tolerable at temperatures around 50°C while dry saunas are tolerated at temperatures above 100°C.

While the clinical application of heat has promise in the prevention and treatment of COVID-19, there are significant challenges in implementing heat-based therapies. The current pandemic has seen the fear of infection lead to the widespread closure of public facilities such as bathing facilities, commercial hot springs, spas, gymnasiums, hotels and fitness centers that offer saunas and heat treatments, and while some countries such as Finland have a large number of private saunas, in most other locations private sauna ownership is limited to people with high socio-economic status. Thus, if sauna bathing is to be widely implemented, public bathing and sauna facilities will need to re-open and adopt infection control measures similar to those for dealing with COVID-19 in other public facilities ( Liang, 2020).

Heat is one of oldest forms of microbial control and still remains one of the most common methods for controlling and eradicating pathogens. The temperatures achieved within a sauna are well within the range required for pathogen control and often exceed temperatures of 60°C for 30 min, 65°C for 15 min or 80°C for 1 min, which have been shown to reduce coronavirus infectivity by at least 4 log10 ( Kampf ). While the temperatures, humidity and times required to specifically deactivate SAR-CoV-2 in vivo are yet to be determined, the temperature within a sauna makes risk of cross infection in public sauna facilities highly unlikely.

Strategies for limiting cross infection have been recently developed for re-opening some of the 3000 hot springs that were recently closed in China ( Wang, 2020). There are also moves to reopen facilities as quarantine zones where people can undergo heat treatments during isolation or as places of respite for overworked medical staff. It may also be possible for saunas and steam rooms to be included within hospitals and rehabilitation facilities for use by both patients and staff. Furthermore, simple home-based protocols can provide guidance on using heat for people who are currently self-isolated in their homes or in quarantine. Such protocols could be evaluated using crowd-sourced, citizen-science platforms, which may help to develop, test and optimize treatment strategies for current and future pandemics.

Conclusion

Heat is a cheap, convenient and widely accessible therapeutic modality with a long history of traditional use, yet it remains to be seen if heat can be effective in the treatment or prevention of COVID-19. The relatively low cost and wide availability of heat-based treatments, along with multiple mechanisms of action that include both physical and psychological dimensions, makes heat an attractive option for combating viral infections. The integration of these ancient forms of treatment with modern technology may lead to a greater integration of natural therapies in mainstream healthcare, with the potential to support the wellbeing of both patients and medical staff. This may also lead to a greater convergence between the healthcare and wellness industries, and the development of systems and activities that build the wellbeing and resilience of the wider community, thereby reducing the impact of future pandemics.

Data availability

No data is associated with this work.

No other comments.

Is the topic of the opinion article discussed accurately in the context of the current literature?

Yes

Are arguments sufficiently supported by evidence from the published literature?

Yes

Are all factual statements correct and adequately supported by citations?

Yes

Are the conclusions drawn balanced and justified on the basis of the presented arguments?

Yes

Reviewer Expertise:

Cardiovascular diseases, sauna and exercise

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Heat is a cheap, convenient and widely accessible therapeutic modality. Sauna bathing is a form of heat therapy. However, there are no very accurate details of temperature, weekly frequency, and duration which would be needed to achieve those beneficial effects. An only traditional Finnish sauna is based on high temperatures.

You should discuss more with the lights of many published original studies on sauna and its protective health effects. The literature review of this narrative has missed many recent papers on this topic. Please consider adding the recently published key references on sauna and health outcomes so that this article would be more up-to-date. [1] , [2] ,[ref-3 , [4] , [5] , [6] , [7]

What is the role of improved hygiene control due to regular sauna bathing?

Warm and cold has any effect on the results?

You could add studies that may indicate that sauna is related to inflammatory markers or cytokines.

It is written that emerging evidence suggests regular sauna bathing enhances cardiovascular function. No relevant references were available in the manuscript.

Is the topic of the opinion article discussed accurately in the context of the current literature?

Yes

Are arguments sufficiently supported by evidence from the published literature?

Yes

Are all factual statements correct and adequately supported by citations?

Yes

Are the conclusions drawn balanced and justified on the basis of the presented arguments?

Yes

Reviewer Expertise:

Cardiovascular diseases, sauna and exercise

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

This is a timely, interesting, and generally well-written article summarizing many of the positive benefits of thermal therapies, provided in the context of potential therapies for patients with COVID-19. In general, the authors cover a wide range of literature related to applications (local/regional, whole body, topical) of elevated temperature. My comments related only to organization and some references and distinguishing better the difference between fever and hyperthermia. Heat treatments are likely to be hyperthermia treatments. While fever contains a thermal element, fever and hyperthermia represent very different physiological circumstances.

For example, statements such as that in Paragraph 2, right column, page3 "Fever has multiple actions with dealing with infections that include direct inhibition of pathogens, stimulation of both the innate and adaptive arms of the immune system and activation....". While the authors provide a review article as a reference here, most of this literature deals with hyperthermia and not actual infectious fever and this difference needs to be highlighted better. One would not be treated with fever. Moreover, there are other fundamental differences. Febrile individuals are usually quite cold and surface vessels constricted to conserve heat and help raise body temperature. Hyperthermia causes sweating and surface blood vessel dilation because the set point is not elevated.

Moreover, there is a massive literature on heat stress/stroke (from hyperthermia, not fever) that can kill people because of excessive adhesion of platelets and white blood cells in capillaries. While the authors do rightly mention some safety concerns, it is perhaps a bit insufficient with regard to the impact of both hyperthermia (and fever). At the same time, the scope of the beneficial effects of mild elevation of body temperature and local temperature (in particular with respect to viral infections) is quite important to remember and hopefully expand upon in future clinical applications.

Some topics should be highlighted more. For example, there is a substantial literature using electromagnetic heating and infrared heating for cancer therapy and so there is already safe equipment available for both local/regional as well as surface heating. Reviews on this topic have been available for some time. This technology could already be available for COVID-19 patients.

I found some of the referencing related to the direct impact of heat on viral replication (either in vivo (e.g., nasal cavities or in vitro) to be scattered a bit throughout the review. Some better reorganization of these various sections would help the reader to assess this very important point.

Is the topic of the opinion article discussed accurately in the context of the current literature?

Partly

Are arguments sufficiently supported by evidence from the published literature?

Yes

Are all factual statements correct and adequately supported by citations?

Yes

Are the conclusions drawn balanced and justified on the basis of the presented arguments?

Yes

Reviewer Expertise:

Immunology; Thermal stress; hyperthermia, anti-tumor immunity; Stress

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.