Pandemic COVID-19. What can/should we do?
Having reached nearly 1.8 million reported cases globally, with reported deaths of nearly 110,000 this pandemic is reaching all corners of the globe and affecting all sections of society.
The impact on each population is profoundly affected by the decisions made by local and federal governments to promote handwashing and early social distancing and the extent to which a society is able to comply with that. The ultimate solution to the pandemic, an effective vaccine is 12-18 months away. At the other end of the clinical course, hospital and ICU staff are either struggling to find adequate PPE, beds, ventilators and new treatments to minimise the substantial morbidity and mortality or preparing for the surge in clinical needs depending on where their city is in the course of the spread of the virus. The resources that are able to be amassed to fight end stage COVID-19 are vastly different depending on the health system of the country affected.
COVID-19 has a known clinical course (with the obvious variation of asymptomatic carriage). On average around day 5 become symptomatic, get tested (if testing available in patients region), then go home to wait and see what happens. If they are lucky they become one of the 80% who recover without hospitalisation or if not, around day 12, they will need to go into a hospital with resources stretched beyond capacity, and will have significantly worse morbidity and mortality. There is no active treatment in this middle stage of the clinical course, the outcome of which predominantly depends on whether their innate immune function is able to overcome SARS CoV-2’s direct impairment. Fever is well known to enhance innate and adaptive immunity.
In Newcastle, Australia, we are proposing research into whether heat applied to the body as a proxy for fever can alter the clinical course of COVID-19 and decrease the likelihood of hospitalisation and poor clinical outcomes. This sort of research is incumbent upon clinicians and countries that have the wherewithal, to support the global fight against COVID-19. In other countries, clinicians may choose to act on biological plausibility and clinical imperative alone.
Immune Pathophysiology of Coronaviruses causing SARS, MERS and COVID-19
Coronavirus infections that result in SARS, MERS and COVID-19 show the viruses are able to actively impair the innate immune response, in particular the Type 1 interferon (IFN) response from infected cells (such as Type 2 alveolar cells and likely macrophages and T cells). They also (either directly or as a result of decreased IFN Type 1) impair monocytes and other innate immune cells (eg natural killer cells) which are required to phagocytose virus and present it to lymphocytes to switch on adaptive immunity [1-3].
…excessive type I IFN with the infiltrated myeloid cells are the main cause of lung dysfunction and negatively impact the outcome of the infection. It is speculated that upon SARS-CoV or MERS-CoV infection, delayed type I IFN compromises the early viral control, leading to influx of hyperinflammatory neutrophils and monocytes-macrophages. The increases in these innate immune cells yields deteriorating consequences to infected host that manifested in lung immunopathology, including pneumonia or acute respiratory distress syndrome. In SARS-CoV-2 infection, similar scenario is expected with varying degree of immune interference. Interestingly, transmission of virus is reported to occur even in asymptomatic infected individuals. This may be indicative of delayed early response of the innate immune response. Based on the accumulated data for previous coronavirus infection, innate immune response plays a crucial role in protective or destructive responses and may open a window for immune intervention. Active viral replication later results in hyperproduction type I IFN and influx of neutrophils and macrophages which are the major sources of pro-inflammatory cytokines. With similar changes in total neutrophils and lymphocytes during COVID19, SARS-CoV-2 probably induces delayed type I IFN and loss of viral control in an early phase of infection. Individuals susceptible to CoVID19 are those with underlying diseases, including diabetes, hypertension, and cardiovascular disease.2 In addition, no severe cases were reported in young children, when innate immune response is highly effective. These facts strongly indicate that innate immune response is a critical factor for disease outcome. 
Eighty percent of patients are able to overcome this direct innate immune suppression by the virus, mount a reasonable innate (and consequently a good adaptive) immune response and clear the virus. In about twenty percent of patients (predominantly those with impaired immunity to start with, for example – from age or obesity and it’s consequent diseases) this direct inhibition by the virus results in it being able to replicate relatively unchecked in the early days of the infection. A few days to a week later, the body is confronted with large amounts of virus and there is an over exuberant immune response from the recruited neutrophils, monocytes and macrophages. The resultant hyperproduction of proinflammatory cytokines, the so-called “cytokine storm”, results in acute lung injury +/- ARDS +/- multi-organ failure +/- death [1-3]. See the diagram on the previous page.
Early research has shown in vitro pretreatment of cells with IFN Type 1 in the days prior to infection shows a massive sustained reduction in viral replication and likely would result in a good in vivo result . However IFN Type 1 is not yet an available experimental treatment. There are a number of other therapeutic trials showing promise with such treatments as vitamin C, plaquenil, zinc, even injection with natural killer cells etc but globally most patients are unable to access these as either in, or outpatients. As for the case of the immune treatments like administered IFN or NK cells: what if we could do more than just increase one cytokine or cell line? What if we could activate the whole of the immune system?
How can we overcome immune inhibition by SARS CoV-2?
Fever is known to increase innate and acquired immune activity in multiple ways including:
- increased release of heat shock proteins
- increased phagocytic potential of dendritic cells and macrophages
- increased migration of APCs to regional lymph nodes,
- increased recruitment of neutrophils to lungs
- increased neutrophil activity
- enhanced natural killer recruitment and activity
- increased numbers of lymphocytes.
This is also true for induced hyperthermia eg as created by injecting lipopolysaccharide (bacterial cell wall component) into mice or sitting in a warm bath for humans.[5,6] Hyperthermia not only optimises immune function it also directly inhibits viral replication . Most importantly in the case of COVID-19, a number of studies have demonstrated that elevated body temperatures substantially augment Interferon Type 1 (IFNα) production/activity in response to viral infection [6-9] AND monocyte function ie the immune processes that the virus directly inhibits. By utilising induced hyperthermia to overcome the initial roadblocks that SARS-CoV-2 setup, the immune system is primed to proceed with a normal inflammatory response and clear the virus, rather than progress to inflammatory complications.
Fever is a good immune system enhancer as discussed above, however, there are two problems:
- Not everyone mounts a good fever response to infection especially not the old and obese. Immunosenescence (the decline in immune function with age, and obesity and its consequences) is mediated in part by impaired monocyte function[12,13].
- Fever is metabolically expensive with every degree of body temperature elevation requiring an increase in BMR of 10-12.5%.
Mild hyperthermia induced by hydrotherapy potentially addresses both of these problems[5,11].
How can immune enhancement by hyperthermia help clinically?
The first week after diagnosis with COVID-19 infection is essentially being wasted at home. If during that time we induced hyperthermia at home, with simple hydrotherapeutic techniques, we could directly stimulate the whole of the innate and adaptive immune response but in particular we may be able to partially or completely overcome the direct immune depressant effects of COVID-19 on INF and monocytes in the early days of infection. If we are able to diminish the need for hospitalisation by even 5% of total infections that would be a 25% decrease in numbers requiring admission, substantially reducing the overstretched resources globally and will potentially save many lives. This potential treatment is even more important as an option for people in developing nations without a readily available hospital system, replete with ICU support.
Hydrotherapy and COVID-19
Hydrotherapeutic hyperthermia can be induced in a number of ways, but one of the easiest involves sitting in a warm to hot bath till sweaty, then having a douse of cold water to vasoconstrict the external vessels and keep the heat in, then resting in a warm bed for ½ an hour. The potential risks of this treatment include vasovagals due to vasodilation or arrhythmias induced by the cold water shock. Hydrotherapy is highly modifiable treatment and can be performed with a patient in bed, in a chair or in a bath/shower with whatever is available to hand. It can also be adapted to suit the patients comorbidities and clinical status. Anecdotally, a physiotherapy colleague of mine has used therapeutic hyperthermia to good effect in many different situations around the globe. For example, by wrapping Karen refugees without access to any medical care, in black plastic to heat and then cooling off with a dip in the river for tropical PUO (likely Dengue or malaria). When utilised in conjunction with standard medical care while working in a hospital in Bangkok, my colleague saw patients in hospital with Dengue fever fit to go home in 3 days when it usually took 7-10 days.
Could inducing a fever early just speed up the time to cytokine storm and not alter the clinical pathway at all?
Reassuringly there is good evidence to suggest that early fever or induced hyperthermia plays a homeostatic role in managing the inflammatory course, and its outcomes, for good or ill. For example, thermal stress initially increases proinflammatory cytokine release from macrophages but, once they are activated, synthesis decreases. In addition, activated or “heat experienced” macrophages produce less TNF, IL6 and IL1beta in febrile temperatures, than heat inexperienced ones.
What about those who are not infected but would like to optimise immune function today? The evidence is a little less clear at a population rather than cellular level, (smaller studies, more observational, hard to blind people etc) but heat, then cold exposure has been shown to improve immune function, especially when used over longer periods [14,15,16].
A case report followed the clinical course of a patient in Melbourne, Australia who recovered from COVID-19 after a brief hospitalisation. There was a marked increase of adaptive immune cells around day 7, three days prior to alleviation of symptoms (still with noticeably low monocytes common to SARS CoV-2 infections). It would be useful to have some comparative case studies showing what happens daily to the clinical course in COVID-19 with hydrotherapy. Taking a FBC at least on days 3 and 6 would show quickly whether immune suppression was taking place, or being overcome by the treatments and give a good prediction as to whether the patient was likely to need hospitalisation on day 12, or go on to make a good clinical resolution. Case reports and historical records from when this treatment was used in the Spanish influenza pandemic suggest that the WCC should surge at day three (illustrating a rapid transition to acquired immunity) and bring about clinical resolution potentially around 4 days earlier than without hydrotherapy.
It is worth noting that practicing Evidence Based Medicine is an excellent thing that helps keep us and our patients safe. However during this pandemic ICUs and health care workers around the globe are just trying to figure out what works. There are no long term, multicentre RCTs to guide us at this stage, just clinical experience that guides expert opinion. Once anecdotal evidence mounts, it is guiding smaller clinical trials and RCTs in regional centres. There are just too many lives to try to save to waste time waiting for someone else to deliver gold standard evidence. Not having an RCT to support a type of treatment is not stopping intensive care clinicians from trying any therapeutic modality that makes physiological sense and is available to hand. I believe in this situation, primary care physicians, public health physicians and ID physicians should be following their lead.
As we are making good progress in “flattening the curve” in Australia we have the opportunity to formally assess whether immune stimulation by mild hyperthermia from hydrotherapy can alter clinical outcomes. Not every country or city is in our position. Some clinicians may choose to trial this old/new treatment for infectious disease without recent trials. This therapy is scientifically plausible, at little to no cost, readily available, and can be safely utilised by patients in their own homes with a little education and common sense. Like all treatments hydrotherapy is not without risks eg falls from postural hypotension or arrythmias triggered by cold stimulation. If clinicians and patients are aware of the risks and contraindications to this therapy it can be considered on a case by case basis.
Detailed protocols, as well as precautions/contraindications, are available at hydro4covid.com. This information is based on clinical experience and historical textbooks/records of treatment of the Spanish Influenza pandemic. These protocols, used with care, can be utilised to possibly:
- help keep patients out of hospital (more acute care for those who really need it)
- diminish asymptomatic and presymptomatic shed in the community (slow community spread) especially in the young who are at least risk from this illness and are the most likely to share it without knowing it
- optimise our own immune function to help keep us all working safely as long as is required..
Author: Dr Emma Campbell BMed FRACGP
Highlighted in bold are the two most useful resources, if you only have time to look at a couple of papers.
- Channappanavar R, Fehr AR, Zheng J, Wohlford-Lenane C, Abrahante JE, Mack M, Sompallae R, McCray PB Jr, Meyerholz DK, Perlman S. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest. 2019 Jul 29;130:3625-3639. doi: 10.1172/JCI126363. eCollection 2019 Jul 29. PubMed PMID: 31355779; PubMed Central PMCID: PMC6715373.
- Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020 Mar;38(1):1-9. doi: 10.12932/AP-200220-0772. Review. PubMed PMID: 32105090.
- Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017 Jul;39(5):529-539. doi: 10.1007/s00281-017-0629-x. Epub 2017 May 2. Review. PubMed PMID: 28466096; PubMed Central PMCID: PMC7079893.
- Lokugamage KG, Schindewolf C, Menachery VD. SARS-CoV-2 sensitive to type I interferon pretreatment. unpublished.Forthcoming;
- Evans SS, Repasky EA, Fisher DT. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat Rev Immunol. 2015 Jun;15(6):335-49. doi: 10.1038/nri3843. Epub 2015 May 15. Review. PubMed PMID: 25976513; PubMed Central PMCID: PMC4786079
- El-Radhi AS. Fever management: Evidence vs current practice. World J Clin Pediatr. 2012 Dec 8;1(4):29-33. doi: 10.5409/wjcp.v1.i4.29. eCollection 2012 Dec 8. Review. PubMed PMID: 25254165; PubMed Central PMCID: PMC4145646.
- Postic B, DeAngelis C, Breinig MK, Monto HO. Effect of temperature on the induction of interferons by endotoxin and virus. J Bacteriol. 1966 Mar;91(3):1277-81. PubMed PMID: 5929756; PubMed Central PMCID: PMC316024.
- Manzella JP, Roberts NJ Jr. Human macrophage and lymphocyte responses to mitogen stimulation after exposure to influenza virus, ascorbic acid, and hyperthermia. J Immunol. 1979 Nov;123(5):1940-4. PubMed PMID: 489966.
- Knippertz I, Stein MF, Dörrie J, Schaft N, Müller I, Deinzer A, Steinkasserer A, Nettelbeck DM. Mild hyperthermia enhances human monocyte-derived dendritic cell functions and offers potential for applications in vaccination strategies. Int J Hyperthermia. 2011;27(6):591-603. doi: 10.3109/02656736.2011.589234. PubMed PMID: 21846195.
- Prow NA, Tang B, Gardner J, Le TT, Taylor A, Poo YS, Nakayama E, Hirata TDC, Nakaya HI, Slonchak A, Mukhopadhyay P, Mahalingam S, Schroder WA, Klimstra W, Suhrbier A. Lower temperatures reduce type I interferon activity and promote alphaviral arthritis. PLoS Pathog. 2017 Dec;13(12):e1006788. doi: 10.1371/journal.ppat.1006788. eCollection 2017 Dec. PubMed PMID: 29281739; PubMed Central PMCID: PMC5770078
- Zellner M, Hergovics N, Roth E, Jilma B, Spittler A, Oehler R. Human monocyte stimulation by experimental whole body hyperthermia. Wien Klin Wochenschr. 2002 Feb 15;114(3):102-7. PubMed PMID: 12060966
- Rao DV, Watson K, Jones GL. Age-related attenuation in the expression of the major heat shock proteins in human peripheral lymphocytes. Mech Ageing Dev. 1999 Feb 1;107(1):105-18. doi: 10.1016/s0047-6374(98)00143-2. PubMed PMID: 10197792.
- Parisi MM, Grun LK, Lavandoski P, Alves LB, Bristot IJ, Mattiello R, Mottin CC, Klamt F, Jones MH, Padoin AV, Guma FCR, Barbé-Tuana FM. Immunosenescence Induced by Plasma from Individuals with Obesity Caused Cell Signaling Dysfunction and Inflammation. Obesity (Silver Spring). 2017 Sep;25(9):1523-1531. doi: 10.1002/oby.21888. Epub 2017 Jul 14. PubMed PMID: 28707376
- Brenner IK, Castellani JW, Gabaree C, Young AJ, Zamecnik J, Shephard RJ, Shek PN. Immune changes in humans during cold exposure: effects of prior heating and exercise. J Appl Physiol (1985). 1999 Aug;87(2):699-710. doi: 10.1152/jappl.1922.214.171.1249. PubMed PMID: 10444630.
- Dugue B, Lappanen E, Grasbeck R. Effect of thermal stress (sauna + swimming in ice-cold water) in man on the blood concentration and production of pro-inflammatory cytokines and stress hormones. Pathophysiology. 1998; 1001(5):149.
- Ernst E, Pecho E, Wirz P, Saradeth T. Regular sauna bathing and the incidence of common colds. Ann Med. 1990;22(4):225-7. doi: 10.3109/07853899009148930. PubMed PMID: 2248758.
- Thevarajan I, Nguyen T, Koutsakos M, Druce J, Caly L, van de Sandt C, Jia X, Nicholson S, Catton M, Cowie B, Tong S, Lewin S, Kedzierska K. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nature Medicine. 2020/03; doi: 10.1038/s41591-020-0819-2