Jeffrey S. Bland, PhD
There is an emerging understanding that the severity of viral infections is not only related to the nature of the viral vector, but also to various social and biological factors, a number of which can be modified. The recent COVID-19 pandemic raises the issue as to what approaches might be important in reducing the severity of future viral pandemics beyond that of the pursuit of specific immunization to the vector and the development of drugs to treat its unique mechanism of replication. There is now evidence that lifestyle and environmental factors can serve as immunoadjuvants. Personalized lifestyle and environmental factors may therefore play a significant role in determining both the infectivity and pathogenicity of viruses. Once identified, these factors lend themselves to specific personalized intervention. This intervention focuses on renewal of immune system function through diet, activity, fluid intake, sleep, intestinal microbiome composition, and stress management. As more is learned about the factors that influence the function of specific components of the immune system, it becomes more evident that these modifiable factors have significant impact on the individual response to a viral exposure.
I clearly remember the day in 1982 when my thinking about viral infections shifted from one point of view to another in the space of time it took me to listen to a lecture. I was living in Northern California then, and participating in a sabbatical year at the Linus Pauling Institute of Science and Medicine in Palo Alto. As I sat in a lecture hall among colleagues, a prominent young physician from the University of San Francisco Medical Center stepped up to the podium to give a presentation. His name was Paul Volberding. In July 1981, Dr. Volberding had identified one of the first reported cases of Human Immunodeficiency Virus (HIV) infection. Not long after, it was determined that HIV was caused by a mutant RNA retrovirus, and its origins were tracked to transmission from animals to humans in Africa. Social contact was a hallmark of this virus. Everyone in the room that day was stunned by Dr. Volberding’s account of the severity of the infection and its infectivity. Nearly 40 years on, data related to HIV continues to be sobering. The World Health Organization reports that more than 75 million people globally have been infected with the virus since it was identified, and of those, 32 million have died. It’s important to understand that this is still very much an active and unresolved medical crisis that impacts people all over the world. In 2018, 34 million people were reported to be infected and 770 000 deaths were recorded. Although there is no immunization to prevent HIV infection nor is there a drug that truly eliminates it, somehow the passage of time, and perhaps also the awareness that antiretoviral drugs are used for treatment, has somehow dampened concerns about this virus in the United States and other western countries.
Today, as I write this, the world is grappling with the coronavirus (COVID-19) pandemic. This is also an infection involving a mutant RNA retrovirus, but fortunately it is less pathogenic than HIV. Public health crises like HIV and COVID-19 can prompt an array of cultural changes. It should never be forgotten that many health care workers lost their lives while treating patients with HIV/AIDS in the early 1980s. During that era, fear was a constant presence, and indeed we are again seeing widespread fear as we watch the number of COVID-19 cases rise while extreme attempts at control involving social distancing and stay-at-home orders are enacted. Historically it has been the case that truthful information can diffuse anxiety at the cultural level.
While exploring this concept, I came to recognize that viral pandemics occur on a regular basis. Here is a look back at the some of the viral pandemics of the last century: the 1918 flu is estimated to have killed 20 to 30 million people; over two years, 1956 and1957, the Asian flu is believed to have taken two million lives; in 1968, the Hong Kong flu killed one million people; and more recently, the 2009 H1N1 swine flu infected 61 million Americans and killed 12 500 people. With viruses, some are more infectious than others and some are more lethal than others.
In 2012, Anthony Fauci, MD, who is (and was then) the Director of the National Institute of Allergy and Infectious Diseases, published an article in the New England Journal of Medicine with David M Morens, MD, titled “The Perpetual Challenge of Infectious Diseases.” They wrote: “Unlike many chronic and lifestyle-associated diseases resulting from multiple, interacting risk cofactors, most infectious diseases are caused by a single agent.” They continue: “Given their nature, infectious diseases are potentially preventable with personal protection, general public health measures, or immunologic approaches such as vaccination.”1
Although the review article by Drs. Fauci and Morens is very informative as it relates to the origin of viral epidemics, I question the statement that infectious diseases are caused by a single agent. My reasons stem from the study of the history of global viral pandemics and their pathogenicity and demographics. While there is no doubt that specific organisms are seen as the infectious vectors associated with specific pandemics, I believe history tells us that these viruses do not work alone. In fact, I believe a very different dynamic exists: these viruses work in combination with other factors—both social and biological—and some may be modifiable.
There is now evidence that certain lifestyle and environmental factors can serve as immunoadjuvants. Once identified, these factors can lend themselves to specific personalized intervention that is focused on renewal of immune system function, as well as increased resilience. I break down the social and biological categories mentioned in the preceding paragraph in the following way. Potentially modifiable social factors include things related to structure and behavior, such as housing, transportation, communication, health care systems, politics, and economics. What about biology? Here I would place potentially modifiable factors like stress, environmental toxicity, diet and nutrition, physical activity, sleep, hydration, intestinal microbiome composition, and biological rhythms. It is generally recognized that social factors are challenging to modify, whereas biological factors are personal and therefore an individual has a greater focus of control.
Hygiene, sanitation, and immunization are the three pillars of public health that are emphasized in the prevention of pandemic viral infections. All are important in reducing risk, but they do not adequately address the biological modifiable factors that play a very important and personal role in susceptibility to infection, as well as pathogenicity. I feel this observation has been validated by significant work done on HIV/AIDS pathology. There is strong evidence that personal factors such as diet quality, exercise, sleep, microbiome composition, and stress reduction can be significant in determining the course of HIV/AIDS in an individual who has become infected.2,3 This concept has been advanced recently with the recognition that an important way to approach the treatment of a viral or bacterial infection beyond that of immunization and antimicrobial/antiviral medications is through activation of specific components of the immune system. In a March 28, 2020 article titled “Activating Immunity to Fight a Foe—A New Path” that was published in the New England Journal of Medicine, Richard S Hotchkiss, MD and Steven M Opal, MD highlight their belief that both the pharmaceutical industry and leaders at the National Institutes of Health need vision and courage to support trials that boost immunity in infectious diseases.4
COVID-19: Is Risk and Severity Modifiable through Personal Lifestyle Factors?
From past pandemics we know that different viral infections influence differing percentages of people within a population, but that the majority is generally not infected. There are many reasons for this that are not fully understood. The biological factors I have outlined–environmental exposures, diet, stress, medications, and sleep—are becoming more well established as key factors that influence immune system integrity and defense against viral infection. It is now recognized that more than 20 million Americans are routinely taking various drugs that suppress the immune system and can change the way the body responds to viral and bacterial infections. This means that other lifestyle and dietary factors that influence the integrity of the immune system have become even more important in the age of globally transmitted viral diseases.
In a study of lifestyle factors and the incidence of community-acquired pneumonia in men and women living in the United States, it was found that smoking and weight-gain, along with reduced physical activity, were associated with increased incidence.5 Additionally, there is extensive research demonstrating that regular physical activity improves immune response to viral infections.6 In a March 2020 study published in the Journal of the American Medical Association titled “Association of Daily Step Count and Step Intensity with Mortality Among US Adults,” researchers found that a greater number of daily steps was significantly associated with lower all-cause mortality. This was independent of step intensity.7
An overview of nutritional findings looks like this: a study of people who followed an unprocessed diet plan rich in plant foods, and also engaged in regular daily activity plus time spent outdoors in cooler temperatures, revealed that their immune system function and resistance to infection was improved.8 It has also been reported that the Mediterranean Diet improves immune function and lowers the incidence of recurring viral respiratory infections.9 Vitamin and mineral content of the diet may play an important role in reducing the risk to hepatitis C viral infection.10 Plant foods that contain phytochemicals such as flavonoids have been found to improve immune resistance to viral infection.11 Finally, probiotics that help support a healthy intestinal microbiome have been reported to enhance the antiviral effects of vaccination in elderly patients, which demonstrates the important role the microbiome has in immune function.12
A deeper look at individual nutrients is revealing. Numerous studies spanning 30 years have demonstrated the anti-viral influence of vitamin C and its importance in reducing the risk and severity of infections.13,14 Significantly, the resistance to viral infections that is linked to vitamin C has been demonstrated in children as well adults.15 Vitamin C use that exceeds dietary intake has also been shown to be valuable in improving immune response to viral infection.16
It is well established that vitamin A also has a very important role in promoting proper immune function in response to viral exposure.17 Supplemental vitamin A use needs to be monitored because excessive, long-term intake of this nutrient, which is stored in the liver, can cause damage. Zinc is an important mineral that works alongside vitamin A in influencing immune function.18 There are numerous studies demonstrating a synergistic relationship between zinc and vitamin A. Daily intakes that support immune function are 10-30 mg of zinc along with 2500 IU of vitamin A. Another nutritional trace mineral of importance in supporting immune function is selenium.19 Daily intake of selenium in the range of 50-100 mcg is considered important, but—like vitamin A—it should not be consumed in high amounts due to potential toxicity.
Lastly, vitamin D has also been identified to be a very important nutrient for the support of immune function.20 Vitamin D is often called the “sun vitamin” because it can be synthesized in the skin upon exposure to full spectrum sunlight. With cold and flu more prevalent during winter months, it has been suggested that this may be due to a lower level of sun exposure at that time of year, and therefore reduced vitamin D production.21 Daily intake of vitamin D in the range of 800-2000 IU is considered safe and supports many functions, including bone formation as well as immune function.
In 2005, the Institute for Functional Medicine was privileged to host a presentation by Wafaie W Fawzi, PhD, MB, BS, from the Department of Nutrition, Harvard School of Public Health. Dr. Fawzi and his research group had published a landmark paper in the July 7, 2004 issue of the New England Journal of Medicine that was titled “A Randomized Trial of Multivitamin Supplements and HIV Disease Progression and Mortality.”22 For this study, the investigators compared supplementation consisting of multivitamins alone, vitamin A alone, or both with placebo in women in Tanzania, Africa who had HIV infection. They found that women who were randomly assigned to receive multivitamin supplementation were less likely to have progression to advanced stages of HIV disease. These women were found to have better preservation of CD4+ T cell counts and lower viral loads. They also had lower HIV-associated illness and mortality. Interestingly, it was found that vitamin A appeared to reduce the effect of the other multivitamins, and vitamin A alone had some negative outcomes. In a companion editorial commenting on the study, Barbara Marston, MD and Kevin M De Cock, MD stated the following: “Although definitive policy recommendations concerning multivitamin supplementation must await the appropriate evidence (ideally from a large, simple trial in a population with access to antiretroviral drugs), individual treatment programs and clinicians would be justified in routinely prescribing this nutritional support, since it may provide a benefit and does no harm.”23
In the context of the many studies demonstrating that lifestyle, dietary, and environmental factors play important roles in improving immune defense capability, do we give these variables enough consideration when analyzing why some people contract a viral illness when exposed while others do not? COVID-19 is certainly not the last pandemic the world will face. In truth, it represents a unique opportunity for us to seriously examine modifiable factors that may influence both the infectivity and pathogenicity of viral infections. To do this we must expand our thinking beyond the traditional public health model for the prevention of viral infection. A more panoramic view would include personally modifiable biological factors that decrease the susceptibility to viral infections and the reduction in their virulence by the improvement in immune response, and a greater emergent understanding of immune mechanisms by these variables to help reduce the number of serious cases of infection. In turn, the burden on the disease care system, which can be strained to capacity during a pandemic event, would be reduced. Active application of the principles that underlie personalized lifestyle health care, as described in an article I authored with my colleague Deanna Minich, PhD, in 2013, and a focus on the modifiable biological factors associated with immune defense to viral infection creates a significant opportunity to reduce both morbidity and mortality associated with viral crises.24 This was a lesson we learned in the 1980s with HIV/AIDS, and this is an important lesson to relearn as the battle to contain and mitigate COVID-19 approaches new levels of global uncertainty and concern.
- Fauci AS, Morens DM. The perpetual challenge of infectious diseases. N Engl J Med. 2012 Feb 2;366(5):454-61.
- Practice Paper of the American Academy of Nutrition and Dietectics: Nutrition Intervention and Human Immunodeficiency Virus Infection. J Acad Nutr Diet. 2018 March; 118(3):486-98.
- Young JS. HIV and Medical Nutrition Therapy. J Am Diet Assoc. 1997 October; 97 (10 Suppl 2):S161-66.
- Hotchkiss RS, Opal SM. Activating Immunity to Fight a Foe-A New Path. N Engl J Med. 2020; 392 (March 28):1270-71.
- Balk I, Curhan GC, Rimin EB, Bendich A, Willett W, Fawzi WW. A Prospective Study of Age and Lifestyle Factors in Relation to Community-Acquired Pneumonia in US Men and Women. Arch Intern Med. 2000 Nov 13; 160:3082-88.
- Warren KJ, Olson MM, Thompson NJ, Cahill ML, Wyatt TA, Yoon KJ, Loiacono CM, Kohut ML. Exercise Improves Host Response to Influenza Viral Infection in Obese and Non-Obese Mice Through Different Mechanisms. PLoS One. 2015 June25;e0129713.
- Saint-Maurice PF, Troiano RP, Bassett DR Jr, et al. Association of Daily Step Count and Step Intensity with Mortality Among US Adults. JAMA. 2020 Mar 24;323(12):1151-1160.
- Pruimboom L, Ruiz-Nunez B, Ralson CL, Muskiet FAJ. Influence of a 10-Day Mimic of Our Ancient Lifestyle on Anthropometrics and Parameters of Metabolism and Inflammation: The “Study of Origin.” Biomed Res. 2016;e6935123
- Calatayud FM, Calatayud B, Gallego JG, Gonzalez-Martin C, Alguacil LF. Effects of Mediterranean Diet in Patients with Recurring Colds and Frequent Complications. Allergol Immunopathol. 2017 Sept-Oct (5):217-24.
- Gupta S, Read SA, Shackel NA, Hebbard L, George J, Ahlenstiel G. The Role of Micronutrients in the Infection and Subsequent Response to Hepatitis C Virus. Cell. 2019 Jun17; 8 (6):120-24.
- Burkard M, Leischner C, Lauer UM, Busch C, Venturelli S, Frank J. Dietary Flavonoids and Modulation of Natural Killer Cells: Implications in Malignant and Viral Diseases. J Nutr Biochem. 2017 Aug; 46:1-12.
- Akatsu H, Nagafuchi S, Kunhara R, Okuda K, Yarnaji M, Yamamoto T, Ohara H, Maruyama M. Enhanced Vaccination Effect Against Influenza by Prebiotics in Elderly Patients Receiving Enteral Nutrition. Geriatr Gerontol Int. 2016 Feb; 16(2):205-13.
- Herruila H. Vitamin C and Infections. Nutrients. 2017 March; 9(4):12-16.
- Bissell MJ, Hatie C, Farson DA, Schwarz RI, Soo WJ. Ascorbic Acid Inhibits Replication and Infectivity of Avian RNA Tumor Virus. Proc Natl Acad Sci USA. 1980 May; 77 (5):2711-75.
- Vorilhon P, Arpajou B, Roussel HV, Merlin E, Pereira B, Cabaillot A. Efficacy of Vitamin C for the Prevention and Treatment of Upper Respiratory Tract Infections. A Meta-Analysis in Children. Eur J Clin Pharmacol. 2019 March;75 (3): 303-11.
- Ran L, Zhao W, Wang J, Wang H, Zhao Ye, Tseng Y, Bu H. Extra Dose of Vitamin C Based on a Daily Supplementation Shortens the Common Cold: A Meta-Analysis of 9 Randomized Trials. Biomed Res Int. 2018 July 5; e1837634.
- Ross DA. Vitamin A and Public Health: Challenges for the Next Decade. Proc Nutr Soc. 1998 Feb; 57(1):159-65.
- Singh KP, Zaidi SI, Raisuddin S, Saxena AK, Murthy RC, Ray PK. Effect of Zinc on Immune Functions and Host Resistance Against Infection and Tumor Challenge. Immunopharmacol Immunotoxicol. 1992;14(4);813-40.
- Guillin OM, Vindry C, Ohlmann T, Chavette L. Selenium, Selenoproteins and Viral Infections. Nutrients. 2019 Sept 4;11(9):15-25.
- Gruber-Bzura BM. Vitamin D and Influenza- Prevention or Therapy? Int J Mol Sci. 2018 Aug 16;19(8):40-44.
- Trymoori-Rad M, Shokri F, Salimi V, Marashi SM. The Interplay Between Vitamin D and Viral Infections. Rev Med Virol. 2019 March;29(2):e2032.
- Fawzi WW, Msamariga GI, Spiegelman D, Wei R, Kapiga S, Villamor E, Murakagile D, Mugus F, Hertzmark E, Essex M, Hunter DJ. A Randomized Trial of Multivitamin Supplementation and HIV Disease Progression and Mortality. N Engl J Med. 2004 July 7;351:23-32.
- Marston B, DeCock KM. Multivitamins Nutrition and Antiretroviral Therapy for HIV Disease in Africa. N Engl J Med. 2004 July 7; 351:78-80.
- Minich DM, Bland JS. Personalized Lifestyle Medicine: Relevance for Nutrition and Lifestyle Recommendations. Sci World J. 2013 Jun 26; PMID 23878520.