Over the past 100 years, there have been 4 major pandemics that have collectively killed more than 60 mil- lion people. The most notorious of these pandemics is the 1918 Spanish flu, which infected 50% of the world’s population and killed over 50 million people. That’s nearly double the number of deaths associated with World War I. The Spanish flu was caused by an H1N1 influenza A virus, which is named by its hemagglutinin (H) and neuraminidase (N) surface antigens. The Spanish flu first appeared in the United States in the spring of 1918, and initially was confined to army barracks of soldiers returning from World War I. At first, the death rate associated with this flu was relatively low and many states practiced social distancing and mask wearing, which produced temporary reduction in outbreaks over the summer. Unfortunately, the following fall the Spanish flu returned with a vengeance, killing nearly 4 times as many people as the first wave.

One of the most disturbing aspects of the Spanish flu was that it specifically targeted young adults. People between the ages of 25 and 29 had a particularly high morbidity/mortality rate, as nearly 30% of this population was infected and 1% died of pneumonia or influenza. The mechanism for the high death rate in such a healthy population had been a mystery until 2009, when Karen Starko published a paper in Clinical Infectious Diseases (1). Dr. Starko points out that because Bayer Pharmaceutical’s patent on aspirin expired in 1917, this drug suddenly become available in large quantities for very low costs. As hundreds of thousands of infected people presented with high fevers, doctors began prescribing aspirin in doses 3 to 10 times greater than the current prescription levels. Official recommendations for the widespread use of aspirin were issued by the Surgeon General in September 1918, and this order was almost immediately followed with a large spike in deaths, initially peaking in the Armed Forces and then rapidly spreading throughout the rest of the US population. The highest death rate was in a U.S. Army camp where army doctors ordered more than 100,000 aspirin tablets, which were prescribed at nearly toxic levels. Although medical experts were unaware of it at the time, salicylates in high doses predispose to bacterial pneumonia by increasing lung fluid and impairing mucociliary clearance. Interestingly, homeopaths at the time noticed that influenza patients who avoided aspirin had lower mortality rates (2).

Following the 1918 epidemic, influenza went back to typical patterns of regional epidemics from the 1930s through the mid-1950s that were relatively benign. That all changed in 1957 when the Asian flu arrived in the US following initial outbreaks in Hong Kong. The antigenic sequence of the 1957 pandemic was a H2N2 influenza A. This new virus was the result of a re-assortment between the 1918 H1N1 and a less lethal circulating avian influenza strain. Unlike the Spanish flu, the H2N2 influenza produced rapid death and lung consolidation without bacterial infection. Oddly, the H2N2 virus targeted women in their third trimester of pregnancy. Similar to the Spanish flu, the H2N2 influenza had early outbreaks in the spring that were followed by much more lethal outbreaks the following fall. By the time it was over, the 1957 pandemic killed 4 million people worldwide and 116,000 in the United States (3). Keep in mind that the population of the US at the time was 170 million, which would be the equivalent of 230,000 deaths given our current population. One of the most surprising aspects of the 1957 pandemic is that so few people were aware of it. There was no social distancing and businesses were not forced to shut down (4). The economic impact was insignificant and the GDP in the United States dropped only 1% (5). In contrast to today’s COVID-19 crisis, hospitals were not overloaded as there was a concerted effort to promote homecare for uncomplicated cases.

After the initial H2N2 outbreak, scientists rapidly developed a vaccine that was available for mass distribution in less than 3 months after the virus’s arrival. Despite widespread distribution of the vaccine, deaths continued to mount and even today, it is difficult to find information on the efficacy of the 1957 vaccine. The CDC website has less than a paragraph on the 1957 H2N2 pandemic and no information at all on the vaccine. After going through everything I could find on the ‘57 pandemic, I found a great paper published in 2006 by Edwin Kilbourne, a world-famous virologist who summarized vaccine research on pandemics and epidemics over the past 60 years (6). Dr. Kilbourne cites a research paper from 1961 in which experts from the time state the vaccination was initially ineffective as it was given in doses too low to initiate a primary antibody response (7). The authors state that as recurrent infections occurred in the population between 1958 and 1960, antibody levels increased and the vaccine eventually became effective. Apparently, the prior infections “primed” the infected individuals, allowing their immune system to respond to the virus. By the time the ’57 flu had passed, nearly 40% of the American population had antibodies to H2N2.

The next major pandemic was the H3N2 Hong Kong influenza of 1968. This influenza had the same rate of infection as the Spanish flu, in which each infected person infected 1.8 others. (Individuals with typical seasonal flus infect 1.27 others.) Because the Hong Kong influenza had the same N2 antigen as the 1957 pandemic, the death rates were relatively low as so many people had partial immunity following widespread exposure to H2N2 influenza in 1957. Dr. Kilburn states “the amelioration of the H3N2 virus by immunity to the N antigen alone is all the more remarkable because of the capacity of the virus to kill” (7). The H3N2 pandemic followed a typical influenza-like seasonal pattern, as it began in the late fall of 1968, disappeared over the summer, and was followed by a second wave the next winter. Worldwide, the 1968 pandemic killed nearly 2 million people, with 100,000 deaths occurring in the United States.

The 1968 outbreak of the H3N2 flu was followed by a long quiet period in pandemics, until another H1N1 surfaced in 2009. Unlike its 1918 predecessor, this H1N1 influenza virus was far less virulent than the Spanish flu, resulting in only 3,400 deaths in the US and somewhere between 150,000 and 570,000 deaths worldwide (4). This mortality rate is not that different from the typical seasonal flu, which kills between 250,000 and 500,000 people annually. As with prior pandemics, the initial wave of deaths occurring in the spring of 2009 were followed by another wave in the fall. Despite a relatively low death rate, the 2009 H1N1 was frightening as it targeted children, young adults, and pregnant women. The average age of confirmed death in the United States was 37 (8). The 2009 pandemic was also unusual in that it also targeted obese individuals. Following the pandemic, researchers from Germany showed that individuals with body mass indexes over 30 had suppressed activity of their T lymphocytes, greatly increasing risk of viral infection (9).

Owing to the virulence of the H1N1 virus, the World Health Organization pushed for the rapid development of a vaccine. Within 6 months after the onset of the pandemic, a vaccine had been developed although widespread distribution did not occur until after the pandemic had peaked (10). The CDC states that the vaccination program for this H1N1 influenza saved roughly 350 lives in the United States (11). Following the pandemic, the British Medical Journal published an editorial criticizing the World Health Organization for overstating the risks associated with the 2009 pandemic and for failing to disclose financial ties between WHO members supporting the multimillion-dollar vaccination effort and their ties to the manufacturers of the vaccine (12).

In December 2019, a novel coronavirus appeared in Hunan province of China that everyone now knows as COVID-19. Unlike influenza A, this coronavirus is comprised of long chains of RNA with S-spikes on the surface that bind to ACE receptors in the respiratory endothelium (Fig. 1). Following their attachment, this virus initiates a cytokine storm in which the body releases a wide range of pro-inflammatory mediators to combat the viral infection. Despite the fact that 95% of infected people develop either no symptoms or mild symptoms only (10), this particular coronavirus spread rapidly throughout the world, because of its high rate of infection (each individual infected with COVID-19 will infect between 2.2 and 2.5 others), and the fact that it can be spread by asymptomatic individuals.

For unknown reasons, certain countries are being decimated by COVID-19 while others remain relatively unscathed. While some experts claim the different fatality rates in various countries may be attributed to greater compliance with social distancing guidelines and/or widespread access to testing, this theory doesn’t hold up as many countries with low death rates have limited testing abilities and poor overall health.

After looking at all possible causes for variation in worldwide mortality rates, researchers from the University of Michigan (13) noted that countries with mandated childhood tuberculosis vaccines have far lower mortality rates than countries that do not vaccinate children against tuberculosis. Lifelong improvement in respiratory health following the BCG tuberculosis vaccine was recently proven in a long-term controlled study in which nearly 3,000 Native American and Alaskan schoolchildren were injected either with the anti-tuberculosis vaccine BCG or a placebo vaccine (14). Follow-up evaluation of these children 60 years later showed that individuals receiving BCG vaccine were 60% less likely to develop lung cancer. Another systematic review of 5 clinical trials found that the antituberculosis vaccine produced significant reductions at all-cause mortality, particularly from respiratory infections (15). These combined studies explain why countries like China, South Korea, Australia, and New Zealand have such low rates of infection since the BCG tuberculosis vaccine during childhood is mandated in those countries.

In contrast, the United States, Italy, and most of Europe stopped giving the BCG vaccine more than 50 years ago and these countries have significantly higher rates of morbidity/mortality associated with the COVID-19 pandemic. Apparently, the BCG vaccination results in epigenetic reprogramming of monocytes, providing lifelong immunity against viral infection (16). While it is currently unknown if giving an adult the BCG vaccine will protect against COVID-19 infection, researchers are looking into that possibility as the vaccine is extremely safe and affordable. If there is one saving grace about the COVID-19 pandemic it’s that this coronavirus pandemic, unlike all prior influenza pandemics, has an extremely low mortality rate among young people. The average age of death is between 80 and 82, and the probability of someone in their 20s or 30s dying from COVID-19 is almost 0 (17). This contrasts markedly with the 1918 and 2009 pandemics, in which the average age of death was 27 and 37, respectively, and the 1974 Russian flu, which was an epidemic in adults but a pandemic in children.

As of early May, the CDC is predicting approximately 147,000 deaths in the US by August, and as with most pandemics, a recurrence is expected in the fall. The Center for Infectious Disease Research and Policy states that COVID-19 will most likely be with us for another 18 to 24 months, as it gradually synchronizes to a seasonal pattern with diminished severity over time (10).

In addition to targeting the elderly, COVID-19 is more likely to produce serious complications in individuals with hypertension, diabetes, obesity, cardiovascular disease, hyperlipidemia, and prior stroke. The common factor between all of these comorbidities is that people with the worst outcomes tend to have the highest levels of C-reactive protein upon initial presentation. Originally discovered in the 1930s, C-reactive protein is a marker for inflammation and when levels are low, the risk of fatal infection is greatly reduced, regardless of the comorbidities. In my opinion, obesity should not necessarily be considered a comorbidity, as approximately 20% of individuals with high body mass indexes are metabolically healthy, and have stable lipid profiles and low C-reactive proteins (18).

Diabetics are high risk for coronavirus infection for reasons independent of C-reactive protein. When diabetics fail to manage their blood sugar levels properly, the excess glucose inappropriately elevates production of methylglyoxal and glyoxal, which suppress beta defensins, a series of peptides located in respiratory epithelium that are essential for regulating inflammation and controlling the immune system (19). A disturbing trend in the United States is that the number of people who are prediabetic is constantly increasing. Between 1994 and 2010, the prediabetic percentage of the population increased from 6% to 26% (16). Most of these people are unaware of their elevated glucose levels, which puts them at risk for respiratory tract infections due to suppressed beta defensins. Home testing devices for measuring fasting blood glucose are available for less than $30 and given the connection between elevated glucose and impaired immune function, everyone should know their fasting blood glucose level.

Despite the fact that COVID-19 targets the respiratory system, asthmatics are not considered high-risk individuals. In fact, some evidence suggests that the corticosteroid inhalers used to treat asthma may actually be protective, as a May 2020 study out of China showed the people with asthma were less likely to have complications following COVID-19 infection (21). Because the increased activity of the ACE receptors to which COVID attaches, ACE-2 antihypertensive drugs were originally listed as a potential factor in severe COVID-19 infections. Fortunately, research confirms that this is not the case, as these drugs have been proven to be safe and effective (22).

Given the fact that COVID-19 will be with us for at least the next year or so, it‘s important to understand what can be done to protect those at risk while the pandemic runs its eventual course. Recently, the World Health Organization launched an international trial called Solidarity to test for promising therapies. These drugs include the antimalarial chloroquine and hydroxychloroquine; the antiviral remdesivir; the antivirals lopinavir and ritonavir (used for the treatment of HIV); and the HIV antivirals plus the anti-inflammatory protein beta interferon. Unfortunately, most recent research on hydroxychloroquine is that the risks outweigh the benefits. Serious side effects including cardiac arrhythmias made researchers question the efficacy of this intervention (23). Remdesivir looks more promising, but it’s expensive and must be given intravenously in a hospital early in the course of the disease. Although effective at preventing AIDS, some experts feel the HIV antivirals will be ineffective for managing COVID-19. Because enzymes function by recognizing shapes of antigens, one author states that the probability that an enzyme that works for HIV will also work for COVID-19 is equal to the probability that the key that starts your car will also start your neighbor’s car: about one in a million (24). Nonetheless, some scientists feel that the HIV antivirals might be more effective when used in combination with interferon beta, a medication used in multiple sclerosis to suppress immune response. When given early in the treatment of mice infected with SARS-1 and MERS, this combination of drugs rapidly halted infections. Unfortunately, when given later in the disease, the mice died. Suppressing the immune function in an individual dealing with COVID-19 is a difficult balancing act, as it can prevent the body’s deadly overreaction to the coronavirus, but allow a secondary invasion, which may be fatal.

Perhaps the most promising new drugs for managing COVID-19 are the immune system inhibitors Actemra and sarilumab. These drugs suppress the activity of interleukin 6, pro-inflammatory mediator responsible for the cytokine storm that floods the immune cells in the lungs, leading to death. Because these drugs have been successfully used to manage rheumatoid arthritis, they have a proven track record for being safe, and they are affordable. Phase 3 trials have already been started and according to the NIH website, should be completed by the end of the summer.

An important concern regarding the management of pandemics is that almost all medical interventions have significant side effects, are expensive, and phase 3 testing for some of these medications won’t be completed for a while to come. This is especially true for a potential vaccine for COVID-19, which has a completion date sometime in 2021, which should be about the same time the pandemic is ending. In the meantime, a more logical and cost-effective approach to managing the COVID-19 pandemic is to enhance immune function through diet and exercise. This approach is more effective than you might think. In a 16-week study of 83 healthy adults aged 65 to 85 who were assigned to either continue their normal diets, or consume 5 or more portions of fruits and vegetables per day, the extra consumption of fruits and vegetables produced significant increases in antibody response to a Pneumovax II vaccination (25). Importantly, fruits are an excellent source of vitamin C, which has been shown to reduce C-reactive protein levels by as much as 25% (26). While statin drugs have been praised as being beneficial in the management of COVID-19, these drugs have significant side effects, including myopathies and cognitive impairments. In contrast, 1000 mg of vitamin C is safe, effective, and is an inexpensive way to reduce C-reactive protein levels.

Another simple nutritional recommendation is to get adequate amounts of vitamin D. A 2017 meta-analysis of 10,933 participants confirmed that vitamin D supplementation protected against acute respiratory tract infection by enhancing antimicrobial peptides in response to viral and bacterial stimuli (27). A disturbing statistic is that because people in assisted living have limited access to sunlight, an important natural source of vitamin D, they are extremely susceptible to vitamin D deficiency. One study found that 76% of individuals admitted to hospitals from nursing homes suffered from severe vitamin D deficiency (28). While this study looked specifically at the strong connection between falls, fractures, and low vitamin D levels in the elderly, it could explain why more than 50% of all deaths with COVID-19 occur in senior centers.

In my opinion, the single best way to enhance immune function is with exercise. In 2012, researchers assigned 154 older adults to either an 8-week exercise program or non-exercising control group prior to the beginning of cold and flu season. At the end of the study, the exercising group had 35% fewer viral infections, and had nearly 50% fewer lost days from work (29). This is consistent with a 6-year analysis of data from 19 US states that concluded that every 5% increase in physical activity produces a 7% reduction in influenza -related hospitalizations (25).

In addition to improving immune function, people who engage in a minimum of 2.5 hours of moderate physical activity (e.g., brisk walking) per week have a 22% reduced risk of developing breast-cancer, 43% decreased risk of coronary heart disease, 85% decrease in the risk of type II diabetes, and an 85% decrease in the risk of developing colon cancer (30). A simple 10-week program of resistance exercises produced a 33% reduction in C-reactive protein (31), which when elevated, is an important predictor of poor outcome following COVID-19 infection. Other risk factors such as obesity and hyperglycemia are also favorably modified with exercise as a 2020 paper published in Medicine and Science in Sports and Exercise (32) showed that light aerobic exercise performed 50 minutes per day, 6 days per week produced appreciable reductions in body mass index and improved insulin sensitivity.

Exercise is especially important for people over 60, as they’re higher risk for COVID-19 infection. A 2019 study of more than 16,000 women with an average age of 72 showed significant improvements in overall health with as few as 4400 steps per day, which is a little over 2 miles (35). Health benefits during the 4.3 years of the study continued to increase until the women hit 7500 steps per day, after which there were no significant improvements. Knowing this upper limit is important, since excessive exercise (e.g., marathon training) can actually suppress immune function. If arthritis limits your ability to walk, home exercises with light resistance can also produce significant improvements in health. In 2018, researchers from Japan had 88 men and women aged 70 years or older participate in a weight-training program in which they performed two sets of 10 to 14 repetitions daily for 12 weeks (36). The subjects used body weight alone and performed the movements very slowly (4-seconds up and 4-seconds down). At the end of the 12-week training program, in addition to significant increases in muscle mass, participants also had decreased hip and waist circumference and reduced abdominal fat. This study is remarkable because the participants had no prior experience with weight training, the exercises were performed at home (taking less than 15 minutes each day), and at the end of the study, only two of the 88 people involved dropped out.

While the media has done an excellent job frightening people with comorbidities, they’ve neglected to mention that these comorbidities are modifiable (excluding old age), and diet and exercise can make a huge difference in boosting not just your immune function but your overall health. While the pharmaceutical industry is spending billions of dollars on ways to improve immune function with medication, you can spend the next 12 to 18 weeks improving your immune function by increasing your step count from 2000 steps to 7500 steps per day and swapping out refined sugars for fruits and vegetables. If you’re afraid of being injured while initiating an exercise program, consider hiring a local trainer as most of them have been out of work for the past 2 months and would appreciate the business. In just 8 weeks, forty-five minutes of light exercise each day can markedly improve immune function, lower blood pressure, reduce body fat, and stabilize blood glucose. In addition to improving metabolic markers for health, aerobic exercise has also been proven to be an effective antidepressant, which given what the last few months have been like, is a welcome addition to the numerous benefits associated with regular exercise.

References:

1. Starko K. Salicylates and Pandemic Influenza Mortality,1918–1919 Pharmacology, Pathology, and Historic Evidence. Clinical Infectious Diseases. 2009;49:1405–10.
2. Dewey WA. Homeopathy in influenza—a chorus of 50 in harmony. J Am Inst Homeop. 1921:1038–43
3. www.cdc.gov/flu/pandemic-resources/1957-1958-pandemic.html
4. Saunders-Hastings P, Krewski D. Reviewing the history of pandemic influenza: understanding patterns of emergence and transmission. Pathogens. 2016;5:66.
5. Henderson D, Courtney B, Inglesby T, et al. J. Public health and medical responses to the 1957–58 influenza pandemic. Biosecur Bioterror. 2009; 7:265–273.
6. Kilbourne, E. Influenza pandemics of the 20th century. Emerging Infectious Diseases. 2006; 12:9.
7. Meiklejohn G. International conference on Asian influenza. Am Rev Respir Dis. 1961;83:175–7.
8. Viboud C, Miller M, Olson D, et al. Preliminary estimates of mortality and years of life lost associated with the 2009 a/ H1N1 pandemic in the us and comparison with past influenza seasons. PLoS Curr. Influenza. 2010; 20: 1153.
9. Palch H, Sheridan P, Handy J, et al. Overweight and obese adult humans have a defective cellular immune response to pandemic H1N1 influenza A virus. Obesity (Silver Spring). 2013 November;21: 2377–2386.
10. Moore K, Lipsitch M, Barry J, et al. COVID-19: The CIDRAP Viewpoint. University of Minnesota. April 30, 2020.
11. Borse R, Shrestha S, Fiore A, et al. Effects of vaccine program against pandemic influenza A(H1N1) virus, United States, 2009-2010. Emerg Infect Dis. 2013 Mar;19:439-48
12. Cohen D, Carter P. WHO and the pandemic flu “conspiracies.” BMJ. 2010;340:2912.
13. Berg M, Yu Q, Salvador C, et al. Mandated Bacillus Calmette-Guerin (BCG) vaccination predicts flattened curves for the spread of COVID-19. University of Michigan, April 30, 2020: www.medrxiv.org.
14. Usher N, Chang S, Howard R, et al. The Association of BCG vaccination in childhood with subsequent cancer diagno- ses: A 60-year follow-up of a clinical trial. JAMA Network Open. 2019;2:e1912014
15. de Bree L, Koeken V, Joosten L, et al. Non-specific effects of vaccines: current evidence and potential implications. Semin Immunol. 2018;39:35-43.
16. Arts, R, Moorlag, S, Novakovic, B, et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host & Microbe. 23, 89-100.e5 (2018).
17. www.mass.gov/doc/COVID-19-dashboard-may-19-2020/download
18. Karelis A, Faraj M, Bastard J, et al. The metabolically healthy but obese individual presents a favorable inflammation profile. J Clin Endocrin Met. 2005; 90:4145-4150.
19. Kiselar J, Wang X, Dubyak G, et al. Modification of β-Defensin-2 by Dicarbonyls Methylglyoxal and Glyoxal Inhibits Antibacterial and Chemotactic Function In Vitro. 2015;PLoS ONE 10:e0130533.
20. Ramjee V, Sperling L, Jacobson T. Non–High-Density Lipoprotein Cholesterol Versus Apolipoprotein B in Cardiovas- cular Risk Stratification: Do the Math. J AM Cardiology. 2011; 58:457-463.
21. Wu Z, McGoogan J. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention [e-pub ahead of print]. JAMA; March 25, 2020.
22. Gangopadhyay K, et al. The effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on death and severity of disease in patients with coronavirus disease 2019 (COVID-19): A meta-analysis. MedRxiv 2020.
23. Mehevas M, Tran V, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with COVID-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ.2020;369:m1844.
24. Lewis T. Here’s what we know about the most outer drugs tested for COVID-19. Scientific American. June-July 2020: 14.
25. Charland K, Buckeridge D, Hoen A, et al. Relationship between community prevalence of obesity and associated be- havioral factors and community rates of influenza-related hospitalizations in the United States. Influenza and Other Respiratory Viruses.2013;7:718–728.
26. Block G, Jensen C, Dalvi T, et al. Vitamin C treatment reduces elevated C-reactive protein. Free Radic Biol Med. 2009 January 1; 46: 70–77.
27. Martineau A, Jolliffe D, Hooper R, et al. Vitamin D supplementation to prevent acute respiratory tract infections: sys- tematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583.
28. Bischoff-Ferrari H, Can U, Staehelin H, et al. Severe vitamin D deficiency in Swiss hip fracture patients. Bone. 2008;42:597– 602.
29. Barrett B, Hayney M, Muller D, et al. Meditation or Exercise for Preventing Acute Respiratory Infection: A Random- ized Controlled Trial. Annals of Family Medicine. 2012;10:337-346.
30. Booth F, Chakravarthy M, Spangenburg. Exercise and gene expression: physiological regulation of the human genome through physical activity. Journal of Physiology. 2002;543:399–411.
31. Donges C, Duffiled R, Drinkwater E. Effects of resistance or aerobic exercise training on Interleukin-6, C-Reactive Protein, and body composition. Med Sci Sports Exerc. 2010;42:304-313.
32. Flack K, Hays H, Moreland J, et al. Exercise for weight loss: further evaluating energy consumption with exercise. Med Sci Sports Exerc. 2020: published ahead of print.
33. Lee I, Shirom E, Kamada M, et al. Association of staff volume and intensity with all-cause mortality in older women. JAMA Internal Medicine. May 29, 2019.
34. Tsuzuku S, et al. Slow movement resistance training using body weight improves muscle mass in the elderly: A random- ized controlled trial. Scand J Med Sci Sports. 2018;28:1339–44.