Covid-19: Comorbidities, Long-Haul Symptoms, and Immune Resilience

Vaccines are getting distributed at increasing rates. Researchers are testing 68 vaccines in human clinical trials, 20 are the final stage of testing, and two are approved for full use according to the New York Times vaccine tracker. However, depending on your risk category and the state in which you live, it could be months before a vaccine gets injected into your arm. This lack of certainty continues to add to the overwhelming stress brought about by this pandemic. Patients in my precision medical practice ask me regularly whether a vaccine is a good idea and what they can do in the meantime. When it feels like Covid-19 stress continues to mount, what can you do? Focus on the factors that you can change. In the case of Covid-19, let’s look at what we can do to protect and strengthen immune resilience, i.e., the grit and adaptability of the immune system, and what evidence-based lifestyle changes reduce risk for severe or long-term illness.

Here’s what we know.

Covid-19 and Comorbidities

We know from the most recent studies that the highest risk for severe illness is in men with heart injury, high blood sugar, and high-dose corticosteroid use.¹

The most common comorbidity factors are as follows.²

• hypertension (2.3X increased risk)
• diabetes (2.5X)
• chronic obstructive pulmonary disease (6X)
• cardiovascular disease (2.9X)
• cerebrovascular disease (4X)

Covid-19 and Long-haul Symptoms

After an average of 7.7 days of inoculation, initial symptoms of Covid-19 are well known: loss of taste and/or smell, fever, fatigue, anorexia, muscle pain, shortness of breath, and increased coughing. Severe symptoms occur in less than 20 percent of patients. What happens next? Emerging data show that many people, commonly referred to as ‘long-haulers’, are suffering from long-term symptoms weeks to six months after recovery from Covid-19 infection. Initial and long-haul symptoms are summarized in Figure 1. According to the latest study published in The Lancet, six months after acute infection “Covid-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression.”³ Other symptoms reported by long-haulers include breathlessness, heart palpitations, loss or alteration of taste and smell, gastrointestinal distress, and problems with attention, memory and cognition.⁴

Figure 1. Initial Covid-19 and Long-haul Symptoms

We are learning from clinical research and from anecdotal evidence collected from online patient support groups that ongoing symptoms appear to be unrelated to the severity of the initial infection.⁵

We don’t yet know how many suffer from long-haul COVID, nor is there any data on who is at risk for long-term symptoms. Causes are not unclear. However, some medical experts believe it may be due to the over-activation of the immune system. One viral immunologist and infectious disease expert at University of California, San Francisco, says in a December 2020 article in Scientific American, the cause of long-haul symptoms may be due to “an immune-inflammatory response gone amok.”

What can we do to prevent severe Covid-19 illness and how can we protect ourselves from long-term symptoms post-recovery?

Lifestyle Medicine and Illness Prevention

The basic tenets of lifestyle medicine are discussed so often that they can fall on deaf ears. Yet they are consistently presented as a path to good health because of the large body of evidence that shows eating a healthy diet with lots of colored vegetables, getting regular exercise, and a minimum of 7 to 8.5 hours of sleep improve health outcomes and lower all-cause mortality rates.

When it comes to Covid-19 infection, we know that the risk of dying is increased due to the comorbidity factors mentioned above such as high blood pressure, diabetes, heart disease and cerebrovascular disease. These diseases can be prevented and managed with personalized lifestyle medicine that will be discussed below.

Regulating the Immune System

The adaptability of our immune system is key. While we often limit our understanding of what it takes to boost our immune system to drinking a glass of fresh orange juice or supplementing with vitamin C, the factors that affect our immune response are much more varied and complex. Without doubt, diet is a major factor. Did you know that 70 percent of your immune system is directly below a single layer of cells in your small intestine (that’s the connector between your stomach and large intestine)? That single layer of cells protecting us from the outside world makes us quite vulnerable. We also know sugar suppresses our immune system. Poor sleep, alcohol intake, increased stress levels and the amount of activity we engage in all have an impact on the resilience of our immune system.

Back to Basics

Much of your health is in your hands, which gives you a sense of empowerment and control at a time when everything else is uncertain. Implementing only some of the advice below will have a big impact on your overall health.

Plant-based Mediterranean Diet

Eat more colorful plants. This does not mean becoming vegetarian or vegan. However, I recommend a plant-based and lower carb Mediterranean diet. The benefits of this way of eating are as follows:

• Eating many colors of the rainbow, a minimum of three colors per day in your fruits and vegetables, has been shown to improve immune resilience. It is low-inflammatory. Chronic inflammation in the body triggers and exacerbates chronic conditions such as diabetes and high blood pressure. Eating a plant-based diet helps to reduce the inflammation.
• It feeds the healthy bacteria in your gut. A plant-based diet supports the health of your gut and the fiber found in plants feeds the benevolent microbes found there. The standard American diet, with its emphasis on saturated fats and processed foods, does not nourish your gut microbiome. A healthy gut is the foundation for a healthy immune system. The result is a loss of good bacteria leading to low-grade inflammation in the gut, which in turn fans the flames of inflammation throughout your body. Inflammation causes mental and emotional problems.
• A plant-based diet provides antioxidants that help fight free radicals that can be a cause and exacerbation of the chronic diseases we are talking about here. It is a good source of micronutrients like chromium, for example, that is needed to help regulate blood sugar.

For those with existing blood sugar issues, I recommend that they reduce carbohydrates and replace bread and grains with the slow-burning carbs like sweet potatoes, quinoa, nuts, and seeds. If you need to lose weight, set a limit of 15 grams of net carbohydrates (total carbs less fiber) per meal. I recommend combining low-carb Med Diet with intermittent fasting using the 14/10 to 16/8 protocol (that’s an overnight fast of 14 to 16 hours, combined with a 10-hour to 8-hour eating window). For protein, I recommend non-inflammatory sources such as wild-caught salmon or other small fish such as mackerel or sardines.

What About Alcohol?

Forget the red wine that is associated with the Mediterranean diet. I find that men benefit more from alcohol than women. While an occasional glass is probably fine, I no longer advocate drinking wine or alcohol. In short: eat a plant-based diet, with a pound a day of fresh vegetables. Avoid processed food. If it didn’t come out of or walk on the ground and isn’t recognizable as a plant or meat or fish, avoid it.

Exercise: What Kind and How Much?

Regular exercise: twenty to thirty minutes four days a week. This includes walking! A recent study in Journal of the American Medical Association showed that regular walking is beneficial for your health and can increase longevity in older women.⁶ I also recommend adding in high-intensity exercise as HIIT makes your muscles hungry for glucose so the sugar gets pulled out of your bloodstream, which will help to regulate insulin levels and reduce the likelihood of insulin resistance. For those with long haul symptoms such as shortness of breath, use extreme caution. Start slowly.

Sleep: How Much is Best?

Don’t forget sleep! Poor quality of sleep wreaks havoc on your internal biochemistry and you are more likely to overeat when you are tired. The optimal number of hours we should aim for is 7 to 8 although this does vary between individuals. Additionally, reduce stress levels so that cortisol does not drive up blood sugar levels.

I’m a biohacker and like to track my health using various feedback devices. My current favorite for tracking sleep is the Oura ring.

Key Supplements

For Blood Sugar Balance

Balancing your blood sugar reduces your risk of diabetes. When it comes to managing your blood glucose levels, I always advocate a food first approach combined with regular exercise. For those who are overweight or obese, it is important to look at the root causes. The eat less-move more approach is not for everyone, especially women as their hormones play a major role in weight loss. In treating women for hormonal imbalances such as polycystic ovary syndrome, I have found the following supplements to be helpful to manage blood sugar.

• Berberine is a bioactive found in several plants including European barberry, goldenseal, Oregon grape, and others—that has been shown to help lower blood sugar and decrease total and LDL cholesterol. When taken for 12 weeks, it reduces weight by 5 pounds in obese patients.⁷ Berberine also helps activate thermogenesis (heat production) in white and brown fat.⁸ Dose: 500 mg, three times per day. I recommend pulsing for 6-8 weeks, then take at least a 2-week break. Combine berberine with milk thistle at a dose of 105 mg to improve effectiveness.
• Chromium is a mineral that acts as an insulin sensitizer, which means it helps to reverse insulin resistance and lowers both your serum insulin and glucose levels when they are high. Folks with type 2 diabetes, the type that results from insulin resistance, have lower blood chromium levels compared with nondiabetic people. Chromium is a safe supplement worth trying if you are insulin resistant. I recommend a dose of 200 to 1,000 mcg per day of chromium picolinate. Foods high in chromium include eggs, nuts, green beans, and broccoli. Fish oil is also associated with improved insulin levels as is lipoic acid.

For Immune Resilience

A healthy immune system that responds intelligently to a viral infection or other attack is the goal. We want just the right response, not too much and not too little. What do we know from the literature regarding supplements that benefit our immune system, in particular as they relate to Covid-19?

Vitamin D

Vitamin D deficiency and its impact on morbidity and mortality in Covid patients has been researched intensively over the last year investigating the association between vitamin D deficiency and Covid-19 severity. Vitamin D deficiency is categorized as serum levels below <20 ng/mL and in one November 2020 meta-analysis it was shown to aggravate Covid-19 illness.⁹ Another study analyzed vitamin D levels among asymptomatic and critically ill Covid-19 patients and observed increased mortality in vitamin D deficient Covid-19 patients to the extent that the study called for mass administration of vitamin D for at-risk populations.¹⁰ Further studies show that high-dose supplementation of vitamin-D in the treatment of Covid-19 illness reduced its severity.^{11, 12}

It is imperative to say clearly that vitamin D supplementation has not been shown to prevent Covid-19 infection nor cure it. Thus far, the studies show that it may reduce severity of the infection but further studies are needed. However, we know that vitamin D has so many benefits for the body and supplementing is safe so it makes sense to add vitamin D to your daily regimen. The optimal range for vitamin D that I usually recommend is 25(OH)D 52-90 ng/ml but with the current crisis, I would recommend keeping serum vitamin D levels greater than 70 ng/ml.

Quercetin

Quercetin has been shown previously to have an antiviral effect.¹³ A recent study from 2020 looked specifically at quercetin’s role in the prevention and treatment of COVID19 and its ability to “interfere at multiple steps of pathogen virulence -virus entry, virus replication, protein assembly.” Quercetin has a good safety profile and for this reason the study called for its use in the treatment of respiratory tract infections, including Covid-19.¹⁴

Stress, Mental Health and COVID

We are experiencing a difficult time and depression symptoms have tripled compared with before the pandemic. Your food shapes your brain, so I recommend starting first with a healthy diet, and what’s most proven is a low-carb Mediterranean diet adapted to your tastes. Include olive oil, nuts, and seeds to support your mood. Inflammation causes mental and emotional problems. Mindset is very important too—while it’s important to express feelings, we know that a growth mindset, gratitude and optimism help bolster resilience. What is resilience? The process of adapting well to adversity, trauma, tragedy, threats or significant sources of stress – such as family and relationship problems, serious health problems or workplace and financial stressor, according to the American Psychological Association. Resilience is possible for all of us as part of the normal arc of being confronted with difficulty like a pandemic. It is ordinary, not extraordinary, and therefore accessible by all.

There’s a fascinating study that showed that kindness towards others improves stress levels, even more than kindness towards one’s self.¹⁵ That’s where I like to start. Express the fear, then let it go. Focus on gratitude. I encourage my patients to make a list every day before bed in 5 minutes of what went well, and what is expected to go well the next day. Be kind to at least one person each day—shine your love lights on them.

The same principles apply to reduce the risk of long haul Covid-19. It bears repeating the connection between metabolism (being overweight and/or sedentary) and immune function. The gut is so important for prevention of the brain effects of long haul Covid-19, what some are referring to as brain fog, so have a food first philosophy. Eat a pound of vegetables per day. You don’t have to be perfect, but it’s important to take small steps each day to improve your immune resilience. Small steps aggregated over time can add up to major transformation.

Endnotes
1. Li X, et al. Risk factors for severity and mortality in adult Covid-19 inpatients in Wuhan. J Allergy Clin Immunol. 2020 Jul;146(1):110-118. doi: 10.1016/j.jaci.2020.04.006. Epub 2020 Apr 12. PMID: 32294485; PMCID: PMC7152876.
2. Wang B, et al. Does comorbidity increase the risk of patients with Covid-19: evidence from meta-analysis. Aging (Albany NY). 2020 Apr 8;12(7):6049-6057. doi: 10.18632/aging.103000. Epub 2020 Apr 8. PMID: 32267833; PMCID: PMC7185114.
3. Huang, C, et al. 6-month consequences of Covid-19 in patients discharged from hospital: A cohort study. The Lancet. 2021. Vol. 397 DOI:https://doi.org/10.1016/S0140-6736(20)32656-8
4. Meeting the challenge of long COVID. Nature Medicine 26, 1803. 2020. https://doi.org/10.1038/s41591-020-01177-6
5. Townsend L, Dowds J Persistent poor health post- Covid-19 is not associated with respiratory complications or initial disease severity. Annals of the American Thoracic Society. 2021 https://doi.org/10.1513/AnnalsATS.202009-1175OC
6. Lee IM, et al. Association of step volume and intensity with all-cause mortality in older women. JAMA Intern Med. 2019 May 29;179(8):1105–12. doi: 10.1001/jamainternmed.2019.0899
7. Hu Y, et al. Lipid-lowering effect of berberine in human subjects and rats. Phytomedicine. 2012 Jul 15;19(10):861-7. doi: 10.1016/j.phymed.2012.05.009. Epub 2012 Jun 26. PMID: 22739410.
8. Zhang Z, et al. Berberine activates thermogenesis in white and brown adipose tissue. Nat Commun. 2014 Nov 25;5:5493. doi: 10.1038/ncomms6493. PMID: 25423280.
9. Pereira, M., et al. Vitamin D deficiency aggravates Covid-19: systematic review and meta-analysis. Critical Reviews in Food Science and Nutrition. 2020. https://doi.org/10.1080/10408398.2020.1841090
10. Jain, A, et al. Analysis of vitamin D level among asymptomatic and critically ill Covid-19 patients and its correlation with inflammatory markers. Sci Rep 10, 20191 (2020). https://doi.org/10.1038/s41598-020-77093-z
11. Rastogi A, et al. Short term, high-dose vitamin D supplementation for Covid-19 disease: a randomised, placebo-controlled, study (SHADE study) Postgraduate Medical Journal Published Online First: 12 November 2020. doi: 10.1136/postgradmedj-2020-139065
12. Castillo, ME, et al. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for Covid-19: A pilot randomized clinical study, The Journal of Steroid Biochemistry and Molecular Biology, 203, 2020. https://doi.org/10.1016/j.jsbmb.2020.105751.
13. Wenjiao, W., et al. Quercetin as an antiviral agent inhibits Influenza A virus (IAV) entry. Viruses. 2016 Jan; 8(1): 6.
14. Colunga Biancatelli, R, et.al. (2020). Quercetin and vitamin C: An experimental, synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Frontiers in immunology, 11, 1451. https://doi.org/10.3389/fimmu.2020.01451
15. Nelson-Coffey SK, et al. Kindness in the blood: A randomized controlled trial of the gene regulatory impact of prosocial behavior. Psychoneuroendocrinology. 2017 Jul;81:8-13. doi: 10.1016/j.psyneuen.2017.03.025. Epub 2017 Mar 31. PMID: 28395185.