Lifestyle & Longevity: Health optimisation in the age of COVID-19
“Can we feasibly optimise our lifestyles to minimise vulnerability and bolster our immune system against Covid-19, its resurgence and similar viruses?”
Introduction
Upon writing this paper, the world is in the midst of a significant health pandemic. Covid-19 appeared in China at the end of 2019, as a previously unknown disease and was declared a Public Health Emergency by the World Health Organisation (WHO) on 30th January 2020. Primary research has started to emerge from the hospitals and clinicians treating patients. So, what do we know about the implications of our current health on infection, disease prognosis and outcome? And, can we feasibly optimise our lifestyles to minimise vulnerability and bolster our immune system against Covid-19, its resurgence and similar viruses? Here, we explore some of the preliminary studies to help gain insights.
Covid-19 (also known as 2019-nCoV or SARS-Cov-2) has been identified as a novel betacoronavirus. Coronaviruses encompass a large family of pathogens that cause respiratory infections, including the common cold and more severe diseases such as Middle East Respiratory Syndrome (MERS) and a precursor to Covid-19 — Severe Acute Respiratory Syndrome (SARS). MERS, SARS and the currently circulating Covid-19 are zoonotic diseases, which means they have jumped from infecting animals to humans. [Zhang et al., 2020].
The first line of defence against viruses is to avoid contagion sources. This has resulted in affected countries introducing social distancing measures— to avert the spread of Covid-19 by the inhalation of infected respiratory droplets from others. The message for good hand hygiene and repeated, thorough hand washing using soap and water, to avoid picking up the virus through contact and transferring it to airways, has also been enforced.
“We need to glean insights from any research observations from the current pandemic to ensure precautions for our immediate health are taken, and in addition, take stock for future resurgences of the disease or related viruses.”
The body’s primary defence against viruses is innate immunity. This includes the physical and chemical barriers of the body, plasma proteins and a range of immune cells, which help elicit responses to protect tissues and attack any foreign invading pathogens. This is followed by an adaptive immune response, where highly specific antibodies are produced against a pathogen to provide immunity from re-infection long-term. Much of what we currently know about the innate and adaptive immune response to Covid-19 are from previous studies on SARS patients. There is evidence that some of the individuals infected with SARS produced antibodies that conferred them with immunity for up to 2 years [Wu LP, et al 2007].
Research on the novel virus is emerging. It is being expedited into the public domain, sometimes prior to peer-review by other scientists, in an effort to maximise help with global health responses. We need to glean insights from any research observations from the current pandemic to ensure precautions for our immediate health are taken, and in addition, take stock for future resurgences of the disease or related viruses.
A true halt to the pandemic would require a viable vaccine, or alternatively a successful drug treatment, fully validated as being effective through clinical trials. As of now, there are several commercial and academic research groups working on a combination of 115 vaccines against SARS-Cov-2. Human clinical trials are now underway for 5 vaccine candidates [Tung Thanh Le et al., 2020]. The drug treatment landscape has anecdotal evidence of efficacy from small cohorts of Covid-19 patients treated globally. These need validation and there are currently some 80 drug clinical trials in progress, as a result. Many companies have made their anti-viral drugs available for testing. It may be months of testing and optimisation before a vaccine or drug is available for the general population. [Rosa, Santos, 2020; Ekins et al 2020].
So what do we know about the implications of what an individual’s current health may have on infection, disease prognosis and outcome? Are there any lifestyle changes we can feasibly take as individuals to minimise vulnerabilities to both Covid-19, it’s resurgence or other coronaviruses? We explore some of the emerging research to help answer these questions below.
Emerging observations on co-morbidities and Covid-19
“Many [studies] have linked a number of underlying health conditions with the severity of illness and a risk of mortality in their observations. These include cardiovascular disease (CVD), obesity, hypertension, diabetes, chronic obstructive pulmonary disease (COPD), a weak or compromised immune system, and advanced age.”
As the pandemic has gripped the globe, primary data and observations have started to emerge from hospitals and clinicians at the forefront of treating patients suffering with Covid-19. At present, there are a limited number of studies, mainly done in China. Many have linked a number of underlying health conditions with the severity of illness and a risk of mortality in their observations. These include cardiovascular disease (CVD), hypertension, diabetes, chronic obstructive pulmonary disease (COPD), obesity, a weak or compromised immune system, and advanced age. Another observation is that more men than women are being treated in hospital from the severe form of the disease. The reasons for this are still not clear.
Cardiovascular disease
A meta-analysis from several studies, covering 1527 patients in Wuhan, China, where the outbreak first started, showed that those with pre-existing cardiovascular diseases (CVD), hypertension and diabetes had a much higher chance of having a severe form of Covid-19 requiring intensive care (ICU) treatment. These were two-fold of those of patients who didn’t have the condition, in the cases of diabetes and hypertension, and three-fold higher in individuals with CVD [Li et al., 2020]. Note that this study is a pre-publication and yet to be peer-reviewed by the scientific community.
Authors of a peer-reviewed, single centre study from 179 patients with Covid-19 induced pneumonia admitted to Wuhan Pulmonary Hospital, between Dec 2019 and Feb 2020, also identified pre-existing cardiovascular or cerebrovascular diseases as one of four predictors of mortality [Rong-Hui Du et al., 2020]. This was alongside an age >65 yrs, low levels of circulating CD3+CD8+ T lymphocytes (immune cells essential for killing infected cells and combatting viral replication, amongst many other essential roles) and cardiac damage (demonstrated by elevated levels of the protein troponin).
Another descriptive analysis published in the medical journal The Lancet noted the clinical observations, demographics and lab testing data of 99 patients who developed the severe form of Covid-19 in a single hospital in Wuhan [Chen, Nanshan et al., 2020]. They observed that 68% of these patients were men, the majority of whom were aged 50+, with underlying health conditions. The most prevalent of these illnesses was cardiovascular disease (40% of patients). Other major groups were digestive diseases (11%) and endocrine system diseases (11%). The latter encompassed diabetes. Immune disfunction was also recorded in these patients, including elevated levels of neutrophils (a type of white blood cell that is part of the innate immune response producing signalling proteins called cytokines) and a decrease in T-lymphocytes in many patients. We discuss the significance of some of the key components of the immune system later on in this paper.
It is important to acknowledge that the Covid-19 infection has been shown to produce pneumonia-like symptoms that aggravate damage to the lungs and heart, as the disease progresses. Elevated markers for inflammation, cardiac damage and low oxygen levels are observed in critically ill individuals, which therefore may be as a result of the disease [Petrilli et al 2020, Rong-Hui Du et al., 2020]. However, the emerging research suggests that several pre-existing conditions appear to be a distinct causal risk factor, rather than a disease consequence.
For additional context, it is relevant to note that CVD (cardiovascular disease) is a significant risk factor for mortality in itself. According to WHO figures, it is the number 1 cause of death globally, and accounts for just under a third (31%) of all reported deaths.
Obesity
“The outcomes from the current pandemic may help bolster the case in the wider global medical community to acknowledge obesity as a disease, and encourage individuals to seek treatment for this chronic condition.”
As the virus has spread globally, New York has emerged as an epicentre for COVID-19 cases in the US. In a letter sent to the New England Journal of Medicine, clinicians reviewing the first 393 Covid-19 patients admitted to two New York hospitals, identified obesity as an important risk factor [Goyal et al., 2020 ]. Over 35% of all those admitted were obese, (BMI>30). Patients who went on to require mechanical ventilation were also more likely to be obese, and have elevated liver function-values and inflammatory markers.
A separate, larger observational study, also in New York state, looked to identify risk factors for hospitalisations and adverse outcomes in 4,103 patients [Petrilli et al., 2020]. The strongest risk factors for patients for admission was also obesity (identified here as individuals with a BMI>40), alongside advanced age — individuals >65 yrs. The authors noted that low levels of oxygen (<88%) and elevated inflammatory markers upon admission (d-dimer>2500, ferritin >2500 and C-reactive protein >200) were also indicators of adverse outcomes for patients that included intensive care, mechanical ventilation, hospice admission and/or death.
Although obesity is not recognised as a disease in most countries outside of the US, there has been growing pressure globally to do so by prominent health organisations [Bray, G.A., et al 2017]. In theory, it was classified as a disease by the World Health Organisation at its establishment in 1948 [James, WPT. 2008]. The outcomes from the current pandemic may help bolster the case in the wider global medical community to acknowledge obesity as a disease, and encourage individuals to seek treatment for this chronic condition.
Age-related factors and immunity
Advanced age has been highlighted as a risk factor. Several of the studies cited in this paper [Petrilli et al., 2020; Rong Hui Du et al., 2020] show those >65 yrs of age have the highest risk. Increasingly, elevated death rates proportional to age have been documented in several studies globally. In a statement at the start of April 2020, the WHO European Director confirmed that 95% of deaths in Europe’s 30 member states occurred in those >60 yrs of age. In addition, 50% of all deaths were of individuals aged 80 yrs or older [Kluge H. 2020].
As an individual’s age advances their propensity to develop one or more underlying health conditions increases. This may be a contributory factor. For example in the UK, a national study published in 2019 on obesity, highlighted that the proportion of adults who were overweight or obese increased significantly with age, amongst both men and women. The highest levels were observed in men aged between 45 and 74 (78% across these age groups), and women aged between 65 and 74 (73%).
There is also significant evidence that immune function declines with age. The thymus, a critical organ for immunity is known to shrink with age (known as thymic involution in medical terms) [Palmer., 2013]. Since it has a critical role in helping the production of diverse T lymphocytes essential for immunity, this leaves an individual more susceptible to infection, with a reduced ability to generate what’s known as an adaptive (antigen-specific) response to pathogens.
A decrease in essential circulating macronutrients to maintain the immune system, is sometimes seen in those of advanced age. This may be caused by aging-related inefficiencies in absorption and utilization, or because the diet becomes less varied in some cases. In fact, although energy needs may be less as we age, some essential nutrients can be required in higher amounts, through diet or the use of supplements to compensate. [Rémond D et al., 2015,]
Smoking and Chronic Obstructive Pulmonary Disease (COPD)
The SARS-Cov-2 virus has been confirmed as gaining entry to cells in the respiratory system by binding to the Angiotensin-Converting Enzyme II (ACE-2) receptor [Zhou P, et al.]. Active smokers and those with chronic obstructive pulmonary disease (COPD) have been shown to express higher levels of this receptor, so may be at increased risk of the severe versions of the disease as a result. Conversely, there is some, yet to be fully verified evidence, that children and adolescents have low levels of expression, which may explain their reduced susceptibility [Skarstein Kolberg E. 2020].
Smokers have a reduced capacity for the blood to carry oxygen and are at increased risk of respiratory infection. There is damage observed to the microscopic hairs, called cilia, on cell surfaces in the airways and lungs in smokers. The vapour inhaled during vaping has a similar effect. Since cilia play a key role in removing debris, mucous and infectious agents, it is plausible that it could leave them more vulnerable. Furthermore, smokers are more likely to have pre-existing cardiovascular and respiratory disease.
This is backed by some clinical observations. A review published in Mar 2020 [Vardavas, C,I and Nikitara, 2020] identified five studies reporting data on the smoking status of patients infected with COVID-19 in China. While not all of the studies were conclusive, the data from the largest of these (1099 patients), showed that smokers were more likely to have severe symptoms of COVID-19, and be admitted to an ICU, need mechanical ventilation or die, compared to non-smokers. A critical limitation of the study was that results were unadjusted for other factors that may impact disease progression.
Indeed, the picture is far from clear cut. There is a research group in France that is currently exploring trialling nicotine patches to determine if they have a protective role, following their findings that smokers are under-represented in those being treated in a Parisian university hospital with coronavirus.
A retrospective analysis on critically ill patients admitted into intensive care in Lombardy, Italy, 1043 of whom had data available, showed 4% had COPD as an existing condition. Other notable outcomes of this analysis were that 82% of patients were male, the most prevalent co-morbidities were hypertension (49%), cardiovascular disease (22%), followed by hypercholesterolemia (18%) [Graselli, G et al., 2020]
Are there lifestyle adaptions that can improve our health defences?
“What we can conclude is that there are ongoing lifestyle optimisations, based on what we do know, that can stand us in good stead to fight infection more effectively, both in the case of this pandemic, or similar viruses that may emerge long term”
Given the current climate, with so much global data still to emerge, it would be naive to suggest there is a quick fix approach to our health that would mitigate the risk of contracting and developing Covid-19. Indeed, the entire learned scientific community is working towards this goal, a validated drug treatment and vaccine. However, what we can conclude is that there are ongoing lifestyle optimisations, based on what we do know, that can stand us in good stead to fight infection more effectively, both in the case of this pandemic, or similar viruses that may emerge long term.
There is a recurrent link emerging between CVD, hypertension, type 2 diabetes, obesity, elevated cholesterol and outcomes for the disease. These co-morbidities can be preventable and are often caused, or exacerbated by a choice of poor diet and lifestyle [Bodai B I, et al., 2018]. There are of course genetic components, and ethnic propensities. For example, CVD is thought to cluster in families. Also, those of South East Asian origin are thought to be pre-disposed to developing Type 2 diabetes at a lower BMI than other ethnicities, due in part to their predisposition to gain visceral fat. [Ma, R. C and Chan J.C. 2013]
However, maintaining a healthy weight, where BMI is 20-25, is a critical first step and one that can be achieved by reducing calorie and saturated fat intake to that recommended for your age and gender, whilst increasing your activity and level of exercise. Physical exercise and regular activity can help maintain a good level of cardiovascular fitness, keep weight under control and, in addition, improve circulation. The latter also allows improved accessibility of circulating immune defence cells to tissues and organs.
It’s important to identify if you’re classified as a borderline individual prior to developing cardiovascular disease, or type 2 diabetes to pre-empt their occurrence. This is sometimes referred to as having ‘metabolic syndrome’ or ‘syndrome X’. Individuals here show raised blood pressure, blood glucose, hypercholesterolemia (high overall levels of cholesterol), an elevated LDL to HDL ratio (bad to good cholesterol), excess abdominal fat and may be overweight (BMI 25+), but not necessarily obese (BMI 30+) [Pérez-Martínez P et al., 2017].
Early interventions, through regular health checks, consultations and blood tests can help pinpoint this, and is something that is sometimes missed in primary healthcare due to a lack of resource and manpower. In the meantime, an individual may have progressed to the preliminary stages of chronic disease development and may require clinical intervention. Alternatively, when metabolic syndrome is identified, ongoing support is often not provided to help instigate the lifestyle changes required longer term.
Can we bolster our immune system by healthy-living strategies?
“The idea of ‘boosting’ our immunity with a magic bullet agent is, therefore, far too simplistic. It’s actually a fine balance between multiple components.”
A healthy immune system is critical to fighting pathogens. Several emerging studies on Covid-19 discussed in this paper have identified lymphopenia (low levels of T lymphocytes), suggesting immune damage or compromise, as one of four risk factors for more severe forms of the Covid-19 disease. Many have also indicated high levels of immune cells, called neutrophils, that release molecules called cytokines — resulting in what is described as a ‘cytokine storm’ that causes inflammation and contribute to the damage to the lungs that is seen in severe cases [Shi, Y., et al 2020]
A good question to ask is — what actually constitutes healthy immunity and can you boost it? In reality, our immune system is an infinitely complex network of tissues, organs, millions of circulating cells of different functions, numerous protein pathways and regulatory molecules that are involved in its regulation. The idea of ‘boosting’ our immunity with a magic bullet agent is, therefore, far too simplistic. It’s actually a fine balance between multiple components.
However, there are some key micronutrients that we need for our immune function, and a healthy dietary intake can help us ensure we get those to a required level. Eating a balanced diet, rich in fruit and vegetables is beneficial to health. Vitamins A, C, D, E, B2, B6 and B12, folic acid, beta carotene, iron, selenium, and zinc have all been shown to have a role in immunocompetence [Alpert B, 2017], and there are daily recommendations on their intake.
As we get older, poor absorption can affect the bioavailability of such nutrients. Supplementation can be necessary in these cases. However, there is a difference between this and over-supplementing with one vitamin, without knowing whether we are deficient in the first place. [Maggini S et al., 2018]
Smoking cessation can improve immune function, leaving us less vulnerable to respiratory illness, improving our blood oxygen levels and overall fitness. Specifically with Covid-19, there’s evidence smoking may increase entry points for the virus in the lungs, as discussed previously.
In terms of other lifestyle factors, alcohol consumption has also been shown to be deleterious for immune function in a dose dependent manner. Whilst moderate alcohol consumption does not show detrimental effect, heavier drinking is shown to disrupt innate and adaptive immunity, and the ability to fight infectious disease [Barr T, et al 2017].
It’s important to note that in the UK the Chief Medical Officer recommends a maximum of 14 alcohol units a week, for both men and women with designated drink free days (equivalent to 6 glasses of 175ml wine, 6 pints of beer, or 10 X 25ml shots over 7 days). The dietary guidelines for Americans are comparable, recommending no more than 1 drink per day for women and up to 2 drinks per day for men (note that 1 drink here constitutes 150 ml of 12% wine, 350 ml of beer or 45 ml of 40% spirit).
Sleep and its accompanying circadian rhythm is intricately linked with activity in our immune system. Some immune processes, including the adaptive immune response are known to peak during a specific phase of nocturnal sleep. Chronic sleep loss can be correlated with an increase in inflammatory markers and immunodeficiency [Besedovsky et al., 2012]. For example, individuals show a diminished response to vaccination after 6 days of restricted sleep [Spiegel K., et al]. There has also been evidence for enhanced susceptibility to viruses like the common cold in the case of poor sleep efficiency.
The optimal sleep is between 7-8 hrs per night for adults [Daza EJ et al., 2019; Chaput J,P et al., 2018]
There have been a number of studies on the effects of stress on the human immune system. Research to date describes a critical distinction seen between short-term stress, lasting a maximum of minutes and hours that actually resulted in some immune enhancement, to chronic long-term stress that was very detrimental to immune function [Dhabhar, F.S. 2014]. Long-term stress was shown to suppress innate and adaptive immune responses, induce low-grade chronic inflammation, and decrease the function and amount of immunoprotective cells.
Summary
The epidemiology, and the potential for immunity to Covid-19 are emerging areas of research. We cannot definitively make any assumptions about individual immune response to the virus threat and risk of infection, or outcome yet. We need large scale epidemiological studies for that, which will be available in the coming year, once the peak of the virus has passed and it is under control globally. With the development of a vaccine months or possibly a year or more away, and larger scale clinical trials required to prove the efficacies of drug treatments and avert continued or resurgent infection, Covid-19 may pose a significant threat for the foreseeable future. However, this paper has set out to discuss how we can give our bodies the best fighting chance in the event of immune assaults like the current global pandemic, lower our risk of developing co-morbidities – a known risk factor, and adopt lifestyle adaptations to bolster our immune system.
Dr. Seema Sharma for SX2 Ventures
References
Alpert P. The role of vitamins and minerals on the immune system. Home Health Care Manag. Pract. 2017;29:199–202. doi: 10.1177/1084822317713300.
Barr T, Helms C, Grant K, Messaoudi I. Opposing effects of alcohol on the immune system. Prog Neuropsychopharmacol Biol Psychiatry. 2016;65:242–251. doi:10.1016/j.pnpbp.2015.09.001
Besedovsky, L., Lange, T. & Born, J. Sleep and immune function. Pflugers Arch – Eur J Physiol 463, 121–137 (2012). https://doi.org/10.1007/s00424-011-1044-0<
Bo Li and Jing Yang et al., Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol. 2020 Mar 11 : 1–8. doi: [Epub ahead of print]
Bodai BI, Nakata TE, Wong WT, et al. Lifestyle Medicine: A Brief Review of Its Dramatic Impact on Health and Survival. Perm J. 2018;22:17–025. doi:10.7812/TPP/17-025
Bray, G. A., Kim, K. K., Wilding, J. P. H., and ( 2017) Obesity: a chronic relapsing progressive disease process. A position statement of the World Obesity Federation. Obesity Reviews, 18: 715– 723. doi: 10.1111/obr.12551
Chaput JP, Dutil C, Sampasa-Kanyinga H. Sleeping hours: what is the ideal number and how does age impact this?. Nat Sci Sleep. 2018;10:421–430. Published 2018 Nov 27. doi:10.2147/NSS.S163071
Chen, Nanshan et al., Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study The Lancet, Volume 395, Issue 10223, 507 – 513
Daza EJ, Wac K, Oppezzo M. Effects of Sleep Deprivation on Blood Glucose, Food Cravings, and Affect in a Non-Diabetic: An N-of-1 Randomized Pilot Study. Healthcare (Basel). 2019;8(1):6. Published 2019 Dec 25. doi:10.3390/healthcare8010006
Dhabhar, F.S. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol Res 58, 193–210 (2014). https://doi.org/10.1007/s12026-014-8517-0
Donald B. Palmer. The Effect of Age on Thymic Function. Front Immunol. 2013; 4: 316. Published online 2013 Oct 7. doi: 10.3389/fimmu.2013.00316
Ekins S, Mottin M, Ramos PRPS, et al. Déjà vu: Stimulating open drug discovery for SARS-CoV-2 [published online ahead of print, 2020 Apr 19]. Drug Discov Today. 2020;doi:10.1016/j.drudis.2020.03.019
Goyal P, Choi JJ, Pinheiro LC, et al. Clinical characteristics of Covid-19 in New York City. N Engl J Med. April 2020 DOI: 10.1056/NEJMc2010419
Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. Published online April 06, 2020. doi:10.1001/jama.2020.5394
James, WPT. WHO recognition of the global obesity epidemic. International Journal of Obesity (2008) 32, S120–S126
Kluge, Hans Henri P. WHO Regional Director for Europe, Copenhagen, 2 April 2020. Statement – Older people are at highest risk from COVID-19, but all must act to prevent community spread.
Leung J.M et al., ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19. European Respiratory Journal Jan 2020, 2000688; DOI: 10.1183/13993003.00688-2020
Ma RC, Chan JC. Type 2 diabetes in East Asians: similarities and differences with populations in Europe and the United States. Ann N Y Acad Sci. 2013;1281(1):64–91. doi:10.1111/nyas.12098
Maggini S, Pierre A, Calder PC. Immune Function and Micronutrient Requirements Change over the Life Course. Nutrients. 2018;10(10):1531. Published 2018 Oct 17. doi:10.3390/nu10101531
Pérez-Martínez P, Mikhailidis DP, Athyros VG, et al. Lifestyle recommendations for the prevention and management of metabolic syndrome: an international panel recommendation. Nutr Rev. 2017;75(5):307–326. doi:10.1093/nutrit/nux014
Petrilli, C.M et al., Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City medRxiv 2020.04.08.20057794; doi: https://doi.org/10.1101/2020.04.08.20057794 [pre-publication]
Rémond D et al., Understanding the gastrointestinal tract of the elderly to develop dietary solutions that prevent malnutrition. Oncotarget. 2015 Jun 10; 6(16):13858-98
Rong-Hui Du et al., Predictors of Mortality for Patients with COVID-19 Pneumonia Caused by SARS-CoV-2: A Prospective Cohort Study European Respiratory Journal 2020; DOI: 10.1183/13993003.00524-2020
Rosa SGV, Santos WC. Clinical trials on drug repositioning for COVID-19 treatment. Rev Panam Salud Publica. 2020;44:e40. Published 2020 Mar 20. doi:10.26633/RPSP.2020.40
Shi, Y., Wang, Y., Shao, C. et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ 27, 1451–1454 (2020). https://doi.org/10.1038/s41418-020-0530-3
Shlisky, J, et al., Nutritional Considerations for Healthy Aging and Reduction in Age-Related Chronic Disease. Adv Nutr. 2017 Jan; 8(1): 17–26. doi: 10.3945/an.116.013474
Skarstein Kolberg E. ACE2, COVID19 and serum ACE as a possible biomarker to predict severity of disease [published online ahead of print, 2020 Apr 2]. J Clin Virol. 2020;126:104350. doi:10.1016/j.jcv.2020.104350
Spiegel K, Sheridan JF, Van Cauter E (2002) Effect of sleep deprivation on response to immunization. JAMA 288:1471–1472
Tung Thanh Le et al., The COVID-19 vaccine development landscape Nature 09 April ,2020 https://www.nature.com/articles/d41573-020-00073-5
Vardavas, C,I and Nikitara, K. COVID-19 and smoking: A systematic review of the evidence
Tob Induc Dis. 2020; 18: 20. Published online 2020 Mar 20. doi: 10.18332/tid/119324
Wu LP, Wang NC, Chang YH, et al. Duration of antibody responses after severe acute respiratory syndrome. Emerg Infect Dis. 2007;13(10):1562–1564. doi:10.3201/eid1310.070576
Zhang T, Wu Q, Zhang Z. Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak. Curr Biol. 2020 Apr 6;30(7):1346-1351.e2. doi: 10.1016/j.cub.2020.03.022. Epub 2020 Mar 19.
Zhou P, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579: 270–273. doi:10.1038/s41586-020-2012-7