Preventing a covid-19 pandemic

Dear Editor,

I read with interest this article and related rapid responses, and I would like to contribute with some observations and hypotheses that will hopefully take us closer to understanding the role of smoking in the ongoing spread of the disease COVID-19.

But first let us note that medicine is a statistical science, where sometimes false statements are embedded among true relationships. For instance, the same studies that reveal the risk factors of comorbidities such as obesity and diabetes on the prognosis of COVID-19, seem to tiptoe around the issue of data in relation to alcohol consumption and smoking habits.

Indeed, in the New York City area, mortality has been null for patients younger than 20 years but above 30% for those over 70 yr. old [1]. In addition, preliminary analysis suggests that serum 25-hydroxyvitamin D status may play a role in COVID-19 fatality [2], which confirms clinical observations among patients admitted to hospital in England that being overweight and non-Caucasian (i.e. Blacks, Asians, Hispanics or the like) is associated with a higher odds of testing positive for COVID-19 [3], while surprisingly, a regular smoker has reduced odds. The same is true among an ample cohort of patients from a hospital in Wuhan, China: few patients had a current or former cigarette smoking history [4]. Notably, it might seem that alcohol drinking also has a protective effect against COVID-19 [5]. Similar results can be concluded from a multicentre cohort study throughout Spain [6].

Exposure to tobacco has consistently been associated with several autoimmune diseases, including systemic lupus erythematosus [7], yet a lower risk of developing inflammatory and neurodegenerative diseases such as Parkinson’s. The mechanism by which this occurs is unclear, although it has been recently suggested that nicotine regulates the ACE2 enzyme pathway involved in the “cytokine storm syndrome”, a systemic inflammatory response in many COVID-19 patients [8].

However, we prefer to hypothesize that it is not the nicotine, but the tobacco virus that cross-react with coronaviruses, and thus, may play a key role in the prognosis of COVID-19 infection.

Although it is usually claimed that tobacco plants cannot host human pathogens, tobacco virus has been described as viable in cigarettes and recovered from smokers' saliva [9]. In line with our hypothesis, it is suspected that immunological cross-protection from previous exposure to A-type influenza viruses other than H1N1 (e.g. 1889 pandemic) may have played a role in the low mortality rates among the middle-aged and older individuals during the Spanish Flu [10]. Similarly, evidence of SARS-CoV-2 immunity induced by antibodies from memory B cells of an individual who was infected with SARS-CoV in 2003 [11], probably stems from the fact that spike proteins of SARS-CoV-2 and SARS-CoV are structurally very similar [12].

As we have previously highlighted, shape and size matter when it comes to determining the characteristics of nanoentities [13]. In this regard, we note positive-stranded RNA tobacco virions (for which tomatoes, peppers, and cucumbers are also a host) are hollow rod-shaped particles about ~300 nm in length and ~18 nm in diameter [14], while the positive-stranded RNA SARS-CoV-2 virus has round crown-like appearance and a diameter of approximately 100 nm [15], which is perhaps consistent with the speculation that they share structural similarity of antigenic determinants. In this regard one should note that smokers have a higher level of serum immunoglobulin IgG antibodies [16], the receptor for viruses that cause cold-like symptoms, fever, sore throat, bronchitis, pneumonia, diarrhea, and conjunctivitis, much like the COVID-19 [17]. As such, cross-reactivity against coronaviruses has recently been demonstrated by connecting human ACE2 to immunoglobulin IgG1 [18]. But, unfortunately, on the sad side is the fact that ACE2 expression mediates both in infections by coronaviruses and influenza A [19], and could pose a higher level of infectivity for vaccinated individuals [20]. This could explain the worsening of disease among the elderly with comorbidities, which are included among the high priority groups for routine influenza vaccination by many national health authorities. If confirmed, this observation would have implications for annual vaccination recommendations and policies, given the little impact on mortality rates that would have occurred during flu season had none of the elderly been vaccinated [21].

In conclusion, I have described what I believe is the first instance of tobacco virus is confirmed as the cause of smoking oddity when it comes to coronavirus disease. If this is proven to be correct, there is a possibility of effective adaptive immune responses in a naïve vaccination model [22]. Something similar has been developed against avian influenza [23, 24].

We finish by noting that tobacco and tomatoes are extensively cultivated in the Mediterranean area…I let the reader wonder whether this has something to do with the significant regional differences in the COVID-19 epidemic.

References
1. S. Richardson, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA (2020); doi:10.1001/jama.2020.6775
2. A. Daneshkhah, et al. The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients. (2020). medRxiv 2020.04.08.20058578; doi:10.1101/2020.04.08.20058578
3. A. L. Darling, et al. Vitamin D status, body mass index, ethnicity and COVID-19: Initial analysis of the first-reported UK Biobank COVID-19 positive cases (n 580) compared with negative controls (n 723). (2020). medRxiv 2020.04.29.20084277; doi:10.1101/2020.04.29.20084277
4. T. Chen, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 368, m1091 (2020)
5. S. Liu, et al. Characteristics and Associations with Severity in COVID-19 Patients: A Multicentre Cohort Study from Jiangsu Province, China. (2020). https://ssrn.com/abstract=3548753; doi:10.2139/ssrn.3548753
6. J. M. Casas Rojo, et al. Clinical characteristics of patients hospitalized with COVID-19 in Spain: results from the SEMI-COVID-19 Network. (2020). medRxiv 2020.05.24.20111971; doi:10.1101/2020.05.24.20111971
7. D. S. Majka & V. M. Holers. Cigarette smoking and the risk of systemic lupus erythematosus and rheumatoid arthritis. Ann. Rheum. Dis. 65, 561-563 (2006)
8. K. Farsalinos, et al. Editorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system. Toxicol. Rep. 7, 658–663 (2020). doi:10.1016/j.toxrep.2020.04.012
9. F. Balique, et al. Tobacco mosaic virus in cigarettes and saliva of smokers. J. Clin. Virol. 55, 374‐376 (2012)
10. S. E. Mamelund, et al. A Missed Summer Wave of the 1918-1919 Influenza Pandemic: Evidence From Household Surveys in the United States and Norway. Open Forum Infect. Dis. 3, ofw040 (2016)
11. D. Pinto, et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature (2020). doi:10.1038/s41586-020-2349-y
12. C. Wang, et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nature Comm. 11, 2251 (2020)
13. C. Martinez-Boubeta, et al. Learning from Nature to Improve the Heat Generation of Iron-Oxide Nanoparticles for Magnetic Hyperthermia Applications. Sci. Rep. 3, 1652 (2013)
14. K. C. Holmes. Flexibility in tobacco mosaic virus. Ciba Found Symp. 93, 116‐138 (1983)
15. S. Prasad, et al. Transmission electron microscopy imaging of SARS-CoV-2. Indian J. Med. Res. 151, 241-243 (2020)
16. R. Liu, et al. Humans have antibodies against a plant virus: evidence from tobacco mosaic virus. PLoS One 8, e60621 (2013)
17. J. Sui, et al. Evaluation of human monoclonal antibody 80R for immunoprophylaxis of severe acute respiratory syndrome by an animal study, epitope mapping, and analysis of spike variants. J. Virol. 79, 5900-5906 (2005)
18. C. Lei, et al. Neutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig. Nat. Commun. 11, 2070 (2020)
19. P. Yang, et al. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep. 4, 7027 (2014)
20. L. Zhang & Y. Zhang. Influenza Viral Infection is a High-Risk Factor for Developing Coronavirus Disease 2019 (COVID-19). (2020). doi: 10.20944/preprints202003.0307.v1
21. B. Fireman, et al. Influenza Vaccination and Mortality: Differentiating Vaccine Effects From Bias. Am. J. Epidemiol. 170, 650–656 (2009)
22. M. D. Langowski, et al. Optimization of a Plasmodium falciparum circumsporozoite protein repeat vaccine using the tobacco mosaic virus platform. Proc. Natl. Acad. Sci. U.S.A. 117, 3114-3122 (2020)
23. J. K. Mallajosyula, et al. A Single Dose TMV-HA Vaccine Protects Mice from H5N1 Influenza Challenge. Int. J. Vaccine Res. 1, 6 (2016)
24. Y. Ceballo, et al. High accumulation in tobacco seeds of hemagglutinin antigen from avian (H5N1) influenza. Transgenic Res. 26, 775‐789 (2017)

Dear Editor

On 12 March in a rapid response, I suggested that the sewage be examined to form an idea of where there are excreters of Coronavirus.
No one has debunked the suggestion. It is not a brand new idea - it has been used, for example, in Poliomyelitis epidemiology.

Is PUBLIC HEALTH ENGLAND carrying out this work? [1]

And if not, is it not criminally negligent?

1 Mallapaty S. How sewage could reveal true scale of coronavirus outbreak. How sewage water testing could also be used as an early warning sign if the virus returns. Nature 2020 Apr 9;580:176-7.

Dear Editor

I'm responding to the response made by Emilio Maestri (endocrinologist) on 12 March 2020 regarding contradictory studies using 'vitamin' D supplementation.

I have not read the references he has cited but, although I am not a nutritionist, I have read enough over the years to know that supplementation of just one micronutrient in large doses is not necessarily advisable and may well give poor results. In the case of 'vitamin/hormone' D, I am aware that a deficiency of magnesium, said to be rife in developed countries (due to modern farming methods and depletion through what we call "stress"), can manifest also as a vitamin D deficiency so that increasing supplemental dose of vitamin D will not have the desired effect precisely because the deficiency concerned is magnesium (which is needed to 'activate' vitamin D.)

Furthermore, in the case of trying to improve osteoporosis with supplemental vitamin D, there is the necessity of vitamin K (in the form of K2) which 'directs' dietary calcium in the presence of vitamin D to the bone rather than soft tissues. Vitamin K is found, for example, in dark green leafy vegetables in the form of K1, but is not always easily converted to K2 in the body and therefore animal sources are preferable, a factor which may produce even more health problems in the future with the increasing popularity of a vegan diet.

As I have said, I am not a nutritionist and may have simplified my explanations somewhat, but merely wished to point out that micronutrients work in harmony with one another and studies focusing on just one discrete micronutrient are likely to have already failed at the outset.

Dear Editor

In the prevention of COVID-19 pandemic, Robert A Brown suggests that vitamin D may contribute to the prevention of COVID-19 and should be applied in a wider clinical practice immediately. The reason was that the higher mortality rates in Spain and Italy in comparison with northern European Countries may arise from vitamin D deficiency. [1] However, I have the same concerns as George Trovas. [2] Although there is probably a correlation between the level of vitamin D and the epidemiological data of COVID-19, it may be caused by other underlying risk factors.

A meta-analysis reported that vitamin D supplementation alone had no connection with the mortality in adults. [3] Another study demonstrated that sufficient vitamin D supplementation (≥ 25 nmol/L) did not improve the condition of patients with chronic obstructive pulmonary disease (COPD), compared with patients taking a placebo. Thus the NICE 2018 guideline does not suggest vitamin D. [4]

The data of global incidence and deaths from the World Health Organization showed that the morbidity of COVID-19 in developed countries is obviously higher than that in developing countries. The data of Max Roser and colleagues indicated that total tests for COVID-19 in Germany was 918 460, which was 454 030 in Italy as of 29 March 2020. [5] Although Germany has more people than Italy, total tests for COVID-19 per thousand people was 11.13 in Germany, 48.03 in Iceland, and only 7.68 in Italy. On 5 April 2020, daily COVID-19 tests per thousand people in Iceland were 7.24, Italy was 0.58, South Africa was 0.0.5, and India was less than 0.01. [5] Mild cases took up a major part of the COVID-19 in Germany. Therefore, the high mortality rates in Italy may because many mild COVID-19 patients were not detected. And the most notable point is that low incidence does not mean a mild epidemic: on the contrary, there may be a large number of undetected COVID-19 patients which could make the outbreak worse in developing countries.

In conclusion, vitamin D should not be used blindly in wider clinical trials because of the urgent epidemic. If not, it may cause people to miss more effective treatments, and more valuable research may lose subject resources. Researchers should confront COVID-19 rationally and scientifically, especially when the epidemic is serious.

References

1. Robert A Brown. (7th April 2020). BMJ 2020;368:m810 doi: https://doi.org/10.1136/bmj.m810
2. George Trovas. (2nd April 2020). BMJ 2020;368:m810 doi: https://doi.org/10.1136/bmj.m810
3. Yu Zhang, Fang Fang, Jingjing Tang, et al. Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ 2019;366: l4673.
4. Cook R, Thomas V, Martin R. Can treating vitamin D deficiency reduce exacerbations of chronic obstructive pulmonary disease? BMJ. 2019;364:l1025. doi: 10.1136/bmj.l1025.
5. Max Roser, Hannah Ritchie, Esteban Ortiz-Ospina. Coronavirus Disease (COVID-19) – Statistics and Research. Our World In Data. 2020. Retrieved from: https://ourworldindata.org/coronavirus. [Online Resource]