Covid-19: risk factors for severe disease and death
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m1198 (Published 26 March 2020) Cite this as: BMJ 2020;368:m1198Read our latest coverage of the coronavirus outbreak
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Dear Editor
In view of the 26 March Editorial's subheadline implicating age as a prime risk factor, I wonder if any research has tried to disentangle age from known comorbidities correlated with age, so we can tell whether and how much the healthy elderly without the known risky comorbidities are indeed at special risk due to age alone.
Risk should also be highly sensitive to individual immune competence. Obvious and accepted ways to strengthen immune and repair competences in the general population (and especially in at-risk subpopulations)—sleep, hydration, nutrition, exercise, calm, alcohol and toxin avoidance, physiological balance—should slow contagion just as isolation, distancing, and hygiene for exposure avoidance do. Yet of these two complementary classes of ways to flatten the curve, 'community immunity' seems oddly absent from official guidance (WHO, USCDC,...) so few practitioners and citizens emphasise it. Surely we need wide adoption of both modalities now.
A US internist/intensivist (with strong Ebola experience) and I published on 29 March two informal posts [1,2] (the first, and its accompanying material, documented to the medical literature) suggesting both canonical and less orthodox—but strongly supported by 2018–20 clinical trials [3-6]—ways to repel and resist infection by SARS-CoV-2, other viruses, and other pathogens.
Inter alia we suggested offering multi-gram, fully reduced, fully buffered oral l-ascorbate, divided through each day, to at-risk populations including healthcare providers. This agent's prophylactic value against viral respiratory infections was clearly established in Korean Army recruits (n=1444) [3] and indicated against pneumonia by three trials [4]. Its therapeutic value against colds was found by all 21 1970–17 trials dosing ≥1 g/d, and against pneumonia by two trials [4]. New metastudies demonstrate its ability to reduce ventilator hours (in patients requiring >10) by 25% [5] and ICU days by 9% [6], stretching these scarce resources; needing 3/4 as many ventilator hours is equivalent to having 4/3 as many ventilators. (Of note, reference [4] is by the senior author of the 2013 Cochrane Review [7], often misinterpreted as having disproven l-ascorbate's value.) These multi-g/d oral doses are of course clinically different from tens-of-g/d IV infusions now proving safe and effective from Shanghai to New York as adjunctive acute therapies for influenza- and COVID-19-related ARDS [e g 8]. Yet similar mechanisms are at work, from setting cellular redox potential low (suppressing viruses) to quenching free radicals that cause disease symptoms. In all, l-ascorbate may well be the most potent known antiviral agent.
So what are we waiting for? This agent is so safe, inexpensive, and ubiquitous that not taking it, whilst we ponder its value amidst the exponential phase of a pandemic, seems riskier than straightaway having a go.
[1] https://medium.com/@amorylovins/dont-just-avoid-the-virus-defeat-it-by-s...
[2] https://medium.com/@amorylovins/a-users-guide-to-vitamin-c-in-the-contex...
[3] BMJ Mil Health 2020, pubmed/32139409
[4] Nutrients 2017, 9, 339, doi:10.3390/nu9040339
[5] J Intens Care 8(15), 2020, doi:10.1186/s40560-020-0432-y
[6] Nutrients 2019 Mar 27:11(4), doi:10.3390/nu11040708
[7] doi:10.1002/14651858.CD000980.pub4
[8] Expert Rev Anti-infective Therapy 18(2), 2020, doi: 10.1080/14787210.2020.1706483
Competing interests: No competing interests
Dear Editor,
The pathogenicity of the SARS-Cov 2 virus and the risk factors for disease severity of Covid-19 are still being elucidated amongst different population groups(1). Meanwhile, the Opioid crisis is estimated to cause the deaths of 130 people in the USA per day(2), and opioid prescribing has been rising in many other countries(3). The use of opioids for chronic non-cancer pain is controversial and this has led to the World Health Organization withdrawing its opioid guidelines in 2019(4). As Stannard states, the “US opioid crisis is a story that keeps on giving”(5), and we wonder what effect Covid-19 will have on those members of the population who are using high-dose opioids, especially when the benefits are questionable.
Whilst the benefits may be questionable, the harms are not. The chronic use of high dose of opioids is associated with side effects which may increase disease severity of Covid-19. Opioids definitely interact with the immune system(6) and may decrease immune responses(7). Sleep-disordered breathing is exacerbated by opioids(8) and opioid induced ventilatory impairment is well described in both the post-operative(9) and obese(10) population groups. These opioid effects may point to pathophysiological causes for the increased the risk of pneumonia(7) seen in patients on opioids. Our own anecdotal (non-Covid-19) experience is that patients on high dose opioids are commonly only a severe infection away from opioid toxicity. In addition, opioids and other sedating agents are often weaned and ceased during their intensive care stays.
We acknowledge the importance of patients remaining on opioid agonist treatment in a harm minimisation paradigm(11). However, in some situations (where the patients and their treating clinicians are willing and able) the Covid-19 pandemic may provide further motivation, incentive and opportunity to reflect on opioid prescribing practices given the risks might outweigh the benefits. Opioid use, in our opinion, is modifiable, and by extension a modifiable potential risk factor during the Covid-19 pandemic.
At this point, we must stress that this link between Covid-19 and opioid use is purely speculative, as we were unable to find any published data looking specifically at associations between Covid-19 and opioid use. Given that most early data emerged from China, and given China’s history with opioids, it is unlikely that opioids played a role in disease severity there. However, now that Covid-19 is spreading quickly in Western countries where opioid use is problematic, we feel that collecting this data should be a matter of some urgency. This data may be difficult to collect but it is certainly not impossible in the age of electronic medical records. We therefore call for formal epidemiological studies analysing the relationship between Covid-19 disease severity and opioid use so that we might better stratify patient population risk to guide treatment decisions.
References:
1. Jordan RE, Adab P, Cheng KK. Covid-19: risk factors for severe disease and death. BMJ [Internet]. 2020 Mar 26 [cited 2020 Apr 3];368. Available from: https://www.bmj.com/content/368/bmj.m1198
2. NIDA, National Institute on Drug Abuse. Opioid Overdose Crisis [Internet]. 2019 [cited 2019 May 12]. Available from: https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis
3. Smith BH, Fletcher EH, Colvin LA. Opioid prescribing is rising in many countries. BMJ [Internet]. 2019 Oct 17 [cited 2020 Apr 4];367. Available from: https://www.bmj.com/content/367/bmj.l5823
4. Dyer O. WHO retracts opioid guidelines after accepting that industry had an influence. BMJ [Internet]. 2020 Jan 10 [cited 2020 Apr 3];368. Available from: https://www.bmj.com/content/368/bmj.m105
5. Stannard C. Tramadol is not ‘opioid-lite’. BMJ [Internet]. 2019 May 14 [cited 2020 Apr 3];365. Available from: https://www.bmj.com/content/365/bmj.l2095
6. Sacerdote P. Opioids and the immune system. Palliat Med. 2006 Jan 1;20(8_suppl):9–15.
7. Plein LM, Rittner HL. Opioids and the immune system – friend or foe. Br J Pharmacol. 2018 Jul 1;175(14):2717–25.
8. Grote L. Drug-Induced Sleep-Disordered Breathing and Ventilatory Impairment. Sleep Med Clin. 2018 Jun;13(2):161–8.
9. Gupta K, Prasad A, Nagappa M, Wong J, Abrahamyan L, Chung FF. Risk factors for opioid-induced respiratory depression and failure to rescue: a review. Curr Opin Anaesthesiol. 2018 Feb;31(1):110–9.
10. Raveendran R, Wong J, Chung F. Morbid obesity, sleep apnea, obesity hypoventilation syndrome: Are we sleepwalking into disaster? Perioper Care Oper Room Manag. 2017 Dec 1;9:24–32.
11. Pearce LA, Min JE, Piske M, Zhou H, Homayra F, Slaunwhite A, et al. Opioid agonist treatment and risk of mortality during opioid overdose public health emergency: population based retrospective cohort study. BMJ [Internet]. 2020 Mar 31 [cited 2020 Apr 3];368. Available from: https://www.bmj.com/content/368/bmj.m772
Competing interests: No competing interests
Dear Editor
Need For World/International Infectious Diseases Day By WHO
As of today, 3.4.2020, the coronavirus COVID-19 is reported in 204 countries and territories around the world and 2 international conveyances: the Diamond Princess cruise ship harbored in Yokohama, Japan, and the Holland America's MS Zaandam cruise ship. Globally over 1 Million (1 039 922) people were reported positive for this rapidly spreading COVID-19 infection through contact and by air borne route.
United states of America tops the list of the number of people (245 442) infected with COVID-19. Italy as of today lead the table with greatest number of death (13 915) in the world due to COVID-19 infection.
The death rate of this 2020 coronavirus Pandemic infection is 20% (55 170) and the recovery rate is 80% (222 240) as of 3.4.2020.
From this week the number of infected people started declining in Asia, Africa and Australasia.
More cases are reported in America and in a few countries in the European continent.
Risk factors for getting the COVID-19 infection and its progression may differ from individual to individual and country to country.
Acquiring the COVID-19 infection and its progression may depend on climatic conditions, individual 's genetic factors, immunological status, nutritional status, behaviours, habits, addiction to substances, drug intake and other associated comorbid diseases status.
We hope that personal hygiene and keeping the social distance are really giving benefits in preventing the COVID-19 spread in the community.
At this juncture I want to request the World Health Organisation, the apex body for Global Health, to consider and declare JANUARY 11th (When the first death was recorded from Wuhan, China, due to COVID-19 Pandemic) as "INTERNATIONAL INFECTIOUS DISEASES DAY". Every year a theme can be adopted on this day to increase awareness of infectious diseases globally.
Each and every country in the world has started the fight against COVID-19 from January 1st, 2020. So WHO should also consider announcing the year 2020 as the YEAR FOR INFECTIOUS DISEASES to continue the mitigation measures and fight against coronavirus throughout this year in every country.
Competing interests: No competing interests
Dear Editor
It was interesting reading the editorial. Though children of all ages are affected by SARS-Cov-2 infection, it seems that the severity of the disease is lesser in comparison to that in adults. However, the issue of vertical transmission to neonates from SARS-Cov-2 exposed mothers is yet unclear. Some researchers could not find any evidence of Perinatal transmission, while some did find an elevated IgM level in the serum of such neonates. It is also claimed that exposure to SARS-Cov-2 leads to generation of enough antibodies in maternal serum. The trans placental transfer of these antibodies may result in passive immunity in the neonate.
Finally, the issue of breast feeding also needs to be looked into. It is unethical to abstain frombreast feeding by an asymptomatic SARS-Cov-2 exposed mother without any definite evidence of shedding of the virus in her breast milk. These issues are particularly relevant in dealing with babies born to SARS-Cov-2 exposed mothers in resource limited set ups.
Competing interests: No competing interests
Dear Editor,
We peruse with interest in the Editorial.
In the etiopathogenesis of any illness, a triad comprising the vulnerability of the patient, the agent/inciting stimulus and the environmental factors has equally important roles. In COVID-19 disease, besides the virus, the immunity of the patient is also a determinant factor. There are many situations leading to a decrease in immunity like ingestion of refined sugar, particularly in large quantities, and sudden emotional trauma and stress can depress immunity for several hours. This may make an individual more susceptible to infection, particularly with this new virus with poor herd immunity.
Competing interests: No competing interests
COVID-19 pandemic and developing countries: is there a link between low Helicobacter pylori prevalence and severe cases?
Dear Editor
Thinking globally, it is noted in this pandemic that the mortality rates per million of population are much higher in the industrialized countries than in the developing countries, where the most favourable conditions for the spread of the virus are available and health systems are poor.
In fact, COVID-19 has been shown to have a wide spectrum of severity [1]. A majority of patients (80%) experience a mild illness that can be managed in the community. Around 15% typically need hospitalization, and another 5% have critical illness requiring more intensive support [2] [3] [4].
Risk factors for getting the coronavirus disease 2019 (COVID-19) and its progression may differ from individual to individual and country to country. Several hypotheses have been put forward to explain this, including the BCG vaccine, but they are not completely sufficient. The difference in mortality rates cannot be explained solely by the quality of the health system in the affected countries, and several mechanisms have been proposed, including racial differences and genetics.
We assume that there are at least one or more protective factors against the severe form of COVID-19 in developing countries. These countries are distributed on different continents and vary greatly in their food habits, lifestyle, and their political, social and health systems. However, from an epidemiological point of view, they share the presence of many infectious diseases, there epidemics vary greatly from country to country in a way that does not allow convincing conclusions to be drawn. However, it should be remembered that infection with Helicobacter pylori is one of the most common infections that affects the human race with high prevalence in developing countries [5] and is an ongoing infection.
Based on the following data, we can assume that helicobacter pylori play at least a role in preventing severe infection.
Firstly, a closer look at the distribution map of COVID-19 cases and mortality rates in different countries show that mortality rates per million of the population are e.g. very low in Russia (0.7deaths / 1m. Pop) and low in Portugal (compared to its neighbor Spain) and Eastern Europe (https://www.worldometers.info/coronavirus/); these regions have higher rates of helicobacter pylori prevalence (Russia 78.5%, Portugal 86.4% (compared to Spain (54.9%) and Italy (56.2%). [5]
Secondly, while the pathogenesis of COVID-19 is still poorly understood, current knowledge on COVID-19-induced pneumonia resembles very closely autoimmune/autoinflammatory syndromes [6]. Both genetic and environmental factors are thought to contribute to the severity of viral infections and in determining who will develop autoimmune conditions [7]. It is suggested that COVID-19 could act as a triggering factor for the development of a rapid autoimmune and/or autoinflammatory dysregulation, leading to severe interstitial pneumonia, in genetically predisposed individuals [8].
Thirdly, possible immunoregulatory role of H. pylori. It is known that H. pylori, especially Cag + strains, seropositivity inversely correlates with the incidence and severity of asthma in human [9] and mouse models [10]. H pylori treatment was associated with a significant increase in the risk of autoimmunity and/or inflammatory bowel disease (adjusted HR 2.36) [11]. This effect may be mediated by diminishing TH 17 response [12][10]. Indeed, experimental data support the protective immunoregulatory of H pylori. This protection occurs through H pylori–induced alterations in signaling pathways that are implicated similarly in inflammatory bowel disease, asthma, and allergy, such as attenuation of inflammatory Th1 and Th17 signaling pathways with or without up-regulation of T-helper 2 or T-regulatory pathways [13].
These data support the rationale to suppose that gastric H. pylori colonization affects immune homeostasis and may play a role in damping the hyperinflammation characteristic of severe COVID-19 cases [14].
We suggest that chronic Helicobacter pylori infection may, among other factors, attenuate severe COVID-19 in developing countries and prevent high mortalities. However, studies are needed to test this possible association. If this issue is proven in well-designed studies, it will have consequences, including avoiding widespread eradication of Helicobacter pylori.
[1] Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020:1–13. https://doi.org/10.1056/nejmoa2002032.
[2] Thevarajan I. The Medical Journal of Australia – Preprint only – 8 April 2020 Clinical presentation and management of COVID-19 The Medical Journal of Australia – Preprint only – 8 April 2020 2020.
[3] Wu Z, McGoogan JM. 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. JAMA - J Am Med Assoc 2020;323. https://doi.org/10.1001/jama.2020.2648.
[4] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497–506. https://doi.org/10.1016/S0140-6736(20)30183-5.
[5] Hooi JKY, Lai WY, Ng WK, Suen MMY, Underwood FE, Tanyingoh D, et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology 2017;153:420–9. https://doi.org/10.1053/j.gastro.2017.04.022.
[6] Editor D. Autoimmunity Reviews: Introduction. Autoimmun Rev 2005;4:485. https://doi.org/10.1016/j.autrev.2005.04.003.
[7] Lyons-weiler J. Pathogenic Priming Likely Contributes to Serious and Critical Illness and Mortality in COVID-19 via Autoimmunity. J Transl Autoimmun 2020:100051. https://doi.org/10.1016/j.jtauto.2020.100051.
[8] Editor D. Autoimmunity Reviews 2020:2019–20. https://doi.org/10.1016/j.autrev.2020.102524.
[9] Malfertheiner M V., Kandulski A, Schreiber J, Malfertheiner P. Helicobacter pylori infection and the respiratory system: A systematic review of the literature. Digestion 2011;84:212–20. https://doi.org/10.1159/000329351.
[10] Arnold IC, Dehzad N, Reuter S, Martin H, Becher B, Taube C, et al. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. J Clin Invest 2011;121:3088–93. https://doi.org/10.1172/JCI45041.
[11] El-zaatari M, Bishu S, Grasberger H, Zhang M. Effects of Anti – Helicobacter pylori Therapy on Incidence of Autoimmune Diseases , Including Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2019;17:1991–9. https://doi.org/10.1016/j.cgh.2018.12.014.
[12] Zhang H, Dai Y, Liu Y, Wu T, Li J, Wang X, et al. Helicobacter pylori colonization protects against chronic experimental colitis by regulating Th17/Treg Balance. Inflamm Bowel Dis 2018;24:1481–92. https://doi.org/10.1093/ibd/izy107.
[13] Shah SC, Tepler A, Jr RMP, Colombel J, Hirano I, Narula N. SYSTEMATIC REVIEWS AND META-ANALYSES Association Between Helicobacter pylori Exposure and Decreased Odds of Eosinophilic Esophagitis — A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2019;17:2185-2198.e3. https://doi.org/10.1016/j.cgh.2019.01.013.
[14] Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033–4. https://doi.org/10.1016/S0140-6736(20)30628-0.
Competing interests: No competing interests