Covid-19: a puzzle with many missing pieces
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m627 (Published 19 February 2020) Cite this as: BMJ 2020;368:m627Read our latest coverage of the Coronavirus outbreak
Linked Research
Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2)
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,
Thanks to the project funded by the Italian Ministry of Health (MoH) in 2017, the Italian Network of Sentinel Physicians for the Environment (in Italian RIMSA) is underway[1].
Some of the main activities of the network are:
• A modular object-oriented dynamic learning environment (Moodle) platform for training initiatives and an e-learning community of practice.
• A WhatsApp chat group (WCG) (115 professionals), mainly involving Family Doctors (FDs) throughout Italy, providing scientific reports and daily news dealing with Environment and Health (EH) setting.
• A few local pilot experiences of Sentinel Physicians to address some EH concerns (i.e. diseases in urban, industrial, agricultural and mixed area) devoted to training FDs on environmental threats as well as collecting EH data.
RIMSA and COVID-19
From February 2020, the outbreak of COVID-19 has captured most of the interest of the participants of the RIMSA WCG. WhatsApp is representing a powerful and helpful tool at the time of the COVID-19 pandemic. Even the World Health Organization has started using WhatsApp as a communication tool for the general public [2].
The abrupt overall socio-sanitary change generated by the epidemic has caused new needs in knowledge building and sharing processes, which had to be implemented according to the lockdown phase.
The dedicated section of the Moodle platform dealing with COVID-19 provides a repository of relevant international and national scientific articles, documents and news. These are classified by topic and specific thematic areas (i.e., epidemiology, therapy, laws, journal news) to facilitate the navigation. To further promote the sharing of information, a dedicated forum section has also been created.
Based on RIMSA's experience with the WCG and the Moodle platform, some general take-home messages on the role of FDs in the COVID-19 emergency can be profitably shared:
• Some GPs have observed cases of interstitial pneumonia already in late January 2020, before the first Italian case of COVID-19 infection was officially identified in Codogno (Lombardy Region).
• Despite no systematic assessments having been carried out, one hypothesis under (speculative) development is that the regions where health care systems are mainly based on hospital activities are showing the highest case fatality rates, much more than in the areas where FDs have been more involved in contact tracing and patients management;
• FDs can be handy to capture more quickly new cases, either in terms of timely surveillance and, above all, in triggering immediate and appropriate health interventions as well as in allowing the right level of patient's seclusion, far better than in hospitals.
Basically, according to Li [3] "FDs have a 'first in, last out' role in COVID-19 pandemic.
Furthermore, it should be underlined that epidemiological Primary Health Care (PHC) based surveillance could be essential in the "coming year to anticipate the possibility of resurgence." [4].
COVID-19 and the Environment
In this field, many issues should be further investigated. Still, it is undoubtedly necessary to point out that the origin and the effects of COVID-19 pandemic are inextricably linked to the Environment as a whole [5-19].
The authors believe that Sentinel Physicians for the Environment contributions could be beneficial in investigating the COVID-19 trend as well as the relationship between environmental determinants, mainly air pollution, heat, humidity. As such RIMSA is committed to promoting some initiatives involving local FDs' networks.
Finally, ethical issues must be taken into due consideration: COVID-19 pandemic and the deteriorated environment affect, first and foremost, vulnerable and most deprived people.
In sum, we think that the contributions by Sentinel Physicians for the Environment could be beneficial to investigate the COVID-19 trend as well as the relationship between environmental determinants, mainly air pollution, heat, humidity. We are committed to arranging some initiatives involving local FDs networks.
Last but not least, we are actively available to be involved and promote some international initiatives dealing with COVID-19 pandemics, such as the one shared by WONCA[20] and the environment [21].
In some cases, comparisons between similar initiatives across countries may provide an opportunity for enhanced understanding of several complex social and environmental factors overlapping in affecting COVID-19 virus transmission.
Such knowledge would depend on collaboration by FDs with national surveys conducted by epidemiologists, and this could be combined with the role of primary care services as contributing to public health response in terms of case identification and contact tracing at the community level. This is expected to result in an improvement of existing interventions at the community level, as well as in the identification of possible novel ones.
Based on the success of similar approaches in Germany and South Korea, the overall benefit of involving FDs and primary health care services into public health responses to COVID-19 could be substantial at the global level.
Conclusions
This paper attempts to highlight that the environmental sensitivity of individual physicians and knowledge of their area, together with clinical expertise, can help detect critical situations and encourage appropriate actions to prevent recurrent threats.
But they need to be supported by providing them instruments to gather sound and evidence-based scientific knowledge both in terms of information and document delivered in timely and proper manner and specific, effective, and motivating training.
Starting from a voluntary initiative such as a WhatsApp chat network, we showed that it could be better developed by using a community of practice device such as Moodle.
This lesson should be taken into proper account in the case of COVID-19 pandemic, but also in facing other global threats such as Climate Change and environmental pollution at the local level.
Corresponding Author:
Dr Paolo Lauriola, MD, Associate
Italian National Research Council, Institute of Clinical Physiology,
Unit of Environmental Epidemiology and disease registries.
Scientific Coordinator, RIMSA (ISDE-FNOMCeO);
Via Cimone, 41100 Modena
e-mail: paolo.lauriola@gmail.com
skype: plauriola
Authors:
1. Vitalia Murgia, Primary care paediatrician, RIMSA (ISDE-FNOMCeO), Italy
2. Francesco Romizi, Journalist, communication manager of the International Society Doctors for the Environment ISDE Italia, RIMSA (ISDE-FNOMCeO), Italy
3. Roberto Romizi, Family doctor, International Society Doctors for the Environment (ISDE) Italy
4. Paula de Waal, Università Ca' Foscari Venezia, Italy
5. Fabrizio Bianchi, Epidemiology Unit, Institute of Clinical Physiology, National Research Council, Pisa, Italy
6. Francesco De Tommasi, Family doctor - Local Health Authority, BA; RIMSA (ISDE-FNOMCeO), Italy
7. Marco Calgaro, Family doctor - Local Health Authority, 13 Novara; RIMSA (ISDE-FNOMCeO), Italy
8. Samantha Pegoraro, Italian Climate Network; RIMSA (ISDE-FNOMCeO), Italy
9. Maria Grazia Santamaria, Family doctor, Local Health Authority, Foggia; RIMSA (ISDE-FNOMCeO) Italy,
10. Alice Serafini, General Practitioners’ training course trainee, Local Health Authority Modena; RIMSA (ISDE-FNOMCeO) Italy
11. Emanuele Vinci,” Health and Environment” working group, National Medical Boards Federation (FNOMCeO), Italy
12. Giovanni Leonardi, Epidemiologist, London School of Hygiene and topical Medicine, UK
13. Paolo Lauriola. Scientific Coordinator, RIMSA (ISDE-FNOMCeO); Epidemiology Unit, Institute of Clinical Physiology, National Research Council, Pisa, Italy
References
1. Lauriola P, Pegoraro S, Serafini A, Murgia V, Di Ciaula A, De Tommasi F, Ross Ai, Santamaria M, Toffol G, Bianchi R, Romizi R, Vinci V, Behbod B, Zeka A, Verheij R, Leonardi G, Agius R, (2018)The Role of General Practices for Monitoring and Protecting the Environment and Health. Results and Proposals of the Italian Project Aimed at Creating an "Italian Network of Sentinel Physicians for the Environment" (RIMSA) within an International Perspective, J Family Med Community Health 5(5): 1160. DOI http://jscimedcentral.com/FamilyMedicine/familymedicine-5-1160.pdf
2. https://www.whatsapp.com/coronavirus/who
3. Li DKT. Challenges and responsibilities of family doctors in the new global coronavirus outbreak. Fam Med Com Health, 2020;8:e000333. DOI:10.1136/ fmch-2020-000333
4. Kissler SM, Tedijanto C, Goldstein E, GradmmYH1, Lipsitchm M.Projecting the transmission dynamics of SARS-CoV-2 through the post-pandemic period. Science 14 Apr 2020: DOI: 10.1126/science.abb5793
5. Katherine F. Smith, Michael Goldberg, Samantha Rosenthal, Lynn Carlson, Jane Chen, Cici Chen and Sohini Ramachandran.. Global rise in human infectious disease outbreaks. (2014) J. R. Soc. Interface.1120140950 http://doi.org/10.1098/rsif.2014.0950
6. Qu, G., LI X, Hu L, et al. "An Imperative Need for Research on the Role of Environmental Factors in Transmission of Novel Coronavirus (COVID-19)." Environmental Science & Technology
7. Ghirga G. COVID-19 and air pollution BMJ (2020);368:m627
8. Bianchi F, Cibella F. COVID-19: a puzzle with many missing pieces BMJ (2020);368:m627
9. Lubrano C. Colao A Covid-19: a puzzle with many missing pieces. Air pollution, climate and obesity could be the COVID 19 puzzle missing pieces BMJ 2020;368:m627
10. Conticini E, Frediani B, Caro D, Can atmospheric Pollution be considered a co-factor in extremely high level of SARS-CoV-2 lethality in Northern Italy? Environmental Pollution, (2020) https://doi.org/10.1016/j.envpol.2020.114465
11. Sajadi HM Habibzadeh P Vintzileo A et Temperature and Latitude Analysis to Predict Potential Spread and Seasonality for COVID-19 January 2020SSRN Electronic Journal (2020) DOI: 10.2139/ssrn.3550308
12. Wang, J., Tang, K., Feng, K., & Lv, W. High temperature and high humidity reduce the transmission of COVID-19. (2020). Available at SSRN 3551767.
13. Oliveiros, B., Caramelo, L., Ferreira, N. C., & Caramelo, F. Role of temperature and humidity in the modulation of the doubling time of COVID-19 cases. . (2020). medRxiv.
14. Luo, W., Majumder, M., Liu, D., Poirier, C., Mandl, K., Lipsitch, M., & Santillana, M. The role of absolute humidity on transmission rates of the COVID-19 outbreak. (2020) medRxiv..
15. Wang, M., Jiang, A., Gong, L., Luo, L., Guo, W., Li, C., et al. Temperature significant change COVID-19 Transmission in 429 cities. (2020). medRxiv.
16. Chen, B., Liang, H., Yuan, X., Hu, Y., Xu, M., Zhao, Y., et al, X.). Roles of meteorological conditions in COVID-19 transmission on a worldwide scale. (2020medRxiv.
17. Notari, A. Temperature dependence of COVID-19 transmission. arXiv preprint (2020). arXiv:2003.12417.
18. Morawska, L. and J. Cao "Airborne transmission of SARS-CoV-2: The world should face the reality." Environ Int (2020). 139: 105730.
19. Ogen Y., Assessing nitrogen dioxide (NO2) levels as a contributing factor to coronavirus (COVID-19) fatality, Science of the Total Environment 726 (2020) 138605.
20. https://auckland.au1.qualtrics.com/jfe/form/SV_bK697wFCa9WNGYZ
21. https://www.gov.uk/government/publications/coronavirus-covid-19-scaling-...
Competing interests: No competing interests
Dear Editor,
Your article on the missing pieces of the COVID-19 puzzle highlights the many aspects of the disease yet to be investigated. Beside epidemiology and pathogenesis, current therapeutic approaches, especially for those with respiratory failure, the major cause of death in COVID-19, are unsatisfactory. The mechanism for the lung injury remains to be elucidated. However, in addition to the effects from cytokine storm (CS), molecular mimicry in genetically susceptible individuals may play a part. Molecular mimicry results from the antiviral immune responses cross-reacting with some protein components in normal human cells. The detection of antiphospholipid antibodies in Covid-19 patients (1) supports the presence of this complication. The autoimmune T cells may contribute to tissue injury.
While treating the cause of COVID-19 is the ultimate goal, until an effective antiviral therapy is available, targeting the downstream effects from the infection is appropriate. One obvious downstream effect of the infection is CS, arisen from exaggerated and dysregulated immune responses. Various immunomodulatory agents such as azithromycin/hydroxychloroquine, anti-IL1, anti-IL6, and corticosteroids, aimed at inhibiting the cytokines or downregulating the immune responses, are currently being administered to these patients, both in and outside the context of clinical trials. Ruxolitinib, an inhibitor of the Jak 2 signaling pathway involved in T-cell activation, is also being studied.
Although anti-cytokine antibodies may calm some of the inflammatory processes induced by CS, the lung injuries in many patients continue to progress and lead to death. Autopsies in these patients showed that the lungs were infiltrated by CD8 cells (2). The nature of these CD8 T cells remains to be determined. However, it is possible that they are either autoimmune T cells, directed at the alveolar epithelium and induced by the dysregulated immune responses, or antiviral cytotoxic T cells that cross react with the alveolar epithelium. Eradicating these T cells, the mediator of the counter-productive immune chaos, is a logical approach. These T cells may be rapidly eradicated by extracorporal photophoresis, specific anti-T cell antibodies, or lympholytic agents. Cyclophosphamide, a widely available and inexpensive drug, is an attractive agent for this purpose. It is highly lympholytic. At doses for autoimmune diseases, including acute lung diseases, and post-haploidentical stem cell transplant, it has a good safety profile and is effective in abrogating activated T cells. If used early, cyclophosphamide could, therefore, modulate the disease course.
There are obvious theoretical risks associated with inducing immunosuppression, in the form of functional or numeric lymphopenia, in COVID-19 patients using any immunosuppressive agents. Immunosuppression may delay or prevent viral clearance. The worry about viral clearance has further been compounded by the association between lymphopenia and severity of COVID-19 (3). Lymphoid hypoplasia has also been reported in these patients (4). However, T cells from patients with less severe disease are highly activated (5). The lymphopenia and lymphoid hypoplasia are, therefore, more likely the result of uncontrolled apoptosis of the dysregulated T cells than the causes for any delay in viral clearance and ultimate fatality.
Until all convalescent patients, treated by any methods, are routinely retested for viral persistence, the clinical implications of delayed viral clearance are currently unknown. Although delay in viral clearance may be important for public health purposes, two observations suggest that it may not be the pre-requisite for health in most individuals, provided dysregulated immune responses do not occur. First, many patients with COVID-19 are asymptomatic. Second, some Korean patients who recovered from the infection continued to test positive for the virus.
In conclusion, another piece for the COVID-19 puzzle in terms of therapy may be the pool of dysregulated T cells. In the absence of an effective antiviral therapy, the dysregulated T cells may be a therapeutic target for immunomodulatory agents such as cyclophosphamide.
References
1. Zhang Y, Xiao M, Zhang S, et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med. 2020 Apr 8. doi: 10.1056/NEJMc2007575. [Epub ahead of print].
2. Fox R, Akmatbekov A, Harbert J, et al. Pulmonary and cardiac Pathology in COVID -19; the first autopsy series from New Orleans. medRxiv. doi: 10.1101/2020.04.06.20050575
3. Tan L, Wang Q, Zhang D, et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther. 2020; 5: 33.
4. Yao X, Li T, He Z, et al. A pathological report of three COVID⁃19 cases by minimally invasive autopsies. Chin J Pathol. 2020; 49: 411-418.
5. Xu Z, Shi L, Wang Y, Zhang J, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020; 8: 420-422.
Seah H Lim MD PhD
Division of Hematology and Oncology
Department of Medicine
New York Medical College
Valhalla, New York, USA
email: seah.lim@wmchealth.org
Jason Gonsky MD PhD
Division of Hematology and Oncology
Department of Medicine
SUNY Downstate Health Sciences University
Brooklyn, New York, USA
Oleg Epelbaum MD
Division of Pulmonary, Critical Care and Sleep Medicine
Department of Medicine
New York Medical College
Valhalla, New York, USA
Peter Gillette MD
Division of Hematology and Oncology
Department of Medicine
SUNY Downstate Health Sciences University
Brooklyn, New York, USA
Competing interests: No competing interests
Dear Editor
The features most associated with novel coronavirus disease 2019 (COVID-19) infection and its respiratory complications are male sex, older age, cardiovascular disease, diabetes and perhaps higher BMI [1-4], but assessment of obesity is rarely reported in clinical studies.
An article regarding COVID-19 fatalities In Italy didn’t mention obesity as a comorbid disease associated with death and in a recent report from ISS about comorbid conditions in SARS-CoV-2 positive deceased patients, obesity is present in only 11,8 %, whilst type 2 diabetes accounts for 32% and hypertension for 69,7% of deceased patients [5-7]: these data appear to be inexplicably in relation to the known strong association between obesity and these pathologies. In Bergamo, where the disease is particularly severe, a large portion of adult (36.2%) and young population (23.9%) is overweight or obese [8]. Patients with BMI ≥ 40 kg/m2 are at risk for flu complications [9]. Excess fat is known to be associated with several respiratory conditions [10], and the possible link between severe pulmonary manifestations of COVID-19 and obesity is conceivable.
Recent evidence indicates that accumulation of adipose tissue within the lung of obese subjects correlates with inflammatory infiltrate [11]. Air pollution may induce lung dysfunction and some studies have highlighted the possibility that adipose tissue -- namely, visceral fat -- may mediate air pollution-induced lung dysfunction [12-13]. Furthermore, it is well known the causal association between pollution and obesity and related metabolic derangements [14-15]. In fact, both air pollution and high adiposity are closely related to increased inflammation [16-17]. Most of the diseases reported in Italian deceased patients, especially respiratory and cardiovascular diseases, have also been shown to be associated with exposure to air pollution [18].
Evidence exists correlating viral infection with atmospheric particulate matter (PM) concentrations (e.g. PM10 and PM2.5) [19-21]. A recent study demonstrates that aerosol transmission of SARS-CoV-2 is possible, since the virus remains viable and infectious in aerosols for hours [22]. Atmospheric PM constitutes a carrier for both chemical pollutants and viruses and allows viruses to persist in the air in vital conditions for hours or days, depending on the relative humidity and temperature [23-24]. Wuhan and Po Valley are high polluted areas characterized by similar thermo-hygrometric conditions [25-27].
It is tempting to speculate that the spread of the infection -- as well as international travel and individual behavior -- is also linked to the local differences in total and aged population, air pollution and climate [28-29]. Accordingly these situations, and especially pollution, may explain the high virulence, the fast spread and the greater mortality of SARS-CoV-2 in Northern Italy, directly through PMs being a possible carrier of viable viral particles and indirectly through a chronic inflammatory stimulus, especially in obese subjects even if young.
Considering all the above, while we are waiting conclusive investigations, it is advisable to reinforce the importance of staying at home until the weather and pollution improve, in order to avoid breathing polluted air possibly coated by SARS-CoV-2 and to recommend not only social distancing but also individual risk factor management, limiting overeating and promoting, as far as possible, physical activity to avoid weight gain and a subsequent increase in the global prevalence of obesity.
Carla Lubrano MD PhD
Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology,
Sapienza University of Rome
Annamaria Colao MD PhD
UNESCO Chair for Health Education and Sustainable Development,
Federico II University of Naples
Conflict of interests
The authors declare no competing interest.
Bibliography
1. Bianchi F Re: Air pollution and Covid19: how to compose the puzzle BMJ 2020;368:m627
2. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497-506.
3. Peng YD, Meng K, Guan HQ et al. Clinical Characteristics and Outcomes of 112 Cardiovascular Disease Patients Infected by 2019-nCoV. Zhonghua Xin Xue Guan Bing Za Zhi, 48 (0), E004 2020 Mar 2
4. Liu M, He P, Liu HGet al. Clinical characteristics of 30 medical workers infected with new coronavirus pneumonia Zhonghua Jie He He Hu Xi Za Zhi. 2020 Mar 12;43(3):209-214
5. Coronavirus disease 2019 (COVID-19) pandemic: increased transmission in the EU/EEA and the UK – seventh update, 25 March 2020. Stockholm: ECDC; 2020.
6. Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy [published online ahead of print, 2020 Mar 23]. JAMA. 2020; 10.1001/jama.2020.4683. doi: 10.1001/jama.2020.4683
7. https://www.epicentro.iss.it/coronavirus/bollettino/Report-COVID-2019_24...
8. Press release 61/2019 8/11/2019 ATS Bergamo Lombardy Region
9. Ryan DH, Ravussin E, Heymsfield S. COVID 19 and the Patient With Obesity - The Editors Speak Out Obesity (Silver Spring). 2020 Apr 1. doi: 10.1002/oby.22808.
10. Mancuso P. Obesity and lung inflammation. J Appl Physiol (1985) 2010; 108(3): 722-8.4.
11. Elliot JG, Donovan GM, Wang KCW, Green FHY, James AL, Noble PB. Fatty airways: implications for obstructive disease. Eur Respir J 2019; 54(6).
12. Conti S, Harari S, Caminati A, et al. The association between air pollution and the incidence of idiopathic pulmonary fibrosis in Northern Italy. Eur Respir J 2018; 51: 1700397 [https://doi.org/10.1183/13993003.00397-2017
13. Kim H-J, Park J-H, Min J-Y et al., Abdominal adiposity intensifies the negative effects of ambient air pollution on lung function in Korean men Int J Obes (2017) 41, 1218–1223
14. Yang Z, Song Q, Li J et al Air Pollution as a Cause of Obesity: Micro-Level Evidence from Chinese Cities Int. J. Environ. Res. Public Health 2019, 16, 4296
15. Lubrano C, Genovesi G, Specchia P et al Obesity and metabolic comorbidities: environmental diseases? Oxid Med Cell Longev. 2013; 2013:640673
16. Wei Y, Zhang JJ, Li Z, et al. Chronic exposure to air pollution particles increases the risk of obesity and metabolic syndrome: findings from a natural experiment in Beijing. FASEB J. 2016;30(6):2115–2122. doi: 10.1096/fj.201500142
17. WHO. Noncommunicable Diseases and Air Pollution. WHO European High-Level Conference on Noncommunicable Diseases. Time to Deliver: meeting NCD targets to achieve Sustainable Development Goals in Europe 9-10 April 2019, Ashgabat, Turkmenistan. Available at: http://www.euro.who.int/__data/assets/pdf_file/0005/397787/Air-Pollution...).
18. Bastard JP, Jardel C, Bruckert E, et al. Elevated Levels of Interleukin 6 Are Reduced in Serum and Subcutaneous Adipose Tissue of Obese Women after Weight Loss J Clin Endocrinol Metab 2000, 85: 3338–3342,
19. Ciencewicki J et al.,. “Air Pollution and Respiratory Viral Infection” Inhalation Toxicology, (2007) 19: 1135-1146
20. Carugno M, Dentali F, Mathieu G et al PM10 exposure is associated with increased hospitalizations for respiratory syncytial virus bronchiolitis among infants in Lombardy, Italy. Environ Res. 2018 Oct; 166:452-457. doi: 10.1016/j.envres.2018.06.016.
21. Nenna R, Evangelisti M, Frassanito A, Respiratory Syncytial Virus Bronchiolitis, Weather Conditions and Air Pollution in an Italian Urban Area: An Observational Study Environ Res. 2017 Oct; 158:188-193
22. Cui Y, Zhang Z-F, Froines Jet al. Air pollution and case fatality of SARS in the People's Republic of China: an ecologic study. Environmental Health 2003, 2:15
23. Van Doremalen, Morris DH, HolbrookMG et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1 N Engl J Med. 2020 Mar 17
24. Despres V.R., et al., “Primary biological aerosol particles in the atmosphere: a review” Tellus B: Chemical and Physical Meteorology, 2012 - Issue 1 Tellus B, 64, 15598
25. Liu F, Lai S, Reinmuth-Selzle K, Scheel JF Metaproteomic Analysis of Atmospheric Aerosol Samples Anal Bioanal Chem. 2016 Sep;408(23):6337-48
26. World Air Quality Index https://aqicn.org/city/wuhan/, https://aqicn.org/city/italy/lombardia/bergamo-via-meucci/
27. Sajadi, M M. Habibzadeh, P, Vintzileos, A et al Temperature, Humidity and Latitude Analysis to Predict Potential Spread and Seasonality for COVID-19 (March 5, 2020). Available at SSRN: https://ssrn.com/abstract=3550308 or http://dx.doi.org/10.2139/ssrn.3550308
28. Setti L, Passarini F, de Gennaro G et al. POSITION PAPER: Relazione circa l’effetto dell’inquinamento da particolato atmosferico e la diffusione di virus nella popolazione 2020 http://www.simaonlus.it/wpsima/wp-content/uploads/2020/03/COVID19_Positi...
29. Pluchino A. , Inturri G, Rapisarda A. et al. A Novel Methodology for Epidemic Risk Assessment: the case of COVID-19 outbreak in Italy arXiv:2004.02739 [physics.soc-ph]
Competing interests: No competing interests
Dear Editor
Pneumonitis in COVID-19: parallels with checkpoint Inhibitor related Immune Pneumonitis
Your report rightly highlights the major problem that there are many missing pieces in COVID-19 science.
We write to a highlight a new insight on the type of pneumonia caused by SARS CoV 2 from the many reports on COVID-19.
Pneumonitis of COVID-19 appears to be similar to immune pneumonitis associated with immune checkpoint-inhibitor therapy for cancers.
‘Immune checkpoint’ is a term used for processing of regulatory T lymphocytes in lymph nodes and in peripheral tissues, prior to proliferation or suppression of effector T cells as orchestrated by these regulatory T Lymphocytes.
Two checkpoints exist in the pathway to modulate the immune system. Firstly, a central checkpoint tolerance regulator: Regulation of T cells based on CTLA-4 (Cytotoxic Lymphocyte Antigen) in Lymph Nodes and secondly a peripheral checkpoint tolerance regulator: Regulation of T cells based on PD-1 (Programmed Death-1) in all tissues. Thereafter immune-mediated countering of the pathogenic antigen occurs ( 1,2 ).
Fox et al, have reported findings in COVID-19 post-mortem pathology analysis found CD 8+ and CD 4+ T lymphocytes in the alveoli in patients who died of COVID-19 indicating immune attack in COVID-19 [3].
It has been reported that a rare but major life-threatening complication for checkpoint inhibitor therapy with monoclonal antibodies for cancers is immune pneumonitis [1,2]. Acute colitis, as an immune injury, has also been widely reported as an adverse event [1,2].
Cancer immunotherapy utilises adaptive immunity to attack cancer cells. Naive T lymphocytes are in the Thymus and enter the circulation. The T cell receptors bind to antigens displayed in Major Histocompatibility Complex (MHC) of macrophages.
Cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) and programmed death 1 (PD-1) are receptors in regulatory T lymphocytes which are critical in this process of immune checkpoint assessments. When these receptors are activated, by a binding process, they down regulate T-cell immune function.
Inhibition of these receptors has the effect of activating T-cell receptors (TCR) to antigens displayed in the major histocompatibility complex (MHC) on the surface of an antigen-presenting cells such as macrophages.
Dysregulation of checkpoints would result in proliferation of of specific Cytotoxic Lymphocytes as regulated by regulatory T lymphocytes.
The therapy recommended for Immune Pneumonitis is steroids and Anti Tumour Necrosis Factor ( TNF ). Unlike in cancer therapy, with the potential surge in viral load with steroids and the risk of secondary bacterial infection, steroids are best avoided in viral infections,
Programmed Cell Death-1 (PD-1) molecules have the ability to influence the down regulation of cytotoxic T cells.PD-1 binding inhibits T-lymphocyte proliferation, and resultant interferon-gamma (IFN-g), TNF , and Interleukin ( IL-2 ) production, and reduces T lymphocyte survival.
PD-1 expression is up-regulated in T lymphocytes that have chronically been exposed to the same antigen as in chronic infections (such as Mycobacterium Tuberculosis ).
This has significance for the prevention of cytokine storm, as persistent stimulation in the checkpoint pathway will lead to reduced cytokine responses and could explain the potential benefit of prior BCG vaccination on severity of COVID by a process of being in ‘trained immunity ’ state.
BCG would modulate secretion of TNF that is orchestrated at the peripheral checkpoint by regulatory T lymphocytes through T Lymphocyte-macrophage binding processes. However, such ‘trained immunity 'may also prevent a surge in TNF stimulation with a second viral trigger that has a similar antigen as the system is already active.
The CTLA-4 and PD-1 pathways are considered to be important in different phases of an immune response. CTLA-4 is considered as the key immune molecule that inhibits T cell proliferation when lymph nodes receive thymus primed T lymphocytes [1,2].
Proliferation of T lymphocytes will result in elimination of pathogens by triggering production of cytokines, in particular Interleukin 2 (IL 2).
SARS-CoV-2 virus would appear to trigger an immune over-reaction similar to that produced by checkpoint inhibitors. This is supported by the post pathology reports on several patients who died of COVID-19 (3 )
Conclusions
The preliminary inferences, that can be derived from the similarities between immune pneumonitis in checkpoint inhibitor therapy and COVID-19, are that prior BCG vaccination may be preventative against severe COVID-19 and Anti-TNF biological therapy could be a good therapeutic option for SARS CoV 2 triggered immune-pneumonitis,
Dr Ahran Arnold MBChB MRCP
Clinical Research Fellow Clinical Research Fellow in Cardiology, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0HS, United Kingdom
Dr Nina Stafford MBBS MRCP *
Specialty Registrar in Gastroenterology
Professor Andrew Scurr MBBS FRCA *
Consultant in Intensive Care
Professor Jayantha Arnold MBBS FRCP *
Consultant Physician and Gastroenterologist
*Ealing Hospital, London North West University Healthcare NHS Trust, Uxbridge Road, Southall, UB1 3HW, United Kingdom
References
1. Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol 2016;39:98–106. doi: 10.1097/COC.0000000000000239.
2. Chuzi S, Tavora F, Cruz M, Costa R, Chae YK, Carneiro BA, Giles FJ. Clinical features, diagnostic challenges, and management strategies in checkpoint inhibitor-related pneumonitis. Cancer Manag Res. 2017;9:207-213. doi: 10.2147/CMAR.S136818
3. Fox R, Akmatbekov A, Harbert J, Li G, Brown Q, Vander Heide RS. Pulmonary and cardiac Pathology in COVID -19; the first autopsy series from New Orleans. medRxiv. doi: 10.1101/2020.04.06.20050575
Competing interests: No competing interests
Dear Editor
Because COVID-19 primarily manifests as a respiratory infection, airway exposure is intuitively assumed to be the infection route. However, we postulate SARS-COV-2 lung infection could be acquired upon exposure to the virus through the gastrointestinal tract, subsequently, the virus could be further transported to the lungs leading to a respiratory infection.
Several studies included a systematic review of imaging findings in 919 patients, showed that most of the lesions started from the periphery, particularly the subpleural region mainly in the lower lobe (1). The periphery and the lower lobe are the most frequently affected even in asymptomatic cases (2).
In an erect individual, the lung apex is relatively overventilated (ratio of ventilation to perfusion, 3:1), and the base is relatively overperfused (ratio, 0.6:1) (3). Furthermore, lymphatic particle clearance is relatively decreased in the apices because the lymphatic flow is driven by perfusion as well as respiratory excursion, both of which are relatively decreased in the upper lung zones (4). Prolonged transit time can increase the interaction between pathogenic factors and the peripheral lung. This suggests different viral distribution or spreading rather than direct inhalation. If SARS-COV-2 spread to the lung through inhalation we would expect upper lobe predominance.
The peripheral and lower lung predominance observed in SARS-COV-2 lung infections may be driven by the relative basilar overperfusion and the prolonged peripheral transit time (3). Hematogenous and/or lymphatic SARS-CoV-2 lung distribution or spreading could follow the viral infection of the gastrointestinal tract.
Many patients with COVID-19 present initially with digestive symptoms, such as diarrhea, anorexia, and vomiting. Early gastrointestinal symptoms could be explained by the gastrointestinal tract be the primary site of invasion by SARS-CoV-2. Several recent studies have documented the presence of SARS-CoV-2 ribonucleic acid (RNA) and/or SARS-CoV-2 virus in the stool of infected individuals. Furthermore, patients with COVID-19 had persistently positive rectal swabs even after their nasopharyngeal tests were negative (5). Extended duration of viral shedding in feces for nearly 5 weeks after the patients' respiratory samples tested negative for SARS-CoV-2 RNA, suggests high intestinal viral load distribution during Covid-19 (6).
The interaction between the SARS viruses and ACE2 has been proposed as a potential factor in their infectivity. ACE2 is in large measure present in humans in the epithelia of lung and small intestine, which might provide possible routes of entry for the SARS-CoV-2. ACE2 protein is abundantly expressed in the brush border of enterocytes of all parts of the small intestine, including the duodenum, jejunum, and ileum. The fact that enterocytes of the small intestine are in contact with the external environment and the surface expression of ACE2 protein in these cells is remarkable (7).
The pathological features of COVID-19 greatly resemble those seen in SARS-CoV and MERS (8). Using in situ hybridization, SARS-CoV has been found on the surface of small intestinal enterocytes. Active viral replication in the enterocytes of the small intestine has been reported (9). The abundant expression of ACE2 on endothelia and smooth muscle cells in virtually all organs suggests that the SARS-CoV, once present in the circulation, can spread easily hematogenously (7). Via the abundant lymphatic vessels and venules in the lamina propria of the small intestine, the virus could be transported to the right heart via the thoracic duct and superior vena cava, and disseminate mainly to the lower lung. The lung tissues of intragastrically inoculated mice with MERS-CoV exhibited minimal lung pathology at the early phase. Prominent interstitial pneumonia with thickened alveolar septa and mononuclear cell filtration occurred as the enteric infection developed; meanwhile, NP-positive cells emerged in the pulmonary parenchyma (10).
If the gastrointestinal system reveals playing a relevant role in the pathogenesis of SARS-CoV-2 infection, research should focus on boosting intestinal innate immunity as an effective strategy for overcoming insufficient antiviral immunity in the gut (11).
In conclusion, we highlight the possibility of the gastrointestinal system as a potential first route of SARS-CoV-2 invasion and transmission.
1) Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus Disease 2019 (COVID-19): A Systematic Review of Imaging Findings in 919 Patients. AJR Am J Roentgenol. 2020 Mar 14:1-7. DOI: 10.2214/AJR.20.23034.
2) 2) Inui S, Fujikawa A, Jitsu M, Kunishima N, Watanabe S, Suzuki Y, Umeda S, Uwabe Y. Chest CT Findings in Cases from the Cruise Ship “Diamond Princess” with Coronavirus Disease 2019 (COVID-19). Published Online: Mar 17 2020. https://doi.org/10.1148/ryct.2020200110.
3) Nemec SF1, Bankier AA, Eisenberg RL. Lower lobe-predominant diseases of the lung. AJR Am J Roentgenol. 2013 Apr;200(4):712-28. DOI: 10.2214/AJR.12.9253.
4) Stefan F, Nemec A, Bankier A, Eisenberg RL. Upper Lobe–Predominant Diseases of the Lung. American Journal of Roentgenology. 2013;200: W222-W237. 10.2214/AJR.12.8961
5) Wenling W, Yanli X, Ruqin G, alRoujian L, Kai H, Guizhen W, Wenjie T. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA. Published online March 11, 2020. DOI:10.1001/jama.2020.3786.
6) Yongjian W, Cheng G, Lantian T, Zhongsi H, Jianhui Z, et al. Prolonged presence of SARS-CoV-2 viral RNA in fecal samples. 2020. Vol.5;5:434-435. DOI:https://doi.org/10.1016/S2468-1253(20)30083-2
7) Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004 Jun;203(2):631-7.
8) Zhe Xu*, Lei Shi*, Yijin Wang*, Jiyuan Zhang, Lei Huang, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. Published Online. February 17, 2020. https://doi.org/10.1016/S2213-2600(20)30076-X
9) To KF, Tong JH, Chan PK, Au FW, Chim SS, Chan KC, Cheung JL, Liu EY, Tse GM, Lo AW, Lo YM, Ng HK. Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases. J Pathol. 2004 Feb;202(2):157-63.
10) Zhou J, Li C, Zhao G, Chu H, Wang D, Yan HH, et al. Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus. Sci Adv. 2017 Nov 15;3(11):eaao4966. DOI: 10.1126/sciadv.aao4966. eCollection 2017 Nov.
11) Neil JA, Cadwell A. The Intestinal Virome and Immunity. The Intestinal Virome and Immunity Jessica A. J Immunol. 2018; 201:1615-1624; DOI: 10.4049/jimmunol.18006312018
Competing interests: No competing interests
Dear Editor
Yes. Many missing pieces. Some hidden in the Govt archives?
1. The Ministers claim that they have been guided by science. Even astrologers claim to be scientists. Mathematical modellers too. But I would be guided solely by the science of clinical epidemiology.
I ask the GOVT, Did you obtain the pure public health advice from the Chief Medical Officer, unadulterated by the scientists practising economics, on the effects of public health measures on the economy of Britain?
2. I was begging in the BMJ rapid responses for a ban on swimming pools.
The Government did not. The Government failed to do so for weeks. Why? Did the Chief Medical Officer advise the government to do so until much later? Or, was the government guided by its desire to show that "we British are made of sterner stuff?"
3. Now the Minister is saying that Social Distancing will be maintained till we have a vaccine (apparently within a year). Does the Minister not know that it takes far far longer to check that the vaccine does not cause harm? And that it actually protects? Do I have to remind the Minister that this virus is rapidly mutating?
I could give you chapter snd verse of my rapid responses on CORONA. But if anyone is in doubt, it is simple to look up the rapid responses: they are searchable on bmj.com.
Competing interests: Might be caught by it (I won’t go out of my way to catch it).
Dear Editor
Alastair M Sammon states 'chloroquine good, NSAIDs bad.'
These currently are opinions, one backed by President Trump, one backed by NICE. Neither have any published robust evidence behind them at today's date (16.4.2020). So important that need to ensure responses don't infer 'fact'.
Competing interests: No competing interests
Dear Editor
Covid-19: a puzzle with many missing pieces
TO THE EDITOR:
Emerging pieces of the Covid-19 puzzle include:
Very strong gender bias
Strong age bias
An observed but unclear relationship with BCG
Chloroquine good, NSAIDs bad – both drugs with effects on immune function
Unexpected delay in spread of the epidemic in Africa
What connects these? A possibility that fits with the facts is that the lung pathology of severe Covid-19 infection is dependent on a strong Type IV cellular response, known to be a factor in men and in older people.
History and theory suggest a low Th1 activity in East African countries with a poor maize-based diet 1, where TB and measles have been common killers, and where kwashiorkor children were once described as having a nutritional thymectomy 2. The almost exclusive dominance of dietary omega-6 in a maize-based diet is a background to this.
Poverty of Th1 response may therefore have changed from liability to asset. This interpretation does not predict less infection, but does predict a reduction in severe lung pathology in countries with reduced Th1 immune competence – for example East, Central and Southern Africa.
The Veneto region of Italy has historically been a maize dependent area also, and while other good explanations have been offered, it is fascinating to see a much lower reported Covid-19 mortality rate there than in other parts of Italy where a ‘Mediterranean’ diet, containing much Omega-3, is normal.
It is perhaps too early to see the pattern clearly. Africa must hold its breath.
Alastair M Sammon
Honorary Professor of Human Biology
Walter Sisulu University, South Africa
1) Sammon AM. Dietary linoleic acid, immune inhibition and disease. Postgraduate Medical Journal. 1999; 75(881);129-132. DOI:10.1046/j1365-2168.1998.00780.x
2) Smythe PM, Schonland M, Brereton-Stiles GG et al. Thymolymphatic deficiency and depression of cell-mediated immunity in protein-calorie malnutrition. Lancet 1971; 2:939-944 DOI:10.1016/s0140-6736(71)90267-4
Competing interests: No competing interests
Dear Editor
Dear Editor
In Italy, the debate on Covid-19 has been extended to its possible link with air pollution, above all due to the high concentration of Covid-19 in the Po Valley, which is recognized as one of the most polluted large geographical areas in Europe. A BMJ rapid-response letter on February 26 2020, in response to a previous one published on 19 February 2020 (BMJ 2020;368:m627), had already urged for studing exposure–response relationship between air pollutant concentrations and Covid-19 cases during the current outbreak.
Covid-19 affects many organs of the human system, including the upper respiratory tract and lungs.
Of the 5,542 deaths in Italy due to Covid-19, 7 out of 10 were male, the majority were elderly (median age 78 years), compared to a median of 63 years of live patients with positive test [1].
The medical records of 514 deceased patients show that over two thirds had two or more diseases: ischemic heart disease (24.5%), hypertension (74.7%), renal failure (23.2%), diabetes (30.5%), and COPD (19.1%). There is an increasing focus on the comorbidity in terms both of managing Covid-19 patients and not slowing down the prevention and treatment of comorbidities.
Most of the diseases involved, especially respiratory and cardiovascular diseases, have also been shown to be associated with exposure to air pollution [2].
These findings have undoubtedly increased the public concern, largely amplified by media and social media, and the need to investigate the relationship between diseases, pollution and Covid-19.
To contribute to knowledge advancement, study proposals should take into account the strength of the evidence on environment-health relationships and the potential link with Covid-19.
Evidence of a causal link between air pollution and many diseases are robust [3], with estimates of disease risk and premature death from various causes [4-7].
Evidence that long-term exposure to atmospheric particulates decreases the body's defences against bacterial and viral pathogens appear sufficient, particularly by altering the response of bronchial epithelial cells via inflammatory processes and endothelial dysfunction, and exacerbating the conditions of chronically ill patients, particularly those with COPD and asthma [8-14], and children with acute respiratory infections [15].
Knowledge concerning how atmospheric particulates facilitate the transport of pathogens is weaker [16 – 20], and needs to be strengthened.
Assessing the effects of air pollution on the spread of COVID-19 is challenging as it entails considering all of, or at least the main, local conditions relating to air quality trends, the characteristics of the resident communities, the pre-existing state of health and co-factors linked to both pollution and diseases (e.g. age and socio-economic conditions), and possibly also information on the adopted Covid-19 containment measures and indicators of a decrease in ordinary disease prevention and control during the critical phase. In the dramatic current phase, we believe that this is not the time for ecological studies, involving work and resources, leading to the classic conclusion "further studies are needed". Instead, studies with etiological design to investigate the influence of pollution on Covid-19 and on other related recognized diseases should be carried out. Such studies should take into account the trend of Covid-19 indicators and of the concentration of air particulates in the epidemic period, as well as the related (confounding) factors. These studies should be carried out on small geographical areas or, where possible, by individual residential data.
This type of study is complex, requiring the collaboration of many disciplines - other than environmental epidemiology. The Italian Environment and Health Network funded by the Ministry of Health (RIAS project) should also be involved, as it brings together the principle actors operating in the health field and in the national system of environmental agencies Non-profit associations and citizen’s committees should also be included, thus giving full meaning to the concept of citizen science, which is often lauded but rarely practiced.
Our institutes have presented a proposal to the National Research Council to study the relationship between air pollution and viral transmission in the human population, exploiting the current information on health flows and integrating them with the spatial and temporal modeling of data on concentrations of air pollutants, obtained both from terrestrial monitoring stations and from satellite models. By comparing different geographical areas and taking into account all the confounding factors, our aim is to provide key evidence on whether air pollution facilitates viral transport and thus inter-human contagion.
In support of the Covid-19 containment measures established by law, while we wait to begin the research investigations, we aim to promote recommendations regarding environmental and individual risk factors. In addition to maintaining the high focus on outdoor pollution, given the amount of time spent in the home, tobacco smoke - the greatest risk for the respiratory system - should be avoided or at least limited, and all environments should be adequately ventilated.
Fabrizio Bianchi (PhD, epidemiologist) 1 and Fabio Cibella (MD, epidemiologis) 2
1 Environmental Epidemiology Unit, Institute of Clinical Physiology, National Research Council, Pisa, Italy
2 Institute for Biomedical Research and Innovationa, National Research Council, Palermo, Italy
References
1. https://www.epicentro.iss.it/coronavirus/bollettino/Report-COVID-2019_24...
2. WHO. Noncommunicable Diseases and Air Pollution. WHO European High-Level Conference on Noncommunicable Diseases. Time to Deliver: meeting NCD targets to achieve Sustainable Development Goals in Europe 9-10 April 2019, Ashgabat, Turkmenistan. Available at: http://www.euro.who.int/__data/assets/pdf_file/0005/397787/Air-Pollution...).
3. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Outdoor Air Pollution. Volume 109. Lyon, France - 2016
4. Schraufnagel DE, Balmes JR, Cowl CT, De Matteis S, Jung SH, Mortimer K, Perez-Padilla R, Rice MB, Riojas-Rodriguez H, Sood A, Thurston GD, To T, Vanker A, Wuebbles DJ. Air Pollution and Noncommunicable Diseases: A Review by the Forum of International Respiratory Societies' Environmental Committee, Part 2: Air Pollution and Organ Systems. Chest. 2019 Feb;155(2):417-426. doi:10.1016/j.chest.2018.10.041
5. Chen S, Bloom DE. The macroeconomic burden of noncommunicable diseases associated with air pollution in China. PLoS One. 2019 Apr 18;14(4):e0215663. doi: 10.1371/journal.pone.0215663
6. Campbell-Lendrum D, Prüss-Ustün A. Climate change, air pollution and noncommunicable diseases. Bull World Health Organ. 2019 Feb 1;97(2):160-161. doi:10.2471/BLT.18.224295
7. Figueres C, Landrigan PJ, Fuller R. Tackling air pollution, climate change, and NCDs: time to pull together. Lancet. 2018 Oct 27;392(10157):1502-1503. doi:10.1016/S0140-6736(18)32740-5
8. Yang L, Li C, Tang X. The Impact of PM2.5 on the Host Defense of Respiratory System. Front Cell Dev Biol. 2020 Mar 4;8:91.
9. Glencross DA, Ho TR, Camiña N, Hawrylowicz CM, Pfeffer PE. Air pollution and its effects on the immune system. Free Radic Biol Med. 2020 Jan 30. pii:S0891-5849(19)31521-7.
10. Zarcone MC, van Schadewijk A. Duistermaat E, Hiemstra PS, Kooter IM. Diesel exhaust alters the response of cultured primary bronchial epithelial cells from patients with chronic obstructive pulmonary disease (COPD) to non-typeable Haemophilus influenzae. Respir Res. 2017 Jan 28;18(1):27.
11. Ghio AJ. Particle exposures and infections. Infection. 2014;42:459–67.
12. Alexis NE, Carlsten C. Interplay of air pollution and asthma immunopathogenesis: a focused review of diesel exhaust and ozone. Int Immunopharmacol. 2014;23:347–55
13. Steiling K, van den Berge M, Hijazi K, Florido R, Campbell J, Liu G, Xiao J, Zhang X, Duclos G, Drizik E, et al. A dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment. Am J Respir Crit Care Med. 2013;187:933–42
14. Abe S, Takizawa H, Sugawara I, Kudoh S. Diesel exhaust (DE)-induced cytokine expression in human bronchial epithelial cells: a study with a new cell exposure system to freshly generated DE in vitro. Am J Respir Cell Mol Biol. 2000;22:296–303
15. Mehta S, Shin H, Burnett R, North T, Cohen AJ. Ambient particulate air pollution and acute lower respiratory infections: a systematic review and implications for estimating the global burden of disease. Air Qual Atmos Health. 2013 Mar;6(1):69-83
16. Khare P, Marr LC. Simulation of vertical concentration gradient of influenza viruses in dust resuspended by walking. Indoor Air. 2015 Aug;25(4):428-40. Alonso et al. Concentration, Size Distribution, and Infectivity of Airborne Particles Carrying Swine Viruses. PLoS One. 2015 Aug;25(4):428-40.
17. Gralton J, Tovey ER, McLaws ML, Rawlinson WD. Respiratory virus RNA is detectable in airborne and droplet particles. J Med Virol. 2013 Dec;85(12):2151-9.
18. Chen G, Zhang W, Li S, Williams G, Liu C, Morgan GG, Jaakkola JJK, Guo Y. Is short-term exposure to ambient fine particles associated with measles incidence in China? A multi-city study. Environ Res. 2017 Jul;156:306-311. doi:10.1016/j.envres.2017.03.046.
19. Ye Q, Fu JF, Mao JH, Shang SQ. Haze is a risk factor contributing to the rapid spread of respiratory syncytial virus in children. Environ Sci Pollut Res Int. 2016 Oct;23(20):20178-20185.
20. Cui Y, Zhang ZF, Froines J, Zhao J, Wang H, Yu SZ, Detels R. Air pollution and case fatality of SARS in the People's Republic of China: an ecologic study. Environ Health. 2003 Nov 20;2(1):15.
Competing interests: No competing interests
Fasting Ramadan During the COVID-19 Pandemic
Dear Editor
Fasting Ramadan During the COVID-19 Pandemic
Ramadan is a holy month for Muslims. The vast majority of healthy adult Muslims practice fasting by abstaining from any food, drinks, and medications from dawn until sunset for 30 days. This year, approximately1.9 billion will observe the month of Ramadan during an unprecedented time; the pandemic of Coronavirus Disease 2019 (COVID-19) which has beena major global threat [1]. Herein, we discuss some of the implications of fasting amid the COVID-19 pandemic.
Currently, there is no evidence suggesting that fasting increases thevulnerability for COVID-19 infection [1], but some studies previously evaluated the effect of fasting on other viral infections. In one animalmodel, anorexia associated with acute influenza illness induced by blocking glucose utilization had a lethal effect [2]. Although intermittent fasting could lead to an early increase in body stress by transient alteration in circadian rhythm and cause a significant diurnalvariation in serum cortisol level which normalises after fasting cessation [3]. One study of 608 healthy non-fasting volunteers showed that a high level of basal salivary cortisol increased the susceptibility to rhinovirus infection and prolonged the viral shedding duration. However, this did not translate into subsequent clinical illness [4]. Supporting this notion, a systematic review of 25 observational studies on healthy individuals found that fasting had no or only mild transient alteration in immune system response [5]. Collectively, these findings suggest that intermittent fasting might increase viral shedding among other non-coronaviruses, but overall the increase in serum cortisol levels due to fasting does not seem to translate to worsening clinical manifestations among the studied viral infections. Whether these findings are applicable to COVID-19 infection is yet to be determined.
Intermittent fasting triggers metabolic switching from glucose based to ketone based energy, which promotes cellular stress resistance, hemopoiteic stem cells self-renewal, and reverses immunosuppression. As aresult, several makers of systemic inflammation and oxidative stress decrease [6]. In a small sized cross-over randomised trial of pre-diabetic men who underwent intermittent fasting for 18 hours a day for 5 weeks, there was a significant improvement in oxidative stress levels without a significant effect on cortisol level or increase risk of infectious events [7]. Middle-Eastern countries with high representation of Muslims have a high prevalence of cardiovascular disease and cardiovascular risk factors [8], which have been linked to worse clinical outcomes among patients with COVID-19 infections [9]. Intermittent fasting promotes cardio-metabolic profile by improving blood pressure, body weight, lipid profile, glucose tolerance, and insulin resistance. These cardio-protective mechanisms are more evident within 2 to 4 weeks of fasting [3,5,6]. Whether these observed cardiometabolic improvements at cellular and metabolic levels are protective against serious adverse events with COVID-19 infection remains an interesting knowledge gap.
Fasting Ramadan has a great spiritual significance for Muslims. As such, we urge Muslim communities to ensure safe Ramadan practices such as maintaining social distancing, healthy hygiene and self-being, with potential cancellation of all social, communal meals, and religious gatherings [1]. Also we suggest modified or extended quarantine protocols up to 21 days for those who have asymptomatic or mildly symptomatic COVID-19 given the theoretical risk of prolonged viral shedding associated with fasting which has been observed with other viral infections, until further evidence becomes available [10]. Although, there have been no studies on fasting and risk of COVID-19 infection; healthy individuals can safely fast. However, high-risk individuals should consult their physicians prior to fasting for their candidacy for fasting and reconciliation of their chronic medical conditions.
References:
1. Safe Ramadan practices in the context of the COVID-19. Interim guidance. https://apps.who.int/iris/handle/10665/331767 (accessed April 23 2020).
2. Wang A, Huen SC, Luan HH, et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell2016;166:1512-25.
3. Roky R, Houti I, Moussamih S, et al. Physiological and chronobiological changes during Ramadan intermittent fasting. Ann Nutr Metab 2004;48:296-303.
4. Janicki-Deverts D, Cohen S, Turner RB, et al. Basal salivary cortisolsecretion and susceptibility to upper respiratory infection. Brain Behav Immun 2016;53:255-61.
5. Adawi M, Watad A, Brown S, et al. Ramadan fasting exerts immunomodulatory effects: Insights from a systematic review. Front Immunol 2017;8:1144.
6. de Cabo R, Mattson MP. Effects of intermittent fasting on health, aging, and disease. N Engl J Med 2019;381:2541-51.
7. Sutton EF, Beyl R, Early KS, et al. Early time-restricted feeding improves insulin sensitivity, blood Pressure, and oxidative stress even without weight loss in men with prediabetes. Cell Metab 2018;27:1212-21.
8. Roth GA, Johnson C, Abajobir A, et al, et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. JAm Coll Cardiol 2017;70:1-25.
9. hou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-62.
10. To KK, Tsang OT, Leung WS, et al. Temporal profiles of viral load inposterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis 2020. pii: S1473-3099(20)30196-1.
Competing interests: No competing interests