Response to the emerging novel coronavirus outbreak
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m406 (Published 31 January 2020) Cite this as: BMJ 2020;368:m406Read our latest coverage of the Coronavirus outbreak
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Dear Editor,
The possible therapeutic role of Angiotensin II receptor blockers (ARIIB) in the Corona epidemic.
There is evidence to support that Covid-19 virus is using the ACE2 receptor for cell entry(1,2). We are extremely lucky if this is the case as Renin Angiotensin System (RAS) is one of the best studied and manipulated pathways in medicine.
If we look at the available research on ACE2 it is evident that ACE2 plays a crucial role in Angiotensinogen II metabolism. ACE2 converts Angiotensin II to Angiotensin 1-7 a molecule with vasodilator properties. ACE2 plays a role in converting Ang II (Vasoconstrictor) to Ang 1-7 production (Ang 1-7 is a potent vasodilators). Angiotensinogen II is a potent vasoconstrictor and can cause oxidative stress to lung tissue.
Therefore, ACEII plays a significant role in preventing deleterious effects of Angiotensin II in lung tissue(3). When the virus interacts with the ACEII molecule it gets internalized exposing lungs to unopposed action of ACEII. It has been postulated that one of the mechanisms of corona virus related lung injury is that lack of ACEII on surface of pneumocytes.
Furthermore, ACE2 expression is abundant in the kidney and is thought to provide protection against injury(4).
There are articles published in Chinese language suggesting that ACE inhibitors and ARIIB can be used as a therapeutic agent (5). However, looking at the above-mentioned lung/renal injury mechanism ACE Inhibitors are unlikely to be helpful.
In light of this evidence there is a need to:
1. see the prevalence of ARDS among corona virus infected patients who are already on ARII blockers.
2. assess ARIIB (a well tested drug for other indications) as a therapeutic agent to prevent ARDS and AKI in corona virus infected high-risk patients. (Not ACE Inhibitors)
References.
1. Bosch BJ, Smits SL, Haagmans BL. Membrane ectopeptidases targeted by human coronaviruses. Curr Opin Virol. 2014 Jun;6:55-60. doi: 10.1016/j.coviro.2014.03.011. Epub 2014 Apr 22. PMID: 24762977; PMCID: PMC4072739
2. Wan Y, Shang J, Graham R, Ralph S. Baric, Fang Li. Receptor recognition by novel coronavirus from Wuhan: 3 An analysis based on decade-long structural studies of SARS. Journal of virology. J. Virol. doi:10.1128/JVI.00127-20
3. Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, Crackower MA, Fukamizu A, Hui CC, Hein L, Uhlig S, Slutsky AS, Jiang C, Penninger JM. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005; 436:112–116. [PubMed] [Google Scholar
4. Williams, Vanessa R., Scholey, James W.Angiotensin-converting enzyme 2 and renal disease. Current Opinion in Nephrology and Hypertension: January 2018: Volume 27-Issue 1 p 35-41.doi: 10.1097/MNH.0000000000000378.
5. Sun M, Yang J, Sun Y, Su GH.Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia 2020 Feb 16;43(0):E014. doi: 10.3760/cma.j.issn.1001-0939.2020.0014. [Epub ahead of print]
Competing interests: No competing interests
SARS-CoV-2 was recently declared a pandemic by the World Health Organization with over 175,000 cases identified globally.(1) There is a great urgency to develop and evaluate vaccines, but we are some time away from a vaccine or vaccines to protect against this novel coronavirus. Even then, immunization would only protect against the spread of new cases, whereas treatment options for current and future cases are limited to mostly supportive care. Several studies have now described the clinical course and outcomes of those who contracted SARS-CoV-2, with a majority of moderately or severely ill patients requiring high flow nasal cannula or mechanical ventilation. A proportion of patients were treated with various antiviral agents, glucocorticoids, and immunoglobulin therapy.(2,3)
Various pharmaceuticals therapies such as ARBs, antivirals, Ribavirin, Chloroquine, protease inhibitors, immunosuppressive compounds, monoclonal antibodies, oligonucleotide-based therapies, peptides, interferon therapies, or their combinations have been recently proposed for or used as treatment in patients with SARS-CoV-2.(4-6) However, these therapies pose serious side effects when given systemically, and could lead to the deterioration of the clinical status of these fragile patients. Direct pulmonary delivery (Aerosol, Inhalers, etc.) is a more selective mode of drug delivery, requires less quantity of drug, however, it has a limited efficacy due improper dosing, stability, and difficulty in producing optimum particle size. Additionally, not all drugs can be delivered via a pulmonary route due to formulation difficulties. Nanoparticles or other carrier-based drug delivery could prove to be an excellent alternative; however, they too require a substantial time for development and testing.
Ongoing research so far suggests that SARS-CoV-2 demonstrates tissue tropism for the lower respiratory system, which would favor the local delivery of a therapeutic to the lungs versus a systemic approach. In addition, a small study recently reported that a very small proportion of blood samples demonstrated viral loads, in contrast to samples taken from the lungs. (7) Therefore, we propose a transcatheter-based, local delivery of pharmaceuticals in this cohort of critically ill patients. Unlike systemic delivery, this mode of drug delivery would target the tissue at greatest risk.
Percutaneous catheter based local delivery of pharmaceuticals is a well-established procedure, such as trans-arterial chemotherapy using micro-catheters for the treatment of lung malignances. (8) Recently another trans-venous route via pulmonary arteries were also studied. Standard bronchoscopes are not able to reach the distal branches of the bronchi due to size and flexibility constraints. Alternatively, the drug could be delivered into the lung using an airway Micro catheter via bronchoscope, distributed across the airway epithelium, and absorbed locally. Therefore, a flexible, small diameter micro-catheter can aid in targeted delivery. However, there are certain logistical challenges one would need to overcome, specifically when dealing with patients suffering from a viral infection. These challenges include the transfer of critically ill and contagious patients from isolation wards to the bronchoscopy suits or catheterization labs, the tolerance to contrast mediums, and which commercially available pharmaceuticals to use. Nonetheless, we believe this would be a worthwhile effort to increase the efficacy and safety of possible SARS-CoV-2 treatment options.
References:
1. Coronavirus disease 2019 (COVID-19): Situation Report – 51: World Health Organization, 2020.
2. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020 doi: 10.1001/jama.2020.1585 [published Online First: 2020/02/08]
3. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020 doi: 10.1016/S2213-2600(20)30079-5 [published Online First: 2020/02/28]
4. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020 doi: 10.1016/j.cell.2020.02.052 [published Online First: 2020/03/07]
5. Sun ML, Yang JM, Sun YP, et al. [Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi 2020;43(0):E014. doi: 10.3760/cma.j.issn.1001-0939.2020.0014 [published Online First: 2020/02/16]
6. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30(3):269-71. doi: 10.1038/s41422-020-0282-0 [published Online First: 2020/02/06]
7. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA 2020 doi: 10.1001/jama.2020.3786 [published Online First: 2020/03/12]
8. Yuan Z, Li WT, Ye XD, et al. Intra-arterial infusion chemotherapy for advanced non-small-cell lung cancer: preliminary experience on the safety, efficacy, and clinical outcomes. J Vasc Interv Radiol 2013;24(10):1521-8 e4. doi: 10.1016/j.jvir.2013.05.065 [published Online First: 2013/08/03]
Competing interests: No competing interests
Dear Editor,
Angiotensin II receptor blockers (ARB) are currently debated as an option for treatment of coronavirus disease 2019 (COVID-19).
Angiotensin I is converted to Angiotensin II by angiotensin converting enzyme (ACE). Angiotensin II is responsible for vasoconstriction and proinflammatory effects mediated by angiotensin receptor type I (AT1). Angiotensin converting enzyme 2 (ACE2) converts Angiotensin II to Angiotensin 1-7 which on the contrary exhibits vasodilatory and antiinflammatory effects and outweights the effect of angiotensin II mediated by AT1. Patients on chronic treatment with ACE inhibitors upregulate both AT1 receptors and ACE2 that are affected by diminished amount of Angiotensin II produced by alternative enzymatic pathways (e.g. by chymases), nevertheless still in a balanced manner. It has been demonstrated that ACE2 serves as a binding site for SARS-CoV-2 enabling viral entry. Continuous elimination of ACE 2 from the cell surface decreases residual ACE2 activity shifting the balance towards AT1 activation causing pulmonary vasoconstriction, excessive inflammation and finally acute lung injury. At the same time unoppossed effect of angiotensin II leads to mycardial injury and elevation of blood pressure which are observed in the most severe cases.
Therefore switching from ACE inhibitors to ARB might be beneficial in patients at risk or with COVID-19 in prevention of such sequelae when they are already on therapy affecting the Renin-Angiotensin System. Both ACE inhibitor and ARB have shown comparable long-term benefit in prevention of adverse cardiovascular events which makes the switch justifiable, moreover with reduction of cough which can be misinterpreted as one of COVID-19 signs.
On the contrary switching to other antihypertensive drugs at the moment of upregulation of AT1 receptors and ACE2 or even starting the treatment with ARB in ARB-naïve patients is controversial.
References:
1, https://www.bmj.com/content/368/bmj.m406/rr-19
2, Kuba, Keiji et al. Lessons from SARS: control of acute lung failure by the SARS receptor ACE2. Journal of Molecular Medicine 84 (2006): 814-820.
3, Zheng, Y., Ma, Y., Zhang, J. et al. COVID-19 and the cardiovascular system. Nat Rev Cardiol (2020). https://doi.org/10.1038/s41569-020-0360-5
Competing interests: No competing interests
Dear Editor,
Several authors have debated the potential role of angiotensin converting enzyme (ACE) inhibitors (ACEi) and angiotensin receptor blockers (ARBs) in treatment of coronavirus disease 2019 (COVID-19) [1-6], based on the evidence that ACE 2 (ACE2) has been identified as the host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [7]. We support the hypothesis that dysregulation of the renin angiotensin system (RAS) may serve a central role in the pathophysiology of COVID-19 associated acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). However, we believe that some clarification is needed.
Angiotensin I is converted to angiotensin II (AngII) by ACE. AngII mediates vasoconstrictive, pro-inflammatory and pro-oxidative effects through agonism at AngII receptor type 1 (AT1) [8]. ACE2 converts AngII to angiotensin 1-7 (Ang1-7), which through binding Mas receptor (MasR) mediates anti-inflammatory, anti-oxidative and vasodilatory effects [8]. Hence, the ACE2/Ang1-7/MasR axis opposes the actions of the ACE/AngII/AT1 axis.
COVID-19 appears more severe in patients with hypertension, cardiovascular disease and diabetes [9, 10]. These disorders are associated with decreased baseline levels of ACE2 expression [3]. We postulate here that SARS-CoV-2 binding to ACE2 may attenuate residual ACE2 activity, further skewing the ACE/ACE2 balance to a state of predominant ACE/AngII/AT1 axis signaling, in which AngII causes pulmonary vasoconstriction, and inflammatory and oxidative organ damage, ultimately progressing towards ALI/ARDS [11].
This theory is supported by a recent publication by Liu et al, demonstrating that serum AngII levels in patients with COVID-19 were significantly higher than in non-infected individuals, and more importantly, were linearly associated with viral load and lung injury [12].
As such, we believe that RAS modulation may have a potential role in treatment of selected patients with severe COVID-19 at risk for ALI/ARDS. Since ACEi can lead to cough secondary to accumulation of bradykinin, we believe ARBs, recombinant ACE2 or Ang1-7 may be more favorable treatment options. Of note, a pilot clinical trial of recombinant ACE2 in ARDS showed that the treatment was well tolerated and led to decreased serum AngII and increased serum Ang1-7 levels [13]. To further evaluate the role of RAS modulation in COVID-19, datasets should be analyzed to investigate if use of ACEi and ARBs on admission could be associated with ALI/ARDS and/or mortality in patients with diabetes, hypertension and cardiovascular disease.
Brandon Michael Henry, M.D.
Cincinnati Children’s Hospital Medical Center
3333 Burnet Ave., Cincinnati, OH, USA 45229
brandon.henry@cchmc.org
Jens Vikse, M.D.
Stavanger University Hospital
Gerd-Ragna Bloch Thorsens gate 8, 4011 Stavanger, Norway
jens.vikse@sus.no
Giuseppe Lippi, M.D.
University Hospital of Verona
Piazzale Scuro 10, 37134 Verona, Italy
giuseppe.lippi@univr.it
References
1) https://www.bmj.com/content/368/bmj.m406/rr-2
2) https://www.bmj.com/content/368/bmj.m406/rr-7
3) https://www.bmj.com/content/368/bmj.m406/rr-11
4) https://www.bmj.com/content/368/bmj.m406/rr-12
5) https://www.bmj.com/content/368/bmj.m406/rr-13
6) https://www.bmj.com/content/368/bmj.m406/rr-15
7) Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. Journal of Virology 2020.
8) Tikellis C, Thomas MC. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. Int J Pept .2012;2012:256294.
9) Guan W-J, Ni Z-Y, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020.
10) Zhou 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
11) Zhang H, Baker A. Recombinant human ACE2: acing out angiotensin II in ARDS therapy. Crit Care. 2017;21(1):305.
12) Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364-374.
13) Khan A, Benthin C, Zeno B, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017;21(1):234.
Competing interests: No competing interests
Dear Editor
I know nothing of this disease. But I have lived through and worked through smallpox - in England and abroad.
May I be permitted to offer my thoughts to Mr Alireza Sherafat, medical student ( Response 10:March).
Your para 3.
Agreed. It would be difficult, almost impossible to impose quarantine on the whole of the UK. BUT there is no need to do so. All we need to do is to slow down the spread. This can be done by banning such activities as bring lots of people together unnecessarily in this case.. We can stop going to cinemas, for example. The government could close down cinemas, theatres, matches.
Your para 4.
It is not just difficult. It is impossible to diagnose cases without laboratory aids. Even these have been found to give false positives, false negatives, negatives one day, positive another day. Firm Clinical diagnosis is impossible. You can have a wager - putting history, clinical findings and lab test results together. But that is all.
Para 5.
Medical students, juniors doctors, even consultants, are not particularly prone to develop an infection within the clinical environment. They will do so most often when they have broken some red line or another. (That is my explanation of having picked up, Hepatitis A, half a century ago.) Are you washing hands before sticking them in your mouth, or picking up the sandwich, stuffing it in the mouth as you dash from the ward to the theatre? Do you use gloves whenever you can? Admittedly the pulp of your index finger is the best means of palpating.......
Para 6.
Workshops, small rooms.
Have you checked if the rooms are air-conditioned, or, whether there is good ventilation?
Para 7.
International students and holidays abroad. This is in the students’ own hands. Stay put, I say.
Finally, might I suggest that something has to give. You could cut down on socialising outside your familiar circle. If you are married - stay clear of your spouse and infants after working with a known patient.
In my public health days, before setting out to see a case of suspected smallpox, I would ask my wife to put clean clothes in the bed-room, to keep the washing machine empty, the hot water or a shower ready. On returning from seeing the patient, having checked that my wife and children were out of sight, I would put my “possibly” infected clothes in the washing machine at 60 degree C, have a shower, put on clean clothes and only then return to my family.
You could do the same after your Corona encounter?
Now I look forward to corrections, improvements.
Competing interests: I am aged. Might need doctors!
Dear Editor,
It seems everyone is getting concerned about corona virus these days and members of the public frequently refer to their concerns on multiple occasions each day. On Tuesday 5th of March 2020; the first death due to infection with Corona Virus occurred in the UK which will turn all the public concerns into a new phase of anxiety1.
In December 2020, the Corona Virus outbreak began in Wuhan City, China. Since then, there has been growing concern about worldwide spread of the disease1. Later in February 2020, with further spread to South Korea , Japan, Italy and Iran; it turned into a global concern 1.
There has been no specific geographical patterns in diagnosis of cases within the UK as opposed to Italy, Korea, and China; so it would be difficult practically to impose quarantine regulations 1.
Vague presentations and long incubation period of Corona Virus (up to 2 weeks) makes it particularly difficult to screen for and diagnose at an early stage to initiate isolation and prevention methods2. Contact tracing has not been completely successful in the UK as on 29th February 2020 the first case to be infected within the UK was diagnosed 3.
Medical students are particularly prone to develop an infection within the clinical environment and becoming an asymptomatic carrier of Corona Virus and pass it to the immunocompromised patients, especially those from the elderly population.
The main fear of Corona Virus originates from its novelty and lack of enough evidence-based knowledge on its surveillance and treatment protocols 6 .
Medical courses are amongst the most populated Higher Education programmes in the UK. Lectures with significant number of attendees (over 1,000 at some medical schools), PBL/CBL sessions in small rooms, anatomy sessions and clinical skills workshops often involve a significant amount of exposure to airborne pathogens and risk of human to human transmission of viral illnesses such as Corona Virus7.
Medical schools with high proportion of international medical students are at particular risk due to the frequency of students travelling abroad. For example, a significant number of international students travelled abroad during the Chinese New Year in January 2020. Moreover, Iranian new year will be in March 2020 very close to the Easter holidays.
One of the likely scenarios in the UK is to close universities and schools to prevent further spread of the disease. In the event of medical schools not running the lectures; how would they ensure the learning objectives of MBBS/MBChB courses are still addressed? also those delivering CBL/PBL model would struggle to run teamwork-based sessions. Closing medical schools would also affect practical and simulation sessions such as anatomy practical sessions and simulated skills lab workshops with volunteer patients. Although some would argue online teaching can be a temporary substitute, it would not be feasible to teach practical skills online.
The following questions are amongst main concerns of UK medical students:
• What sort of specific measures do medical schools and teaching hospitals have in preparation for a Corona Virus outbreak?
• What are the implications of a possible closure of medical schools on teaching sessions and delivery of practical material?
• How would medical schools address the concerns regarding the Health and Safety of medical students while on clinical placements at major NHS Teaching Hospitals?
• As the NHS is currently under significant pressure from the winter crisis, what would be the impact of a new outbreak on the quality of care provided to patients?
The Corona Virus outbreak seems to be closer than ever to the UK and medical students are going to be affected in many ways. It is certainly the time to raise awareness and discuss the issues surrounding prevention, surveillance, diagnosis, treatment and likely complications of Corona Virus particularly in those with underlying health conditions. Finally, concerns of medical students with regards to their education should be addressed and they ought to be involved in making decisions and raising Public Health awareness on the issues surrounding Corona Virus.
1. Older patient becomes first virus fatality in UK [Internet]. BBC News. 2020 [cited 5 March 2020]. Available from: https://www.bbc.co.uk/news/uk-51759602
2. Overview of coronaviruses - Summary of relevant conditions | BMJ Best Practice [Internet]. Bestpractice.bmj.com. 2020 [cited 5 March 2020]. Available from: https://bestpractice.bmj.com/topics/en-gb/3000165
3. Coronavirus patient first to be infected in UK [Internet]. BBC News. 2020 [cited 5 March 2020]. Available from: https://www.bbc.co.uk/news/uk-51683428
4. Coronavirus: Italy and Iran close schools and universities - BBC News [Internet]. BBC News. 2020 [cited 5 March 2020]. Available from: https://www.bbc.co.uk/news/live/world-51747782
5. Coronavirus Disease 2019 (COVID-19) [Internet]. Centers for Disease Control and Prevention. 2020 [cited 5 March 2020]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/summary.html
6. London firms send staff home amid coronavirus fear [Internet]. BBC News. 2020 [cited 5 March 2020]. Available from: https://www.bbc.co.uk/news/business-51643621
7. Rapid risk assessment: Outbreak of novel coronavirus disease 2019 (COVID-19): increased transmission globally – fifth update [Internet]. European Centre for Disease Prevention and Control. 2020 [cited 5 March 2020]. Available from: https://www.ecdc.europa.eu/en/publications-data/rapid-risk-assessment-ou...
Competing interests: No competing interests
Dear Editor
Regarding the possible use of angiotensin II receptor antagonists (ARBs) to mitigate the lung damage caused by corona virus, some clarifications are necessary.
1- ACE1 is the enzyme that causes the formation of the vasoconstrictor hormone angiotensin II (Ang II)
2- Ang II shows a powerful pro-inflammatory action in lung tissue
3- ACE2 is the enzyme that deactivates Ang II by forming the angiotensin vasodilator hormone (1-7) (rebalancing the effects of Ang II)
4- ACE2 is also the receptor for the spike protein (protein present outside the coronavirus: MERS, SARS1 and SARS2)
5- The binding of viruses attenuates or cancels the activity of ACE2, causing the circulation of an excess of Ang II with consequent inflammatory damage
6- Ang II acts through AT1R receptors; this activity can be inhibited / attenuated by some well-known drugs (sartans or ARBs) widely used in antihypertensive therapy
I believe these premises may suggest the possibility of the use of ARBs to ameliorate pulmonary injury caused by coronavirus infections.
Various scientific articles, and also a patent application, can be found in support of this hypothesis.
References:
- A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus induced lung injury (NATURE MEDICINE VOL
11 | Nr 8 | pag 875 | 2005)
- US20060135422A1 USE OF ANGOTENSIN RECEPTOR BLOCKERS (ARBS) TO TREAT DISEASES ASSOCATED WITH EXCESS
ACE
- Reducing mortality from 2019-nCoV: host-directed therapies should be an option
(the lancet Vol 395 | e35 | 2020)
Competing interests: No competing interests
Dear Editor
1. Our Minister and our Chief Medical Officer announced that the government has prepared plans for countering CORONA if an epidemic hits us.
Q. Why is the Govt keeping its perfect plans under wraps? Why are we being told NOW, what the plans are?
2. Another matter concerns the public and the veterinary surgeons. It is reported from Hong Kong that a pet dog has been found to harbour the virus. Presumably caught from its master who is a known patient. But we cannot be sure that it was not the already infected dog whose loving master caught it from the pet.
Q, Has the Chief Veterinary Officer advised the veterinarians to sample the virology of such animals ( dogs AND cats) who are presented with symptoms related to the respiratory tract?
3. Travellers will inevitably import sometimes, the Corona Virus.
Q. Have the airport and seaport Medical staff been instructed to obtain correct temperature readings? The electronic scan is utterly useless unless the operator has allowed time for the external body temperature to
be fully representative of the blood temperature. This matter has been known for generations. We were taught that rectal temperature is THE correct body temperature, you could use the sublingual temperature if the patient has not , in the previous 15 minutes or so, drunk or eaten material at other than the body temperature.
I appreciate that the modern electronic instruments are supposed to gauge the body temperature without touching the skin. But are we sure that the operator has allowed sufficient time for the blood flow in the skin to give the correct reading? Will the cold ambient air not interfere with the reading?
Perhaps I am looking for problems where there are none. In which case please tell me so.
4. Saudi Arabia has banned pilgrimages. Very sensible.
Will the governments of other holy places - Jerusalem,( Israel), the Vatican, Qom,( Iran) Hardwar, Mathura, Benarus, and such like ( India) follow the Saudi example?
.I apologise to the travel agents, the airlines, the traders, as my proposals , if accepted, will hit their profits.
Competing interests: No competing interests
Dear Editor
It has been established that the ACE2 receptor is the entry point for COVID-19.
The ACE2 receptor acts as an Angiotensin 2 (AT2) converter to into the vasodilator and antitrophic heptapeptide, angiotensin-(1–7).
It has 60% homology with ACE1 receptor but ACE inhibitors have no ACE2 activity.
Angiotensin Receptor Blockers (ARBs) block AT2 receptors and increase circulating Angiotensin 2 levels approximately 6 fold.
A paper published in Circulation in 2005(ref) showed that ACE Inhibitors increase cardiac ACE2 receptor mRNA significantly and ACE2 levels less significantly.
ARBs were shown to increase both ACE2 mRNA and to more than double cardiac ACE2 levels.
Both of these drug classes are very widely prescribed. It can be reasonably hypothesised that ARBs, and to a lesser extent ACE inhibitors, could potentially increase the levels of ACE2 receptors in type 2 Pneumocytes - the putative entry point of COVID 19 to lung tissue. Could this potentially lead to increased viral load and more severe lung injury?
Reference:
Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2
Carlos M. Ferrario , Jewell Jessup , Mark C. Chappell , David B. Averill , K. Bridget Brosnihan , E. Ann Tallant , Debra I. Diz , and Patricia E. Gallagher
Originally published16 May 2005https://doi.org/10.1161/CIRCULATIONAHA.104.510461Circulation. 2005;111:2605–2610
Competing interests: No competing interests
Re: Response to the emerging novel coronavirus outbreak Angiotensin converting enzyme (ACE) inhibition may have role in the symptoms and progression of COVID-19 infection
Angiotensin converting enzyme (ACE) inhibition may have a role in the symptoms and progression of COVID-19 infection
Dear Editor,
The SARS-CoV-2 virus has been shown to use angiotensin-converting enzyme 2 (ACE2) for cell entry [1]. SARS-CoV-2 binding to ACE2 may attenuate residual ACE2 activity and shift to predominant ACE/AngII/AT1 axis signalling. This activation of AngII system causes deleterious effects, including vasoconstriction, inflammation, fibrosis, cellular growth and migration and fluid retention [2]. In this regard, it has been shown that serum AngII levels in patients with COVID-19 were high and associated with viral load and lung injury [3].
The pulmonary ACE expression is subject to negative feedback by AngII, meaning that increased AngII causes decreased ACE mRNA levels in the lung and decrease in pulmonary ACE activity [4]. As so, the increased AngII causes physiological ACE inhibition. This translates that there seems to be some ongoing ACE inhibition during the COVID-19 infectious process. ACE inhibition also causes decreased break down of bradykinin as ACE is also known as kininase-II. The dry cough related to the treatment of antihypertensive ACE inhibitors (ACEIs) is attributed to accumulation of bradykinin [5,6]. We suggest that the dry cough, which is present in 59% at the onset of the COVID-19 disease [7], may be related to this physiological/pathophysiological process. Therefore, we suggest that continuing ACEIs treatment in COVID-19 infection may have some deleterious effect on the disease state and outcome through the increase in the bradykinin system. The agents demonstrating the ability to attenuate cough due to ACE inhibitors in small randomized, double-blind, placebo-controlled trials include inhaled sodium cromoglycate, theophylline, sulindac, indomethacin, the calcium-channel antagonists amlodipine and nifedipine, ferrous sulfate, and the thromboxane receptor antagonist picotamide [8] and may therefore have a place in the treatment.
Another point is that the accumulated bradykinins may also be associated with other symptoms/signs of the COVID-19 infection. Bradykinin is a well-known 9 amino acid peptide with potent pro-inflammatory and vasodilator properties via its G-protein-coupled receptors [9]. It is generated as a product of the contact system. The role and pathophysiological importance of the contact system has been considered undeniable in septic shock [10]. Reducing bradykinin levels and/or effects by antagonism have been shown to reverse hypotension animal models [11,12]. In humans, a bradykinin-2-receptor antagonist deltibant reduced mortality among patients with purely gram-negative infection with the systemic inflammatory response syndrome (SIRS) [13]. Hence, we suggest that bradykinin antagonism may be an area for future therapeutics for COVID-19 infection.
References
1. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270-273.
2. Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev. 2000;52:11-34.
3. Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63:364-374.
4. Schunkert H, Ingelfinger JR, Hirsch AT, Pinto Y, Remme WJ, Jacob H, Dzau VJ. Feedback regulation of angiotensin converting enzyme activity and mRNA levels by angiotensin II. Circ Res. 1993;72:312-8.
5. Fisher N. Overview of the renin-angiotensin system. UpToDate.
6. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med. 1992;117:234-42.
7. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Feb 7. doi: 10.1001/jama.2020.1585.
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Competing interests: No competing interests