The consensus from the World Health Organization (WHO), the Centre for Disease Control and Prevention (CDC), and the U.S. Food and Drug Administration (FDA) confirms that there is currently no approved therapeutics or vaccine for the treatment or prevention of the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

In the absence of an approved treatment protocol, the China International Exchange and Promotive Association for Medical and Health Care (CPAM) issued a novel 2019 coronavirus disease (COVID-19) guideline in February 2020 with recommendations on methodology, epidemiological characteristics, disease screening and prevention, diagnosis, treatment and control, nosocomial infection prevention and control, and disease management. For direct antiviral treatment of SARS-CoV-2, CPAM recommends use of lopinavir/ritonavir [2 capsules (dose undefined) by mouth twice daily] in combination with nebulized alfa-interferon (5 million units in Sterile Water for Injection inhaled twice daily). CPAM has based this recommendation on weak evidence from retrospective cohort, historically controlled studies, case reports, and case series that suggest clinical benefit of lopinavir/ritonavir in the treatment of other coronavirus infections [namely 2002 SARS-CoV and 2012 Middle East respiratory syndrome coronavirus (MERS-CoV)].

In addition to CPAM, a group of Korean physicians with experience in treating SARS-CoV-2 infected patients have developed recommendations for the treatment of COVID-19. According to these physicians, antiviral medications are not recommended for use in young, healthy patients with mild symptoms and no underlying comorbidities. However, treatment with lopinavir 400 mg; ritonavir 100 mg (2 tablets by mouth twice daily) or chloroquine (500 mg by mouth twice daily) should be considered for use in older patients or patients with underlying conditions and serious symptoms. If chloroquine is unavailable, the use of hydroxychloroquine (400 mg by mouth once daily) is recommended. Use of ribavirin and interferon are not recommended as first-line treatments due to risk of side effects. However, use of these medications may be considered if treatment with lopinavir; ritonavir, chloroquine, or hydroxychloroquine are ineffective.

A Vaccine?

Since this is the first time that homo sapiens appear to be exposed to the novel coronavirus (SARS-CoV-2), emerging data is indicating variability in the immune response with some individuals succumbing to the virus. A vaccine would allow the body to safely develop an immune response to COVID-19 that could prevent or control infection. However, the process of vaccine development is lengthy and complex, and scientists advise that it will take a minimum of 12-18 months to develop a safe and effective vaccine, nevertheless representative of an expedited route which conventionally can take five to ten years on average.

However, it should be pointed out that thanks to impressive molecular and pharmacological tools, it is now significantly quicker to engineer new vaccines. In this unprecedented period, we have witnessed a phenomenon never seen before, that is extravagant resources and funding becoming available as small and giant pharma organizations join forces in a global effort to find a vaccine for COVID-19. Existing therapeutics validated for other viral diseases, broad-range disease modifiers and immunity enhancing techniques have also begun to be considered for use under the FDA Emergency Use Authorization (EUA).

Foresight or serendipity, the race for the development of a potential novel coronavirus vaccine includes experts who were already working on vaccines for other coronaviruses. As a matter of fact, this type of virus had been identified as a possible cause of the next big pandemic as the other coronaviruses SARS and MERS have been responsible for two global outbreaks in the last 20 years. We now know that investment on vaccines for these coronaviruses was already preparing the ground for clinical trials.

The first new vaccine to enter human trials for COVID-19 was developed by the US firm Moderna Therapeutics. About 35 other companies and academic institutions are also working on COVID-19 vaccines. Most are currently in “pre-clinical testing”, including one being developed by a team of researchers at the Jenner Institute, University of Oxford. The vaccine candidate was identified in January and is nearing its pre-clinical testing phase, ready for further testing in humans.

Is there a metabolic link with COVID-19 infection?

A review of the article by Borstein et al., Nature Reviews Endocrinology, 2020

Type 2 diabetes (T2D), hypertension and cardiovascular diseases have all been highlighted as risk factors for infection with COVID-19. However, it should be pointed out that generally, people with such co-morbidities are more prone to illnesses such as the common cold, flu and other coronavirus infections, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS-CoV)1.

Reports from the Centre for Disease Control and Prevention (CDC) have indicated that T2D and the metabolic syndrome may increase the risk of death from COVID-19 by about ten-times (CDC coronavirus reports). Similar to other infectious diseases, the presence of co-morbidities is well known to enhance the risk of more severe symptoms as well as mortality. Specifically for COVID-19, a number of additional mechanistic aspects call for additional attention, with associated clinical impact on improved management of patients suffering from more severe forms of the disease.

Hyperglycaemia and existence of T2D are independent predictors of mortality and morbidity in patients with SARS1. Borstein and colleagues argue that patients who suffer from these underlying conditions are in an ongoing state of metabolic inflammation, which triggers an exaggerated release of cytokines. In cases of COVID-19, exaggerated amounts of inflammatory cytokines, also known as a cytokine storm, is believed to be the causal factor of multi-organ failure in patients suffering from severe form of the disease3.

The so-called metabolic inflammation is thought to be detrimental to the immune system, with a reduced ability to respond to the infection. Data from an in vivo animal model demonstrates that the presence of T2D can lead to dysregulation of the immune system and enhancement of disease severity following MERS-CoV infection2. In this study, the authors observed that diabetic mice expressing the human DPP4 (resulting in MERS-CoV susceptibility) exhibited altered cytokine production, with increased expression of IL-17α upon infection. These results point to the possibility that concomitant coronavirus infection and T2D can unleash a dysregulated immune response, leading to more aggravated and prolonged lung pathology2.

A direct endocrine link?

The coronavirus SARS-CoV-2 gains entry into human cells via the envelope spike of glycoprotein, which is also responsible for host-to-host transmission4. The glycoprotein, located on the surface of the virus, binds to the abundantly-occurring ectoenzyme angiotensin-converting enzyme 2 (ACE2), on human cells to gain entry via the ACE2 receptor. In addition, the cellular serine protease TMPRSS2 is required to prime viral entry via ACE24. In the respiratory system, ACE2 serves to breakdown angiotensin II into angiotensin (1–7) and acts as a key regulatory point for the angiotensin system. When ACE1 activity is increased and ACE2 inhibited, intact angiotensin II acts via the angiotensin 1 receptor (AT1R) or AT2R to exert pro-inflammatory responses and stimulate aldosterone secretion; these effects are thought to not only increase blood pressure and potentially cause hypokalaemia, but to also increase vascular permeability locally, increasing the likelihood of respiratory distress syndrome. In contrast, angiotensin (1–7) acts on the Mas receptor pathway, resulting in anti-inflammatory and anti-fibrotic responses that would be favourable to the recovery of patients with COVID-195. Thus, it would be plausible that individuals with more severe COVID-19 have an imbalance in the activation of these pathways, with an increase in the activation of AT1R and AT2R, which could be the case in T2D, hypertension and insulin-resistant states.

A direct metabolic link

In addition to a link between coronavirus infection and hypertension, there seems to be a direct link to T2D. The pancreas is enriched with ACE2 receptors, and it is thought that binding of the SARS coronavirus to these receptors damages the insulin-producing beta-cells within the islets (which are richly vascularized), resulting in reduced or impaired secretion of insulin6. In one study, patients with SARS with no history of T2D and no steroid treatment were compared with their healthy siblings during a 3-year follow-up period. Interestingly, over 50% of patients in the study developed diabetes during hospitalization for the SARS-CoV infection.
It was noted that following 3 years of recovery from the viral infection, only 5% of patients remained diabetic6. These findings indicate that virus entry via the ACE2 receptors into the pancreatic islets may be associated with acute beta-cell dysfunction, acute hyperglycaemia and transient T2D6. It is noteworthy that in the study with diabetic mice, ACE2 receptor activity levels were enhanced in the pancreas7. These observations collectively suggest that patients with T2D may be particularly vulnerable to a coronavirus infection. T2D can also induce expression of angiotensin-converting enzymes in other major organs, including the lung, liver and heart7, which can explain how T2D can contribute mechanistically to multiple organ failure in SARS-CoV infections.

Immediate clinical consequences

It is clear that optimal metabolic control of T2D and associated metabolic parameters in patients with COVID-19 is critical. These approaches are not only recommended because of the obvious danger and increased risk of complications in patients with T2D and a severe infectious disease, but also for the treatment of all patients with COVID-19. It is anticipated that blood glucose-lowering medications, such as GLP-1 analogues, which are known to ameliorate metabolic function and induce the activity of the protective ACE2 and Mas receptor pathways might also have the advantage of regulating blood pressure, and also preventing coronaviruses from entering cells as a result of competitive binding to ACE2. This effect might help to protect and restore pulmonary function5. Likewise, early treatment with angiotensin II receptor blockers (such as losartan or telmisartan) or, more directly, recombinant ACE2, might be useful to enhance the ACE2 and Mas system in preference to the pathways mediated by angiotensin receptors. This approach would enable the combination of an antidiabetic, anti-inflammatory and antiviral effect. Finally, the synthetic protease inhibitor camustat, which blocks the serine protease TMPRSS2 required for ACE2-mediated coronavirus entry into the cells4, also reverses dyslipidaemia and hyperglycaemia8.

The intriguing link between coronavirus infections and these endocrine and metabolic pathways will have an important effect on the general medical management of severe COVID-19. Glucocorticoids that have been helpful in the treatment of acute respiratory distress syndrome might not be indicated in patients with coronavirus infection. Glucocorticoids are known not only to aggravate metabolic control, but also attenuate angiotensin (1–70 and Mas receptor expression9. Hence, they might be of limited clinical use in the management of patients with COVID-19. By contrast, the anti-rheumatic drug hydroxychloroquine, which is being widely used in many centres around the world as an experimental treatment for COVID-19, has also attracted interest as a potential therapeutic intervention for patients with T2D10. Currently, it is unclear whether hydroxychloroquine in addition to anti-inflammatory and antidiabetic drugs will also directly interfere with the coronavirus–ACE2 pathways. In conclusion, COVID-19 itself is not primarily a metabolic disease, but metabolic control of glucose, lipid levels and blood pressure are key in patients afflicted with COVID-19. This approach is important to address the well-established metabolic and cardiovascular complications of this primary comorbidity. Moreover, effective control of these metabolic parameters might represent a specific and mechanistic approach to prevent and ameliorate the acute effects of this virus by reducing the local inflammatory response and blocking its entry into cells.

This article is intended for medical professionals.


Read also:

Compassionate Use of Remdesivir for Patients with Severe COVID-19
Effectiveness of convalescent plasma therapy in severe COVID-19 patients



References:
1. Yang, J. K. et al. Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS. Diabet. Med. 23, 623–628 (2006).
2. Kulcsar, K. A., Coleman, C. M., Beck, S. E. & Frieman, M. B. Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection. JCI Insight. 4, 131774 (2019).
3. Mehta, D. et al. Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet https://doi.org/10.1016/S0140-6736(20)30628-0 (2020).
4. Hoffmann, M. et al. SARS-CoV-2 Cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell https://doi.org/10.1016/j.cell.2020.02.05 (2020).
5. Simões e Silva, A. C., Silveira, K. D., Ferreira, A. J. & Teixeira, M. M. ACE2, angiotensin-(1–7) and Mas receptor axis in inflammation and fibrosis. Br. J. Pharmacol. 169, 477–492 (2013).
6. Yang, J. K., Lin, S. S., Ji, X. J. & Guo, L. M. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol. 47, 193–199 (2010).
7. Roca-Ho, H., Riera, M., Palau, V., Pascual, J. & Soler, M. J. Characterization of ACE and ACE2 expression within different organs of the NOD mouse. Int. J. Mol. Sci. 18, E563 (2017).
8. Jia, D., Taguchi, M. & Otsuki, M. Synthetic protease inhibitor camostat prevents and reverses dyslipidemia, insulin secretory defects, and histological abnormalities of the pancreas in genetically obese and diabetic rats. Metabolism. 54, 619–627 (2005).
9. Marshall, A. C. et al. Betamethasone exposure attenuates angiotensin-(1–7)-Mas receptor expression in the dorsal medulla of adult sheep. Peptides 44, 25–31 (2013).
10. Gupta, A. Real-world clinical effectiveness and tolerability of hydroxychloroquine 400mg in uncontrolled type 2 diabetes subjects who are not willing to initiate insulin therapy (HYQ-Real-World Study). Curr. Diabetes Rev. 15, 510–519 (2019).


Prepared by:
Dr Reshma Ramracheya
Research Scientist & University Research Lecturer at the University of Oxford
Senior Research Fellow at Wolfson College, University of Oxford
Reshma.ramracheya@ocdem.ox.ac.uk