The new challenge in fighting old sepsis

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“Patients typically develop a high fever, their Interleukin 6 (IL-6) is high. If we can get them to pass the two-week mark, they will survive.”

Dr. Masab Moumneh, MD, ICU physician
While we have been battling with sepsis for centuries, now COVID19 added new challenges to this battle. Can Aquaporin-based therapy be our newest weapon against this malicious viral sepsis?

Sepsis – an elusive syndrome

Sepsis has been defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. First described by Hippocrates, it is one of the oldest topics in the history of medicine. Even with advances in care, it remains a global public health emergency affecting millions of people worldwide and one of the main causes of death across the world. Sepsis is also one of the costliest conditions in hospitals. Accounting for more than US$20 billion (5.2 percent) of total US hospital costs, it was the most expensive condition treated in US hospitals in 2011.

Despite the worldwide importance of sepsis, public awareness remains low. In a survey conducted in 2009 in Italy, Spain, the UK, France, and the US, 88 percent of interviewees had never heard of the term “sepsis” – and from those who did recognize the term, 58 percent were not aware that sepsis is a leading cause of death. Similar results were found in another survey in 2014 in South Korea.

The reason for the elusiveness of sepsis probably lies in the fact that sepsis is not a specific illness, but rather a syndrome encompassing a still-uncertain pathobiology. It is recognized today that a complex and multi-factorial host response is responsible for the development of sepsis. Infection triggers both pro-inflammatory and anti-inflammatory processes that ultimately contribute to both the clearance of infection and the tissue damage that lead to organ failure.

Viral sepsis and cytokine storm

Previously, bacterial infections were usually regarded as a leading cause of sepsis. The COVID-19 crisis has brought viral sepsis into the spotlight. In a study of 191 COVID-19 patients treated in December 2019 and January 2020 in Wuhan (China), sepsis was found to be the most frequently observed complication. Sepsis was diagnosed in 59 percent of all patients included in the study. Furthermore, 100 percent of the non-survivor patients were diagnosed with sepsis. Was it viral sepsis that was killing the COVID-19 patients?

To understand the immune reaction in viral infections, we have to understand the phenomena triggered by cytokine and cytokine storms. Cytokines are a group of proteins. Through a process called cell signaling (communication between cells), cytokines control inflammation in our body. When we get an infection, our immune system releases more cytokines. Unfortunately, sometimes the body goes into overdrive and releases more cytokines than it should. As the body loses control of cytokine production, a “cytokine storm” is created. Cytokine storms might explain why some people have severe reactions to the coronavirus while others only experience mild symptoms.

In another study from Wuhan, viral sepsis and cytokine storms were more directly linked to critically ill COVID-19 patients. This study found that pro-inflammatory cytokines and chemokines were significantly elevated in COVID-19 patients. It further suggested that the cytokine storm might play an important role in the immunopathology of COVID-19.

“I have never seen anything as bad as this. COVID-19 patients were killed by cytokine storms,” said Dr. Masab Moumneh, who has been an ICU physician in Abu Dhabi for the past ten years. Of the 700 hospital beds in the public hospital where Dr. Moumneh works, 110 are ICU beds. From April to June 2020, at the height of the COVID-19 crisis in the United Arab Emirates, Dr. Moumneh and his colleagues saw a 38 percent mortality rate in their ICU COVID-19 patients – a very respectable survival rate.

A search for dedicated immune suppressor

Working on the assumption that it was the cytokine storms that were causing the deaths of COVID-19 patients, Dr. Moumneh and his colleagues tried to use drugs that could reduce the overreaction of the immune system. In their ICU wards, corticosteroids – the standard anti-inflammatory medicine – were administered once COVID-19 patients were admitted. Although they were not included in the official guideline of sepsis management[1], corticosteroids were the only immunomodulator that was recommended for regulating overreacting immune systems in the guidance on “Care of Critically Ill Patients With COVID-19”, published by US National Institutes of Health [2].

Discovered in the 1940s, corticosteroids are one of the most widely used and effective treatments for inflammatory and autoimmune diseases. However, they do cause serious adverse effects, especially if used over a longer term or in high doses. Doctors have been looking at using newer immunosuppressants to develop more effective treatment options. Attempts by Dr. Moumneh and his colleagues to find other effective and safe immunosuppressants were unsuccessful. “One of the newer immunosuppressants caused bowel perforation, and the patient died,” Dr. Moumneh said regretfully. The fact is that at the moment, there is no dedicated medicine that explicitly targets immune over-reaction in sepsis or viral sepsis.

Can an Aquaporin-based drug fill the gap?

Aquaporins (AQPs) are channel proteins that form pores in cell membranes. As such, they are involved in a wide range of physiological functions. In general, aquaporins play a role in maintaining a constant water homeostasis and homeostasis of many physiological processes. There is solid evidence that AQPs facilitate both phagocytic functions of immune cells and migration of immune cells [3] [4] [5]. Furthermore, research has demonstrated that AQPs contribute to regulating fluid trafficking and inflammation process in lung infection [6]. This could be particularly helpful in seeking remedies for COVID-19 patients. Clinical data indicate that mortality attributable to COVID-19 infection is mainly due to the development of viral pneumonia-induced acute respiratory distress syndrome (ARDS) [7].

Cytokine storms and viral sepsis are serious complications of virus infections such as COVID-19, SARS, MERS, and the flu. They have caused hundreds of thousands of deaths around the world. Supertrends would like to help by supporting a community that focuses on fighting sepsis, especially viral sepsis. If you are interested in joining our community, please reach out to us to share your ideas, research, or inspirations at https://www.supertrends.com/call-for-experts/.
© 2020 Supertrends

Reference

[1] Rhodes, A, LE Evans et al. 2017. “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.” Intensive Care Med 43:304–377.

[2] NIH. 2020. COVID-19 Treatment Guidelines. 27 August. https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/.

[3] Zhu, N., X. Feng, C. He, H. Gao, L. Yang, and Q Ma. 2011. “Defective macrophage function in aquaporin-3 deficiency.” FASEB J. 25, 4233–4239.

[4] Loitto, V. M., T. Forslund, T. Sundqvist, K. E. Magnusson, and M. Gustafsson. 2002. “Neutrophil leukocyte motility requires directed water influx.” J. Leukoc. Biol. 71, 212–222.

[5] Tyteca, D., T. Nishino, H. Debaix, P. Van Der Smissen, F. N’Kuli, and D. Hoffmann. 2015. “Regulation of macrophage motility by the water channel aquaporin-1: crucial role of M0/M2 phenotype switch.” PLoS ONE 10: e0117398.

[6] Towne, J. E., K. S. Harrod, C. M. Krane, and A. G. Menon. 2000. “Decreased expression of aquaporin (AQP1) and AQP5 in mouse lung following acute viral infection.” Am. J. Respir. Cell Mol. Biol. 22, 34–44.

[7] WHO. 2020. Coronavirus disease (COVID-19) Pandemic. https://www.who.int/emergencies/diseases/novel-coronavirus-2019.

aquaporin, Coronavirus, COVID-19, sepsis


Jiqing Hansen

Having worked passionately for 15+ years in Medicine, I felt that I yearned to do something a little bit different, something that satisfies my curiosity and creativity, maybe something that helps to inform me and others what our world will look like in the future. That's when I took on the challenge of being the editor & expert relationship manager at Supertrends. I love the fact that I can still be in touch with my academic background when I am trying to understand and reach out to the experts in the most exciting fields. I also love the diverse and enthusiastic team at Supertrends. The best of all, I get to have a peek into the future, and I am at the position of helping many others to get the opportunity to look into the future.

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