key: cord-292606-tqjmg3qb
authors: Testori, Alessandro
title: THE “PERFECT CYTOKINE STORM” OF COVID-19
date: 2020-05-29
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.05.015
sha: 
doc_id: 292606
cord_uid: tqjmg3qb

nan

I have read with great interest the recent article by Vijayvargiva et al 1 

Proceedings. The vast majority of the deaths caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) are patients over the age of 55, which died of Acute Respiratory Distress Syndrome (ARDS).

At the histological level ARDS is characterized by an intense inflammatory response occurring in the lungs of patients. 2 Human aging is associated with an up-regulated inflammatory response. 3 Inflammation is involved in the mechanisms underlying the pathogenesis of several age-associated diseases such as cardiovascular disease, type 2 diabetes, Alzheimer disease (AD), Parkinson disease, rheumatoid arthritis (RA), and osteoporosis.

Elderly individuals have lost the ability to control and contain inflammatory processes to the same degree of which younger individuals are capable. The innate immune system plays a central role in inflammation and is also key in its ability to slow down and arrest inflammatory processes. Interleukin-10 (IL-10) and C1-esterase inhibitors (C1-INH) are two molecules that help contain and slow down inflammatory processes, while Interlukin-6 (IL-6) promotes and intensifies inflammation (though it has also some anti-inflammatory properties in muscle cells). Given the up-regulation of inflammatory processes with aging, it is not surprising that ARDS is usually more severe and more lethal in the elderly resulting in death rates over 50% in the current epidemic. But this "Cytokine storm" is not limited to the lungs, and also involves the kidneys, causing renal insufficiency and failure, and the vascular system, causing a vasculitis which is at first visible in the toes and is now known as "Coronavirus toes." The "cytokine storm" does not spare the Central Nervous System (CNS) either, resulting in headaches, altered mental status, confusion or inability to arouse and the loss of the sense of smell, which is reportedly one of the early symptoms of the disease. 36% of patients experienced some type of neurological symptom. On the mild end of the spectrum, people commonly experienced the loss of taste and smell. Headache was reported in 13% of the patients, dizziness was observed in about 17%, and muscle inflammation and nerve pain occurred in about 19%. Autopsy reports have revealed brain tissue edema and partial neuronal degeneration in deceased patients. To effectively treat the "Citokine Storm" Tocilizumab (Actemra) has been used to block the pro-inflammatory action of Il-6, and seems to have been helpful in anecdotal cases (3 patients treated in Italy). C1-esterase Inhibitor (Berinert, Cynrize, Ruconest) could also be tested to see if it is capable slow the inflammatory response. But these are very expensive medications and difficult to produce rapidly in quantities. Using them to treat tens of thousands of patients may prove impossible because of cost and logistics. IL -10 is another anti-inflammatory molecule that could be tested and it could be administered via a genetherapy approach using naked plasmid DNA vectors 4 engineered to produce IL-10 inside the recipient cells, thus reducing the cost and simplifying production. It would be more cost-effective for treating many thousands of patients.

Covid-19 infection involves multiple organs and systems, with symptoms developing rapidly over 2-14 days. Most infections however produce mild or minimal symptoms and up to 80% of persons infected may have mild disease or even be asymptomatic. Reports from Italy indicate that some individuals have remained positive to nasal swabs for Covid-19 for at least 50 days since their initial positive test, and after having apparently healed from the illness. There is one case of a person that has had positive nasal swabs for 57 days. This raises the possibility that some individuals, after recovering from their illness may become asymptomatic carriers of the virus for extended periods of time, further complicating efforts at containing the pandemic and requiring that patients be tested after their recovery to make sure they clear the virus. This means that antivirals and vaccines will be needed. Countries need to invest in technologies like DNA vaccines 5 and antiviral gene therapy strategies, like RNAi technology, which is an ideal tool for inhibiting viral replication in host cells as the siRNA can interact with certain viral genes and silence their expression. 6 DNA based therapeutics can be developed immediately after a virus DNA sequence becomes known. Modular plasmid vectors could be created that allow to switch one viral sequence for another and produce a new vaccine with minimal manipulation. The same applies to RNAi vectors. These strategies are also likely to be much more costefficient than other methods, a consideration that becomes important as the population needing treatment expands.

We need to develop detailed protocols now on how to quickly produce vaccines and antivirals, that can be adapted to future viral pandemics. We also need to develop protocols for the most effective containment and mitigation strategies, so they can be implemented without hesitation in future emergencies.

Alessandro Testori, MD Immunoe Health Research Centers Longmont, Colorado

Treatment considerations for COVID-19: A critical review of the evidence (or lack thereof)

The acute respiratory distress syndrome

Inflammatory networks in ageing, age-related diseases and longevity

Progress and prospects: naked DNA Gene transfer and therapy

Generation and characterization of DNA vaccines targeting the nucleocapsid protein of Severe Acute Respiratory Syndrome Coronavirus

Inhibition of SARS-CoV replication by siRNA