








key: cord-270740-3su8pc3f
authors: Sultan, Sherif; Sultan, Mohamed
title: COVID-19 Cytokine Storm and Novel Truth
date: 2020-05-22
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.109875
sha: 
doc_id: 270740
cord_uid: 3su8pc3f

nan

While the world is facing an unprecedented crisis with novel coronavirus disease (nCoV) 2019/ COVID-19, there are no proven effective pharmacological agents (1) . Following the detection of Severe Acute Respiratory Syndrome coronavirus(2) (SARS-CoV-2) in December 2019 in Wuhan, China, we witnessed a massive surge in the number of cases globally, until WHO declared a pandemic on March 11, 2020 (2). The search for a 'Novel' agent is ongoing and as of 7 April 2020, 'TrialsTracker' project(3) had listed 883 clinical trials on COVID-19, including 344 intervention trials.

During an evolving pandemic the real-world evidence can only be obtained from respected sources. Unfortunately, by the time a manuscript is produced and accepted for publication, we might have missed the boat.

WHO failed us and some governments opted to protect the economy rather than controlling the spread of the COVID 19 pandemic. Investigational journalism had the upper hand in exposing the problem with China and later on, in South Korea and Italy. During the same time WHO was assuring the world that there was nothing to worry about. When the death rate mushroomed in Italy, everything had exploded, the world knew that a new era had arrived with the greatest lockdown of all time. Corona's correction will allow us to get rid of all the dinosaurs for every top position in any organization and to evolve to a world of trust and confidence.

Based on observations in the USA, Spain, Italy, France and the UK, and from the postmortem of lung involvement in COVID 19, all revealed pulmonary thrombosis, which is not typical ARDS. More alarming was that patient hypoxemia was not responding to PEEP but high oxygen flow(4).

A Chinese scientist(5) used a bio-informatics model to describe the hypothesis of COVID 19 as methemoglobin, where the COVID-19 virus structural protein sticks to heme -displaces oxygen -which alters the iron-free ion, leading to inflammation of alveolar macrophages, which culminate in a systemic response ending in a cytokine storm . They suggested that if free radical scavengers and iron chelating agents are added to the protocol of management, these might ameliorate the inflammatory response.

What we must focus on is that COVID19 attacks RBCs. Patients have frequently been found COVID-19, SARS2 is not 'pneumonia' nor ARDS Through the current experience across the world, invasive ventilation is becoming the last resort, as emergency intubation from the Chinese, Italian and American experience evidences higher mortality, not to mention complications from tracheal scarring and stiff lung during the duration of intubation. Furthermore, a new treatment protocol needs to be established in order to control the prolonged and progressive hypoxia of COVID19(4).

People are desaturating due to failure of the blood to carry oxygen. This will lead to multiorgan failure and high mortality. The lung damage seen on CT scans is due to the oxidative stress released from the hemolysed red blood cells, which in turn overwhelm the natural defenses against pulmonary oxidative stress and cause a cytokine storm. There is alwaysbilateral ground-glass opacity in the lungs. Recurrent admission for post-hypoxic leukoencephalopathy strengthens the findings of the Italians, Spanish and Americans(4) that COVID-19 patients are suffering from metabolic hypoxia due to blood capacity failure.

The Chinese hypothesis(5) that had been publicized, theoretically, via bioinformatics modeling, postulated that the catastrophic cascade of oxidative stress explains the vicious cycle as follows:

1) Without the iron ion, hemoglobin can no longer bind to oxygen. Once the hemoglobin is impaired, the red blood cell is essentially unable to carry and deliver oxygen to any tissues. drop significantly.

In COVID-19 patients, unlike with CO poisoning in which eventually the CO can break off, the affected hemoglobin is permanently stripped of its ability to carry oxygen. The body compensates by secreting excess erythropoietin to stimulate the bone marrow to secrete new red blood cells. This is the reason we find thrombocytosis, or thrombocytopenia depending on the stage and severity of COVID-19, a high ferritin level and D-Dimer with decreased blood oxygen saturation as the primary indicators of the COVID-19 severity score.

2) The free-floating iron ions(5) are highly reactive and cause oxidative damage. This always happens physiologically and is natural to a limited extent in our bodies, and such cleanup is a defense mechanism to keep the balance.

Of the Three Primary Lung defenses to maintain "iron homeostasis", two are in the alveoli.

The first of the two are macrophages that roam around and scavenge the free radicals of the oxidative iron. The second is a lining on the epithelial surface which has a thin layer of fluid packed with high levels of antioxidant molecules such as ascorbic acid.

When too much iron is in circulation, it begins to overwhelm the lungs' countermeasures and the process of pulmonary oxidative stress begins. This leads to damage and inflammation, which leads to the so-called cytokine storm (5) ; this can be documented on high-resolution CT scans of COVID-19 patients' lungs.

The liver attempts its best to remove the iron, but only becomes overwhelmed too. It is starved of oxygen. The liver function will deteriorate with elevated alanine aminotransferase (ALT), which is one of the primary COVID-19 severity score indicators.

Through extensive discussion with some of our colleagues in Beijing, Milan, Sienna, Paris, Barcelona, London and New York(6), we have reached a consensus to recommend that the patient might be better managed on maximum oxygen flow through a hyperbaric chamber (7, 8) on 100% oxygen at double or multiple atmospheres of pressure for 90 minutes twice per day for five days. The randomized clinical trial of hyperbaric medicine started in USA in the first week of April (7) . This is in order to give what is left of a patient's functioning hemoglobin a chance to carry enough oxygen to the organs and keep them alive.

As we do not have nearly enough of those hyperbaric chambers, we might use all the parked grounded airplanes as a ready-made functional hyperbaric chamber with the advantage of providing double atmospheric pressure with an aerosol of prostacyclin as a pulmonary hypertension modulator. Some Chinese physicians tried blood transfusion with packed fresh red blood cells to patients after plasmapheresis(9,10) , and witnessed some amelioration of the cytokine storm.

The main point is that patients will require ventilators if they present late with multi-organ system failure to tide them over this life or death scenario. However, intubation is futile unless the patient's immune system modulates the situation (11) . We must address the root of the illness and avoid using traditional teachings to manage a failing system (12, 13) .

Armchair pseudo-physicians an no longer sit in their ivory towers proclaiming "Chloroquine use is stupid as malaria is a bacterium, COVID-19 a virus: anti-bacterial drugs do not work on a virus!". A drug does not need to act on the pathogen to be effective. A few key opinion leaders advised that Chloroquine lowers the blood pH and interferes with replication of the virus. However, a publication in press at the New England Journal of Medicine advises against the use of Chloroquine (14) . Sweden has decided to halt its use, as have some parts of France.

We recommend that if COVID-19 positive patients are conscious, alert and compliant, they should be kept on maximum oxygen. A prone position allows better lung perfusion, and we may have to initiate hyperbaric oxygen as early as possible (8, 9, 10) .

If we reach the inevitable and need to ventilate, USA pulmonologists (15) have recommended that this should be performed at low pressure but with maximum oxygen flow.

We must avoid tearing up the lungs with maximum PEEP as this does more harm to the patient because we may be addressing the wrong organ (16) .

Last week, a discussion on Medscape about COVID 19 Virus and diabetes mellitus illustrated that the virus may be attacking the Islets of Langerhans in the pancreas and causing insulin deficiency (17) . As those patients had good reserve they present late with diabetic ketoacidosis. The main focus of management I these cases needs to be high flow oxygen plus insulin supplementation.

It is crucial not to underestimate COVID-19 severity in patients with diabetes even in the absence of classical worrisome signs and symptoms, and we must develop different clinical early severity scores for patients with diabetes. Although acute inflammatory states and acute stress responses will certainly raise glucose levels, the SARS-CoV-2 virus is actually damaging the pancreatic islet cells.

A study was done during the SARS 2003 coronavirus outbreak in China in which diabetes developed within two weeks of hospitalization in patients who did not previously have diabetes. Immuno-staining in patients who had died after contacting COVID-19 showed strong staining of the angiotensin-converting enzyme 2 (ACE2) protein -the coronavirus binding site -in the islets but not the exocrine pancreatic tissue, which means coronavirus causes diabetes by damaging pancreatic islets.

COVID-19 causes insulin deficiency, meaning many patients require markedly elevated insulin drip rates. This is not just pressor/steroid related. Something else is going on here.

We've not seen this pattern of glycaemia with associated insulin requirements before. This is a new beast. The degree of glucose toxicity is profound and independent of preadmission diabetes control. Patients with seemingly well-controlled diabetes at home with HBA1cs in the single digits experience severe dysglycaemia. There is a subset of patients presenting with euglycaemic DKA with normal lactate, with other causes of ketoacidosis ruled out. Diabetics had higher levels of biomarkers due to an inflammatory "cytokine storm" preceding rapid deterioration of COVID-19 (17, 20) .

There is a small village in northern Italy where the majority of its population suffers from thalassemia. These individuals have had no deaths and no cross-community spread, due to the abnormal shape of the red blood cells. Moreover, parts of Nepal that are 1km above sea level are COVID-19 free, the same logic applies, abnormal shape of the red blood cell. All the evidence suggests that we are chasing the wrong organ: it is not the lungs, it is a blood problem.

We advised a few international organizations that AL & ML must be utilized in analyzing Big data. AI, Big data analysis and bioinformatics must be harnessed to allow us to scrutinize how can we provide the best options for our patients, creating bioinformatics modelling that can surpass any RCT. Adaptive platform designs must be structured to promote maximum learning from around the world to adjust how we deliver the best care to our patients (21, 22, 23, 24, 25, 26, 27) .

People are desaturating due to failure of the blood to carry oxygen (17) . This will lead to multi-organ failure and high mortality due to Cytokine Storm. We believe that management protocols for ARDS should not be applied for COVID-19 patients (18, 19, 21, 22, 23, 24, 25, 26, 27) .

We recommend the following:

1. Inhibit viral growth and replication by any proven means. Currently the adjuvant use of CHQ+ZPAK+ZINC appears indicated, or the rising star of Ramedesivir, which has proven effectiveness in ameliorating COVID-19 mortality. Other retroviral therapies are being studied. The less viral load we have, the less severity of the damage with the prevention of cytokine storm.

2. Theoretical use of hyperbaric medicine or pressurized grounded airplanes may prevent rapid ascent into the abyss.

3. Plasmapheresis and blood transfusions may give supportive symptomatic relief when indicated.

4. No international travel until an effective vaccine is available.

5. Cessation of tobacco, vaping, and the use of alcohol products.

Until we create a sound protocol for managing our sick patients and understand why chloroquine and invasive ventilation have failed, as both have been unable to bail out our oxygen-starved patients, the only available option is symptomatic relief.

Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review

Director-General's opening remarks at the media briefing on COVID-19 -11

Mike Stobbe -Why Some Doctors Are Now Moving Away From Ventilator Treatments for Coronavirus Patients

Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism

A bridge between life and death: Most COVID-19 patients put on ventilators will not survive

Hyperbaric Oxygen for COVID-19 Patients

Vasculogenic Stem Cells, and Wound Healing -Antioxid Redox Signal

A Novel Coronavirus from Patients with Pneumonia in China

Adam Wells -A novel treatment approach to the novel coronavirus: an argument for the use of therapeutic plasma exchange for fulminant COVID-19

Sharon Worcester -Is Protocol-Driven COVID-19 Ventilation Doing More Harm Than Good?

Sharon Begley -With ventilators running out, doctors say the machines are overused for Covid-19

Xihui Lin -Clinical Outcomes of Hydroxychloroquine in Hospitalized Patients with COVID-19: A Quasi Randomized Comparative Study

Paul Marik -Critical Care Covid-19 Management Protocol

Why some doctors are moving away from ventilators for virus patients

More than 65% of people put on ventilators will die, NHS data shows

80% of NYC's coronavirus patients who are put on ventilators ultimately die, and some doctors are trying to stop using them

Over 80% of COVID Patients Placed on Ventilators in New York City Have Died

COVID-19 and Diabetes: Known Mechanisms and a 'New Beast

HRCT Imaging Features in Representative Imported Cases of 2019 Novel Coronavirus Pneumonia. Precision Clinical Medicine

Epidemiologic and clinical characteristics of novel coronavirus infections involving 13 patients outside Wuhan, China

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Potential of large 'first generation'human-to-human transmission of 2019-nCoV

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirusinfected pneumonia in Wuhan

Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia

A novel coronavirus from patients with pneumonia in China

Professor of Vascular & Endovascular Surgeon Chairman of the Western Vascular Institute University college Hospital Galway Ireland Re: Cover Letter & Conflict of Interest COVID19 Cytokine Storm and Novel Truth Dear Chief Editor, I wish to submit this editorial to the journal of medical hypothesis about 'COVID19 Cytokine Storm and Novel Truth'. We declare no conflict of interest and have received no such funding to write the editorial. I hope the journal reviewer board and the readers find this interesting. Yours sincerely



