Annually, about 200,000 patients/year are diagnosed with non-COVID-19 ARDS in the United States. This indication yields a mortality rate of about 30% and these non-COVID-19 ARDS therefore cause about 60,000 in annual deaths. The mortality from COVID-19 lung death was approximately seven-fold that of typical ARDS in 2020.

 

Successfully addressing COVID-19 induced ARDS will provide a therapy for non-COVID-19 ARDS for 200,000 patients per year in the USA and 170,000 in Europe, an unmet need unrelated to COVID-19.

 

COVID-19 viral infection has filled and brought to a breaking point the intensive care units all over the world. Most patients are dying a lung death; they die from acute respiratory failure, ARDS. One function of the lung is gas exchange. The organ contains delicate and thin alveolar-capillary membranes, and to function as a gas exchanger, the organ must stay dry. ARDS creates a catastrophic breakdown of the integrity of barriers and a loss of homeostatic maintenance due to inadequate stress responses resulting in a fluid-filled organ.

 

We believe that current supportive care – which has arrived at “intelligent “ventilation strategies” and “chicken little” (not too much to flood the lung—and not too little to starve the kidneys) fluid regimens in the setting of ARDS, is actually amounting more or less to “palliative care” and unacceptable outcomes.

 

We believe that the current practice goals of ventilator and fluid management are wanting, and they need to be complemented by strategies that address lung cell homeostasis and cellular repair. One of the lessons that COVID-19-induced lung injury may provide is that the virus can destroy the lung repair program. In fact, sequelae of COVID -19 lung disease may be the permanent damage to the alveolar membranes (e.g. fibrosis) – with no repair. In short, the rationale for using pharmacotherapy to protect the alveolar-capillary barrier is strong.

 

It is historically important to note that the need to care for patients with respiratory failure and to manage the patient-ventilator “interface” have challenged respiratory care units and shaped the specialty of Pulmonary and Critical Care Medicine. COVID-19 has turned intensive care units into combat zones, forced physicians (“First do no harm”) to apply triage algorithms and painfully laid bare our state of ignorance of "what ARDS is."

 

Conceptual Barriers and Approach

There are many Conceptual barriers, beginning with the misconception that ARDS “lives mostly in the airspaces”, neglecting the fact that in ARDS the whole lung is sick, including the vasculature. Although this is not new information, pulmonary thrombotic obliterations and pulmonary hypertension have been recognized for decades, the description of the microvascular component of severe COVID-19-triggered lung disease has now stimulated the investigation of the intravascular inflammation. COVID-19 infects and damages endothelial cells in addition to infecting epithelial cells and activating inflammatory cells. The COVID-19-triggered disease also permits us to pose the hypothesis that the “sick lung circulation” releases cells, cell fragments, mediators and free DNA that impact other organ circulations - in the heart, the kidneys and the brain. The ARDS lung then needs to be seen in the center of an integrated system. The injured lung's pleas for help are answered by a host of cells released by the bone marrow, while kidney failure may amplify the inflammation in the lung.

 

It has been reported that diabetes, hypertension and obesity in COVID-19-infected patients are predictors of bad outcome. We hypothesize that endothelial cell dysfunction and the low-grade inflammation of obesity enable the virus to invade and do damage. While diabetes may protect against ARDS, paradoxically a diabetic vasculopathy may render the lung rather defenseless when attacked by COVID-19.

  

ARDS Susceptibility Conundrum

Provided identical insults to the lung tissue, like aspiration, pneumonia or mass transfusion, not every patient develops ARDS. Prior to COVID-19, this was first observed by Drs. Fowler and Petty at the University of Colorado where patients with known risk factors or triggers were followed in order to estimate the incidence of ARDS during a period of one year.  Of 936 patients with one or more risk factors, 10% developed ARDS. The question ”why only 10 %?” has still not been answered. While there are susceptibility factors and potentially genetic determinants, vitamin D deficiency, abnormal haptoglobin levels and elevated plasminogen levels that may cause the 10%, what is clear is that COVID-19 for some patients leads to ARDS, and a treatment is needed to address the patients that are far along with COVID-19 and entering into the hyperinflammation phase and then ARDS and death. 

 

Ventilator Induced Lung Injury and Steroids

When connecting a patient with respiratory failure to a mechanical ventilator the hope is that this support system will be required only for a “short term" in part because the machine-delivered pressure and volume parenchyma stress triggers inflammation and further lung injury.

 

Within a short time following the lung tissue damage-triggering event, there is a rapid influx of inflammatory cells into the tissue. Thus, chemotaxis and mediators of inflammation contribute to the avalanche-like disaster. It had been postulated that steroids would be effective in this setting, and in the present COVID-19 disease, dexamethasone has been reported to have some mitigating effects. These reports contrast with the results of previous ARDS steroid trials where steroid treatment had no effect, and in spite of the availability of steroid treatments, COVID-19 ARDS deaths continue.

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Adding Endothelial Barrier-Protecting Properties:

Whether lung endothelial cell damage in ARDS reduces or eliminates the capacity of these endothelial cells to function is unknown. Additional treatment we propose for ARDS is to include anti-thrombotic, anti-inflammatory, and endothelial barrier-protecting properties in order to improve gas exchange.

     

ADVIR’s Approach to Addressing ARDS is therefore Based on the Following:

1. An understanding of the pathobiology of COVID-19 disease and the progression of this disease to ARDS.

2. A strong bias that ventilator therapy strategies alone will not change the outcome of Covid-19 disease.

3. Understanding the conceptual barriers that may have prevented progress - as the mortality from ARDS has hardly improved over the years. 

4. Acceptance that ARDS is Diffuse Alveolar Damage (DAD) but also an endothelial cell disease.

5. A departure from the present therapeutic nihilism and a rationale for the use of non-steroid pharmacotherapy.

6. The recognition that ARDS has to be treated early in order to mitigate or modify the disease and that treatment ideally will be systemic and targeting the lung via the use of inhaled drugs.

 

ARDVIR’s approach is unique as we believe we can address ARDS in COVID-19 patients with multiple mechanisms of action that will be effective and be available for the non-COVID-19 ARDS indication. The Mechanisms of action will be as follows:

 

Anti-Inflammatory Actions:

1. Inhibit Cell-to-Cell interactions within the vessel.

2. Inhibit chemotaxis of inflammatory cells into the injured lung and the heart.

3. Inhibit the formation of leukotriene B4 that activates the chemotaxis of neutrophils and macrophages into the injured lung and also causes endothelial cell damage.

4. Inhibit the activation of the transcription factor Nfkappa B.

5. Protect the integrity of the alveolar-capillary barrier and prevent thrombosis.

 

Inhibition of Vascular Permeability:

1. Apply an antioxidant and inhibitor of VEGF production to inhibit the intravascular inflammatory and procoagulant  mechanisms that pave the way to lung damage and heart failure.

2. Inhibit the activity of the important hypoxia-induced transcription factors HIF-1alpha  and HIF-2 alpha. (Bridges Hypoxia and inflammation)

 

Inhibition of chemotaxis and amplification of inflammation

1. Inhibit TNF alpha and nitric oxide production.

2. Address cytokines that play an important part in the manifestation of the inflammatory response, including IL-1, IL-6, IL-8, RP, bradykinin receptor, activation of 5-LO and COX1.

3. Address LTB4, and in addition to the synthesis of LTC4, address peptido-leukotrienes that are vaso-and bronchospastic.