Blog Post

Dear Colleagues,

I’m a board-certified medical doctor in South Florida practicing since 2001. I grew up in NYC and studied at Columbia University and NY Medical College. I’ve written this letter in response to a plea from an ER/ICU doctor in NYC named Cameron Kyle-Sidell of Maimonides Hospital in Brooklyn. I don’t know him personally but he came to my attention when a friend texted me his video. Based on his findings and those of doctors expressing similar concerns in Italy, I’ve done my best to look at the medical literature for answers to this seemingly insurmountable crisis to join the medical community in finding an answer.

There have been concerns among critical care physicians on the front lines of the COVID-19 crisis that current management of this condition needs to change because it’s unlike anything we’ve ever seen and is not following the expected pathophysiology of ARDS. Front line physicians are reporting that the typical ARDS protocols are not working in COVID-19 and positive airway pressure isn’t the answer.

Doctors in Italy and now NY are reporting that despite good lung compliance, these severely impacted COVID-19 infected patients cannot get oxygen into their tissues. They report that these patients are slowly being starved of oxygen for unclear reasons. There are limited autopsy reports available to date on COVID-19 patients but there are autopsy reports from the original Coronavirus epidemic of 2003 (SARS-Cov-1). The two autopsy reports from COVID-19 patients performed in China seem to mirror the reports from the original coronavirus epidemic. They show significant necrosis, fibrin deposition, inflammation and all the hallmarks of ARDS.

There are medical studies dating back to 1992 that show viruses’ ability to inhibit tissue plasminogen activator, urokinase, and plasminogen activator. Some examples of these viruses are myxoma virus, hepatitis B, and hepatitis C viruses. This mechanism leads to increased Serp1 protein which causes increased fibrin production in alveoli and the subsequent cascade of reactions leading to poor oxygenation, inflammation and hypoxemia causing damage to pneumocytes, inducing oxygen exchange and surfactant levels.

I don’t think COVID-19 is novel so much as it’s possibly borrowed from the playbooks of other successful viruses. I think we’re still dealing with ARDS but a different presentation than what we’re used to seeing.

A study released by Cambridge University in the Journal of Biological Chemistry on Jan 5, 1992 showed that myxoma virus secretes proteinase inhibitor, Serp1, leading to significant lethality in rabbits.
Another study released in the journal Cancer Genomics and Proteomics proposed similar mechanisms for Hepatits B virus and Hepatitis C virus in hepatocellular carcinoma human patients.

There are limited studies on SARS-Cov 1, the Coronavirus epidemic of 2003; however, a paper released in 2013 by the American Society for Microbiology postulated that SARS-Cov 1-induced lung injury may be caused by serpin 1 inhibition of urokinase leading to elevated fibrin debris in the lungs. This combined with low surfactant levels leads to increased collagen deposition and pulmonary fibrosis. This cascade also leads to vascular permeability, migration and proliferation of inflammatory cells, and recruitment of neutrophils to the lungs.

These findings are also seen in certain influenza strains and may be related to the lethality of influenza as well. Although their findings were determined in mice, this model is very plausible in humans and may be the missing link in successfully treating the respiratory failure that’s causing death in COVID-19 patients.

There are medical studies and papers as far back as the 1960s performed on small and large animals suggesting that the impairment of the microcirculation or disseminated intravascular coagulation (DIC) leading to hypoxemia and low surfactant levels is a significant etiology of ARDS. This concept hasn’t been extensively studied in humans, but given the refractory nature of COVID and influenza related ARDS, it seems that this avenue should be more aggressively pursued. It’s very unlikely that this

pandemic is the last that we’ll see of COVID or influenza and it’s clear that more effective treatments for ARDS and its prevention are urgently needed.

There are small studies showing efficacy in the use of urokinase in refractory ARDS cases that don’t respond to positive airway pressures-the situation now being described by frontline physicians. A study released in the American Journal of Surgery showed efficacy of urokinase for severe ARDS based on the premise that ARDS is caused by DIC and microcoagulation leading to hypoxia and deficiency of surfactant.

A paper published by the American Journal of Physiology- Lung Cellular and Molecular Physiology in 2000 by German physicians at Justis-Liebig University showed efficacy using co-nebulized urokinase and surfactant to improve induced ARDS in rabbits.

Another study published in the Journal of Applied Physiology in 1985 showed improvement in pigs with induced septic shock/DIC given an IV bolus of urokinase.

More recent studies seem to leave out the idea of ARDS being a result of DIC or microcoagulation, and urokinase or other plasminogen activators are no longer discussed as treatment options for ARDS although the science is there to back up the idea.
It seems that based on previous studies, this important treatment modality should be reconsidered either alone or in combination with surfactant.

A recent study published March 20, 2020 in the journal Trauma and Acute Care Surgery is looking at tissue Plasminogen activator as a possible salvage drug in COVID-19 cases.

This may be an important reason that studies on surfactant for ARDS have been disappointing although the science is there to explain why it should work. It’s possible that surfactant alone cannot surmount the microcoagulation caused by the concurrent DIC seen in patients with ARDS.

The data seems to be pointing to the need to improve microcirculation in the lung in order to facilitate oxygen exchange rather than inducing positive airway pressure through a lung that cannot exchange oxygen. This may explain why several doctors in Italy and now here in the United States are meeting insurmountable obstacles in their efforts to mechanically ventilate COVID-19 patients.

I hope that this information may be of service and assist in finding a solution for our current crisis. Although I don’t suggest that this is the answer, I hope to inspire some brainstorming that may lead to a breakthrough.

Best Regards,
Mylaine Riobé, MD, FABOIM, FACOG

(561) 244-5880

info@RiobeIntegrativeMedicine.com

References:

1. Zebialowicz Ahlström, J., Massaro, F., Mikolka, P. et al.Synthetic surfactant with a recombinant surfactant protein C analogue improves lung function and attenuates inflammation in a model of acute respiratory distress syndrome in adult rabbits. Respir Res 20, 245 (2019). https://doi.org/10.1186/s12931-019-1220-x

2. Lisa E. Gralinski, Armand Bankhead III, Sophia Jeng, Vineet D. Menachery, et al. Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury. mBio Aug 2013, 4 (4) e00271-13; DOI: 10.1128/mBio.00271-13. https://www.ncbi.nlm.nih.gov/pubmed/10147145
3.  Ralph Theo Schermuly,1 Andreas Gunther,1 Monika Ermert,2 et al. Departments of 1Internal Medicine, 2Anatomy, and 3Pathology, Justus-Liebig-University Giessen, D-35392 Giessen, Germany, Conebulization of surfactant and urokinase restores gas exchange in perfused lungs with alveolar fibrin formation, Am J Physiol Lung Cell Mol Physiol , 280: L792–L800, 2001

4. Hardaway RM, Harke H, Tyroch AH, Williams CH, Vazquez Y, Krause GF. Treatment of severe acute         respiratory distress syndrome: a final report on a phase I study. Am Surg. 2001;67(4):377–382.

5. Divella R, Mazzocca A, Gadaleta C, et al. Influence of plasminogen activator inhibitor-1 (SERPINE1)    4G/5G polymorphism on circulating SERPINE-1 antigen expression in HCC associated with viral infection. Cancer Genomics Proteomics. 2012;9(4):193–198.

6. Ding Y, Wang H, Shen H, et al. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J Pathol. 2003;200(3):282–289. doi:10.1002/path.1440

7. Liu C, Ma Y, Su Z, et al. Meta-Analysis of Preclinical Studies of Fibrinolytic Therapy for Acute Lung Injury. Front Immunol. 2018;9:1898. Published 2018 Aug 20. doi:10.3389/fimmu.2018.0189

8. Ogawa R, Takano Y, Fujita T. Disseminated intravascular coagulation in the pathogenesis of adult  respiratory distress syndrome: 2. Experimental study. Jpn J Surg. 1977;7(4):223–229. doi:10.1007/bf0246935

9. Vasquez Y, Williams CH, Hardaway RM. Effect of urokinase on disseminated intravascular coagulation. J Appl Physiol (1985). 1998;85(4):1421–1428. doi:10.1152/jappl.1998.85.4.1421

10. Moore, Hunter B.¹; Barrett, Christopher D.^2,3; Moore, Ernest E.^1,4; McIntyre, Robert C.¹; Moore, Peter K.⁵; Talmor, Daniel S.⁶; Moore, Frederick A.⁷; Yaffe, Michael B.^2,3,8 Is There a Role for Tissue Plasminogen Activator (tPA) as a Novel Treatment for Refractory COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS)?.Journal of Trauma and Acute Care Surgery: March 20, 2020 – Volume Publish Ahead of Print – Issue –