What Doctors Know About COVID-19 Associated Respiratory Distress Syndrome (CARDS) & What’s Still a Mystery

Previous assumptions may be costing lives.

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April 13, 2020 — 3 p.m. EST

This article was written and produced by Dr. Ditchek and Dr. Kyle-Sidell.

What we do know: Although treatment for CARDS has followed the Berlin Criteria and accepted protocols for treatment of Adult Respiratory Distress Syndrome (ARDS) and complications of multifocal pneumonia (ARDS Task Force 2012), there has been a resounding 60-86% death rate of patients who are intubated for complications from COVID-19 (Meng et al.,2020).  Currently, treatment as well as research protocols are heavily focused on immune modulation, drug strategies and plasma convalescent antibody infusion. While these life saving efforts are admirable, to date there have been no clear breakthroughs to reduce the dramatically high death rate for COVID-19  patients on invasive mechanical ventilation. 

We know that the COVID-19 virus enters the human lungs and infects the pneumocyte cells directly responsible for the production of a critical phospholipid called surfactant (type II pneumocyte). This molecule is essential in order for humans to exchange oxygen for carbon dioxide and maintain respiration at the alveolar level. 

figure 1

Figure 1: “Bunch of grapes” model of lung alveolar anatomy (i.e.: where the gas exchange of oxygen and carbon dioxide occurs)

We know that the lungs of COVID-19 patients suffer from direct pulmonary injury as well as indirect systemic injury. COVID-19 infection in critically ill patients triggers a cascade of events resulting in severe oxygen starvation or hypoxemia. There is no doubt COVID-19 patients present very differently clinically and radiologically from those suffering classical ARDS. It is this difference that needs to be addressed urgently as a paradigm shift in order to save more lives of patients on invasive mechanical ventilation.

We also know from previous literature that hydroxychloroquine has a positive effect on surfactant production in the pneumocyte cells of the lung (Okanlawon et al. 1993; Hepping et al., 2013). If we determine that hyrdoxychloroquine plays a role in treating COVID patients, it will likely be not only as a result of combating the virus directly but also by exerting a direct pulmonary protective mechanism, possibly by augmenting the surfactant cascade.

What we do not know: While we are treating the disease as ARDS, is COVID-19 really causing classical ARDS? Or could this be a dangerous assumption leading to direct injury of the COVID patient’s lungs from current ICU protocols, which call for high pressure ventilation on severely hypoxemic patients? Radiography(X-ray) is one of the preferred tools for detection and monitoring of symptomatic COVID-19 pneumonia. While CAT(CT) scan changes reflect a snapshot in time, radiography or serial radiographs tells the story of COVID-19 timeline in the lungs. The initial CT of COVID-19 patients is often followed by multiple radiographs creating a “cine” of radiographic timeline. Several pediatric radiologists have suggested this pattern more closely resembles the chronologic pattern of premature infants Respiratory Distress Syndrome (RDS) rather than adult respiratory distress (ARDS).  Should we start to view COVID-19 patients as suffering from a similar pathology to infant RDS and attempt similar successful interventions used in those children? 

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Figure 2: Serial radiography of chest: Day 1, Day 4 and Day 7 of COVID positive patient demonstrating deterioration (between Day 4 and Day 7)

Knowledge of COVID-19 is still ever-growing, and our understanding of the radiologic features of COVID-19 is likewise still in its “infancy.” The most dramatic radiological findings demonstrate that once intubated and administered initial high pressure ventilation, there is often an observed acute radiological deterioration in these patients. Radiographically these ground glass opacities (which are typical of infant RDS) as well “flare” almost immediately after intubation and positive pressure ventilation. 

The CT scans confirm almost universally the new appearance of multi-focal opacifications at the alveolar level where “cytokine storms” now attack and limit oxygenation (Shohei et al., 2020). The premise is that the same life saving invasive mechanical ventilation that normally promotes oxygenation may possibly damage areas of the lung triggered by the virus and aggravate the “cytokine storm” response. This is not typical of garden variety ARDS which is also usually associated with interstitial fluid and pleural effusions, whereas COVID patients are not showing this “wet appearance” ( Ming-Yen Ng et al., 2020). This unusual clinical and radiographic evolution of disease is quite often however seen in cases of RDS in premature infants who do not yet possess the adequate protective surfactant to accept the newly introduced high pressure ventilation. The experience in Italy has documented that only 20-30% of critically ill COVID patients demonstrated classical ARDS (Gattinoni et al., 2020).  Innovative treatments such as high frequency oscillatory ventilation (HFOV) or noninvasive ventilation with or without surfactant therapy may produce a superior chance of survival for these critically ill ventilated patients.

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Figure 3: increased prominence of groundglass opacities after intubation

It is critical that all hospitals caring for COVID-19 patients look very closely at this paradigm change in the current early stage management of respiratory failure. The extremely high mortality rate of intubated COVID-19 patients requires all centers to reassess and adapt quickly and efficiently.

1) The existing panacea of ventilator support in critically ill COVID patients must be reviewed and reconsidered. High-Frequency Oscillatory Ventilation (HFOV) will likely be lung protective and will reduce the damage being caused by the current strategies. In the past, HFOV has been used in classical ARDS patients once conventional invasive mechanical ventilation fails. While HFOV has typically been used as a rescue therapy for ventilator associated lung injury in classical ARDS, our proposal is that the injury can be reduced by use of HFOV from the outset at the first sign of respiratory failure.  This gentle but effective ventilator strategy has been used in infant RDS for many years successfully.

2) Employ noninvasive low positive pressure ventilation(NIPPV) techniques such as high flow nasal canula (HFNC), helmet masks, BIPAP/CPAP and others for as long as possible. If and when intubation becomes necessary, avoid high PEEP in the poorly recruitable lung of critically ill COVID-19 patients.  High PEEP tends to result in severe hemodynamic impairment and fluid retention.

3) We suggest that centers treating COVID-19 patients consider initiating live trials with surfactant therapy immediately upon intubation or as part of nebulized surfactant with helmet mask trials. This can be carried out through expedited Institutional Review Board (IRB) approval. This method of improving oxygenation has been used successfully in neonates with a very reassuring safety profile. While reviewing data of surfactant use in classical ARDS, which COVID-19 ARDS is distinctly different, the primary limitation was the presence of bacterial sepsis which affected outcomes. COVID-19 associated ARDS (CARDS) is not a disease in which bacterial sepsis has been a significant outcome in most patients.  

4) Many medical centers have enrolled COVID patients in newly created trials with a variety of treatments including remdesevir, hydroxychloroquine, convalescent plasma treatment and others. There will likely be an objection that the recommendations above will interfere with the data being aggregated by these ongoing studies. With a mortality rate in ventilated patients of 60-80% depending on certain factors, there should be no hesitation to consider these newer ventilator recommendations for the critically ill intubated COVID-19 patient. Furthermore, there are centers across the United States where patients are not enrolled in the previously noted live trials.

A mortality rate of 60%-80% in ventilated COVID patients is simply not acceptable and should trigger an immediate review and a changing paradigm. Centers should consider adopting any or all of the recommendations above or at least start having important conversations for novel disease management. Academic centers have an obligation during this novel challenge to encourage-not discourage-novel ideas for innovation that could save lives. This document should serve as a model to open dialogue amongst clinicians and turn the tide in a possible paradigm shift.

Stuart H. Ditchek, MD, FAAP
Pandemic Task Force Working Group, New York Lead
Board Certified General Pediatrics
Faculty, New York University School of Medicine
Attending Physician, NYU-Langone Medical Center, New York City
Attending Physician, Maimonides Medical Center, Brooklyn, NY

Cameron Kyle-Sidell, MD, FACEP
Board Certified Critical Care Medicine
Board Certified Emergency Medicine
Maimonides Medical Center, Brooklyn, NY 

 References:

1. The ARDS Definition Task Force. Acute Respiratory Distress Syndrome: The Berlin Definition. JAMA. 2012;307(23):2526–2533. doi:10.1001/jama.2012.5669

2. Meng, L., H. Qiu, L. Wan, Y. Ai, Z. Xue, Q. Guo, R. Deshpande et al. "Intubation and Ventilation amid the COVID-19 Outbreak: Wuhan's Experience." Anesthesiology (2020).

3. Shohei Inui et al., Chest CT Findings In Cases from the Cruise Ship “Diamond Princess” with Coronavirus Disease 2019 (COVID-19) Radiology: Cardiothoracic Imaging 2020 2:2 

4. Gattinoni, Luciano, Silvia Coppola, Massimo Cressoni, Mattia Busana, and Davide Chiumello. "Covid-19 Does Not Lead to a “Typical” Acute Respiratory Distress Syndrome." American Journal of Respiratory and Critical Care Medicine (2020).

5. Imaging Profile of the COVID-19 Infection: Radiologic Findings and Literature Review. Radiology: Cardiothoracic Imaging 2020 2:1 

6. Zhou X. et al., Follow-up of asymptomatic patients with SARS-CoV-2 infection, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2020.03.024 

7. Zixing Huang et al., The Battle Against Coronavirus Disease 2019 (COVID19): Emergency Management and Infection Control 

8. Timothy J Judson et al., Rapid Design and Implementation of an Integrated Patient Self-Triage and Self-Scheduling Tool for COVID-19, Journal of the American Medical Informatics Association, , ocaa051, https://doi.org/10.1093/jamia/ocaa051

9. Jeffrey P. Kanne, Brent P. Little, Jonathan H. Chung, Brett M. Elicker, and Loren H. Ketai. Essentials for Radiologists on COVID-19: An Update – Radiology Scientific Expert Panel. Radiology 0 0:0 

10. Shohei Inui et al., Chest CT Findings In Cases from the Cruise Ship “Diamond Princess” with Coronavirus Disease 2019 (COVID-19) Radiology: Cardiothoracic Imaging 2020 2:2 

11. Imaging Profile of the COVID-19 Infection: Radiologic Findings and Literature Review. Radiology: Cardiothoracic Imaging 2020 2:1 

12. Zhou X. et al., Follow-up of asymptomatic patients with SARS-CoV-2 infection, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2020.03.024 

13. Zixing Huang et al., The Battle Against Coronavirus Disease 2019 (COVID19): Emergency Management and Infection Control 

14. Timothy J Judson et al., Rapid Design and Implementation of an Integrated Patient Self-Triage and Self-Scheduling Tool for COVID-19, Journal of the American Medical Informatics Association, , ocaa051, https://doi.org/10.1093/jamia/ocaa051

15. Jeffrey P. Kanne, Brent P. Little, Jonathan H. Chung, Brett M. Elicker, and Loren H. Ketai. Essentials for Radiologists on COVID-19: An Update – Radiology Scientific Expert Panel. Radiology 0 0:0 

16. Hepping N. et al., Successful treatment of neonatal respiratory failure caused by a novel surfactant protein C p.Cys121Gly mutation with hydroxychloroquine, Journal of Perinatology, 2013 Jun;33(6):492-4. doi: 10.1038/jp.2012.131.

17. Okanlawon et al., Chloroquine Induced Retardation of Foetal Lung Maturation in Rats, African Journal of Medicine and Medical Sciences, 1993 June;22(2):61-67