COVID-19 biophysics
In severe cases of COVID-19 infections, patients develop acute respiratory distress syndrome (ARDS) and thick, jelly-like fluid builds up in the lungs. This fluid buildup hinders oxygen diffusion into the blood, making it difficult to breathe, and is difficult to clear by natural clearance (i.e. coughing) due to the jelly-like consistency. The limited information on the composition of this fluid has hindered development of effective treatment strategies, with current practices restricted to placing patients on ventilators. From clinically-obtained respiratory secretions from intubated COVID-19 patients, we found that DNA content and hyaluronan content were greatly elevated in COVID-19 secretions compared to healthy respiratory secretions. Using dynamic light scattering microrheology, I measured and analyzed the rheological properties of COVID-19 lung fluid and found that secretions from COVID-19 were more resistant to flow than healthy secretions. By enzymatically degrading two target polymers, DNA and hyaluronan in the secretions, I demonstrated that more jelly-like secretions underwent a larger change to a more fluid-like consistency due to the enzymes. The results of this study suggested that DNA and hyaluronan may be viable therapeutic targets in severe COVID-19 infections to lessen patients’ breathing difficulty. Since the enzymes used in this study are already FDA-approved and currently used for other indications, these results hold an immediate promise of relief for patients experiencing severe cases of COVID-19 infections. Given that the fluid buildup is mainly a symptom of ARDS rather than COVID-19 specifically, the results of this study will further transform the field by suggesting viable treatment strategies for other forms of ARDS, including from excessive smoke inhalation or trauma.
Articles
MJ Kratochvil, G Kaber, S Demirdjian, PC Cai, EB Burgener, N Nagy, GL Barlow, MC Popescu, MR Nicolls, MG Ozawa, DP Regula, AE Pacheco-Navarro, S Yang, V de Jesus Perez, H Karmouty-Quintana, A Peters, B Zhao, LM Buja, PY Johnson, RB Vernon, TN Wight, Stanford COVID-19 Biobank Study Group, AJ Rogers, AJ Spakowitz, CE Milla, SC Heilshorn, PL Bollyky. “Biochemical, biophysical, and immunological characterization of respiratory secretions in severe SARS-CoV-2 infections.” *JCI Insight.
Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19 disease, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e. resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We found the percent solids and protein content are all greatly elevated in COVID-19 compared to heathy control samples and closely resemble levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan are major components of respiratory secretions in COVID-19 and are likewise abundant in cadaveric lung tissues from these patients. COVID-19 secretions exhibited heterogeneous rheological behaviors with thicker samples showing increased sensitivity to DNase and hyaluronidase treatment. These results highlight the dramatic biophysical properties of COVID-19 respiratory secretions and suggest that DNA and hyaluronan may be viable therapeutic targets in COVID-19 infection. In histologic sections from these same patients, we observed increased expression of the hyaladherin versican but reduced TSG6, consistent with the inflammatory nature of these secretions. Finally, we observed diminished type I interferon and enhanced inflammatory cytokines in these secretions. Overall, our studies support that increases in HA and DNA in COVID-19 respiratory secretion samples correlate with enhanced inflammatory burden in COVID-19.