COVID-19: Therapeutic Use of Modified Albumin

Low albumin levels and intensity of albumin level decrease are predictors of disease severity.

There is an established correlation between low albumin levels and patient outcomes. “Albumin was significantly lower in the progression group than in the improvement/stabilization group (36.62 ± 6.60 vs. 41.27 ± 4.55 g/L, U = 2.843, P = 0.006).”  See article HERE. “The albumin is decreased in severe cases and the level of albumin is around 26.3-30.9 g/l” Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study[J]. Lancet,2020,395(10223):507 -513.

The intensity of the albumin level decrease was a predictor of disease severity in MERS-CoV. Saad M, Omrani AS, Baig K, et al. Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single -center experience in Saudi Arabia[J]. Int J Infect Dis,2014,29:301 -306.

Preserving the Glycocalyx

Many cells are protected by a network of polysaccharides called glycocalyx. The glycocalyx (400 nm or more) layer protects the cell from hostile environments, and prevents viruses from reaching their entry receptor at the cell surface . Bacterial viruses infecting encapsulated cell carry an exopolysaccharide (EPS) degrading enzymes as tailspike proteins in order to digest this sugar coat and reach the outer membrane or the peptidoglycan layer . The capsule can be composed of various EPS such as alginates, polysialic acids (PSAs), and hyaluronic acid (HA). https://viralzone.expasy.org/3896?outline=all_by_species

“In addition to ARDS, the endothelial glycocalyx has been demonstrated to play an important role in several diseases, such as acute kidney injury (Libório et al., 2015), diabetes (Dogné et al., 2016), ischemia/reperfusion (van Golen et al., 2014), and hemorrhagic shock (Naumann et al., 2017). Therefore, approaches to protect against glycocalyx damage and promote glycocalyx restoration have an important clinical significance (Martin et al., 2016; Yang et al., 2017).” Id. https://doi.org/10.1186/s13054-019-2534-2

“Glycocalyx degradation occurs in sepsis and septic shock and is associated with in-hospital mortality. The volume of intravenous fluids administered during sepsis resuscitation is independently associated with the degree of glycocalyx degradation. These findings suggest a potential mechanism by which intravenous fluid resuscitation strategies may induce iatrogenic endothelial injury.” Id. https://doi.org/10.1186/s13054-019-2534-2

There is evidence that the thickness of the glycocalyx is a balance between the rate of synthesis of glycocalyx components and the rate of degradation.24,46 Synthesis can be modulated by the supply of precursors of matrix components;6 degradation is modulated by enzymes such as heparinase, hyaluronidase, and metalloproteases.46” Curry, F.E., Adamson R.H., Entotheliial Glycocalyx: Permatbility Barrier and Mechanosensor, Ann Biomed Eng. 2012 Apr; 40(4) 828-839 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042904/

It is also widely recognized that removal of plasma proteins can reduce the thickness and disrupt the organization of the endothelial layer structure.1,16,77 Id

Albumin aids and reduces damage to glycocalyx.

“Albumin has been shown to reduce glycocalyx shedding caused by cold ischemia [83]. Also fresh frozen plasma (FFP) has been shown to protect vascular endothelial permeability [84]. Glycocalyx layer is coated by albumin and proteins; thus, these natural components may not only constitute the barrier against flowing substances but may nourish the glycocalyx. Schött et al. hypothesize that FFP may inhibit or neutralize sheddases (a diverse group of proteases) and/or that FFP mobilizes intracellular stores of preformed syndecans [85]. Further research to elucidate natural turn-over of GCX may disclose the theoretical protection of GCX.” Usiyama D, Kataoka H, Lijima T, Glycocalyx and its involvement in clinical pathophysiologies, Journal of Intensive Care, 2016; 4(1): 59 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017018/

“Albumin, a colloid commonly used for volume resuscitation, has been proposed to be glycocalyx-protective as it carries erythrocyte-derived sphingosine-1-phosphate (S1P) to the endothelium, where it can mediate glycocalyx recovery by suppressing MMP activity [58, 59]. Jacob et al. [60] showed albumin prevents glycocalyx degradation more effectively than HES and 0.9% normal saline in their animal heart model.” Uchimido, R., Schmidt, E.P. & Shapiro, N.I. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care 23, 16 (2019). https://doi.org/10.1186/s13054-018-2292-6

“Since glycocalyx degradation is strongly correlated with disease progression, pharmacological intervention to prevent glycocalyx degradation has been widely considered.” Id.

“Intravenous fluids, an essential component of sepsis resuscitation, may paradoxically worsen outcomes by exacerbating endothelial injury. Preclinical models suggest that fluid resuscitation degrades the endothelial glycocalyx, a heparan sulfate-enriched structure necessary for vascular homeostasis. We hypothesized that endothelial glycocalyx degradation is associated with the volume of intravenous fluids administered during early sepsis resuscitation.” Hippensteel, J.A., Uchimido, R., Tyler, P.D. et al. Intravenous fluid resuscitation is associated with septic endothelial glycocalyx degradation. Crit Care 23, 259 (2019). https://doi.org/10.1186/s13054-019-2534-2.

MODIFIED ALBUMIN FORMULATION and THEORY:

“Albumin is 67 kDa and has a net negative charge but binds tightly to the glycoclayx [5] because of its amphoteric nature (it carries some positive charges along the protein chain). This binding reduces the hydraulic conductivity across the vascular barrier; therefore, some albumin leaks through the glycocalyx [19]. Some pathophysiological statuses that are accompanied by the disruption of the glycocalyx can lead to hyperpermeability. Even at a low capillary pressure, absorption rarely occurs, and water movement is unidirectional. Under septic conditions, the profile for large pore filtration increases as the capillary pressure increases; this explains why fluid leakage is enhanced under septic conditions.” Usiyama D, Kataoka H, Lijima T, Glycocalyx and its involvement in clinical pathophysiologies, Journal of Intensive Care, 2016; 4(1): 59 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017018/

Dr. William Norberg combined albumin with amino acids leading to increased size - The Norberg Solution - “TNS”. The clinical response of patients administered TNS is much better than that historically seen with administration of plain albumin. We postulate the addition of amino acids facilitates unfolding or refolding of protein chains altered during the sterilization process of albumin; restoring the albumin to more closely approximate its in vivo configuration. We have measured a 17% increase in the size of the TNS compounded albumin molecule compared to processed albumin. TNS seems to rehabilitate the Glycocalyx and result in fluid mobilization from the extracellular space and secondarily reconstitute this layer over those processes that lead to cytokine release and inflammation and the disease process. Further study on mechanism is required.

The mechanism of death due to COVID-19 is presumed to be similar to the problems of other viral diseases. That of cytokine storm leading to respiratory distress, multiorgan failure and death. The inflammatory cytokine storm is observed in severe COVID-19 cases. Liu J, Li S, Liu J, et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS -CoV -2 infected patients[J]. medRxiv,2020. https://doi.org/10.1101/2020.02.16.20023671

SEE ALSO:

Endothelial Glycocalyx Repair: Building a Wall to Protect the Lung during Sepsis: Rizzo, Alicia, Dudek, Steven https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516297/

The Pulmonary Endothelial Glycocalyx in ARDS: A Critical Role for Heparan Sulfate: LaRiviere WB, Schmidt EP

https://www.ncbi.nlm.nih.gov/pubmed/30360782