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\begin{document}

\title{Polyethylene glycol as a potential adjuvant treatment for
COVID-19-induced ARDS}



\author[1]{Mohamed Bejaoui}%
\affil[1]{University of Monastir Faculty of Pharmacy of Monastir}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Coronavirus disease 2019 (COVID-19), an infectious disease caused by the
novel coronavirus SARS-CoV-2, represent an ongoing global health
emergency. Common symptoms are mild including fever, cough, myalgia and
difficulty breathing. In patients most severely affected, COVID-19 can
be complicated by the acute respiratory distress syndrome (ARDS). The
management of ARDS mainly focuses on the provision of supportive care,
e.g., oxygenation, ventilation, and fluid management. Polyethylene
glycol (PEG) is a water soluble non-toxic polymer approved by FDA and
widely used in food, cosmetics and pharmaceutics. PEG has interesting
properties that makes it suitable for use as an adjuvant treatment in
COVID-19 patient with ARDS: (1) PEG could create a physical barrier that
inhibits virus entry and invasion; (2) PEG reduces inactivation and
enhances the surface activity of pulmonary surfactant; (3) PEG decrease
cytokine release and (4) PEG preserve lung endothelial cells integrity.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by
the novel coronavirus SARS-CoV-2. Common symptoms are mild including
fever, cough, myalgia and difficulty breathing. Sputum production,
diarrhea, sore throat and headache are less common. While most cases
report a mild illness, in some cases, COVID-19 may affect the lungs
causing pneumonia (Huang et al., 2020). In patients most severely
affected, COVID-19 can be complicated by the acute respiratory distress
syndrome (ARDS) or sepsis with acute organ dysfunction leading to
significant morbidity, mortality and healthcare resource utilization
(Huang et al., 2020, Wu and McGoogan, 2020).

ARDS is a life-threatening condition characterized by severe lung
inflammation and reduced pulmonary gas exchange. Vascular endothelium
and alveolar epithelium are damaged and alveolus is filled with
protein-rich inflammatory edematous fluid. ARDS impairs the lungs'
ability to exchange oxygen and carbon dioxide resulting in hypoxia
(Baudouin, 2004).

Coronavirus SARS-CoV-2 uses its surface glycosylated spike-protein
(S-protein) to accesses type II alveolar cells of the lungs, which are
the cells responsible for lung surfactant synthesis (Wan et al., 2020).
In addition to the damage to type II alveolar cells, reductions in
surfactant concentrations and functional alterations in surfactant
composition have been described in ARDS (Raghavendran et al., 2011,
Lewis and Veldhuizen, 2006).

Viral replication in COVID-19 activates the innate immune system to
secrete various signaling proteins such as inflammatory cytokines,
resulting in a cytokine storm and further lung damage (Mehta et al.,
2020). This acute inflammation could also lead to heart failure, sepsis,
and sudden cardiac arrest.

Polyethylene glycol (PEG) compounds are non-toxic, water soluble polymer
with different molecular weight and numerous applications (Bejaoui et
al., 2015). PEG has been used \emph{in vivo} and \emph{in vitro} in
different model of tissue injury and it has shown many interesting
biological properties; it has cytoprotective, anti-oxydant,
immunosuppressive and anti-inflammatory effects (Lazar, 2015, Shi, 2013,
Bejaoui et al., 2015, Bejaoui et al., 2016, Malhotra et al., 2011).

Here, we hypothesize that PEG alone or in combination with other agents
could be an adjuvant treatment of COVID-19 patients with ARDS.
Mechanisms may include immunocamouflage of cell membrane, enhancing
surfactant protective properties, decreasing lung inflammation and
protecting vascular endothelium and alveolar epithelium.

\textbf{PEG immunocamouflage}

PEG has been shown to protect cell membrane by creating a physical
barrier that prevents antigen recognition (Eugene, 2004). This effect
has been commonly denoted as immunocamouflage or immunomaskage. In fact,
the high number of water molecules binding on PEG chain produces a
physical and charge-neutralization barrier making cell membrane less
permeable to extracellular elements (Wicomb et al., 1990, Zheng et al.,
1991, Shi, 2013). Immunomasking effect of PEG has been used to reduce
host immune reaction after organ transplantation (Perrin et al., 2009)
and to decrease the risk of transfusion reactions and alloimmunization
of donor red blood cells (Bradley and Scott, 2007). Also, PEG has been
used to coat gene therapy vectors, such as adenovirus, to protect them
from inactivation by the immune system \emph{in vivo} (Mok et al.,
2005).

Taking this into account, PEG could create a neutralization barrier
preventing coronavirus recognition of its receptors and thus inhibiting
virus entry and invasion.

\textbf{PEG enhance performance of lung surfactant}

ARDS is characterized by surfactant dysfunction (Baudouin, 2004).
Enhancing surfactant performance could reduce COVID-19-ARDS-induced
injury. PEG, while not surface active itself, enhances the surface
activity of pulmonary surfactant (Yu et al., 2004). Yu, et al. suggest
that high molecular weight PEG (8000 to 35,000) bind to phospholipid
vesicles and enhance the rate of surface film formation (Yu et al.,
2004). PEG reduces inactivation of surfactant and enhances rates of
surfactant transfer from bulk lipid to air liquid surfaces (Yu et al.,
2004, Taeusch et al., 2008). Research findings by Taeusch, et al.
demonstrated that PEG can reverse inactivation of surfactant by meconium
and other substances (William Taeusch et al., 1999). Moreover, it has
been shown that PEG promotes surfactant aggregation, separates
surfactant from surfactant inhibitors, and enhances access of surfactant
to the gas--liquid interface (Lu et al., 2001). Taking together, we
hypothesize that PEG administration could protect the lung through
enhancing the performance of endogenous surfactant.

\textbf{PEG reduces cytokine release}

Accumulating evidence suggests that a subgroup of patients with severe
COVID-19 might have a cytokine storm syndrome which is considered one of
the major causes of ARDS and multiple-organ failure (Ye et al., 2020).
The serum levels of interleukin 2R (IL-2R) and IL-6 in patients with
COVID-19 are positively correlated with the severity of the disease
(i.e., critically ill patients \textgreater{} severely ill patients
\textgreater{} ordinary patients). PEG has been shown to reduce cytokine
release \emph{in-vivo} and \emph{in-vitro} . Ackland et al. have shown
that low molecular weight PEG reduced IL-6, IL-10 and tumor necrosis
factor \selectlanguage{greek}α \selectlanguage{english}(TNF\selectlanguage{greek}α\selectlanguage{english}) release form isolated human peripheral blood mononuclear
cells incubated with lipopolysaccharide (LPS) (Ackland et al., 2010).
PEG also reduced human neutrophil activation after incubation with LPS
or zymosan (Ackland et al., 2010). Recently, it has been shown that
intravenous administration of PEG35 in rats protected against acute
necrotizing pancreatitis (ANP) associated inflammatory process
(Ferrero-Andres et al., 2020). PEG35 was able to downregulate IL-6,
IL1-\selectlanguage{greek}β, \selectlanguage{english}TNF\selectlanguage{greek}α \selectlanguage{english}and chemokine ligand 2 (CXCL2) in both pancreas and lung.
Histologic findings show that PEG35 treatment normalized alveolar septal
thickening and neutrophils infiltration (Ferrero-Andres et al., 2020).

\textbf{PEG protects lung endothelial cells}

The release of pro-inflammatory cytokines and extravasation of blood
neutrophils into the bronchi may lead to tissue injury, particularly to
airway epithelial cells and vascular endothelial cells. This causes an
increase in the permeability of the microvascular membrane and the
development of interstitial and alveolar protein-rich edema that hinders
gas exchange and results in respiratory failure. Thus, therapeutic
strategies that target vascular membrane integrity would have obvious
clinical impact utility.

PEG has great potential in maintaining the integrity, or repairing lung
endothelial cell (EC). Indeed, PEG induced rapid, dose-dependent
augmentation in transendothelial electrical resistance (TER) in human
pulmonary endothelium, reflecting increased paracellular integrity
(Chiang et al., 2009). PEG also effectively reversed both thrombin and
LPS-induced EC barrier dysfunction. PEG induced significant cytoskeletal
rearrangement with the formation of well-defined cortical actin (Chiang
et al., 2009). Consistent with this, Bejaoui et al have shown that PEG35
contributes to the regulation of endothelial cell barrier by rearranging
the actin cytoskeleton (Bejaoui et al., 2016). Moreover, it has been
shown that PEG induced membrane stabilization through the preservation
of sarcolemmal lipid-raft architecture (Malhotra et al., 2011). Also,
PEG repairs neuronal membrane injury and enhances functional recovery by
at least two different mechanisms: resealing of the disrupted membrane
and direct protection of mitochondria (Shi, 2013).

\textbf{Discussion}

COVID-19 is an ongoing pandemic with no vaccine or treatment. PEG
potentially exhibits clinically beneficial properties. Here, we
hypothesize that PEG could be a promising adjuvant treatment for
COVID-19-induced ARDS by multifactorial mechanism: PEG could inhibit
viral invasion, enhance performance of lung surfactant, prevent cytokine
storm syndrome and preserve endothelial integrity.

PEG could inhibit virus adhesion by immunocamouflage. The mechanism of
this protection is biophysical and depends on charge maskage and steric
hindrance induced by the polymer. Immunocamouflage depends on molecular
weight: high molecular weights PEG of 10 kDa to 35 kDa are better
absorbed and consequently they are more effective (Giraud et al., 2014,
Kyluik et al., 2011). It depends also on cell surface type: small
molecular weight PEG of 2 kDa were effective to bind to respiratory
Syncytial Virus (RSV) but they were completely ineffective in the host
cell (Kyluik et al., 2011). The efficacy of the immunocamouflage is also
concentration dependent (Eugene, 2004, Yu et al., 2004, Taeusch et al.,
2008).

For optimal immunocamouflage, PEG should be covalently grafted. This
could be challenging to realize \emph{in-vivo} . In fact, intravenous
activated PEG will be covalently adsorbed to the vein wall and will not
reach the lung. Although less effective, PEG could also spontaneously
bind to cell and tissues surfaces and sterically stabilize the
underlying surface from interactions with other components. In a
clinical trials, PEG based gel applied to the lips (not covalently
bound) has shown an impressive reduction in herpes labialis relapses
(Senti et al., 2013).

Lung surfactant play a major role against pathogens including virus
(Glasser and Mallampalli, 2012). It prevents viral adhesion and destroy
free virus (Donovan et al., 2000, Glasser and Mallampalli, 2012).
Structural damage and destruction of endogenous surfactant is well known
features of ARDS. Surfactant replacement therapy substantially
contributes to lung compliance, minimizes fluid accumulation within the
alveoli, helps to maintain a uniform alveolar size during ventilation
and decrease pulmonary inflammation. This contributes to decrease
morbidity (need for mechanical ventilation and time on ventilator) and
mortality (Baudouin, 2004, Raghavendran et al., 2011). Unfortunately,
although surfactant replacement therapy is considered a life-saving
treatment for neonatal respiratory distress syndrome, the evidence of
therapeutic efficacy in adult ARDS is more limited (Baudouin, 2004).
Inadequate dosage, difficulty of effectively delivering surfactants to
injured lungs and inactivation of surfactant have been postulated for
its limited success. Here, the strategy proposed is enhancing endogenous
surfactant performance by PEG rather than surfactant replacement. This
could be achieved by PEG aerosolization or intravenous administration
which is much easier and less invasive than surfactant replacement.

SARS-CoV-2 infection induced exaggerated oxidative stress, severe immune
system overreaction and excessive pro-inflammatory cytokine production
characterized as cytokine storm which lead to subsequent progression to
ARDS and multiorgan failure (Ye et al., 2020). Interestingly, high
molecular weight PEGs have been shown to reduce cytokine production and
neutrophil activation \emph{in vitro} and \emph{in vivo} (Ferrero-Andres
et al., 2020, Ackland et al., 2010). The mechanism by which PEG reduces
inflammation is not elucidated. The decrease of leukocyte adhesion by
immunocamouflage could be implicated. Indeed, in a model of rat
peritoneal inflammation, the number of leukocytes decreased by 43\% in
PEG treatment group (Nagelschmidt et al., 1998). Also, PEG probably
reduces inflammation by decreasing oxidative stress. In fact, although
PEG is not a radical scavenger, it likely prevents oxidative stress by
preserving membrane integrity. Here, membrane stabilization effect of
PEG has also been proposed as a mechanism of protecting against
COVID-19-induced ARDS.

In addition to the main mechanisms described above, PEG could protect
against COVID-19 by several other ways. In fact, ARDS impairs the lungs'
ability to exchange oxygen and carbon dioxide resulting in hypoxia.
Severe hypoxemia (PaO2/FiO2 \textless{} 100 mmHg) can be found in 20--30
\% of COVID-19 patients and is associated with the highest mortality
rate (Chiumello and Brioni, 2016, Gattinoni et al., 2020).
Interestingly, PEG has been shown to decrease hypoxic injury and cell
death in cardiac myocytes (Malhotra et al., 2011). Moreover, Bejaoui et
al. have demonstrated that intravenous administration of PEG35 protect
rat liver against ischemia reperfusion injury \emph{in-vivo} (Bejaoui et
al., 2016). The protective effects of PEG are associated with the
decreased formation of reactive oxygen species (ROS), prevention of
endothelial cell injury, decreased vascular permeability and
mitochondrial preservation (Lazar, 2015).

PEG could also protect against sepsis-induced-COVID-19. In fact, low
molecular weight PEG has been shown to decrease the mortality in both
lipopolysaccharide (LPS) and zymosan models of sepsis by greater than
50\% (Ackland et al., 2010). Also, high molecular weight PEG prevented
lethal sepsis in a murine model of lethal sepsis induced by intestinal
Pseudomonas aeruginosa (Wu et al., 2004). Moreover, recent study has
demonstrated that administration of PEG20 protected myocardial and
neurological functions, ameliorates microcirculation, and improves
survival in a rat model of cardiopulmonary resuscitation (Yang et al.,
2018).

Last but not least, PEG could prevent acute platelet deposition on
damaged arteries (Deible et al., 1998), strongly reduced platelet
induced clot retraction (Bakaltcheva et al., 2000) and reduced leucocyte
adhesion (Bertuglia et al., 2006) which could reduce coagulopathy in
COVID-19 patients (Xiong et al., 2020).

\textbf{Conclusion}

PEG is a non-toxic, non-immunogenic polymer with multifunctional
unappreciated biologic properties. It can target several pathologic
processes associated with COVID-19-induced ARDS such as virus adhesion
and invasion, surfactant dysfunction, inflammation and endothelial
injuries. These features are particularly relevant in the clinical
setting where new therapeutic strategies are urgently required.

\textbf{References}

ACKLAND, G. L., GUTIERREZ DEL ARROYO, A., YAO, S. T., STEPHENS, R. C.,
DYSON, A., KLEIN, N. J., SINGER, M. \& GOURINE, A. V. 2010.
Low-molecular-weight polyethylene glycol improves survival in
experimental sepsis. \emph{Crit Care Med,} 38\textbf{,} 629-36.

BAKALTCHEVA, I., GANONG, J. P., HOLTZ, B. L., PEAT, R. A. \& REID, T.
2000. Effects of high-molecular-weight cryoprotectants on platelets and
the coagulation system. \emph{Cryobiology,} 40\textbf{,} 283-93.

BAUDOUIN, S. V. 2004. Exogenous surfactant replacement in ARDS--one day,
someday, or never? \emph{N Engl J Med,} 351\textbf{,} 853-5.

BEJAOUI, M., PANTAZI, E., CALVO, M., FOLCH-PUY, E., SERAFIN, A., PASUT,
G., PANISELLO, A., ADAM, R. \& ROSELLO-CATAFAU, J. 2016. Polyethylene
Glycol Preconditioning: An Effective Strategy to Prevent Liver Ischemia
Reperfusion Injury. \emph{Oxid Med Cell Longev,} 2016\textbf{,} 9096549.

BEJAOUI, M., PANTAZI, E., FOLCH-PUY, E., PANISELLO, A., CALVO, M.,
PASUT, G., RIMOLA, A., NAVASA, M., ADAM, R. \& ROSELLO-CATAFAU, J. 2015.
Protective Effect of Intravenous High Molecular Weight Polyethylene
Glycol on Fatty Liver Preservation. \emph{Biomed Res Int,}2015\textbf{,}
794287.

BERTUGLIA, S., VERONESE, F. M. \& PASUT, G. 2006. Polyethylene glycol
and a novel developed polyethylene glycol-nitric oxide normalize
arteriolar response and oxidative stress in
ischemia-reperfusion.\emph{Am J Physiol Heart Circ Physiol,}
291\textbf{,} H1536-44.

BRADLEY, A. J. \& SCOTT, M. D. 2007. Immune complex binding by
immunocamouflaged {[}poly(ethylene glycol)-grafted{]}
erythrocytes.\emph{Am J Hematol,} 82\textbf{,} 970-5.

CHIANG, E. T., CAMP, S. M., DUDEK, S. M., BROWN, M. E., USATYUK, P. V.,
ZABORINA, O., ALVERDY, J. C. \& GARCIA, J. G. 2009. Protective effects
of high-molecular weight polyethylene glycol (PEG) in human lung
endothelial cell barrier regulation: role of actin cytoskeletal
rearrangement. \emph{Microvasc Res,} 77\textbf{,} 174-86.

CHIUMELLO, D. \& BRIONI, M. 2016. Severe hypoxemia: which strategy to
choose. \emph{Crit Care,} 20\textbf{,} 132.

DEIBLE, C. R., BECKMAN, E. J., RUSSELL, A. J. \& WAGNER, W. R. 1998.
Creating molecular barriers to acute platelet deposition on damaged
arteries with reactive polyethylene glycol. \emph{J Biomed Mater
Res,}41\textbf{,} 251-6.

DONOVAN, B. W., REUTER, J. D., CAO, Z., MYC, A., JOHNSON, K. J. \&
BAKER, J. R., JR. 2000. Prevention of murine influenza A virus
pneumonitis by surfactant nano-emulsions. \emph{Antivir Chem
Chemother,}11\textbf{,} 41-9.

EUGENE, M. 2004. Polyethyleneglycols and immunocamouflage of the cells
tissues and organs for transplantation. \emph{Cell Mol Biol
(Noisy-le-grand),} 50\textbf{,} 209-15.

FERRERO-ANDRES, A., PANISELLO-ROSELLO, A., SERAFIN, A., ROSELLO-CATAFAU,
J. \& FOLCH-PUY, E. 2020. Polyethylene Glycol 35 (PEG35) Protects
against Inflammation in Experimental Acute Necrotizing Pancreatitis and
Associated Lung Injury. \emph{Int J Mol Sci,} 21.

GATTINONI, L., CHIUMELLO, D. \& ROSSI, S. 2020. COVID-19 pneumonia: ARDS
or not? \emph{Crit Care,} 24\textbf{,} 154.

GIRAUD, S., CODAS, R., HAUET, T., EUGENE, M. \& BADET, L. 2014.
Polyethylene glycols and organ protection against I/R injury. \emph{Prog
Urol,} 24 Suppl 1\textbf{,} S37-43.

GLASSER, J. R. \& MALLAMPALLI, R. K. 2012. Surfactant and its role in
the pathobiology of pulmonary infection. \emph{Microbes
Infect,}14\textbf{,} 17-25.

HUANG, C., WANG, Y., LI, X., REN, L., ZHAO, J., HU, Y., ZHANG, L., FAN,
G., XU, J., GU, X., CHENG, Z., YU, T., XIA, J., WEI, Y., WU, W., XIE,
X., YIN, W., LI, H., LIU, M., XIAO, Y., GAO, H., GUO, L., XIE, J., WANG,
G., JIANG, R., GAO, Z., JIN, Q., WANG, J. \& CAO, B. 2020. Clinical
features of patients infected with 2019 novel coronavirus in Wuhan,
China. \emph{Lancet,} 395\textbf{,} 497-506.

KYLUIK, D. L., SUTTON, T. C., LE, Y. \& SCOTT, M. D. 2011.
Polymer-mediated broad spectrum antiviral prophylaxis: utility in high
risk environments. \emph{In:} CARPI, A. (ed.) \emph{Progress in
molecular and environmental bioengineering- from analysis and modeling
to technology applications.} Intech.

LAZAR, H. L. 2015. High-molecular-weight polyethylene glycol: a new
strategy to limit ischemia-reperfusion injury. \emph{J Thorac Cardiovasc
Surg,} 149\textbf{,} 594-5.

LEWIS, J. F. \& VELDHUIZEN, R. A. 2006. The future of surfactant therapy
during ALI/ARDS. \emph{Semin Respir Crit Care Med,} 27\textbf{,} 377-88.

LU, K. W., TAEUSCH, H. W., ROBERTSON, B., GOERKE, J. \& CLEMENTS, J. A.
2001. Polyethylene glycol/surfactant mixtures improve lung function
after HCl and endotoxin lung injuries. \emph{Am J Respir Crit Care
Med,}164\textbf{,} 1531-6.

MALHOTRA, R., VALUCKAITE, V., STARON, M. L., THECCANAT, T., D'SOUZA, K.
M., ALVERDY, J. C. \& AKHTER, S. A. 2011. High-molecular-weight
polyethylene glycol protects cardiac myocytes from hypoxia- and
reoxygenation-induced cell death and preserves ventricular
function.\emph{Am J Physiol Heart Circ Physiol,} 300\textbf{,} H1733-42.

MEHTA, P., MCAULEY, D. F., BROWN, M., SANCHEZ, E., TATTERSALL, R. S.,
MANSON, J. J. \& HLH ACROSS SPECIALITY COLLABORATION, U. K. 2020.
COVID-19: consider cytokine storm syndromes and
immunosuppression.\emph{Lancet,} 395\textbf{,} 1033-1034.

MOK, H., PALMER, D. J., NG, P. \& BARRY, M. A. 2005. Evaluation of
polyethylene glycol modification of first-generation and
helper-dependent adenoviral vectors to reduce innate immune
responses.\emph{Mol Ther,} 11\textbf{,} 66-79.

NAGELSCHMIDT, M., MINOR, T. \& SAAD, S. 1998. Polyethylene glycol 4000
attenuates adhesion formation in rats by suppression of peritoneal
inflammation and collagen incorporation. \emph{Am J Surg,}
176\textbf{,}76-80.

PERRIN, H., THAUNAT, O., MALCUS, C., BADET, L., HENNINO, A., CODAS, R.,
TOURAINE-MOULIN, F., NICOLAS, J. F. \& MORELON, E. 2009.
Immunoprotection by polyethylene glycol in organ preservation solutions
is not due to an immunomasking effect. \emph{Nephrol Dial
Transplant,}24\textbf{,} 1682-5.

RAGHAVENDRAN, K., WILLSON, D. \& NOTTER, R. H. 2011. Surfactant therapy
for acute lung injury and acute respiratory distress syndrome.\emph{Crit
Care Clin,} 27\textbf{,} 525-59.

SENTI, G., IANNACCONE, R., GRAF, N., FELDER, M., TAY, F. \& KUNDIG, T.
2013. A randomized, double-blind, placebo-controlled study to test the
efficacy of topical 2-hydroxypropyl-Beta-cyclodextrin in the prophylaxis
of recurrent herpes labialis. \emph{Dermatology,} 226\textbf{,} 247-52.

SHI, R. 2013. Polyethylene glycol repairs membrane damage and enhances
functional recovery: a tissue engineering approach to spinal cord
injury. \emph{Neurosci Bull,} 29\textbf{,} 460-6.

TAEUSCH, H. W., DYBBRO, E. \& LU, K. W. 2008. Pulmonary surfactant
adsorption is increased by hyaluronan or polyethylene
glycol.\emph{Colloids Surf B Biointerfaces,} 62\textbf{,} 243-9.

WAN, Y., SHANG, J., GRAHAM, R., BARIC, R. S. \& LI, F. 2020. Receptor
Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on
Decade-Long Structural Studies of SARS Coronavirus. \emph{J Virol,} 94.

WICOMB, W. N., HILL, J. D., AVERY, J. \& COLLINS, G. M. 1990. Optimal
cardioplegia and 24-hour heart storage with simplified UW solution
containing polyethylene glycol. \emph{Transplantation,}
49\textbf{,}261-4.

WILLIAM TAEUSCH, H., LU, K. W., GOERKE, J. \& CLEMENTS, J. A. 1999.
Nonionic polymers reverse inactivation of surfactant by meconium and
other substances. \emph{Am J Respir Crit Care Med,} 159\textbf{,}1391-5.

WU, L., ZABORINA, O., ZABORIN, A., CHANG, E. B., MUSCH, M., HOLBROOK,
C., SHAPIRO, J., TURNER, J. R., WU, G., LEE, K. Y. \& ALVERDY, J. C.
2004. High-molecular-weight polyethylene glycol prevents lethal sepsis
due to intestinal Pseudomonas aeruginosa.
\emph{Gastroenterology,}126\textbf{,} 488-98.

WU, Z. \& MCGOOGAN, J. M. 2020. Characteristics of and Important Lessons
From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary
of a Report of 72314 Cases From the Chinese Center for Disease Control
and Prevention. \emph{JAMA} .

XIONG, M., LIANG, X. \& WEI, Y. D. 2020. Changes in Blood Coagulation in
Patients with Severe Coronavirus Disease 2019 (COVID-19): a
Meta-Analysis. \emph{Br J Haematol} .

YANG, J., XIAO, Y., QUAN, E. Y., HU, Z., GUO, Q., MIAO, C., BRADLEY, J.
L., PEBERDY, M. A., ORNATO, J. P., MANGINO, M. J. \& TANG, W. 2018.
Effects of Polyethylene Glycol-20k on Postresuscitation Myocardial and
Cerebral Function in a Rat Model of Cardiopulmonary
Resuscitation.\emph{Crit Care Med,} 46\textbf{,} e1190-e1195.

YE, Q., WANG, B. \& MAO, J. 2020. The pathogenesis and treatment of the
`Cytokine Storm' in COVID-19. \emph{J Infect} .

YU, L. M., LU, J. J., CHIU, I. W., LEUNG, K. S., CHAN, Y. W., ZHANG, L.,
POLICOVA, Z., HAIR, M. L. \& NEUMANN, A. W. 2004. Poly(ethylene glycol)
enhances the surface activity of a pulmonary surfactant. \emph{Colloids
Surf B Biointerfaces,} 36\textbf{,} 167-76.

ZHENG, T. L., LANZA, R. P. \& SOON-SHIONG, P. 1991. Prolonged pancreas
preservation using a simplified UW solution containing polyethylene
glycol. \emph{Transplantation,} 51\textbf{,} 63-6.

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