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\begin{document}

\title{Potential Agents Therapy Strategies Rounding up Immunopathology of
COVID-19}



\author[1]{Hong Peng Li}%
\author[1]{Liu Zhang}%
\author[1]{Li Qing Yun}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
The novel coronavirus 2019 (COVID-19) pandemic, which has resulted in
nearly 700 thousand deaths, is rapidly spreading across the globe
despite drastic public and personal health measures. As showed in Figure
1, the direct attack from SARS-CoV-2 and hyperactivated immune response
contribute to the progress and deterioration of COVID-19 infection.
Eliminating virus and blocking cytokine are important check-points of
COVID-19 therapy. Based on our successful experience in Wuhan and
current progress of the therapeutic strategies, several agents targeting
immunopathology have displayed marked effects on COVID-19 patients,
including interferons, immunoglobulin, and glucocorticoid, etc. Here, we
want to review the novel progress of therapy strategies related to
immunopathology and share our Wuhan experience with the colleagues in
the field by reviewing the underlying the pharmacologic mechanisms of
these agents.%
\end{abstract}%



\sloppy


\textbf{Potential Agents Therapy Strategies Rounding up Immunopathology
of COVID-19}

Hong Peng Li\textsuperscript{1,2}, Liu Zhang\textsuperscript{1,2}, Qing
Yun Li\textsuperscript{1,2}

\textsuperscript{1}Department of Respiratory and Critical Care Medicine,
Ruijin Hospital, Shanghai Jiao Tong University School of Medicine,
Shanghai, 200025, China

\textsuperscript{2}Institute of Respiratory Medicine, Shanghai Jiao Tong
University School of Medicine, Shanghai, 200025, China

Correspondence: Qing Yun Li

Department of Respiratory and Critical Care Medicine, Ruijin Hospital,
Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

Phone: +86-21-64370045

Email address:\emph{liqingyun68@hotmail.com}

\textbf{Conflicts of interest}

The authors declare no conflicts of interest and do not receive any
funding source related their professional activity that could influence
the preparation of the manuscript.

\textbf{Acknowledgements}

Not Applicable.

\textbf{Funding information}

Grants supported: the National Key Technology Research and Development
Program of China (2018YFC1311900), the Key Research Program of Shanghai
Science and Technology Commission (grant number 18140903600) and the
National Nature Science Foundation of China (81770084 and 81570082).

\textbf{{[}Abstract{]}} : The novel coronavirus 2019 (COVID-19)
pandemic, which has resulted in nearly 800 thousand deaths, is rapidly
spreading across the globe despite drastic public and personal health
measures. As showed in Figure 1, the direct attack from SARS-CoV-2 and
hyperactivated immune response contribute to the progress and
deterioration of COVID-19 infection. Eliminating virus and blocking
cytokine are important check-points of COVID-19 therapy. Based on our
successful experience in Wuhan and current progress of the therapeutic
strategies, several agents targeting immunopathology have displayed
marked effects on COVID-19 patients, including interferons,
immunoglobulin, and glucocorticoid, etc. Here, we want to review the
novel progress of therapy strategies related to immunopathology and
share our Wuhan experience with the colleagues in the field by reviewing
the underlying the pharmacologic mechanisms of these agents.

\textbf{{[}keyword{]}} : immunotherapy; cytokines; corticosteroids;
inflammation;monoclonal antibodies;

The novel coronavirus 2019 (COVID-19) pandemic is rapidly spreading
across the globe despite drastic public and personal health measures.
Until this report is written, COVID-19 has resulted in nearly 800
thousand deaths. The lack of potent antiviral countermeasures is one of
the main reasons of this rapid outbreak. Therefore, it is urgent to seek
effective agents to rescue more patients with COVID-19. Based on our
successful experience in Wuhan and current progress of the therapeutic
strategies, several agents targeting immunopathology in COVID-19 have
displayed marked therapeutic effects on COVID-19 patients, including
interferons, immunoglobulin, and glucocorticoid, etc.

The direct attack from severe acute respiratory syndrome coronavirus
2(SARS-CoV-2) and hyperactivated immune response contribute to the
progress and deterioration of COVID-19 infection {[}1, 2{]}. As showed
in Figure 1, the decrease of lymphocytes (lymphopenia) caused by direct
attack of SARS-CoV-2, including T cells, B cells, and natural killer
(NK) cells, is thought to be associated with the delay for virus
elimination and increased mortality{[}3-5{]}. It was reported that
plasmatic T lymphocyte count 0.8 \selectlanguage{ngerman}× 10\textsuperscript{9}/L, 1.0 ×
10\textsuperscript{9} /L and 1.1 × 10\textsuperscript{9} /L corresponded
to the mortality of 4.6\%, 1.9\% and 0.9\%, respectively {[}6{]}.
Meanwhile, hyperactivated immune response was indicated by high
proportions of HLA-DR (CD4+ 3.47\%) and CD38 (CD8+ 39.4\%)
double-positive fractions {[}3{]}. In turn, these trigger the cytokine
storm by producing large amount of cytokines including IL-6 and IL-1\selectlanguage{greek}β,
\selectlanguage{english}as well as IL-2, IL-8, IL-17, G- CSF, GM- CSF, IP10, MCP1, and
MIP1\selectlanguage{greek}α,\selectlanguage{english}\emph{etc.} {[}7{]}. IL-6 is a crucial protagonist for the
development of cytokine storm with increased level and lasted for longer
duration in severe patients {[}5, 8, 9{]}, and further promotes a
waterfall-like release of inflammatory mediators {[}7, 10,
11{]}.Besides, monocytes and neutrophils could also involve in cytokines
releasing of IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-6, and TNF-\selectlanguage{greek}α \selectlanguage{english}in severe disease {[}12, 13{]}.
Eventually, cytokine storm leads to the multiple organs dysfunction
syndrome (MODS) and death. Thus, the agents rounding up the
immunopathology have become major treatment strategies against COVID-19
(Figure 1).

Type I interferons (IFNs), including interferon-\selectlanguage{greek}α \selectlanguage{english}and interferon-\selectlanguage{greek}β, \selectlanguage{english}help
to eliminate the SARS-CoV-2 by improving the phagocytic function of
macrophages and the immune activity of T lymphocytes, or by inducing the
synthesis of antiviral protein (AVP) of host cells. Type I IFNs have
emerged as potentially effective drugs against SARS-CoV-2 {[}14{]}. Zhou
and colleagues {[}15{]} found IFN-\selectlanguage{greek}α\selectlanguage{english}2b, with or without oral umifenovir
hydrochloride, significantly reduced the duration of detectable virus in
the upper respiratory tract in 53 moderate COVID-19 patients than those
who used umifenovir hydrochloride only (21.1 days \emph{vs.} 27.9 days),
and over the time period day 12 to day 42 (from onset of symptoms),
patients without treatment of IFN-\selectlanguage{greek}α\selectlanguage{english}2b had higher IL-6 levels (by 33.5
pg/mL) and higher CRP levels (by 25.7 mg/L) than the patients treated
with IFN-\selectlanguage{greek}α\selectlanguage{english}2b. Chinese guidelines listed interferon-\selectlanguage{greek}α \selectlanguage{english}as an alternative
for antivirus combination therapy {[}16{]}. Interferon-\selectlanguage{greek}β \selectlanguage{english}has also been
recommended at the early stage of COVID-19 {[}17{]} . A multicenter
study reported that the antivirus therapy combined with Interferon-\selectlanguage{greek}β
\selectlanguage{english}(subcutaneous injection of interferon beta-1b 8 million international
units on alternate days) had a significantly shorter median time from
start of study treatment to negative nasopharyngeal swab (7 days {[}IQR
5--11{]}) than the control group (12 days {[}8--15{]}; hazard ratio 4\selectlanguage{ngerman}·37
{[}95\% CI 1·86--10·24{]}, p=0·0010), and days of hospital stay in 86
patients with mild to moderate COVID-19 (9.0 days {[}7.0--13.0{]} vs
14.5 days {[}9.3--16.0{]}; HR 2.72{[}1.2--6.13{]}, p=0·016){[}18{]}. A
further study should be conducted to explore the effects of IFNs on
severe and critical patients who also have obvious immunosuppression. A
recent study demonstrated that the severe and critical patients, who
were characterized by no interferon-\selectlanguage{greek}β \selectlanguage{english}and low interferon-\selectlanguage{greek}α \selectlanguage{english}production
and activity, were often associated with a persistent blood viral load
and an exacerbated inflammatory response. This appears to suggest that
type-I interferons deficiency in the blood might be an important marker
of severe COVID-19 and provide a rationale for combined therapeutic
approaches {[}19{]}. Besides, IFN III (IFN-\selectlanguage{greek}λ\selectlanguage{english}) imposes the antivirus
effects via binding and inducing signaling through the heterodimeric
IFN-\selectlanguage{greek}λ \selectlanguage{english}receptor (IFNLR). However, IFN-\selectlanguage{greek}λ \selectlanguage{english}has been showed to increase
susceptibility to pneumonia caused by methicillin resistant
Staphylococcus aureus in response to influenza virus infection in
mice{[}20{]}. Broggi and co-workers {[}21{]} showed that IFN-\selectlanguage{greek}λ \selectlanguage{english}induced
barrier damage of airway epithelium in mice and the amounts of
IFN-\selectlanguage{greek}λ\selectlanguage{english}messenger RNA (mRNA) from bronchoalveolar lavage fluid and
naso-oropharyngeal samples were correlated with disease morbidity in
SARS-CoV-2--positive patients. Thus, it is needed to outweigh the
benefit of a deficient epithelial IFN-l response in the lungs for
SARS-CoV-2 infection.

The use of commercial intravenous \selectlanguage{greek}γ-\selectlanguage{english}Immunoglobulin, convalescent plasma,
and protective monoclonal antibodies is a potential antiviral
immunotherapy for COVID-19{[}22, 23{]}. (1) The commercial intravenous
\selectlanguage{greek}γ-\selectlanguage{english}Immunoglobulin (IVIG) exerts non-specific antiviral effect, and been
used as an adjunctive drug in the treatment of severe pneumonia caused
by influenza{[}24{]}. In critically ill patients with COVID-19, the
innate immunity is not enough to limit virus, and the adaptive immune
usually establishes about 10 days after the onset. Thus, injection of
IVIG may help to eliminate the virus partially. Cao and colleagues
investigated 58 cases of severe or critical illness due to COVID-19 who
received intravenous immunoglobulin at 20 g/day when the absolute
lymphocyte count fell to \textless{} 0.5 \selectlanguage{ngerman}×10 9 /L. The results showed
that treatment with IVIG within 48 h of admission reduced duration of
ventilator use, hospital and ICU length of stay, and ultimately
improving 28-day mortality. Currently, the pool of recovered patients
with COVID-19 increases globally, immunoglobulin from these population
will contain specific antibodies to SARS-CoV-2. (2) The convalescent
plasma containing neutralizing antibodies could reduce mortality in
patients with severe influenza A, MERS-CoV and SARS-CoV
infections{[}25{]},which meant immunotherapeutic potential of
convalescent plasma for patients with COVID-19 for virological and
clinical characteristics among SARS, MERS, and COVID-19 were
comparable{[}26{]}. Duan and colleagues {[}27{]} reported that 200ml of
convalescent plasma brought clinical improvement of oxygen saturation,
lymphopenia, and CT scan in 10 patients with severe COVID-19. With the
lack of prospective random controlled trials, the optimal dose and
treatment time point, as well as the therapeutic indications of
convalescent blood products in COVID-19 remain uncertain. (3) The
specific human monoclonal antibody CR3022 of SARS-CoV can also bind to
the receptor binding domain of SARS-CoV-2 effectively, suggesting that
the antibody may become a potential therapeutic choice {[}28{]}. It is
cautious for the use in the patients with antibody-dependent enhancement
(ADE) of SARS-CoV-2 infection, which may associate with worse outcome
{[}29, 30{]}. ADE has been observed in various viral infections,
characterized as increased IgG response and a higher titer of total
antibodies, leading to antibody-mediated enhancement of viral entry and
induction of a severe inflammatory response.

Glucocorticoid (GC) can suppress the binding of NF-\selectlanguage{russian}кB to GC response
elements on DNA directly, reducing the expression of cytokines like
IL-6, TNF-\selectlanguage{greek}α, \selectlanguage{english}and IL-1\selectlanguage{greek}β, \selectlanguage{english}etc. It can also activate the inhibitory nuclear
factor I\selectlanguage{greek}κ\selectlanguage{english}B\selectlanguage{greek}α, \selectlanguage{english}initiating the transcription of anti-inflammatory factor
IL-10 {[}31{]}. It is reported that GC can inhibit pulmonary
inflammation of acute respiratory distress syndrome (ARDS) with strong
inflammatory response effectively {[}32{]}. Medium-to-low-dose
glucocorticoids may play a protective role in the respiratory and
digestive systems by activating ACE2 and suppressing cytokine storm in
severe or critical patients with COVID-19{[}33{]}. A recent randomized
clinical trial showed that dexamethasone reduced 28-day mortality among
the patients with COVID-19 receiving invasive mechanical ventilation or
oxygen at randomization {[}34{]}. In this study, 2,104 patients
allocated to receive dexamethasone were compared with 4321 patients
concurrently allocated to usual care, Dexamethasone(6 mg, once daily,
oral or intravenous for up to 10 days) reduced deaths by one-third in
patients receiving invasive mechanical ventilation (29.0\% vs. 40.7\%),
by one-fifth in patients receiving oxygen without invasive mechanical
ventilation (21.5\% vs. 25.0\%), but did not reduce mortality in
patients not receiving respiratory support at randomization (17.0\%
vs.13.2\%, p=0.14). However, the immunosuppressed effect of GC should be
considered for it may bring an unfavorable side for delaying virus
clearance and increasing risk of secondly infection. Thus, a suitable GC
administration juncture timepoint might be subjected to further
exploration to prevent the progression of ARDS. Based on Chinese
experience, it is recommended when the onset of cytokine storm was
indicated by increased resting respiratory rate ( \textgreater{} 30
breaths/minute), ongoing deterioration in oxygenation index,
multi-lobular progression ( \textgreater{} 50\%) on imaging within 48 h,
consistent lymphopenia, etc.{[}35, 36{]}.

Tocilizumab (TCZ), a humanized IgG1k monoclonal antibody, can
specifically bind soluble or membrane-type IL-6 receptors (Sil-6R and
Mil-6R), and has been widely used in the treatment of autoimmune
diseases such as rheumatoid. It was found to reduce the 28-day mortality
of patients with sepsis (IL-6\textgreater{}1000 pg/ml) {[}37{]}. For
COVID-19 infection, clinical studies have shown that serum levels of
inflammatory mediators in severe patients are significantly higher than
those in common patients. Excessive inflammation response can trigger
cytokine storms and cause damage to multiple target organs{[}12{]}. As
IL-6 played major role in the development of cytokine storm, and is an
indicator of poor outcome of severe patients with COVID-19, Tocilizumab
was recommended to the patients with COVID-19 who have elevated IL-6
levels to suppress the cytokine storm{[}9{]}. Thus, the efficacy of
tocilizumab could be expected in severe and critical patients. A case
report showed {[}38{]} that in 42-year-old male suffering from
respiratory failure due to SARS-CoV-2 infection, after 4 days of TCZ
treatment, the CRP decreased from 225 to 33 mg/L and ultimately
clinically fully recovered. A retrospective study analyzing 15 cases of
COVID-19 by Luo and colleagues found that Tocilizumab deceased the plasm
level of CRP and IL-6 in 10 patients{[}39{]}. A clinical study
(registration number: ChiCTR2000029765) showed that quick control of
fever and improvement of respiratory function in 21 patients with severe
COVID-19. However, a cautionary case report by Radbel et al.
demonstrated that two patients were diagnosed with COVID19 complicated
by cytokines release syndrome (CRS) and treated with TCZ, and
unfortunately, both patients progressed to severe
hemophagocyic~histiocytosis~(HLH), and one developed to viral
myocarditis.

Thymosin is widely used for antiviral treatment of hepatitis B and HIV.
Acting as an immune potentiator, thymosin promotes the differentiation
and maturation of thymocytes, increases the number and activity of T
cells {[}40{]}. It can also promote the recruitment of precursor NK
cells, differentiation and function enhancement of bone marrow-derived
dendritic cells (DC) {[}41{]}. Although scarce of clinical evidence,
thymosin might restrict the progression of COVID-19 by stimulating the
production and activity of lymphocytes in theory especially for those
with lymphopenia.

In conclusion, the development and evolution of covid-19 is closely
related to immune function. Maintaining appropriate immune response of
patients promotes to eliminate SARS-CoV-2 without causing
immunopathological injury by cytokine storm. Immune dysfunction can
contribute to the spread of virus, and immunopathological damage play an
important role in the progression of the disease. Crucially, the agents
rounding up the immunopathology for COVID-19 may bring hope under the
scenario of the lacking in ineffective antiviral drugs. Based on our
successful experience in Wuhan and the novel progress of therapy
strategies related to immunopathology, the agents listed above are
worthy of further exploration in practice.

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