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Immunotherapies and COVID-19 related
Neurological manifestations: A Comprehensive
Review Article
Mai M. Anwar
To cite this article: Mai M. Anwar (2021): Immunotherapies and COVID-19 related Neurological
manifestations: A Comprehensive Review Article, Journal of Immunoassay and Immunochemistry,
DOI: 10.1080/15321819.2020.1865400
To link to this article: https://doi.org/10.1080/15321819.2020.1865400
Published online: 03 Jan 2021.
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Immunotherapies and COVID-19 related Neurological
manifestations: A Comprehensive Review Article
Mai M. Anwar
Department of Biochemistry, National Organization for Drug Control and Research (Nodcar)/egyptian
Drug Authority, Cairo, Egypt
ABSTRACT
In December 2019, an outbreak of pandemic severe respiratory
distress syndrome coronavirus disease 2019 (COVID-19) initially
occurred in China, has spread the world resulted in serious threats
to human public health. Uncommon neurological manifestations
with pathophysiological symptoms were observed in infected
patients including headache, seizures, and neuroimmunological
disorders. Regardless of whether these neurological symptoms
are direct or indirect casual infection relationship, this novel viral
infection has a relevant impact on the neuroimmune system that
requires a neurologist’s careful assessment. Recently, the use of
immunotherapy has been emerged in ghting against COVID-19
infection despite the uncertain eciency in managing COVID-
19 related disorders or even its proven failure by increasing its
severity. Herein, the author is addressing the rst approaches in
using immunotherapies in controlling COVID-19 viral impact on the
brain by highlighting their role in decreasing or increasing infection
risks among subjects. This point of view review article supports the
use of immunotherapies in managing COVID-19 neurological dis-
orders but in optimal timing and duration to ensure the maximum
therapeutic outcome by reducing morbidity and mortality rate.
Based on recently published data, the current review article high-
lights the benecial eects and drawbacks of using immunothera-
pies to combat COVID-19 and its neurological symptoms.
KEYWORDS
COVID-19; cytokines storm;
inflammation;
immunotherapies;
neurological disorders;
vaccines
Introduction
The new pandemic threatening infection COVID-19 is a worldwide outbreak
previously declared as a public health emergency by the WHO and was officially
named as SARS-CoV-2. The uncontrolled COVID-19 outbreak throughout the
world resulted in several economic, social, and financial drawbacks in addition to
extreme lockdown measures.
[1,2]
Coronavirus is a single-stranded envelope crown-
like shape RNA virus that can spread via personal contact and respiratory
droplets.
[3]
The most common COVID-19 respiratory infection symptoms include
cough, fever, and shortness of breath. Additionally, COVID-19 may also develop
several related neurological disorders ranging from severe headache to neurode-
generative diseases.
[4–6]
It has been previously reported that COVID-19 associated
CONTACT Mai M. Anwar mainwr@hotmail.com Lecturer at the Department of Biochemistry, National
Organization for Drug Control and Research (Nodcar)/egyptian Drug Authority, Cairo, Egypt.
JOURNAL OF IMMUNOASSAY AND IMMUNOCHEMISTRY
https://doi.org/10.1080/15321819.2020.1865400
© 2020 Taylor & Francis
acute respiratory failure is directly related to brain stem damage caused by SARS-
CoV-2 brain infection.
[7,8]
Several questions regarding the hypothetical mechan-
ism and routes via which the COVID-19 can penetrate the brain have been recently
declared with the real need for more distinctive clarifications on the appropriate
prophylaxis, and treatment of COVID-19 complications.
[4,5]
Table 1.
Review literature methods
A relevant search was conducted using google scholar, PubMed, Scopus,
Science Direct, and Web of Science to find out published articles mainly
related to COVID-19 and neurological aspects. Type of articles used in the
current review included research articles, review articles, case series, case
reports, letter to editors, randomized controlled trials, and clinical trials
using relevant keywords in search strategy methods. Inclusion search criteria
were any published English language articles from reputable journals with
a publication date starting from January 2020 to December 2020 with exclu-
sion to any non-relevant topics and non-English language articles.
The neurotropic potentials of COVID-19 on the central nervous system (CNS)
SARS-CoV-2 is considered as the seventh type of coronavirus family with about
82% similarity to SARS coronavirus (SARS-CoV) and 60% to the Middle East
respiratory syndrome (MERS-CoV). Recently, SARS-CoV-2 viral nucleic acid was
observed in the cerebrospinal fluid of several infected patients along with its
presence among brain autopsy which can be directly justified to its neurotropic
penetration action using both hematogenous and/or non-hematogenous
routes.
[4,9–11]
Several epidemiological studies reported various COVID-19 neuro-
logical manifestations commonly found among infected persons such as headache,
loss of consciousness, and delirium.
[4,12]
The COVID-19 neuropenetration
hypothesis was initially suggested based on the temporary or permanent anosmia
symptom mostly found among infected patients along with the novel approach
toward highlighting that neurological symptoms might be the second drawback of
respiratory infection.
[4–6,11,13,14]
Multiples routes via which the COVID-19 can
penetrate the brain
[15]
[Figure 1] include (a) direct infection injury via nasal
olfactory bulb route;
[16]
(b) through ACE-2 functional receptors;
[10]
(c) neuronal
pathways and nerve ending dissemination;
[16,17]
(d) synapse conjugated route;
[17]
and (e) hypoxic metabolic injury.
[5]
COVID-19 and CNS immune-mediated system injuries
COVID-19 brain infection can results in severe CNS damages as
a drawback of disturbances in brain homeostasis with direct polarization
toward microglia pro-inflammatory M1 type resulting in the release of
2M. M. ANWAR
Table 1. Brief of immunomodulatory agents and recommended doses for the management of COVID-19 patients with neurological disorders.
Treatment Mode of action Common adverse
events
Recommendations Recommended
doses
References
Corticosteroids -Act as anti-inflammatory
to prevent exaggerated
cytokine release.
-Water and sodium retention,
lymphopenia,
myasthenia gravis, and
infections.
-To be used with high caution in elderly and
immunocompromised COVID-19 patients using the
smallest recommended dose for the shortest duration of
time.
-General health advice and monitoring for patients on
immunotherapies.
- Dexamethasone IV:
6 mg daily dose for
10 days.
- Dexamethasone
orally:
20 mg for 5 days
followed by 10 mg for
other 5 days.
- Methylprednisolone
orally:
0.5–1 mg/kg daily or
60–125 mg (high dose)
every 6 hr for 3 days in
case of sever cytokines
storm.
25–28
Tocilizumab -Anti-cytokine, IL-6 antagonist. -Upper respiratory
tract infections,
hypertension,
and elevated liver enzymes.
-General health advice and monitoring for the probability
of secondary infection.
-Not recommended in pregnant and Lactating women.
-4–8 mg/kg
or
single maximum
dose 800 mg which
may be repeated after
12 hr.
30–32
Teriflunomide -Teriflunomide selectively
inhibits dihydroorotate
dehydrogenase (DHODH),
a key enzyme in the novo
pyrimidine synthesis
pathway.
-Lymphopenia with a mild
decreases in lymphocyte count
Probability of increasing the risk
of severe COVID-19 symptoms
due to known risk of
lymphopenia.
-In case of initiating teriflunomide in COVID-19 patients
with previous neurological disorders, subjects will
undego a required weekly blood monitoring tests to
screen for any uncomman drawbacks.
-General health advice for high probability of other risk
severe infections.
-14 mg daily
recommended dose in
COVID-19 patients with
neurological disorders.
35–37
IVIg -Antibodiesto provide short-
termpassive type of immunity
by Pleiotropic immune-
modulation actions.
-Anaphylactic shock
or severe systemic
hypersensitivity
action.
-Use with caution in elderly COVID-19 patients, with a high
attention to immunocompromised patients.
-0.5 g/kg daily for
5 consequent days IV.
40–43
Treatment Mode of action Common adverse
events
Recommendations Recommended
doses
References
(Continued)
JOURNAL OF IMMUNOASSAY AND IMMUNOCHEMISTRY 3
Table 1. (Continued).
Cladribine -Type of synthetic purine
nucleoside analog by
inhibiting DNA synthesis via
depleting B and
T cells.
-Risk of increased COVID-19 viral
infection symptoms with
a decreased lymphocyte counts.
-General health advice and monitoring for COVID-19
patients with neurological disorders on treatment
initiation.
-3.5 mg/kg for 1 to
2 weeks.
44–48
Rituximab -Anti-cytokine and act as JAK1/
JAK2 inhibitor.
-Thrombocytopenia,
neutropenia,
severe infections,
headache, anemia, and
dizziness.
-Not recommended in pregnant and
lactating women.
-Dose monitoring and reduction in renal and hepatic
impairment.
-5 mg bid for 14 days/
5 mg bid for 3 days
followed by 10 mg bid
for other 7 days.
49–54
IFN-β -Antiviral and
immunomodulatory action.
-Severe peripheral edema,
skin rash, leukopenia,
neutropenia, ataxia,
hypertonia, and
neurological symptoms.
-To be used with caution in patients with bone
marrow suppression, cardiac patients
, and hepatic impairment.
-0.25 mg (8 million
IU) for 3 days.
55–58
Remdesivir -Antiviral nucleotide analog. -Nausea, acute respiratory failure,
hypokalemia, hypotension,
acute kidney injury, and
elevated liver enzymes.
-The neuropsychiatric adverse effect should be monitored
following treatment initiation for patients infected with
COVID-19.
-200 mg loading dose for
1 day, followed by
100 mg daily for other
9 days.
59–65
Natalizumab -Monoclonal antibodies (mAbs)
that act by blocking the
migration of lymphocytes
into the brain.
-Rarely brain and respiratory tract
infection.
-General health monitoring. -300 mg for2-4 weeks.
66–69
4M. M. ANWAR
associated inflammatory cascades and cytokines including Interleukin-6
(IL-6) defined as the syndrome of cytokine storm
[18,19]
[Figure 2]. The
consequences of COVID-19 penetration to the CNS directly activate
CD4+ immune cells, IL-6, and tumor necrosis factor-alpha (TNF-α) pro-
inflammatory factors resulting in Neurodegeneration and CNS comor-
bidities. Consequently, IL-6 is the main predominant component of
COVID-19 cytokine syndrome along with TNF-α, and interferon-
gamma (IFNγ) leading to several organ damages including the
brain.
[9,18,19]
It was also reported that the peripheral nervous system
(PNS) is mainly being vulnerable during mediated immune infectious
diseases such as COVID-19 resulting in prolonged immobilization.
[20]
Figure 1. Hypothetical illustration of COVID-19 possible routes of entry into the CNS resulting in
severe nerves damage along with post-infection neurological manifestation.
JOURNAL OF IMMUNOASSAY AND IMMUNOCHEMISTRY 5
Recently, attention has been given to COVID-19 patients suffering from
neuroimmunological diseases including multiple sclerosis (MS) which
mainly results from severe dysfunction in the immune regulatory net-
works and necessitating a continual administration of immunomodula-
tory or immunosuppressive agents.
[5]
The action of Immunomodulatory
agents mainly depends on adjusting the immune system or amplifying
the host immune responses while the immunosuppressive agent sup-
presses the immune responses by limiting the immune competence
activity. The beneficial rational use of immunotherapies in the manage-
ment of COVID-19 complications such as neurological disorders and
acute respiratory distress syndrome (ARDS) requires causative attention
to avoid no deleterious effect and to ensure an efficient action.
[11,20,21]
Figure 2. Hypothetical illustration of cytokine storm syndrome following COVID-19 brain penetra-
tion resulting in neurodegeneration and several CNS comorbidities.
6M. M. ANWAR
The impact of immunotherapies in managing neurological manifestations
of COVID-19
Regardless of the exact mechanism of how COVID-19 penetrates the brain,
direct or indirect post-infection neurological manifestations require onset
management and assessment to avoid case progression and irreversible neu-
rological damage. Further attention and considerations must be given to
COVID-19 patients with previous neurological disorders who require the
administration of immunotherapies that could result in increasing the severity
of the viral infection.
[11,20,21]
However, some recent reports suggest their
efficiency in managing COVID-19 neurological symptoms.
[19–21]
Recently,
physicians are using various types of immunotherapies in managing COVID
infection due to their known pharmacokinetics and safety profile. Many
immune-modulating agents previously used to regulate different aspects of
inflammatory cascades are being used lately among physicians in the manage-
ment of COVID-19 severe immune imbalance.
[19,20]
Since hyperinflammation
is the determinant factor of COVID-19 infection, immunosuppressive agents
are also considered to be beneficial in reducing the mortality rate of hospita-
lized COVID-19 patients.
[18–20,22]
It is highly required to monitor and balance
the risk to benefit ratio before immunotherapy initiation and optimization for
COVID-19 patients with neurological manifestations.
[23]
Glucocorticoids and their synthetic analogs were widely used in managing
rheumatic disease-related autoimmune disorders by suppressing cytokine release
and T-cell activation. Due to their rapid immunosuppressive actions, glucocorti-
coids are mainly used in the management of severe hyperinflammatory syndromes
including acute respiratory distress syndrome (ARDS). Lately, corticosteroid ther-
apy has been effectively used in managing SARS and MERS acquired pneumonia
infection associated with some hazard drawbacks. Clear evidence regarding the use
of corticosteroids in managing COVID-19 is still unclear in addition to the huge
scientific debate on the announced recommendations for its vital usage in severe
hospitalized ARDS COVID-19 patients.
[24–26]
Although the use of corticosteroid
therapy in the case of COVID-19 related neurological disorders has not been well
addressed, relevant positive feedback was observed related to its efficiency in
controlling elevated CSF cytokines suggesting its efficiency in managing
COVID-19-related encephalitis disorders.
[26–28]
However, corticosteroids may
also increase the risk of infection due to short-term lymphopenia but this is mainly
associated with long-term doses of steroids, not with short-term use.
[25–28]
IL-6 is a key point inflammatory cytokine that acts as the main regulator for
the cytokine storm syndrome and was found to be elevated in COVID-19
patients. Tocilizumab is categorized as a recombinant monoclonal antibody
acting as an IL-6 blocking agent widely used in the treatment of autoimmune
diseases such as rheumatoid arthritis.
[29,30]
A significant relevant increase in
the production of IL-6-with simultaneous elevated release of CD14+ and
JOURNAL OF IMMUNOASSAY AND IMMUNOCHEMISTRY 7
CD16+ inflammatory monocytes were observed among COVID-19-infected
subjects. The hyperactivated T helper cells (Th1) suggested being found
among COVID-19 patients potentially provoke the elevation of IFNγ in the
lung along with IL-6, suggesting that blocking the IL-6 signaling cascade might
be potential as therapeutic agents in COVID-19 patients.
[5,18,19]
Tocilizumab
act as the first-line treatment for managing cytokine release syndrome in
severely infected subjects. Repeated observational studies previously con-
ducted in China and Italy reported the efficacy of tocilizumab treatment in
hindering severe COVID-19 neurological disorders.
[31,32]
Based on these
approaches, blocking the IL-6 signaling pathway represents a major therapeu-
tic potential for the treatment of neuroinflammatory and neurodegenerative
diseases as a drawback of COVID-19 infection.
[33,34]
Recent reports demon-
strated that the administration of tocilizumab was associated with a high rate
of secondary infection. These findings raised a lot of concerns about the use of
anti-IL-6 tocilizumab therapy to attenuate cytokine storm syndrome in
COVID-19 patients.
[30]
Teriflunomide selectively inhibits the mitochondrial enzyme Dihydroorotate
dehydrogenase (DHODH) in the de novo pyrimidine pathway. It selectively
results in relevant immunosuppression by inhibiting the division and growth of
replicating cells, including activated B and T cells along with decreasing lym-
phocyte counts.
[35,36]
Huge scientific debates among neurologists on the ability
of teriflunomide to increase the severity of COVID-19 which is considered
heterogeneous, due to its lymphopenia associated risk occurring within the
first few weeks of treatment initiation. On the other hand, several other recom-
mendations suggest that teriflunomide may not increase the severity of COVID-
19 manifestation indicating its safety but these recommendations require more
potential monitoring and justifications especially in the first 2 weeks of treat-
ment initiation.
[35–37]
Intravenous immunoglobulins (IVIg) are an efficient treatment for several
patients with antibody deficiencies. IVIg therapy contains immunoglobulin
G obtained from pooled type healthy donor plasma that can act on both body
initiative and adaptive immune type.
[38,39]
Additionally, IVIg was previously
indicated in managing neuroimmunological diseases such as MS and myasthe-
nia gravis.
[38,39]
Although the use of IVIg on COVID-19 patients is somehow
limited, the risk of increasing disease-related severity including neurological
symptoms is considered mild. It was reported that IVIg is effective against
thromboembolism and elevated D-dimer levels in hospitalized COVID-19
patients. Moreover, IVIg may have promising effects on reducing the antiviral
neutralizing antibody level by activating both natural killer cells (NK) and
macrophages in addition to its TNF-α inhibiting actions.
[40–43]
Recently,
several COVID-19 cases have been reported to administrate IVIg therapy
with observed anaphylactic shock and hypersensitivity symptoms following
treatment initiations.
[41–43]
8M. M. ANWAR
Cladribine is characterized as a synthetic purine analog that directly disrupts the
DNA synthesis process and repair. Upon using cladribine for more than 4 months,
a relevant decrease in circulating CD4 + T, NK cells, B cells, and T cells resulting in
lymphopenia which makes COVID-19 patients more susceptible to infection
severity and secondary infection.
[44–47]
The observed relevant immunosuppression
actions following cladribine administration are mainly associated with higher
infectious risk.
[46,47]
Several studies also suggest that cladribine treatments can be
initiated in COVID-19 patients with demandable general health monitoring, but
the risk-to-benefit ratio should be taken into consideration especially for aged
immunocompromised patients.
[48]
Rituximab is one of the main B cells targeting monoclonal antibody agents
(mAB) frequently used in managing neuroinflammatory disorders by acting as
anti-CD20 mAB.
[49,50]
The expression of CD20 molecule is associated with B cell
maturation, rituximab works effectively by depleting pre-B and memory B cells.
[50]
The use of rituximab can be considered as one of the highest risk agents to be used
in hindering COVID-19 pandemic infection due to its toxic and dangerous side
effects with a recommendation on considering the delay of rituximab treatment
initiation in managing COVID-19 neurological symptoms.
[51–54]
Human interferon beta (IFN-β) was the first disease-modifying agent previously
used in MS by modulating the cytokines immune responsive action through
shifting cytokine toward the production of anti-inflammatory B cell types. No
observed drawbacks were associated with IFN-β administration except
lymphopenia.
[55,56]
Studies regarding the IFN-β antiviral COVID-19 replication
are suggested to be effective through activating Janus kinases (JAKs) pathways
leading to activated antiviral and antiproliferative actions.
[57,58]
It was severally
reported an increase in COVID-19 neurological manifestations as a drawback of
IFN-β administration in infected patients.
[55–57]
Remdesivir is a promising nucleoside antiviral analog drug currently used
in controlling COVID-19 delirium complications.
[59,60]
Although Remdesivir
has been widely used in COVID-19 treatment protocols, no significant clinical
or antiviral effective actions were observed.
[61,62]
Its safety is still under
evaluation as numerous studies reported neuropsychiatric adverse effects
and neurological complications associated with remdesivir administration in
COVID-19 patients.
[63–65]
Natalizumab is a humanized recombinant mAb that acts by blocking leukocyte
alpha 4-integrin molecules along with transferring peripheral immune cells into
the CNS by acting as prophylaxis against COVID-19 infection and its related
neurological disorders.
[66]
The administration of natalizumab results in a relevant
exaggerated increase in NK, B, and T cells in the peripheral blood tissues.
[66,67]
The
higher the elevated B cell-mediated inflammatory level, the better would be
favorable against viral infectious disease resulting in an observed decrease in
lymphocyte migration in COVID-19-infected cases indicating its efficacy as
a protective agent against COVID-19 viral infection.
[66–68]
Some reports suggested
JOURNAL OF IMMUNOASSAY AND IMMUNOCHEMISTRY 9
the possible role of natalizumab administration in preventing COVID-19 from
binding to some of its receptors with a recommendation toward interval dosing to
avoid rebound.
[69]
Since the spread of this sudden pandemic viral infection and the world has been
calling scientists for the discovery of the COVID-19 vaccine. Although we are a few
steps away from the release of more the one type of vaccine, many questions have
been raised regarding whether it would be efficient for immunocompromised and
neurologically impaired COVID-19 patients. Unfortunately, till now no clear
results have been declared. Successful vaccination with minor side effects depends
mainly on immune reconstitution factors following cell depletion.
[70,71]
On the
other hand, a suggested increase in the immune responsive action against vaccine’s
different types including live attenuated, inactive viruses, and adjuvant-containing
type could result in triggering aggressive autoimmune responsive actions along
with increasing the incidence of relapse. Furthermore, restrictions on using live
attenuated vaccines along with immunotherapy agents must be taken into
consideration.
[70–72]
The impact of immunotherapies in the pandemic era of COVID-19
infection
Although relevant data are still lacking, the author suggests that the use of
immunotherapy agents might be associated with higher infection risk and severe
neurological manifestations as a result of long-lasting lymphopenia. On the other
hand, the justification for using immunotherapy agents in the era of pandemic
COVID-19 despite their various drawbacks and severe side-effects, all can all be
related to the unavailable alternatives and rarely conducted clinical studies.
[73,74]
Thus, immunotherapy treatment risks in severe COVID-19 patients with neuro-
logical symptoms might be relieved by attentive hospitalization and great precision
regarding the initiation and optimization of therapy protocol. Features of using
suitable immunotherapy mainly depend on patient health status and other related
conditions as misleading usage may lead to severe neurological disorders and
persistent irreversible disability.
[73,74]
Conclusion
In conclusion, the observed neurological manifestations of COVID-19 are severe,
but neither their clear reasons for incidence nor their causative symptoms have
been clearly demonstrated. However, COVID-19 directly affects the assessments
and monitoring of patients with neurological disorders in several ways, but
evidence concerning the use of immunotherapy in their management is still
unclear due to fluctuations in drawbacks among subjects participated in research
studies. Conduction of clinical studies is urgently required to attain more accurate
data on neuroimmunological disease and COVID-19 infection for better future
10 M. M. ANWAR
management approaches. These clinical studies should answer whether immu-
notherapy agents can control COVID-19 neurological manifestations and respira-
tory distress syndrome along with estimating the probability of resulting in
comorbidities. The careful risk-to-benefit balance along with initiation and dis-
continuation administration time has to be taken into consideration while practi-
cing immunotherapy among hospitalized infected subjects till obtaining unbiased
answers. Patients’ inclusion and exclusion criteria mainly depend on the response
of subject host phase biomarkers. These findings may help the upcoming future
research on the accurate diagnosis, treatment, and prophylaxis of COVID-19
severe symptoms.
Data accessibility
This article has no further additional data.
Competing interests
I declare no competing interest with others.
ORCID
Mai M. Anwar http://orcid.org/0000-0002-1991-2945
References
[1] Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.;
et al. Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan,
China. Lancet. 2020, 395(10223), 497–506.
[2] Wang, C.; Horby, P. W.; Hayden, F. G.; Gao, G. F. A Novel Coronavirus Outbreak of
Global Health Concern. Lancet. 2020, 395(10223), 470–473. DOI: 10.1016/S0140-
6736(20)30185-9.
[3] Chen, Y.; Chen, L.; Deng, Q.; Zhang, G.; Wu, K.; Ni, L.; Yang, Y.; Liu, B.; Wang, W.;
Wei, C.; et al. The Presence of SARS-CoV-2 RNA in the Feces of COVID-19 Patients. J
Med Virol. 2020, 92(7), 833–840. DOI: 10.1002/jmv.25825.
[4] Anwar, M. M.; Badawi, A. M.; Eltablawy, N. A. Can the Coronavirus Infection Penetrates
the Brain Resulting in Sudden Anosmia Followed by Severe Neurological Disorders?
eNeurologicalSci. 2020, 21, 100290. DOI: 10.1016/j.ensci.2020.100290.
[5] Mao, L.; Jin, H.; Wang, M.; Hu, Y.; Chen, S.; He, Q.; Chang, J.; Hong, C.; Zhou, Y.;
Wang, D.; et al. Neurologic Manifestations of Hospitalized Patients with Coronavirus
Disease 2019 in Wuhan, China. JAMA neurol. 2020, 77(6), 683–690.
[6] Li, Y. C.; Bai, W. Z.; Hashikawa, T. The Neuroinvasive Potential of SARS-CoV2 May
Play a Role in the Respiratory Failure of COVID-19 Patients. J. Med. Virol. 2020, 92(6),
552–555. DOI: 10.1002/jmv.25728.
JOURNAL OF IMMUNOASSAY AND IMMUNOCHEMISTRY 11
[7] Xu, Z.; Shi, L.; Wang, Y.; Zhang, J.; Huang, L.; Zhang, C.; Liu, S.; Zhao, P.; Liu, H.;
Zhu, L.; et al. Pathological Findings of COVID-19 Associated with Acute Respiratory
Distress Syndrome. Lancet Respir Med. 2020, 8(4), 420–422.
[8] Lu, H.; Stratton, C. W.; Tang, Y. W. Outbreak of Pneumonia of Unknown Etiology in
Wuhan, China: The Mystery and the Miracle. J Med Virol. 2020, 92(4), 401–402. DOI:
10.1002/jmv.25678.
[9] Fu, Y.; Cheng, Y.; Wu, Y. Understanding SARS-CoV-2-Mediated Inflammatory
Responses: From Mechanisms to Potential Therapeutic Tools. Virologica Sin. 2020, 35
(3), 266–271. DOI: 10.1007/s12250-020-00207-4.
[10] Yan, R.; Zhang, Y.; Li, Y.; Xia, L.; Guo, Y.; Zhou, Q. Structural Basis for the Recognition
of SARS-CoV-2 by Full-length Human ACE2. Science (New York, NY). 2020, 367(6485),
1444–1448. DOI: 10.1126/science.abb2762.
[11] Zou, L.; Ruan, F.; Huang, M.; Liang, L.; Huang, H.; Hong, Z.; Yu, J.; Kang, M.; Song, Y.;
Xia, J.; et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected
Patients. N. Engl. J. Med. 2020, 382(12), 1177–1179.
[12] Liguori, C.; Pierantozzi, M.; Spanetta, M.; Sarmati, L.; Cesta, N.; Iannetta, M.; Ora, J.;
Mina, G. G.; Puxeddu, E.; Balbi, O.; et al. Subjective Neurological Symptoms Frequently
Occur in Patients with SARS-CoV2 Infection. Brain Behav. Immun. 2020, 88, 11–16.
DOI: 10.1016/j.bbi.2020.05.037.
[13] Asadi-Pooya, A. A.; Simani, L. Central Nervous System Manifestations of COVID-19:
A Systematic Review. J. Neurol. Sci. 2020, 413, 116832. DOI: 10.1016/j.jns.2020.116832.
[14] Tsai, S. T.; Lu, M. K.; San, S.; Tsai, C. H. The Neurologic Manifestations of Coronavirus
Disease 2019 Pandemic: A Systemic Review. Front. Neurol. 2020, 11, 498. DOI: 10.3389/
fneur.2020.00498.
[15] Xydakis, M. S.; Dehgani-Mobaraki, P.; Holbrook, E. H.; Geisthoff, U. W.; Bauer, C.;
Hautefort, C.; Herman, P.; Manley, G. T.; Lyon, D. M.; Hopkins, C.; et al. Smell and Taste
Dysfunction in Patients with COVID-19. Lancet Infect Dis. 2020, 20(9), 1015–1016.
[16] Zhou, L.; Zhang, M.; Wang, J.; Gao, J. Sars-Cov-2: Underestimated Damage to Nervous
System. Travel Med Infectious Dis. 2020, 36, 101642. DOI: 10.1016/j.tmaid.2020.101642.
[17] Zubair, A. S.; McAlpine, L. S.; Gardin, T.; Farhadian, S.; Kuruvilla, D. E.; Spudich, S.
Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of
Coronavirus Disease 2019: A Review. JAMA neurol. 2020, 77(8), 1018–1027. DOI:
10.1001/jamaneurol.2020.2065.
[18] Chen, C.; Zhang, X. R.; Ju, Z. Y.; He, W. F. [Advances in the Research of Mechanism and
Related Immunotherapy on the Cytokine Storm Induced by Coronavirus Disease 2019].
Zhonghua Shao Shang Za Zhi = Zhonghua Shaoshang Zazhi = Chin J Burns. 2020, 36(6),
471–475. DOI: 10.3760/cma.j.cn501120-20200224-00088.
[19] Wan S, Yi Q, Fan S, et al. Characteristics of Lymphocyte Subsets and Cytokines in
Peripheral Blood of 123 Hospitalized Patients with 2019 Novel Coronavirus Pneumonia
(NCP). medRxiv. 2020, 2020.02.10.20021832.
[20] Mehta, P.; McAuley, D. F.; Brown, M.; Sanchez, E.; Tattersall, R. S.; Manson, J. J.
COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression. Lancet.
2020, 395(10229), 1033–1034. DOI: 10.1016/S0140-6736(20)30628-0.
[21] Sellner, J.; Taba, P. The Need for Neurologists in the Care of COVID-19 Patients.Eur J
Neurol. 2020, 27(9), e31–e2. DOI: 10.1111/ene.14257.
[22] Pereira, A.;. Long-Term Neurological Threats of COVID-19: A Call to Update the
Thinking about the Outcomes of the Coronavirus Pandemic. Front. Neurol. 2020, 11,
308. DOI: 10.3389/fneur.2020.00308.
12 M. M. ANWAR
[23] Guan, W.-J.; Ni, Z.-Y.; Hu, Y.; Liang, W.-H.; Ou, C.-Q.; He, J.-X.; Liu, L.; Shan, H.;
Lei, C.-L.; Hui, D. S. C.; et al. Clinical Characteristics of Coronavirus Disease 2019 in
China. N. Engl. J. Med. 2020, 382(18), 1708–1720.
[24] Hardy, R. S.; Raza, K.; Cooper, M. S. Therapeutic Glucocorticoids: Mechanisms of
Actions in Rheumatic Diseases. Nat Rev Rheumatol. 2020, 16(3), 133–144. DOI:
10.1038/s41584-020-0371-y.
[25] Alhazzani, W.; Møller, M. H.; Arabi, Y. M.; Loeb, M.; Gong, M. N.; Fan, E.;
Oczkowski, S.; Levy, M. M.; Derde, L.; Dzierba, A.; et al. Surviving Sepsis Campaign:
Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019
(COVID-19). Crit. Care Med. 2020, 48(6), e440–e69.
[26] Horby, P.; Lim, W. S.; Emberson, J.; Mafham, M.; Bell, J.; Linsell, L.; et al. Effect of
Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv.
2020, 2020.06.22.20137273.
[27] Villar, J.; Ferrando, C.; Martínez, D.; Ambrós, A.; Muñoz, T.; Soler, J. A.; Aguilar, G.;
Alba, F.; González-Higueras, E.; Conesa, L. A.; et al. Dexamethasone Treatment for the
Acute Respiratory Distress Syndrome: A Multicentre, Randomised Controlled Trial.
Lancet Respir Med. 2020, 8(3), 267–276.
[28] Russell, C. D.; Millar, J. E.; Baillie, J. K. Clinical Evidence Does Not Support
Corticosteroid Treatment for 2019-nCoV Lung Injury. Lancet. 2020, 395(10223),
473–475. DOI: 10.1016/S0140-6736(20)30317-2.
[29] Zhou Y, Fu B, Zheng X, et al. Aberrant Pathogenic GM-CSF+ T Cells and Inflammatory
CD14+CD16+ Monocytes in Severe Pulmonary Syndrome Patients of a New
Coronavirus. bioRxiv. 2020, 2020.02.12.945576.
[30] Kimmig LM, Wu D, Gold M, Pettit NN, Pitrak D, Mueller J, et al. IL-6 Inhibition in
Critically Ill COVID-19 Patients Is Associated With Increased Secondary Infections.
Front Med (Lausanne). 2020;7:583897.
[31] Xu, X.; Han, M.; Li, T.; Sun, W.; Wang, D.; Fu, B.; Zhou, Y.; Zheng, X.; Yang, Y.; Li, X.;
et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab. Proc. National
Academy Sci. 2020, 117(20), 10970–10975.
[32] De Luna, G.; Habibi, A.; Deux, J. F.; Colard, M.; Pham Hung d’Alexandry
d’Orengiani, A. L.; Schlemmer, F.; Joher, N.; Kassasseya, C.; Pawlotsky, J. M.;
Ourghanlian, C.; et al. Rapid and Severe Covid-19 Pneumonia with Severe Acute
Chest Syndrome in a Sickle Cell Patient Successfully Treated with Tocilizumab. Am.
J. Hematol. 2020, 95(7), 876–878.
[33] Cellina, M.; Orsi, M.; Bombaci, F.; Sala, M.; Marino, P.; Oliva, G. Favorable Changes of
CT Findings in a Patient with COVID-19 Pneumonia after Treatment with Tocilizumab.
Diagnostic and Interventional Imaging. 2020, 101(5), 323–324. DOI: 10.1016/j.
diii.2020.03.010.
[34] Zhang, C.; Wu, Z.; Li, J. W.; Zhao, H.; Wang, G. Q. Cytokine Release Syndrome in Severe
COVID-19: Interleukin-6 Receptor Antagonist Tocilizumab May Be the Key to Reduce
Mortality. Int. J. Antimicrob. Agents. 2020, 55(5), 105954. DOI: 10.1016/j.
ijantimicag.2020.105954.
[35] Vermersch P, Oh J, Cascione M, Oreja-Guevara C, Gobbi C, Travis LH, et al.
Teriflunomide Vs Injectable Disease Modifying Therapies for Relapsing Forms of MS.
Mult. Scler. Relat. Disord. 2020, 43, 102158.
[36] Comi, G.; Miller, A. E.; Benamor, M.; Truffinet, P.; Poole, E. M.; Freedman, M. S.
Characterizing Lymphocyte Counts and Infection Rates with Long-term
Teriflunomide Treatment: Pooled Analysis of Clinical Trials. Mult. Scler. 2020, 26(9),
1083–1092. DOI: 10.1177/1352458519851981.
JOURNAL OF IMMUNOASSAY AND IMMUNOCHEMISTRY 13
[37] Maghzi, A. H.; Houtchens, M. K.; Preziosa, P.; Ionete, C.; Beretich, B. D.;
Stankiewicz, J. M.; Tauhid, S.; Cabot, A.; Berriosmorales, I.; Schwartz, T. H. W.; et al.
COVID-19 in Teriflunomide-treated Patients with Multiple Sclerosis. J. Neurol. 2020,
267(10), 2790–2796.
[38] Galeotti, C.; Kaveri, S. V.; Bayry, J. Intravenous Immunoglobulin Immunotherapy for
Coronavirus Disease-19 (COVID-19). Clin. Transl. Immunol. 2020, 9(10), e1198. DOI:
10.1002/cti2.1198.
[39] Nierhaus, A.; Berlot, G.; Kindgen-Milles, D.; Müller, E.; Girardis, M. Best-practice IgM-
and IgA-enriched Immunoglobulin Use in Patients with Sepsis. Ann Intens Care. 2020,
10(1), 132. DOI: 10.1186/s13613-020-00740-1.
[40] Muccioli, L.; Pensato, U.; Bernabè, G.; Ferri, L.; Tappatà, M.; Volpi, L.; et al.
Intravenous Immunoglobulin Therapy in COVID-19-related Encephalopathy.
J. Neurol. 2020, 1–5.
[41] Klok, F. A.; Kruip, M.; van der Meer, N. J. M.; Arbous, M. S.; Gommers, D.; Kant, K. M.;
Kaptein, F. H. J.; van Paassen, J.; Stals, M. A. M.; Huisman, M. V.; et al. Confirmation of
the High Cumulative Incidence of Thrombotic Complications in Critically Ill ICU
Patients with COVID-19: An Updated Analysis. Thromb. Res. 2020, 191, 148–150.
DOI: 10.1016/j.thromres.2020.04.041.
[42] Chiarini, M.; Paghera, S.; Moratto, D.; Rossi, N.; Giacomelli, M.; Badolato, R.; Capra, R.;
Imberti, L.; et al. Immunologic Characterization of a Immunosuppressed Multiple
Sclerosis Patient that Recovered from SARS-CoV-2 Infection. J. Neuroimmunol. 2020,
345, 577282. DOI: 10.1016/j.jneuroim.2020.577282.
[43] Tzilas, V.; Manali, E.; Papiris, S.; Bouros, D. Intravenous Immunoglobulin for the
Treatment of COVID-19: A Promising Tool. Respiration. 2020, 1–3. DOI: 10.1159/
000512727.
[44] Dersch, R.; Wehrum, T.; Fähndrich, S.; Engelhardt, M.; Rauer, S.; Berger, B. COVID-19
Pneumonia in a Multiple Sclerosis Patient with Severe Lymphopenia Due to Recent
Cladribine Treatment. Mult. Scler. 2020, 26(10), 1264–1266.
[45] Schweitzer, F.; Laurent, S.; Fink, G. R.; Barnett, M. H.; Hartung, H. P.; Warnke, C. Effects
of Disease-modifying Therapy on Peripheral Leukocytes in Patients with Multiple
Sclerosis. J. Neurol. 2020. DOI: 10.1007/s00415-019-09690-6.
[46] Jack, D.; Nolting, A.; Galazka, A. Favorable Outcomes after COVID-19 Infection in
Multiple Sclerosis Patients Treated with Cladribine Tablets. Mult. Scler. Relat. Disord.
2020, 46, 102469. DOI: 10.1016/j.msard.2020.102469.
[47] Moser, T.; Schwenker, K.; Seiberl, M.; Feige, J.; Akgün, K.; Haschke-Becher, E.;
Ziemssen, T.; Sellner, J.; et al. Long-term Peripheral Immune Cell Profiling Reveals
Further Targets of Oral Cladribine in MS. Ann. Clin. Transl. Neurol. 2020, 7(11),
2199–2212.
[48] De Angelis, M.; Petracca, M.; Lanzillo, R.; Brescia Morra, V.; Moccia, M. Mild or No
COVID-19 Symptoms in Cladribine-treated Multiple Sclerosis: Two Cases and
Implications for Clinical Practice. Mult. Scler. Relat. Disord. 2020, 45, 102452. DOI:
10.1016/j.msard.2020.102452.
[49] Garcia-Montoya, L.; Villota-Eraso, C.; Yusof, M. Y. M.; Vital, E. M.; Emery, P. Lessons
for Rituximab Therapy in Patients with Rheumatoid Arthritis. Lancet Rheumatol. 2020,
2(8), e497–e509. DOI: 10.1016/S2665-9913(20)30033-3.
[50] Luna, G.; Alping, P.; Burman, J.; Fink, K.; Fogdell-Hahn, A.; Gunnarsson, M.; et al.
Infection Risks among Patients with Multiple Sclerosis Treated with Fingolimod,
Natalizumab, Rituximab, and Injectable Therapies. JAMA neurol. 2020, 77(2), 184–191.
14 M. M. ANWAR
[51] Kondratiuk, A.; Muraro, P.; Johnson, M.; Sing-Curry, V.; Pritchard, J.; Dorsey, R.; et al.
The Use of Rituximab in Neurological Diseases; Real World Data from a Neuroscience
Centre (2575). Neurology. 2020, 94(15 Supplement), 2575.
[52] Wurm, H.; Attfield, K.; Iversen, A. K. N.; Gold, R.; Fugger, L.; Haghikia, A. Recovery
from COVID-19 in a B-cell-depleted Multiple Sclerosis Patient. Mult. Scler. J. 2020, 26
(10), 1261–1264. DOI: 10.1177/1352458520943791.
[53] Mehta, P.; Porter, J. C.; Chambers, R. C.; Isenberg, D. A.; Reddy, V. B-cell Depletion with
Rituximab in the COVID-19 Pandemic: Where Do We Stand? Lancet Rheumatol. 2020,
2(10), e589–e90. DOI: 10.1016/S2665-9913(20)30270-8.
[54] Guilpain, P.; Le Bihan, C.; Foulongne, V.; Taourel, P.; Pansu, N.; Maria, A. T. J.; et al.
Rituximab for Granulomatosis with Polyangiitis in the Pandemic of Covid-19: Lessons
from a Case with Severe Pneumonia. Ann. Rheumatic Dis. 2020, annrheumdis-2020-
217549.
[55] Goldschmidt, C. H.; Hua, L. H. Re-Evaluating the Use of IFN-β and Relapsing Multiple
Sclerosis: Safety, Efficacy and Place in Therapy. Degener Neurol Neuromuscul Dis. 2020,
10, 29–38. DOI: 10.2147/DNND.S224912.
[56] Severa, M.; Farina, C.; Salvetti, M.; Coccia, E. M. Three Decades of Interferon-β in
Multiple Sclerosis: Can We RepurposeThis Information for the Management of SARS-
CoV2 Infection? Front. Immunol. 2020, 11, 1459. DOI: 10.3389/fimmu.2020.01459.
[57] Alhazzani, W.; Møller, M. H.; Arabi, Y. M.; Loeb, M.; Gong, M. N.; Fan, E.; et al.
Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults
with Coronavirus Disease 2019 (COVID-19). Crit. Care Med. 2020, 48(6), e440–e69.
[58] Sallard, E.; Lescure, F.-X.; Yazdanpanah, Y.; Mentre, F.; Peiffer-Smadja, N. Type 1
Interferons as a Potential Treatment against COVID-19. Antiviral Res. 2020, 178,
104791. DOI: 10.1016/j.antiviral.2020.104791.
[59] Hsu, J.;. Covid-19: What Now for Remdesivir? BMJ. 2020, 371, m4457. DOI: 10.1136/
bmj.m4457.
[60] Grein, J.; Ohmagari, N.; Shin, D.; Diaz, G.; Asperges, E.; Castagna, A.; Feldt, T.;
Green, G.; Green, M. L.; Lescure, F.-X.; et al. Compassionate Use of Remdesivir for
Patients with Severe Covid-19. N. Engl. J. Med. 2020, 382(24), 2327–2336.
[61] Wang, L.-Y.; Cui, -J.-J.; Ouyang, Q.-Y.; Zhan, Y.; Guo, C.-X.; Yin, J.-Y. Remdesivir and
COVID-19. Lancet. 2020, 396(10256), 953–954. DOI: 10.1016/S0140-6736(20)32019-5.
[62] Wang, Y.; Zhang, D.; Du, G.; Du, R.; Zhao, J.; Jin, Y.; Fu, S.; Gao, L.; Cheng, Z.; Lu, Q.;
et al. Remdesivir in Adults with Severe COVID-19: A Randomised, Double-blind,
Placebo-controlled, Multicentre Trial. Lancet. 2020, 395(10236), 1569–1578.
[63] Gulati, G.; Kelly, B. D. Does Remdesivir Have Any Neuropsychiatric Adverse Effects?
Irish J Psychol Med. 2020, 1–2.
[64] Sheahan, T. P.; Sims, A. C.; Leist, S. R.; Schäfer, A.; Won, J.; Brown, A. J.; Montgomery, S. A.;
Hogg, A.; Babusis, D.; Clarke, M. O.; et al. Comparative Therapeutic Efficacy of Remdesivir
and Combination Lopinavir, Ritonavir, and Interferon Beta against MERS-CoV. 2020, 11(1),
222. DOI: 10.1038/s41467-019-13940-6.
[65] Wang, M.; Cao, R.; Zhang, L.; Yang, X.; Liu, J.; Xu, M.; Shi, Z.; Hu, Z.; Zhong, W.;
Xiao, G.; et al. Remdesivir and Chloroquine Effectively Inhibit the Recently Emerged
Novel Coronavirus (2019-ncov) in Vitro. Nat Commun, 2020, 30(3), 269–271. DOI:
10.1038/s41422-020-0282-0.
[66] Butzkueven, H.; Kappos, L.; Wiendl, H.; Trojano, M.; Spelman, T.; Chang, I.; et al. Long-
term Safety and Effectiveness of Natalizumab Treatment in Clinical Practice: 10 Years of
Real-world Data from the Tysabri Observational Program (TOP). J Neurol Neurosurg
Psychiatry. 2020, 91(6), 660–668.
JOURNAL OF IMMUNOASSAY AND IMMUNOCHEMISTRY 15
[67] Abraham, A.; Nicholson, L.; Dick, A.; Rice, C.; Atan, D. Intermediate Uveitis Associated
with MS. Diagn. Clin. Features Pathogen. Mech. Recommendations Manage. 2021, 8(1),
e909.
[68] Borriello, G.; Ianniello, A. COVID-19 Occurring during Natalizumab Treatment: A Case
Report in a Patient with Extended Interval Dosing Approach. Multiple sclerosis and
related disorders. 2020;41:102165.
[69] Aguirre, C.; Meca-Lallana, V.; Barrios-Blandino, A.; Del Río, B.; Vivancos, J. Covid-19 in
a Patient with Multiple Sclerosis Treated with Natalizumab: May the Blockade of
Integrins Have a Protective Role? Mult. Scler. Relat. Disord. 2020, 44, 102250. DOI:
10.1016/j.msard.2020.102250.
[70] Jeyanathan, M.; Afkhami, S.; Smaill, F.; Miller, M. S.; Lichty, B. D.; Xing, Z.
Immunological Considerations for COVID-19 Vaccine Strategies. Nat. Rev. Immunol.
2020, 20(10), 615–632. DOI: 10.1038/s41577-020-00434-6.
[71] Yang, L.; Tian, D.; Liu, W. [Strategies for Vaccine Development of COVID-19]. Sheng
Wu Gong Cheng Xue Bao = Chin J Biotechnol. 2020, 36(4), 593–604. DOI: 10.13345/j.
cjb.200094.
[72] Bennet, B. M.; Wolf, J.; Laureano, R.; Sellers, R. S. Review of Current Vaccine
Development Strategies to Prevent Coronavirus Disease 2019 (COVID-19). Toxicol
Pathol. 2020, 48(7), 800–809. DOI: 10.1177/0192623320959090.
[73] Bonam, S. R.; Kaveri, S. V.; Sakuntabhai, A.; Gilardin, L.; Bayry, J. Adjunct
Immunotherapies for the Management of Severely Ill COVID-19 Patients. Cell Rep
Med. 2020, 1(2), 100016. DOI: 10.1016/j.xcrm.2020.100016.
[74] Mansourabadi, A. H.; Sadeghalvad, M.; Mohammadi-Motlagh, H.-R.; Rezaei, N. The
Immune System as a Target for Therapy of SARS-CoV-2: A Systematic Review of the
Current Immunotherapies for COVID-19. Life Sci. 2020, 258, 118185. DOI: 10.1016/j.
lfs.2020.118185.
16 M. M. ANWAR
