Sistem Kekebalan Sebagai Target Terapi SARS-CoV-2 Tinjauan Sistematis Imunoterapi Terkini Untuk COVID-19
Sistem Kekebalan Sebagai Target Terapi SARS-CoV-2 Tinjauan Sistematis Imunoterapi Terkini Untuk COVID-19
Sistem Kekebalan Sebagai Target Terapi SARS-CoV-2 Tinjauan Sistematis Imunoterapi Terkini Untuk COVID-19
Life Sciences
journal homepage: www.elsevier.com/locate/lifescie
Review article
A R T I C LE I N FO A B S T R A C T
Keywords: Aims: The immune response is essential for the control and resolution of viral infections. Following the outbreak
COVID-19 of novel coronavirus disease (COVID-19), several immunotherapies were applied to modulate the immune re-
SARS-COV-2 sponses of the affected patients. In this review, we aimed to describe the role of the immune system in response
Coronavirus to COVID-19. We also provide a systematic review to collate and describe all published reports of the using
Immune system
immunotherapies, including convalescent plasma therapy, monoclonal antibodies, cytokine therapy, mesench-
Immunotherapy
ymal stem cell therapy, and intravenous immunoglobulin and their important outcomes in COVID-19 patients.
Material and methods: A thorough search strategy was applied to identify published research trials in PubMed,
Scopus, Medline, and EMBASE from Dec 1, 2019, to May 4, 2020, for studies reporting clinical outcomes of
COVID-19 patients treated with immunotherapies along with other standard cares.
Key findings: From an initial screen of 80 identified studies, 24 studies provided clinical outcome data on the use
of immunotherapies for the treatment of COVID-19 patients, including convalescent plasma therapy (33 pa-
tients), monoclonal antibodies (55 patients), interferon (31 patients), mesenchymal stem cell therapy (8 patient),
and immunoglobulin (63 patients). Except for nine severe patients who died after treatment, most patients were
recovered from COVID-19 with improved clinical symptoms and laboratory assessment.
Significance: Based on the available evidence, it seems that treatment with immunotherapy along with other
standard cares could be an effective and safe approach to modulate the immune system and improvement of
clinical outcomes.
1. Introduction to prevent or treat this infection, its rapid dissemination may affect
public healthcare systems and severe economic and social distress
The newly emerged SARS-CoV-2 (severe acute respiratory syndrome worldwide [11,12]. Up to now, several immunotherapy strategies have
coronavirus-2), is a positive-sense single-stranded RNA (+ssRNA) virus been used to treat or prevent virus infection in patients with COVID-19
that causes COVID-19 (coronavirus disease 2019), which has been [13]. These approaches, including convalescent plasma therapy,
getting global concern since December 2019 [1–4]. Coronaviruses be- monoclonal antibodies against IL-6 receptor and complement protein
long to the subfamily Coronavirinae, in the family Coronaviridae of the C5, cytokine therapy, mesenchymal stem cell therapy, and intravenous
order Nidovirales. Like the other strains of coronavirus, SARS-CoV-2 has immunoglobulin, have been applied with varied efficiency in COVID-19
phospholipid bilayers envelop and the genome codes almost five types [14–17]. Interaction of the virus with the immune system mediators
of structural proteins [5–8] (Fig. 1). The typical clinical manifestations leads to triggering an immune response that may determine the out-
of COVID-19 include a non-productive cough, fever, and dyspnea, while come of the viral infection [18]. Controlling viral replication in the
acute respiratory distress syndrome (ARDS) is the leading cause of early phase of the disease could be applied through virus recognition by
death in COVID-19 [9,10]. Unfortunately, the outbreak is rapidly Pattern recognition receptors (PRRs), including toll-like receptor (TLR),
spreading worldwide. In the absence of effective treatments or vaccines NOD-like receptor (NLR), RIG-I-like receptor (RLR), melanoma
⁎
Corresponding author at: Research Center for Immunodeficiencies, Children's Medical Center Hospital, Dr. Qarib St, Keshavarz Blvd, Tehran 14194, Iran.
E-mail address: rezaei_nima@tums.ac.ir (N. Rezaei).
https://doi.org/10.1016/j.lfs.2020.118185
Received 25 June 2020; Received in revised form 21 July 2020; Accepted 28 July 2020
Available online 01 August 2020
0024-3205/ © 2020 Elsevier Inc. All rights reserved.
A.H. Mansourabadi, et al. Life Sciences 258 (2020) 118185
Fig. 1. Structural proteins of SARS-CoV-2: Sprotein (spike glycoprotein trimmer), M protein (a type III transmembrane glycoprotein), E protein (located among the S
proteins in the virus envelope), N proteins (nucleocapsid), HE (hemagglutinin-esterase) dimer (exists in some CoVs).
differentiation-associated gene 5 (MDA5), C-type lectin-like receptors [39,40], while polymorphisms in the HLA-A∗0201, HLA-DR0301, and
(CLR), complement proteins, and the other unclassified receptors in the HLA-Cw1502 are related to the protection from SARS infection [41].
cytoplasm, like Stimulator of interferon genes (STING), DAI, and other According to Wang et al., different subsets of lymphocyte, including
innate immune mediators as a part of the innate immune system that CD4+ and CD8+T lymphocytes, B lymphocytes as well as natural
may limit SARS-CoV-2 spread within the host [19–23]. killer (NK) cells are decreased in COVID-19 patients, and this reduction
According to the recent findings, SARS-CoV-2 replication starts is more significant in the severe cases compared to moderate ones.
when the S (Spike) proteins attach to the membrane of the lung cells via Peripheral lymphocyte subset alteration is associated with clinical
angiotensin-converting enzyme 2 (ACE2) receptor, by the clathrin-de- outcome and treatment efficacy of COVID-19 [42].; the number of
pendent and -independent endocytosis, and release their RNA that CD8+ T cells and CD4+/CD8+ ratio showed a significant association
senses by endosomal TLRs (TLR3, TLR7, TLR8, and TLR9), RIG-I, MDA5 with inflammatory status in COVID-19; CD4+/CD8+ ratio was in-
and cGAS (nucleotidyltransferase cyclic GMP-AMP synthase) in the dicated as independent predictors of poor efficacy [41]. While the virus
cytoplasm [24–26]. Interactions between SARS-CoV-2 and alveolar enters the cells, its antigen will be presented to the APC. According to Li
cells, trigger downstream signaling pathway via TIR-domain-containing et al., the number of TCD4+ and CD8+ in the peripheral blood of
adapter-inducing interferon-β (TRIF), and STING adaptor molecules COVID-19 patients is significantly reduced. In contrast, they are ex-
lead to triggering MyD88 adaptor molecule, following that activation of cessively active, as evidenced by high proportions of HLA-DR (CD4
the NF-κB and interferon regulatory factor 3 (IRF3) [27–29]. The result 3.47%) and CD38 (CD8 39.4%) double-positive fractions [43].
of this complex pathway is the production of IFN-α and -β and varied According to the various case studies, those patients who have been
set of pro-inflammatory mediators. According to the recently published infected with SARS-CoV-2 developed a protective antibody, but it is not
researches, increased levels of some plasma mediators, including IL-1, apparent how long this protection lasts. The quantity and quality of the
IL-2, IL-4, IL-7, IL-10, IL-12, IL-13, IL-17, TNF-α, MIP-1α, IP-10, IFN-γ, antibody response may determine the fate of a viral infection [44].
GCSF, MCP-1, MCSF, and hepatocyte growth factor (HGF) lead to the High-affinity neutralizing antibodies can recognize particular viral
lung injury in some patients with COVID-19 [30–33]. The viral invasion epitopes without additional mediators via Fc regions. It seems that si-
occurred, when the virus particles fuse to the respiratory mucosal tissue milar to SARS-CoV infection, in the case of SARS-CoV-2, viral fusing via
and infect other cells, resulting in a chain of the immune system re- ACE2 to the lung epithelia is blocked, when neutralizing antibodies
sponses and cytokine storm, which may be associated with the severe recognize the particular domains on the S protein [45,46]. Moreover,
condition of COVID-19 patients [34–36]. In most studies, it was ob- these antibodies can also interact with the other immune cells, in-
viously proved that severe pneumonia and consequently respiratory cluding NK cells, phagocytes, and complement systems, as a bridge
failure and death are due to acute inflammation rather than a direct between acquired immune responses and innate immune responses.
damaging effect of the virus itself [37,38]. After recognizing viral antigens via specific antibodies, phosphorylation
While SARS-CoV-2 attaches and enters the alveolar cells, its antigen of ITAMs in the cytoplasmic tail segments of the Igα and Igβ in B cells
will be presented to virus-specific cytotoxic T lymphocytes (CTLs) via occurs by SRC kinase family, lead to trigger downstream signaling to
major histocompatibility complex (MHC) class I (and less via MHC II) up-regulate pro-inflammatory cytokines and down-regulate anti-in-
existing on the surface of antigen presentation cells (APC). Antigen flammatory cytokines [47,48]. Viral components in the endosomes re-
presentation subsequently stimulates the cellular and humoral im- cognized by multiple endosomal TLRs, including TLR3, TLR7, and
munity. According to the researches, multiple HLA alleles polymorph- TLR8, resulting in immunopathology. In this systematic review, we
isms such as HLA-B∗0703, HLA-B∗4601, HLA-Cw∗0801, HLA-DR provide an update on the treatment of the COVID-19 patients with fo-
B1∗1202 have shown a correlation to the susceptibility of SARS-CoV-2 cused on the immunotherapies. Immunology knowledge along with
2
A.H. Mansourabadi, et al. Life Sciences 258 (2020) 118185
advanced vaccine technology is expected to help us find more effective 2.3. Study quality assessment
ways to cure the disease.
Two authors (S.M. and M.M.H.R.) independently evaluated the
2. Methods quality of each publication according to the PRISMA checklist.
This systematic review was conducted based on the Preferred 2.4. Data extraction
Reporting Items for systematic review and Meta-Analysis Protocols
(PRISMA-P) 2015 checklist (Supplementary data, Table 1) [49]. Three authors (M.A.H., S.M., and M.M.H.R.) reviewed the full texts
of potentially relevant articles for eligibility according to the inclusion
2.1. Search strategy criteria. Then excluded ineligible studies, and documenting reasons for
exclusion. The authors extracted data from all included articles to
To identify published research trials in PubMed, Scopus, Medline, Tables 1 and 2.
and EMBASE from Dec 1, 2019, to May 4, 2020, comprehensive search
strategies were performed (Fig. 2). The language was not restricted. We 3. Results
also searched the Clinical Trials.gov, clinicaltrialsregister.eu, and
chictr.org for registered ongoing clinical trials. The search keywords are From an initial screen of 80 identified studies, 24 studies provided
available in Supplementary data, Table 2. clinical outcome data on the use of immunotherapies for the treatment
of COVID-19 patients, including convalescent plasma therapy, mono-
2.2. Study eligibility criteria clonal antibodies, interferon, mesenchymal stem cell therapy, and im-
munoglobulin. Totally, 157 patients met our inclusion criteria that were
Two authors (M.A.H. and S.M.) screened the titles and abstracts included in this study. Characteristics of included studies and patient
from the search results, using the predefined inclusion criteria and outcomes are summarized in Tables 1 and 2.
excluded duplicate publications. The authors recorded the reasons for
excluding studies. Disagreement was resolved through discussion with 3.1. Convalescent plasma therapy
two more authors (R.N. and M.M.H.R.).
To be eligible, studies had to meet the following criteria: Of 24 studies screened, 6 studies with a total of 33 patients were
identified that provided clinical outcomes data on the use of con-
1) The studies included COVID-19 patients with no restrictions on valescent plasma (CP) therapy for the treatment of COVID-19 patients.
patient age, sex, and ethnicity. These studies include two case reports [50,51], one descriptive study
2) Enrolled patients in the intervention group must have treated with [52], one preliminary uncontrolled case series [53], one pilot study
the immunotherapy agents alone or in combination with other [54], and one retrospective study [55].
drugs, including anti-viral agents, corticosteroids, and antibiotics. Except for one retrospective study that out of 6 patients with
COVID-19, only one patient recovered after CP therapy, five studies
Meanwhile, trials were excluded directly, if: have shown optimistic results in using CP therapy to treat severe
COVID-19 patients.
1) The review articles, systematic reviews, and hypothesis articles. In one pilot study, one dose of CP collected from recently recovered
2) The articles about other respiratory infected diseases such as SARS COVID-19 patients was administered to 10 sever COVID-19 patients. In
and MERS. this trial, the neutralizing antibody titers greater than 1:640 were
3) The patients were received other therapies except for im- transfused to the patients in addition to anti-viral drugs and corticos-
munotherapies, as mentioned above. teroid therapy. The outcome was the amelioration of clinical symptoms,
pulmonary lesions, pulmonary function, improved lymphocytopenia,
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A.H. Mansourabadi, et al.
Table 1
The extracted data from 24 included studies.
# Author Type of immunotherapy Treatment by Number of treated Outcomes Fatality Ref
patients
1 Ahn JY et al Plasma therapy CP 2 Subsiding the fever, decrease oxygen demand, decreased level of CRP and IL-6 to normal range, chest X-ray None [50]
improvement, negative SARS-CoV-2 RNA
2 Zhang B et al Plasma therapy CP 4 Decreased viral load, increased anti-SARS-COV-2 titer in serum, chest X-ray improvement None [51]
3 Mingxiang et al. Plasma therapy CP 6 Improvement of clinical symptoms, chest X-ray improvement, increased anti-SARS-COV-2 titer in serum None [52]
4 Shen C et al Plasma therapy CP 5 Changes of body temperature, improvement Sequential Organ Failure Assessment (SOFA) score, decrease viral load, None [53]
increased serum antibody titer, decreased CRP level and procalcitonin to the normal range
5 Duan K et al Plasma therapy CP 10 Improvement of clinical symptoms, decreased pulmonary lesions, improved pulmonary function, improved None [54]
lymphocytopenia, decreased SARS-CoV-2 RNA to undetectable level
6 Zeng QL et al Plasma therapy CP 6 Decreased viral load, decreased SARS-CoV-2 RNA to undetectable level 5 patients [55]
7 Xu X et al Monoclonal antibody TCZ 21 Subsiding the fever, decreased level of CRP to normal range (in 16 patients), decreased oxygen demand (in 15 patients), None [57]
chest X-ray improvement (in 19 patients), little improvement in chest X-ray (in 3 patients)
8 Giambenedetto SD et al Monoclonal antibody TCZ 3 Subsiding the fever, PaO2/FiO2 ratio improvement, decreased level of CRP to normal range None [58]
9 Diurno F et al Monoclonal antibody Eculizumab 4 Improvement of clinical symptoms and laboratory tests, improvement in chest X-ray None [59]
10 Fontana F et al Monoclonal antibody TCZ, IVIg 1 Subsiding the fever, decreased oxygen demand, Pseudomonas aeruginosa infection in urine culture None [60]
11 Michot JM Monoclonal antibody TCZ 1 Improvement of clinical symptoms, subsiding the fever, decreased oxygen consumption, chest X-ray improvement, None [61]
decreased level of CRP to normal range
12 Zhang X et al Monoclonal antibody TCZ 1 Disappeared chest tightness, decreased level of IL-6, chest X-ray improvement, decreased the SARS-CoV-2 RNA to None [62]
undetectable level
13 Mihai C et al Monoclonal antibody TCZ 1 Control of arthritis, improvement of musculoskeletal and respiratory symptoms, lung function and chest X-ray None [63]
improvement
The patients developed cough, headache and general malaise 4 weeks after the last TCZ transfusion
14 Morrison AR et al Monoclonal antibody TCZ 2 Subsiding the fever, decreased level of inflammatory markers, hypertriglyceridemia, acute pancreatitis (elevated level of None [64]
lipase and amylase) in one patient with 65 years old age.
15 Luna GD et al Monoclonal antibody TCZ 1 Improvement of clinical symptoms None [65]
16 Cellina Met al Monoclonal antibody TCZ 1 Improvement of clinical symptoms and laboratory tests None [66]
17 Hammami MB et al Monoclonal antibody TCZ 1 Subsiding the fever, chest pain and abdominal pain improvement None [67]
18 Odievre MH et al Monoclonal antibody TCZ 1 Improvement of clinical symptoms, decreased oxygen demand, improvement in chest X-ray None [68]
19 Radbel J et al Monoclonal antibody TCZ 2 Worsened the clinical symptoms, myocarditis in one patient, cytopenias, hypertriglyceridemia, elevated ferritin and 1 patient [69]
lactate dehydrogenase, hypofibrinogenemia, decreased level of CRP
20 Luo P et al Monoclonal antibody TCZ 15 Death 3/15 3 patients [70]
Clinical stabilization 9/15
Clinical improvement 1/15
Disease aggravation 2/15
21 Liang B et al Cell therapy hUCMSC 1 The pneumonia greatly relieved, Improvement of clinical symptoms and laboratory tests, the throat swabs tests reported None [71]
IVIg negative
22 Leng Z et al Cell therapy MSC 7 Increased the peripheral lymphocytes, decreased level of CRP None [74]
The overactivated cytokine-secreting immune cells including CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and
CXCR3+ NK cells disappeared in 3–6 days
Increased CD14+ CD11c+ CD11b regulatory DC cell population, decreased level of TNF-α, increased level of IL-10
23 Xie Y et al Immunoglobulin G IVIg, Thymosin 58 Outcomes in treated patients with IVIg within 48 h (≤48 h) after admission: reduced the 28-day mortality rate, shorter None [75]
length of stay in the hospital and/or in ICU, reduced ventilator use.
Outcomes in treated patients with IVIg > 48 h after admission: high mortality rate in 28-day follow up, longer length of
stay in the hospital and/or in ICU, increased ventilator use
*23 of the 58 patients died within 28 days of admission
24 Cao W et al Immunoglobulin G IVIg 3 Improvement of clinical symptoms, recovered lymphocyte count, decreased level of ESR and CRP to normal range, chest None [76]
X-ray improvement
CP: convalescent plasma therapy; TCZ: Tocilizumab; hUCMSC: human umbilical cord mesenchymal stem cell.
4
A.H. Mansourabadi, et al.
Table 2
Demographic and clinical data of included studies.
N Gender Age (y) Comorbidities IAI (days) CPI TI Dose/times of transfusion OT Ref
2 Male 71 None 10 Fever, cough, pneumonia, acute CP Two doses of 250 mL of CP (500 mL in Lopinavir/ritonavir, methylprednisolone [50]
respiratory distress syndrome total) at 12 h interval
Female 67 HTN 6 Fever, myalgia, pneumonia, CP Two doses of 250 mL of CP (500 mL in Lopinavir/ritonavir
acute respiratory distress total) at 12 h interval
syndrome
4 Female 69 None 17 Fever CP 900 mL of CP in three doses Arbidol, lopinavir/ritonavir, oseltamivir, [51]
IFN-alpha-2b
Male 55 COPD 11 Nausea, poor appetite, cough CP 900 mL of CP in three doses Arbidol, lopinavir/ritonavir, IFN-alpha-2b
Male 73 HTN, chronic renal failure 14 Cough CP 900 mL of CP in three doses Arbidol, lopinavir/ritonavir, oseltamivir,
IFN-alpha-2b, ribavirin
Female 31 None 19 Pharyngalgia, fever, dyspnea CP 900 mL of CP in three doses Lopinavir/ritonavir, ribavirin
6 Male 69 None 13 Fever, myalgia, dyspnea CP Three doses of 200 mL of CP (600 mL Arbidol, corticosteroids [52]
in total)
Female 75 None 28 Fatigue, dyspnea CP Two doses of 200 mL of CP (400 mL in Arbidol, corticosteroids
total)
Male 56 Bronchitis 31 Fever, cough CP Three doses of 200 mL of CP (600 mL Arbidol, corticosteroids
in total)
Female 63 Sjogren syndrome 27 Fever, cough, fatigue, dyspnea CP One dose of 200 mL of CP Arbidol
Female 28 None 8 None CP One dose of 200 mL of CP Arbidol, corticosteroids
Male 57 None 6 Fever, cough, myalgia, dyspnea CP One dose of 200 mL of CP Arbidol, corticosteroids
5 Male 70 None 22 Bacterial pneumonia; ARDS; CP Two doses of 200 to 250 mL (400 mL Lopinavir/ritonavir, IFN-ɑlpha-1b, [53]
multiple organ dysfunction in total) of CP on the same day favipiravir, methylprednisolone
syndrome
Male 60 HTN, MI 10 Bacterial pneumonia; fungal CP Two doses of 200 to 250 mL (400 mL Lopinavir/ritonavir, arbidol; darunavir,
pneumonia; ARDS; myocardial in total) of CP on the same day methylprednisolone
damage
Female 50 None 20 ARDS CP Two doses of 200 to 250 mL (400 mL Lopinavir/ritonavir, IFN-ɑlpha-1b,
in total) of CP on the same day methylprednisolone
Female 30 None 19 ARDS CP Two doses of 200 to 250 mL (400 mL IFN-ɑlpha-1b, favipiravir,
in total) of CP on the same day methylprednisolone
Male 60 None 20 ARDS CP Two doses of 200 to 250 mL (400 mL Lopinavir/ritonavir, IFN-ɑlpha-1b,
in total) of CP on the same day methylprednisolone
10 Male 46 HTN 11 Fever, cough, sputum CP One dose of 200 mL of CP Arbidol, ribavirin [54]
production, shortness of breath,
chest pain
Female 34 None 11 Cough, shortness of breath, chest CP One dose of 200 mL of CP Arbidol
pain, nausea and vomiting
Male 42 HTN 19 Fever, cough, sputum CP One dose of 200 mL of CP Arbidol, methylprednisolone
production, shortness of breath,
sore throat, diarrhea
Female 55 None 19 Fever, cough, sputum CP One dose of 200 mL of CP Ribavirin, methylprednisolone
production, shortness of breath
Male 57 None 14 Fever, shortness of breath CP One dose of 200 mL of CP Arbidol, remdesivir, IFN-alpha,
methylprednisolone
Female 78 None 17 Fever, cough, sputum CP One dose of 200 mL of CP Arbidol, methylprednisolone
production, shortness of breath,
muscle ache
Male 56 None 16 Fever, cough, sputum CP One dose of 200 mL of CP Arbidol, methylprednisolone
production, arthralgia
Male 67 CD 20 Fever, cough, headache, CP One dose of 200 mL of CP Arbidol, ribavirin
diarrhea, vomiting
Female 49 None 10 Cough, shortness of breath CP One dose of 200 mL of CP Arbidol, oseltamivir, Peramivir
Male 50 HTN 20 Shortness of breath CP One dose of 200 mL of CP Arbidol, IFN-alpha, methylprednisolone
(continued on next page)
5
A.H. Mansourabadi, et al.
Table 2 (continued)
N Gender Age (y) Comorbidities IAI (days) CPI TI Dose/times of transfusion OT Ref
6 Male: 5/6 Median age: 61.5 None 4/6 Median: Fever 6/6 CP Median volume of CP: 300 mL N/A [55]
Female: 1/ 21.5 days Cough 6/6 (200–600)
6 HTN 1/6 Fatigue 5/6
CVD 1/6 Shortness of breath 5/5
Dyspnea 4/5
21 Male: 18/ Range: HTN 9/21 N/A Fever 21/21 TCZ 8 mg/kg IV All patients: Lopinavir, ritonavir, IFN [57]
21 56.8 ± 16.5 Diabetes 5/21 Cough 14/21 18/21 patients received one dose alpha, ribavirin
Female: 3/ CHD 2/21 dyspnea 6/21 3/21 patients received two doses (due For patients with rapid progress in
21 COPD 1/21 Phlegm 9/21 to fever within 12 h) respiratory function: Methylprednisolone
Brain Infarction 1/21 Fatigue 6/21 was also administered
Nausea 4/21
Bronchiectasis 1/21 Rhinorrhea 1/21
Auricular fibrillation 1/21 Chest pain 1/21
CKD 1/21
3 Male 71 HTN 9 Flu-like symptoms, dyspnea TCZ Two dose of TCZ at 8 mg/kg IV, 12 h Lopinavir/ritonavir, [58]
apart hydroxycholoroquine
Male 45 None 4 Fever, dyspnea, chest pain TCZ Two doses of TCZ at 8 mg/kg IV, 12 h Lopinavir/ritonavir,
apart hydroxycholoroquine
Male 53 HTN 2 Flu-like symptoms, dyspnea TCZ Three doses of TCZ 12 h after the first Lopinavir/ritonavir,
and a third dose after further 24–36 h hydroxycholoroquine
4 Female 54 β-Thalassemia N/A Fever, cough, dyspnea, Eculizumab Two doses of Eculizumab at 900 mg Enoxaparin 4000, Lopinavir/ritonavir, [59]
respiratory failure hydroxycholoroquine
Male 73 HTN N/A Fever, cough, respiratory failure Eculizumab Two doses of Eculizumab at 900 mg
Female 82 HTN N/A Fever, cough, dyspnea, Eculizumab Two doses of Eculizumab at 900 mg
respiratory failure
Male 53 HTN N/A Fever, cough, dyspnea, Eculizumab Two doses of Eculizumab at 900 mg
respiratory failure
1 Male 61 Kidney transplant, chronic kidney disease 11 Fever TCZ 324 mg of TCZ via subcutaneous route Methylprednisolone, [60]
stage IIIa, lymphoma, unprovoked IVIg 0.3 g/kg IVIg hydroxycholoroquine, IVIg
pulmonary embolism, urinary tract
infection
1 Male 42 MRC 8 Fever, cough, dyspnea TCZ Two doses of TCZ, at 8 mg/kg Lopinavir/ritonavir [61]
intravenously (IV) for each dose, 8 h
apart
1 Male 60 MM 9 chest tightness and shortness of TCZ One dose of TCZ at 8 mg/kg IV Arbidol, methylprednisolone [62]
breath without fever and cough
1 Female 57 SSC, IDDM, WHO grade I obesity N/A Cough, dyspnea, arthritis TCZ 8 mg/kg every 4 weeks IV N/A [63]
2 Male 65 None 9 Fever, ARDS TCZ Two doses of TCZ Lopinavir/ritonavir, ribavirin/ [64]
hydroxycholoroquine
Male 43 None 13 Respiratory failure, ARDS, fever TCZ Two doses of TCZ Lopinavir/ritonavir, ribavirin
1 Male 45 SCD 2 Fever, pneumonia, acute chest TCZ One dose of TCZ at 8 mg/kg IV Hydroxycholoroquine [65]
syndrome
1 Male 65 None 7 Syncope, fever, dyspnea TCZ Two doses of TCZ at 8 mg/kg IV, 12 h N/A [66]
apart
1 Male 63 Liver cancer, liver transplant (end-stage 12 Fever, cough, fatigue, headache, TCZ One dose of TCZ at 800 mg (9 mg/kg) Hydroxycholoroquine [67]
renal disease), HTN, diabetes, peripheral myalgia, malaise
vascular disease, heart failure, smoking
1 Female 16 SCD N/A Fever, acute chest syndrome, TCZ One dose of TCZ at 8 mg/kg N/A [68]
respiratory distress syndrome, Red blood cell exchange transfusion
2 Male 40 None 4 Fever, cough, dyspnea, ARDS, TCZ One dose of TCZ at 400 mg N/A [69]
septic shock
Female 69 Type II diabetes mellitus, rheumatoid 4 Fever, cough, chest pain, fatigue, TCZ Two dose of TCZ at 560 mg and
arthritis, aplastic anemia abdominal pain 700 mg
(continued on next page)
6
A.H. Mansourabadi, et al.
Table 2 (continued)
N Gender Age (y) Comorbidities IAI (days) CPI TI Dose/times of transfusion OT Ref
15 Male: 12/ 71 ± 9 HTN 3/15 0 Critically ill 7/15 TCZ 80–600 mg of TCZ per time. Methylprednisolone: 8/15 [70]
15 HTN + stroke history 2/15 Seriously ill 6/15 10/15 patients received one dose of None: 2/15
Female: 3/ HTN+ diabetes 4/15 TCZ, 3/15 patients received two dose
15 Stroke history 1/15 Moderately ill 2/15 of TCZ, 2/15 patients received three
dose of TCZ
1 Female 65 N/A 10 Fatigue, fever, cough chest hUCMSC Three doses of MSC at 5 × 107 cells Lopinavir/ritonavir, IFN-alpha, [71]
tightness IVIg oseltamivir, methylprednisolone
6
7 Male 65 N/A 8 Fever, shortness of breath, MSC 1 × 10 cells per kilogram of weight Standard treatments [74]
Female 63 N/A 6 cough, poor appetite, diarrhea
Female 65 N/A 10 (1/7)
Female 51 N/A 1
Male 57 N/A 2
Male 45 N/A 10
Male 53 N/A 3
58 Male: 36/ Median age: 63 N/A > 48 h N/A IVIg N/A Arbidol + all other treatment according [75]
58 ≤48 h to WHO (not detected)
Female:
22/58
3 Male 56 None 7 Sore throat, fever, cough, IVIg 25 g per day for five days (body Oseltamivir [76]
dyspnea weight: 66 kg)
Male 34 HTN 2 Fever, cough, dyspnea IVIg 25 g per day for five days (body None
weight: 63 kg)
Female 35 None 6 Fever, cough, dyspnea IVIg 25 g/day for five days (body weight: Lopinavir/ritonavir, corticosteroids
56 kg)
Y: years; N: number of patients; IAI: interval between admission and immunotherapy (days); CPI: complication prior to immunotherapy or principal symptoms; TI: type of immunotherapy; OT: other anti-viral and steroid
therapies; CP: convalescent plasma therapy; TCZ: Tocilizumab; MSC: mesenchymal stem cell; hUCMSC: human umbilical cord mesenchymal stem cell; ARDS: acute respiratory distress syndrome; HTN: hypertension; MI:
mitral insufficiency; CD: cardiovascular and cerebrovascular diseases; MRC: metastatic sarcomatoid clear cell renal cell carcinoma; SSC: systemic sclerosis; IDDM: insulin-dependent type 2 diabetes mellitus; CHD:
coronary heart disease; COPD: chronic obstructive pulmonary disease; CKD: chronic kidney disease; MM: multiple myeloma; SCD: homozygous sickle cell disease; N/A: not applicable; CVD: cardiovascular disease.
7
A.H. Mansourabadi, et al. Life Sciences 258 (2020) 118185
and decreased the SARS-CoV-2 RNA to an undetectable level [54]. Two studies evaluated the efficacy of TCZ in two patients with organ
In a case series trial, five COVID-19 patients with severe pneumonia transplantation [60,67]. Subsiding the fever, decreased oxygen de-
were assessed who were treated with CP therapy. The neutralizing mand, and Pseudomonas aeruginosa infection in urine culture were seen
antibody titers above 1:40 were transfused to the patients in addition to in one of them who was treated with TCZ and IVIg [60]. Another pa-
anti-viral drugs and corticosteroid therapy. The outcome was an im- tient showed the reduced fever, improved chest pain and abdominal
provement of the clinical symptoms and laboratory assessments in- pain [67].
cluding, changes in body temperature, improvement Sequential Organ The adverse effects of TCZ were reported in three studies. Two
Failure Assessment (SOFA) score, decrease viral load, increased serum studies have shown hypertriglyceridemia in four COVID-19 patients
antibody titer, and decreased CRP level to the normal range [53]. treated with TCZ. Hypertriglyceridemia could be related to the dis-
One case report study has shown a favorable outcome after CP ruption of triglyceride uptake which caused by TCZ. Besides, cytope-
therapy in two COVID-19 patients with severe pneumonia. Both two nias, hypertriglyceridemia, elevated ferritin and lactate dehydrogenase,
cases showed chest X-ray improvement, decrease oxygen demand, and hypofibrinogenemia [69] and acute pancreatitis (elevated level of li-
subsiding the fever. Their laboratory assessments showed a reduced pase and amylase) [64] have been also shown in two studies. In another
level of CRP and IL-6 to the normal range and negative SARS-COV-2 study [60], in a patient with chronic kidney disease stage IIIa, Pseu-
RNA [50]. domonas aeruginosa infection was found in the urinary culture as an
In a descriptive study by Mingxiang et al., six COVID-19 patients adverse effect of TCZ.
were treated with CP therapy. An increased titer of anti-SARS-COV-2 One study [70] reported disease aggravation after treatment with
and computed tomography (CT) scan improvement were observed in all TCZ in COVID-19 patients. In this trial, among 15 patients who were
six patients [52]. treated with TCZ, two patients showed disease aggravation, nine pa-
Zhang B et al. evaluated the efficiency of CP therapy in 4 patients. tients showed clinical stabilization, one patient showed clinical im-
The viral load significantly dropped in one case after CP transfusion. provement, and three patients died.
Totally, decreased viral load was observed in 3–22 days and anti-SARS- One study reported treatment with TCZ in COVID-19 pediatric pa-
COV-2 IgG was developed in all patients in this trial 14 days after CP tients with homozygous sickle cell disease (SCD) who was treated
therapy [51]. On the other hand, researchers at Johns Hopkins Uni- successfully [68].
versity obtained FDA approval to test CP therapy for COVID19 patients A total number of 29 clinical trials were registered in clinical-
in large-scale clinical trials [56]. By 4th May 2020, there were 11 trials.gov until 4 May 2020 in order to evaluate the efficacy of TCZ for
clinical trials registered in China (Supplementary data, Table 3) and 43 treatment of COVID-19 patients (Supplementary data, Table 5).
trials have registered in clinicaltrials.gov (Supplementary data, Table 4) Moreover, some of the clinical trials have been approved for the effi-
for large-scale treatment of COVID-19 patients with CP. cacy assessment of other monoclonal antibodies, including
Adalimumab, Camrelizumab, Eculizumab, Meplazumab, PD-1 mab,
3.2. Monoclonal antibodies Anakinra, and Siltuximab to treatment of COVID-19 patients. These
monoclonal antibodies are summarized in Supplementary data, Table 6.
Of the 24 included studies screened, 14 studies with a total of 55
patients have identified that met inclusion criteria for monoclonal an- 3.3. Cytokines and interferons
tibodies, including 3 case series [57–59], 10 case reports [60–69], and
one retrospective study [70]. Of the 24 studies included, 5 studies [51,53,54,57,71] with a total
Except for four patients who were successfully treated with of 31 patients included that received type 1 interferon (IFN) apart from
Eculizumab [59], the others (51 patients) were treated with Tocili- other immunotherapies. These studies include one case report [51], one
zumab (TCZ). One patient also received intravenous immunoglobulin preliminary uncontrolled case series [53], one pilot study [54], one
(IVIg) in combination with TCZ [60]. 47 patients were recovered after retrospective study [57], and one case report in registered clinical trials
TCZ; among them, 4 patients have shown adverse effects [60,64,69]. in china [71].
The fatality was also reported in 4 patients, who received TCZ [69,70]. Three patients received IFN-α-2b apart from CP therapy and anti-
In a case series study, 21 severe COVID-19 patients were treated viral drugs. Among them, two patients had comorbidities including
with TCZ. Improvement of clinical symptoms in this trial was observed chronic obstructive pulmonary disease (COPD) and chronic renal
within a few days. Fifteen of the 20 patients had reduced demand for failure. In this trial, decreased viral load, increased anti-SARS-COV-2
oxygen, and one patient did not require oxygen therapy within five titer in serum, and improvement in chest X-rays were observed in all
days after TCZ. In 16 of the 19 patients, the elevated C-reactive protein three patients [51].
(CRP) levels returned to normal range. Improvement in Chest X-rays Four patients received IFN-α-1b apart from CP therapy, anti-viral
was observed in 19 cases, and other patients showed little improvement drugs, and methylprednisolone. The outcome was including changes in
in their chest X-rays [59]. In accordance with this trial, 3 studies have body temperature, improved Sequential Organ Failure Assessment
also shown improved clinical symptoms and laboratory tests after TCZ (SOFA) score, decreased viral load, increased serum antibody titer,
treatment [58,65,66]. decreased CRP and procalcitonin levels to the normal range [53].
Three studies have assessed the TCZ effectiveness in treating pa- Type of IFN-α has not mentioned in 24 other patients [54,57,71].
tients with cancer or autoimmune disorders. In the first study, treat- Among them, two patients received IFN-α apart from CP therapy, anti-
ment with TCZ with favorable outcome was reported in a patient with viral drugs, and methylprednisolone. Amelioration of clinical symp-
metastatic sarcomatoid clear cell renal cell carcinoma, including gra- toms, decreased pulmonary lesions, improved pulmonary function,
dually decreased oxygen consumption, improvement in chest CT, and improved lymphocytopenia, and decreased the SARS-CoV-2 RNA to an
decreased level of CRP. However, it should be noted that this patient undetectable level were observed upon treatment [54].
had an immunosuppressed condition due to his cancer [61]. The second 21 patients received IFN-α apart from Tocilizumab, anti-viral drugs,
study reported a patient with multiple myeloma (MM) who was suc- with or without methylprednisolone [57].
cessfully treated with TCZ. The outcomes in this trial were improved in One patient received IFN-α apart from human umbilical cord me-
chest tightness and chest CT, decreased level of IL-6, and decreased the senchymal stem cell (hUCMSC), IVIg, anti-viral drugs, and methyl-
SARS-CoV-2 RNA to undetectable levels [62]. Another study demon- prednisolone. The outcome was an improvement of clinical symptoms
strated TCZ performance in a patient with systemic sclerosis and IDDM. and laboratory tests [71].
Treatment with TCZ in this trial improved musculoskeletal and re- Treatment with IFN-α in combination with anti-viral drugs such as
spiratory symptoms, lung function, and CT imaging [63]. ribavirin is recommended for treatment COVID-19 patients in china
8
A.H. Mansourabadi, et al. Life Sciences 258 (2020) 118185
9
A.H. Mansourabadi, et al. Life Sciences 258 (2020) 118185
Fig. 3. The mechanism of the innate and acquired immune response following by attaching the virus to the ACE2 receptor and the current immunotherapies for
treatment the COVID-19 patients. Viral interactions with the innate and acquired immune system play a central role in determining the outcome of infection. Local
inflammation formed in the site of the infection, triggers immune cells to limit viral spread within the host during the early phases of the disease via producing
cytokines and other chemokines. Current immunotherapies including monoclonal antibodies, convalescent plasma therapy, IVIg, mesenchymal stem cell therapy in
COVID-19 patients are also shown. Up to now, most clinical trials have been performed on Tocilizumab and convalescent plasma therapy with inspiring outcomes.
Depicted monoclonal antibodies are currently being evaluated by registered clinical trials. ACE2R: angiotensin-converting enzyme 2 receptor; IL: interleukin; MCP1:
monocyte chemoattractant protein1; IP10: interferon-inducible protein 10; IF: interferon; PD-1: programmed cell death protein 1; MIP1: macrophage inflammatory
proteins1; TNF: tumor necrosis factor; PMN: polymorphonuclear granulocyte; NK: natural killer; Treg cell: regulatory T cell; CSF: colony stimulating factor; IVIg:
intravenous immunoglobulin.
10
A.H. Mansourabadi, et al. Life Sciences 258 (2020) 118185
various viral infections including hepatitis B, C, and HIV [101]. An in preclinical models of sepsis, ARDS, and cystic fibrosis infection. The
vitro study showed that SARS-CoV-2 is more sensitive to IFN-I com- mechanism of action proposed for their antimicrobial activities are the
pared to SARS-CoV. This discrepancy may be due to the changes that dynamic coordination of the pro- and anti-inflammatory elements of
occurred in proteins of SARS-CoV-2, such as the loss of ORF3b, that the immune system or increasing the activity of phagocytes, and also
would be resulted in a changed response to IFN-I [102]. After treatment the secretion of antimicrobial factors and molecules [119,120]. In
COVID-19 patients with IFN-I along with other standard cares, favor- conclusion, umbilical cord MSCs as a main type of the stem cells show a
able outcomes were observed due to improvement of the anti-viral re- gene expression profile more similar to that of embryonic stem cells due
sponse. to the fact that they have faster doubling times, more plasticity, and
IVIg is referred to as polyclonal IgG isolated from healthy donors. possibly more potency. Fortunately, unlike embryonic stem cells, they
IVIg has long been used to treat the patients, who suffered from primary are not tumorigenic [121]. Thus, MSCs therapy against COVID-19 could
antibody deficiencies, vasculitis, rheumatologic disorders, chronic in- be a promising approach to managing this world-threatening disease.
flammatory diseases, systemic lupus erythematosus (SLE) as well as However, the appropriate cell dose, cell concentration, the cell infusion
treat several hematological and neurological disorders [103]. Treat- rate should be determined to maximize efficacy and safety. Cell passage
ment with IVIg has also been effective in the treatment or prevention of numbers should be limited to increase potency and decrease cell size.
the infectious disease caused by viruses, bacteria, and fungi in human
patients [104,105]. Acknowledgment
Previous studies were shown the encouraging outcomes in patients
with SARS and MERS after treatment with IVIg [106–108]. Using IVIg None.
for COVID-19 treatment has been performed only in a small number of
patients. Good results were observed after treatment with IVIg in Funding
combination with other standard anti-viral drugs. The immune system
modulation by IVIg could be conducted by improving passive immunity None.
and anti-inflammatory response. Although the role of IVIg in COVID-19
patients requires more investigations, it seems that this approach has Declaration of competing interest
promising effects, if administered in the early stage of disease.
Cell-based therapies have been used to management of several ill- The authors declare that there are no conflicts of interest.
nesses including pulmonary [109–111], cardiovascular [112,113], he-
patic [114], and renal [115] diseases. Also, the safety and effectiveness Author contributions
of the treatment with stem cells have been documented in many clinical
trials, especially in immune-mediated inflammatory diseases, such as R.N. directed the project. M.A.H., S.M., and R.N. designed research.
SLE and graft-versus-host disease (GVHD) [110,116]. Data extraction performed by M.A.H., S.M., and M.M.H.R. The paper
In line with finding effective drug therapies and immunological was drafted by M.A.H., S.M., and M.M.H.R.
treatments for COVID-19, mesenchymal stem cells (MSCs) may have R.N. did critical revision of the paper. All the authors contributed to
significant immunomodulatory ability. On the other hand, these cells protocol development, read and finally approved the paper.
secret many anti-inflammatory factors through paracrine route or direct
interactions with immune cells, including T and B cells, macrophages, Appendix A. Supplementary data
dendritic cells (DCs), and NK cells. The outcome of these events may
lead to preventing or inhibiting the cytokine storm, regulating the in- Supplementary data to this article can be found online at https://
flammatory response as well as decreased morbidity and mortality in doi.org/10.1016/j.lfs.2020.118185.
the treated patients.
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