key: cord-0795946-1vaxmmv8 authors: Mansourabadi, Amir Hossein; Sadeghalvad, Mona; Mohammadi-Motlagh, Hamid-Reza; Rezaei, Nima title: The immune system as a target for therapy of SARS-CoV-2: A systematic review of the current immunotherapies for COVID-19 date: 2020-08-01 journal: Life Sci DOI: 10.1016/j.lfs.2020.118185 sha: 317c469596ab38cd276c5c848d768e8341a8e6a6 doc_id: 795946 cord_uid: 1vaxmmv8 AIMS: The immune response is essential for the control and resolution of viral infections. Following the outbreak of novel coronavirus disease (COVID-19), several immunotherapies were applied to modulate the immune responses of the affected patients. In this review, we aimed to describe the role of the immune system in response to COVID-19. We also provide a systematic review to collate and describe all published reports of the using immunotherapies, including convalescent plasma therapy, monoclonal antibodies, cytokine therapy, mesenchymal 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 patients), 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. J o u r n a l P r e -p r o o f viral antigens via specific antibodies, phosphorylation of ITAMs in the cytoplasmic tail segments of the Igα and Igβ in B cells occurs by SRC kinase family, lead to trigger downstream signaling to up-regulate pro-inflammatory cytokines and down-regulate anti-inflammatory cytokines [47, 48] . Viral components in the endosomes recognized by multiple endosomal TLRs, including TLR3, TLR7, and TLR8, resulting in immunopathology. In this systematic review, we provide an update on the treatment of the COVID-19 patients with focused on the immunotherapies. Immunology knowledge along with advanced vaccine technology is expected to help us find more effective ways to cure the disease. This systematic review was conducted based on the Preferred Reporting Items for systematic review and Meta-Analysis Protocols (PRISMA-P) 2015 checklist (supplementary data, Table 1 ) [49] . Except for one retrospective study that out of 6 patients with COVID-19, only one patient recovered after CP therapy, five studies have shown optimistic results in using CP therapy to treat severe COVID-19 patients. In one pilot study, one dose of CP collected from recently recovered COVID-19 patients was administered to 10 sever COVID-19 patients. In this trial, the neutralizing antibody titers greater than 1:640 were transfused to the patients in addition to anti-viral drugs and corticosteroid therapy. The outcome was the amelioration of clinical symptoms, pulmonary lesions, pulmonary function, improved lymphocytopenia, and decreased the SARS-CoV-2 RNA to an undetectable level [54] . In a case series trial, five COVID-19 patients with severe pneumonia were assessed who were treated with CP therapy. The neutralizing antibody titers above 1:40 were transfused to the patients in addition to anti-viral drugs and corticosteroid therapy. The outcome was an improvement of the clinical symptoms and laboratory assessments including, changes in body temperature, improvement Sequential Organ Failure Assessment (SOFA) score, decrease viral load, increased serum antibody titer, and decreased CRP level to the normal range [53]. One case report study has shown a favorable outcome after CP therapy in two COVID-19 patients with severe pneumonia. Both two cases showed chest X-ray improvement, decrease oxygen demand, and subsiding the fever. Their laboratory assessments showed a reduced level of CRP and IL-6 to the normal range and negative SARS-COV-2 RNA [50] . In a descriptive study by Mingxiang et al., six COVID-19 patients were treated with CP therapy. An increased titer of anti-SARS-COV-2 and computed tomography (CT) scan improvement were observed in all six patients [52] . days after CP therapy [51] . On the other hand, researchers at Johns Hopkins University obtained FDA approval to test CP therapy for COVID19 patients in large-scale clinical trials [56] . By 4th May 2020, there were 11 clinical trials registered in China (supplementary data, Table 3 ) and 43 trials have registered in clinicaltrials.gov (supplementary data, Table 4 ) for large-scale treatment of COVID-19 patients with CP. Of the 24 included studies screened, 14 studies with a total of 55 patients have identified that met inclusion criteria for monoclonal antibodies, including 3 case series [57-59], 10 case reports [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] , and one retrospective study [70] . Except for four patients who were successfully treated with Eculizumab [59], the others (51 patients) were treated with Tocilizumab (TCZ). One patient also received intravenous immunoglobulin (IVIg) in combination with TCZ [60] . 47 patients patients were recovered after TCZ; among them, 4 patients have shown adverse effects [60, 64, 69] . The fatality was also reported in 4 patients, who received TCZ [69, 70] . [61] . The second study reported a patient with multiple myeloma (MM) who was successfully treated with TCZ. The outcomes in this trial were improved in chest tightness and chest CT, decreased level of IL-6, and decreased the SARS-CoV-2 RNA to undetectable levels [62] . Another study demonstrated TCZ performance in a patient with systemic sclerosis and IDDM. Treatment with TCZ in this trial improved musculoskeletal and respiratory symptoms, lung function, and CT imaging [63] . Two studies evaluated the efficacy of TCZ in two patients with organ transplantation [60, 67] . Subsiding the fever, decreased oxygen demand, and Pseudomonas Aeruginosa infection in urine culture were seen in one of them who was treated with TCZ and IVIg [60] . Another patient showed the reduced fever, improved chest pain and abdominal pain [67] . [64] have been also shown in two studies. In another study [60] , in a patient with chronic kidney disease stage IIIa, Pseudomonas J o u r n a l P r e -p r o o f Aeruginosa infection was found in the urinary culture as an adverse effect of TCZ. One study [70] reported disease aggravation after treatment with TCZ in COVID-19 patients. In this trial, among 15 patients who were treated with TCZ, two patients showed disease aggravation, nine patients showed clinical stabilization, one patient showed clinical improvement, and three patients died. One study reported treatment with TCZ in COVID-19 pediatric patients with homozygous sickle cell disease (SCD) who was treated successfully [68] . A total number of 29 clinical trials were registered in clinicaltrials.gov until 4 May 2020 in order to evaluate the efficacy of TCZ for treatment of COVID-19 patients (supplementary data, Table 5 ). Moreover, some of the clinical trials have been approved for the efficacy assessment of other monoclonal antibodies, including Adalimumab, Camrelizumab, Eculizumab, Meplazumab, PD-1 mab, Anakinra, and Siltuximab to treatment of COVID-19 patients. These monoclonal antibodies are summarized in supplementary data, Table 6 . Of the 24 studies included, 5 studies [51, 53, 54, 57, 71 ] with a total of 31 patients included that received type 1 interferon (IFN) apart from other immunotherapies. These studies include one case report [51] , one preliminary uncontrolled case series [53], one pilot study [54] , one retrospective study [57] , and one case report in registered clinical trials in china [71] . Three patients received IFN-α-2b apart from CP therapy and anti-viral drugs. Among them, two patients had comorbidities including chronic obstructive pulmonary disease (COPD) and chronic renal failure. In this trial, decreased viral load, increased anti-SARS-COV-2 titer in serum, and J o u r n a l P r e -p r o o f improvement in chest X-rays were observed in all three patients [51] . One patient received IFN-α apart from human umbilical cord mesenchymal stem cell (hUCMSC), IVIg, anti-viral drugs, and methylprednisolone. The outcome was an improvement of clinical symptoms and laboratory tests [71] . Treatment with IFN-α in combination with anti-viral drugs such as ribavirin is recommended for treatment COVID-19 patients in china [72, 73] . There are also 20 registered clinical trials up to 4 May 2020 to evaluate the treatment efficiency of COVID-19 patients with IFN in clinicaltrials.gov (supplementary data, Out of the 24 studies included, two studies, with a total of 8 patients included a case-control study with 7 patients in the treatment group and 3 in the control group [74] , a case report in registered china clinical trials [71] were identified that received MSCT. In the first case study carried out in China, a 65 years old woman with severe pneumonia was treated with the umbilical cord stem cells, apart from IVIg, IFN-α, anti-viral drugs, and methylprednisolone [71] . Before stem cell therapy, the patient had respiratory and multi-organ failure requiring mechanical ventilation. She was not responding to conventional therapy. So, she received three doses of allogeneic stem cells (50 million per dose) within three days, along with conventional therapy. One day after the second infusion, her vital signs were stabilized and she was no longer requiring the ventilator. Two days upon the third dose, she was getting out of the ICU and most of the laboratory indexes were normal. Two days upon the third dose, her throat specimen was negative for Coronavirus. Finally, six days after the third infusion, the CT scan of her lungs significantly improved. Another study was a short-term (14 days' follow-up) and a small clinical trial with only 10 coronavirus patients [74] . The patients were divided into 7 patients (including 1 critically serious, 4 serious, and 2 commons) who were treated with one dose of stem cells and 3 serious patients in the control group who did not. The patients were not responding to standard conventional therapy. All 7 patients were recovered following the receiving stem cell therapy. Conversely, the results obtained from the control group were one dead, one patient with developed ARDS, and only one patient with stable conditions. In the treated group within a few J o u r n a l P r e -p r o o f days, the oxygen saturation, the laboratory indexes such as CRP, aspartic aminotransferase, creatine kinase activity, and myoglobin changed to normal. Furthermore, significant improvements were observed in the signs in CT scans of the lungs in the treatment group [74] . There are also 29 registered clinical trials up to 4 May, to evaluate the treatment efficiency of COVID-19 patients by cell therapy including MSCT in clinicaltrials.gov (supplementary data, Table 8 ). Of the 24 studies included, 4 observational studies with a total of 63 patients were identified that received IVIg apart from anti viral drugs or other immunotherapies. These studies included one case report [60] , one case report in registered china clinical trials [71] , one retrospective study [75] , and one case series [76] . Among them, one patient received IVIg alone [76] , 60 patients received IVIg apart from antiviral drugs or corticosteroids [75, 76] , one patient received IVIg apart from Tocilizumab, corticosteroid, and hydroxychloroquine [60] , and one patient received IVIg apart from hUCMSC, IFN-alpha, anti viral, and corticosteroid [71] . In the first clinical trial, three patients were treated with anti-viral drugs and IVIg (0.3-0.5g per kg weight per day for five days) in about one week after admission (in two patients) and 2 days after admission (in one patient). The clinical observations in all three patients were improved, including fever, CT-scan, and oxygen consumption [76] . In the second study, 28-day mortality rate was assessed in 58 sever COVID-19 patients who were treated with IVIg in China. The patients were divided into two groups, the patients who received IVIg within 48h (≤ 48h) after admission and the patients who received IVIg >48 hours J o u r n a l P r e -p r o o f after admission. All patients received IVIg when their total lymphocyte count decreased to < 0.5× 109/L at 20 g/day. The patients were also treated with Thymosin if the total number of lymphocytes had not increased 5 days after IVIg administration. The results showed the reduced 28-day mortality rate, reduced ventilator use, and shorter length of stay in hospital in the patients who received IVIg within 48h after admission in comparison to the patients who received IVIg >48 hours after admission [75] . One study assessed the efficiency of IVIg in a COVID-19 patient with chronic kidney disease stage IIIa. In this trial, the patient received IVIg at the dose of 0.3 g/kg, Tocilizumab, hydroxychloroquine, corticosteroid, and cyclosporine A. The outcome was a subsiding the fever and normal peripheral oxygen saturation. Progressive leukopenia and neutropenia, stopped oxygen treatment, and stability in kidney function were observed after Tocilizumab, and then IVIg was administered to immune system modulation [60] . In addition to the mentioned ongoing clinical trials, we found five clinical trials for Thymosin (supplementary data, Table 9 ) and four clinical trials for immunosuppressive drugs, including Fingolimod, Leflunomide, Thalidomide (supplementary data, Table 10 ) in order to evaluate their efficiency in COVID-19 patients. It seems that CP therapy could be used in newly infected COVID-19 patients to improve the immune response, probably through neutralizing the virus, suppress viremia, and viral clearance. No adverse effects were observed in all included patients in this study. Nevertheless, some precautions should be considered, including evaluating the neutralizing Ab activity titer and J o u r n a l P r e -p r o o f accurate time for plasma collection and administration [83] . Besides, CP therapy might be more effective if administered at the initial stage of the disease [55, 79] . Immunotherapy using monoclonal antibodies as another inspiring approach is progressing to treat COVID-19 patients [84] . Up to now, most clinical trials have been performed on TCZ. However, one study reported good results in treating patients with Eculizumab, a humanized monoclonal antibody against complement protein C5. TCZ is a humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody that has long been These studies could be helpful to improve our knowledge to design effective monoclonal antibodies to treat COVID-19 patients. Cytokine therapy is also another approach to treat COVID-19 patients. Type 1 interferons (IFN-I) are a group of cytokines produced by various types of immune cells, particularly plasmacytoid dendritic cells during the first stages of a response against viral infection [99] . Different subtypes of IFN-I are recognized including α, β, ε, ω, and κ [100] . It has been shown that IFN-I could be an efficient agent against various viral infections including hepatitis B, C, and HIV [101] . An in vitro study showed that SARS-CoV-2 is more sensitive to IFN-I compared to SARS-CoV. This discrepancy may be due to the changes that occurred in proteins of SARS-CoV-2, such as the loss of ORF3b, that would be resulted in a changed response to IFN-I [102] . After treatment COVID-19 patients with IFN-I along with other standard cares, favorable outcomes were observed due to improvement of the anti-viral response. IVIg is referred to as polyclonal IgG isolated from healthy donors. IVIg has long been used to treat the patients, who suffered from primary antibody deficiencies, vasculitis, rheumatologic disorders, chronic inflammatory diseases, systemic lupus erythematosus (SLE) as well as treat several hematological and neurological disorders [103] . Treatment with IVIg has also been effective in the treatment or prevention of the infectious disease caused by viruses, bacteria, and fungi in human patients [104, 105] . Previous studies were shown the encouraging outcomes in patients with SARS and MERS after treatment with IVIg [106] [107] [108] . Using IVIg for COVID-19 treatment has been performed only in a small number of patients. Good results were observed after treatment with IVIg in combination with other standard anti-viral drugs. The immune system modulation by IVIg could be conducted by improving passive immunity and anti-inflammatory response. Although the role of IVIg in COVID-19 patients requires more investigations, it seems that this approach has promising effects, if administered in the early stage of disease. Cell-based therapies have been used to management of several illnesses including pulmonary [109] [110] [111] , cardiovascular [112, 113] , hepatic [114] , and renal [115] diseases. Also, the safety and effectiveness of the treatment with stem cells have been documented in many clinical trials, especially in immune-mediated inflammatory diseases, such as SLE and graft-versus-host disease (GVHD) [110, 116] . In line with finding effective drug therapies and immunological treatments for COVID-19, infection. The mechanism of action proposed for their antimicrobial activities are the dynamic coordination of the pro-and anti-inflammatory elements of the immune system or increasing the activity of phagocytes, and also the secretion of antimicrobial factors and molecules [119, 120] . In conclusion, umbilical cord MSCs as a main type of the stem cells show a gene expression profile more similar to that of embryonic stem cells due to the fact that they have faster doubling times, more plasticity, and possibly more potency. Fortunately, unlike embryonic stem cells, they are not tumorigenic [121] . 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