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      Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review

      review-article
      Author(s): a , b , c , * , d , e , f , g , h , a , c , a , i , j , k , j , j
      Publication date (Electronic):
      Journal: Autoimmunity Reviews
      Publisher: Published by Elsevier B.V.
      Keywords: Acute respiratory distress syndrome, COVID-19, Cytokine storm, Immunosuppressive, SARS-CoV-2, Treatment, ACE-2, Angiotensin-converting enzyme-2, AD, Autoimmune diseases, ADE, Antibody dependent enhancement, ADRS, Acute distress respiratory syndrome, APC, Antigen-presenting cells, aPL, Antiphospholipid antibodies, CD, Cluster of differentiation or cluster of designation or classification determinant, CDC, Centres for disease control, COVID-19, Coronavirus disease 2019, CQ, Chloroquine, CyA, Cyclosporine A, FDA, Food and Drugs Administration, GCS, Glucocorticoids, HCQ, Hydroxychloroquine, HPS, Haemophagocytic syndrome, IFNγ, Interferon gamma, IL, Interleukin, JAK, Janus-Kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), IVIG, Intravenous immunoglobulins, MDA5, Melanoma differentiation-associated gene 5, MHC-II, Major histocompatibility type-II, LMWH, Low-molecular weight heparin, MAS, Macrophage activation syndrome, MERS-CoV, Middle East Respiratory Syndrome Coronavirus, mTOR, Mammalian target of Rapamycin, NHC, National Health Council, NK, natural killer cells, NF-kβ, Nuclear Factor-Kβ, PIC, Pulmonary intravascular coagulation, PTE, Pulmonary thromboembolism, RA, Rheumatoid arthritis, SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus-2, SLE, Systemic Lupus Erythematosus, TCZ, Tocilizumab, TLR, Toll-Like Receptor, TNF-α, Tumour necrosis factor-alpha, TRAASVIR, Thrombotic Risk Associated with Antiphospholipid Syndrome after Viral infection, TRALI, Transfusion-related acute lung injury, TGF-β, Transforming growth factor-beta, Tregs, Regulatory T-cells, WHO, World Health Organization

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          Abstract

          Severe Acute Respiratory Syndrome related to Coronavirus-2 (SARS-CoV-2), coronavirus disease-2019 (COVID-19) may cause severe illness in 20% of patients. This may be in part due to an uncontrolled immune-response to SARS-CoV-2 infection triggering a systemic hyperinflammatory response, the so-called “cytokine storm”. The reduction of this inflammatory immune-response could be considered as a potential therapeutic target against severe COVID-19. The relationship between inflammation and clot activation must also be considered. Furthermore, we must keep in mind that currently, no specific antiviral treatment is available for SARS-CoV-2. While moderate-severe forms need in-hospital surveillance plus antivirals and/or hydroxychloroquine; in severe and life-threating subsets a high intensity anti-inflammatory and immunomodulatory therapy could be a therapeutic option. However, right data on the effectiveness of different immunomodulating drugs are scarce. Herein, we discuss the pathogenesis and the possible role played by drugs such as: antimalarials, anti-IL6, anti-IL-1, calcineurin and JAK inhibitors, corticosteroids, immunoglobulins, heparins, angiotensin-converting enzyme agonists and statins in severe COVID-19.

          Higlights

          • •

            Severe COVID-19 forms may be related to a hyperinflammatory syndrome.

          • •

            Severe COVID-19 is associated with clot pathway hyperactivity and sometimes, with thromboses.

          • •

            Immunosuppression may be a complementary therapy in COVID-19 patients.

          • •

            Antimalarials, heparin, cytokine blockers, JAK-inhibitors, IVIG could be useful for treating severe COVID-19 patients.

          • •

            In SARS-CoV-2 infections the effectiveness of the hyperimmune plasma remains uncertain.

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          Most cited references70

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Chaolin Huang, Yeming Wang, Xingwang Li … (2020)
          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

            Fei Zhou, Ting Yu, Ronghui Du … (2020)
            Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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              Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

              Nanshan Chen, Min Zhou, Xuan Dong … (2022)
              Summary Background In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia. Methods In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020. Findings Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure. Interpretation The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection. Funding National Key R&D Program of China.
              Article 0 comments Cited 9341 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jaume Alijotas-Reig
                Journal
                Journal ID (nlm-ta): Autoimmun Rev
                Journal ID (iso-abbrev): Autoimmun Rev
                Title: Autoimmunity Reviews
                Publisher: Published by Elsevier B.V.
                ISSN (Print): 1568-9972
                ISSN (Electronic): 1873-0183
                Publication date PMC-release: 3 May 2020
                Publication date (Electronic): 3 May 2020
                Electronic Location Identifier: 102569
                Affiliations
                [a ]Systemic Autoimmune Diseases Unit, Department of Internal Medicine-1, Vall d’Hebron University Hospital, Barcelona, Spain
                [b ]Systemic Autoimmune Research Unit, Vall d’Hebron Reseacrh Institute, Spain
                [c ]Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
                [d ]Department of Internal Medicine, Althaia Network Health, Manresa, Barcelona, Spain
                [e ]Universitat Central de Catalunya, Spain
                [f ]Vascular and Coagulation Department, University Hospital Angers, Angers, France
                [g ]UMR CNRS 6015, Angers, France
                [h ]INSERM U1083, Angers, France
                [i ]Universitat Autònoma de Barcelona, Barcelona, Spain
                [j ]Systemic Autoimmune Research Unit, Vall d’Hebron Research Institute, Barcelona, Spain
                [k ]Service de Médecine Interne, Centre de référence AO Bradykiniques et compétence Maladies Auto-immunes FAI2R, Hôpital Saint Antoine Hôpitaux Universitaires de l'Est Parisien, Professeur des Universités-Praticien Hospitalier Sorbonne Université, France
                Author notes
                [* ]Corresponding author at: Systemic Autoimmune Diseases Unit, Department of Internal Medicine-1, Vall d'Hebron University Hospital, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain. jalijotas@ 123456vhebron.net
                Article
                Publisher ID: S1568-9972(20)30131-2 Publisher ID: 102569
                DOI: 10.1016/j.autrev.2020.102569
                PMC ID: 7252146
                PubMed ID: 32376394
                SO-VID: 0de1dab9-719c-499a-a3f8-c63fb4d94976
                Copyright © © 2020 Published by Elsevier B.V.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 14 April 2020
                Date accepted : 15 April 2020
                Categories
                Subject: Article

                ScienceOpen disciplines: Immunology
                Keywords: acute respiratory distress syndrome,covid-19,cytokine storm,immunosuppressive,sars-cov-2,treatment,ace-2, angiotensin-converting enzyme-2,ad, autoimmune diseases,ade, antibody dependent enhancement,adrs, acute distress respiratory syndrome,apc, antigen-presenting cells,apl, antiphospholipid antibodies,cd, cluster of differentiation or cluster of designation or classification determinant,cdc, centres for disease control,covid-19, coronavirus disease 2019,cq, chloroquine,cya, cyclosporine a,fda, food and drugs administration,gcs, glucocorticoids,hcq, hydroxychloroquine,hps, haemophagocytic syndrome,ifnγ, interferon gamma,il, interleukin,jak, janus-kinase family of enzymes (jak1, jak2, jak3, tyk2),ivig, intravenous immunoglobulins,mda5, melanoma differentiation-associated gene 5,mhc-ii, major histocompatibility type-ii,lmwh, low-molecular weight heparin,mas, macrophage activation syndrome,mers-cov, middle east respiratory syndrome coronavirus,mtor, mammalian target of rapamycin,nhc, national health council,nk, natural killer cells,nf-kβ, nuclear factor-kβ,pic, pulmonary intravascular coagulation,pte, pulmonary thromboembolism,ra, rheumatoid arthritis,sars-cov-2, severe acute respiratory syndrome coronavirus-2,sle, systemic lupus erythematosus,tcz, tocilizumab,tlr, toll-like receptor,tnf-α, tumour necrosis factor-alpha,traasvir, thrombotic risk associated with antiphospholipid syndrome after viral infection,trali, transfusion-related acute lung injury,tgf-β, transforming growth factor-beta,tregs, regulatory t-cells,who, world health organization
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: acute respiratory distress syndrome, covid-19, cytokine storm, immunosuppressive, sars-cov-2, treatment, ace-2, angiotensin-converting enzyme-2, ad, autoimmune diseases, ade, antibody dependent enhancement, adrs, acute distress respiratory syndrome, apc, antigen-presenting cells, apl, antiphospholipid antibodies, cd, cluster of differentiation or cluster of designation or classification determinant, cdc, centres for disease control, covid-19, coronavirus disease 2019, cq, chloroquine, cya, cyclosporine a, fda, food and drugs administration, gcs, glucocorticoids, hcq, hydroxychloroquine, hps, haemophagocytic syndrome, ifnγ, interferon gamma, il, interleukin, jak, janus-kinase family of enzymes (jak1, jak2, jak3, tyk2), ivig, intravenous immunoglobulins, mda5, melanoma differentiation-associated gene 5, mhc-ii, major histocompatibility type-ii, lmwh, low-molecular weight heparin, mas, macrophage activation syndrome, mers-cov, middle east respiratory syndrome coronavirus, mtor, mammalian target of rapamycin, nhc, national health council, nk, natural killer cells, nf-kβ, nuclear factor-kβ, pic, pulmonary intravascular coagulation, pte, pulmonary thromboembolism, ra, rheumatoid arthritis, sars-cov-2, severe acute respiratory syndrome coronavirus-2, sle, systemic lupus erythematosus, tcz, tocilizumab, tlr, toll-like receptor, tnf-α, tumour necrosis factor-alpha, traasvir, thrombotic risk associated with antiphospholipid syndrome after viral infection, trali, transfusion-related acute lung injury, tgf-β, transforming growth factor-beta, tregs, regulatory t-cells, who, world health organization

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