key: cord-332480-3uodkrkp
authors: Bonam, Srinivasa Reddy; Kaveri, Srini V.; Sakuntabhai, Anavaj; Gilardin, Laurent; Bayry, Jagadeesh
title: Adjunct immunotherapies for the management of severely ill COVID-19 patients
date: 2020-04-30
journal: Cell reports medicine
DOI: 10.1016/j.xcrm.2020.100016
sha: 
doc_id: 332480
cord_uid: 3uodkrkp

Abstract Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has infected millions with more than 181,000 fatal cases as of 22nd April 2020. Currently, there are no specific COVID-19 therapies. Most patients depend on mechanical ventilation. Current COVID-19 data clearly highlight that cytokine storm and activated immune cell migration to the lungs characterize the early immune response to COVID-19 that causes severe lung damage and development of acute respiratory distress syndrome. In view of uncertainty associated with immunosuppressive treatments such as corticosteroids and their possible secondary effects, including risks of secondary infections, we suggest immunotherapies as an adjunct therapy in severe COVID-19 cases. Such immunotherapies based on inflammatory cytokine neutralization, immunomodulation and passive viral neutralization, not only reduce inflammation, inflammation-associated lung damage, or viral load, but could also prevent intensive care unit hospitalization and dependency on mechanical ventilation both of which are limited resources.

Coronavirus disease 2019 (COVID-19) is caused by "Severe Acute Respiratory Syndrome Coronavirus 2" (SARS-CoV-2). It has affected over 2.6 million people with more than 181,000 fatal cases as of 22 nd April 2020 (https://coronavirus.jhu.edu/map.html). While the majority of cases result in mild symptoms such as fever and cough, about 10-15% progress to severe pneumonia and respiratory failure requiring intensive care unit hospitalization and mechanical ventilation. The death rate in intensive care unit (ICU) admitted patients could reach up to 26%.

Age and other health problems such as chronic pulmonary or cardiac disease conditions are the risk factors that determine the mortality rate. [1] [2] [3] [4] A systematic review and meta-analysis confirmed that old age and/or associated comorbidity are the common risk factors that predict death in all three major respiratory diseases caused by coronaviruses including COVID-19, Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). 5 Obesity is another risk factor for the development of severe SARS-CoV-2. 6 Though anti-viral molecules and hydroxychloroquine are under investigation to avert severe disease, [7] [8] [9] [10] [11] currently, there are no specific therapies for COVID-19, particularly when severe acute respiratory distress syndrome (ARDS) occurs. Most COVID-19 patients with ARDS required intensive care unit hospitalization and prolonged supportive mechanical ventilator management. 1, 2, 4 ARDS can lead to other complications, including secondary bacterial infection and lung fibrosis.

Recent clinical data suggest that severe COVID-19 is due to an overreactive immune response leading to a cytokine storm and development of acute respiratory distress syndrome. 12, 13 Plasma obtained from COVID-19 patients, in particular moribund patients, demonstrated increased concentrations of various inflammation-related cytokines and chemokines implicated in the recruitment of immune cells including interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-2, IL-6, IL-7, IL-8, IL-9, IL-17, granulocyte-colony stimulating factor (G-CSF), granulocytemacrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, C-X-C motif chemokine 10 (CXCL10), chemokine ligand 2 (CCL2), CCL3 and CCL4. 1, 14, 15 In addition, COVID-19 patients showed relatively increased neutrophil counts in the blood. 15 On the other hand, monocytes, basophils and T cells, especially CD4 + and CD8 + T cells, were decreased in the peripheral blood, possibly due to their migration to the lungs. [13] [14] [15] [16] [17] However, these T cells exhibited enhanced activated markers (CD69, CD38 and CD44). 17 Single-cell RNA sequencing of bronchoalveolar lavage (BAL) fluid immune cells from a small number of mild to severely ill COVID-19 patients suggested that balance in the lung macrophage populations is highly dysregulated in severely ill COVID-19 patients. These data indicate that monocyte-derived macrophages (FCN1 + ) rather than FABP4 + alveolar macrophages contribute to lung inflammation and lung damage in severe cases. 18 This study thus confirms another report based on lung postmortem biopsy of a patient that revealed the presence of bilateral diffuse alveolar damage and recruitment of monocytes. 13 The study by Liao et al. also observed an increased proportion of clonally expanded CD8 + T cells in the BAL fluid of mild cases as compared to severe cases. 18 Another investigation that compared BAL fluid immune cells in various respiratory pathologies highlighted a more prominent surge of neutrophils in COVID-19 patients as compared to pneumonia caused by other pathogens. 19 By metatranscriptome sequencing of BAL fluid and global functional analyses of differentially expressed genes, this report also identified strong upregulation of numerous type I IFN-inducible genes. 19 However, caution needs to be exercised while interpreting these data due to potential influence of therapies such as IFNα-2b, ant-viral and/or steroids on the landscape of immune cells and immune signatures of BAL fluid or lungs. Nevertheless, these reports confirm the proposition that an influx of immune cells to the lungs follows SARS-CoV-2 infection (Figure 1 ).

Severely ill COVID-19 patients also displayed reduced peripheral blood regulatory T cells (Tregs), the immune suppressor cells critical for reducing inflammation and inflammationassociated tissue damage. 15 Another report suggested that activated GM-CSF + IFNγ + pathogenic Th1 cells that secrete GM-CSF promote inflammatory CD14 + CD16 + monocyte responses with enhanced IL-6. 17 GM-CSF + IFNγ + Th1 cells and inflammatory monocytes were positively correlated with the severe pulmonary syndrome characteristic of COVID-19 patients. 17 The simultaneous increase in IL-1 receptor antagonist (IL-1RA) and IL-10 also suggest that antiinflammatory responses, though induced, are not sufficient to reduce inflammation and eventually lead to severe lung damage.

Various reports have shown that higher inflammation-related biomarkers such as plasma Creactive protein (CRP), ferritin and IL-6 were significantly associated with higher risks of developing ARDS. [20] [21] [22] [23] [24] Of note, IL-6 levels were associated with course of the disease and death from COVID-19. 20 5 The massive increase in plasma ferritin levels is indicative of haemophagocytic lymphohistiocytosis activation syndrome in these patients. These studies thus provide a rationale for targeting inflammatory mediators for the management of severely ill COVID-19 patients.

Currently, there is no clear evidence for the use of steroids in SARS-CoV-2 infections and their use is highly debated, particularly with respect to the window of treatment, dose and management of patients in cases of bacterial co-infection. A retrospective cohort analysis of 201 patients from Wuhan suggested that methylprednisolone might benefit patients who develop ARDS (n=88) by reducing the death rate. 20 A retrospective analysis of hospitalized patients with severe COVID-19 pneumonia (n=46) indicated that an early low-dose steroid therapy (1-2 mg/kg/day) in 26 patients for a short duration (5-7 days) reduced the oxygen requirement period and improved disease course. 25 However, COVID-19 patients treated with methylprednisolone were sicker and had a higher pneumonia severity index than those patients who did not receive methylprednisolone. 20 Recently, an additional retrospective matched case-control study involving 31 paired patients in several ICUs in China showed that treatment with steroids for 8 days (4-12 days) in addition to antiviral drugs was associated with a 39% 28-day death rate, compared to 16% in a propensity score matched control group. 26 Clinical evidence is also lacking for the use of steroids in other coronavirus diseases (SARS-CoV, MERS-CoV), 27, 28 and steroids might even impair viral clearance mechanisms of patients and predispose them to secondary infections. Double-blinded randomized clinical trials involving a large number of patients should be conducted to evaluate the use of steroids in severely ill COVID-19 patients with reduction in intensive care unit requirement as the primary endpoint.

Therefore, as per WHO interim guidance of 13 th March 2020, 29 and some local guidelines (covidprotocols.org), 30 steroids are not recommended at present as a treatment for COVID-19. If steroids are used for a particular pathological condition, low dose and short duration of treatment is recommended. Similarly, as per a survey from the French National Agency for Medicines and Health Products Safety (ANSM), non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen are also not recommended due to infectious complications and kidney, cardiac and gastrointestinal adverse effects. 31 In view of an uncertain prognosis and complications due to generalized immunosuppression from corticosteroid and NSAID treatment, immunotherapies based on immunomodulatory approaches appear promising in the treatment of COVID-19 to regulate inflammation and antiviral immune responses. We believe that the immunotherapies discussed next could result in a quicker therapeutic response with minimal adverse effects.

The current clinical data on COVID-19 patients clearly highlight that cytokine storm and an influx of activated immune cells to the lungs characterize the early immune response to COVID-19 that causes severe lung damage. Therefore, we suggest host-directed immunotherapies as an adjunct therapy in severe cases to not only reduce inflammation and inflammation-associated lung damage, but also to prevent ICU hospitalization and dependency on mechanical ventilation that are limited resources in the context of SARS-CoV-2 pandemic. In fact, several immunotherapeutic approaches that target either inflammatory mediators, passively neutralize SARS-CoV-2, or prevent viral entry are under evaluation at various centers (Table 1 patients. 27, 32, 33 

An increase in IL-6 leading to lung tissue damage has been observed in a majority of the COVID-19 patients. 13, 14, 16, 17 Of note, similar to severely ill COVID-19 cases, elevated serum levels of IL-6, TNF-α and IFN-γ have been consistently observed in cytokine release syndrome (CRS) that is common in the patients receiving T cell-engaging immunotherapies (bispecific antibody constructs or chimeric antigen receptor (CAR) T cell therapies). 34 Targeting either IL-6 (siltuximab, a chimeric monoclonal antibody) or IL-6 receptor (tocilizumab, a recombinant humanized monoclonal antibody) led to rapid resolution of CRS symptoms in those patients. 34 Severe CRS can also lead to hypotension, pulmonary edema and cardiac dysfunction that are commonly observed in severely ill COVID-19 patients. These data provide justification for targeting IL-6 in severely ill COVID-19 patients.

Both anti-IL-6 receptor antibodies (tocilizumab, and a human monoclonal antibody sarilumab (Kevzara®)), and anti-IL-6 antibody siltuximab (Sylvant®) are under evaluation in COVID-19 patients at various centers (Table 1 ). An immunosuppressed patient with severe COVID-19related lung disease was successfully treated with tocilizumab and therapy led to a partial decrease in the pulmonary infiltrates. 35 Unpublished data based on off-label use of tocilizumab along with lopinavir and methylprednisolone in 21 severely ill COVID-19 patients suggested that the addition of tocilizumab not only quickly reduced their clinical symptoms (fever, oxygen requirement) and inflammation, but also normalized peripheral blood T cell counts in the majority of patients. 36 Additional targets include TNF-α (infliximab, a chimeric monoclonal antibody to TNF-α;

etanercept, a recombinant fusion TNF-R that binds soluble TNF-α) and IFN-γ (emapalumab, a fully human IgG1 monoclonal antibody against IFN-γ) ( Table 1) . Of note, clinical trials in idiopathic pneumonia syndrome have reported favorable response to etanercept therapy. 37, 38 GM-CSF represents another target for severe cases of COVID-19. GM-CSF stimulates the influx of granulocytes and monocytes from bone marrow, and hence further enhances inflammatory responses. A randomized Phase 1b/2, double-blind, placebo-controlled clinical trial is currently recruiting patients to investigate the therapeutic efficacy of a humanized anti-GM-CSF IgG1 monoclonal antibody TJ003234 in severely ill COVID-19 patients (NCT04341116). In addition, another human monoclonal antibody that targets GM-CSF (gimsilumab; Roivant Sciences Ltd., Altasciences Co. Inc.) is under consideration for treating ARDS in COVID-19 patients. 39, 40 Likewise, baricitinib, a selective Janus kinase (JAK1/JAK2) inhibitor, inhibits gp130 family cytokines (such as IL-6, IL-12, IL-23 and IFN-γ). 41 In addition, baricitinib inhibits the AP2associated protein kinase 1 and cyclin G-associated kinases that are regulators of viral endocytosis process and hence could block viral infection of cells. 41 Similarly, anakinra (Kineret®), a recombinant human IL-1RA and FDA-approved Janus kinase 2 inhibitor, fedratinib (Inrebic®) also possess the capacity to suppress inflammation (Table 1) . 42 Though, JAK inhibitors can impair type I IFN-mediated anti-viral responses, recent data from metatranscriptome sequencing of BAL fluid from eight COVID-19 patients highlight that SARS-CoV-2 induces strong type I IFN responses with an overexpression of a large number of type I IFN-inducible genes implicated in inflammation. 19 Therefore, use of JAK inhibitors might help in alleviating inflammation, but dose and window of treatment should be tailored to ensure that anti-viral response of the patient is not totally curtailed.

Type I IFN (β1α and β2α) is under consideration for severe COVID-19 ( Table 1) . Type I IFN signals through JAK-STAT (signal transducers and activators of transcription) pathway and upregulates IFN-stimulated genes that kill viruses in the infected cells. Our knowledge on the role of type I IFN in the pathogenesis of SARS-CoV-2 infection is not complete. Current evidence, however, reveals an overexpression of a large number of type I IFN-inducible genes with immunopathogenic potentials in COVID-19 patients. 19 Also, results on the use of IFN-α in SARS patients are inconclusive. 27 Therefore, care should be taken regarding the dosage of type I IFN and timing of treatment to avoid deleterious effects.

Additional immunotherapies that could be considered for COVID-19 include immunomodulators that have broad anti-inflammatory effects such as pooled normal IgG or intravenous immunoglobulin (IVIG) therapy. Obtained from the pooled plasma of several thousand healthy donors, IVIG is one of the most widely used immunotherapies for a large number of autoimmune and inflammatory diseases. 43, 44 A recent open-label trial in three patients reported benefits of IVIG therapy (0.4 g/kg for five days) in severe SARS-CoV-2-induced pneumonia 45 thus providing another option for the management of COVID-19 patients. Another multicenter retrospective cohort study indicated that IVIG therapy could benefit critical COVID-19 patients, but dose (0.1-0.5 g/kg) and duration of therapy (5-10 days) were too variable. 46 However, grouping of patients based on the dose of IVIG (>15g/day or ≤15g/day) and timing of infusion (>7 or ≤7 days since hospitalization) implied that beneficial effects are associated with high dose and early IVIG treatment. 46 A retrospective study on 58 severe or critically ill cases of COVID-19 also found that adjunct therapy with IVIG within 48 hours of hospitalization reduced hospital stay and ventilator use, and improved 28-day mortality. 47 Other than IL-6 and CRP, inflammatory parameters following IVIG immunotherapy were not evaluated in detail in these patients. 46 Based on the vast literature on the mechanisms of IVIG, we suggest that IVIG suppresses the activation and secretion of inflammatory cytokines from the innate immune cells, blocks the inflammatory Th1 and Th17 responses, exerts scavenging effects on complement cascade and possibly enhances Tregs. 48, 49 In addition, IVIG contains antibodies to diverse pathogens and their antigens, 50, 51 and hence secondary infections could also be prevented in IVIG-treated patients.

Though these studies provide a pointer for initiating a randomized clinical trial with a large number of patients (NCT04261426) ( Table 1) , certain key aspects need to be considered. First, the cost associated with IVIG immunotherapy could be considered prohibitive, and second, the necessity to reserve IVIG for patients whose survival essentially depends on this immunotherapy, particularly primary immunodeficient patients, must be weighed. Currently, there is a worldwide shortage of IVIG and the COVID-19 pandemic will affect the collection of plasma from donors for IVIG production. Therefore, during this emergency period, providing IVIG to those patients who depend on it should take priority over initiating an IVIG trial in COVID-19 patients.

Studies on COVID-19 patients' sera confirmed the presence of seroconverted antibodies, such as IgG, IgM, and IgA with varying kinetics and sensitivities. 52, 53 Findings in a monkey SARS-CoV-2 infection model confirmed that primary infection could protect the host from reinfection perhaps aided by humoral immune responses. 54 Therefore, passive immunization of SARS-CoV-2 by using convalescent plasma, intravenous hyperimmune globulin (containing high concentrations of neutralizing antibodies obtained from the pooled plasma of large number of recovered patients) or neutralizing monoclonal antibodies represent another potential therapeutic option.

A meta-analysis reported a significantly reduced mortality rate in SARS-CoV-infected patients following infusion of convalescent plasma. These patients recorded a rapid decline in their virus load. 55 Although not conclusive, a report with MERS-CoV also suggested that the use of convalescent plasma could be an option for COVID-19. 56 Similarly, a meta-analysis of patients with Spanish influenza pneumonia concluded that influenza-convalescent human blood products reduced the death risk. 57 Hyperimmune globulin treatment in severe H1N1 influenza within five days of symptoms also reduced viral load and mortality in patients. 58 represent an additional possibility. 63, 64 It is important to validate the neutralizing activity of aforementioned plasma or antibody preparations before using with COVID-19 patients; particularly in the case of convalescent plasma as neutralizing activity might significantly differ in mildly vs. severely ill patients.

Because, neutralizing monoclonal antibodies or hyperimmune globulins are pre-validated for their neutralizing activity, they do not pose such a dilemma. It is essential to note that the median seroconversion time for IgM and IgG was day 12 and day 14 respectively following onset of COVID-19. 65, 66 At day-15 following onset of disease, the presence of antibodies was 94.3% in case of IgM and 79.8% for IgG. 65 Therefore, convalescent plasma and hyperimmune globulins should be collected at least three-weeks post SARS-CoV-2 infection to increase the chances of obtaining high titer neutralizing antibodies.

A preliminary report from China suggested that convalescent plasma therapy leads to improvement in 91 of 245 COVID-19 patients treated. 67 An uncontrolled trial on transfusion of 400 mL of convalescent plasma (with viral neutralizing titers more than 1:40) in five patients critically ill with COVID-19 led to resolution of pulmonary lesions, and reduction in the severity of the disease and viral loads. 68 Similarly, treatment of ten severely ill COVID-19 patients with 200 mL of convalescent plasma containing viral neutralizing antibody titers more than 1:640 (A dilution of plasma that neutralized 100 TCID 50 (50% tissue-culture-infective dose) of SARS-CoV-2) led to reduced CRP levels, undetectable viremia and improved clinical symptoms. 69 Several randomized Phase 2 and 3 clinical trials are already planned with convalescent plasma or hyper immunoglobulin in many centers ( Table 1 ) and the plasma fractionation industry has offered support for such efforts. 70, 71 Meplazumab, a humanized anti-CD147 IgG2 monoclonal antibody is under evaluation for COVID-19 pneumonia. 72 This antibody therapy was aimed at preventing CD147-mediated SARS-CoV-2 viral entry and T cell chemotaxis. Preliminary data in a small number of patients indicated that meplazumab improved clinical course of the disease, and normalized the peripheral lymphocyte count and CRP level. 72

Tregs are classically known to suppress anti-microbial protective immunity by affecting the activation of both innate and adaptive immune cells. However, Tregs are also important for preventing inflammation-associated tissue damage in acute infections. 73 IL-2-based therapies to expand Tregs: IL-2 complexed to a monoclonal antibody that recognizes the CD122/γc (dimeric IL-2 receptor) epitope of IL-2 was constructed in order to selectively activate Tregs that constitutively express trimeric IL-2R (dimeric IL-2 and CD25). This monoclonal antibody-IL-2 complex displayed promising results in experimental models of several autoimmune and inflammatory diseases. 75 Recently, a human anti-IL-2 antibody named F5111.2 has been designed that potentiates Tregs by a structure-based mechanism wherein this antibody stabilizes IL-2 in a conformation that results in the preferential STAT5 phosphorylation of Tregs. 76 Though not yet tested in humans, such approaches could boost Treg number in COVID-19 patients and reduce inflammation. On the other hand, low dose-IL-2 therapy has been explored in the clinic for several autoimmune diseases to expand Tregs. 77 But due to the fact that COVID-19 patients are reported to have high IL-2 in the blood, this option might not be useful.

Our opinion is that neutralization of cytokines or immunomodulatory therapies are preferred over Treg expansion strategies in view of the fact that due to cytokine storm, Tregs might not be fully functional unless inflammatory cytokines are nullified. 

Currently, cellular therapies have not been given much consideration for COVID-19, possibly due to uncertainties of such approaches, time and economic reasons. Nevertheless, because of their anti-viral effector functions, several NK cell-based approaches are under consideration.

Little is known about the efficacy of NK cell therapy in infectious diseases. Conventional treatment in combination with NK cells (twice a week, 0.1-2 x 10 7 NK cells/kg body weight) is under clinical evaluation (NCT04280224) ( Table 1) . However, the source of NK cells for the therapy is not precise in this trial. Recently, FDA has given permission to Celularity Inc, to investigate an universal NK cell therapy CYNK-001 in COVID-19 patients. 79 CYNK-001 contains human placental CD34 + stem cell-derived NK cells and are culture-expanded.

An innovative NK cell-based therapy with multipronged actions called NKG2D-ACE2 CAR-NK cell therapy is currently recruiting patients (NCT04324996) ( Table 1) . NKG2D-ACE2 CAR-NK cells secrete IL-15 (to ensure long-term survival of NK cells) and GM-CSF neutralizing scFv (to prevent CRS). In addition to clearance of virus-infected cells through ACE2, these NK cells can competitively inhibit SARS-CoV-2 infection of susceptible cells including alveolar epithelial cells. Although the strategy looks rational, toxicity due to clearance of virus-infected lung cells, should be closely monitored.

In addition to NK cell therapy, other cell-based therapies like SARS-CoV-2-specific T cell therapies are also on the horizon.

Many anti-viral drugs such as protease inhibitors (camostat mesilate, lopinavir/ritonavir, and darunavir/cobicistat), nucleoside analogues (remdesivir, ribavirin), neuraminidase inhibitors 10 Lopinavir/ritonavir, and remdesivir were also found to be effective for MERS-CoV and SARS-CoV. 8 Ribavirin however, did not show benefits for MERS-CoV and SARS-CoV and was associated with severe side effects like hemolytic anemia and liver dysfunction. 27, 32 The window of treatment is critical with anti-viral drugs, and they need to be used early in a disease. Late initiation of therapy with anti-viral drugs, particularly after 10-14 days post appearance of clinical symptoms, might lead to a poor outcome. 7 Though the study design and results were controversial, data from a small number of patients suggested utility of hydroxychloroquine for COVID-19 treatment. 11 The follow-up study by the same group in a cohort of 1061 COVID-19 patients demonstrated that a hydroxychloroquine and azithromycin combination when given during the early phase of the disease, prevents aggravation of the disease and viral persistence. 80 Further details of this study are awaited. A randomized trial also observed improved pneumonia in hydroxychloroquine-treated patients. 81 Chloroquine and hydroxychloroquine possess an unique ability to increase the pH of lysosomes and hence prevent SARS-CoV-2 viral fusion and replication. In vitro studies on chloroquine suggested anti-SARS-CoV-2 effects of these molecules. 82, 83 Interestingly, previous studies have demonstrated anti-inflammatory activity of chloroquine for the treatment of autoimmune diseases. But other clinical trials did not support the use of hydroxychloroquine, particularly in hospitalized COVID-19 patients with hypoxic pneumonia or severe COVID-19 cases. 84, 85 Therefore, it appears that any efficacy hydroxychloroquine might have requires that it be given during the early phase of COVID-19 before progression to more severe disease. However, due to side effects, particularly cardiac, it is recommended to use chloroquine and hydroxychloroquine under strict medical surveillance. More evidence from randomized clinical trials is required

The immediate surge in COVID-19 positive cases prompted clinicians all around the world to explore a range of therapeutic interventions for severely ill COVD-19 patients. Due to the lack of specific therapies and time required to develop potent vaccines for SARS-CoV-2, current investigations are focused on available anti-viral drugs.

As inflammation is the hallmark of SARS-CoV-2 infections, immunotherapies that target various players of inflammation are currently being investigated. We propose that a combination of antiviral drugs and anti-inflammatory immunotherapies during early phase of the disease would function in a synergistic manner and provide maximum benefits. Anti-viral drugs would reduce the viral load and hence lessen the stimuli for inflammatory responses, while immunotherapies would correct the dysregulated inflammatory response and prevent lung damage. Care must be taken regarding an appropriate window of treatment and selecting the dose of anti-inflammatory immunotherapies as excessive suppression of inflammation might reduce the capacity of the patient to mount anti-viral responses. Data from randomized trials are urgently needed to confirm the utility of the aforementioned immunotherapies in the management of critically ill COVID-19 patients.

The majority of the articles referred to in this manuscript are unpublished and have not yet undergone the peer-review process. They were obtained from the various preprint servers. 

An overreactive immune response, cytokine storm and development of acute respiratory distress syndrome characterize severe cases of COVID-19. Bonam et al. present a Perspective on diverse immunotherapeutic approaches based on the neutralization of inflammatory cytokines, immunomodulation and passive viral neutralization for treating severely ill COVID-19 patients.

• Inflammation is the hallmark of SARS-CoV-2 infection

• Cytokine storm characterizes severely ill COVID-19 cases

• Immunotherapies represent promising options for the management of severe COVID-19

• Immunotherapies either neutralize cytokines, SARS-CoV-2 or exert immunomodulation

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We thank three anonymous reviewers for their suggestions. Supported by the Institut National de 

The authors declare no competing interests