Cytokine blockers

The hypothesis that quelling the cytokine storm with anti-inflammatory therapies directed at reducing interleukin-6 (IL-6), IL-1, or even tumour necrosis factor TNF alpha might be beneficial has led to several ongoing trials. It is suggestive that interleukin blocking strategies might improve the hyperinflammatory state seen in severe COVID-19. A recent review on this strategy, however, was less enthusiastic and urged caution (Remy 2020). Past attempts to block the cytokine storm associated with other microbial infections and with sepsis have not been successful and, in some cases, have worsened outcomes. Moreover, there is concern that suppressing the innate and adaptive immune system to address increased cytokine concentrations, could enable unfettered viral replication, suppress adaptive immunity, and delay recovery processes. There is growing recognition that potent immunosuppressive mechanisms are also prevalent in such patients. Following, we will briefly discuss the evidence on cytokine blockers.

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AcalabrutinibAnticomplement therapiesAzithromycinCamostatChloroquineColchicineConvalescent plasmaCorticosteroidsCytokine blockersFamotidineFavipiravirG-CSFHuman recombinant soluble ACE2HydroxychloroquineIbrutinibIloprostInterferonsJAK inhibitorsLeflunomideLopinavirMonoclonal antibodiesN-acetylcysteineOseltamivir(other) Protease inhibitors(other) RdRp inhibitorsREGN-COV2Umifenovir

Outlook | References

Anakinra (Kineret®) is an FDA-approved treatment for rheumatoid arthritis and neonatal onset multisystem inflammatory disease. It is a recombinant human IL-1 receptor antagonist that prevents the binding of IL-1 and blocks signal transduction. Anakinra is thought to abrogate the dysfunctional immune response in hyperinflammatory COVID-19 and is currently being investigated in almost 20 clinical trials. Some case series have reported on encouraging results.

  • A study from Paris, comparing 52 “consecutive” patients treated with anakinra with 44 historical patients. Admission to the ICU for invasive mechanical ventilation or death occurred in 25% of patients in the anakinra group and 73% of patients in the historical group. The treatment effect of anakinra remained significant in the multivariate analysis (Hayem 2020). According to the authors, their study was “not perfect from a statistical point of view…”
  • A retrospective cohort study at the San Raffaele Hospital in Milan, Italy, including 29 patients with moderate-to-severe ARDS and hyperinflammation (serum C reactive protein, CRP ≥ 100 mg/L) who were managed with non-invasive ventilation and HCQ and lopinavir/r (Cavalli 2020). At 21 days, treatment with high-dose anakinra was associated with reductions in CRP and progressive improvements in respiratory function in 21/29 (72%) patients.
  • Another small case series of critically ill patients with secondary hemophagocytic lymphohistocytosis (sHLH) characterized by pancytopenia, hypercoagulation, acute kidney injury and hepatobiliary dysfunction. At the end of treatment, ICU patients had less need for vasopressors and significantly improved respiratory function. Although 3/8 patients died, the mortality was lower than historical series of patients with sHLH in sepsis (Dimopoulos 2020).

Canakinumab (Illaris®) is human monoclonal antibody against IL-1β, approved for the treatment of juvenile rheumatoid arthritis and other chronic autoinflammatory syndromes. In a pilot trial, 10 patients with hyperinflammation (defined as CRP ≥ 50 mg/L) and respiratory failure showed a rapid improvement in serum inflammatory biomarkers and an improvement in oxygenation (Ucciferri 2020).

Infliximab (Remicade®) is a chimeric monoclonal anti-TNF antibody, approved to treat a number of autoimmune diseases, including Crohn’s disease, ulcerative colitis, rheumatoid arthritis and psoriasis. As a major component of deteriorating lung function in patients with COVID-19 is capillary leak, a result of inflammation driven by key inflammatory cytokines such as TNF, making TNF-blocking agents an attractive strategy (Robinson 2020). Administration of anti-TNF to patients for treatment of autoimmune disease leads to reductions in all of these key inflammatory cytokines. A small case series of seven patients who were treated with a single infusion of IFX (5 mg/kg body weight) has been reported (Stallmach 2020).

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Epidemiology | Transmission | Prevention | Virology | Immunology | Diagnosis | Clinical Manifestations | Treatment | Severe COVID-19 | Comorbidities / Special Populations | Pediatrics| Timeline | Preface

Mavrilimumab is an anti-granulocyte–macrophage colony-stimulating factor (GM-CSF) receptor-α monoclonal antibody. GM-CSF is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases (Mehta 2020). In small uncontrolled pilot trial on 13 patients, mavrilimumab treatment was associated with improved clinical outcomes compared with standard of care in non-mechanically ventilated patients with severe COVID-19 pneumonia and systemic hyperinflammation. Treatment was well tolerated (De Luca 2020).

Tocilizumab (TCZ, RoActemra® or Actemra®) is a monoclonal antibody that targets the interleukin-6 receptor. It is used for rheumatic arthritis and has a good safety profile. The initial dose should be 4-8 mg/kg, with the recommended dosage being 400 mg (infusion over more than 1 hour). Several RCTs are underway. Of note, the current level of evidence supporting the use of TCZ is weak.

  • In a retrospective cohort of COVID-19 patients who required ICU support, deaths occurred in 102/210 (49%) patients with TCZ and in 256/420 (61%) who did not receive TCZ (Biran 2020). After propensity matching, an association was noted between receiving TCZ and decreased mortality (HR 0.64, 95% CI 0.47–0.87).
  • In another cohort from Italy (Guaraldi 2020), fewer deaths occurred in 179 patients treated with TCZ compared to 365 patients without TCZ (7% vs 20%). After adjustment for sex, age, duration of symptoms, and SOFA score, TCZ treatment was associated with a reduced risk of ventilation or death (adjusted HR 0.61, 95% CI 0.40–0.92).
  • A large multicenter cohort included 3924 critically ill patients admitted to ICU at 68 hospitals across the US (Gupta 2020). The risk of in-hospital death was lower with TCZ (29% versus 41%). However, TCZ patients were younger and had fewer comorbidities. According to the authors, the findings “may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed”.
  • On July 29, Hoffmann-La Roche announced disappointing results from its much-anticipated Phase III COVACTA trial. TCZ did not improve patient mortality, although patients spent roughly a week less in hospital compared with those given placebo (the full results of the trial have not yet been published). However, it may be too early to quit this strategy (Furlow 2020). Cautious interpretation of COVACTA is needed, in view of the study’s broad patient selection criteria and other study design factors.
  • A double-blind, placebo-controlled RCT in 243 moderately ill hospitalized patients, TCZ was not effective for preventing intubation or death (Stone 2020).
  • An open label RCT in 126 patients hospitalized with COVID-19 pneumonia, the rate of the primary clinical endpoint (clinical worsening) was not significantly different between the control group and the TCZ group (Salvarani 2020). The proportion of patients discharged within 14 and 30 days was the same. According to the authors, however, their results “do not allow ruling out the possible role of tocilizumab in reducing the risk of death or intubation in patients presenting with more advanced disease”.


Siltuximab (Sylvant®) is another anti-IL-6-blocking agent. However, this chimeric monoclonal antibody targets interleukin-6 directly and not the receptor. Siltuximab has been approved for idiopathic multicentric Castleman’s disease (iMCD). In these patients it is well tolerated. First results of a pilot trial in Italy (“SISCO trial”) have shown encouraging results. According to interim interim data, presented on April 2 from the first 21 patients treated with siltuximab and followed for up to seven days, one-third (33%) of patients experienced a clinical improvement with a reduced need for oxygen support and 43% of patients saw their condition stabilise, indicated by no clinically relevant changes (McKee 2020).

Sarilumab (Kevzara®) is another recombinant human IL-6 receptor antagonist. An open-label study of sarilumab in severe COVID-19 pneumonia with hyperinflammation. Sarilumab 400 mg was administered intravenously in addition to standard of care to 28 patients and results were compared with 28 contemporary matched patients treated with standard of care alone. At day 28, 61% of patients treated with sarilumab experienced clinical improvement and 7% died. These findings were not significantly different from the comparison group. However, sarilumab was associated with faster recovery in a subset of patients showing minor lung consolidation at baseline (Della-Torre 2020).

Vilobelimab is an anaphylatoxin and complement protein C5a blocking monoclonal antibody. In an open-label, randomized Phase II trial (part of the PANAMO trial), 30 patients with severe COVID-19 were randomly assigned 1:1 to receive vilobelimab (up to seven doses of 800 mg intravenously) or best supportive care only (control group). At day 5 after randomization, the primary endpoint of mean relative change in the ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO2/FiO2) was not significantly different between groups. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0–31) for the vilobelimab group and 27% (4–49) for the control group. The frequency of serious adverse events was similar between groups and no deaths were considered related to treatment assignment. According to the authors, the secondary outcome results support the investigation of vilobelimab in a Phase III trial using 28-day mortality as the primary endpoint. Pharmacokinetic and pharmacodynamic data, including C5a, have not yet been published (Campbell 2020). Investigators using the other C5 complement pathway inhibitors eculizumab and ravulizumab have significantly increased their dose and dosing frequency in the acute setting of COVID-19 compared with the doses approved for use in atypical hemolytic uremic syndrome.

By Christian Hoffmann