Baricitinib for patients with severe COVID-19—time to change the standard of care?

AuthorsAlexander Supadya,c,d and Robert Zeiserb Lancet Respir Med. 2022 Feb 3doi: 10.1016/S2213-2600(22)00021-2 [Epub ahead of print]PMCID: PMC8813061PMID: 35123659

Mortality is high among patients with severe COVID-19 who require invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO).12 Therefore, further specific treatment options for these patients are urgently needed.

Early in the COVID-19 pandemic, Janus kinase (JAK) inhibitors were identified as potential therapeutic agents for the treatment of SARS-CoV-2 infections.34 JAK inhibitors, such as ruxolitinib, fedratinib, and baricitinib, have strong anti-inflammatory properties and are already in clinical use for the treatment of graft-versus-host disease, myelofibrosis, and rheumatoid arthritis.567

Two large, randomised, controlled trials have assessed the use of baricitinib in hospitalised patients with COVID-19.89 The Second Adaptive COVID-19 Treatment Trial (ACTT-2)8 showed that administration of baricitinib in combination with remdesivir shortened the time to recovery in hospitalised patients with COVID-19 compared with remdesivir alone. The COV-BARRIER trial9 did not show a significant benefit of baricitinib plus standard of care compared with placebo plus standard of care in the primary endpoint of disease progression by day 28. Nevertheless, although these were only secondary endpoints, 28-day mortality and 60-day mortality were significantly lower in patients who received baricitinib than in those who received placebo.

However, important questions remain, especially regarding the effect of baricitinib in patients with severe COVID-19 who require IMV or even ECMO. In the ACTT-2 trial, only 111 (11%) of 1033 patients were receiving IMV or ECMO at study inclusion; whereas in the primary COV-BARRIER trial, these severely affected patients were excluded.

In The Lancet Respiratory Medicine, E Wesley Ely and colleagues10 report the findings of an exploratory trial that followed the design of the COV-BARRIER trial and aimed to evaluate the efficacy and safety of baricitinib in addition to standard of care in critically ill hospitalised adults with COVID-19 who were receiving IMV or ECMO. Patients were randomly assigned to receive baricitinib 4 mg (n=51) or matched placebo (n=50) once daily for up to 14 days in addition to standard of care. All-cause mortality by day 28 was significantly lower in patients who received baricitinib than in those who received placebo (20 [39%] of 51 participants died in the baricitinib group vs 29 [58%] of 50 in the placebo group; hazard ratio [HR] 0·54 [95% CI 0·31–0·96]; p=0·030); this finding persisted through day 60 (23 events [45%] vs 31 [62%]; HR 0·56 [95% CI 0·33–0·97]; p=0·027). The authors concluded that baricitinib might represent a novel option for the reduction of mortality in patients with COVID-19, even in progressed disease stages (ie, when already receiving IMV or ECMO).

Although the assignment of participants to the treatment groups was randomised and masked, the mortality benefit determined in this exploratory trial should be interpreted with caution. Important baseline data for the assessment of disease severity and comparison of the study cohort with other cohorts were not provided, including duration of IMV and ECMO before study inclusion, ventilator settings, ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, and prognostic scores, such as Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score (SAPS) II, or Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP). Without these supporting data, it cannot be assumed that the study groups were balanced in terms of baseline disease severity and that quality of care was consistent across study locations. Therefore, the results from this study cannot match the level of evidence from a phase 3 randomised, controlled trial with well-defined primary and secondary endpoints, accompanying sample size estimations, and a prespecified statistical analysis plan.

Interestingly, the all-cause mortality by day 60 in the placebo group in this study was high (62%), despite the baseline use of corticosteroids in 44 (88%) of 50 patients in this group.10 A meta-analysis summarising data from more than 50 000 patients with COVID-19 receiving IMV showed a mortality of only 45%, although a large number of these patients were treated without corticosteroids at the beginning of the pandemic.1 Furthermore, by contrast with the findings from this trial, in ACTT-2, in the subgroup of patients receiving IMV or ECMO at baseline, who were randomly assigned to receive baricitinib (n=54) or placebo (n=57) in addition to remdesivir but without corticosteroids, there was no significant difference between the treatment groups with respect to the outcomes of recovery time or survival by day 28.8 These observations contradict the results of the study by Ely and colleagues. At this time, we can only speculate about the reasons for these conflicting results; possible explanations are a potential influence of the concomitant treatment with remdesivir, the effect of corticosteroids, or any other differences between the groups or the treatments they received.

Taken together, we believe that the level of evidence provided by the results from this study is not sufficient to change standard of care and introduce baricitinib into clinical routine for COVID-19 patients with severe respiratory failure. However, the results of this exploratory trial and the data from COV-BARRIER and ACTT-2 reflect clinical equipoise for the addition of baricitinib to standard of care for patients with severe COVID-19 requiring IMV or ECMO, and provide a sound basis for a well-designed phase 3 trial to confirm these findings.

Open in a separate windowCopyright © 2022 Dr Barry Slaven/Science Photo Library

AS reports research grants and lecture fees from CytoSorbents and lecture fees from Abiomed, outside of the submitted work. RZ reports lecture fees from Novartis, Incyte, and Mallinckrodt, outside of the submitted work.

References

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Evolution of NETosis markers and DAMPs have prognostic value in critically ill COVID-19 patients

  1. Authors: Joram HuckriedeSara Bülow AnderbergAlbert MoralesFemke de VriesMichael HultströmAnders BergqvistJosé T. Ortiz-PérezJan Willem SelsKanin WichapongMiklos LipcseyMarcel van de PollAnders LarssonTomas LutherChris ReutelingspergerPablo Garcia de FrutosRobert Frithiof & Gerry A. F. Nicolaes  Scientific Reports volume 11, Article number: 15701 (2021) Cite this article

Abstract

Coronavirus disease 19 (COVID-19) presents with disease severities of varying degree. In its most severe form, infection may lead to respiratory failure and multi-organ dysfunction. Here we study the levels and evolution of the damage associated molecular patterns (DAMPS) cell free DNA (cfDNA), extracellular histone H3 (H3) and neutrophil elastase (NE), and the immune modulators GAS6 and AXL in relation to clinical parameters, ICU scoring systems and mortality in patients (n = 100) with severe COVID-19. cfDNA, H3, NE, GAS6 and AXL were increased in COVID-19 patients compared to controls. These measures associated with occurrence of clinical events and intensive care unit acquired weakness (ICUAW). cfDNA and GAS6 decreased in time in patients surviving to 30 days post ICU admission. A decrease of 27.2 ng/mL cfDNA during ICU stay associated with patient survival, whereas levels of GAS6 decreasing more than 4.0 ng/mL associated with survival. The presence of H3 in plasma was a common feature of COVID-19 patients, detected in 38% of the patients at ICU admission. NETosis markers cfDNA, H3 and NE correlated well with parameters of tissue damage and neutrophil counts. Furthermore, cfDNA correlated with lowest p/f ratio and a lowering in cfDNA was observed in patients with ventilator-free days.

Introduction

In severe cases, COVID-19 disease develops into acute respiratory distress syndrome (ARDS), an acute lung injury causing patients to be dependent of ventilator support, which may be accompanied by development of multiple organ failure (MOF)1. Mortality is seen primarily in patients over the age of 652,3,4,5 and is highest for infected individuals with underlying comorbidities such as hypertension, cardiovascular disease or diabetes6,7,8. For patients who are taken into the intensive care unit (ICU), a high SOFA (sequential organ failure assessment) score and increased levels of fibrin D-dimers have been reported9 to associate with poor prognosis. Thromboembolic complications develop in 35–45% of COVID-19 patients10, including thrombotic microangiopathies and disseminated intravascular coagulation (DIC) reminiscent of bacterial sepsis. Yet, COVID-19 has distinct features11 that point at a somewhat different pathological mechanism. The involvement of immune regulatory and hemostatic pathways appears evident, and recent findings have confirmed that the innate immune system and more in particular neutrophil extracellular traps (NETs) play a role in COVID-19 disease pathogenesis. NETs, networks of DNA fibers that are decorated with proteins such as histones and elastase, are released from neutrophils to bind and neutralize viral proteins, bacteria and fungi12. While extracellular histones and NE serve a protective, antimicrobial function, they are potentially harmful to the host.

NETs are abundant in lung capillaries13 and are known to be pro-coagulant due to their intrinsic capacity to activate platelets14.

Excessive NET production, initiated by several pathways that also include complement activation13, results in collateral damage to lung tissues, a disturbed microcirculation of the lung15, loss of alveolar-capillary barrier function and further release of pro-inflammatory cytokines16.

During the preparation of this work it was reported that cellular components that are released upon cellular disruption, so-called damage associated molecular patterns (DAMPs) and NETosis are involved in COVID-19 disease1718. This is fully in line with the observation that in ARDS, NETs contribute to disease progress19. Extracellular histones are cytotoxic DAMPs irrespective of their origin. They may appear during NETosis12,14,20 or originate from damaged tissues21, while cell free DNA (cfDNA) and the protease neutrophil elastase (NE) are released concomitantly22. Cellular free deoxyribonucleic acid (cfDNA) and histones promote proinflammatory cytokine release23,24. Histones have been shown to activate and recruit leukocytes25, damage alveolar macrophages26, activate erythrocytes27, epithelial and endothelial cells, in particular pulmonary endothelial cells28,29,30. If not cleared from circulation, cfDNA as well as histones facilitate severe systemic inflammation and worsen the clinical condition31,32. Presence of NE in plasma is associated with exacerbations, lung function decline and disease severity in patients with chronic obstructive pulmonary disease (COPD), bronchiectasis and cystic fibrosis33,34,35 and decrease of NE levels in bronchiectasis patients improved lung function and airway inflammation36.

At the same time that it provides a first line of defense against infections, the innate immune system initiates self-control responses to prevent damage to the host. One mechanism involved in early immunomodulation is the growth arrest-specific 6 (GAS6)/TAM ligand/receptor system37,38. The GAS6/AXL axis regulates the immune response by modulating cytokine production, inducing a reparative cellular response and by mediating efferocytosis, removing irreversibly damaged cells. The system also provides a mechanism of regulating endothelial and platelet activation and interaction39. Plasma concentrations of GAS6 and AXL increase in a diverse spectrum of inflammatory conditions40, including sepsis and septic shock; but also systemic inflammatory response syndrome (SIRS) without infection41. In several studies, GAS6 at IC admission correlated with severity of organ damage (i.e. SOFA) or with damage of specific organs41,42,43,44,45. This is also the case in viral infections46. These studies illustrate the modulatory role of the innate response provided by GAS6 and suggest that the presence of these components in plasma could be an early event in the orchestration of the immune response to viral infections.

cfDNA, extracellular histones and GAS6 are implicated in regulation of inflammatory and hemostatic pathways in the context of severe viral infections and ARDS, all of which are implicated in COVID-19. While other studies have reported the presence of DAMPs and NETosis markers in smaller COVID-19 populations, here we study a group of 100 severely ill COVID-19 patients admitted to the intensive care unit (ICU). Our hypothesis was twofold:

First, cfDNA, NE, histones and GAS6/AXL are activated in severe COVID-19. Second, cfDNA, NE, histones and GAS6/AXL are related to the severity of illness and reflect organ dysfunction in severe COVID-19.

For More Information: https://www.nature.com/articles/s41598-021-95209-x