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Sequential Use of Sarilumab and Baricitinib in Severe COVID-19 Pneumonia: A Case Report

Background: Severe COVID-19 associated pneumonia patients may exhibit features of systemic hyperinflammation. Both anti-IL-6 and anti-JAK drugs are curently under investigation for the hyperinflammatory syndrome of COVID-19 disease. Here we report a clinical case with a complete panel of cytokine levels and immunological profiling of T cell, plasmacytoid and myeloid dendritic cells. Case Presentation: An adult patient with severe COVID-19 pneumonia and documented hyper-inflammation has been treated with antivirals and off-label sarilumab intravenously, with poor response. Subsequently, he was treated with off-label oral baricitinib for 14 days, with clinical, radiological and laboratoristic response, measured also with IL1b, IL-6, IL-8 and TNF-a levels. Conclusions: Baricitinib was well tolerated and was able to reduce the inflammatory mediators, confirming its role in diminishing the excessive inflammatory response. This case is the first presented with an extensive characterization and shows a possible use of baricitinib as rescue therapy, after anti-IL6 treatment, for COVID-19.


Introduction
The pandemic expansion of coronavirus disease 2019 (COVID-19) presents an extraordinary challenge to identify possible effective drugs for treatment. COVID-19 infection results in a complex disease and COVID-19 associated pneumonia may provoke respiratory failure from acute respiratory distress syndrome (ARDS) and systemic hyperinflammation with cytokine storm syndrome, probably triggered by Sars-Cov-2 itself [1]. In fact, high concentrations of cytokines were recorded in plasma of critically ill patients infected, especially IL (interleukin)-6, IL-2, IL-7, IL-10, granulocyte-colony stimulating factor, interferon-γ-inducible protein, monocyte chemoattractant protein-1, Macrophage Inflammatory Proteins 1A and Tumor Necrosis Factor-α (TNF-α), and it has been hypothesized that the cytokine storm could be associated with disease severity [2]. Consequently, possible treatment strategies should be aimed not only to eliminate the virus but also to block the hyperinflammatory syndrome [3].
Tocilizumab and sarilumab, humanized monoclonal antibodies directed against IL-6 receptor (IL-6R), block IL-6, which dysregulates the local inflammatory responses, inhibiting host innate defences against respiratory infections and leading to an exaggerated inflammatory cascades and severe tissue damage in SARS-cov-2 patients. They are both approved for use in rheumatoid arthritis, with tocilizumab also approved for cytokine release syndrome (induced by Chimeric Antigen Receptor T cell therapies). Cohort studies and press-release of randomized clinical trials showed interesting results in patients with COVID-19 pneumonia with both these drugs, with reduction in C reactive protein (CRP) levels and in mortality, but complete results are still pending [4][5][6][7]. Janus Kinase (JAK) Inhibitors works by inhibiting the JAK signal transducer and activator of transcription pathway. Among them, baricitinib has a potent anti-inflammatory activity, especially against interferon-associated inflammation and has also a possible antiviral effect, linked to the interference with SARS-CoV-2 receptor-mediated endocytosis in lung alveolar epithelial cells [8].
Hereby we report the first case of an adult patient with severe COVID-19 pneumonia that has been treated with anti-IL-6 (sarilumab) and subsequently with baricitinib, with a complete panel of cytokine levels and immunological profiling of T cell, plasmacytoid and myeloid dendritic cells, with good results.

Archives of Clinical and Medical Case Reports 1215
Because of the persistence of respiratory failure and of the lack of radiological and laboratoristic improvement, offlabel anti-JAK therapy with oral baricitinib 4 mg/die was started, 10 days after anti-IL-6R administration, and continued for 14 days with good tolerance and no adverse effects. Four days after anti-JAK was started, he stopped non-invasive ventilation and started oxygen supplementation with Venturi mask, definitely removed after 10 days.
Pulmonary CT performed once baricitinib was stopped, revealed reduction of peripheral, bilateral lesions (GGO and crazy paving) and inflammatory markers were in the normal ranges (Figure 1 and 3). Accordingly, the levels of

Discussion and Conclusions
This case presents a possible use of baricitinib as rescue therapy, after an anti-IL6 treatment, for COVID-19. Both these products are not labeled for the use in Covid-19, so their use is still investigational. Baricitinib has already been explored in a small pilot study of 12 patients, showing improvement in clinical and laboratory parameters and good safety [9], but no data for its use as rescue therapy are available. A recently published paper raised doubts towards the use of baricitinib for COVID-19 patients. In fact, baricitinib cannot be initiated in patients with an absolute neutrophil count less than 1 × 10 9 cells/L or in patients with an absolute lymphocyte count less than 0.5 × 10 9 cells/L and various studies reported neutropenia and lymphopenia in patients with severe COVID-19, making this drug not suitable for many patients [10]. Other concerns were the risk of anaemia, the possible reactivation of latent infections or the detrimental impact in viral shedding, but we did not observe any of these complications in this case.
A relevant improvement in pulmonary images has been documented: the first CT scan showed peripheral, bilateral GGO; CT examination after 1 week from the beginning of sarilumab showed an increase of pulmonary lesions with interstitial-reticular involvement and crazy paving; a relevant reduction of pathological CT pictures was visible after 2 weeks from baricitinib. One month after discharge the radiological lung pattern was negative for GGO and crazy paving with periferic residual thin scars. Baricitinib was able to strongly reduce the inflammatory mediators, confirming its role in dampening the excessive inflammatory response. Moreover, we showed here that effective To conclude, in this case we have illustrated a possible use of baricitinib as rescue therapy, after sarilumab iv therapy, for COVID-19 severe pneumonia.

Declarations
Authors' contributions: RG was a major contributor in writing the manuscript; AS analyzed and interpreted the patient data regarding the immunological analyses; PC analyzed and interpreted the patient data regarding radiological images and revised the work; SC contributed to interpretation of data; GG analyzed and interpreted the patient data regarding the immunological analyses; OS contributed to interpretation of data; CC contributed to analysis of data and revised the work; CA analyzed and interpreted the patient data regarding the immunological analyses and revised the work; AA made substantial contributions to the conception of the work and to interpretation of data.