Tocilizumab for severe COVID-19 related illness - A community academic medical center experience

Abstract

The SARS-CoV-2 virus responsible for the COVID-19 pandemic can result in severe or fatal disease in a subset of infected patients. While the pathogenesis of severe COVID-19 disease has yet to be fully elucidated, an overexuberant and harmful immune response to the SARS-CoV-2 virus may be a pivotal aspect of critical illness in this patient population. The inflammatory cytokine, IL-6, has been found to be consistently elevated in severely ill COVID-19 patients, prompting speculation that IL-6 is an important driver of the pathologic process. The inappropriately elevated levels of inflammatory cytokines in COVID-19 patients is similar to cytokine release syndrome (CRS) observed in cell therapy patients. We sought to describe outcomes in a series of severely ill patients with COVID-19 CRS following treatment with anti-IL-6/IL-6-Receptor (anti-IL-6/IL-6-R) therapy, including tocilizumab or siltuximab. At our academic community medical center, we formed a multi-disciplinary committee for selecting severely ill COVID-19 patients for therapy with anti-IL-6 or IL-6-R agents. Key selection criteria included evidence of hyperinflammation, most notably elevated levels of C-reactive protein (CRP) and ferritin, and an increasing oxygen requirement. By the data cutoff point, we treated 31 patients with anti-IL-6/IL-6-R agents including 12 who had already been intubated. Overall, 27 (87%) patients are alive and 24 (77%) have been discharged from the hospital. Clinical responses to anti-IL-6/IL-6-R therapy were accompanied by significant decreases in temperature, oxygen requirement, CRP, IL-6, and IL-10 levels. Based on these data, we believe anti-IL-6/IL-6-R therapy can be effective in managing early CRS related to COVID-19 disease. Further study of anti-IL-6/IL-6-R therapy alone and in combination with other classes of therapeutics is warranted and trials are underway.

Keywords: (ALC), Absolute Lymphocyte Count; (ARDS), Acute respiratory distress syndrome; (BMI), Body mass index; (CRP), C-reactive protein; (CRS), Cytokine release syndrome; (DNR/DNI), Do not resuscitate/do not intubate; (ECMO), Extracorporeal membrane oxygenation; (ESR), Erythrocyte sedimentation rate; (IRB), Institutional review board; (LDH), Lactate dehydrogenase; (NIV), Noninvasive ventilation; (PaO2/FiO2), Arterial oxygen partial pressure/fraction of inspired oxygen; (RT-PCR), Reverse-transcriptase polymerase-chain-reaction; (RWMC), Roger Williams Medical Center; (SITC), Society for Immunotherapy of Cancer; (SpO2), Peripheral capillary oxygen saturation; (anti-IL-6/IL-6-R), Anti-IL-6/IL-6-Receptor; C-reactive protein; IL-6; Infectious disease; SARS-CoV-2.

Fig. 1

Radiological changes noted in chest X-ray (CXR) in response to tocilizumab in one of the patients. (A) Admission CXR showing moderate multifocal airspace disease with diffuse bilateral infiltrates. (B) CXR within 24 h prior to tocilizumab showing marked worsening of bilateral airspace infiltrates. (C) CXR 36 h after tocilizumab infusion showing improvement in the infiltrates.

Fig. 2

Clinical response to anti-IL-6/IL-6-R therapy. (A) Body temperature elevations decreased quickly and significantly and remained significantly lowered through day 10 (p < 0.001). (B) FiO2 levels following treatment trended downward. Comparisons for day 10 (p = 0.78) and day 25 (p = 0.32) were not significant. (C) CRP levels decreased dramatically, beginning within two days of therapy and were significantly lower at day 10 (p < 0.0001). (D) Ferritin decreased slowly, reaching a significantly reduced level by day 10 (p = 0.052). (E) LDH decreased slowly, but not significantly within ten days of anti-IL-6/IL-6-R therapy (p = 0.45). (F) D-dimer increased gradually and was significantly elevated on day 10 (p = 0.0016).

Fig. 3

Serum cytokine response to anti-IL-6/IL-6-R therapy. (A) Serum IL-6 gradually increased over several days but decreased significantly by day 10 (p = 0.003). (B) Serum IL-10 decreased slowly, reaching a significantly reduced level by day 10 (p = 0.002). (C) Serum TNFα remained elevated for several days but decreased slowly, although not significantly (p = 0.07). (D) Serum GM-CSF decreased significantly ten days following anti-IL-6/IL-6-R therapy (p = 0.02).

Fig. 4

Clinical outcomes of all treated patients. The diagram depicts the clinical outcomes for all patients in our series.