**4. Conclusions**

We present the case of a patient with COVID-19 whose condition improved after the use of tocilizumab, obviating the need for mechanical ventilation. He tolerated tocilizumab well and did not experience any known adverse e ffects. Our experience appears to mirror other cases in the literature that sugges<sup>t</sup> a potential e fficacious role of IL-6 receptor inhibition in attenuating cytokine release syndrome in patients with severe COVID-19.

Avoiding the need for mechanical ventilation is a key therapeutic strategy in COVID-19 management. Current evidence suggests that approximately 79–86% of patients who require ventilator support experience mortality [22]. Therefore, the period of time before respiratory decline to the point at which ventilator support is needed may be especially important during the COVID-19 disease course. Therefore, although all reports to date are anecdotal and evidence is circumstantial, there may be a role for early aggressive immunosuppressive managemen<sup>t</sup> to avert the need for ventilator support; this time period may be crucial for recovery and for preventing progression to ARDS, which can cause irreversible lung damage.

Our case highlights the importance of the early recognition of the cytokine storm and of prompt immunosuppressive measures to halt disease progression. The early identification of clinical deterioration (as assessed by levels of cytokine storm-associated acute phase reactants) and subsequent aggressive managemen<sup>t</sup> of patients with severe COVID-19 during the onset of respiratory decline may be key for preventing mortality. As suggested by both our experience and anecdotal cases described in the literature, acute phase reactant proteins may play an important role in the diagnosis and prognosis in severe COVID-19. Future studies are needed to determine their potential in risk stratification. According to the results of recent studies, clinicians should consider initiating measurements of IL-6 levels, the WBC count, lymphocytes, platelets, ferritin, D-dimer, CRP, and LDH for the risk stratification of cytokine storm [30–33].

The e fficacy of combination therapy of IL-6 inhibitors with other drugs, such as hydroxychloroquine (in conjunction with azithromycin) and zinc, or other currently used COVID-19 treatments requires further investigation. Several therapies when used in concert might potentially attenuate disease pathology. We administered a smaller dose of tocilizumab than is typically used in patients with cytokine release syndrome, but slightly higher than the amounts used in previous studies. Therefore, our experience may shed light on the need for optimal therapeutic doses, which must still be established. Further investigations should explore the potential of dosages not based on weight to determine whether this approach would yield di fferent therapeutic results. According to the literature describing cases in which variable dosing led to recovery, determining whether a single or multiple dose is most e ffective in COVID-19 is also needed. The optimal timing of use remains to be determined. Additionally, not all patients may be candidates for IL-6 inhibitor treatment. Decisions to administer the drug should consider co-morbidities, such as inactive tuberculosis, in conjunction with the patient's current immune status.

Therapeutic horizons in the treatment for COVID-19 may entail various methods for preventing or disrupting disease progression in ARDS. Further investigations are warranted to shed light on alternative potential therapeutic targets for cytokine storm disruption, particularly in the IL-6 signaling pathway. For example, inhibitors of the JAK/STAT signaling pathway, which could help decrease the levels of cytokines (including IL-6 and IFN-γ) observed in severe COVID-19, have been suggested as a potential therapy [49,100]. However, to date, IL-6 receptor inhibition has garnered substantial attention in the scientific community worldwide, and the upcoming results of current trials of tocilizumab may provide a clearer picture of its efficacy. Until large randomized-controlled studies reveal conclusive evidence of the large-scale efficacy of IL-6 receptor inhibition as a viable therapeutic option in patients with severe COVID-19, clinicians should consider the anecdotal cases of the successful aversion of both cytokine storm and disease progression through the use of these drugs. Such decisions, however, must be made with caution and a consideration of the potential adverse immunomodulatory effects of IL-6 receptor inhibitor therapy. Despite the potential adverse effects of IL-6, the use of tocilizumab in conjunction with other immune-mediating medications may be a promising treatment for severe COVID-19.

Informed consent was obtained from the patient to describe and publish his case.

**Author Contributions:** Attending physician, G.Y.; conceptualization, F.F.; writing—original draft preparation, F.F., N.D.; writing—review and editing, F.F., N.D., G.Y., J.D., K.N., and R.M.; supervision/staff doctor/patient diagnosis, F.F., G.Y., J.D., R.M., and K.N. All authors have read and agreed to the published version of the manuscript.

**Funding:** The research received no external funding.

**Acknowledgments:** The authors are grateful to the hospital staff for their assistance. We thank Marcos Sanchez for his guidance.

**Conflicts of Interest:** The authors declare no conflict of interest.
