**1. Introduction**

The novel coronavirus disease 2019 (COVID-19) outbreak started in December 2019 in Wuhan, China, and has emerged as a major pandemic [1,2]. Severe acute respiratory syndrome coronavirus (SARS-CoV-2), an enveloped positive-stranded RNA virus, was later identified as the causative agen<sup>t</sup> [3,4]. As of April 28, 2020, there were more than 3,000,000 reported cases and 200,00 deaths from COVID-19 worldwide [5]. The case-fatality rate of COVID-19 has been estimated to be 2–3%, although estimates vary [6]. Patients with severe cases develop pneumonia that can lead to acute respiratory distress syndrome (ARDS) [3]. Respiratory failure secondary to ARDS in patients with COVID-19 is the most common cause of death [7].

Currently, no specific effective drug treatment or vaccine is available for COVID-19 [8,9]. Therapeutic managemen<sup>t</sup> is supportive, but some repurposed off-label anti-HIV and anti-viral medications are currently in use, including hydroxychloroquine, remdesevir, lopinavir/ritonavir, and interleukin 6 (IL-6) receptor inhibitors, in addition to convalescent plasma therapy [9–12]. Although several trials are underway, the use of these drugs remains to be substantiated by large, randomized clinical studies; to date, they have only shown promise in anecdotal experiences and circumstantial evidence mostly derived from studies conducted in vitro or in patients in single-arm studies with limited sample sizes and nonrandomized subject populations, which have yielded mixed results [10,13–18].

A major clinical feature of COVID-19 is lung-centric pathology resulting in respiratory deterioration, and the most common cause of death is acute respiratory failure due to ARDS [3,19]. According to current data, only 5% of all COVID-19 infections result in ARDS requiring mechanical ventilation, because most infected individuals experience complete recovery [20]. However, 25% of all patients with COVID-19 are believed to clinically progress and acquire critical complications, including ARDS, in which patients may quickly deteriorate and succumb to respiratory failure [21]. In particular, the survival rate among patients who require ventilator support remains poor. In a recent study on ICU patients with COVID-19 in Wuhan, China, only 21% of patients requiring non-invasive mechanical ventilation and 14% of patients requiring invasive mechanical ventilation survived [22]. Therefore, the early managemen<sup>t</sup> of respiratory symptoms to prevent progression to ARDS and avert the need for mechanical ventilation is critical for preventing mortality.

Cytokine storm, a hyperinflammatory state mediated by the release of cytokines, is known to be a key cause of ARDS [21]. In this regard, disrupting cytokine storm is an important potential therapeutic approach [21]. Interleukin 6 (IL-6), a multifunctional mediator of inflammation, is widely believed to play a pivotal role in the development of cytokine storm and to eventually cause the ARDS and interstitial pneumonia seen in severe COVID-19 [7,20,23,24]. The attenuation of IL-6 through receptor blockade has been hypothesized to blunt the cytokine storm responsible for respiratory disease progression [20].

Promising results of a recent single-arm trial of 21 patients with severe COVID-19 in China in February 2020 showed clinical improvements after therapy with the IL-6 receptor antagonist tocilizumab. Consequently, the Chinese National Health Commission included tocilizumab in the 7th edition of its guide for COVID-19 diagnosis and treatment [20,21,25]. Italian guidelines followed suit and began to sugges<sup>t</sup> the use of tocilizumab in cases of rapid radiologic and clinical deterioration [26,27]. Other trials are currently underway worldwide to better understand the potential therapeutic e ffects of IL-6 receptor inhibitors for COVID-19 treatment [28,29]. Currently, 23 trials are investigating the use of tocilizumab worldwide [28]. Additionally, ten trials are underway to investigate the role of the IL-6 receptor inhibitor sarilumab for treating COVID-19 [29].

Here, we present the case of a patient with severe COVID-19 who was administered tocilizumab, combined with generally accepted therapy at the time (hydroxychloroquine, azithromycin, and zinc), in an ICU setting. From a clinical standpoint, cytokine storm development was observed, as the patient required incremental increases in oxygen therapy (L/min) just prior to tocilizumab administration. He was on the verge of requiring intubation and mechanical ventilation, on the basis of his apparent respiratory distress and arterial blood gas measurements. Interestingly, the patient showed immediate improvement and did not require ventilatory support after he received the IL-6 inhibitor. He eventually recovered and

was sufficiently stable for hospital discharge shortly thereafter. The present case highlights the importance of addressing a mounting cytokine storm in its early stages. Our findings imply that inhibition of the IL-6 receptor has profound benefits under certain circumstances of severe COVID-19.

### **2. Case Presentation**

A 48-year-old male cruise ship worker with no significant past medical history presented to our hospital with shortness of breath and the production of sputum. He had reportedly tested positive for COVID-19 before arrival at our hospital. He described having felt sick for seven days while on a cruise ship, with an initial acute onset of symptoms that developed over the course of a day and rapid progression to dyspnea on exertion. He also reported a productive cough with yellow sputum, fever, occasional hemoptysis, nasal congestion, a sore throat, and concomitant nausea and vomiting during the few days before admission. The patient denied experiencing any similar previous episodes.

On hospital admission, the patient was hypoxic in the emergency department and was placed on a non-rebreather mask. Arterial blood gas analysis after admission revealed a pH of 7.44, PCO2 of 34, PO2 of 113, and SaO2 of 98.2% (with a 15% non-rebreather mask). When the non-rebreather mask was momentarily removed, desaturation occurred, and the SaO2 decreased to 88%.

A chest X-ray revealed infiltrates visible as bilateral hazy opacities (in the right lung more than the left lung), thus suggesting possible multifocal pneumonia or pulmonary edema due to ARDS, along with cardiomegaly. Laboratory results revealed elevated acute phase reactants (erythrocyte sedimentation rate (ESR) 50, C-reactive protein (CRP) > 16, ferritin 672, and lactate dehydrogenase (LDH) 460) and lymphopenia (lymphocyte count 1.2). Additionally, the blood laboratory results showed transaminitis, with elevated aspartate aminotransferase (AST) at 58 and normal alanine aminotransferase (ALT) at 34.

The increased levels of acute phase reactants, an inflammatory biomarker profile elevated from baseline, and lymphopenia supported our suspicion of cytokine storm as a feature of COVID-19 [30]. The broader di fferential included acute hypoxic respiratory failure and early onset multifocal viral pneumonia with impending ARDS. Importantly, some of the primary acute phase reactants believed to be associated with cytokine storm include ferritin, D-dimer, CRP, troponin, and LDH [31–33]. The clinical values of ferritin, D-dimer, and CRP, in addition to the ESR, which is a general marker of inflammation, were closely monitored on a regular basis. Lymphocyte counts were regularly assessed as lymphopenia, which is also believed to be associated with cytokine storm in COVID-19 [31–33]. Oxygen saturation was also carefully monitored each day. To confirm SARS-CoV-2 infection, we conducted a nasopharyngeal swab test. The real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assay results later revealed a positive result on day 5.

The treatment included high-flow oxygen, hydroxychloroquine, azithromycin, zinc, guaifenesin, acetaminophen, meropenem, vitamin c, cefepime, albuterol, atrovent, mucomyst, dexamethasone, and methylpredisolone. Additionally, the patient received two doses of tocilizumab (*Actemra*) at 500 mg administered 12 h apart. One dose was administered during the night of day 1, and a subsequent dose was administered the following morning. Overnight, the patient remained on the non-rebreather mask with 98% saturation.

On day 2, the patient began to feel fatigued and experienced greater di fficulty breathing. Because the patient had not improved on the non-rebreather mask, he was switched to BiPAP with 100% oxygen. The IL-6 levels were elevated (66 pg/mL). The acute phase reactants remained elevated: D-dimer 2027, ferritin 588.1, ESR 100 (representing an increase), and CRP > 16. AST remained elevated (55), whereas ALT was normal (40). The lymphocyte count was 1.1.

On day 3, the laboratory results revealed leukocytosis (WBC 13.1). Both AST (48) and ALT (50) remained elevated. The acute phase reactants remained high (CRP trended downward but remained elevated (14.4), ESR 102, D-dimer 2660, and ferritin 824.8 (representing an increase)). The lymphocyte counts remained low (1.12). Troponin was measured on that day and was found to be low (<0.05). The patient's oxygen saturation remained low (88–89%), and then rose to 93% and later to 96%. The patient remained on BiPAP overnight and was then shifted to a non-rebreather mask and finally a nasal canula.

On day 4, the patient became more stable. He reported mild shortness of breath with no acute complaints. He was taken off the BiPAP and put on the 100% non-rebreather mask. The O2 saturation was 99% peripherally. The acute phase reactants, although still elevated, had improved markedly from the previous day (CRP 4.7, ESR 89, D-dimer 1388, and ferritin 584.2). AST remained normal (27), and ALT was elevated (45). The lymphocyte counts were within normal limits (1.4). Leukocytosis persisted (WBC 16.7).

On day 5, the patient was stable and experienced only mild shortness of breath and no other complaints. He was still on a non-rebreather at 50%. The O2 saturation was 96%. The acute phase reactant levels remained elevated, but most values showed improvement (D-dimer 1093, ESR 40, and CRP 3.6 (representing a decrease), and ferritin 682 (representing an increase from the previous day)). The lymphocyte count was 1.3. ALT was elevated (54), and AST was normal (29). The WBC level was 14.2. A chest X-ray revealed diminished infiltrates as patchy opacities compared with imaging on day 2 (Figure 1).

**Figure 1.** Chest X-rays on day 1, day 2, and day 5. Tocilizumab was administered as two doses of 500 mg Q12 (during the night of day 1 and the morning of day 2).

On day 6, the patient remained stable with even respiration and unlabored breathing. He continued on the non-rebreather mask at 98–99% levels. All acute phase reactant levels had decreased (CRP 1.5, ESR 25, D-dimer 724, and ferritin 564.1). ALT (37) and AST (25) were both normal. Lymphocyte (3.0) and WBC (9.03) counts were in normal ranges.

On day 7, the patient's condition further improved. The acute phase reactants had mostly further improved; CRP (1.1), D-dimer (811), and ferritin (538.3) remained at elevated levels, and ESR was in a normal range at 10. The lymphocyte count was 1.15. ALT remained elevated (43), and AST was normal (25). The patient continued on a non-rebreather mask and was transferred out of the ICU unit. The remainder of his hospital stay was unremarkable. He eventually fully recovered and was discharged from our hospital on day 17. The patient's clinical progression, as shown by acute phase reactants (ferritin, D-dimer, and CRP), the lymphocyte count, ESR, and O2 saturation, are depicted in Figure 2.

**Figure 2.** Line charts of trends in acute phase reactant biomarkers of cytokine storm—ferritin, D-dimer, and C-reactive protein (CRP) levels—along with the lymphocyte count and O2 saturation during the hospital stay (day 1 refers to the first day of the hospital stay). The acute phase reactants displayed an overall decline from peak levels. (**A**) Ferritin levels. (**B**) D-Dimer trends (levels first measured on day 2 of the hospital stay). (**C**) CRP levels, which were >16 for days 1 and 2 of the hospital stay. (**D**) Erythrocyte sedimentation rate (ESR) levels (reference interval 0–15). (**E**) Lymphocyte count. (**F**) Oxygen saturation (SO2, pulse oximetry) levels during the hospital stay. The patient was initially started on a non-rebreather mask and then switched to BiPAP on day 3.
