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Table of Contents
Year : 2021  |  Volume : 7  |  Issue : 2  |  Page : 45-52

Tocilizumab for treatment of severe COVID morbidly obese patient with comorbidities

Department of Anaesthesiology, Santosh Medical College and Hospital, Ghaziabad, Uttar Pradesh, India

Date of Web Publication6-Dec-2021

Correspondence Address:
Isha Yadav
Department of Anaesthesiology, Santosh Medical College and Hospital, Ghaziabad, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2455-1732.331787

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COVID-19, caused by the novel severe acute respiratory coronavirus 2, emerged in Wuhan, China, in 2019 and has resulted in the current pandemic. The disease continues to pose a major therapeutic challenge. Patient mortality is ultimately caused by acute respiratory distress syndrome (ARDS). Because interleukin-6 (IL-6) is known to play a key role in inflammation, IL-6 receptor inhibitors such as tocilizumab may potentially treat COVID-19 by attenuating cytokine release. Tocilizumab is a recombinant humanized monoclonal antibody that serves as an IL-6 receptor inhibitor. Tocilizumab is beneficial for the treatment of inflammatory and autoimmune conditions and rheumatoid arthritis, giant cell arteritis, and systemic juvenile idiopathic arthritis. It is also under used in the treatment of severely ill patients with COVID-19. Patients with moderate-to-severe disease with progressively increasing oxygen requirements, with inadequate response to corticosteroids, and with raised levels of inflammatory markers (MoHFW, June 2020). It is used in dose of 8 mg/kg in 100 ml NS over 60 minutes (maximum dose 800 mg/infusion). It can be repeated once after 12 − 24 hours if needed. Careful monitoring for secondary infection and neutropenia should be done. It is contraindicated in people with HIV, active infections, tuberculosis, active hepatitis, ANC is <2000/mm3 and platelet count <100,000/mm3. We present the first case of our institution in which we administered tocilizumab, a 57-year-old female with moderate-to-severe COVID-19, on the verge of meeting intubation requirements, who needed progressive oxygen support for respiratory distress. The patient was treated with tocilizumab to prevent the cytokine storm. We chose early administration of an IL-6 inhibitor because of the gradually increasing levels of inflammatory markers and her deteriorating respiratory status. The treatment was well-tolerated in conjunction with standard drug therapies for COVID-19 (hydroxychloroquine, tazar, and zinc). The patient subsequently experienced marked improvements in his respiratory symptoms and overall clinical status over the following days. We believe that tocilizumab played a substantial role in her ability to overcome clinical decline, particularly the need for mechanical ventilation. Ultimately, the patient was shifted from the intensive care unit (ICU) and discharged within few days. We highlight the potential of IL-6 inhibitors to prevent the progression of respiratory disease to a point requiring ventilator support. This case underscores the potential importance of early serial measurements of IL-6 and cytokine storm-associated inflammatory markers, such as serum ferritin, D-dimer, and C-reactive protein, in guiding clinical decision-making in the management of patients with suspected COVID-19. The early identification of inflammatory markers should be implemented in the treatment of COVID-19 in order to screen for a primary contributor to mortality − the cytokine storm. This screening, when followed by aggressive early treatment for cytokine storm, may have optimal therapeutic benefits and obviate the need for mechanical ventilation, thereby decreasing mortality. In addition, we review current evidence regarding cytokine release syndrome in COVID-19 and the use of IL-6 receptor inhibition as a therapeutic strategy and examine other reported cases in the literature describing IL-6 antagonist treatment for patients with COVID-19.

How to cite this article:
Aggarwal A, Yadav I, Lakhanpal M. Tocilizumab for treatment of severe COVID morbidly obese patient with comorbidities. Santosh Univ J Health Sci 2021;7:45-52

How to cite this URL:
Aggarwal A, Yadav I, Lakhanpal M. Tocilizumab for treatment of severe COVID morbidly obese patient with comorbidities. Santosh Univ J Health Sci [serial online] 2021 [cited 2022 Dec 8];7:45-52. Available from: http://www.sujhs.org/text.asp?2021/7/2/45/331787

  Introduction Top

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 agent.[3],[4] The case-fatality rate of COVID-19 has been estimated to be 2%–3%, although estimates vary.[5] 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.[33] Currently, no specific effective drug treatment or vaccine is available for COVID-19.[6],[7] Therapeutic management 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.[7],[8],[9],[10] 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],[14] According to the current data, only 5% of all COVID-19 infections result in ARDS requiring mechanical ventilation, because most infected individuals experience complete recovery.[34] 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.[15] In particular, the survival rate among patients who require ventilator support remains poor. Cytokine storm, a hyperinflammatory state mediated by the release of cytokines, is known to be a key cause of ARDS.[15] In this regard, disrupting cytokine storm is an important potential therapeutic approach.[15] 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.[17],[18],[32],[33]

Here, we present the first case of our institution in which a patient with severe COVID-19 with DM (newly diagnosed), hypothyroidism was administered tocilizumab, combined with generally accepted therapy at the time (hydroxychloroquine, tazar, and zinc), in an ICU setting. Cytokine storm was observed, as the patient required incremental increases in oxygen therapy (L/min) just before tocilizumab administration. She was on the verge of requiring intubation and mechanical ventilation, on the basis of her respiratory distress and arterial blood gas measurements. Fortunately, the patient showed immediate improvement and did not require ventilatory support after she received the IL-6 inhibitor. She eventually recovered and was discharge. 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.[11],[12],[19],[31]
Figure 1:

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  Case Report Top

A 57-year-old female patient having h/o hypothyroidism for 4 year on regular medication (eltroxin 50 mcg OD) and diagnosed with SARS-COVID positive and new diagnosed DM and patient was morbidity obese (body mass index 41) admitted in the isolation ward on June 26, 2020 with complain of fever, breathlessness, and cough. After admission, the patient was immediately shifted to ICU where the patient SpO2 was 70% @ rheumatoid arthritis and on NRBM 93% but dyspnoic (RR = 40-42) and was immediately put on NIV FiO2=0.50, PS = 14 and PEEP = 6 (SPO2 = 96%).

Arterial blood gases (ABG) showed respiratory acidosis with hypoxemia (pH = 7.3, pCO2 = 38.9, HCO3 = 22.8, pO2 = 60.2, PaO2/FiO2 = 120 @ NRBM 15lit of O2) and patient comes under moderate-to-severe category. Initial physical examination revealed criteria body temperature = Afebrile, RR = 42, HR = 112, BP = 136/90, SPO2 = 94 condition = sick. Patient was put on NIV =0.50, PS = 16, PEEP=8 immediately after ABG report.

All routine investigations were sent. Complete blood count, LFT, RFT, HbA1c, C-X-ray, HRCT, C-reactive protein (CRP), lactate dehydrogenase (LDH), S. Ferritin, S. PCT, PT (INR), and serum fibrinogen were done. Chest X-ray revealed infiltrates visible as bilateral hazy opacities suggestive of COVID. Laboratory reports results revealed elevated acute-phase reactants erythrocyte sedimentation rate (ESR) (50) CRP (60) FERRITIN (650) LDH (465) AND LYMPHOPENIA (12).

High level of acute-phase reactants, an inflammatory marker were elevated from baseline supported our suspicion of cytokine storm as a feature of COVID. The clinical values of S. Ferritin (550), D-dimer (1), and CRP (60) in addition to ESR (50) which is general marker of inflammation which was monitored daily, lymphocyte count was regularly decreased which is also raised and its believed to be associated with cytokine storm, oxygen saturation, and along with other parameter were monitored. The patient was fulfilling the criteria for tocilizumab.

We started the treatment with high flow oxygen, hydroxychloroquine, zinc, tazar, clindamycin, dexamethasone, ivermectin, clexane (lwmh), and mucinac.

As the patient condition was deteriorating, ICU team decide to inject 2 dose of inj. Tocilizumab 400 mg in 100 ml NS (6 hourly) on 3 day after admission in ICU and monitored for adverse event. However, the inflammatory markers were raised, patient saturation was still low (87–89) so we increased the NIV support, i.e., FiO2 = 0.7, ps over peep 16, PEEP = 8. Moreover, then on increasing Fio2, patient saturation increased to 93%–95%. The patient started improving after 2 dose and on this NIV setting; then, we gradually decreased the NIV setting and patient's saturation started improving, patient become clinically stable with unlabored breathing, on day 8, we put the patient on intermittent niv and nrbm. As the patient was maintaining saturation (97%–98%), we put the patient on NRBM 15L/MIN on day 9 and continued. All inflammatory marker level decreased ESR (35), CRP (70), FERRITIN (605), LDH (400), and lymphopenia (30). Patient condition was further improved and shifted to facemask on day 12 and was shifted to the isolation ward after observing for 2 days, i.e. day 15.

Line charts of trends in inflammatory markers − S. ferritin, D-dimer, and 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 markers displayed an overall decline from peak levels (A) Ferritin levels; (B) D-Dimer trends (levels first measured on day 1 of the hospital stay); (C) CRP levels, which were >6 for days 1 and 2 of the hospital stay; (D) Lymphocyte count; (E) Oxygen saturation (SO2, pulse oximetry) levels during the hospital stay. The patient was initially started on a nonrebreather mask and then put on NIV on the same day.

X-ray of the patient before tocilizumab injection [Figure 2]a and [Figure 2]b and after both dose of tocilizumab [Figure 2]c and last day of ICU [Figure 2]d.
Figure 2: (a and b) Both X-ray before tocilizumab injection. (c) Patient X-ray after giving tocilizumab. (d) Patient X-ray of last day in intensive care unit

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  Discussion Top

Cytokine storm is seen in a variety of syndromes, including macrophage activation syndrome, hemophagocytic lymphohistiocytosis, and chimeric antigen receptor (CAR) T-cell therapy (used to treat lymphomas and leukemias) associated with hyperinflammation (known as cytokine release syndrome).[3],[20],[21],[22],[39] Importantly, not all patients with COVID-19 undergo cytokine storm; this phenomenon only occurs in a certain subset of severe cases.[10] The patient with cytokine storm involves rapid respiratory deterioration.[40],[41] Our patient began to decline and demonstrated the symptoms of respiratory distress (labored breathing) on the first day of admission and had reportedly been experiencing symptoms for 5 days prior. Cytokine storm instigates a robust immune-driven attack on the body, leading to ARDS (and multi-organ failure) and ultimately causing morbidity in severe COVID-19.[23],[24] The pathophysiology of cytokine storm is not fully understood but is currently thought to be based on the mechanisms of inflammatory disorders. Initially, SARS-CoV-2 binds angiotensin-converting enzyme 2 (ACE-2) receptors and then invades the respiratory epithelium.[22],[25] Dendritic cells and alveolar macrophages are activated because of the presence of SARS-CoV-2 and subsequently release IL-6, which is also secreted by the respiratory epithelium.[22],[25] A cascade of the cytokines IL-1B, IL-12, and TNF-α results and their secretion induces WBCs to release cytokines, thus effectively perpetuating an inflammatory cycle.[10],[25] These cytokines also enter the circulation and cause systemic multisystem pathology.[26]
Table 1: Comparison of tocilizumab with other drugs currently in use or under investigation for the treatment of patients with coronavirus disease 2019

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The robust hyperinflammatory cytokine response induces the apoptosis of endothelial and epithelial cells in the lungs, resulting in tissue injury, leakage and edema, and ARDS.[26] As immune cells destroy alveolar tissue, permeability increases, thus resulting in fluid entry into the alveoli; less oxygen enters the blood, because alveolar type I cells are diminished, and a loss of surfactant leads to alveolar collapse. These responses together impair normal gas exchange.[3],[42] In addition, cytokines cause vasodilation, thereby contributing to a build-up of fluid in the alveoli, diluting surfactant, and causing alveolar collapse; as alveolar type I and alveolar type II cells are destroyed, the alveoli collapse, and ARDS ensues.[42]

An increased synthesis of collagen and TGF-α and deposition of fibrin are also observed in the development of ARDS.[3] The features of ARDS additionally include alveolar exudate, edema, and cellular infiltration, thus resulting in damaged alveoli and limited gas exchange.[15] Xu et al.[24] have described postmortem biopsies of COVID-19 patients with ARDS in China that showed classic ARDS-related features, such as pneumocyte desquamation, the formation of hyaline membranes, and pulmonary edema. In addition, the presence of lymphocyte-dominated mononuclear inflammatory infiltrate in the interstitium was observed bilaterally.[24] Because of the high numbers of mononuclear lymphocytes, these T-cells have been thought to potentially enter the pulmonary circulation and trigger an inflammatory storm.[15]

ARDS and severe illness in patients with COVID-19 usually develop 1–2 weeks after the onset of symptoms.[43] Our understanding of ARDS in COVID-19 is still evolving. It has been suggested that COVID-19 may be characterized by a unique form of ARDS, marked by a feature not seen in classic ARDS: the seemingly preserved compliance and respiratory mechanics relative to the high degree of hypoxemia.[44] [Figure 3] depicts the alveolar changes that occur in COVID-19.
Figure 3:

Click here to view

The onset of the hyperinflammation in cytokine storm may be evidenced by coagulopathy, cytopenia, tissue damage, the inflammation of liver tissue, and the activation of macrophages and hepatocytes.[39] Therefore, laboratory findings potentially suggesting the onset of cytokine storm in patients with COVID-19 may include increased levels of acute-phase markers (such as D-dimer, CRP, LDH, ferritin, and troponin), low platelets, decreased fibrinogen, lymphopenia, thrombocytopenia, increased LDH, and elevated AST and ALT.[36],[37],[38],[39] Lymphopenia is a commonly reported feature of COVID-19 cytokine storm, and given that the cytokine storm must be orchestrated by other leukocytes (not T-cells), an elevated WBC count is also common, suggesting that lymphopenia with leukocytosis may be a key feature in the differential diagnosis of COVID-19.[45] In our patient, lymphopenia was observed on day 1, and on day 3, the patient developed leukocytosis.

Interestingly, cytokine storm in COVID-19 differs from that associated with other viruses as the increase in ferritin in COVID-19 is relatively modest.[39] Ferritin has been suggested as a prognostic indicator for cytokine storm in COVID-19.[39],[46]

Serum inflammatory biomarkers may have a role in assessing disease progression, since a poor prognosis in COVID-19 appears to be correlated with abnormal serum markers and clinical attributes of cytokine storm.[39] A recent retrospective observational study of 21 patients in China comparing the attributes of moderate versus severe COVID-19 found that severe cases are more often typified by hypoalbuminemia and lymphopenia, with relatively high levels of ALT, LDH, and CRP, and particularly high levels of TNF-α, IL-2R, IL-6, and IL-10.[47]

The study also showed that patients who experienced severe disease and even mortality had thrombocytopenia, lymphocytopenia, and higher WBC counts compared with those with moderate disease and disease resolution.[35] Mehta et al.[10] have suggested that inflammatory biomarkers, including ESR, decreased platelets, and increased ferritin, should be used by clinicians to risk-stratify patients who might benefit from immunomodulating treatments (such as IL-6 inhibitors). One recent study of 343 hospitalized patients with COVID-19 in Wuhan showed that D-dimer levels above 2.0 μg/mL on admission were predictive of mortality, thereby suggesting a potential prognostic role of D-dimer.[48] Therefore, an early assessment of these biomarkers may be critical, since rapidly identifying an emerging cytokine storm and targeting immune dysregulation in patients with COVID-19 before the rapid progression to ARDS has the potential to avoid the need for mechanical ventilation, given the low rates of survival among patients with COVID-19 who are placed on ventilators.[16],[39] IL-6 is a pleiotropic cytokine in the glycoprotein-130 (gp130) family of cytokines.[49],[50] It has a myriad of physiological functions, including the production of acute phase reactants, stimulation of immunoglobulin production by activated B-cells, regulation of bone homeostasis, lipid oxidation, glucose metabolism, and regulation of energy expenditure and appetite.[50],[51],[52],[53] Therefore, the role of IL-6 in COVID-19 is complex and not fully elucidated.[3] For instance, theoretically, the high IL-6 levels in COVID-19 pneumonia have been suggested to have beneficial or deleterious effects, since IL-6 in other infections can enhance viral replication or suppression in the experimental models.[3] However, emphasis has been placed on its mainly pro-inflammatory nature in COVID-19, as confirmed by clinical reports on patients with COVID-19. The activation of IL-6 is thought to be the key feature of the progression of COVID-19 pneumonia to ARDS and hyperinflammation.[25]

Tocilizumab has an additional use in treating the cytokine release syndrome that specifically results from CAR T-cell therapy used in B-cell malignancies.[19],[38] Therefore, tocilizumab and sarilumab have been suggested to have therapeutic potential in patients with COVID-19 when there is a suspicion of a cytokine storm according to elevated acute-phase reactant markers (e.g. ferritin, D-dimer, CRP, and LDH), as was the case in our patient.[36],[37],[38]

Accordingly, on day 1 of admission, we initiated an intravenous (IV) administration of tocilizumab. For the treatment for CAR-T therapy-initiated cytokine release syndrome, a conventional IV infusion of tocilizumab (alone or with corticosteroids) is indicated with a weight-based dose at 8 mg/kg for patients weighing at least 30 kg, which corresponded to a dose of 1005 mg in our patient.[55] We administered two smaller doses (500 mg each) with a 12 h interval not based on weight, given the experimental nature of its use in COVID-19 and to mitigate any adverse effects. Importantly, IL-6 inhibitors attenuate the immune response, increasing the risk of opportunistic infections, leukopenia, and liver injury.[54],[56] Some known adverse effects of tocilizumab include liver disease, allergic reactions, anaphylaxis, stomach and abdominal pain, skin and soft-tissue infections, neutropenia, and hypercholesterolemia.[54],[57]

The patients received a single 400 mg tocilizumab dose and standard recommended therapy with lopinavir, methylprednisolone, oxygen treatment, and symptom relief medications. The fever declined in several days, and marked improvement was observed in all patients. Lymphocyte and CRP levels decreased after tocilizumab therapy.

Luo et al.[58] conducted a retrospective study of 15 patients with COVID-19 in Wuhan, China. The study assessed 15 patients with COVID-19 treated with tocilizumab (eight patients were given a combination with methylprednisolone). Ten patients were administered a single dose and two were given double doses of tocilizumab. Serum acute-phase reactants CRP and IL-6 were measured before and after therapy. Two patients were “moderately ill,” and the rest were in a serious or critical condition. Ten patients had at least one comorbidity. The CRP levels decreased in all patients. The IL-6 levels decreased in most nine patients. Mortality was seen in three patients and disease exacerbation occurred in two patients. The remaining ten patients showed stabilization. A total of four critically ill patients were given a single dose; three patients died and one experienced disease aggravation. The authors concluded that tocilizumab may have benefits. The study further suggested that a single dose of tocilizumab (even when used with glucocorticoids) may not be sufficient for improvement in critical patients, whereas repeated doses may result in improvement. The limitations of the study were its retrospective and observational nature, small sample size, and nonrandomized sample, with a substantial number of patients with comorbidities. Doses of tocilizumab varied among patients, some of whom received a double dose and approximately half of whom received methylprednisolone in addition to tocilizumab.

De Luna et al.[32] have reported the case of a 45-year-old patient with COVID-19 in France who had sickle cell anemia with acute chest syndrome and pneumonia, and who was administered tocilizumab (in addition to hydroxychloroquine) and showed subsequent improvement. He presented on day 1 with an oxygen saturation of 91% and then deteriorated to 80% oxygen saturation on day 2, at which time he was administered IV tocilizumab (8 mg/kg dose), in addition to the ongoing hydroxychloroquine (200 mg every 8 hours) and supplemental oxygen. On day 3, he showed improvement. In our patient, tocilizumab was administered in conjunction with ongoing hydroxychloroquine and other standard medications on day 1, followed by a second dose 12 hours later on the morning of day 2. Our patient also showed major improvement after tocilizumab administration, although we administered two doses rather than one.

Cellina et al.[65] have characterized the case of a 64-year-old male with no comorbidities who developed COVID-19 and experienced dyspnea and decreased oxygen saturation at 90% on day 6 of his hospital stay. On day 7, he was started on assisted ventilation, and tocilizumab was administered in two doses of 8 mg/kg, with 12 hours between doses (days 7 and 8). On day 9, the CRP and WBC count declined, and his condition improved. He was weaned off ventilatory support. On day 14, his CT revealed improvements.

In another observational study, Giamarellos-Bourboulis et al.[66] administered tocilizumab to six patients who were the part of a group of 54 patients with COVID-19 under the study for immunedysregulation and immune responses. The plasma of these patients was also studied. The absolute lymphocyte levels in the six patients decreased after tocilizumab therapy. The introduction of tocilizumab in plasma-enriched cell medium partially restored HLA-DR expression on cells. Importantly, IL-6 is believed to be the cause of decreased HLA-DR on CD14 monocytes.[66] Severe respiratory failure is associated with a significant decrease in HLA-DR expression on CD14 monocytes.[66] Therefore, the investigators suggested that tocilizumab partially relieves the immune dysregulation seen in COVID-19.

  Conclusions Top

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 effects. Treatment with tocilizumab might reduce the risk of invasive mechanical ventilation or decrease mortality in patient with moderate-to-severe COVID.

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.[16] 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.

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 the levels of cytokine storm-associated acute-phase reactants) and subsequent aggressive management of patients with severe COVID-19 during the onset of respiratory decline may be the key for preventing mortality.

The efficacy 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.

The optimal timing of use remains to be determined. In addition, not all patients may be candidates for IL-6 inhibitor treatment. Decisions to administer the drug should consider comorbidities, such as inactive tuberculosis, in conjunction with the patient's current immune status.

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Conflicts of interest

There are no conflicts of interest.

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