|Year : 2022 | Volume
| Issue : 2 | Page : 176-180
A retrospective analysis of moderate and severe COVID-19 pneumonia with special reference to the use of Adjuvant Tocilizumab
Pratik Raval1, Benny Jose Panakkal2, Dinesh Joshi1, Karthik Natrajan1, Anand Shukla1, Gajendra Dubey1, Sibasis Sahoo1, Subhendu Bajpai1
1 Department of Cardiology, U. N. Mehta Institute of Cardiology and Research Centre, B. J. Medical College, Ahmedabad, Gujarat, India
2 Interventional Cardiologist at Jupiter Hospital, Pune, Maharashtra, India
|Date of Submission||11-Nov-2021|
|Date of Acceptance||08-Jan-2022|
|Date of Web Publication||23-Dec-2022|
Dr. Karthik Natrajan
Department of Cardiology, U. N. Mehta Institute of Cardiology and Research Centre, Civil Hospital Campus, Asarwa, Ahmedabad - 380 016, Gujarat
Source of Support: None, Conflict of Interest: None
Background and Aim: Coronavirus disease 2019 (COVID-19) pneumonia is associated with a hyper-inflammatory syndrome which may cause life-threatening acute respiratory distress syndrome. The aim of this study was to evaluate the safety and efficacy of an anti-inflammatory agent, tocilizumab (TCZ), a monoclonal antibody that targets the interleukin 6 receptor. Materials and Methods: We included 53 patients admitted between April and July 2020 with COVID-19 pneumonia who received TCZ. Patients received one intravenous infusion of TCZ, dosed at 8 mg/kg, up to a maximum dose of 800 mg. All patients were evaluated with clinical, laboratory, and radiological parameters. Results: Out of 53 patients 28 (52.8%) had severe disease and 25 (47.2%) had the moderate disease. The mean age was 55 years. The most common presenting symptom was fever (73%; n = 39). C-reactive protein (CRP), neutrophil-lymphocyte ratio (NLR), d-dimer, and ferritin levels were elevated at baseline. After TCZ administration CRP, ferritin and NLR levels reduced significantly whereas d-dimer levels did not fall. Pulmonary fibrosis may be observed later in the course of the disease. All the mortality occurred in patients who had severe disease on presentation. There was no difference in outcomes according to gender, diabetic status, and presence of preexisting cardiac disease. Conclusion: Overall, TCZ administration is safe and effective in improving clinical and laboratory parameters with a possible reduction in the need for ventilatory care and duration of intensive care unit stay, particularly in patients with moderate severe acute respiratory syndrome coronavirus- 2 disease. However, our results should be considered preliminary and should be interpreted with caution as they stem from an uncontrolled series.
Keywords: Coronavirus disease 2019 pneumonia, interleukin 6, severe acute respiratory syndrome coronavirus 2, tocilizumab
|How to cite this article:|
Raval P, Panakkal BJ, Joshi D, Natrajan K, Shukla A, Dubey G, Sahoo S, Bajpai S. A retrospective analysis of moderate and severe COVID-19 pneumonia with special reference to the use of Adjuvant Tocilizumab. Arch Med Health Sci 2022;10:176-80
|How to cite this URL:|
Raval P, Panakkal BJ, Joshi D, Natrajan K, Shukla A, Dubey G, Sahoo S, Bajpai S. A retrospective analysis of moderate and severe COVID-19 pneumonia with special reference to the use of Adjuvant Tocilizumab. Arch Med Health Sci [serial online] 2022 [cited 2023 Jan 31];10:176-80. Available from: https://www.amhsjournal.org/text.asp?2022/10/2/176/364974
| Introduction|| |
Coronavirus disease 2019 (COVID-19) is a major health concern and can be devastating, especially for the elderly and those with co-morbidities. The inhaled virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) likely binds to epithelial cells in the nasal cavity and starts replicating. Angiotensin-converting enzyme 2 is the main receptor for both SARS-CoV2 and SARS-CoV., In the second stage, the virus propagates and migrates down the respiratory tract along the conducting airways, and a more robust innate immune response is triggered. For about 80% of the infected patients, the disease will be mild and mostly restricted to the upper and conducting airways. The remaining patients will progress to stage 3 disease and will develop pulmonary infiltrates, and some of these will develop acute respiratory distress syndrome. Both SARS-CoV and influenza preferentially infect type II alveolar cells compared to type I alveolar cells., The infected alveolar units tend to be peripheral and subpleural.,
Some patients with severe COVID-19 have laboratory evidence of an exuberant inflammatory response, similar to cytokine release syndrome, with persistent fevers, elevated inflammatory markers (e.g., C-reactive protein [CRP], D-dimer, ferritin), and elevated pro-inflammatory cytokines; these laboratory abnormalities have been associated with critical and fatal illnesses., Some of the severe cases that were admitted to the intensive care unit (ICU) showed high levels of pro-inflammatory cytokines including interleukin (IL) 2, IL7, IL10, granulocyte colony-stimulating factor, IP10, MCP1, MIP1α, and tumor necrosis factor alpha that are reasoned to promote disease severity. Patients suffering from cytokine storms progress to cardiovascular collapse, multiple organ dysfunction, and death rapidly. Therefore, early identification, treatment, and prevention of the cytokine storms are of crucial importance for the patients.
IL-6 is a cytokine that plays an important role in inflammatory reaction and immune response. Tocilizumab (TCZ), an interleukin (IL)-6 receptor inhibitor, has been used for rheumatic diseases and cytokine release syndrome. Elevated IL-6 levels have been described in patients with severe COVID-19, and case reports have described good outcomes with TCZ.,,,, Various treatment guidelines include the IL-6 inhibitor TCZ for patients with severe COVID-19 and elevated IL-6 levels. This study is aimed at evaluating the efficacy and safety of TCZ in patients with severe COVID-19 pneumonia. The current Centers for Disease Control and Prevention guidelines recommend adding a second immunomodulatory drug (e.g., TCZ or baricitinib) for patients who are already on dexamethasone and have rapidly increasing oxygen needs and systemic inflammation.
| Materials and Methods|| |
We retrospectively studied 53 patients who were admitted in our institute between April and July 2020 with SARS CoV-2 pneumonia who received TCZ. Patients received one intravenous infusion of TCZ, dosed at 8 mg/kg, up to a maximum dose of 800 mg. Up to one additional dose was given if clinical symptoms worsened or showed no improvement. All patients were evaluated with clinical and laboratory parameters. Neutrophil: lymphocyte ratio, CRP, D-dimer, and serum ferritin levels and chest X ray were done at the onset of treatment. Thereafter, the same tests were repeated on day 3 and day 7. The tests were repeated more frequently according to discretion of the treating physician. Chest computed tomography (CT) scan was done as required. Severe illness was defined as SpO2 <90% on room air, PaO2/FiO2 <300 mmHg, a respiratory rate >30 breaths/min, or lung infiltrates >50%. Clinical improvement was defined as reduction in oxygen requirement and with or without improvement in various laboratory markers (CRP, neutrophil-lymphocyte ratio [NLR], D-dimer and ferritin). Clinical failure was defined as either death or need for invasive ventilation.
All patients with COVID-19 confirmed by reverse transcription-polymerase chain reaction, adult (age >18 years), SPO2 ≤93% or PaO2/FiO2 <300 mmHg, patients with cytokine storm: [CRP >150 (15 X upper limit of normal [ULN]), D-dimer more than 2.5 mcg/ml, worsening respiratory status were included in the study. Patients with known severe allergic reactions to TCZ or other monoclonal antibodies, active tuberculosis infection, suspected active bacterial, fungal, viral, or other infection (besides COVID-19), pregnant and lactating women, patients with serum glutamic pyruvic transaminase (SGPT) or serum glutamic oxaloacetic transaminase more than 10 times ULN, absolute neutrophil count <1000/mL, platelet count <50,000/mL, and those who did not give consent were excluded from the study. The study was approved by ethics committee (EC/Approval/41/2020).
All statistical analysis was performed using SPSS v 22.0 (Chicago, IL, USA). Continuous variables were compared using the unpaired student's t-test. Continuous variables were summarized as mean ± standard deviation and as median with interquartile range, whereas categorical variables were expressed as percentage of the sample. Group differences associated with a P ≤ 0.05 were considered statistically significant.
| Results|| |
Out of 53, patients 28 (52.8%) had severe disease and 25 (47.2%) patients had moderate disease. Baseline demographic features of patients are shown in [Table 1]. The mean age was 55 years. 38 (71.7%) patients were male and 15 (28.3%) were female. The most common presenting symptoms were fever (73%; n = 39) and shortness of breath (64%; n = 34), followed by cough (47%; n = 25). Other presenting symptoms were bodyache, diarrhea, and chest pain. The mean duration for fever, breathlessness, and cough was 4.2, 3.9, and 4.7 days, respectively, at the time of hospitalization. Thirty-five percent of the patients (n = 19) had diabetes, 28% (n = 15) had hypertension, 32% (n = 17) had coronary artery disease, and 26% (n = 14) had left ventricle dysfunction.
All patients received various combinations of antibiotic regimen including ceftriaxone alone, azithromycin and ceftriaxone, azithromycin and cefoperazone or azithromycin and meropenem. Twenty-four percent of patients (n = 13) received hydroxychloroquine. In addition, 77% of the patients (n = 41) also received corticosteroids before TCZ. The choice of corticosteroids was either methylprednisone or dexamethasone. Ninety percent (n = 48) patients received anticoagulation with either low-molecular-weight heparin or unfractionated heparin. Fifty-four percent patients received aspirin (n = 29). Five patients received antiviral therapy with either fevipiravir (n = 4) or remdesivir (n = 1).
The median time to TCZ administration was 7.4 days from symptom onset. Five patients received second dose of TCZ after 24 h. At baseline, 47% (n = 25) of patients had moderate disease and 53% (n = 28) of patients had severe disease. Forty-five patients were admitted to ICU. All patients required oxygen at admission. Five patients were on mechanical ventilator at baseline and another five patients eventually required ventilator support after administration of TCZ. One patient was successfully extubated.
The mean duration of ICU stay was 9.3 days. The cumulative incidence of clinical improvement was 79% (n = 42). The mean time to clinical improvement was 5.5 ± 3.7 days. The cumulative incidence of mortality was 20.7% (n = 11) and mean time to mortality was 8.1 days. Median time to clinical failure was 4.3 days whereas mean time to hospital discharge was 12.8 ± 6.8 days. All the mortality occurred in patients who had severe disease on presentation (characteristics of those with severe diseases should be there to arrive at useful conclusions). There was no difference in outcomes according to gender, diabetic status, and presence of preexisting cardiac disease. All patients, who had high-grade fever, became afebrile within 24 h of TCZ.
The primary outcome was defined as need for mechanical ventilation or death. [Table 2] shows comparison of change in various laboratory parameters between those without and with primary outcome after administration of TCZ. Comparison of changes in laboratory parameters in outcome groups shows in [Figure 1].
|Table 2: Change in laboratory parameters after tocilizumab administration|
Click here to view
The baseline median NLR was 5.9 and 12.5 in those without and with primary outcome, respectively. NLR decreased significantly at day 7 in those without primary outcome whereas it increased in those with primary outcome.
C-reactive protein test
The baseline median CRP was 73.5 mg/L and 117 mg/L in those without and with primary outcome, respectively. The CRP decreased significantly at day 7 in both the groups.
The baseline median d-dimer was 826 ng/mL and 1539 ng/mL in those without and with primary outcome, respectively. The change in d-dimer level was not significant in both the groups; however, the magnitude of increase in d-dimer level was very high in those with primary outcome.
The baseline median ferritin level was 619 ng/mL and 805 ng/mL in those without and with primary outcome, respectively. Like NLR, the ferritin level decreased significantly at day 7 in those without primary outcome whereas it increased in those with primary outcome.
The median of PaO2/FiO2 ratio was 168 and 83 in those without and with primary outcome, respectively, at baseline. The PaO2/FiO2 ratio improved significantly at day 7 in those without primary outcome as compared to those with primary outcome.
Serum glutamic-pyruvic transaminase
The median SGPT was 53.9 U/L at baseline which increased to 89.6 U/L on day 3. The change in SGPT levels from baseline to day 3 (P = 0.04) was statistically significant. However, in majority patients SGPT level came down to baseline level.
Changes in radiological assessment
Chest x-ray was performed in all patients. At baseline 37 patients had abnormal chest x ray. Out of this, eight patients showed improvement in chest X-ray after 24–48 h. Three patients showed worsening of chest X-ray while in remaining patients no significant changes were noted. Out of 16 patients with unremarkable X-ray findings at baseline five patients showed worsening. Forty-two patients underwent high-resolution computed tomography (HRCT) scan of the thorax. Follow-up CT scan was performed in 13 patients within 2 weeks of the initial scan. Two patients showed improvement in HRCT while five patients did not show any significant change as compared to previous scan. HRCT thorax worsened in three patients and remaining three patients showed changes of pulmonary fibrosis.
Overall, the TCZ injection was well tolerated, and none of the patients had an infusion-related adverse drug event. Asymptomatic elevation of SGPT was seen in majority of patients but none of the patients exhibited significant liver injury. Three patients had marked rise in leukocyte count and slightly elevated procalcitonin level, however, no organism could be isolated. One patient died due to septicemia.
Patients were followed at 2 and 4-week interval either telephonically or in clinic. Total 20 patients were lost to follow-up. Twenty-eight patients remained asymptomatic following discharge. Three patients had persistent shortness of breath on exertion. One patient developed urinary tract infection after discharge which was treated with oral antibiotics. One patient was readmitted after 10 days for worsening breathlessness.
| Discussion|| |
In this retrospective single-arm cohort study, we evaluated the effectiveness of TCZ therapy in patients with moderate-to-severe COVID-19 pneumonia. Critically ill COVID-19 patients often exhibit exuberant inflammatory response, similar to cytokine release syndrome, with elevated inflammatory markers and elevated proinflammatory cytokines. Corticosteroids are the conventional agents used to fight cytokine storms. However, corticosteroids therapy is associated with prolonged treatment and subsequent risk of side effects. The rationale for the use of the anti-IL-6 receptor antibody TCZ in COVID-19 patients is based on the role of IL-6 in this disease and the experience with this drug in the treatment of rheumatoid arthritis and cytokine release syndrome.
One of the most striking effects of TCZ was prompt resolution of fever, usually within 24 h of administration. CRP levels were elevated in both the groups; however, the mean CRP level was higher in those with primary outcome. Following TCZ administration, CRP level dropped significantly in both the groups and reached to normal level by 7th day. Studies have shown that elevated CRP levels correlate with disease severity. Our study validates these findings. CRP level, however, failed to predict outcome in our study. Similarly, NLR, d-dimer and ferritin levels were elevated at baseline. After TCZ administration, ferritin and NLR levels reduced significantly in those without primary outcome whereas d-dimer level did not fall in either group. NLR, d-dimer, and ferritin levels actually increased in those with primary outcome. These findings suggest that these markers can serve as prognostic indicators and serial monitoring of their values can help in predicting worsening clinical status. Numerous studies have shown prognostic value of NLR, D-dimer, and ferritin.,,,, TCZ failed to reduce d-dimer level, pointing toward alternative mechanisms involved in hypercoagulability and necessitating additional treatment with anticoagulants. Our study also demonstrated that initial chest X-ray may be normal in patients with moderate or severe disease and subsequent improvement in radiological findings may lag behind clinical improvement. Some patients exhibited pulmonary fibrosis on follow-up CT chest. These findings are consistent with previously published studies.,
Mortality in patients admitted to ICU can be as high as 33%–36% as reported previously., The mortality reported in our study was 20% with majority of patients being admitted to ICU, suggesting a potential role of TCZ in reducing the need for invasive ventilation. However, the results of our retrospective study needs to be viewed with caution as a recent randomized control trial did show a reduction in the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve the survival. In our study also, only five patients eventually required ventilatory support after TCZ administration. However, only one patient was successfully weaned off. None of the patient with moderate disease on presentation died in our study whereas 39% (11 out of 28) with initial severe disease died. This finding could suggest that early administration of TCZ before progression to severe disease may be helpful in reducing the need for invasive ventilation and might prevent progression of disease.
Three (5%) patients had increase in leukocyte count and procalcitonin level. Apart from those, no major side effects were observed in our study. Four patients had persistent dyspnea at 1 month. The time to recovery from COVID-19 is highly variable and potential for ongoing respiratory impairment has been observed.,
A major limitation of our study the was retrospective nature and the lack of a control arm which was difficult for us to design given the scenario of acute crisis in healthcare. Another limitation is that the majority of our patients also received corticosteroid which has shown beneficial effect in hyperinflammation induced by COVID-19, making it difficult to interpret the results.
| Conclusion|| |
Overall, TCZ administration is safe and appears to be effective in improving clinical and laboratory parameters with a possible reduction in the need for ventilatory care and duration of ICU stay, particularly in patients with moderate disease. However, our results should be considered preliminary and should be interpreted with caution as they stem from an uncontrolled series.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS coronavirus. J Virol 2020;94:e00127-20.
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al.
SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-80.e8.
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese center for disease control and prevention. JAMA 2020;323:1239-42.
Mossel EC, Wang J, Jeffers S, Edeen KE, Wang S, Cosgrove GP, et al.
SARS-CoV replicates in primary human alveolar type II cell cultures but not in type I-like cells. Virology 2008;372:127-35.
Weinheimer VK, Becher A, Tönnies M, Holland G, Knepper J, Bauer TT, et al.
Influenza A viruses target type II pneumocytes in the human lung. J Infect Dis 2012;206:1685-94.
Wu J, Wu X, Zeng W, Guo D, Fang Z, Chen L, et al.
Chest CT findings in patients with coronavirus disease 2019 and its relationship with clinical features. Invest Radiol 2020;55:257-61.
Zhang S, Li H, Huang S, You W, Sun H. High-resolution computed tomography features of 17 cases of coronavirus disease 2019 in Sichuan province, China. Eur Respir J 2020;55:2000334.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al.
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al.
COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4.
Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol 2020;92:814-8.
Michot JM, Albiges L, Chaput N, Saada V, Pommeret F, Griscelli F, et al.
Tocilizumab, an anti-IL-6 receptor antibody, to treat COVID-19-related respiratory failure: A case report. Ann Oncol 2020;31:961-4.
Zhang X, Song K, Tong F, Fei M, Guo H, Lu Z, et al.
First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab. Blood Adv 2020;4:1307-10.
Kotch C, Barrett D, Teachey DT. Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome. Expert Rev Clin Immunol 2019;15:813-22.
Yao Y, Cao J, Wang Q, Shi Q, Liu K, Luo Z, et al.
D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: A case control study. J Intensive Care 2020;8:49.
Wang L. C-reactive protein levels in the early stage of COVID-19. Med Mal Infect 2020;50:332-4.
Cheng L, Li H, Li L, Liu C, Yan S, Chen H, et al.
Ferritin in the coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis. J Clin Lab Anal 2020;34:e23618.
Yang AP, Liu JP, Tao WQ, Li HM. The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients. Int Immunopharmacol 2020;84:106504.
Velavan TP, Meyer CG. Mild versus severe COVID-19: Laboratory markers. Int J Infect Dis 2020;95:304-7.
Han X, Cao Y, Jiang N, Chen Y, Alwalid O, Zhang X, et al.
Novel coronavirus disease 2019 (COVID-19) pneumonia progression course in 17 discharged patients: Comparison of clinical and thin-section computed tomography features during recovery. Clin Infect Dis 2020;71:723-31.
Ojo AS, Balogun SA, Williams OT, Ojo OS. Pulmonary fibrosis in COVID-19 survivors: Predictive factors and risk reduction strategies. Pulm Med 2020;2020:6175964.
Horby PW, Campbell M, Staplin N, Spata E, Emberson JR, Pessoa-Amorim G, et al
. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): Preliminary results of a randomised, controlled, open-label, platform trial. Medrxiv 2021;397:1637-45.
REMAP-CAP Investigators; Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, et al.
Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med 2021;384:1491-502.
Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, et al.
Tocilizumab in patients hospitalized with COVID-19 pneumonia. N Engl J Med 2021;384:20-30.
Huang Y, Tan C, Wu J, Chen M, Wang Z, Luo L, et al.
Impact of coronavirus disease 2019 on pulmonary function in early convalescence phase. Respir Res 2020;21:163.
You J, Zhang L, Ni-Jia-Ti MY, Zhang J, Hu F, Chen L, et al.
Anormal pulmonary function and residual CT abnormalities in rehabilitating COVID-19 patients after discharge. J Infect 2020;81:e150-2.
[Table 1], [Table 2]