Comparative study of tocilizumab versus itolizumab in coronavirus disease 2019-infected patients: a randomized controlled trial

Objective We aimed to compare the effect of tocilizumab and itolizumab in terms of PaO2/FiO2 ratio (P/F ratio), interleukin 6 (IL-6) level, serum ferritin, C-reactive protein, and a reduction in mortality. Our primary objective was to compare P/F ratio at various time intervals: baseline (before administering the drug), 12 h after drug administration, once a day for the next 7 days, and on the 14th day. Our secondary objective was to evaluate serum level of biomarkers like IL-6, ferritin, and C-reactive protein before start of drug infusion and following drug infusion at 72 h and on 7th day. Patients and methods A total of 50 patients, age between 18 and 60 years, having moderate Acute Respiratory distress syndrome (ARDS) following coronavirus disease 2019 infection were recruited. Patients of group I received a single dose of injection of tocilizumab 8 mg/kg intravenously (i.v.) via infusion over 1–2 h. Group II patients received premedication with hydrocortisone 100 mg and pheniramine 30 mg and a single dose of injection itolizumab 1.6 mg/kg dissolved in 250 ml of 0.9% normal saline infusion over 5–6 h. Results We observed significantly higher P/F ratio in the itolizumab group (239.18±97.31) than in the tocilizumab group (104.87±75.25) on the 3rd day following drug administration (P<0.001). Similarly, the IL-6 level was lower in the itolizumab group (72±100) in comparison with the tocilizumab group (682±1360), and the differences were statistically significant (P<0.05). We identified adverse effects of the drugs in 10 patients who have received itolizumab. Conclusion We observed an increasing trend in P/F ratio on the 3rd day following itolizumab administration in comparison with tocilizumab, and the difference was statistically significant (P<0.001).

A Pilot Study on Blood Components in COVID-19 Affected Subjects: A Correlation to UPR Signalling and ER-Stress

The endoplasmic reticulum (ER) is the site for protein synthesis, its folding and secretion. An intricate set of signalling pathways, called UPR pathways, have been evolved by ER in mammalian cells, to allow the cell to respond the presence of misfolded proteins within the ER. Breaching of these signalling systems by disease oriented accumulation of unfolded proteins may develop cellular stress. The aim of this study is to explore whether COVID-19 infection is responsible for developing this kind of endoplasmic reticulum related stress (ER-stress). ER-stress was evaluated by checking the expression of ER-stress markers e.g. PERK (adapting) and TRAF2 (alarming). ER-stress was correlated to several blood parameters viz. IgG, pro- and anti-inflammatory cytokines, leukocytes, lymphocytes, RBC, haemoglobin and PaO2/FiO2 ratio (ratio of arterial oxygen partial pressure to fractional inspired oxygen) in COVID-19 affected subjects. COVID-19 infection was found to be a state of protein homeostasis (proteostasis) collapse. Changes in IgG levels showed very poor immune response by the infected subjects. At the initial phase of the disease, pro-inflammatory cytokine levels were high and anti-inflammatory cytokines levels were low;though they were partly compromised at later phase of the disease. Total leukocyte concentration increased over the period of time;while percentage of lymphocytes were dropped. No significant changes were observed in cases of RBC counts and haemoglobin (Hb) levels. Both RBC and Hb were maintained at their normal range. In mildly stressed group, PaO2/FiO2 ratio (oxygenation status) was in the higher side of normal range;whereas in other two groups the ratio was in respiratory distress syndrome mode. Virus could induce mild to severe ER-stress, which could be the cause of cellular death and systemic dysfunction introducing fatal consequences. Graphical Schematic representation of SARS-CoV-2 infection and related consequences.

A Pilot Study on Blood Components in COVID-19 Affected Subjects: A Correlation to UPR Signalling and ER-Stress.

Abstract: The endoplasmic reticulum (ER) is the site for protein synthesis, its folding and secretion. An intricate set of signalling pathways, called UPR pathways, have been evolved by ER in mammalian cells, to allow the cell to respond the presence of misfolded proteins within the ER. Breaching of these signalling systems by disease oriented accumulation of unfolded proteins may develop cellular stress. The aim of this study is to explore whether COVID-19 infection is responsible for developing this kind of endoplasmic reticulum related stress (ER-stress). ER-stress was evaluated by checking the expression of ER-stress markers e.g. PERK (adapting) and TRAF2 (alarming). ER-stress was correlated to several blood parameters viz. IgG, pro- and anti-inflammatory cytokines, leukocytes, lymphocytes, RBC, haemoglobin and PaO2/FiO2 ratio (ratio of arterial oxygen partial pressure to fractional inspired oxygen) in COVID-19 affected subjects. COVID-19 infection was found to be a state of protein homeostasis (proteostasis) collapse. Changes in IgG levels showed very poor immune response by the infected subjects. At the initial phase of the disease, pro-inflammatory cytokine levels were high and anti-inflammatory cytokines levels were low; though they were partly compromised at later phase of the disease. Total leukocyte concentration increased over the period of time; while percentage of lymphocytes were dropped. No significant changes were observed in cases of RBC counts and haemoglobin (Hb) levels. Both RBC and Hb were maintained at their normal range. In mildly stressed group, PaO2/FiO2 ratio (oxygenation status) was in the higher side of normal range; whereas in other two groups the ratio was in respiratory distress syndrome mode. Virus could induce mild to severe ER-stress, which could be the cause of cellular death and systemic dysfunction introducing fatal consequences. Graphical Abstract: Schematic representation of SARS-CoV-2 infection and related consequences.

Does Long-term Oxygen Therapy and Noninvasive Ventilation Predispose Rhino-orbital-cerebral Mucormycosis in COVID-19 Patients?

How to cite this article: Kumar A, Kumar A, Kumar N, Kumar A, Sinha C, Singh PK. Does Long-term Oxygen Therapy and Noninvasive Ventilation Predispose Rhino-orbital-cerebral Mucormycosis in COVID-19 Patients? Indian J Crit Care Med 2022;26(9):1063-1064.

NUTRIC score as a predictor of outcome in COVID-19 ARDS patients: A retrospective observational study.

BACKGROUND AND AIMS: The Nutrition Risk in Critically ill (NUTRIC) score is an appropriate nutritional assessment tool in mechanically ventilated patients. We retrospectively observed the applicability of the NUTRIC score for predicting outcomes in coronavirus disease (COVID)-19 acute respiratory distress syndrome (ARDS) patients. METHODS: All adult COVID-19 ARDS patients admitted to the intensive care unit and requiring various forms of oxygen therapy were included in the study. The demographic characteristics and clinical information about the patients were obtained from the hospital's medical records department. The nutritional risk for each patient was assessed using the NUTRIC score at 72 hours of ICU admission. The discriminating power and ability of NUTRIC score, Sequential Organ Failure Assessment (SOFA) score, age and Acute Physiology and Chronic Health Evaluation (APACHE) II to predict the 28-day mortality and need for mechanical ventilation (MV) was calculated using receiver operating characteristic curves and area under this curve. RESULTS: A total of 80 COVID-19 ARDS patients fitted into the inclusion criteria. Among non-survivors, the median Glasgow Coma Score, APACHE II score, NUTRIC score and SOFA score were 10, 16, 6 and 4, respectively. The cut-off values for NUTRIC score, SOFA, and APACHE II to predict 28-day mortality and need for MV was obtained as 3.5, 3.5 and 11.5, respectively. These cut-off values of NUTRIC score, SOFA score, and APACHE II have a sensitivity of 62%, 72.5% and 75.5%, respectively, and specificity of 95%, 72% and 83% for predicting mortality. CONCLUSIONS: Most COVID-19 ARDS patients requiring MV in the ICU are at nutritional risk, and a high NUTRIC score is associated with higher mortality.

Acute Exacerbation of Cough as a Precipitating Cause of Hypoxia in COVID-19 Patients.

Kumar A, Kumar A, Kumar A, Sinha C, Kumar N, Singh PK. Acute Exacerbation of Cough as a Precipitating Cause of Hypoxia in COVID-19 Patients. Indian J Crit Care Med 2021;25(11):1324-1325.

The COSEVAST Study Outcome: Evidence of COVID-19 Severity Proportionate to Surge in Arterial Stiffness.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection affects the cardiovascular system at many levels. It initially infects endothelial cells, inducing marked endothelial damage and inflammation. However, there was no empirical evidence of functional compromise of arterial walls. AIMS AND OBJECTIVE: Our primary objective was to study functional arterial damage in coronavirus disease 2019 (COVID-19) and establish the noninvasive measurement of arterial stiffness as an independent marker of disease severity. MATERIALS AND METHODS: We recorded the arterial stiffness of 23 mild, 21 moderate, and 20 severe COVID-19 patients grouped on the latest National Institute of Health (NIH) severity criteria. We observed arterial stiffness of COVID-19 patients with standard parameters like noninvasive estimated carotid-femoral pulse wave velocity (cfPWV), age-normalized increase in cfPWV (ANI_cfPWV), age-normalized increase in aortic augmentation pressure (ANI_AugP), and heart rate-normalized augmentation index (HRN_ AIx). All the parameters were also corrected for statistically significant confounding factors. RESULTS: Moderate and severe COVID-19 patients have extremely significantly elevated arterial stiffness than mild patients. In mild patients, cfPWV (829.1 ± 139.2 cm/second) was significantly lower than both moderate (1067 ± 152.5 cm/second, p <0.0001) and severe (1416 ± 253.9 cm/second, p <0.0001) patients. ANI_cfPWV in moderate and severe patients was significantly higher than mild patients (mild: 101.2 ± 126.1 cm/second; moderate: 279 ± 114.4 cm/second; severe: 580.1 ± 216.4 cm/second; intergroup p <0.0001). The results even after correction for significant confounding factors did not show any considerable change in the increasing trend of arterial stiffness. CONCLUSION: This study establishes the functional deterioration of arteries in proportion to the severity of COVID-19. HOW TO CITE THIS ARTICLE: Kumar N, Kumar S, Kumar A, Bhushan D, Kumar A, Kumar A, et al. The COSEVAST Study Outcome: Evidence of COVID-19 Severity Proportionate to Surge in Arterial Stiffness. Indian J Crit Care Med 2021;25(10):1113-1119.

Repackaging of Malfunctioning High-flow Nasal Cannula as a Rescue Oxygen Therapy: An Innovation amid COVID-19 Crisis.

Oxygen supplementation is required for approximately 14% of the patients diagnosed of having COVID-19 infection. Despite the use of conventional oxygen therapy, 5% among these require treatment in the intensive care unit (ICU). Here, we are describing a situation in which oxygen therapy was delivered to the patients by making an assembly of oxygen tubing, three-way stopcock, and high-flow nasal cannula (HFNC) present in the hospital setting following the malfunction of air blender of HFNC machine (Fig. 1). This assembly might be useful as rescue oxygen therapy during a malfunction of HFNC machine and in resource-limited settings where HFNC machine is not available. The mechanisms of action could be (1) washout of anatomic dead space due to medium oxygen flow, (2) improved gas mixing in large airways, and (3) increased oxygen concentration inside the conducting airway. How to cite this article: Kumar A, Kumar A, Kumar N, Kumar A, Singh V, Kumar S, et al. Repackaging of Malfunctioning High-flow Nasal Cannula as a Rescue Oxygen Therapy: An Innovation amid COVID-19 Crisis. Indian J Crit Care Med 2021;25(8):948-949.

Multiple Peaked Cytokine Storm: Is Multiple Exposures to the COVID-19 Virus a Possible Cause?

Severe acute respiratory syndrome coronavirus 2 is the pathogen that causes coronavirus disease-2019 (COVID-19). Recent studies have shown that the "cytokine storm" (high concentration of proinflammatory cytokines) may contribute to the mortality of COVID-19. Repeated exposure to the virus can lead to a dose-dependent immune response that may be associated with more disease severity and higher mortality. Sudden deterioration/increased oxygen consumption after initial improvement may be due to multiple surges of cytokines storm within a short period, the possible cause may be due to multiple exposures within the incubation period. We hypothesize that multiple surges in cytokines storm in some patients may be due to multiple exposures of the same patient within the incubation period, sepsis, or other inflammatory lesions inside the body. In our cases, sepsis as a cause of cytokine storm was ruled out by doing the procalcitonin test, which was within the normal limit. HOW TO CITE THIS ARTICLE: Kumar A, Kumar A, Kumar A, Kumar N, Sinha C, Singh V. Multiple Peaked Cytokine Storm: Is Multiple Exposures to the COVID-19 Virus a Possible Cause? Indian J Crit Care Med 2021;25(4):463-464.

Off-label Use of Itolizumab in Patients with COVID-19 ARDS: Our Clinical Experience in a Dedicated COVID Center.

Severe acute respiratory syndrome coronavirus 2 has affected millions of people worldwide. This pandemic requires newer medical management strategies to control the morbidity and mortality associated with the disease. Several approaches, including global targeting of inflammation or neutralizing a single key inflammatory mediator, are being employed to cope with cytokine storms in coronavirus disease-2019 (COVID-19). The role of anti-inflammatory biologics, such as acalabrutinib, tocilizumab, anakinra, and itolizumab can become relevant. Itolizumab is a humanized recombinant immunoglobulin G1 monoclonal antibody. It targets the extracellular, scavenger receptor cysteine-rich (SRCR) distal domain 1 of CD6 and is responsible for priming, activation, and differentiation of T-cells. Itolizumab has been approved by the Drug Controller General of India for the treatment of COVID-19 in India. Here, we shared our clinical experience of 20 patients having moderate acute respiratory distress syndrome (ARDS) due to COVID-19 on treatment with itolizumab. We observed the mortality benefit with single-dose itolizumab (1.6 mg/kg) in patients having moderate COVID-19 ARDS. HOW TO CITE THIS ARTICLE: Kumari P, Kumar A, Sinha C, Kumar A, Singh PK, Arun SK. Off-label Use of Itolizumab in Patients with COVID-19 ARDS: Our Clinical Experience in a Dedicated COVID Center. Indian J Crit Care Med 2021;25(4):467-469.

Dual Oxygen Therapy in COVID-19 Patient: A Method to Improve Oxygenation.

Approximately 5-6% of patients diagnosed to have COVID-19 infection present with severe hypoxemia requiring invasive ventilation or non-invasive ventilation (NIV). Additional oxygen to patients on NIV can be given by nasal prong or by connecting oxygen tubing directly to the O2 pick-off port of the NIV mask or by connecting oxygen tubing to the single-limb circuit in between ventilator and patient. Dual oxygen therapy improves oxygenation in COVID-19 patients on NIV. This method may make the patient more comfortable, increase tolerance to NIV, increase the usefulness of NIV for moderate and severe COVID-19 acute respiratory distress syndrome (ARDS). How to cite this article: Kumar A, Kumar A, Sinha C, Kumar N, Singh K, Singh PK. Dual Oxygen Therapy in COVID-19 Patient: A Method to Improve Oxygenation. Indian J Crit Care Med 2021;25(2):231-233.

Comparative Analysis of Commercial Colloidal Silver Products.

PURPOSE: The public fear associated with the novel coronavirus (SARS-CoV-2) pandemic has triggered recently a significant proliferation of supplements touted as potential cures against bacteria and viruses. Colloidal silver has particularly benefited from this rush given its empirically and scientifically documented anti-bacterial and anti-viral actions. The lack of standards in the unregulated supplements industry remains a major roadblock in evaluating the quality and consistency of marketed products or assessing the accuracy of the information provided by manufacturers. This study is the first scientifically rigorous attempt to evaluate commercial silver colloidal products offered for sale on the internet. METHODS: Fourteen of the most popular colloidal silver products purchased from Amazon (www.amazon.com) were evaluated using state-of-the-art analytical techniques widely accepted as gold standards for investigating the properties (size, shape) and the dispersion of silver nanoparticles. RESULTS: Commercial samples were analysed using UV-Vis, FE-SEM and AAS techniques. In general, the Ag concentration was very close to those claimed by the manufacturer. The colorless product shows no absorbance in the UV-Vis analysis. The FESEM and STEM images confirmed the conclusions of the UV-Vis analysis. CONCLUSION: The results of this evaluation show clearly that 70% of the commercial products evaluated contain only ionic silver. Despite the evidence showing that silver nanoparticles are not present, eight of these products are promoted by the manufacturers as 'colloidal silver'. Considering the extensive scientific research showing major differences between silver ionic and silver nanoparticles in terms of mechanisms of action, efficacy and safety, it is clear that this misrepresentation impacts the consumers and must be addressed. This study serves as blueprint for a scientific protocol to be followed by manufacturers for characterizing their silver supplements.