Death In COVID-19 Patients Research Articles

BCR, not TCR, repertoire diversity is associated with favorable COVID-19 prognosis.

The SARS-CoV-2 pandemic has had a widespread and severe impact on society, yet there have also been instances of remarkable recovery, even in critically ill patients. In this study, we used single-cell RNA sequencing to analyze the immune responses in recovered and deceased COVID-19 patients during moderate and critical stages. Expanded T cell receptor (TCR) clones were predominantly SARS-CoV-2-specific, but represented only a small fraction of the total repertoire in all patients. In contrast, while deceased patients exhibited monoclonal B cell receptor (BCR) expansions without COVID-19 specificity, survivors demonstrated diverse and specific BCR clones. These findings suggest that neither TCR diversity nor BCR monoclonal expansions are sufficient for viral clearance and subsequent recovery. Differential gene expression analysis revealed that protein biosynthetic processes were enriched in survivors, but that potentially damaging mitochondrial ATP metabolism was activated in the deceased. This study underscores that BCR repertoire diversity, but not TCR diversity, correlates with favorable outcomes in COVID-19.

Histological analysis of the spleen of rats immunized with SARS-CoV-2 S protein

SARS-CoV-2 infection can lead to pathological disorders in various organs due to the ubiquitous of angiotensin-converting enzyme 2 (ACE2), which serves as a receptor for SARS-CoV-2. However, tissue damage may not only be the result of viral infection. SARS-CoV-2 has been shown to induce the production of autoantibodies to ACE2, and their presence is associated with disease severity. The spleen is one of the targets for COVID-19. The presence of ACE2 in the red pulp sinus endothelium cells of the spleen and in tissue-resident CD169+ macrophages positioned in the splenic marginal zone makes these cells a potential target of autoimmune reactions to ACE2 triggered by SARS-CoV-2. In addition, antibodies to the SARS-CoV-2 S protein cross-react with a wide range of human tissue proteins and can cause tissue damage. The most common splenic pathologies in deceased COVID-19 patients are lymphocyte depletion and subsequent hemaphagocytosis. Since the spleen plays a fundamental role in the immune response regulation, splenic damage could be one of the causes of immune perturbations associated with severe COVID-19. To test the hypothesis of the autoimmune nature of COVID-19, we developed a non-infectious experimental model of autoimmune multiorgan damage caused by immunization with SARS-CoV-2 S protein. The purpose of this work was to study the spleen in rats with induced multiorgan damage caused by immunization with SARS-CoV-2 S protein, as well as the influence of pre-existing autoimmune disease on the severity of splenic damage caused by an immune response against S protein. Intact Wistar rats and Wistar rats with completed experimental autoimmune encephalomyelitis were immunized with S protein in incomplete Freund’s adjuvant (IFA). Control rats received an injection of IFA. No changes were detected in the secondary follicles number in the spleen of rats immunized with the SARS-CoV-2 S protein. However, in the spleen of rats with previously induced autoimmune encephalomyelitis, immunization with SARS-CoV-2 S protein caused a significant decrease in the number of secondary follicles relative to the control group. Hemosiderin deposits and macrophage hyperplasia of the marginal zones of the white pulp were detected in both groups immunized with S protein. Thus, immunization with the S protein of SARS-CoV-2 causes changes in the spleen of rats similar to those detected in patients who died from COVID-19. Damage to the spleen is more varied and pronounced in rats with previous experimental encephalomyelitis.

SARS-CoV-2 infection induces hyaluronan production in vitro and hyaluronan levels in COVID-19 patients relate to morbidity and long-term lung impairment: a prospective cohort study.

We previously demonstrated that the lungs of deceased COVID-19 patients were filled with a clear hydrogel consisting of hyaluronan (HA). In this translational study, we investigated the role of HA at all stages of COVID-19 disease to map the consequences of elevated HA on morbidity and identify the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced HA production. A reduced alveolar surface area was observed in the lungs of deceased COVID-19 patients compared to healthy controls, as visualized by a 3D rendering of lung morphology using light-sheet fluorescence microscopy. We confirmed the presence of HA in lung biopsies and found large quantities of proinflammatory fragmented HA. The association of systemic HA in blood plasma and disease severity was assessed in patients with mild (WHO Clinical Progression Scale, WHO-CPS, 1-5) and severe COVID-19 (WHO-CPS, 6-9) during the acute and convalescent phases and related to lung function. We found that systemic levels of HA were high during acute COVID-19 disease, remained elevated during convalescence, and were associated with a reduced diffusion capacity. In vitro 3D-lung models, differentiated from primary human bronchial epithelial cells, were used to study the effects of SARS-CoV-2 infection on HA metabolism, and transcriptomic analyses revealed a dysregulation of HA synthases and hyaluronidases, both contributing to increased HA in apical secretions. Furthermore, corticosteroid treatment reduced the inflammation and downregulated HA synthases. Our findings demonstrate that HA plays a role in COVID-19 morbidity and that sustained elevated HA concentrations may contribute to long-term respiratory impairment.IMPORTANCEThis study provides insights into the role of hyaluronan (HA) in the severity and long-term impact of COVID-19 on lung function. Through extensive morphological examination of lung tissues and a multicenter study, we identified that HA levels are significantly elevated in COVID-19 patients, correlating with a reduced lung diffusion capacity during convalescence. Using a 3D-lung model, we further uncovered how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 infection causes a dysregulated HA metabolism, leading to increased HA production. Our findings provide valuable insights into the pathogenesis of SARS-CoV-2 and suggest that targeting HA metabolism could offer new therapeutic avenues for managing COVID-19, particularly to prevent long-term lung impairment. Additionally, HA holds potential as a biomarker for predicting disease severity, which could guide personalized treatment strategies.

Promises and Pitfalls of Calcineurin Inhibitors in COVID-19: A Systematic Review and Meta-analysis of Controlled Trials.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a violent attack on the body that leads to multi-organ failure and death in COVID-19 patients. The aim of this study was to systematically review the existing literature on the potential benefits of calcineurin inhibitors (CIs) as anti-vascular endothelial growth factor (VEGF) agents in improving the clinical outcomes of COVID-19 patients. We searched various databases, including PubMed, Scopus, ISI Web of Science, Google Scholar, Cochrane databases, and ClinicalTrials.gov from 31st December, 2019, to 3rd February, 2023, for relevant controlled trials. The quality of the evidence was assessed using the Cochrane Collaboration tool. Comprehensive Meta-Analysis Software was used for the statistical analyses using a random-effects model. Three trials enrolling 293 participants were reviewed in the present systematic review and meta-analysis. The results showed CIs to lead to a significant reduction in mortality rate [risk ratio (RR): 0.598, 95% CI: 0.404-0.885, P-value = 0.010] with a low between-study heterogeneity (Cochrane Q test: I2 = 0.000%, P-value = 0.371). Pooled analysis of two studies (84 patients) illustrated that CIs could not significantly increase the rate of hospital discharge (RR: 1.161, 95% CI: 0.764-1.764, P-value = 0.485) and heterogeneity was not significant (Cochrane Q test: I2 = 26.798%, P-value = 0.242). CIs are able to inhibit the virus nucleocapsid protein so that they can prevent replication and respiratory tract tissue damage caused by SARS-CoV-2. Based on the characteristics mentioned in detail, CIs can play a potential therapeutic role for COVID-19 patients.

Deciphering gender disparities in laboratory biomarkers among deceased COVID-19 patients in Erbil city-Iraq: A retrospective study

Introduction: SARS-CoV-2 was a new strain of the Coronaviridae family. It caused the coronavirus disease in December 2019 that first arose in Wuhan, China, and it developed into a worldwide health issue. COVID-19 gives rise to a wide range of symptoms which can range from having no symptoms to having extensive fatal pneumonia. Objectives: The purpose of the study was to figure out how infecting the virus could influence and impact the various laboratory biomarkers among dead male and female patients. Patients and Methods: The data and statistics were obtained from the dead patients of West Emergency Hospital and the data was investigated directly. The investigation was conducted from June 1st to November 1st, 2020. Epidemiological, clinical as well as lab data of approximately 659 dead cases of SARS-CoV-2 infected individuals were examined in that period. A real-time polymerase chain reaction (RT-PCR) technique was applied to confirm infecting of SARS-CoV-2. The deceased cases were categorized into 2 fractions, which were a male and female group. The male group had 407 individuals and the female group had 252 individuals. Results: This study revealed that the male cases had lower lymphocyte and platelet counts than females but substantially higher levels of urea and creatinine, also the male cases were older compared to the female cases. However, D-dimer and C-reactive protein (CRP ) levels did not indicate any notable differences between the two groups. Conclusion: The study showed a gender-situated differences in the laboratory biomarkers of dead COVID-19 cases.

Necroptosis in alveolar epithelial cells drives lung inflammation and injury caused by SARS-CoV-2 infection

COVID-19, caused by SARS-CoV-2 infection, results in irreversible or fatal lung injury. We assumed that necroptosis of virus-infected alveolar epithelial cells (AEC) could promote local inflammation and further lung injury in COVID-19. Since CD8+ lymphocytes induced AEC cell death via cytotoxic molecules such as FAS ligands, we examined the involvement of FAS-mediated cell death in COVID-19 patients and murine COVID-19 model. We identified the occurrence of necroptosis and subsequent release of HMGB1 in the admitted patients with COVID-19. In the mouse model of COVID-19, lung inflammation and injury were attenuated in Fas-deficient mice compared to Fas-intact mice. The infection enhanced Type I interferon-inducible genes in both groups, while inflammasome-associated genes were specifically upregulated in Fas-intact mice. The treatment with necroptosis inhibitor, Nec1s, improved survival rate, lung injury, and systemic inflammation. SARS-CoV-2 induced necroptosis causes cytokine induction and lung damage, and its inhibition could be a novel therapeutic strategy for COVID-19.

Predictive value of inflammatory factors and lymphocyte counts in tracheal intubation and death after infection with COVID-19

ObjectiveThis study aims to investigate the prognostic significance of inflammatory cytokines and lymphocyte levels in predicting disease progression among patients with COVID-19 infection.MethodsNinety-two hospitalized COVID-19 patients were retrospectively included as subjects for this study. General clinical information and various indicators, including lymphocyte count, interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor (TNF), were collected. All patients received treatment according to the ninth edition of the guidelines for COVID-19. Incidences of endotracheal intubation and mortality within 28 days were observed.Results1.In the analysis of intubation impact, multivariate analysis identified age, immunoglobulins, lymphocytes, and IL-6 as independent risk factors. When analyzing the impact on patient mortality, multivariate analysis revealed age, prealbumin, and BNP as independent risk factors. 2. Lymphocyte count and inflammatory factors demonstrated predictive value for endotracheal intubation in COVID-19 patients. The critical lymphocyte count value was 0.91, with a sensitivity of 38.8%, specificity of 92.9%, and AUC of 0.687 (95% CI: 0.580–0.795). The critical IL-6 value was 38.21, with a sensitivity of 81%, specificity of 63.3%, and AUC of 0.771 (95% CI: 0.6670.872). The area under the ROC curve for IL-8, IL-10 and TNF is 0.665, 0.712 and 0.648, respectively. 3.Lymphocyte count and inflammatory factors also exhibited predictive value for death in COVID-19 patients. The critical lymphocyte count value was 0.56, with a sensitivity of 71.2%, specificity of 57.5%, and AUC of 0.641 (95% CI: 0.528–0.754). The critical IL-6 value was 53.05, with a sensitivity of 75%, specificity of 71.2%, and AUC of 0.770 (95% CI: 0.6690.870). The area under the ROC curve for IL-8, IL-10 and TNF is 0.687, 0.683 and 0.636, respectively.ConclusionElevated inflammatory factors and decreased lymphocyte levels have prognostic value for predicting endotracheal intubation and mortality in COVID-19 patients, providing valuable insights for clinicians in anticipating disease progression.

Inflammation in the COVID-19 airway is due to inhibition of CFTR signaling by the SARS-CoV-2 spike protein

SARS-CoV-2-contributes to sickness and death in COVID-19 patients partly by inducing a hyper-proinflammatory immune response in the host airway. This hyper-proinflammatory state involves activation of signaling by NFκB, and unexpectedly, ENaC, the epithelial sodium channel. Post-infection inflammation may also contribute to "Long COVID"/PASC. Enhanced signaling by NFκB and ENaC also marks the airway of patients suffering from cystic fibrosis, a life-limiting proinflammatory genetic disease due to inactivating mutations in the CFTR gene. We therefore hypothesized that inflammation in the COVID-19 airway might similarly be due to inhibition of CFTR signaling by SARS-CoV-2 spike protein, and therefore activation of both NFκB and ENaC signaling. We used western blot and electrophysiological techniques, and an organoid model of normal airway epithelia, differentiated on an air–liquid-interface (ALI). We found that CFTR protein expression and CFTR cAMP-activated chloride channel activity were lost when the model epithelium was exposed to SARS-CoV-2 spike proteins. As hypothesized, the absence of CFTR led to activation of both TNFα/NFκB signaling and α and γ ENaC. We had previously shown that the cardiac glycoside drugs digoxin, digitoxin and ouabain blocked interaction of spike protein and ACE2. Consistently, addition of 30 nM concentrations of the cardiac glycoside drugs, prevented loss of both CFTR protein and CFTR channel activity. ACE2 and CFTR were found to co-immunoprecipitate in both basal cells and differentiated epithelia. Thus spike-dependent CFTR loss might involve ACE2 as a bridge between Spike and CFTR. In addition, spike exposure to the epithelia resulted in failure of endosomal recycling to return CFTR to the plasma membrane. Thus, failure of CFTR recovery from endosomal recycling might be a mechanism for spike-dependent loss of CFTR. Finally, we found that authentic SARS-CoV-2 virus infection induced loss of CFTR protein, which was rescued by the cardiac glycoside drugs digitoxin and ouabain. Based on experiments with this organoid model of small airway epithelia, and comparisons with 16HBE14o- and other cell types expressing normal CFTR, we predict that inflammation in the COVID-19 airway may be mediated by inhibition of CFTR signaling by the SARS-CoV-2 spike protein, thus inducing a cystic fibrosis-like clinical phenotype. To our knowledge this is the first time COVID-19 airway inflammation has been experimentally traced in normal subjects to a contribution from SARS-CoV-2 spike-dependent inhibition of CFTR signaling.

Profile of patients died as a result of covid-19 with comorbid diabetes mellitus who was treated in the ICU with mechanical ventilation at Airlangga university hospital for the period of January - December 2021

COVID-19 is an acute respiratory infection caused by the SARS- Cov-2 type coronavirus. The severity of death in COVID-19 patients can also be influenced by the morbidity of diabetes mellitus. However, currently there is still controversy regarding the results of research regarding comorbid factors of diabetes mellitus (DM) with COVID-19. In my research, the aim is to find out whether there is an influence between Diabetes Mellitus (DM) on the level of severity and mortality in COVID-19 patients at Airlangga University Hospital in 2021. This research uses a data collection method in the form of total sampling. The sample used in this study was medical record data on all COVID-19 patients treated at Airlangga University Hospital for the period 1 January – 31 December 2021 who met the inclusion criteria. It was found that male gender, old age (56-65 years), high school education, private sector employment, and complaints of shortness of breath had a major contribution to the mortality of COVID-19 patients with diabetes. Based on the Chi Square test, the relationship between blood sugar levels and mortality in COVID-19 patients showed an outcome p of 0.208.

Upregulation of inflammatory genes and pathways links obesity to severe COVID-19

Obesity is a risk factor for developing severe COVID-19. However, the mechanism underlying obesity-accelerated COVID-19 remains unclear. Here, we report results from a study in which 2–3-month-old K18-hACE2 (K18) mice were fed a western high-fat diet (WD) or normal chow (NC) over 3 months before intranasal infection with a sublethal dose of SARS-CoV2 WA1 (a strain ancestral to the Wuhan variant). After infection, the WD-fed K18 mice lost significantly more body weight and had more severe lung inflammation than normal chow (NC)-fed mice. Bulk RNA-seq analysis of lungs and adipose tissue revealed a diverse landscape of various immune cells, inflammatory markers, and pathways upregulated in the infected WD-fed K18 mice when compared with the infected NC-fed control mice. The transcript levels of IL-6, an important marker of COVID-19 disease severity, were upregulated in the lung at 6–9 days post-infection in the WD-fed mice when compared to NC-fed mice. Transcriptome analysis of the lung and adipose tissue obtained from deceased COVID-19 patients found that the obese patients had an increase in the expression of genes and the activation of pathways associated with inflammation as compared to normal-weight patients (n = 2). The K18 mouse model and human COVID-19 patient data support a link between inflammation and an obesity-accelerated COVID-19 disease phenotype. These results also indicate that obesity-accelerated severe COVID-19 caused by SARS-CoV-2 WA1 infection in the K18 mouse model would be a suitable model for dissecting the cellular and molecular mechanisms underlying pathogenesis.

A SYSTEMATIC REVIEW AND META-ANALYSIS: RISK FACTORS OF MORTALITY COVID-19

Background: COVID-19 is still a threat throughout the world because of its high morbidity and mortality. Comorbid diseases like hypertension, diabetes mellitus, and heart disease are some of the factors in the high severity and mortality of COVID-19 patients. Purpose: The study aims to analyze the effect of risk factors on COVID-19 mortality using a systematic review and meta-analysis. Methods: Articles were taken from online journal portals Pubmed, Garuda, and Google Cendekia, and all were published from October 2019 to December 2021 in full text and with an observational study design. The keywords used in searching the articles were "COVID-19", "sars cov 2", "2019-nCoV", "2019 novel coronavirus", "COVID-19 deaths", and "COVID-19 mortality". The articles were collected using a PRISMA diagram; then, data extraction was carried out in a systematic review. The data was synthesized by using a meta-analysis technique using the RevMan application. Results: This study analyzed 59 articles and found that age, hypertension OR=3.09 (2.69-3.56), sex OR= 1.29 (1.08-1.53), and diabetes mellitus OR=3.03 (2.66-3.44) are the risk factors for COVID-19 death. Conclusion: The death in COVID-19 patients is influenced by elderly age, gender, and comorbid disease (diabetes and hypertension). These COVID-19-death-related factors can help health workers recognize and prevent a more severe stage of the disease through more appropriate handling and treatment.

The Relationship of Hypertension with Death in Covid-19 Patients Treated at Tugurejo Hospital Semarang

Covid-19 is a disease caused by SARS-CoV-2. Hypertension is a comorbidity that can be experienced by COVID-19 patients and is associated with an increased risk of severity and death. The purpose of this study is to look at the relationship between hypertension and death in COVID-19 patients treated at Tugurejo Hospital Semarang. This study is a quantitative study that uses an analytical observational design and a cross-sectional approach. The sampling technique was purposive sampling (judgment sampling) on 84 COVID-19 patients treated at Tugurejo Hospital Semarang for the May-November 2021 period. Data were obtained from medical records and analyzed univariately and bivariately with the Chi-Square test. Most patients were aged ≥50 years (40.5%), male (53.6%), high school educated (51.2%), employed as private employees (42.9%), suffered from hypertension (53.6%) and did not experience death (51.2%). The Chi-Square test resulted in a significant association between hypertension and death of COVID-19 patients (p = 0.031). There is an essential relationship between hypertension and death in COVID-19 patients at Tugurejo Hospital Semarang.

Abstract 1068: Peak Gamma' Fibrinogen Levels Are Associated With Death In COVID-19 Patients

Introduction: COVID-19 is associated with high levels of inflammation and high rates of thrombosis. We have shown previously that the inflammatory biomarker gamma' fibrinogen (GPF) is significantly associated with COVID-19 severity, as judged by SpO 2 levels. In addition, up to 70% of long COVID patients have GPF levels above the range of normal, even 6 weeks after infection. Hypothesis: We assessed the hypothesis that high GPF levels, by virtue of GPF's ability to bind and sequester active thrombin and prevent its inhibition by heparin/antithrombin III, would be associated with thrombotic events and adverse outcomes in COVID-19 patients. Methods: 52 COVID-19 patients at a tertiary care medical center in the IMPACC and Biobank studies were retrospectively enrolled, and GPF levels were measured using a commercial ELISA. Results: 11 patients died, and they had significantly higher peak levels of GPF, 135.2 ± 18.3 mg/dL (mean ± SE), compared to patients who lived, 87.5 ± 7.3 mg/dL, using a Wilcoxon rank-sum test (p = 0.013). Ten patients developed a VTE, either a deep vein thrombosis or a pulmonary embolism. The patients that developed a VTE had a trend towards higher levels of GPF, 125.4 ± 19.1 mg/dL (mean ± SE), compared to patients who did not develop a VTE (91.0 ± 7.7 mg/dL), but these results did not reach statistical significance (p = 0.067). ROC curve analysis revealed an area under the curve of 0.74 for GPF and death, whereas the area under the curve for GPF and VTE was 0.69. Conclusions: In conclusion, GPF levels are significantly associated with death in COVID-19 patients. Monitoring GPF levels in COVID-19 patients may therefore be warranted. Further studies are necessary to determine if the heparin resistance associated with GPF is involved.

Analysis of Risk Factors for Death in COVID-19 Patients at Bahteramas Regional General Hospital, Southeast Sulawesi Province

Background: Coronavirus disease 2019, or COVID-19, is an infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). COVID-19 has been classified as a pandemic since 2020. Purpose: The purpose of this study was to determine the risk factors for death due to COVID-19 at the Bahteramas Public Hospital, Southeast Sulawesi Province. Method: This research is a retrospective analytic study with a cross sectional approach. The number of samples is 85 samples. The sampling technique was purposive sampling. The data were processed using the Chi-Square test and Odds Ratio. Results: This study shows that 47 people died at the Bahteramas Hospital in Southeast Sulawesi Province from March to November 2020, the variable age (p value = 0.001 and OR value 5.216), gender (p value = 0.078 and OR value = 2.180), hypertension variable (p value = 0.071 and OR value = 2.510), and diabetes mellitus variable (p value = 0.013 and OR value = 3.300). Conclusion: Age, sex, hypertension, and diabetes mellitus are risk factors for death due to COVID-19 at Bahteramas Public Hospital, Southeast Sulawesi Province.

Assessing the effect of remdesivir alone and in combination with corticosteroids on time to death in COVID-19: A propensity score-matched analysis

BackgroundThis study aimed to evaluate the impact of remdesivir, alone or in combination with corticosteroids, on the time to death in COVID-19 patients. MethodsThis retrospective cohort study was conducted between March 20, 2020, and March 18, 2021, on 5318 patients with confirmed COVID-19 at three tertiary educational hospitals in Tehran, Iran. The treated group consisted of COVID-19 patients who received remdesivir, either alone or in combination with corticosteroids, while the untreated group included infected patients who did not receive these treatments. The two groups were matched by propensity score matching method, which adjusted for 92 confounding factors such as demographic, sign and symptom, clinical, and treatment-related factors, to provide balanced covariates between the treated and untreated groups. ResultsOf the 4,322 patients, 791 received remdesivir alone and 694 received remdesivir combined with corticosteroids. Among the patients who received remdesivir, 456 were male, and the mean (±standard deviation) age was 59.52±16.49 with a median hospitalization stay of 8 (interquartile range: 5–13) days. After applying the nearest neighbor propensity score matching method, there were no significant differences found in the hazard of death between patients who received remdesivir alone and those who did not receive treatment (hazard ratio: 0.94; 95 % confidence interval: 0.76, 1.16). In addition, the combination of remdesivir and corticosteroids was not associated with a reduced hazard of death (hazard ratio: 1.00; 95 % confidence interval: 0.80, 1.26). The median hospitalization stay was significantly longer in the group treated with remdesivir (alone/combined with corticosteroids) compared to the untreated group, both before and after matching. ConclusionNo association was observed between remdesivir treatment (alone/combined with corticosteroids) and a reduced hazard of death among COVID-19 patients. However, longer hospitalization stays were observed in patients receiving remdesivir, either alone or in combination with corticosteroids, compared to the untreated group.

Tocilizumab in Severe and Critical COVID-19 Pneumonia: Streamlining the Mixed Signals

Four years since the start of the pandemic, the first lockdown in Manila happened on March 15, 2020 causing a pandemonium in the metro as the Filipinos gear up for the unexpected. As the suspected and confirmed cases grew, case numbers of unidentified patients soon became friends, relatives, and loved ones. As of May 2023 1 , there have been more than 1.3 million confirmed COVID-19 cases in Metro Manila alone with almost 14,000 deaths from severe and critical cases.
 The current knowledge about the disease as well as the explanation of its widely varied symptomatology continues to evolve. 2-4 At the center of the discussion for severe and critical COVID-19 requiring hospitalization is the hyperactivation ofthe inflammatory response resulting to simultaneous increase in multiple cytokines. 4,5 Such an inflammatory cascade results in nonspecific inflammatory reaction from damaged or dysfunctional virus-infected host cells making it difficult to identify a specific mediator of inflammatory response. 5,6 It is therefore not surprising that multiple therapeutic trials done targeting specific cytokines such as IL-6 and TNF-a have also led to mixed results. 7-10
 Since 2020, aggressive research has allowed both the development of new medications as well as repurposing of other molecules in the treatment of COVID-19. Antiviral drugs, monoclonal antibodies, IL-6R inhibitor/immune modulators, andsystemic corticosteroids have become household names. 6 IL-6, an identified key propagator of the cytokine storm in severe and critical COVID, has been the focus of the noise as mechanistically, IL-6 blockers including tocilizumab and sarilumabtheoretically disrupt the inflammatory cascade. 5-7
 If mechanistically, IL-6 blockers, particularly tocilizumab can block the inflammatory cascade, why are there mixed signals on its benefit based on real-world evidence? 7-10
 One of the largest and most recently published systematic review and meta-analysis of 15 randomized and two non- randomized clinical trials evaluating the effect of tocilizumab on the clinical outcomes of COVID-19 patients11 showed acombined cumulative risk of death in COVID-19 patients of 0.93 (RR 0.93, 95% CI 0.86 – 1.00, i 2 72.39%). The need for invasive ventilation, ICU admission was at 1.04 (RR 1.04, 95% CI 0.90 – 1.20, i 2 0.00). These figures indicate a 7% decreasedrisk of death with a 4% increased risk of ICU admission and need for invasive ventilation, again indicating mixed signals on the perceived benefit of tocilizumab. 11 Limitations in the study results compared to controlled clinical trials are probablydue to (1) heterogeneity of the patients with severe and critically ill COVID-19 patients potentially having different degrees of inflammatory activities; (2) timing of administration of tocilizumab; (3) different administrative and hospital policies inthe management of more ill patients suffering from COVID-19; and (4) presence of multiple inflammatory cytokines aside from IL-6, making it difficult to pinpoint the specific key mediator of inflammatory response on a per-patient basis.
 The local randomized controlled trial published by Amante et al.12 agree with these mixed signals from the published literature in COVID-19. In both intention-to-treat and per-protocol-analysis, there was no statistical significance and clinicalbenefit of using tocilizumab for severe and critically ill patients. Four years later, the picture is clearer now as real-world evidence coupled with carefully conducted clinical trials provide us a better understanding of the use of tocilizumab for current cases. However, back in 2020, when this mysterious respiratory illness is wreaking havoc, medications both newly developed and repurposed were offered as the medical research community was challenged by a pandemic in an unprecedented manner.
 As COVID-19 becomes endemic, the search for the cure for severe COVID-19 remains to be discovered. Given its mixed signals, shared decision making (pending confirmation in further studies) between the patient, caregiver, and the physician remains the cornerstone of management.

Hubungan Hipertensi Terhadap Kematian Pasien Covid-19 Dengan Diabetes Melitus Tipe 2 di RSUP dr. Sardjito

Diabetes mellitus and hypertension are co-morbidities that are often found in COVID-19 patients. Diabetes can reduce the body's immunity and increase the rate of viral replication, and is associated with vascular problems. Hypertension is one of the comorbid diabetes with high morbidity and mortality. To determine the relationship between hypertension and the death of COVID-19 patients with type 2 diabetes mellitus at Dr Sardjito General Hospital. Observational study with a retrospective cohort study design, using COVID-19 registry data at Dr Sardjito General Hospital for the period March 2020-July 2021. COVID-19 patients with type 2 diabetes mellitus who had hypertension and those who did not have hypertension were selected at Dr Sardjito General Hospital and Collected data on mortality, age, sex, other comorbidities, severity and length of stay. Data were processed using SPSS, in univariate, bivariate, and multivariate analysis models. the results of multivariate analysis using logistic regression found that hypertension, age, and ischemic heart disease did not have a significant association with the death of COVID-19 patients with type 2 diabetes mellitus. The variable that had the greatest power as a predictor of death in COVID-19 patients with diabetes mellitus type 2 is ARDS with a risk of death 20.8 times higher than without ARDS. Patients with kidney failure are at risk of dying 2.7 times higher than those without kidney failure. The addition of length of stay (LOS) 1 day of treatment reduces the risk of death by 16.3%. Hypertension has no significant relationship as a predictor of death in COVID-19 patients with type 2 diabetes mellitus at Dr Sardjito General Hospital. Significant predictors of death in this study were ARDS, kidney failure, and were associated with length of stay (LOS).

D-Dimer As A Parameter Of Disease And Death Of Covid-19 Patients In Islamic Hospital, Surabaya

Background: Previous studies of Community Associated Pneumonia (CAP) and Chronic Obstructive Pulmonary Disease (COPD), patients have shown that D-Dimer increases higher in severe cases and can be used as a prognostic biomarker and whilst D-Dimer> 1 mcg/ ml tends to be death for hospitalized adult patient with a diagnosis of Covid-19. However, D-Dimer's role in Covid-19 patients has not been fully studied. We aim to conduct research on D-Dimer as a parameter of Clinical Severity and Death of Covid-19 Patients in Islamic Hospital, in Surabaya. Methods: This type of research is an analytic observational study with a retrospective approach. The population in this study were all patient’s data retrieved from the Dahlia Room’s database from June to July 2020 which were taken through EMR (an Electrical Medical Records) from a total of 189 patients with the total sample of 82 patients. Data analysis in this study used chi-square (X2) with a significant value of p <0.05. Results: Age over 60 years is associated with a higher risk of severe Covid-19 infection (P<0.05). A history of hypertension significantly affects the severity of Covid-19 infection (P < 0.05). The proportion of recoveries (53.7%) was higher than the number of deaths (46.3%), although the majority of patients experienced severe clinical severity (39%). Laboratory parameters, such as D-dimer values, correlated significantly with patient age (P = 0.027, <0.05). Conclusion: The study highlights the importance of factors such as age and history of comorbid diseases in predicting the severity of Covid-19 infection. A better understanding of these risk factors can help in more effective management and management of Covid-19 patients.

Analysis of the Relationship between Neutrophils, Lymphocytes, and Comorbidities with Time to Death in COVID-19 Patients

BACKGROUND: COVID-19 caused 5.4 million deaths in 2021. Various parameters such as comorbidities and laboratory findings are known to be predictors of death in COVID-19, but these findings differ in each country, and their relationship to time of death has not been widely studied. This study was conducted to determine the relationship between levels of neutrophils, lymphocytes, neutrophil to lymphocyte ratio (NLR), and comorbidities with time to death in COVID-19. METHODS: A retrospective cohort study was conducted from April 2020 to September 2021 in the COVID-19 Inpatient Room at RSUD dr. Saiful Anwar Malang with 300 COVID-19 patient subjects aged 18 years and over. Data on comorbidities (hypertension, CAD, HF, obesity, COPD, CKD, cancer), time to death, and laboratory were taken from medical records. The Kolmogorov-Smirnov test, Chi square test and Mann Whitney test were carried out to analyze the data. RESULTS: There was a significant relationship between neutrophil levels and time to death, as well as a significant difference in neutrophil levels in the group with time to death >48 hours with comorbidities compared to <48 hours with and without comorbidities. There was a significant difference in lymphocyte levels and NLR in patients with comorbidities with time to death <48 hours and >48 hours (p < 0.05). CONCLUSION: There is a significant relationship between neutrophil levels and time to death, both in subjects with and without comorbidities showing the potential of neutrophil levels as a predictor of time to death in COVID-19.

The effect of malnutrition on adult Covid-19 patient's ICU admission and mortality in Covid-19 isolation and treatment centers in Ethiopia: A prospective cohort study.

A new coronavirus was first identified in Wuhan, China in December 2019. Since the times of the 1918 influenza pandemic, malnutrition has been known as a risk factor for severity and mortality from viral pneumonia. Similarly, the recently identified SARS-Cov2 infection (COVID-19) and related pneumonia may be closely linked to malnutrition. Therefore, this study will contribute to new knowledge and awareness of the recording and evaluation of each COVID-19 patient's nutritional status by assessing the effect of malnutrition on ICU admission and death of COVID-19 patients in developing countries. We conducted a prospective cohort study in adult COVID-19 patients admitted to selected COVID-19 Isolation and Treatment Centers, Addis Ababa, Ethiopia. Baseline data of the patients were collected using interviewer-administered structured questionnaire and data on the adverse outcomes of follow up were extracted from follow up chart. The main clinical outcomes (ICU admission and death) were captured every week of follow up. We ran a multivariate Cox's regression analysis to determine the relationship between malnutrition at admission and its effect on ICU admission and death. A total of 581 COVID-19 patients were enrolled. From the total of recruited patients, 346 (59.6%) were males and 235 (40.4%) were females. The mean age of the respondents was 55 years (16.45) years. The Cox proportional hazard model controlled for sex, age group, number of co-morbidities, and number of medications found that malnutrition at admission was associated with ICU admission and death. When compared to well-nourished patients, the rate of ICU admission was significantly associated and found to be higher among underweight [(adjusted hazard ratio (AHR) = 10.02, 95% CI: (8.64-12.10)] and overweight [(AHR = 7.7, 95% CI: (6.41-9.62)] patients. The rate of survival probability was significantly associated and was found to be better among well-nourished patients (AHR = 0.06, 95% CI : (0.01-0.44) when compared with malnourished COVID-19 patients. Malnutrition at the time of admission was shown to increase the risk of ICU admission and mortality among COVID-19 patients. Therefore, it is vital to evaluate patients' nutritional condition early in their admission and provide timely intervention to minimize the effects on patients and the healthcare system.