Role of CCL2/CCR2 axis in the pathogenesis of COVID-19 and possible Treatments: All options on the Table.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is cause of the novel coronavirus disease (COVID-19). In the last two years, SARS-CoV-2 has infected millions of people worldwide with different waves, resulting in the death of many individuals. The evidence disclosed that the host immune responses to SARS-CoV-2 play a pivotal role in COVID-19 pathogenesis and clinical manifestations. In addition to inducing antiviral immune responses, SARS-CoV-2 can also cause dysregulated inflammatory responses characterized by the noticeable release of proinflammatory mediators in COVID-19 patients. Among these proinflammatory mediators, chemokines are considered a subset of cytokines that participate in the chemotaxis process to recruit immune and non-immune cells to the site of inflammation and infection. Researchers have demonstrated that monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor (CCR2) are involved in the recruitment of monocytes and infiltration of these cells into the lungs of patients suffering from COVID-19. Moreover, elevated levels of CCL2 have been reported in the bronchoalveolar lavage fluid (BALF) obtained from patients with severe COVID-19, initiating cytokine storm and promoting CD163+ myeloid cells infiltration in the airways and further alveolar damage. Therefore, CCL2/CCR axis plays a key role in the immunopathogenesis of COVID-19 and targeted therapy of involved molecules in this axis can be a potential therapeutic approach for these patients. This review discusses the biology of the CCL2/CCR2 axis as well as the role of this axis in COVID-19 immunopathogenesis, along with therapeutic options aimed at inhibiting CCL2/CCR2 and modulating dysregulated inflammatory responses in patients with severe SARS-CoV-2 infection.

Troponin is a useful marker in clinical decision making in hospitalized patients with COVID-19 infections

BACKGROUND COVID-19 was introduced by the World Health Organization (WHO) as a global pandemic. The disease manifestations ranges from a mild common cold to severe disease and death. It has a higher mortality rate in people with a history of comorbidities, including cardiovascular disease (CVD) and can also contribute to cardiac injury. This study was conducted to evaluate the relationship between troponin levels as a cardiac marker and adverse outcomes in this disease. METHODS The study sample included 438 patients hospitalized with COVID-19;however, the troponin data of 6 patients were not available. The need to be admitted to the intensive care unit (ICU), and death were considered the adverse outcome in patients with COVID-19. Troponin levels were checked in all patients on day 1 and day 3 of hospitalization. Multiple logistic regression analysis was performed to determine whether there was an independent association between the adverse outcomes and troponin enzyme in hospitalized patients with COVID-19. RESULTS The mean age of patients was 61.29 ± 15.84 years. Among the 432 patients tested on day 1 of hospitalization, 24 patients (5.6%) tested positive (Troponin 1), and among the 303 patients tested on day 3, 13 patients (4.3%) tested positive (Troponin 2). Based on our results, Troponin 1 showed an independent association with both death (3.008 [95%CI = 1.091-8.290];P = 0.033) and need for ICU admission (8.499 [95%CI = 3.316-21.788];P < 0.001) in multiple logistic regression analysis. Moreover, the status of Troponin 2 had an independent significant association with both death (4.159 [95%CI = 1.156-14.961];P = 0.029) and ICU admission (7.796 [95%CI = 1.954-31.097];P = 0.004). CONCLUSION Troponin showed a significant association with adverse outcomes in people who were hospitalized with COVID-19. The periodical assessment of this enzyme from the time of hospitalization may improve the clinical decision making of clinicians.

Angiotensin Converting Enzyme Inhibitors, A Risk Factor of Poor Outcome in Diabetic Patients with COVID-19 Infection

Introduction. Diabetes mellitus and hypertension are described as the most common comorbidities among COVID-19 patients. We investigated the adverse effect of ACEIs in diabetic and nondiabetic patients with COVID-19. Methods. This prospective study consisted of 617 RT-PCR-confirmed COVID-19 inpatients. Demographic and baseline characteristics, underlying comorbid diseases, and antihypertensive drugs were evaluated. Study outcome (in-hospital death) was evaluated with the Kaplan-Meyer method and Cox regression model. Statistical analyses were performed with SPSS software for Windows. P values < .05 were considered significant. Results. Mean ± SD age was 58.49 ± 15.80 (range: 18 to 94) years old. Cox regression analysis revealed that age (adjusted hazard ratio [HR] = 1.04, 95% CI: 1.03 to 1.06), diabetes mellitus (adjusted HR = 2.07, 95% CI: 1.32 to 3.26), immunocompromised patients (adjusted HR = 2.33, 95% CI: 1.29 to 4.21), acute kidney injury (AKI) (adjusted HR = 3.23, 95% CI: 2.01 to 5.19), ICU admission (adjusted HR = 2.48, 95% CI: 1.46 to 4.21), Asthma and COPD (adjusted HR = 2.13, CI:1.6 to 4.28) and ACEI (adjusted HR = 3.08, 95% CI: 1.56 to 6.06), respectively were associated with in-hospital death. Among diabetic patients, ACEI (adjusted HR = 3.51, 95% CI: 1.59 to 7.75), AKI (adjusted HR = 3.32, 95% CI: 1.76 to 6.45) and ICU admission (adjusted HR = 3.64, 95% CI: 1.530 to 8.65) were associated with increased mortality. The Kaplan-Meier survival curve showed a lower survival rate in diabetic patients with ACE inhibitor (adjusted HR = 3.36, 95% CI: 2.25 to 7.71). Conclusion. ACEIs may harm the diabetic patient’s outcome with COVID-19. Further studies can confirm if ACE inhibitors have an adverse effect on COVID-19 diabetic patient’s mortality.

Nonsteroidal anti-inflammatory drugs in acute viral respiratory tract infections: An updated systematic review.

In this systematic review, we aimed to assess the efficacy and safety of nonsteroidal anti-inflammatory drugs (NSAIDs) in treating respiratory tract infections in adults and children. PubMed, Scopus, Web of Science, Cochrane, and Embase databases were searched. A total of 34 randomized clinical trials were included in this systematic review. We assessed the risk of bias of all included studies using the Cochrane tool for risk of bias assessment. The evidence on ibuprofen, naproxen, aspirin, diclofenac, and other NSAIDs were rated for degree of uncertainty for each of the study outcomes and summarized using the grading of recommendations assessment, development, and evaluation (GRADE) approach. Our findings suggest that high-quality evidence supports the use of NSAIDs to reduce fever in both adults and children. However, the evidence was uncertain for the use of NSAIDs to reduce cough. Most studies showed that NSAIDs significantly relieved sore throat. The evidence for mortality and oxygenation is limited. Regarding the adverse events, gastrointestinal discomfort was more frequently reported in children. For adults, our overall certainty in effect estimates was low and the increase in gastrointestinal adverse events was not clinically significant. In conclusion, NSAIDs seem to be beneficial in the outpatient management of fever and sore throat in adults and children. Although the evidence does not support their use to decrease mortality nor improve oxygenation in inpatient settings, the use of NSAIDs did not increase the rate of death or the need for ventilation in patients with respiratory tract infections. Further studies with a robust methodology and larger sample sizes are recommended.

Serum level of Vitamin D is associated with COVID-19 mortality rate in hospitalized patients.

BACKGROUND: Due to widespread of coronavirus disease 2019 (COVID-19) infection, identification of its risk factors and clinical characteristics are important. The aim of the present study was to assess Vitamin D levels in individuals with severe acute respiratory syndrome coronavirus-19 infection and to report on its potential as a predictive marker. MATERIALS AND METHODS: All patients, diagnosed with COVID-19 infection from February 16 to March 21, 2020, and referred to Firoozgar Hospital, Tehran, Iran, were enrolled in this study. Vitamin D analysis was undertaken on patient serum samples using a commercial kit (Pars Azmoon Co., Tehran, Iran). SPSS v. 22 was used for statistical analysis. RESULTS: Vitamin D serum concentration was analyzed in a total of 317 patients whose mean age ± standard deviation was 62.05 ± 15 years and with 62.5% being male. A significant association of Vitamin D level and death was observed. Higher levels of serum Vitamin D had protection against death (odds ratio = 0.955 [95% confidence interval = 0.923-0.988], P = 0.008). CONCLUSION: As a preliminary study in the Iranian population who suffered COVID-19 disease, we identified that Vitamin D deficiency was associated with a higher death rate and intensive care unit admission.

Efficacy and safety of chloroquine and hydroxychloroquine for COVID-19: A comprehensive evidence synthesis of clinical, animal, and in vitro studies.

Background: The world is facing a pandemic of COVID-19, a respiratory disease caused by a novel coronavirus which is now called SARS-CoV-2. Current treatment recommendations for the infection are mainly repurposed drugs based on experience with other clinically similar conditions and are not backed by direct evidence. Chloroquine (CQ) and its derivative Hydroxychloroquine (HCQ) are among the candidates. We aimed to synthesize current evidence systematically for in vitro, animal, and human studies on the efficacy and safety of chloroquine in patients with COVID-19. Methods: The Cochrane Library, Google Scholar, PubMed (via Medline), Embase, Scopus, and Web of Science, MedRxiv, clinical trial registries including clinicaltrials.gov, ChiCTR (Chinese Clinical Trial Registry), IRCT (Iranian Registry of Clinical Trials), and the EU Clinical Trials Register. We used the Cochrane tool for risk of bias assessment in randomized studies, the ROBINS tool for non-randomized studies, and the GRADE methodology to summarize the evidence and certainty in effect estimates. Results: The initial database searching retrieved 24,752 studies. Of these, 15,435 abstracts were screened and 115 were selected for full-text review. Finally, 20 human studies, 3 animal studies, and 4 in vitro studies were included in this systematic review. The risk of bias within studies was unclear to high and the overall certainty in evidence-based on GRADES- was very low. HCQ may be effective in clinical improvement in a subset of patients with COVID-19. However, the frequency of adverse events was higher in patients taking HCQ compared to standard of care alone. In contrast, animal studies, did not report any adverse effects. Furthermore, clear benefit of the drug in the survival of the animals has been reported. Most in vitro studies indicated a high selectivity index for the drug and one study that used a human coronavirus reported blockage of virus replication. Conclusion: Current evidence background is limited to six poorly conducted clinical studies with inconsistent findings which fail to show significant efficacy for HCQ. Safety data is also limited but the drug may increase adverse outcomes. Routine use of the drug is not recommended based on limited efficacy and concerns about the drug safety especially in high-risk populations.

Infliximab and Intravenous Gammaglobulin in Hospitalized Severe COVID-19 Patients in Intensive Care Unit.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) may lead to the cytokine storm syndrome which may cause acute respiratory failure syndrome and death. Our aim was to investigate the therapeutic effects of infliximab, intravenous gammaglobulin (IVIg) or combination therapy in patients with severe COVID-19 disease admitted to the intensive care unit (ICU). METHODS: In this observational research, we studied 104 intubated adult patients with severe COVID-19 infection (based on clinical symptoms, and radiographic or CT scan parameters) who were admitted to the ICU of a multispecialty hospital during March 2020 in Tehran, Iran. All cases received standard treatment regimens as local protocol (Oseltamivir + hydroxychloroquine + lopinavir/ritonavir or sofosbuvir or atazanavir ± ribavirin). The cases were grouped as controls (n = 43), infliximab (n = 27), IVIg (n = 23) and combination (n = 11). RESULTS: There was no significant difference between controls and treatment groups in terms of underlying diseases or the number of underlying diseases. The mean age (SD) of cases was 72.42 (16.06) in the control group, 64.52 (12.965) in IVIg, 63.40 (17.57) in infliximab and 64.00 (11.679) in combination therapy; (P = 0.047, 0.031 and 0.11, respectively). Also, 37% in the infliximab group, 26.1% in IVIg, 45.5% in combination therapy, and 62.8% in the control group expired (all P < 0.05). Hazard ratios were 0.31 in IVIg (95% CI: 0.12-0.76, P = 0.01), 0.30 in infliximab (95% CI: 0.13-0.67, P = 0.004), 0.39 in combination therapy (95% CI: 0.12-1.09, P = 0.071). CONCLUSION: According to the findings of this study, it seems that infliximab and IVIg, alone or together, in patients with severe COVID-19 disease can be considered an effective treatment.

Effect of Arbidol (Umifenovir) on COVID-19: a randomized controlled trial.

BACKGROUND: Treatment of patients with COVID-19 has included supportive care to mainly relief symptoms of the disease. Although World Health Organization (WHO) has not recommended any effective treatments for COVID-19, there are some reports about use of antiviral drugs. The aim of this study is to determine the effect of Arbidol (ARB) on COVID-19 disease. METHODS: Using an open-label randomized controlled trial, we examined the efficacy of ARB in patients with COVID-19 in a teaching hospital. One hundred eligible patients with diagnosis of COVID-19 were recruited in the study and assigned randomly to two groups of either hydroxychloroquine followed by KALETRA (Lopinavir/ritonavir) or hydroxychloroquine followed by ARB. The primary outcome was hospitalization duration and clinical improvement 7 days after admission. The criteria of improvement were relief of cough, dyspnea, and fever. Time to relief from fever was also assessed across the two groups. Without any dropouts, 100 patients were entered into the study for the final analysis at significance level of 0.05. RESULTS: The mean age of patients was 56.6 (17.8) years and 56.2 (14.8) years in ARB and KALETRA groups, respectively. Majority of patients were male across two groups (66 and 54%). The duration of hospitalization in ARB group was significantly less than KALETRA arm (7.2 versus 9.6 days; P = 0.02). Time to relief fever was almost similar across two groups (2.7 versus 3.1 days in ARB and KALETRA arms, respectively). Peripheral oxygen saturation rate was significantly different after 7 days of admission across two groups (94% versus 92% in ARB and KALETRA groups respectively) (P = 0.02). Based on multiple linear regression analysis, IHD, Na level, and oxygen saturation at the time of admission and type of therapy were the independent adjusted variables that determined the duration of hospitalization in patients with COVID-19. CONCLUSION: Our findings showed that Arbidol, compared to KALETRA, significantly contributes to clinical and laboratory improvements, including peripheral oxygen saturation, requiring ICU admissions, duration of hospitalization, chest CT involvements, WBC, and ESR. We suggest further studies on ARB against COVID-19 using larger sample size and multicenter design. TRIAL REGISTRATION: IRCT20180725040596N2 on 18 April 2020.