The role of lovastatin in the attenuation of COVID-19.

The mounting evidence regarding the pathogenesis of COVID-19 indicated that the cytokine storm has an axial role in the severity of this disease, which may lead to thrombotic complications, acute respiratory distress syndrome (ARDS), and myocardial damage, among other consequences. It has recently been demonstrated that statins are known to have anti-viral, anti-inflammatory, anti-thrombotic, and immunomodulatory features; however, their advantage has not been evaluated in COVID-19. This study aimed to investigate the protective effects of lovastatin in intensive care unit (ICU) patients with COVID-19. The case-control study consists of 284 ICU patients, which classified into three groups as follows: 1) the patients who no received lovastatin as a control (92 patients), 2) patients received 20 mg per day lovastatin (99 patients), and 3) patients received 40 mg per day lovastatin (93 patients). Each group's demographic and clinical parameters, along with CRP, interleukin (IL)-6, IL-8 levels, and mortality rate, were studied in three-time points. The results showed that there was no statistically significant difference between our study groups in terms of age and sex. (P > 0.05). Besides, in patients, receiving lovastatin the CRP, IL-6, IL-8 levels were significantly decreased from T1 to T3 than to the control group. Our results also showed that the use of lovastatin in COVID-19 patients significantly reduced the length of hospitalization in the ICU compared with the control group. In addition, our results showed that the mortality rate in patients receiving lovastatin was lower when compared to the control group; however, this difference was not statistically significant. Since the cytokine storm is a significant factor in the pathology of SARS-CoV-2, our findings highlighted the potential use of lovastatin to mitigate the inflammatory response induced by SARS-CoV-2 infection.

A possible pathogenic correlation between neutrophil elastase (NE) enzyme and inflammation in the pathogenesis of coronavirus disease 2019 (COVID-19).

A growing body of evidence indicates that neutrophil elastase (NE) is involved in the pathogenesis of respiratory infectious diseases, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to analyze the dynamic changes in serum levels of NE associated with inflammation, disease activity, and mortality rate in patients with COVID-19. We measured the serum concentrations of NE, C-Reactive protein (CRP), interleukin (IL)- 4, IL-6, IL-8, IL-10, and vitamin D levels in 83 ICU and 69 non-ICU patients compared with 82 healthy subjects (HS) in three-time points (T1-T3). Serum levels of NE, IL-6, IL-8, and CRP in ICU and non-ICU patients were significantly higher than HS (P < 0.001) in three-time points. Also, serum levels of NE, IL-6, IL-8, and CRP in ICU patients were significantly higher than in non-ICU patients (P < 0.05). On the day of admission (T1), the levels of NE, CRP, IL-6, IL-8 were gradually decreased from T1 to T3. At the same time, IL-4 and IL-10 were gradually increased from T1 to T2 and then reduced to T3. Further analyses demonstrated that the levels of NE, IL-6, and IL-8 in deceased patients were significantly higher than in recovered patients (P < 0.05). The ROC curve analysis demonstrated that markers, including NE, IL-6, and IL-8, were valuable indicators in evaluating the activity of COVID-19. Overall, our results signify the critical role of NE in the pathogenesis of COVID-19, and also, further support that NE has a potential therapeutic target for the attenuation of COVID-19 severity.

Genetically engineered fusion of allergen and viral-like particle induces a more effective allergen-specific immune response than a combination of them.

Chimeric virus-like particles (VLPs) were developed as a candidate for allergen-specific immunotherapy. In this study, hepatitis B core antigen (HBcAg) that genetically fused to Chenopodium album polcalcin (Che a 3)-derived peptide was expressed in E. coli BL21, purified, and VLP formation was evaluated using native agarose gel electrophoresis (NAGE) and transmission electron microscopy (TEM). Chimeric HBc VLPs were characterized in terms of their reactivity to IgE, the induction of blocking IgG and allergen-specific IgE, basophil-activating capacity, and Th1-type immune responses. Results from IgE reactivity and basophil activation test showed that chimeric HBc VLPs lack IgE-binding capacity and basophil degranulation activity. Although chimeric HBc VLPs induced the highest level of efficient polcalcin-specific IgG antibody in comparison to those induced by recombinant Che a 3 (rChe a 3) mixed either with HBc VLPs or alum, they triggered the lowest level of polcalcin-specific IgE in mice following immunization. Furthermore, in comparison to the other antigens, chimeric HBc VLPs produced a polcalcin-specific Th1 cell response. Taken together, genetically fusion of allergen derivatives to HBc VLPs, in comparison to a mix of them, may be a more effective way to induce appropriate immune responses in allergen-specific immunotherapy. KEY POINTS: • The insertion of allergen-derived peptide into major insertion region (MIR) of hepatitis B virus core (HBc) antigen resulted in nanoparticles displaying allergen-derived peptide upon its expression in prokaryotic host. • The resultant VLPs (chimeric HBc VLPs) did not exhibit IgE reactivity with allergic patients' sera and were not able to degranulate basophils. • Chimeric HBc VLPs dramatically improved protective IgG antibody response compared with those induced by allergen mixed either with HBc VLPs or alum. • Chimeric HBc VLPs induced Th1 responses that were counterparts of Th2 responses (allergic). • Chimeric HBc VLPs increased IgG2a/ IgG1 ratio and the level of IFN-γ compared to those induced by allergen mixed with either HBc VLPs or alum. Graphical Abstract.

Incorporation of the Tat cell-penetrating peptide into nanofibers improves the respective antitumor immune response.

A major challenge for the development of anticancer vaccines is the induction of a safe and effective immune response, particularly mediated by CD8+ T lymphocytes, in an adjuvant-free manner. In this respect, we present a simple strategy to improve the specific CD8+ T cell responses using KFE8 nanofibers bearing a Class I (Kb)-restricted peptide epitope (called E. nanofibers) without the use of adjuvant. We demonstrate that incorporation of Tat, a cell-penetrating peptide (CPP) of the HIV transactivator protein, into E. nanofibers remarkably enhanced tumor-specific CD8+ T cell responses. E. nanofibers containing 12.5% Tat peptide (E.Tat12.5 nanofiber) increased antigen cross-presentation by bone marrow-derived dendritic cells as compared with E. nanofibers, or E. nanofibers containing 25 or 50% the Tat peptide. Uptake of KFE8.Tat12.5 nanofibers by dendritic cells (DCs) was significantly increased compared with KFE8 nanofiber lacking Tat. Peritoneal and lymph node DCs of mice immunized with E.Tat12.5 nanofibers exhibited increased presentation of the H2kb-epitope (reminiscent for cross-presentation) compared with DCs obtained from E. nanofiber vaccinated mice. Tetrameric and intracellular cytokine staining revealed that vaccination with E.Tat12.5 triggered a robust and specific CD8+ T lymphocyte response, which was more pronounced than in mice vaccinated with E. nanofibers alone. Furthermore, E.Tat12.5 nanofibers were more potent than E. nanofiber to induce antitumor immune response and tumor-infiltrating IFN-γ CD8 T lymphocyte. In terms of cancer vaccine development, we propose that harnessing the nanofiber-based vaccine platform with incorporated Tat peptide could present a simple and promising strategy to induce highly effective antitumor immune response.

Peg-interferon Plus Ribavirin Combination Therapy in HCV Mono-infected and HCV/HIV Co-infected Patients in Iran.

Background: Hepatitis C virus (HCV) infection is a cause of major liver complications, particularly in patients infected with human immunodeficiency virus (HIV). This study aimed to evaluate the efficacy of pegylated interferon (Peg-IFN) and a fixed dose of ribavirin treatment among Iranian HCV mono-infected and HCV/HIV-co-infected patients. Methods: A total of 214 HCV mono-infected and HCV/HIV co-infected patients attending Liver Disease Center in Tehran were assigned to receive treatment with Peg-IFN-α2a or -α2b plus ribavirin for 24-48 weeks. Sustained virologic response (SVR) was used as the primary efficacy endpoint of Peg-IFN and ribavirin therapy. Results: Treatment with Peg-IFN and ribavirin has been associated with a considerably higher rate of SVR (24 weeks for HCV genotype 3 and 48 weeks for HCV/HIV co-infected and HCV genotype 1 patients). Overall, the clearance of HCV-RNA at the end of therapy occurred in 48.6% of patients. Adverse events leading to treatment discontinuation were seen in 14% of patients. Conclusion: This retrospective study revealed a relatively well-tolerated response in both HCV mono-infected and HCV/HIV coinfected patients during treatment with Peg-IFN and ribavirin. However, the recent revolutionized interferon-free therapies for chronic HCV infection should be taken into account for achieving a greater response and minimal adverse events.

Combination of Ledipasvir and Sofosbuvir for Treatment of Hepatitis C Virus Genotype 1 Infection: Systematic Review and Meta-Analysis

ABSTRACT Background and aim. The combination of Sofosbuvir (SOF) and Ledipasvir (LDV) has been lead to considerable enhancement of treatment of hepatitis C virus (HCV) genotype 1 infection. A meta-analysis of the currently available studies was undertaken with the aim to evaluate the antiviral efficacy of SOF/LDV therapy for 12 or 24 weeks with or without Ribavirin (RBV) in patients with HCV genotype 1 infection. Material and methods. In this meta-analysis, we searched databases including PubMed, Scopus, Science Direct and Web of Science using appropriate keywords. All papers which evaluated the efficacy of combination therapy of SOF/LDV with or without RBV for 12 or 24 weeks among patients with HCV genotype 1 infection were included. Results. The 20 published articles were assessed for eligibility and finally 10 articles pooling 2248 participants were included in this meta-analysis. Pooled SVR12 for four SOF/LDV regimens were 95% (95%CI = 93%-97%) for 12 weeks of treatment with SOF/LDV, 97% (95%CI = 95%-98%) for 24 weeks of treatment with SOF/LDV, 96% (95%CI = 94%-97%) for 12 weeks of treatment with SOF/ LDV/RBV and 98% (95%CI = 97%-99%) for 24 weeks of treatment with SOF/LDV/RBV. Only in treatment regimen of SOF/LDV for 12 weeks, cirrhosis had a significant effect on the SVR12 (OR = 0.21, 95%CI = 0.07-0.66). Furthermore, NS5A resistance-associated substitutions at baseline were associated with decrease in the rate of SVR (OR = 0.31, 95%CI = 0.2-0.5). Conclusions. The Interferon-free regimen of SOF/LDV for 12 or 24 weeks with or without RBV is highly effective for treatment of patients with HCV genotype 1 infection.

Recommendations for the Clinical Management of Hepatitis C in Iran: A Consensus-Based National Guideline.

CONTEXT: Hepatitis C virus (HCV) infection is a major public health issue worldwide, including Iran. The new direct-acting antiviral agents (DAAs) with high efficacy have changed the landscape of HCV treatment. This guideline provides updated recommendations for clinical management of HCV infection in Iran. EVIDENCE ACQUISITION: The recommendations of this guideline are based on international and national scientific evidences and consensus-based expert opinion. Scientific evidences were collected through a systematic review of studies that evaluated efficacy and safety of DAA regimens, using PubMed, Scopus and Web of Science. Expert opinion was based on the consensus of Iran Hepatitis Scientific Board (IHSB) in the 3rd national consensus on management of Hepatitis C in Iran, held on 22nd of July 2016. RESULTS: Pegylated Interferon alpha (PegIFN), Ribavirin (RBV), Sofosbuvir (SOF), Ledipasvir (LDV) and Daclatasvir (DCV) are currently available in Iran. Pre-treatment assessments include HCV RNA level, HCV genotype and resistance testing, assessment of liver fibrosis, and underlying diseases. In HCV genotype 1 and 4, DCV/SOF and LDV/SOF are recommended. In HCV genotype 2, SOF plus RBV and in HCV genotype 3, DCV/SOF is recommended. Additional care for underlying diseases should be considered. CONCLUSIONS: Affordable new HCV treatment regimens are available in Iran, providing an opportunity for HCV elimination. Recommendations provided in this current national guideline can facilitate evidence-based management of HCV infection.

Next Steps Toward Eradication of Hepatitis C in the Era of Direct Acting Antivirals.

CONTEXT: After the introduction of safe and highly effective hepatitis C virus (HCV) treatments, eradication of HCV in the next 20 years is the ultimate goal. Since 2011, the advent of first generation direct acting antivirals (DAAs) were started and followed by the introduction of a new wave of DAAs in 2013 which exhibit outstanding efficacy. It is obvious that the eradication of hepatitis C is not restricted to development of DAAs. EVIDENCE ACQUISITION: An electronic search of available literature published was conducted in all peer-reviewed journal indexed in PubMed, Scopus and Google scholar. The literature search was done among articles related treatment of hepatitis C with DAAs in different patient groups with mass screening of the patients and cost benefit of new treatments as main key words. RESULTS: There are major steps that should be taken to eradicate HCV, including (1) the development of screening strategies, particularly for groups such as intravenous drug users and recipients of blood or blood products before the introduction of HCV screening in donors; (2) the development of strategies to overcome issues with the high cost of recently introduced treatments; (3) special attention to special patient groups, such as HIV/HCV co-infection, hemophilia, thalassemia, hemodialysis, and liver-transplant patients; and (4) development of preventive strategies, such as the development of an efficient HCV vaccine, special attention to harm reduction in high-risk groups, and promotion of mass awareness of HCV. CONCLUSIONS: The eradication of HCV will require significant governmental financial investment for screening, prevention, and treatment of infected patients. Although, we have a long way to eradication of HCV, the next steps could be including proper planning to patient finding, availability of new treatments to all patients and development of HCV prevention strategies such as vaccines.

Hepatitis A Virus and Hepatitis E Virus Seroprevalence Among Blood Donors in Tehran, Iran.

BACKGROUND: Hepatitis A virus (HAV) and Hepatitis E virus (HEV) are both transmitted by the fecal-oral route and are known as the leading causes of acute viral hepatitis in the world, especially in developing countries. There is a lack of updated data on HAV and HEV seroprevalence in Iran. OBJECTIVES: The aim of this study was to determine the seroprevalence of HAV and HEV among a group of blood donors in Tehran, Iran. MATERIALS AND METHODS: A cross-sectional study was performed from July 2014 to December 2014, on a total of 559 blood donors referred to the Tehran blood transfusion center. The serum samples were tested for antibodies to HAV and HEV, using the enzyme-linked immunosorbent assay. RESULTS: In the present study, 536 (95.9%) cases were male and 23 (4.1%) female with mean age of 38 years. Out of 559 blood donors, 107 (19.1%) were first-time donors, 163 (29.2%) lapsed donors and 289 (51.7%) regular donors. Anti-HAV was found in 395 (70.7%) and anti-HEV in 45 (8.1%) of the blood donors. The HAV and HEV seroprevalence increased by age. There was no significant difference between genders in terms of anti-HAV and anti-HEV status. The HAV and HEV seroprevalence was significantly related to the level of education, where the donors with higher level of education had lower rate of HAV and HEV seroprevalence. The HAV and HEV seroprevalence was significantly higher in regular and lapsed donors than in first-time donors. CONCLUSIONS: The present study showed that both HAV and HEV infections are still endemic in Iran.

Molecular Epidemiology of Kaposi's Sarcoma-Associated Herpes Virus, and Risk Factors in HIV-infected Patients in Tehran, 2014.

BACKGROUND: Kaposi's sarcoma (KS) remains the most common malignancy among HIV-infected patients. Human herpesvirus type-8 (HHV-8) is regarded as the infectious etiological agent of Kaposi's sarcoma (KSHV). Diagnostic procedures associated with KSHV are not routinely performed in HIV-infected subjects. OBJECTIVES: The main objective of this study is to obtain information on KSHV epidemiology in Iranian HIV-infected individuals. PATIENTS AND METHODS: In the present cross-sectional study, 109 patients with established HIV infection, who visited a governmental and referral center for HIV screening in Tehran (Tehran west health center (TWHC)) between May 2014 and July 2015 were enrolled according to the convenience sample strategy. After peripheral blood collection, isolation of plasma and peripheral blood mononuclear cell (PBMC) compartments, DNA extraction was performed. KSHV DNA was analyzed by nested polymerase chain reaction (nested PCR) using primers from ORF-26 (virus minor capsid). RESULTS: Among all 109 HIV-infected patients, 67 (61.5%) were male, with an age range of 2 - 64 years (mean ± standard deviation 35.8 ± 13.3). KSHV DNA was found in PBMC and plasma samples of six (5.5%) and four (3.6%) patients, respectively. CONCLUSIONS: This study revealed a considerable prevalence of KSHV DNA, during latent and lytic phases, among HIV-infected patients. Risk factors for KSHV infection acquisition and concurrent. 0+infection with HIV were also evaluated. Diagnosis of KSHV in the group could be helpful for prognosis of Kaposi's sarcoma and clinical management.

Molecular Tracing of Hepatitis C Virus Genotype 1 Isolates in Iran: A NS5B Phylogenetic Analysis with Systematic Review.

CONTEXT: Hepatitis C virus (HCV) is characterized by a high degree of genetic heterogeneity and classified into 7 genotypes and different subtypes. It heterogeneously distributed through various risk groups and geographical regions. A well-established phylogenetic relationship can simplify the tracing of HCV hierarchical strata into geographical regions. The current study aimed to find genetic phylogeny of subtypes 1a and 1b of HCV isolates based on NS5B nucleotide sequences in Iran and other members of Eastern Mediterranean regional office of world health organization, as well as other Middle Eastern countries, with a systematic review of available published and unpublished studies. EVIDENCE ACQUISITION: The phylogenetic analyses were performed based on the nucleotide sequences of NS5B gene of HCV genotype 1 (HCV-1), which were registered in the GenBank database. The literature review was performed in two steps: 1) searching studies evaluating the NS5B sequences of HCV-1, on PubMed, Scopus, and Web of Science, and 2) Searching sequences of unpublished studies registered in the GenBank database. RESULTS: In this study, 442 sequences from HCV-1a and 232 from HCV-1b underwent phylogenetic analysis. Phylogenetic analysis of all sequences revealed different clusters in the phylogenetic trees. The results showed that the proportion of HCV-1a and -1b isolates from Iranian patients probably originated from domestic sources. Moreover, the HCV-1b isolates from Iranian patients may have similarities with the European ones. CONCLUSIONS: In this study, phylogenetic reconstruction of HCV-1 sequences clearly indicated for molecular tracing and ancestral relationships of the HCV genotypes in Iran, and showed the likelihood of domestic origin for HCV-1a and various origin for HCV-1b.