Effect of tofacitinib on clinical and laboratory findings in severe and resistant patients with COVID-19.

BACKGROUND: The efficacy and safety of a strong Janus kinase inhibitor, tofacitinib, in individuals suffering from severe coronavirus disease 2019 (Covid-19) pneumonia are not definite well. METHODS: In this non-randomized and non-blinded trial, a total of 52 Iranian patients with severe COVID-19 associated with decreased oxygen saturation, elevated C-reactive protein, and/or persistent fever were included. A total of 52 patients were included in this study. Tofacitinib was administered to 29 patients (55.8%) in addition to the standard care treatments, whereas 23 patients (44.2%) were treated with the standard of care alone (mostly antiviral agents and corticosteroids). Tofacitinib was administered at a dose of 5 mg twice daily for up to 10 days. The primary outcomes were mortality rate, oxygen saturation level, CT findings, rate of breath, heart rate, and level of consciousness. Inflammatory cytokines and blood biomarkers were considered as the secondary outcomes. RESULTS: Death from any cause through day 14 occurred in 51.7% of the tofacitinib group and 65.2% of the control group. There was no significant difference in lung radiographic findings between the intervention and control groups at the first day of the study and after the study period. However, a significant decrease was observed in the extent of lung tissue involvement in the intervention group after administration of tofacitinib. Regarding cell and blood biomarkers, a significant decrease in the CPK levels in the intervention group and Hct and ACE levels in the control group was observed after fourteen days of the study. Moreover, a significant increase in SGOT and ferritin values was detected in the control group 14 days after the beginning tofacitinib administration. Comparing control and intervention groups, there was a significant difference in hemoglobin, SGOT, LDH, ferritin, and ACE values between groups before the intervention, while after fourteen days of the study, no significant difference was found. In case of DHEAS and TSH levels, a significant decrease was seen in the intervention group compared to the control after the study period. No other significant improvement was detected in other outcomes of the tofacitinib group compared to the control. CONCLUSIONS: The administration of tofacitinib combined with corticosteroids, is not effective enough to treat severe COVID-19 patients and the use of this medication should be considered before the disease deterioration.

Impact of the MCP-1-2518A>G polymorphism on COVID-19 severity in the Iranian population: A case-control study.

As a result of SARS-CoV-2 infection, the host's immune system is disrupted, and chemokines and cytokines are intensified to eliminate the virus, resulting in cytokine storm syndrome and acute respiratory distress syndrome (ARDS). Patients with COVID-19 have been observed to have elevated levels of MCP-1, a chemokine associated with the severity of the disease. In some diseases, polymorphisms in the regulatory region of the MCP-1 gene correspond to serum levels and disease severity. An attempt was made in this study to assess the relationship between MCP-1 G-2518A and serum MCP-1 levels in Iranian COVID-19 patients and the severity of the disease. In this study, patients were randomly sampled from outpatients on the first day of diagnosis and from inpatients on the first day of their hospitalization. Patients were classified into the outpatient (without symptoms or with mild symptoms) and inpatient (with moderate, severe, and critical symptoms) groups. The serum level of MCP-1 was measured by ELISA and the frequency of MCP-1 G-2518A gene polymorphism genotypes in COVID-19 patients was checked by the RFLP-PCR method. Participants with COVID-19 infection had a higher rate of underlying diseases, such as diabetes, high blood pressure, kidney disease, and cardiovascular disease than the control group (P-value < 0.001). Also, the frequency of these factors in inpatients was significantly higher compared to outpatients (P-value < 0.001). Additionally, the level of MCP-1 in serum was significantly different with an average of 11.90 in comparison to 2.98 in the control group (P-value, 0.05), which is attributed to elevated serum levels among patients in hospitals with an average of 11.72 in comparison to 2.98 in the control group. Compared with outpatients, inpatients had a higher frequency of the G allele of the MCP-1-2518 polymorphism (P-value < 0.05), while a notable difference was observed in the serum level of MCP-1 in COVID-19 patients with the MCP-1-2518 AA genotype in the whole group in comparison to the control group (P-value: 0.024). Totally, the results showed that a high frequency of the G allele is related to hospitalization and poor outcome in COVID-19 cases.

The role of ACE1 I/D and ACE2 polymorphism in the outcome of Iranian COVID-19 patients: A case-control study.

Background: Since the beginning of the pandemic of coronavirus disease 2019 (COVID-19), many countries have experienced a considerable number of COVID-19 cases and deaths. The etiology of a broad spectrum of symptoms is still debated. Host genetic variants might also significantly influence the outcome of the disease. This study aimed to evaluate the association of angiotensin-converting enzyme (ACE1) gene Insertion/Deletion (I/D) polymorphism (rs1799752) and ACE2 gene rs1978124 single nucleotide polymorphism with the COVID-19 severity. Methods: This study was conducted on 470 COVID-19 patients and a control group of 56 healthy individuals across several major cities in Iran. The blood sample and clinical data were collected from the participants, and their ACE1 I/D and ACE2 rs1978124 polymorphisms were determined using polymerase chain reaction and PCR-RFLP, respectively. Serum levels of C-reactive protein (CRP), interleukin 6 (IL-6), and ACE1 were measured in the blood samples. Results: We found that the ACE1 DD genotype frequency was inversely correlated with the risk of intubation (p = 0.017) and mortality in COVID-19 patients (p = 0.049). Even after adjustment, logistic regression demonstrated that this significant inverse association remained constant for the above variables at odds ratios of (OR) = 0.35 and Odds Ratio = 0.49, respectively. Also, in the expired (p = 0.042) and intubated (p = 0.048) groups with II + ID genotypes, the mean level of CRP was significantly higher than in the DD genotype group. Furthermore, in both intubated and expired groups, the mean serum level of ACE1 was higher compared with non-intubated and survived groups with II or II + ID genotypes. The results also indicated that ACE2 rs1978124 TT + CT genotypes in females have a significant positive role in susceptibility to COVID-19; however, in females, the TT + CT genotypes had a protective effect (OR = 0.098) against the severity of COVID-19. Conclusion: These findings suggest that ACE1 I/D and ACE2 rs1978124 polymorphism could potentially influence the outcome of COVID-19 in the Iranian population.

Neutrophil to Lymphocyte Ratio (NLR) and Derived NLR Combination: A Cost-effective Predictor of Moderate to Severe COVID-19 Progression.

Inflammation is an essential contributor to Coronavirus disease 2019 (COVID-19).   In this regard, finding a prognostic indicator is valuable because the treatment will be more effective if critical patients with high inflammation are diagnosed earlier. We aimed to evaluate some hematologic markers for COVID-19 and assess their association with the severity of the disease. A total of 154 COVID-19 patients were laboratory-confirmed and admitted to Imam Khomeini Hospital Complex, Tehran, Iran, from February 12, 2020, to April 4, 2020, and 55 healthy individuals were enrolled in the study. The severity of the patients' illnesses was classified into three subgroups according to the types of oxygen therapies (moderate (61), severe (28), and critical (43)) and examined the different ratios of total white blood cell (WBC) count, neutrophil to lymphocyte ratio (NLR), platelet to monocyte ratio (PLR), macrophage to lymphocyte ratio (MLR), derived NLR ratio (dNLR), and some biochemical tests. COVID-19 patients had higher levels of NLR, MLR, PLR, and dNLR than healthy subjects. receiver operating characteristic (ROC) analysis of the curve revealed that NLR and dNLR had a high diagnostic value to differentiate COVID-19 patients from healthy subjects (area under the curve [AUC]=0.923 and 0.910, respectively) and predict mortality (AUC=0.726 and 0.735, respectively). NLR and dNLR may be reliable markers to evaluate the severity of COVID-19. NLR and dNLR had a high diagnostic value for differentiating COVID-19 patients from healthy subjects, and they could predict the severity and outcome of the disease.

Interpretation of Hematological, Biochemical, and Immunological Findings of COVID-19 Disease: Biomarkers Associated with Severity and Mortality.

The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) spread rapidly all over the world in late 2019 and caused critical illness and death in some infected patients. This study aimed at examining several laboratory factors, especially inflammatory and immunological mediators, to identify severity and mortality associated biomarkers. Ninety-three hospitalized patients with confirmed coronavirus disease 2019 (COVID-19) were classified based on disease severity. The levels of biochemical, hematological, immunological, and inflammatory mediators were assessed, and their association with severity and mortality were evaluated. Hospitalized patients were mostly men (77.4%) with an average (standard deviation) age of 59.14 (14.81) years. The mortality rate was significantly higher in critical patients (85.7%). Increased serum levels of blood sugar, urea, creatinine, uric acid, phosphorus, total bilirubin, serum glutamic-oxaloacetic transaminase, serum glutamic-oxaloacetic transaminase, lactic dehydrogenase, C-reactive protein, ferritin, and procalcitonin were significantly prevalent (p=0.002, p<0.001, p<0.001, p=0.014, p=0.047, p=0.003, p<0.001, p<0.001, p<0.001, p<0.001, P<0.001, and p<0.001, respectively) in COVID-19 patients. Decreased red blood cell, hemoglobin, and hematocrit were significantly prevalent among COVID-19 patients than healthy control subjects (p<0.001 for all). Troponin-I, interleukin-6, neutrophil/lymphocyte ratio (NLR), procalcitonin, and D-dimer showed a significant association with the mortality of patients with specificity and sensitivity more than 60%. Age, sex, underlying diseases, blood oxygen pressure, complete blood count along with C-reactive protein, lactic dehydrogenase, procalcitonin, D-dimer, and interleukin-6 evaluation help to predict the severity and required management for COVID-19 patients. Further investigations are highly recommended in a larger cohort study for validation of the present findings.

SP-A and TLR4 localization in lung tissue of SM-exposed patients.

INTRODUCTION: Long-term pulmonary complications are one of the major long-term consequences of sulfur mustard (SM) exposure. Toll-like receptor 4 (TLR4) involves in the pathogenesis of several pulmonary disorders. Surfactant protein-A (SP-A) regulates LPS-induced TLR4 localization and activation responses. However, the intensity and significance of TLR4 and SP-A expression by lung cells in SM-exposed patients is not clear. METHODS: The gene expression of TLR4 (through real-time PCR) and TLR4 and SP-A positive cells and alveolar type II cells, as SP-A producers, (using IHC) were assessed in formalin fixed paraffin embedded (FFPE) specimens from SM-exposed (n = 17), and non-SM exposed individuals (n = 12). RESULTS: TLR4 gene expression did not change between study groups. However, its cell surface presentation was significantly reduced in SM-exposed patients and particularly in which with constrictive bronchiolitis compared with the control group (P < 0.001 and P = 0.002, respectively). Frequency of alveolar type II cells was lower in the case group rather than the control group while the number of SP-A positive cells did not alter. CONCLUSIONS: These findings suggest that reduced TLR4 cell surface presentation may have anti-inflammatory function and SP-A may have a critical role in regulation of inflammatory responses in SM-exposed patients. Further investigation on other possible mechanisms involved in TLR4 internalization maybe help to illustrate the modulatory or inflammatory activity of TLR4 in these patients.

Angiogenesis modulatory factors in subjects with chronic ocular complications of Sulfur Mustard exposure: A case-control study.

BACKGROUND: Chronic ocular complications of Sulfur Mustard (SM) exposure leads to severe ocular morbidity during time. The aim of this study was to compare serum levels of Interleukin 17 (IL-17), IL-12, vascular endothelial growth factor (VEGF)-C, VEGF-D and nitric oxide (NO) in SM-exposed patients versus the control group and to measure tear concentration of VEGF-C only in the SM-exposed group. METHODS: In this prospective case control, 128 SM-exposed patients and 31 healthy control subjects were included. In the case group ocular manifestations were classified to three subgroups of mild (19 cases), moderate (31 cases) and severe (78 cases) forms of disease. Serum levels of IL-17, IL-12, NO, VEGF-C and VEGF-D, in all subjects and tear concentration of VEGF-C in SM-exposed group was evaluated. RESULTS: All subjects were male and mean ±â€¯standard deviation (SD) of age in the case and control groups were 44.9 ±â€¯8.8 and 40.9 ±â€¯10.1 years, respectively. Except for significantly lower serum level of IL-17 (p < 0.001) and NO (p = 0.003), other values were not significantly different. The tear concentration of VEGF-C and serum level of IL-12 were not different between subgroups in the SM-exposed group, yet were significantly lower among those with abnormally dilated and tortuous conjunctival vessels and corneal pannus, respectively (p = 0.01, p = 0.015). CONCLUSIONS: Exposure to SM significantly reduced serum level of IL-17 and NO in the delayed phase, yet did not influence VEGF-C; VEGF-D or IL-12.

Expression of miR-15b-5p, miR-21-5p, and SMAD7 in Lung Tissue of Sulfur Mustard-exposed Individuals with Long-term Pulmonary Complications.

Sulfur mustard (SM)-exposed individuals develop late pulmonary complications, which are associated with chronic inflammation and fibrotic changes in the lung tissue. MicroRNAs are known to act as important regulators of inflammatory responses, including inflammation and fibrosis-related cytokine signaling. In this study, we investigated the expression miR-15b-5p and miR-21-5p, two regulators of TGF-ß signaling, as well as their target molecule, SMAD7, in lung tissues from SM-exposed and control individuals. Total RNA was extracted from formalin-fixed paraffin-embedded (FFPE) lung tissue biopsies obtained during surgery from SM-exposed (n=20) or control (n=20) cases. Quality of the extracted RNA was evaluated by an Agilent Bioanalyzer and RNA was quantified using a NanoDrop. MiR-21-5p, miR-15b-5p and SMAD7 expression levels were measured by real-time RT-PCR. miR-21-5p expression levels were significantly decreased (2.7 fold) in the lung tissues from SM-exposed individuals compared with tissues obtained from the control group (p=0.02). There were no significant differences in miR-15b-5p expression levels between the two groups (p=0.94). Interestingly, SMAD7 expression levels were significantly higher (5.8 fold) in SM-exposed individuals' lung tissues compared with the control group (p=0.045). Our data indicate that exposure to sulfur mustard affects the expression of miR-21-5p as well as its target, SMAD7, in lung tissues many years after exposure. Considering the role of SMAD7 in the regulation of TGF-ß signaling, these changes might point to a potential mechanism by which SM-exposure regulates inflammatory/fibrotic alterations in lung tissue.

Circulating mesenchymal stem cells in sulfur mustard-exposed patients with long-term pulmonary complications.

Sulfur mustard (SM) is a toxic agent that causes acute and long-term pulmonary complications. Recent evidence has shown the impact of SM on mesenchymal stem cells (MSCs). These cells have a critical role in repairing the damaged tissues. In this study, we evaluated the mobilization of MSCs in SM-exposed patients with long-term pulmonary complications. Fifty-nine SM-injured patients with prolonged pulmonary complications and 20 healthy individuals were included. Patients were classified based on taking drugs, having comorbidities, and severity of respiratory consequence. MSCs with phenotype of CD45-CD44+CD29+CD105+ were evaluated in peripheral blood using flow cytometry. Circulating MSCs were lower in SM-exposed patients compared to the control group (0.93 vs. 2.72 respectively, P = 0.005). No significant difference was observed in the MSC count between patients taking corticosteroids or antibiotics and those patients not taking them. Comorbidities like liver and kidney diseases had changed the count of MSCs in SM-exposed subjects. In addition, the frequency of MSCs did not show any association with the severity of long-term pulmonary complications. In conclusion, SM-exposure causes a decline in the frequency of circulating MSCs in survivors. The lower number of the peripheral MSC population in SM-exposed patients was not affected by taking corticosteroids or antibiotics, but comorbidities are probably involved in MSC frequency. The decreases observed in the number of circulating MSCs was not associated with the severity of the pulmonary complications; however, further studies in mustard lung models are required to demonstrate the therapeutic or pathologic role of MSCs in SM injuries.

Evaluation of the LTBP1 and Smad6 Genes Expression in Lung Tissue of Sulfur Mustard-exposed Individuals with Long-term Pulmonary Complications.

Sulfur mustard (SM) exposure injures different organs such as the lungs and leads to short and long term complications Transforming growth factor beta (TGF-ß) has the main role in altering fibroblast activities linked to airways remodeling. Latency TGF beta binding proteins 1 (LTBP1 facilitates localization of TGF-ß in the extracellular matrix. Mothers against decapentaplegic homolog 6 (Smad6) negatively regulates TGF-ß signaling, thus establishing a main negative feedback loop. In this study, we investigated the expression of LTBP1 and Smad6 in the lung tissues of SM-exposed and control individuals. Lung formalin-fixed paraffin-embedded (FFPE) blocks of SM-exposed (20 samples) and control groups (20 samples) were collected from archival pathology department of several general hospitals. The total mRNA of lung FFPE tissues was extracted. Quality of the extracted mRNA was evaluated by an Agilent Bio analyzer and RNA was quantified using a Nano Drop. LTBP1 and Smad6 expression levels were evaluated by real-time PCR. LTBP1 expression levels did not change between the two groups (p=0.626), howeverSmad6 expression levels were significantly higher (2.6 fold) in SM-exposed individuals compared to the control group (p=0.001). Our results revealed that Smad6 may be involved in lung tissue remodeling process in SM-exposed patients. Smad6 regulates fibrotic alterations in lung tissue and its function as negative feedback mechanisms in TGF-ß.

Correlation between MMP-9 and MMP-9/ TIMPs Complex with Pulmonary Function in Sulfur Mustard Exposed Civilians: Sardasht-Iran Cohort Study.

BACKGROUND: Matrix metalloproteinases (MMPs) are a family of proteinases and have the vigorous capacity to degrade all parts of the extracellular matrix. MMP enzymes strongly participate in physiological processes such as normal tissue remodeling and wound healing and in pathology of pulmonary diseases. They are released in response to environmental stimuli such as toxins and regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Sulfur mustard (SM) is a chemical toxic which can cause severe permanent damages to lung tissues. The aim of this study was assessing the possible role of MMP-9 and TIMPs in SM-induced lung symptoms and signs in exposed patients 20 years after exposure. METHODS: Totally, 372 male volunteers with a history of SM- exposure and 128 age- and sex-matched unexposed controls participated and were divided into three groups: normal, mild and moderate-severe. All participants underwent clinical evaluation and pulmonary function tests and serum concentrations of MMP-9 and its inhibitors were measured using the ELISA technique. RESULTS: Serum level of MMP-9 was increased in the SM exposed group who had moderate-severe pulmonary complications compared with the SM exposed with normal lung (2.321 ± 2.836 vs. 1.546 ± 2.176, P = 0.001) while only the MMP-9/TIMP-4 complex was elevated in the SM exposed with normal lung individuals compared to its corresponding control group (85 ± 265 vs. 82 ± 222, P = 0.025). Although MMP-9 and its inhibitors did not show any correlation with spirometry findings, elevated circulating MMP-9 was detected in SM exposed patients with chronic chough and hemoptysis (P = 0.013 and P = 0.013 respectively). CONCLUSION: High level of tissue disruption and remodeling mediators could influence lung structure in long-term after SM-exposure. The correlation of clinical evaluation with these factors efficiently helps us to identify important effectors.

Female Sexual Dysfunction Among the Wives of Opioid-Dependent Males in Iran.

BACKGROUND: Opiate abuse in males has significant effects on their sexual functions. In contrast, sexuality in females is a multidimensional issue that can strongly be affected by several factors in their partners. However, only a limited number of studies have assessed the role of males' opioid dependency in their female partners' sexual function. OBJECTIVES: The present study aimed to evaluate the effect of males' opioid dependency on their wives' sexual function compared to the sexual function of the females whose husbands were not opioid dependent. PATIENTS AND METHODS: This study included 340 women who were selected through convenience sampling and divided into a control (females whose husbands were not opioid dependent) and a case group (women whose husbands were opioid dependent). The data were collected through an interview according to the DSM-IV-R criteria for female sexual dysfunctions by a senior female medical student who was one of the researchers. Finally, the data were entered into the SPSS statistical software (v. 15) and analyzed using the t-test and chi-square test. RESULTS: According to the results, the frequency of hypoactive sexual desire disorder and sexual aversion disorder in the control group was significantly higher than that of the case group (P < 0.05). CONCLUSIONS: The results showed that having an addicted husband could strongly affect some sexual domains in women. It could change the pattern of desire and motivation for sexual contact in females and alter their attitude toward the sexual relationship, thereby causing disturbances in the females' normal sexual function.