Clinical and genomic evaluations of a persistent fatal SARS-CoV-2 infection in a goods syndrome patient: a case report.

The coronavirus disease of 2019 (COVID-19) resulted from an infection by severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) which is the main cause of acute respiratory distress syndrome (ARDS) in global population from 2019 on. It may contribute to higher rate of death among the patients with immunodeficiency based on recent reports. In addition, Good syndrome (GS) as a result of thymoma removal might cause in some long-lasting microbial infections. We described clinical aspects and viral mutations on a case of GS suffering from COVID-19. A 46-year-old man with fever, common respiratory disease symptoms and positive COVID-19 polymerase chain reaction (PCR) test, with the history of thymoma removal surgery was admitted to Masih Daneshvari Hospital, Tehran, Iran. Lung radiographs and oxygen saturation measurement disclosed considerable implication resulted in application of several anti-microbial medication. The delta variant (B.1.617.2 (21 J Clade)) was the strain isolated from the patient by sequencing methods done by the COVID-19 National Reference Laboratory (CNRL), Pasteur Institute of Iran, while the dominant strain circulated mostly among population was Omicron (B.1.1.529) at the time of sampling. Unfortunately, the patient had passed away a month later by sudden respiratory failure progressed in refractory septic shock. Despite the fact that opportunistic infections may lead the GS patients to a major health problematic condition, unusual persistent of infections such as non-dominant variant of SARS-Cov-2 could be observed through the disease timeline. Therefore, a fully screening of thymoma plus intra-host evolution monitoring of SARS-CoV-2 is highly recommended in immunocompromised patients.

Diminution of STING Expression in the Blood of Patients with Severe or Critical COVID-19 Pneumonia.

INTRODUCTION: Cytokine storm and critical COVID-19 pneumonia are caused in at least 10% of patients by inborn errors of or auto-Abs to type I IFNs. The pathogenesis of life-threatening COVID-19 pneumonia in other patients remains unknown. METHODS: This study was conducted at Masih Daneshvari Hospital, Tehran, Iran. In the period of study, 75 confirmed cases of COVID-19 with presentations ranging from mild upper respiratory tract infection to lower respiratory tract infection, including moderate, severe, and critical disease, were recruited. Expression of STING mRNA was measured in peripheral blood mononuclear cells (PBMCs) and compared between patients with different severity and outcome. RESULTS: There was a significant negative correlation between age and STING expression level (p value = 0.010). Patients with "severe to critical" illness had a 20-fold lower STING expression level compared to the "mild to moderate" group (p value = 0.001). Also, the results showed lower expressions of STING in the patients admitted to the ICU (p value = 0.015). Patients who finally died had lower expression of STING at the time of sampling (p value = 0.041). CONCLUSION: STING mRNA expression in PBMCs was significantly lower in older COVID-19 cases, the patients with more severe illness, who needed intensive care, and who eventually died.

Clinical epidemiology of pulmonary aspergillosis in hospitalized patients and contribution of Cyp51A, Yap1, and Cdr1B mutations to voriconazole resistance in etiologic Aspergillus species.

Pulmonary aspergillosis is a life-threatening fungal infection with worldwide distribution. In the present study, clinical epidemiology of pulmonary aspergillosis and antifungal susceptibility of etiologic Aspergillus species were evaluated in one-hundred fifty patients with special focus on the frequency of voriconazole resistance. All the cases were confirmed by the clinical pictures, laboratory findings, and isolation of etiologic Aspergillus species which belonged to two major species, i.e., A. flavus and A. fumigatus. Seventeen isolates displayed voriconazole MIC greater than or equal to the epidemiological cutoff value. Expression of cyp51A, Cdr1B, and Yap1 genes was analyzed in voriconazole-intermediate/resistant isolates. In A. flavus, Cyp51A protein sequencing showed the substitutions T335A and D282E. In the Yap1 gene, A78C replacement led to Q26H amino acid substitution that was not reported previously in A. flavus resistant to voriconazole. No mutations associated with voriconazole resistance were found in the three genes of A. fumigatus. The expression of Yap1 was higher than that of two other genes in both A. flavus and A. fumigatus. Overall, voriconazole-resistant strains of both A. fumigatus and A. flavus demonstrated overexpression of Cdr1B, Cyp51A, and Yap1 genes compared to voriconazole-susceptible strains. Although there are still ambiguous points about the mechanisms of azole resistance, our results showed that mutations were not present in majority of resistant and intermediate isolates, while all of these isolates showed overexpression in all three genes studied. As a conclusion, it seems that the main reason of the emergence of mutation in voriconazole-resistant isolates of A. flavus and A. fumigatus is previous or prolonged exposure to azoles.

Factors Associated with Medication Adherence in Elderly Individuals with Tuberculosis: A Qualitative Study.

Methods: This qualitative study was conducted in two phases, using an integrative literature review and individual interviews. Studies were gathered without time restriction from MEDLINE databases, Institute for Scientific Information (ISI), Google Scholar, Scopus, and EMBASE, as well as national databases, including Scientific Information Database and Magiran. The findings of 38 studies that met the inclusion criteria were analyzed through the conventional content analysis method based on the ecological approach. After reviewing and forming the data matrix, purposive sampling was performed among healthcare professionals, elderly tuberculosis patients aged 60 and over, and family caregivers of elderly patients to conduct individual interviews. Data obtained from 20 interviews were analyzed using the directed content analysis method. After coding, the data from individual interviews were entered based on similarity and difference in the categories of data matrix obtained from the literature review. Results: In general, the aforementioned codes were placed in four main categories, including individual factors (i.e., biological factors, affective-emotional factors, behavioral factors, cognitive factors, tuberculosis-related factors, and economic factors), interpersonal factors (i.e., patient's relationship with treatment team and family-related factors), factors related to healthcare service provider centers (i.e., medical centers' facilities and capacity building in healthcare service provider), and extraorganizational factors (i.e., social factors and health policymaking). Conclusion: The results of this study showed that medication adherence in elderly patients with tuberculosis was a complex and multidimensional phenomenon. Therefore, society, policymakers, and healthcare providers should scrutinize the factors affecting medication adherence in this group of patients to plan and implement more effective interventions.

Immunogenicity and safety of SpikoGen®, an adjuvanted recombinant SARS-CoV-2 spike protein vaccine as a homologous and heterologous booster vaccination: A randomized placebo-controlled trial.

SpikoGen® is a subunit recombinant spike protein vaccine combined with Advax-CpG55.2™ adjuvant. This COVID-19 vaccine was shown to be safe, immunogenic and efficacious in previous clinical trials. This study aimed to assess the safety and immunogenicity of SpikoGen® vaccine as a homologous and heterologous booster vaccination. This double-blind and randomized placebo-controlled (5:1) trial was performed on 300 already vaccinated participants. SpikoGen® or saline placebo was administered as a booster dose to participants who had received a full two-dose COVID-19 vaccination course. Immunogenicity assessments were done 14 days after the booster dose with the primary immunogenicity outcome seroconversion rate of neutralizing antibodies. Safety outcomes included the incidence of solicited adverse events up to 7 days after the booster dose. SpikoGen® vaccine induced a robust humoral response both as a homologous and heterologous booster, when compared to the placebo. At Day 14, seroconversion of neutralizing antibodies was 76% (95% confidence interval [CI]: 69%-82%) in the SpikoGen® group versus 3% (95% CI: 0%-13%) in the placebo group. The most common local and systemic reported adverse events were injection site pain and fatigue. No serious adverse events were reported. The SpikoGen®-booster induced cross-neutralization of other SARS-CoV-2 variants. Irrespective of the primary vaccine course received, SpikoGen® vaccine showed promising effects as both a homologous and heterologous booster dose. This vaccine also had a good safety profile with no vaccine-associated serious adverse events. On the basis of these results, SpikoGen® vaccine has been approved as a booster dose.

Effective anti-mycobacterial treatment for BCG disease in patients with Mendelian Susceptibility to Mycobacterial Disease (MSMD): a case series.

BACKGROUND: Post-vaccination BCG disease typically attests to underlying inborn errors of immunity (IEIs), with the highest rates of complications in patients with Mendelian susceptibility to mycobacterial disease (MSMD). However, therapeutic protocols for the management of BCG-osis (disseminated) and persistent BCG-itis (localized) are still controversial. METHODS: Twenty-four Iranian patients with MSMD (BCG-osis or BCG-itis), followed from 2009 to 2020 in Tehran, were included in the study. Their medical records were retrospectively reviewed for demographics, clinical features, laboratory findings, and molecular diagnosis. The therapeutic protocol sheets were prepared to contain the types and duration of anti-mycobacterial agents. RESULTS: BCG disease either as BCG-itis (33.3%) or BCG-osis (66.7%) was confirmed in all patients by positive gastric washing test (54.2%), microbial smear and culture (58.3%), or purified protein derivative (PPD) test (4.2%). The duration between BCG-osis onset and MSMD diagnosis was 21.6 months. All except three patients were initiated on second-line anti-mycobacterial agents with either a fluoroquinolone (levofloxacin: 15 mg/kg/day, ciprofloxacin: 20 mg/kg/day, ofloxacin: 15 mg/kg/day), aminoglycoside (amikacin: 10-15 mg/kg/day, streptomycin: 15 mg/kg/day), and/or macrolide (clarithromycin: 15 mg/kg/day) along with oral rifampin (10 mg/kg/day), isoniazid (15 mg/kg/day), and ethambutol (20 mg/kg/day). Three patients showed a clinical response to rifampin, despite in vitro resistance. Fourteen (58.3%) patients received also adjuvant subcutaneous IFN-γ therapy, 50 µ/m2 every other day. At the end of survey, most patients (n = 22, 91.7%) were alive and two patients died following BCG-osis and respiratory failure. CONCLUSIONS: We recommend the early instigation of second-line anti-mycobacterial agents in MSMD patients with BCG disease.

Extracellular vesicles from serum samples of mycobacteria patients induced cell death of THP-1 monocyte and PBMC.

BACKGROUND: Extracellular vesicles (EVs) play a key role in cell communication and the pathogenesis of some diseases. EVs may accelerate cell death during the course of mycobacterial infection and are also considered as a new vaccine design, drug delivery, and biomarker candidates. The current study evaluates the effects of EVs from serum samples of mycobacteria-infected patients on THP-1 monocytes and PBMC cells. METHOD: EVs were purified from the serum, then cultured separately with THP-1 monocytes and PBMCs. The cell death was determined through annexin V-FITC and PI staining. GW4869, an EVs inhibitor, was used to determine if EVs released from serum could increase THP-1 monocytes cell death. RESULTS: The cell death was significantly increased in the presence of 10 µg/ml and 5 µg/ml concentrations of the purified EVs (p < 0.05). Minimal cell death was determined in 2.5 µg/ml and 1.2 µg/ml (p < 0.05). Up to 85% of the cells were viable in the presence of the GW4869 inhibitor (p < 0.05). CONCLUSION: Direct infection of the cells with EVs released from mycobacteria-infected patients samples, the multiplicity of infection with the EVs, and virulent or avirulent mycobacteria may change the status of the cell death. The isolated EVs  from serum samples of patients with mycobacterial  infection accelerated cell death, which means that they might   not be considered as an optimal tool for developing drug delivery and vaccine against tuberculosis.

Antibiotic use during the first 6 months of COVID-19 pandemic in Iran: A large-scale multi-centre study.

WHAT IS KNOWN AND OBJECTIVE: Although antibiotics are ineffective against viral infections, epidemiological studies have revealed that the COVID-19 pandemic resulted in the overuse of antibiotics and disruption of antimicrobial stewardship programmes. We investigated the pattern of antibiotic use during the first 6 months of the COVID-19 pandemic in Iran. METHODS: A multi-centre retrospective study was designed to investigate the use of 16 broad-spectrum antibiotics in 12 medical centres. The rate of antibiotic use was calculated and reported based on the Defined Daily Dose (DDD) per 100 hospital bed-days. The bacterial co-infection rate was also reported. RESULTS AND DISCUSSION: Totally, 43,791 hospitalized COVID-19 patients were recruited in this study. It was found that 121.6 DDD of antibiotics were used per 100 hospital bed-days, which estimated that each patient received approximately 1.21 DDDs of antibiotics every day. However, the bacterial co-infections were detected only in 14.4% of the cases. A direct correlation was observed between the rate of antibiotic use and mortality (r[142] = 0.237, p = 0.004). The rate of antibiotic consumption was not significantly different between the ICU and non-ICU settings (p = 0.15). WHAT IS NEW AND CONCLUSION: In this study, widespread antibiotic use was detected in the absence of the confirmed bacterial coinfection in COVID-19 patients. This over-consumption of broad-spectrum antibiotics may be associated with increased mortality in hospitalized COVID-19 patients, which can be an alarming finding.

Pulmonary manifestations in a cohort of patients with inborn errors of immunity: an 8-year follow-up study.

BACKGROUND: Inborn errors of immunity (IEIs) are a group of congenital diseases caused by genetic defects in the development and function of the immune system. The involvement of the respiratory tract is one of the most common presentations in IEIs. METHODS: Overall, 117 patients with diagnosed IEIs were followed-up within 8 years at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD). Demographic, clinical, and laboratory data were collected in a questionnaire. Pulmonary function test (PFT), chest X-ray (CXR), and high-resolution computed tomography (HRCT) scans were obtained where applicable. RESULTS: Our study population consisted of 48 (41%) patients with predominantly antibody deficiencies (PADs), 39 (32%) patients with congenital defects of phagocytes, 14 (11.9%) patients with combined immunodeficiency (CID), and 16 (14%) patients with Mendelian susceptibility to mycobacterial diseases (MSMD). . Recurrent pneumonia was the most common manifestation, while productive cough appeared to be the most common symptom in almost all diseases. PFT showed an obstructive pattern in patients with PAD, a restrictive pattern in patients with CID, and a mixed pattern in patients with CGD. HRCT findings were consistent with bronchiectasis in most PAD patients, whereas consolidation and mediastinal lesions were more common in the other groups. CONCLUSIONS: Pulmonary manifestations vary among different groups of IEIs. The screening for lung complications should be performed regularly to reveal respiratory pathologies in early stages and follow-up on already existing abnormalities.

Mortality in adults with multidrug-resistant tuberculosis and HIV by antiretroviral therapy and tuberculosis drug use: an individual patient data meta-analysis.

BACKGROUND: HIV-infection is associated with increased mortality during multidrug-resistant tuberculosis treatment, but the extent to which the use of antiretroviral therapy (ART) and anti-tuberculosis medications modify this risk are unclear. Our objective was to evaluate how use of these treatments altered mortality risk in HIV-positive adults with multidrug-resistant tuberculosis. METHODS: We did an individual patient data meta-analysis of adults 18 years or older with confirmed or presumed multidrug-resistant tuberculosis initiating tuberculosis treatment between 1993 and 2016. Data included ART use and anti-tuberculosis medications grouped according to WHO effectiveness categories. The primary analysis compared HIV-positive with HIV-negative patients in terms of death during multidrug-resistant tuberculosis treatment, excluding those lost to follow up, and was stratified by ART use. Analyses used logistic regression after exact matching on country World Bank income classification and drug resistance and propensity-score matching on age, sex, geographic site, year of multidrug-resistant tuberculosis treatment initiation, previous tuberculosis treatment, directly observed therapy, and acid-fast-bacilli smear-positivity to obtain adjusted odds ratios (aORs) and 95% CIs. Secondary analyses were conducted among those with HIV-infection. FINDINGS: We included 11 920 multidrug-resistant tuberculosis patients. 2997 (25%) were HIV-positive and on ART, 886 (7%) were HIV-positive and not on ART, and 1749 (15%) had extensively drug-resistant tuberculosis. By use of HIV-negative patients as reference, the aOR of death was 2·4 (95% CI 2·0-2·9) for all patients with HIV-infection, 1·8 (1·5-2·2) for HIV-positive patients on ART, and 4·2 (3·0-5·9) for HIV-positive patients with no or unknown ART. Among patients with HIV, use of at least one WHO Group A drug and specific use of moxifloxacin, levofloxacin, bedaquiline, or linezolid were associated with significantly decreased odds of death. INTERPRETATION: Use of ART and more effective anti-tuberculosis drugs is associated with lower odds of death among HIV-positive patients with multidrug-resistant tuberculosis. Access to these therapies should be urgently pursued. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Decreased neutrophil-mediated bacterial killing in COVID-19 patients.

The coronavirus disease COVID-19 was first described in December 2019. The peripheral blood of COVID-19 patients have increased numbers of neutrophils which are important in controlling the bacterial infections observed in COVID-19. We sought to evaluate the cytotoxic capacity of neutrophils in COVID-19 patients. 34 confirmed COVID-19 patients (29 severe, five mild disease), and nine healthy controls were recruited from the Masih Daneshvari Hospital (Tehran, Iran) from March to May 2020. Polymorphonuclear (PMN) cells were isolated from whole blood and incubated with green fluorescent protein (GFP)-labelled methicillin-resistant Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA). Bacterial growth was determined by measuring the florescence of co-cultures of bacteria and neutrophils and reported as the lag time before exponential growth. The number of viable bacteria was determined after 70 hours as colony-forming units (CFU). The immunophenotype of tested cells was evaluated by flow cytometry. Isolated neutrophils have higher surface expression of CD16 and CD62L with negative markers for PMN-MDSC. Bacterial growth in the presence of SA (22 ± 0.9 versus 9.2 ± 0.5 h, P < .01) and PA (12.4 ± 0.6 versus 4.5 ± 0.22, P < .01) was significantly reduced in COVID-19 patients. After 70 h incubation of PMN with bacteria (SA and PA), CFUs were significant increased in COVID-19 patients SA (2.6 ± 0.09 × 108 CFU/mL-severe patients and 1.4 ± 0.06 × 108 CFU/mL-mild patients, P < .001) and PA (2.2 ± 0.09 × 109 CFU/mL-severe patients and 1.6 ± 0.03 × 109 CFU/mL-mild patients, P < .001). Gentamycin proliferation assays confirmed the presence of intracellular bacteria. Reduced bacterial killing by neutrophils from COVID-19 patients may be responsible for the high bacterial yield seen in these patients.

Management of ST-segment-elevation myocardial infarction during the coronavirus disease 2019 (COVID-19) outbreak: Iranian"247" National Committee's position paper on primary percutaneous coronary intervention.

World Health Organization has designated coronavirus disease 2019 (COVID-19) as a pandemic. During the past several weeks, a considerable burden has been imposed on the Iranian's healthcare system. The present document reviewed the latest evidence and expert opinion regarding the management of ST-segment-elevation myocardial infarction during the outbreak of COVID-19 and outlines a practical algorithm for it.

Successful Treatment of Covid-19 Associated Cytokine Release Syndrome with Colchicine. A Case Report and Review of Literature.

We describe the case of a 42 year old, healthy patient with Covid-19 who despite improvement in his respiratory symptoms developed a mild to moderate cytokine release syndrome (CRS) and an associated monoarticular gout flare. Since the patient refused admission to the hospital and had stable vital signs, we chose to treat him with a safe anti-inflammatory and non-immunosuppressive therapy. To hit two birds with one stone, we considered colchicine, as it has systemic anti-inflammatory effects and is also effective in gout flare. Unexpectedly, 48 hours after treatment, not only did his ongoing fever and toe pain disappear, he also had significant improvements in his general state of health and all his inflammatory markers including fibrinogen, ferritin, D-dimer, and IL-6 levels normalized. To our knowledge, the use of colchicine in Covid-19 and CRS has not been reported. This observation merits the consideration of colchicine as a safe, inexpensive and oral medication for the treatment of mild to moderate CRS in Covid-19 patients. More importantly, in Covid-19 patients with early lung involvement colchicine may be an appropriate candidate to prevent CRS in adjunction with routine antiviral agents. Indeed, multicenter, randomized controlled studies are required to evaluate the benefits of this therapy.

Single-pill sofosbuvir and daclatasvir for treating hepatis C in patients co-infected with human immunodeficiency virus.

BACKGROUND: The current recommendation for treating hepatitis C virus (HCV) in HIV patients includes the combination of sofosbuvir (SOF) and daclatasvir (DCV). DCV should be used at different doses to compensate for interactions with antiretroviral therapy (ART). Up to three pills a day might be required which will significantly add to the pill burden of these patients. In this study, we have used a single-tablet approach to treating HCV-HIV coinfection. METHODS: Patients coinfected with HIV and HCV were prospectively enrolled from 10 centers throughout the country. Patients received a single once-daily fixed dose combination (FDC) pill containing 400 mg SOF and 30, 60 or 90 mg DCV depending on the type of ART they were receiving for 12 or 24 weeks. (ClinicalTrials.gov ID: NCT03369327). RESULTS: Two hundred thirty-three patients were enrolled from 10 centers. Twenty-three patients were lost to follow-up and two patients died from causes unrelated to treatment. Two hundred eight patients completed the treatment course of which 201 achieved SVR (96.6%). CONCLUSION: Single-tablet combination of DCV and SOF is an effective and safe treatment for patients coinfected with HIV and HCV. The combination works well in patients on ART in which dose adjustment is required. Patients with cirrhosis, previous treatment failure and various genotypes respond identically. The expenses of genotyping can be saved.

Determination of Voriconazole Plasma Concentration by HPLC Technique and Evaluating Its Association with Clinical Outcome and Adverse Effects in Patients with Invasive Aspergillosis.

PURPOSE: Invasive aspergillosis is a prevalent fungal disease, especially in Asian countries with a high mortality rate. Voriconazole (VRZ) is the first choice for invasive aspergillosis treatment. Plasma concentration of this drug is unpredictable and varies among individuals. This variability is influenced by many factors leading to clinical implication. Therapeutic drug monitoring (TDM) may have a crucial role in the patients' treatment process. The HPLC method provides sufficient specificity and sensitivity for plasma VRZ concentration determination for TDM purposes of this drug. METHODS: Patients who initiated oral or intravenous VRZ for invasive aspergillosis were enrolled in this study. Demographic characteristics and clinical data, outcome, and adverse effects were documented. For each patient, the plasma sample was collected under steady-state condition and analyzed using a validated HPLC method. RESULTS: A total of 22 measurements were performed. Fifty percent of patients were out of the therapeutic range. From them, 27.27% and 22.73% were in subtherapeutic and supratherapeutic ranges (<1 µg/mL and >5.5 µg/mL), respectively. There was a significant correlation between VRZ plasma concentration and treatment outcomes (P=0.022). Treatment failure was five times higher than treatment success in those in the subtherapeutic range. Adverse effects were observed more frequently in patients with supratherapeutic concentrations compared to those with non-supratherapeutic levels. Furthermore, the mortality rate in patients experiencing treatment failure was 2.17 times higher than those with treatment success. CONCLUSIONS: TDM of VRZ plays an important role in better evaluation of efficacy and toxicity during treatment. Therefore, determination of the drug level may be of clinical significance.

Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical and Genetic Features of 32 Iranian Patients.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital condition characterized by a selective predisposition to infections caused by weakly virulent mycobacteria and other types of intra-macrophagic pathogens. The 16 genes associated with MSMD display a considerable level of allelic heterogeneity, accounting for 31 distinct disorders with variable clinical presentations and prognosis. Most of MSMD deficiencies are isolated, referred to as selective susceptibility to mycobacterial diseases. However, other deficiencies are syndromic MSMD, defined by the combination of the mycobacterial infection with another, equally common, infectious, specific phenotypes. Herein, we described a series of 32 Iranian MSMD cases identified with seven distinct types of molecular defects, all of which are involved in the interferon gamma (IFNγ) immunity, including interleukin IL-12 receptor-ß1 (IL-12Rß1) deficiency (fifteen cases), IL-12p40 deficiency (ten cases), and IL-23R deficiency (three cases), as well as IFNγ receptor 1 (IFNγR1) deficiency, IFNγ receptor 2 (IFNγR2) deficiency, interferon-stimulated gene 15 (ISG15) deficiency, and tyrosine kinase 2 (TYK2) deficiency each in one case. Since the first report of two MSMD patients in our center, we identified 30 other affected patients with similar clinical manifestations. As the number of reported Iranian cases with MSMD diagnosis has increased in recent years and according to the national vaccination protocol, all Iranian newborns receive BCG vaccination at birth, early diagnosis, and therapeutic intervention which are required for a better outcome and also prevention of similar birth defects. Therefore, we investigated the clinical and molecular features of these 32 patients. The current report also defined novel classes of pathological mutations, further expanding our knowledge of the MSMD molecular basis and associated clinical manifestations.

Clinical efficacy of convalescent plasma for treatment of COVID-19 infections: Results of a multicenter clinical study.

Since Dec. 2019 the new coronavirus (SARS-CoV-2) has infected millions and claimed life of several hundred thousand worldwide. However, so far no approved vaccine or drug therapy is available for treatment of virus infection. Convalescent plasma has been considered a potential modality for COVID-19 infection. One hundred eighty-nine COVID-19 positive patients including 115 patients in plasma therapy group and 74 patients in control group, registered in the hospitals with confirmed COVID-19 infection, entered this multi-center clinical study. Comparison of outcomes including all-cause mortality, total hospitalization days and patients' need for intubation between the two patient groups shows that total of 98 (98.2 %) of patients who received convalescent plasma were discharged from hospital which is substantially higher compared to 56 (78.7 %) patients in control group. Length of hospitalization days was significantly lower (9.54 days) in convalescent plasma group compared with that of control group (12.88 days). Only 8 patients (7%) in convalescent plasma group required intubation while that was 20 % in control group. This clinical study provides strong evidence to support the efficacy of convalescent plasma therapy in COVID-19 patients and recommends this treatment for management of these patients. Clinical efficacy, immediate availability and potential cost effectiveness could be considered as main advantages of convalescent plasma therapy.

Correction to: Silent hypoxia: higher NO in red blood cells of COVID-19 patients.

An amendment to this paper has been published and can be accessed via the original article.

Silent hypoxia: higher NO in red blood cells of COVID-19 patients.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has spread to almost 100 countries, infected over 31 M patients and resulted in 961 K deaths worldwide as of 21st September 2020. The major clinical feature of severe COVID-19 requiring ventilation is acute respiratory distress syndrome (ARDS) with multi-functional failure as a result of a cytokine storm with increased serum levels of cytokines. The pathogenesis of the respiratory failure in COVID-19 is yet unknown, but diffuse alveolar damage with interstitial thickening leading to compromised gas exchange is a plausible mechanism. Hypoxia is seen in the COVID-19 patients, however, patients present with a distinct phenotype. Intracellular levels of nitric oxide (NO) play an important role in the vasodilation of small vessels. To elucidate the intracellular levels of NO inside of RBCs in COVID-19 patients compared with that of healthy control subjects. METHODS: We recruited 14 COVID-19 infected cases who had pulmonary involvement of their disease, 4 non-COVID-19 healthy controls (without pulmonary involvement and were not hypoxic) and 2 hypoxic non-COVID-19 patients subjects who presented at the Masih Daneshvari Hospital of Tehran, Iran between March-May 2020. Whole blood samples were harvested from patients and intracellular NO levels in 1 × 106 red blood cells (RBC) was measured by DAF staining using flow cytometry (FACS Calibour, BD, CA, USA). RESULTS: The Mean florescent of intensity for NO was significantly enhanced in COVID-19 patients compared with healthy control subjects (P ≤ 0.05). As a further control for whether hypoxia induced this higher intracellular NO, we evaluated the levels of NO inside RBC of hypoxic patients. No significant differences in NO levels were seen between the hypoxic and non-hypoxic control group. CONCLUSIONS: This pilot study demonstrates increased levels of intracellular NO in RBCs from COVID-19 patients. Future multi-centre studies should examine whether this is seen in a larger number of COVID-19 patients and whether NO therapy may be of use in these severe COVID-19 patients.

Extracorporeal membrane oxygenation and COVID-19: The causes of failure.

INTRODUCTION: Venovenous extracorporeal membrane oxygenation (VV-ECMO) is a therapeutic strategy for the coronavirus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS). There are inconclusive data in this regard and causes of VV-ECMO failure are not yet understood well. CASE SERIES: Here, seven patients with COVID-19-induced ARDS who underwent VV-ECMO introduced and causes of VV-ECMO failure discussed. Medical records of seven COVID-19 patients treated with VV-ECMO were retrospectively evaluated to determine the clinical outcomes of VV-ECMO. Oxygenator failure occurred in four patients whom needed to oxygenator replacement. Successful VV-ECMO decannulation was done in three patients, however finally one patient survived. CONCLUSIONS: Hypercoagulability state and oxygenator failure were the most main etiologies for VV-ECMO failure in our study. All patients with COVID-19 undergoing VV-ECMO should be monitored for such problems and highly specialized healthcare team should monitor the patients during VV-ECMO.