Endotoxin Inflammatory Action on Cells by Dysregulated-Immunological-Barrier-Linked ROS-Apoptosis Mechanisms in Gut-Liver Axis.

Our study highlighted the immune changes by pro-inflammatory biomarkers in the gut-liver-axis-linked ROS-cell death mechanisms in chronic and acute inflammations when gut cells are exposed to endotoxins in patients with hepatic cirrhosis or steatosis. In duodenal tissue samples, gut immune barrier dysfunction was analyzed by pro-inflammatory biomarker expressions, oxidative stress, and cell death by flow cytometry methods. A significant innate and adaptative immune system reaction was observed as result of persistent endotoxin action in gut cells in chronic inflammation tissue samples recovered from hepatic cirrhosis with the A-B child stage. Instead, in patients with C child stage of HC, the endotoxin tolerance was installed in cells, characterized by T lymphocyte silent activation and increased Th1 cytokines expression. Interesting mechanisms of ROS-cell death were observed in chronic and acute inflammation samples when gut cells were exposed to endotoxins and immune changes in the gut-liver axis. Late apoptosis represents the chronic response to injury induction by the gut immune barrier dysfunction, oxidative stress, and liver-dysregulated barrier. Meanwhile, necrosis represents an acute and severe reply to endotoxin action on gut cells when the immune system reacts to pro-inflammatory Th1 and Th2 cytokines releasing, offering protection against PAMPs/DAMPs by monocytes and T lymphocyte activation. Flow cytometric analysis of pro-inflammatory biomarkers linked to oxidative stress-cell death mechanisms shown in our study recommends laboratory techniques in diagnostic fields.

Associated factors for bacterial colonization in patients admitted to the intensive care unit of the Clinical Hospital of Infectious Diseases.

Introduction: This study aimed to identify isolates from colonization and assess the risk factors for bacterial colonization and the risk of death in patients admitted to the intensive care unit (ICU) of the Constanta County Infectious Diseases Hospital between September 2017 and September 2019. Methods: This was a retrospective case-control study in a single center that included all patients admitted to the ICU in Constanta, Romania, who underwent bacteriological screening upon admission and 7 days after admission, between September 2017 and September 2019. In total, 253 patients were included in this study. The nasal exudate, pharyngeal exudate, and rectal swab samples were screened. Results: In this study, 253 patients were screened bacteriologically, of which 53 had bacterial colonization and 200 did not. Among the bacterial strains, Klebsiella spp. (43.39%) was the most frequently isolated. The predominant resistance mechanism detected in the bacterial isolates was extended-spectrum ß-lactamase (ESBL). Multivariate analysis identified a Carmeli score of 3 as an independent risk factor for acquiring bacterial colonization in the ICU. The mortality rate of patients with bacterial colonization was 11.32% and 6% for the patients without colonization (p>0.05). Conclusions: Our study revealed an increased prevalence of Enterobacterales colonization in the ICU. Risk factors for acquiring bacterial colonization differed depending on the type of bacterial colonization, such as ESBL, carbapenemases, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci (VRE). An independent risk factor for acquiring bacterial colonization was the Carmeli score of 3.

Particular Aspects Related to CD4+ Level in a Group of HIV-Infected Patients and Associated Acute Coronary Syndrome.

People living with HIV infection are at high risk for cardiovascular events due to inflammation and atherosclerosis. Also, some antiretroviral therapies may contribute to the risk of cardiovascular complications. Immune status is highly dependent on the level of lymphocyte T helper CD4+. There are data suggesting that immune status and CD4+ cell count may be involved in the development of cardiovascular complications in these patients. Our study is longitudinal and retrospective and included a total number of 50 patients with HIV infection associated with acute coronary syndrome, divided into two subgroups based on the nadir of CD4+ cells. This study analyzes the relationship between the immune status of HIV patients, assessed by the nadir of the CD4+ T-cell count, and the outcome of these patients. Also, secondary endpoints were the assessment of the magnitude of coronary lesions and of thrombotic and bleeding risk assessed by specific scores. Clinical and biological parameters and also the extension and complexity of coronary lesions were assessed. Although patients with poor immune status had more complex coronary lesions and increased operative risk and bleeding risk at one year, this was not associated with significant differences in major adverse cardiac and cerebrovascular events at the 30-day and 1-year outcomes.

Cardiovascular Risk Factors, Angiographical Features and Short-Term Prognosis of Acute Coronary Syndrome in People Living with Human Immunodeficiency Virus: Results of a Retrospective Observational Multicentric Romanian Study.

People living with human immunodeficiency virus have increased cardiovascular risk due to a higher prevalence of traditional and particular risk factors such as chronic inflammation, immune dysregulation, endothelial dysfunction, coagulation abnormalities and antiretroviral therapy. In developed countries, coronary artery disease has become the most frequent cardiovascular disease and an important cause of mortality in these patients. The symptomatology of an acute coronary syndrome can be atypical, and the prevalence of each type of acute coronary syndrome is reported differently. Regarding coronary artery disease severity in people living with HIV, the literature data indicates that the presence of single-vessel disease is akin to that of HIV-negative patients, and their short-term prognosis is unclear. This study aims to assess the clinical characteristics, biological parameters, angiographical features and short-term prognosis of acute coronary syndrome in a cohort of Romanian people living with human immunodeficiency virus.

Porcelain Aorta in a Young Person Living with HIV Who Presented with Angina.

People living with human immunodeficiency virus have an increased cardiovascular risk due to higher prevalence of traditional risk factors, such as smoking, dyslipidemia, hypertension, diabetes, or obesity, and particular risk factors, such as inflammation, endothelial dysfunction, and antiretroviral therapy. Thus, people living with human immunodeficiency virus can develop accelerated atherosclerosis. The incidence of coronary artery disease in these patients may be twice as high compared with that of HIV-negative individuals with similar characteristics. "Porcelain aorta" is a term used to describe extensive circumferential calcification of the thoracic aorta. The pathophysiology of porcelain aorta is not fully understood. We present a case of a young man who was a smoker and living with HIV since childhood, without other traditional cardiovascular risk factors, who presented to the emergency room with a positive stress test for myocardial ischemia. Transthoracic echocardiography revealed normal regional and global myocardial wall motion, ascending aorta ectasia, and moderate aortic regurgitation. Coronary angiography showed a critical calcified proximal left anterior descending artery stenosis and an important calcification of the thoracic aorta. Therefore, the most important challenge was the management of coronary syndrome in a young person living with HIV, with associated porcelain aorta and aortic regurgitation.

Predictors of carbapenem-resistant Enterobacteriaceae (CRE) strains in patients with COVID-19 in the ICU ward: a retrospective case-control study.

OBJECTIVE: To identify carbapenem-resistant Enterobacteriaceae (CRE) in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) and to determine whether they had different risk factors for the acquisition of CRE than patients without COVID-19. METHODS: This retrospective single-centre, case-control study enrolled patients with and without COVID-19. The demographic, clinical, infection, colonization and mortality data were compared between the two groups. RESULTS: A total of 38 patients with COVID-19 and 26 patients without COVID-19 were enrolled. The majority of isolates detected in COVID-19 patients were Klebsiella spp. Leukopenia at admission (odds ratio [OR] 4.70; 95% confidence interval [CI] 1.37, 16.10), invasive mechanical ventilation (OR 5.74; 95% CI 1.07, 30.63), carbapenem treatment (OR 5.09; 95% CI 1.21, 21.27) and corticosteroid treatment (OR 7.06; 95% CI 1.53, 32.39) were independent risk factors for CRE acquisition in COVID-19 patients. Intensive care unit (ICU) mortality was significantly higher in COVID-19 patients compared with patients without COVID-19 (OR 20.62; 95% CI 5.50, 77.23). Length of ICU stay increased the risk of death in patients with COVID-19 (subdistribution hazard ratio 3.81; 95% CI 1.33, 10.92). CONCLUSION: CRE strains were more common in patients with COVID-19 and they had different risks for CRE compared with patients without COVID-19.

Bacterial endocarditis masked by COVID-19: A case report.

Infective endocarditis represents a rare complication among patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); it is often a nosocomial infection and the symptomatology can be masked by respiratory failure symptoms from SARS-CoV-2 bronchopneumonia. Management of patients with severe forms of SARS-COV-2 infection who also have associated infective endocarditis is very difficult, especially in mono-specialty hospitals (such as infectious diseases hospitals) where access to cardiological investigations is limited. The current study presents the case of a 73-year-old woman with increased cardiovascular risk (high blood pressure, diabetes mellitus and obesity), with uninvestigated ischaemic heart disease, who was admitted to the Department of Infectious Diseases in the Clinical Infectious Diseases Hospital (Constanta, Romania) due to SARS-CoV-2. Although the evolution was initially favorable, the condition of the patient significantly deteriorated on the 14th day of hospitalization due to the development of Enterococcus faecium infective endocarditis. Despite the therapy, the evolution was fulminant. Infection with coronavirus disease 2019 can result in numerous comorbidities, which cause higher mortality rates than in the general population.

Immune thrombocytopenic purpura secondary to COVID-19 - case report.

INTRODUCTION: Thrombocytopenia is common in SARS-COV-2 infection, and about a quarter of cases have moderate thrombocytopenia. Severe thrombocytopenia is less common and is associated with severe forms of COVID-19. The pathogenesis of this thrombocytopenia appears to be complex, the immune mechanism being incriminated. Immune thrombocytopenic purpura (ITP) is one of the severe complications of COVID-19 and has an increased risk of mucosal or cutaneous bleeding. CASE REPORT: We present the case of a 72-year-old woman admitted to the hospital with moderate COVID-19 who developed severe thrombocytopenia 13 days after the onset of COVID symptoms. Nine days after admission, her platelets decreased from 149×109/L to 3×109/L and numerous patches appeared on the skin and mucous membranes. She was responsive to corticosteroids and platelet transfusion, after five days, the platelet level returned to normal. CONCLUSIONS: Close hematological monitoring of patients with COVID is necessary to prevent severe complications. Even if this patient did not receive immunoglobulins, corticosteroid therapy and platelet administration led to a favorable outcome.

SARS-CoV-2 Infection and Emery-Dreifuss Syndrome in a Young Patient with a Family History of Dilated Cardiomyopathy.

Emery-Dreifuss muscular dystrophy (EDMD) is a rare genetic disease that affects the musculoskeletal system, including the heart, causing rhythm disorders and cardiomyopathy, sometimes requiring an implantable cardioverter-defibrillator (ICD) or heart transplantation due to severe heart damage. The case described herein concerns a 16-year-old girl, with grade II obesity, without other known pathological antecedents or cardiac pathology diagnosis given an annual history of cardiological investigations. She was admitted to the Infectious Diseases Department with SARS-CoV-2 virus infection. The anamnesis showed that the cardiological investigations performed in the past were completed due to the medical history antecedents of her sister, who had been diagnosed with dilated cardiomyopathy, having undergone the placement of an ICD and a heart transplant. Numerous investigations were performed during hospitalization, which revealed high levels of high-sensitive cardiac troponin I (hs-cTnI), creatine kinase (CK) and N-terminal pro b-type natriuretic peptide (NT-proBNP). Dynamic electrocardiographic evaluations showed ventricular extrasystoles, without clinical manifestations. The patient presented stage 2 arterial hypertension (AHT) during hospitalization. A cardiac ultrasound was also performed, which revealed suspected mild subacute viral myocarditis with cardiomyopathy, and antihypertensive medication was initiated. A heart MRI was performed, and the patient was diagnosed with dilated cardiomyopathy, refuting the suspicion of viral subacute myocarditis. After discharge, as the patient developed gait disorders with an impossible heel strike upon walking and limitation of the extension of the arms and ankles, was hospitalized in the Neurology Department. Electrocardiograms (ECGs) were dynamically performed, and because the rhythm disorders persisted, the patient was transferred to the Cardiology Department. On Holter monitoring, non-sustained ventricular tachycardia (NSVT) was detected, so antiarrhythmic treatment was initiated, and placement of an ICD was subsequently decided and was diagnosed with EDMD. Genetic tests were also performed, and a mutation of the lamin A/C gene was detected (LMNA gene exon 2, variant c448A > C (p.Thr150pro), heterozygous form, AD).

Severe Coronary Artery Disease in a Person Living with HIV.

The pathophysiology of accelerated atherosclerosis in people living with Human Immunofediciency virus (HIV) is complex. Coronary artery disease (CAD) has become an important cause of mortality in these patients. They often have atypical symptoms, leading to frequently missed diagnoses. We report a case of a 51-year-old male undergoing antiretroviral therapy who was admitted for acute coronary syndrome. He had severe coronary artery disease that involved difficult management.

Carbapenem-Resistant Klebsiella pneumoniae Associated with COVID-19.

Infections with carbapenem-resistant Enterobacteriaceae are emerging as an important challenge in healthcare settings. Currently, carbapenem-resistant Klebsiella pneumoniae (CRKP) are the species of CRE most commonly encountered in hospitals. CRKP is resistant to almost all available antimicrobial agents, and infections with CRKP have been associated with high rates of morbidity and mortality, particularly among persons with prolonged hospitalization exposed to invasive devices. We report nine patients hospitalized in an intensive care unit (ICU) with severe coronavirus disease 2019 (COVID-19) who developed invasive infections due to carbapenemase-producing Klebsiella pneumoniae (CP-Kp), KPC and OXA-48, strains that have not been previously identified in our hospital. Despite ceftazidime/avibactam therapy, five patients died. Coinfections can contribute to a poor prognosis for patients with COVID-19, especially for high-risk populations such as elderly patients. Therefore, it is crucial to establish a rigorous program of antibiotic administration in intensive care units.

Doravirine dose selection and 96-week safety and efficacy versus efavirenz in antiretroviral therapy-naive adults with HIV-1 infection in a Phase IIb trial.

BACKGROUND: The safety and efficacy of doravirine were compared with that of efavirenz as initial treatment of adults living with HIV-1 infection (NCT01632345). METHODS: A Phase IIb double-blind trial with participants stratified by screening HIV-1 RNA (≤ or >100,000 copies/ml) and randomized 1:1:1:1:1 to receive once-daily doravirine (25, 50, 100 or 200 mg) or efavirenz 600 mg (Part I) for up to 96 weeks, with open-label tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (TDF/FTC). After dose selection at week 24, doravirine 100 mg was provided to participants receiving the other doses of doravirine and additional participants were randomized 1:1 to receive once-daily doravirine 100 mg or efavirenz 600 mg for 96 weeks with TDF/FTC (Part II). Primary outcomes were the proportion of participants with HIV-1 RNA <40 copies/ml at week 24, and central nervous system (CNS) adverse events (AEs) by weeks 8 and 24 (Parts I+II combined). RESULTS: 210 and 132 participants were randomized in Parts I and II, respectively, and 216 (108 on doravirine 100 mg, 108 on efavirenz) were evaluable for Parts I+II combined. At week 24, the proportion of participants with HIV-1 RNA <40 copies/ml was 72.9% for doravirine 100 mg and 73.1% for efavirenz (difference -0.5 [95% CI -12.3, 11.2]). In addition, CNS AEs were reported by 26.9% and 47.2% of doravirine and efavirenz recipients, respectively (difference -20.4 [95% CI -32.6, -7.5]; P=0.002). CONCLUSIONS: Doravirine 100 mg with TDF/FTC demonstrated similar antiretroviral activity and superior CNS safety compared with efavirenz 600 mg with TDF/FTC.

Toxic Megacolon - A Three Case Presentation.

INTRODUCTION: Toxic megacolon is a life-threatening disease and is one of the most serious complications of Clostridium difficile infection (CDI), usually needing prompt surgical intervention. Early diagnosis and adequate medical treatment are mandatory. CASES PRESENTATION: In the last two years, three Caucasian female patients have been diagnosed with toxic megacolon and treated in the Clinical Infectious Diseases Hospital, Constanta. All patients had been hospitalized for nonrelated conditions. The first patient was in chemotherapy for non-Hodgkin's lymphoma, the second patient had undergone surgery for colon cancer, and the third patient had surgery for disc herniation. In all cases the toxin test (A+B) was positive and ribotype 027 was present. Abdominal CT examination, both native and after intravenous contrast, showed significant colon dilation, with marked thickening of the wall. Resolution of the condition did not occur using the standard treatment of metronidazole and oral vancomycin, therefore the therapy was altered in two cases using intracolonic administration of vancomycin and intravenous tigecycline. CONCLUSIONS: In these three cases of CDI, the risk factors for severe evolution were: concurrent malignancy, renal failure, obesity, and immune deficiencies. Ribotype 027, a marker for a virulent strain of CD, was found in all three cases complicated by toxic megacolon. The intracolonic administration of vancomycin, and intravenous tigecycline was successful when prior standard therapy had failed, and surgery was avoided.

HLA class II alleles in Romanian patients with chronic hepatitis C.

INTRODUCTION: The objective of the study was to determine the association of host human leukocyte antigen (HLA) class II genotype DRB1 alleles with the response to interferon therapy, viral loads and extent of liver fibrosis in a group of Romanian patients diagnosed with chronic hepatitis C, with different clinical outcomes. Class II HLA genes, particularly the HLA-DRB1 and DQB1 genes, have been shown to have an important role in self-limiting or persistent viral infection, in different genetic populations. In chronic hepatitis C both susceptible and protective alleles have been described, influencing the development of autoimmunity and progression to cirrhosis and hepatocellular carcinoma. METHODS: The study included 54 patients diagnosed with chronic hepatitis C, registered and monitored from January 2014 to January 2015 at the Clinical Hospital of Infectious Diseases, Constanta, Romania. The selected patients were positive for anti-HCV antibodies and HCV-RNA, with screening laboratory results indicating HCV genotype 1b. The method used for the assignment of alleles at HLA-DRB1 and DQB1 loci was molecular genotyping, by the sequence specific oligonucleotide (SSO) hybridization method, and when required, by the sequence specific primers method (SSP). The presence of different alleles in patients has been analyzed for statistical significance. RESULTS: The presence of HLA-DRB1*0301 had a high frequency (14.8%) in null-responders (NR) while alleles DRB1*0701 (11.1%), DRB1*11# (22.2%) and DRB1*0101 (16.7%) were prevalent in sustained virologic responders (SVR). No significant correlation was found between the presence of HLA-DRB1* alleles and viral loads or liver fibrosis with p values not statistically significant after the Bonferroni correction. CONCLUSION: The presented data suggest that in this group of Romanian patients, certain HLA alleles influence the therapeutic response in HCV infection and genetic predisposition may play a role in hepatitis C virus infection in those patients.

Forty-eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC in ART-naive HIV-positive patients.

INTRODUCTION: Doravirine (DOR) is an investigational NNRTI (aka MK-1439) that retains activity against common NNRTI-resistant mutants. We have previously reported the Part 1 results from a two-part, randomized, double-blind, Phase IIb study in ART-naïve HIV-1-positive patients (1). At doses of 25, 50, 100 and 200 mg qd, DOR plus open-label tenofovir/emtricitabine (TDF/FTC) demonstrated potent antiretroviral activity comparable to EFV 600 mg qhs plus TDF/FTC and was generally well tolerated at week 24. DOR 100 mg was selected for use in patients continuing in Part 1 and those newly enrolled in Part 2. METHODS: Patients receiving DOR 25, 50 or 200 mg in Part 1 were switched to 100 mg after dose selection. In Part 2, 132 additional patients were randomized 1:1 to DOR 100 mg qd or EFV 600 mg qhs (each with TDF/FTC). We present week 48 efficacy and safety results for all patients in Part 1, and early (week 8) CNS tolerability only for patients randomized to DOR 100 mg or to EFV in Parts 1 and 2 combined. The primary safety endpoint is the % of patients with pre-specified CNS events (all causality) by week 8 for DOR 100 mg qd vs EFV (Parts 1 + 2 combined). RESULTS: Part 1 week 48 efficacy and safety results are shown below. CONCLUSIONS: In ART-naïve, HIV-1-positive patients also receiving TDF/FTC, DOR 100 mg qd demonstrated potent antiretroviral activity and immunological effect at week 48 and was generally safe and well tolerated. Patients who received DOR 100 mg qd had significantly fewer treatment-emergent CNS AEs by week 8 than those who received EFV.

Efficacy and safety of darunavir (Prezista(®)) with low-dose ritonavir and other antiretroviral medications in subtype F HIV-1 infected, treatment-experienced subjects in Romania: a post-authorization, open-label, one-cohort, non-interventional, prospective study.

INTRODUCTION: The aim of the study was to assess the safety and efficacy of darunavir (Prezista(®)) used in subtype F human immunodeficiency virus - type 1 (HIV-1) infected, antiretroviral therapy (ART)-experienced patients in Romania in routine clinical practice. METHODS: This was a post-authorization, open-label, one-cohort, non-interventional, prospective study conducted at multiple sites in Romania to assess efficacy (CD4 cell count, viral load, and treatment compliance) and safety ([serious] adverse events, clinical laboratory evaluation, and vital signs) of darunavir in combination with low-dose ritonavir (DRV/r) and other antiretroviral (ARV) medications in subtype F HIV-1 infected subjects in naturalistic settings. Seventy-eight subjects were recruited by 9 investigational sites and received 600/100 mg DRV/r twice daily. RESULTS: Treatment with DRV/r administered with other ARV medications resulted in the expected, statistically relevant improvement of CD4 cell count and viral load in subjects eligible for such treatment. In addition, adherence to treatment was high and the treatment-emergent safety profile observed during this study was consistent with the established safety profile of darunavir. CONCLUSION: DRV/r administered in combination with other ARV medications in subtype F HIV-1 infected subjects in naturalistic settings proved to be an effective and safe treatment in Romania. TRIAL REGISTRATION: NCT01253967.

Hospital-based surveillance to estimate the burden of rotavirus gastroenteritis in children below five years of age in Romania.

INTRODUCTION: Rotavirus (RV) is a leading cause of acute gastroenteritis (AGE), affecting 95% of children below five years of age. METHODS: In this prospective, multi-center study, children below five years of age who were hospitalized or those who visited the emergency room (ER) due to AGE or who developed AGE at least 48 hours after hospitalization (nosocomial infection) and had a RV-positive stool sample were included (n=1,222). RV-positive samples were genotyped by reverse-transcriptase polymerase chain reaction. RESULTS: RV test results were available for 1,212 children (hospitalizations [n=677], ER visits [n=398] and nosocomial AGE cases [n=137]). Proportions of rotavirus gastroenteritis (RVGE) hospitalizations and ER visits were 51.70% (350/677; 95%CI: 47.86-55.52) and 36.18% (144/398; 95%CI: 31.45-41.12), respectively. Overall, 45.95% (494/1075) of all community-acquired AGE cases were due to RV. High numbers of RVGE cases were recorded between January and March. Most common genotypes were G9P[8] (34.27%) followed by G4P[8] (25.83%) and G1P[8] (23.02%). Of all community-acquired RVGE cases, the highest number of cases was observed in children aged 12-23 months. Median duration of hospitalization among RV-positive subjects was six days (range: 2-31 days). Incidence of nosocomial RVGE was 0.52 (95%CI: 0.45-0.60) cases per 1,000 child-days hospitalization. Median duration for additional hospitalization due to nosocomial RVGE was five days (range: 1-10). The highest burden of nosocomial RVGE was observed in children aged 12-23 months (42.34%, 58/137). Our findings confirm a high burden of acute RVGE disease in Romania and provide useful data to support the implementation of RV vaccination in Romania. TRIAL REGISTRATION: NCT01253967.