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The diagnosis of COVID-19 relies on the direct detection of SARS-CoV-2 RNA in respiratory specimens by RT-PCR. The pandemic spread of the disease caused an imbalance between demand and supply of materials and reagents needed for diagnostic purposes including swab sets. In a comparative effectiveness study, we conducted serial follow-up swabs in hospitalized laboratory-confirmed COVID-19 patients. We assessed the diagnostic performance of an in-house system developed according to recommendations by the US CDC. In a total of 96 serial swabs, we found significant differences in the accuracy of the different swab systems to generate a positive result in SARS-CoV-2 RT-PCR, ranging from around 50 to 80%. Of note, an in-house swab system was superior to most commercially available sets as reflected by significantly lower Ct values of viral genes. Thus, a simple combination of broadly available materials may enable diagnostic laboratories to bypass global limitations in the supply of swab sets. [ABSTRACT FROM AUTHOR]

This study evaluates the predictive value of circulating inflammatory markers, especially neopterin, in patients with coronavirus disease 2019 (COVID-19). Within this retrospective analysis of 115 hospitalized COVID-19 patients, elevated neopterin levels upon admission were significantly associated with disease severity, risk for intensive care unit admission, need for mechanical ventilation, and death. Therefore, neopterin is a reliable predictive marker in patients with COVID-19 and may help to improve the clinical management of patients. [ABSTRACT FROM AUTHOR]

Omicron variants are still the dominant SARS-CoV-2 viruses worldwide, therefore determining the level of protection from infection and severe disease is essential. Here, we investigated humoral and cellular immunity of individuals immunized by ChAdOx1, BNT162b2 and mRNA-1273 and our results show that IgG and neutralization titers wane over time. However, strongest neutralization against Omicron BA.1 and T cell responses were detected in ChAdOx1 vaccinees six months after the second dose, while no long lasting neutralization was shown against BA.2 in any cohort. Crucially, our investigation revealed that immunity against variants of concern is heterogenic and dependent on the immunization status. [ABSTRACT FROM AUTHOR]

Abstract: Neutrophil gelatinase-associated lipocalin (NGAL/Lipocalin-2/Lcn-2) is a 25kDa protein which is involved in host defence against certain Gram negative bacteria upon binding of iron loaded bacterial siderophores thereby limiting the availability of this essential nutrient to bacteria resulting in inhibition of their growth and pathogenicity. As iron is important for the growth of the intracellular bacterium Chlamydia pneumoniae we questioned whether Lcn-2 affects the course of this infection. We employed primary peritoneal macrophages obtained from wildtype and Lcn-2 −/− mice and RAW 264.7 cells which were infected with C. pneumoniae. In addition, we studied C. pneumoniae multiplication in vivo in mice receiving diets with varying iron contents. We analyzed C. pneumoniae numbers by immunohistochemistry and RT-PCR and studied the expression of iron metabolism and cytokine genes by RT-PCR, Western blot or ELISA. Infection with Chlamydiae ex vivo and in vivo revealed a significantly higher bacterial growth in peritoneal macrophages of Lcn-2 −/− than of wildtype mice. These differences were significantly more pronounced upon iron challenge, which stimulated bacterial growth. Accordingly, treatment with an anti-Lnc-2 antibody increased whereas addition of recombinant Lcn-2 reduced bacterial growth in infected macrophages. When investigating the underlying mechanisms we observed partly different expression of several iron metabolism genes between Lcn-2 +/+ and Lcn-2 −/− macrophages and most strikingly an increased formation of the anti-inflammatory cytokine IL-10 by Lcn-2 −/− macrophages. Upon treatment with an anti-IL10 antibody we experienced a significant increase of Chlamydial growth within Lcn-2 −/− macrophages along with a reduction of the major iron storage protein ferritin. Herein we provide first time evidence that Lcn-2 is involved in host defence against Chlamydia presumably by limiting the availability of iron to the pathogen. In the absence of Lcn-2, increased formation of IL-10 exerts protective effects by increasing the intracellular formation of ferritin, thereby reducing the access of iron for bacteria. [Copyright &y& Elsevier]

Abstract: Chlamydia pneumoniae is an obligatory intracellular bacterium causing chronic inflammatory diseases in humans. We studied the role of the nutritive factors, iron and tryptophan, towards the course of infection and immune response pathways in C. pneumoniae infected endothelial cells and monocytes. Human endothelial (EA.hy923) and monocytic cells (THP-1) were infected with C. pneumoniae, supplemented with iron or 1-methyltryptophan (1-MT), an inhibitor of the tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO), and subsequently stimulated with IFN-γ or left untreated. The number of infected cells, the morphology and quantity of C. pneumoniae inclusion bodies, IDO activity and innate immune effector pathways were analysed. While neither iron challenge, IDO inhibition or IFN-γ treatment had a significant effect on C. pneumoniae morphology or numbers within THP-1 monocytic cells, iron supplementation to EA.hy926 cells resulted in promotion of C. pneumoniae proliferation and differentiation while IFN-γ had an inhibitory effect. Furthermore, the number of infected endothelial cells was significantly decreased upon 1-MT treatment. C. pneumoniae infection induced a pro-inflammatory immune response as evidenced by increased IDO activity, neopterin formation or TNF-α production in THP-1 but not in endothelial cells. These pathways were superinduced upon IFN-γ treatment and partly modulated by iron supplementation. Our results demonstrate that the infectious cycle of C. pneumoniae behaves differently between monocytic and endothelial cells. While the intracellular pathogen remains in a persistent form within monocytes, it can differentiate and proliferate within endothelial cells indicating that endothelial cells are a preferred environment for Chlamydia. Nutritive factors such as iron have subtle effects on C. pneumoniae biology in endothelial, but not monocytic cells. Our results contribute to a better understanding of C. pneumoniae infection and its role in chronic inflammatory diseases such as atherosclerosis. [Copyright &y& Elsevier]

Extended life expectancy is paralleled by an increasing number of patients older than 65 years suffering from severe infections. Infections in this group of patients are generally more severe and associated with an increased risk of death. This is related to several factors which are discussed in this review. Specifically, immunosenescence and an atypical presentation of infection-associated symptoms with a subsequent delay of diagnosis and initiation of antimicrobial treatment are cornerstones in this dilemma. In addition, comorbidities and comedications, a changing spectrum of pathogens with a higher percentage of multiresistant pathogens, and more importantly, an altered pharmacokinetics of antimicrobial drugs are further contributing factors to the adverse outcome of infections in elderly subjects. Infections in the elderly demand special attention in terms of diagnosis and treatment. As the mortality rates are high, special emphasis must be put on preventive measures including effective vaccination strategies and establishment of hygiene standards to prevent transmission of multiresistant pathogens among elderly patients, both in health care centers and nursing homes. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Chronic active Epstein Barr virus (EBV)-infection is characterized by mononucleosis like symptoms including fatigue, lymphadenopathy and/or hepatosplenomegaly and serologic evidence for ongoing EBV replication. Interferon-gamma (IFN-γ) triggers several antiviral mechanisms in target cells including the induction of indoleamine-2,3-dioxygenase (IDO), which degrades the essential amino acid tryptophan to kynurenine. Because tryptophan is a precursor of the neurotransmitter 5-hydroxytryptamine (serotonin), tryptophan depletion by IDO can cause mood disturbances in patients with chronic immune activation. Methods: This study investigated the tryptophan metabolism in 20 patients with chronic active EBV-infection, who were followed up for 4 to 8 months and in 10 healthy age-matched controls. The clinical suspicion of chronic active EBV infection was verified by the presence of circulating antibodies against EBV early antigen (EA) and virus capsid antigen (VCA). Results: Patients with detectable EBV–DNA had higher serum neopterin (p <0.01) and lower tryptophan concentrations (p =0.01) than EBV–DNA negative patients. Serum concentrations of neopterin, indicating Th-1 mediated immune activation via IFN-γ, were positively correlated to enhanced tryptophan degradation (rs=0.650, p <0.001) in patients, but not in healthy individuals. Patients suffering from more severe symptoms (as assessed by questionnaires) tended to have aggravated tryptophan degradation. Conclusion: Our data show that EBV viremia is associated with cell-mediated immune activation and increased tryptophan degradation, which may partly account for the symptoms found in this disorder. [Copyright &y& Elsevier]

Infections with SARS-CoV-2 can result in severe clinical manifestations. As such patients present with systemic inflammation, we studied the prevalence and predictive value of anemia of inflammation (AI) or functional iron deficiency (FID), originating from immune-mediated alterations of iron homeostasis. Within this retrospective analysis of 259 hospitalized patients with COVID-19, we found that, upon admission, 24.7% were anemic, with the majority suffering from AI (68.8%). Anemia was associated with a significantly higher in-hospital mortality (OR 3.729 (95%CI 1.739–7.995), p = 0.001) but not an increased frequency of intensive care unit (ICU) admission or need for mechanical ventilation. FID was present in 80.0% of patients upon admission, linked to more advanced inflammation and associated with significantly longer hospital stay. Notably, a ferritin/transferrin ratio > 10 predicted a five-fold higher risk of ICU admission and an eight-fold higher risk of the need for mechanical ventilation. Anemia and alterations of iron homeostasis are highly prevalent in hospitalized COVID-19 patients. Iron metabolism biomarkers and hemoglobin can contribute to risk stratification of patients, as initial anemia is associated with increased mortality, whereas alterations of iron homeostasis with a higher ferritin/transferrin ratio reflect more advanced inflammation and predicts subsequent insufficient pulmonary oxygenation with the need for ICU admission and mechanical ventilation. [ABSTRACT FROM AUTHOR]

Seasonally circulating viruses, such as Influenza, as well as newly emerging viruses and variants thereof, and waning immunity urge the need for safe, easy-to-use and inexpensive drugs to protect from these challenges. To prevent transmission of these viruses and subsequent excessive inflammatory reactions on mucous membranes, we tested the efficacy of the natural essence P80 as spray and in form of lozenges against respiratory infections caused by SARS-CoV-2 variants of concern (VoCs), influenza A (H3N2) and influenza B (Victoria). P80 natural essence, a Dimocarpus longan extract, shielded highly differentiated human airway epithelia from SARS-CoV-2 wildtype and Omicron variant as well as Influenza A and B infection and dampened inflammation by down-modulating pro-inflammatory cytokine and anaphylatoxin secretion. A single application of P80 natural essence spray maintained tissue integrity long-term. This also significantly reduced the release of infectious viral particles and the secretion of IP10, MCP1, RANTES and C3a, all of which mediate the migration of immune cells to the sites of infection. Even P80 lozenges dissolved in distilled water or non-neutralizing saliva efficiently prevented SARS-CoV-2 and Influenza-induced tissue destruction. Consequently, our in vitro data suggest that P80 natural essence can act as antiviral prophylactic, both in form of nasal or oral spray and in form of lozenges, independent of circulating respiratory challenges. [ABSTRACT FROM AUTHOR]

Immune checkpoints play an important role in maintaining the balance of the immune system and in the development of autoimmune diseases. A central checkpoint molecule is the programmed cell death protein 1 (PD-1, CD279) which is typically located on the surface of T cells. Its primary ligand PD-L1 is expressed on antigen presenting cells and on cancer cells. Several variants of PD-L1 exist, among these soluble molecules (sPD-L1) present in serum at low concentrations. sPD-L1 was found elevated in cancer and several other diseases. sPD-L1 in infectious diseases has received relatively little attention so far and is therefore subject of this study. sPD-L1 serum levels were determined in 170 patients with viral infections (influenza, varicella, measles, Dengue fever, SARS-CoV2) or bacterial sepsis by ELISA and compared to the levels obtained in 11 healthy controls. Patients with viral infections and bacterial sepsis generally show significantly higher sPD-L1 serum levels compared to healthy donors, except for varicella samples where results do not reach significance. sPD-L1 is increased in patients with impaired renal function compared to those with normal renal function, and sPD-L1 correlates significantly with serum creatinine. Among sepsis patients with normal renal function, sPD-L1 serum levels are significantly higher in Gram-negative sepsis compared to Gram-positive sepsis. In addition, in sepsis patients with impaired renal function, sPD-L1 correlates positively with ferritin and negatively with transferrin. sPD-L1 serum levels are significantly elevated in patients with sepsis, influenza, mesasles, Dengue fever or SARS-CoV2. Highest levels are detectable in patients with measles and Dengue fever. Also impaired renal function causes an increase in levels of sPD-L1. As a consequence, renal function has to be taken into account in the interpretation of sPD-L1 levels in patients. [ABSTRACT FROM AUTHOR]

Immunothrombosis, an excessive inflammatory response with simultaneous overactivation of the coagulation system, is a central pathomechanism in sepsis and COVID-19. It is associated with cellular activation, vascular damage, and microvascular thrombosis, which can lead to multiple organ failure and death. Here, we characterized factors related to immunothrombosis in plasma samples from 78 sepsis patients. In the course of routine clinical testing, SARS-CoV-2 was detected in 14 of these patients. Viral infection was associated with a higher mortality. Both, COVID-19 negative and COVID-19 positive sepsis patients showed increased levels of effectors of immunothrombosis, including platelet factor 4, D-dimer, nucleosomes, citrullinated histone H3, high mobility group box-1 protein, as well as phosphatidylserine-expressing platelet-derived extracellular vesicles, compared to healthy controls (n = 25). Using a 27-plex cytokine bead array, we found that Interleukin (IL)-1ra, IL-6, IL-8, IL-13, tumor necrosis factor (TNF)-α, interferon inducible protein (IP)-10, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and granulocyte-colony stimulating factor (G-CSF) were elevated in both, COVID-19 negative and COVID-19 positive sepsis patients, as compared to healthy controls. SARS-CoV-2 infection was associated with elevated levels of IP-10, MCP-1, and IL-13, while all other mediators widely overlapped between COVID-19 negative and COVID-19 positive patients. [ABSTRACT FROM AUTHOR]

Reverse transcription polymerase chain reaction (RT-PCR) on respiratory tract swabs has become the gold standard for sensitive and specific detection of influenza virus, respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this retrospective analysis, we report on the successive implementation and routine use of multiplex RT-PCR testing for patients admitted to the Internal Medicine Emergency Department (ED) at a tertiary care center in Western Austria, one of the hotspots in the early coronavirus disease 2019 (COVID-19) pandemic in Europe. Our description focuses on the use of the Cepheid® Xpert® Xpress closed RT-PCR system in point-of-care testing (POCT). Our indications for RT-PCR testing changed during the observation period: From the cold season 2016/2017 until the cold season 2019/2020, we used RT-PCR to diagnose influenza or RSV infection in patients with fever and/or respiratory symptoms. Starting in March 2020, we used the RT-PCR for SARS-CoV-2 and a multiplex version for the combined detection of all these three respiratory viruses to also screen subjects who did not present with symptoms of infection but needed in-hospital medical treatment for other reasons. Expectedly, the switch to a more liberal RT-PCR test strategy resulted in a substantial increase in the number of tests. Nevertheless, we observed an immediate decline in influenza virus and RSV detections in early 2020 that coincided with public SARS-CoV-2 containment measures. In contrast, the extensive use of the combined RT-PCR test enabled us to monitor the re-emergence of influenza and RSV detections, including asymptomatic cases, at the end of 2022 when COVID-19 containment measures were no longer in place. Our analysis of PCR results for respiratory viruses from a real-life setting at an ED provides valuable information on the epidemiology of those infections over several years, their contribution to morbidity and need for hospital admission, the risk for nosocomial introduction of such infection into hospitals from asymptomatic carriers, and guidance as to how general precautions and prophylactic strategies affect the dynamics of those infections. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis is a systemic inflammatory disease that is characterized by non-caseating epithelioid-cell granulomas upon histology. However, similar histological findings may also be seen with certain infections. Thus, differentiation from infection is pivotal to ensure appropriate treatment. Here, we present a case of a disseminated infection with Mycobacterium genavense owing to an interleukin 12 receptor subunit beta 1 (IL-12Rβ1) associated immunodeficiency in a previously healthy female who was initially misdiagnosed with sarcoidosis. M. genavense is a nontuberculous mycobacterium which can cause lymphadenopathy, gastrointestinal and bone marrow infiltration in immunocompromised patients. With this case report we aim to highlight that an infection with M. genavense on the ground of a genetic defect of mycobacterial immune control may represent a rare differential diagnosis of sarcoidosis.Case Presentation: A 31-year-old female was referred to our hospital with progressive lymphadenopathy, hepatosplenomegaly, pancytopenia and systemic inflammation. She had previously been evaluated for generalized lymphadenopathy in another hospital. At that time, lymph node biopsies had revealed sarcoid-like lesions and a systemic corticosteroid treatment was initiated based on a putative diagnosis of sarcoidosis. When her condition worsened, she was transferred to our university clinic, where the diagnosis of disseminated M. genavense infection owing to an inborn interferonopathy was made. Her family history revealed that her brother had also suffered from IL-12Rβ1 deficiency and had died from a systemic infection with M. genavense at the age of 21. The patient received antimycobacterial treatment combined with subcutaneous type I interferon, which eventually led to a gradual improvement over the next months.Conclusions: Differentiating between sarcoidosis and sarcoid-like lesions secondary to infections may be challenging, especially when pathogens are difficult to detect or not expected in an apparently immunocompetent patient. Patients with IL-12Rβ1-associated immunodeficiency may be asymptomatic until adulthood, and disseminated M. genavense infection on the grounds of an IL-12Rβ1-associated immunodeficiency may represent a rare differential diagnosis of sarcoidosis. [ABSTRACT FROM AUTHOR]

The CovILD study is a prospective, multicenter, observational cohort study to systematically follow up patients after coronavirus disease-2019 (COVID-19). We extensively evaluated 145 COVID-19 patients at 3 follow-up visits scheduled for 60, 100, and 180 days after initial confirmed diagnosis based on typical symptoms and a positive reverse transcription-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We employed comprehensive pulmonary function and laboratory tests, including serum concentrations of IgG against the viral spike (S) glycoprotein, and compared the results to clinical data and chest computed tomography (CT). We found that at the 60 day follow-up, 131 of 145 (90.3%) participants displayed S-specific serum IgG levels above the cut-off threshold. Notably, the highly elevated IgG levels against S glycoprotein positively correlated with biomarkers of immune activation and negatively correlated with pulmonary function and the extent of pulmonary CT abnormalities. Based on the association between serum S glycoprotein-specific IgG and clinical outcome, we generated an S-specific IgG-based recovery score that, when applied in the early convalescent phase, accurately predicted delayed pulmonary recovery after COVID-19. Therefore, we propose that S-specific IgG levels serve as a useful immunological surrogate marker for identifying at-risk individuals with persistent pulmonary injury who may require intensive follow-up care after COVID-19. [ABSTRACT FROM AUTHOR]

Abstract: US guided procedures for diagnosis or treatment of different forms of arthritis are becoming more and more important. This review describes general considerations for fluid aspiration, articular or periarticular injections and biopsies by US guidance according to the recent literature. Guidelines regarding instrumentation, different techniques, pre- and postprocedural care as well as complications are outlined and in the second part a more detailed overview of different interventions in joints, tendons and other periarticular regions (nerves, bursae, etc.) is included. Furthermore, some newer, more sophisticated techniques are briefly discussed. [Copyright &y& Elsevier]

The article presents a study which evaluates the potential of a second-generation contrast agent for the detection of vascularity at the dorsocaudal part of the sacroiliac joints in patients with sacroiliitis. The subjects of the study were investigated by contrast-enhanced ultrasound (CEUS). It was found in the study that CEUS allowed the differentiation of acute sacroiliitis from inactive SI joint, and is a feasible method for the detection of vascularity in clinically active sacroiliitis.

Background and purpose: To assess neurological manifestations and health‐related quality of life (QoL) 3 months after COVID‐19. Methods: In this prospective, multicenter, observational cohort study we systematically evaluated neurological signs and diseases by detailed neurological examination and a predefined test battery assessing smelling disorders (16‐item Sniffin Sticks test), cognitive deficits (Montreal Cognitive Assessment), QoL (36‐item Short Form), and mental health (Hospital Anxiety and Depression Scale, Posttraumatic Stress Disorder Checklist–5) 3 months after disease onset. Results: Of 135 consecutive COVID‐19 patients, 31 (23%) required intensive care unit (ICU) care (severe), 72 (53%) were admitted to the regular ward (moderate), and 32 (24%) underwent outpatient care (mild) during acute disease. At the 3‐month follow‐up, 20 patients (15%) presented with one or more neurological syndromes that were not evident before COVID‐19. These included polyneuro/myopathy (n = 17, 13%) with one patient presenting with Guillain‐Barré syndrome, mild encephalopathy (n = 2, 2%), parkinsonism (n = 1, 1%), orthostatic hypotension (n = 1, 1%), and ischemic stroke (n = 1, 1%). Objective testing revealed hyposmia/anosmia in 57/127 (45%) patients at the 3‐month follow‐up. Self‐reported hyposmia/anosmia was lower (17%) at 3 months, however, improved when compared to the acute disease phase (44%; p < 0.001). At follow‐up, cognitive deficits were apparent in 23%, and QoL was impaired in 31%. Assessment of mental health revealed symptoms of depression, anxiety, and posttraumatic stress disorders in 11%, 25%, and 11%, respectively. Conclusions: Despite recovery from the acute infection, neurological symptoms were prevalent at the 3‐month follow‐up. Above all, smelling disorders were persistent in a large proportion of patients. [ABSTRACT FROM AUTHOR]

Background and Purpose: Since the outbreak of the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) pandemic, several reports indicated neurological involvement in COVID‐19 disease. Muscle involvement has also been reported as evidenced by creatine kinase (CK) elevations and reports of myalgia. Methods: Creatine kinase, markers of inflammation, pre‐existing diseases and statin use were extracted from records of Austrian hospitalised COVID‐19 patients. Disease severity was classified as severe in case of intensive care unit (ICU) admission or mortality. COVID‐19 patients were additionally compared to an historical group of hospitalised influenza patients. Results: Three hundred fifty‐one patients with SARS‐CoV‐2 and 258 with influenza were included in the final analysis. CK was elevated in 27% of COVID‐19 and in 28% of influenza patients. CK was higher in severe COVID‐19 as were markers of inflammation. CK correlated significantly with inflammation markers, which had an independent impact on CK when adjusted for demographic variables and disease severity. Compared to influenza patients, COVID‐19 patients were older, more frequently male, had more comorbidities, and more frequently had a severe disease course. Nevertheless, influenza patients had higher baseline CK than COVID‐19, and 35.7% of intensive care unit (ICU)‐admitted patients had CK levels >1,000 U/L compared to only 4.7% of ICU‐admitted COVID‐19 patients. Conclusions: HyperCKemia occurs in a similar frequency in COVID‐19 and influenza infection. CK levels were lower in COVID‐19 than in influenza in mild and severe disease. CK levels strongly correlate with disease severity and markers of inflammation. To date, it remains unclear whether hyperCKemia is due to a virus‐triggered inflammatory response or direct muscle toxicity. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections cause coronavirus disease 2019 (COVID-19) and induce a specific antibody response. Serological assays detecting IgG against the receptor binding domain (RBD) of the spike (S) protein are useful to monitor the immune response after infection or vaccination. The objective of our study was to evaluate the clinical performance of the Siemens SARS-CoV-2 IgG (sCOVG) assay. Sensitivity and specificity of the Siemens sCOVG test were evaluated on 178 patients with SARS-CoV-2-infection and 160 pre-pandemic samples in comparison with its predecessor test COV2G. Furthermore, correlation with virus neutralization titers was investigated on 134 samples of convalescent COVID-19 patients. Specificity of the sCOVG test was 99.4% and sensitivity was 90.5% (COV2G assay 78.7%; p<0.0001). S1-RBD antibody levels showed a good correlation with virus neutralization titers (r=0.843; p<0.0001) and an overall qualitative agreement of 98.5%. Finally, median S1-RBD IgG levels increase with age and were significantly higher in hospitalized COVID-19 patients (median levels general ward: 25.7 U/mL; intensive care: 59.5 U/mL) than in outpatients (3.8 U/mL; p<0.0001). Performance characteristics of the sCOVG assay have been improved compared to the predecessor test COV2G. Quantitative SARS-CoV-2 S1-RBD IgG levels could be used as a surrogate for virus neutralization capacity. Further harmonization of antibody quantification might assist to monitor the humoral immune response after COVID-19 disease or vaccination. [ABSTRACT FROM AUTHOR]

Serological tests detect antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the ongoing coronavirus disease-19 (COVID-19) pandemic. Independent external clinical validation of performance characteristics is of paramount importance. Four fully automated assays, Roche Elecsys Anti-SARS-CoV-2, Abbott SARS-CoV-2 IgG, Siemens SARS-CoV-2 total (COV2T) and SARS-CoV-2 IgG (COV2G) were evaluated using 350 pre-pandemic samples and 700 samples from 245 COVID-19 patients (158 hospitalized, 87 outpatients). All tests showed very high diagnostic specificity. Sensitivities in samples collected at least 14 days after disease onset were slightly lower than manufacturers' claims for Roche (93.0%), Abbott (90.8%), and Siemens COV2T (90.3%), and distinctly lower for Siemens COV2G (78.8%). Concordantly negative results were enriched for immunocompromised patients. ROC curve analyses suggest a lowering of the cut-off index for the Siemens COV2G assay. Finally, the combination of two anti-SARS-CoV-2 antibody assays is feasible when considering borderline reactive results. Thorough on-site evaluation of commercially available serologic tests for detection of antibodies against SARS-CoV-2 remains imperative for laboratories. The potentially impaired sensitivity of the Siemens COV2G necessitates a switch to the company's newly filed SARS-CoV-2 IgG assay for follow-up studies. A combination of tests could be considered in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Influenza A virus (IAV) causes a wide range of extrarespiratory complications. However, the role of host factors in these complications of influenza virus infection remains to be defined.Methods: Here, we sought to use transcriptional profiling, virology, histology, and echocardiograms to investigate the role of a high-fat diet in IAV-associated cardiac damage.Results: Transcriptional profiling showed that, compared to their low-fat counterparts (LF mice), mice fed a high-fat diet (HF mice) had impairments in inflammatory signaling in the lung and heart after IAV infection. This was associated with increased viral titers in the heart, increased left ventricular mass, and thickening of the left ventricular wall in IAV-infected HF mice compared to both IAV-infected LF mice and uninfected HF mice. Retrospective analysis of clinical data revealed that cardiac complications were more common in patients with excess weight, an association which was significant in 2 out of 4 studies.Conclusions: Together, these data provide the first evidence that a high-fat diet may be a risk factor for the development of IAV-associated cardiovascular damage and emphasizes the need for further clinical research in this area. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the effect of continuous renal replacement therapy (CRRT) on the pharmacokinetics of trimethoprim and sulfametrole.Patients and Methods: We enrolled critically ill adults undergoing CRRT and critically ill adults with normal or slightly impaired renal function (plasma creatinine concentration <1.5 mg/dL, control group). All patients received trimethoprim/sulfametrole at standard doses. Pharmacokinetics were determined after the first dose and at steady-state. In addition, a population pharmacokinetic model using plasma data was built. We also assessed the renal clearance (CLR) and the extracorporeal clearance in patients undergoing CRRT.Results: Twelve patients were enrolled in the CRRT group and 12 patients in the control group. There was no statistically significant difference in trimethoprim pharmacokinetics between the two groups. In patients on CRRT, total plasma clearance (CLtot) and V of sulfametrole were significantly higher than in the control group. However, sulfametrole exposure was not significantly altered during CRRT. The population pharmacokinetic analysis indicated that neither CRRT intensity nor residual diuresis were significant covariates on trimethoprim or sulfametrole CL. Median CL by continuous venovenous haemofiltration accounted for about one-third of CLtot of trimethoprim and for about one-half of CLtot of sulfametrole. In patients on CRRT, CLR of trimethoprim and sulfametrole were <5% of CLtot.Conclusions: During CRRT, standard doses of trimethoprim/sulfametrole appear to be adequate. [ABSTRACT FROM AUTHOR]

Background: Seasonal influenza is an important cause of morbidity and mortality worldwide. Immune activation after stimulation with interferon‐gamma leads to increased production of neopterin but also results in increased tryptophan catabolism through indoleamine 2,3‐dioxygenase (IDO). Our pilot study determined neopterin serum levels and IDO activity in patients with influenza infection and investigated whether neopterin is linked to clinical outcome parameters (mortality ≤30 days, acute cardiac events (ACE) length of hospitalization, ICU admission). Methods: Neopterin concentrations were analyzed in serum samples of 40 patients with a confirmed diagnosis of influenza infection and in‐hospital treatment for >24 hours. Data were compared to values of 100 healthy blood donors and 48 age‐matched pneumonia patients. In a subgroup of 14 patients, tryptophan and kynurenine concentrations, as well as kynurenine‐to‐tryptophan ratio, were analyzed. Results: In all influenza patients, neopterin concentrations were increased and significantly higher compared to those determined in patients with pneumonia and healthy controls. Positive correlations between the duration of hospitalization and neopterin were found. Significantly higher levels of kynurenine, kynurenine‐to‐tryptophan ratio, and lower levels of tryptophan were seen in influenza patients compared to healthy controls. Conclusions: Neopterin seems to be related to the course of the disease and could be a valuable biomarker to identify patients at an elevated risk of a worsened outcome; however, further prospective validation studies are needed to support the here presented preliminary results. [ABSTRACT FROM AUTHOR]

• SARS-CoV-2 antigen tests allow rapid identification of symptomatic subjects. • Out of four antigen tests, one showed insufficient sensitivity in COVID-19 patients. • Antigen tests can stay positive after patients are no longer considered contagious. Rapid identification of infected subjects is a cornerstone for controlling a pandemic like the current one with the SARS-CoV-2. Easy to handle antigen tests can provide timely results, which is of particular importance in a primary care setting. However, concerns exist regarding their sensitivity, which led us to evaluate four commercially available tests in patients hospitalized for COVID-19. We analyzed in parallel nasopharyngeal/oropharyngeal swabs from 154 consecutive patients admitted to our department with moderate to severe COVID-19, using quantitative RT-PCR (Cobas, Roche) and up to four antigen tests from different distributors. Antigen test results were linked to Ct (cycle threshold) values as markers for patients' infectivity. We found that two out of four antigen tests correctly identified subjects with high viral loads (Ct ≤ 25), and three out of four tests detected more than 80% of subjects with a Ct ≤ 30, which is considered the threshold for infectivity. However, one test investigated had a poor clinical performance. When investigating subjects with Ct values >30, we found that the antigen test was still positive in up to 45% of those cases. Most antigen tests had a sufficient sensitivity to identify symptomatic subjects infected with SARS-CoV-2 and with transmissible infection. On the other hand, antigen testing may not be suitable to identify loss of infectivity in COVID-19 subjects during follow-up. Newly introduced antigen tests need to be validated in a clinical or primary care setting to define their clinical usefulness. [ABSTRACT FROM AUTHOR]

Bacteremia is a major clinical challenge requiring early treatment. Metabolic alterations occur during bacteremia, and accordingly plasma concentrations of lipoproteins LDL-C and HDL-C are substantially changed. We questioned whether bacteremia with Gram-negative versus Gram-positive bacteria causes contrasting changes of lipoprotein levels in order to differentiate between the 2-g stain types and if there is a relation with outcome parameters namely ICU-admission, 30-day mortality, duration of hospitalization. This is a retrospective dual-center cross-sectional study, including 258 patients with bacteremia. Plasma lipid levels were analyzed within 48 h to positive blood culture. Upon admission, HDL-C, LDL-C, and total cholesterol (p = 0.99) in plasma did not significantly differ between patients with Gram-negative and Gram-positive bacteremia, while significantly higher triglyceride concentrations were found in Gram-negative bacteremia (p < 0.05). 30-day mortality and ICU admission were associated with lower LDL-C and HDL-C concentrations as compared to survivors and non-ICU patients, and patients with HDL-C < 20 mg dl−1 and LDL-C < 55 mg dl−1 had a relative risk (RR) of 2.85 for ICU therapy requirement and RR = 2 of death within 30 days. Reduced HDL-C and LDL-C concentrations were associated with adverse patient's outcome in bacteremia. Discrimination between Gram-negative and Gram-positive pathogens upon lipoprotein patterns is unlikely. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to compare findings of ultrasound (US) with dual-energy CT (DECT) in patients presenting with suspected gouty hand and wrist arthritis.Methods: This prospective study included 180 patients (136 men and 44 women, age range, 31- 94 years; mean age, 65.9 years) with an initial clinical diagnosis of acute gouty arthritis who underwent DECT and US examination. Intra- and extra-articular findings of each modality were tabulated and calculated with DECT as gold standard.Results: The final diagnosis of gout was positive in 97/180 patients (53.9%) by DECT, an alternative diagnosis confirmed in 83 patients. US showed a sensitivity of 70.1% (extra-articular: 42.5%, p < 0.0001; intra-articular: 80.3%, p = 0.14) and specificity of 51%. The double contour sign (DCS) was present in 58/61 patients with a positive US study for intra-articular gout (95.1%).Conclusions: Sensitivity of US for diagnosis of gouty arthritis in hand and wrist is limited, particularly with respect to extra-articular urate deposition. The DCS is the most sensitive sign for the assessment of gouty hand and wrist arthritis by US.Key Points: • Sensitivity of US for diagnosis of gouty arthritis in hand and wrist is limited, particularly with respect to extra-articular gouty deposits. • The double contour sign is the most sensitive finding for the assessment of gouty hand and wrist arthritis by US. • Although the sensitivity of US for diagnosis of gouty hand and wrist arthritis is limited, it can be used as a first-line imaging modality in the presence of the DCS. [ABSTRACT FROM AUTHOR]

Acute exacerbations and community-acquired pneumonia (CAP) are severe complications in patients with chronic obstructive pulmonary disease (COPD). In this study, we analyzed inflammatory parameters in serum including C-reactive protein (CRP), procalcitonin (PCT), and serum neopterin (NPT) to determine their potential to differentiate between patients with CAP+COPD and with acute exacerbations of COPD (AECOPD) without pneumonia. 102 (39 women and 63 men) patients were included in this retrospective study, of whom 48 presented with CAP without underlying COPD, 20 with CAP+COPD and 34 with AECOPD. CRP, PCT, and blood counts were determined by routine automated tests, and NPT concentrations were determined by ELISA. The ratios of CRP to NPT levels were calculated. Upon patient admission, CRP, PCT, and NPT levels were significantly higher in patients with CAP compared to those in AECOPD patients. CRP/NPT ratio was lower in AECOPD compared to CAP (+/−COPD) patients. Positive correlations were found between duration of hospitalization and CRP levels and the CRP/NPT ratio at study entry. Patients who were readmitted within 30 days tended to have higher NPT levels at initial presentation. Patients under ongoing corticosteroid treatment presented with lower inflammatory parameters. The CRP/NPT-ratio was suited well to discriminate between AECOPD and CAP on the basis of COPD, a CRP/NPT cutoff of 0.346 provided a sensitivity of 65% and a specificity of 79%. The combinatory use of inflammatory patterns might help to differentiate patients with AECOPD from those with CAP on the basis of COPD. [ABSTRACT FROM AUTHOR]

Fungal cholangitis is a potentially life-threatening condition. As amphotericin B (AmB) has a broad antimycotic spectrum, in this study its biliary penetration and activity was determined in two patients treated with liposomal AmB (L-AmB) and in one patient receiving AmB colloidal dispersion (ABCD). Biliary and plasma AmB levels were quantified by high-performance liquid chromatography after purification by solid-phase extraction. For assessment of biliary AmB activity, isolates of Candida albicans , Candida tropicalis , Candida glabrata and Candida krusei were incubated in porcine bile at AmB concentrations of 0.025–5.00 mg/L. In addition, patient bile samples retrieved for AmB quantification were inoculated with the same Candida strains. Biliary AmB concentrations were lower and displayed a slower rise and decline than plasma levels. The highest penetration ratio, as expressed by the ratio between the area under the AmB concentration–time curve in bile and plasma (liberated AmB) over the sampling period (AUC 0– n bile /AUC 0– n LI plasma ), was 0.28. Proliferation of C. albicans and C. tropicalis in bile was similar to that in culture medium, whereas growth of C. glabrata was diminished and proliferation of C. krusei was absent in bile. In comparison with culture medium, AmB activity decreased in spiked porcine bile. In all but one patient bile sample, fungal growth was delayed or lacking even when AmB was not detectable. However, no fungicidal effect was observed in patient bile at AmB concentrations up to 1.28 mg/L. Thus, a reliable response of fungal cholangitis to treatment with L-AmB or ABCD cannot be anticipated. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the accuracy of two different sonographic median nerve measurement calculations in predicting carpal tunnel syndrome (CTS) severity in a study population with clinically and electrophysiologically confirmed CTS.Methods: 643 wrists of 427 patients (325 females and 102 males, age range: 17-90 years, mean ± SD: 57.9 ± 14.7) were included with CTS diagnosis based on clinical and nerve conduction studies (NCS). Cross-sectional area (CSA) measurement of the median nerve was performed at the carpal tunnel level (CSAc) and at the pronator quadratus muscle level (CSAp). Two parameters were calculated: delta (∆-CSA), which is the difference between proximal and distal measurements, and ratio (R-CSA), calculated by dividing distal over proximal measurements.Results: Patients were classified into mild, moderate and severe CTS based upon NCS. The mean ∆-CSA (4.2 ± 2.6, 6.95 ± 2.2 and 10.7 ± 4.9 mm(2)) and mean R-CSA (1.5 ± 0.4, 1.95 ± 0.4 and 2.4 ± 0.7) values were significantly different between all groups (p < 0.001). Optimal cut-off values for ∆-CSA and R-CSA were 6 mm(2) and 1.7, respectively, to distinguish mild from moderate disease, and 9 mm(2) and 2.2, respectively, to distinguish moderate from severe disease.Conclusion: Threshold values for the calculated sonographic parameters ∆-CSA and R-CSA are useful in predicting CTS severity compared to NCS.Key Points: • Two proposed parameters were calculated (∆-CSA, R-CSA) and compared to NCS. • A defined sonoanatomical proximal landmark was used for the calculation. • Both parameters showed ability to detect CTS severity comparable to NCS. • Cut-off values could be determined for both parameters. [ABSTRACT FROM AUTHOR]

Pain around the greater trochanter is still a common clinical problem that may be secondary to a variety of either intra-articular or periarticular pathologies. Gluteal tendon pathologies are one of the primary causes of greater trochanteric pain, with attrition of the fasciae latae against the gluteus medius and minimus tendons, and the trochanteric bursa being possible causes. Key sonographic findings of gluteal tendinopathy, bursitis, and differential diagnosis are described in this overview. Clinical diagnosis and treatment of greater trochanteric pain syndrome is still challenging; therefore ultrasound is helpful to localize the origin of pain, determine underlying pathology, and, based on these findings, to guide local aspiration and/or injection in cases of tendinopathy and/or bursitis. [ABSTRACT FROM AUTHOR]

An abstract of the article "Nifedipine Affects the Course of Salmonella enterica Serovar Typhimurium Infection by Modulating Macrophage Iron Homeostasis," by Patrizia L. Moser and colleagues is presented.

Recently, the iron and erythropoiesis-controlled growth differentiation factor 15 (GDF15) has been shown to inhibit the expression of hepcidin in β-thalassaemia patients, thereby increasing iron absorption despite iron overload. To access the diagnostic and pathogenic impact of GDF15 in inflammatory anaemia the association of GDF15 expression with serum iron parameters and hepcidin was studied in patients suffering from iron deficiency anaemia (IDA), anaemia of chronic disease (ACD) and ACD subjects with true iron deficiency (ACD/IDA). GDF15 was significantly increased in both ACD and ACD/IDA, but not in IDA subjects as compared to controls. In contrast, hepcidin levels were significantly lower in IDA and ACD/IDA subjects than in ACD patients . IDA and ACD/IDA, but not ACD, showed an association between GDF15 and soluble transferrin receptor, an indicator of iron requirement for erythropoiesis. However, GDF15 did not correlate to hepcidin in either patient group. While GDF15 levels were linked to the needs for erythropoiesis and iron homeostasis in IDA, the immunity-driven increase of GDF15 may not primarily affect iron homeostasis and hepcidin expression. This indicates that other ACD-related factors may overcome the regulatory effects of GDF15 on hepcidin expression during inflammation. [ABSTRACT FROM AUTHOR]

Abstract: In mice, the expression of the phagolysosomal protein natural-resistance associated macrophage protein 1 (Nramp1, Slc11a1) is associated with host resistance to various intracellular pathogens. Nramp1 acts as a transporter for protons, iron, and other divalent cations, and Nramp1 functionality is associated with an enhanced activity of pro-inflammatory immune pathways, including the formation of nitric oxide (NO) via transcriptional stimulation of inducible nitric oxide synthase (iNOS) expression. As iron availability also strongly influences iNOS expression, we studied the effects of Nramp1 functionality on iron homeostasis in the RAW264.7 macrophage cell line stably transfected with functional or non-functional Nramp1. We found that macrophages lacking functional Nramp1 exhibited a significantly higher iron uptake via transferrin receptor 1 and, as a consequence of this, an increased iron release which is mediated via the iron export protein ferroportin-1. RNA-bandshift experiments for determination of iron regulatory protein activity showed that, as a net effect of the altered expression of iron transporters, the overall cellular iron content was lower in macrophages bearing functional Nramp1. Since low intracellular iron availability enhances iNOS transcription, Nramp1 could exert its effect on NO formation and other pro-inflammatory immune pathways via modulation of iron homeostasis. [Copyright &y& Elsevier]

Extracorporeal blood purification techniques such as hemofiltration or albumin dialysis can exert a significant, but not easily predictable influence on plasma pharmacokinetics of antimicrobial agents. The effect of albumin dialysis on the pharmacokinetics of liposomal amphotericin B (AMB) and other lipid-formulated drugs has not been investigated so far. Therefore, plasma concentrations of liberated and liposomal AMB were measured in a patient, who obtained liposomal AMB for suspected invasive mycosis and required albumin dialysis because of cholestatic liver failure caused by graft versus host disease after bone marrow transplantation. Liberated and liposomal AMB were separated by solid phase extraction and measured by high performance liquid chromatography. No excessive AMB elimination took place during albumin dialysis. Plasma levels of liposomal AMB exceeded those of liberated AMB. Pharmacokinetic data were comparable to those obtained previously in patients on hemofiltration and in critically ill patients without extracorporeal blood purification. [ABSTRACT FROM AUTHOR]

To determine an adequate dosage of ciprofloxacin in critically ill medical patients on continuous venovenous haemofiltration, we studied the pharmacokinetics of ciprofloxacin in eight critically ill medical patients with renal failure treated with continuous venovenous heamofiltration using polysulfone membranes. Three of those patients also presented with severe liver dysfunction. For comparison, three patients with approximately normal renal function and two patients with impaired renal function were included. During haemofiltration, plasma concentrations of ciprofloxacin were variable. In all critically ill patients ciprofloxacin elimination was significantly slowed; the mean half-life was similarly prolonged to about 14 h in patients on haemofiltration and those with approximately normal renal function. in critically ill patients with impaired renal function not on haemofiltration, the mean half-life was longest. Ciprofloxacin clearance by haemofiltration was a quarter of the total clearance. Although a unique dose recommendation can hardly be made because of the high variability of pharmacokinetics during haemofiltration, a daily dose of 800 mg (400 mg b.i.d.)in average can be regarded as appropriated for reaching a target plasma concentration of 2 to 3 μg/mL (mean concentration). Because the half-life of ciprofloxacin was further prolonged by the presence of liver cirrhosis, the dose should be reduced to 600 mg in patients on haemofiltration with concomitant severe liver dysfunction. [ABSTRACT FROM AUTHOR]

Background: Severe coronavirus disease 2019 (COVID-19) is frequently associated with hyperinflammation and hyperferritinemia. The latter is related to increased mortality in COVID-19. Still, it is not clear if iron dysmetabolism is mechanistically linked to COVID-19 pathobiology.Methods: We herein present data from the ongoing prospective, multicentre, observational CovILD cohort study (ClinicalTrials.gov number, NCT04416100), which systematically follows up patients after COVID-19. 109 participants were evaluated 60 days after onset of first COVID-19 symptoms including clinical examination, chest computed tomography and laboratory testing.Results: We investigated subjects with mild to critical COVID-19, of which the majority received hospital treatment. 60 days after disease onset, 30% of subjects still presented with iron deficiency and 9% had anemia, mostly categorized as anemia of inflammation. Anemic patients had increased levels of inflammation markers such as interleukin-6 and C-reactive protein and survived a more severe course of COVID-19. Hyperferritinemia was still present in 38% of all individuals and was more frequent in subjects with preceding severe or critical COVID-19. Analysis of the mRNA expression of peripheral blood mononuclear cells demonstrated a correlation of increased ferritin and cytokine mRNA expression in these patients. Finally, persisting hyperferritinemia was significantly associated with severe lung pathologies in computed tomography scans and a decreased performance status as compared to patients without hyperferritinemia.Discussion: Alterations of iron homeostasis can persist for at least two months after the onset of COVID-19 and are closely associated with non-resolving lung pathologies and impaired physical performance. Determination of serum iron parameters may thus be a easy to access measure to monitor the resolution of COVID-19.Trial Registration: ClinicalTrials.gov number: NCT04416100. [ABSTRACT FROM AUTHOR]