Cause Of Systemic Inflammation Research Articles

The Role of Biomarkers in Distinguishing Infectious From Non-Infectious Diseases

Abstract Background. The use of C-reactive protein (CRP) and procalcitonin (PCT) as guiding biomarkers in treating severe infections could improve the use of antibiotics. Biomarker dynamics are more reliable than single values in predicting sepsis when making the diagnosis and evaluating the response to antibiotic therapy. Both CRP and PCT used protocols have to be consistent with the clinical context and patient populations. Objectives: reviewing the use of PCT and CRP in various clinical contexts and the patient population Sources. We analyzed the most recent studies of these biomarkers for antimicrobial stewardship, including meta-analyses and original trials. Content. According to several studies, critically ill patients who get antibiotic treatment under the guidance of CRP and PCT see a decrease in antibiotic exposure and related adverse effects. When patients are hospitalized in intensive care units (ICUs), CRP and PCT can be used to distinguish between viral and non-infectious causes of systemic inflammation. In septic patients, CRP levels are reliable to show a high negative predictive value (NPV), especially on day 1 of ICU admission. Consequently, CRP levels decrease during therapy with appropriate antibiotics in the next 3 days. Implication. In addition to other clinical and laboratory parameters, CRP and PCT provide information about the risk of the bacterial infection worsening or improving under appropriate treatment. These improve antibiotic treatment decisions, allowing individualized treatment regimens with reduced overall antibiotic exposure.

About the associations of vitamin D deficiency and biomarkers of systemic inflammatory response with all-cause and cause-specific mortality in a general population sample of almost 400,000 UK Biobank participants

It is unknown whether the well-known association between vitamin D deficiency and mortality could be explained by the immune system modulating effects of vitamin D, which may protect from a systemic inflammatory response (SIR) to adverse health conditions. This study aims to investigate the interrelationships of vitamin D deficiency, biomarkers of SIR, and mortality. We used multivariate logistic regression with adjustment for 51 covariates to assess the associations of vitamin D deficiency with disadvantageous levels of nine biomarkers of SIR in the UK Biobank cohort. Furthermore, we tested with Cox regression and mediation analysis whether biomarkers of SIR and vitamin D deficiency were independently associated with mortality. We included 397,737 participants aged 37–73 years. Vitamin D deficiency was associated with disadvantageous levels of all blood cell count-based biomarkers, but not with C-reactive protein (CRP)-based biomarkers after adjustment for body weight. Vitamin D deficiency and all biomarkers of SIR were significantly associated with all-cause mortality and mortality from cancer, cardiovascular and respiratory disease. The strength of these associations was unaltered if vitamin D deficiency and biomarkers of SIR were put in the same model. This finding was further supported by the mediation analyses. This study showed that vitamin D deficiency is associated with disadvantageous levels of blood cell count-based but not CRP-based biomarkers of SIR. Vitamin D deficiency and systemic inflammation were independently and strongly associated with mortality. The potential of clinical interventions against both vitamin D deficiency and underlying causes of systemic inflammation should be explored.

#4219 NON-INVASIVE ASSESSMENT OF LIVER STIFFNESS, HEPATIC FIBROSIS RISK MARKERS AND OUTCOMES IN A DIALYSIS POPULATION

Abstract Background and Aims People with end stage kidney disease (ESKD) commonly co-exhibit multiple risk factors (type 2 diabetes mellitus, obesity and hypertension) for non-alcoholic fatty liver disease (NAFLD) and its progressive, fibroinflammatory form non-alcoholic steatohepatitis (NASH). NAFLD and NASH both associate with increased risk of fatal cardiovascular events. NASH will additionally soon become the leading cause of cirrhosis both in the UK and worldwide. The cause of systemic inflammation driving early mortality in patients with ESKD is unclear. It is thought that liver disease can contribute to inflammation due to reduced reticuloendothelial function and subsequent penetration of gut-derived toxins into the systemic circulation. Very little is currently known about prevalence of NAFLD and NASH in ESKD, or how these conditions affect patients. By identifying the scale of the risk, this study will help better understand the extent of NAFLD and NASH and their links to clinical outcomes in advanced kidney disease. We report interim results from this study looking non-invasively for liver disease in patients with ESKD. Method This prospective study involves prevalent patients with ESKD treated with dialysis (for >3 months) at five participating UK kidney centres. Results from this study are derived from analysis of the first 238 patients (final recruitment target 450). A FibroScan® (Echosens) device was used to measure both hepatic steatosis using controlled attenuation parametrography (CAP) and fibrosis using transient elastography. A fibrosis-4 index score was calculated to assess fibrosis risk. These results were supplemented by baseline clinical and radiological data, serum beta-D-glucan levels taken pre- and post-dialysis, clinical assessment of fluid status, and bioimpedance spectroscopy (Fresenius Medical Care). Survival analyses were performed using Kaplan-Meier estimates. Results The mean age of participants was 63 years (67% male). Mean body mass index was 27.8kg/m2. 97% of participants had hypertension, 53% diabetes mellitus and 65% hyperlipidaemia. 231 participant FibroScan scores (97%) were valid (interquartile range ≤30% over 10 consecutive readings) and available for analysis. 74 participants (31%) had suspected hepatic steatosis of grade S1-S3 and 72 participants (30%) had suspected hepatic fibrosis of grade F2-F4. 53 participants (22%) had suspected F2-F3 fibrosis (moderate fibrosis) and 19 (8%) had suspected F4 fibrosis (advanced fibrosis/cirrhosis). There was increased mortality associated with suspected hepatic fibrosis/steatosis (9.1% absolute risk of mortality with an abnormal CAP or fibrosis score compared to 1.6% in those with normal FibroScan imaging). The majority of mortality in people with suspected hepatic fibrosis was from cardiovascular disease. Overall mortality in participants with suspected hepatic fibrosis remained significant even after adjustment for univariate predictors of survival (median CRP, baseline BDG levels and age) (Figure 1). Other univariate predictors of survival were Charlson Comorbidity Score and diabetes status. Conclusion These results demonstrate a significant burden of suspected hepatic steatosis and hepatic fibrosis in people with ESKD. Suspected hepatic fibrosis assessed by FibroScan imaging is an independent risk factor for mortality based on this interim analysis and strategies to improve liver health in the setting of advanced kidney disease may be of benefit to this group of patients.

Spectrum of clonal hematopoiesis in VEXAS syndrome

AbstractVacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic autoinflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 patients with VEXAS for CH in their peripheral blood (PB) and correlated the findings with clinical outcomes in 77 of them. UBA1mut were most common at hot spot p.M41 (median variant allele frequency [VAF] = 75%). Typical CH mutations cooccurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mut was the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed 2 major patterns: with either typical CH preceding UBA1mut selection in a clone (pattern 1) or occurring as an UBA1mut subclone or in independent clones (pattern 2). VAF in the PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.

Critical evaluation on roles of macrophagic myofasciitis and aluminum adjuvants in HPV vaccine-induced adverse events.

Cervical cancer is caused by human papillomavirus (HPV) infection, which is preventable by HPV vaccines. In Japan, the HPV vaccination rate has remained extremely low due to the concerns for alleged neuropsychological symptoms or "diverse symptoms" following injections of two HPV vaccines, Cervarix and Gardasil, in HPV vaccine lawsuits. In the lawsuits, the attorneys' group has used several manuscripts proposing that aluminum (Al) adjuvant contained in HPV vaccines causes an immune-mediated disease, called macrophagic myofasciitis (MMF), as well as pathology in the central nervous system (CNS). We scientifically evaluated these manuscripts describing the "Al adjuvant-induced pathologies," particularly MMF. Although MMF patients have been reported to develop clinical symptoms/signs in various organs, including the CNS, muscle biopsy of the patients and animal experiments demonstrated that MMF pathology was localized only at the injected muscle. No muscle pathology which characterizes MMF was observed in any other muscles; thus, the systemic and neurological signs of MMF cases were irrelevant to localized MMF pathology. We evaluated that MMF-like pathology was induced as a local inflammatory response following vaccinations; MMF pathology was not the cause of systemic inflammation or "diverse symptoms." Lastly, MMF cases have been reported after vaccinations with Al-hydroxide-containing vaccines exclusively. As Al-hydroxide is a component of Cervarix, but not Gardasil, "diverse symptoms" following two HPV vaccinations in Japan cannot be explained by MMF. Our evaluation would help readers understand the validity of the manuscripts on the role of Al adjuvants or MMF for the alleged "diverse symptoms."

Osteoarthritis of the joints of the hands. Review of clinical recommendations

The article discusses the prevalence of osteoarthritis of the joints of the hands. The modern aspects of pathogenesis and the leading role of inflammation in it are highlighted. The article assesses the risk factors for osteoarthritis of the joints of the hands. According to recent studies, one of the important factors that increase the risk of developing osteoarthritis of the joints of the hands are gender (in premenopausal women, due to a decrease in estrogen levels, a higher risk of developing osteoarthritis of the joints of the hands is determined compared to men of the same age) and obesity as one of the causes of systemic inflammation. The article draws attention to studies studying a wide range of serum biomarkers with diagnostic and prognostic value, as well as the role of synovitis imaging as a factor contributing to the progression of the disease. The article also discusses the latest recommendations of the leading professional communities of EULAR and ARC on the treatment of patients with osteoarthritis of the joints of the hands. According to modern principles, the treatment of patients should include a combination of pharmacological and non-pharmacological methods and is aimed not only at reducing pain and improving the functional state of the joints, the quality of life of patients, but also at preventing / slowing the progression of the disease. Attention is also drawn to the main provisions on the rational use of NSAIDs by leading Russian associations and communities, which focus on possible adverse reactions of NSAIDs. The article pays great attention to the use of chondroitin sulfate as a substance recommended for the treatment of osteoarthritis of the joints of the hands by leading international communities. The authors present the results of a number of studies proving the safety and effectiveness of the use of chondroitin sulfate in osteoarthritis of the joints of the hands.

Single-cell RNA-seq uncovers cellular heterogeneity and provides a signature for paediatric sleep apnoea.

Obstructive sleep apnoea (OSA) is a highly prevalent disease and a major cause of systemic inflammation leading to neurocognitive, behavioural, metabolic and cardiovascular dysfunction in children and adults. However, the impact of OSA on the heterogeneity of circulating immune cells remains to be determined. We applied single-cell transcriptomics analysis (scRNA-seq) to identify OSA-induced changes in transcriptional landscape in peripheral blood mononuclear cell (PBMC) composition, which uncovered severity-dependent differences in several cell lineages. Furthermore, a machine-learning approach was used to combine scRNAs-seq cell-specific markers with those differentially expressed in OSA. scRNA-seq demonstrated OSA-induced heterogeneity in cellular composition and enabled the identification of previously undescribed cell types in PBMCs. We identified a molecular signature consisting of 32 genes, which distinguished OSA patients from various controls with high precision (area under the curve 0.96) and accuracy (93% positive predictive value and 95% negative predictive value) in an independent PBMC bulk RNA expression dataset. OSA deregulates systemic immune function and displays a molecular signature that can be assessed in standard cellular RNA without the need for pre-analytical cell separation, thereby making the assay amenable to application in a molecular diagnostic setting.

Цитомегаловирусная и смешанные вирусные инфекции у пациентов с воспалительными заболеваниями кишечника

Актуальность. Вопрос распространенности оппортунистических инфекций у лиц с воспалительными заболеваниями кишечника (ВЗК) остается актуальным. Особое внимание среди оппортунистических инфекций уделяется цитомегаловирусной (ЦМВ) инфекции. Клиническая активность ЦМВ-ассоциированного ВЗК, его длительность и степень тяжести, а также использование стероидов и анти-ФНО-α-агентов были идентифицированы как факторы риска неблагоприятных исходов. В диагностике ЦМВ важно не просто выявить наличие вируса в организме пациента, но и уточнить его этиологическую роль в развитии заболевания. В настоящее время рекомендуется проведение скрининга на ЦМВ у всех пациентов с ВЗК при гормональной резистентности, потере эффекта от поддерживающей терапии и при тяжелых эпизодах заболевания. Цель исследования: оценка частоты выявления изолированной цитомегаловирусной инфекции и смешанных (герпес и парвовирус В19) вирусных инфекций у пациентов с ВЗК и их влияние на активность заболевания. Материалы и методы. Обследовано 189 пациентов с ВЗК, 102 с язвенным колитом и 87 с болезнью Крона, среди них 98 женщин и 91 мужчина. Возраст пациентов составлял от 16 до 63 лет, в среднем (41,4 ± 4,8) года. Кроме стандартного клинико-эндоскопического обследования в соответствии с положениями Европейской организации по изучению болезни Крона и язвенного колита (ЕССО), активность заболевания оценивалась по показателям высокочувствительного С-реактивного белка, гомоцистеина, витамина D в сыворотке крови, альбумина в моче, кальпротектина и лактоферрина в кале. Всем пациентам проведено серологическое исследование крови методом иммуноферментного анализа на специфические антитела к герпесвирусам и IgG-/IgM-антитела к парвовирусу В19, а также определение ДНК вирусов простого герпеса 1, 2, 6-го типов, вируса Эпштейна — Барр, цитомегаловируса, герпеса зостер методом полимеразной цепной реакции. У всех пациентов также определяли уровни цитокинов в крови (фактор некроза опухоли α, интерлейкины 1β, -2, -4, -6, -8, -10, -18). Результаты. У пациентов с ВЗК частота выявления изолированной цитомегаловирусной инфекции составляет, по нашим данным, 19,5 %, а с учетом смешанных поражений — 29,6 %. Клинико-эндоскопическая картина (рефрактерность к базисной терапии, несоответствие между эндоскопической картиной и патоморфологическим заключением), а также данные лабораторных исследований указывают на более тяжелое течение заболевания при наличии цитомегаловирусной инфекции. Выводы. Полученные данные позволяют нам рекомендовать в дополнение к протоколам ЕССО определение наличия оппортунистических инфекций у пациентов с впервые выявленным ВЗК до начала базисной терапии, не дожидаясь развития рефрактерных к лечению форм заболевания.

What do the White Spots in the Second Part of Duodenum Tell Us?

Abstract: Objective: The underlying conditions/diseases of scattered white spots in the duodenum are rather not very clear in the literature. We aimed to find out whether Helicobacter pylori, diabetes mellitus or inflammation has an impact on the presence of duodenal white spots. Materials & Methods: We included all patients who underwent endoscopy between the time-period 2007-2017 in the Endoscopy Unit of Cumhuriyet University and had scattered white spots in the duodenum. Our control group was formed by randomly selected patients who underwent endoscopy at the same time period in whom duodenal biopsy was taken. The demographic data of both the patient and the control group, the presence of diabetes, endoscopic and histological diagnoses, neutrophil lymphocyte ratio, thrombocyte lymphocyte ratio, mean platelet volume and erythrocyte distribution width were obtained from the computer system of the hospital in detail. Results: Peptic ulcer disease was found to be significantly more prevalent in patients with white spots than the control group. We could not find any difference between the patient and control groups by means of either neutrophil lymphocyte ratio, platelet lymphocyte ratio, mean platelet volume and erythrocyte distribution width, Helicobacter pylori, positivity or presence of diabetes. Conclusion: Both diabetes mellitus and H. pylori are causes of systemic inflammation. In our study, we evaluated whether patients with white spots were associated with systemic inflammation by looking at popular inflammation markers. We could not find any difference between the two groups in terms of these markers. Keywords: White spots, Duodenum, Diabetes mellitus, Systemic inflammation, Lymphangiectasia, Giardiasis, Chronic nonspecific duonetitis.

P234 Frequency detectiveness of some viral infections in patients with inflammatory bowel diseases

Abstract Background The prevalence of opportunistic infections in individuals with inflammatory bowel disease (IBD) remains relevant. Viral infections are a common cause of systemic inflammation of the digestive tract. Clinically expressed herpes and parvovirus infections are a serious problem, especially for people with prolonged immunosuppression. The aim of the study was t o assess the incidence of certain herpes and parvovirus infections in patients with IBD. Methods In total, 189 patients with IBD, 102 with ulcerative colitis and 87 with Crohn’s disease were examined. Of the number of patients: 98 women, 91man. The age of patients is from 16 to 63 years (mean age 41.4 ± 4.8). In addition to a standard examination, disease activity was assessed by indicators of highly sensitive C-reactive protein, homocysteine, vitamin D in blood serum, albumin in urine, calprotectin and lactoferrin in faeces. All patients underwent serological blood tests by ELISA for specific antibodies to herpes viruses and IgG/IgM antibodies to parvovirus B19, determination of DNA to herpes simplex viruses of types 1-2,6(HSV1-2?HSV6), Epstein–Barr (EBV}, cytomegalovirus (CMV), herpes zoster (HZV) by PCR in blood and mucosal biopsy, and also avidity. Results Among patients with IBD, active infections (herpes and parvoviruses) in the blood occurred in 81 patients (42.8%); of them, 39 patients (20.6%) were diagnosed with monoherpesvirus infections, in 16 patients parvovirus (8.4%), and in 26 (13.8%) cases, active mixed viral infections were detected. In 79 cases (41.7%) of PCR biopsy material was positive for isolated infection: 36 cases (19%) of CMV, 21 cases (11.1%) of EBV, 22 cases (11.6%) of HSV6. Tissue viral infection was found in 34 patients (17.9%). Clinical endoscopic and laboratory indicators of activity in IBD were significantly higher in patients with active viral infections (p ˂ 0.05), which indicates the negative effect of chronic active herpes and parvovirus infections on the course of inflammatory bowel diseases. However, significant differences between patients with ulcerative colitis and Crohn’s disease were not detected. Conclusion The frequency of occurrence of herpes and parvovirus lesions in patients with IBD in the blood is more than 42.8%, isolated infection in the tissue in 41.7%, and mixed infection in 17.9% of the number of patients. The clinical endoscopic picture, as well as laboratory data indicate a more severe course of diseases in the presence of these infections.

P253 The prevalence of type 6 herpes with polyps in patients with inflammatory bowel disease

Abstract Background The prevalence of opportunistic infections in individuals with inflammatory bowel disease (IBD) remains relevant. Viral infections are a common cause of systemic inflammation of the digestive tract. Clinically expressed herpes infections are a serious problem, especially for individuals with prolonged immunosuppression. The aim of this study was t o assess the frequency of detection of herpes-6 type with polyps in patients with IBD. Methods 189 patients with IBD, 102 with ulcerative colitis and 87 with Crohn’s disease were examined. Of the number of patients: 98women, 91man. The age of the patients is from 16 to 63 years (mean age 41.4 ± 4.8), out of 189 patients intestinal polyps were identified in 61 patients with a colonoscopy. In addition to standard clinical and endoscopic examinations, disease activity was assessed by indicators of highly sensitive C-reactive protein, homocysteine, vitamin D in blood serum, albumin in urine, calprotectin, lactoferrin and pyruvate kinase in faeces. All patients underwent a serological blood test by ELISA for specific antibodies to herpesvirus type 1–6 IgG/IgM antibodies, as well as avidity, determination of DNA to herpes viruses of types 1–6 species by PCR in blood and mucosal biopsy. Results Among patients with IBD (n = 189), active herpes viruses in the blood were found in 65 patients (34.4%); of them, 39 patients (20.6% (n = 189) and 60%(n = 65),respectively) were diagnosed with monoherpesvirus infections, and 26 (13.7%(n = 189) and 40%(n = 65), respectively) of myxedvirus infections. PCR of the biopsy material was positive in isolation for type 6 herpes virus in 22 cases (11.6% (n = 189) and 33.8% (n = 65)) and in 34 cases (17.9% (n = 189) and 52.3% (n = 65)) a myxedvirus lesion was detected in the tissue (HV6 + EPB, HV6 + CMV), these indicators were detected in patients with intestinal polyps. Although clinical and endoscopic and laboratory indicators of disease activity were significantly higher in patients with mixed tissue lesions (p˂0.05), the level of faecal pyruvate kinase was higher in patients with polyps, indicating a negative effect of herpes type 6 on the course of inflammatory bowel diseases. At the same time, no significant differences were found between patients with ulcerative colitis and Crohn’s disease. Conclusion The frequency of occurrence of herpes type 6 on PCR biopsy in patients with polyps with IBD is more than 91.8% (36.5% in isolation and 55.7% of mixed lesions) and is accompanied by higher rates of faecal pyruvate kinase, which is already an indicator of emerging malignancy. The authors propose the determination of polyps in patients with IBD HV6 by PCR biopsy of intestinal tissue.

Periodontitis, oral hygiene habits, and risk of upper aerodigestive tract cancers: a case-control study in Maharashtra, India.

Chronic destructive periodontitis, a cause of systemic inflammation, affects some 10% to 15% of adults across the globe, with severity of disease increasing with age. The aim of this study was to explore the relationship between periodontitis and oral hygiene habits and upper aerodigestive tract(UADT) cancers. We conducted a case-control study, which included 240 UADT cancer cases and 240 controls matched by gender and age (±5years) from 2 different hospitals in Pune, India.In-person interviews and intraoral examinations were conducted for all patients. Severe periodontitis and greater than 5 missing teeth were associated with a significant risk of UADT cancers (adjusted odds ratio [OR] 2.25, 95% confidence interval [CI] 1.12-4.91; adjusted OR 3.28, 95% CI 1.95-5.49). Among the self-reported oral hygiene habits, dental checkups only at the time of pain was associated with an elevated risk for UADT cancers (adjusted OR 4.12; 95% CI 2.63-6.47). Topical application of mishri (black powder obtained by roasting and grinding tobacco) on gums (adjusted OR 3.06; 95% CI 1.75-5.35) and toothbrushing frequency less than once daily; (adjusted OR 2.09; 95% CI 1.27-3.45) were also associated with an elevated risk. Furthermore, the habit of ever chewing tobacco was associated with an elevated risk of severe periodontitis. Severe periodontitis is associated with an elevated risk for UADT cancers, and tobacco chewing strengthens this association in this population.

Alterations of Gut Microbiome in Untreated Chronic Lymphocytic Leukemia (CLL); Future Therapeutic Potentials

Introduction: Gut dysbiosis is an imbalance of the gut microbiome. The presence of dysbiosis can be a cause of systemic inflammation in the body or can be a contributing factor to it. Chronic systemic inflammation is a common feature of CLL, creating an environment in which CLL cells have a survival advantage. NF-κB and STAT3, master transcriptional regulators of pro-inflammatory markers, like IL-1 and IL-6, are reported to be involved in this process as are the Toll-like receptors (TLRs), key innate immunity receptors that are implicated in CLL pathophysiology. With increasing evidence for the role of dysbiosis in chronic inflammation, as well as the role of systemic inflammation in CLL, it seems relevant to prove the presence and the possible role of microbiome in the pathophysiology of CLL, to unravel the complex interaction between microbiome, nutrition and the host in patients with CLL. Our research investigate the hypothesis that dysbiosis i.e. the loss of "health-promoting" commensal gut microbes and/or the overgrowth of pathogenic bacteria distinguishes untreated patients with CLL versus aged-matched unaffected individuals. Methodology: Eight untreated CLL patients were with no history of gastrointestinal disorders, other malignancies and have not been on antibiotics for 4 weeks prior to samples collection. Two of them were not followed for logistical reasons. Six healthy volunteers matched for sex and age were also enrolled in the study. Stool samples from six patients and additional six matched healthy controls were collected and stored in a -40 freezer immediately until they were used for DNA isolation. Total genomic DNA was extracted using the Qiamp DNA stool mini kit and sequenced using Next Generation Sequencing and then analysis were done as per the manufacturer recommendations. Results: Our data indicates a reduced diversity and variability in bacterial phyla of gut microbiota in CLL patients as compare to healthy controls. Lower diversity with increase in certain bacterial types is a well-accepted sign of gut dysbiosis, which have been shown in many disorders such as; type-2 diabetes, obesity, and various autoimmune and neurological diseases. An increase in Proteobacteria numbers has been recognized as the signature of gut dysbiosis which we confirmed in our cohort of patients. Proteobacteria, Firmicutes and Bacteriodetes were also the most abundant bacterial phyla in CLL patients of our study which were reported previously in breast cancer patients. An elevated Firmicutes to Bacteroidetes ratio with altered gut microbiota in CLL patients compared with healthy subjects was also suggested in clinical studies involving obese individuals with insulin resistance. We have observed in CLL patients of this study relative increase in the numbers of Firmicutes and reduction in Bacteriodetes which is considered to be an inverted ratio as compared to healthy individuals which were also reported in ulcerative colitis, colonic and ileal crohn's disease as compared to healthy subjects. . Our finding of gut dysbiosis in this study is linked the association between CLL, inflammatory processes and dysbiosis. The microbiota may play a role in promoting malignancy through chronic inflammation, by disturbing the balance of cell proliferation, death and by initiating unwanted innate and adaptive immune responses. Conclusion: Restoring gut microbiota might open a new avenue for future researches as potential therapeutic intervention in CLL patients. Figure Disclosures No relevant conflicts of interest to declare.

An unusual presentation of purine nucleoside phosphorylase deficiency mimicking systemic juvenile idiopathic arthritis complicated by macrophage activation syndrome

BackgroundSystemic juvenile idiopathic arthritis (sJIA) is an inflammatory condition that presents with fever, rash and arthritis. At onset systemic features are predominant and the diagnosis may be a challenge. Secondary hemophagocytic lymphohistiocytosis (sHLH) forms may be associated with different disorders, including rheumatic diseases, and this form is called macrophage activation syndrome (MAS). CXCL9 levels, a chemokine induced by IFNγ, are significantly elevated in patients with sHLH or MAS and are correlated with laboratory features of disease activity. High levels of IL-18 have been reported in patients with MAS during sJIA, as well as in some patients with sHLH and IL-18 is indeed known to induce IFNγ production.FindingsWe report a patient with a clinical presentation highly suggestive for systemic juvenile idiopathic arthritis (sJIA) onset complicated by MAS, and was later diagnosed with purine nucleoside phosphorylase (PNP)-deficiency with HLH. Some unusual features appeared when HLH was controlled and further investigations provided the correct diagnosis. Serum CXCL9 and IL-18 levels were found markedly elevated at disease onset, during the active phase of MAS and decreased progressively during the course.ConclusionThe reported case underlines the potential difficulties in discriminating sJIA from other causes of systemic inflammation. Furthermore, this supports the notion that especially in young children with a sJIA-like disease other mimicking conditions should be actively sought for. CXCL9 and IL-18 levels suggested that patients with PNP-deficiency may have a subclinical activation of the IFNγ pathway and indeed they are predisposed to develop sHLH.

Diagnostic value of procalcitonin and presepsin for sepsis in critically ill adult patients: a systematic review and meta-analysis

BackgroundEarly and accurate diagnosis of sepsis is challenging. Although procalcitonin and presepsin have been identified as potential biomarkers to differentiate between sepsis and other non-infectious causes of systemic inflammation, the diagnostic accuracy of these biomarkers remains controversial. Herein, we performed a comprehensive meta-analysis to assess the overall diagnostic value of procalcitonin and presepsin for the diagnosis of sepsis.MethodsWe searched three electronic databases (MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials) for relevant studies. Two authors independently screened articles on the basis of inclusion and exclusion criteria. The pooled sensitivity, specificity, and summary receiver operating characteristic curves were estimated. The quality of evidence for diagnostic accuracy in absolute effects, i.e., the number of true or false positives and true or false negatives, gave a particular pre-test probability.ResultsWe included 19 studies (19 observational studies and no randomized controlled trials) that had enrolled 3012 patients. Analyses of summary receiver operating characteristic curves revealed areas under the receiver operating characteristic curves of 0.84 for procalcitonin and 0.87 for presepsin. The pooled sensitivities and specificities were 0.80 (95% confidence interval 0.75 to 0.84) and 0.75 (95% confidence interval 0.67 to 0.81) for procalcitonin. For presepsin, these values were 0.84 (95% confidence interval 0.80 to 0.88) and 0.73 (95% confidence interval 0.61 to 0.82), respectively. There were no statistically significant differences in both pooled sensitivities (p = 0.48) and specificities (p = 0.57) between procalcitonin and presepsin.ConclusionOur meta-analysis provided evidence that the diagnostic accuracy of procalcitonin and presepsin in detecting infection was similar and that both are useful for early diagnosis of sepsis and subsequent reduction of mortality in critically ill adult patients.Systematic review registrationThe study was registered in PROSPERO under the registration number CRD42016035784.

Profile of the SeptiCyte™ LAB gene expression assay to diagnose infection in critically ill patients

ABSTRACTSepsis is a severe and frequently occurring clinical syndrome, caused by the inflammatory response to infections. Recent studies on the human transcriptome during sepsis have yielded several gene-expression assays that might assist physicians during clinical assessment of patients suspected of sepsis. SeptiCyte™ LAB (Immunexpress, Seattle, WA) is the first gene expression assay that was cleared by the FDA in the United States to distinguish infectious from non-infectious causes of systemic inflammation in critically ill patients. The test consists of the simultaneous amplification of four RNA transcripts (CEACAM4, LAMP1, PLAC8, and PLA2G7) in whole blood using a quantitative real-time PCR reaction. This review provides an overview of the challenges in the diagnosis of sepsis, the development of gene expression signatures, and a detailed description of available clinical performance studies evaluating SeptiCyte™ LAB.

Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial

Chronic inflammation is believed to be a major mechanism underlying the pathophysiology of type 2 diabetes. Periodontitis is a cause of systemic inflammation. We aimed to assess the effects of periodontal treatment on glycaemic control in people with type 2 diabetes. In this 12 month, single-centre, parallel-group, investigator-masked, randomised trial, we recruited patients with type 2 diabetes, moderate-to-severe periodontitis, and at least 15 teeth from four local hospitals and 15 medical or dental practices in the UK. We randomly assigned patients (1:1) using a computer-generated table to receive intensive periodontal treatment (IPT; whole mouth subgingival scaling, surgical periodontal therapy [if the participants showed good oral hygiene practice; otherwise dental cleaning again], and supportive periodontal therapy every 3 months until completion of the study) or control periodontal treatment (CPT; supra-gingival scaling and polishing at the same timepoints as in the IPT group). Treatment allocation included a process of minimisation in terms of diabetes onset, smoking status, sex, and periodontitis severity. Allocation to treatment was concealed in an opaque envelope and revealed to the clinician on the day of first treatment. With the exception of dental staff who performed the treatment and clinical examinations, all study investigators were masked to group allocation. The primary outcome was between-group difference in HbA1c at 12 months in the intention-to-treat population. This study is registered with the ISRCTN registry, number ISRCTN83229304. Between Oct 1, 2008, and Oct 31, 2012, we randomly assigned 264 patients to IPT (n=133) or CPT (n=131), all of whom were included in the intention-to-treat population. At baseline, mean HbA1c was 8·1% (SD 1·7) in both groups. After 12 months, unadjusted mean HbA1c was 8·3% (SE 0·2) in the CPT group and 7·8% (0·2) in the IPT group; with adjustment for baseline HbA1c, age, sex, ethnicity, smoking status, duration of diabetes, and BMI, HbA1c was 0·6% (95% CI 0·3-0·9; p<0·0001) lower in the IPT group than in the CPT group. At least one adverse event was reported in 30 (23%) of 133 patients in the IPT group and 23 (18%) of 131 patients in the CPT group. Serious adverse events were reported in 11 (8%) patients in the IPT group, including one (1%) death, and 11 (8%) patients in the CPT group, including three (2%) deaths. Compared with CPT, IPT reduced HbA1c in patients with type 2 diabetes and moderate-to-severe periodontitis after 12 months. These results suggest that routine oral health assessment and treatment of periodontitis could be important for effective management of type 2 diabetes. Diabetes UK and UK National Institute for Health Research.

Vasodilator function worsens after cessation of tumour necrosis factor inhibitor therapy in patients with rheumatoid arthritis only if a flare occurs.

NCT02130076.

Determination of Interference During In Vitro Pyrogen Detection: Development and Characterization of a Cell-Based Assay.

Contamination of pharmaceutical products and medical devices with pyrogens such as endotoxins is the most common cause of systemic inflammation and, in worst cases, of septic shock. Thus, quantification of pyrogens is crucial. The limulus amebocyte lysate (LAL)-based assays are the reference tests for in vitro endotoxin detection, in association with the in vivo rabbit pyrogen test (RPT), according to European Pharmacopoeia (EP 2.6.14), and U.S. Pharmacopoeia (USP <85>). However, several substances interfere with LAL assay, while RPT is not accurate, not quantitative, and raises ethical limits. Biological assays, as monocyte activation tests, have been developed and included in European Pharmacopoeia (EP 7.0; 04/2010:20630) guidelines as an alternative to RPT and proved relevant to the febrile reaction in vivo. Because this reaction is carried out by endogenous mediators under the transcriptional control of nuclear factor-kappaB (NF-kappaB), we sought to determine whether a NF-kappaB reporter-gene assay, based on MonoMac-6 (MM6) cells, could reconcile the basic mechanism of innate immune response with the relevance of monocytoid cell lines to the organism reaction to endotoxins. This article describes both optimization and characterization of the reporter cells-based assay, which overall proved the linearity, accuracy, and precision of the test, and demonstrated the sensitivity of the assay to 0.24 EU/mL endotoxin, close to the pyrogenic threshold in humans. Moreover, the assay was experimentally compared to the LAL test in the evaluation of selected interfering samples. The good performance of the MM6 reporter test demonstrates the suitability of this assay to evaluate interfering or false-positive samples.

Editorial Comment

This interesting work has the merit of bringing attention to some important aspects of prostatic pathology, which have not yet received the necessary attention. 1 De Nunzio C. Brassetti A. Gacci M. Patients with prostatic inflammation undergoing transurethral prostatic resection have a larger early improvement of storage symptoms. Urology. 2015; 86: 359-367 Abstract Full Text Full Text PDF Scopus (18) Google Scholar Patients With Prostatic Inflammation Undergoing Transurethral Prostatic Resection Have a Larger Early Improvement of Storage SymptomsUrologyVol. 86Issue 2PreviewTo evaluate the association between prostate inflammation, metabolic syndrome (MetS), and postoperative lower urinary tract symptoms in patients treated with transurethral resection of the prostate (TURP). Full-Text PDF ReplyUrologyVol. 86Issue 2PreviewEmerging evidence suggests that prostatic inflammation may play a role in benign prostatic hyperplasia (BPH) development and progression.1 Furthermore, the presence of prostatic inflammatory infiltrates may influence the expression and the severity of lower urinary tract symptoms (LUTS) and/or BPH at different stage. In particular, in naïve and/or untreated patients with BPH, metabolic syndrome (MetS), a well-established cause of systemic inflammation, is associated with an increased risk of storage symptoms2; in pharmacologically treated patients, those with low-grade inflammation presented a 3.5 higher LUTS improvement than high-grade group3; in patients undergoing transurethral resection of the prostate (TURP), we confirmed the association between MetS and prostate inflammation and demonstrated that patients with inflammatory infiltrates mostly benefit from TURP, particularly regarding storage symptoms. Full-Text PDF