Resilient anatomy and local plasticity of naive and stress haematopoiesis.

The bone marrow adjusts blood cell production to meet physiological demands in response to insults. The spatial organization of normal and stress responses are unknown owing to the lack of methods to visualize most steps of blood production. Here we develop strategies to image multipotent haematopoiesis, erythropoiesis and lymphopoiesis in mice. We combine these with imaging of myelopoiesis1 to define the anatomy of normal and stress haematopoiesis. In the steady state, across the skeleton, single stem cells and multipotent progenitors distribute through the marrow enriched near megakaryocytes. Lineage-committed progenitors are recruited to blood vessels, where they contribute to lineage-specific microanatomical structures composed of progenitors and immature cells, which function as the production sites for each major blood lineage. This overall anatomy is resilient to insults, as it was maintained after haemorrhage, systemic bacterial infection and granulocyte colony-stimulating factor (G-CSF) treatment, and during ageing. Production sites enable haematopoietic plasticity as they differentially and selectively modulate their numbers and output in response to insults. We found that stress responses are variable across the skeleton: the tibia and the sternum respond in opposite ways to G-CSF, and the skull does not increase erythropoiesis after haemorrhage. Our studies enable in situ analyses of haematopoiesis, define the anatomy of normal and stress responses, identify discrete microanatomical production sites that confer plasticity to haematopoiesis, and uncover unprecedented heterogeneity of stress responses across the skeleton.

Bacterial detection by NAIP/NLRC4 elicits prompt contractions of intestinal epithelial cell layers.

The gut epithelium serves to maximize the surface for nutrient and fluid uptake, but at the same time must provide a tight barrier to pathogens and remove damaged intestinal epithelial cells (IECs) without jeopardizing barrier integrity. How the epithelium coordinates these tasks remains a question of significant interest. We used imaging and an optical flow analysis pipeline to study the dynamicity of untransformed murine and human intestinal epithelia, cultured atop flexible hydrogel supports. Infection with the pathogen Salmonella Typhimurium (STm) within minutes elicited focal contractions with inward movements of up to ∼1,000 IECs. Genetics approaches and chimeric epithelial monolayers revealed contractions to be triggered by the NAIP/NLRC4 inflammasome, which sensed type-III secretion system and flagellar ligands upon bacterial invasion, converting the local tissue into a contraction epicenter. Execution of the response required swift sublytic Gasdermin D pore formation, ion fluxes, and the propagation of a myosin contraction pulse across the tissue. Importantly, focal contractions preceded, and could be uncoupled from, the death and expulsion of infected IECs. In both two-dimensional monolayers and three-dimensional enteroids, multiple infection-elicited contractions coalesced to produce shrinkage of the epithelium as a whole. Monolayers deficient for Caspase-1(-11) or Gasdermin D failed to elicit focal contractions but were still capable of infected IEC death and expulsion. Strikingly, these monolayers lost their integrity to a markedly higher extent than wild-type counterparts. We propose that prompt NAIP/NLRC4/Caspase-1/Gasdermin D/myosin-dependent contractions allow the epithelium to densify its cell packing in infected regions, thereby preventing tissue disintegration due to the subsequent IEC death and expulsion process.

Cytosolic detection of phagosomal bacteria-Mechanisms underlying PAMP exodus from the phagosome into the cytosol.

The metazoan innate immune system senses bacterial infections by detecting highly conserved bacterial molecules, termed pathogen-associated molecular patterns (PAMPs). PAMPs are detected by a variety of host pattern recognition receptors (PRRs), whose function is to coordinate downstream immune responses. PRR activities are, in part, regulated by their subcellular localizations. Accordingly, professional phagocytes can detect extracellular bacteria and their PAMPs via plasma membrane-oriented PRRs. Conversely, phagocytosed bacteria and their PAMPs are detected by transmembrane PRRs oriented toward the phagosomal lumen. Even though PAMPs are unable to passively diffuse across membranes, phagocytosed bacteria are also detected by PRRs localized within the host cell cytosol. This phenomenon is explained by phagocytosis of bacteria that specialize in phagosomal escape and cytosolic residence. Contrary to this cytosolic lifestyle, most bacteria studied to date spend their entire intracellular lifestyle contained within phagosomes, yet they also stimulate cytosolic PRRs. Herein, we will review our current understanding of how phagosomal PAMPs become accessible to cytosolic PRRs, as well as highlight knowledge gaps that should inspire future investigations.

Necroptosis: the release of damage-associated molecular patterns and its physiological relevance.

Regulated necrosis, termed necroptosis, is negatively regulated by caspase-8 and is dependent on the kinase activity of RIPK1 and RIPK3. Necroptosis leads to rapid plasma membrane permeabilization and to the release of cell contents and exposure of damage-associated molecular patterns (DAMPs). We are only beginning to identify the necroptotic DAMPs, their modifications, and their potential role in the regulation of inflammation. In this review, we discuss the physiological relevance of necroptosis and its role in the modulation of inflammation. For example, during viral infection, RIPK3-mediated necroptosis acts as a backup mechanism to clear pathogens. Necroptosis is also involved in apparently immunologically silent maintenance of T cell homeostasis. In contrast, the induction of necroptosis in skin, intestine, systemic inflammatory response syndrome, and ischemia reperfusion injury provoke a strong inflammatory response, which might be triggered by emission of DAMPs from necroptotic cells, showing the detrimental side of necroptosis.

Bacterial infections adversely influence the risk of decompensation and survival in compensated cirrhosis.

BACKGROUND & AIMS: The prognosis of compensated cirrhosis is good until decompensation. In decompensated cirrhosis, bacterial infections (BIs) are common and increase the risk of death. The incidence and prognostic implications of BIs in compensated cirrhosis are less-well characterized. This study aimed to assess whether BIs influence the risk of decompensation and survival in patients with compensated cirrhosis. METHODS: This is a cohort study nested to the PREDESCI study, a double-blind, multicenter, randomized controlled trial designed to assess whether ß-blockers could prevent decompensation of cirrhosis. Patients with compensated cirrhosis and hepatic venous pressure gradient ≥10 mmHg were included. Development of BIs during follow-up was prospectively registered. Using a competing-risk time-dependent regression analysis, we investigated whether BIs affect the risk of decompensation and survival. Decompensation was defined as development of ascites, bleeding or overt encephalopathy. RESULTS: A total of 201 patients were randomized and followed for a median of 36 months (IQR 24-47 months); 34 patients (17%) developed BIs, which occurred before decompensation in 33 cases, and 29 (14%) developed ascites. Respiratory and urinary tract infections were the most frequent BIs. Decompensation occurred in 26% patients with BIs vs. 16% without BIs. Patients with BIs were at higher risk of decompensation (subdistribution hazard ratio [SHR] 2.93; 95% CI 1.02-8.42; p = 0.047) and of developing ascites (SHR 3.55; 95% CI 1.21-10.47; p = 0.022) than those without BIs. Risk of death was also higher in patients with BIs (subdistribution HR 6.93; 95% CI 2.64-18.18; p <0.001), although decompensation occurred before death in 71% of such cases. CONCLUSIONS: BIs have a marked impact on the natural history of compensated cirrhosis, significantly increasing the risk of decompensation, mainly that of ascites, and increasing the risk of death, which usually occurs after decompensation. Our results suggest that BIs may constitute a target to prevent decompensation. LAY SUMMARY: It is widely known that bacterial infections are common and increase the mortality risk in patients with decompensated cirrhosis. However, the relevance of bacterial infections in compensated cirrhosis has not been well studied. This study shows that in patients with compensated cirrhosis and clinically significant portal hypertension, bacterial infections occur as frequently as the development of ascites, which is the most frequent decompensating event. Bacterial infections increase the risk of progression to decompensation, mainly by increasing the risk of ascites, and also increase the risk of death, which usually occurs after decompensation. CLINICALTRIALS. GOV IDENTIFIER: NCT01059396.

A Novel 29-Messenger RNA Host-Response Assay From Whole Blood Accurately Identifies Bacterial and Viral Infections in Patients Presenting to the Emergency Department With Suspected Infections: A Prospective Observational Study.

OBJECTIVES: The rapid diagnosis of acute infections and sepsis remains a serious challenge. As a result of limitations in current diagnostics, guidelines recommend early antimicrobials for suspected sepsis patients to improve outcomes at a cost to antimicrobial stewardship. We aimed to develop and prospectively validate a new, 29-messenger RNA blood-based host-response classifier Inflammatix Bacterial Viral Non-Infected version 2 (IMX-BVN-2) to determine the likelihood of bacterial and viral infections. DESIGN: Prospective observational study. SETTING: Emergency Department, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Germany. PATIENTS: Three hundred twelve adult patients presenting to the emergency department with suspected acute infections or sepsis with at least one vital sign change. INTERVENTIONS: None (observational study only). MEASUREMENTS AND MAIN RESULTS: Gene expression levels from extracted whole blood RNA was quantified on a NanoString nCounter SPRINT (NanoString Technologies, Seattle, WA). Two predicted probability scores for the presence of bacterial and viral infection were calculated using the IMX-BVN-2 neural network classifier, which was trained on an independent development set. The IMX-BVN-2 bacterial score showed an area under the receiver operating curve for adjudicated bacterial versus ruled out bacterial infection of 0.90 (95% CI, 0.85-0.95) compared with 0.89 (95% CI, 0.84-0.94) for procalcitonin with procalcitonin being used in the adjudication. The IMX-BVN-2 viral score area under the receiver operating curve for adjudicated versus ruled out viral infection was 0.83 (95% CI, 0.77-0.89). CONCLUSIONS: IMX-BVN-2 demonstrated accuracy for detecting both viral infections and bacterial infections. This shows the potential of host-response tests as a novel and practical approach for determining the causes of infections, which could improve patient outcomes while upholding antimicrobial stewardship.

Clinicopathological profile and outcomes of infection-related glomerulonephritis in adults.

INTRODUCTION: Infection-related glomerulonephritis (IRGN) is an example of immune-mediated glomerular injury, with changing profile over the years. We analyzed the clinicopathological profile of IRGN from a single center. MATERIALS AND METHODS: Adult renal biopsies between July 2018 and January 2020 were screened, and biopsies with IRGN were included. The demographic, clinical, and laboratory data up to 6 months were analyzed. RESULTS: 27 patients were included, with 63% having evidence of current/recent infection, Staphylococcus and Streptococcus being most common (29.4%). The mean eGFR at presentation was 16.7 mL/min/1.73m2, with crescents in 70.4% of cases. 59.3% required dialysis, and 40.7% received steroids. Complete recovery was seen in 84.6%, while 11.1% developed chronic kidney disease, and 3.7% progressed to end-stage renal disease. Persistent proteinuria, hematuria, and hypertension at 6 months were seen in 11.1, 7.4, and 3.7%, respectively. There was significant negative correlation between renal recovery and history of diabetes, interstitial fibrosis and tubular atrophy (IFTA), glomerulosclerosis, and IgA deposits. There was no significant impact of steroid use on outcome. CONCLUSION: IRGN can have an aggressive course in adults, with renal recovery continuing beyond 3 months. IFTA, glomerulosclerosis, IgA deposits, and history of DM are significant negative predictors of clinical outcome, and there is no proven benefit of steroids.

Fever response to ibuprofen in viral and bacterial childhood infections.

OBJECTIVE: to compare the antipyretic effects of ibuprofen in febrile children with serious bacterial infections (SBI), and children with a presumed viral infection. METHODS: A prospective cross- sectional study was conducted in a pediatric Emergency department between October 2018 and March 2020 for children aged 3 months to 4 years with a rectal temperature ≥ 38.5 °C. Patients received 10 mg/kg of ibuprofen oral suspension. Rectal temperature was measured 60 and 120 min after administration. Laboratory and imaging evaluations were performed for each study participant in order to identify serious bacterial infection. RESULTS: Ninety patients were included, of which 18 were diagnosed with serious bacterial infections. There was no significant difference in age, fever at presentation and duration of fever between the groups. No significant difference was noted in body temperature reduction at 60 and 120 min after ibuprofen administration (1.09 ± 0.75 °C vs 0.89 ± 0.58 °C, mean difference -0.12 °C, 95% CI -0.54-0.15 °C; 1.85 ± 0.53 °C vs 1.78 ± 0.83 °C, mean difference - 0.07 °C, 95% CI -0.49-0.36 °C, in the SBI and non-SBI groups respectively). CONCLUSION: Fever response to Ibuprofen administration is not indicative of serious bacterial infections in children under 4 years of age. Larger prospective studies are required to define whether the lack of response to Ibuprofen has any impact on the management of febrile children.

Microbiome: Effects of Ageing and Diet.

The microbial community inhabiting our intestine, known as 'microbiota', and the ensemble of their genomes (microbiome) regulate important functions of the host, being essential for health maintenance. The recent development of next-generation sequencing (NGS) methods has greatly facilitated the study of the microbiota and has contributed to evidence of the strong influence exerted by age and diet. However, the precise way in which the diet and its components modify the functionality of the intestinal microbiome is far from being completely known. Changes in the intestinal microbiota occur during ageing, frequently accompanied by physiological changes of the digestive tract, modification of dietary patterns and impairment of the immune system. Establishing nutritional strategies aiming to counterbalance the specific alterations taking place in the microbiota during ageing would contribute to improved health status in the elderly. This review will analyse changes appearing in the intestinal microbiota from adulthood to old age and their association with dietary patterns and lifestyle factors.

Effects of Albumin Treatment on Systemic and Portal Hemodynamics and Systemic Inflammation in Patients With Decompensated Cirrhosis.

BACKGROUND & AIMS: We investigated the effect of albumin treatment (20% solution) on hypoalbuminemia, cardiocirculatory dysfunction, portal hypertension, and systemic inflammation in patients with decompensated cirrhosis with and without bacterial infections. METHODS: We performed a prospective study to assess the effects of long-term (12 weeks) treatment with low doses (1 g/kg body weight every 2 weeks) and high doses (1.5 g/kg every week) of albumin on serum albumin, plasma renin, cardiocirculatory function, portal pressure, and plasma levels of cytokines, collecting data from 18 patients without bacterial infections (the Pilot-PRECIOSA study). We also assessed the effect of short-term (1 week) treatment with antibiotics alone vs the combination of albumin plus antibiotics (1.5 g/kg on day 1 and 1 g/kg on day 3) on plasma levels of cytokines in biobanked samples from 78 patients with bacterial infections included in a randomized controlled trial (INFECIR-2 study). RESULTS: Circulatory dysfunction and systemic inflammation were extremely unstable in many patients included in the Pilot-PRECIOSA study; these patients had intense and reversible peaks in plasma levels of renin and interleukin 6. Long-term high-dose albumin, but not low-dose albumin, was associated with normalization of serum level of albumin, improved stability of the circulation and left ventricular function, and reduced plasma levels of cytokines (interleukin 6, granulocyte colony-stimulating factor, interleukin 1 receptor antagonist, and vascular endothelial growth factor) without significant changes in portal pressure. The immune-modulatory effects of albumin observed in the Pilot-PRECIOSA study were confirmed in the INFECIR-2 study. In this study, patients given albumin had significant reductions in plasma levels of cytokines. CONCLUSIONS: In an analysis of data from 2 trials (Pilot-PRECIOSA study and INFECIR-2 study), we found that albumin treatment reduced systemic inflammation and cardiocirculatory dysfunction in patients with decompensated cirrhosis. These effects might be responsible for the beneficial effects of albumin therapy on outcomes of patients with decompensated cirrhosis. ClinicalTrials.gov, Numbers: NCT00968695 and NCT03451292.

Combination of herbal components (curcumin, carvacrol, thymol, cinnamaldehyde) in broiler chicken feed: Impacts on response parameters, performance, fatty acid profiles, meat quality and control of coccidia and bacteria.

The objective of this study was to determine whether curcumin and a commercial microencapsulated phytogenic supplement containing thymol, cinnamaldehyde and carvacrol in broiler chicken feed would improve health and meat quality (fatty acid profile), as well as to determine the coccidiostatic and bactericidal potential of the additives. The broiler chickens were divided into five groups: NC - negative control feed; PC - positive control; CU - with 50 mg/kg of curcumin, PHY - 100 mg/kg phytogenic; and PHY + CU, a combination of both additives at 50 mg/kg (curcumin) and 100 mg/kg (phytogenic). We observed significantly higher levels of total proteins associated with increased circulating globulins, as well as lower levels of uric acid, cholesterol and triglycerides in the PHY + CU group than in the NC. There were significantly fewer oocysts in birds supplemented with additives in the NC group on day 21; on day 35, the NC, PHY and PHY + CU groups had significantly lower counts than the PC and CU groups; however, at 44 days, the lowest counts were in PC group. The bacterial counts were significantly lower on day 21 in all groups that received additives than those of the control group; however, at 44 days, the bacterial and Escherichia coli counts in these groups were significantly higher than those of the control. Curcumin with or without phytogenic agent improved meat quality, with increased antioxidant levels and reduction of lipid peroxidation. There were significantly lower total saturated fatty acid levels and significantly greater monounsaturated/polyunsaturated fatty acid levels in broilers that consumed additives individually and in combination. The combination of additives significantly increased the crypt/villus ratio, a marker of improved intestinal health and performance. Additives potentiated their individual effects, suggesting they can replace conventional growth promoters without compromising health, intestinal mucosa or meat quality.

Incidence, clinical profile, and risk factors for serious bacterial infections in children hospitalized with fever in Ujjain, India.

BACKGROUND: Fever is a cause for concern for both parents and the treating pediatrician and a common reason for antibiotic overuse. However, the proportion of children hospitalized for fever with serious bacterial infection (SBI) is uncertain. We aimed to evaluate the epidemiological, clinical, hematological, and biochemical risks for SBI among the children admitted with fever. METHOD: This prospective study was conducted in a rural teaching hospital in India on consecutive children, aged 3 months-12 years, presenting with fever 100 °F (37.7 °C) or higher. The presence of SBI was confirmed with one of the following criteria: (a) a positive blood culture; (b) roentgenographically confirmed pneumonia with high titres of C-reactive protein; (c) a culture-confirmed urinary tract infection; (d) enteric fever diagnosed clinically in addition to either a positive blood culture or high Widal titers; and (e) meningitis diagnosed clinically in addition to either a positive blood culture or cerebrospinal fluid culture. A predefined questionnaire was filled. RESULTS: A total of 302 children were included in the study, out of which 47% (95% CI 41.4-52.7%) presented with SBI. The factors associated with confirmed SBI in bivariate analysis were history of previous hospitalization, history of chronic illness, history of medication in the previous 1 week, a partially immunized child, history of common cold, moderate-grade fever, toxic look, significant lymphadenopathy, absence of BCG scar, delayed development, irritability, breathlessness, respiratory distress, poor feeding, significant weight loss, suspected urinary tract infection, hyponatremia, hypokalemia, and abnormal leucocyte count. The final generalized logistic regression model revealed partially immunized child (RR 4.26), breathlessness (RR 1.80), weight loss (RR 2.28), and suspected urinary tract infection (RR 1.95) as risk factors for the increased risk of SBI. CONCLUSION: The study identified multiple risk factors for SBI. Pediatricians can be made aware of these risk factors. Further studies are warranted to identify age-specific risk factors for SBI because most clinicians depend on clinical signs and symptoms to identify SBI.

Question 4: Is there a role for antibiotics in infantile wheeze?

Acute wheezing episodes are frequent in young children and are associated with high morbidity and healthcare utilization. The role of respiratory viruses in triggering acute wheezing is well known. There is also accumulating evidence that airway bacteria, either alone or as part of bacteria-virus interaction, are important determinants of acute asthma exacerbations. Targeting airway bacteria with antibiotics to reduce the severity of acute wheezing episodes and prevent recurrent wheezing among preschool children has been recently evaluated in three randomized, double-blind, placebo-controlled trials. The results of these studies are controversial. An interventional approach with azithromycin in young children during acute wheezing episodes cannot be generically incorporated into clinical practice, due to the potential consequences of widespread use of antibiotics in such a common clinical setting. This intervention may be reserved for children with really severe, recurrent wheezing episodes. Future research should focus on risk factors that facilitate acquisition of bacterial airway infection in young children and better understanding how virus and bacteria interact with each other during wheezing attacks. Identifying objective biomarkers that may direct the treatment to specific groups of children may represent a significant step forward in the clinical approach of acute wheezing.

Neonatal care and community-level treatment seeking for possible severe bacterial infection (PSBI) in Amhara, Ethiopia.

BACKGROUND: In Ethiopia, neonatal mortality accounts for approximately 54% of under-five deaths with the majority of these deaths driven by infections. Possible Severe Bacterial Infection (PSBI) in neonates is a syndromic diagnosis that non-clinical health care providers use to identify and treat newborns with signs of sepsis. In low- and middle-income countries, referral to a hospital may not be feasible due to transportation, distance or finances. Growing evidence suggests health extension workers (HEWs) can identify and manage PSBI at the community level when referral to a hospital is not possible. However, community-based PSBI care strategies have not been widely scaled-up. This study aims to understand general determinants of household-level care as well as household care seeking and decision-making strategies for neonatal PSBI symptoms. METHODS: We conducted eleven focus group discussions (FGDs) to explore illness recognition and care seeking intentions from four rural kebeles in Amhara, Ethiopia. FGDs were conducted among mothers, fathers and households with recruitment stratified among households that have had a newborn with at least one symptom of PSBI (Symptomatic Group), and households that have had a newborn regardless of the child's health status (Community Group). Data were thematically analyzed using MAXQDA software. RESULTS: Mothers were described as primary caretakers of the newborn and were often appreciated for making decisions for treatment, even when the father was not present. Type of care accessed was often dependent on conceptualization of the illness as simple or complex. When symptoms were not relieved with clinical care, or treatments at facilities were perceived as ineffective, alternative methods were sought. Most participants identified the health center as a reliable facility. While designed to be the first point of access for primary care, health posts were not mentioned as locations where families seek clinical treatment. CONCLUSIONS: This study describes socio-contextual drivers for PSBI treatment at the community level. Future programming should consider the role community members have in planning interventions to increase demand for neonatal care at primary facilities. Encouragement of health post utilization could further allow for heightened accessibility-acceptability of a simplified PSBI regimen.

Calcium Regulation of Bacterial Virulence.

Calcium (Ca2+) is a universal signaling ion, whose major informational role shaped the evolution of signaling pathways, enabling cellular communications and responsiveness to both the intracellular and extracellular environments. Elaborate Ca2+ regulatory networks have been well characterized in eukaryotic cells, where Ca2+ regulates a number of essential cellular processes, ranging from cell division, transport and motility, to apoptosis and pathogenesis. However, in bacteria, the knowledge on Ca2+ signaling is still fragmentary. This is complicated by the large variability of environments that bacteria inhabit with diverse levels of Ca2+. Yet another complication arises when bacterial pathogens invade a host and become exposed to different levels of Ca2+ that (1) are tightly regulated by the host, (2) control host defenses including immune responses to bacterial infections, and (3) become impaired during diseases. The invading pathogens evolved to recognize and respond to the host Ca2+, triggering the molecular mechanisms of adhesion, biofilm formation, host cellular damage, and host-defense resistance, processes enabling the development of persistent infections. In this review, we discuss: (1) Ca2+ as a determinant of a host environment for invading bacterial pathogens, (2) the role of Ca2+ in regulating main events of host colonization and bacterial virulence, and (3) the molecular mechanisms of Ca2+ signaling in bacterial pathogens.

Advances in Optical Detection of Human-Associated Pathogenic Bacteria.

Bacterial infection is a global burden that results in numerous hospital visits and deaths annually. The rise of multi-drug resistant bacteria has dramatically increased this burden. Therefore, there is a clinical need to detect and identify bacteria rapidly and accurately in their native state or a culture-free environment. Current diagnostic techniques lack speed and effectiveness in detecting bacteria that are culture-negative, as well as options for in vivo detection. The optical detection of bacteria offers the potential to overcome these obstacles by providing various platforms that can detect bacteria rapidly, with minimum sample preparation, and, in some cases, culture-free directly from patient fluids or even in vivo. These modalities include infrared, Raman, and fluorescence spectroscopy, along with optical coherence tomography, interference, polarization, and laser speckle. However, these techniques are not without their own set of limitations. This review summarizes the strengths and weaknesses of utilizing each of these optical tools for rapid bacteria detection and identification.

Bacterial growth: a statistical physicist's guide.

Bacterial growth presents many beautiful phenomena that pose new theoretical challenges to statistical physicists, and are also amenable to laboratory experimentation. This review provides some of the essential biological background, discusses recent applications of statistical physics in this field, and highlights the potential for future research.

Time-course of upper respiratory tract viral infection and COPD exacerbation.

Viral respiratory tract infections have been implicated as the predominant risk factor for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). We aimed to evaluate, longitudinally, the association between upper respiratory tract infections (URTI) caused by viruses and AECOPD.Detection of 18 viruses was performed in naso- and orοpharyngeal swabs from 450 COPD patients (Global Initiative for Chronic Obstructive Lung Disease stages 2-4) who were followed for a mean of 27 months. Swabs were taken during stable periods (n=1909), at URTI onset (n=391), 10 days after the URTI (n=356) and during an AECOPD (n=177) and tested using a multiplex nucleic acid amplification test.Evidence of at least one respiratory virus was significantly higher at URTI onset (52.7%), 10 days after the URTI (15.2%) and during an AECOPD (38.4%), compared with the stable period (5.3%, p<0.001). During stable visits, rhinovirus accounted for 54.2% of all viral infections, followed by coronavirus (20.5%). None of the viruses were identified in two consecutive stable visits. Patients with a viral infection at URTI onset did not have a higher incidence of exacerbation than patients without viral infection (p=0.993). Τhe incidence of any viral infection during an AECOPD was similar between URTI-related AECOPD and non-URTI-related AECOPD (p=0.359). Only 24% of the patients that had a URTI-related AECOPD had the same virus at URTI onset and during an AECOPD. Detection of parainfluenza 3 at URTI onset was associated with a higher risk of an AECOPD (p=0.003). Rhinovirus and coronavirus were the most frequently detected viruses during AECOPD visits, accounting for 35.7% and 25.9% of all viral infections, respectively.The prevalence of viral infection during the stable period of COPD was low. The risk of exacerbation following the onset of URTI symptoms depends on the particular virus associated with the event and was significant only for parainfluenza 3.

Leucocyte adhesion deficiency-A multicentre national experience.

Leucocyte adhesion deficiency (LAD) is a rare, innate autosomal recessive immunodeficiency with three subtypes. Twenty-nine patients with LADs were diagnosed and treated in Israeli Medical Centers and in the Palestinian Authority. We discuss the phenotypic, genotypic and biochemical features of LAD-I, LAD-II and LAD-III diagnosed during the neonatal period and early infancy in 18, 6 and 5 patients, respectively. Consanguinity was frequent. Common features were severe infections of variable aetiology, excessive leukocytosis and delayed umbilical cord detachment. In LAD-I, the integrin CD18 expression varied from negligible to normal. However, CD11a expression was negligible in all tested patients, suggesting both CD11a and CD18 should be used to assess this subtype. LAD-II patients showed distinctive facial features, physical malformations, short stature and developmental delay. These patients show defective expression of SLeX (CD15a) on cell surface glycoproteins and lack of H antigen on erythroid cell surfaces resulting in Bombay blood group (hh). LAD-III showed intact but inactive ß2 integrins associated with severe infections and significant bleeding disorders caused by defective platelet aggregation and thrombocytopenia. We report four patients with two new unpublished mutations: two LAD-I patients with c.1099delG in ITGB2 and two LAD-III patients with c.1069C>T in FERMT3. LAD-I patients harbouring the c.119_128 deletion in ITGB2 seemed to have better outcomes as compared to other LAD-I patients. Eight patients with LAD-I and -III underwent successful haematopoietic stem cell transplantation. Cumulative survival was 75%, 50% and 40% for LAD-I, LAD-II and LAD-III, with a median follow-up of 4 (0.08-19), 3.25 (1-32) and 6 (0.08-8) years, respectively. Prenatal diagnosis is recommended in families with LAD syndromes.

Accuracy of Signs and Symptoms for the Diagnosis of Acute Rhinosinusitis and Acute Bacterial Rhinosinusitis.

PURPOSE: To evaluate the accuracy of signs and symptoms for the diagnosis of acute rhinosinusitis (ARS). METHODS: We searched Medline to identify studies of outpatients with clinically suspected ARS and sufficient data reported to calculate the sensitivity and specificity. Of 1,649 studies initially identified, 17 met our inclusion criteria. Acute rhinosinusitis was diagnosed by any valid reference standard, whereas acute bacterial rhinosinusitis (ABRS) was diagnosed by purulence on antral puncture or positive bacterial culture. We used bivariate meta-analysis to calculate summary estimates of test accuracy. RESULTS: Among patients with clinically suspected ARS, the prevalence of imaging confirmed ARS is 51% and ABRS is 31%. Clinical findings that best rule in ARS are purulent secretions in the middle meatus (positive likelihood ratio [LR+] 3.2) and the overall clinical impression (LR+ 3.0). The findings that best rule out ARS are the overall clinical impression (negative likelihood ratio [LR-] 0.37), normal transillumination (LR- 0.55), the absence of preceding respiratory tract infection (LR- 0.48), any nasal discharge (LR- 0.49), and purulent nasal discharge (LR- 0.54). Based on limited data, the overall clinical impression (LR+ 3.8, LR- 0.34), cacosmia (fetid odor on the breath) (LR+ 4.3, LR- 0.86) and pain in the teeth (LR+ 2.0, LR- 0.77) are the best predictors of ABRS. While several clinical decision rules have been proposed, none have been prospectively validated. CONCLUSIONS: Among patients with clinically suspected ARS, only about one-third have ABRS. The overall clinical impression, cacosmia, and pain in the teeth are the best predictors of ABRS. Clinical decision rules, including those incorporating C-reactive protein, and use of urine dipsticks are promising, but require prospective validation.