Clinical Exacerbation Research Articles

79 Excessive reactive oxygen species production by cystic fibrosis phagocytes against Aspergillus fumigatus is adversely associated with number of clinical exacerbations and lung function

79 Excessive reactive oxygen species production by cystic fibrosis phagocytes against Aspergillus fumigatus is adversely associated with number of clinical exacerbations and lung function

The majority of natalizumab-treated MS patients have high natalizumab concentrations at time of re-dosing

Background: Natalizumab is efficacious in the treatment of relapsing-remitting multiple sclerosis. All patients receive the same treatment regimen of 300 mg every 4 weeks, despite differences in pharmacokinetics between individual patients. Objective: To give neurologists insight into natalizumab concentrations at time of re-dosing, we investigated longitudinal natalizumab concentrations in 80 patients in relation to disease activity, with possible influencing factors. Methods: In a prospective observational cohort study, natalizumab trough serum concentrations were measured in 80 patients. Data on demographics, duration of treatment, Expanded Disability Status Scale, clinical exacerbations, brain magnetic resonance imaging (MRI), and body weight were collected. Results: We measured high (≥10 µg/mL) natalizumab trough concentrations in 94% of patients. Intra-individual concentrations were stable. The spread in concentrations was substantial and did not correlate with disease activity. We found a negative association between natalizumab concentration and body weight (β = −0.30, p = 0.010). Interpretation: The majority of patients showed high natalizumab serum concentrations at time of re-dosing. Alternative treatment regimens could lead to more efficient use of natalizumab, but caution is warranted regarding the possibility of recurrence of disease activity. Prospective clinical trials are needed to establish the safety of extended dose intervals in natalizumab treatment.

Aspergillose bronchopulmonaire allergique : évaluation d’un traitement d’entretien par Ambisome® nébulisé

Allergic bronchopulmonary aspergillosis (ABPA) affects 3-13% of patients with asthma. Its natural history includes possibly life-threatening exacerbations and evolution towards fixed obstructive ventilatory disorders or even irreversible lung fibrosis lesions. ABPA prognosis is directly associated with exacerbation control and the main objective of the treatment is to decrease their frequency and duration. Recommendations regarding dosage and duration of treatment are not very precise. The currently used combination of itraconazole and corticosteroid therapy has many limitations. The interests of a therapeutic strategy using nebulized liposomal amphotericin B (LAmB) are to heighten antifungal lung tissue concentration, to circumvent drug interactions and decrease the potential toxicity of systemic antifungal treatments. Finally, this association leads to improved eradication of Aspergillus, thereby limiting the risk of side effects and the emergence of treatment-resistant Aspergillus strains. This is a phase II, multicentre, randomized, single blind, controlled therapeutic study, with the objective of comparing the potential benefit on exacerbation control of a maintenance therapy by LAmB nebulization. The main objective of the study is to compare the incidence of severe clinical exacerbations in ABPA treatment, between a maintenance treatment strategy with nebulized LAmB and a conventional strategy without antifungal maintenance therapy. The results will guide practitioners in the management of ABPA treatments and help to define the place of aerosols of LAmB on "evidence base medicine" criteria.

What's new in the management of adult bronchiectasis?

Bronchiectasis is a heterogeneous, chronic condition with many aetiologies. It poses a significant burden on patients and healthcare practitioners and services. Clinical exacerbations often result in reduced quality of life, increased rate of lung function decline, increased hospitalisation, and mortality. Recent focus in respiratory research, guidelines, and future management options has improved this clinical field in evidence-based practice, but further work and phase III clinical trials are required. This article aims to summarise and explore advances in management strategies in recent years and highlight areas of research and future focus.

Reslizumab in Eosinophilic Asthma: A Review.

Reslizumab (Cinqaero®; Cinqair®) is a humanized monoclonal antibody against interleukin-5 (IL-5), a cytokine mediator of eosinophilic airway inflammation. Reslizumab is indicated as an add-on treatment for severe eosinophilic asthma in adults, on the basis of data from the BREATH phase III clinical trial programme. In three double-blind BREATH studies of up to 52weeks' duration, adding intravenous reslizumab (3mg/kg, once every 4weeks) to the current asthma therapy of patients (aged 12-75years) with eosinophilic asthma inadequately controlled with inhaled corticosteroids resulted in significant reductions in clinical asthma exacerbation frequency and significant improvements in lung function, asthma control and health-related quality of life relative to adding placebo. Pooled data from the two trials of 52weeks' duration indicated similar benefits with reslizumab across various patient subgroups, including patients with severe eosinophilic asthma. Reslizumab was generally well tolerated, with very few recipients experiencing severe or serious treatment-related adverse events. Moreover, in an open-label extension study, continued use of reslizumab for up to 2years was associated with durable lung function benefit, without any new tolerability concerns. Thus, intravenous reslizumab extends the valuable add-on treatment options for adults with severe eosinophilic asthma inadequately controlled with standard therapies.

Reasons to choose a long acting antipsychotic and tolerability

IntroductionAripiprazole depot is an atypical antipshycotic used to treat positive and negative symptoms of psychosis or acute mania.AimDescribe the reason why psychiatrists switch the current antipsychotic treatment on to aripiprazol depot, its tolerability and the reasons to stop aripiprazol depot treatment.MethodsDescriptive analysis based on a sample of 37 patients, aged 18–65 years, treated during one year with antipsychotics at two community mental health units.ResultsSwitching on to aripiprazole depot principal reasons: promote adherence (25%), persistence of symptoms (25%) and high levels of prolactin or sexual dysfunction (16.66%):– side effects of aripiprazole depot: insomnia (11.11%), inquietude (8.33%), sexual dysfunction (2.77%) and hypertensive crisis during administration (2.77%);– 83.33% of the patients are still taking it after one year. The most common reasons to stop or change it were the presence of secondaries (11.11%) and clinical exacerbation (5.55%).ConclusionsAripiprazole depot is well tolerated (even better than other antipsychotics). Common side effects are not severe and appear in a small percent of patients.Disclosure of interestThe authors have not supplied their declaration of competing interest.

126: THE EFFECT OF ESTABLISHING RAPID RESPONSE NURSING TEAM IN OUTCOME OF PATIENTS CARE IN EMERGENCY WARD

Background and aims:Rapid response nursing team evaluates the patients in the early stages of clinical exacerbation and prevents unexpected cardiopulmonary arrest. The present study aimed to determine the effect of...

Reslizumab in patients with inadequately controlled late-onset asthma and elevated blood eosinophils

IntroductionAsthma with adult onset and elevated blood eosinophils is a difficult-to-treat subgroup. This post hoc analysis evaluated reslizumab, an anti-interleukin-5 monoclonal antibody, in patients with late-onset eosinophilic asthma. MethodsData from two 52-week placebo-controlled trials of reslizumab IV 3 mg/kg every 4 weeks in patients aged 12–75 years with inadequately controlled asthma, ≥1 asthma exacerbation within 12 months, and screening blood eosinophils ≥400/μL (NCT01287039/NCT01285323) were stratified by age of asthma onset (<40 or ≥40 years). Annual clinical asthma exacerbation rates, change in lung function, and patient-reported outcomes were analyzed. Results273 patients with late-onset asthma (placebo, n = 130; reslizumab, n = 143) and 658 with early-onset asthma (placebo, n = 336; reslizumab, n = 322) were included. Baseline demographics were similar between groups. The interaction between age at onset of asthma and effect of reslizumab on asthma exacerbations was statistically significant (p = 0.0083). Compared with placebo, reslizumab produced a 75% relative reduction in asthma exacerbations in patients with late-onset asthma (rate ratio [RR] 0.25; 95% confidence interval [CI], 0.16, 0.40), substantially larger than the reduction in earlier onset patients (RR 0.58; 95% CI, 0.44, 0.76). Similar findings were observed for other measures of asthma, including forced expiratory volume in 1 s (FEV1). The adverse event profile of reslizumab was similar in patients with early- or late-onset asthma. ConclusionsCompared with placebo, reslizumab produced larger reductions in asthma exacerbations and larger improvements in lung function in patients with late versus early-onset asthma.

No Major Differences in Outcomes Between the Initial and Relapse Episodes in Patients with Thrombotic Thrombocytopenic Purpura: The Experience from the Ohio State University Registry

Background:Thrombotic thrombocytopenic purpura (TTP) is characterized by consumptive thrombocytopenia and microangiopathic hemolytic anemia. At least a third of the patients with TTP will have one or more relapses throughout their life. There is very little data regarding the differences, if any, in clinical presentation and outcomes between the initial and subsequent TTP episodes. This information is relevant to understand if patients that present initially and those that present with a relapse can be seen as equal when being considered for clinical trials. Identifying the characteristics of patients that are prone to relapse will help guide the monitoring of patients after an acute episode of TTP to help to prevent relapse.Methods:Between March 2003 and June 2016 we collected clinical and laboratory data on all patients that presented to the Ohio State University with a diagnosis of acquired TTP (aTTP). The diagnostic criteria for aTTP included: thrombocytopenia, and a microangiopathic hemolytic anemia without an alternative explanation. The diagnosis was confirmed by the finding of severely deficient ADAMTS13 activity (<10%). Patients were consented to participate in our TTP registry and the information obtained included initial clinical presentation, platelets, LDH, kidney function, ADAMTS13 activity and inhibitor titer, number of plasma exchange (PEX) to achieve remission (defined as number of PEX needed to obtain a normal platelet count), and the outcome of the episode; clinical response (normal platelet count and LDH), exacerbation (recurrent TTP within 30 days of last PEX procedure), refractory (more than 30 PEX needed to obtain a clinical response), or death.Results:- All the patients enrolled were included in the study, except those with active cancer, leaving a total of 125 episodes from 57 patients.- 36 of the 57 patients had two or more TTP episodes (relapse rate 63.1%), with 21 of the 57 patients having 3 or more episodes. The time between episodes varied greatly, from 2 months to 8 years.- Of the 125 episodes, there were 42 initial and 83 relapses.- The initial group presented with central nervous system (CNS) symptoms more commonly than the relapse group. They also had significantly lower platelets and a higher LDH than the relapse group.- Regarding treatment, there was no significant difference in the number of PEX needed to achieve remission between the 2 groups. However, there was a significant number of patients in the initial group that needed more than 5 PEX to achieve remission, compared to the relapse group (p<0.0001)- There were no significant differences in the main clinical outcomes between the initial and relapse groups in rates of clinical response (p=0.267), exacerbation (p=0.483), refractory (p=0.075) or death (p=0.066)Conclusions:In their first episode of TTP, patients may present more ill than those patients having relapses (with more CNS symptoms, lower platelets and higher LDH), and may also require more PEX sessions to achieve remission. However, these findings do not change outcomes, and patients in their initial presentation and relapses can be seen as equal in terms of clinical response, exacerbation, refractory disease, and mortality rates. The high relapse rate seen in our registry may be due to the prolonged follow up (13 years) which is more than other series reported. Patients may have a relapse even after several years of being stable. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Right-to-Left Shunts Are Unexpectedly Common in Adults with HbSS

INTRODUCTIONPatients with homozygous sickle cell anemia (SCA) have frequent cardiopulmonary complications. The clinical prevalence and consequences of intracardiac or intrapulmonary right-to-left shunts in SCA are unknown. Here we report a retrospective examination of this complication, and clinical and laboratory correlates at clinical baseline, in an adult population with SCA. These shunts may be of particular relevance, due to the susceptibility of these patients to thrombosis and the role that desaturated hemoglobin plays in the underlying pathophysiology of this disease. METHODSThis single-institution study included 153 patients with homozygous HbSS, who are followed at Case-UH Medical Center, Cleveland. Clinical and laboratory data were gathered on patients who underwent an echocardiogram with bubble contrast. Echocardiograms were reviewed to confirm the presence, characteristics, and degree of a right-to-left shunt. Immediate (intracardiac) or delayed (intrapulmonary) shunts were identified; the latter were quantitated as <5, 5-15, or >15 bubbles visualized in the left heart. Continuous variables were described, using mean ± standard deviation (SD) and nominal variables were described as N (%). The relationship between clinical characteristics and echo results was determined using linear regression. All analyses were undertaken using SAS v9.4 The SAS Institute, Cary, NC. n.b. Compound heterozygous sickle cell disease patients showed this complication rarely, and were not examined systematically. RESULTS82/153 (53.6%) of studied SCA patients were female. Mean (SD) age in years was 32.2 (11.8). 90 (58.8%) patients had an echo with bubble study. In our population, 27 (17.6%) patients had an intracardiac shunt, 41 (26.8%) had an intrapulmonary shunt, and 22 (14.4%) had no shunt present; 63 (41.2%) patients did not have a bubble study.Mean (SD) LDH was 523.3 (318.1) for those with intracardiac shunts and 570.5 (205.4) for those with intrapulmonary shunts. Mean (SD) LDH for all shunt patients combined was 551.3 (255.9). Mean LDH (SD) for patients either with no shunt or no contrast echocardiogram was 415.5 (193.0).In a combined analysis, patients with shunts (N=68) showed a statistically higher baseline mean LDH when compared to a mean LDH of patients with either a negative bubble study or no bubble study (N=85), (551.3 vs 415.5, p<0.001).No difference was seen in prevalence of clinical outcomes of acute chest syndrome or stroke between groups. Laboratory markers of disease activity, such as absolute reticulocyte count or baseline hemoglobin were not different in shunt versus non-shunt patients.8 patients had <5 bubbles in the left atrium or ventricle, 7 had 5-15 and 25 >15 bubbles. There was no evidence that this had an effect at clinical baseline, but the impact of such shunts during crises or multi-organ failure has not yet been assessed. A small number of individuals with shunts showed significant oxygen desaturation with exercise, but these were not statistically distinct from other groups. CONCLUSIONS68 patients with HbSS, or almost half of the adult SCA population, had right-to-left shunting on echocardiograms, either intracardiac or intrapulmonary, when evaluated at clinical baseline. These patients had significantly higher LDH than did patients with no bubble study or a negative bubble study, when evaluated in a combined post hoc analysis. The pathophysiology of these shunts is not known, but these have the potential to delay reoxygenation of sickle hemoglobin at clinical baseline and to facilitate right-to-left passage of fat or thrombotic emboli during clinical exacerbation.We are currently evaluating the potential impact of these shunts in patients with HbSS prospectively, both at baseline and during clinical exacerbation. DisclosuresSchilz:Genetech: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Actelion: Consultancy, Speakers Bureau; United Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Arena: Research Funding; Eiger: Research Funding.

Influenza virus infection exacerbates experimental autoimmune encephalomyelitis disease by promoting type I T cells infiltration into central nervous system

Multiple sclerosis starts with increased migration of auto-reactive lymphocytes across the blood-brain barrier, resulting in persistent neurodegeneration. Clinical and epidemiological studies indicated upper respiratory viral infections are associated with clinical exacerbation of multiple sclerosis. However, so far there is no any direct evidence to support it. Using the experimental autoimmune encephalomyelitis mice as the model for multiple sclerosis, we demonstrated that mice experienced with influenza virus infection were unable to recover from experimental autoimmune encephalomyelitis with a long-term exacerbation. The exacerbated disease was due to more type I T cells, such as CD45highCD4+CD44high, CD45highCD4+CCR5+, CD45high IFNγ+CD4+, MOG35-55-specific IFNγ+CD4+ and influenza virus-specific IFNγ+CD4+ T cells, infiltrating central nervous system in mice with prior influenza virus infection. Influenza virus infection created a notable inflammatory environment in lung and mediastinal lymph node after influenza virus inoculation, suggesting the lung may constitute an inflammatory niche in which auto-aggressive T cells gain the capacity to enter CNS. Indeed, the early stage of EAE disease was accompanied by increased CCR5+CD4+, CXCR3+CD4+ T cell and MOG35-55 specific CD4+ T cells localized in the lung in influenza virus-infected mice. CCL5/CCR5 might mediate the infiltration of type I T cells into CNS during the disease development after influenza infection. Administration of CCR5 antagonist could significantly attenuate the exacerbated disease. Our study provided the evidence that the prior influenza virus infection may promote the type I T cells infiltration into the CNS, and subsequently cause a long-term exacerbation of experimental autoimmune encephalomyelitis.

Histological Disease Activity as a Predictor of Clinical Relapse Among Patients With Ulcerative Colitis: Systematic Review and Meta-Analysis.

Endoscopic remission in ulcerative colitis (UC) is associated with improved clinical outcomes. We assessed whether histological remission predicts clinical outcomes, estimated the magnitude of effect, and determined whether histological remission provides additional prognostic utility beyond clinical or endoscopic remission. Bibliographic databases were searched for studies in inflammatory bowel disease providing baseline histological status and relation to an outcome of clinical relapse or exacerbation. Our primary analysis compared the proportion of patients with study-defined histological remission vs. the proportion with histological activity who developed clinical relapse/exacerbation. Additional analyses compared the proportion with relapse/exacerbation for the presence vs. absence of different histological features and for histological remission vs. endoscopic remission and clinical remission. A fixed-effect model was used for meta-analysis, with a random-effects model if statistical heterogeneity was present. Fifteen studies met inclusion criteria. The major methodological shortcoming was lack of blinding of the assessor of clinical relapse/exacerbation to baseline histological status in 13 of the 15 studies. Relapse/exacerbation was less frequent with baseline histological remission vs. histological activity (relative risk (RR)=0.48, 95% confidence interval (CI) 0.39-0.60) and vs. baseline clinical and endoscopic remission (RR=0.81, 95% CI 0.70-0.94). Relapse/exacerbation was also less common in the absence vs. presence of specific histological features: neutrophils in epithelium (RR=0.32, 95% CI 0.23-0.45), neutrophils in lamina propria (RR=0.43, 95% CI 0.32-0.59), crypt abscesses (RR=0.38, 95% CI 0.27-0.54), eosinophils in the lamina propria (RR=0.43, 95% CI 0.21-0.91), and chronic inflammatory cell infiltrate (RR=0.28, 95% CI 0.10-0.75). Histological remission was present in 964 (71%) of the 1360 patients with combined endoscopic and clinical remission at baseline. UC patients with histological remission have a significant 52% RR reduction in clinical relapse/exacerbation compared with those with histological activity. Histological remission is also superior to endoscopic and clinical remission in predicting clinical outcomes. As ~30% of patients with endoscopic and clinical remission still have histological activity, addition of histological status as an end point in clinical trials or practice has the potential to improve clinical outcomes.

Serotonin-norepinephrine reuptake inhibitors may exacerbate stiff-person syndrome.

Stiff-person syndrome (SPS) is a neuroimmunologic disorder characterized by painful spasms and muscle rigidity attributed to impaired inhibitory γ-aminobutyric acid (GABA) descending pathways.1 The immunopathogenesis remains unknown and the pathogenic significance of antibodies against glutamic acid decarboxylase (GAD) is controversial. Herein, we report 4 cases of anti-GAD65-positive patients with SPS (table e-1 at [Neurology.org/nn][1]) who had significant worsening of symptoms and disability with the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine (table e-2). While causation cannot be proven, these observations suggest the importance of investigating the relationship between SNRI use and SPS clinical exacerbations (figure, A). [1]: /lookup/doi/10.1212/NXI.0000000000000281

Safety of regadenoson in patients with severe chronic obstructive pulmonary disease

ObjectiveTo assess the safety of regadenoson, a selective agonist of A2A adenosine receptors, combined with low-level exercise in subjects with severe chronic obstructive pulmonary disease (COPD), referred for myocardial perfusion imaging (MPI). MethodsWe studied prospectively 12 male patients with severe COPD. Stress was 4min of low-level exercise with bolus injection of regadenoson (0.4mg) at 1.5min, followed by 99mTc-MPI agent injection. Demographics, medical history, lung medications, adverse events, oxygen saturation (SatO2), MPI findings for coronary artery disease (CAD), and changes in systolic blood pressure (SBP), and heart rate (HR) were registered. ResultsThe observed adverse event profile of regadenoson was similar to that of patients with mild–moderate COPD. There was no clinical exacerbation of COPD. Adverse events were self-limiting: dyspnea (33.3%), fatigue (25.0%), chest pain, headache (16.7%, respectively), and gastrointestinal discomfort, dry mouth, flushing, feeling hot and dizziness (8.3%, respectively). 25.0% of patients did not report any symptoms. We observed significant increases in SBP and HR from baseline (142.6mmHg±22.3 vs 152.5mmHg±18.5, and 80 b.p.m.±18 vs 105 b.p.m.±22, respectively; p<0.05). ConclusionsRegadenoson combined with low-level exercise is safe and well tolerated in stable patients with severe COPD undergoing MPI.

Early indicators of relapses vs pseudorelapses in neuromyelitis optica spectrum disorder.

Objective:The purpose of this study was to review cases of neuromyelitis optica spectrum disorder (NMOSD) relapses and pseudorelapses to identify early features that differentiate between them at onset of symptoms.Methods:This was a retrospective analysis of 74 hospitalizations of patients with NMOSD who were admitted to the Johns Hopkins Hospital for workup and treatment of a presumed relapse. Standard workup included MRI and blood and urine testing for metabolic and infectious etiologies. The gold standard for a relapse was defined as new or worsening symptoms and a change in neurologic examination correlating with a new or enhancing MRI lesion. A pseudorelapse was a clinical exacerbation with similar symptoms and signs but the MRI was negative, and workup identified an alternative cause for the symptoms that, when treated, resulted in the improvement of neurologic symptoms. Factors considered to be early predictors of relapses vs pseudorelapses were analyzed using the Fisher test.Results:Among 74 NMOSD hospitalizations for presumed relapse, 57 were confirmed relapses while 17 had a negative MRI and an identifiable cause of pseudorelapse. The most common causes of pseudorelapse were infection, pain, and dysautonomia. The only early predictor that reliably differentiated relapse from pseudorelapse among this NMOSD patient population was vision loss (p = 0.039). Race, sex, presentations of weakness, numbness, and bowel/bladder dysfunction, white blood cell count, and urinary tract infection were not different among patients with relapses vs pseudorelapses.Conclusions:Vision loss in NMOSD is strongly suggestive of a true relapse vs a pseudorelapse. Pseudorelapses localized to the spinal cord in patients with previous myelitis presented similarly to true relapses and could only be ruled out by a negative MRI.

Recombinant Tissue Plasminogen Activator Induces Neurological Side Effects Independent on Thrombolysis in Mechanical Animal Models of Focal Cerebral Infarction: A Systematic Review and Meta-Analysis.

Background and PurposeRecombinant tissue plasminogen activator (rtPA) is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides thrombolysis. We performed a meta-analysis to clarify effect of tissue plasminogen activator (tPA) on cerebral infarction besides its thrombolysis property in mechanical animal stroke.MethodsRelevant studies were identified by two reviewers after searching online databases, including Pubmed, Embase, and ScienceDirect, from 1979 to 2016. We identified 6, 65, 17, 12, 16, 12 and 13 comparisons reporting effect of endogenous tPA on infarction volume and effects of rtPA on infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological function and mortality rate in all 47 included studies. Standardized mean differences for continuous measures and risk ratio for dichotomous measures were calculated to assess the effects of endogenous tPA and rtPA on cerebral infarction in animals. The quality of included studies was assessed using the Stroke Therapy Academic Industry Roundtable score. Subgroup analysis, meta-regression and sensitivity analysis were performed to explore sources of heterogeneity. Funnel plot, Trim and Fill method and Egger’s test were obtained to detect publication bias.ResultsWe found that both endogenous tPA and rtPA had not enlarged infarction volume, or deteriorated neurological function. However, rtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate.ConclusionsThis meta-analysis reveals rtPA can lead to neurological side effects besides thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA.

Focal epileptic seizures, electroencephalography and outcome of sepsis associated encephalopathy—A pilot study

ObjectivesSepsis associated encephalopathy (SAE) represents a diffuse and/or multifactorial cerebral dysfunction during response to systemic infection. Study aim was to compare clinical and electroencephalogram (EEG) characteristics and intrahospital survival rate among SAE patients. Patients and methodsA prospective study, during 42 months’ period, included 39 SAE patients assigned in two groups according the outcome (survival: 19, and death: 20 patients). All the patients' features were registered: demography, neurological status, infection type, seizure appearance, brain computerized tomography (CT), EEG, EEG reactivity, Glasgow Coma Score (GCS) and Acute Physiology and Chronic Health Evaluation II (APACHE II) Score. The analysis included EEGs obtained during patients' consciousness change (improvement or deterioration) and the level of consciousness during and at the end of hospitalization. ResultsSAE was detected in 29.5% of patients with encephalopathy (2.8% of all patients hospitalized). Patients with lethal outcome were more likely to be female (p=0.0011), to have focal seizures (p=0.034), lower values of GCS during hospitalization (p<0.05) and longer lasting nosocomial infections (p=0.029). At the time of clinical exacerbation, patients were more likely to have suppression on EEG and less likely theta activity. Delta waves, TW waves and suppression of EEG activity were the most common findings 24h prior to death (p=0.0004). The lack of EEG reactivity was associated with death (p=0.00043). ConclusionPresence of focal seizures, EEG suppression at the time of exacerbation in SAE elderly patients, particularly women, with longer infection duration and lower values of GCS, is associated with intrahospital death.

Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study

BackgroundAcute pulmonary exacerbations are associated with progressive lung function decline and increased mortality in cystic fibrosis (CF). The role of pulmonary vascular disease in pulmonary exacerbations is unknown. We investigated the association between pulmonary artery enlargement (PA:A>1), a marker of pulmonary vascular disease, and exacerbations.MethodsWe analyzed clinical, computed tomography (CT), and prospective exacerbation data in a derivation cohort of 74 adult CF patients, measuring the PA:A at the level of the PA bifurcation. We then replicated our findings in a validation cohort of 190 adult CF patients. Patients were separated into groups based on the presence or absence of a PA:A>1 and were followed for 1-year in the derivation cohort and 2-years in the validation cohort. The primary endpoint was developing ≥1 acute pulmonary exacerbation during follow-up. Linear and logistic regression models were used to determine associations between clinical factors, the PA:A ratio, and pulmonary exacerbations. We used Cox regression to determine time to first exacerbation in the validation cohort.FindingsWe found that PA:A>1 was present in n=37/74 (50%) of the derivation and n=89/190 (47%) of the validation cohort. In the derivation cohort, n=50/74 (68%) had ≥1 exacerbation at 1 year and n=133/190 (70%) in the validation cohort had ≥1 exacerbation after 2 years. PA:A>1 was associated with younger age in both cohorts and with elevated sweat chloride (100.5±10.9 versus 90.4±19.9mmol/L, difference between groups 10.1mmol/L [95%CI 2.5–17.7], P=0.017) in the derivation group. PA:A>1 was associated with exacerbations in the derivation (OR 3.49, 95%CI 1.18–10.3, P=0.023) and validation (OR 2.41, 95%CI 1.06–5.52, P=0.037) cohorts when adjusted for confounders. Time to first exacerbation was shorter in PA:A>1 versus PA:A<1 [HR 1.66 (95%CI 1.18–2.34), P=0.004] in unadjusted analysis, but not when adjusted for sex, BMI, prior exacerbation, positive Pseudomonas status, and FEV1/FVC [HR 1.14 (95%CI 0.80–1.62), P=0.82]).InterpretationPA enlargement is prevalent in adult CF patients and is associated with acute pulmonary exacerbation risk in two well-characterized cohorts. PA:A may be a predictive marker in CF.

T-bet promotes the accumulation of encephalitogenic Th17 cells in the CNS

T-bet enhances the encephalitogenicity of myelin-reactive CD4+ T cells, however its mechanism of action is unknown. In this study we show that T-bet confers a competitive advantage for the accumulation of IL-23 conditioned Th17 effector cells in the central nervous system (CNS). Impaired migration of T-bet deficient Th17 cells to the CNS is associated with altered expression of adhesion molecules and chemokine receptors on their cell surface. Our data suggest that therapeutic targeting of T-bet in individuals with Th17-mediated autoimmune demyelinating disease may inhibit inflammatory infiltration of the CNS and, hence, clinical exacerbations.

Increased prevalence of Pneumocystis jirovecii colonisation in acute pulmonary exacerbations of cystic fibrosis

This study examined the prevalence of Pneumocystis jirovecii in the sputum of adults with cystic fibrosis during clinical stability and acute pulmonary exacerbation. This was a prospective, longitudinal observational study of patients attending the Manchester Adult Cystic Fibrosis Centre. Sputum samples were analysed for P. jirovecii DNA using PCR at enrolment and up to 5 follow-up visits. Patients were classified as stable or exacerbating using a modified Fuch's pulmonary exacerbation score. 226 samples were tested from 111 patients. P. jirovecii was more likely to be detected in samples at acute pulmonary exacerbation (7/76 (9.2%)) compared with stable visits (3/150 (2%)), p=0.03. P. jirovecii was detected less frequently if patients had received co-trimoxazole within 3 months of sample collection (0% versus 29.7%, p=0.03). Prevalence of P. jirovecii in stable patients is low, but P. jirovecii is detected in approximately 1 in 10 patients experiencing an acute pulmonary exacerbation.