Web-based guided self-help cognitive behavioral therapy-enhanced versus treatment as usual for binge-eating disorder: a randomized controlled trial protocol.

Binge-eating disorder (BED) is a psychiatric disorder characterized by recurrent episodes of eating a large amount of food in a discrete period of time while experiencing a loss of control. Cognitive behavioral therapy-enhanced (CBT-E) is a recommended treatment for binge-eating disorder and is typically offered through 20 sessions. Although binge-eating disorder is highly responsive to CBT-E, the cost of treating these patients is high. Therefore, it is crucial to evaluate the efficacy of low-intensity and low-cost treatments for binge-eating disorder that can be offered as a first line of treatment and be widely disseminated. The proposed noninferiority randomized controlled trial aims to determine the efficacy of web-based guided self-help CBT-E compared to treatment-as-usual CBT-E. Guided self-help will be based on a self-help program to stop binge eating, will be shorter in duration and lower intensity, and will require fewer therapist hours. Patients with binge-eating disorder (N = 180) will be randomly assigned to receive guided self-help or treatment-as-usual. Assessments will take place at baseline, mid-treatment, at the end of treatment, and at 20- and 40-weeks post-treatment. Treatment efficacy will be measured by examining the reduction in binge-eating days in the previous 28 days between baseline and the end of treatment between groups, with a noninferiority margin (Δ) of 1 binge-eating day. Secondary outcomes will include full remission, body shape dissatisfaction, therapeutic alliance, clinical impairment, health-related quality of life, attrition, and an economic evaluation to assess cost-effectiveness and cost-utility. The moderators examined will be baseline scores, demographic variables, and body mass index. It is expected that guided self-help is noninferior in efficacy compared to treatment-as-usual. The proposed study will be the first to directly compare the efficacy and economically evaluate a low-intensity and low-cost binge-eating disorder treatment compared to treatment-as-usual. If guided self-help is noninferior to treatment-as-usual in efficacy, it can be widely disseminated and used as a first line of treatment for patients with binge-eating disorder. The Dutch trial register number is R21.016. The study has been approved by the Medical Research Ethics Committees United on May 25th, 2021, case number NL76368.100.21.

Treatment of patients with anorexia nervosa and comorbid post-traumatic stress disorder; where do we stand? A systematic scoping review.

Objective: Comorbid post-traumatic stress disorder in patients with anorexia nervosa may negatively affect the course of anorexia nervosa treatment, which is already challenging. There are currently no guidelines or recommendations on concurrent treatment approaches for both anorexia nervosa and post-traumatic stress disorder. This systematic scoping review aims to explore the feasibility, acceptability and effectiveness of psychological trauma-focused treatment concurrently offered to underweight patients receiving anorexia nervosa treatment. Method: A multi-step literature search, according to an a priori protocol was performed. Databases PubMed, Embase, APA PsycINFO, Web of Science, Scopus and Cochrane Central were searched up to September 19th 2022, and the search was rerun June 19th 2023. For quality assessment, Risk of Bias in Non-randomised Studies-of Interventions tool was used. Results: The extensive search yielded 1769 reports, out of which only three observational pilot studies, both English and German, published between 2004 and 2022, could be included. The included studies reported on a total of 13 female participants between 16 and 58 years old, with anorexia nervosa or otherwise specified feeding or eating disorder, baseline BMI ranging between 14.6 and 16.5, who received concurrent anorexia and post-traumatic stress disorder treatment. In all participants, the emotional and cognitive functioning was sufficient to process the offered trauma-focused interventions, despite their significantly low body weight. Discussion: The findings of this review identify a dearth of treatment research on knowledge of concurrent trauma-focused treatments for patients with anorexia nervosa. Refraining patients with anorexia nervosa from trauma-focused treatment may not be warranted.

Effectiveness of web-based guided self-help cognitive behavioral therapy-enhanced for binge-eating disorder: An implementation study.

INTRODUCTION: Web-based guided self-help cognitive behavioral therapy-enhanced (CBT-E) is a 12-weeks, 12-sessions, digitalized version of part II of the self-help book Overcoming Binge Eating. This intervention is effective when offered under controlled circumstances in a randomized-controlled-trial. It is unknown how patients with binge-eating disorder (BED) respond to this intervention when offered in real-world clinical-settings. The aim of this study is to examine post-intervention effectiveness of guided self-help CBT-E for BED in real-world settings. METHOD: The present study used a cohort-design examining the effectiveness of web-based guided self-help CBT-E according to an intention-to-treat (ITT) analysis. BED patients (n = 278) were assessed pre- and post-intervention. The primary outcome was reduction in binge-eating episodes. Other outcomes were full-recovery (EDE-Q score <2.77 and abstinence from binge-eating episodes), impaired psychosocial functioning, defined as secondary impairment, and general psychopathology post-intervention. RESULTS: The number of binge-eating episodes reduced by an average of 16 binge-eating episodes per 4 weeks pre-intervention to five binge-eating episodes during the last 4 weeks of treatment. Abstinence from binge eating was reported by 30%, and 28% reported full recovery. Effect sizes (Cohen's d) were large (d ≥ 1.0) for all outcome measures. There were no differences in outcomes between the ITT and the completers sample. DISCUSSION: Guided self-help CBT-E is associated with significant improvements. The effects of guided self-help CBT-E offered in a real-world-setting are comparable to self-help CBT-E offered in a randomized-controlled-trial. However, it should be noted that comparisons with randomized-controlled-trials requires caution. Longer-term follow-up data are necessary to measure persistence of treatment benefits. PUBLIC SIGNIFICANCE: Offering CBT-E as a web-based guided self-help intervention has several benefits for patients with BED. Guided self-help CBT-E is associated with significant improvements on the short term when offered in real-world clinical settings.

Economic evaluation of web-based guided self-help cognitive behavioral therapy-enhanced for binge-eating disorder compared to a waiting list: A randomized controlled trial.

INTRODUCTION: The aim is to perform an economic evaluation alongside a randomized controlled trial comparing guided self-help cognitive behavioral therapy-enhanced (CBT-E) for binge-eating disorder (BED) to a waiting list control condition. METHODS: BED patients (N = 212) were randomly assigned to guided self-help CBT-E or the 3-month waiting list. Measurements took place at baseline and the end-of-treatment. The cost-effectiveness analysis was performed using the number of binge-eating episodes during the last 28 days as an outcome indicator according to the eating disorder examination. A cost-utility analysis was performed using the EuroQol-5D. RESULTS: The difference in societal costs over the 3 months of the intervention between both conditions was €679 (confidence interval [CI] 50-1330). The incremental costs associated with one incremental binge eating episode prevented in the guided self-help condition was approximately €18 (CI 1-41). From a societal perspective there was a 96% likelihood that guided self-help CBT-E led to a greater number of binge-eating episodes prevented, but at higher costs. Each additional quality-adjusted life year (QALY) gained was associated with incremental costs of €34,000 (CI 2494-154,530). With a 95% likelihood guided self-help CBT-E led to greater QALY gain at higher costs compared to waiting for treatment. Based on the National Institute for Health and Clinical Excellence willingness-to-pay threshold of €35,000 per QALY, guided self-help CBT-E can be considered cost-effective with a likelihood of 95% from a societal perspective. DISCUSSION: Guided self-help CBT-E is likely a cost-effective treatment for BED in the short-term (3-month course of treatment). Comparison to treatment-as-usual is recommended for future research, as it enables an economic evaluation with a longer time horizon. PUBLIC SIGNIFICANCE: Offering treatment remotely has several benefits for patients suffering from binge-eating disorders. Guided self-help CBT-E is an efficacious and likely cost-effective treatment, reducing binge eating and improving quality-of-life, albeit at higher societal costs.

Exploring effectiveness of CBT in obese patients with binge eating disorder: personality functioning is associated with clinically significant change.

BACKGROUND: Binge eating disorder (BED), as the most prevalent eating disorder, is strongly related to obesity and other somatic and psychiatric morbidity. Despite evidence-based treatments a considerable number of BED patients fail to recover. There is preliminary evidence for the association between psychodynamic personality functioning and personality traits on treatment outcome. However, research is limited and results are still contradictory. Identifying variables associated with treatment outcome could improve treatment programs. The aim of the study was to explore whether personality functioning or personality traits are associated with Cognitive Behavioral Therapy (CBT) outcome in obese female patients with BED or subthreshold BED. METHODS: Eating disorder symptoms and clinical variables were assessed in 168 obese female patients with DSM-5 BED or subthreshold BED, referred to a 6-month outpatient CBT program in a pre-post measurement design. Personality functioning was assessed by the Developmental Profile Inventory (DPI), personality traits by the Temperament and Character Inventory (TCI). Treatment outcome was assessed by the Eating Disorder Examination-Questionnaire (EDE-Q) global score and self-reported binge eating frequency. According to the criteria of clinical significance, 140 treatment completers were categorized in four outcome groups (recovered, improved, unchanged, deteriorated). RESULTS: EDE-Q global scores, self-reported binge eating frequency and BMI significantly decreased during CBT, where 44.3% of patients showed clinically significant change in EDE-Q global score. Treatment outcome groups showed significant overall differences on the DPI Resistance and Dependence scales and the aggregated 'neurotic' scale. Significant overall differences were found between groups on TCI Harm avoidance, although post hoc t-tests were non-significant. Furthermore, multiple logistic regression analysis, controlling for mild to moderate depressive disorder and TCI harm avoidance showed that 'neurotic' personality functioning was a significant negative predictor of clinically significant change. CONCLUSION: Maladaptive ('neurotic') personality functioning is significantly associated with a less favorable outcome after CBT in patients with binge eating. Moreover, 'neurotic' personality functioning is a predictor of clinically significant change. Assessment of personality functioning and personality traits could support indication for more specified or augmented care, tailored towards the patients' individual strengths and vulnerabilities. TRIAL REGISTRATION: This study protocol was retrospectively evaluated and approved on 16-06-2022 by the Medical Ethical Review Committee (METC) of the Amsterdam Medical Centre (AMC). Reference number W22_219#22.271.

Spinal cord anomalies in children with anorectal malformations: a retrospective cohort study.

PURPOSE: First, to assess the number of spinal cord anomalies (SCA), specifically tethered spinal cord (TSC) in patients with anorectal malformations (ARM), identified with spinal cord imaging (i.e. spinal cord US and/or MRI). Second, to report outcomes after TSC treatment. METHODS: A retrospective mono-center study was performed. All ARM patients born between January 2000 and December 2021 were included. Screening for SCA consisted of spinal cord US and/or MRI. Radiology reports were scored on presence of SCA. Data were presented with descriptive statistics. RESULTS: In total, 254 patients were eligible for inclusion, of whom 234 (92.1%) underwent spinal cord imaging. In total, 52 (22.2%) patients had a SCA, diagnosed with US (n = 20, 38.5%), MRI (n = 10, 19.2%), or both US and MRI (n = 22, 42.3%), of whom 12 (23.5%) with simple, 27 (52.7%) intermediate, and 12 (23.5%) complex ARM types. TSC was identified in 19 patients (8.1%), of whom 4 (21.1%) underwent uncomplicated neurosurgical intervention. CONCLUSIONS: SCA were present in 22% of ARM patients both in simple, as well as more complex ARM types. TSC was present in 19 patients with SCA, of whom 4 underwent uncomplicated neurosurgical intervention. Therefore, screening for SCA seems to be important for all ARM patients, regardless of ARM type. LEVEL OF EVIDENCE: Level III.

Effectiveness and cost-effectiveness of cognitive behavior therapy-enhanced compared with treatment-as-usual for anorexia nervosa in an inpatient and outpatient routine setting: a consecutive cohort study.

BACKGROUND: For anorexia nervosa, firm evidence of the superiority of specialized psychological treatments is limited and economic evaluations of such treatments in real world settings are scarce. This consecutive cohort study examined differential (cost-)effectiveness for adult inpatients and outpatients with anorexia nervosa, after implementing cognitive behavioral therapy-enhanced (CBT-E) throughout a routine setting. METHODS: Differences in remission, weight regain and direct eating disorder treatment costs were examined between one cohort (N = 75) receiving treatment-as-usual (TAU) between 2012-2014, and the other (N = 88) CBT-E between 2015-2017. The economic evaluation was performed from a health care perspective with a one-year time horizon, using EDE global score < 2.77, the absence of eating disorder behaviors combined with a BMI ≥ 18.5, as effect measure. Incremental cost-effectiveness ratios were calculated and cost-effectiveness planes and cost-effectiveness acceptability curves were displayed to assess the probability that CBT-E is cost effective compared to TAU. RESULTS: Using direct eating disorder treatment costs in the cost-effectiveness analysis, the cost-effectiveness plane of the base case scenario for all patients indicated a 84% likelihood of CBT-E generating better health gain at additional costs. The median ICER is €51,081, indicating a probable preference for CBT-E (> 50% probability of cost-effectiveness) assuming a WTP of €51,081 or more for each additional remission, On remission, no difference was found with 9.3% remission during TAU and 14.6% during CBT-E (p = .304). Weight regain was higher during CBT-E (EMD = 1.33 kg/m2, SE = .29, 95% CI [0.76-1.9], p < .001). CONCLUSIONS: In this mixed inpatient and outpatient cohort study, findings indicate a probability of CBT-Ebeing more effective at higher costs. These findings may contribute to the knowledge of effectiveness and cost-effectiveness of specialized psychological treatments. In this study, the effectiveness and treatment costs of a specialized psychological treatment for adult clients with anorexia nervosa were compared with a regular, non-specialist treatment. One group of inpatients and outpatients did receive non-specialist treatment, the next group of inpatients and outpatients received CBT-E, a specialized treatment, later on. CBT-E is recommended for clients with bulimia and with binge eating disorder, for clients with anorexia nervosa it is less clear which specialized psychological treatment should be recommended. Results indicate that at end-of-treatment, CBT-E was not superior on remission. When looking at weight regain, CBT-E seemed superior than the treatment offered earlier. Economic evaluation suggests that CBT-E generates better health gain, but at additional costs. This study contributes to the knowledge on the effectiveness and treatment costs of psychological treatments, as they are offered in routine practice, to adults with anorexia nervosa.

Behavioral and psychological factors associated with suboptimal weight loss in post-bariatric surgery patients.

PURPOSE: Bariatric surgery is the most effective long-term treatment for sustained weight loss in obesity. Studies have shown that not all patients lose the expected amount of weight. The aim of this study was to develop a better understanding of which behavioral and psychological factors are associated with suboptimal weight loss. METHODS: The present paper describes a cross-sectional study that included 140 participants. The mean follow-up period after bariatric surgery was 3.16 years. Eating disorder pathology (Eating Disorder Examination-Questionnaire), impulsivity (Barratt Impulsiveness scale-II) and depressive symptoms (Beck Depression Inventory) were compared with successful and suboptimal participants. A weight loss of more than or equal to 50% of excess weight, was considered to be successful. RESULTS: More than 81% of the participants met the criterion for successful weight loss. The suboptimal weight loss group reported more symptoms of eating disorder pathology (p = .001), more loss of control over eating (p = .001), and more avoidant behavior due to poor body image (p < .001). The suboptimal weight loss group scored higher on impulsivity (p = .007) and on depression (p < .001). More early weight loss was associated with better weight outcome later on (r = .491). Reporting more eating disorder pathology, a longer follow-up period and pre-operative super-obesity (body mass index ≥ 50 kg/m2) at the time of surgery were associated with poorer weight loss (p < .001). CONCLUSION: Eating disorder pathology, loss of control over eating and avoidant behavior due to poor body image, as well as depressive symptoms and impulsivity, (as reported postoperatively) are associated with suboptimal weight loss. Level III: Case-control analytic study.

Personality Functioning in Obesity and Binge Eating Disorder: Combining a Psychodynamic and Trait Perspective.

OBJECTIVE: There is preliminary evidence for an association between personality traits and binge eating disorder (BED) in obese patients. In addition, recent studies have shown impaired psychodynamic personality functioning in BED. However, these results are partly inconsistent. The goal of this study was to explore and evaluate personality traits and personality functioning in obese patients with BED or subthreshold BED. Moreover, we aimed to explore the additional value of combined assessment of personality traits and personality functioning. METHODS: Treatment-seeking obese female patients with BED (n=129) or subthreshold BED (n=91) were compared with obese (n=107) and nonobese (n=90) female community controls in terms of personality traits (using the Temperament and Character Inventory) and personality functioning (using the Developmental Profile Inventory) in univariate and multivariate analyses. RESULTS: Harm Avoidance was higher and Self-Directedness was lower in obese patients with BED or subthreshold BED compared with obese and nonobese community controls. In addition, obese patients with BED or subthreshold BED presented more maladaptive and less adaptive personality functioning than controls. Although univariate analyses did not find significant differences in personality traits or personality functioning between obese patients with BED and those with subthreshold BED, when both personality traits and personality functioning were combined in multivariate analysis (data from both the Temperament and Character Inventory and Developmental Profile Inventory), obese patients with BED showed greater vulnerabilities in personality traits and functioning than obese patients with subthreshold BED. CONCLUSIONS: Obese patients with BED or subthreshold BED had specific impairments in personality traits and personality functioning. Combined assessment indicated that patients with BED had the most vulnerable personality profile of the 4 groups. The results support the added value of assessment of both personality traits and psychodynamic personality functioning, in line with the alternative Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) model for personality disorders.

Online cognitive behavioral therapy enhanced for binge eating disorder: study protocol for a randomized controlled trial.

BACKGROUND: Binge eating disorder is characterized by recurrent episodes of binge eating accompanied by a sense of lack of control. Of the different treatments available, Cognitive Behavioral Therapy-Enhanced and guided self-help treatment are recommended. As online treatment offers several additional advantages, we have developed a CBT-Enhanced online guided self-help intervention. The aim of this study is to determine whether this intervention reduces eating disorder pathology and increases the amount of binge free days in adults classified with binge eating disorder or other specified feeding or eating disorder- binge eating disorder, compared to an untreated waiting list condition. The experimental condition is hypothesized to be superior to the waiting list condition. METHODS: The efficacy of an online guided self-help intervention for binge eating disorder will be assessed by conducting a randomized controlled trial. The trial will target adult individuals classified with binge eating disorder or other specified feeding or eating disorder- binge eating disorder with a body mass index between 19.5 and 40, referred to an eating disorder treatment center. Dual arm allotment will be performed in a 1:1 ratio stratified for BMI above or below 30. Randomization will be blinded to the online intervention (n = 90), or to the control waiting list condition (n = 90). Assessors will be blinded and assessments will be administered at baseline, week 5, at end-of-treatment, and at 12 and 24 weeks follow-up. Primary outcome will be eating disorder pathology, operationalized as number of days on which binge eating occurred between the two conditions during the period of the intervention. Secondary outcome measures will be differences in other eating disorder pathology, clinical impairment and in quality of life, while therapeutic alliance, demographic characteristics and followed treatment module will serve as effect moderators. Several types of costs will be assessed. DISCUSSION: This paper presents an online guided self-help Cognitive Behavioral Therapy- Enhanced study protocol for individuals classified with binge eating disorder or other specified feeding or eating disorder. Efficacy will be examined through a Randomized Controlled Trial. TRIAL REGISTRATION: The study protocol is registered with the Netherlands Trial Registry NTR (NTR 7994) since 6 September 2019.

Implementing cognitive behavioral therapy-enhanced in a routine inpatient and outpatient setting: Comparing effectiveness and treatment costs in two consecutive cohorts.

BACKGROUND: Even though evidence-based interventions can enhance clinical outcomes and cost effectiveness, in the field of eating disorders, implementation of empirically supported treatments (ESTs) in routine inpatient and outpatient settings is slow. OBJECTIVE: This study examined differential (cost-) effectiveness, after implementing evidence-based cognitive behavioral therapy-enhanced (CBT-E) throughout a Dutch treatment center. METHOD: Two consecutive cohorts of adult patients, BMI between 17.5 and 40, were compared, with one cohort (N = 239) receiving treatment-as-usual (TAU) between 2012 and 2014 and the other (N = 320) receiving CBT-E between 2015 and 2017. RESULTS: Eating disorder pathology, measured with self-reports, decreased significantly in both cohorts; overall, no differences in clinical outcomes between both cohorts were found. Treatment costs and treatment duration were considerably lower in 2015-2017. When limiting the cost analysis to direct costs, there is a 71% likelihood that CBT-E is more cost-effective and a 29% likelihood that CBT-E leads to fewer remissions at lower costs, based on the distribution of the cost-effectiveness plane. The likelihood that TAU leads to lower costs is 0%. DISCUSSION: Findings show that implementing an EST throughout inpatient and outpatient settings leads to lower costs with similar treatment effect and has the advantage of shorter treatment duration and a shorter inpatient stay.

Meta-analysis on the efficacy of psychological treatments for anorexia nervosa.

OBJECTIVE: This meta-analysis examines the efficacy of recently developed psychological treatments for anorexia nervosa, compared with control condition. Outcome criteria are weight gain, eating disorder pathology, and quality of life. METHOD: Twelve thousand nine hundred ninety-seven abstracts, published between 1980 and 2017, were retrieved. End-of-treatment data from 1,279 participants, from 15 of 17 eligible studies, were used to calculate pooled-effect sizes (Hedges' g) for outcome using random-effects model. Subgroup analyses were used to explore the influence of various patient and study characteristics. RESULTS: No significant differences between psychological treatment and controls were found on weight gain, g = 0.07, 95% CI [-0.09, 0.23], eating disorder pathology, g = 0.06, 95% CI [-0.10, 0.21], and quality of life, g = -0.11, 95% CI [-0.36, 0.15]. Studies including only patients over 18 years of age were more effective on weight gain than studies including adolescents as well. High-quality studies and studies with reported therapist training had larger effects on weight gain and quality of life compared with low-quality studies and studies without reported training. CONCLUSIONS: Despite progress in the development of specialized treatments, the efficacy of psychological treatment over an active control condition could not be established. Outcomes, however, are obscured by low-quality and heterogeneous studies.

The caspase inhibitor zVAD increases lung inflammation in pneumovirus infection in mice.

Severe respiratory syncytial virus (RSV) disease is a frequent cause of acute respiratory distress syndrome (ARDS) in young children, and is associated with marked lung epithelial injury and neutrophilic inflammation. Experimental studies on ARDS have shown that inhibition of apoptosis in the lungs reduces lung epithelial injury. However, the blockade of apoptosis in the lungs may also have deleterious effects by hampering viral clearance, and importantly, by enhancing or prolonging local proinflammatory responses. The aim of this study was to determine the effect of the broad caspase inhibitor Z-VAD(OMe)-FMK (zVAD) on inflammation and lung injury in a mouse pneumovirus model for severe RSV disease. Eight- to 11-week-old female C57BL/6OlaHsd mice were inoculated with the rodent-specific pneumovirus pneumonia virus of mice (PVM) strain J3666 and received multiple injections of zVAD or vehicle (control) during the course of disease, after which they were studied for markers of apoptosis, inflammation, and lung injury on day 7 after infection. PVM-infected mice that received zVAD had a strong increase in neutrophil numbers in the lungs, which was associated with decreased neutrophil apoptosis. Furthermore, zVAD treatment led to higher concentrations of several proinflammatory cytokines in the lungs and more weight loss in PVM-infected mice. In contrast, zVAD did not reduce apoptosis of lung epithelial cells and did not affect the degree of lung injury, permeability, and viral titers in PVM disease. We conclude that zVAD has an adverse effect in severe pneumovirus disease in mice by enhancing the lung proinflammatory response.

The effect of TIP on pneumovirus-induced pulmonary edema in mice.

BACKGROUND: Pulmonary edema plays a pivotal role in the pathophysiology of respiratory syncytial virus (RSV)-induced respiratory failure. In this study we determined whether treatment with TIP (AP301), a synthetic cyclic peptide that mimics the lectin-like domain of human TNF, decreases pulmonary edema in a mouse model of severe human RSV infection. TIP is currently undergoing clinical trials as a therapy for pulmonary permeability edema and has been shown to decrease pulmonary edema in different lung injury models. METHODS: C57BL/6 mice were infected with pneumonia virus of mice (PVM) and received TIP or saline (control group) by intratracheal instillation on day five (early administration) or day seven (late administration) after infection. In a separate set of experiments the effect of multiple dose administration of TIP versus saline was tested. Pulmonary edema was determined by the lung wet-to-dry (W/D) weight ratio and was assessed at different time-points after the administration of TIP. Secondary outcomes included clinical scores and lung cellular response. RESULTS: TIP did not have an effect on pulmonary edema in different dose regimens at different time points during PVM infection. In addition, TIP administration did not affect clinical severity scores or lung cellular response. CONCLUSION: In this murine model of severe RSV infection TIP did not affect pulmonary edema nor course of disease.

FiO2 predicts outcome in infants with respiratory syncytial virus-induced acute respiratory distress syndrome.

OBJECTIVE: Respiratory syncytial virus (RSV) infection can progress to acute respiratory distress syndrome (ARDS) in infants. ARDS is a life-threatening condition that is characterized by severe hypoxemia, defined as PaO(2)/FiO(2) ratio <300 mmHg. This ratio is used in many trials as the sole oxygenation criterion for ARDS. Recently, however, it has been shown in adults with ARDS that FiO(2), independently of the PaO(2)/FiO(2) ratio predicts mortality. Because epidemiology and outcome of ARDS differ strongly between children and adults, we determined if FiO(2) on admission (baseline FiO(2)) independently predicted the duration of mechanical ventilation (MV) and length of stay (LOS) in the pediatric intensive care unit (PICU) in infants with RSV-induced ARDS. DESIGN: Retrospective observational study. SETTING: A 14-bed pediatric intensive care unit. PATIENTS: One hundred twenty-nine mechanically ventilated infants with RSV-induced ARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Independent predictors for outcome, including baseline FiO(2) and PEEP, were analyzed using the cox regression model. Endpoints were duration of MV and LOS in the PICU. A higher baseline FiO(2) was independently associated with a longer duration of MV (HR 0.12, CI 0.02-0.87, P = 0.036) and increased LOS in the PICU (HR 0.09, CI 0.01-0.57, P = 0.023). Neither baseline PEEP nor PaO(2)/FiO(2) ratio correlated with outcome. CONCLUSIONS: FiO(2) level independently predicted outcome in infants with RSV-induced ARDS, whereas both PEEP and the PaO(2)/FiO(2) ratio did not. This suggests that FiO(2) should be taken into account in defining disease severity in infants with RSV-induced ARDS.

Imbalance between pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome.

OBJECTIVE: Angiotensin-converting enzyme and its effector peptide angiotensin II have been implicated in the pathogenesis of acute respiratory distress syndrome. Recently, angiotensin-converting enzyme 2 was identified as the counter-regulatory enzyme of angiotensin-converting enzyme that converts angiotensin II into angiotensin-(1-7). The aim of this study was to determine pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in patients with acute respiratory distress syndrome. DESIGN: Prospective observational pilot study. SETTING: A PICU of a university hospital. PATIENTS: Fourteen patients admitted, requiring mechanical ventilation for respiratory syncytial virus lower respiratory tract infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two groups of patients were distinguished at admission: a group fulfilling the criteria for acute respiratory distress syndrome and a non-acute respiratory distress syndrome group. Angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity were measured in bronchoalveolar lavage fluid. Patients with acute respiratory distress syndrome had increased angiotensin-converting enzyme activity and decreased angiotensin-converting enzyme 2 activity (p < 0.001) compared with the control group. CONCLUSION: It is shown for the first time that in acute respiratory distress syndrome, enhanced angiotensin-converting enzyme activity is paralleled by a reduced angiotensin-converting enzyme 2 activity, similar to that found in an experimental rat model of acute respiratory distress syndrome. The reduced angiotensin-converting enzyme 2 activity may be counteracted by restoring angiotensin-(1-7) level, thereby offering a novel treatment modality for this syndrome.

High levels of S100A8/A9 proteins aggravate ventilator-induced lung injury via TLR4 signaling.

BACKGROUND: Bacterial products add to mechanical ventilation in enhancing lung injury. The role of endogenous triggers of innate immunity herein is less well understood. S100A8/A9 proteins are released by phagocytes during inflammation. The present study investigates the role of S100A8/A9 proteins in ventilator-induced lung injury. METHODS: Pulmonary S100A8/A9 levels were measured in samples obtained from patients with and without lung injury. Furthermore, wild-type and S100A9 knock-out mice, naive and with lipopolysaccharide-induced injured lungs, were randomized to 5 hours of spontaneously breathing or mechanical ventilation with low or high tidal volume (VT). In addition, healthy spontaneously breathing and high VT ventilated mice received S100A8/A9, S100A8 or vehicle intratracheal. Furthermore, the role of Toll-like receptor 4 herein was investigated. RESULTS: S100A8/A9 protein levels were elevated in patients and mice with lung injury. S100A8/A9 levels synergistically increased upon the lipopolysaccharide/high VT MV double hit. Markers of alveolar barrier dysfunction, cytokine and chemokine levels, and histology scores were attenuated in S100A9 knockout mice undergoing the double-hit. Exogenous S100A8/A9 and S100A8 induced neutrophil influx in spontaneously breathing mice. In ventilated mice, these proteins clearly amplified inflammation: neutrophil influx, cytokine, and chemokine levels were increased compared to ventilated vehicle-treated mice. In contrast, administration of S100A8/A9 to ventilated Toll-like receptor 4 mutant mice did not augment inflammation. CONCLUSION: S100A8/A9 proteins increase during lung injury and contribute to inflammation induced by HVT MV combined with lipopolysaccharide. In the absence of lipopolysaccharide, high levels of extracellular S100A8/A9 still amplify ventilator-induced lung injury via Toll-like receptor 4.

Cardiac dysfunction in pneumovirus-induced lung injury in mice.

OBJECTIVE: To determine biventricular cardiac function in pneumovirus-induced acute lung injury in spontaneously breathing mice. DESIGN: Experimental animal study. SETTING: Animal laboratory. SUBJECTS: C57Bl/6 mice. INTERVENTION: Mice were inoculated with the rodent pneumovirus, pneumonia virus of mice. MEASUREMENTS AND MAIN RESULTS: Pneumonia virus of mice-infected mice were studied for right and left ventricular function variables by high-field strength (7 Tesla) cardiac MRI at specific time points during the course of disease compared with baseline. One day before and at peak disease severity, pneumonia virus of mice-infected mice showed significant right and left ventricular systolic and diastolic volume changes, with a progressive decrease in stroke volume and ejection fraction. No evidence for viral myocarditis or viral presence in heart tissue was found. CONCLUSIONS: These findings show adverse pulmonary-cardiac interaction in pneumovirus-induced acute lung injury, unrelated to direct virus-mediated effects on the heart.

Apoptosis in pneumovirus infection.

Pneumovirus infections cause a wide spectrum of respiratory disease in humans and animals. The airway epithelium is the major site of pneumovirus replication. Apoptosis or regulated cell death, may contribute to the host anti-viral response by limiting viral replication. However, apoptosis of lung epithelial cells may also exacerbate lung injury, depending on the extent, the timing and specific location in the lungs. Differential apoptotic responses of epithelial cells versus innate immune cells (e.g., neutrophils, macrophages) during pneumovirus infection can further contribute to the complex and delicate balance between host defense and disease pathogenesis. The purpose of this manuscript is to give an overview of the role of apoptosis in pneumovirus infection. We will examine clinical and experimental data concerning the various pro-apoptotic stimuli and the roles of apoptotic epithelial and innate immune cells during pneumovirus disease. Finally, we will discuss potential therapeutic interventions targeting apoptosis in the lungs.