Search Vanderbilt Publications

Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.

Chorioamnionitis is a common precipitant of preterm birth and is associated with many of the morbidities of prematurity, including necrotizing enterocolitis (NEC). However, a mechanistic link between these two conditions remains yet to be discovered. We have adopted a murine model of chorioamnionitis involving lipopolysaccharide (LPS)-induced fetal exposure to maternal inflammation (FEMI). This model of FEMI induces a sterile maternal, placental, and fetal inflammatory cascade, which is also present in many cases of clinical chorioamnionitis. Although models exist that utilize live bacteria and more accurately mimic the pathophysiology of an ascending infection resulting in chorioamnionitis, these methods may cause indirect effects on development of the immature intestinal tract and the associated developing microbiome. Using this protocol, we have demonstrated that LPS-induced FEMI results in a dose-dependent increase in pregnancy loss and preterm birth, as well as disruption of normal intestinal development in offspring. Further, we have demonstrated that FEMI significantly increases intestinal injury and serum cytokines in offspring, while simultaneously decreasing goblet and Paneth cells, both of which provide a first line of innate immunity against intestinal inflammation. Although a similar model of LPS-induced FEMI has been used to model the association between chorioamnionitis and subsequent abnormalities of the central nervous system, to our knowledge, this protocol is the first to attempt to elucidate a mechanistic link between chorioamnionitis and later perturbations in intestinal development as a potential link between chorioamnionitis and NEC.

OBJECTIVES - Upper airway injury is a recognized complication of prolonged endotracheal intubation, yet little attention has been paid to the consequences of laryngeal injury and functional impact. The purpose of our study was to prospectively define the incidence of acute laryngeal injury and investigate the impact of injury on breathing and voice outcomes.
DESIGN - Prospective cohort study.
SETTING - Tertiary referral critical care center.
PATIENTS - Consecutive adult patients intubated greater than 12 hours in the medical ICU from August 2017 to May 2018 who underwent laryngoscopy within 36 hours of extubation.
INTERVENTIONS - Laryngoscopy following endotracheal intubation.
MEASUREMENTS AND MAIN RESULTS - One hundred consecutive patients (62% male; median age, 58.5 yr) underwent endoscopic examination after extubation. Acute laryngeal injury (i.e., mucosal ulceration or granulation tissue in the larynx) was present in 57 patients (57%). Patients with laryngeal injury had significantly worse patient-reported breathing (Clinical Chronic Obstructive Pulmonary Disease Questionnaire: median, 1.05; interquartile range, 0.48-2.10) and vocal symptoms (Voice Handicap Index-10: median, 2; interquartile range, 0-6) compared with patients without injury (Clinical Chronic Obstructive Pulmonary Disease Questionnaire: median, 0.20; interquartile range, 0-0.80; p < 0.001; and Voice Handicap Index-10: median, 0; interquartile range, 0-1; p = 0.005). Multivariable logistic regression independently associated diabetes, body habitus, and endotracheal tube size greater than 7.0 with the development of laryngeal injury.
CONCLUSIONS - Acute laryngeal injury occurs in more than half of patients who receive mechanical ventilation and is associated with significantly worse breathing and voicing 10 weeks after extubation. An endotracheal tube greater than size 7.0, diabetes, and larger body habitus may predispose to injury. Our results suggest that acute laryngeal injury impacts functional recovery from critical illness.

INTRODUCTION - Respiratory failure requiring endotracheal intubation accounts for a significant proportion of intensive care unit (ICU) admissions. Little attention has been paid to the laryngeal consequences of endotracheal intubation. Acute laryngeal injury (ALgI) after intubation occurs at the mucosal interface of the endotracheal tube and posterior larynx and although not immediately manifest at extubation, can progress to mature fibrosis, restricted glottic mobility and clinically significant ventilatory impairment. A recent prospective observational study has shown that >50% of patients intubated >24 hours in an ICU develop ALgI. Strikingly, patients with AlgI manifest significantly worse subjective breathing at 12 weeks. Current ALgI treatments are largely surgical yet offer a marginal improvement in symptoms. METHODS AND ANALYSIS: A prospective, single-centre, double-blinded, randomised, control trial will be conducted at Vanderbilt Medical Center. Participants will be recruited from adult patients in ICUs. Participants will undergo a bedside flexible nasolaryngoscopy for the identification of ALgI within 72 hours postextubation. In addition, participants will be asked to complete peak expiratory flow measurements immediately postintubation. Patients found to have ALgI will be randomised to the placebo control or medical therapy group (azithromycin 250 mg and budesonide 0.5 mg for 14 days). Repeat peak expiratory flow, examination of the larynx and patient-reported Clinical COPD (chronic obstructive pulmonary disease) Questionnaire, Voice Handicap Index and 12-Item Short Form Health Survey questionnaires will be conducted at 12 weeks postextubation. Consented patients will also have patient-specific, disease-specific and procedure-specific covariates abstracted from their medical record.
ETHICS AND DISSEMINATION - The Institutional Review Board (IRB) Committee of the Vanderbilt University Medical Center has approved this protocol (IRB #171066). The findings of the trial will be disseminated through peer-reviewed journals, national and international conferences.
TRIAL REGISTRATION NUMBER - NCT03250975.
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Acinetobacter baumannii is a Gram-negative opportunistic pathogen and a leading cause of ventilator-associated pneumonia. Murine models of A. baumannii lung infection allow researchers to experimentally assess A. baumannii virulence and host response. Intranasal administration of A. baumannii models acute lung infection. This chapter describes the methods to test A. baumannii virulence in a murine model of lung infection, including assessing the competitive index of a bacterial mutant and the associated inflammatory responses.

BACKGROUND - Infliximab is an effective salvage therapy in acute severe ulcerative colitis; however, the optimal dosing strategy is unknown. We performed a systematic review and meta-analysis to examine the impact of infliximab dosage and intensification on colectomy-free survival in acute severe ulcerative colitis.
METHODS - Studies reporting outcomes of hospitalized steroid-refractory acute severe ulcerative colitis treated with infliximab salvage were identified. Infliximab use was categorized by dose, dose number, and schedule. The primary outcome was colectomy-free survival at 3 months. Pooled proportions and odds ratios with 95% confidence intervals were reported.
RESULTS - Forty-one cohorts (n = 2158 cases) were included. Overall colectomy-free survival with infliximab salvage was 79.7% (95% confidence interval [CI], 75.48% to 83.6%) at 3 months and 69.8% (95% CI, 65.7% to 73.7%) at 12 months. Colectomy-free survival at 3 months was superior with 5-mg/kg multiple (≥2) doses compared with single-dose induction (odds ratio [OR], 4.24; 95% CI, 2.44 to 7.36; P < 0.001). However, dose intensification with either high-dose or accelerated strategies was not significantly different to 5-mg/kg standard induction at 3 months (OR, 0.70; 95% CI, 0.39 to 1.27; P = 0.24) despite being utilized in patients with a significantly higher mean C-reactive protein and lower albumin levels.
CONCLUSIONS - In acute severe ulcerative colitis, multiple 5-mg/kg infliximab doses are superior to single-dose salvage. Dose-intensified induction outcomes were not significantly different compared to standard induction and were more often used in patients with increased disease severity, which may have confounded the results. This meta-analysis highlights the marked variability in the management of infliximab salvage therapy and the need for further studies to determine the optimal dose strategy.
© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

AIMS - We conducted a prospective study of emergency department (ED) patients with acute heart failure (AHF) to determine if worsening HF (WHF) could be predicted based on urinary electrolytes during the first 1-2 h of ED care. Loop diuretics are standard therapy for AHF patients. A subset of patients hospitalized for AHF will develop a blunted natriuretic response to loop diuretics, termed diuretic resistance, which often leads to WHF. Early detection of diuretic resistance could facilitate escalation of therapy and prevention of WHF.
METHODS AND RESULTS - Patients were eligible if they had an ED AHF diagnosis, had not yet received intravenous diuretics, had a systolic blood pressure > 90 mmHg, and were not on dialysis. Urine electrolytes and urine output were collected at 1, 2, 4, and 6 h after diuretic administration. Worsening HF was defined as clinically persistent or WHF requiring escalation of diuretics or administration of intravenous vasoactives after the ED stay. Of the 61 patients who qualified in this pilot study, there were 10 (16.3%) patients who fulfilled our definition of WHF. At 1 h after diuretic administration, patients who developed WHF were more likely to have low urinary sodium (9.5 vs. 43.0 mmol; P < 0.001) and decreased urine sodium concentration (48 vs. 80 mmol/L; P = 0.004) than patients without WHF. All patients with WHF had a total urine sodium of <35.4 mmol at 1 h (100% sensitivity and 60% specificity).
CONCLUSIONS - One hour after diuretic administration, a urine sodium excretion of <35.4 mmol was highly suggestive of the development of WHF. These relationships require further testing to determine if early intervention with alternative agents can prevent WHF.
© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

OBJECTIVES - This study sought to compare a continuous infusion diuretic strategy versus an intermittent bolus diuretic strategy, with the addition of low-dose dopamine (3 μg/kg/min) in the treatment of hospitalized patients with heart failure with preserved ejection fraction (HFpEF).
BACKGROUND - HFpEF patients are susceptible to development of worsening renal function (WRF) when hospitalized with acute heart failure; however, inpatient treatment strategies to achieve safe and effective diuresis in HFpEF patients have not been studied to date.
METHODS - In a prospective, randomized, clinical trial, 90 HFpEF patients hospitalized with acute heart failure were randomized within 24 h of admission to 1 of 4 treatments: 1) intravenous bolus furosemide administered every 12 h; 2) continuous infusion furosemide; 3) intermittent bolus furosemide with low-dose dopamine; and 4) continuous infusion furosemide with low-dose dopamine. The primary endpoint was percent change in creatinine from baseline to 72 h. Linear and logistic regression analyses with tests for interactions between diuretic and dopamine strategies were performed.
RESULTS - Compared to intermittent bolus strategy, the continuous infusion strategy was associated with higher percent increase in creatinine (continuous infusion: 16.01%; 95% confidence interval [CI]: 8.58% to 23.45% vs. intermittent bolus: 4.62%; 95% CI: -1.15% to 10.39%; p = 0.02). Low-dose dopamine had no significant effect on percent change in creatinine (low-dose dopamine: 12.79%; 95% CI: 5.66% to 19.92%, vs. no-dopamine: 8.03%; 95% CI: 1.44% to 14.62%; p = 0.33). Continuous infusion was also associated with greater risk of WRF than intermittent bolus (odds ratio [OR]: 4.32; 95% CI: 1.26 to 14.74; p = 0.02); no differences in WRF risk were seen with low-dose dopamine. No significant interaction was seen between diuretic strategy and low-dose dopamine (p > 0.10).
CONCLUSIONS - In HFpEF patients hospitalized with acute heart failure, low-dose dopamine had no significant impact on renal function, and a continuous infusion diuretic strategy was associated with renal impairment. (Diuretics and Dopamine in Heart Failure With Preserved Ejection Fraction [ROPA-DOP]; NCT01901809).
Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

BACKGROUND - Early life acute respiratory infection (ARI) with respiratory syncytial virus (RSV) has been strongly associated with the development of childhood wheezing illnesses, but the pathways underlying this association are poorly understood.
OBJECTIVE - To examine the role of the nasopharyngeal microbiome in the development of childhood wheezing illnesses following RSV ARI in infancy.
METHODS - We conducted a nested cohort study of 118 previously healthy, term infants with confirmed RSV ARI by RT-PCR. We used next-generation sequencing of the V4 region of the 16S ribosomal RNA gene to characterize the nasopharyngeal microbiome during RSV ARI. Our main outcome of interest was 2-year subsequent wheeze.
RESULTS - Of the 118 infants, 113 (95.8%) had 2-year outcome data. Of these, 46 (40.7%) had parental report of subsequent wheeze. There was no association between the overall taxonomic composition, diversity, and richness of the nasopharyngeal microbiome during RSV ARI with the development of subsequent wheeze. However, the nasopharyngeal detection and abundance of Lactobacillus was consistently higher in infants who did not develop this outcome. Lactobacillus also ranked first among the different genera in a model distinguishing infants with and without subsequent wheeze.
CONCLUSIONS - The nasopharyngeal detection and increased abundance of Lactobacillus during RSV ARI in infancy are associated with a reduced risk of childhood wheezing illnesses at age 2 years.
Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

PURPOSE - To compare the electrophysiological and morphological responses to acute, moderately elevated intraocular pressure (IOP) in Sprague-Dawley (SD), Long-Evans (LE) and Brown Norway (BN) rat eyes.
METHODS - Eleven-week-old SD (n = 5), LE (n = 5) and BN (n = 5) rats were used. Scotopic threshold responses (STRs), Maxwellian flash electroretinograms (ERGs) or ultrahigh-resolution optical coherence tomography (UHR-OCT) images of the rat retinas were collected from both eyes before, during and after IOP elevation of one eye. IOP was raised to ~35 mmHg for 1 h using a vascular loop, while the other eye served as a control. STRs, ERGs and UHR-OCT images were acquired on 3 days separated by 1 day of no experimental manipulation.
RESULTS - There were no significant differences between species in baseline electroretinography. However, during IOP elevation, peak positive STR amplitudes in LE (mean ± standard deviation 259 ± 124 µV) and BN (228 ± 96 µV) rats were about fourfold higher than those in SD rats (56 ± 46 µV) rats (p = 0.0002 for both). Similarly, during elevated IOP, ERG b-wave amplitudes were twofold higher in LE and BN rats compared to those of SD rats (947 ± 129 µV and 892 ± 184 µV, vs 427 ± 138 µV; p = 0.0002 for both). UHR-OCT images showed backward bowing in all groups during IOP elevation, with a return to typical form about 30 min after IOP elevation.
CONCLUSION - Differences in the loop-induced responses between the strains are likely due to different inherent retinal morphology and physiology.