Randomized trial to evaluate azithromycin's effects on serum and upper airway IL-8 levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis.

BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis in infancy is a major risk factor for recurrent wheezing and asthma. Because azithromycin attenuated neutrophilic airway inflammation in a murine viral bronchiolitis model, demonstration of similar effects in human subjects might provide a strategy for the prevention of postbronchiolitis recurrent wheezing. OBJECTIVES: We sought to investigate whether azithromycin treatment during RSV bronchiolitis reduces serum and nasal lavage IL-8 levels and the occurrence of postbronchiolitis recurrent wheezing. METHOD: We performed a randomized, double-masked, placebo-controlled proof-of-concept trial in 40 otherwise healthy infants hospitalized with RSV bronchiolitis who were treated with azithromycin or placebo for 14 days. IL-8 levels were measured in nasal lavage fluid and serum on randomization, day 8, and day 15 (nasal lavage only). The occurrence of wheezing episodes was assessed monthly over the ensuing 50 weeks. RESULTS: Compared with placebo, azithromycin treatment did not reduce serum IL-8 levels at day 8 (P = .6) but resulted in a greater decrease in nasal lavage fluid IL-8 levels by day 15 (P = .03). Twenty-two percent of azithromycin-treated participants experienced at least 3 wheezing episodes compared with 50% of participants in the placebo group (P = .07). Azithromycin treatment resulted in prolonged time to the third wheezing episode (P = .048) and in fewer days with respiratory symptoms over the subsequent year in comparison with placebo (36.7 vs 70.1 days, P = .01). CONCLUSION: In this proof-of-concept study azithromycin treatment during RSV bronchiolitis reduced upper airway IL-8 levels, prolonged the time to the third wheezing episode, and reduced overall respiratory morbidity over the subsequent year.

Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection.

Chronic infections are an increasing problem due to the aging population and the increase in antibiotic resistant organisms. Therefore, understanding the host-pathogen interactions that result in chronic infection is of great importance. Here, we investigate the molecular basis of chronic bacterial cystitis. We establish that introduction of uropathogenic E. coli (UPEC) into the bladders of C3H mice results in two distinct disease outcomes: resolution of acute infection or development of chronic cystitis lasting months. The incidence of chronic cystitis is both host strain and infectious dose-dependent. Further, development of chronic cystitis is preceded by biomarkers of local and systemic acute inflammation at 24 hours post-infection, including severe pyuria and bladder inflammation with mucosal injury, and a distinct serum cytokine signature consisting of elevated IL-5, IL-6, G-CSF, and the IL-8 analog KC. Mice deficient in TLR4 signaling or lymphocytes lack these innate responses and are resistant, to varying degrees, to developing chronic cystitis. Treatment of C3H mice with the glucocorticoid anti-inflammatory drug dexamethasone prior to UPEC infection also suppresses the development of chronic cystitis. Finally, individuals with a history of chronic cystitis, lasting at least 14 days, are significantly more susceptible to redeveloping severe, chronic cystitis upon bacterial challenge. Thus, we have discovered that the development of chronic cystitis in C3H mice by UPEC is facilitated by severe acute inflammatory responses early in infection, which subsequently are predisposing to recurrent cystitis, an insidious problem in women. Overall, these results have significant implications for our understanding of how early host-pathogen interactions at the mucosal surface determines the fate of disease.

Colonization with 19F and other pneumococcal conjugate vaccine serotypes in children in St. Louis, Missouri, USA.

BACKGROUND: The epidemiology of nasopharyngeal (NP) pneumococcal carriage varies with geography and has changed in response to pneumococcal conjugate vaccine (PCV): a low prevalence (3% or less of colonizing isolates) of colonization by vaccine-type (VT) pneumococcal serotypes after PCV introduction has been reported. The primary goal of this study was to determine the VT serotype prevalence of NP pneumococcal colonization of children residing in the St. Louis, MO, USA metropolitan area following introduction of the 13-valent PCV in 2010. The secondary goal of this study was to identify characteristics associated with NP pneumococcal carriage of any serotype. METHODS: Between July 2013 and April 2016, we enrolled 397 healthy children, aged 0-17years, who required sedation for procedures or minor surgeries at St. Louis Children's Hospital. NP swabs were collected after sedation or anesthesia and cultured for pneumococcus. Vaccine records were obtained from primary care providers or from state immunization databases. Parents/guardians completed a questionnaire to provide demographics, past medical history and household characteristics. RESULTS: Of the 88 pneumococcal isolates recovered from 84 colonized subjects (21.2% of all enrolled subjects; 95% CI 17.2-25.2%), 16 were VT. Eleven isolates were serotype 19F (12.5%), four (4.5%) were 6A and one (1.1%) was 19A. Prevalence of VT among colonizing isolates was thus 18.2% (CI 10.1-26.1%) in our cohort, despite complete PCV vaccination in 87% of colonized children. Factors associated with pneumococcal colonization by any serotype included younger age and daycare attendance. CONCLUSION: Children in St. Louis exhibit a higher prevalence of VT serotypes among pneumococcal carriage isolates than has been reported in other areas in the US, demonstrating the necessity of ongoing surveillance of local epidemiology and providing evidence that serotype 19F can remain prevalent in a pediatric population despite high vaccine uptake.

Prevalence of nasopharyngeal pneumococcal colonization in children and antimicrobial susceptibility profiles of carriage isolates.

Nasopharyngeal (NP) pneumococcal carriage predisposes children to pneumococcal infections. Defining the proportion of pneumococcal isolates that are antibiotic-resistant enables the appropriate choice of empiric therapies. The antibiogram of NP carriage isolates derived from a pediatric population following the introduction of the 13-valent pneumococcal conjugate vaccine was defined in this study.

Vitamin D Levels Are Unrelated to the Severity of Respiratory Syncytial Virus Bronchiolitis Among Hospitalized Infants.

BACKGROUND: Vitamin D deficiency at birth has been reported as a risk factor for respiratory syncytial virus (RSV) lower respiratory tract infection during the first year of life. Limited data are available on whether an infant's vitamin D status is associated with the severity of acute RSV bronchiolitis. METHODS: Infants < 1 year of age and hospitalized with their first episode of RSV bronchiolitis were enrolled into the RSV Bronchiolitis in Early Life II cohort. We investigated the relationships between vitamin D status at enrollment and the following indicators of bronchiolitis severity: duration of hospitalization, lowest oxygen saturation measured during hospitalization, and bronchiolitis severity score. RESULTS: Among the 145 enrolled infants, the median (quartile 1 [Q1], Q3) serum 25-OH-VitD level was 36.8 (29.8, 42.3) ng/mL, with 14 infants (9.7%) having deficient serum vitamin D levels (25-OH-VitD <20 ng/mL). Vitamin D-deficient infants were younger than infants with 25-OH-VitD ≥ 20 ng/mL (2.8 vs 4.5 months, respectively; P = .04) and were less likely to consume infant's formula (42.9% vs 87.0%, respectively; P < .01). The following indicators of acute bronchiolitis severity did not differ between infants who were vitamin D-deficient and nondeficient: duration of hospitalization (P = .53), lowest oxygen saturation (P = .45), and bronchiolitis severity score (P = .97), even after adjusting for age, and for infant's formula consumption. CONCLUSIONS: Among this cohort of infants that were hospitalized for RSV bronchiolitis, vitamin D status at the time of bronchiolitis was not associated with indicators of acute bronchiolitis severity.

Estrogen affects the glycosaminoglycan layer of the murine bladder.

OBJECTIVES: Urinary tract infections (UTIs), commonly caused by uropathogenic Escherichia coli (UPEC), confer significant morbidity among postmenopausal women. Glycosaminoglycans (GAGs) comprise the first line of defense at the bladder's luminal surface. Our objective was to use a murine model of menopause to determine whether estrogen status affects the GAG layer in response to UPEC infection. METHODS: Adult female mice underwent sham surgery (SHAM, n = 18) or oophorectomy (OVX, n = 66) to establish a murine model of menopause. A subset of oophorectomized mice underwent hormone therapy (HT, n = 33) with 17ß-estradiol. Mice were inoculated with UPEC and killed at various time points; bladders were collected and GAG layer thickness was assessed in multiple bladder sections. Sixteen measurements were made per bladder. A repeated-measures 2-way analysis of variance was performed to determine the effect of time after infection and hormonal condition on GAG thickness. We also investigated the molecular underpinnings of GAG biosynthesis in response to alterations in estrogen status and infection. RESULTS: We did not observe significant difference of GAG thickness among the 3 hormonal conditions; however, the time course of GAG thickness was significantly different (P < 0.05). The OVX mice demonstrated significantly greater thickness at 72 hours after infection (P = 0.0001), and this effect was shifted earlier (24 hours after infection) on the addition of HT (P = 0.001). At 2 to 4 weeks after infection, GAG thickness among all cohorts was not significantly different from baseline. In addition, quantitative reverse transcription-polymerase chain reaction analysis revealed that GAG biosynthesis is altered by estrogen status at basal level and on infection. CONCLUSIONS: The GAG layer is dynamically altered during the course of UTI. Our data show that HT positively regulates GAG layer thickness over time, as well as the composition of the GAGs. In addition, the GAG sulfation status can be influenced by estrogen levels in response to UPEC infection. The protective effects of the GAG layer in UTI may represent pharmacologic targets for the treatment and prevention of postmenopausal UTI.

Bone morphogenetic protein 4 signaling regulates epithelial renewal in the urinary tract in response to uropathogenic infection.

The transitional epithelium of the bladder normally turns over slowly but upon injury undergoes rapid regeneration fueled by basal uroepithelial stem and/or early progenitor cells (USCs). Little is known about the mechanisms underlying the injury response. We investigate the mechanism of bladder epithelial regeneration in response to infection with uropathogenic E. coli (UPEC). Infection resulted in rapid sloughing of superficial cells, a marked inflammatory response, and a substantial spike in basal cell proliferation. In mice with induced urothelial ablation of a member of the TGF-beta receptor superfamily, bone morphogenetic protein (Bmp)-4 receptor, infection led to aberrant urothelial renewal resulting from a block in USC differentiation into superficial cells. Chemical injury also caused sloughing but no inflammation or USC activation. Together, our study indicates that UPEC infection but not chemical injury activates the USC niche, and Bmp signaling is required for regulation of the USC response to infection.