Longitudinal changes in the cystic fibrosis airway microbiota with time and treatment.

BACKGROUND: Whether there is any benefit in integrating culture-independent molecular analysis of the lower airway microbiota of people with cystic fibrosis into clinical care is unclear. This study determined the longitudinal trajectory of the microbiota and if there were microbiota characteristics that corresponded with response to treatment or predicted a future pulmonary exacerbation. METHODS: At least one sputum sample was collected from 149 participants enrolled in this prospective longitudinal multi-centre study and total bacterial density and microbiota community measurements were determined and compared with clinical parameters. RESULTS: In 114 participants with paired samples when clinically stable, ∼8 months apart, the microbiota remained conserved between timepoints, regardless of whether participants received acute intravenous antibiotic treatment or not. In 62 participants, who presented with an acute exacerbation, a decrease in community richness correlated best with patient response to antibiotic treatment. Analysis of baseline samples from 30 participants who exacerbated within 4 months of their stable sample being collected and 72 participants who remained stable throughout the study showed that community characteristics such as lower richness at baseline may be predictive of an exacerbation in addition to several clinical parameters. However, lasso regression analysis indicated that only lung function (p = 0.014) was associated with a future exacerbation. CONCLUSIONS: The airway microbiota remains stable over periods <1 year with modest shifts related to treatment apparent which might provide some additional insights to patient-level measurements.

In focus: perplexing increase of urinary stone disease in children, adolescent and young adult women and its economic impact.

Background: Urinary stone disease (USD) historically has affected older men, but studies suggest recent increases in women, leading to a near identical sex incidence ratio. USD incidence has doubled every 10 years, with disproportionate increases amongst children, adolescent, and young adult (AYA) women. USD stone composition in women is frequently apatite (calcium phosphate), which forms in a higher urine pH, low urinary citrate, and an abundance of urinary uric acid, while men produce more calcium oxalate stones. The reasons for this epidemiological trend are unknown. Methods: This perspective presents the extent of USD with data from a Canadian Province and a North American institution, explanations for these findings and offers potential solutions to decrease this trend. We describe the economic impact of USD. Findings: There was a significant increase of 46% in overall surgical interventions for USD in Ontario. The incidence rose from 47.0/100,000 in 2002 to 68.7/100,000 population in 2016. In a single United States institution, the overall USD annual unique patient count rose from 10,612 to 17,706 from 2015 to 2019, and the proportion of women with USD was much higher than expected. In the 10-17-year-old patients, 50.1% were girls; with 57.5% in the 18-34 age group and 53.6% in the 35-44 age group. The roles of obesity, diet, hormones, environmental factors, infections, and antibiotics, as well as the economic impact, are discussed. Interpretation: We confirm the significant increase in USD among women. We offer potential explanations for this sex disparity, including microbiological and pathophysiological aspects. We also outline innovative solutions - that may require steps beyond typical preventive and treatment recommendations.

Building a pediatric rare lung disease program: It takes a community of villages.

Pediatric rare lung disease programs are increasing in number due to an increase in recognition of the diseases, increased clinical and research interest in children's interstitial lung disease, and the expansion of the children's interstitial lung disease research network. Due to this increased interest newly graduated trainees in pediatric pulmonology and other physicians are often starting new programs, which can be daunting. We provide some guidance for new programs based on our experiences.

Association between early respiratory viral infections and structural lung disease in infants with cystic fibrosis.

BACKGROUND: Infants with cystic fibrosis (CF) develop structural lung disease early in life, and viral infections are associated with progressive lung disease. We hypothesized that the presence of respiratory viruses would be associated with structural lung disease on computed tomography (CT) of the chest in infants with CF. METHODS: Infants with CF were enrolled before 4 months of age. Multiplex PCR assays were performed on nasal swabs to detect respiratory viruses during routine visits and when symptomatic. Participants underwent CT imaging at approximately 12 months of age. Associations between Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) CT scores and respiratory viruses and symptoms were assessed with Spearman correlation coefficients. RESULTS: Sixty infants were included for analysis. Human rhinovirus was the most common virus detected, on 28% of tested nasal swabs and in 85% of participants. The median (IQR) extent of lung fields that was healthy based on PRAGMA-CF was 98.7 (0.8)%. There were no associations between PRAGMA-CF and age at first virus, or detection of any virus, including rhinovirus, respiratory syncytial virus, or parainfluenza. The extent of airway wall thickening was associated with ever having wheezed (ρ = 0.31, p = 0.02) and number of encounters with cough (ρ = 0.25, p = 0.0495). CONCLUSIONS: Infants with CF had minimal structural lung disease. We did not find an association between respiratory viruses and CT abnormalities. Wheezing and frequency of cough were associated with early structural changes.

Timing of Vaccine Decision-Making Among First-Time Parents.

OBJECTIVE: Decreased childhood vaccination can lead to local outbreaks of vaccine-preventable disease. In a pilot study from our group, 72% of parents of newborns reported initiating their vaccine decision-making for that child prior to conception. Since a sound understanding of the timing of parental vaccine decision-making is needed to direct educational efforts, we surveyed a national cohort of first-time parents to extend our preliminary findings. METHODS: From March 2019 to March 2020, first-time parents of newborns in mother-baby units of the Better Outcomes through Research for Newborns (BORN) network completed the Vaccine Preference Development Survey (VPDS). The VPDS measures intent to vaccinate, timing of vaccine decision-making, and sources of influence. Univariate and multivariate analyses explored associations between intent to vaccinate and timing of vaccine decision-making with demographic variables. RESULTS: Twenty-three sites provided surveys through site-specific nonrandom systemic sampling; 91% (1393/1524) of surveys were used in the analysis. Most parents planned to fully vaccinate (1191/1380, 86.3%) and started vaccine decision-making prior to conception (850/1378, 61.7%). Maternal age, race and ethnicity, relationship status, and education were all significantly associated with planning to fully vaccinate and preconception decision-making (P < .001). Preconception decision-making correlated strongly with intent to fully vaccinate (P < .001). Parents influenced by personal education, medical professionals, and family/friends were more likely to endorse preconception decision-making; those strongly influenced by internet/social media were less likely to allow all vaccines or start decision-making prior to conception. CONCLUSIONS: Vaccine decision-making occurs preconception for most new parents. Initiating vaccine discussions during the birth hospitalization may be too late.

Lung inflammation and simulated airway resistance in infants with cystic fibrosis.

Cystic fibrosis (CF) is characterized by small airway disease; but central airways may also be affected. We hypothesized that airway resistance estimated from computational fluid dynamic (CFD) methodology in infants with CF was higher than controls and that early airway inflammation in infants with CF is associated with airway resistance. Central airway models with a median of 51 bronchial outlets per model (interquartile range 46,56) were created from chest computed tomography scans of 18 infants with CF and 7 controls. Steady state airflow into the trachea was simulated to estimate central airway resistance in each model. Airway resistance was increased in the full airway models of infants with CF versus controls and in models trimmed to 33 bronchi. Airway resistance was associated with markers of inflammation in bronchoalveolar lavage fluid obtained approximately 8 months earlier but not with markers obtained at the same time. In conclusion, airway resistance estimated by CFD modeling is increased in infants with CF compared to controls and may be related to early airway inflammation.

Lung clearance index in children with sickle cell disease.

INTRODUCTION: The lung clearance index (LCI) derived from the multiple breath washout test (MBW), is both feasible and sensitive to early lung disease detection in young children with cystic fibrosis and asthma. The utility of LCI has not been studied in children with sickle cell disease (SCD). We hypothesized that children with SCD, with or without asthma or airway hyperreactivity (AHR), would have an elevated LCI compared to healthy controls. METHODS: Children with SCD from a single center between the ages of 6 and 18 years were studied at baseline health and completed MBW, spirometry, plethysmography and blood was drawn for serum markers. Results were compared to healthy controls of similar race, age, and gender. RESULTS: Healthy controls (n = 35) had a significantly higher daytime oxygen saturation level, weight and body mass index but not height compared to participants with SCD (n = 34). Total lung capacity (TLC) z-scores were significantly higher in the healthy controls compared to those with SCD (0.87 [1.13] vs. 0.02 [1.27]; p = .005) while differences in forced expiratory volume in 1 s z-scores approached significance (0.26 [0.97] vs. -0.22 [1.09]; p = .055). There was no significant difference in LCI between the healthy controls compared to participants with SCD (7.29 [0.72] vs. 7.40 [0.69]; p = .514). CONCLUSION: LCI did not differentiate SCD from healthy controls in children between the ages of 6 and 18 years at baseline health. TLC may be an important pulmonary function measure to follow longitudinally in the pediatric SCD population.

Early respiratory viral infections in infants with cystic fibrosis.

BACKGROUND: Viral infections contribute to morbidity in cystic fibrosis (CF), but the impact of respiratory viruses on the development of airway disease is poorly understood. METHODS: Infants with CF identified by newborn screening were enrolled prior to 4 months of age to participate in a prospective observational study at 4 centers. Clinical data were collected at clinic visits and weekly phone calls. Multiplex PCR assays were performed on nasopharyngeal swabs to detect respiratory viruses during routine visits and when symptomatic. Participants underwent bronchoscopy with bronchoalveolar lavage (BAL) and a subset underwent pulmonary function testing. We present findings through 8.5 months of life. RESULTS: Seventy infants were enrolled, mean age 3.1 ±â€¯0.8 months. Rhinovirus was the most prevalent virus (66%), followed by parainfluenza (19%), and coronavirus (16%). Participants had a median of 1.5 viral positive swabs (range 0-10). Past viral infection was associated with elevated neutrophil concentrations and bacterial isolates in BAL fluid, including recovery of classic CF bacterial pathogens. When antibiotics were prescribed for respiratory-related indications, viruses were identified in 52% of those instances. CONCLUSIONS: Early viral infections were associated with greater neutrophilic inflammation and bacterial pathogens. Early viral infections appear to contribute to initiation of lower airway inflammation in infants with CF. Antibiotics were commonly prescribed in the setting of a viral infection. Future investigations examining longitudinal relationships between viral infections, airway microbiome, and antibiotic use will allow us to elucidate the interplay between these factors in young children with CF.

Anaerobic bacteria cultured from cystic fibrosis airways correlate to milder disease: a multisite study.

Anaerobic and aerobic bacteria were quantitated in respiratory samples across three cystic fibrosis (CF) centres using extended culture methods. Subjects aged 1-69 years who were clinically stable provided sputum (n=200) or bronchoalveolar lavage (n=55). 18 anaerobic and 39 aerobic genera were cultured from 59% and 95% of samples, respectively; 16 out of 57 genera had a ≥5% prevalence across centres.Analyses of microbial communities using co-occurrence networks in sputum samples showed groupings of oral, including anaerobic, bacteria, whereas typical CF pathogens formed distinct entities. Pseudomonas was associated with worse nutrition and F508del genotype, whereas anaerobe prevalence was positively associated with pancreatic sufficiency, better nutrition and better lung function. A higher total anaerobe/total aerobe CFU ratio was associated with pancreatic sufficiency and better nutrition. Subjects grouped by factor analysis who had relative dominance of anaerobes over aerobes had milder disease compared with a Pseudomonas-dominated group with similar proportions of subjects that were homozygous for F508del.In summary, anaerobic bacteria occurred at an early age. In sputum-producing subjects anaerobic bacteria were associated with milder disease, suggesting that targeted eradication of anaerobes may not be warranted in sputum-producing CF subjects.

Initial acquisition and succession of the cystic fibrosis lung microbiome is associated with disease progression in infants and preschool children.

The cystic fibrosis (CF) lung microbiome has been studied in children and adults; however, little is known about its relationship to early disease progression. To better understand the relationship between the lung microbiome and early respiratory disease, we characterized the lower airways microbiome using bronchoalveolar lavage (BAL) samples obtained from clinically stable CF infants and preschoolers who underwent bronchoscopy and chest computed tomography (CT). Cross-sectional samples suggested a progression of the lower airways microbiome with age, beginning with relatively sterile airways in infancy. By age two, bacterial sequences typically associated with the oral cavity dominated lower airways samples in many CF subjects. The presence of an oral-like lower airways microbiome correlated with a significant increase in bacterial density and inflammation. These early changes occurred in many patients, despite the use of antibiotic prophylaxis in our cohort during the first two years of life. The majority of CF subjects older than four harbored a pathogen dominated airway microbiome, which was associated with a further increase in inflammation and the onset of structural lung disease, despite a negligible increase in bacterial density compared to younger patients with an oral-like airway microbiome. Our findings suggest that changes within the CF lower airways microbiome occur during the first years of life and that distinct microbial signatures are associated with the progression of early CF lung disease.

Prospective study of the ARCHITECTHIV Ag/Ab Combo fourth generation assay to detect HIV infection in sexually transmitted infection clinics.

This prospective, cross-sectional study of HIV testing at two sexually transmitted infection clinics compares testing results from the ARCHITECT HIV Ag/Ab Combo fourth generation assay against the current standard of care in North Carolina (third generation enzyme immunoassay testing with western blot confirmation and reflex nucleic acid amplification testing of pooled seronegative samples). In this setting, the assay reported a sensitivity of 100%, a specificity of 99.9%, and a median turn-around time of 26.1 h.