Alarmins and innate lymphoid cells 2 activation: A common pathogenetic link connecting respiratory syncytial virus bronchiolitis and later wheezing/asthma?

Severe respiratory syncytial virus (RSV) infection in infancy is associated with increased risk of recurrent wheezing in childhood. Both acute and long-term alterations in airway functions are thought to be related to inefficient antiviral immune response. The airway epithelium, the first target of RSV, normally acts as an immunological barrier able to elicit an effective immune reaction but may also be programmed to directly promote a Th2 response, independently from Th2 lymphocyte involvement. Recognition of RSV transcripts and viral replication intermediates by bronchial epithelial cells brings about release of TSLP, IL-33, HMGB1, and IL-25, dubbed "alarmins." These epithelial cell-derived proteins are particularly effective in stimulating innate lymphoid cells 2 (ILC2) to release IL-4, IL-5, and IL-13. ILC2, reflect the innate counterparts of Th2 cells and, when activate, are potent promoters of airway inflammation and hyperresponsiveness in RSV bronchiolitis and childhood wheezing/asthma. Long-term epithelial progenitors or persistent epigenetic modifications of the airway epithelium following RSV infection may play a pathogenetic role in the short- and long-term increased susceptibility to obstructive lung diseases in response to RSV in the young. Additionally, ILC2 function may be further regulated by RSV-induced changes in gut microbiota community composition that can be associated with disease severity in infants. A better understanding of the alarmin-ILC interactions in childhood might provide insights into the mechanisms characterizing these immune-mediated diseases and indicate new targets for prevention and therapeutic interventions.

Complicated pneumonia in children.

Complicated community-acquired pneumonia in a previously well child is a severe illness characterised by combinations of local complications (eg, parapneumonic effusion, empyema, necrotising pneumonia, and lung abscess) and systemic complications (eg, bacteraemia, metastatic infection, multiorgan failure, acute respiratory distress syndrome, disseminated intravascular coagulation, and, rarely, death). Complicated community-acquired pneumonia should be suspected in any child with pneumonia not responding to appropriate antibiotic treatment within 48-72 h. Common causative organisms are Streptococcus pneumoniae and Staphylococcus aureus. Patients have initial imaging with chest radiography and ultrasound, which can also be used to assess the lung parenchyma, to identify pleural fluid; CT scanning is not usually indicated. Complicated pneumonia is treated with a prolonged course of intravenous antibiotics, and then oral antibiotics. The initial choice of antibiotic is guided by local microbiological knowledge and by subsequent positive cultures and molecular testing, including on pleural fluid if a drainage procedure is done. Information from pleural space imaging and drainage should guide the decision on whether to administer intrapleural fibrinolytics. Most patients are treated by drainage and more extensive surgery is rarely needed; in any event, in low-income and middle-income countries, resources for extensive surgeries are scarce. The clinical course of complicated community-acquired pneumonia can be prolonged, especially when patients have necrotising pneumonia, but complete recovery is the usual outcome.

Respiratory syncytial virus and airway microbiota - A complex interplay and its reflection on morbidity.

The immunopathology of respiratory syncytial virus (RSV) infection varies considerably, severe disease occurring only in a minority of the affected children. The variability of the clinical presentation is in part explained by viral and environmental factors but, in infants and young children, disease severity is certainly linked to the physiologic immaturity of the innate and adaptive immune system. There is evidence that the maturation of the host immune response is positively influenced by the composition of the nasopharyngeal microbiome that, promoting an efficient reaction, can counteract the predisposition to develop viral respiratory infections and lower the risk of disease severity. However, interaction between the nasopharyngeal microbiota and respiratory viruses can be bidirectional since microbial dysbiosis may also represent a reflection of the disease-induced alterations of the local milieu. Moreover, viruses like RSV can also increase the virulence of potential pathogens in nasopharynx, a main reservoir of bacteria, and therefore promote their spread to the lower airways causing superinfection. Moreover, if negative changes in microbial community composition in early life may constitute a heightened risk toward severe RSV respiratory infection, on the contrary specific groups of microorganisms seem to be associated with protection. A better understanding into the potential negative and positive role of the different nasopharyngeal bacterial species on RSV infection may improve primary prevention and possibly care of this highly contagious disorder.

European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia.

This document provides recommendations for monitoring and treatment of children in whom bronchopulmonary dysplasia (BPD) has been established and who have been discharged from the hospital, or who were >36 weeks of postmenstrual age. The guideline was based on predefined Population, Intervention, Comparison and Outcomes (PICO) questions relevant for clinical care, a systematic review of the literature and assessment of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. After considering the balance of desirable (benefits) and undesirable (burden, adverse effects) consequences of the intervention, the certainty of the evidence, and values, the task force made conditional recommendations for monitoring and treatment of BPD based on very low to low quality of evidence. We suggest monitoring with lung imaging using ionising radiation in a subgroup only, for example severe BPD or recurrent hospitalisations, and monitoring with lung function in all children. We suggest to give individual advice to parents regarding daycare attendance. With regards to treatment, we suggest the use of bronchodilators in a subgroup only, for example asthma-like symptoms, or reversibility in lung function; no treatment with inhaled or systemic corticosteroids; natural weaning of diuretics by the relative decrease in dose with increasing weight gain if diuretics are started in the neonatal period; and treatment with supplemental oxygen with a saturation target range of 90-95%. A multidisciplinary approach for children with established severe BPD after the neonatal period into adulthood is preferable. These recommendations should be considered until new and urgently needed evidence becomes available.

Long-term pulmonary complications in perinatally HIV-infected youth.

BACKGROUND: Increased incidence and prevalence of asthma have been documented for perinatally HIV-infected youth 10 to 21 years of age compared with HIV-exposed uninfected (HEU) youth. OBJECTIVE: We sought to perform objective pulmonary function tests (PFTs) in HIV-infected and HEU youth with and without diagnosed asthma. METHOD: Asthma was determined in 370 participants (218 HIV-infected and 152 HEU participants) by means of chart review and self-report at 13 sites. Interpretable PFTs (188 HIV-infected and 132 HEU participants) were classified as obstructive, restrictive, or normal, and reversibility was determined after bronchodilator inhalation. Values for HIV-1 RNA, CD4 and CD8 T cells, eosinophils, total IgE, allergen-specific IgE, and urinary cotinine were measured. Adjusted prevalence ratios (PRs) of asthma and PFT outcomes were determined for HIV-infected participants relative to HEU participants, controlling for age, race/ethnicity, and sex. RESULTS: Current asthma was identified in 75 (34%) of 218 HIV-infected participants and 38 (25%) of 152 HEU participants (adjusted PR, 1.33; P = .11). The prevalence of obstructive disease did not differ by HIV status. Reversibility was less likely in HIV-infected youth than in HEU youth (17/183 [9%] vs 21/126 [17%]; adjusted PR, 0.47; P = .020) overall and among just those with obstructive PFT results (adjusted PR, 0.46; P = .016). Among HIV-infected youth with current asthma, serum IgE levels were inversely correlated with CD8 T-cell counts and positively correlated with eosinophil counts and not associated with CD4 T-cell counts. HIV-infected youth had lower association of specific IgE levels to several inhalant and food allergens compared with HEU participants and significantly lower CD4/CD8 T-cell ratios (suggesting immune imbalance). CONCLUSION: Compared with HEU youth, HIV-infected youth demonstrated decreased reversibility of obstructive lung disease, which is atypical of asthma. This might indicate an early stage of chronic obstructive pulmonary disease. Follow-up into adulthood is warranted to further define their pulmonary outcomes.

Respiratory syncytial virus-Host interaction in the pathogenesis of bronchiolitis and its impact on respiratory morbidity in later life.

Respiratory syncytial virus (RSV) is the most common agent of severe airway disease in infants and young children. Large epidemiologic studies have demonstrated a clear relationship between RSV infection and subsequent recurrent wheezing and asthma into childhood, thought to be predominantly related to long-term changes in neuroimmune control of airway tone rather than to allergic sensitization. These changes appear to be governed by the severity of the first RSV infection in infancy which in term depends on viral characteristics and load, but perhaps as importantly, on the genetic susceptibility and on the constitutional characteristic of the host. A variety of viral and host factors and their interplay modify the efficiency of the response to infection, including viral replication and the magnitude of structural and functional damage to the respiratory structures, and ultimately the extent, severity, and duration of subsequent wheezing.

Infantile respiratory syncytial virus and human rhinovirus infections: respective role in inception and persistence of wheezing.

There is evidence that respiratory viruses play a key role in the development and exacerbation of obstructive respiratory diseases in children. This review attempts to juxtapose the separate profiles and prototypes of pathogenetic mechanisms represented by the two most common amongst such viruses: respiratory syncytial virus (RSV) and human rhinovirus (HRV). RSV represents the most common agent of severe airway disease in infants and young children, and is predominant in winter months. Large epidemiological studies have revealed an unequivocal relationship between RSV infection and subsequent wheezing into childhood, thought to be related to long-term changes in neuroimmune control of the airways rather than allergic sensitisation. HRV is a highly diverse group of viruses that affect subjects of all ages, is ubiquitous and occurs year-round. In contrast to RSV, infections with HRV cause minimal cytotoxicity but induce a rapid production of cytokines and chemokines with amplification of the inflammatory response. The susceptibility to HRV-induced bronchiolitis and subsequent wheezing appears to be linked to individual predisposition since it is often associated with a family or personal history of asthma/atopy. Thus, RSV probably serves as an "inducer" rather than a "trigger". Conversely, HRVs seem to serve as a "trigger" rather than an "inducer" in predisposed individuals.

Association of lung function, chest radiographs and clinical features in infants with cystic fibrosis.

The optimal strategy for monitoring cystic fibrosis lung disease in infancy remains unclear. Our objective was to describe longitudinal associations between infant pulmonary function tests, chest radiograph scores and other characteristics. Cystic fibrosis patients aged ≤24 months were enrolled in a 10-centre study evaluating infant pulmonary function tests four times over a year. Chest radiographs ∼1 year apart were scored using the Wisconsin and Brasfield systems. Associations of infant pulmonary function tests with clinical characteristics were evaluated with mixed effects models. The 100 participants contributed 246 acceptable flow/volume (forced expiratory volume in 0.5 s (FEV0.5) and forced expiratory flow at 75% of the forced vital capacity (FEF75%)), 303 functional residual capacity measurements and 171 chest radiographs. Both Brasfield and Wisconsin chest radiograph scores worsened significantly over the 1-year interval. Worse Wisconsin chest radiograph scores and Staphylococcus aureus were both associated with hyperinflation (significantly increased functional residual capacity), but not with diminished FEV0.5 or FEF75%. Parent-reported cough was associated with significantly diminished forced expiratory flow at 75% but not with hyperinflation. In this infant cohort in whom we previously reported worsening in average lung function, chest radiograph scores also worsened over a year. The significant associations detected between both Wisconsin chest radiograph score and S. aureus and hyperinflation, as well as between cough and diminished flows, reinforce the ability of infant pulmonary function tests and chest radiographs to detect early cystic fibrosis lung disease.

Increased risk of asthma and atopic dermatitis in perinatally HIV-infected children and adolescents.

The incidence of asthma and atopic dermatitis (AD) was evaluated in HIV-infected (n = 451) compared to HIV-exposed (n = 227) but uninfected (HEU) children and adolescents by abstraction from clinical charts. Asthma was more common in HIV-infected compared to HEU children by clinical diagnosis (25% vs. 20%, p = 0.101), by asthma medication use, (31% vs. 22%, p = 0.012), and by clinical diagnosis and/or medication use, (34% vs. 25%, p = 0.012). HIV-infected children had a greater risk of asthma compared to HEU children (HR = 1.37, 95% CI: 1.01 to 1.86). AD was more common in HIV-infected than HEU children (20% vs. 12%, p = 0.009)) and children with AD were more likely to have asthma in both cohorts (41% vs. 29%, p = 0.010). HIV-infected children and adolescents in this study had an increased incidence of asthma and AD, a finding critical for millions of HIV-infected children worldwide.

Associations of cytokines, sleep patterns, and neurocognitive function in youth with HIV infection.

Youth infected with HIV at birth often have sleep disturbances, neurocognitive deficits, and abnormal psychosocial function which are associated with and possibly resulted from elevated blood cytokine levels that may lead to a decreased quality of life. To identify molecular pathways that might be associated with these disorders, we evaluated 38 HIV-infected and 35 uninfected subjects over 18-months for intracellular cytokine levels, sleep patterns and duration of sleep, and neurodevelopmental abilities. HIV infection was significantly associated with alterations of intracellular pro-inflammatory cytokines (TNF-α, IFN-γ, IL-12), sleep factors (total time asleep and daytime sleep patterns), and neurocognitive factors (parent and patient reported problems with socio-emotional, behavioral, and executive functions; working memory-mental fatigue; verbal memory; and sustained concentration and vigilance. By better defining the relationships between HIV infection, sleep disturbances, and poor psychosocial behavior and neurocognition, it may be possible to provide targeted pharmacologic and procedural interventions to improve these debilitating conditions.

Corticosteroids in the prevention and treatment of infants with bronchopulmonary dysplasia: Part I. systemic corticosteroids.

Bronchopulmonary dysplasia (BPD) is the most significant respiratory complication of prematurity, and its consequences last from birth into adulthood. Unfortunately, the dramatic improvements in the management of premature infants have not led to a decreased incidence of BPD, or to breakthroughs in treatments offered for this long-lasting chronic respiratory disorder. Over recent decades the pathological picture of BPD has changed from inflammation, interstitial fibrosis and emphysema attributed to volu-, barotrauma and oxygen toxicity to larger, simplified alveoli and dysmorphic vessels related to arrested alveolarization and vasculogenesis with inflammation maintaining a central role. Corticosteroids (CSs) play a key role in the development of respiratory epithelial cells and lung maturation. These potent anti-inflammatory agents have long been used for the prevention and treatment of BPD; however, the risk/benefit ratio of their use remains unresolved. CSs administered antenatally have contributed to reduce mortality and respiratory distress syndrome, no such effect on BPD reduction has been observed. Postnatal systemic CSs reduced the rate and severity of BPD, yet their long-term neurodevelopmental and respiratory consequences markedly limit routine administration. This is the first in a two-part State-of-the-Art series that reviews the latest relevant clinical trials investigating the short-term and long-term effects of CSs in the prevention and treatment of BPD.

Corticosteroids in the prevention and treatment of infants with bronchopulmonary dysplasia: Part II. Inhaled corticosteroids alone or in combination with surfactants.

This paper is the second in a two-part State-of-the-Art series that reviews the latest relevant clinical trials investigating the short-term and long-term effects of corticosteroids in the prevention and treatment of bronchopulmonary dysplasia (BPD). Inhaled postnatal corticosteroids demonstrate low systemic bioavailability and rapid systemic clearance with high pulmonary deposition and were expected to reduce the incidence of BPD with reduced adverse effects, however, increased rate of mortality in the neonatal period and at the 18-24 months follow-up was observed. In a milestone study, intratracheal instillation of corticosteroids combined with surfactant decreased the incidence of BPD without increasing the mortality or the long-term neurodevelopmental adverse outcomes. However, subsequent trials using different types of surfactants, different surfactant to budesonide ratio, different time of the drug administration for infants with different severity of respiratory distress syndrome could not reproduce all the beneficial effects. Future perspectives for the identification of premature infants at high risk of BPD and the prevention or treatment of established BPD are discussed.

Genomic heterogeneity underlies multidrug resistance in Pseudomonas aeruginosa: A population-level analysis beyond susceptibility testing.

BACKGROUND: Pseudomonas aeruginosa is a persistent and difficult-to-treat pathogen in many patients, especially those with Cystic Fibrosis (CF). Herein, we describe a longitudinal analysis of a series of multidrug resistant (MDR) P. aeruginosa isolates recovered in a 17-month period, from a young female CF patient who underwent double lung transplantation. Our goal was to understand the genetic basis of the observed resistance phenotypes, establish the genomic population diversity, and define the nature of sequence evolution over time. METHODS: Twenty-two sequential P. aeruginosa isolates were obtained within a 17-month period, before and after a double-lung transplant. At the end of the study period, antimicrobial susceptibility testing, whole genome sequencing (WGS), phylogenetic analyses and RNAseq were performed in order to understand the genetic basis of the observed resistance phenotypes, establish the genomic population diversity, and define the nature of sequence changes over time. RESULTS: The majority of isolates were resistant to almost all tested antibiotics. A phylogenetic reconstruction revealed 3 major clades representing a genotypically and phenotypically heterogeneous population. The pattern of mutation accumulation and variation of gene expression suggested that a group of closely related strains was present in the patient prior to transplantation and continued to change throughout the course of treatment. A trend toward accumulation of mutations over time was observed. Different mutations in the DNA mismatch repair gene mutL consistent with a hypermutator phenotype were observed in two clades. RNAseq performed on 12 representative isolates revealed substantial differences in the expression of genes associated with antibiotic resistance and virulence traits. CONCLUSIONS: The overwhelming current practice in the clinical laboratories setting relies on obtaining a pure culture and reporting the antibiogram from a few isolated colonies to inform therapy decisions. Our analyses revealed significant underlying genomic heterogeneity and unpredictable evolutionary patterns that were independent of prior antibiotic treatment, highlighting the need for comprehensive sampling and population-level analysis when gathering microbiological data in the context of CF P. aeruginosa chronic infection. Our findings challenge the applicability of antimicrobial stewardship programs based on single-isolate resistance profiles for the selection of antibiotic regimens in chronic infections such as CF.

Multicenter evaluation of infant lung function tests as cystic fibrosis clinical trial endpoints.

RATIONALE: The conducting of clinical trials in infants with cystic fibrosis (CF) has been hindered by lack of sensitive outcome measures. OBJECTIVES: To evaluate safety, feasibility, and ability to detect abnormalities in lung function of serial pulmonary function tests (PFTs) in infants with CF. METHODS: Multicenter observational study using a commercial device, rigorous training, ongoing quality control, and over-reading of data by an independent panel. Raised volume rapid thoracoabdominal compression technique and plethysmography were performed at enrollment and at 6 and 12 months, with an additional 1-month reproducibility visit. MEASUREMENTS AND MAIN RESULTS: A total of 342 procedures were performed in 100 infants with CF at 10 centers. FRC measurements were acceptable at a higher proportion of study visits (89%) than raised volume (72%) or fractional lung volume (68%) measurements. Average Z scores for many parameters differed significantly from historical control values. Mean (95% confidence interval) Z scores were: -0.52 (-0.78 to -0.25) for forced expiratory flow at 75% (FEF75) for FVC; 1.92 (1.39-2.45) for FRC; 1.22 (0.68-1.76) for residual volume; 0.87 (0.60-1.13) for FRC/total lung capacity; and 0.66 (0.27-1.06) for residual volume/total lung capacity. For future multicenter clinical trials using infant PFTs as primary endpoints, minimum detectable treatment effects are presented for several sample sizes. CONCLUSIONS: In this 10-center study, key PFT measures were significantly different in infants with CF than in historical control subjects. However, infant PFTs do not yet appear ready as primary efficacy endpoints for multicenter clinical trials, particularly at inexperienced sites, based on acceptability rates, variability, and potentially large sample sizes required to detect reasonable treatment effects.

Pediatric Asthma Attack and Home Paint Exposure.

Although asthma mortality has been declining for the past several decades, asthma morbidity is on the rise, largely due to deteriorating indoor air quality and comorbidities, such as allergies. Consumer products and building materials including paints emit volatile organic compounds (VOCs), such as propylene glycol (PG), which is shown to dehydrate respiratory tracts and can contributor to airway remodeling. We hypothesize that paint exposure increases the risk of asthma attacks among children because high levels of VOCs persist indoors for many weeks after painting. Children 1-15 years old visiting two of the University of Miami general pediatric clinics were screened for their history of asthma and paint exposure by interviewing their parents and/or guardians accompanying them to the clinic. They were also asked questions about asthma diagnosis, severity of asthma and allergies and their sociodemographics. The risk of asthma attack among asthmatic children was modeled with respect to paint exposure adjusting for potential confounders using multivariate logistic regressions. Of 163 children, 36 (22%) reported physician-diagnosed asthma and of these, 13 (33%) had an asthma attack during the last one year. Paint exposure was marginally significant in the univariate analysis (OR = 4.04; 95% CI = 0.90-18.87; p < 0.1). However, exposed asthmatic children were 10 times more likely to experience an asthma attack than unexposed asthmatic children (OR = 10.49; CI = 1.16-94.85, p < 0.05) when adjusted for other risk factors. Given paint is one of the sources of indoor VOCs, multiple strategies are warranted to manage the health effects of VOC exposure from paint, including the use of zero-VOC water-based paint, exposure avoidance and clinical interventions.

Upregulation of neuropeptides and obstructive airway disorder in infancy: A review with focus on post-RSV wheezing and NEHI.

Obstructive airway disorders, common in infancy and early childhood, include some entities that are recognized to have neuro immune mediators as their underlying pathogenetic mechanisms. The best characterized example amongst post-viral wheezing phenotypes is the disorder that follows respiratory syncytial virus (RSV) infection and leads to intermittent, long-term wheezing. The underlying mechanisms of the airway reactivity related to RSV infection have been extensively studies and are associated with dysregulation of the nonadrenergic-noncholinergic (NANC) system, via upregulation of neurotransmitters, typically Substance P. Neuroendocrine hyperplasia of infancy (NEHI), while a less common entity, is a disorder characterized by more severe and long-term obstructive airway disease. NEHI is pathophysiologically characterized by abundance of neuroendocrine cells in the airways containing the neuroimmune mediator bombesin, the release of which is presumed to be the driver of the persistent small airway obstruction and functional air-trapping. Here we review the NANC and neuroendocrine cells, the neurotransmitter systems and their studied roles in pulmonary diseases with a focus on their role in lung development, and subsequent various pediatric lung diseases. We focus on the juxtaposition of the separate neuroimmune mechanisms underlying the pathogenesis of post-RSV recurrent wheezing and NEHI's persistent small airway obstruction. We finally propose a unifying concept of neuropeptides in obstructive disorders that may encompass these two entities and possibly others.

Allergies, Allergic Comorbidities and the Home Environment in Pediatric Asthma in Southern Florida.

Background: Environmental exposure is critical in sensitization to environmental allergens and pediatric asthma morbidity, especially in tropical climates where children are perennially exposed to bioaerosols, such as pollen and mold spores, and endotoxins. Objective: This cross-sectional study examines the association of allergies, associated allergic comorbidities, and the home environment separately and synergistically in pediatric asthma, including in asthma prevalence, severity of asthma, and undiagnosed asthma, in South Florida. Methods: An online survey was administered to the parents of children attending two of the University of Miami pediatric clinics from June to October 2016. Descriptive, factor, and multivariate regression analyses were used to analyze the data. Results: Of 163 children, 22% (36) children had physician-diagnosed asthma; 10% and 32% had allergic rhinitis diagnosis and rhinitis symptoms, respectively, in the past. The allergy diagnosis age was 2.3 years higher than the asthma diagnosis age (p < 0.01). Children with ≥ 2 allergies were 12.8 times more likely to have physician-diagnosed asthma than those without allergies (p < 0.01). Children with allergies and allergic rhinitis were 4.3 (p < 0.05) times more likely to have asthma, and those with asthma were 15 (p < 0.05) times more likely to have an asthma attack than those without known allergies and allergic rhinitis. Conclusion: Allergies and associated comorbidities are risk factors of asthma, asthma persistence, and multiple allergies exacerbate their effects. Early screening for allergies and treatment are warranted to manage asthma. Since the home environment plays an important role in sensitization to allergens, further research is needed to assess home-environment-mediated allergic conditions in the onset and persistence of asthma.

Viral strategies predisposing to respiratory bacterial superinfections.

Acute respiratory infections are amongst the leading causes of childhood morbidity and mortality globally. Viruses are the predominant cause of such infections, but mixed etiologies with bacteria has for decades raised the question of the interplay between them in causality and determination of the outcome of such infections. In this review, we examine recent microbiological, biochemical, and immunological advances that contribute to elucidating the mechanisms by which infections by specific viruses enable bacterial infections in the airway, and exacerbate them. We analyze specific domains in which viruses play such facilitating role including enhancement of bacterial adhesion by unmasking cryptic receptors and upregulation of adhesion proteins, disruption of tight junction integrity favoring paracellular transmigration of bacteria and loss of epithelial barrier integrity, increased availability of nutrient, such as mucins and iron, alteration of innate and adaptive immune responses, and disabling defense against bacteria, and lastly, changes in airway microbiome that render the lung more vulnerable to pathogens. Separate exhaustive analysis of each domain focuses on individuals with cystic fibrosis (CF), in whom viruses may play a key role in paving the way for the primary injury that leads to permanence of bacterial pathogens, viruses may then serve as triggers for "CF exacerbations"; these constituting the signature and ultimately the outcome determinants of these patients.