Cause Of Exacerbations Research Articles

Aspergillus tracheobronchitis in critically ill patients with chronic obstructive pulmonary diseases

Aspergillus tracheobronchitis (ATB) is considered as an unusual form of invasive aspergillosis and has a fatal outcome. There is little current information on several aspects of chronic obstructive pulmonary diseases (COPD) complicated by ATB, the frequency of which is expected to increase in the coming years. In a prospective study of invasive bronchial-pulmonary aspergillosis (IBPA) in a critically ill COPD population, three proven cases of ATB were identified. The three new cases, combined with eight previously reported cases of COPD with ATB over a 30-year period (1983-2013), were analysed. Among 153 critically ill COPD patients admitted to the ICU, eight cases were complicated by ATB [23.5% of IBPA (8 of 34); and 5.2% of COPD (8 of 153)], and three cases were finally diagnosed as proven ATB by histopathological findings. Among the three new cases reported and the eight published cases, the overall mortality rate was 72.7% (8 of 11 cases), with a median of 11.5 days (range, 7-27 days) between admission to death. The mortality rate was significantly higher in patients with invasive pulmonary aspergillosis (IPA) [100% (8 of 8 patients)] than in patients without parenchyma invasion [0% (0 of 3 patient), P = 0.006]. Seven patients (77.8%) received systemic corticosteroid therapy and three patients (33.3%) inhaled corticosteroids before diagnosis with ATB. Dyspnoea resistant to corticosteroids (77.8%) was the most frequent symptom. The radiological manifestations progressed rapidly in three patients (75%) who had normal chest X-rays (CXRs) at admission. Pseudomembranous lesions were the most frequent form (54.5%) observed by bronchoscopy. Aspergillus fumigatus was the most frequently isolated pathogen (40%). ATB is an uncommon cause of exacerbation in approximately 5% of critically ill COPD patients admitted to the ICU, and may progress rapidly to IPA with a high mortality rate. Dyspnoea resistant to corticosteroids and appropriate antibiotics with a negative CXR should raise the suspicion of ATB. Early diagnosis of ATB is based on bronchoscopic examination and proven diagnosis maybe safely established with a bronchial mucous biopsy.

Th2-Type Cytokine–Induced Mucus Metaplasia Decreases Susceptibility of Human Bronchial Epithelium to Rhinovirus Infection

Human rhinoviruses (RVs) are a major cause of exacerbations in asthma and other chronic airway diseases. A characteristic feature of asthmatic epithelium is goblet cell metaplasia and mucus hypersecretion. Bronchial epithelium is also an important source of lipid mediators, including pro- and antiinflammatory eicosanoids. By using air-liquid interface cultures of airway epithelium from patients with asthma and nonasthmatic control subjects, we compared RV16 replication-induced changes in mRNA expression of asthma candidate genes and eicosanoid production in the epithelium with or without IL-13-induced mucus metaplasia. Mucus metaplastic epithelium was characterized by a 20-fold less effective replication of RV16 and blunted changes in gene expression; this effect was seen to the same extent in patients with asthma and control subjects. We identified ciliary cells as the main target for RV16 by immunofluorescence imaging and demonstrated that the numbers of ciliary cells decreased in RV16-infected epithelium. RV16 infection of mucociliary epithelium resulted in overexpression of genes associated with bronchial remodeling (e.g., MUC5AC, FGF2, and HBEGF), induction of cyclooxygenase-2, and increased secretion of prostaglandins. These responses were similar in both studied groups. These data indicate that structural changes associated with mucus metaplasia renders airway epithelium less susceptible to RV infection. Thus, exacerbations of the lung disease caused by RV may result from severe impairment in mucociliary clearance or activation of immune defense rather than from preferential infection of mucus metaplastic epithelium. Repeated rhinoviral infections of compromised epithelium may contribute to the remodeling of the airways.

Pre-existing human rhinovirus infection modulates host response to secondary bacterial infections

Background Secondary bacterial infections following viral infections of the airways are well documented and are associated with increased severity of respiratory disease compared to virus or bacterial infections alone. Human rhinovirus (HRV) infections are the most common causes of exacerbations in individuals with chronic airways diseases such as asthma and COPD. Moreover, bacterial colonization is commonly found in the airways of patients experiencing exacerbations of these chronic airways diseases and linked to increased severity and duration of these exacerbations. The mechanisms underlying the increased prevalence of secondary bacterial infections and the association with more severe outcomes following viral infections is not known. It has been suggested that viral infection of the airways cause dysregulation of innate host defense mechanisms, such as, impaired antimicrobial peptide expression of the airways. Antimicrobial peptides are key components of the innate immune response after infection and are important in efficient clearance of microbial colonization to prevent infection. We sought to determine whether HRV modulates the innate host defense response to secondary bacterial infections of the airways.

P.12.6 Congenital myasthenic syndromes: Diagnosis difficulties, course and prognosis, and therapy – The French CMS network experience

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. Three different aspects have been investigated by the members of the French CMS network: the difficulties to make a proper diagnosis, the course and long term prognosis, and the response to therapy, especially for the CMS that do not respond to cholinesterase inhibitors. CMS diagnosis was late in most cases due to confusion with other entities: congenital myopathies, due to the frequent myopathic presentation of patients including permanent weakness, atrophy, scoliosis, and biopsy often showing abnormalities of internal structure, diameter and distribution of fibers (type I predominance, type II atrophy); seronegative autoimmune myasthenia gravis when CMS was late onset; metabolic myopathy, with presence of lipidosis in muscle. We studied long term prognosis of CMS in a series of 81 patients recruited with the following mutated genes: CHRNA, CHRNE, DOK7, COLQ, RAPSN, AGRN, MUSK. Course pattern (progressive worsening, exacerbation, stability, improvement) could be variable along the life in one single patient. DOK7 patients had the most severe course with progressive worsening: among the 8 wheel-chair bound and ventilated, 6 were mutated for this gene. Pregnancy was a frequent cause of exacerbation. Anticholinesterase agents are the first line therapy for CMS patients, except for Slow-Channel, COLQ and DOK7. In our experience, 3,4-DAP was a useful complement for several patients harboring CMS with AChR loss CMS or RAPSN gene mutations. Ephedrine was given to 18 patients (8 DOK7, 5 COLQ, 4 AGRN, 1 RAPSN). Tolerance was good. Therapeutic response was encouraging even in the most severely affected patients, particularly with DOK7 and COLQ. Salbutamol was a good alternative in one patient, allergic to Ephedrine.

Chronic Rhinovirus Infection in an Adult with Cystic Fibrosis

Rhinovirus is a common cause of exacerbations of cystic fibrosis (CF) and is usually considered a self-limiting infection. We report a case of chronic infection with rhinovirus A type 33 in a 43-year-old male with CF which has persisted for over 2 years.

Tulobuterol inhibits rhinovirus infection in primary cultures of human tracheal epithelial cells.

A transdermal patch preparation of the β2 agonist tulobuterol has been designed to yield sustained β2 agonistic effects and has been used as a long-acting β2 agonist (LABA) in Japan. LABAs reduce the frequency of exacerbations of chronic obstructive pulmonary disease and bronchial asthma. However, inhibitory effects of LABAs on the replication of rhinovirus (RV), the major cause of exacerbations, have not been demonstrated. To examine the effects of tulobuterol on RV replication and on the production of the replication-induced pro-inflammatory cytokines, human tracheal epithelial cells were infected with a major group RV, type 14 rhinovirus (RV14). Tulobuterol reduced the RV14 titers and RNA levels; the concentrations of cytokines, including interleukin (IL)-1β, IL-6, and IL-8, in the supernatants; and susceptibility to RV14 infection. Tulobuterol reduced the expression of intercellular adhesion molecule-1 (ICAM-1), the receptor for RV14, and the number of acidic endosomes in the cells in which RV14 RNA enters the cytoplasm. Tulobuterol inhibited the activation of nuclear factor kappa B (NF-κB) proteins in nuclear extracts. A selective β2-adrenergic receptor antagonist, ICI 118551 [erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol], reversed the inhibitory effects of tulobuterol on the RV14 titers and RNA levels, the susceptibility to RV14 infection, cytokine production, and ICAM-1 expression. Tulobuterol may inhibit RV replication by reducing ICAM-1 expression and acidic endosomes and modulate airway inflammation during RV replication.

Exacerbation of myasthenia gravis with voriconazole

We describe a patient with stable generalized myasthenia gravis who presented with new onset severe ophthalmoplegia and ptosis after initiation of voriconazole for aspergillosis. Ligand-protein docking software was used to simulate the interaction of voriconazole with the acetylcholine receptor (AChR). We tested voriconazole binding to AChR in comparison to high affinity and neutral compounds. There was no clinical improvement after intravenous immunoglobulin infusion and plasmapheresis. However, the patient improved slowly after withdrawal of voriconazole. Based on our results, voriconazole binds favorably to AChR and may putatively block muscle nicotinic AChRs. Other theoretical explanations include blocking potassium channels and reducing their intracellular trafficking. The mechanisms involved in ocular exacerbation may be multi-factorial, reflecting the intricate dynamics of the neuromuscular junction. It is important to consider medications that harbor pyridine or pyrimidine moieties as potential causes of exacerbation in myasthenic patients, especially those who present with ocular symptoms.

Syndromes myasthéniques congénitaux : difficultés diagnostiques, évolution et pronostic, thérapeutique L’expérience du réseau national « Syndromes Myasthéniques Congénitaux »

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. Three different aspects have been investigated by members of the national French CMS Networ: the difficulties in making a proper diagnosis; the course and long-term prognosis; and the response to therapy, especially for CMS that do not respond to cholinesterase inhibitors. CMS diagnosis is late in most cases because of confusion with other entities such as: congenital myopathies, due to the frequent presentation in patients of myopathies such as permanent muscle weakness, atrophy and scoliosis, and the abnormalities of internal structure, diameter and distribution of fibers (type I predominance, type II atrophy) seen on biopsy; seronegative autoimmune myasthenia gravis, when CMS is of late onset; and metabolic myopathy, with the presence of lipidosis in muscle. The long-term prognosis of CMS was studied in a series of 79 patients recruited with the following gene mutations: CHRNA; CHRNE; DOK7; COLQ; RAPSN; AGRN; and MUSK. Disease-course patterns (progressive worsening, exacerbation, stability, improvement) could be variable throughout life in a given patient. DOK7 patients had the most severe disease course with progressive worsening: of the eight wheelchair-bound and ventilated patients, six had mutations of this gene. Pregnancy was a frequent cause of exacerbation. Anticholinesterase agents are the first-line therapy for CMS patients, except for cases of slow-channel CMS, COLQ and DOK7. In our experience, 3,4-DAP was a useful complement for several patients harboring CMS with AChR loss or RAPSN gene mutations. Ephedrine was given to 18 patients (eight DOK7, five COLQ, four AGRN and one RAPSN). Tolerability was good. Therapeutic responses were encouraging even in the most severely affected patients, particularly with DOK7 and COLQ. Salbutamol was a good alternative in one patient who was allergic to ephedrine.

Rhinovirus has the unique ability to directly activate human T cells in vitro

Rhinovirus infection is a leading cause of exacerbation of airway diseases. We hypothesize that airway viruses activate inflammatory cells, inducing airway dysfunction. We have previously shown that airway viruses can induce eosinophil degranulation when cocultured with T cells and monocyte-derived dendritic cells (moDCs). These findings suggested that antigen presentation was important for T-cell activation. Given the clinical importance of rhinovirus, we sought to determine whether it had any unique abilities to activate inflammatory cells compared with another common virus, such as respiratory syncytial virus (RSV). We cocultured combinations of human leukocytes (T cells, moDCs, and eosinophils) with each virus. Using assays of BrdU incorporation, flow cytometry, and ELISA, we measured T-cell activation, rhinovirus expression, T-cell death, and eosinophil cysteinyl leukotriene release. In contrast to RSV, rhinovirus induced T-cell activation without the involvement of moDCs. Without moDCs, rhinovirus induced T-cell proliferation of both CD4 and CD8(+) cells, cytokine production, and ultimately, eosinophil stimulation. Although chloroquine inhibited RSV-induced activation of T cells through moDCs, rhinovirus was not inhibited; UV inactivation did block the rhinovirus effect. We also found that T cells could be infected by rhinovirus in vitro and within human nasal explant tissue. Although Toll-like receptors did not appear to be involved in T-cell activation, antagonists of Jun N-terminal kinase and nuclear factor κB did inhibit T-cell responses to rhinovirus. Rhinovirus has the unique ability to bypass antigen presentation and directly infect and activate human T cells. This could explain the strong association of rhinovirus with exacerbation of airway diseases.

Rhinovirus-Induced Exacerbations of Asthma and COPD

Over the past two decades, increasing evidence has shown that, in patients with chronic airways disease, viral infection is the most common cause of exacerbation. This review will examine the evidence for viral-induced exacerbations of asthma and chronic obstructive lung disease and the potential mechanisms by which viruses cause exacerbations. Attention will be focused on rhinovirus, the most common cause of respiratory exacerbations. Exacerbations due to rhinovirus, which infects relatively few cells in the airway and does not cause the cytotoxicity of other viruses such as influenza or respiratory syncytial virus, are particularly poorly understood. While the innate immune response likely plays a role in rhinovirus-induced exacerbations, its precise role, either adaptive or maladaptive, is debated. Because current treatment strategies are only partially effective, further research examining the cellular and molecular mechanisms underlying viral-induced exacerbations of chronic airways diseases is warranted.

Significance of sputum purulence to guide antibiotic therapy in exacerbations of COPD

From the authors: We thank D. Aggarwal and co-workers for their interest in our recently published paper regarding a sputum purulence-guided strategy of antibiotic treatment in patients with exacerbations of chronic obstructive pulmonary disease (COPD) requiring hospitalisation [1]. Their comments highlight important issues relating to the discrepancies reported in the literature about the relationship between sputum colour and the presence of pathogenic bacteria in the lower respiratory tract. First, the question of whether isolation of bacteria from the sputum of patients with COPD is or is not directly related to exacerbations is still a subject of controversy. Classically, the Anthonisen criteria ( i.e . increased dyspnoea, sputum production and sputum purulence) have been considered the most reliable predictors of bacterial infection as a cause of exacerbation [2]. Moreover, the most relevant advance in our ability to predict bacterial …

Association of CHI3L1 in African-Americans with Prior History of Asthma Exacerbations and Stress

Rationale. Asthma exacerbations are influenced by multiple factors including environmental exposures, psychosocial interactions, and genetic variations. Aim. To better understand the correlation between clinical, physiologic, genetic, and psychological dimensions in asthma phenotypes and exacerbations. Methods. Supervised cluster analysis of a previously conducted clinical trial of asthma was used to identify subpopulations with differing exacerbation rates in an African-American study population (n = 475). The clusters were characterized by their clinical characteristics and genetic variations. The genetic analysis (n = 322) compared subgroups across 40 different polymorphisms of 10 genes associated with asthma exacerbations. Results. Four clusters were identified with varying annualized rates of exacerbations. Cluster 1 (n = 272) was represented by subjects with a mean age of 25 years and 52% females. In contrast, cluster 4, most divergent from cluster 1, was represented by subjects with the highest rate of asthma exacerbations (1.18 events per year), was mostly female (>80%), with a mean body mass index of 34, and was distinguished by the report of stress and emotions as the cause for prior exacerbations. Lower lung function and increased rescue medication use was also reported in cluster 4. Additionally, genetic analysis revealed a significant difference in distribution of genotypes among the four clusters for rs4950928, a single nucleotide polymorphism (SNP) located in the promoter region of the CHI3L1, the chitinase 3-like 1 gene encoding YKL-40. Conclusions. African-Americans who reported stress and emotions as a primary historical cause of exacerbations had the highest annualized rate of exacerbation. Further, a significant correlation with the genotypes in CHI3L1/YKL-40 was observed in the context of stress and asthma severity.

Serum level of specific IgG antibody for Aspergillus and its association with severity of asthma in asthmatic children

Aspergillosis is one of the frequent causes of exacerbation of asthma depending on the geographical regions. The specific serum IgG level for aspergillus is a major diagnostic criterion in aspergillosis.Ninety-six asthmatic patients, with mean age of 5.4 ± 3.0 years who were referred to the asthma clinic of the Mofid Children's Hospital, were enrolled in this study. Serum specific IgG for aspergillus was measured and its association with severity of asthma was evaluated.Nineteen asthmatic patients (10 females and 9 males) had aspergillus IgG antibody. Among them, severe persistent asthma and moderate persistent asthma were detected in 5 and 13 cases, respectively, whereas only one patient suffered from mildpersistent asthma. A total of 36.5% of the 96 patients had a history of atopy, while 26% had allergic rhinitis. There was an association between the severity of asthma and the presence of aspergillus IgG antibody. Moreover, the positivity for aspergillus IgG antibody was higher in older patients.Our results indicated an association between aspergillus antibody level and severity of asthma. It could be recommended that the IgG titer for aspergillus is measured in pediatric patients with asthma, whereas co-morbidity of aspergillosis and asthma increases the risk of asthma exacerbation.

LPS induced inflammatory responses in human peripheral blood mononuclear cells is mediated through NOX4 and Giα dependent PI-3kinase signalling

COPD is a disease of innate immunity and bacterial infections are a dominant cause of exacerbations in the later stages resulting in poor health and high mortality. The pathogen-associated molecular pattern (PAMP) lipopolysaccharide (LPS) is sensed by immune cells through activation of the toll-like receptor 4 (TLR4). This leads to the activation of NADPH oxidase (NOX) and NF-κB which together drive COPD inflammation. In this study we show in human PBMCs that LPS stimulated proinflammatory cytokine release (CXCL8 and IL6) was inhibited by approximately 50% by the broad specificity phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. Our results also demonstrate that activation of PI3K following LPS stimulation is mediated by a NOX4 dependent mechanism releasing endogenous H2O2, as the NOX4 inhibitor apocynin blocked LPS induced AKT phosphorylation. Moreover, LPS-induced PI3K activation was inhibited by the anti-oxidant N-acetylcysteine in a concentration dependent manner (IC50 ~100 μM). In addition, our data demonstrated that inhibition of small G proteins, by pre-treatment with pertussis toxin, inhibited LPS-induced AKT phosphorylation. Furthermore, the G-protein inhibitors pertussis toxin and mastoparan both inhibited LPS-induced CXCL8 and IL-6 release by approximately 50%. Together, these data indicate there is a mechanism in human PBMCs where TLR4 activation by LPS leads to ROS generation through NOX4 and activation of the PI3K pathway. This effect is apparently mediated through small G proteins facilitating the release of pro-inflammatory cytokines.

Lung microbiology and exacerbations in COPD

Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory condition in adults and is characterized by progressive airflow limitation that is not fully reversible. The main etiological agents linked with COPD are cigarette smoking and biomass exposure but respiratory infection is believed to play a major role in the pathogenesis of both stable COPD and in acute exacerbations. Acute exacerbations are associated with more rapid decline in lung function and impaired quality of life and are the major causes of morbidity and mortality in COPD. Preventing exacerbations is a major therapeutic goal but currently available treatments for exacerbations are not very effective. Historically, bacteria were considered the main infective cause of exacerbations but with the development of new diagnostic techniques, respiratory viruses are also frequently detected in COPD exacerbations. This article aims to provide a state-of-the art review of current knowledge regarding the role of infection in COPD, highlight the areas of ongoing debate and controversy, and outline emerging technologies and therapies that will influence future diagnostic and therapeutic pathways in COPD.

Respiratory Syncytial Virus Persistence in Macrophages Downregulates Intercellular Adhesion Molecule-1 Expression and Reduces Adhesion of Non-Typeable Haemophilus influenzae

Background: Persistence of respiratory syncytial virus (RSV) has been associated with episodes of chronic obstructive pulmonary disease (COPD); furthermore, co-infection of RSV with non-typeable Haemophilus influenzae (NTHi) is increasingly recognized as a cause of exacerbations of COPD. Objective: To study whether RSV persistence in a macrophage (Mφ)-like cell line alters NTHi uptake (adhesion and ingestion). Methods: A murine Mφ-like cell line persistently infected with RSV (MφP) was used. The effects of RSV persistence on NTHi uptake by MφP and mock-infected Mφ (MφN) were determined by flow-cytometric assays with NTHi labelled with either ethidium bromide or FITC. Expression of intercellular adhesion molecule-1 (ICAM-1), a ligand for NTHi, was determined by measuring mRNA through real-time PCR and protein by Western blot assays. Results: RSV persistence reduced both the capacity of Mφ to take up bacteria and the expression of ICAM-1 mRNA and protein. Furthermore, when ICAM-1 was blocked with anti-ICAM-1 antibody, the adhesion capacity of NTHi was significantly reduced for MφN, whereas for MφP the effect was less evident, implying that ICAM-1 participates in NTHi adhesion to Mφ. Conclusion: RSV persistence in murine Mφ diminishes their capacity to adhere and ingest NTHi through downregulation of ICAM-1 expression at the transcriptional level.

Bronchial leiomyoma in a chemical warfare victim—a causative agent or an incidental finding: A case report

INTRODUCTIONBronchial leiomyoma is one of the rarest benign tumors of the lower respiratory system, compromising less than 2% of reported benign pulmonary tumors. Chemical warfare is a known cause of chronic pulmonary diseases in soldiers who survives of the chemical wars. Most of these patients are chronically under treatment by respiratory drugs and acute exacerbations of their symptoms prompt for investigations for diagnosis of a new complication in these patients. PRESENTATION OF CASEIn this case report we present a 43 y/o male chemical warfare victim who was under treatment for his respiratory disease for near 20 years but at last bronchial leiomyoma was diagnosed as the cause of exacerbation of his symptoms. He was undergone right thoracotomy and sleeve resection of left main bronchus. Severe adhesions plus lymphadenitis in the mediastinum might be due to the effects of prior inflammatory process. DISCUSSIONBecause of rarity of this tumor, bronchial leiomyoma in this patient may be the result of previous exposure to nitrogen mustard but the exact relationship remained to be confirmed. CONCLUSIONAlthough the association between chemical warfare and lung neoplasias has not been well understood, it is the first time that a bronchial leiomyoma is reported in a nitrogen mustard survivor.

Factors influencing the length of hospital stay among patients resident in Blackpool admitted with COPD: a cross-sectional study

ObjectivesTo identify the differential effects of patient, health service, temporal and geographic factors on length of stay (LOS) for chronic obstructive pulmonary disease (COPD)-related admissions.DesignWe used stratified Cox proportional hazard...

Enteric viral pathogens in children with inflammatory bowel disease

The causes of exacerbations of inflammatory bowel disease (IBD) are unknown. The presence of RNA of an enterovirus, norovirus GI, norovirus GII, rotavirus, astrovirus, and sapovirus was sought in stool samples of 50 children (median age 12.9 years) undergoing gastrointestinal endoscopies for IBD or its exclusion (Crohn's disease n = 18, ulcerative colitis n = 13, indeterminate colitis n = 2, non-IBD n = 17). Viral RNA was found in three fecal samples (norovirus GII n = 2, sapovirus n = 1), all in children without IBD. Therefore, enteral viruses may play only a minor role in IBD.

Lower Airway Rhinovirus Burden and the Seasonal Risk of Asthma Exacerbation

Most asthma exacerbations are initiated by viral upper respiratory illnesses. It is unclear whether human rhinovirus (HRV)–induced exacerbations are associated with greater viral replication and neutrophilic inflammation compared with HRV colds. To evaluate viral strain and load in a prospective asthma cohort during a natural cold. Adults were enrolled at the first sign of a cold, with daily monitoring of symptoms, medication use, and peak expiratory flow rate until resolution. Serial nasal lavage and induced sputum samples were assessed for viral copy number and inflammatory cell counts. A total of 52 persons with asthma and 14 control subjects without atopy or asthma were studied for over 10 weeks per subject on average; 25 participants developed an asthma exacerbation. Detection of HRVs in the preceding 5 days was the most common attributable exposure related to exacerbation. Compared with other infections, those by a minor group A HRV were 4.4- fold more likely to cause exacerbation (P = 0.038). Overall, sputum neutrophils and the burden of rhinovirus in the lower airway were similar in control subjects without atopy and the asthma group. However, among HRV-infected participants with asthma, exacerbations were associated with greater sputum neutrophil counts (P = 0.005). HRV infection is a frequent cause of exacerbations in adults with asthma and a cold, and there may be group-specific differences in severity of these events. The absence of large differences in viral burden among groups suggests differential lower airway sensitization to the effects of neutrophilic inflammation in the patients having exacerbations.