Hyperpolarized Xenon-129: A New Tool to Assess Pulmonary Physiology in Patients with Pulmonary Fibrosis.

PURPOSE: The existing tools to quantify lung function in interstitial lung diseases have significant limitations. Lung MRI imaging using inhaled hyperpolarized xenon-129 gas (129Xe) as a contrast agent is a new technology for measuring regional lung physiology. We sought to assess the utility of the 129Xe MRI in detecting impaired lung physiology in usual interstitial pneumonia (UIP). MATERIALS AND METHODS: After institutional review board approval and informed consent and in compliance with HIPAA regulations, we performed chest CT, pulmonary function tests (PFTs), and 129Xe MRI in 10 UIP subjects and 10 healthy controls. RESULTS: The 129Xe MRI detected highly heterogeneous abnormalities within individual UIP subjects as compared to controls. Subjects with UIP had markedly impaired ventilation (ventilation defect fraction: UIP: 30 ± 9%; healthy: 21 ± 9%; p = 0.026), a greater amount of 129Xe dissolved in the lung interstitium (tissue-to-gas ratio: UIP: 1.45 ± 0.35%; healthy: 1.10 ± 0.17%; p = 0.014), and impaired 129Xe diffusion into the blood (RBC-to-tissue ratio: UIP: 0.20 ± 0.06; healthy: 0.28 ± 0.05; p = 0.004). Most MRI variables had no correlation with the CT and PFT measurements. The elevated level of 129Xe dissolved in the lung interstitium, in particular, was detectable even in subjects with normal or mildly impaired PFTs, suggesting that this measurement may represent a new method for detecting early fibrosis. CONCLUSION: The hyperpolarized 129Xe MRI was highly sensitive to regional functional changes in subjects with UIP and may represent a new tool for understanding the pathophysiology, monitoring the progression, and assessing the effectiveness of treatment in UIP.

Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination.

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19-vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.

Older age and obesity are associated with increased airway closure in response to methacholine in patients with asthma.

BACKGROUND AND OBJECTIVE: The reduction of forced expiratory volume in 1 s (FEV1 ) in response to methacholine challenge in asthma may reflect two components: airway narrowing, assessed by the change in FEV1 /forced vital capacity (FVC), and airway closure, assessed by the change in FVC. The purpose of this study was to determine the degree and determinants of airway closure in response to methacholine in a large group of asthmatic patients participating in studies conducted by the American Lung Association-Airways Clinical Research Centers (ALA-ACRC). METHODS: We used the methacholine challenge data from participants in five studies of the ALA-ACRC to determine the closing index, defined as the contribution of airway closure to the decrease in FEV1 , and calculated as %ΔFVC/%ΔFEV1 . RESULTS: There were a total of 936 participants with asthma, among whom the median closing index was 0.67 relative to that of a published healthy population of 0.54. A higher closing index was associated with increased age (10-year increments) (0.04, 95% CI = 0.02, 0.05, P < 0.005) and obesity (0.07, 95% CI = 0.03, 0.10, P < 0.001). There was no association between the closing index and asthma control. CONCLUSION: Our findings confirm that airway closure in response to methacholine occurs in a large, diverse population of asthmatic participants, and that increased airway closure is associated with older age and obesity. These findings suggest that therapies targeting airway closure may be important in patients with a high closing index.

Clinical characterization of children with resistant airflow obstruction, a multicenter study.

OBJECTIVE: To characterize a cohort of children with airflow limitation resistant to bronchodilator (BD) therapy. METHODS: Pulmonary function tests performed in children 6-17 years of age at 15 centers in a clinical research consortium were screened for resistant airflow limitation, defined as a post-BD FEV1 and/or an FEV1/FVC less than the lower limits of normal. Demographic and clinical data were analyzed for associations with pulmonary function. RESULTS: 582 children were identified. Median age was 13 years (IQR: 11, 16), 60% were males; 62% were Caucasian, 28% were African-American; 19% were obese; 32% were born prematurely and 21% exposed to second hand smoke. Pulmonary diagnoses included asthma (93%), prior significant pneumonia (28%), and bronchiectasis (5%). 65% reported allergic rhinitis, and 11% chronic sinusitis. Subjects without a history of asthma had significantly lower post-BD FEV1% predicted (p = 0.008). Subjects without allergic rhinitis had lower post-BD FEV1% predicted (p = 0.003). Children with allergic rhinitis, male sex, obesity and Black race had better pulmonary function post-BD. There was lower pulmonary function in children after age 11 years without a history of allergic rhinitis, as compared to those with a history of allergic rhinitis. CONCLUSIONS: The most prevalent diagnosis in children with BD-resistant airflow limitation is asthma. Allergic rhinitis and premature birth are common co-morbidities. Children without a history of asthma, as well as those with asthma but no allergic rhinitis, had lower pulmonary function. Children with BD-resistant airflow limitation may represent a sub-group of children with persistent obstruction and high risk for life-long airway disease.

Measurement characteristics of the childhood Asthma-Control Test and a shortened, child-only version.

The childhood Asthma-Control Test (C-ACT) is validated for assessing asthma control in paediatric asthma. Among children aged 4-11 years, the C-ACT requires the simultaneous presence of both parent and child. There is an unmet need for a tool that can be used to assess asthma control in children when parents or caregivers are not present such as in the school setting. We assessed the psychometric properties and estimated the minimally important difference (MID) of the C-ACT and a modified version, comprising only the child responses (C-ACTc). Asthma patients aged 6-11 years (n=161) from a previously completed multicenter randomised trial were included. Demographic information, spirometry and questionnaire scores were obtained at baseline and during follow-up. Participants or their guardians kept a daily asthma diary. Internal consistency reliabilities of the C-ACT and C-ACTc were 0.76 and 0.67 (Cronbach's α), respectively. Test-retest reliabilities of the C-ACT and C-ACTc were 0.72 and 0.66 (intra-class correlation), respectively. Significant correlations were noted between C-ACT scores and ACQ scores (Spearman's correlation r=-0.56, 95% CI (-0.66, -0.44), P<0.001). The strength of the correlation between C-ACTc scores and ACQ scores was weaker (Spearman's correlation r=-0.46, 95% CI (-0.58, -0.33), P<0.001). We estimated the MID for the C-ACT and C-ACTc to be 2 points and 1 point, respectively. Among asthma patients aged 6-11 years, the C-ACT had good psychometric properties. The psychometric properties of a shortened child-only version (C-ACTc), although acceptable, are not as strong.

Predictors of asthma exacerbation among patients with poorly controlled asthma despite inhaled corticosteroid treatment.

BACKGROUND: Asthma exacerbations are associated with decreased quality of life and increased health care usage. Identification of characteristics that predict increased risk of future exacerbations in patients with suboptimal control of asthma could guide treatment decisions. OBJECTIVE: To examine patient characteristics associated with risk of asthma exacerbations in patients with uncontrolled persistent asthma. METHODS: A retrospective analysis of adults and children with inadequately controlled asthma despite asthma controller therapy and enrolled in 2 randomized trials was conducted. Baseline characteristics of subjects who experienced an asthma exacerbation during the treatment period were compared with those of subjects who did not experience an exacerbation. RESULTS: Of 718 subjects (402 adults and 295 children), 108 adults (27%) and 110 children (37%) experienced an asthma exacerbation during the study period. Unscheduled health care visits for asthma or use of oral corticosteroids in the previous year were significantly associated with asthma exacerbation during the study period (P < .01). Adult subjects who experienced an exacerbation had significantly lower forced expiratory volume in 1 second compared with those who did not (2.3 vs 2.5 L, respectively, P = .02). Children who experienced an exacerbation had lower baseline pre- and post-bronchodilator ratios of forced expiratory volume in 1 second to forced vital capacity (77% vs 81%, P < .01; 82% vs 86%, P < .001, respectively). Symptom scores on validated questionnaires were significantly worse in adults but not in children who developed an exacerbation. CONCLUSION: Spirometric measurements can help identify adults and children at increased risk for asthma exacerbation. Symptom scores could be helpful in identifying adults who are at high risk for exacerbations but could be less helpful in children.

Gastroesophageal reflux disease and childhood asthma.

PURPOSE OF REVIEW: Gastroesophageal reflux disease (GERD) is common in children with asthma and may be present with or without symptoms. Clinicians, influenced by position statements in national guidelines, have routinely treated children with poorly controlled asthma with various anti-GERD medications. This practice is based on the pervasive but unproven belief that GERD is an important determinant of poor asthma control. RECENT FINDINGS: Clinical studies show that GERD is highly prevalent in children with asthma, with estimates as high as 80%, but nearly half of the children are asymptomatic. However, there is no conclusive evidence per se that asymptomatic GERD informs asthma control, and treatment of GERD in the few controlled trials available for review does not substantively improve asthma outcomes. In a recent large controlled clinical trial, treatment with a proton-pump inhibitor (PPI) was not only ineffective, but adverse effects were common, including an increased prevalence of symptomatic respiratory infections. SUMMARY: Current evidence does not support the routine use of anti-GERD medications in the treatment of poorly controlled asthma of childhood. However large controlled trials of children symptomatic of both GERD and asthma have not been conducted, and in this case the benefits of treatment, although unproven, might outweigh the risks.

Asthma outcomes: exacerbations.

BACKGROUND: The goals of asthma treatment include preventing recurrent exacerbations. Yet there is no consensus about the terminology for describing or defining "exacerbation" or about how to characterize an episode's severity. OBJECTIVE: National Institutes of Health institutes and other federal agencies convened an expert group to propose how asthma exacerbation should be assessed as a standardized asthma outcome in future asthma clinical research studies. METHODS: We used comprehensive literature reviews and expert opinion to compile a list of asthma exacerbation outcomes and classified them as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at a National Institutes of Health-organized workshop in March 2010 and finalized in September 2011. RESULTS: No dominant definition of "exacerbation" was found. The most widely used definitions included 3 components, all related to treatment, rather than symptoms: (1) systemic use of corticosteroids, (2) asthma-specific emergency department visits or hospitalizations, and (3) use of short-acting ß-agonists as quick-relief (sometimes referred to as "rescue" or "reliever") medications. CONCLUSIONS: The working group participants propose that the definition of "asthma exacerbation" be "a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome." As core outcomes, they propose inclusion and separate reporting of several essential variables of an exacerbation. Furthermore, they propose the development of a standardized, component-based definition of "exacerbation" with clear thresholds of severity for each component.

Use of flexible bronchoscopy in pediatric patients receiving extracorporeal membrane oxygenation (ECMO) support.

INTRODUCTION: Critically ill children treated with extracorporeal membrane oxygenation (ECMO) support frequently have respiratory complications amenable to evaluation by flexible bronchoscopy (FB). The safety and efficacy of FB in this setting has not been well described in children. METHODS: Retrospective analysis of 153 FBs in 79 children treated with ECMO at a single institution from 2000 to 2008. Demographic data, clinical findings, and complications were obtained. Chest radiographs reports were evaluated prior to and following FB. Physiologic variables were compared prior to and following FB. RESULTS: Seventy-nine patients underwent FB on ECMO [58 veno-venous (VV) and 21 veno-arterial (VA) ECMO], with 153 total FBs performed. Indications for FB included clearance of tenacious airway secretions (n = 118, 77%), or evaluation of suspected secondary infections with bronchoalveolar lavage (n = 26, 17%). Two patients also had surfactant instillation following secretion removal. FB was performed a median 5 days following cannulation for ECMO (range 2-14 days). Most common findings included thick secretions (n = 77, 50.3%), mucoid secretions (n = 15, 9.8%), and mucopurulent secretions (n = 28, 18.3%). No deterioration in radiographic lung findings was described post-FB. FB was not associated with any significant change in heart rate, systemic blood pressure, or temperature. No significant changes in ECMO pump flow rate or sweep gas flow was seen during or after FB. Cannula dislodgement, inadvertent extubation, fever, pneumothorax, or intraprocedural hypoxemia was not reported. Fifty-three FBs (35%) resulted in blood-tinged secretions from the endotracheal tube post-FB, which resolved spontaneously. Three patients received high frequency oscillatory ventilation (HFOV) following FB in association with mild hemorrhage. CONCLUSIONS: FB is a well-tolerated and safe procedure in critically ill pediatric patients on ECMO. FB may have a diagnostic as well as therapeutic benefit in such patients.