Mark W. Millard

Active Intestinal Chloride Secretion in Human Carriers of Cystic Fibrosis Mutations: An Evaluation of the Hypothesis That Heterozygotes Have Subnormal Active Intestinal Chloride Secretion

To explain the very high frequency of cystic fibrosis (CF) mutations in most populations of European descent, it has been proposed that CF heterozygotes have a survival advantage when infected with Vibrio cholerae or Escherichia coli, the toxins of which induce diarrhea by stimulation of active intestinal chloride secretion. Two assumptions underlie this hypothesis: (1) chloride conductance by the CF transmembrane conductance regulator (CFTR) is the rate-limiting step for active intestinal chloride secretion at all levels of expression, from approximately zero in patients with CF to normal levels in people who are not carriers of a mutation; and (2) heterozygotes have smaller amounts of functional intestinal CFTR than do people who are not carriers, and heterozygotes therefore secrete less chloride when exposed to secretagogues. The authors used an intestinal perfusion technique to measure in vivo basal and prostaglandin-stimulated jejunal chloride secretion in normal subjects, CF heterozygotes, and patients with CF. Patients with CF had essentially no active chloride secretion in the basal state, and secretion was not stimulated by a prostaglandin analogue. However, CF heterozygotes secreted chloride at the same rate as did people without a CF mutation. If heterozygotes are assumed to have less-than-normal intestinal CFTR function, these results mean that CFTR expression is not rate limiting for active chloride secretion in heterozygotes. The results do not support the theory that the very high frequency of CF mutations is due to a survival advantage that is conferred on heterozygotes who contract diarrheal illnesses mediated by intestinal hypersecretion of chloride.

A randomized controlled trial using the School for anti-inflammatory therapy in asthma

This study investigated the impact of providing low-dose inhaled corticosteroids (ICS) at school or at home to asthmatic inner city children over a 14-week period, compared with the existing community standard. Eight elementary schools in the Dallas Independent School District with a high incidence of asthma located in predominantly urban African-American communities were randomly assigned to one of four groups. The treatment arms were school-based delivery of inhaled steroids, home-based delivery of inhaled steroids, and home-based delivery of inhaled steroids with school-based asthma education, and the control group was no change in current therapy. Fifty students were objectively diagnosed with mild, persistent asthma and participated in the study. Students in the treatment arms received beclomethasone (42 mcg/puff) 4 puffs, twice a day, either at school or at home. Students in the control, “community standard of care” group received no additional medical intervention. Higher peak flows for the treatment groups were seen in the first week and maintained throughout the study (P = .047). By week 5 significant differences were found in frequency of bronchodilator use (P = .025), episodes of nocturnal awakening with asthma symptoms (P = .022), and visits to the primary health care provider (P = .022). Treatment groups rated their asthma as “better than the week before” more frequently than the control group (P = .001). Delivering ICS in school is associated with improved asthma control than when anti-inflammatory medication was delivered to children with asthma in a home-based setting, and both are superior when compared with a control, “community standard of care” group in which no additional medical intervention occurred.

Quality of life and physical performance in land- and water-based pulmonary rehabilitation

PURPOSE: Traditional land-based pulmonary rehabilitation (PR) has been shown to provide improvement in physical performance and quality of life in patients with chronic obstructive pulmonary disease (COPD). The training effects of a water environment in pulmonary patients have only been briefly investigated. The purpose of this retrospective study was to compare quality of life and physical performance in land- and water-based PR. METHODS: The study included participants of a land- or water-based PR program. Twenty land- and water-based participants with stable COPD disease were retrospectively matched within 20 mL of their forced expiratory ventilation in 1 second. A multivariate analysis of variance was performed on each groups 6-minute walk test distance; 6-repetition maximum strength tests for the knee, hip, and shoulder; and mental and physical health summary scores of the Medical Outcomes Short-form 36. RESULTS: Each group significantly improved in all outcome measurements, but there was no difference found in the improvements between the land- or water-based groups. CONCLUSION: Clinicians can consider water-based PR exercise program as another treatment option, if available, for patients with COPD and expect similar benefits to traditional land-based PR programs including improved walk distances, strength, and perception of well-being.

Children With Asthma Miss More School: Fact or Fiction?

BACKGROUND It is widely believed that children with asthma miss considerably more school than children without asthma. Previous surveys have indicated that 49% of children with asthma miss school (Asthma in America, 1998), but only a few studies have attempted to quantify the amount of school missed. Understanding the role of asthma in school attendance will help direct limited health-care resources to the children who need them most. METHODS We investigated school absence rates in fourth- through sixth-grade students in 19 inner-city schools in the Dallas Independent School District (DISD). The sample consisted of 353 students who were identified as possibly having asthma based on responses to a modified Brief Pediatric Screen instrument and who underwent spirometry and/or exercise challenge (EC) testing to confirm the diagnosis of asthma: 25 students were excluded for FEV(1) < 70% and without bronchodilator response, while 157 students had EC-positive test results, and 171 students had EC-negative test results. We compared yearly absences for these students with each other, with all fourth- through sixth-grade students in the 19 study schools, and with all fourth- through sixth-grade students in the district. We also tabulated data from a separate database that included asthma patients identified by the school registered nurse (RN). Absence data by school and by grade level were provided by the school district for the 2002-2003 school year. RESULTS Absence rates were as follows: 2.54% (EC positive), 2.12% (EC negative), 2.59% (abnormal FEV(1)), 2.86% (RN identified), 2.85% (all fourth- through sixth-grade students in study schools), and 2.95% (all fourth- through sixth-grade students in the DISD). CONCLUSION Students with asthma in the DISD miss no more school their classmates without asthma.

Controlling Asthma by Training of Capnometry-Assisted Hypoventilation (CATCH) vs Slow Breathing: A Randomized Controlled Trial

BACKGROUND Hyperventilation has been associated with adverse effects on lung function, symptoms, and well-being in asthma. We examined whether raising end-tidal CO2 levels (ie, Pco2) compared with slow breathing is associated with improvements in asthma control, including peak flow variability. METHODS One hundred twenty patients with asthma were randomly assigned to capnometry-assisted respiratory training (CART) for raising Pco2 or slow breathing and awareness training (SLOW) for slowing respiratory rate. Patients received five weekly sessions and completed bid homework exercises over 4 weeks. Blinded assessments at baseline, posttreatment, 1- and 6-month follow-up of asthma control, Pco2, and diurnal peak flow variability were primary outcome measures. Additionally, we measured pulmonary function (spirometry, forced oscillation, exhaled nitric oxide, and methacholine challenge), symptoms, quality of life, and bronchodilator use. Because the control group received active treatment, we expected improvements in asthma control in both groups but more pronounced benefits from CART. RESULTS Improvements were seen in 17 of 21 clinical indexes (81.0%) in both interventions, including the primary outcome variables asthma control (d = 0.81), peak flow variability (d = 0.54), quality of life, bronchodilator use, lung function, and airway hyperreactivity. Most improvements were sustained across the 6-month follow-up. Compared with slow breathing, CART showed greater increases in Pco2 (d = 1.45 vs 0.64 for CART vs SLOW, respectively) and greater reductions in respiratory impedance during treatment, less distress during methacholine challenge, and greater reduction in asthma symptoms at follow-up (P < .05). CONCLUSIONS Brief interventions aimed at raising Pco2 or slowing respiratory rate provide significant, sustained, and clinically meaningful improvements in asthma control. Raising Pco2 was associated with greater benefits in aspects of lung function and long-term symptoms. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00975273; URL: www.clinicaltrials.gov.

Discrepancies between lung function and asthma control: Asthma perception and association with demographics and anxiety

Understanding asthma symptom perception is necessary for reducing unnecessary costs both for asthma sufferers and society and will contribute to improving asthma management. The primary aim of this study was to develop and test a standardized method for classification of asthma perceiver categories into under-, normal, and overperceiver groups based on the comparison between self-report and lung function components of asthma control. Additionally, the degree to which demographic variables and anxiety contributed to the classification of patients into perceiver groups was examined. Patients underwent methacholine or reversibility testing to confirm asthma diagnosis. Next, participants completed lung function testing over 3 days before their next appointment. Finally, patients filled out demographic and self-report measures including the Asthma Control Test (ACT). Each self-report category of control assessed by the ACT (interference, shortness of breath, nighttime awakenings, rescue inhaler usage, and a composite total score) was compared with lung function measurements using a modified version of the asthma risk grid. Using the modified asthma risk grid to determine perceiver categorization, this sample included 14 underperceivers, 29 normal perceivers, and 36 overperceivers. A discriminant analysis was performed that indicated that a majority of underperceivers were characterized by being African American and having low asthma-specific anxiety. Normal perceivers in this sample tended to be older. Overperceivers tended to be female. Our findings encourage further research using the reported method of classifying asthma patients into perceiver categories.

Impact of the national asthma guidelines on internal medicine primary care and specialty practice

Objective To evaluate documentation of compliance with the National Asthma Education and Prevention Program publication Guidelines for the Diagnosis and Management of Asthma. Design A retrospective review of 114 charts coded as asthma. Fourteen chart evaluation questions were developed based on the 4 management components in the guidelines: assessment and monitoring of asthma, control of asthma factors, pharmacotherapy, and patient education. Setting A hospital-based asthma clinic, a private pulmonary group, and a general internal medicine group in Dallas, Texas. Results Nearly all physicians documented inquiries about daytime asthma symptoms, but only 64% of pulmonary group and 58% of internal medicine physicians documented inquiries about nighttime symptoms. In addition, in 14% of pulmonary group charts and 74% of internal medicine charts, no spirometry or peak flow data were documented. Most asthma clinic and pulmonary group charts (98% and 78%, respectively) included a history of triggers, but the pulmonary group and internal medicine group were more likely to document administration of the influenza vaccine than the asthma clinic (25% and 26% vs 13%). Of 38 patients with ≥1 recorded forced expiratory volume in 1 second <60%, all but 1 were on inhaled steroids. However, many charts lacked adequate documentation to match drug selection to asthma severity. The asthma clinic group documented the 4 educational interventions 65% to 83% of the time, compared with the pulmonary group, at 17% to 50%, and the internal medicine group, at 5% to 18%. Conclusions Results showed significant variation with the recommendations. Areas in particular need of improvement were objective diagnosis and assessment, control of asthma-associated factors, and patient education. Furthermore, the study demonstrated significant variation between specialists and primary care physicians, with the more specialized clinics demonstrating better guideline compliance.

Towards an assessment of perceived COPD exacerbation triggers: Initial development and validation of a questionnaire: COPD exacerbation triggers

Prevention of exacerbations in chronic obstructive pulmonary disease (COPD) is important to decrease overall declines in functioning and improve quality of life. The present study sought to develop a psychometrically valid measure of perceived triggers of exacerbations in COPD patients, the COPD Exacerbation Trigger Inventory (CETI).

Validation of Rules of Two™ as a paradigm for assessing asthma control

Assessing asthma control at each patient encounter is an essential task to determine pharmacologic requirements. Rules of Two (Ro2) was created from the original 1991 National Asthma Education Program guidelines to determine the need for controller therapy. This study determined the degree of agreement between Ro2 and the Expert Panel Report (EPR-3) definition of “in control” asthma and compared that value with the Asthma Control Test (ACT) in a group of asthmatics for the purpose of validating this tool. Patients with documented asthma were randomized to complete Ro2 or ACT prior to being assessed for asthma control by certified asthma educators using an EPR-3 template. Assessments occurred in either a specialty asthma clinic or at a local health fair. Patients were also queried for their personal assessment of asthma control. The primary statistical methodology employed was the degree of agreement (kappa) between each survey tool and the EPR-3 template. Of 150 patients, 72% did not have their asthma in control, based on the EPR-3 template. Ro2 identified 58% of patients not in control of their asthma, whereas ACT identified 36%, with kappa scores of 0.41 for Ro2 and 0.37 for ACT compared with the EPR-3 template. These were not significantly different. Of the 150 patients, 75% considered their asthma in control based on self-assessments, with a kappa of 0.23. In 14 of 73 ACT questionnaires, scores were not added or were misadded. Eliminating evaluation of static lung function significantly improved both kappa scores of Ro2 and ACT. In conclusion, Ro2 identifies patients with uncontrolled asthma as well as ACT and may be useful to the primary assessing clinician in determining asthma control.

Asthmatic granulomatosis as a rare variant of uncontrolled severe asthma

Abstract Asthmatic granulomatosis (AG) is a variant of severe asthma, first described in 2012, that consists of small airway changes compatible with asthma as well as interstitial nonnecrotizing granulomas. Treatment of AG requires immunosuppression as opposed to the traditional asthma therapy of inhaled steroids. We describe a 5-year course of a patient with AG that has shown no improvement with immunosuppression or other standards of therapy.