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Objective Modifications in residency educational programs are needed to comply with the work-hour limitations introduced by the Accreditation Council for Graduate Medical Education. The objective of this study was to determine the impact of rescheduling critical care didactic sessions on medicine residents' education during their medical intensive care unit (MICU) rotation and on outcomes. Design A pilot program of nonrandomized design. Setting A graduate school of medicine. Patients All patients admitted during the study periods who authorized their medical records to be reviewed. Interventions None. Measurements and main results We instituted a pilot program that replaced the daily traditional 1-hour post-rounds didactic session with an 8:00 am 30-min session, conducted before work rounds, on weekdays from July 2003 through December 2003. The residents' end-of-rotation examination scores were used to assess the impact on education. The pilot period residents' examination results were compared with the examination results from July 2002 through December 2002. To evaluate the effect on patient care, the Acute Physiology Score, Acute Physiology and Chronic Health Evaluation III score, and predicted and observed lengths of MICU and hospital stay of all patients during these two study periods were abstracted and compared. Forty-eight residents were included in each period of the study. The residents' performance on the examination at the end of MICU rotation improved when the didactic session was moved to 8:00 am (67.9 +/- 13.8 vs. 73.9 +/- 12.1; p = .0270). The statistically significant improvement was limited to the first-year residents. There were 751 and 903 patients, respectively, admitted to the MICU during the 2002 and 2003 study periods. There were no significant differences in Acute Physiology Score and Acute Physiology and Chronic Health Evaluation III score between patients admitted during the two study periods. The observed hospital mortality rate was lower during the second period. There were no statistically significant differences in the adjusted length of MICU and hospital stay between the two periods. Conclusion Early morning didactic sessions improve the educational experience of internal medicine residents rotating in the MICU without compromising patient care.

Study objectives: To assess the clinical utility of flexible bronchoscopy (FB) in the evaluation of patients with chronic cough and normal or nonlocalizing chest radiographic findings. Design: Retrospective chart review. Setting: Tertiary referral center. Patients: Forty-eight patients with chronic cough and no other clinical or radiographic indications for FB who underwent the procedure from 1996 to 2001. Results: Before FB, 45 patients had a chest radiograph and 21 patients had a chest CT performed. On visual inspection, 37 of 48 of the FB findings (82%) were normal, 9 were consistent with “bronchitis,” one patient had a “small tracheal plaque,” and one patient had “minimal arytentoid redundancy.” Three of the 27 patients who had a microbiologic assessment performed during their FB demonstrated potentially pathogenic organisms. Antibiotic treatment based on culture data did not result in improvement in cough. Cytologic examination was performed in specimens from 33 patients; 1 patient was noted to have reactive squamous atypia, and the remainder were normal. The patient noted to have minimal arytenoid redundancy and the patient with a tracheal plaque each had another etiology for their cough identified, the treatment of which resulted in cough improvement. Conclusions: FB adds little to the diagnosis of chronic cough in the context of normal or nonlocalizing chest radiographic or CT findings. FB did not result in successful treatment alteration, nor did it contribute to the identification of the cough etiology. (CHEST 2004; 126:268 –272)

Chyloptysis is a rare finding, and the accompanying respiratory symptoms are usually nonspecific. The recognition of the chylous nature of the sputum is requisite for proper diagnosis, especially if chyloptysis is not accompanied by chylous pleural effusion. The key to the differential diagnosis of chyloptysis is to consider illnesses that can induce reflux of chyle into the bronchial tree. There are two mechanisms postulated: the first requires the presence of an abnormal communication between the bronchial tree and the lymphatic channels, and the second requires a bronchopleural fistula in the context of a chylous pleural effusion. Chyloptysis in adults should prompt assessment for evidence of lymphatic obstruction from trauma, radiation, and malignancy, and to exclude diseases with known association with chyloptysis, ie, lymphangioleiomyomatosis, yellow nail syndrome, or thoracic lymphangiectasis. A lymphangiogram is recommended to define the abnormality. In the case of lymphangiectasis, patients respond to either dietary modification and/or ligation of the thoracic duct.

The main goals of asthma therapy are to control symptoms, prevent acute attacks, and maintain lung function as close to normal as possible. Customizing the regimen to relieve the patient's symptoms and control airway inflammation is important. If asthma is not well controlled, an initial inhaled corticosteroid boost will treat the underlying heightened airway inflammation, and the addition of a long-acting beta2-adrenergic agonist or leukotriene receptor antagonist will rapidly control symptoms. Most patients do not require prolonged treatment with expensive combination or additive agents. Exercise-induced bronchoconstriction is a common source of symptoms. Treatments for scheduled and unscheduled exercises differ. Inhaled corticosteroids prevent frequent and severe asthma exacerbations. When patients have persistent symptoms despite a pharmacological regimen, environmental factors and nonpharmacological interventions must be considered before medication is increased. When an inhaled corticosteroid is being considered, issues of compliance, drug delivery device, and proper inhaler techniques are as important as issues of potency, clinical efficacy, and adverse effects. The new hydrofluoroalkane preparations offer more lung deposition and may be important in treating inflammation of the small airways in patients with asthma.

Bronchial thermoplasty (BT) involves the application of radiofrequency energy to visible proximal airways to selectively ablate airway smooth muscle. BT is the first nonpharmacologic interventional therapy approved by the US Food and Drug Administration (FDA) for severe asthma. This approval was based on the results of the pivotal Asthma Intervention Research (AIR)-2 trial, which is the only randomized, double-blind, sham-controlled trial of BT. The primary end point of the AIR-2 trial was improvement in the Asthma Quality of Life Questionnaire (AQLQ). The results of the AIR-2 trial have generated enormous interest, controversy, and confusion regarding the true efficacy of BT for severe asthma. Current marketing of BT highlights its use for patients with "severe" asthma, which is interpreted by most practicing clinicians as meaning oral corticosteroid dependence, frequent exacerbations, or a significantly reduced FEV1 with a poor quality of life. Did the AIR-2 trial include patients with a low FEV1, oral steroid dependence, or frequent exacerbations? Did the trial show efficacy for any of the primary or secondary end points? The FDA approved the device based on the reduction in severe asthma exacerbations. However, were the rates of asthma exacerbations, ED visits, or hospitalizations truly different between the two groups, and was this type of analysis even justified given the original study design? This commentary is designed to specifically answer these questions and help the practicing clinician navigate the thermoplasty literature with confidence and clarity. We carefully dissect the design, conduct, and results of the AIR-2 trial and raise serious questions about the efficacy of bronchial thermoplasty.

Problem The Accreditation Council for Graduate Medical Education emphasizes quality improvement (QI) education in residency/fellowship training programs. The Mayo Clinic Combined Critical Care Fellowship (CCF) program conducted a pilot QI education program to incorporate QI training as a required curriculum for the 2010-2011 academic year. Approach CCF collaborated with the Mayo Quality Academy to customize and teach the existing Mayo Quality Fellows curriculum to the CCF fellows with the help of two quality coaches over five months starting July 2010. All fellows were to achieve Bronze and Silver certification prior to graduation. Silver required passing four written exams and submitting a health care QI project. Five projects were selected on the basis of the Impact-Effort Prioritization matrix, and DMAIC (Define, Measure, Analyze, Improve, and Control) methodology was used to complete the projects. The primary outcome was to assess learners' satisfaction, knowledge, and skill transfer. Outcomes All 20 fellows were Bronze certified, and 14 (70%) were Silver certified by the time of graduation. All five QI projects were completed and showed positive impacts on patient safety and care. Surveys showed improved learner satisfaction. Graduates felt the QI training improved their QI skills and employment and career advancement. The QI curriculum had appropriate content and teaching pace and did not significantly displace other important clinical core curriculum topics. Next steps The pilot was successfully implemented in the CCF program and now is in the fourth academic year as an established and integral part of the fellowship core curriculum.

Temozolomide is an oral alkylating agent recently approved for the treatment of glioblastoma multiforme. It has a favorable side effect profile and is generally well tolerated. Although mild respiratory symptoms have been described, pulmonary toxicity that requires discontinuation of therapy is rare. To our knowledge, this is the first case of temozolomide-associated organizing pneumonitis.

While the eosinophil's effector functions clearly can contribute to the pathogenesis of allergic diseases, the evolutionary benefit to having eosinophils as a distinct class of leukocyte is not clear, especially if one must reconsider the nominally beneficial role of eosinophils in parasite host defense, Eosinophils are equipped to respond to lymphocytes and their cytokines (and not solely the eosinophil growth factor cytokines), but the functional consequences of such eosinophil responses need to be defined. Conversely, eosinophils, as antigen-presenting cells (APCs) or sources of lymphocyte-active cytokines, may stimulate and affect lymphocyte functioning. Eosinophils share with CD4+ lymphocytes expression of a number of receptors, including CD4 and IL-2R, and specific alpha-4 integrins that may help in their common recruitment and activation. Further, elucidation of the interactions between lymphocytes and eosinophils will contribute to a broader understanding of the functioning of eosinophils in "normal" ongoing immune responses and in allergic disorders.

Cough persisting beyond 8 weeks (ie, chronic cough) is one of the most common reasons for an outpatient visit. A protracted cough can negatively affect one's quality of life by causing anxiety, physical discomfort, social isolation, and personal embarrassment. Herein, the anatomy and physiology of the cough reflex are reviewed. Upper airway cough syndrome, asthma, eosinophilic bronchitis, and gastroesophageal reflux disease account for most chronic cough after excluding smoking, angiotensin-converting enzyme inhibitor use, and chronic bronchitis. Many patients have more than one reason for chronic cough. Treating the underlying cause(s) resolves cough in most instances. There are some coughs that seem refractory despite an extensive work-up. The possibility of a hypersensitive cough reflex response has been proposed to explain these cases. Several clinical algorithms to evaluate chronic cough are presented.

The long-term safety of patient-administered nebulized lidocaine for control of chronic cough has not been established.We performed a retrospective study of adults who received a prescription and nurse education for nebulized lidocaine for chronic cough between 2002 and 2007. A survey questionnaire inquiring about adverse reactions and the effectiveness of nebulized lidocaine was developed and administered to these individuals after the nebulized lidocaine trial. We conducted two mailings and a postmailing phone follow-up to nonresponders. When adverse events were reported in the questionnaire response, a structured phone interview was conducted to obtain additional details.Of 165 eligible patients, 99 (60%) responded to the survey. Responders were a median age of 62 years (range, 29-87 years); 77 (79%) were women, and 80 (82%) were white. The median duration of cough was 5 years before treatment with nebulized lidocaine. Of the patients who used nebulized lidocaine (93% of survey responders), 43% reported an adverse event. However, none of these events required an emergency visit, hospitalization, or antibiotic therapy for aspiration pneumonia. The mean (SD) of the pretreatment cough severity score was 8.4 (1.6) and posttreatment was 5.9 (3.4) (Plt; .001). Of the patients reporting improvement in cough symptoms (49%), 80% reported improvement within the first 2 weeks.Adults tolerated self-administration of nebulized lidocaine for difficult-to-control chronic cough. No serious adverse effects occurred while providing symptomatic control in 49% of patients.

To describe how the types of healthcare expenditures for patients with asthma have changed over the past decade.Cross-sectional comparison between individuals from 1996 to 1998 and 2004 to 2006.Expenditures among US individuals (aged 5 to 56 years) with asthma were compared using the 1996 to 1998 and the 2004 to 2006 Medical Expenditure Panel Surveys. Direct expenditures (medications, inpatient, outpatient, and emergency services) and changes in productivity (missed school and work days) were compared over this time frame. The adjusted analyses controlled for age, education level, race/ethnicity, gender, poverty, region, metropolitan statistical area, self-reported health, and Charlson Comorbidity Index.Mean annual per capita healthcare expenditures increased between 1996 to 1998 and 2004 to 2006 ($3802 vs $5322 inflated to 2010 US dollars, P.0001). Annual medication expenditures doubled from $974 to $2010 per person (P.0001) and outpatient visit expenditures increased from $861 to $1174 (P.0001) while hospitalization and emergency department (ED) visit expenditures were similar over the same time period. Missed school and work days decreased between the 2 periods (9.23 days in 1996-1998 vs 6.39 days in 2004-2006, P = .001).An increase in total direct expenditures in individuals with asthma was largely driven by an increase in spending on medications comparing 2004 to 2006 and 1996 to 1998 data. However, this increase was not offset by lower spending on hospitalization and ED visits.

This study tested the ability of an electronic prompt to promote an asthma assessment during primary care visits.We performed a prospective study of all eligible adult patients with previously diagnosed asthma in three geographically distinct ambulatory family medicine clinics within a 4-month period. The usual clinic visit process was performed at two geographically distinct control sites (n = 75 and n = 55 patients, respectively). The intervention group site (n = 64) had an electronic flag embedded in the Patient Check-in Locator field which prompted the distribution of a self-administered Asthma Management Questionnaire (AMQ) in the waiting room. The primary outcome measure was a documented asthma severity assessment.The front desk distributed the AMQ successfully in 100% of possible opportunities and the AMQ was completed by 84% of patients. Providers in the intervention group were significantly more likely than providers in the two non-intervention groups to document asthma severity in the medical record during a non-asthma ambulatory clinic visit (63.3% vs. 18.7% vs. 3.6%; p.001).The provision of standardized asthma information triggered by an electronic prompt at the time of check-in effectively initiates an asthma assessment during the primary care visits.

INSTRUCTIONS Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the instructions listed below: 1. Review the target audience, learning objectives and author disclosures. 2. Complete the pre-test online at www.jacionline.org (click on the Online CME heading). 3. Follow the online instructions to read the full version of the article, including the clinical vignette and review components. 4. Complete the post-test. At this time, you will have earned 1.00 AMA PRA Category 1 CME Credit . 5. Approximately 4 weeks later youwill receive an online assessment regarding your application of this article to your practice. Once you have completed this assessment, you will be eligible to receive Part II MOC credit from the American Board of Allergy and Immunology.

Self-report is the most commonly used method for collecting information regarding asthma medication possession and adherence in clinical practice.To determine the agreement between self-report and pharmacy claims data for asthma medication possession.This is a retrospective study that examined pharmacy claims data 12 months before and after participants completed a structured asthma survey. This study was performed in a sample of health care workers and dependents17 years old in a large, self-insured Midwestern United States health care center. The main outcome measure was agreement (kappa calculation) between self-report and pharmacy claims data of asthma medication possession.Self-report of asthma medication use agreed moderately with pharmacy claims data for short-acting albuterol (κ=0.47 ± 0.03), salmeterol (κ=0.79 ± 0.04), and montelukast (κ=0.69 ± 0.03) but only slightly for inhaled corticosteroids (κ=0.18 ± 0.03) and prednisone (κ=0.10 ± 0.03) (n=1050 respondents). Both under self-reporting and over self-reporting were common with inhaled corticosteroids (14.4% and 23.1%, respectively) and varied significantly by specific drug type.Self-report moderately agrees with asthma medication possession for most adult asthma patients, though the agreement differs considerably between and within asthma medication classes.

A 58-year-old nonsmoker female was referred for evaluation of chronic cough of 13 months duration. After an initial work-up, the patient was diagnosed to have chronic cough due to eosinophilic bronchitis. The diagnostic work-up for eosinophilic bronchitis and bronchial biopsy is discussed. Eosinophilic bronchitis is differentiated from asthma. In addition, the patient developed dyspnea, flushing, and wheezing after the administration of adenosine during a cardiac stress test in spite of a negative methacholine challenge. This indirect stimulus of airway hyperresponsiveness suggests the possible involvement of mast cells in eosinophilic bronchitis.

Written asthma action plans (WAAPs) are recommended by national and international guidelines to help patients recognize and manage asthma exacerbations. Despite this recommendation, many patients with asthma do not have a WAAP. In addition, WAAPs vary widely in their readability and usability. To promote issuance and patient use, the WAAP should clearly define the decision (action) points, expected response, and expected time of response. The WAAP should also be easily integrated into a physician's busy practice. Herein, we describe the key elements of an effective WAAP, including concise, detailed recommendations regarding asthma exacerbation recognition (patient self-monitoring) and treatment.

To test several patient-oriented asthma outcome measures and the Healthcare Effectiveness Data and Information Set (HEDIS) measure of appropriate medication for persistent asthma to determine the most useful quality indicator of asthma care.Prospective mail survey of adult employees and dependents with asthma.The medical and pharmacy claims of all subjects from 12 months before and after the survey were abstracted. Outcomes measures included the Asthma Control Test (ACT), workday loss, unscheduled healthcare utilization (emergency department and inpatient care), and satisfaction with care.Although 81% of all responders had wellcontrolled asthma, persistent asthma was uncontrolled in 28%. Only 64.5% received appropriate controller medication. Well-controlled asthma is associated with a high degree of satisfaction, less workday loss, fewer prednisone bursts, and minimal unscheduled healthcare utilization. Except for a reduced incidence of more than 2 oral corticosteroid dispensings (6.4% vs 13.6%, P = .012), compliance with the HEDIS appropriate medication for asthma was not positively associated with any of the patient-centered outcomes studied.Asthma control was the most useful patient outcome quality indicator in this study. Compliance with the HEDIS asthma measure in this population was not associated with a better patient-oriented outcome. This finding may be different with different levels of asthma control. The positive association between well-controlled asthma and patient satisfaction, minimal unscheduled healthcare utilization, and low workday loss suggests that asthma control as measured by ACT may be a better performance measure in asthma.

The measurement of the fractional concentration of exhaled nitric oxide (FeNO) is a convenient, noninvasive, point-of-service office test for airway inflammation. The first half of this practice management review presents the methodological, interpretative, and clinical applications of FeNO. The second half discusses practical management issues, including current and future technology, equipment specifications, US Food and Drug Administration regulations, cost, current procedural terminology coding, and reimbursement. The measurement of FeNO is helpful in the diagnosis of asthma. It is predictive of a response to inhaled corticosteroids (ICSs). Monitoring FeNO is useful in maintaining asthma control by allowing the assessment of adherence to medication and dose titration of ICSs. An elevated level of FeNO is predictive of asthma relapse following corticosteroid withdrawal especially in children. The advances in technology, ease of use, and clinical utility will lead to greater availability, acceptance, and routine application in the care of asthma.

Temozolomide is an oral alkylating agent recently approved for the treatment of glioblastoma multiforme. It has a favorable side effect profile and is generally well tolerated. Although mild respiratory symptoms have been described, pulmonary toxicity that requires discontinuation of therapy is rare. To our knowledge, this is the first case of temozolomide-associated organizing pneumonitis.

Objective To develop and validate a questionnaire for supraesophageal manifestations of reflux (SER) that will facilitate its study in clinical and research settings. Study design The Supraesophageal Reflux Questionnaire (SERQ) and previously validated Reflux Symptom Index (RSI) were subjected to multiple types of validity testing, including content validity, concurrent validity, reproducibility, and predictive validity. Results The concurrent validity and reproducibility of both instruments was good to excellent for most items tested. The predictive validity of the SERQ was superior to the RSI when it included the covariates of history of sinusitis, use of over-the-counter antacid medications, age, gender, and body mass index. Conclusions The SERQ will serve as both a useful clinical and research tool by offering not only SER symptom information, like the RSI, but also information about the patient’s medical history and medication usage that will facilitate use of the SERQ in research protocols. EBM rating: B-2b

To assess the clinical utility of flexible bronchoscopy (FB) in the evaluation of patients with chronic cough and normal or nonlocalizing chest radiographic findings.Retrospective chart review.Tertiary referral center.Forty-eight patients with chronic cough and no other clinical or radiographic indications for FB who underwent the procedure from 1996 to 2001.Before FB, 45 patients had a chest radiograph and 21 patients had a chest CT performed. On visual inspection, 37 of 48 of the FB findings (82%) were normal, 9 were consistent with "bronchitis," one patient had a "small tracheal plaque," and one patient had "minimal arytentoid redundancy." Three of the 27 patients who had a microbiologic assessment performed during their FB demonstrated potentially pathogenic organisms. Antibiotic treatment based on culture data did not result in improvement in cough. Cytologic examination was performed in specimens from 33 patients; 1 patient was noted to have reactive squamous atypia, and the remainder were normal. The patient noted to have minimal arytenoid redundancy and the patient with a tracheal plaque each had another etiology for their cough identified, the treatment of which resulted in cough improvement.FB adds little to the diagnosis of chronic cough in the context of normal or nonlocalizing chest radiographic or CT findings. FB did not result in successful treatment alteration, nor did it contribute to the identification of the cough etiology.

Mild persistent asthma has greater airway hyperresponsiveness than mild intermittent asthma and may also have more persistent respiratory symptoms and more severe consequences. By other measures, the two conditions are not always easy to differentiate. Nevertheless, primary care physicians need to be able to recognize and treat mild persistent asthma in order to reduce the number of severe exacerbations, and even fatalities, that can occur if it is not properly managed. In this article, Dr Lim discusses how to differentiate mild persistent asthma from mild intermittent asthma and explores the best options for pharmacologic treatment.

Agnogenic myeloid metaplasia (AMM) is one of the myeloproliferative disorders, and is usually accompanied by extramedullary hematopoiesis (EMH) in various organs, mainly in the liver, spleen and lymph nodes. Extramedullary hematopoiesis and/or leukemic transformation of EMH in the pleura is a rare occurrence and is usually asymptomatic. Pleural involvement is usually diagnosed on postmortem examination. Herein we describe a 71-year-old man with newly diagnosed agnogenic myeloid metaplasia who was evaluated for progressively worsening dyspnea, pulmonary hypertension and bilateral pleural effusions. EMH involving the lungs and pleura was suspected. A sulfur colloid technetium 99m bone marrow scan performed to detect extramedullary hematopoiesis was negative. The diagnostic thoracentesis yielded bloody fluid that contained a large population of myeloblasts, indicating pleural leukemic transformation. The patient received 100 cGy to the whole lung for treatment of pulmonary hypertension due to EMH. This was followed by 1500 cGy total dose of radiation to the left lung for pleural extramedullary leukemic transformation. Pleural effusions resolved and repeat echocardiography showed reduction of the pulmonary artery pressure. Three months later he had leukemic transformation involving the skin and lymph nodes. Four months after radiation therapy, he had full-blown acute myeloid leukemia. He received 2 cycles of Gemtuzumab ozogamicin (Mylotarg), allopurinol and hydroxyurea. Three months after initiation of chemotherapy, he deteriorated and received salvage chemotherapy of prednisone, VP-16 and imatinib mesylate (Gleevec). He was hospitalized for neutropenic fever and was diagnosed to have pulmonary aspergillosis. He died of multisystem failure 8 1/2 months after being diagnosed with AMM.

Chyloptysis is a rare finding, and the accompanying respiratory symptoms are usually nonspecific. The recognition of the chylous nature of the sputum is requisite for proper diagnosis, especially if chyloptysis is not accompanied by chylous pleural effusion. The key to the differential diagnosis of chyloptysis is to consider illnesses that can induce reflux of chyle into the bronchial tree. There are two mechanisms postulated: the first requires the presence of an abnormal communication between the bronchial tree and the lymphatic channels, and the second requires a bronchopleural fistula in the context of a chylous pleural effusion. Chyloptysis in adults should prompt assessment for evidence of lymphatic obstruction from trauma, radiation, and malignancy, and to exclude diseases with known association with chyloptysis, ie, lymphangioleiomyomatosis, yellow nail syndrome, or thoracic lymphangiectasis. A lymphangiogram is recommended to define the abnormality. In the case of lymphangiectasis, patients respond to either dietary modification and/or ligation of the thoracic duct.

Objective: We have previously demonstrated that the earliest lymphocyte chemotactic factors present in bronchoalveolar lavage fluid (BALF) of subjects with atopic asthma after subsegmental antigen challenge are IL-16 and MIP-1α, of which IL-16 appears to contribute a majority of the chemotactic activity. Because IL-16 is released in vitro after histamine stimulation of CD8 + T cells and epithelial cells, we evaluated the potential role of histamine in the release of IL-16 into the airways of allergic asthmatics in vivo. Methods: Eight allergic asthmatic subjects, six normal subjects, and six atopic nonasthmatic subjects were challenged with saline in the lingula and with serial concentrations of histamine (1 × 10 -7 to 5 × 10 -5 mol/L) in the right middle lobe followed by bronchoalveolar lavage (BAL) 15 minutes and 6 hours later. Results: The BALF from saline- and histamine-challenged lobes of normal subjects and atopic nonasthmatic subjects contained no significant lymphocyte chemoattractant activity. In six of the eight atopic asthmatic subjects, the histamine-challenged but not saline-challenged segment contained IL-16 chemotactic activity but no other identifiable lymphocyte chemoattractant activities at 6 hours. Conclusions: IL-16 appears in the airways after histamine challenge and therefore could contribute to the earliest infiltration of CD4 + T cells and eosinophils observed after antigen challenge due to histamine release from mast cells. (J Allergy Clin Immunol 1998;101:786-792.)

Interleukin 16 (IL-16) is a chemoattractant immunomodulatory cytokine that initiates its cellular responses through interaction with membrane-expressed CD4. The protein may be detected by a number of methods; the choice of protocol will depend on the ultimate object of a particular experiment. The first method presented is the use of ELISA to measure IL-16 in cell culture supernatants or biological fluids. For some applications, such as identification of IL-16 in an unknown fluid or medium or direct assessment of its bioactivity, functional assays of IL-16-induced responses may be more appropriate. The chemotactic effects of IL-16 on CD4+ T cells and its specific inhibition may be measured using anti-IL-16 antibodies; the same approach may also be applied to monocytes or eosinophils. Another effect of IL-16 is the induction of CD25, which can be assayed using immunological staining. Finally, cell cycle progression in target cells can be measured by the incorporation of radiolabeled thymidine and confirmed by inhibition with neutralizing antibody.

Highly purified eosinophils can be isolated from peripheral blood by negative selection using anti-CD16 immunomagnetic beads. The basic protocol describes a sequential fractionation of peripheral blood in which eosinophils are separated first from mononuclear cells and then from CD16(+) neutrophils. This technique is easy to use, fast, and highly reproducible. A support protocol describes a staining method that can be used to evaluate the purity of eosinphils.

In this study, we have investigated CD40 expression in human peripheral blood eosinophils and in human chronically inflamed nasal tissues, i.e., nasal polyps. We show by both reverse transcriptase-PCR and Northern blot analysis that eosinophils from allergic subjects express human CD40 mRNA. We also show that constitutive CD40 mRNA expression in eosinophils could be upregulated by exposure to IgA immune complexes and downregulated by IL-10 and the synthetic steroid budesonide. In addition, we demonstrate that eosinophils express CD40 protein by flow cytometry. Such expression is biologically functional as cross-linking CD40 with CD40 mAbs enhances eosinophil survival in a dose-dependent fashion; in addition, CD40 ligation stimulates eosinophils to release GM-CSF. CD40-mediated eosinophil survival was largely inhibited by an anti-GM-CSF neutralizing antibody suggesting GM-CSF involvement in the survival enhancing mechanism. CD40 mRNA was also detected in total RNA extracted from nasal polyp tissues but not in RNA isolated from normal nasal mucosa (inferior turbinate); by immunohistochemistry, we were able to detect immunoreactive CD40 protein in a variety of cell types in the polyp stroma, but primarily in eosinophils. These observations suggest previously unforeseen interactions between eosinophils and cells expressing the CD40 ligand and, thus, novel pathways by which eosinophils may contribute to the regulation of airway inflammation.

Publisher Summary This chapter discusses the eosinophil effector mechanism. The presence of eosinophils in asthmatic sputum was reported in 1889, and a positive association between circulating eosinophil levels and asthma was made in 1922. Circumstantial evidence linking eosinophils and asthma began to accrue when eosinophilic infiltration of airways was found to be a regular feature of fatal asthma and of mucosal biopsies obtained from asthmatic patients. The mechanisms by which eosinophils selectively accumulate in areas of allergic inflammation involve interactions via adhesion molecules, eosinophil chemoattractants, and prolonged tissue survival by delaying apoptosis. The effector role of the eosinophil in the pathogenesis of asthma is mediated in part by the release of eosinophil-specific granular proteins. The four principal basic proteins in the secondary granules of the eosinophil are discussed in the chapter. Eosinophils possess a unique array of biological functions. As effector granulocytes, they contribute to the inflammation in asthma by releasing cytotoxic granule proteins, lipid mediators, oxygen free radicals, and cytokines. By these actions, eosinophils are involved in the initiation and perpetuation of airway inflammation in asthma.

We report a case of pancreatitis, which occurred while the patient was on a propofol drip and then recurred after resolution following an inadvertent rechallenge with propofol. The initial episode was associated with hypertriglyceridemia, whereas the latter was not. The association between propofol and pancreatitis is definite and may occur independently of significant hypertriglyceridemia.