High economic burden of caring for patients with suspected extraesophageal reflux.

OBJECTIVES: Extraesophageal symptoms are common manifestations of gastroesophageal reflux disease (GERD). Lack of a definitive diagnostic or treatment standards complicate management, which often leads to multiple specialty consultations, procedures, pharmaceuticals and diagnostic tests. The aim of this study was to determine the economic burden associated with extraesophageal reflux (EER). METHODS: Direct costs of evaluation were estimated for patients referred with symptoms attributed to EER between 2007 and 2011. Medicare payment for evaluation and management and pharmaceutical prices was used to calculate first year and overall costs of evaluating and treating extraesophageal symptoms attributed to reflux. RESULTS: Overall, 281 patients were studied (cough (50%), hoarseness (23%), globus/post-nasal drainage (15%), asthma (9%), and sore throat (3%)). Over a median (interquartile range) of 32 (16-46) months follow-up, patients had a mean (95% confidence interval) of 10.1 (9.4-10.9) consultations with specialists and underwent 6.4 (3-9) diagnostic procedures. Overall, the mean initial year direct cost was $5,438 per patient being evaluated for EER. Medical and non-medical components contributed $5,154 and $283. Of the overall cost, 52% were attributable to the use of proton pump inhibitors. During the initial year, direct costs were 5.6 times higher than those reported for typical GERD ($971). A total of 54% of patients reported improvement of symptoms. Overall cost per improved patient was $13,700. CONCLUSIONS: EER contributes substantially to health-care expenditures. In this cohort, the cost for initial year's evaluation and treatment of EER symptoms was quintuple that of typical GERD. Prescription costs and, in particular, proton pump inhibitors were the single greatest contributor to the cost of EER management.

New allergies after cord blood transplantation.

BACKGROUND AIMS: Umbilical cord blood transplantation (CBT) is an effective treatment for benign and malignant diseases. Late effects of CBT are not well described in the literature. In the present study, we present our experience of new-onset allergies in long-term survivors after CBT. METHODS: After an initial patient had a severe peanut allergic reaction after CBT, all CBT patients were prospectively followed for new allergy development. Fifty patients received CBT between March 2006 and June 2011. RESULTS: The median follow-up after CBT was 447 days (range, 12-2022). At the time of analysis, 30 patients were alive, with 3-year survival of 55.5%; median follow-up of surviving patients was 910 days (range, 68-2022). The allergic syndrome developed in five patients, with the cumulative incidence of new allergies at 2 years of 18.4% (95% confidence interval, 10.8-26). The median time to onset of new allergy after transplantation was 298 days (range, 250-809). CONCLUSIONS: Allergy development has been linked to a delayed maturation of the immune system in several studies. We present the first case series of patients who had new allergies after CBT. Further study of this novel complication as well as counseling of patients after CBT would be important.

Nonlinear relationship between body mass index and esophageal acid exposure in the extraesophageal manifestations of reflux.

BACKGROUND & AIMS: Obesity is believed to be an important etiologic factor in gastroesophageal reflux disease. However, it is not clear how obesity might affect esophageal acid exposure in patients with extraesophageal manifestations of reflux. METHODS: We conducted a cross-sectional study of 223 patients with extraesophageal symptoms suspected of being related to reflux. Participants underwent endoscopy and 48-hour wireless pH testing. The percentage of time at a pH of less than 4 (total, upright, and supine) was measured for each patient, and data were compared with corresponding body mass index (BMI), as continuous and categoric variables (normal, 18.5 to <25; overweight, 25 to <30; and obese, >30). Multivariable linear regression was used to identify variables associated with percentage of total time at a pH less than 4. The primary predictor of interest was BMI; age, sex, esophagitis, and hiatal hernia status were considered potential confounders or precision variables. RESULTS: Esophageal acid exposure was associated significantly (P < .001) with BMI. The percentage of time at a pH less than 4 and total symptomatic reflux events increased significantly (P = .005) with increasing BMI. The relationship between percentage of time at a pH less than 4 and BMI was nonlinear and S-shaped. With BMI ranges, the percentage of time at a pH less than 4 increased by 0.23% (normal BMI), 0.75% (overweight), and 0.07% (obese) for every 1-kg/m(2) increase in BMI (P < .001). CONCLUSIONS: Increases in esophageal acid exposure are greatest among overweight patients and plateau in obese patients. The findings have implications for benefit of weight loss in patients with suspected extraesophageal manifestations of gastroesophageal reflux disease.

Symptom reports are not reliable during ambulatory reflux monitoring.

OBJECTIVES: Patient reporting of symptom events during ambulatory reflux monitoring is commonly performed with little data regarding its accuracy. We employed a novel time-synchronized ambulatory audio recording of symptom events simultaneously with prolonged pH/impedance monitoring to assess temporal accuracy of patient-reported symptoms. METHODS: An acoustic monitoring system was employed to detect cough events via tracheal and chest wall sounds and it was temporally synchronized with an ambulatory impedance/pH monitoring system. Patients were instructed to record their symptoms in the usual manner. Six separate observers independently listened to the 24-h audio recordings and logged the exact timing of each cough event. Patients were blinded to study design and the audio reviewers were blinded to their own reports and those of patients and other reviewers. Concurrence of audio recordings and patient-reported symptoms were tested for three separate time thresholds: 1, 2, and 5 min. RESULTS: The median (interquartile range (IQR)) number of cough events by audio detection was significantly (P<0.001) higher than those reported by patients: 216 (90-275) and 34 (22-60), respectively. There was significantly (P<0.001) higher agreement among the audio recording listeners (substantial to almost perfect agreement; kappa=0.77-0.82) than between the audio recording and patient-reported symptoms (slight to fair agreement; kappa=0.13-0.27). Patients did not report 91, 82, and 71% of audible cough events based on 1-, 2-, and 5-min concordance time windows, respectively. CONCLUSIONS: We found that patients do not report the majority of their symptoms during ambulatory reflux monitoring even within a 5-min time window of the true event and advise caution in clinical decision-making based solely on symptom indices.

Caution about overinterpretation of symptom indexes in reflux monitoring for refractory gastroesophageal reflux disease.

BACKGROUND & AIMS: Symptom index (SI) and symptom association probability (SAP) are indexes used to analyze data collected from ambulatory pH and/or impedance monitoring and quantify the association between symptoms and reflux events. However, their characteristics are not well defined. We measured factors that affect SI and SAP values to determine their utility in assessing patients with refractory gastroesophageal reflux disease (GERD). METHODS: We conducted a cross-sectional study of 254 patients with poor responses to proton pump inhibitor (PPI) therapy. Participants underwent esophagogastroduodenoscopy and wireless pH (n = 127) or impedance/pH monitoring when they were not receiving PPI therapy (n = 41) or impedance/pH monitoring while they received twice-daily PPI therapy (n = 86). SI and SAP values were calculated individually; ranges of values for each cell in the 2 × 2 contingency table were determined. Monte Carlo simulation was conducted to determine how varying reflux and symptom rates within the contingency table impacted the expected value and variability in SI and SAP. RESULTS: At best, only 33% of patients who were refractory to PPI therapy had positive SI or SAP scores for acid or nonacid reflux events. Abnormal SAP (>95%) and SI (>50%) scores required high rates of reflux. At reflux rates less than 10%, observed in 70% of the studied population, SI and SAP values were largely determined by chance occurrences, rather than the relationship between symptoms and reflux. The values for each index varied significantly day-to-day. CONCLUSIONS: SI or SAP indexes can be overinterpreted, unless patients with gastroesophageal reflux disease who are refractory to PPI therapy have high rates of reflux.

Proton pump inhibitor therapy improves symptoms in postnasal drainage.

BACKGROUND & AIMS: Gastroesophageal reflux is common among patients with postnasal drainage. We investigated whether proton pump inhibitor therapy improved symptoms in patients with postnasal drainage without sinusitis or allergies. METHODS: In a parallel-group, double-blind, multi-specialty trial, we randomly assigned 75 participants with continued symptoms of chronic postnasal drainage to groups that were given 30 mg of lansoprazole twice daily or placebo. Participants were followed up for 16 weeks. Symptoms were assessed at baseline and after 8 and 16 weeks. Ambulatory pH and impedance monitoring assessed presence of baseline reflux. The primary objective of the study was to determine if acid suppressive therapy improved postnasal drainage symptoms. The secondary objective was to assess if pH and impedance monitoring at baseline predicted response to treatment. RESULTS: Postnasal drainage symptoms improved significantly among patients given lansoprazole compared with placebo. After 8 and 16 weeks, participants given lansoprazole were 3.12-fold (1.28-7.59) and 3.50-fold (1.41-8.67) more likely to respond, respectively, than participants given placebo. After 16 weeks, median (interquartile) percent symptom improvements were 50.0% (10.0%-72.0%) for participants given lansoprazole and 5.0% (0.0%-40.0%) for participants given placebo (P = .006). Neither baseline presence of typical reflux symptoms nor esophageal physiologic parameters predicted response to therapy. CONCLUSIONS: Among participants with chronic postnasal drainage without evidence of sinusitis and allergies, twice-daily therapy with proton pump inhibitors significantly improved symptoms after 8 and 16 weeks. The presence of heartburn, regurgitation, abnormal levels of esophageal acid, or nonacid reflux did not predict response to therapy.

An immunological approach to chronic and recurrent sinusitis.

PURPOSE OF REVIEW: Sinusitis is an illness that is often successfully treated by primary care physicians. Recurrent or chronic rhinosinusitis, however, can be frustrating for patients as well as primary care and subspecialty providers. The present review details the approach to recurrent or chronic sinusitis. We give a broad overview of the workup of chronic rhinosinusitis, focusing on immune deficiency, an often overlooked but clinically important aspect of the sinusitis workup. RECENT FINDINGS: Immune deficiency is prevalent in patients with recurrent or chronic sinus disease. An immunologic workup, as well as a workup for other chronic treatable diseases, should be undertaken before sinus surgery or in patients who have been unresponsive to surgery. This approach can enhance visualization during surgery, minimize postoperative complications, improve surgical outcomes, and possibly obviate the need for surgery altogether. SUMMARY: Elucidating the cause of recurrent or refractory sinus disease can be challenging. Allergic disease should be evaluated and treated early in the process. An immunologic evaluation should be performed and uncommon causes of sinus inflammation should be addressed later in the course to reduce inflammation either to avoid surgery or improve surgical outcomes.

Activation of human mast cells through the high affinity IgG receptor.

Mast cells are known to participate in the induction of inflammation through interaction of antigen with specific IgE bound to the high affinity receptor for IgE (FcepsilonRI). Human mast cells, derived from CD34(+) hematopoietic precursors, not only express FcepsilonRI but also express high affinity receptors for IgG (FcgammaRI), the latter only after IFN-gamma exposure. Human mast cells that express FcgammaRI are activated following FcgammaRI aggregation, either using antibodies directed to the receptor or through IgG bound to the receptor. This activation results in degranulation, with the release of granule-associated mediators, and the generation of metabolites of arachidonic acid and secretion of chemokines and cytokines. These observations provide evidence that human mast cells may also be recruited into inflammation through IgG-dependent mechanisms.

The prostaglandin E agonist, misoprostol, inhibits airway IL-5 production in atopic asthmatics.

BACKGROUND: Prostaglandin E2 is a potent immunomodulator that inhibits the early and late bronchoconstriction to inhaled allergen, as well as inhibiting the acute allergen-induced release of mediators into the human airway. To determine if the stable prostaglandin E agonist misoprostol could alter the late allergic formation of mediators we measured the appearance of eosinophils and key cytokines in the bronchoalveolar lavage fluid 24 h after allergen instillation. METHODS: Six atopic asthmatics underwent bronchoscopy, alveolar lavage and antigen instillation followed 24 h later by bronchoalveolar lavage. Eosinophil counts were done, together with measurements of IL-4, IL-5, eotaxin, RANTES and cysteinyl leukotrienes by immunoassay. The study was done in randomized blinded fashion while the volunteers took placebo or 600 microg of misoprostol four times a day (QID). RESULTS: Misoprostol significantly decreased the appearance of IL-5 late after allergen challenge. Eotaxin levels were reduced, but not statistically significantly. Eosinophil number, RANTES, eosinophil cationic protein and cysteinyl leukotrienes were not altered by misoprostol. CONCLUSIONS: Misoprostol reduces the formation of IL-5 late after allergen challenge, perhaps by inhibiting eosinophil, mast cell, and/or T lymphocyte production of IL-5. Despite decreases in IL-5 and eotaxin, eosinophils were recruited and activated by allergen.

Practical aspects of integrating allergy and pulmonology management into a rhinology practice: the Vanderbilt ASAP experience.

PURPOSE OF REVIEW: In the aftermath of reforms in healthcare laws, there is a focused conversation concerning healthcare delivery with an increasing emphasis on quality, cost containment, improved outcomes and access. Concurrently, providers are experiencing pressure as patient volume escalates yet while funding levels fail to keep pace. Addressing these issues is imperative to the medical practices. In this review, the integration of an allergy and rhinology practice into a center focused on managing chronic airway disease is detailed in the examination of an existing practice. RECENT FINDINGS: In 2010, healthcare spending in the Unites States was nearly US$ 2.6 trillion, 17.9% of the nation's gross domestic product and 10 times 1980 levels. Insurance premiums have increased 113% since 2001 and continue to outpace income gains. Seventy-five percent of spending is attributed to chronic diseases such as stroke, cancer, heart disease, diabetes, Parkinson's disease and Alzheimer's. Airway disease (rhinitis, sinusitis, asthma, chronic obstructive pulmonary disease) is one of the largest chronic disease states. In fact, more patients suffer from airway disease than the aforementioned diseases in total. Any effort to affect costs must include a chronic disease strategy. This review will focus on the nature of the integrated program and its relation to the nature of airway diseases; a detailed description of how it works and why it is different from traditional models. SUMMARY: This integrated model of healthcare will improve the quality of care provided to airway disease patients as well as help contain overall healthcare cost.

The role of impedance monitoring in patients with extraesophageal symptoms.

OBJECTIVES/HYPOTHESIS: Ambulatory esophageal impedance monitoring is commonly employed to assess for nonacid reflux in patients with extraesophageal reflux. We aimed to determine if on therapy impedance data can be predicted from off therapy upper endoscopy, manometry, or pH parameters. STUDY DESIGN: Prospective Cohort Study. METHODS: Patients with extraesophageal reflux symptoms and either partial- or nonresponders to twice-daily PPI underwent impedance monitoring on twice-daily PPI, as well as manometry, upper endoscopy, and 48-hour wireless pH monitoring off acid-suppressive medications for 1 week. Percent time pH < 4 and number of reflux episodes were obtained. Multivariable linear regression was used to determine association between the impedance data on therapy and upper endoscopy, manometry, and pH parameters measured off therapy. RESULTS: Seventy-five patients (77% female, median BMI 29, 38% with hiatal hernia, and 19% with esophagitis) were studied both on and off therapy. Thirty-five percent had abnormal impedance monitoring on therapy and 84% had abnormal pH testing off therapy. There was no significant (P = 0.184) overall correlation between total number of impedance events and the baseline physiologic parameters of hiatal hernia, degree of acid reflux, or manometric findings, with only weak correlation (r = 0.54, P = 0.045) with % time pH < 4 among patients with esophagitis. CONCLUSIONS: In patients with suspected extraesophageal reflux refractory to PPI therapy, impedance measures on therapy cannot be predicted from traditional baseline esophageal physiologic parameters. We recommend caution regarding over-interpretation of impedance data. LEVEL OF EVIDENCE: 2b.

Feasibility of dual wireless esophageal pH monitoring: randomized blinded sham-controlled trial.

OBJECTIVE: Wireless pH monitoring is currently employed in the distal esophagus. There are no controlled studies on the feasibility/safety of proximal esophageal wireless pH capsule placement. We tested the hypothesis that there will be no difference in patient perception of a more proximally placed pH capsule. STUDY DESIGN: Randomized single-blinded sham-controlled trial. SETTING: Tertiary care center. SUBJECTS AND METHODS: All patients had a wireless pH capsule positioned 6 cm proximal to the gastroesophageal junction. They were randomized into intervention or sham groups after distal capsule placement. The delivery introducer was positioned 10 cm proximal to the distal esophageal capsule, and a second capsule was either deployed (intervention) or not (sham) based on group allocation. Patients were blinded to group assignment. Modified Edmonton Score was used to assess for chest pain, dysphagia, and odynophagia. The primary endpoints were (1) required endoscopic removal because of discomfort and (2) change in chest pain scores, controlling for baseline pain. RESULTS: Patients were randomized to either the intervention, proximal esophageal capsule (n = 11), or sham (n = 11). Patients with proximal pH probes had higher odds of having their chest pain (odds ratio [OR], 8.44; 95% confidence interval [CI], 1.35-52.6; P = .02), odynophagia (OR, 49.5; 95% CI, 4.70-520; P = .001), and dysphagia (OR, 14.3; 95% CI, 2.12-96.6; P = .006) exacerbated. Two (2/11; 18%) proximally deployed probes required endoscopic removal because of patient intolerance or discomfort. CONCLUSION: A proximal esophageal wireless pH monitor placement is feasible but results in increased chest pain, odynophagia, and dysphagia that can be severe enough to require endoscopic removal. These limitations preclude its potential clinical benefit.

Traditional reflux parameters and not impedance monitoring predict outcome after fundoplication in extraesophageal reflux.

OBJECTIVES/HYPOTHESIS: Fundoplication is considered in patients with refractory extraesophageal reflux symptoms. However, postoperative symptom resolution is inconsistent. This analysis investigates which presenting symptoms and preoperative objective parameters predict postoperative symptom improvement. STUDY DESIGN: Retrospective cohort study. METHODS: A total of 237 patients referred for extraesophageal reflux symptoms refractory to medical therapy underwent esophageal function testing. Fundoplication was performed in 27 patients with objective evidence of gastroesophageal reflux disease. Symptomatic improvement was assessed at postoperative intervals. Logistic regression determined which symptoms and objective parameters predicted improvement of the presenting extraesophageal reflux symptom. RESULTS: Overall, 59% of patients reported at least partial improvement of their presenting extraesophageal symptom after fundoplication. Predictors of symptomatic improvement were the presence of heartburn with or without regurgitation concomitant to their primary presenting symptom (odds ratio [OR], 6.6; 95% confidence interval [CI], 0.97-44.9; P = .05) and pH < 4 more than 12% of a 24-hour period (OR, 10.5; 95% CI, 1.36-81.1; P = .02). Probability of postoperative extraesophageal reflux symptom improvement was 90% if both conditions were present. CONCLUSIONS: Both heartburn with or without regurgitation and esophageal pH < 4 more than 12% of a 24-hour period predicted postfundoplication resolution of the presenting extraesophageal reflux symptom.

Impact of chronic rhinosinusitis on work productivity through one-year follow-up after balloon dilation of the ethmoid infundibulum.

BACKGROUND: Although multiple clinical trials have demonstrated that balloon dilation of sinus ostia in patients diagnosed with chronic rhinosinusitis (CRS) results in sustained symptomatic improvement, less data are available to measure the effects of sinusitis on worker productivity. The objective of our research was to analyze work and activity impairment before and after transantral, endoscopically-guided balloon dilation of the maxillary sinus ostia and ethmoid infundibulum. METHODS: Subjects diagnosed with CRS and computed tomography (CT) evidence of disease in the maxillary sinuses alone, or maxillary and anterior ethmoid sinuses, completed the Work Productivity and Activity Impairment (WPAI) questionnaire and the Work Limitation Questionnaire (WLQ) before treatment and at 3, 6, and 12 months postprocedure. RESULTS: A total of 56 subjects were enrolled and 53 completed the 1-year follow-up. The lost productivity composite score computed from the WLQ improved by 73% (9.0 to 2.4; p < 0.0001) at 1-year follow-up whereas lost productivity at work as measured by the WPAI improved by approximately 76% (38.3 to 9.2; p < 0.0001) 12 months after treatment. CONCLUSION: These results indicate that sinus-related health problems impose a substantial burden on work productivity and physical/mental activity levels. Treatment of CRS by dilating the maxillary sinus ostium and ethmoid infundibulum can significantly improve quality of life (QOL) and work productivity.

Soluble CD23 and interleukin-1 receptor antagonist in human asthmatics following antigen challenge.

Two postulated intrinsic anti-inflammatory mechanisms in asthma include the low affinity IgE receptor, or CD23, and interleukin 1 receptor antagonist (IL-1ra). We investigated the role these mediators play in the asthmatic response by measuring local levels in human asthmatics before and after segmental allergen challenge and examined the effect of inhaled corticosteroids on soluble CD23 and IL-1ra levels. Ten subjects underwent bronchoscopy at baseline and 24 hours after antigen challenge. Prior to challenge and every 12 hours afterward subjects received beclomethasone 252 microg or placebo. Fluid was analyzed for sCD23 and IL-1ra using ELISA immunoassays. Eosinophil percentages significantly increased at 24 hours following antigen challenge. sCD23 levels were generally undetectable at baseline and increased significantly following antigen challenge. IL-1ra levels increased 28-fold in the late-phase response. Beclomethasone significantly reduced the late-phase eosinophil percentage at 24 hours compared with placebo but did not attenuate late-phase sCD23 or IL-1ra levels. Our data showed a significant rise in the levels of two mediators thought to play an important role in the attenuation of the asthmatic response. The finding that steroid treatment did not enhance these levels suggests that this may be an independent approach to asthma therapy that should be investigated.

Topical pimecrolimus in the treatment of human allergic contact dermatitis.

BACKGROUND: Contact dermatitis is a common clinical problem, with prevalent sensitizers being cosmetics, metals, medicines, and plants. Plants of the Toxicodendron species cause allergic contact dermatitis (ACD) in 50% to 70% of the population. Pimecrolimus is an ascomycin macrolactam developed for the treatment of inflammatory skin diseases and approved by the US Food and Drug Administration for atopic dermatitis. There are studies supporting the effectiveness of macrolactams when administered before antigen challenge, but there are no studies describing the effectiveness of these drugs in the treatment of established human ACD. OBJECTIVE: To investigate the effect of topical pimecrolimus in the treatment of Toxicodendron-induced ACD once rash is evident. METHODS: Poison ivy tincture was applied to the bilateral anterior forearms of 12 subjects with Finn Chambers (Allerderm Diagnostic Products, Petaluma, CA). After dermatitis was evident, volunteers treated each arm twice daily with either 1% topical pimecrolimus cream or placebo in a blinded fashion. Outcomes measured were a dermatitis grading score and time to rash and itch resolution. RESULTS: The median +/- SEM time for rash resolution was 16.55 +/- 1.59 days in the treatment group and 16.27 +/- 1.82 days in the placebo group (P = 0.601). The median time for itch resolution was 4.73 +/- 1.56 days in the treatment group and 4.91 +/- 1.59 days in the placebo group (P = 0.167). The average dermatitis score was 2.26 +/- 0.17 in the treatment group and 2.32 +/- 0.15 in the placebo group (P = 0.62). CONCLUSIONS: The application of topical pimecrolimus is ineffective in the treatment of ongoing Toxicodendron-induced ACD.