How do we improve patient compliance and adherence to long-term statin therapy?

Statins are highly effective drugs prescribed to millions of people to lower LDL-cholesterol and decrease cardiovascular risk. The benefits of statin therapy seen in randomized clinical trials will only be replicated in real-life if patients adhere to the prescribed treatment regimen. But, about half of patients discontinue statin therapy within the first year, and adherence decreases with time. Patient, physician and healthcare system-related factors play a role in this problem. Recent studies have focused more on the patients' perspectives on non-adherence. Adverse events are cited as the most common cause of statin discontinuation; thus, the healthcare provider must be willing to ally and dialogue with patients to address concerns and assess the risks and benefits of continued statin therapy.

Gene expression signatures: a new approach to understanding the pathophysiology of chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a complex inflammatory disease with variable disease manifestation. Though external risk factors are associated with development and/or persistence of CRS, the host mucosal response is also important, as nasal epithelium acts as a physical and immune barrier. Under inflammatory stress, the nasal epithelium can undergo injury, followed by a rapid remodeling response ranging from epithelial hyperplasia, to goblet-cell metaplasia, to denudation, loss of cilia, fibrosis, and basement membrane thickening. Identification of gene expression signatures and molecular pathways in CRS pathogenesis have now begun to contribute significantly to a better understanding of the genetic and molecular alterations underlying CRS development and progression. Genetic studies are especially illuminating when multiple gene variants synergize within a permissive environmental context, and are expected to guide development of more effective therapeutic targets for CRS treatment.

Intradermal Testing Doubles Identification of Allergy among 110 Immunotherapy-Responsive Patients with Eustachian Tube Dysfunction.

The purpose of this study was to determine whether the sensitivity advantage of intradermal dilutional testing (IDT) is clinically relevant in patients with obstructive Eustachian tube dysfunction (ETD) or otitis media with effusion (OME). This retrospective, private-practice cohort study compared the sensitivity of skin prick tests (SPT) vs. IDT in 110 adults and children with suspected allergy and OME. Primary outcome measure was symptom resolution from allergy immunotherapy (AIT). IDT identified 57% more patients as being allergic, and 8.6 times more reactive allergens than would have been diagnosed using only SPT. Patients diagnosed by IDT had the same degree of symptom improvement from immunotherapy, independent of allergen sensitivity (66% by SPT vs. 63% by IDT; p = 0.69, not different). Low-sensitivity allergy tests, which may fail to identify allergy in over two thirds of children aged 3 to 15 as being atopic, or among 60% of patients with ETD, may explain why many physicians do not consider allergy as a treatable etiology for their patient's OME/ETD. IDT offers superior sensitivity over SPT for detecting allergens clinically relevant to treating OME/ETD. These data strongly support increased utilization of intradermal testing and invite additional clinical outcome studies.

Burden of allergic rhinitis: results from the Pediatric Allergies in America survey.

Allergic rhinitis (AR), a chronic inflammatory disease of the upper airway, is one of the most common chronic diseases in the United States and is estimated to affect up to 60 million people. Pediatric Allergies in America is the largest and most comprehensive survey to date of pediatric patients and parents of patients with allergy, as well as health care providers (HCPs), regarding AR in children and its treatment. The goals of the survey were to determine the prevalence of AR in the US pediatric population and to collect information on what effect the condition has on patients in terms of symptom burden, quality of life, productivity, disease management, and pharmacologic treatment. This national survey screened 35,757 households to identify 500 children with HCP-diagnosed nasal allergies and 504 children without nasal allergies who were between the ages of 4 and 17 years. Parents of young children, as well as children 10 to 17 years of age, were questioned about the condition and its treatment. In parallel, 501 HCPs were interviewed. This survey has captured previously unavailable data on the prevalence of nasal allergies and their most common and most bothersome symptoms, on the effect of nasal allergies on the quality of life of children, and on medication use, including both over-the-counter and prescription medications, and has identified factors affecting satisfaction with treatment. The Pediatric Allergies in America survey also identifies distinct areas for improvement in the management of AR in children. In fact, based on the results of this survey, it appears that HCPs overestimate patients' and parents' satisfaction with disease management and the benefit of medications used for the treatment of nasal allergies in children. Findings from this national survey have identified important challenges to the management of AR, suggesting that its burden on children in the United States has been significantly underestimated.

Asthma history and presentation.

Asthma is suspected from a history of key symptoms, including cough, wheezing, dyspnea, chest tightness, and increased mucus production. A positive family or personal history of atopic diseases and diseases that are comorbid with asthma, such as allergic rhinitis and rhinosinusitis, is also important. The differential diagnosis of asthma is broad and includes potentially life-threatening diseases. Pediatric asthma and psychiatric mimics require special attention to prevent misdiagnosis. Differentiating asthma from these other disease states by history alone is not always possible. Because accurate diagnosis is critical to successful treatment, objective testing by spirometry and methacholine challenge should be employed.

Potential non-immunoglobulin E-mediated food allergies: comparison of open challenge and double-blind placebo-controlled food challenge.

OBJECTIVE: Comparison of open food challenge (OFC) with double-blind placebo-controlled food challenge (DBPCFC). STUDY DESIGN: Prospective sequential randomized challenges. METHODS: Twenty adults with chronic allergy symptoms and at least 1 positive intradermal food wheal response recorded symptoms during DBPCFC and OFC provoked using organic foods, normal portions, and normal food preparation. Acoustic Rhinometry and biochemical tests were done during DBPCFC. RESULTS: All patients reacted to at least 1 food and to all challenges with the same food, with multiorgan symptoms in the nose, nervous system, throat, and lung. There was a correlation in the type and severity of symptoms (P = 0.015) for OFC and DBPCFC, and both were significantly (P < 0.01) more severe than placebo. Compared with DBPCFC, OFC sensitivity was 66%, and positive predictive value was 89%. CONCLUSION: This is the first study showing both concordance of OFC and DBPCFC and also that intradermal tests can identify reactive foods that can be verified by DBPCFC. Because most tests for IgE-mediated food allergy were negative, observed reactions were probably non-IgE mediated.

Elevated soluble tumor necrosis factor receptor levels in non-obese adults with the atherogenic dyslipoproteinemia.

Adipose tissue expression of tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of obesity-linked insulin resistance and the dyslipoproteinemia of insulin resistance. This study has two aims: (1) to compare select inflammatory mediators in non-smoking, normoglycemic male subjects with and without the atherogenic dyslipoproteinemia (ADL), and (2) to determine the effects of statin therapy on select inflammatory mediators. ADL subjects had higher levels of insulin (16.7 +/- 7.5 versus 11.6 +/- 5.9 microIU/mL, P=0.008), soluble TNF receptor superfamily 1B (sTNFRSF1B) (3.3 +/- 0.7 versus 2.7 +/- 0.5 ng/mL, P=0.005), and interleukin-6 (IL-6) (2.6 +/- 2.2 versus 1.3 +/- 1.8 pg/mL, P=0.006) as compared to those of the non-ADL subjects. After adjustment for age, sTNFRSF1B (P=0.003) was more predictive of ADL than high-sensitivity C-reactive protein (hs-CRP) (P=0.047). Statin therapy did not change sTNFRSF1B, TNF-alpha, IL-6, hs-CRP, whereas soluble TNF receptor superfamily 1A (sTNFRSF1A) increased slightly (P=0.048). A high level of sTNFRSF1B is a strong marker of the pro-inflammatory state in this sample of male ADL subjects.

Control of nasal obstruction in perennial allergic rhinitis.

PURPOSE OF REVIEW: Nasal obstruction, the cardinal symptom of persistent (perennial) allergic rhinitis, is one of the most common symptoms encountered in primary care and in specialist clinics. It is difficult to quantify by clinical examination, and, hence, objective assessment of the nasal airway is critical to rhinologic research. Nasal obstruction in persistent allergic rhinitis must be treated the year round, and therefore treatment choices, costs, and compliance all become important public health issues. RECENT FINDINGS: Many inflammatory and neurogenic mediators released during allergic reactions are able to cause plasma exudation and vasodilatation, with resultant edema and swelling of the nasal mucosa. Recently, technological advancements have made it possible to qualitatively and quantitatively study the nasal airway, providing greater insights into the understanding of physiological fluctuation and pathophysiological manifestations of nasal patency. From recent international guidelines, the management of allergic rhinitis includes combining treatments of the upper and lower airways, by using patient education, allergen avoidance, pharmacological treatment, and specific immunotherapy. Surgery may be needed as an adjunctive intervention. Multiple methods have been introduced to treat turbinate hypertrophy. However, preservation of adequate nasal mucosal function is important, together with long-term results. SUMMARY: It is important that consensus recommendations for the management of allergic rhinitis be designed and implemented by all levels of medical specialists in order to improve treatment outcomes.

The relationships of hypocholesterolemia to cytokine concentrations and mortality in critically ill patients with systemic inflammatory response syndrome.

BACKGROUND: Decreased concentrations of total cholesterol, lipoproteins, and lipoprotein cholesterols occur early in the course of critical illness. Low cholesterol concentrations correlate with high concentrations of cytokines such as interleukin (IL)-6 and IL-10, and may be due to decreased synthesis or increased catabolism of cholesterol. Low cholesterol concentrations have been associated clinically with several adverse outcomes, including the development of nosocomial infections. The study was performed to test the hypothesis that a low cholesterol concentration predicts mortality and secondarily predicts the development of organ dysfunction in critical surgical illness. METHODS: A prospective study was undertaken of 215 patients admitted to a university surgical ICU with systemic inflammatory response syndrome (SIRS). Serial blood samples were collected within 24 h of admission, as well as on the morning of days 2, 4, and 7 of the ICU stay for as long as the patients were in the ICU. Demographic data and predetermined outcomes were noted. RESULTS: One hundred nine patients had at least two samples drawn and form the population for analysis. Sixty-two of the patients had three samples obtained, whereas 42 patients had four samples obtained. By univariate analysis, non-survivors were more severely ill on admission (APACHE III), more likely to have been admitted to the ICU as an emergency, more likely to develop a nosocomial infection, and more likely to develop severe organ dysfunction (MODS) (all, p < 0.05). Death was associated on day 1 with increased concentrations of sIL2R, IL-6, IL-10, and sTNFR-p75 (all, p < 0.01), but there were initially no differences in serum lipid concentrations. However, by day 2, concentrations of IL-6, IL-10, and cholesterol had decreased significantly (all, p < 0.05) from day 1 in non-survivors but not in survivors; the difference in serum cholesterol concentration persisted to day 7 (p < 0.05). Persistently elevated concentrations of IL-6 and IL-10 were observed in patients who developed severe MODS. By logistic regression, increased APACHE III score, development of a nosocomial infection, and decreased cholesterol concentration were independently associated with mortality. CONCLUSIONS: Decreased serum cholesterol concentration is an independent predictor of mortality in critically ill surgical patients. Repletion of serum lipids is a feasible therapeutic approach for the management of critical illness.

Safety and efficacy of radioallergosorbent test-based allergen immunotherapy in treatment of perennial allergic rhinitis and asthma.

OBJECTIVE: This study was undertaken to demonstrate the safety and efficacy of in vitro, radioallergosorbent test (RAST)-based inhalant allergen immunotherapy. STUDY DESIGN AND SETTING: Prospective 22 year single site clinical study, with outcome evaluations of 480 perennial allergic rhinitis patients, including 96 with concomitant asthma. RESULTS: Rhinitis symptom control after 2 years of immunotherapy was excellent in 32.5% of patients, good in 45.6%, and fair in 14.2%. There was no improvement in 7.7%. For patients with asthma, 81% had good or excellent pulmonary symptom improvement, and no patient failed to improve. No severe reactions occurred, but there were 5 limited systemic reactions, or 0.008% of injections, during a 2.5-year mean immunotherapy treatment course. CONCLUSION: RAST-based immunotherapy is safe and effective for patients with perennial allergic rhinitis, with or without concomitant asthma. Significance This is the first large, multiyear study of safety and efficacy of RAST-based immunotherapy for treatment of perennial allergic rhinitis and asthma. EBM RATING: C.

The importance of glycerin-containing negative control tests in allergy research studies that use intradermal skin tests.

OBJECTIVE: We sought to assess skin whealing with glycerin-containing control injections for intradermal skin tests. DESIGN: Observational. METHODS: Wheal sizes were measured at 0, 10, and 15 minutes after intradermal injection of 0.01 and 0.02 mL of phenolated normal saline and 0.5% and 5% concentrations of glycerin in the same quantity of phenolated saline. RESULTS: Intradermal injection of 0.01 mL of phenolated saline produced an average 4.9-mm wheal, which expanded to 5.2 mm at 10 minutes and to 6.0 mm at 15 minutes. Intradermal injection of 0.02 mL of phenolated saline produced a 6.4-mm wheal, which expanded to 7.0 mm at 10 minutes and 8.0 mm at 15 minutes. The addition of glycerin produced proportionally larger wheals. CONCLUSIONS: Because glycerin increases whealing beyond that with phenolated saline, skin tests containing glycerin must be compared with glycerin-containing negative controls. Intradermal skin tests that fail to compare findings in this manner contain an inherent methodologic flaw and are uninterpretable.

Approaches to testing for food and chemical sensitivities.

Testing for food and chemical sensitivities usually becomes necessary as part of the evaluation of otolaryngology patients who have chronic illness. The more complex the patient, and the more recalcitrant the problem is to treatment, the more likely it is that allergies, and especially food or chemical sensitivities, are involved in the pathogenesis of the illness. Failure to consider all major allergen contacts, including foods and chemicals, can lead to inadequate therapy. Similarly, failure to understand total allergic and oxidant load and the effects of chemical toxicity can lead to inappropriate or ineffective treatment. Clinically, food allergies occur in two different types: immediate, anaphylactic, fixed reactions and delayed, chronic, cyclic reactions. Different test methods have been developed for the two types. Fixed food allergies can be safely and efficiently detected by in vitro specific IgE or histamine release tests. Cyclic food allergies are best detected by either oral food challenges or by the IPDFT test. Choosing the best test for a particular patient requires a clear understanding of the two food allergy types and how their clinical presentations differ. Other tests for food allergies are compared and contrasted with these primary tests. Chemical sensitivity also occurs in two different clinical types: allergic, and toxic. True allergy to chemical haptens, either type I, IgE-mediated, or type IV, delayed hypersensitivity, occurs with significant frequency but is often unsuspected. Chemical toxicity can be caused by the aftereffects of an acute exposure or as a result of chronic, low-level exposure, but is even more frequently unsuspected and will not be diagnosed without a high index of suspicion. Both types of chemical sensitivity need to be addressed in any patients who have either a high allergen or chemical exposure load [105]. Either in vitro or in vivo tests can be used for chemical allergy detection; the advantages of each are outlined. Chemical toxicity screening tests are available and useful but do not detect all possible toxicants. Definitive toxic chemical tests usually require specialized laboratory facilities and expert consultation, for which possible sources are specified. The most important point in testing for food or chemical sensitivity is to be aware that food or chemical sensitivity can be contributing to a specific patient's clinical problems. Only then can appropriate investigations be undertaken to understand and then, perhaps, to intervene successfully in that illness.

Cholesterol and interleukin-6 concentrations relate to outcomes in burn-injured patients.

The goal of this study was to determine the relationship among lipid concentrations, cytokine concentrations, and clinical outcomes of burn patients. Twenty-eight patients admitted within 24 hours of burn injury, segregated based on burn size, had blood samples drawn 24 and 48 hours after burn injury and then weekly for 3 weeks. Measurements included total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, interleukin (IL)-6, soluble IL-2 receptor, and soluble necrosis factor p55 and p75 receptors. Infection, length of stay (LOS), and survival were monitored. Cholesterol and lipoprotein concentrations decreased by at least 40% in patients with burns >20% total body surface area and inversely correlated with IL-6. Lower cholesterol and higher IL-6 values correlated with higher infection rates and longer LOS. IL-6 was the strongest predictor for LOS. In conclusion, outcomes after burn injury are related to low cholesterol and elevated IL-6 levels.

Effect of administration of a phospholipid emulsion on the initial response of horses administered endotoxin.

OBJECTIVE: To evaluate the effect of a phospholipid emulsion (PLE) on the initial response of horses to administration of endotoxin. ANIMALS: 12 healthy adult horses. PROCEDURES: Horses were assigned to 2 treatment groups (6 horses/group). The control group was administered 1 L of saline (0.9% NaCl) solution, and the treated group was administered PLE (200 mg/kg, IV); treatments were administered during a period of 120 minutes. An infusion of endotoxin was initiated in both groups starting 1 hour after initiation of the saline or PLE solutions. Physical examination and hemodynamic variables were recorded, and blood samples were analyzed for concentrations of tumor necrosis factor (TNF)-alpha, interleukin-6, thromboxane B2 (TxB2), 6 keto-prostaglandin F (PGF)1alpha, total leukocyte count, and PLE concentrations. An ANOVA was used to detect significant differences. RESULTS: Administration of PLE resulted in significantly lower rectal temperature, heart rate, cardiac output, right atrial pressure, and pulmonary artery pressure and higher total leukocyte counts in treated horses, compared with values for control horses. The TNF-alpha concentration was significantly less in treated horses than in control horses. The TxB2 and 6 keto-PGFF1alpha concentrations were significantly different between treated and control horses at 30 minutes (TxB2) and at 30 and 60 minutes (6 keto-PGF1alpha). CONCLUSIONS AND CLINICAL RELEVANCE: Prior infusion of PLE in horses administered a low dose of endotoxin decreased rectal temperature, heart rate, pulmonary artery pressure, and TNF-alpha concentrations. Results of this study support further evaluation of PLE for use in the treatment of horses with endotoxemia.

Should vitamin D supplementation be a regular part of asthma care?

Vitamin D (vitD3) deficiency occurs frequently and has profound effects on health, especially asthma. This article examines how current knowledge of vitD3 actions and the worldwide distribution of vitD3 deficiency influences everyday clinical allergy practice. Within the limits of current knowledge, the article concisely explains the molecular nature of vitD3 actions, reviews key vitD3 research as it applies to clinical care, answers questions about the potential clinical impact of low vitD3 levels, and discusses use and safety of vitD3 supplements.

Safety of intradermal skin tests for inhalants and foods: a prospective study.

BACKGROUND: Intradermal skin testing is a useful allergy diagnostic tool. Although considered safe when properly performed, systemic reactions have been reported. This is the first large, prospective study to record and evaluate all systemic reactions from intradermal skin testing (IDT) to inhalant or food antigens. METHODS: A 24-month prospective study by 40 physician practices, recording all IDT tests, including reactions, symptoms, severity, time after injection, and reaction treatments. RESULTS: Eighty systemic reactions (22 major) occurred among 20,530 patients (878,583 wheals). Nine had epinephrine treatment, 4 were observed in an emergency department, and there were no hospitalizations or fatalities. The overall systemic reaction risk was 0.009%. The risk of having a major reaction was 0.003%, or 1 reaction per 933 patients. CONCLUSION: Intradermal skin tests for inhalants or foods, when performed with appropriate precautions, have a safety profile comparable to skin prick tests.

Impacts of fluid dynamics simulation in study of nasal airflow physiology and pathophysiology in realistic human three-dimensional nose models.

During the past decades, numerous computational fluid dynamics (CFD) studies, constructed from CT or MRI images, have simulated human nasal models. As compared to rhinomanometry and acoustic rhinometry, which provide quantitative information only of nasal airflow, resistance, and cross sectional areas, CFD enables additional measurements of airflow passing through the nasal cavity that help visualize the physiologic impact of alterations in intranasal structures. Therefore, it becomes possible to quantitatively measure, and visually appreciate, the airflow pattern (laminar or turbulent), velocity, pressure, wall shear stress, particle deposition, and temperature changes at different flow rates, in different parts of the nasal cavity. The effects of both existing anatomical factors, as well as post-operative changes, can be assessed. With recent improvements in CFD technology and computing power, there is a promising future for CFD to become a useful tool in planning, predicting, and evaluating outcomes of nasal surgery. This review discusses the possibilities and potential impacts, as well as technical limitations, of using CFD simulation to better understand nasal airflow physiology.

Effect of accessory ostia on maxillary sinus ventilation: a computational fluid dynamics (CFD) study.

We evaluated, by CFD simulation, effects of accessory ostium (AO) on maxillary sinus ventilation. A three-dimensional nasal model was constructed from an adult CT scan with two left maxillary AOs (sinus I) and one right AO (sinus II), then compared to an identical control model with all AOs sealed (sinuses III and IV). Transient simulations of quiet inspiration and expiration at 15 L/min, and nasal blow at 48 L/min, were calculated for both models using low-Reynolds-number turbulent analysis. At low flows, ventilation rates in sinuses with AOs (I ≈ 0.46 L/min, II ≈ 0.54 L/min), were both more than a magnitude higher than sinuses without AOs (II I ≈ 0.019 L/min, IV ≈ 0.020 L/min). Absence of AO almost completely prevented sinus ventilation. Increased ventilation of sinuses with AOs is complex. Under high flow conditions mimicking nose blowing, in sinuses II, III, and IV, the sinus flow rate increased. In contrast, the airflow direction through sinus I reversed between inspiration and expiration, while it remained almost constant throughout the respiration cycle in sinus II. CFD simulation demonstrated that AOs markedly increase maxillary sinus airflow rates and alter sinus air circulation patterns. Whether these airflow changes impact maxillary sinus physiology or pathophysiology is unknown.

Airway stem cells: review of potential impact on understanding of upper airway diseases.

Epithelial remodeling is a part of our natural defense mechanisms, and includes migration, proliferation, and differentiation of epithelial cells, as well as the interactions between epithelial and stromal cells. It is not yet possible to distinguish between cause and effect during epithelium remodeling, and are there no clear roles for the many factors involved in respiratory infectious and inflammatory diseases due to a lack of critical information about epithelial cell responses. Most reported data are from lower airway studies or animal models. Therefore, research based on human nasal epithelial stem/progenitor cells can illuminate the pathophysiology of nasal airway disease from a different, more specific perspective. In this review, we discuss epithelial stem/progenitor cell research throughout the airway, with special attention to phenotypes and characterization of these cells from the nasal airway. Recently, we have isolated and cultured P63-positive human epithelial stem/progenitor cells from turbinate biopsies of healthy volunteers and from inflamed mucosa of patients with chronic rhinosinusitis with and without nasal polyposis. These cells propagate in serum-free, growth factor-supplemented, Dulbecco's modified Eagle's medium/F12 media, on either human fibroblast or 3T3 feeder layers. Self-renewal, proliferation, and differentiation potential at an air-liquid interface are being investigated to understand the molecular pathways underlying nasal inflammation. This in vitro culture system for nasal epithelial regeneration will allow molecular studies of human nasal epithelial cell interactions, differentiation, and repair, as well as responses to both environmental agents and to potential anti-inflammatory treatments.

The allergic march: can we prevent allergies and asthma?

The allergic march is a progression of atopic disease from eczema to asthma, and then to allergic rhinoconjunctivitis. It appears to be caused by a regional allergic response with breakdown of the local epithelial barrier that initiates systemic allergic inflammation. Genetic and environmental factors predispose to developing the allergic march. There are data to support 4 possible interventions to prevent the allergic march from progressing to asthma: (1) supplements of dietary probiotics, (2) exclusive breast feeding during the first few months of life, or, alternatively (3) use of extensively hydrolyzed infant formulas, (4) treatment with inhalant allergen immunotherapy by either subcutaneous or sublingual methods.