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This chapter examines a variety of immunologic-mediated lung diseases. Hypersensitivity pneumonitis is caused by exposure to a variety of antigens that elicit a Th1-mediated hypersensitivity response in the lungs. In contrast eosinophilic lung disease is typically a Th2-mediated response manifested by a prominent eosinophilic inflammatory response in the lungs. Eosinophilic lung diseases in which a causative antigen exposure has been identified include allergic bronchopulmonary aspergillosis, drug induced eosinophilia, and helminth associated eosinophilic lung disease. There are other eosinophilic lung diseases in which a causative exposure has not been identified, such as acute and chronic eosinophilic pneumonia, eosinophilic granuloma, and Churg-Strauss syndrome. Finally, hypereosinophilic syndrome, a systemic eosinophilic disorder in which the lung may be affected, is described.

Allergic fungal rhinosinusitis (AFRS) is a subset of chronic rhinosinusitis with nasal polyps (CRSwNP) characterized by antifungal IgE sensitivity, eosinophil-rich mucus (ie, allergic mucin), and characteristic computed tomographic and magnetic resonance imaging findings in paranasal sinuses. AFRS develops in immunocompetent patients, with occurrence influenced by climate, geography, and several identified host factors. Molecular pathways and immune responses driving AFRS are still being delineated, but prominent adaptive and more recently recognized innate type 2 immune responses are important, many similar to those established in patients with other forms of CRSwNP. It is unclear whether AFRS represents merely a more extreme expression of pathways important in patients with CRSwNP or whether there are other disordered immune responses that would define a distinct endotype or endotypes. Although AFRS and allergic bronchopulmonary aspergillosis share some analogous immune mechanisms, the 2 conditions do not occur commonly in the same patient. Treatment of AFRS almost always requires surgical debridement of the involved sinuses. Oral corticosteroids decrease recurrence after surgery, but other adjunctive pharmacologic agents, including topical and oral antifungal agents, do not have a firm evidence basis for use. There is good rationale for use of biologic agents that target eosinophilic inflammation or other type 2 responses, but studies in patients with AFRS are required.

Fungi cause a wide spectrum of fungal diseases of the upper and lower airways. There are three main phyla involved in allergic fungal disease: (1) Ascomycota (2) Basidiomycota (3) Zygomycota. Allergic fungal rhinosinusitis (AFRS) causes chronic rhinosinusitis symptoms and is caused predominantly by Aspergillus fumigatus in India and Bipolaris in the United States. The recommended treatment approach for AFRS is surgical intervention and systemic steroids. Allergic bronchopulmonary aspergillosis (APBA) is most commonly diagnosed in patients with asthma or cystic fibrosis. Long term systemic steroids are the mainstay treatment option for ABPA with the addition of an antifungal medication. Fungal sensitization or exposure increases a patient's risk of developing severe asthma and has been termed severe asthma associated with fungal sensitivity (SAFS). Investigating for triggers and causes of a patient's asthma should be sought to decrease worsening progression of the disease.

A 61-year-old woman presented to our Allergy/Immunology clinic for pruritic dermatitis of both arms since 2006. Initial symptoms included pruritus and burning dysesthesias of the upper extremities without a rash. Months later an excoriated, papular rash developed along the upper extremities. Cold compresses provided some relief, whereas sun exposure worsened symptoms. Over the years consultations with multiple dermatologists did not elicit a diagnosis, and symptoms did not improve after numerous trials of topical corticosteroids and systemic antihistamines. The differential diagnosis of pruritic rash is extensive; however, in the case of chronic pruritus without a primary rash other diagnoses should come to mind. Although pruritus is a hallmark of many atopic conditions, as allergists-immunologists it is important to remember that not all pruritus is atopic in nature. Prompt recognition and treatment of an occult process presenting primarily with pruritus will likely result in improved outcomes for the patient.

Asthma is a common disorder that in 2009 afflicted 8.2% of adults and children, 24.6 million persons, in the United States. In patients with moderate and severe persistent asthma, there is significantly increased morbidity, use of health care support, and health care costs. Epidemiologic studies in the United States and Europe have associated mold sensitivity, particularly to Alternaria alternata and Cladosporium herbarum, with the development, persistence, and severity of asthma. In addition, sensitivity to Aspergillus fumigatus has been associated with severe persistent asthma in adults. Allergic bronchopulmonary aspergillosis (ABPA) is caused by A fumigatus and is characterized by exacerbations of asthma, recurrent transient chest radiographic infiltrates, coughing up thick mucus plugs, peripheral and pulmonary eosinophilia, and increased total serum IgE and fungus-specific IgE levels, especially during exacerbation. The airways appear to be chronically or intermittently colonized by A fumigatus in patients with ABPA. ABPA is the most common form of allergic bronchopulmonary mycosis (ABPM); other fungi, including Candida, Penicillium, and Curvularia species, are implicated. The characteristics of ABPM include severe asthma, eosinophilia, markedly increased total IgE and specific IgE levels, bronchiectasis, and mold colonization of the airways. The term severe asthma associated with fungal sensitization (SAFS) has been coined to illustrate the high rate of fungal sensitivity in patients with persistent severe asthma and improvement with antifungal treatment. The immunopathology of ABPA, ABPM, and SAFS is incompletely understood. Genetic risks identified in patients with ABPA include HLA association and certain T(H)2-prominent and cystic fibrosis variants, but these have not been studied in patients with ABPM and SAFS. Oral corticosteroid and antifungal therapies appear to be partially successful in patients with ABPA. However, the role of antifungal and immunomodulating therapies in patients with ABPA, ABPM, and SAFS requires additional larger studies.

Background Recent reports have attempted to redefine the accepted diagnostic criteria for allergic fungal rhinosinusitis (AFRS), a form of chronic rhinosinusitis (CRS) with nasal polyps. As a result, the existence of AFRS as a distinct entity has been questioned, suggesting that allergy has no role in CRS with sinonasal eosinophilia, and the condition should be referred to as eosinophilic fungal rhinosinusitis. The purpose of the study was to differentiate between AFRS and CRS by studying antibody responses in these two clearly defined patient groups. Methods Ninety-nine patients were enrolled and classified as AFRS or CRS (without AFRS). Serum total IgE, IgG anti–Alternaria-specific antibodies (UniCAP 100), and IgE antifungal antibodies (immunoblotting) were compared between the groups. Results Sixty-four patients fit the traditional criteria for AFRS, with 35 as CRS. Mean serum total IgE and mean IgG anti–Alternaria-specific antibodies were statistically significantly increased in AFRS over CRS patients. There was also a statistically significant increase in the mean number of IgE antifungal bands from AFRS compared with CRS patients. Conclusion We have shown a clear immunologic difference between AFRS and CRS patients. The overwhelming evidence of increased total IgE and fungal-specific IgE in AFRS supports an allergic component in AFRS. IgG anti–Alternaria-specific antibodies also point to an exaggerated fungal immune response in these patients. These results support the existence of AFRS as a separate, distinct entity of CRS. It is important to recognize AFRS to ensure proper treatment in these patients.

Once viewed as a "young person's disease," allergic rhinitis (AR) is becoming increasingly common in the elderly. Effective treatment is necessary not only to minimize the impact of AR in the older population, but to prevent the onset or exacerbation of asthma. This review was conducted to examine the clinical evidence regarding the efficacy and safety of therapies for AR in the elderly. MEDLINE searches of the literature were performed to identify key consensus statements, expert opinions, and clinical trials related to the management of AR in older individuals. The selection of treatment for elderly patients with AR must consider age-dependent physiologic factors (such as metabolic alterations, changes in the nasal mucosa, difficulty swallowing, and visual or motor problems) that may affect responses to therapy. Both first- and second-generation antihistamines are associated with a higher incidence of adverse events and drug:drug interactions in older than younger individuals, and oral decongestants pose risks in the presence of a variety of comorbidities known to be more common in the elderly. Leukotriene receptor antagonists are as effective as antihistamines, but are inferior to intranasal corticosteroids and have the potential for interactions with a wide range of drugs. Intranasal corticosteroids have the most favorable safety and efficacy profiles in older individuals with AR. The diagnosis and management of AR in the elderly require approaches tailored to specific age-related factors. Based on the available evidence, intranasal corticosteroids offer the best option for the treatment of older patients with AR.

Background: Allergic bronchopulmonary aspergillosis (ABPA) is a bronchial allergic inflammatory reaction to Aspergillus fumigatus that occurs in a minority of susceptible asthmatic and cystic fibrosis (CF) patients. Previous studies identified that HLA-DR2/DR5 was associated with susceptibility to develop ABPA; however, HLA-DR2/DR5 occurs frequently in non-ABPA patients as well.Objective: We hypothesize that in addition to HLA-DR restriction, other genetic risk factors predispose asthmatic and CF patients to develop ABPA. Methods: HLA-DR and interleukin-4 (IL-4) receptor α-chain (IL-4RA), IL-13, and IL-10 -1082 polymorphisms were examined in 41 asthmatic and CF patients with ABPA and in 84 asthmatic and CF non-ABPA patients.Results: HLA-DR2 and/or DR5 were identified in 70.7% of ABPA patients and in 35.7% of non-ABPA patients. IL-4RA single-nucleotide polymorphisms (SNPs) were present in 95% of ABPA patients, with the ile75val SNP in 80.5% of ABPA patients. Both HLA-DR2/DR5 and IL-4RA SNPs individually we...

Background Hypersensitivity pneumonitis (HP) is an immune-mediated hypersensitivity reaction to a variety of inhaled particles that may lead to acute, subacute, or chronic interstitial pneumonitis and possibly end-stage lung disease. Avian antigens most commonly cause HP in children, but fungi have also been implicated. Objective To describe a 15-year-old girl and her 6-year-old brother who developed HP from residential exposure to Aureobasidium pullulans . Methods Allergy skin testing, serum precipitating antibodies, pulmonary function testing, chest radiography, chest computed tomography, bronchoalveolar lavage, and a home survey for possible causative antigens were performed. Results Both patients lived on a horse farm and had fatigue, weight loss, cough, and dyspnea. The siblings had restrictive patterns on pulmonary function tests, with decreased diffusion capacity of carbon monoxide, ground-glass opacities on high-resolution chest computed tomography, and serum precipitins to A pullulans . Bronchoalveolar lavage in the girl demonstrated lymphocytosis, with a preponderance of CD8 + T cells and natural killer cells. Symptoms improved after the children vacated the home and recurred on repeated exposure in both patients. Home evaluation revealed extensive mold contamination, with A pullulans counts of 659, 329, and 71 CFU/m 3 in the boy's bedroom, the girl's bedroom, and outdoors, respectively. Conclusions The diagnosis of HP in these siblings is supported by the clinical history, the diagnostic findings, and the recurrence of symptoms on repeated exposure. These cases represent the second report of HP resulting from nonoccupational exposure to A pullulans in North America and the first report in children.

The etiology of allergic bronchopulmonary aspergillosis (ABPA) is not well understood. A clinical phenotype resembling the pulmonary disease seen in cystic fibrosis (CF) patients can occur in some individuals with ABPA. Reports of familial occurrence of ABPA and increased incidence in CF patients suggest a possible genetic basis for the disease. To test this possibility, the entire coding region of the cystic fibrosis transmembrane regulator (CFTR) gene was analyzed in 11 individuals who met strict criteria for the diagnosis of ABPA and had normal sweat electrolytes (< or = 40 mmol/liter). One patient carried two CF mutations (deltaF508/R347H), and five were found to carry one CF mutation (four deltaF508; one R117H). The frequency of the deltaF508 mutation in patients with ABPA was significantly higher than in 53 Caucasian patients with chronic bronchitis (P < .0003) and the general population (P < .003). These results suggest that CFTR plays an etiologic role in a subset of ABPA patients.

Importance Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control. Objective To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease. Design, Setting, and Participants Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24. Interventions Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. Main Outcomes and Measures The primary outcome measure was change in forced expiratory volume in the first second (FEV 1 ) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5-25; higher scores indicate better control), and systemic and airway biomarkers of inflammation. Results Mean changes in prebronchodilator FEV 1 over 24 weeks were 0.03 L (95% CI, −0.01 to 0.08 L) in the placebo group and 0.01 L (95% CI, −0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different ( P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% CI, 1.42-2.54] vs soy isoflavones, 2.20 [95% CI, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% CI, 2.7-4.1] vs soy isoflavones, 3.0 [95% CI, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, −3.48 ppb [95% CI, −5.99 to −0.97 ppb] vs soy isoflavones, 1.39 ppb [95% CI, −1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL ( P Conclusions and Relevance Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma. Trial Registration clinicaltrials.gov Identifier:NCT01052116

Recently, it has been recognized that inflammation is the major cause of chronic rhinosinusitis (CRS) rather than bacterial infection. Fungi have emerged as a possible pathogenic agent that drives CRS. One clear-cut group of fungal sinusitis can be divided into invasive and noninvasive. The condition that the allergist is most likely to see is allergic fungal sinusitis. Generally, it appears in atopic, immunocompetent, adolescents and young adults and is marked by the presence of nasal polyps and allergic mucin, which includes eosinophils, Charcot-Leyden crystals, and fungal hyphae. Computer tomographic imaging shows sinus opacification with hyperdense areas. Treatment has been successful with definitive nasosinus surgery and long-term oral prednisone. There is some evidence that fungi also may account for a large percentage of the remaining CRS patients. In this instance, the immune response to common airborne fungi appears to be IgG mediated rather than IgE mediated. Promising therapeutic results have been seen with intranasal antifungal agents but larger multicenter double-blinded placebo-controlled studies are needed. Another unanswered question includes the possible role of staphylococcus-derived enterotoxins in the pathogenesis of CRS.

The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) was a 3-year, multicenter, observational study of 4,756 patients 6 years or older with severe or difficult-to-treat asthma by physician evaluation. More than 280 pulmonologist and allergist sites across the United States participated.To compare health care utilization (HCU), medication use, asthma control, and quality of life (QoL) in older (or =65 years; n = 566) and younger (18-64 years; n = 2,912) adult patients in TENOR.Patients had to be under a physician's care for at least 1 year and have high medication use or HCU in the past year. Heavy smokers (or =30 pack-years) and patients with cystic fibrosis were excluded.Although older patients in TENOR had worse lung function as measured by decreased percent predicted forced expiratory volume in 1 second (FEV1) (P.001), they had significantly lower HCU compared with younger patients. They also had higher use of inhaled corticosteroids and better QoL than younger patients. Older patients reported fewer problems controlling their asthma (P.001) but reported worse communication with their physicians (P = .02).Older patients in TENOR appeared to do better than younger patients, despite having worse lung function. Older patients in TENOR may have received more aggressive care than older asthmatic patients in other studies, based on a higher use of inhaled and oral corticosteroids. Whether differences in treatment or disease influenced other physiologic or inflammatory outcomes that contribute to the disconnect between HCU and FEV1 awaits further study.

Asthma is an important problem in the elderly, our fastest growing age group. Asthma in the elderly is sometimes underdiagnosed and undertreated. The elderly asthmatic has a poorer quality of life, is hospitalized more often and is more likely to die. Comorbid conditions are much more common in the elderly and impact greatly on the diagnosis and management of asthma in this age group. While allergy is less common in the elderly than in younger age groups, it should still be considered in any patient with asthma. The management of asthma in the elderly must take into consideration comorbid conditions, polypharmacy and the increased probability of adverse reactions from medications.

Many common chronic inflammatory disorders have strong HLA gene associations, particularly with MHC class II. Allergic fungal rhinosinusitis (AFS) and hypertrophic sinus disease (HSD) are chronic sinonasal mucosal inflammatory disorders. Allergic bronchopulmonary aspergillosis, a disorder analogous to AFS, was recently reported to have HLA-MHC class II associations.We sought to determine whether MHC class II is also associated with AFS and HSD.HLA DNA genotyping was obtained on 44 patients with AFS and 30 patients with HSD (of which 21 were atopic).Sixty-six percent of patients with AFS carried at least one HLA-DQB1 *03 allele; DQB1 *0301 and DQB1 *0302 were the most frequent allelic variants (odds ratio [OR] vs healthy subjects = 8.22; 95% CI, 4.30-15.73; P.001; OR vs all patients with HSD = 1.93; 95% CI, 1.09-3.41; P.01; OR vs atopic patients with HSD = 2.57; 95% CI, 1.46-4.53; P.001). Of the 31 patients with AFS and positive Bipolaris spicifera cultures, 68% had DQB1 *03, with DQB1 *0301 and DQB1 *0302 being most frequent (OR vs healthy subjects = 8.93; 95% CI, 4.65-17.15; P.001; OR vs patients with HSD = 2.10; 95% CI, 1.18-3.73; P.001). Of the 30 patients with HSD, 50% carried DQB1 *03 (OR vs healthy subjects = 4.25; 95% CI, 2.25-8.02; P.001) but differed in frequencies of DQB1 *03 allelic variants compared with patients with AFS ( P = .0004). For HSD, nonatopic subjects had the highest DQB1 *03 association (OR vs healthy subjects = 8.63; 95% CI, 4.50-16.54; P.001). DQB1 *03 allelic variants did not correlate with allergy skin test results, atopic status, total serum IgE levels, culture results, asthma, or aspirin-nonsteroidal anti-inflammatory drug hypersensitivity.Patients with AFS and HSD have HLA-DQB1 *03 alleles as a risk factor for disease, with AFS having the highest association. However, they differ in DQB1 *03 allelic variant frequencies, suggesting several potential roles for MHC class II in their immunopathogenesis.

Allergic bronchopulmonary aspergillosis (ABPA) is a rare complication in patients with asthma but more common in patients with cystic fibrosis. In the presence of the fungus Aspergillus fumigatus (Af) in the lower respiratory tract, patients mount a heightened IgG and IgE humoral response specific for Af antigens. Studies on ABPA have suggested a pathogenic role for antigen specific CD4+ Th2 like T lymphocytes producing increased levels of IL-4 and IL-5. MHC class II genes coding for highly polymorphic HLA molecules have been shown to be the likely candidates for controlling immune responses to common allergens. However there has been a lack of information on the pathophysiological role of HLA genes in the development of ABPA. This review describes an association between HLA- class II alleles and the specific responses to Af antigen (Asp f 1) in ABPA. These studies focused on MHC restriction and distribution of HLA- class II alleles in two groups of unrelated North American Caucasian patients with cystic fibrosis and/or asthma. One group consisted of patients with a confirmed diagnosis of ABPA and a second group of patients with Af sensitivity but no ABPA. HLA association studies revealed that the predisposition to develop ABPA is associated with HLA-DR2 and DR5, and possibly DR4 or DR7. A strong association of HLA-DR antigens with ABPA reflects that HLA-DR molecules may present disease-causing peptides. On the other hand a significant association of HLA-DQ2 with Af sensitive nonABPA indicates the involvement of HLA-DQ molecules in protection. A combination of these genetic factors determines the outcome of ABPA in patients with cystic fibrosis and asthma.

Background Primary paranasal aspergillus granuloma (PPAG) is a slowly progressive chronic infection of the sinus extending beyond the confines of the sinus. It has been reported only in patients from the Sudan and India. Microscopically, it differs from chronic invasive fungal sinusitis in that there are pseudotubercles containing giant cells, histiocytes, lymphocytes, plasma cells, newly formed capillaries, eosinophils, and Aspergillus fungal elements. Conclusion We describe the first case of PPAG in the United States in an immunocompetent nonatopic woman who had never left Missouri.

Background In 1971, we published a survey regarding pediatricians' attitudes toward the field of allergy/immunology (A/I). Results indicated general attitudes and practices fell short of what most allergist-immunologists would hope. We revisited this in 1998 to determine how pediatricians' attitudes toward A/I had changed nearly 3 decades later. Despite some advances, results from 1998 revealed that A/I remained a misunderstood specialty. With the increasing incidence of atopic disorders and improving awareness of primary immunodeficiency, it is more important today than ever before that pediatricians and general practitioners have a strong appreciation for the scope of disorders the subspecialty of A/I encompasses. Objective To reevaluate attitudes and practices of pediatricians toward A/I 40 years after the initial study and 13 years after this topic was last addressed. Methods A 25-question survey was mailed to 293 pediatricians in the St Louis area. Surveys were completed confidentially. Pearson correlation and χ 2 analyses were performed. Results Of 293 pediatricians polled, 135 (46%) responded. Referrals to allergist-immunologists for urticaria have increased. Fewer pediatricians are referring asthma and atopic dermatitis patients to allergist-immunologists. Personal experience referring to an allergist-immunologist remains the greatest influence on current attitudes toward A/I. Prior exposure to A/I during medical education continues to have the least influence on pediatricians' attitudes toward A/I. Conclusion Increased appropriate referrals and improved patient outcomes could result from efforts to enhance A/I education during medical school and residency, maintain effective communication with referring physicians, and break down referral barriers to improve physicians' attitudes toward A/I.

Background "Allergic sinusitis" is a frequently used term but there is question about its true existence. Objective To detect the presence of allergic inflammation of the sinuses in five highly symptomatic ragweed sensitive adults. Method Three imaging techniques were utilized: SPECT bone imaging, SPECT Indium 111 labeled WBC uptake, and FDG F-18 (PET scanning). Results We could find no evidence of sinus involvement in association with severe allergic rhinitis. Conclusions Employing three different imaging modalities, we were unable to demonstrate inflammation of the sinuses in patients with allergic rhinitis.

Background In 1971 we published a survey of pediatricians' knowledge, attitudes, and practices relative to the field of allergy. This current survey was conducted to determine how these attitudes and practices have changed over the past 27 years. Methods Our survey, consisting of 17 questions, was sent to 250 board certified pediatricians in the St. Louis area. Seven of the questions were similar to those in the 1971 survey, while the other ten were new questions which we thought were pertinent to the field of allergy currently. Results In 1971, 75% of the pediatricians felt the specialty of allergy had great or moderate importance for the practice of pediatrics compared with 99% in 1998. In 1998, the number of physicians who felt that there was at least some value to skin testing had increased from 1971, although, only 36% felt it had great value. In 1971, 23% of pediatricians performed their own skin tests compared with 3% in 1998. Nine percent indicated that they had never referred a patient to an allergist in 1971, compared with 2% in 1998. Our new questions looked at to whom respondents were more likely to refer patients with: (1) asthma (68% allergy, 27% pulmonary, 4% both), (2) urticaria (53% allergy, 41% dermatology, 2% both), (3) chronic eczema (45% allergy, 50% dermatology, 2% both), and (4) chronic sinusitis (24% allergy, 74% otolaryngology, 2% both). Older physicians placed greater importance on the field of allergy and skin testing and were more likely to refer to an allergist than physicians under the age of 40 years. Conclusion Our results indicate that although there has been significant change in 27 years, allergists must be more aggressive in developing the knowledge, attitudes, and practices of physicians relative to the field of allergy.

The fatty liver dystrophy ( fld ) mutant mouse is characterized by neonatal fatty liver and hypertriglyceri- demia that resolve at weaning, and neuropathy affecting pe- ripheral nerve in adulthood. We now report additional sig- nificant manifestations of this single gene mutation, which include adipose tissue deficiency, glucose intolerance, and increased susceptibility to atherosclerosis. In adult fld/fld mice, both white and brown fat pads exhibit an 80% reduc- tion in mass compared with wild-type controls, and consist of immature adipocytes as assessed by morphological and molecular criteria. The lack of lipid accumulation in fld/fld adipose tissue could be attributed, in part, to a failure to in- duce expression of lipoprotein lipase and enzymes involved in fatty acid synthesis, such as fatty acid synthase and acetyl- CoA carboxylase. Related to the deficiency of adipose tissue, fld/fld mice were also found to exhibit profound glucose in- tolerance, modest hyperinsulinemia, and reduced tissue re- sponse to insulin. As insulin resistance is a important risk factor in vascular disease, we examined susceptibility of fld/fld mice to diet-induced atherosclerosis. Mutant mice fed an atherogenic diet developed 2-fold greater aortic lesions than their wild-type counterparts, despite having a less atherogenic lipoprotein cholesterol profile. The fld adipose-deficient phe- notype has both similarities to and distinctions from the group of rare human diseases known as lipodystrophies. — Reue, K., P. Xu, X-P. Wang, and B. G. Slavin. Adipose tissue deficiency, glucose intolerance, and increased atherosclero- sis result from mutation in the mouse fatty liver dystrophy ( fld ) gene. J. Lipid Res. 2000. 41: 1067-1076.

Cockroach allergen is important in asthma. Practical methods to reduce exposure are needed.We sought to evaluate the effectiveness of house cleaning and professional extermination on lowering cockroach antigen levels in inner-city dwellings.As part of the National Cooperative Inner-City Asthma Study intervention, 265 of 331 families with asthmatic children who had positive skin test responses to cockroach allergen consented to a professional home extermination with 2 applications of a cockroach insecticide (Abamectin, Avert) combined with directed education on cockroach allergen removal. On a random subset of 48 homes undergoing cockroach extermination in the intervention group, Bla g 1 was measured in settled dust from the kitchen, bedroom, and TV/living room. The first sample was collected 1 week before extermination, with additional samples after the exterminations at approximately 2, 6, and 12 months after the first sample. Self-reported problems with cockroaches were collected at baseline and after 12 months of follow-up in both the intervention and control group.The geometric mean kitchen level of Bla g 1 decreased at 2 months (33.6 U/g) relative to preextermination levels (68.7 U/g, P.05). The percent of kitchens with over 8 U/g of Bla g 1 followed a similar pattern, but only the decrease from preextermination to 6-month levels was significant (86.8% vs 64.3%, P.05). By the 12-month visit, the allergen burden had returned to or exceeded baseline levels. Except for an increase in the bedroom at 2 months (8.9 U/g vs 11.1 U/g, P.05), no other significant change was seen. Only about 50% of the families followed the cleaning instructions; no greater effect was found in these homes. Self-reported problems with cockroaches showed no difference between the intervention and control group after 1 year of follow-up.Despite a significant, but short-lived, decrease the cockroach allergen burden remained well above levels previously found to be clinically significant.

Fatty liver dystrophy (fld) is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and fatty liver during neonatal development. The fatty liver in fld/fld mice spontaneously resolves between the age of 14–18 days, at which point the animals develop a neuropathy associated with abnormal myelin formation in peripheral nerve. We have investigated the morphological and biochemical alterations that occur in the fatty liver of neonatal fld/fld mice. Studies at the light and electron microscopic level demonstrated the accumulation of lipid droplets and hypertrophic parenchymal cells in fld neonates, with no apparent liver pathology after resolution of the fatty liver. To better characterize the biochemical basis for the development of fatty liver in fld mice, we compared protein expression patterns in the fatty liver of fld mice and in the liver of phenotypically normal (wild-type) littermates using quantitative two-dimensional gel electrophoresis. We detected 24 proteins with significantly altered expression levels (P < 0.001) in the fld fatty liver, 15 of which are proteins that are altered in abundance by peroxisome proliferating chemicals. As these compounds characteristically elicit changes in the expression of mitochondrial and peroxisomal enzymes involved in fatty acid oxidation, we quantitated rates of fatty acid oxidation in hepatocytes isolated from fld and wild-type mice. These studies revealed that hepatic fatty acid oxidation in fld neonates is reduced by 60“% compared to wild-type littermates. In hepatocytes from adult fld mice that no longer exhibit a fatty liver, oxidation rates were similar to those in hepatocytes from age-matched wild-type mice. These findings indicate that altered expression of proteins involved in fatty acid oxidation is associated with triglyceride accumulation in the fld fatty liver. —Rehnmark, S., C. S. Giometti, B. G. Slavin, M. H. Doolittle, and K. Reue. The fatty liver dystrophy mutant mouse: microvesicular steatosis associated with altered expression levels of peroxisome proliferator-regulated proteins. J. Lipid Res. 1998. 39: 2209–2217.

Background While there is evidence of an increased incidence of sinusitis in patients with allergic rhinitis, it is unclear whether an allergic process occurs in the sinus tissues per se. Objective The purpose of this study was to determine whether inhaled pollen reaches the sinus mucosa. Methods Tc99m labeled ragweed pollen was inhaled by five non-atopic adults. Imaging studies of the sinuses were performed with a tomographic rotating gamma camera. To determine the sensitivity of the technique, the nose and the maxillary sinuses of cadaver heads were painted with varying amounts of Tc99m and then similarly scanned. Results Scans of the cadaver heads showed clear resolution between the nasal cavity and the maxillary sinus. It was determined that 20 microcuries was the smallest amount of Tc99m that could be resolved to be in the sinuses. Scans of subjects showed intense activity in the nasal cavity but none in the paranasal sinuses despite the delivery of a supraphysiologic dose of Tc99m ragweed pollen. Conclusion Inhaled ragweed pollen does not appear to enter the paranasal sinuses. It is unlikely that an inhaled antigen-IgE antibody reaction occurs in the sinus mucosa.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease mediated by an allergic late-phase inflammatory response to Aspergillus fumigatus antigens characterized by markedly elevated allergen specific and total immunoglobulin E (IgE) levels and eosinophilia, and manifested by wheezing, pulmonary infiltrates, and pulmonary bronchiectasis and fibrosis. ABPA afflicts only a small percentage of susceptible atopic individuals with either asthma or cystic fibrosis (CF). ABPA is unique in that it is caused by A. fumigatus, a living fungus growing within the mucosal lumen of the bronchi that releases a multitude of proteins whose biologic function alters the host immune responses in addition to being immunogenic. Elucidation of the immunopathogenesis of ABPA has provided valuable information related to allergen-induced chronic asthma. More recently, immunogenetic studies have further contributed to the understanding of the immunopathogenesis of why certain individuals are susceptible to develop ABPA. Immunologic responses to Aspergillus, as well as to other microorganisms, may be categorized as either T helper (Th)1 or Th2 CD4+ T-cell responses. 61,110,128 Th1 CD4+ T-cell cytokines, such as interferon gamma (IFN-γ), interleukin 2 (IL-2), and tumor necrosis factor (TNF)-β, enhance cytotoxic and macrophage activity (e.g., cellular immunity), whereas Th2 CD4+ T-cell cytokines, such as IL-4, IL-5, IL-10, and IL-13, promote antibody synthesis (e.g., humoral antibody immunity) (Table 1). It is hypothesized that protective host immunity to A. fumigatus is a Th1 CD4+ T-cell response, whereas a Th2 CD4+ T-cell humoral response found in ABPA is nonprotective and leads to a hypersensitivity pulmonary lung disease.

The relationship between infectious rhinitis and sinusitis is so clear that the suggestion has been made that the term “rhinosinusitis” might more precisely define the disease state.1 Several considerations support this contention. Rhinitis typically precedes sinusitis, and sinusitis without rhinitis is rare. The mucosae of the nasal and sinus tissues are contiguous, and the symptoms of nasal obstruction and nasal discharge are prominent in sinusitis. In certain clinical situations, either rhinitis (i.e., allergic rhinitis) or sinusitis (i.e., acute frontal sinusitis) may occur alone, but in most instances there is some involvement of the contiguous secondary site. A recent study, using computerized tomography (CT), documented that radiographic changes do occur in the sinuses of otherwise healthy patients with uncomplicated viral upper respiratory infections of brief duration.2 It is therefore clear that infectious rhinitis will predispose to the development of sinusitis. Before discussing the possibility that allergic rhinitis is associated with or is a cause of sinusitis, we will review some basic aspects of sinus anatomy and physiology.

Background Only 9 adult cases of immediate-hypersensitivity reaction to ladybugs, also known as Asian lady beetles ( Harmonia axyridis ), have been documented in the literature. These patients have all shown symptoms of allergic rhinoconjunctivitis or asthma from exposure to ladybugs. Objective To describe the first pediatric patients with severe allergic facial angioedema requiring emergency department management after exposure to ladybugs. Methods Evidence of IgE-mediated hypersensitivity to ladybugs was documented by positive skin prick test reactions, correlating with exposure history. Results Two cases in preschool boys had similar features, although they were evaluated and tested by 2 different allergists. Both patients developed severe facial or periocular angioedema with no significant respiratory involvement after exposure to ladybugs outside their infested homes. Both patients required an emergency department visit for treatment. Allergy evaluation using ladybug extract for skin prick testing showed markedly positive reactions in both patients. There were no further episodes after environmental control measures were instituted. Conclusions Although allergic respiratory or cutaneous reactions to ladybugs are uncommon, a high index of suspicion from exposure history and confirmatory skin testing can be conclusive for the diagnosis.

Rhinitis and sinusitis are common bothersome conditions in the elderly. Despite the importance of these diseases to the clinician, little information exists in the medical literature. A review of four recently published geriatric medicine textbooks reveals that not one includes rhinitis or sinusitis in the index. 6,7,13,14 It is interesting to note that, on the other hand, all four indexes include sinoatrial disease.

Allergic bronchopulmonary aspergillosis (ABPA) occurs with a prevalence of 5% to 15% in patients with cystic fibrosis (CF). Because of the frequent colonization with Aspergillus fumigatus (Af) in CF, the causative agent of ABPA, antibody reactivity to Af proteins is frequently observed, which obscures the diagnosis of ABPA. Patients with CF are also categorized according to the presence of positive skin test responses to Af and/or the presence of positive precipitins. In this study we used ELISA and immunoblot assay to detect IgE and IgG anti-Af antibodies in patients with CF and ABPA ( n = 13) compared with other groups of patients with CF: those with positive skin test and positive precipitin results ( n = 18), those with positive skin test and negative precipitin results ( n = 14), those with negative skin test and positive precipitin results ( n = 10), and those with negative skin test and negative precipitin results ( n = 35). IgE and IgG anti-Af antibodies were significantly elevated in patients with ABPA as determined by both immunoblot assay ( p p

The workplace is emerging as an increasingly important venue for the development of rhinitis and asthma. There is no question that allergic diseases of the respiratory tract caused by occupational exposure are on the increase. The clinician's diagnostic index of suspicion must be high so that a diagnosis of occupational rhinitis and/or asthma can be made in a timely fashion. Altering the environment of the workplace or removing the patient from that workplace may spare the patient permanent damage.

Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 hypersensitivity lung disease in response toAspergillus fumigatusthat affects asthmatic and cystic fibrosis (CF) patients. Sensitization toA. fumigatusis common in both atopic asthmatic and CF patients, yet only 1-2% of asthmatic and 7–9% of CF patients develop ABPA. ABPA is characterized by wheezing and pulmonary infiltrates which may lead to pulmonary fibrosis and/or bronchiectasis. The inflammatory response is characterized by Th2 responses toAspergillusallergens, increased serum IgE and eosinophilia. A number of genetic risks have recently been identified in the development of ABPA. These include HLA-DR and HLA-DQ, IL-4 receptor alpha chain (IL-4RA) polymorphisms, IL-10-1082GA promoter polymorphisms, surfactant protein A2 (SP-A2) polymorphisms, and cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations. The studies indicate that ABPA patients are genetically at risk to develop skewed and heightened Th2 responses toA. fumigatusantigens. These genetic risk studies and their consequences of elevated biologic markers may aid in identifying asthmatic and CF patients who are at risk to the development of ABPA. Furthermore, these studies suggest that immune modulation with medications such as anti-IgE, anti-IL-4 and/or IL-13 monoclonal antibodies may be helpful in the treatment of ABPA.

The syndrome of Henoch-Schoenlein purpura developed in a 74-year-old woman after receiving streptokinase as thrombolytic therapy for an acute myocardial infarction. Renal biopsy revealed mesangial hypercellularity with deposits of IgA. Skin biopsy also revealed IgA deposition. Immunological studies showed evidence of sensitization to streptokinase. Elevated IgG, IgA, IgM, and IgE antistreptokinase antibodies were detected in the acute serum. Positive immediate skin reactivity to streptokinase was also present. Serum precipitins to streptokinase disappeared when IgA was removed from the serum. Positive staining with biotinylated streptokinase was seen in the skin in the same pattern of distribution as IgA. These findings strongly support the role of streptokinase and IgA in the pathogenesis of Henoch-Schoenlein purpura in this patient. A control group of streptococcal-infected patients showed no immune response to streptokinase. Another control group of streptokinase-treated patients, who had no untoward reaction, had elevated immunoglobulin classes and precipitins to streptokinase. However, the precipitating antibody was IgG and streptokinase skin tests were negative.

Epstein-Barr virus (EBV) has been proposed as a possible infective agent involved in the pathogenesis of angioimmunoblastic lymphadenopathy (AIL), a progressive and often fatal lymphoproliferative disorder. We have studied 19 cases of AIL-like lymphomas for the presence of EBV using a sensitive in situ hybridization technique based on the detection of Epstein-Barr encoded RNAs with digoxigenin-labelled oligonucleotide probes. EBV was found in 11 cases; in seven of these EBV was detected in occasional cells. Immunocytochemical studies to investigate viral gene expression, revealed the presence of EBV-encoded latent membrane protein only in those cases which had appreciable numbers of positive cells by in situ hybridization. The intensity of staining varied from case to case and the overall proportion of cells staining for latent membrane protein in a given case was considerably less than that by in situ hybridization. In situ hybridization for cytomegalovirus and human herpes virus type-6 was negative in all cases. We discuss these findings in the light of the proposed role of EBV in the pathogenesis of AIL and conclude that the presence of EBV is a consequence of the disease rather than the cause.

Nonisotopic in situ hybridization has been used to investigate the role of Epstein-Barr virus (EBV) in the aetiology of pediatric Hodgkin's disease. Sections from 24 cases arising in children under the age of 15 years were hybridised with digoxigenin-labelled probes for both EBV and cytomegalovirus, and reactive sites were identified by a sensitive three-layer immunoperoxidase technique. EBV was identified in Reed-Sternberg and mononuclear Hodgkin's cells in five samples (21%). No samples were positive when the cytomegalovirus probe was employed. The specific identification of EBV in the malignant cells of Hodgkin's disease arising in children lends further support for a role of EBV in the aetiology of this disorder. © 1993 Wiley-Liss, Inc.

Summary The inoculation of a 24 hour, serum broth culture of Staphylococcus aureus containing 500 million organisms per c.c. into the udders of three lactating ewes via the teat canal set up an acute mastitis. A similar result was obtained with one-tenth of the dose, but one-hundredth of it produced only a mild reaction in two ewes and a moderate infection in the third. Thirty-six ewes in late lactation developed mastitis in one half of the udder by the inoculation of approximately 14 million haemolytic staphylococci. The infection was severe in the majority of sheep but there was considerable individual variation amongst the remainder. Cultural examination of the blood at six, 12, 18, 24 and 48 hours after inoculation failed to demonstrate a bacteraemic phase. Treatment of three groups of nine affected ewes with sulphathiazole, sulphapyridine and staphylococcus toxoid respectively proved ineffective. In spite of the initiation of treatment as soon as the first symptoms of mastitis were detected (13 hours after inoculation), the disease progressed, and staphylococci were still present in the udders 14 days after inoculation.

Important relationships exist between the upper and lower airways. It is well known that sinusitis and asthma coexist in many patients, and evidence is accumulating that there may be a cause-and-effect relationship, that is, that sinusitis is an important trigger for asthma. Studies in children and adults indicate that appropriate medical and/or surgical therapy of sinusitis frequently leads to improvement in the asthmatic state. Possible mechanisms for this relationship include the eosinophil acting as an effector cell, inflammatory mediators, and a vagal reflex. Further investigations need to examine both prospective studies of the effect of medical therapy for sinusitis on asthma and basic mechanisms relating the upper and lower airways.

A consecutive series of 71 children (mean age 8.6 years) with recurrent abdominal pain underwent endoscopic oesophageal, gastric and duodenal biopsy in order to determine whether the pain was of gastro-intestinal origin. Of these 71 children, 27 (38%) showed oesophagitis, 14 (20%) cardiac gastritis, 29 (41%) body gastritis, 38 (54%) antral gastritis, and 29 (41%) duodenitis. Thus, 66 of the 71 children studied had an inflammatory lesion explaining their complaints. One of the patients had a gastric ulcer. Helicobacter pylori colonisation was found in 5 of the children: One had H. pylori associated antral and body gastritis and 4 H. pylori associated antral gastritis only. Body gastritis without H. pylori was present in three of these four children. Our data do not support the widespread assumption that recurrent abdominal pain for which no medical cause can be found, is psychogenic; neither do they establish an association between H. pylori antral gastritis and recurrent abdominal pain. However, our data provide strong evidence that there is a gastro-intestinal origin of these patients' complaints.

Rhinitis in the elderly is a common but often neglected condition. Structural changes in the nose associated with aging, predisposes the elderly to rhinitis. There are a number of specific factors that affect medical treatment of the elderly including polypharmacy, cognitive dysfunction, changes in body composition, impairment of liver and renal function and the cost of medications in the face of limited resources. Rhinitis in the elderly can be placed in several categories and treatment should be appropriate for each condition. The most important aim is to moisten the nasal mucosa since the nose of the elderly is so dry. Great caution should be used in treatment with first generation antihistamines and decongestants. Medications generally well tolerated by the elderly are second generation antihistamines, intra-nasal anti-inflammatory agents, leukotriene modifiers and iprapropium nasal spray.

This article presents biochemical data on the BSB mouse model of multigenic obesity indicating increased percentage body fat, increased fasting plasma insulin, and increased insulin resistance in male and female obese mice compared with lean controls. Plasma glucose was significantly increased only in male obese mice. Morphological and morphometrical analyses of pancreatic islets showed increased islet size and number in all obese mice compared with lean controls. Immuno-staining results for insulin-positive islet cells showed greater levels of insulin in male and female obese versus lean mice, while the percent or proportion of insulin immuno-staining, as expected, was not significantly different between obese and lean. The percent or proportion of immuno-staining for islet glucagon and somatostatin showed reduced staining in islets from obese compared with lean mice. The significance of these findings shows, for the first time, the morphologic appearance of pancreatic islets and the quantitative distribution of the three major islet cell hormonal populations in BSB obese mice. The correlation between this descriptive information and physiological data might lend insights to the cause of obesity-related diabetes.

Background: Sinusitis and rhinitis are associated with uncontrolled asthma. There are no simple, validated tools to screen for these diseases. The objective of this study was to assess instruments to assist in the diagnosis of chronic sinonasal disease. Methods: Participants without acute sinonasal symptoms underwent an extensive evaluation. The results were submitted to an expert panel that used the Delphi method to achieve consensus. Using the consensus diagnosis of the panel, we determined the sensitivity and specificity of test procedures to diagnose chronic sinonasal disease. We determined the reproducibility of the most sensitive and specific instrument in a separate cohort. Results: Fifty-nine participants were evaluated, and the expert panel reached consensus for all (42 participants with chronic sinonasal disease, 17 participants without chronic sinonasal disease). A six-item questionnaire based on the frequency of nasal symptoms was the most sensitive tool used to diagnose sinonasal disease (minimum specificity, 0.90). Reproducibility testing in a separate cohort of 63 participants (41 chronic sinonasal disease with asthma, 22 chronic sinonasal disease without asthma) showed a concordance correlation coefficient of 0.91 (95% CI, 0.85 to 0.94) when this questionnaire was limited to five items (ie, excluding a question on smell). This five-item questionnaire had a sensitivity of 0.90 (95% CI, 0.77 to 0.97), a specificity of 0.94 (95% CI, 0.71 to 1.00), and an area under the receiver operating characteristic curve of 0.97 (95% CI, 0.93 to 1.0). Sinus CT scans and nasal endoscopy lacked sensitivity for use in the diagnosis of chronic sinonasal disease. Conclusions: We have developed a sensitive, specific, and reproducible instrument to screen for chronic sinonasal disease. Validation studies of this five-item questionnaire are needed, including in patients with asthma. (CHEST 2009; 136:1324–1332) Abbreviations: AUC area under the curve; ROC receiver operating characteristic; SNQ sinonasal questionnaire

The upper and lower airways do not exist as anatomically and functionally distinct areas. There are important relationships between both the nose and the paranasal sinuses and asthma. Both allergic rhinitis and rhinosinusitis may impact bronchial asthma. The patient with rhinitis should be observed carefully for the development of asthma, and those with asthma should be considered to have either rhinitis or rhinosinusitis.

Seventy-nine patients with cystic fibrosis (CF) were evaluated and were followed in a longitudinal, prospective fashion during a 6-year period for the development of immune parameters indicating Aspergillus fumigatus (Af) sensitization and allergic bronchopulmonary aspergillosis (ABPA). Although four patients developed frank ABPA, there was considerable variability in immune parameters in non-ABPA. Twenty-four patients became skin test positive to Af with none losing skin reactivity. Twenty-five patients developed serum precipitins to Af, whereas 12 patients lost their precipitins. Of 15 patients with an elevated total serum IgE of greater than or equal to 2 SD, five demonstrated a marked decline of at least 40%. Three of 16 patients with IgE-Af became negative, whereas eight of 27 patients lost their IgG-Af. None of these patients had received corticosteroid therapy that could have accounted for the findings. Thus, patients with CF frequently lose evidence of Af sensitivity spontaneously without corticosteroid intervention. The diagnosis of ABPA in CF should not be based solely on serology and skin test results, since at any point in time, patients with CF may demonstrate variable responses to Af.

Nasal polyps and sinusitis have come of age in the view of the allergist. Professional meetings, seminars, and abstracts abound related to nasal polyps and sinusitis. Allergy and immunology journals in the last decade have been replete with articles dealing with these subjects. The presence of sinusitis in some 31 million Americans, many of whom present to the allergist, mandates our interest and attention to this important entity.

Non-isotopic in situ hybridization employing digoxigenin-labelled DNA probes has been used to localize Epstein–Barr virus (EBV) in 55 cases of Hodgkin's disease (HD). The virus was found in Reed–Sternberg (RS) and mononuclear Hodgkin's cells in nine patients (16 per cent). Further samples taken at different times from three patients also showed the presence of EBV in the malignant cell population. Estimations of the number of EBV genomes present per cell suggested wide variations between different patients, but relatively constant amounts in different samples from the same patient. These findings are compatible with a stable infection of the neoplastic cells and support the notion that EBV may play a role in the development of HD in these patients. We also found evidence for the presence of EBV in a small percentage of non-neoplastic cells in 8 of the 55 samples. This suggests that isolation of EBV from HD tissue does not always signify a pathogenetic role for the virus. Furthermore, it is apparent that a high percentage of HD tissues do not contain demonstrable EBV, and the virus is therefore unlikely to be a causative agent for all cases of HD.

A continuous ambulatory peritoneal dialysis patient developed eosinophilic peritonitis and was followed for 7 months. After 1 month, the peritonitis resolved, with a concomitant drop in percentage of hypodense eosinophils (Eos) recovered from peritoneal dialysate (PD) as well as a drop in fluid major basic protein levels. Blood eosinophil differential percentages were low, but the percentage of hypodense Eos in the blood tended to be relatively increased. Stool samples showed no evidence of parasitic infection, and epicutaneous skin tests were negative. Leukotriene C4 levels remained relatively constant as did white blood cell counts. Flow cytometric analysis of lymphocytes and granulocytes from PD and blood revealed high levels of CD23-positive lymphocytes.