Hypersensitivity Lung Disease Research Articles

S1159 The Relationship Between Patient Satisfaction and Use of Healthcare Services in Patients With Barrett's Esophagus Using Confocal Laser Endomicroscopy versus Standard of Care

Introduction: The global prevalence and burden of Barrett's esophagus, a precursor to esophageal adenocarcinoma, is increasing. The object of the present study was to analyze patient satisfaction while comparing differences in gastroenterology health services utilization among patients treated using Cellvizio (Confocal Laser Endomicroscopy, CLE) versus standard of care. Methods: A retrospective, multicenter chart review was conducted on 60 patients with Barrett’s esophagus. Individuals were classified into 1 of 2 cohorts of 30 patients each according to whether they received at least 1 Cellvizio procedure (i.e., Cellvizio versus random 4-quadrant biopsy standard of care—also known as the Seattle Protocol). Patient age, gender, and 12 comorbidity indicators were also captured as covariates. Bivariate differences in variable means across the 2 groups were assessed using the Kruskal-Wallis equality of populations test. Finally, linear multivariate models of the 8 health services measures were estimated. Patient’s were also given a survey requesting them to rank their experience utilizing Cellvizio versus standard of care. The satisfaction scale went from 1 (would not undergo again) to 10 (highly recommend). Results: Compared to those receiving standard of care, Cellvizio patients were older (71 versus 63 years; p=0.002). No other statistically significant differences in gender or comorbidities were detected. Controlling for covariates, while patients in the Cellvizio cohort had greater use of Cellvizio and fluorescein (3.94 more of each than standard of care; p< 0.001), they also had 1.04 fewer endoscopies and anesthesia services (p=0.001), 7.49 less biopsy bottles (p< 0.001), 1.30 fewer ablations (p< 0.001), and 1.46 less brush cytology services (p< 0.001). The patient’s surveys also revealed a satisfaction score of 8.5 with Cellvizio and 6.3 with standard of care. (Table) Conclusion: Barrett’s esophagus, a precursor to esophageal adenocarcinoma, is a common condition with increasing global prevalence and burden. Screening for gastrointestinal adenocarcinomas using conventional endoscopy and biopsies has showed success, however, Cellvizio showcases a lot of potential due to its specificity of producing high resolution images of the mucosal layer as well as the reduced number of biopsies needed. We reveal that the use of Cellvizio is associated with lower health services utilization of endoscopy, anesthesia, biopsy, ablation and higher patient satisfaction. Table 1. - A list of different variables in patients who underwent standard of care versus cellvizio Variable Standard of Care (N=30) Cellvizio (N=30) p-value Male 0.63 0.43 0.18 Age (years) 63.13 71.23 0.00 Hospital: Advocate 0.00 0.23 0.12 Advocate/St. Joseph 0.00 0.03 0.82 Christ 0.10 0.00 0.51 Good Samaritan 0.23 0.00 0.12 Oak Lawn 0.27 0.03 0.12 Silvercross 0.23 0.40 0.27 St. Joseph 0.17 0.30 0.38 Comorbidities: Hypertension 0.73 0.67 0.66 Asthma/Chronic Obstructive Pulmonary Disease 0.07 0.13 0.66 Diabetes 0.27 0.30 0.82 Hypersensitivity Lung Disease 0.37 0.37 1.00 Coronary Artery Disease 0.17 0.17 1.00 Thyroid Disease 0.10 0.07 0.82 Anxiety/Depression 0.10 0.07 0.82 Pancreatitis 0.03 0.10 0.66 Dyslipidemia 0.10 0.07 0.82 Liver Disease 0.10 0.00 0.51 Atrial Fibrillation 0.07 0.10 0.82 Rheumatoid Arthritis 0.03 0.07 0.82 Number of: Endoscopy 5.03 4.13 0.0003 Cellvizio 0.00 4.13 0.0000 Biopsy Bottle 8.60 1.17 0.0000 Ablation 2.43 1.33 0.0000 Brush Cytology 1.60 0.00 0.0000 Anesthesia 5.03 4.13 0.0003 Fluorescein 0.00 4.13 0.0000 Endoscopy Suite 5.03 4.13 0.0003

Comprehensive transcriptome analysis of peripheral blood unravels key lncRNAs implicated in ABPA and asthma

Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity lung disease caused by a fungus known as Aspergillus fumigatus. It complicates and aggravates asthma. Despite their potential associations, the underlying mechanisms of asthma developing into ABPA remain obscure. Here we performed an integrative transcriptome analysis based on three types of human peripheral blood, which derived from ABPA patients, asthmatic patients and health controls, aiming to identify crucial lncRNAs implicated in ABPA and asthma. Initially, a high-confidence dataset of lncRNAs was identified using a stringent filtering pipeline. A comparative mutational analysis revealed no significant difference among these samples. Differential expression analysis disclosed several immune-related mRNAs and lncRNAs differentially expressed in ABPA and asthma. For each disease, three sub-networks were established using differential network analysis. Many key lncRNAs implicated in ABPA and asthma were identified, respectively, i.e., AL139423.1-201, AC106028.4-201, HNRNPUL1-210, PUF60-218 and SREBF1-208. Our analysis indicated that these lncRNAs exhibits in the loss-of-function networks, and the expression of which were repressed in the occurrences of both diseases, implying their important roles in the immune-related processes in response to the occurrence of both diseases. Above all, our analysis proposed a new point of view to explore the relationship between ABPA and asthma, which might provide new clues to unveil the pathogenic mechanisms for both diseases.

An investigation into biomarkers for the diagnosis of ABPA and aspergillus disease in cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease due to Aspergillus fumigatus (Af) which occurs in 10% of patients with cystic fibrosis (CF). ABPA is associated with increased morbidity and accelerated lung function decline; however, existing diagnostic criteria are nonspecific and diagnosis remains challenging. As ABPA is driven by Th2 inflammation, the aim of this study was to evaluate exhaled nitric oxide (FE NO ), eosinophilic cationic protein (ECP), peripheral eosinophil count, and bronchodilator response (BDR) in patients with CF. A prospective observational cohort study of pediatric CF patients in a tertiary center. Patients had a clinical and serologic ABPA assessment, FENO , serum ECP, peripheral eosinophil count, and assessment of BDR. Patients were stratified into threegroups; ABPA, Af sensitized (AFS), and non-ABPA non-Af-sensitized (non-AFS). A total of 62 patients were included in the study: 13% ABPA, 19% AFS, and 68% non-AFS. Mean FENO was higher in the ABPA group at 37.8 ppb compared to AFS 15.1 ppb (P = .05) and non-AFS 13.7 ppb (P = .04). Mean peripheral eosinophil count in ABPA group was also higher at 1000 cells/uL, compared to AFS 221 cells/uL (P = .03) and non-AFS 220 cells/uL (P = .03). Mean BDR in ABPA group was 13% compared to 5.5% in non-AFS (P = .01). Serum ECP was higher in patients with ABPA positive compared to the other groups, although this was not statistically significant. In children with cystic fibrosis, FENO and peripheral eosinophil counts are elevated in ABPA compared to those that are just sensitized to Aspergillus and may serve as useful diagnostic tests.

Case of seropositive allergic bronchopulmonary aspergillosis in a 10-year-old girl without previously documented asthma.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease due to bronchial colonization of Aspergillus fumigatus that occurs in susceptible patients with asthma or cystic fibrosis. A 10-year-old girl was referred to the Department of Pediatric Pulmonology for persistent consolidations on chest radiography. Pulmonary consolidations were observed in the right upper and left lower lobes and were not resolved with a 4-week prescription of broad-spectrum antibiotics. The patient had a history of atopic dermatitis and allergic rhinitis but no history of asthma. She had no fever but produced thick and greenish sputum. Her breathing sounds were clear. On laboratory testing, her total blood eosinophil count was 1,412/mm3 and total serum IgE level was 2,200 kU/L. Aspergillus was isolated in the sputum culture. The A. fumigatus-specific IgE level was 15.4 kU/L, and the Aspergillus antibody test was also positive. A chest computed tomography scan demonstrated bronchial wall thickening and consolidation without bronchiectasis. An antifungal agent was added but resulted in no improvement of pulmonary consolidations after 3 weeks. Pulmonary function test was normal. Methacholine provocation test was performed, revealing bronchial hyperreactivity (PC20=5.31 mg/mL). Although the patient had no history of asthma or bronchiectasis, ABPA-seropositivity was suspected. Oral prednisolone (1 mg/kg/day) combined with antifungal therapy was started. Pulmonary consolidations began decreasing after 1 week of treatment and completely resolved after 1 month. This is the first observed and treated case of seropositive ABPA in Korean children without previously documented asthma.

일부 종합 병원 로비의 공기 중 엔도톡신 농도에 미치는 환경 요인 평가

Backgrounds: Endotoxin, which found in the outer membrane of the gram-negative bacteria cell wall, makes up almost all of the lipopolysaccharide(LPS). When people are exposed to endotoxin,it can result in diverse health effects such as an airway irritation and inflammation, fever, malaise, bronchitis, allergic asthma, toxic pneumonitis, hypersensitivity lung disease. Cases among the elderly, children or pregnant can occur more frequently than a healthy adult if they are repeatedly exposed to the existing endotoxin. Therefore, we investigated and assessed the environmental characteristics associated with the airborne endotoxin concentration level in six hospital lobbies. Method: Endotoxin from indoor air in six hospital lobbies was measured by an area sampling method and analyzed according to American Society for Testing and Materials International(ASTM international) E2144-01. Total suspended particulate(TSP), carbon dioxide(<TEX>$CO_2$</TEX>), temperature and humidity were also measured by using direct reading measurements or airborne sampling equipment at the same time. Environmental characteristics were appropriately divided into two or three groups for a statistics analysis. One-way analysis variable(one-way ANOVA) was used to examine a difference of the endotoxin concentration, depending on the environmental characteristics. In addition, only variables with p-value(p<0.25) were eventually designed to the best model by using multiple regression analysis. Results: The correlation analysis result indicated that TSP(p=0.003) and <TEX>$CO_2$</TEX>(p<0.0001) levels were significantly associated with endotoxin concentration levels. In contrast, temperature(p<0.068) and humidity(p<0.365) were not associated with endotoxin concentration. Levels of endotoxin concentration were statistically different among the environmental characteristics of Service time(p=0.01), Establishment of hospital(p<0.001), Scale of hospital(p=0.01), Day average people using hospital(p=0.03), Cleaning time of lobby(p=0.05), Season(p<0.001), and Cleaning of ventilation system(p<0.001) according to ANOVA. Finally, the best model(Adjusted R-square=72%) that we designed through a multiple regression test included environmental characteristics related to Service time, Area of lobby, Season, Cleaning of ventilation system, and Temperature. Conclusions: According to this study, our result showed a normal level of endotoxin concentration in the hospital lobbies and found environmental management methods to reduce the level of endotoxin concentration to a minimum. Consequently, this study recognized to be requirement for the management of ventilation systems and an indoor temperature in order to reduce the level of endotoxin concentration in the hospital lobbies.

Allergic Aspects of Aspergillosis

Aspergillus species and principally A. fumigatus cause a spectrum of pulmonary diseases depending on underlying host genetic risk factors. These include invasive aspergillosis, hypersensitivity lung disease, allergic asthma, allergic bronchopulmonary aspergillosis, and mycetomas. These disorders, pathogenesis and host risk factors will be discussed.

Immunopathology and Immunogenetics of Allergic Bronchopulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 hypersensitivity lung disease in response to Aspergillus fumigatus that affects asthmatic and cystic fibrosis (CF) patients. Sensitization to A. fumigatus is 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 to Aspergillus allergens, 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 to A. fumigatus antigens. 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.

Bipolarishawaiiensisas etiologic agent of allergic bronchopulmonary mycosis: first case in a paediatric patient

Allergic bronchopulmonary mycosis (ABPM) is a worldwide hypersensitivity lung disease of multiple etiologies with Aspergillus fumigatus as the most common etiologic agent. We report the first instance of Bipolaris hawaiiensis causing ABPM in a paediatric patient. A six-year-old girl presented in June 2009 with productive cough, exertional dyspnoea, occasional wheezing, restricted air entry in left infra-scapular and infra-axillary areas, 7% eosinophils (absolute count 540/mm(3)) and total IgE 1051.3 IU/m in the sera. Bronchoscopy revealed narrowing of left main bronchus and mucoid impaction of the left lower lobe segmental bronchi. Cytological examination of BAL revealed few eosinophils, Charcot-Leyden crystals and mucus embedded hyphae. Examination of KOH wet mounts of repeated sputum and BAL specimens revealed septate, brownish hyphae and culture of the specimens resulted in the isolation of multiple colonies of a fungus later identified as B. hawaiiensis based on phenotypic characters and sequencing of internal transcribed spacer and D1/D2 regions of rDNA. In addition, (1-3)-β-D-glucan was demonstrated in serum (316 pg/ml) by Fungitell kit, supportive of fungal infection/colonization. Histopathologic studies of a bronchial biopsy revealed necrotic debris, macrophage aggregates, lymphocytes, polymorphs and PAS positive hypae. The patient was administered oral itraconazole for 12 weeks, intravenous liposomal amphotericin B for one month, weekly bronchoscopic suctioning and voriconazole instillation, resulting in reduced mucopurulent secretions and considerable clinical improvement. A serum sample collected on 5 November demonstrated precipitins against antigens of the B. hawaiiensis isolate. In March 2010, intradermal skin testing revealed a strong, type I hypersensitivity (induration diam-12 mm) against B. hawaiiensis. The patient relapsed with wheezing and difficulty in respiration in April 2010. Considering the positive type I cutaneous hypersensitivity, the aforementioned laboratory and clinical observations, the patient was finally diagnosed as having ABPM and was successfully treated with oral prednisone. A high index of clinical suspicion with requisite investigations is crucial for early diagnosis and appropriate therapy of ABPM in order to prevent the late sequelae of irreversible broncho-pulmonary damage.

Allergic Bronchopulmonary Aspergillosis in Asthma and Cystic Fibrosis

Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 hypersensitivity lung disease in response to Aspergillus fumigatus that affects asthmatic and cystic fibrosis (CF) patients. Sensitization to A. fumigatus is 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 to Aspergillus allergens, 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 to A. fumigatus antigens. 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.

Effect of a CD4-Depleting Antibody on the Development ofCryptococcus neoformans-Induced Allergic Bronchopulmonary Mycosis in Mice

Allergic bronchopulmonary mycosis (ABPM) is a hypersensitivity lung disease in which fungal colonization is accompanied by an allergic response to the fungus. Using a mouse model of ABPM caused by Cryptococcus neoformans infection of C57BL/6 mice, the goal of the present studies was to determine the effect of the CD4-depleting monoclonal antibody GK1.5 on the development of the allergic responses seen during active fungal infection. These results would provide insight into the role of CD4(+) T cells in this disease. Our results show that GK1.5 treatment resulted in attenuation of pulmonary inflammation and eosinophilia in these animals. These mice also had reduced T2 cytokine production and no serum immunoglobulin E production. Absence of CD4(+) T cells did not affect recruitment of CD8(+) T cells to the site of infection; however, the numbers of CD19(+) B cells were severely reduced in the lungs of CD4(+) T-cell-depleted animals. We also examined changes in the pulmonary architecture and found that depletion of CD4(+) T cells was associated with a significant reduction in mucus production and goblet cell metaplasia in these mice. Interestingly, attenuation of Th2 responses in CD4(+) T-cell-depleted animals did not increase the fungal load in their lungs. We also compared development of ABPM in young and mature mice and did not find any differences at any of the time points. Overall, our results show that depletion of CD4(+) T cells prevents the development of Th2 responses seen during ABPM.

Genetic and respiratory tract risk factors for aspergillosis: ABPA and asthma with fungal sensitization.

Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 allergic hypersensitivity lung disease due to bronchial colonization of Aspergillus fumigatus that affects 1-2% of asthmatic and 7-9% of cystic fibrosis (CF) patients. We hypothesize that genetic risk factors predispose these patients to develop ABPA. We previously reported HLA-DR2 and DR5 restriction as a risk factor for the development of ABPA. We further propose that HLA-DR restriction is necessary but not sufficient for the development of ABPA. Recently, we reported that IL-4Rα single nucleotide polymorphisms (SNP) and in particular the ile75val SNP in the IL-4 binding region is another risk factor and is associated with increased sensitivity to IL-4 stimulation. It has been reported that the combination of IL-4Rα and IL-13 SNP, ile75val/arg110gln, is associated with more severe asthma. In preliminary studies, we have observed increased frequency of this combination in ABPA asthmatic and CF patients. Another genetic risk factor reported by Brouard et al. is the -1082 GG genotype in the IL-10 promoter in CF patients for the colonization of A. fumigatus and development of ABPA. This genotype was associated with increased plasma IL-10 levels, and perhaps may be associated with increased skewing of Th2 Aspergillus responses rather than down-regulation of inflammatory responses. We hypothesize that increased sensitivity of IL-4 mediated activities secondary to polymorphisms IL-4R in conjunction of other polymorphisms such as IL-13 and IL-10 in conjunction with HLA-DR2/DR5 restriction to Aspergillus antigens in ABPA patients result in increased B-cell activity, monocyte/dendritic cell phenotype that skews Th2 responses, and skewing of Aspergillus-specific Th2 cells. This model system may be applicable to other fungi such as Alternaria and Cladosporium which is associated with increased asthma severity.

Methotrexate pulmonary toxicity

Methotrexate is a commonly prescribed antineoplastic and immune modulating compound that has gained wide acceptance in the management of rheumatoid arthritis, psoriasis, sarcoidosis and a number of neoplastic disorders. Although generally considered safe and easy to use, methotrexate has been associated with a number of adverse reactions. Pulmonary toxicity has been well-described and may take a variety of forms. Pulmonary infiltrates are the most commonly encountered form of methotrexate pulmonary toxicity and these infiltrates resemble hypersensitivity lung disease. This discussion focuses primarily on low-dose methotrexate pulmonary toxicity and will discuss the diagnosis using clinical, pulmonary function, radiographical and pathological manifestations. Suggestions for clinical monitoring to detect adverse effects are given. In addition, management of pulmonary toxicity through discontinuation of the methotrexate, support and possibly the administration of corticosteroids is discussed.

Ultraviolet Radiation Downregulates Allergy in Balb/c Mice

The immunosuppressive effects of exposure to ultraviolet radiation (UVR) are well known and the underlying mechanisms extensively studied. The suppression of Th1 appears to account for UVR suppression of contact hypersensitivity and delayed-type hypersensitivity responses and increased susceptibility to certain infections and tumor development. The underlying mechanisms suggest Th2-mediated responses associated with immediate-type hypersensitivity and allergic lung disease should be unchanged or possibly enhanced by UVR. The hypothesis that UVR exposure enhances allergic lung disease in BALB/ c mice was tested. Effects of UVR on sensitization and elicitation of respiratory hypersensitivity were assessed using a fungal extract Metarhizium anisopliae (MACA), as the allergen. BALB/ c mice were sham or UVR (8 KJ/m2) exposed 3d before involuntary aspiration (IA) of MACA or vehicle. The mice received UVR exposures before the first and second of three IAs in the sensitization protocol and 3 d before the fourth IA in the elicitation protocol. Serum and bronchoalveolar lavage fluid (BALF) were harvested before (d 21, sensitization/d 24, elicitation) and at 1 (d 22/d 28), 3 (d 24/d 29), and 7 (d 28/d 35) d following the last IA. UVR exposure prior to sensitization suppressed two hallmarks of allergic disease, immune-mediated inflammation (eosinophil influx) and total immunoglobulin (Ig)E compared to the sham-UVR controls. There were no differences attributable to UVR exposure in previously sensitized mice. These data suggest that UVR exposure prior to sensitization suppresses allergic responses but has no effect on the elicitation of allergic responses in previously sensitized individuals. Consequently, there is no evidence that exposure to UVR enhances the induction or expression of allergic lung disease.

Immunopathogenesis of allergic bronchopulmonary aspergillosis and airway remodeling.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease clinically characterized by manifestation of wheezing, pulmonary infiltrates and bronchiectasis and fibrosis which afflicts asthmatic and cystic fibrosis (CF) patients. The pathophysiologic mechanisms are mediated by a first and direct interaction of Aspergillus fumigatus (Af) antigens with airway epithelial cells, followed by an immunologic/allergic inflammatory response to Af antigens. In the first phase, Af proteases directly activate epithelial cells by damaging the epithelial integrity and by a direct interaction with epithelial cells, resulting in a rapid wave of pro-inflammatory cytokines and chemokines that initiates an inflammatory response. During the second phase, this fungus induces a strong Th2-type immunological response with markedly elevated Aspergillus-specific and total serum IgE levels and a strong eosinophilic inflammatory response. It is proposed that strong repair reactions, similar to that described for asthmatic patients, are induced by fungal proteinases followed by concurrent release of epithelial derived growth factors. Furthermore, Th2-type cytokines e.g. IL-4 and IL-13 and proteases from inflammatory cells and mast cells, will also promote the release of growth factors from airway epithelial cells driving a strong and irreversible remodeling reactions in airways of patient with ABPA, resulting in bronchiectatic lesions and fibrosis.

Lymphocytes in allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease mediated by an allergic late-phase inflammatory response to Aspergillus fumigatus antigens. ABPA is characterized by markedly elevated Aspergillus-specific and total IgE levels and eosinophilia, and manifested by wheezing, pulmonary infiltrates and bronchiectasis and fibrosis, which affect asthmatic and cystic fibrosis (CF) patients. In the pathogenesis of ABPA, A. fumigatus proteases play a role in facilitation of antigen transport across the epithelial cell layer by damaging the epithelial integrity and by a direct interaction with epithelial cell surface receptors, resulting in pro-inflammatory cytokine production and corresponding inflammatory responses. In genetically susceptible asthmatic and CF patients, this leads to an allergic inflammatory response to Aspergillus allergens. A genetic susceptibility is HLA-DR restriction demonstrated by increased frequency of HLA-DR2 and/or DR5 and lack HLA-DQ2. IL-4 plays a central role in the development of allergic inflammatory responses. Our group has demonstrated that ABPA patients have increased sensitivity to IL-4 stimulation and skewing of Th2 responses to Aspergillus allergens in ABPA subjects and a Th1 response in non-ABPA subjects. Interestingly, Aspergillus allergens stimulate IL-10 synthesis is both ABPA and non-ABPA subjects.

Selected recombinant Aspergillus fumigatus allergens bind specifically to IgE in ABPA.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease resulting from exposure to Aspergillus fumigatus allergens. Patients with ABPA show elevated Aspergillus-specific serum IgE, a major criterion used in the diagnosis of the disease. Crude culture filtrate and mycelial antigens have been used widely to demonstrate IgE antibody to Aspergillus in the sera of patients. While these antigens have been useful in the diagnosis of ABPA, occasionally they present inconsistency in their reactivity and lack of specificity. Although in recent years, a number of purified A. fumigatus allergens have been produced by molecular cloning, no attempt was made to evaluate them systematically. To evaluate the recombinant proteins from A. fumigatus for their IgE antibody binding, we studied sera from ABPA patients and controls by antigen specific enzyme linked immunosorbent assay (ELISA). Recombinant Aspergillus allergens Asp f 1, f 2, f 3, f 4, and f 6 were studied for their specific binding to IgE in the sera of ABPA patients, A. fumigatus skin prick test positive asthmatics, and normal controls from the USA and Switzerland. The sera were blinded and studied by ELISA in two different laboratories. All the recombinant allergens showed IgE antibody binding with sera from patients with ABPA, whereas only fewer asthmatics and normal sera showed significant binding. The three selected recombinant allergens together reacted with all the ABPA patients studied. The results demonstrate that Asp f 2, f 4, and f 6 can be used in the serodiagnosis of ABPA, while IgE antibody binding to Asp f 1 and f 3 was not specific.

Hypersensitivity Pneumonitis Due to Humidifier Disease: Seek and Ye Shall Find

This study reports a classic case of hypersensitivity pneumonitis (HP) with classic histologic changes in lung tissue and the research used to identify the causative antigens. A patient with clinical, radiographic, pulmonary function abnormalities and a lung biopsy consistent with HP had no identifiable antigen exposure. Evaluation of the patient's activities provided no suggestion of antigen exposure. Her home was evaluated. It was found that her humidifier ran continually without being cleaned but water was added periodically. Serologic analysis demonstrated precipitating antibodies against her humidifier water and ten antigens in the hypersensitivity lung disease serologic panel. Removal of the humidifier, cleaning of the house, and a course of prednisone resulted in the return of the patient to a normal state.

CELL-MEDIATED IMMUNITY IN ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS

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 association of HLA-DR alleles and T cell activation with allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease caused by the mold Aspergillus fumigatus. We previously reported that the majority of T cell clones (TCC) isolated from three ABPA patients, and specific for a dominant Ag of A. fumigatus, Asp f 1, were IL-4-producing CD4+ Th2 cells capable of responding to Ag in association with the HLA-DR subtypes DRB1*1501, *1503, and *1601 for HLA-DR2, and DRB1*1101, *1104, and *1202 for HLA-DR5. In the present study we extended the previous findings to determine whether the observed restriction with the HLA-DR2/5 subtypes held importance in a larger patient population. Serotyping revealed that 16 of 18 ABPA patients were either HLA-DR2, HLA-DR5, or both. Compared with a normal control population, the frequencies of HLA-DR2 (50 vs 22.3%) and HLA-DR5 (44.4 vs 19.8%) were significantly increased in these ABPA patients. Genotype analyses of an additional 15 patients identified the same HLA-DR subtypes previously shown functional for Asp f 1 Ag presentation. The relative avidities of Asp f 1 peptides for the purified HLA-DR subtypes, DRB1*1501 (functional) and DRB1*1502 (nonfunctional), were examined to determine whether differential binding to the HLA-DR subtypes explains successful Ag presentation. Similar low binding avidities were detected for both HLA-DR subtypes, indicating that the functionality cannot be simply explained by differences in binding affinities. Thus, the limited number and their role in Ag presentation emphasizes the possibility that the six identified HLA-DR subtypes are important in the pathophysiology of ABPA.

Pulmonary involvement in unusual multisystem disorders.

The clinical syndrome of interstitial lung disease encompasses a number of clinical disorders that affect the alveolar walls, interstitium, and vicinal structures including small airway and pulmonary vasculature. The syndrome has more than 200 causes including bacterial, viral, fungal, protozoal, and parasitic infections; collagen vascular disorders including systemic lupus erythematosus, rheumatoid arthritis, progressive systemic sclerosis, ankylosing spondylitis, mixed connective tissue disease, Sjögren's syndrome, and various vasculitides; hypersensitivity lung disease or extrinsic allergic alveolitis; inorganic neumoconioses including silicosis, asbestosis, and berylliosis; drug-induced and iatrogenic entities; and disorders of unknown origin including sarcoidosis, idiopathic pulmonary fibrosis, eosinophilic granulomatosis, lymphangioleiomyomatosis, and bronchiolitis obliterans-organizing pneumonitis. Apart from these, there are many uncommon metabolic and immune disorders that can involve pulmonary interstitium. Recently developed epidemiologic, immunologic, and molecular biology techniques undoubtedly will add to the list other entities that may produce interstitial lung disease.