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Ige-Mediated Immune Responses and Airway Detection of Aspergillus and Candida in Adult Cystic Fibrosis

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Ige-Mediated Immune Responses and Airway Detection of Aspergillus and Candida in Adult Cystic Fibrosis CHEST Original Research GENETIC AND DEVELOPMENTAL DISORDERS IgE-Mediated Immune Responses and Airway Detection of Aspergillus and Candida in Adult Cystic Fibrosis Caroline G. Baxter , PhD ; Caroline B. Moore , PhD ; Andrew M. Jones , MD ; A. Kevin Webb , MD ; and David W. Denning , MD Background: The recovery of Aspergillus and Candida from the respiratory secretions of patients with cystic fi brosis (CF) is common. Their relationship to the development of allergic sensitization and effect on lung function has not been established. Improved techniques to detect these organ- isms are needed to increase knowledge of these effects. Methods: A 2-year prospective observational cohort study was performed. Fifty-fi ve adult patients with CF had sputum monitored for Aspergillus by culture and real-time polymerase chain reaction and Candida by CHROMagar and carbon assimilation profi le (API/ID 32C). Skin prick tests and ImmunoCAP IgEs to a panel of common and fungal allergens were performed. Lung function and pulmonary exacerbation rates were monitored over 2 years. Results: Sixty-nine percent of patient sputum samples showed chronic colonization with Candida and 60% showed colonization with Aspergillus . There was no association between the recovery of either organism and the presence of specifi c IgE responses. There was no difference in lung func- tion decline for patients with Aspergillus or Candida colonization compared with those without 5 5 5 5 (FEV1 percent predicted, P .41 and P .90, respectively; FVC % predicted, P .87 and P .37, respectively). However, there was a signifi cantly greater decline in FEV1 and increase in IV anti- 5 5 biotic days for those sensitized to Aspergillus (FEV1 decline, P .03; IV antibiotics days, P .03). Conclusions: Allergic sensitization is not associated with recovery of Candida or Aspergillus from the sputum of patients with CF. Aspergillus but not Candida sensitization is associated with greater lung function decline and pulmonary exacerbations. CHEST 2013; 143(5):1351–1357 Abbreviations: CF 5 cystic fi brosis; ICS 5 inhaled corticosteroid; PCR 5 polymerase chain reaction; SABC 5 Sabouraud dextrose with chloramphenicol agar; sIgE 5 specifi c IgE; sIgG 5 specifi c IgG; SPT 5 skin prick test he incidence and diversity of fungi isolated from The prevalence of positive serologic IgE responses Tthe sputum of patients with cystic fi brosis (CF) is to A fumigatus in CF is high; up to 65% of patients increasing. The most common fi lamentous fungus cul- have values ranging from low to those consistent with tured from CF sputum is Aspergillus fumigatus and allergic bronchopulmonary aspergillosis. 3 No link has the most common yeast is Candida albicans . 1,2 been found between culture-positive sputum and the development of Aspergillus IgE sensitization. How- Manuscript received May 31, 2012; revision accepted October 16, ever, culture may not be the method of choice to eval- 2012. Affi liations: From the National Aspergillosis Centre (Drs Baxter uate this relationship because the sensitivity and the and Denning ), Manchester Adult Cystic Fibrosis Unit (Drs Baxter, repeatability of standard Aspergillus culture are low. 4 Jones, and Webb), and Mycology Reference Laboratory (Dr Moore), Although evidence supports reduced lung function University Hospital of South Manchester, and School of Trans- lational Medicine (Drs Baxter, Moore, and Denning), University with Aspergillus sensitization, the association between of Manchester, Manchester, England. colonization and lung function has not yet been estab- Funding/Support: This study was supported by the National lished and requires further prospective studies.3,5,6 Commissioning Group, National Aspergillosis Centre, University Hospital of South Manchester. Correspondence to: Caroline G. Baxter, PhD, 2nd Floor Edu- © 2013 American College of Chest Physicians . Reproduction cation and Research Centre, University Hospital of South of this article is prohibited without written permission from the Manchester, Southmoor Rd, Manchester M23 9LT, England; American College of Chest Physicians. See online for more details. e-mail: [email protected] DOI: 10.1378/chest.12-1363 journal.publications.chestnet.org CHEST / 143 / 5 / MAY 2013 1351 Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 05/15/2013 The prevalence of C albicans IgE sensitization is Following culture, the remaining sputum sample underwent lower than that of Aspergillus but is still high at a additional homogenization using sonication (Sonics VC505; 11 3 Sonics & Materials, Inc). Fungal DNA was extracted using the reported 27%. Candida species is far easier and more MycXtra DNA extraction kit (Myconostica). reliably isolated by standard culture. However, com- pared with Aspergillus , there are fewer studies of Real-Time PCR the clinical impact of Candida colonization and IgE Real-time PCR to detect Aspergillus DNA was performed on a sensitization.7,8 SmartCycler (Cepheid) using a validated commercial PCR kit tar- The primary objective of the present study was geting the 18S ribosomal gene of Aspergillus, MycAssay Aspergillus to determine whether a relationship exists between (Myconostica).12 The assay limit of blank was a crossing threshold the presence of Candida (determined by culture) or of 38 cycles. Aspergillus (determined by real-time polymerase chain Immunology reaction [PCR]) and the development of serologic A 7-mL clotted blood sample was taken from each patient for IgE responses. Secondly, the study aimed to assess fungal serology. ImmunoCAP (Phadia AB) total IgE, specifi c IgG the clinical impact of Aspergillus and Candida colo- (sIgG) to A fumigatus , and specifi c IgEs (sIgEs) to A fumigatus, nization and sensitization on lung function and pul- C albicans, Alternaria alternata, Penicillium chrysogenum (notatum) , monary exacerbation rates. and Cladosporium herbarum were measured. A cutoff level of Ն 0.4 International Units/mL was considered positive for sIgE assays, and a cutoff of . 40 mg/L was considered positive for sIgG. Materials and Methods Skin prick tests (SPTs) were performed by standard methods to a panel of 10 allergens, using the following antigens (Allergopharma): Study Design grass pollen mix, tree pollen mix, Dermatophagoides pteronyssinus (house dust mite), cat and dog dander, A fumigatus, C albicans, This prospective observational cohort study was carried out A alternata, P chrysogenum, and C herbarum .13 between October 2008 and February 2011. Approval was obtained from the South Manchester research ethics committee (07/Q1403/70). Candida Species Identifi cation Patients were invited to participate between October 2008 and Candida species identifi cation was performed using three methods February 2009 if they were aged Ն 18 years and given a diagno- for the fi rst positive sputum sample from each patient. First, the sis of CF confi rmed by genetic or sweat testing. Patients were color and appearance of the yeast colonies growing on CHROMagar enrolled during routine outpatient appointments at the Man- were recorded. This was then followed by a germ tube test. Using chester Adult Cystic Fibrosis Centre, and all gave written informed a sterile loop, a pure colony of yeast cells was inoculated into ster- consent. Patients were excluded at enrollment if they were unable ile tubes containing 0.5 mL horse serum. The tube was incubated to produce a Ն 2-mL sputum sample spontaneously or had an for 2 h at 37°C, then 10 m L was examined microscopically for the exacerbation of pulmonary symptoms requiring additional therapy. presence of germ tubes. Finally, carbon assimilation profi le was performed using the commercial API/ID 32C kit (bioMérieux SA) Lung Function and Clinical Data Collection according to manufacturer instructions. 14 Baseline demographic and clinical details were collected from Antifungal Resistance Testing medical case records. Lung function (FEV1 and FVC % predicted) at enrollment and 2 years after enrollment was obtained by docu- Each Candida colony was tested for resistance to fl uconazole menting the patient’s best lung function achieved within that year. using the European Committee on Antimicrobial Susceptibil- This method was chosen to minimize the wide variability in lung ity Testing microdilution method.15,16 A fl uconazole minimum function measurements observed in patients with CF. All lung inhibitory concentration of Յ 2 mg/L was considered sensitive, function was performed postbronchodilator by experienced clin- and . 4 mg/L was considered resistant. 16 ical staff according to European Respiratory Society guidelines.9 Total days of IV antibiotics were prospectively monitored over Statistical Analysis 2 years to examine exacerbation rates. Statistical analysis was performed using SPSS version 16 Sputum Processing and DNA Extraction (Inter national Business Machines Corp) software. Parametric data were expressed as mean Ϯ SD, and nonparametric data were Each patient was given 10 mL of sterile water and asked to expressed as medians with interquartile ranges. After natural log rinse his or her mouth for 30 s and return the water to a sterile transforma tion, simple logistic regression was performed to eval- universal container. A sputum sample was then collected without uate the asso ciations between lung function decline and clinical sputum induction. This was done to differentiate oral cavity and data. Between-group comparisons were analyzed using x 2 tests lower respiratory tract colonization. Patients provided two spu- and Mann-Whitney
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