James D Chalmers1, Brian J McHugh2, Catherine Doherty3, Maeve P Smith4, John R Govan3, David C Kilpatrick5, Adam T Hill4. 1. Tayside Respiratory Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. Electronic address: jameschalmers1@nhs.net. 2. MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK. 3. School of Medicine and Veterinary Medicine, Cystic Fibrosis Group, and Centre for Infectious Diseases, University of Edinburgh, Edinburgh, UK. 4. Department of Respiratory Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK. 5. Scottish National Blood Transfusion Service, Edinburgh, UK.
Abstract
BACKGROUND: Mannose-binding lectin (MBL) is a key component of innate immunity. MBL deficiency is common (10-30% of the general population depending on the definition used) and has been associated with disease progression in cystic fibrosis. We aimed to assess the effect of MBL deficiency on disease severity in non-cystic fibrosis bronchiectasis. METHODS: We recruited patients with non-cystic fibrosis bronchiectasis and age-matched and sex-matched controls at a specialist bronchiectasis clinic in Edinburgh, UK. We assessed MBL function with genotyping (low-expressing genotype [deficiency] defined as homozygosity for exon 1 mutations [YO/YO] or compound heterozygosity [XA/YO]; YA/YO and XA/XA genotypes were defined as intermediate-expressing with all other genotypes defined as high-expressing) and serum measurements (deficiency defined with two parameters: <500 ng/mL or <200 ng/mL). We assessed rates of exacerbation, chronic bacterial colonisation, and lung function during 4 years of follow-up. FINDINGS: We included 470 patients with bronchiectasis and 414 controls. MBL genotype frequencies and MBL serum concentrations did not differ between patients and controls. 55 (12%) patients with bronchiectasis had low-expressing genotypes. These patients had a mean of 2·7 exacerbations per year (SD 1·8), compared with 1·9 per year (1·2) for 135 patients with intermediate-expressing genotypes and 1·9 per year (1·3) for 280 patients with high-expressing genotypes (p<0·0001). Chronic colonisation with bacteria was most frequent in patients with low-expressing genotypes (47 [85%] patients vs 82 [61%] patients with intermediate-expressing genotypes and 183 [65%] patients with high-expressing genotypes; p=0·0041); especially P aeruginosa colonisation (19 [35%] patients vs 13 [10%] patients and 36 [13%] patients; p<0·0001). Patients with low-expressing genotypes were more likely to be admitted to hospital for severe exacerbations during follow-up (27 [49%] patients vs 42 [31%] patients and 87 [31%] patients; p=0·032). Patients with low-expressing genotypes also had increased scores for radiological severity and worse quality of life compared with the other two groups. MBL serum deficiency (<200 ng/mL) was associated with increased exacerbations, hospital admissions, and radiological severity. When <500 ng/mL was used as the definition of deficiency, the associations with exacerbation frequency and radiological severity were no longer significant. INTERPRETATION: MBL might be an important modifier of disease severity in non-CF bronchiectasis. FUNDING: UK Medical Research Council, UK Chief Scientists Office.
BACKGROUND: Mannose-binding lectin (MBL) is a key component of innate immunity. MBL deficiency is common (10-30% of the general population depending on the definition used) and has been associated with disease progression in cystic fibrosis. We aimed to assess the effect of MBL deficiency on disease severity in non-cystic fibrosis bronchiectasis. METHODS: We recruited patients with non-cystic fibrosis bronchiectasis and age-matched and sex-matched controls at a specialist bronchiectasis clinic in Edinburgh, UK. We assessed MBL function with genotyping (low-expressing genotype [deficiency] defined as homozygosity for exon 1 mutations [YO/YO] or compound heterozygosity [XA/YO]; YA/YO and XA/XA genotypes were defined as intermediate-expressing with all other genotypes defined as high-expressing) and serum measurements (deficiency defined with two parameters: <500 ng/mL or <200 ng/mL). We assessed rates of exacerbation, chronic bacterial colonisation, and lung function during 4 years of follow-up. FINDINGS: We included 470 patients with bronchiectasis and 414 controls. MBL genotype frequencies and MBL serum concentrations did not differ between patients and controls. 55 (12%) patients with bronchiectasis had low-expressing genotypes. These patients had a mean of 2·7 exacerbations per year (SD 1·8), compared with 1·9 per year (1·2) for 135 patients with intermediate-expressing genotypes and 1·9 per year (1·3) for 280 patients with high-expressing genotypes (p<0·0001). Chronic colonisation with bacteria was most frequent in patients with low-expressing genotypes (47 [85%] patients vs 82 [61%] patients with intermediate-expressing genotypes and 183 [65%] patients with high-expressing genotypes; p=0·0041); especially P aeruginosa colonisation (19 [35%] patients vs 13 [10%] patients and 36 [13%] patients; p<0·0001). Patients with low-expressing genotypes were more likely to be admitted to hospital for severe exacerbations during follow-up (27 [49%] patients vs 42 [31%] patients and 87 [31%] patients; p=0·032). Patients with low-expressing genotypes also had increased scores for radiological severity and worse quality of life compared with the other two groups. MBL serum deficiency (<200 ng/mL) was associated with increased exacerbations, hospital admissions, and radiological severity. When <500 ng/mL was used as the definition of deficiency, the associations with exacerbation frequency and radiological severity were no longer significant. INTERPRETATION: MBL might be an important modifier of disease severity in non-CF bronchiectasis. FUNDING: UK Medical Research Council, UK Chief Scientists Office.
Authors: James D Chalmers; Gilly B Fleming; Julia Rutherford; Misao Matsushita; David C Kilpatrick; Adam T Hill Journal: Inflammation Date: 2014-10 Impact factor: 4.092
Authors: James D Chalmers; Pieter Goeminne; Stefano Aliberti; Melissa J McDonnell; Sara Lonni; John Davidson; Lucy Poppelwell; Waleed Salih; Alberto Pesci; Lieven J Dupont; Thomas C Fardon; Anthony De Soyza; Adam T Hill Journal: Am J Respir Crit Care Med Date: 2014-03-01 Impact factor: 30.528
Authors: Jyotshna Mandal; Bijaya Malla; Rudi Steffensen; Luigi Costa; Adrian Egli; Marten Trendelenburg; Francesco Blasi; Kostantinos Kostikas; Tobias Welte; Antoni Torres; Renaud Louis; Wim Boersma; Branislava Milenkovic; Joachim Aerts; Gernot G U Rohde; Alicia Lacoma; Katharina Rentsch; Michael Roth; Michael Tamm; Daiana Stolz Journal: Respir Res Date: 2015-12-18