Mannose binding lectin deficient haplotypes are associated with fewer exacerbations and a more diverse microbiome in chronic obstructive pulmonary disease

Rationale: Mannose binding lectin (MBL) is a pro-inflammatory protein involved in bacterial clearance. Genetic deficiency of MBL is found in up to 10% of humans. In chronic airway inflammatory diseases, such as cystic fibrosis and bronchiectasis, MBL deficiency is associated with increased exacerbations and earlier mortality. We investigated whether MBL deficiency was associated with increased exacerbations and other clinical outcomes in patients with COPD, and if there was an association between MBL deficiency and lung microbiome diversity.

Methods: 1796 COPD patients enrolled in the Tayside Allergies & Respiratory Disease Information System (TARDIS) study were evaluated for haplotypes associated with MBL deficiency. MBL status was analysed for its association with exacerbations (including severe exacerbations requiring hospital admission), FEV1 decline, and mortality. Subsequently, an observational sub-cohort of 173 COPD patients, recruited according to MBL genotype and not on long-term antibiotics, were followed for 6 months to determine if MBL deficiency was associated with altered respiratory microbiota profiles, determined by 16S rRNA sequencing on the Illumina MiSeq platform, or with an altered airway inflammation profile during stable and exacerbated COPD.

Results: Patients with a MBL deficient haplotype were less likely to be hospitalised for exacerbations (Odds ratio 0.66, 95% CI 0.48 - 0.90, P= 0.009), or to have a moderate or severe exacerbation (Odds ratio 0.77, 95% CI 0.60 - 0.99. P= 0.047). There was no difference in rate of FEV1 decline or mortality between individuals with MBL deficient or non-deficient haplotypes. In the longitudinal cohort study, MBL deficient and non-deficient patients were well matched in terms of MRC dyspnoea, SGRQ, CAT and GOLD scores and Percent Predicted FEV1. Sputum EN-RAGE showed increased concentrations (P= 0.005) in stable non-deficient haplotype patients compared to stable deficient haplotype patients; all other airway inflammatory markers showed no significant difference. MBL deficient patients had a more diverse lung microbiome (P= 0.02) as determined by Shannon-Wiener Diversity Index (S-WDI), which accounts for abundance and evenness of the taxa present; S-WDI in this cohort was associated with more severe COPD as determined by the GOLD score (P = 0.01).