Pathogenic microorganisms often thrive in the inflammatory milieu of the bronchiectatic airway where innate and adaptive defence mechanisms can be impaired. Although genetic defects of the adaptive immune system causing immunodeficiency syndromes are well characterised, genetic defects that impair the recognition of microbes by the innate immune system have only recently been identified.1 For example, polymorphisms in the gene for mannose-binding lectin (MBL), a receptor of the innate immune system that recognises microbial carbohydrates, can lead to deficiency of MBL and increased susceptibility to infection.

When the lungs are exposed to a new pathogen, the first line of defence is the innate immune system, which results in a swift and semi-specific response. Cells of the innate immune system, which include dendritic cells and macrophages, recognise highly conserved structures called pathogen-associated molecular patterns (PAMPs) that are shared by large groups of microorganisms. PAMPs are recognised by pattern-recognition receptors, which activate the cells of the innate immune system to rapidly attack and kill microbes.2

MBL is a soluble pattern-recognition receptor that is synthesised in the liver and is released into the systemic circulation as a component of the acute-phase response. It is not produced locally in the lungs and is thought to leak into the airways and alveoli from the systemic circulation, particularly in the presence of inflammation.3 MBL binds to various respiratory pathogens including Haemophilus influenzae and Pseudomonas aeruginosa, which are commonly identified in the airways of patients with bronchiectasis, and enhances the killing of these organisms by activation of the lectin complement pathway and by facilitating phagocytosis by opsonisation.4

In The Lancet Respiratory Medicine, James Chalmers and colleagues report a large, prospective study5 assessing the relation between MBL deficiency and clinical outcomes during a 4 year follow-up of patients with non-cystic fibrosis bronchiectasis. 55 (12%) of 470 patients with bronchiectasis had genotypes associated with MBL deficiency. These patients had more frequent exacerbations and were more likely to be chronically colonised with bacteria, particularly by P aeruginosa, than were patients with genotypes not associated with MBL deficiency. One strength of the study was the measurement of both MBL deficient genotypes and serum concentrations, which were strongly correlated. Serum MBL deficiency (<200 ng/mL) was also associated with increased exacerbation frequency.

The results of Chalmers and colleagues’ study5 are consistent with the findings from studies of patients with cystic fibrosis in which MBL deficiency has been associated with increased severity of disease. In patients with cystic fibrosis, MBL deficiency results in earlier acquisition of P aeruginosa, reduced pulmonary function, and increased mortality.6 However, a retrospective study7 of patients with non-cystic fibrosis bronchiectasis reported no association between low MBL concentrations and exacerbation frequency. Several conflicting results have also been published from studies8 assessing the association between low levels of MBL and acute exacerbations of chronic obstructive pulmonary disease.

What are the clinical implications of Chalmers and colleagues’ study? The study provides evidence that MBL deficiency is a new risk factor for infection and acute exacerbations in patients with non-cystic fibrosis bronchiectasis. Identification of patients at high risk of development of severe disease could direct clinicians to undertake more intensive management and follow-up of these patients with a view to reducing rates of hospital admission and mortality. Such stratification is increasingly relevant because of the growing range of treatments that is emerging for bronchiectasis. These treatments include long-term azithromycin, nebulised gentamicin, inhaled mannitol, inhaled dry powder ciprofloxacin, and nebulised liposomal ciprofloxacin. Recombinant human MBL might also become a treatment option, after it was reported in a phase 1 study9 to be safe, well tolerated, and able to restore activity of the lectin pathway of complement.

A standard definition of clinically significant MBL deficiency is not presently available but a diagnostic approach that incorporates both serum concentrations and genotyping seems sensible. Some patients with genotypes that are not associated with deficiency can still have very low MBL serum concentrations and, alternatively, serum concentrations can increase with the acute-phase response. One pragmatic approach analogous to that recommended by the American Thoracic Society and European Respiratory Society for α1-antitrypsin deficiency might be for clinicians to initially measure the serum concentration of MBL in patients with bronchiectasis. If the serum level is low, genotyping could then be undertaken. A cutoff of 200 ng/mL, as used in the study by Chalmers and colleagues, classified 19% of patients with bronchiectasis as MBL deficient. Better access to testing facilities and further studies are required to confirm the findings of the present study5before testing for MBL deficiency becomes routine practice in non-cystic fibrosis bronchiectasis. The present findings also raise some interesting questions for future research. MBL deficiency is relatively common in the general population and does not seem to predispose to an increased risk of infection in the absence of other predisposing factors. How do other predisposing factors interact with MBL deficiency to increase the risk of infection and cause severe disease or poor longitudinal outcomes in bronchiectasis? Could serial MBL concentrations in serum and sputum be used as markers for early detection of exacerbations or determination of the duration of antibiotic treatment? Does azithromycin interact with MBL to improve phagocytic activity in macrophages? Although some evidence suggests that azithromycin increases mannose receptor (a pattern-recognition receptor in the same family as MBL) expression and phagocytic activity in alveolar macrophages, the effect of azithromycin on MBL expression is unclear.

Source: lancet