Bronchiectasis is defined as permanently dilated airways due to chronic bronchial inflammation caused by inappropriate clearance of various microorganisms and recurrent or chronic infection1. It was once considered to be an orphan disease with fading relevance in the developed world in the late 20th century2. Although the true prevalence is unknown for most regions, bronchiectasis is now being diagnosed with increasing frequency in North America and around the globe. The rate of bronchiectasis-associated hospitalizations increased markedly, starting around age 50, with the highest rate in the oldest age groups and particularly in older women in the United States3. Currently just under 1,000 people die from bronchiectasis each year, and the mortality rate also is increasing at 3% per year in England and Wales4. Clinical features of bronchiectasis include chronic production of sputum often mucopurulent or purulent in nature, persistent bacterial colonization and recurrent lower respiratory tract infections. Symptoms include hemoptysis and breathlessness characterized by mild to moderate airflow obstruction, lethargy and reduced health status5.

Bronchiectasis is a pathological description of lung damage, namely inflamed thick walled and dilated bronchi. Such damage is the ultimate consequence of inflammation and infection arising from various causes either inherited or acquired. Cystic fibrosis is the most common inherited cause of bronchiectasis in white populations, but there is increasing recognition of significant numbers of patients with bronchiectasis from a variety of causes6. Post-infectious damage is no longer the most common cause of bronchiectasis in developed countries following the introduction of antibiotic therapy and immunization programs. Irrespective of the underlying cause, patients with bronchiectasis are often colonized with bacterial species. This indicates failure of the usual host defense to maintain sterility of the respiratory tract, so the importance of identifying immunodeficiency has been underlined7.

In this review, we will focus on the immunological abnormalities that cause bronchiectasis in patients in whom cystic fibrosis has been excluded, and discuss several controversies in the current management of this disorder.

The underlying conditions associated with bronchiectasis are listed in Table 1. It is an important question whether knowledge of the underlying medical cause leads to a change in management of patients with bronchiectasis. One study conducted in two pediatric respiratory clinics identified the etiology in 77% of cases with non-cystic fibrosis bronchiectasis. Furthermore, they found that immunodeficiency and intrinsic abnormalities accounted for the majority of cases and that knowledge of a specific causal agent led to a modification in management8. This has been confirmed in the adult setting in a study performed at a tertiary hospital in the United Kingdom9. Among 165 patients confirmed to have bronchiectasis on computed tomography scan, an underlying cause was identified in 74% of patients. Knowledge of the underlying cause directly affected management in 37% of patients. These studies suggest that investigation of the underlying causes of bronchiectasis leads to an alteration in therapy to target these specific conditions in many more cases than was previously thought, which can have significant prognostic implications. As the treatable causes of bronchiectasis, primary immune deficiency, allergic bronchopulmonary aspergillosis, nontuberculous mycobacterial infection, airway obstruction, inflammatory bowel disease, rheumatoid arthritis and aspiration can be included10.

A range of immunologic abnormalities are associated with non-cystic fibrosis bronchiectasis, and the prevalence of each in bronchiectasis varies from study to study11. Primary antibody deficiency is the most common primary immunodeficiencies12. It is characterized by a defect in the production of normal amounts of antigen-specific antibodies. These antibodies or immunoglobulins are essential for the adaptive immune response against various pathogens. A defect in antibody production causes recurrent and severe infections. Primary antibody deficiency represents a heterogeneous spectrum of conditions, including congenital agammaglobulinemia, common variable immunodeficiency, class switch recombination deficiency, selective immunoglobulin A deficiency, specific antibody deficiency, and immunoglobulin G subclass deficiency13. The key features of primary antibody deficiencies are summarized in Table 2.

Congenital agammaglobulinemia is a genetic defect which impairs antibody production of all immunoglobulin isotypes and response to vaccinations. X-linked agammaglobulinemia accounts for 85% of all cases of congenital agammaglobulinemia, and autosomal recessive forms account for the rest12. Class switch recombination deficiencies, formerly known as hyper-immunoglobulin M syndromes, are very rare conditions characterized by decreased serum immunoglobulin G and A levels, but increased immunoglobulin M levels14. Common variable immunodeficiency is an idiopathic antibody deficiency, defined by serum immunoglobulin G levels below 2 SD of normal controls in the presence of decreased immunoglobulin A and/or immunoglobulin M levels, recurrent infections, impaired response to immunization, exclusion of defined causes of hypogammaglobulinemia, and an age above 2 years15. These 3 entities (congenital agammaglobulinemia, class switch recombination deficiency, and common variable immunodeficiency) have been commonly associated with development of bronchiectasis as a clinical complication12.

Selective immunoglobulin A deficiency is defined as a decrease of serum immunoglobulin A levels below 2 SD of age-matched controls (or less than 0.07 g/L) but normal serum immunoglobulin G and M levels12,16. The clinical course is asymptomatic in many patients, and only a minority of patients develops recurrent lower respiratory tract infections and/or bronchiectasis12.

Immunoglobulin G subclass deficiency is defined as an abnormally low level of one or more immunoglobulin G subclasses in patients with normal levels of total immunoglobulin G and M. Immunoglobulin A level may also be low. Some patients with subclass deficiency exhibit impaired specific antibody production16. By the way, there is some controversy over whether deficiencies of immunoglobulin G subclasses have a role in the development of bronchiectasis. In a study estimating immune function in adults with bronchectasis, a number of subjects (14%) had low level of immunoglobulin G3, but the significance of this finding was uncertain17. Another small, single center, case-control study showed that almost half (48%) of the patients with bronchiectasis of unknown etiology have low serum concentrations of one or more immunoglobulin G subclasses, and the patients with immunoglobulin subclass deficiency revealed impaired antibody response to H. influenza type b conjugated vaccine18. A study recently conducted in Korea also showed that the frequency of immunoglobulin G subclass deficiency was high (45%) in patients with bronchiectasis of unclear etiology19. These results suggests that immunoglobulin G subclass deficiency is not an unusual cause of bronchiectasis, and that detailed investigation of humoral immune status, including the level of immunoglobulin G subclasses and antibody response to specific antigen is needed in cases of bronchiectasis without definite causes.

Finally, specific antibody deficiency is characterized by normal concentrations of immunoglobulin G, A, M and immunoglobulin G subclasses and abnormal antibody responses to polysaccharide vaccines16. The prevalence is unknown, but it may be a frequent finding in patients evaluated for recurrent respiratory tract infections. It has been proven through a number of studies that specific antibody deficiency is a recognized cause of bronchiectasis9,20,21.

The interpretation of anti-pneumococcal antibody concentration results is based on antibody increases over pre-immunization concentrations and on final concentrations following immunization. Traditionally, adequate responses to individual pneumococcal serotypes were defined as a post-immunization antibody concentration of 1.3 g/mL or higher or at least 4-fold over baseline22, but recent two reports have shown new cutoffs for identifying individual with an inadequate response to vaccine23,24.

Bronchiectasis occurring unrelated to cystic fibrosis is a common and difficult respiratory condition to manage. However, it has historically received little attention, and many of the recommendations for its management have been extrapolated from the studies for the management of cystic fibrosis rather than based on appropriate research25. In 2010, British Thoracic Society extensively reviewed this condition and first developed a comprehensive guideline for its management26. In this section, we will discuss recent evidences of therapeutic options available to treat patients with non-cystic fibrosis bronchiectasis.

Awareness of non-cystic fibrosis bronchiectasis has increased over the past few years with a concomitant increase in publications. Investigation of the underlying cause of bronchiectasis is the most important key to effective management. The uses of intravenous immunoglobulin is helpful in reducing the frequency of infection and preventing further airway destruction in selected patients with primary immune deficiencies. The effectiveness of long-acting beta agonists with or without inhaled corticosteroid and long-acting anticholinergics is uncertain. New inhaled antibiotics under investigation are expected to be used for controlling recurrent infections. Patients with selective antibody deficiency may benefit from additional immunization with conjugate pneumococcal vaccines. There is a clear need for well designed large-scale randomized trials to answer these questions regarding the optimum therapeutic approach for the patients with bronchiectasis.