INTRODUCTION
Bronchiectasis is a heterogeneous disease characterized by abnormal dilatation and distortion of bronchi associated with recurrent respiratory tract infections and sputum production.[1] It is a progressive disease associated with high morbidity and reduced quality of life.[2]The management of bronchiectasis focuses mainly on two aspects: sputum clearance and appropriate use of antibiotics. Identifying the aetiology will refine the management.[3]
Bronchiectasis can be considered as an end result of multiple factors. It is a heterogeneous disease with varying clinical, radiological and microbiological features.[4] The most common cause for bronchiectasis is post-infective sequelae.[3,5,6] Other important causes include ciliary dyskinesia, allergic bronchopulmonary aspergillosis (ABPA), immunodeficiency and connective tissue disorders.[7] In many cases, no specific aetiology is found.[5] In developed countries, childhood immunizations, early and frequent use of antibiotics, and improved sanitation and nutrition have led to a reduced incidence of non-cystic fibrosis bronchiectasis.[8] However in developing countries like India, tuberculosis and other infections are the leading aetiology.[9]
The primary objective of this study was to evaluate the prevalence of humoral immune deficiency in a cohort of adult patients with bilateral non-infectious bronchiectasis.
METHODS
This is a single-site study conducted within the department of pulmonary medicine at Christian Medical College (Vellore, India) from February 2015 to July 2016. Both outpatient and inpatient adults with (HRCT) high-resolution computed tomography-proven non-infectious bronchiectasis were recruited to participate. Patients were triaged according to the protocol illustrated in Figure 1. Ethics committee agreed the project on 8-12-2014.
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Figure 1: Algorithm for bronchiectasis evaluation
The primary inclusion criterion was the presence of bilateral bronchiectasis on HRCT of the chest. Exclusion criteria included a positive acid-fast bacillus smear, a positive Mycobacterium tuberculosis culture, a positive M. tuberculosis polymerase chain reaction, active tuberculosis and radiological features suggestive of post-infectious bronchiectasis. Patients with a previous history of post-infectious bronchiectasis, interstitial lung disease, connective tissue disease, COPD and any other chronic lung disorder other than asthma were also excluded.
After obtaining informed consent, eligible participants were evaluated for humoral immune deficiency by measurement of serum immunoglobulins (IgM, IgG, IgA and IgE). ANA and rheumatoid factor were also obtained to screen for connective tissue disease. Subjects with a serum IgE >1000 IU/ml and a history of symptoms consistent with asthma were screened for ABPA via skin prick test and measurement of Aspergillus-specific IgE (IMMULITE 2000 3g Allergy, Siemens). Subjects with no obvious aetiology and normal serum immunoglobulin levels were further assessed for IgG subclass deficiency (Invitrogen Human IgG Subclass Profile, ThermoFisher Scientific). Values were compared with reference values derived from age- and sex-matched normal individuals. A sputum culture was obtained from 97 subjects.
Statistical analysis
The data were recorded in Excel (Microsoft), and statistical analysis was done using SPSS 16.0 (IBM). Association of normal or abnormal immunoglobulin levels was tested using Chi-square test. A Fisher’s test was used for categorical variables such as sex, symptoms, lower versus higher age group and so on. Comparison of mean immunoglobulin levels with respect to sex was done using two independent “t” test after checking for normality assumption. One-way ANOVA was used for more than two categories like immunoglobulin levels in normal, above or below ranges.
RESULTS
A total of 158 adults with bilateral non-infectious bronchiectasis were recruited from February 2015 to July 2016. Baseline characteristics of the subjects are shown in Table 1.
Table 1: Baseline characteristics
The mean age of patients was 42.1 ± 13.8 years; 57% of subjects were males; 12% were active smokers. Mean age at onset of symptoms was 25.7 ± 17.8 years, while mean age of diagnosis was 36.4 ± 16.1 years (diagnostic delay of 10.6 ± 11.2 years). A percentage of 15.1 of subjects were empirically treated with anti-tuberculosis therapy.
Cough, dyspnoea and haemoptysis were among the most common clinical features [Table 1]. Two subjects presented with symptoms of malabsorption. They were subsequently diagnosed with common variable immunodeficiency (CVID) and cystic fibrosis, respectively.
Sputum culture was obtained from 97 subjects. The most common isolated organism was Pseudomonas aeruginosa (33%) followed by Haemophilus influenzae (16%). The presence of either was not found to have any significant association between age of onset and duration of illness. A positive ANA was found in 9.7% of subjects whereas 5.8% of subjects tested positive to the rheumatoid factor. However, none of them had clinical manifestations suggestive of an underlying connective tissue disorder.
One hundred and fifty three of 158 subjects underwent measurement of serum immunoglobulins (IgM, IgG, IgA and IgE). Five subjects did not undergo immunoglobulin evaluation, as they were suspected of having other diseases: Young syndrome,[2] cystic fibrosis,[1] Kartagener syndrome[1] and Mounier–Kuhn syndrome.[1] The majority of subjects had normal immunoglobulin levels except for IgE, which was elevated in 66% of subjects [Table 2]. Among subjects with a serum IgE >1000 U/ml and a history of symptoms suggestive of asthma, five were diagnosed with ABPA based on positive skin prick test and Aspergillus-specific IgE assay.
Table 2: Immunoglobulin levels
Immunoglobulin deficiency was found in 24 subjects (15%). Low IgM deficiency was the most predominant finding (7%), followed by CVID (3.2%) and low IgA (2.5%) [Table 3].
Table 3: Immunoglobulin deficiency
Out of 129 subjects with normal immunoglobulin levels, 93 subjects underwent IgG subclass assay. Out of these, eight subjects [Table 4] were found to have IgG subtype deficiency (8.6%). The majority (7/8) were female. Most commonly observed finding was low level of IgG3. No patients had combined deficiency.
Table 4: IgG subtype deficiency
DISCUSSION
To our knowledge, this study is the first one of its kind to assess humoral immunodeficiency among Indian patients with non-infectious bronchiectasis. Our study found a significantly higher incidence of immunoglobulin deficiency compared with other studies [Table 5]. This could be explained by the fact that our institution is a large referral centre across India for respiratory-related diseases. The most common immunodeficiency was low IgM. Note that IgM and IgA are both physiologically important for protecting mucosal surfaces from microbes, and it has been suggested that IgA and/or IgM deficiency may create a permissive mucosal environment for the development of infective complications.[10]
Table 5: Different studies and aetiologies of bronchiectasis
IgG1 to IgG4, respectively, constitute 60%, 32%, 4% and 4% of total serum IgG.[14] Consequently, deficiencies of IgG2, IgG3 or IgG4 may occur in the presence of normal concentrations of total serum IgG.[15] We therefore conducted IgG subclass analyses among subjects in whom serum immunoglobulin levels were normal. Interestingly, out of eight subjects found to have IgG subclass deficiency, seven were females. Among children with IgG subclass deficiencies, there is 3:1 male: female predominance with IgG2 deficiency being the most common, whereas the situation is reversed after puberty, with IgG3 deficiency becoming more common.[15] Unfortunately, our study is limited by the fact that antibody titres to proteins and polysaccharide antigens, such as diphtheria toxoid, tetanus toxoid, H. influenzae type b (Hib) and Streptococcus pneumoniae pneumonia, were not obtained.
We recommend screening for immunoglobulin deficiency by obtaining IgG, IgA, IgM and IgE levels, and IgG subclasses when serum immunoglobulin levels are normal. Immune globulin replacement will reduce the rate of bacterial infections, and consequently, may slow the progression of bronchiectasis and improve lung function. Several studies have also demonstrated reduced days of antibiotic usage, hospital admissions and increased patient quality of life.
Our data showed an average delay of 10.6 years from symptom onset to diagnosis of bronchiectasis, which is shorter than the study by Anwar et al.[12] (17 years). This could be accounted for the fact that Kartagener syndrome, Young syndrome and cystic fibrosis all present early in life. In addition, ABPA also tends to present earlier in life.
Clinical history is critical when trying to determine the aetiology of bronchiectasis. History-taking may also help identify infective causes and their temporal relation to developing bronchiectasis. Though our study revealed 9.7% and 5.8% ANA and RF positivity rates, respectively, none of our patients had a history of arthralgias or other signs or symptoms suggestive of a connective tissue disorder. These patients, nonetheless, will require long-term follow-up to monitor for early symptoms. Similar results were found by Anwar et al.,[12] in which 10% of bronchiectasis patients had a positive RF, but none had any definite clinical features of a connective tissue disorder.
CONCLUSION
Our study, similar to other studies, demonstrated the presence of immunoglobulin deficiency in a significant number of patients with non-infectious bronchiectasis. While such evaluations may not always be economically feasible in low-income countries like India, they should nonetheless be encouraged. Indeed, immune deficiency can play an important role in the pathogenesis of bronchiectasis, and it is vital to identify this since immunoglobulin replacement therapy may slow the progression of the disease and offer an improved long-term prognosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Pasteur MC, Helliwell SM, Houghton SJ, Webb SC, Foweraker JE, Coulden RA, et al. An investigation into causative factors in patients with bronchiectasis. Am J Respir Crit Care Med 2000;162:1277–84.
2. Keistinen T, Säynäjäkangas O, Tuuponen T, Kivelä SL. Bronchiectasis: An orphan disease with a poorly-understood prognosis. Eur Respir J 1997;10:2784–7.
3. Babayigit A, Olmez D, Uzuner N, Cakmakci H, Tuncel T, Karaman O. A neglected problem of developing countries: Noncystic fibrosis bronchiectasis. Ann Thorac Med 2009;4:21–4.
4. Barker AF. Bronchiectasis. N Engl J Med 2002;346:1383–93.
5. Shoemark A, Ozerovitch L, Wilson R. Aetiology in adult patients with bronchiectasis. Respir Med 2007;101:1163–70.
6. Lonni S, Chalmers JD, Goeminne PC, McDonnell MJ, Dimakou K, De Soyza A, et al. Etiology of non-cystic fibrosis bronchiectasis in adults and its correlation to disease severity. Ann Am Thorac Soc 2015;12:1764–70.
7. Stafler P, Carr SB. Non-cystic fibrosis bronchiectasis: its diagnosis and management. Arch Dis Child Educ Pract Ed 2010;95:73–82.
8. Mobaireek KF. Noncystic fibrosis bronchiectasis: Is it an orphan disease?. Ann Thorac Med 2007;2:2.
9. Nag VK, Nandan D, Singh S, Arora SK, Tsanglao W, Arya N. Pulmonary tuberculosis: A predominant cause of childhood bronchiectasis in India. J Commun Dis 2015;47:14–8.
10. Kiani-Alikhan S, Yong PF, Grosse-Kreul D, Elston C, Ibrahim MA. Immunoglobulin replacement therapy: Is there a role for IgA and IgM?. J Allergy Clin Immunol 2012;130:553–4.
11. King PT, Holdsworth SR, Freezer NJ, Villanueva E, Holmes PW. Characterisation of the onset and presenting clinical features of adult bronchiectasis. Respir Med 2006;100:2183–9.
12. Anwar GA, McDonnell MJ, Worthy SA, Bourke SC, Afolabi G, Lordan J, et al. Phenotyping adults with non-cystic fibrosis bronchiectasis: A prospective observational cohort study. Respir Med 2013;107:1001–7.
13. Aliberti S, Lonni S, Dore S, McDonnell MJ, Goeminne PC, Dimakou K, et al. Clinical phenotypes in adult patients with bronchiectasis. Eur Respir J 2016;47:1113–22.
14. Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: From structure to effector functions. Front Immunol 2014 5. Available from:
https://www.frontiersin.org/articles/100.3389/fimmu.2014.00520/full. Last accessed on 2020 Jul 08.
15. Morgan G, Levinsky RJ. Clinical significance of IgG subclass deficiency. Arch Dis Child 1988;63:771–3.
