Risk Factors of Bronchiectasis in Adult Patients with Common Variable Immunodeficiency

Objective: Common Variable Immunodeficiency (CVID) is a heterogeneous immune disorder characterized by frequent and recurrent upper and lower respiratory tract infections. Although immunoglobulin (Ig) replacement therapy (IgRT) reduces the frequency of infections, complications due to infections of the respiratory tract, particularly bronchiectasis, is still challenging and occur in approximately 20% of patients. Therefore, we aimed to identify independent predictors of bronchiectasis in adult patients with CVID. Materials and Methods: We retrospectively analyzed the hospital records of 45 CVID patients (26 male, 19 female). Additionally, we classified the patients according to the presence of bronchiectasis. Bronciectasis was confirmed by high resolution computed tomography of thorax. Results: Forty-five patients with CVID (F:19 [42.2%], M: 26 [57.8%]) were included in the study (age: 36.52 ± 12.86). Bronchiectasis was observed in 60% of the study group. Univariate regression analysis revealed that IgG levels (OR: 4.889, 95% CI, 0.485-0.959, p: 0.012) and IgA levels (OR: 2.559, 95% CI, 0.097-1.235, p: 0.030) at the time of diagnosis and the percentage of switched memory B cells (OR: 0.848, 95% CI, 0.730-0.984, p: 0.030) were significantly associated with bronchiectasis. Multivariate regression analysis showed that a lower percentage of switched memory B cells (OR: 0.853, 95% CI, 0.733-0.991, p: 0.038) and a low platelet count (OR: 1.000, 95% CI, 1.000-1000, p: 0.026) were also independent predictors of bronchiectasis. Conclusion: Clinicians should be alert for CVID patients with reduced switched memory B cells and low platelet counts in order to detect and treat complications associated with bronchiectasis at an early stage.


INTRODUCTION
Common Variable Immunodeficiency (CVID) is a heterogeneous immune disorder characterized by frequent and recurrent upper and lower respiratory tract infections, autoimmune disorders, granulomatous diseases and predisposition to malignancy (1,2). In addition, CVID is the most common symptomatic antibody disorder in adults (1). In the absence of other well-defined immunodeficiency conditions, CVID is diagnosed with low levels of immunoglobulin (Ig) G (IgG), IgA and/or IgM, and inadequate antibody response to vaccines or infections (3,4). Ig replacement therapy (IgRT) either by the intravenous or subcutaneous route is the cornerstone of treatment. Although IgRT, use of prophylactic antibiotics and monoclonal antibodies such as infliximab, rituximab, adalimumab etc. reduce the frequency of infections, complications due to recurrent and frequent infections of the respiratory tract, particularly bronchiectasis and granulomatous lung disease, are still challenging and occur in approximately 20% of patients (5). In this study, we aimed to investigate the risk factors associated with bronchiectasis in adult patients with CVID who were followed-up at our Clinical Immunology Department.

MATERIALS and METHODS
In our study, we retrospectively analyzed the data in the personal hospital records of 45 patients (26 male, 19 female), in case they have been sufficient. CVID was diagnosed according to the updated diagnostic criteria of the European Society for Immunodeficiency (ESID) (3). Bronchiectasis have been confirmed by high-resolution computed tomography. The study protocol was approved by the Ethics committee. Informed consent was obtained from study participants.
A statistical analysis was performed with IBM SPSS Statistics, Version 22 software (New York, United States). Parametric statistics were presented as mean ± standard deviation and nonparametric statistics were expressed as median (minimum-maximum). Descriptive data were presented as frequencies and percentages and compared using the Chi-square test. Comparisons between baseline characteristics were performed with an independent Student's t-test or Chi-square test where appropriate. A binary logistic regression analysis was performed to determine the independent predictors of bronchiectasis.  (Table II).

DISCUSSION
CVID is the most common symptomatic immune disorder in adults with a deficiency of switched memory B cells (5,6). Although adequate Ig replacement in addition to use of prophylactic antibiotics and monoclonal antibodies such as infliximab, rituximab, adalimumab etc. have reduced the mortality and morbidity rates associated with CVID, complications due to recurrent and frequent infections of the respiratory tract, particularly bronchiectasis and granulomatous lung disease, are still challenging and occur in approximately 20% of patients (5).
In our study group, parental consanguinity was found in 53.3% of patients, which was an unexpectedly high rate. In studies conducted in Turkey, Ardeniz et al. reported a rate of 30% and Musabak et al. reported a rate of 12.9% for consanguineous marriages (7,8). In studies conducted in other countries, Oksenhendler et al. and Aghamohammadi et al. reported lower rates at 5.4% and 8% , respectively (9,10). Additionally, in this study, 45 Turkish CVID patients were classified according to the presence of bronchiectasis. Bronchiectasis was reported in 60% of these CVID patients. Thickett et al. reported that 51% of patients with CVID had bronchiectasis (11). In another study consisting of 27 CVID and 10 XLA patients, 55% of the patients had bronchiectasis (12). As far as we know, the highest percentage for bronchiectasis was given as 73% in a study by Kainulainen et al (13). In Turkey, Ardeniz at al. reported that 48% of patients with CVID had bronchiectasis (7).
Our results showed a higher rate compared to theirs In our study, parental consanguinity was found in 53.3% of patients. Kutukculer et al. and Rivoisy et al. reported that parental consanguinity was associated with a severe phenotype in CVID and this may be the main reason for the high percentages of bronchiectasis in our study group (14,15). Due to the heterogeneity of the disease, lack of awareness among clinicians concerning primary immunodeficiencies (PID) and the misconception that immunodeficiencies are childhood diseases, delayed diagnosis is common especially in adult CVID patients (11). The mean diagnostic delay was 104 ± 91.9 months in the present study, which is consistent with Quinti et al.'s report (16). Furthermore, Ardeniz et al. and Musabak et al. also reported similar periods of delayed diagnosis in Turkey (7,8).
Patients with bronchiectasis had statistically significantly lower IgG and IgA levels and switched memory B cells at the time of diagnosis compared to the patients    (17). Although, decreased switched memory B cells (IgD-IgM-CD27+) in CVID patients are a well-defined characteristic of the disease (18,19) and CVID has been classified based on memory B cells for over two decades (20), there are conflicting reports on the association between chronic lung disease and decreased isotypeswitched memory B cells (21)(22)(23)(24) Bronchiectasis is not only associated with recurrent sinopulmonary infections, but is also proof and indication of other inflammatory conditions (27). Kellner et. al reported that CVID patients with bronchiectasis had more autoimmune complications such as autoimmune hematologic diseases, hepatomegaly, splenomegaly and lymphadenopathy than CVID patients without bronchiectasis (28). Regulatory T cells (T-regs) play an important role in the preservation of immune homeostasis (29). Romberg et al. reported that a decreased number of T-regs, reduced T-reg function and an increased number of follicular T cells in the germinal center of lymph nodes might correlate with fewer isotype switched memory B cells (30). Therefore, reduced T-reg function may contribute to the development of bronchiectasis. Although some monogenic immunodeficiencies such as PI3KD (A phosphoinositide 3-kinase delta) gain of function mutation may lead to bronchiectasis, the genetic analysis of any of our patients has not been concluded yet.
Although thrombocytes may not have a direct association with chronic lung disease, the relationship between these two conditions in CVID patients has been shown in many studies (6,31). In this patient group, low platelet counts may be an indicator of splenic sequestration due to splenomegaly, and/or may be an expression of increased immune dysregulation and autoimmunity. Maglione et al. found that thrombocytopenia was significantly associated with chronic lung disease in patients with CVID (32). In the current study, we found that platelet counts were lower in patients with bronchiectasis than in those without bronchiectasis, and low platelet counts were independent risk factors for the development of bronchiectasis. Although infections are the main cause of bronchiectasis, there are other inflammatory conditions in addition to infections in the continuation of bronchiectasis (27) and presumably, decreased platelet count in CVID patients is a reflection of these additional inflammatory conditions.
Our study has some limitations, such as a small study population, a single center experience and cross-sectional design. Also, we could not analyze the relationship between the severity of bronchiectasis and other immunological parameters.

CONCLUSION
In conclusion reduced percentage of switched memory B cells and reduced platelet counts are independent predictors for the development of bronchiectasis, and therefore, patients with CVID who have decreased switched memory B cells and reduced platelet counts require close clinical monitoring to detect and treat complications associated with bronchiectasis at an early stage.