Received: 31 July 2019 | Accepted: 26 November 2019 DOI: 10.1002/ppul.24599 REVIEW Bronchiectasis in common variable immunodeficiency: A systematic review and meta‐analysis Nasim Ramzi MD1,2 | Mahnaz Jamee MD1,2 4 Hosein Rafiemanesh PhD Amir Rezaei MD 6 | | Hamed Mohammadi PhD | Hassan Abolhassani MD, PhD Mahmood Bakhtiyari PhD2,3 Hamed Zainaldain MD Mustafa Kalvandi MD 2 | 1,2 | 5 | Marzieh Tavakol MD2 Zeineb Zian PhD 8,9 Farhad Jadidi‐Niaragh PhD 10 | | | 7 | | Reza Yazdani PhD5 5 Asghar Aghamohammadi MD, PhD | | 2 Gholamreza Azizi PhD 1 Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran 2 Non‐Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran 3 Department of Community Medicine, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran 4 Student Research Committee, Department of Epidemiology, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran 5 Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran 6 Department of Pediatrics, Imam Ali Hospital, Alborz University of Medical Sciences, Karaj, Iran 7 Biomedical Genomics and Oncogenetics Research Laboratory, Faculty of Sciences and Techniques of Tangier, Abdelmalek Essaadi University, Tetouan, Morocco 8 Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 9 Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran 10 Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden Correspondence Gholamreza Azizi, PhD, Vice Chancellor for Research, Non‐Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj 3198764653, Iran. Email: azizi@abzums.ac.ir Funding information Alborz University of Medical Sciences, Grant/Award Number: 1397‐03‐25‐2037 Abstract Background: Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency disorder characterized by infectious and noninfectious complications. Bronchiectasis continues to be a common respiratory problem and therapeutic challenge in CVID. The aim of this study is to estimate the overall prevalence of bronchiectasis and its associated phenotype in patients with CVID. Methods: A systematic literature search was performed in Web of Science, PubMed, and Scopus from the earliest available date to February 2019 with standard keywords. All pooled analyses of bronchiectasis prevalence and the corresponding 95% confidence intervals (CIs) were based on random‐effects models. Results: Fifty‐five studies comprising 8535 patients with CVID were included in the meta‐analysis. Overall prevalence of bronchiectasis was 34% (95% CI: 30‐38; I2 = 90.19%). CVID patients with bronchiectasis had significantly lower serum immunoglobulin A (IgA) and IgM levels at the time of diagnosis compared with those without bronchiectasis. Among the clinical features, the frequencies of splenomegaly, pneumonia, otitis media, and lymphocytic interstitial pneumonia were significantly Pediatric Pulmonology. 2019;1–8. wileyonlinelibrary.com/journal/ppul © 2019 Wiley Periodicals, Inc. | 1 2 | RAMZI ET AL. higher in CVID patients with bronchiectasis compared with those without bronchiectasis, respectively. Conclusion: A higher prevalence of bronchiectasis in patients with CVID should be managed by controlling recurrent and severe pneumonia episodes which are immune dysregulation since this complication is associated with poor prognosis in these patients. KEYWORDS bronchiectasis, common variable immunodeficiency, pneumonia, primary immunodeficiency 1 | INTRODUCTION 2 | M A T E R I A L S AN D M E T H O D S Common variable immunodeficiency (CVID) is the most prevalent 2.1 | Search strategy symptomatic immune disorder characterized by hypogammaglobulinemia.1 Patients with CVID have a marked reduction in serum First, we perform a comprehensive searching of international levels of immunoglobulin G (IgG) with IgA, and/or IgM, and impaired electronic databases for published articles; second, the hand antibody response to vaccine due to impaired B cell differentiation searching of the reference section of the review articles was done; to memory B cell and plasma cell.2 However, the specific and third, we contacting the corresponding authors to assess mechanisms mediating immunodeficiency in CVID remain to be unavailable papers or data. unclear.1,3 In addition to defects in B cell, defects in other components of the immune system are reported in almost one‐ third of patients with CVID.4,5 Clinical phenotypes are varying: most 2.2 | Databases searched of the patients have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias, enteropathy, and/or 6 A systematic literature search was performed in Scopus, PubMed, Clinically, patients with CVID have recurrent and Web of Science databases for English articles until February bacterial infections of the upper and lower respiratory tract and 2019. The keywords used were in three groups and combined: (a) chronic inflammation of lower airways. These recurrent pulmonary “CVID” or “hypogammaglobulinemia,” or “primary antibody defi- infections and immune dysregulation can lead to chronic diseases ciency” and (b) “bronchiectasis.” malignancies. such as bronchiectasis. 7 Bronchiectasis continues to be a common respiratory complication of varied etiologies, and CVID is introduced as an uncommon 2.3 | Screening process and data extraction cause for bronchiectasis. The prevalence of bronchiectasis in the large cohort and cross‐sectional studies in patients with CVID varies The screening process was done in two stages: first, the screening of significantly and the associated clinical and immunologic conditions papers was done based on title and abstract to include all relevant are controversial in different cohorts.7-10 Bronchiectasis often affects studies, and second, full‐text screening for eligibility criteria was multiple lobes of the lung. It is commonly found in the middle or done. Articles with these criteria were included in this study: (a) their lower lobes and is usually the cause of lower quality of life and subject of evaluation was the clinical and immunological features of 11 mortality. The most common etiology of bronchiectasis in patients patients with definite diagnosis of CVID, (b) the prevalence of with CVID is recurrent and severe infection particularly in those with bronchiectasis was the main or alternative outcome of interest, (c) considerable delay in diagnosis. The persistent infections lead to written in English language, (d) designed as cross‐sectional or cohort recurrent episodes of inflammation leading to structural lung (include for meta‐analysis), and (e) designed as cross‐sectional or damage.12 However, the phenomenon has been identified in early‐ cohort or case‐control or case series include for comparison of the diagnosed patients with CVID under Ig replacement therapy without clinical and immunological findings of the patients with and without severe infections. That indicates the role of uncontrolled inflamma- bronchiectasis. tory reactions in the development of bronchiectasis despite the absence of infection. 7-10 To gain further insight into the characteristics of CVID patients with bronchiectasis, demographic, clinical, and immunological data In this study, we aimed to systematically evaluate the existing from all studies describing the patients with CVID either with evidence for the frequency of bronchiectasis in patients with CVID. bronchiectasis or without bronchiectasis were obtained. For articles Another goal of this systematic review is a comparison of the clinical with overlapping data, those with the largest dataset were included. and immunological findings of the patients with and without Finally, data were extracted from the included studies in a bronchiectasis. standardized Microsoft Excel spreadsheet. All stages were done RAMZI | ET AL. independently by two reviewers and disagreement was resolved by 3 3.2 | Meta‐analysis the third reviewer. As illustrated in Figure 2, the highest and lowest prevalence of bronchiectasis was reported by Aydogan et al9 in Turkey (90.0%, 2.4 | Statistical analysis 95%, confidence intervals [CIs]: 55‐100) and Yong et al2 in a study We used descriptive statistics like frequency and percentage for reported the prevalence of bronchiectasis of more than 70%.9,13,14 the presentation of characteristics of the included study. Meta‐ On the basis of the results of the random‐effect method, the pooled analysis based on the random‐effects model was performed for the prevalence of bronchiectasis in 8535 patients was 34% (95% CI: 30‐ assessed pooled prevalence of bronchiectasis in patients with 38; I2 = 90.19%). Also, the results of stratified meta‐analysis based on CVID and also reported prevalence in included study presented study type (cohort and cross‐sectional studies) showed that the from USA (4.0%, 95% CI: 0.7‐1.6), respectively. Only three studies with a forest plot. Heterogeneity was assessed using the I‐square pooled prevalences of bronchiectasis using the random‐effect model (I2) statistic, and then the subgroup analysis conducted for were 35% (95% CI: 31‐39; I2 = 90.25%) and 28% (95% CI: 14‐44; discovery of heterogeneity, as far as possible. A comparison of I2 = 77.28%), respectively (test for heterogeneity between subgroups; CVID patients with and without bronchiectasis was performed for P < .001; Figure S1). As shown in Figure S2, a cumulative meta‐ demographic, immunological, and clinical variables. We extracted analysis of changes in prevalence over time was also performed by available data of related studies and then conducted aggregated sorting the studies based on the publication time which revealed that data analysis with simple pooled data to provide an overall the overall prevalence estimates were independent of the time of the summary of subgroup data. In this analysis, data of different study. Figure S3 depicts the Galbraith plot of the meta‐analysis on included studies were combined without being weighted. In the prevalence of bronchiectasis representing heterogeneity among addition to providing frequencies and percentages for categorical studies; however, all studies were within −2 to +2 Z‐score range variables, mean with standard deviation (SD), and median with without an outlier point. interquartile range (IQR) was reported, as appropriate based on In two studies, the involved lobe was reported. In a study by normality. Normality assumption checked with Shapiro‐Wilk test Bondioni et al,15 nine patients diagnosed with bronchiectasis from and graphical approaches. Analytical analyses were performed which four were unilobar, three were bilobar, and two were using Mann‐Whitney U, χ2, and Fisher exact tests; P < .05 was multilobar. In another study by Martínez García et al,11 bronchiec- considered statistically significant. Data analysis was conducted in tasis was diagnosed in 11 patients from which 3 of them were Stata v.14 (StataCorp, College Station, TX). unilobar and 8 were multilobar bronchiectasis. 3 | RES U LTS 3.3 | Comparison of CVID patients with and without bronchiectasis 3.1 | Study selection and studies’ characteristics The demographic, immunological, and clinical findings of CVID In this study, a total of 4286 articles were retrieved from the initial patients with and without bronchiectasis were compared in 37 search, while 3569 articles were excluded because they were completely defined articles that reported individual patients’ data. duplicated studies. After screening the process of remaining 717 The sample size of these studies was 665 patients with CVID, from articles based on titles and abstracts, 221 articles that reporting which 296 patients had a diagnosis of bronchiectasis. The frequency CVID patients with clinical findings were selected and their full of bronchiectasis was higher in female than male patients (51.6% vs texts were assessed for the frequency of bronchiectasis. In the 39.7%; P = .006), and in patients with parental consanguinity than qualitative synthesis stage, 55 studies included for meta‐analysis. those without parental consanguinity (41.2% vs 18.8%; P = .048). The process of the literature search and selection based on the Nevertheless, the age of onset and diagnosis of CVID as well as the PRISMA flowchart for systematic reviews has been shown in diagnostic delay was not statistically different in two groups. Figure 1. Bronchiectasis frequency was higher in patients with the delay in The characteristics of 55 included articles are shown in Table S1. diagnosis more than 3 years than those with the diagnostic delay less The sample sizes of patients with CVID in included articles were than 3 years (37.4% vs 25.8%; P = .122), however the differences varied from 8 of the Affiliated Hospital of Qingdao University up to were not significant. Moreover, CVID patients with bronchiectasis 2700 in a study from the European Society for Immunodeficiency had significantly lower serum levels of IgA (median [IQR]: 8.0 [0.5‐ (ESID). These 55 studies have been conducted in 17 different 24.0] vs 14.0 [6.0‐30.0] mg/dL; P = .022) and IgM (median [IQR]: 18.0 countries (mostly originated from USA [n = 12], UK [n = 7], and Italy [8.0‐31.0] vs 23.0 [10.0‐48.0] mg/dL; P = .019) compared with those [n = 6]) and two originated from ESID; the latest study was performed without bronchiectasis. The comparison of detailed parameters is in 2019 and the eldest in 1991. shown in Table 1. IgG trough level was reported in two studies16,17 4 | RAMZI ET AL. F I G U R E 1 Flow diagram of the systematic review and meta‐analysis for bronchiectasis in CVID. CVID, common variable immunodeficiency [Color figure can be viewed at wileyonlinelibrary.com] for 33 patients (20 with and 13 without bronchiectasis). The mean Among the clinical features, the frequency of splenomegaly, (SD) of IgG trough level in CVID patients with bronchiectasis was pneumonia, otitis media, and LIP was significantly higher in CVID higher than those without (740 [184] vs 671 [170]; P = .285), patients with bronchiectasis compared with those without bronch- however the differences were not significant. iectasis (57.1% vs 36.9%, P < .001; 84.2% vs 47.1%, P < .001; 51.7% vs The most frequent manifestation in these selected 665 patients 30.0%, P = .01; and 46.2% vs 8.9%, P < .001), respectively. Entero- with CVID were splenomegaly (45.6%), respiratory tract infections pathy (24.5% vs 14.7%; P = .052), sinusitis (48.6% vs 35.2%; P = .05), (76.3%) (including pneumonia [60.3%], sinusitis [41.9%], otitis media failure to thrive (62.5% vs 36.4%; P = .085), ILD (17.9% vs 10.4%; [39.1%], and bronchitis [13.9%]), autoimmunity (35.7%), and failure to P = .097), and clubbing (44.4% vs 10%; P = .056) were more prevalent thrive (44.9%) (Table 2). Granulomatous lesions were observed in 42 in CVID patients with bronchiectasis in comparison with those patients (20.2%), while only in 18 patients, the site of granuloma was without bronchiectasis, however the differences were not statisti- clear (8 of them have pulmonary granulomatosis). Furthermore, cally significant. The frequency of bronchiectasis was higher in lymphocytic interstitial pneumonia (LIP) and interstitial lung disease patients with rheumatologic complications than those without this (ILD) were observed in 17 (20.7%) and 19 (28.4%) patients, complication (8.1% vs 5.4%; P = .278), however the differences were respectively, from which 5 patients had granulomatous‐lymphocytic not significant. interstitial lung disease. Asthma and allergic airway diseases were Among all patients with bronchiectasis, the age at diagnosis also documented in 28.2% of patients. Tuberculosis was reported in was reported only in eight patients (median [IQR] = 9.0 [4.0‐14.0]), four patients. No cystic fibrosis or lung cancer was reported. which all had a pediatric onset. There was no differences in the RAMZI | ET AL. 5 considerably and have been reported from 11.2% to 90%.8 It has been evident that bronchiectasis is often progressive and is usually the cause of mortality and morbidity. According to the current systematic review, the highest and lowest prevalence of bronchiectasis was reported by Aydogan et al9 at 90.0% and Yong et al2 at 4.0%, respectively. However, the results of the meta‐analysis showed that the pooled prevalence of bronchiectasis was 34%. Therefore, it can be concluded that bronchiectasis is a common finding in CVID that needs preventive measures, as many physicians believe; CVID patients with bronchiectasis should receive a higher dose of intravenous immunoglobulin (IVIG) than those without bronchiectasis, because IVIG administration reduces airways inflammation with improvement in the transportability of the respiratory mucus by cough.20 Bronchiectasis is one of the most commonly reported structural complications in both pediatric‐onset and adult‐onset CVID; however, its etiology and frequency may differ by age. Our results showed that in patients with bronchiectasis, the frequency of splenomegaly, allergy and asthma and otitis media was higher in pediatric‐onset than the patients with adult‐onset CVID. Nevertheless, in a report by Sanchez et al,21 the frequency of bronchiectasis (12.4% vs 20.8%), ILD (4.2% vs 9.9%), and pulmonary nodules (1.6% vs 3.4%) was lower in pediatric‐onset than adult‐onset CVID. It was reported that patients with CVID and parental consanguinity that diagnosed in childhood are more severely affected by autoimmunity, inflammatory lung disease, and enteropathy than adults diagnosed later in life.21,22 In addition, the patients with early‐ onset CVID are more likely to have a monogenetic defect (such as, LRBA, CTLA‐4, PIK3CD) that may lead to bronchiectasis to due severe immune dysregulations that are associated with an inflamF I G U R E 2 The pooled prevalence of bronchiectasis assessed with a random‐effects method. CI, confidence interval; ES, effect size [Color figure can be viewed at wileyonlinelibrary.com] matory response in the lung.23-26 This may be different from the development of bronchiectasis in patients with adult‐onset CVID, in which the etiology may be more chronic and patients may less often have inflammatory lung disease. In addition to the delay in diagnosis and low‐memory B cell frequency of bronchiectasis in pediatric‐onset (ages 17 or young- numbers as risk factors for bronchiectasis in patients with CVID, the er) and adult‐onset (ages 18 or older) CVID patients (48.6% vs main mechanism of this respiratory complication in CVID is due to 48.1%; P = .94). When patients with bronchiectasis split based on impaired immune clearance with recurrent or severe infections. the age of CVID onset, the frequency of splenomegaly (60.7% vs Other underlying immune dysregulation, in this case, may lead to 43.5%; P = .22), allergy and asthma (50% vs 0.0%; P = .11), and chronic airway inflammation and structural damage. It has been otitis media (61.9% vs 25.0%; P = .26) was higher in pediatric‐onset reported that the development of bronchiectasis, in spite of Ig than the adult‐onset CVID patients, however the differences were replacement therapy, to be due to ongoing inflammation and mucous not significant. plugging in immunodeficient patients.27 Pneumonia is a common respiratory complication in patients with CVID.28 In addition, bronchiectasis and structural airway diseases have been associated 4 | D IS C U S S IO N with recurrent lower respiratory tract infection.29 Patients with CVID who had severe pneumonia before the disease diagnosis are Chronic lung disease is among the most frequent CVID complica- susceptible to develop bronchiectasis.30 Consistent with this notion, tions, effecting approximately between 30% and 60% of pa- our results showed that the frequency of pneumonia was significantly tients.8,18,19 Bronchiectasis is the most common chronic lung disease higher in patients with CVID and bronchiectasis compared with those and cause of mortality and morbidity in patients with CVID. Several without bronchiectasis. However, Maarschalk‐Ellerbroek et al31 studies reported the different frequency of bronchiectasis in these reported that bronchiectasis can be shown in patients with CVID patients. Its prevalence in the large cohort studies varied who had never been diagnosed with pneumonia and this can be 6 | RAMZI ET AL. T A B L E 1 Demographic and corresponding immunologic data of CVID patients with and without bronchiectasis Patients with bronchiectasis (n = 296) Patients without bronchiectasis (n = 369) P value Parameters Total (n = 665) Sex ratio (M/F), (%) 345/283 (51.9/42.6) 137/146 (46.3/49.3) 208/137 (56.4/37.1) .006* Consanguinity (%) 34 (5.1) 14 (4.7) 20 (5.4) .048* Age at onset of CVID, y; median (IQR) 13.0 (6.0‐29.0) 13.0 (5.0‐25.0) 13.0 (7.0‐30.0) .248 Age at diagnosis of CVID, y; median (IQR) 17.0 (9.0‐33.0) 19.0 (11.0‐33.0) 14.5 (7.2‐33.0) .154 Diagnosis delay of CVID, y; median (IQR) 4.0 (2.0‐10.3) 5.4 (2.9‐10.0) 4.0 (1.3‐11.0) .364 IgG (mg/dL), median (IQR) 277.0 (138.0‐426.5) 291.5 (154.5‐495.0) 251.0 (125. 0‐404.0) .069 IgA (mg/dL), median (IQR) 13.0 (6.0‐25.0) 8.00 (5.0‐24.0) 14.0 (6.0‐30.0) .022* IgM (mg/dL), median (IQR) 20.0 (10.0‐41.2) 18.0 (8.0‐31.0) 23.0 (10.0‐48.0) .019* IgE (mg/dL), median (IQR) 11.8 (2.7‐18.0) 13.5 (1.7‐17.0) 8.3 (3.9‐18.1) .903 WBC (cell/µL), median (IQR) 5600 (4400‐8300) 5550 (4050‐8800) 5700 (4750‐7600) .809 Lymphocyte (cell/µL), median (IQR) 1540.0 (970.0‐ 2140.5) 1610.0 (1000.0‐2131.0) 1440.0 (938.7‐2320.0) .932 CD3+ lymphocytes (cell/µL), median (IQR) 1070.0 (779.9‐ 1660.0) 1190.0 (760.0‐1660.0) 1030.0 (786.6‐1685.0) .916 CD4+ T cells (cell/µL), median (IQR) 545.0 (370.0‐791.2) 567.0 (370.0‐829.2) 527.5 (379.2‐737.0) .381 CD8+ T cells (cell/µL), median (IQR) 591.0 (346.0‐910.0) 530.0 (320.0‐865.0) 607.0 (364.0‐940.0) .344 NK cell (cell/µL), median (IQR) 99.0 (45.5‐228.7) 116.5 (60.0‐228.7) 88.5 (41.5‐235.0) .540 CD19+ lymphocytes (cell/µL), median (IQR) 168.0 (64.0‐312.0) 146.2 (50.5‐309.0) 174.0 (70.0‐317.0) .404 Note: For age, age at onset, age at diagnosis, delay in diagnosis, the median is shown (with 25th and 75th percentiles). The Mann‐Whitney U test for a numerical variable and the χ2 test or Fisher’s exact test for the nominal variable was used. Abbreviations: CVID, common variable immunodeficiency; F; female; Ig, immunoglobulin; IQR, interquartile range; M, male; N, count; NK, natural killer; WBC, white blood cell; y, year. *P < .05 is statistically significant. because of subclinical immune dysregulation and uncontrolled the other hand, patients with CVID and bronchiectasis had inflammation. significantly fewer CD4+ T cells than those without bronchiecta- Several studies reported that patients with CVID and bronch- sis.37 Moreover, Maarschalk‐Ellerbroek et al31 reported that there iectasis have low B‐cell counts and low IgG levels.32-34 Moreover, were no significant differences in T and B cell proportions between 35 reported that patients with CVID were more likely to patients with or without bronchiectasis. Our findings as a result of have bronchiectasis, possibly associated with lower baseline IgG a systematic review showed that patients with CVID and levels. Another study showed that patients with CVID and bronchiectasis had significantly lower IgA and IgM serum levels bronchiectasis were found to have significantly lower serum IgM compared with those without bronchiectasis. Finally, low B cell Filion et al levels than those without bronchiectasis. 30 Alachkar et al found count and serum Igs at diagnosis of immunodeficiency might help that the absolute number of switched memory B cells was us to identify patients with CVID with a high risk of developing significantly lower in patients with CVID and bronchiectasis.36 bronchiectasis. It could also be an important indicator for early However, there are conflicting findings in this regard. Our findings antibiotic prophylaxis and a higher dose of Ig replacement therapy showed that the IgG trough level was higher in patients with CVID or additional immunomodulatory agent.9 and bronchiectasis than those without. Although, our sample size In conclusion, our results showed that bronchiectasis is a serious was very low to draw this conclusion, this may be related to the complication in patients with CVID and the treating physicians fact that patients with bronchiectasis received a higher dose of should be cognizant of the development of bronchiectasis in any IVIG than those without bronchiectasis. In another study, patient with CVID, who has a chronic wet cough. Moreover, early Maglione et al reported no significant differences in serum Ig investigations and management should be undertaken for bronch- levels between patients with and without bronchiectasis. In iectasis in patients with CVID because early detection and treatment addition, there were no significant differences in the counts of of respiratory symptoms may prevent the development of bronch- total B cells, switched memory B cells, and natural killer cells. On iectasis in patients with CVID. RAMZI | ET AL. 7 T A B L E 2 Main clinical characteristics of CVID patients with and without bronchiectasis Clinical manifestation (evaluated patients with or without malignancy) Total patient with clinical presentation (%) Patients with bronchiectasis (%) Patients without bronchiectasis (%) Granuloma (n = 208) 42 (20.2) 16 (25.0) 26 (18.1) .250 Splenomegaly (n = 375) 171 (45.6) 92 (57.1) 79 (36.9) <.001* Hepatomegaly (n = 132) 37 (28.0) 16 (26.2) 21 (29.6) .669 Lymphadenopathy (n = 165) 50 (30.3) 22 (28.6) 28 (37.8) .651 Autoimmunity (n = 456) 163 (35.7) 72 (37.7) 91 (34.3) .461 Rheumatologic complications (n = 384) 25 (6.5) 13 (8.1) 12 (5.4) .278 P value Enteropathy (n = 254) 47 (18.5) 24 (24.5) 23 (14.7) .052 RTIs (n = 270) 206 (76.3) 101 (86.3) 105 (68.6) .001 Pneumonia (n = 214) 129 (60.3) 64 (84.2) 65 (47.1) .001* Sinusitis (n = 210) 88 (41.9) 51 (48.6) 37 (35.2) .05 Otitis media (n = 138) 54 (39.1) 30 (51.7) 24 (30.0) .01* Bronchitis (n = 101) 14 (13.9) 6 (17.6) 8 (11.9) .544 Asthma or allergy (n = 213) 60 (28.2) 29 (30.9) 31 (26.1) .439 Failure to thrive (49) 22 (44.9) 10 (62.5) 12 (36.4) LIP (n = 82) 17 (20.7) 12 (46.2) 5 (8.9) <.001* .085 ILD (n = 67) 19 (28.4) 12 (17.9) 7 (10.4) .097 Clubbing (n = 29) 6 (20.7) 4 (44.4) 2 (10.0) .056 Malignancy (n = 153) 28 (18.3) 12 (24.0) 16 (15.5) .204 Note: The value is presented as absolute frequency and the numbers in the parentheses are the corresponding percent values. Abbreviations: CVID, common variable immunodeficiency; ILD, interstitial lung disease; LIP, lymphoid interstitial pneumonia; RTI, respiratory tract infections. *P < .05 is statistically significant. A C K N O W L E D GM E N T S This study was supported by Vice Chancellor for Research, Alborz University of Medical Sciences, under Grant Number 1397‐03‐25‐ 2037. The authors would like to thank the Clinical Research Development Center of Imam Ali‐Karaj Hospital. CO NFLICT OF I NTERE STS The authors declare that there are no conflict of interests. OR CID Gholamreza Azizi http://orcid.org/0000-0001-5658-2511 REFERENC ES 1. Tam JS, Routes JM. Common variable immunodeficiency. Am J Rhinol Allergy. 2013;27(4):260‐265. 2. Yong PL, Orange JS, Sullivan KE. Pediatric common variable immunodeficiency: immunologic and phenotypic associations with switched memory B cells. Pediatr Allergy Immunol. 2010;21(5):852‐858. 3. Vlkova M, Chovancova Z, Nechvatalova J, et al. 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