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Hypogammaglobulinemia E in 216 adults with IgG subclass deficiency and respiratory tract infections
Ann Allergy Asthma Immunol xxx (2017) 1e2
Contents lists available at ScienceDirect
Letter
Hypogammaglobulinemia E in 216 adults with IgG subclass deficiency and respiratory tract infections Hypogammaglobulinemia E has been reported in 0.8% to 3.0% of adults unselected for disease associations.1,2 In persons with subnormal serum immunoglobulin (Ig) E, the prevalence of frequent or severe respiratory tract infections,3,4 other subnormal immunoglobulin isotypes,3,5 and autoimmune conditions3,4 was significantly greater than that in control subjects.3e5 To learn more, we performed a retrospective study to determine clinical and laboratory associations of hypogammaglobulinemia E (serum IgE <1 IU/L [<2.4 mg/L]) and IgE levels at diagnosis in 216 index adult patients with IgG subclass deficiency (IgGSD).6 We studied the records of non-Hispanic white adults (18 years of age) referred to a single practice in a large suburban medical center that evaluates and treats many adults with primary immunodeficiency. All patients had frequent or severe bacterial infections of the upper or lower respiratory tract6; all were diagnosed to have IgGSD6; all were advised to undergo IgG replacement therapy; and all had serum IgE measurements at initial evaluation. Fifty-five patients (24.5%) also had subnormal serum total IgG. Autoimmune conditions, atopy, other allergy, and corticosteroid therapy were defined as previously described.6 Testing was performed before initial IgG replacement therapy. Serum immunoglobulin levels and blood lymphocyte subsets were measured at the Laboratory Corporation of America (Burlington, North Carolina). We defined mean 2 SD as the reference range (Table 1). Human leukocyte antigen (HLA) A and B alleles were detected using low-resolution DNA-based typing.6 We studied the haplotypes A*01, B*08; A*02, B*44; A*03, B*07; and A*29, B*44.6 We performed logistic regression on hypogammaglobulinemia E and multivariable regression on IgE levels using all available independent variables. Mean age was 49 12 years. There were 180 women (83.3%). The 5 most common infections were sinusitis (88.9%), bronchitis (72.2%), pneumonia (51.4%), otitis media (31.5%), and cutaneous or mucosal yeast infections (interpreted as Candida species; 30.1%). Seventy patients (32.4%) reported corticosteroid therapy. The most common subnormal IgG isotypes were IgG3 (88 patients, 40.7%), IgG1 (55, 25.5%), and IgG1/IgG3 (51, 23.6%). Thirteen patients (6.0%) had subnormal IgA. Twenty-two patients (10.2%) had subnormal IgM. Autoimmune conditions were diagnosed in 76 patients (35.2%). Atopy was reported by 63 patients (29.2%), including allergic asthma (51 patients, 23.6%), allergic rhinitis (13, 6.0%), and allergic dermatitis or eczema (8, 3.7%). Sixty-eight patients (31.5%) reported other allergy. Hypogammaglobulinemia E occurred in 37 patients (17.1%). The prevalence of bronchitis reports was significantly lower in patients Disclosures: Authors have nothing to disclose. Funding Sources: This work was supported in part by Southern Iron Disorders Center and Brookwood Biomedical.
with hypogammaglobulinemia E (Table 1). No other attributes of patients with vs without hypogammaglobulinemia E differed significantly after Bonferroni correction (Table 1). The prevalence of subnormal total IgG, IgG subclasses, IgA, and IgM did not differ significantly between patients with and those without hypogammaglobulinemia E. Because HLA-A*29, B*44 was observed only in patients with normal or increased IgE (Table 1), this haplotype could not be used as an independent regression variable. Immunoglobulin E was increased (>100 IU/L [>240 mg/L]) in 32 patients. There was a significant upward trend in the proportions of patients with allergic asthma in the hypogammaglobulinemia E, normal IgE, and increased IgE subgroups (8.1%, 21.1%, and 53.1%, respectively; P < .0001). Logistic regression on hypogammaglobulinemia E showed 3 significant negative associations: asthma (P ¼ .0298; odds ratio 0.24, 95% confidence interval 0.07e0.88), CD4þ lymphocytes (P ¼ .0138; odds ratio 0.99, 95% confidence interval 0.99e1.00), and IgG1 (P ¼ .0352; OR 0.99, 95% confidence interval 0.99e1.00). Multivariable regression on serum IgE levels showed 4 significant positive associations: allergic asthma (P ¼ .0044), allergic dermatitis or eczema (P < .0001), IgG4 (P ¼ .0003), and HLA-A*03, B*07 (P ¼ .0039). The most common non-IgG isotype deficiency in the present patients was hypogammaglobulinemia E. The prevalence of hypogammaglobulinemia E was greater in the present patients (17.1%) than in unselected adults (0.8e3.0%)1,2 and in 420 adults in an allergy-immunology clinic (10.5%).3 The prevalence of chronic sinusitis and recurrent otitis media in 158 patients at least 12 years old with hypogammaglobulinemia E was significantly greater than that in 600 controls.4 These observations suggest that hypogammaglobulinemia E contributes to increased risks of respiratory tract infections in adults. In contrast, serum IgE level lower than 6.3 IU/L (<15 mg/L) was observed in 7 of 73 normal adults (9.6%), none of whom reported having respiratory tract disease.7 In an allergyimmunology clinic, the prevalence of respiratory symptoms did not differ significantly in patients with vs without hypogammaglobulinemia E.3 The prevalence of bronchitis reports was significantly lower in the present patients with hypogammaglobulinemia E. Higher serum IgE levels were significantly associated with allergic asthma, consistent with other reports. The risk of lower respiratory tract infections was increased in subjects with allergic asthma unselected for subnormal immunoglobulin levels.8 Regardless of IgE levels, manifestations interpreted as asthma in some patients might be due to infections or other non-allergy mechanisms. Allergic dermatitis or eczema also was significantly associated with serum IgE levels in the present patients, after adjustment for other variables. Serum IgE levels were significantly associated with HLA-A*03, B*07 in the present index patients. In a Framingham genomewide
http://dx.doi.org/10.1016/j.anai.2017.07.005 1081-1206/Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
2
Letter / Ann Allergy Asthma Immunol xxx (2017) 1e2
Table 1 Hypogammaglobulinemia E in 216 Adult Index Patients With IgG Subclass Deficiencya Characteristic
Hypogammaglobulinemia E (n ¼ 37)
No hypogammaglobulinemia E (n ¼ 179)
P valueb
Reference ranges
Men, % (n) Age (y), mean (SD) BMI (kg/m2), mean (SD) Bronchitis, % (n)c Diabetes mellitus, % (n)d Autoimmune condition, % (n)c Allergic asthma, % (n)d Allergic rhinitis, % (n)d Allergic dermatitis or eczema, % (n)c Other allergy, % (n)d Corticosteroid therapy, % (n) Total IgG (g/L) IgG1 (g/L) IgG2 (g/L) IgG3 (g/L) IgG4 (g/L) IgA (mg/L) IgM (mg/L) IgE (mg/L) CD19þ cells/mL CD4þ cells/m/L CD8þ cells/m/L CD56þ/16þ cells/m/L HLA-A*01, B*08 positivity, % (n) HLA-A*02, B*44 positivity, % (n) HLA-A*03, B*07 positivity, % (n) HLA-A*29, B*44 positivity, % (n)
13.5 (5) 49 12 26.7 7.1 45.9 (17) 8.1 (3) 40.5 (15) 8.1 (3) 2.7 (1) 5.4 (2) 29.7 (11) 24.3 (9) 7.42 (4.70e13.90) 3.83 (2.49e6.69) 2.43 (0.45e6.34) 0.34 (0.10e1.04) 0.09 (0e1.39) 1,390 (40e4,350) 1,100 (100e5,110) 1.2 (1.2e1.2)e 244 (42e979) 826 (108e2,040) 334 (48e1,043) 149 (15e523) 13.5 (5) 16.2 (6) 10.8 (4) 0 (0)
17.3 (31) 49 12 28.9 7.1 77.7 (139) 8.4 (15) 34.1 (61) 26.8 (48) 6.7 (12) 3.4 (6) 31.8 (57) 34.1 (61) 7.96 (4.01e17.51) 4.17 (2.38e8.83) 2.64 (0.31e7.24) 0.34 (0.07e1.76) 0.16 (0e1.45) 1,620 (140e5,550) 1,020 (240e5,160) 57.6 (4.8e15,355) 186 (5e193) 1,012 (253e2,984) 457 (90e2,106) 146 (5e656) 21.8 (39) 17.9 (32) 11.2 (20) 8.4 (15)
.5718 .8420 .0945 <.0001 .9566 .4797 .0147 .3515 .4112 .8010 .2485 .0463 .0109 .0845 .6466 .0237 .1489 .4455 <.0001 .0042 .0086 .0673 .5598 .2553 .8091 .6065 .0537
e e e e e e e e e e e 7.0e16.0 g/L 4.2e12.9 g/L 4.2e12.9 g/L 0.4e1.3 g/L 0e2.9 g/L 700e4000 mg/L 400e2300 mg/L 2.4e240 mg/L 12e645 cells/mL 359e1,519 cells/mL 109e897 cells/mL 24e406 cells/mL e e e e
Abbreviations: HLA, human leukocyte antigen; Ig, immunoglobulin. Observations for serum immunoglobulin levels and blood lymphocyte subsets are expressed as median (range). Reference ranges were defined as mean 2 SD. Comparisons were made with Mann-Whitney U test, Pearson c2 test, or Fisher exact test, as appropriate. These are nominal P values. Bonferroni correction for 27 comparisons yielded a revised value for significance (P < .0019). c The prevalence of sinusitis, pneumonia, otitis media, and cutaneous or mucosal yeast infections (interpreted as Candida species) did not differ significantly between patients with and those without hypogammaglobulinemia. d These conditions were diagnosed before referral for the present evaluations. e Serum IgE levels lower than 1 IU/mL (<2.4 mg/L) were imputed as 0.5 IU/mL (1.2 mg/L). a
b
association study, plasma IgE levels were significantly associated with the major histocompatibility complex (MHC) markers HLA-A, HLA-G, and HLA-DQA2.9 Concurrence of subnormal serum IgE and other immunoglobulin isotypes in some patients also could be linked to the MHC. IgE levels are linked to the MHC9 and were associated with common HLA-A and -B haplotypes in the present report. IgGSD phenotypes in other non-Hispanic white adults also were linked to HLA-A*03, B*07.6,10 The present study was limited to observations in non-Hispanic white adults and did not include analyses of all infections or measurements of serum levels of antigen-specific IgG, IgA, or IgM, allergen-specific IgE, IgA subclasses, or IgD. The prevalence of some conditions and HLA-A and -B haplotypes we studied could differ across geographic regions or racial and ethnic groups. Longitudinal follow-up of the present patients was beyond the scope of our study. We conclude that hypogammaglobulinemia E is common in non-Hispanic white adults with IgGSD and is negatively associated with bronchitis, allergic asthma, IgG1, and CD4þ lymphocytes. Serum IgE was positively associated with allergic asthma, allergic dermatitis or eczema, IgG4, and HLA-A*03, B*07. James C. Barton, MD*,y,z J. Clayborn Barton, BSy Luigi F. Bertoli, MD*,y,x *Department of Medicine Brookwood Medical Center Birmingham, Alabama y Southern Iron Disorders Center Birmingham, Alabama
z
Department of Medicine University of Alabama at Birmingham Birmingham, Alabama x Brookwood Biomedical Birmingham, Alabama [email protected] References [1] Pate MB, Smith JK, Chi DS, et al. Regulation and dysregulation of immunoglobulin E: a molecular and clinical perspective. Clin Mol Allergy. 2010;8:3. [2] Kazmirchuk VI, Tsaryk VV, Sydorenko OI, et al. [Frequency of immunoglobulin E deficiency among patients with immunodependent disorders]. Lik Sprava. 2014;7e8:3e9 (in Ukrainian). [3] Smith JK, Krishnaswamy GH, Dykes R, et al. Clinical manifestations of IgE hypogammaglobulinemia. Ann Allergy Asthma Immunol. 1997;78:313e318. [4] Magen E, Schlesinger M, David M, et al. Selective IgE deficiency, immune dysregulation, and autoimmunity. Allergy Asthma Proc. 2014;35:e27ee33. [5] McVicker S, Karim MY. IgE deficiency may indicate underlying hypogammaglobulinaemia? J Clin Pathol. 2014;67:832e833. [6] Barton JC, Bertoli LF, Barton JC. Comparisons of CVID and IgGSD: referring physicians, autoimmune conditions, Pneumovax reactivity, immunoglobulin levels, blood lymphocyte subsets, and HLA-A and -B typing in 432 adult index patients. J Immunol Res. 2014;2014:542706. [7] Polmar SH, Waldmann TA, Balestra ST, et al. Immunoglobulin E in immunologic deficiency diseases. I. Relation of IgE and IgA to respiratory tract disease in isolated IgE deficiency, IgA deficiency, and ataxia telangiectasia. J Clin Invest. 1972;51:326e330. [8] Mao W, Cui EH. Distribution of pathogens causing nosocomial infection in patients with bronchial asthma. Genet Mol Res. 2015;14:16146e16150. [9] Granada M, Wilk JB, Tuzova M, et al. A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study. J Allergy Clin Immunol. 2012;129:840e845. [10] Barton JC, Bertoli LF, Acton RT. HLA-A and -B alleles and haplotypes in 240 index patients with common variable immunodeficiency and selective IgG subclass deficiency in central Alabama. BMC Med Genet. 2003;4:3.
Contents lists available at ScienceDirect
Letter
Hypogammaglobulinemia E in 216 adults with IgG subclass deficiency and respiratory tract infections Hypogammaglobulinemia E has been reported in 0.8% to 3.0% of adults unselected for disease associations.1,2 In persons with subnormal serum immunoglobulin (Ig) E, the prevalence of frequent or severe respiratory tract infections,3,4 other subnormal immunoglobulin isotypes,3,5 and autoimmune conditions3,4 was significantly greater than that in control subjects.3e5 To learn more, we performed a retrospective study to determine clinical and laboratory associations of hypogammaglobulinemia E (serum IgE <1 IU/L [<2.4 mg/L]) and IgE levels at diagnosis in 216 index adult patients with IgG subclass deficiency (IgGSD).6 We studied the records of non-Hispanic white adults (18 years of age) referred to a single practice in a large suburban medical center that evaluates and treats many adults with primary immunodeficiency. All patients had frequent or severe bacterial infections of the upper or lower respiratory tract6; all were diagnosed to have IgGSD6; all were advised to undergo IgG replacement therapy; and all had serum IgE measurements at initial evaluation. Fifty-five patients (24.5%) also had subnormal serum total IgG. Autoimmune conditions, atopy, other allergy, and corticosteroid therapy were defined as previously described.6 Testing was performed before initial IgG replacement therapy. Serum immunoglobulin levels and blood lymphocyte subsets were measured at the Laboratory Corporation of America (Burlington, North Carolina). We defined mean 2 SD as the reference range (Table 1). Human leukocyte antigen (HLA) A and B alleles were detected using low-resolution DNA-based typing.6 We studied the haplotypes A*01, B*08; A*02, B*44; A*03, B*07; and A*29, B*44.6 We performed logistic regression on hypogammaglobulinemia E and multivariable regression on IgE levels using all available independent variables. Mean age was 49 12 years. There were 180 women (83.3%). The 5 most common infections were sinusitis (88.9%), bronchitis (72.2%), pneumonia (51.4%), otitis media (31.5%), and cutaneous or mucosal yeast infections (interpreted as Candida species; 30.1%). Seventy patients (32.4%) reported corticosteroid therapy. The most common subnormal IgG isotypes were IgG3 (88 patients, 40.7%), IgG1 (55, 25.5%), and IgG1/IgG3 (51, 23.6%). Thirteen patients (6.0%) had subnormal IgA. Twenty-two patients (10.2%) had subnormal IgM. Autoimmune conditions were diagnosed in 76 patients (35.2%). Atopy was reported by 63 patients (29.2%), including allergic asthma (51 patients, 23.6%), allergic rhinitis (13, 6.0%), and allergic dermatitis or eczema (8, 3.7%). Sixty-eight patients (31.5%) reported other allergy. Hypogammaglobulinemia E occurred in 37 patients (17.1%). The prevalence of bronchitis reports was significantly lower in patients Disclosures: Authors have nothing to disclose. Funding Sources: This work was supported in part by Southern Iron Disorders Center and Brookwood Biomedical.
with hypogammaglobulinemia E (Table 1). No other attributes of patients with vs without hypogammaglobulinemia E differed significantly after Bonferroni correction (Table 1). The prevalence of subnormal total IgG, IgG subclasses, IgA, and IgM did not differ significantly between patients with and those without hypogammaglobulinemia E. Because HLA-A*29, B*44 was observed only in patients with normal or increased IgE (Table 1), this haplotype could not be used as an independent regression variable. Immunoglobulin E was increased (>100 IU/L [>240 mg/L]) in 32 patients. There was a significant upward trend in the proportions of patients with allergic asthma in the hypogammaglobulinemia E, normal IgE, and increased IgE subgroups (8.1%, 21.1%, and 53.1%, respectively; P < .0001). Logistic regression on hypogammaglobulinemia E showed 3 significant negative associations: asthma (P ¼ .0298; odds ratio 0.24, 95% confidence interval 0.07e0.88), CD4þ lymphocytes (P ¼ .0138; odds ratio 0.99, 95% confidence interval 0.99e1.00), and IgG1 (P ¼ .0352; OR 0.99, 95% confidence interval 0.99e1.00). Multivariable regression on serum IgE levels showed 4 significant positive associations: allergic asthma (P ¼ .0044), allergic dermatitis or eczema (P < .0001), IgG4 (P ¼ .0003), and HLA-A*03, B*07 (P ¼ .0039). The most common non-IgG isotype deficiency in the present patients was hypogammaglobulinemia E. The prevalence of hypogammaglobulinemia E was greater in the present patients (17.1%) than in unselected adults (0.8e3.0%)1,2 and in 420 adults in an allergy-immunology clinic (10.5%).3 The prevalence of chronic sinusitis and recurrent otitis media in 158 patients at least 12 years old with hypogammaglobulinemia E was significantly greater than that in 600 controls.4 These observations suggest that hypogammaglobulinemia E contributes to increased risks of respiratory tract infections in adults. In contrast, serum IgE level lower than 6.3 IU/L (<15 mg/L) was observed in 7 of 73 normal adults (9.6%), none of whom reported having respiratory tract disease.7 In an allergyimmunology clinic, the prevalence of respiratory symptoms did not differ significantly in patients with vs without hypogammaglobulinemia E.3 The prevalence of bronchitis reports was significantly lower in the present patients with hypogammaglobulinemia E. Higher serum IgE levels were significantly associated with allergic asthma, consistent with other reports. The risk of lower respiratory tract infections was increased in subjects with allergic asthma unselected for subnormal immunoglobulin levels.8 Regardless of IgE levels, manifestations interpreted as asthma in some patients might be due to infections or other non-allergy mechanisms. Allergic dermatitis or eczema also was significantly associated with serum IgE levels in the present patients, after adjustment for other variables. Serum IgE levels were significantly associated with HLA-A*03, B*07 in the present index patients. In a Framingham genomewide
http://dx.doi.org/10.1016/j.anai.2017.07.005 1081-1206/Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
2
Letter / Ann Allergy Asthma Immunol xxx (2017) 1e2
Table 1 Hypogammaglobulinemia E in 216 Adult Index Patients With IgG Subclass Deficiencya Characteristic
Hypogammaglobulinemia E (n ¼ 37)
No hypogammaglobulinemia E (n ¼ 179)
P valueb
Reference ranges
Men, % (n) Age (y), mean (SD) BMI (kg/m2), mean (SD) Bronchitis, % (n)c Diabetes mellitus, % (n)d Autoimmune condition, % (n)c Allergic asthma, % (n)d Allergic rhinitis, % (n)d Allergic dermatitis or eczema, % (n)c Other allergy, % (n)d Corticosteroid therapy, % (n) Total IgG (g/L) IgG1 (g/L) IgG2 (g/L) IgG3 (g/L) IgG4 (g/L) IgA (mg/L) IgM (mg/L) IgE (mg/L) CD19þ cells/mL CD4þ cells/m/L CD8þ cells/m/L CD56þ/16þ cells/m/L HLA-A*01, B*08 positivity, % (n) HLA-A*02, B*44 positivity, % (n) HLA-A*03, B*07 positivity, % (n) HLA-A*29, B*44 positivity, % (n)
13.5 (5) 49 12 26.7 7.1 45.9 (17) 8.1 (3) 40.5 (15) 8.1 (3) 2.7 (1) 5.4 (2) 29.7 (11) 24.3 (9) 7.42 (4.70e13.90) 3.83 (2.49e6.69) 2.43 (0.45e6.34) 0.34 (0.10e1.04) 0.09 (0e1.39) 1,390 (40e4,350) 1,100 (100e5,110) 1.2 (1.2e1.2)e 244 (42e979) 826 (108e2,040) 334 (48e1,043) 149 (15e523) 13.5 (5) 16.2 (6) 10.8 (4) 0 (0)
17.3 (31) 49 12 28.9 7.1 77.7 (139) 8.4 (15) 34.1 (61) 26.8 (48) 6.7 (12) 3.4 (6) 31.8 (57) 34.1 (61) 7.96 (4.01e17.51) 4.17 (2.38e8.83) 2.64 (0.31e7.24) 0.34 (0.07e1.76) 0.16 (0e1.45) 1,620 (140e5,550) 1,020 (240e5,160) 57.6 (4.8e15,355) 186 (5e193) 1,012 (253e2,984) 457 (90e2,106) 146 (5e656) 21.8 (39) 17.9 (32) 11.2 (20) 8.4 (15)
.5718 .8420 .0945 <.0001 .9566 .4797 .0147 .3515 .4112 .8010 .2485 .0463 .0109 .0845 .6466 .0237 .1489 .4455 <.0001 .0042 .0086 .0673 .5598 .2553 .8091 .6065 .0537
e e e e e e e e e e e 7.0e16.0 g/L 4.2e12.9 g/L 4.2e12.9 g/L 0.4e1.3 g/L 0e2.9 g/L 700e4000 mg/L 400e2300 mg/L 2.4e240 mg/L 12e645 cells/mL 359e1,519 cells/mL 109e897 cells/mL 24e406 cells/mL e e e e
Abbreviations: HLA, human leukocyte antigen; Ig, immunoglobulin. Observations for serum immunoglobulin levels and blood lymphocyte subsets are expressed as median (range). Reference ranges were defined as mean 2 SD. Comparisons were made with Mann-Whitney U test, Pearson c2 test, or Fisher exact test, as appropriate. These are nominal P values. Bonferroni correction for 27 comparisons yielded a revised value for significance (P < .0019). c The prevalence of sinusitis, pneumonia, otitis media, and cutaneous or mucosal yeast infections (interpreted as Candida species) did not differ significantly between patients with and those without hypogammaglobulinemia. d These conditions were diagnosed before referral for the present evaluations. e Serum IgE levels lower than 1 IU/mL (<2.4 mg/L) were imputed as 0.5 IU/mL (1.2 mg/L). a
b
association study, plasma IgE levels were significantly associated with the major histocompatibility complex (MHC) markers HLA-A, HLA-G, and HLA-DQA2.9 Concurrence of subnormal serum IgE and other immunoglobulin isotypes in some patients also could be linked to the MHC. IgE levels are linked to the MHC9 and were associated with common HLA-A and -B haplotypes in the present report. IgGSD phenotypes in other non-Hispanic white adults also were linked to HLA-A*03, B*07.6,10 The present study was limited to observations in non-Hispanic white adults and did not include analyses of all infections or measurements of serum levels of antigen-specific IgG, IgA, or IgM, allergen-specific IgE, IgA subclasses, or IgD. The prevalence of some conditions and HLA-A and -B haplotypes we studied could differ across geographic regions or racial and ethnic groups. Longitudinal follow-up of the present patients was beyond the scope of our study. We conclude that hypogammaglobulinemia E is common in non-Hispanic white adults with IgGSD and is negatively associated with bronchitis, allergic asthma, IgG1, and CD4þ lymphocytes. Serum IgE was positively associated with allergic asthma, allergic dermatitis or eczema, IgG4, and HLA-A*03, B*07. James C. Barton, MD*,y,z J. Clayborn Barton, BSy Luigi F. Bertoli, MD*,y,x *Department of Medicine Brookwood Medical Center Birmingham, Alabama y Southern Iron Disorders Center Birmingham, Alabama
z
Department of Medicine University of Alabama at Birmingham Birmingham, Alabama x Brookwood Biomedical Birmingham, Alabama [email protected] References [1] Pate MB, Smith JK, Chi DS, et al. Regulation and dysregulation of immunoglobulin E: a molecular and clinical perspective. Clin Mol Allergy. 2010;8:3. [2] Kazmirchuk VI, Tsaryk VV, Sydorenko OI, et al. [Frequency of immunoglobulin E deficiency among patients with immunodependent disorders]. Lik Sprava. 2014;7e8:3e9 (in Ukrainian). [3] Smith JK, Krishnaswamy GH, Dykes R, et al. Clinical manifestations of IgE hypogammaglobulinemia. Ann Allergy Asthma Immunol. 1997;78:313e318. [4] Magen E, Schlesinger M, David M, et al. Selective IgE deficiency, immune dysregulation, and autoimmunity. Allergy Asthma Proc. 2014;35:e27ee33. [5] McVicker S, Karim MY. IgE deficiency may indicate underlying hypogammaglobulinaemia? J Clin Pathol. 2014;67:832e833. [6] Barton JC, Bertoli LF, Barton JC. Comparisons of CVID and IgGSD: referring physicians, autoimmune conditions, Pneumovax reactivity, immunoglobulin levels, blood lymphocyte subsets, and HLA-A and -B typing in 432 adult index patients. J Immunol Res. 2014;2014:542706. [7] Polmar SH, Waldmann TA, Balestra ST, et al. Immunoglobulin E in immunologic deficiency diseases. I. Relation of IgE and IgA to respiratory tract disease in isolated IgE deficiency, IgA deficiency, and ataxia telangiectasia. J Clin Invest. 1972;51:326e330. [8] Mao W, Cui EH. Distribution of pathogens causing nosocomial infection in patients with bronchial asthma. Genet Mol Res. 2015;14:16146e16150. [9] Granada M, Wilk JB, Tuzova M, et al. A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study. J Allergy Clin Immunol. 2012;129:840e845. [10] Barton JC, Bertoli LF, Acton RT. HLA-A and -B alleles and haplotypes in 240 index patients with common variable immunodeficiency and selective IgG subclass deficiency in central Alabama. BMC Med Genet. 2003;4:3.