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(Chest. 2005;127:197-204.)
© 2005 American College of Chest Physicians

Antibody Production Deficiency With Normal IgG Levels in Bronchiectasis of Unknown Etiology*

Montserrat Vendrell, MD; Javier de Gracia, MD, PhD; María-José Rodrigo, MD, PhD; María-Jesús Cruz, MB; Antonio Alvarez, MD; Maria Garcia, MD, PhD and Marc Miravitlles, MD, PhD

* From the Departments of Pneumology (Dr. Vendrell) and Biostatistics (Dr. Garcia), Hospital Josep Trueta, Girona; and Departments of Pneumology (Drs. de Gracia, Alvarez, and Miravitlles) and Immunology (Drs. Rodrigo and Cruz), Hospital Universitari Vall d’Hebron, Barcelona, Spain.

Correspondence to: Montserrat Vendrell, MD, Ps Canalejas n°1 esc 3 3°1, Girona 17001, Spain, e-mail: mont2188{at}separ.es


   Abstract
TOP
 Abstract
Introduction
 Methods and Materials
 Results
 Discussion
 References
 
Background: No defined cause of bronchiectasis is currently found in approximately 50% of cases. Bronchiectasis is a common long-term complication in patients with primary hypogammaglobulinemia.

Study objectives: To ascertain whether antibody production deficiency with normal total serum IgG levels is associated with bronchiectasis.

Design: Antibody response to a pneumococcal unconjugate vaccine and an Haemophilus influenzae type b conjugate vaccine was prospectively studied in all consecutive adult patients with bronchiectasis of unknown etiology who were assessed in our chest outpatient clinic from January 1994 to October 2001. Serum-specific antibodies were measured by enzyme-linked immunosorbent assay, and the results were compared with those obtained in a healthy adult control group. Antibody production deficiency was defined as a failure to respond to either vaccine.

Results: One hundred seven patients were included in the study (mean age, 46.3 years). Antibody production deficiency was diagnosed in 12 patients (11%). A significantly higher incidence of otitis media, lower serum IgG2 subclass levels, and lower preimmunization antibody levels to Streptococcus pneumoniae and H influenzae type b were observed in patients with antibody production deficiency. The probability of antibody production deficiency in patients with a history of otitis media was 20%, 26% in those with low IgG2 subclass levels, and 58% in those with both a history of otitis media and low IgG2 subclass levels.

Conclusions: Antibody production deficiency with normal IgG levels may be associated with bronchiectasis, making it advisable to evaluate the antibody response to both the H influenzae and pneumococcal vaccines in patients with bronchiectasis of unknown etiology, particularly in those with a history of otitis media, low IgG2 subclass levels, and low levels of baseline specific antibodies.

Key Words: antibody deficiency • bronchiectasis • Haemophilus influenzae type b vaccine • pneumococcal vaccine • primary immunodeficiency


   Introduction
TOP
 Abstract
 Introduction
Methods and Materials
 Results
 Discussion
 References
 
Bronchiectasis represents the end stage of a variety of pathologic processes. With the decline in incidence of postinfectious conditions, other extrinsic insults or intrinsic defects that predispose to bronchial inflammation or respiratory infection are likely to be more significant in the etiology of bronchiectasis. However, no defined cause is currently found in approximately 50% of cases.1

Bronchiectasis is a common long-term complication in patients with primary hypogammaglobulinemia, such as X-linked agammaglobulinemia2 and common variable immunodeficiency.3 The diagnosis of these immunodeficiencies can be readily suspected from a serum electrophoresis, and early diagnosis has significant implications for prognosis and management since Ig-replacement therapy may prevent progression of lung damage.45 Other more selective defects of the humoral system, such as selective IgG subclass deficiency,6 have been associated with bronchiectasis.1789 However, since low levels of IgG subclasses have also been described in healthy adults,10 additional evaluation of antibody production is recommended to facilitate the diagnosis of humoral immunodeficiency and selection of patients to receive Ig therapy.11

Failure to produce antibodies to polysaccharide vaccines, however, has been reported in a healthy population12 and in patients with recurrent respiratory infections and normal serum IgG levels.131415 In some cases, however, this lack of response can be overcome by administration of a polysaccharide-protein conjugate vaccine.161718192021 For this reason, the joint evaluation of immune response to a polysaccharide vaccine and a polysaccharide conjugate vaccine appears to be more appropriate to complete the screening for antibody production deficiency.22

To ascertain whether antibody production deficiency with normal total serum IgG levels is associated with bronchiectasis, we studied the antibody response to both the pneumococcal unconjugate vaccine and the Haemophilus influenzae type b (Hib) conjugate vaccine in adult patients with bronchiectasis of unknown etiology.


   Methods and Materials
TOP
 Abstract
 Introduction
 Methods and Materials
Results
 Discussion
 References
 
From January 1994 to October 2001, we studied all consecutive adult patients with bronchiectasis who were assessed in our chest outpatient clinic. A questionnaire was completed for every patient, providing information on smoking habits, drugs used in treatment, and history of infectious and pulmonary diseases. Patients were excluded if they had any recognized cause of bronchiectasis: a history of pulmonary tuberculosis, aspiration or inhalation injury, lung abscess or childhood respiratory infections (pertussis, measles); evidence of cystic fibrosis (CF) [sweat test and CF transmembrane conductance regulator gene analysis; Applied Biosystems; Foster City, CA],23 allergic bronchopulmonary aspergillosis, {alpha}1-antitrypsin deficiency, Kartagener syndrome, Young syndrome, congenital defects, bronchial obstruction, hypogammaglobulinemia, secondary immunodeficiencies, any disease or drug intake that might affect antibody production, or other systemic diseases associated with bronchiectasis.24

Bronchiectasis was diagnosed clinically and by high-resolution CT scan. The presence and extent of bronchiectasis were graded as follows: involvement of one lobe, two lobes, bilateral involvement, and involvement of more than three lobes.

Patients were immunized intramuscularly with Hib conjugate vaccine (PedvaxHIB; Merck Sharp & Dohme; West Point, PA) and polyvalent pneumococcal vaccine (PNU-Immune 23; Lederle Laboratories Division; Pearl River, NY).1222 Blood samples were drawn immediately before and 21 days after vaccination. Patients were required to have no evidence of exacerbations during the month preceding vaccination. This study was approved by the Ethics Committee of the Vall d’Hebron Hospitals.

Serum total IgG, IgA, and IgM levels were measured by kinetic nephelometry, and IgG subclasses by enzyme-linked immunosorbent assay.725 Reference values in adults were 850 to 1,600 mg/dL for IgG, 261 to 1,081 mg/dL for IgG1, 112 to 408 mg/dL for IgG2, 22 to 288 mg/dL for IgG3, and 5 to 156 mg/dL for IgG4.725 Hypogammaglobulinemia was defined as a serum IgG level < 400 mg/dL, IgA deficiency as undetectable IgA serum concentrations (< 7 mg/dL), and low levels of IgG subclasses as serum levels below reference values.7

Antibodies to pneumococcal and Hib antigens were measured by enzyme-linked immunosorbent assay, as previously described;1222 the pneumococcal vaccine and an Hib oligosaccharide conjugated to human serum albumin were used as antigens.1222

The control group was made up of 79 prospectively enrolled healthy adult volunteers, 40 of whom (mean age, 29.5 years) were studied to establish a criterion for a normal response to the pneumococcal vaccine, and 59 of whom (mean age, 32 years) to establish a criterion for a normal response to the Hib conjugate vaccine, as we published previously.1222 Twenty of the 79 healthy adults received both vaccines.22 None had a history of recurrent or severe infections, acute or chronic pulmonary disease, primary or secondary immunodeficiency, autoimmune systemic disorder, or any disease or intake of drugs that might affect antibody production. They had not suffered any infection during the month preceding the vaccination. Forced spirometry, WBC count, creatinine, transaminases, and serum total Ig levels were within normal range. An arbitrary value, corresponding to the lower limit of the two-tailed 90% probability interval of postimmunization specific IgG of the healthy adults, was defined as the minimum significant increase for an adequate response. All subjects showing an increase in specific antibody titers equal to or greater than this value were considered to be responders. In the case of pneumococcal vaccine, this value was 395 arbitrary U/mL; and in the case of Hib, 2.28 µg/mL, as described elsewhere.1222 To determine a diagnostic criterion of antibody production deficiency, we studied specific antibody response to pneumococcal and Hib conjugate vaccine in the 20 of the 79 healthy adults who received the two vaccines, and the results were compared with those obtained in 22 patients (mean age, 32 years) with humoral immunodeficiencies characterized by defective antibody formation (18 common variable immunodeficiency, 2 immunodeficiency with thymoma, and 2 X-linked agammaglobulinemia).22 Antibody production deficiency was defined as a failure to respond to either vaccine.22 At the beginning of the study sera from the control group and from the bronchiectasis patients were simultaneously obtained. Sera from the patients were stored in aliquots frozen at – 20°C until the assay method to quantify specific antibodies was standardized, normal antibody response to both vaccines established, and antibody production deficiency defined, then they were tested. From then on, all sera obtained from patients were sent immediately for testing.

Sputum specimens for bacteria culture were obtained. Pulmonary function parameters studied were FEV1 and FVC. Predicted values were taken from Roca et al.26

Statistical Analysis
Categorical variables are shown as percentages, and continuous variables as a mean and 95% confidence interval (CI). Specific antibody titers were transformed to their natural logarithms to meet the assumption of normality and expressed as the geometric mean and 95% CI. Bivariate analyses for continuous variables were made with Student t test or Mann-Whitney U test, as appropriate. {chi}2 and Fisher exact test were used for comparison of categorical variables, and Spearman test for correlations. The probability of antibody production deficiency was calculated by logistic regression, including significant clinical and Ig variables in bivariate analyses. We calculated the cutoff values27 of preimmunization specific antibody levels that provide the maximum probability of a correct prediction of the response to a vaccine. Significance level was 5% (two-tailed). The statistical software package was used for the analysis (SPSS 10.0.6; SPSS; Chicago, IL).28


   Results
TOP
 Abstract
 Introduction
 Methods and Materials
 Results
Discussion
 References
 
A total of 173 consecutive clinically stable adult patients with bronchiectasis of unknown etiology were assessed during the study period. Sixty-six patients were excluded (46 female and 20 male patients; age range, 15 to 82 years; mean age, 44.4 years) owing to previous pneumococcal or Hib immunization, insufficient data, or their not wishing to take part.

One hundred seven patients were finally included in the study (63 female and 44 male patients; age range, 16 to 77 years; mean age, 46.3 years). Twelve of the 107 patients (11%) failed to respond to either of the vaccines, and an antibody production deficiency was diagnosed. In addition, 15 of the patients (14%) failed to respond to the Hib conjugate vaccine only, and 20 to the pneumococcal unconjugate vaccine only (19%).

No significant differences were detected in specific antibody levels to Hib and Streptococcus pneumoniae between healthy control subjects and patients with bronchiectasis (Table 1 ). Nor were differences found between the two groups when patients with antibody production deficiency were excluded.


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  		Table 1.. Serum-Specific Antibody Concentrations to H influenzae Polyribosylribitol Phosphate and S pneumoniae in Healthy Control Subjects and Patients With Bronchiectasis of Unknown Etiology*

 
Patient characteristics according to antibody deficiency are summarized in Tables 2, 3 . A significantly higher incidence of otitis media (p = 0.01), lower serum IgG2 subclass levels (p = 0.001), and lower preimmunization antibody levels to S pneumoniae and Hib (p = 0.03 and p < 0.0001, respectively) were observed in patients with antibody production deficiency. No significant differences were found between the two groups in the remaining clinical, immunologic, microbiological, and pulmonary function parameters. According to logistic regression, the probability of antibody production deficiency in patients with a history of otitis media was 20%, 26% in those with low IgG2 subclass serum levels, and 58% in those with both a history of otitis media and low IgG2 subclass serum levels.


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  		Table 2.. Characteristics of Patients With Bronchiectasis According to Antibody Deficiency*

 

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  		Table 3.. Characteristics of Patients With Bronchiectasis According to Antibody Deficiency

 
Low levels of any of the IgG subclasses were observed in 46 of the patients (43%) with bronchiectasis, with the greater incidence being found in patients with antibody production deficiency (p = 0.0008), although only for IgG2 subclass was the difference significant (p = 0.0001) [Table 4 ].


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  		Table 4.. Frequency of Low Levels of IgG Subclasses and IgA Deficiency in Patients With Bronchiectasis of Unknown Etiology*

 
Moderate correlations were observed between preimmunization and postimmunization IgG levels to S pneumoniae (r = 0.7), and also between preimmunization and postimmunization IgG to Hib (r = 0.5). Low correlations were found between baseline IgG2 levels and both preimmunization and postimmunization IgG to S pneumoniae (r = 0.4 and r = 0.41, respectively). A low correlation between baseline IgG2 levels and preimmunization IgG to Hib (r = 0.3) was observed, but none between the former and postimmunization IgG to Hib.

The optimal cutoff values of the preimmunization specific antibody levels that provide the maximum probability of a correct prediction of the response to a vaccine were 434 U/mL and 2.2 µg/mL for S pneumoniae and Hib, respectively. These values were close to the 50th percentile of preimmunization specific antibody levels in healthy controls subjects for both vaccines (575 U/mL and 2.3 µg/mL for S pneumoniae and Hib, respectively). The sensitivity of the preimmunization specific antibody level when the 50th percentile was chosen as a cutoff value was 84% for S pneumoniae and 80% for Hib (Fig 1, 2 ).



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  		Figure 1.. Preimmunization antibody levels to H influenzae type b in healthy control subjects, in responding and nonresponding patients to H influenzae vaccine. The 25th and 50th percentiles are those of preimmunization specific antibody levels in healthy control subjects.

 


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  		Figure 2.. Preimmunization antibody levels to S pneumoniae in healthy control subjects, in responding and nonresponding patients to S pneumoniae vaccine. The 25th and 50th percentiles are those of preimmunization specific antibody levels in healthy control subjects.

 

   Discussion
TOP
 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
References
 
This study showed an antibody production deficiency with normal IgG levels in 11% of adult patients with bronchiectasis, in whom most of the known causes had been ruled out. Patients with antibody production deficiency presented a significantly higher incidence of otitis media, lower serum IgG2 subclass levels, and lower preimmunization antibody levels to S pneumoniae and Hib.

The immune response to specific antigens should be tested to diagnose an antibody production deficiency. Identification of this underlying defect may have major implications for management, since Ig therapy might prevent progression of lung damage, as in other antibody deficiencies.45 However, uniform guidelines on such a diagnosis have yet to be adequately defined. This is probably due to the paucity of studies on antibody production in the healthy adult population and lack of a uniform criterion for vaccine response. Furthermore, since a proportion of the healthy population may not respond to a vaccine,1222 the inability to produce a satisfactory response to immunization with a single vaccine may not suffice to diagnose humoral immunodeficiency, and the evaluation of at least two vaccines is advisable. In fact, the percentage of patients with bronchiectasis failing to respond to only one of the vaccines (19% to S pneumoniae vaccine and 14% to Hib conjugate vaccine) in the present study was similar to that observed in the healthy population (20% to S pneumoniae and 15% to Hib conjugate vaccine)1222; however, none of the healthy population who received the two vaccines failed to respond to both,22 and none of the patients with primary humoral immunodeficiencies responded to either of the vaccines.22

Specific antibody levels in patients with bronchiectasis were investigated in two previous studies.19 However, since considerable differences exist regarding criteria for study population selection, vaccination indication, response to a vaccine, and humoral immunodeficiency diagnosis, the results are difficult to compare (Table 5 ). In this work, as distinct from the previous studies, we assessed bronchiectasis patients in whom a comprehensive study had failed to establish a cause. The only criterion for the selection of the study population was to have bronchiectasis of unknown etiology, without establishing any other immunologic criterion that had not been previously demonstrated. The response to two vaccines (a polysaccharide and a polysaccharide conjugate vaccine) was evaluated in all the patients. The criteria of response to each vaccine were based on the results obtained in the healthy adult population; the values used as a measure of the response were not influenced by preimmunization antibody titers and may be applied in the study of response to different vaccines as well as permitting direct comparisons between different populations.1222 The diagnosis criterion of antibody production deficiency was based on the results obtained in both healthy control group and patients with known humoral primary immunodeficiency,1222 all in the same laboratory. Furthermore, this is the first study in which the clinical and immunologic characteristics of patients with antibody production deficiency and bronchiectasis have been reported, and in which the optimal cutoff values of the preimmunization specific antibody levels that provide the maximum probability of a correct prediction of the response to a vaccine were calculated. The great variability in baseline specific antibody levels and the lack of a good correlation between preimmunization and postimmunization specific antibody levels observed in our study render it difficult to establish a value below which vaccination should be indicated to complete the evaluation of antibody-mediated immunity. Although the values of the 25th percentile of the normal range used by Pasteur et al1 may be useful, the 50th percentile could be more appropriate to avoid underdiagnosis, as shown in this study.


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  		Table 5.. Antibody Production Deficiency in Patients With Bronchiectasis: Vaccination Indication, Diagnostic Criteria, and the Results in Different Studies*

 
We found that patients with a history of otitis media were more likely to have an antibody production deficiency; since this is a common infection in patients with primary hypogammaglobulinemia,23 but not in patients with bronchiectasis, a systemic predisposition to the infection, and not just at respiratory level, is suggested. No significant differences in the incidence of other infections also common in patients with primary hypogammaglobulinemia, such as sinusitis, recurrent lower respiratory tract infection, or recurrent pneumonia23 were observed between patients with and without antibody production deficiency. This might be due to the fact that many patients with bronchiectasis may have a tissue predisposition of the whole respiratory tract to development of recurrent infection regardless of their etiology.29

Low IgG subclass levels, however, have been associated with increased susceptibility to respiratory infections and bronchiectasis with variable prevalence depending on selection criteria of the study population, normal reference values, and measurement techniques used.1789 The subclass deficiency related to a greater susceptibility to infection is that of IgG2, which is often associated with an inability to produce antibodies to polysaccharide antigens.11 In this study, 50% of patients with antibody production deficiency had low IgG2 subclass levels. However, not all patients with low IgG2 levels had antibody production deficiency, as had already been observed in a healthy population by Nahm et al.10 This may be due, in part, to the fact that the IgG response to polysaccharide antigens is not limited to IgG2, but may also be due to IgG1.12223031 Therefore, IgG2 levels are probably not predictive of specific antibody levels32 and antibody response,11 as shown by the scant correlation found in this study. Thus, although patients with low IgG2 subclass levels were more likely to have an antibody production deficiency, a study of antibody production should be made before Ig treatment can be recommended. However, the finding of low IgG3 levels or undetectable levels of IgG4 was similar in patients with or without antibody production deficiency, and its role in predisposition to infection remains unclear.33

Although bronchiectasis elicits a hyperimmune response in patients with normal immunologic status, with IgA, IgG, and IgG subclass serum levels often being increased,78934 no differences were observed in specific antibody levels to Hib and to S pneumoniae between patients with bronchiectasis without antibody deficiency and healthy adults. This may be due to the great variability in basal specific antibody levels and antibody response in both populations. Specific antibody levels, however, in the patients with antibody production deficiency were similar to those observed in patients with known humoral immunodeficiencies.22

Based on the results of our study, a 5 to 6% incidence of antibody production deficiency should be expected if the bronchiectasis population is considered as a whole, since in approximately 50% of patients the etiology is unknown.1 Thus, the determination of antibody production does not appear to be warranted in the routine assessment of patients with bronchiectasis, and a guide for study indication would be appropriate. The results of this study showed that antibody production deficiency with normal IgG may be associated with bronchiectasis, making it advisable to evaluate the antibody response to both the Hib conjugate and pneumococcal unconjugate vaccines in patients with bronchiectasis in whom other known causes have been reasonably ruled out, particularly in those with a history of otitis media, low IgG2 subclass serum levels, and low levels of baseline specific antibodies. Future studies should be done to determine the effectiveness of Ig therapy in such patients.


   Acknowledgements
 
The authors thank Edelia Catalan of the nursing staff, and Barry Kench and Christine O’Hara for help with the English translation of the article.


   Footnotes
 
Abbreviations: CF = cystic fibrosis; CI = confidence interval; Hib = Haemophilus influenzae type b

Drs. Vendrell and de Gracia contributed equally to the design of the study and writing of the article.

This work was supported by a grant from the Fundació Catalana de Pneumologia 1994, Fondo de Investigaciones Sanitarias (Exp. No. 97/0925), and Fundación Respira 2003.

Received for publication February 4, 2004. Accepted for publication June 30, 2004.


   References
TOP
 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
 References
 

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M. Miravitlles, M. Vendrell, and J. de Gracia
Antibody deficiency in bronchiectasis
Eur. Respir. J., July 1, 2005; 26(1): 178 - 180.
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