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Original Research: COPD |

Adenovirus-Specific IgG Maturation as a Surrogate Marker in Acute Exacerbations of COPDAdenovirus IgG Maturation in COPD FREE TO VIEW

Lucas Boeck, MD; Mikael Gencay, PhD; Michael Roth, PhD; Hans H. Hirsch, MD; Mirjam Christ-Crain, MD; Beat Mueller, MD; Michael Tamm, MD, FCCP; Daiana Stolz, MD, MPH
Author and Funding Information

From the Clinic of Pulmonary Medicine and Pulmonary Cell Research (Drs Boeck, Gencay, Roth, Tamm, and Stolz), University Hospital Basel, Basel; Department of Biomedicine (Dr Hirsch) and Department of Endocrinology, Diabetes and Metabolism (Dr Christ-Crain), University Basel, Basel; and Medical University Department (Dr Mueller), Kantonsspital Aarau, Aarau, Switzerland.

CORRESPONDENCE TO: Daiana Stolz, MD, MPH, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland; e-mail: daiana.stolz@usb.ch


Drs Boeck and Gencay contribute equally to this work.

FUNDING/SUPPORT: Dr Christ-Crain was supported by the Swiss National Foundation [PP00P3_123346]. Dr Stolz was supported by the Swiss National Foundation [PP00P3_128412/1], the Liechtenstein Foundation, and the Freiwillige Akademische Gesellschaft Basel. Additional funding was granted by the Clinic of Pulmonary Medicine, University Hospital Basel, Basel, Switzerland.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(2):339-347. doi:10.1378/chest.13-2307
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BACKGROUND:  B cells in airways and lung parenchyma may be involved in COPD evolution; however, whether their pathogenic role is beneficial or harmful remains controversial. The objective of this study was to investigate the maturation of adenovirus-specific immunoglobulins in patients with COPD with respect to clinical outcome.

METHODS:  The presence of adenovirus-specific immunoglobulins during acute exacerbation of COPD (AECOPD) was analyzed at exacerbation and 2 to 3 weeks later. Patients with detectable adenovirus-specific IgM and low IgG avidity were grouped into fast and delayed IgG maturation. The clinical outcome of both groups was evaluated.

RESULTS:  Of 208 patients, 43 (20.7%) had serologic evidence of recent adenovirus infection and were grouped by fast IgG maturation (26 patients) and delayed IgG maturation (17 patients). Baseline characteristics, AECOPD therapy, and duration of hospitalization were similar in both groups, but the AECOPD recurrence rate within 6 months was higher (P = .003), and there was a trend for earlier AECOPD-related rehospitalizations (P = .061) in the delayed IgG maturation group. The time to rehospitalization or death within 2 years was shorter in patients with delayed IgG maturation (P = .003). Adenovirus-specific IgG maturation was an independent predictor of the number of AECOPD recurrences within 6 months (P = .001) and the occurrence of hospitalization or death within 2 years (P = .005).

CONCLUSIONS:  Delayed immunoglobulin avidity maturation following COPD exacerbation is associated with worse outcomes.

TRIAL REGISTRY:  ISRCTN Register; No.: ISRCTN77261143; URL: www.isrctn.org

Figures in this Article

COPD is characterized by chronic inflammation of the respiratory tract, which is further intensified during acute exacerbation.1 The degree of inflammation increases with disease severity and persists long after smoking cessation.2 Various immune cells orchestrate recruitment and activation of inflammatory cells that drive the pattern of structural changes in the lung tissue resulting from repeated tissue injury and repair. Alveolar macrophages, neutrophils, and subsets of T cells are considered key inflammatory cell types in COPD.36 The involvement of B cells has gained attention, with increased numbers having been shown in large airways of patients with COPD.7 B cells organized in lymphoid follicles have been recognized in small airways and lung parenchyma of patients with COPD, which further increases with COPD progression.3,8 In these lymphoid follicles, antigen retention, immunoglobulin class switching, and affinity/avidity maturation occur.9 The antigens responsible for this process are yet unknown. Antigens of microbial origin, cigarette smoke-derived antigens, and autoantigens have been suggested to activate B cells.10,11 Thus, a protective as well as a harmful role of B-cell-generated antibodies seem plausible.12 Hypothetically, different COPD phenotypes mount a distinct B-cell response relative to outcome.

The aim of this study was to investigate immunoglobulin avidity maturation in patients with COPD and its possible impact on clinical outcome. Preliminary data indicate serologic evidence of recent adenovirus infection in a considerable proportion of the population with acute exacerbation of COPD (AECOPD) studied. Thus, adenovirus-specific immunoglobulins during COPD exacerbation were investigated as a marker reflecting the individual B-cell response.

Study Population

From November 2003 to March 2005, patients hospitalized for AECOPDs at the University Hospital Basel were recruited. Patients were required to be aged > 40 years and to meet spirometric COPD criteria and the definition of AECOPD. Patients with immunosuppression, asthma, cystic fibrosis, or infiltrates as seen on chest radiographs were not included. AECOPD was defined as an acute, sustained worsening of the patient’s condition beyond normal day-to-day variation.13 Only patients hospitalized for AECOPD (severe AECOPD14) were included in the study.

Patients were monitored for recurrent moderate (requiring treatment with systemic corticosteroids, antibiotics, or both) and severe (requiring hospitalization or a visit to the ED) AECOPDs for 6 months. The trial was approved by the institutional review board and registered as the ProCOLD (Procalcitonin-Guided Antibiotic Therapy in AECOPD) study (Ethics Committee of Basel 232/03). Written informed consent was obtained from all patients. The primary study objective was to improve antibiotic prescription based on procalcitonin guidance as reported previously.15 Herein, a post hoc analysis of the ProCOLD study was performed. A description of study assessments is provided in e-Appendix 1.

Serologic Assessment of Adenovirus Infection

Adenovirus-specific IgG and IgM were detected by enzyme immunoassay (Anibiotech Oy, Orgenium Laboratories Division) as described by the manufacturer. IgM-positive samples were retested after removal of IgG and rheumatoid factor. Serum samples were tested using a noncommercially available adenovirus IgG avidity enzyme-linked immunosorbent assay (Anibiotech Oy, Orgenium Laboratories Division). The adenovirus IgG avidity index was calculated from each specimen and expressed as percentage of IgG reactivity remaining in the urea-treated sample: (ODurea/ODreference) × 100, where OD refers to optical density.1618 Criteria for low and high avidity were evaluated in an independent population. A detailed description is available in e-Appendix 1. Similar assays have been developed and established for other viral and nonviral infections.16,17,1921

Serum samples at the start of hospitalization and after 2 to 3 weeks (14-21 days) were analyzed for adenovirus-specific immunoglobulin levels. Only patients with detectable adenovirus-specific IgM and low-avidity adenovirus-specific IgG on AECOPD hospitalization were analyzed further. These patients with serologic evidence of recent adenovirus infection were stratified into two groups determined by adenovirus-specific IgG avidity after 2 to 3 weeks: fast IgG maturation (high-avidity adenovirus-specific IgG) and delayed IgG maturation (low-avidity adenovirus-specific IgG).

Statistical Analyses

Discrete variables are expressed as counts (percentages) and continuous variables as mean ± SD or median (interquartile range). Comparability of groups was analyzed by the χ2 test, Fisher exact test, Student t test, and Mann-Whitney U test, as appropriate. The Kolmogorov-Smirnov test was applied to assess normal distribution. Time to exacerbation, hospitalization, death, or a combined end point was described by Kaplan-Meier survival curves and compared by the log-rank test. Predictors of clinical outcome were investigated using linear and logistic regression models. All tests were two-tailed, and P < .05 was defined as significant. Data were analyzed using SPSS version 20 for Macintosh (IBM).

Of 208 patients analyzed for adenovirus-specific immunoglobulins, 43 (20.7%) had detectable adenovirus-specific IgM and low-avidity adenovirus-specific IgG within 3 weeks of AECOPD. Twenty-six of these patients (60.5%) had high-avidity adenovirus-specific IgG after 2 to 3 weeks (fast IgG maturation), whereas the remaining 17 (39.5%) had low-avidity adenovirus-specific IgG after 2 to 3 weeks (delayed IgG maturation).

Age, sex, and COPD stage did not significantly differ between patients with fast and delayed adenovirus-specific IgG maturation (P = .18, .57, and .58, respectively). Likewise, other baseline characteristics were similar in both groups (Table 1).

Table Graphic Jump Location
TABLE 1  ] Demographic Characteristics of 43 Patients at Hospitalization for AECOPD Related to Adenovirus-Specific IgG Maturation

Data are presented as No. (%), mean ± SD, or median (interquartile range). The two groups were compared by the χ2 test, Fisher exact test, t test, and Mann-Whitney U test, as appropriate. No differences were observed between the groups. AECOPD = acute exacerbation of COPD; GOLD = Global Initiative for Chronic Obstructive Lung Disease.

Patients with delayed and fast adenovirus-specific IgG avidity maturation received a similar therapy for AECOPD (Table 2). Duration of hospitalization, ICU stay, and death during hospitalization did not differ across the two groups.

Table Graphic Jump Location
TABLE 2  ] Outcome After an AECOPD Related to Adenovirus-Specific IgG Maturation

Data are presented as No. (%), mean ± SD, or median (interquartile range). The two groups were compared by the χ2 test, Fisher exact test, t test, and Mann-Whitney U test, as appropriate. See Table 1 legend for expansion of abbreviation.

Compared with patients with fast adenovirus-specific IgG maturation, patients with delayed IgG maturation had more recurrences of AECOPD within 6 months of the initial exacerbation (P = .001) (Fig 1A). The number of COPD-related rehospitalizations within 6 months of inclusion did not differ according to IgG maturation (P = .177) (Fig 1B). Kaplan-Meier analysis revealed a higher AECOPD recurrence rate within 6 months in patients with delayed adenovirus-specific IgG maturation (log rank P = .003) (Fig 2A). A trend for more AECOPD-related rehospitalizations was seen in this group only (log rank P = .061) (Fig 2B). The time to death within 2 years was similar in both patient groups (log rank P = .31). Of note, time to rehospitalization or death within 2 years was shorter in patients with delayed adenovirus-specific IgG maturation (log rank P = .003) (Fig 2C).

Figure Jump LinkFigure 1  A and B, Number of AECOPDs (A) and AECOPD-related hospitalizations (B) within 6 mo after study inclusion. Light bars indicate patients with fast IgG maturation; dark bars, patients with delayed IgG maturation. AECOPD = acute exacerbation of COPD.Grahic Jump Location
Figure Jump LinkFigure 2  A-C, Kaplan-Meier estimates of the probability to remain AECOPD free (A), free of AECOPD-related hospitalizations (B), and free of hospitalizations or death (C). The solid line indicates patients with fast IgG maturation; dashed line, patients with delayed IgG maturation. See Figure 1 legend for expansion of abbreviation.Grahic Jump Location

In multiple regression analysis, sex, the number of AECOPD recurrences the previous year, and adenovirus-specific IgG maturation were independent predictors of recurrent AECOPD within 6 months (P = .004, .005, and .001, respectively) (Table 3). Interestingly, only adenovirus-specific IgG maturation was independently associated with the composite end point of hospitalization and death within 2 years (P = .005) (Table 4).

Table Graphic Jump Location
TABLE 3  ] Univariate and Multivariate Linear Regression to Predict Number of AECOPD Recurrences Within 6 Mo After Study Inclusion

Male patients, patients with frequent exacerbations the year before study inclusion, and patients with delayed adenovirus-specific IgG maturation had more AECOPD recurrences within 6 mo after study inclusion. LVEF = left ventricular ejection fraction; sPAP = systolic pulmonary artery pressure. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 4  ] Univariate and Multivariate Logistic Regression to Predict Hospitalization or Death Within 2 Y After Study Inclusion

The ORs represent the change in odds in being in one category of outcome when the value of the predictor increases by one unit. See Table 1 and 3 legends for expansion of abbreviations.

Respiratory tract infections and the associated inflammatory responses are regarded as key contributors to AECOPD. The present study associates delayed adenovirus-specific immunoglobulin maturation with worse outcome, as demonstrated by more AECOPD recurrences and earlier hospitalization or death. The implications of the findings raise questions about the importance of pathogen-directed B-cell responses compared with self-directed B-cell responses.

We suggest three potential explanations for poor outcome in patients with delayed adenovirus-specific IgG maturation. First, delayed immunoglobulin maturation might reflect an attenuated adaptive immune response predisposing patients with COPD to recurrent infections. Second, impaired adenovirus clearance might contribute to pulmonary inflammation and COPD progression. Third, delayed immunoglobulin maturation may be an innocent bystander in patients with poor outcome.

In general, immunoglobulin affinity (avidity), the binding strength between antibodies and a monovalent antigen (binding strength between multiple antigen-binding sites and antigen), increases progressively with time after virus infection. Genetic, environmental, and clinical factors potentially contribute to the various durations of immunoglobulin maturation. High-affinity immunoglobulins are more effective in protecting against microbial agents and in preventing reinfection. However, viruses may trigger a destructive response against self-antigens. Viral superantigens, molecular mimicry, or exposure to self-antigens during inflammation might cause autoimmunity.22 Herein, we demonstrate that delayed adenovirus-specific IgG maturation was associated with worse outcome, indicating a protective B-cell response.

Many vaccines are accepted tools to assess individual antibody responses to protein and polysaccharide antigens.23 Similar to quantitative antibody measurement after vaccine administration, it is likely that IgG maturation during a natural virus challenge reflects the individual B-cell response. Acute exacerbations, mainly caused by infection, are considered key events during the COPD disease course, promoting lung function decline, causing morbidity, and increasing mortality.24,25 A minor attenuation of the B-cell response probably elevates the risk of exacerbation and, consequently, worsens outcome. Delayed IgG maturation is associated not only with an increased exacerbation rate and a shorter time to first exacerbation but also with the number of AECOPD recurrences in a single individual, further supporting the hypothesis that an attenuated B-cell response worsens outcome.

Importantly, the adenovirus can comprise specific viral features. Besides acute infection, latent adenovirus infection with E1A protein expression might occur in the absence of a replicating virus. In this regard, it has been shown that E1A DNA is elevated in patients with COPD26,27 and that viral E1A protein amplifies inflammatory and growth promoting mediators28 and might further contribute to airway remodeling.29 Adenovirus persistence has also been implicated in steroid-resistant asthma.30 However, other investigators found infrequent adenovirus persistence in COPD, thus challenging the hypothesis of adenovirus in COPD pathogenesis.31 Furthermore, delayed IgG affinity maturation may enhance respiratory virus disease as shown for the respiratory syncytial virus.32 Of note, in the present study, patients with delayed adenovirus IgG maturation were not affected by medication use, including inhaled and systemic corticosteroids; duration of hospitalization and ICU stay; or death within the first hospitalization period. However, the data demonstrate a difference in outcome beyond the initial exacerbation.

We cannot rule out that delayed IgG maturation reflects a more severe stage of COPD. Subgroups of patients with COPD may have an attenuated humoral immunity. However, evidence that severe COPD promotes deficient B-cell immune responses is lacking. It has been suggested that the opposite might be the case. More patients with more severe COPD have been shown to be at lower risk for lung cancer compared with those in earlier stages.32,33 The authors of these studies argued that a more active immune system in more severe COPD leading to inflammation and lung tissue destruction might also impede tumor development and progression. In the present study, IgG maturation was not confounded by parameters of disease severity, such as age, smoking status, and GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage. The present findings are in-line with the proposal that exacerbation history is one of the best AECOPD predictors.34 Still, adenovirus-specific IgG maturation predicted the number of AECOPD recurrences independent of the number of previous exacerbations.

Some study limitations need to be acknowledged. The most important limitation is that because of a lack of respiratory microbiologic analyses (eg, polymerase chain reaction) and no previous assay verification in adenovirus infection, no inference about acute and latent adenovirus infection can be made. Accordingly, assumptions are restricted to B-cell maturation related to outcome. Because recurrent exacerbations were not sufficiently investigated, we do not know whether IgG maturation is associated with the cause of AECOPD recurrence (infectious vs noninfectious, viral vs bacterial). Due to homing of B-cells to the site of infection, circulating immunoglobulins might imprecisely reflect pulmonary immunoglobulin composition. We exclusively studied adenovirus-specific IgG maturation. Other immunologic compartments (eg, T cell) and responses to other antigens should be the subject of future investigations.

In considering these limitations, we believe nonetheless that these novel, hypothesis-generating findings might have important implications for COPD research. Potential autoantibodies need to be viewed in the light of coexisting beneficial immunoglobulin responses. Poor immunoglobulin maturation may be an independent factor of COPD morbidity and mortality, representing a clinically relevant COPD phenotype. Moreover, therapeutic measures targeting the B-cell response might do more harm than good. Consequently, more longitudinal COPD studies relating distinct immunologic features to outcome are required.

Fast immunoglobulin avidity maturation seems related to an improved outcome, whereas delayed immunoglobulin maturation unfavorably correlates with outcome. The B-cell response appears to be mainly pathogen directed rather than self-directed. Most likely, a strong B-cell response prevents recurrent infectious COPD exacerbations and improves long-term outcome accordingly.

Author contributions: D. S. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. L. B., M. G., M. T., and D. S. contributed to the study concept and design; L. B. and D. S. contributed to statistical analysis and interpretation; M. G., M. C.-C., B. M., M. T., and D. S. contributed to data acquisition; L. B., M. R., and D. S. contributed to the writing of the manuscript; and L. B., M. G., M. R., H. H. H., M. C.-C., B. M., M. T., and D. S. contributed to the review, revision, and approval of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Gencay is an employee of Roche Diagnostics International Ltd. Drs Boeck, Roth, Hirsch, Christ-Crain, Mueller, Tamm, and Stolz have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors of this investigator-initiated project were not involved in the study design or conduct, statistical analysis, or approval of the manuscript.

Other contributions: The authors thank all the general physicians who provided follow-up information; Anja Meyer, RN, Sabina Iannucci, Astrid Vögelin, and Lydia Meier for assistance in data collection; Margherita Leo, Germaine Lüdin, Gordana Novicic, Jessica Gebhar, and Diana Wissler for performing lung function tests; and Andy Schötzau, Dipl Math, for statistical advice.

Additional information: The e-Appendix can be found in the Supplemental Materials section of the online article.

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Shaykhiev R, Krause A, Salit J, et al. Smoking-dependent reprogramming of alveolar macrophage polarization: implication for pathogenesis of chronic obstructive pulmonary disease. J Immunol. 2009;183(4):2867-2883. [CrossRef] [PubMed]
 
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Figures

Figure Jump LinkFigure 1  A and B, Number of AECOPDs (A) and AECOPD-related hospitalizations (B) within 6 mo after study inclusion. Light bars indicate patients with fast IgG maturation; dark bars, patients with delayed IgG maturation. AECOPD = acute exacerbation of COPD.Grahic Jump Location
Figure Jump LinkFigure 2  A-C, Kaplan-Meier estimates of the probability to remain AECOPD free (A), free of AECOPD-related hospitalizations (B), and free of hospitalizations or death (C). The solid line indicates patients with fast IgG maturation; dashed line, patients with delayed IgG maturation. See Figure 1 legend for expansion of abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] Demographic Characteristics of 43 Patients at Hospitalization for AECOPD Related to Adenovirus-Specific IgG Maturation

Data are presented as No. (%), mean ± SD, or median (interquartile range). The two groups were compared by the χ2 test, Fisher exact test, t test, and Mann-Whitney U test, as appropriate. No differences were observed between the groups. AECOPD = acute exacerbation of COPD; GOLD = Global Initiative for Chronic Obstructive Lung Disease.

Table Graphic Jump Location
TABLE 2  ] Outcome After an AECOPD Related to Adenovirus-Specific IgG Maturation

Data are presented as No. (%), mean ± SD, or median (interquartile range). The two groups were compared by the χ2 test, Fisher exact test, t test, and Mann-Whitney U test, as appropriate. See Table 1 legend for expansion of abbreviation.

Table Graphic Jump Location
TABLE 3  ] Univariate and Multivariate Linear Regression to Predict Number of AECOPD Recurrences Within 6 Mo After Study Inclusion

Male patients, patients with frequent exacerbations the year before study inclusion, and patients with delayed adenovirus-specific IgG maturation had more AECOPD recurrences within 6 mo after study inclusion. LVEF = left ventricular ejection fraction; sPAP = systolic pulmonary artery pressure. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 4  ] Univariate and Multivariate Logistic Regression to Predict Hospitalization or Death Within 2 Y After Study Inclusion

The ORs represent the change in odds in being in one category of outcome when the value of the predictor increases by one unit. See Table 1 and 3 legends for expansion of abbreviations.

References

Hurst JR, Perera WR, Wilkinson TMA, Donaldson GC, Wedzicha JA. Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173(1):71-78. [CrossRef] [PubMed]
 
Rutgers SR, Postma DS, ten Hacken NH, et al. Ongoing airway inflammation in patients with COPD who do not currently smoke. Thorax. 2000;55(1):12-18. [CrossRef] [PubMed]
 
Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645-2653. [CrossRef] [PubMed]
 
Shaykhiev R, Krause A, Salit J, et al. Smoking-dependent reprogramming of alveolar macrophage polarization: implication for pathogenesis of chronic obstructive pulmonary disease. J Immunol. 2009;183(4):2867-2883. [CrossRef] [PubMed]
 
Majo J, Ghezzo H, Cosio MG. Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema. Eur Respir J. 2001;17(5):946-953. [CrossRef] [PubMed]
 
Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2008;8(3):183-192. [CrossRef] [PubMed]
 
Gosman MME, Willemse BWM, Jansen DF, et al; Groningen and Leiden Universities Corticosteroids in Obstructive Lung Disease Study Group. Increased number of B-cells in bronchial biopsies in COPD. Eur Respir J. 2006;27(1):60-64. [CrossRef] [PubMed]
 
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