Longitudinal decline in lung function in patients with primary immunoglobulin deficiencies

Abstract

To the Editor: Common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) are 2 primary immunoglobulin deficiency (PID) disorders in which immunoglobulin replacement is indicated.1Orange J.S. Hossny E.M. Weiler C.R. Ballow M. Berger M. Bonilla F.A. et al.Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.J Allergy Clin Immunol. 2006; 117: S525-S553Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar Despite treatment, sinopulmonary infection remains a major cause of morbidity and early mortality in these patients.2Gathmann B. Grimbacher B. Beaute J. Dudoit Y. Mahlaoui N. Fischer A. et al.The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008.Clin Exp Immunol. 2009; 157: 3-11Crossref PubMed Scopus (168) Google Scholar Lung function declines with normal aging, and accelerated decline is a major risk factor for adverse outcomes in healthy people, smokers, and patients with bronchiectasis.3Loebinger M.R. Wells A.U. Hansell D.M. Cinyanganya N. Devaraj A. Meister M. et al.Mortality in bronchiectasis: a long-term study assessing the factors influencing survival.Eur Respir J. 2009; 34: 843-849Crossref PubMed Scopus (285) Google Scholar, 4Kerstjens H.A. Rijcken B. Schouten J.P. Postma D.S. Decline of FEV1 by age and smoking status: facts, figures and fallacies.Thorax. 1997; 52: 820-827Crossref PubMed Scopus (225) Google Scholar, 5Kohansal R. Martinez-Camblor P. Agustí A. Buist A.S. Mannino D.M. Soriano J.B. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham Offspring cohort.Am J Respir Crit Care Med. 2009; 180: 3-10Crossref PubMed Scopus (442) Google Scholar The rate of decline of lung function in patients with PID treated with intravenous immunoglobulin (IVIG) therapy is currently unknown but is likely a prognostic indicator. The aim of this study was to ascertain the rate of decline in FEV1 and forced vital capacity (FVC) in patients with XLA and CVID receiving IVIG. Our secondary aim was to identify clinical variables predictive of lung function decline. We undertook a retrospective study in a tertiary hospital in Melbourne, Australia. All patients age 18 years or older who satisfied stringent diagnostic criteria for CVID or XLA1Orange J.S. Hossny E.M. Weiler C.R. Ballow M. Berger M. Bonilla F.A. et al.Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.J Allergy Clin Immunol. 2006; 117: S525-S553Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar and who were receiving IVIG therapy during the years 2008 to 2009 were identified. For each patient, all available lung function tests (LFTs) were collected, including weight and height at first LFT and age at diagnosis. Factors likely to influence decline in lung function were also recorded, including hospital admissions, pack-years of smoking (20 cigarettes per day for 1 year = 1 pack-year), Pseudomonas aeruginosa airway colonization, the presence of bronchiectasis on chest imaging, and duration of IVIG therapy. Immunoglobulin dose was calculated as grams per kilogram of body weight (g/kg) per month. Serum IgG measurements were taken before infusions, and a weighted mean level was calculated for each patient. Continuous variables were summarized and reported as mean ± SD or median (interquartile range) and categoric variables as number (proportion). Outcome variables FEV1 and FVC were assessed for normality and found to be well approximated by a normal distribution. We used linear regression to estimate slopes and SEs of FEV1 and FVC for each patient. We calculated decline in lung function by using predicted normal values from Knudson et al.6Knudson R.J. Lebowitz M.D. Holberg C.J. Burrows B. Changes in the normal maximal expiratory flow-volume curve with growth and aging.Am Rev Respir Dis. 1983; 127: 725-734PubMed Google Scholar We performed weighted linear regression analyses to examine the association of clinical factors with change in lung function with weights derived by using the inverse variance method7Senn S. Stevens L. Chaturvedi N. Repeated measures in clinical trials: simple strategies for analysis using summary measures.Stat Med. 2000; 19: 861-877Crossref PubMed Scopus (92) Google Scholar and presented results as parameter estimates (PEs) with SEs. A 2-sided P value of .05 was considered statistically significant. Analyses were performed with SAS 9.1 (SAS Institute, Cary, NC). The study was approved by the Alfred Hospital Ethics Committee (Project 156/08). Thirty-seven patients (21 male; 57%) were included in the study, and 375 LFTs were collected, with 10.2 ± 8.6 pulmonary function tests per patient (range, 2-34) spanning a follow-up period of 7.6 ± 5.6 years. Demographic data are presented in Table I. The mean baseline FEV1 for the whole group was 2.83 ± 1.28 L (82% ± 25% predicted), and those for the CVID group and XLA group, 2.77 ± 1.16 L (82% ± 24% predicted) and 3.48 ± 1.39 L (81% ± 29% predicted), respectively. The mean FVC was 3.85 ± 1.35 L (88% ± 21% predicted). The average annual FEV1 decline for all patients with PID was 45 ± 6 mL/y. The XLA group was found to have a more rapid decline in FEV1 (65 ± 11 mL/y) compared with the CVID group (36 ± 7 mL/y; P = .034; Fig 1). The decline in FVC (mean ± SE) was 43 ± 9.0 mL, higher in XLA (58 ± 20 mL/y) compared with CVID (39 ± 10 mL/y. However, the difference between groups was not significant (P = .39; Fig 2).Table IDemographic characteristics of study groupClinical variableTotalCVIDXLASubjects (n)3729 (78%)8 (22%)Age (y)48.34 ± 15.9750.61 ± 16.6340.09 ± 10.29Male (n)21 (57%)13 (44%)8 (100%)Weight (kg)66.84 ± 16.0967.70 ± 17.6463.68 ± 8.52Height (cm)167.48 ± 9.75166.04 ± 9.98172.67 ± 7.15BMI (kg/m2)23.86 ± 5.8724.55 ± 6.3321.36 ± 2.75IVIG dose/mo (g/kg/mo)0.45 ± 0.120.43 ± 0.120.51 ± 0.10IgG trough level (g/L)7.73 ± 1.417.71 ± 1.487.79 ± 1.21Hospital admissions22 (59%)15 (52%)7 (87%)Age at diagnosis (y)34.72 ± 22.443.53 ± 16.753.87 ± 4.42Pack years of smoking0 (0-5)0 (0-2)3.5 (0-22.5)Bronchodilator responsiveness11 (30%)8 (27%)3 (37%)Bronchiectasis17 (46%)12 (41%)5 (63%)Pseudomonas colonization (n)5 (13%)5 (17%)0 (0%)FEV1 predicted (%) at start81.73 ± 25.0981.86 ± 24.3581.26 ± 29.40FVC predicted (%) at start87.83 ± 20.5086.07 ± 21.2894.19 ± 17.04BMI, Body mass index.Data are expressed as mean ± SD, median (interquartile range), or number (proportion). Open table in a new tab Fig 2Average decline in FVC (mL/y) for PID (total group), CVID, and XLA groups. Error bars represent estimates (SEs). Predicted decline is taken from predicted normal values at each time point for each patient.View Large Image Figure ViewerDownload Hi-res image Download (PPT) BMI, Body mass index. Data are expressed as mean ± SD, median (interquartile range), or number (proportion). Univariate analysis identified 3 variables associated with decline in lung function (Table II). These were as follows:1.Increased IVIG dose per kilogram was inversely associated with lung function decline (PE [SE] = –0.121 [0.039]; P = .004), indicating that higher dose per kilogram appeared to be protective of lung function. The related variables IVIG dose per month (g/kg/mo) and IVIG dose (g) were also inversely associated with lung function decline (Table II).2.Diagnosis of XLA compared with CVID was associated with a more rapid decline in lung function (PE [SE] = 0.028 [0.013]; P = .034).3.Younger age at diagnosis (PE [SE] = 0.001 [0.0002]; P = .005).Table IIFactors associated with decline in FEV1 (univariate analysis)VariablePESEP valueIVIG dose (g/kg)−0.1210.039.004Age at diagnosis (y)0.0010.0002.005IVIG dose/mo (g/kg/mo)−0.1380.052.01IVIG dose (g)−0.0020.001.03CVID0.0280.013.03Pack-years of smoking−0.0020.001.06IgG trough level (g/L)−0.0040.006.49PEs describe the effect on FEV1 decline in liters per year. Open table in a new tab PEs describe the effect on FEV1 decline in liters per year. Trough IgG level did not have a statistically significant association with FEV1 decline (P = .485) or FVC decline (P = .69). Similar significant associations with the IVIG dose/kg/mo and IVIG dose (g) were observed for FVC and FEV1. The normal rate of decline in FEV1 (and 95% CI) in healthy nonsmoking men in a population similar to ours is reported to be 19.6 mL (17.1-22.1), and for women, 17.6 mL (13.8-21.4).5Kohansal R. Martinez-Camblor P. Agustí A. Buist A.S. Mannino D.M. Soriano J.B. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham Offspring cohort.Am J Respir Crit Care Med. 2009; 180: 3-10Crossref PubMed Scopus (442) Google Scholar The average decline of FEV1 in our group of 45 mL per year exceeds that associated with heavy smoking.5Kohansal R. Martinez-Camblor P. Agustí A. Buist A.S. Mannino D.M. Soriano J.B. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham Offspring cohort.Am J Respir Crit Care Med. 2009; 180: 3-10Crossref PubMed Scopus (442) Google Scholar Although smoking was recorded as a variable, the average duration of smoking was small (3.5 pack-years), so the decline in lung function associated with smoking just failed to reach statistical significance (P = .06). Previous longitudinal reports of LFT in PID have used predicted normal values to indicate little change in LFT despite radiographic progression.8Haidopolou K. Calder A. Jones A. Jaffe A. Sonnappa S. Bronchiectasis secondary to primary immunodeficiency in children: longitudinal changes in structure and function.Pediatr Pulmonol. 2009; 44: 669-675Crossref PubMed Scopus (59) Google Scholar However cross-sectional data used to derive predicted normal equations overestimate lung function decline by as much as 35 mL/y in the under 50 years age group compared with longitudinal studies4Kerstjens H.A. Rijcken B. Schouten J.P. Postma D.S. Decline of FEV1 by age and smoking status: facts, figures and fallacies.Thorax. 1997; 52: 820-827Crossref PubMed Scopus (225) Google Scholar, 9Van Pelt W. Borsboom G.J. Rijcken B. Schouten J.P. van Zomeren B.C. Quanjer P.H. Discrepancies between longitudinal and cross-sectional change in ventilatory function in 12 years of follow-up.Am J Respir Crit Care Med. 1994; 149: 1218-1226Crossref PubMed Scopus (72) Google Scholar indicating that predicted normal values are inappropriate to monitor longitudinal LFT changes. In this study, higher monthly IVIG dose (g/kg) is significantly linked with decreased lung function decline (0.45 ± 0.12 [g/kg]; PE, –0.121 [0.039]; P = .004). This means that a 1 g per kg dose increase in IVIG was associated in these patients with a reduction in the decline of FEV1 by 121 mL per year. Although such a dose is well beyond a practical therapeutic range, our findings suggest that IVIG dose might be targeted to reduce lung function decline. This approach is supported by a recent publication from Lucas et al10Lucas M. Lee M. Lortan J. Lopez-Granados E. Misbah S. Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years.J Allergy Clin Immunol. 2010; 125: 1354-1360Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar reporting that infection frequency was found to be unrelated to trough IgG levels. Taken together, these results indicate that maintaining a higher dose of IVIG, independent of trough level, may be associated with superior outcomes in PID. Obviously this hypothesis should be tested in prospective trials, but such an approach differs from currently recommended algorithms.1Orange J.S. Hossny E.M. Weiler C.R. Ballow M. Berger M. Bonilla F.A. et al.Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.J Allergy Clin Immunol. 2006; 117: S525-S553Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar One of the limitations of the study is the small number of patients. We were careful to ensure that this group met current definitions of XLA and CVID.1Orange J.S. Hossny E.M. Weiler C.R. Ballow M. Berger M. Bonilla F.A. et al.Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.J Allergy Clin Immunol. 2006; 117: S525-S553Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar The strength of this cohort lies in this diagnostic rigor and the large number of respiratory function tests performed. Larger cohorts of patients with PID are now available through international registries, and such data will enable measurement of lung function decline and provide a basis for comparison of treatment outcomes.2Gathmann B. Grimbacher B. Beaute J. Dudoit Y. Mahlaoui N. Fischer A. et al.The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008.Clin Exp Immunol. 2009; 157: 3-11Crossref PubMed Scopus (168) Google Scholar This database also reveals reduced life expectancy in patients with PID, consistent with reduced lung function. To our knowledge, this is the first study to report longitudinal rate of decline in lung function in well characterized patients with PID. Our findings suggest that studies of the outcomes of immunoglobulin therapy in PID might use change in lung function as an indicator of treatment efficacy. Our study also supports higher doses of IVIG as protective of lung function decline.