IgG trough levels and progression of pulmonary disease in pediatric and adult common variable immunodeficiency disorder patients
2017; Elsevier BV; Volume: 140; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2016.11.050
ISSN1097-6825
AutoresWillemijn J.M. Janssen, Firdaus Mohamed Hoesein, Annick A. J. M. van de Ven, Jacobien Maarschalk, Florien S van Royen, Pim A. de Jong, Elisabeth A. M. Sanders, Joris M. van Montfrans, Pauline M. Ellerbroek,
Tópico(s)Tracheal and airway disorders
ResumoCommon variable immunodeficiency disorder (CVID) is the most prevalent symptomatic primary immunodeficiency in adults and children. Patients encounter recurrent bacterial and viral infections of the respiratory tract, with delayed pathogen clearance due to diminished immunoglobulin levels and insufficient specific antibody responses to encapsulated bacteria. As a result, the most prevalent comorbidities in adult CVID are recurrent pneumonia (32%) and chronic lung disease (28%), with lung failure being the most prevalent cause of death.1Gathmann B. Mahlaoui N. Gerard L. Oksenhendler E. Warnatz K. Schulze I. et al.CEREDIHClinical picture and treatment of 2212 patients with common variable immunodeficiency.J Allergy Clin Immunol. 2014; 134: 116-126Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar Pulmonary comorbidities include structural airway disease (AD) due to recurrent pulmonary infections and interstitial lung disease (ILD), in particular in patients with autoimmune phenomena.2Verma N. Grimbacher B. Hurst J.R. Lung disease in primary antibody deficiency.Lancet Respir Med. 2015; 3: 651-660Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Both disease entities are well detected by high-resolution computed tomography (CT).2Verma N. Grimbacher B. Hurst J.R. Lung disease in primary antibody deficiency.Lancet Respir Med. 2015; 3: 651-660Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 3van de Ven A.A. de Jong P.A. Hoytema van Konijnenburg D.P. Kessels O.A. Boes M. Sanders E.A. et al.Airway and interstitial lung disease are distinct entities in paediatric common variable immunodeficiency.Clin Exp Immunol. 2011; 165: 235-242Crossref PubMed Scopus (10) Google Scholar In this study, we investigated progression of pulmonary disease in pediatric and in adult CVID patients in a 3- to 5-year follow-up period using a uniform CT scanning and scoring protocol.4van Zeggeren L. van de Ven A.A. Terheggen-Lagro S.W. Mets O.M. Beek F.J. van Montfrans J.M. et al.High-resolution computed tomography and pulmonary function in children with common variable immunodeficiency.Eur Respir J. 2011; 38: 1437-1443Crossref PubMed Scopus (6) Google Scholar, 5van de Ven A.A. van Montfrans J.M. Terheggen-Lagro S.W. Beek F.J. Hoytema van Konijnenburg D.P. Kessels O.A. et al.A CT scan score for the assessment of lung disease in children with common variable immunodeficiency disorders.Chest. 2010; 138: 371-379Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Pediatric and adult CVID patients were allocated to low- or high-risk profiles for AD and/or ILD disease progression. This was based on baseline AD and ILD scores, defined comorbidities, and/or immunological parameters (Table I and see this article's Methods section in the Online Repository at www.jacionline.org). The AD and ILD score cutoff values for the high risk for pulmonary disease progression group were 7 and 5, respectively, and were determined based on previously published cross-sectional evaluations of pulmonary CT scans (see the Methods in this article's Online Repository).3van de Ven A.A. de Jong P.A. Hoytema van Konijnenburg D.P. Kessels O.A. Boes M. Sanders E.A. et al.Airway and interstitial lung disease are distinct entities in paediatric common variable immunodeficiency.Clin Exp Immunol. 2011; 165: 235-242Crossref PubMed Scopus (10) Google Scholar, 4van Zeggeren L. van de Ven A.A. Terheggen-Lagro S.W. Mets O.M. Beek F.J. van Montfrans J.M. et al.High-resolution computed tomography and pulmonary function in children with common variable immunodeficiency.Eur Respir J. 2011; 38: 1437-1443Crossref PubMed Scopus (6) Google Scholar, 5van de Ven A.A. van Montfrans J.M. Terheggen-Lagro S.W. Beek F.J. Hoytema van Konijnenburg D.P. Kessels O.A. et al.A CT scan score for the assessment of lung disease in children with common variable immunodeficiency disorders.Chest. 2010; 138: 371-379Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Patients underwent follow-up scanning after 2 to 3 years (adult and pediatric high-risk patients) or 5 years (low-risk patients). Pulmonary function tests (PFTs) were performed at baseline for all patients and at follow-up when clinically necessary (24 of 55; 43% of cases) as determined in our institutional protocol for follow-up of CVID patients. PFT test results were mostly within normal ranges at baseline and at follow-up (see Table E1 in this article's Online Repository at www.jacionline.org). All patients were treated with immunoglobulin replacement therapy. Antibiotic prophylaxis was prescribed in patients with a history of recurrent pulmonary infections despite immunoglobulin therapy (see Table E2 in this article's Online Repository at www.jacionline.org). Two adult patients received immunosuppressive medications (azathioprine and prednisolone) for interstitial lung disease. One low-risk pediatric patient (5%) and 1 high-risk adult (4%) suffered from radiologically proven pneumonia during follow-up. Two of 13 high-risk pediatric patients (15%) developed autoimmune diseases (Table I).Table IPatient characteristics at initial CT scanLow-risk childrenHigh-risk childrenHigh-risk adultsP valueTotalCVID patients (n)19132355Gender (male)13/19 (68%)9/13 (69%)8/23 (35%)30/55 (54%)Median age at initial CT in years (range)13 (6-18)11 (8-17)38 (19-76)Disease duration in years at initial CT (median, range)5 (0.5-11)6.5 (0-10)9.5 (5-16)Baseline AD score >7None6/13 (46%)10/23 (43%)Baseline ILD score >5None6/13 (46%)11/23 (48%)Both ILD and AD highNone2/13 (15%)5/23 (21%)Respiratory tract infections URTI (during FU time)Sinusitis, rhinitis, otitis None8/19 (42%)7/13 (54%)16/23 (70%)ns31/55 (56%) ≥2/y5/19 (26%)2/13 (15%)6/23 (26%)13/55 (24%) >4 times/y6/19 (31%)4/13 (31%)1/23 (4%)11/55 (20%)LRTI (before initial CT scan) Pneumonia9/19 (47%)10/13 (77%)10/23 (44%)ns29/55 (53%)BronchiectasisNone3/13 (23%)11/23 (48%).00815/55 (27%)Autoimmunity Hepatitis, ITPNone3/13 (23%)4/23 (17%)ns9/55 (16%)Lymph proliferationNone2/13 (15%)4/23 (17%).056/55 (11%)EnteropathyNone1/13 (8%)2/23 (9%)ns3/55 (5%)Progression into CIDNone3/13 (23%)Nonens3/55 (5%)CancersNoneNone3/23 (13%)ns3/55 (5%)CID, Combined immunodeficiency disease; ITP, immune thrombocytopenic purpura; LRTI, lower respiratory tract infections; ns, not significant; URTI, upper respiratory tract infections. Open table in a new tab CID, Combined immunodeficiency disease; ITP, immune thrombocytopenic purpura; LRTI, lower respiratory tract infections; ns, not significant; URTI, upper respiratory tract infections. To quantify the progression of AD and ILD, AD and ILD scores were calculated in baseline and in follow-up CT scans. The ILD scores did not increase significantly in high-risk nor in low-risk patients (Fig 1, A). In contrast, the AD scores did increase in all groups after 2 to 5 years of follow-up (Fig 1, B), especially in the pediatric and adult patients with low (<7) AD scores at baseline (n = 35) (P = .001) (Fig 1, C). Importantly, in this group only 1 patient (of 35) suffered from a radiologically proven lower respiratory tract infection during follow-up time, all other patients were clinically stable. In support of the increased AD scores, we found that the AD score progression correlated to a decrease in predicted FEV1/forced vital capacity percentage (FVC%), although still within normal range in the group with low AD scores at baseline (r = −0.6; P = .048) (see Fig E1 in this article's Online Repository at www.jacionline.org). Thus, the AD score increase could not be predicted by upper or lower respiratory tract infection episodes or by abnormal PFTs. Because no radiologically proven pneumonias occurred during follow-up time and immunological phenotypes were normal in most cases in this group, we explored whether treatment parameters influenced AD score progression. Antibiotic prophylaxis did not contribute to differences in AD scores. The IgG trough levels at baseline and follow-up in high- and low-risk patients are depicted in Fig 1, D. Interestingly, the difference (Δ) in AD scores of the pediatric and adult patient groups with low AD scores at baseline were inversely correlated to follow-up IgG trough levels (r = −0.48; P = .009) (Fig 1, E), in other words, AD score progression correlated to lower IgG trough levels at follow-up CT scan. No correlation was detected between IgG trough levels and AD scores at baseline. When dividing these same patients by IgG trough levels ( 10 g/L), we found that individuals with IgG trough levels >10 g/L showed significantly less AD score progression than did pediatric patients with IgG trough levels <10 g/L (P = .004) (Fig 1, F). This observation is in line with a meta-analysis by Orange et al6Orange J.S. Grossman W.J. Navickis R.J. Wilkes M.M. Impact of trough IgG on pneumonia incidence in primary immunodeficiency: A meta-analysis of clinical studies.Clin Immunol. 2010; 137: 21-30Crossref PubMed Scopus (309) Google Scholar that showed that patients with higher IgG trough levels ≤10 g/L had decreased rates of clinical pneumonia. Furthermore, lower IgG trough levels were associated with progression of ILD in CVID patients in a recent study.7Maglione P.J. Overbey J.R. Cunningham-Rundles C. Progression of common variable immunodeficiency interstitial lung disease accompanies distinct pulmonary and laboratory findings.J Allergy Clin Immunol Pract. 2015; 3: 941-950Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Our findings question the current opinion that optimal IgG trough levels should be adjusted to the individual need of the patient to be symptom free (with a minimum advised IgG trough level of 7 g/L and depending on the presence of bronchiectasis8Lucas 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: 1354-1360.e4Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar), as our findings indicate that there may be an additional protective effect of higher IgG trough levels. Taken together, we found that silent progression of pulmonary AD occurs on CT scans of pediatric and adult CVID patients, despite seemingly optimal treatment regimens and no apparent clinical pulmonary infections during follow-up. Especially in patients that were considered to be at low risk for pulmonary AD progression, the AD scores increased significantly. Although the majority of patients did not develop clinically symptomatic lung disease in this 3- to 5-year follow-up period (with mean AD scores remaining <7 and stable PFTs), this finding is likely to become clinically relevant when taken into consideration that with a longer follow-up time, continuously increasing AD scores will eventually result in clinical complications and significant decrease of PFTs.9de Gracia J. Vendrell M. Alvarez A. Pallisa E. Rodrigo M.J. de la Rosa D. et al.Immunoglobulin therapy to control lung damage in patients with common variable immunodeficiency.Int Immunopharmacol. 2004; 4: 745-753Crossref PubMed Scopus (140) Google Scholar Furthermore, our study suggests a correlation between increasing AD scores and lower IgG trough levels at follow-up. As such, these findings stress the urgency for a randomized controlled study in pediatric and adult CVID patients in order to define optimal IgG trough levels for prevention of (silent) AD progression, and possibly ILD progression, as quantified by CT scans and PFTs. Such a study would also provide further insight on the optimal follow-up period of CVID patients for monitoring of pulmonary disease. All patients were treated at a tertiary care center (University Medical Center of Utrecht, The Netherlands). As the study involved analysis of clinical data derived from routine clinical care, informed consent was waived by the Medical Ethical Research Committee of the University Medical Center of Utrecht. A longitudinal observational cohort study was conducted in pediatric and adult CVID patients who underwent structured follow-up at the outpatient clinic. Common variable immunodeficiency was diagnosed according to ESID criteria.E1Gathmann B. Mahlaoui N. Gerard L. Oksenhendler E. Warnatz K. Schulze I. CEREDIH et al.Clinical picture and treatment of 2212 patients with common variable immunodeficiency.J Allergy Clin Immunol. 2014; 134: 116-126Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar In short, CVID was diagnosed in case of the following: (1) a clinical history of recurrent pulmonary and/or gastrointestinal infections, (2) serum IgG and IgA and/or IgM levels <−2 SD for age, (3) insufficient specific responses on receipt of vaccinations, and (4) exclusion of other defined causes of hypogammaglobulinemia. Structured follow-up included monitoring of CVID-related symptoms (see Table E1), IgG trough levels, and measurement of B- and T-lymphocyte subsets. Furthermore, to monitor pulmonary disease, CT scanning was performed at baseline (in 2008-2009) as described previously.E2van de Ven A.A. de Jong P.A. Hoytema van Konijnenburg D.P. Kessels O.A. Boes M. Sanders E.A. et al.Airway and interstitial lung disease are distinct entities in paediatric common variable immunodeficiency.Clin Exp Immunol. 2011; 165: 235-242Crossref PubMed Scopus (26) Google Scholar, E3van Zeggeren L. van de Ven A.A. Terheggen-Lagro S.W. Mets O.M. Beek F.J. van Montfrans J.M. et al.High-resolution computed tomography and pulmonary function in children with common variable immunodeficiency.Eur Respir J. 2011; 38: 1437-1443Crossref PubMed Scopus (12) Google Scholar, E4van de Ven A.A. van Montfrans J.M. Terheggen-Lagro S.W. Beek F.J. Hoytema van Konijnenburg D.P. Kessels O.A. et al.A CT scan score for the assessment of lung disease in children with common variable immunodeficiency disorders.Chest. 2010; 138: 371-379Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Follow-up CT scans were scheduled after 2 years (in adults) and 3 years (in pediatric patients) with high risk for pulmonary disease progression (2011-2013). In all other patients without increased risk for pulmonary disease progression, follow-up CT scans were planned after 5 years (2014). Patients were defined as high risk for pulmonary disease at initial CT scan, in case of the following:•Recurrent (>2) lower airway infections during any time of immunoglobulin replacement therapy•ILD scores >5 and/or•AD scores >7 and/or•Presence of CVID-related autoimmune or autoimmune complications, hepatosplenomegaly, or malignancy and/or•Class-switched memory B cells <2% of total B cells Patients were defined as low risk for pulmonary complications at the initial CT scan in case of the following:•No recurrent lower airway infections during immunoglobulin replacement therapy•ILD scores <5•AD scores 2% of total B cells Follow-up CT scans were evaluated of 32 pediatric CVID patients: 13 high risk and 19 low risk for pulmonary disease progression and 23 high-risk adult CVID patients. These numbers were reached as follows. At baseline, 54 pediatric patients (34 low risk and 20 high risk) and 24 high-risk adult patients were evaluated for CT scanning. Of the pediatric patients, 22 of 54 patients did not undergo follow-up CT scanning for one of the following reasons: (1) relocation to another hospital (n = 9), (2) death due to CVID complications (n = 3), or (3) because the treating clinician or parents decided to postpone scanning to later because of excellent clinical performance (n = 10). One high-risk adult patient was not evaluated for follow-up scan because of relocation abroad. Chest CT scanning was performed by multiple detector-row CT scanners (16-detector row scanners; Philips, Cleveland, Ohio) conforming to a dedicated volumetric protocol. Scans were obtained during both inspiration and expiration using a breath-hold instruction. In children, inspiratory scans were acquired in a caudocranial direction with a collimation of 16 × 0.75 mm, pitch 0.9, rotation time 0.5 seconds, 90 kVp, and milliamperage per second depending on body weight (range 16–60 mA s−1). Expiratory scans were acquired in a caudocranial direction with a collimation of 1660.75 mm, pitch 1.2, rotation time 0.4 seconds, 90 kVp, and 11 mA s−1. The expiratory scan was obtained at end expiration. In adults, thin slice volumetric data were acquired in inspiration at 100 to 120 kVp and 130 mAs and in expiration at 80 to 120 kVp and 20 to 40 mAs depending on body weight. All CT scans were anonymized and scored by the same reader (radiology resident with a PhD in pulmonary imaging) after randomization of baseline and follow-up scans. CT scoring was executed as described previously.E4van de Ven A.A. van Montfrans J.M. Terheggen-Lagro S.W. Beek F.J. Hoytema van Konijnenburg D.P. Kessels O.A. et al.A CT scan score for the assessment of lung disease in children with common variable immunodeficiency disorders.Chest. 2010; 138: 371-379Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar In short, each pulmonary lobe was scored 0 to 3 for the following items: size of largest bronchiectasis, size of average bronchiectasis, extent of bronchiectasis, most severe airway wall thickening, average severity airway wall thickening, extent of airway wall thickening, extent of mucus plugging, extent of tree-in-bud, extent of opacities, extent of ground glass, average size of lung nodules, extent of septa thickening, number bulla/cyst. Extent of air trapping was given a score between 0 and 5. Subsequently, AD scores were calculated from a total bronchiectasis score, total airway wall thickening score, total mucus score, and air trapping. ILD scores were calculated from the total extent of opacities score, total extent of ground glass score, total lung nodules score, total extent of septa thickening score. PFTs were measured with a Jeager Masterscreen CS and Masterlab Systems (Wurzburg, Germany) and carried out according to the American Thoracic Society criteria to determine pulmonary health condition. Measurement of PFT contained the following parameters: percentage of predicted FVC (FVC%), percentage of predicted FEV1 (FEV1%), percentage of predicted total lung capacity (TLC%), percentage of FEV1 as part of vital capacity, percentage of predicted peak expiratory flow rate, and percentage of residual volume (RV%) as part of TLC (RV/TLC%). All statistical analyses were performed with SPSS 20.0 software for Windows (SPSS Inc, IBM, Armonk, NY). To compare continuous data between 2 groups, unpaired t tests were used for parametric data and Mann-Whitney U tests for nonparametric data, respectively. Paired data were tested with the Wilcoxon signed rank test. Categorical data were tested with Pearson chi-square test. For correlations, the Spearman rank correlation was used for nonparametric data and Pearson for parametric data. Tests were performed 2-tailed, and P values of ≤.05 were considered significant.Table E1PFTs at baseline and FU scansFEV1/FVC baseline (% predicted)FEV1/FVC FU (% predicted)FEV1 baseline (% predicted)FEV1FU (% predicted)FVC baseline (% predicted)FVCFU (% predicted)RV/TLC baseline (% predicted)RV/TLCFU (% predicted)Low-risk children (n = 7 of 19)PFT: normal99 (90-117)99 (90-105)92 (75-130)89 (75-96)94 (77-124)92 (78-110)High-risk children (n = 8 of 13)Obstructive (n = 2)98 (73-114)93 (74-104)93 (69-102)83 (57-111)88 (76-100)86 (77-111)High-risk adults (n = 3 of 23)96 (78-99)97 (85-103)102 (86-120)107 (96-109)113 (110-126)116 (108-116)71 (20-134)83 (66-121)PFTs of CVID patients. The 2 patients with obstructive pulmonary disease had high AD scores at baseline and AD scores increased at follow-up. Depicted are FEV1 and FVCs relative (%) to predicted values and medians with range. Open table in a new tab Table E2Treatment regimensLow-risk childrenHigh-risk childrenHigh-risk adultsTotalAB prophylaxis Continuous use4/19 (21)6/13 (46)1/23 (4)11/55 (20) Stopped during FU9/19 (47)5/13 (39)7/23 (30)21/55 (38) None6/19 (32)2/13 (15)15/23 (65)23/55 (42)Immunosuppressives PrednisoloneAzathioprineNoneNone2/23 (9)IgG levels between initial and FU CT, mean ± SD11.4 ± 2.211 ± 2.98.7 ± 1.3Values are n/n (%) or n (%) unless otherwise indicated.AB, Antibiotic. Open table in a new tab PFTs of CVID patients. The 2 patients with obstructive pulmonary disease had high AD scores at baseline and AD scores increased at follow-up. Depicted are FEV1 and FVCs relative (%) to predicted values and medians with range. Values are n/n (%) or n (%) unless otherwise indicated. AB, Antibiotic.
Referência(s)