Multiple-breath washout to detect lung disease in patients with inborn errors of immunity

Leonie M. Busack, Stephanie Thee, Yvonne Liu, Christine Allomba, Niklas Ziegahn, Apolline Tosolini, Charlotte O. Pioch, Alexandra N. Schnorr, Bent R. Fuhlrott, Olga Staudacher, Mirjam Völler, Eva Steinke, Leif G. Hanitsch, Jobst Röhmel, Volker Wahn, Renate Krüger, Marcus A. Mall, Horst von Bernuth, Mirjam Stahl
ERJ Open Research 2024 10: 01019-2023; DOI: 10.1183/23120541.01019-2023

Abstract

Background Pulmonary manifestations are the major cause of morbidity and mortality in patients with inborn errors of immunity (IEI). New and more sensitive diagnostic methods can potentially lead to earlier recognition and treatment of IEI lung disease and improve outcome. The aim of this study was to compare multiple-breath washout (MBW) and spirometry in patients with IEI and cystic fibrosis (CF) as well as healthy controls (HC) and to evaluate the sensitivity of lung clearance index (LCI) to assess lung disease in IEI.

Methods IEI patients (n=114) were recruited from our paediatric and adult immunodeficiency outpatient clinics and compared to age-matched CF patients (n=114) and HC (n=114). MBW measurements and spirometry were performed in the study participants, and MBW testing was repeated after 63–707 days in IEI patients (n=70).

Results The LCI was significantly higher in IEI patients than in HC (p<0.001) and significantly lower than in CF patients (p<0.001). The forced expiratory volume in 1 s (FEV1) z-score was significantly lower in IEI patients than in HC (p<0.01) and significantly higher than in CF patients (p<0.01). LCI and FEV1 z-score correlated moderately negatively in the total cohort, the IEI group and the CF group. Nineteen (20.7%) of 92 IEI patients and 35 (33.3%) of 105 CF patients had an elevated LCI but a normal FEV1 z-score. After a median of 364 days, the median LCI of 70 IEI patients increased significantly by 0.2.

Conclusion MBW is useful to detect lung disease in IEI and is more sensitive than spirometry.

Shareable abstract

LCI can detect lung disease in patients with IEI and is more sensitive than FEV1. https://bit.ly/4b8TsYw

Introduction

Pulmonary symptoms and complications are not only a frequent clinical manifestation of inborn errors of immunity (IEI), but also the major cause of morbidity and mortality in this patient group [1–3]. Despite improved treatment options for defects of the immune system including immunoglobulin replacement therapy, respiratory tract infections continue to occur, leading to chronic structural lung diseases [1, 4, 5]. In Europe, immunodeficiency is the fifth most frequent identified cause of non-cystic fibrosis (CF) bronchiectasis occurring in 4.1% of bronchiectasis patients [6]. Between 20% and >60% of patients with common variable immunodeficiency (CVID) develop bronchiectasis [7, 8]. Furthermore, non-infectious pulmonary complications caused by immune dysregulation, such as granulomatous-lymphocytic interstitial lung disease (GLILD), negatively impact the prognosis of IEI patients [1, 3]. GLILD was shown to negatively impact the outcome and to shorten the survival of patients with CVID [9, 10]. Additionally, IEI patients have an increased risk to develop pulmonary lymphoma [11, 12]. Since the early recognition and treatment of respiratory manifestations in IEI patients can improve their outcome, sensitive diagnostic methods are urgently needed [1, 3]. At present, spirometry is commonly used for the assessment of lung function. Furthermore, in patients with antibody deficiencies, an annual body plethysmography with measurement of the diffusing capacity of the lung for carbon monoxide (DLCO) is recommended, and DLCO was shown to be sensitive to detect GLILD [3, 9, 13]. However, it was demonstrated that spirometry as well as body plethysmography and DLCO do not detect mild structural lung disease in patients with IEI [8].

A promising method for the detection of early lung disease is the multiple-breath washout (MBW) test with the lung clearance index (LCI) as the most reported outcome parameter reflecting global ventilation inhomogeneities, gas mixing and physiological dead space [14]. MBW is performed noninvasively and has shown its feasibility in clinical settings even in early childhood in patients with chronic lung diseases [15–17]. In adult and paediatric patients with CF, studies demonstrated that LCI correlates with other parameters of pulmonary function but is more sensitive to detecting early lung disease than spirometry [18, 19]. In addition, MBW can detect progression of CF lung disease [20, 21]. Further, previous studies in CF patients demonstrated a good correlation of LCI with findings in chest magnetic resonance imaging (MRI) and computed tomography (CT) and that structural lung disease such as bronchiectasis is more readily detected by MBW than by spirometry [22–24]. Furthermore, CF patients with bacterial lung infections seem more likely to have an abnormal LCI than those without, and LCI detects treatment effects even in patients with mild CF lung disease [19, 25–27]. While the high sensitivity of LCI to detect lung disease has also been confirmed in patients with primary ciliary dyskinesia (PCD) and COPD, there is little data available on MBW for detection of different features of lung disease in IEI patients [15, 28–30].

Therefore, the aim of this study was to evaluate the ability of LCI to assess lung disease in comparison to spirometry in children and adults with IEI, CF patients and healthy controls (HC). Additionally, we evaluated longitudinal MBW measurements in IEI patients to assess progression of lung disease.

Methods

Study population and design

We performed a monocentric observational study over 2 years approved by the Ethics Committee of the Charité – Universitätsmedizin Berlin (EA2/003/21). Informed written consent was obtained from all participants and/or their parents or legal guardians. Patients with IEI attending the paediatric or adult outpatient immunodeficiency clinic were eligible for this study if they were able to perform a MBW measurement. Eight patients unable to perform MBW successfully were excluded from this study. Of those, three were below the age of 5 years, one was older than 60 years, two had ataxia telangiectasia and two had DiGeorge syndrome. Study visits took place during routine visits in clinically stable patients. IEI patients were classified according to the International Union of Immunological Societies Classification for Human IEI [31]. In addition, equal-sized and age-matched groups of CF patients as disease control as well as HC were recruited from other ongoing observational studies at our centre. An active lung disease and the use of respiratory medications were exclusion criteria for HC. Medical history and demographics were collected for all participants. Information on lung imaging in the previous 5 years, history of respiratory infections, previous lung surgery, diagnosis of bronchial asthma and lung-specific therapies were collected for IEI and CF patients. Data on previous allogeneic haematopoietic stem cell transplantation (allo-HSCT) and immunoglobulin replacement therapy were collected for IEI patients. For CF patients, data on CF transmembrane conductance regulator (CFTR) mutations, pancreatic insufficiency, chronic Pseudomonas aeruginosa infection according to the Leeds criteria [32] and the use of CFTR modulator therapy were collected. Bronchiectasis was confirmed by CT or MRI and defined as an increased airway diameter with an increased broncho-arterial ratio of >1–1.5 [33].

Lung function testing

MBW was performed in all and spirometry in study participants above 5 years of age at the initial study visit. In IEI patients, MBW measurements were repeated at subsequent outpatient visits after 3 to 24 months. MBW testing was performed with Exhalyzer D and (re-)analysed using spiroware version 3.3.1 (both Eco Medics, Duernten, Switzerland). 100% oxygen was used to wash out resident nitrogen (N2) from the lungs as previously described [22, 34]. Measurements were performed in awake, upright sitting subjects using a mouthpiece as interface while wearing a nose clip. At least two acceptable trials were necessary [34]. In HC, LCI increased from the age of 50 years. Therefore, upper limits of normal (ULN) for LCI were determined separately for patients <50 and ≥50 years of age. ULN were calculated as mean+1.96 × sd of the respective HC subgroup. Spirometry was performed according to the criteria of the American Thoracic Society and European Respiratory Society [34]. Forced expiratory volume in 1 s (FEV1) was used as the primary spirometric outcome parameter and values were converted to z-scores using the Global Lung Function Initiative reference equations [35]. A z-score <−1.96 was classified as abnormal for FEV1.

Statistical analysis

SPSS Version 27 (SPSS Inc., Chicago, IL, USA) was used for the statistical analyses. Data are represented as n (%) or median (interquartile range (IQR)), if not indicated otherwise. Normal distribution of data was assessed by the Shapiro–Wilk test. The Mann–Whitney U-test or Wilcoxon signed rank test were used for comparison of continuous data and chi-square test or Fisher exact test for comparison of categorical data, as appropriate. Correlation analyses were performed by using the Spearman's rank correlation (rs). A p-value <0.05 was considered statistically significant. In the case of multiple comparisons, individual p levels are indicated only if not rejected by Bonferroni correction.

Results

Clinical characteristics of the study population

In total, 114 HC with a median (range) age of 24.4 (3.7–73.8) years, 114 IEI patients with a median (range) age of 20.7 (3.8–76.9) years and 114 CF patients with a median (range) age of 20.4 (3.9–72.7) years were included in this study (table 1). More CF patients than IEI patients had a history of recurrent lower airway infections, were diagnosed with bronchiectasis or received pulmonary therapies (table 1). The diagnosis of bronchial asthma was more prevalent in IEI patients than in CF patients (table 1). The majority of IEI patients received an immunoglobulin replacement therapy (table 1) as about two-thirds of the IEI patients had a predominant antibody deficiency (table 2). The next most common entities were combined immunodeficiencies with associated or syndromic features and congenital defects of phagocyte number, function or both (table 2). 11 IEI patients who underwent allo-HSCT were included (table 2). Five (45.5%) had lung involvement prior to allo-HSCT. The inclusion of these patients did not impact the results (supplementary table S1).

View this table:
TABLE 1

Characteristics of the study population

View this table:
TABLE 2

Diagnosis and classification of the Inborn Errors of Immunity Group according to the International Union of Immunological Societies Classification for Inborn Errors of Immunity [33]

LCI and FEV1 z-score of IEI patients differ significantly from HC and CF patients

Spirometry was performed successfully in 111 (97.4%) HC, 92 (80.7%) IEI patients and 105 (92.1%) CF patients, while successful MBW was an inclusion criterion for this analysis. The median (IQR) LCI was 6.5 (6.2–6.9) in HC, 7.0 (6.5–7.9) in the IEI group and 8.9 (6.8–14.2) in the CF group (figure 1a). The LCI was significantly higher in the IEI patients than in the HC cohort (p<0.001) and significantly lower in the IEI patients than in the CF patients (p<0.001) (figure 1a). FEV1 z-score had a median (IQR) of −0.1 (−0.8–0.5) in the HC group, −0.6 (−1.4–0.1) in the IEI group and −1.1 (−2.7–0.3) in the CF group (figure 1b). The FEV1 z-score of the IEI patients was significantly lower than that of the HC cohort (p<0.01) and significantly higher than that of the CF patients (p<0.01) (figure 1b).

FIGURE 1
FIGURE 1

Lung clearance index (LCI) and forced expiratory volume in 1 s (FEV1) z-score of healthy controls (HC), patients with inborn errors of immunity (IEI) and patients with cystic fibrosis (CF). Comparison of a) LCI and b) FEV1 z-score between HC, patients with IEI and patients with CF. Relationship between LCI and FEV1 in c) participants under 50 years of age and d) 50 years and older. p-values refer to the comparison of LCI and FEV1 z-score between the groups. Triangles represent HC, diamonds represent patients with CF and hexagons represent patients with IEI. The horizontal lines indicate the median value. The dotted lines indicate the lower limit of normal of the FEV1 z-score and the upper limit of normal of the LCI. The grey area highlights patients with elevated LCI values but normal FEV1 z-scores. **p<0.01; ***p<0.001.

LCI is abnormal in more patients than is the FEV1 z-score

The ULN of the LCI derived from HC was 7.2 in participants <50 years of age and 8.7 in participants ≥50 years of age. In total, 40 of 114 IEI patients (35.1%) and 79 of 114 CF patients (69.3%) had an elevated LCI. 19 of 92 IEI patients (20.7%) and 41 of 105 CF patients (39.0%) had a decreased FEV1 z-score. Among participants with both measurements, 14 of 92 IEI patients (15.2%) and 39 of 105 CF patients (37.1%) had both an abnormal LCI and an abnormal FEV1 z-score (figure 1c and d). 19 of 92 IEI patients (20.7%) and 35 of 105 CF patients (33.3%) had an elevated LCI but a normal FEV1 z-score, while five of 92 IEI patients (5.4%) and two of 105 CF patients (1.9%) had a decreased FEV1 z-score and a normal LCI (figure 1c and d).

LCI correlates with age and FEV1 z-score in IEI patients

LCI and age correlated significantly in the total cohort (rs=0.42, p<0.001) as well as in the HC group (rs=0.34, p<0.001), the IEI group (rs=0.53, p<0.001) and the CF group (rs=0.64, p<0.001) (figure 2). FEV1 z-score and age correlated significantly in the HC group (rs=0.24, p<0.05) and in the CF group (rs= −0.34, p<0.001), but not in the IEI group (rs= −0.18, p=0.084) (figure 2). The LCI and the FEV1 z-score negatively correlated in the total cohort (rs= −0.49, p<0.001), the IEI group (rs= −0.52, p<0.001) and the CF group (rs= −0.65, p<0.001) (figure 3).

FIGURE 2
FIGURE 2

Correlation of the lung clearance index (LCI) and the forced expiratory volume in 1 s (FEV1) z-score with age. a and b) Correlation of the LCI and the FEV1 z-score with age is shown for the total cohort, c and d) healthy controls, e and f) patients with inborn errors of immunity and g and h) patients with cystic fibrosis. Spearman's rank correlation coefficients (rs) and p-values are provided for each correlation.

FIGURE 3
FIGURE 3

Correlation between the lung clearance index (LCI) and the forced expiratory volume in 1 s (FEV1) z-score. Correlation between the LCI and the FEV1 z-score is shown for a) the total cohort, b) the healthy controls, c) the patients with inborn errors of immunity and d) the patients with cystic fibrosis. Spearman's rank correlation coefficients (rs) and p-values are provided for each correlation.

LCI and FEV1 z-score in the different IEI categories

The LCI and the FEV1 z-score of the IEI patients were evaluated according to the different IEI categories (figure 4). The median (IQR) LCI and FEV1 z-score were 7.0 (6.4–8.0) and −0.6 (−1.3–0.1) for patients with predominantly antibody deficiencies, 6.7 (6.2–7.2) and −0.7 (−1.8–0.1) for patients with combined immunodeficiencies with associated or syndromic features, 7.3 (6.5–7.7) and −0.1 (−1.7–0.4) for patients with congenital defects of phagocytes number, function or both, 7.1 (6.3–9.1) and −1.3 (−3.6–1.2) for patients with immunodeficiencies affecting cellular and humoral immunity, and 7.1 (6.7–9.3) and −2.1 (−2.8–0.7) for those with other entities (figure 4a and b, and supplementary table S2).

FIGURE 4
FIGURE 4

Lung clearance index (LCI) and forced expiratory volume in 1 s (FEV1) z-score according to entity of inborn errors of immunity (IEI). a) The LCI and b) FEV1 z-score are given for the different IEI groups. Horizontal lines indicate the median value. The relationship between the LCI and the FEV1 z-score in the different IEI groups is shown for c) patients with both measurements under 50 years of age (n=77) and d) 50 years and older (n=15). Symbols reflect the IEI groups: triangle: predominantly antibody deficiencies (PAD) (n=69); squares: combined immunodeficiencies with associated or syndromic features (CIDwF) (n=8); hexagon: congenital defects of phagocyte number, function or both (DP) (n=6); +: immunodeficiencies affecting cellular and humoral immunity (CID) (n=4); *: others (n=5), including ADA2 deficiency (n=1), Good syndrome (n=1), IRAK4 deficiency (n=1), LRBA deficiency (n=1) and XIAP deficiency (n=1). The dotted lines indicate the lower limit of normal of FEV1 z-score and the upper limit of normal of LCI. The grey area highlights patients with elevated LCI values but normal FEV1 z-scores.

LCI and FEV1 z-scores are worse in IEI patients with bronchiectasis than in those without bronchiectasis

32 of 114 (28.1%) IEI patients received a chest CT or MRI within 5 years before the initial MBW measurement. Of those, 14 (43.8%) did not have bronchiectasis, while 18 (56.3%) were diagnosed with bronchiectasis. IEI patients with bronchiectasis had significantly lower body mass index values, more often a history of recurrent lower airway infections and received more frequently pulmonary therapies compared to IEI patients without bronchiectasis (supplementary tables S3 and S4). The median (IQR) LCI and median FEV1 z-score for patients without versus patients with bronchiectasis were 6.9 (6.4–7.6) versus 7.9 (6.8–10.0; p<0.05) and −0.2 (−1.4–0.2) versus −2.9 (−3.6–0.9; p<0.05) (figure 5).

FIGURE 5
FIGURE 5

Comparison of the lung clearance index (LCI) and the forced expiratory volume in 1 s (FEV1) z-score between patients with inborn errors of immunity (IEI) without and with bronchiectasis. Comparison between IEI patients without and with bronchiectasis is shown for a) the LCI and b) the FEV1 z-score. Boxes extend from the 25th to the 75th percentile and horizontal lines indicate the median value. Whiskers mark the minimum and maximum values. p-values refer to the comparison of LCI and FEV1 z-score between the groups. *p<0.05.

LCI in IEI patients increases over time

70 of 114 (61.4%) IEI patients received a second MBW measurement after a median (range) of 364 (63–707) days (supplementary tables S5 and S6). The LCI showed a significant median (IQR) increase of 0.2 (−0.2–0.5; 2.2% (−2.1–7.3)) at the second measurement (p<0.01) (figure 6a). The median (IQR) change in LCI per patient year was 0.1 (−0.2–0.5; 2.2% (−2.6–7.9)) (p<0.01) (figure 6b and c). 13 (18.6%) of 70 patients showed an increase of >10% after 1 patient year.

FIGURE 6
FIGURE 6

Repeated lung clearance index (LCI) measurements in patients with inborn errors of immunity (IEI). a) Change of LCI in clinically stable IEI patients from baseline to a second measurement (follow-up) after a median (range) of 364 (63–707) days. b) Change of baseline LCI after 1 patient year (PY). c) Change in LCI after 1 PY in per cent (%). p-values refer to the longitudinal change of LCI. Boxes extend from the 25th to the 75th percentile and horizontal lines indicate the median value. Whiskers mark the minimum and maximum values. The dashed lines indicate a clinically relevant change of 10%. **p<0.01.

Discussion

This is the largest study to date comparing MBW and spirometry for IEI patients, CF patients and HC, demonstrating that MBW is feasible and sensitive to detect lung disease in IEI patients and that the LCI of IEI patients differs from CF patients and HC. In addition, we show that more patients are identified with abnormal results for LCI than for FEV1. Therefore, LCI is more sensitive than FEV1 to detect lung disease. Furthermore, we found that IEI patients with bronchiectasis have higher LCI values than those without and that LCI increases with time in IEI patients.

Previous studies showed that MBW can assess even mild lung disease in patients with various entities such as CF, PCD and COPD [15–30, 37]. The present study extends the use of MBW to IEI patients of a wide age range and with different underlying disease entities demonstrating that IEI lung disease can be assessed by MBW. As expected, the LCI of patients with lung diseases (both IEI and CF) is significantly higher than in HC [17–19, 22, 28, 30]. However, the level of lung disease detected by the LCI seems to be milder in IEI patients compared to age-matched patients with CF (figure 1). Comparable to previous findings in different lung diseases, we found a moderate negative correlation between LCI and FEV1 in IEI patients (figure 3). In addition, our investigations in both patients with IEI and CF are in line with previous reports on a higher sensitivity of the LCI to identify patients with lung diseases than the FEV1 [18, 19, 24, 30] (figure 1).

Previously, studies in CF and PCD found a correlation between LCI and radiological findings of lung pathology in CT and MRI [22, 24, 30]. In the present study, chest CT or MRI were available in 32 IEI patients at baseline. In this subgroup, IEI patients with bronchiectasis had significantly higher LCI values than those without (figure 5). This suggests a correlation between LCI and bronchial changes in IEI patients. Previous studies also demonstrated that the LCI correlates more strongly with structural lung changes assessed by radiological imaging than FEV1 [24, 30]. However, our radiological data are limited, partially due to limited access to imaging during the COVID-19 pandemic. This resulted in imaging and pulmonary function testing not taking place at the same time. Therefore, structural lung changes could have developed by the time of MBW testing that were not present when lung imaging was performed. To validate our findings on LCI and to evaluate correlations with additional lung function parameters, the use of consensus diagnostic criteria of bronchial and parenchymal pathologies for CT/MRI lung imaging in IEI is warranted for further studies [8].

IEI lung disease was shown to progress with age regardless of immunoglobulin replacement therapy [1, 4, 5]. Therefore, regular assessment of pulmonary function is required which should provide information on even small changes in lung function to adequately adjust therapies to the individual level of lung disease. LCI was found to be the earliest and strongest lung function parameter to predict disease progression in a cohort of CF patients [38]. In the present study, LCI was used to assess lung function in clinically stable IEI patients of which 70 underwent a second MBW measurement after a median of 1 year. The LCI showed a median increase of 0.2 during this period (figure 6), leading to a comparable median increase per patient year. Almost a fifth of the IEI patients had an increase of LCI above 10% after 1 patient year, which is considered the cut-off for a clinically meaningful change [20]. This indicates that the lung disease of IEI patients progresses even in clinically stable patients within a short period of time and that LCI can detect this progression. However, not all IEI patients received a second measurement, and the follow-up period differed between the patients. Therefore, further investigations including lung imaging are needed for verification.

IEI patients who underwent allo-HSCT for IEI were also included in this study. During allo-HSCT, the mutated haematopoietic stem cells are replaced by healthy donor cells and the immunodeficiency is potentially cured in the long-term. However, lung disease can develop already prior to allo-HSCT (without complete reversion after transplant) or afterwards in the form of infectious or non-infectious pulmonary complications caused by graft-versus-host disease [39]. Since we aimed to monitor any respiratory manifestations, we included IEI patients post allo-HSCT. Of note, inclusion of transplanted IEI patients did not impact our results (supplementary table S1).

A limitation of this study is the heterogeneity of diagnoses in the IEI group. While there are a substantial number of patients with antibody deficiency, the numbers of patients for other IEI categories are small. Multicentre studies are required for a more detailed investigation of the LCI in different IEI categories, as well as for a comparison between those groups. However, a strength of our study is that MBW measurements were performed in a clinical setting, supporting the feasibility of lung function monitoring in IEI patients.

In summary, this is the largest study to date comparing LCI and FEV1 z-score in patients with IEI. We demonstrated that the LCI is sufficiently sensitive to detect lung disease in IEI patients. Although our study shows a moderate negative correlation between LCI and FEV1 z-score for IEI and CF patients, we demonstrated that more patients have abnormal LCI values than FEV1 z-scores. In addition, we found that the LCI differs between IEI patients with bronchiectasis and those without. MBW may help to identify patients that should undergo CT or MRI lung imaging for early detection of lung disease facilitating early treatment initiation. We provide supportive evidence for the feasibility and benefit of LCI as an additional outcome parameter for the monitoring of IEI lung disease.

Supplementary material

Supplementary Material

Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

Supplementary material 01019-2023.SUPPLEMENT

Acknowledgements

The authors thank the patients and their parents for their participation in this study.

Footnotes

  • Provenance: Submitted article, peer reviewed.

  • Author contributions: Conception and design of the study: L.M. Busack, S. Thee, H. von Bernuth and M. Stahl; acquisition, analysis and interpretation of data: L.M. Busack, S. Thee, Y. Liu, C. Allomba, N. Ziegahn, A. Tosolini, C.O. Pioch, A.N. Schnorr, B.R. Fuhlrott, O. Staudacher, M. Völler, E. Steinke, L.G. Hanitsch, J. Röhmel, V. Wahn, R. Krüger, M.A. Mall, H. von Bermuth and M. Stahl; drafting the article or revising it critically for important intellectual content: L.M. Busack, S. Thee, Y. Liu, C. Allomba, N. Ziegahn, A. Tosolini, C.O. Pioch, A.N. Schnorr, B.R. Fuhlrott, O. Staudacher, M. Völler, E. Steinke, L.G. Hanitsch, J. Röhmel, V. Wahn, R. Krüger, M.A. Mall, H. von Bernuth and M. Stahl.

  • Conflict of interest: S. Thee declares grants to their institution from the German Innovation Fond; payment or honoraria from Chiesi (European Cystic Fibrosis Society meeting 2022) and Vertex (LEAD meeting, adherence forum); and travel expenses from Chiesi to attend the European Cystic Fibrosis Society meeting 2022.

  • Conflict of interest: O. Staudacher declares a Travel Grant for Young Immunologists from Arbeitsgemeinschaft Pädiatrische Immunologie in the 36 months prior to manuscript submission.

  • Conflict of interest: E. Steinke declares grants or contracts from the Clinician Scientist Program of the Berlin Institute of Health (funded by the German Federal Ministry of Education and Research); payment or honoraria for review of educational manuscripts from Vertex Pharmaceuticals Inc.; and a travel grant for conference attendance from the European Cystic Fibrosis Society, all in the 36 months prior to manuscript submission.

  • Conflict of interest: J. Röhmel declares payment or honoraria, and support for attending meetings and/or travel from Vertex Pharmaceuticals in the 36 months prior to manuscript submission (with permission from their institution); and an unpaid role as a work package leader in BEAT-PCD, a European Research Society Clinical Research Collaboration.

  • Conflict of interest: V. Wahn declares payment or honoraria from CSL Behring (related to www.immundefekt.de) and Pharming (related to a manuscript on APDS); and an honorarium and travel expenses from Pharming for attendance at the DGKJ congress, all in the 36 months prior to manuscript submission.

  • Conflict of interest: H. von Bernuth declares consulting fees from Infill Healthcare Communication (2022); payment or honoraria from Deutsche Selbsthilfe Angeborene Immundefekte) (2023) and CSL Behring (2021); and payment for expert testimony from Bundessozialgericht (2023); as well as that they are a member of the Standing Comission on Vaccination at the Robert Koch Insitut, Ständige Impfkommission (STIKO).

  • Conflict of interest: M.A. Mall declares funding to their institution in connection to the present work from the German Ministry for Education and Research (BMBF; Grant #82DZL009B1); and an unpaid role as a Fellow of the European Respiratory Society.

  • Conflict of interest: M. Stahl declares funding to their institution (Heisenberg professorship) from the German Research Foundation (Deutsche Forschungsgemeinschaft) in connection to the present work; as well as unpaid roles as Chairman of the Forschungsgemeinschaft Mukoviszidose; Secretary of the Cystic Fibrosis Group of the European Respiratory Society; and Treasurer of the German Society of Paediatric Pulmonology.

  • Conflict of interest: All other authors declare no competing interests.

  • Support statement: This study was supported by grants from the German Research Foundation (STA 1685/1–1 to M. Stahl) and the German Federal Ministry of Education and Research (82DZL009B1 to M.A. Mall). The funders had no role in the design, management, data collection, analyses, or interpretation of the data or in the writing of the manuscript or the decision to submit for publication. S. Thee, E. Steinke and M. Stahl are participants of the Berlin Institute of Health (BIH)–Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the BIH. J. Röhmel is participant of the Case Analysis and Decision Support programme funded by the BIH. Funding information for this article has been deposited with the Crossref Funder Registry.

  • Ethics statement: We earned ethical approval for our study by the ethics committee before recruiting the first participant.

  • Received December 17, 2023.
  • Accepted January 15, 2024.
http://creativecommons.org/licenses/by-nc/4.0/

This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org

References

  1. ↵
    1. Gutierrez MJ,
    2. Nino G,
    3. Sun D, et al.
    The lung in inborn errors of immunity: from clinical disease patterns to molecular pathogenesis. J Allergy Clin Immunol 2022; 150: 1314–1324. doi:10.1016/j.jaci.2022.08.024
    OpenUrl
    1. Periselneris J,
    2. Schelenz S,
    3. Loebinger M, et al.
    Bronchiectasis severity correlates with outcome in patients with primary antibody deficiency. Thorax 2021; 76: 1036–1039. doi:10.1136/thoraxjnl-2020-215585
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Hanitsch L,
    2. Baumann U,
    3. Boztug K, et al.
    Treatment and management of primary antibody deficiency: German interdisciplinary evidence-based consensus guideline. Eur J Immunol 2020; 50: 1432–1446. doi:10.1002/eji.202048713
    OpenUrl
  4. ↵
    1. Syed MN,
    2. Kutac C,
    3. Miller JM, et al.
    Risk factors of pneumonia in primary antibody deficiency patients receiving immunoglobulin therapy: data from the US immunodeficiency network (USIDNET). J Clin Immunol 2022; 42: 1545–1552. doi:10.1007/s10875-022-01317-2
    OpenUrl
  5. ↵
    1. Weinberger T,
    2. Fuleihan R,
    3. Cunningham-Rundles C, et al.
    Factors beyond lack of antibody govern pulmonary complications in primary antibody deficiency. J Clin Immunol 2019; 39: 440–447. doi:10.1007/s10875-019-00640-5
    OpenUrl
  6. ↵
    1. Chalmers JD,
    2. Polverino E,
    3. Crichton ML, et al.
    Bronchiectasis in Europe: data on disease characteristics from the European Bronchiectasis registry (EMBARC). Lancet Respir Med 2023; 11: 637–649. doi:10.1016/S2213-2600(23)00093-0
    OpenUrl
  7. ↵
    1. Wall LA,
    2. Wisner EL,
    3. Gipson KS, et al.
    Bronchiectasis in primary antibody deficiencies: a multidisciplinary approach. Front Immunol 2020; 11: 522. doi:10.3389/fimmu.2020.00522
    OpenUrl
  8. ↵
    1. Schütz K,
    2. Alecsandru D,
    3. Grimbacher B, et al.
    Imaging of bronchial pathology in antibody deficiency: data from the European chest CT group. J Clin Immunol 2019; 39: 45–54. doi:10.1007/s10875-018-0577-9
    OpenUrl
  9. ↵
    1. Cinetto F,
    2. Scarpa R,
    3. Carrabba M, et al.
    Granulomatous lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID): a multicenter retrospective study of patients from Italian PID referral centers. Front Immunol 2021; 12: 627423. doi:10.3389/fimmu.2021.627423
    OpenUrl
  10. ↵
    1. Bates CA,
    2. Ellison MC,
    3. Lynch DA, et al.
    Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol 2004; 114: 415–421. doi: 10.1016/j.jaci.2004.05.057
    OpenUrlCrossRefPubMed
  11. ↵
    1. Tiri A,
    2. Masetti R,
    3. Conti F, et al.
    Inborn errors of immunity and cancer. Biology (Basel) 2021; 10: 313. doi:10.3390/biology10040313
    OpenUrl
  12. ↵
    1. Mayor PC,
    2. Eng KH,
    3. Singel KL, et al.
    Cancer in primary immunodeficiency diseases: cancer incidence in the United States Immune Deficiency Network Registry. J Allergy Clin Immunol 2018; 141: 1028. doi:10.1016/j.jaci.2017.05.024
    OpenUrlCrossRefPubMed
  13. ↵
    1. Hurst JR,
    2. Verma N,
    3. Lowe D, et al.
    British Lung Foundation/United Kingdom primary immunodeficiency network consensus statement on the definition, diagnosis, and management of granulomatous-lymphocytic interstitial lung disease in common variable immunodeficiency disorders. J Allergy Clin Immunol Pract 2017; 5: 938–945. doi:10.1016/j.jaip.2017.01.021
    OpenUrl
  14. ↵
    1. Sandhu D,
    2. Redmond JL,
    3. Smith NMJ, et al.
    Computed cardiopulmonography and the idealized lung clearance index, iLCI2.5, in early-stage cystic fibrosis. J Appl Physiol (1985) 2023; 135: 205–216. doi:10.1152/japplphysiol.00744.2022
    OpenUrl
  15. ↵
    1. Roehmel JF,
    2. Doerfler FJ,
    3. Koerner-Rettberg C, et al.
    Comparison of the lung clearance index in preschool children with primary ciliary dyskinesia and cystic fibrosis. Chest 2022; 162: 534–542. doi:10.1016/j.chest.2022.02.052
    OpenUrl
    1. Stahl M,
    2. Joachim C,
    3. Kirsch I, et al.
    Multicentre feasibility of multiple-breath washout in preschool children with cystic fibrosis and other lung diseases. ERJ Open Res 2020; 6: 00408-2020. doi:10.1183/23120541.00408-2020
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Stahl M,
    2. Graeber SY,
    3. Joachim C, et al.
    Three-center feasibility of lung clearance index in infants and preschool children with cystic fibrosis and other lung diseases. J Cyst Fibros 2018; 17: 249. doi:10.1016/j.jcf.2017.08.001
    OpenUrl
  18. ↵
    1. Horsley AR,
    2. Gustafsson PM,
    3. Macleod KA, et al.
    Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis. Thorax 2008; 63: 135–140. doi: 10.1136/thx.2007.082628
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Aurora P,
    2. Bush A,
    3. Gustafsson P, et al.
    Multiple-breath washout as a marker of lung disease in preschool children with cystic fibrosis. Am J Respir Crit Care Med 2005; 171: 249–256. doi: 10.1164/rccm.200407-895OC
    OpenUrlCrossRefPubMed
  20. ↵
    1. Perrem L,
    2. Stanojevic S,
    3. Solomon M, et al.
    Evaluation of clinically relevant changes in the lung clearance index in children with cystic fibrosis and healthy controls. Thorax 2023; 78: 362–367. doi:10.1136/thoraxjnl-2021-218347
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Frauchiger BS,
    2. Binggeli S,
    3. Yammine S, et al.
    Longitudinal course of clinical lung clearance index in children with cystic fibrosis. Eur Respir J 2021; 58: 2002686. doi:10.1183/13993003.02686-2020
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Stahl M,
    2. Wielpütz MO,
    3. Graeber SY, et al.
    Comparison of lung clearance index and magnetic resonance imaging for assessment of lung disease in children with cystic fibrosis. Am J Respir Crit Care Med 2017; 195: 349. doi: 10.1164/rccm.201604-0893OC
    OpenUrlPubMed
    1. Ellemunter H,
    2. Fuchs SI,
    3. Unsinn KM, et al.
    Sensitivity of lung clearance index and chest computed tomography in early CF lung disease. Respir Med 2010; 104: 1834–1842. doi: 10.1016/j.rmed.2010.06.010
    OpenUrlCrossRefPubMed
  24. ↵
    1. Gustafsson PM,
    2. De Jong PA,
    3. Tiddens HA, et al.
    Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis. Thorax 2008; 63: 129–134. doi:10.1136/thx.2007.077784
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Hatziagorou E,
    2. Avramidou V,
    3. Gioulvanidou M, et al.
    Pulmonary exacerbations, airway pathogens, and long-term course of lung clearance index in children and young adults with cystic fibrosis. Pediatr Pulmonol 2022; 57: 3069–3076. doi: 10.1002/ppul.26136
    OpenUrl
    1. Stahl M,
    2. Wielpütz MO,
    3. Ricklefs I, et al.
    Preventive inhalation of hypertonic saline in infants with cystic fibrosis (PRESIS). A randomized, double-blind, controlled study. Am J Respir Crit Care Med 2019; 199: 1238–1248. doi:10.1164/rccm.201807-1203OC
    OpenUrlPubMed
  27. ↵
    1. Amin R,
    2. Subbarao P,
    3. Lou W, et al.
    The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis. Eur Respir J 2011; 37: 806–812. doi: 10.1183/09031936.00072510
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Kinghorn B,
    2. McNamara S,
    3. Genatossio A, et al.
    Comparison of multiple breath washout and spirometry in children with primary ciliary dyskinesia and cystic fibrosis and healthy controls. Ann Am Thorac Soc 2020; 17: 1085–1093. doi: 10.1513/AnnalsATS.201905-375OC
    OpenUrl
    1. Bell AS,
    2. Lawrence PJ,
    3. Singh D, et al.
    Feasibility and challenges of using multiple breath washout in COPD. Int J Chron Obstruct Pulmon Dis 2018; 13: 2113–2119. doi: 10.2147/COPD.S164285
    OpenUrlPubMed
  30. ↵
    1. Boon M,
    2. Vermeulen FL,
    3. Gysemans W, et al.
    Lung structure–function correlation in patients with primary ciliary dyskinesia. Thorax 2015; 70: 339–345. doi: 10.1136/thoraxjnl-2014-206578
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Tangye SG,
    2. Al-Herz W,
    3. Bousfiha A, et al.
    Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022; 42: 1473–1507. doi: 10.1007/s10875-022-01289-3
    OpenUrlCrossRef
  32. ↵
    1. Lee TWR,
    2. Brownlee KG,
    3. Conway SP, et al.
    Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. J Cystic Fibros 2003; 2: 29–34. doi:10.1016/S1569-1993(02)00141-8
    OpenUrlCrossRef
  33. ↵
    1. Chang AB,
    2. Bush A,
    3. Grimwood K
    . Bronchiectasis in children: diagnosis and treatment. Lancet 2018; 392: 866–879. doi:10.1016/S0140-6736(18)31554-X
    OpenUrlCrossRefPubMed
  34. ↵
    1. Robinson PD,
    2. Latzin P,
    3. Verbanck S, et al.
    Consensus statement for inert gas washout measurement using multiple- and single-breath tests. Eur Respir J 2013; 41: 507–522. doi:10.1183/09031936.00069712
    OpenUrlAbstract/FREE Full Text
  35. ↵
    1. Quanjer PH,
    2. Stanojevic S,
    3. Cole TJ, et al.
    Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J 2012; 40: 1324–1343. doi:10.1183/09031936.00080312
    OpenUrlAbstract/FREE Full Text
    1. Kromeyer-Hauschild K,
    2. Wabitsch M,
    3. Kunze D, et al.
    [Percentiles of body mass index in children and adolescents evaluated from different regional German studies]. Monatsschr Kinderheilkd 2001; 149: 807–818. doi:10.1007/s001120170107
    OpenUrlCrossRef
  37. ↵
    1. Stahl M,
    2. Steinke E,
    3. Mall MA
    . Quantification of phenotypic variability of lung disease in children with cystic fibrosis. Genes (Basel) 2021; 12: 803. doi:10.3390/genes12060803
    OpenUrl
  38. ↵
    1. Kraemer R,
    2. Blum A,
    3. Schibler A, et al.
    Ventilation inhomogeneities in relation to standard lung function in patients with cystic fibrosis. Am J Respir Crit Care Med 2005; 171: 371–378. doi: 10.1164/rccm.200407-948OC
    OpenUrlCrossRefPubMed
  39. ↵
    1. Astashchanka A,
    2. Ryan J,
    3. Lin E, et al.
    Pulmonary complications in hematopoietic stem cell transplant recipients: a clinician primer. J Clin Med 2021; 10: 3227. doi: 10.3390/jcm10153227
    OpenUrl
Back to top
Email
Print
Citation Tools
Multiple-breath washout to detect lung disease in patients with inborn errors of immunity
Leonie M. Busack, Stephanie Thee, Yvonne Liu, Christine Allomba, Niklas Ziegahn, Apolline Tosolini, Charlotte O. Pioch, Alexandra N. Schnorr, Bent R. Fuhlrott, Olga Staudacher, Mirjam Völler, Eva Steinke, Leif G. Hanitsch, Jobst Röhmel, Volker Wahn, Renate Krüger, Marcus A. Mall, Horst von Bernuth, Mirjam Stahl
ERJ Open Research Mar 2024, 10 (2) 01019-2023; DOI: 10.1183/23120541.01019-2023
del.icio.us logo Technorati logo Twitter logo Connotea logo Facebook logo Mendeley logo
Full Text (PDF)

Jump To

Subjects