Adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is characterized by impaired T-, B- and NK-cell function. Affected children, in addition to early onset of infections, manifest non-immunologic symptoms including pulmonary dysfunction likely attributable to elevated systemic adenosine levels. Lung disease assessment has primarily employed repetitive radiography and effort-dependent functional studies. Through impulse oscillometry (IOS), which is effort-independent, we prospectively obtained objective measures of lung dysfunction in 10 children with ADA-SCID. These results support the use of IOS in the identification and monitoring of lung function abnormalities in children with primary immunodeficiencies.
The online version of this article (doi:10.1186/s13023-015-0365-z) contains supplementary material, which is available to authorized users.
Hirsh D. Komarow, Robert Sokolic, Dean D. Metcalfe and Fabio Candotti contributed equally to this work.
Competing interests
The authors declare that they have no competing interests.
This work was supported by the Division of Intramural Research, NIAID and NHGRI, NIH and by an UNIL-CHUV grant (CGRB 29583 to F.C.). Support by M.Y. for this project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and [in part] by the National Institute of Allergy and Infectious Diseases. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Authors state no conflict of interest.
Authors’ contributions
Conception or design: HK, RS, DM, FC; Acquisition, analysis, or interpretation: HK, RS, MY, DK, MH, DM, FC; Drafting for important intellectual content: HK, RS, MY, DM, FC; Final approval of the version to be published: HK, RS, DK, MH, MY, DM, FC; Agreement to be accountable for all aspects of the work in ensuring accuracy or integrity: HK, RS, DK, MH, MY, DM, FC. All authors read and approved the final manuscript.
Abkürzungen
ADA-SCID
Adenosine deaminase deficient severe combined immunodeficiency
IOS
Impulse Oscillometry
FVL
Flow-volume loop
PFTs
Pulmonary function tests
ERS/ATS
European respiratory society/American thoracic society
Z
Impedance
R
Resistance
X
Reactance
Hz
Hertz
Background
Children with primary immunodeficiency diseases (PIDs) often suffer from severe and life-threatening illnesses. Adenosine deaminase (ADA) deficiency is among the most severe forms of PIDs, leading to severe combined immunodeficiency (SCID) and susceptibility to severe and recurrent opportunistic infections. In addition, the ubiquitous expression of ADA confers additional clinical phenotypes to patients affected with ADA-SCID that include non-infectious abnormalities of the lung that are incompletely characterized [1, 2]. Assessment of lung disease in children may employ X-ray and conventional tomography imaging, while lung function is usually evaluated using spirometry, which is effort-dependent and thus difficult to perform in younger patients. Impulse oscillometry (IOS) has been suggested as an alternative technique to assess lung function with a particular application to younger children and others unable to perform spirometry [3‐5]. IOS is best understood as a technique that generates small pressure oscillations that are applied at the mouth and transmitted into the lungs, which in turn enables the measurement of resistance and reactance to the impedance of the respiratory system during spontaneous quiet breathing, and therefore provides an indirect quantification of lung function.
Findings
Subject characteristics
We assessed lung function in 10 children (3–18 years of age) with ADA-SCID by IOS and spirometry following informed consent. Seven patients were on treatment with PEG-ADA and 3 with gene therapy. Six patients had undergone CT imaging of their lungs and displayed: diffuse ground glass opacities (n = 3), parenchymal cysts (n = 2), mosaic attenuation (n = 4), bronchiectasis (n = 1), and nodules (n = 1). All patients could perform IOS while only 5 patients were able to complete spirometry (Table 1). In addition, 82 control subjects of ages 4–18 were evaluated following informed consent. Details regarding methodology, demographics, disease presentation, ADA activity, pulmonary and immune status are shown in Additional file 1: Table S1.
Table 1
Patient characteristics and pulmonary imaging and function testing
UPN
Age (years)
Gender
Ethnicitya
Treatmentb
CT
Spirometry
IOS
1-ADA26
3
F
C
1
ND
-
+
2-ADA41
5
F
C
2
ND
-
+
3-ADA14
8
F
C
2
Normal
+
+
4-ADA16
9
M
H
1
dGGO, MA, B
-
+
5-ADA18
10
F
A
2
ND
+
+
6-ADA5
12
M
AA
1
MA
+
+
7-ADA46
14
F
C
2
dGGO, PC, MA, N
-
+
8-ADA17
16
F
AA
2
MA
-
+
9-ADA3
17
M
C
2
dGGO, PC
+
+
10-ADA47
18
M
AA
2
ND
+
+
aC = Caucasian, H = Hispanic, A = Asian, AA = African American
b1 = Gene Therapy; 2 = ADA conjugated with polyethylene glycol (PEG-ADA)
CT findings: ND CT not performed, dGGO diffuse ground glass opacities, PC parenchymal Cysts, MA Mosaic attenuation, B Bronchiectasis, N Nodules
+ Indicates successful completion of Spirometry and/or IOS
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Pulmonary function measurements
Patient characteristics did not differ significantly when subdividing the entire cohort (n = 10) into patients that could (n = 5) and could not (n = 5) perform spirometry (due to intellectual or physical disability) and in comparison to age matched healthy controls (n = 82, Table 2). The mean baseline measurements of patients with ADA-SCID were within the normal range for spirometry and IOS (Table 3). With the exception of a higher expiratory peak flow (PEF), on average, ADA-SCID patients showed spirometry results similar to healthy controls (Table 3). IOS testing, however, revealed that the ADA-SCID patient cohort presented significant increases in baseline percent-predicted values for resistance at 5 Hz (R5, p = 0.032; Student t-test), and 10 Hz (R10, p = 0.044; Student t-test). Peripheral airway reactance was also significantly increased as indicated by higher X values at 5 Hz (X5, p = 0.001, data summarized in Fig. 1a) and change in X5 from reference (X5ref-X5, p = 0.041; Table 3, italicized values). Although, as a group, the R5-R20(%) of ADA-SCID patients did not differ significantly from control subjects, 4 patients had abnormal values (>35 %). Thus, patients with ADA-SCID displayed measurable defects in peripheral airway that was detected by IOS and not spirometry. A more detailed analysis focusing on individual patients revealed that 2 out of 5 patients who completed spirometry (based on FEV1) and 7 out of 10 patients who underwent IOS (based on R5, R5-R20% and X5ref-X5) had abnormal baseline pulmonary function (Additional file 1: Table S2).
Table 2
Pulmonary function testing in patients vs. controls
Baseline and Post bronchodilator Response. The mean % predicted values of all control subjects and patients with ADA-SCID as determined by spirometry and IOS is displayed at baseline (a) and the mean change of the bronchodilator response (b) with significance noted in baseline values for R5, R10 and X5 (p value; * < 0.05, ** <0.005)
×
After bronchodilator administration, the mean response in ADA-SCID patients was within the normal range for both spirometry and IOS, except for an improved mean ΔR10 of −15.4 %, indicating borderline airways hyperreactivity (cutoff −15 %, Table 4, Fig. 1b). An individual analysis of the 4 patients that underwent post-bronchodilator spirometry revealed that none of the patients displayed reversibility (FEV1 cutoff, 12 % change). However, IOS testing was able to detect significant reversible obstruction in half of the cohort, including 2 of the 4 patients who did not show reversibility by spirometry (Additional file 1: Table S2).
Table 4
Bronchodilator response in patients vs. controls
Bronchodilator responsea
Mean % change (SD)
P value (T-test)
Spirometry
Patients n = 4
Controls n = 82
ΔFEV1
3.3 (4.7)
5.5 (9.7)
0.607
ΔFVC
1.3 (6.5)
2.7 (7.0)
0.341
ΔFEV1 / FVC
2.5 (4.6)
4.3 (8.1)
0.672
ΔPEF
−4.5 (13.7)
6.5 (15.5)
0.164
Impulse oscillometry
Patients n = 10
Controls n = 82
ΔR5
−15.3 (15.9)
−14.6 (12.0)
0.438
ΔR10
−15.4 (12.5)
−14.5 (10.7)
0.809
ΔR20
−12.6 (11.1)
−9.6 (12.7)
0.483
ΔR5-R20
−8.5 (28.7)
−11.7 (29.8)
0.745
ΔX5
−18.2 (31.9)
−14.7 (24.0)
0.673
ΔAX
−21.6 (29.7)
−33.3(22.6)
0.139
ΔFres
−13.4 (15.8)
−13.1 (20.9)
0.961
aAirway reversibility was considered evident when there was an improvement in any of the following bronchodilator parameters : ΔR5 ≥ −20 %, ΔR10 ≥ −15 %, ΔR20 ≥ −20 %, ΔAX ≥ −45 %, and ΔFres ≥ −25 %. By design, the percent improvement (reversibility) is displayed as a negative number because it indicates a magnitude decrease in resistance or reactance
Thus, in a cohort of 10 children with ADA-SCID, IOS was easily employed to assess dynamic lung function; while half of the patients could not complete spirometry testing. Baseline abnormality of pulmonary resistance (R) and reactance (X) was detected in the majority of ADA-SCID patients (70 %) using IOS. Undiagnosed reversible airway disease was revealed in half of the patients and only when using IOS. Also, in comparison to a pediatric control group of 82 patients, statistically significant abnormalities of peripheral airways were detected as indicated by measurement of airway resistance and reactance at lower frequencies (R5, R10, and X5).
Discussion
Adenosine deaminase deficiency causes bronchial inflammation, pulmonary fibrosis and alveolar enlargements in Ada knockout mice [6‐8]. Similarly, non-infectious lung abnormalities are emerging as frequent complications in patients with ADA-SCID. In prior reports, these abnormalities appeared to resolve upon enzyme replacement or transplantation [1, 2]. However, our results provide clinical evidence of continuing peripheral airway dysfunction in a significant fraction of patients receiving treatment resulting in sufficient correction of their immune function. These findings suggest that current therapeutic approaches such as ERT and gene therapy may be insufficient in preventing or controlling lung complications in ADA-SCID. Whether this is also the case of hematopoietic stem cell transplantation [9] remains to be investigated. Our IOS data indicates clinical evidence of continuing peripheral airway dysfunction in a significant fraction of patients that received treatment resulting in improvement of their immune function. The majority of patients with persistent lung disease (pneumonias, bronchiectasis) had abnormal findings on IOS. These observations appear to be independent of age and dAXP levels of diagnosis, and type of therapy employed (enzyme replacement or gene therapy). There were no correlations between the presence of lung abnormalities and demographics, therapeutic, and immunological parameters, however, we recognize that the small number of patients studied may have limited the ability to detect the effects of such variables. However, we believe it is important to caution care providers that ADA-SCID patients may benefit from therapies that target peripheral airway inflammation like inhaled corticosteroids and leukotriene inhibitors [10]. The long-term clinical significance in lung abnormalities in ADA-SCID patients is unknown, but our observations support the use of IOS for the identification and monitoring of this complication in children with this and other primary immunodeficiencies.
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Acknowledgements
Appreciate Hans-Juergen Smith providing background testing reference information and Avanti Desai for assisting with statistical analysis and figure display.
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Competing interests
The authors declare that they have no competing interests.
This work was supported by the Division of Intramural Research, NIAID and NHGRI, NIH and by an UNIL-CHUV grant (CGRB 29583 to F.C.). Support by M.Y. for this project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and [in part] by the National Institute of Allergy and Infectious Diseases. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Authors state no conflict of interest.
Authors’ contributions
Conception or design: HK, RS, DM, FC; Acquisition, analysis, or interpretation: HK, RS, MY, DK, MH, DM, FC; Drafting for important intellectual content: HK, RS, MY, DM, FC; Final approval of the version to be published: HK, RS, DK, MH, MY, DM, FC; Agreement to be accountable for all aspects of the work in ensuring accuracy or integrity: HK, RS, DK, MH, MY, DM, FC. All authors read and approved the final manuscript.
