Introduction

Ataxia telangiectasia (AT), a rare autosomal recessive multisystem disorder, is characterized by progressive neurologic impairment with cerebellar ataxia, oculocutaneous telangiectasia, B- and T-cell defects, heightened sensitivity to ionizing radiations, and increased risk of developing lymphoid malignancies [1]. The disease is caused by mutations in the ataxia telangiectasia mutated gene, which encodes a serine/threonine kinase involved in the cellular response to double-stranded DNA breaks [2]. The prognosis of the disease is poor, with a median survival of approximately 25 years [3]. The major cause of morbidity and mortality in AT is represented by chronic lung disease (CLD), developing in more than 70 % of the cases. Recurrent infections, abnormal airway secretion clearance due to ineffective cough, oropharyngeal dysphagia, and recurrent aspiration are all co-factors of CLD in AT [4]. In addition, since patients become wheelchair-bound at an early age, a moderate-to-severe neurological disease may significantly contribute to the pulmonary deterioration [5].

Chest computed tomography (CT) is the gold standard to investigate CLD at any age [6]. However, exposure to ionizing radiations must be carefully avoided in AT individuals due to their radiosensitivity [7, 8]. In this context, a non-ionizing radiation imaging technique is highly desirable to detect and follow lung lesions over time. Chest magnetic resonance imaging (MRI) is emerging as a useful radiation-free tool in several pulmonary diseases, since it is highly comparable to chest CT [9–19].

Thus far, no studies assessing CLD in AT patients through chest MRI have been published, in spite of the great need for a thorough lung evaluation in these subjects [4]. Therefore, the primary aim of this study was to assess lung structural damage in children and young adults with AT using MRI. As secondary aim, we analyzed the relationship among the severity and extent of structural changes, and patients’ clinical, microbiological and lung function data.

Patients and Methods

Patients

The institutional review board of the “Federico II” University, Naples, Italy, approved the study, and informed written consent was obtained from the parent/legal guardian of each child and from adult patients. The study was performed in accordance with the 1964 Declaration of Helsinki and its later amendments. Exclusion criteria were: 1) acute respiratory infection; and 2) severe mental retardation or other conditions that could compromise compliance to MRI, namely, children with age less than 5 years and claustrophobic. Fifteen patients with AT (8 males; median age, 11.3 years; range, 6–31 years; 13 children/2 adults) were prospectively enrolled from five Italian Centers. Diagnosis was made at a median age of 6 years (range, 1–7 years) according to the European Society of Immunodeficiencies criteria. In all cases the diagnosis was confirmed at molecular level. At the entry into the study, 8 subjects (53 % of the total) had a history of recurrent or chronic respiratory symptoms, including dry or wet cough, dyspnea at rest and nasal obstruction with rhinorrea. Median age at the onset of respiratory symptoms was 3 years (range, 0.1–8 years).

MR Scanning

MRI was performed at a single Center, “Federico II” University, with a 3.0-T MR scanner (Magnetom Trio, Siemens Erlangen, Germany), a maximum gradient strength of 40 mT/m, a slew rate of 200 mT/m/ms, and 32 radiofrequency channels. We used a dedicated 12-element integrated matrix coil system, covering the whole thorax, for signal reception. It consisted of one anterior and one posterior flexible phased-array coil, each containing a set of six receiver elements. The applied sequence was a T2-weighted half-Fourier single-shot turbo spin-echo (HASTE) sequence, performed using an electrocardiograph-gating to reduce cardiac motion artefacts and respiratory-gating by a navigator signal that monitored the diaphragm position. Sequence parameters were: repetition time/echo time/flip angle, infinite/92 ms/150°; parallel acquisition factor, 2; 25 to 30 slices; slice thickness, 5 mm; distance factor, 20 %; transversal (matrix, 380 × 256) and coronal (matrix, 400 × 320) orientation; acquisition time, approximately 90 s. The field of view was patient-adapted. No patient required sedation, and all of them well tolerated the procedure. The overall time spent in the MRI room was approximately 5 min.

Image Evaluation

All identifying information was removed from the scans. The images were evaluated in consensus and in a random order by two experienced observers who were blinded to the patients’ clinical data. Images were scored using a modified version of the Helbich system, as previously reported [15]. In order to evaluate extent and severity of interstitial lung involvement, we extended this scoring system by introducing 3 extra categories. Briefly, the abnormalities assessed were bronchiectasis, peribronchial wall thickening, mucous plugging, sacculations or abscesses, bullae, emphysema, collapse or consolidation, thickening of intra-inter lobular septae, ground glass opacities, and nodules measuring 5 to 10 mm in diameter, since nodules larger than 10 mm were scored as consolidations (Online Resource Figure 1). Six lobes were examined, the lingula being scored separately. The maximum possible total score was 34 points, indicating the most severe lung damage.

Lung Function and Microbiological Evaluation

Spirometry with measurement of forced vital capacity (FVC, % predicted), forced expiratory volume at 1 s (FEV1, % predicted), the FEV1/FVC ratio (%), and forced expiratory flow at 25 to 75 % of the pulmonary volume (FEF25–75%, % predicted) was obtained from all cooperating patients on the same day as chest MRI (MasterScreen® Body, VIASYS Healthcare GmbH, Germany), according to published criteria [20]. The reproducibility of spirometry was increased by stabilizing the patient’s head and holding the cheeks, as suggested elsewhere [4]. Therapy with short-acting or long-acting β2-agonists was stopped 6 or 12 h before testing, respectively. A FEV1 >80 % predicted was considered normal. Deep throat or sputum cultures were also obtained in all patients on the same day as chest MRI.

Statistical Analysis

Results are expressed as median and range values. Spearman’s rank correlation coefficient (rho) was used to assess relationships among variables. Patients were also divided into 2 groups based on the presence (Group A) or absence (Group B) of recurrent/chronic respiratory symptoms at the entry into the study, and comparisons were made using the χ 2 and the Mann–Whitney U tests. A two-sided p < 0.05 was considered as significant. Data were analyzed with SPSS-PC, release 13.0, SPSS Inc. (Chicago, IL).

Results

MRI identified lung abnormalities in all patients either they were symptomatic or symptoms free. Peribronchial wall thickening, mucous plugging, bronchiectasis, and collapse or consolidation were present in 87, 67, 60, and 13 % of the cases, respectively. Sacculations/abscesses, bullae, emphysema, thickening of intra-interlobular septae, ground glass opacities, and nodules were absent in all patients. No difference in the frequency of these pulmonary changes was found between subjects with or without respiratory symptoms (p > 0.05 for each abnormality).

Total MRI score was significantly higher in patients with respiratory symptoms than in asymptomatic subjects (6.5 versus 5.0, respectively, p = 0.02) (Table I). However, no significant difference in the specific lung abnormalities was found between the two groups. No significant relationship was found between age at the entry into the study and MRI total or specific scores. Examples of images obtained by MRI are shown in Figs. 1, 2 and 3. Figure 1 shows mild peribronchial wall thickening in the left lower lobe in a boy with AT. Figure 2 illustrates bronchiectasis and mucous plugging in the left lower lobe in a boy with AT. Figure 3 shows an area of consolidation with bronchiectasis in the middle lobe and bronchiectasis, peribronchial wall thickening and mucous plugging in the lower lobes in a female adolescent with AT.

Table I Median MRI scores in the whole study population and in patients with (group A) or without (group B) respiratory symptoms
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Fig. 1
figure 1

Transverse MR image showing mild peribronchial wall thickening in the left lower lobe of a boy with AT

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Fig. 2
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MR image from a boy with AT illustrating bronchiectasis and mucous plugging in the left lower lobe

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Fig. 3
figure 3

Transverse MR image showing an area of consolidation with bronchiectasis in the middle lobe and bronchiectasis, peribronchial wall thickening and mucous plugging in the lower lobes in a female adolescent with AT

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Only 10 patients succeeded in performing acceptable and reproducible spirometry (Table II). Results showed moderately-to-severely reduced FVC and FEV1, and normal-to-high FEV1/FVC ratios. No significant difference in lung function was observed between the patients subgroups. We found a significant relationship between the extent of mucous plugging score and FEV1 (r = 0.7, p = 0.04) or FEF25–75% (r = 0.9, p = 0.001). No other significant associations among MRI scores and functional parameters were observed.

Table II Spirometry data in the whole study population and in patients with (group A) or without (group B) respiratory symptoms
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Positive deep throat or sputum cultures were obtained from 5 subjects (33 %, including 4 patients with recurrent/chronic respiratory symptoms and 1 girl without). Haemophilus influenzae and Klebsiella pneumoniae were isolated in 4 cases and in 1 female adolescent, respectively. In ten cases (67 %) no pathogens were cultured. No significant difference in MRI scores was found between patients with positive and negative cultures.

Discussion

The current study explored for the first time the efficacy of chest high-field MRI in the assessment of severity and extent of lung abnormalities in children and young adults with AT. The following are the main findings. Although about half of the enrolled patients had no history of recurrent/chronic respiratory symptoms at the entry into the study, MRI identified lung abnormalities in all cases. No significant difference in specific lung abnormalities scores was found between patients with or without respiratory symptoms, although the total MRI score was significantly higher in patients with symptoms. Patients’ age was not related to MRI total or specific scores. Furthermore, apart from a significant relationship between the extent of mucous plugging score and FEV1 or FEF25–75% values, no other significant associations were found among MRI scores and lung function parameters. Based on these findings, it appears that most patients with AT have abnormalities at chest MRI, which may suggest that they are at increased risk of complications with respiratory infections and anesthesia. Furthermore, given its accuracy in detecting airway obstruction and small airway disease, MRI represents a useful diagnostic tool in supporting the decision to start a more aggressive airway therapy and in monitoring lung disease over time, particularly in AT patients with airflow obstruction.

Subjects with AT are prone to recurrent respiratory infections as a result of abnormal immune response, recurrent aspiration, and impaired clearance of airways secretions [4]. According to previous studies, the prevalence of recurrent respiratory infections in AT ranges from 38 to 90 % [21–23], while bronchiectasis has been reported in about one half of the cases [24]. Other common lung abnormalities are peribronchial infiltrations and opacities due to pneumonia [21]. The current study, that included all eligible AT patients with no selection criteria based on the severity of clinical picture, confirms these findings since approximately half of our patients had no history of recurrent/chronic respiratory symptoms, and finally, bronchiectasis and peribronchial wall thickening were evident at chest MRI in a high proportion of cases. Therefore, current patients likely reflect the general AT population in terms of severity of lung disease. Interestingly, we observed that MRI identified lung structural changes not only in patients with respiratory symptoms, but also in those without, even though severity and extension of specific lung abnormalities in the two groups were not significantly different. Indeed, it has been suggested that the assessment of pulmonary disease in AT may be difficult or underestimated as abnormal respiratory muscle function progressively develops secondary to neurologic decline, and therefore cough is weak or ineffective [25]. Moreover, many AT patients are also wheelchair-bound and, therefore, may not refer dyspnea on exertion [4]. Our findings indicate that chest MRI is a more effective tool than clinical features for assessing AT lung disease in children and adults.

Early pulmonary assessment in AT is mandatory as CLD is a major cause of morbidity and mortality [22]. Actually, lower respiratory tract infections may present early in life, even before neurological complications occur, and pulmonary deterioration appears associated with worsening clinical outcome of the disease [24]. Patients should be thoroughly assessed for their pulmonary symptoms and signs since early childhood [4]. Interestingly, in the current study we found no relationship between patients’ age at enrolment and the severity or extent of lung structure changes. This finding supports the assumption that in AT CLD due to recurrent airways infections and/or to chronic aspiration associated to neuromuscular impairment and swallowing dysfunction likely occurs since early infancy.

It is well known that lung function measurement is problematic in AT due to patients’ difficulties in both inhaling to total lung capacity and exhaling to residual volume [4, 25–28]. In the current study, only two thirds of the cases succeeded in performing reliable spirometry. We found that most of our study participants had high FEV1/FVC ratios and low FVC predicted values, suggesting a restrictive lung defect. Indeed, it has been previously demonstrated that AT patients have a decreased ability to expire to residual volume rather than a restrictive defect [25]. In this regard, it has been hypothesized that decreased FVC values may be due to expiratory muscle weakness or scoliosis [4]. Thus, spirometry alone may not always be sensitive enough to distinguish between respiratory muscle weakness and/or impaired coordination versus restrictive lung defects in AT. In other words, pulmonary function tests might be relatively insensitive markers of early disease and fail to detect regional structural changes, because these tools reflect the function of the lung as a whole and give no information about localized abnormalities.

To the best of our knowledge, this is the first study that assessed lung structural damage by MRI, and its relationships with clinical, microbiological, and functional data in patients with AT. It is also the first evaluation of chest 3.0-T morphological MRI in patients with primary immune deficiencies and increased radiosensitivity. The scanner we used has several advantages over standard MR units operating at field strengths of 1.5-T, that is: a) it has a high-speed and a high-strength gradient system; b) it is equipped with multiple phased-array coils and receiver channels; and c) it has acquisition acceleration techniques, such as parallel imaging, that improve image quality. Another advantage of the system we used is that cardiac- and respiratory-gating reduce artifacts due to heart/great vessels/chest wall motion, thereby overcoming the need for sedation even in poorly cooperating subjects as AT patients. Nevertheless, our study is limited by the fact that images were read in consensus, there was no longitudinal evaluation of CLD, the study population was not large due to the rarity of the disease, and infants were not included.

Interstitial lung disease may be an issue in immunocompromised patients and it has been adequately identified at MRI [11, 17], particularly 3.0-T MRI [29, 30]. In our population, likely due to the small sample size, we did not detect any interstitial lung changes, despite the presence of respiratory symptoms in approximately one half of them, likely milder than those elsewhere reported [31].

Chest MRI is a valuable radiation-free imaging technique for assessing cystic fibrosis and non-cystic fibrosis lung disease in children and adults [9–19]. The present results provide information on lung structural damage and its relationship with clinical, microbiological, and pulmonary function data in children and young adults with AT. Above all, chest MRI allowed us to identify pulmonary abnormalities also in patients without respiratory symptoms, who constituted about one half of our population, and thus to change the clinical management.

Our data should be hopefully substantiated by further research on larger cohorts of AT patients. However, the rarity of AT and the limited access to the 3.0-T technology make it difficult to design large scale protocols in AT. Notwithstanding this, the absence of correlation between MRI and clinical or spirometry data indicates that MRI lung structure changes may precede the appearance of symptoms or functional impairment in AT.

Generally, early identification of structural changes, particularly bronchiectasis and consolidation, should result in more strict surveillance of the disease course and prompt start of treatment [32]. As some lung changes are potentially reversible when treated early, their detection since the asymptomatic stage contributes to significantly improved patients’ clinical care and better prognosis [33]. Studies from literature suggest that airway clearance techniques may improve sputum expectoration, selected measures of lung function, and health-related quality of life, even though their role on patients’ clinical outcomes has not been completely defined [34]. Although the usefulness of preventive intervention on lung disease progression in AT must be proved on larger patients’ cohorts, early identification of pulmonary lesions, especially if assessed by noninvasive techniques, is expected to affect AT lung disease evolution. Of note, following MRI our AT patients underwent more intensive daily airway clearance treatment by means of chest physiotherapy. The non-execution of MRI would have likely resulted in delayed or missed diagnosis of pulmonary disease, at least in asymptomatic subjects.

Pending further research on larger cohorts that will possibly shed new light on the specific indications of MRI in AT, we suggest that this non-ionizing radiation technique is useful to monitor lung disease over time.

Conclusions

This study demonstrates that chest MRI is a reliable tool for assessing extent and severity of lung structural damage in children and adults with AT, and suggests that it has a role in the management of AT. Given that AT patients should avoid imaging techniques entailing ionizing radiation exposure, chest MRI should be proposed in the diagnostic pathway for AT pulmonary disease assessment.