Rutten et al.

Orphanet Journal of Rare Diseases (2016) 11:50

DOI 10.1186/s13023-016-0425-z

RESEARCH Open Access

Severe tracheal and bronchial collapse in

adults with type II mucopolysaccharidosis
M. Rutten1, P. Ciet2,3, R. van den Biggelaar1, E. Oussoren4, J. G. Langendonk4,5, A. T. van der Ploeg4
and M. Langeveld4,5*

Abstract
Background: Mucopolysaccharidosis type II (MPSII) patients frequently suffer from dyspnoea caused by restrictive
airway disease due to skeletal abnormalities as well as glycosaminoglycans (GAG) accumulation at different levels of
the airway, including the trachea. In this study we describe the extent of the tracheal and bronchial narrowing, the
changes in airway diameter during respiration and the effects of these obstructions on respiratory function in adult
MPSII patients.
Methods: Five adult MPSII patients (mean age 40 years) were included. Pulmonary function tests and in- and expiratory
chest CT scans were obtained. Cross-sectional areas of trachea and main bronchi were measured at end-inspiration and
-expiration and percentage collapse was calculated.
Results: There was diffuse narrowing of the entire intra-thoracic trachea and main bronchi and severe expiratory collapse
of the trachea in all patients. At 1 cm above the aortic arch the median % collapse of the trachea was 68 (range 60 to
77 %), at the level of the aortic arch 64 (range 21–93 %), for the main bronchi this was 58 (range 26–66 %) on the left and
44 (range 9–76 %) on the right side. The pulmonary function tests showed that this airway collapse results in obstructive
airway disease in all patients, which was severe (forced expiratory volume <50 % of predicted) in four out of five patients.
Conclusion: In adult MPS II patients, central airways diameters are strikingly reduced and upon expiration there is
extensive collapse of the trachea and main bronchi. This central airways obstruction explains the severe respiratory
symptoms in MPSII patients.
Keywords: Adults, Airway obstruction, Mucopolysaccharidoses, Mucopolysaccharidosis type II, Respiratory function tests,
Respiratory system abnormalities/complications, Tomography, X-Ray computed, Trachea abnormalities

Background cognitive decline is the most disabling manifestation

Mucopolysaccharidosis type II (MPSII or Hunter syn- of the disease and these severely affected patients die
drome; OMIM +309900) is a rare, X-linked disease in first or second decade of life. The remaining pa-
characterized by lysosomal accumulation of the gly- tients, further referred to as non-neuronopathic pa-
cosaminoglycans (GAGs) heparan and dermatan tients, have normal cognitive function [1, 2]. Other
sulfate due to deficiency of the enzyme iduronate-2- prominent signs and symptoms of MPSII are typical
sulfatase. The intralysosomal accumulation of GAGs facial features, Ear-Nose-Throat (ENT) infections and
causes cellular dysfunction resulting in progressive hearing defects, cardiac valve pathology, respiratory
damage to various organs and tissues. In approxi- disease, skeletal changes, reduced joint mobility and
mately 75 % of patients, progressive neurological and hernias. Extent of organ involvement and disease pro-
gression are highly variable between patients [3].
* Correspondence: m.langeveld.1@erasmusmc.nl
Dyspnea is a frequent symptom in MPSII patients of
4
Center for Lysosomal and Metabolic Diseases, Erasmus University Medical multifactorial etiology. First, GAGs accumulate in mucosa
Center, Rotterdam, The Netherlands and soft tissues of the throat leading to enlargement of the
5
Division of Pharmacology, Vascular and Metabolic Diseases, Department of
Internal Medicine, Erasmus University Medical Center, Rotterdam, The
larynx, tonsils, adenoids and tongue resulting in reduced
Netherlands upper airway mobility and obstruction. Second, the altered
Full list of author information is available at the end of the article

© 2016 Rutten et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Rutten et al. Orphanet Journal of Rare Diseases (2016) 11:50 Page 2 of 6

thorax shape and limited mobility of the ribs and intercos- normal lung mechanical function but can yield differential
tal soft tissue often causes restrictive airway disease [4]. results in patients with airflow obstruction. Whole-body
Third, tracheobronchomalacia causes airway obstruction. plethysmography is more accurate because of the detec-
Tracheobronchial narrowing has been previously de- tion of poorly or non-ventilated lung areas, also known as
scribed in children and adults with MPSII [5–9]. trapped air. A higher TLC measured by bodyplethysmo-
To date changes in airway diameter during respiration graphy compared to that measured by Helium dilution is
in MPSII patients has not been systematically studied. therefore indicative of air trapping [12].
After observing a high prevalence of severe respiratory
symptoms in adult MPSII patients, we decided to investi- Airway imaging and imaging analysis
gate the tracheobronchial collapsibility of these patients We performed in- and expiratory chest CT scans in all pa-
by performing pulmonary function tests (PFTs) and in- tients. Chest CT was done on different multi-detectors
and expiratory chest CT scans. CT scanners, with detectors ranging from 64 (SOMATON
Definition AS+, SIEMENS Healthcare, Forchheim,
Methods Germany) to 192 (SOMATOM Force, SIEMENS Health-
In this study, all adult MPSII patients attending the adult care, Forchheim, Germany) detectors. CT protocol in-
metabolic outpatient clinic at the Erasmus MC, Rotterdam, cluded an end-inspiratory and -expiratory scan starting
the Netherlands were included. All patients signed in- from 2 cm above the lung apices to the bases. Instructions
formed consent for a long-term follow-up study, of which for voluntary breath holds were given before scanning by
pulmonary evaluation is a part. This study was approved by the CT technician. Scanning parameters were: collimation
the Medical Ethical Committee of the Erasmus University 0.625 mm, 50 % overlap, slice thickness 1 mm, pitch 1,
Medical Center. Written informed consent was obtained 110 kV tube voltage and tube current adapted to recom-
from all participants. mended volumetric computer tomography dose index
(CTDIvol), which is 1.6 mGy per adult subject. For expira-
Pulmonary function tests tory CTs, image quality was considered sufficient using a
PFTs were obtained in all patients as part of routine tube current fixed at 25 mA with an effective tube
follow-up. Spirometry was performed in accordance with current-time product of 10 mAs; producing a lower radi-
American Thoracic Society standards [10]. Values of ation dose than the inspiratory protocol. No contrast
percent-predicted for spirometry were calculated using agent was administered. Images were reconstructed with a
reference values based on age, height, sex and race [11]. 2 mm slice thickness as multiplanar reformats (MPR) in
The basic parameters used to properly interpret lung the coronal and sagittal planes. Sharp reconstruction ker-
function were the vital capacity (VC), forced expiratory nel filter without under- or overshoot at edges were used
volume in 1s (FEV1), FEV1/VC ratio and total lung cap- for central airway measurements.
acity (TLC) [11]. The carbon monoxide diffusing capacity Images were transferred to the Myrian dicom viewer
(DLCO) and adjusted DLCO for the measured lung vol- (Intrasense, Montpellier, France). Cross-sectional area
ume (DLCO/VA) assisted to diagnose the underlying dis- (CSA) was measured using a manual tracing tool perpen-
ease, when interpreted in conjunction with the lung dicular to the tracheal midline. To obtain images perpen-
volumes assessment. Airway obstruction was defined by dicular to the midline, double-oblique reformats were
reduction of the FEV1/VC ratio (also known as Tiffeneau- obtained by the axial MPR with sharp kernel (i.e. B50f,
index) below 70 %. A Tiffenau-index below 70 % depicts a I70f, B75f) [13] (Ciet et al. 2015). Measurements of CSA
disproportionate reduction of maximal airflow from the were obtained at five levels throughout the central air-
lung in relation to the maximal expiratory volume (VC), ways: 1 cm above the aortic arch, at the level of the aortic
implying airway narrowing during exhalation. The severity arch, 2 cm above the carina, 1 cm below carina in the
of lung function impairment was based on the forced ex- main left and right bronchi (Fig. 1a). CSA measurements
piratory volume in 1s as a percentage of the normal pre- were performed with constant lung window (WL -600;
dicted value, corrected for sex, age, height and race WW 1200) both in the end-inspiratory and at end-
(FEV1%pred). A restrictive ventilatory defect is character- expiratory images by a single radiologist with extensive
ized by a reduction in total lung capacity (TLC) below experience in thoracic radiology. The percentage airway
80 % of the predicted value. TLC was measured by He- collapse was calculated according the formula:
lium [He] dilution (TLC-He) in all patients and addition-
CSAins−CSAexp
ally by whole-body plethysmography (TLC-Pleth) in a Δ%¼  100:
CSAins
single patient. In body plethysmography, breathing ma-
noeuvres are performed in an airtight box of known vol- Where Δ % is the percentage collapse, and CSAins
ume with fixed barometric pressure. The two techniques and CSAexp are the CSA in the end-inspiratory and
for measuring TLC yield similar results for those with expiratory images respectively.
Rutten et al. Orphanet Journal of Rare Diseases (2016) 11:50 Page 3 of 6

Fig. 1 In- and expiratory chest CT scan. a Central airways measurements were performed at five locations: (a) 1 cm above aortic arch, (b) aortic arch,
(c) 2 cm above carina bifurcation, (d) right main bronchus, (e) left main bronchus. b Tracheal cross section at “b” (1 cm above the aortic arch) in patient 2.
Note abnormal “bell-shaped” trachea in the end-inspiration image. c At end expiration there is almost complete collapse of the trachea (same patient).
d Bronchial cross section at “e”(left main bronchus) at end inspiration (patient 2) and e at end expiration (same patient). f Presence of trapped air at
expiration (patient 1)

Results reactions during enzyme infusion. At the time, he had

Patient characteristics been treated for 2 years. Patient characteristics are sum-
Five adult MPSII patients were enrolled in the study marized in Table 1. Three patients received nightly ven-
(mean age 40 years, age range 29–50). All patients were tilatory support, in one this was bilevel positive airway
male and had normal cognitive function. Four out of five pressure (BiPAP) and in the other two continuous posi-
patients were diagnosed during childhood (age range 3 tive airway pressure (CPAP) (Table 2).
to 9 years), one patient was diagnosed at adult age (age
45 years). In the latter patient the disease was the least Pulmonary function
severe and only at age 45 the cluster of ENT problems, Table 2 shows the results of the PFT measurements, per-
recurrent pulmonary infections, cardiac valve pathology formed at a time point closest to the airway imaging
and skeletal problems were recognized as being caused date (median time gap 14 days). In patients 1, 2, 4 and 5
by MPS II. In all five patients, enzyme replacement ther- the lung function analysis showed airway obstruction
apy (ERT) was started and all but one received ERT at (FEV1/VC <0.7). In three patients this was accompanied
the time of the pulmonary evaluation. Duration of ERT by restriction as the total lung capacity (TLC) measured
at time of evaluation ranged from 3 months to 7 years. was below 80 % of predicted. Thus, mixed obstructive
The single untreated patient discontinued ERT 4 years and restrictive airway disease was present in these
prior to the evaluation because of recurrent anaphylactic patients. Patient 1 showed only obstructive airway
Table 1 Patient characteristics
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Mutation c.806A > T c.1024 C > T c.182 C > A c.1265G > A c.1122C > T
Age (years) 49 45 43 31 29
Age at diagnosis 7 45 7 9 3
Height (m) 1.71 1.76 1.61 1.52 1.44
Weight (kg) 91 111 60 51 44
Age start ERT therapy 47 45 37 25 25
Currently on ERT therapy Yes Yes No Yes Yes
Duration of ERT therapy (years) 2 0.25 2 7 4
N/A not applicable, ERT enzyme replacement therapy
Rutten et al. Orphanet Journal of Rare Diseases (2016) 11:50 Page 4 of 6

Table 2 Pulmonary function tests

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
VC max (L) 4.01 3.79 1.83 1.5 2.01
VC max (%) 91 78 46 40 61
FEV1 (L) 1.32 2.33 1.36 0.55 1.18
FEV1 (%) 38 62 43 18 41
Tiffeneau (FEV1/VC) (%) 33 61 74 37 59
TLC-He (L) 5.52 5.38 2.84 3.6 2.94
TLC-He (%) 84 77 49 71 66
TLC-Pleth 3.50
TLC-Pleth (%) 60
DLCO (%) 73 94 46 44 43
DLCO/VA(%) 108 140 132 109 129
Age at time of start ventilatory support 50 N/A 40 31 N/A
Type of ventilatory support CPAP N/A BiPAP CPAP N/A
VC vital capacity (in litre and as % of predicted), FEV1 forced expiratory volume in 1 s (in litre and as % of predicted), TLC-He total lung capacity measured by
helium dilution (in litre and as % of predicted), TLC-Pleth total lung capacity measured by bodyplethysmography (in liter and as % of predicted), DLCO carbon
monoxide diffusing capacity (% of predicted), DLCO/VA carbon monoxide diffusing capacity adjusted for lung volume (% of predicted). CPAP continuous positive
airway pressure, BiPAP bilevel positive airway pressure

disease. Patient 3 appeared to have only restrictive air- measurements at five different locations at end-
way disease but the marked difference between TLC inspiration and -expiration and the percentage collapse
measured by body plethysmography (60 %) and TLC-He for each patient. Median percentage collapse at different
(49 %) was suggestive of trapped air, which is usually levels of the airway were: 68 % at 1 cm above the aortic
seen in the context of airway obstruction. The concave arch), 64 % at the level of the aortic arch, 58 % 2 cm
shape of the expiratory part of the flow volume loop was above the carina. Main bronchi collapse measured at
indeed indicative of airflow obstruction (Additional file 1 cm below carina was 58 % for the left main bronchus
1: Figure S1). Thus, patient three also had obstructive and 44 % for the right main bronchus (Fig. 1b-e). Be-
airway disease. cause of the already diffusely narrowed central airway
In patient 4 the airway impairment was very severe lumen in inspiration, the remaining airway lumen at end
(FEV1%pred <35). In patients 1, 3 and 5 the airway im- expiration is much smaller than if the collapse would
pairment was severe (FEV1%pred <50). Patient 2 had have occurred in a normally shaped trachea. In the most
moderate airway impairment (FEV1%pred 61). This was severely affected patient, there was an almost complete
the patient diagnosed at adulthood, with an overall mild closure of the trachea during expiration. The expiratory
MPSII phenotype. chest scan also showed the presence of trapped air in all
Diffusing capacity was normal in all patients. The low but one patient (Fig. 1f ).
DLCO but normal DLCO/VA excludes parenchymal dis-
ease and indicates extraparenchymal abnormalities. In Discussion
MPSII these extraparenchymal abnormalities are the This study shows extensive collapse of the trachea and
anomalous thorax shape and mechanics caused by thor- main bronchi, resulting life threatening airway obstruc-
acic spine and rib deformities [4]. tion in adult MPSII patients. Airway collapse was
present in all patients included in this study. Adult
Airway imaging MPSII patients have severely reduced central airway
All patients successfully completed the CT protocol. In calibre caused by diffuse tracheobronchomalacia. Previ-
the inspiratory imaging, all patients had diffusely nar- ous studies in younger MPSII patients [14, 15] (Wooten
rowed and thickened trachea and main bronchi. The tra- et al. 2013 median age 9 years n = 30, Lin et al. 2014
chea showed an abnormal triangular shape with mean age 18 years n = 12) reported PFT outcomes. In
flattening of the cartilaginous portion and enlargement these younger patients, mainly restrictive airway disease
of the pars membranacea (Fig. 1b). As a result, the CSA was observed. In the study of Lin et al. [15], the oldest
was already significantly reduced in the end-inspiratory MPSII patients (age 24 and 33 years) also showed mixed
images. restrictive and obstructive airway disease. In that study,
Severe expiratory collapse of the trachea was seen in there was a clear negative correlation between age and
all patients. Table 3 described the central airways FEV1, indicative of worsening of pulmonary function
Rutten et al. Orphanet Journal of Rare Diseases (2016) 11:50 Page 5 of 6

Table 3 In- and expiratory cross sectional areas at different levels of the central airway
Location Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
1 cm above aortic arch 0.83 → 0.32 (61 %) 2.21 → 0.63 (71 %) 1.66 → 0.67 (60 %) 0.81 → 0.26 (68 %) 0.84 → 0.19 (77 %)
Aortic arch 1.02 → 0.39 (62 %) 2.08 → 0.75 (64 %) 1.58 → 0.11 (93 %) 0.35 → 0.12 (66 %) 0.87 → 0.69 (21 %)
2 cm above carina 1.04 → 0.53 (49 %) 2.07 → 0.98 (53 %) 1.59 → 0.27 (83 %) 0.3 → 0.3 (0 %) 0.80 → 0.53 (34 %)
1 cm below carina left main bronchus 0.54 → 0.4 (26 %) 1.16 → 0.4 (66 %) 1.04 → 0.41 (61 %) 0.31 → 0.13 (58 %) 0.53 → 0.34 (36 %)
1 cm below carina right main bronchus 0.52 → 0.29 (44 %) 1.33 → 0.65 (51 %) 1.55 → 0.37 (76 %) 0.54 → 0.49 (9 %) 0.64 → 0.56 (13 %)
Before arrow: cross sectional area in cm at end inspiration, after the arrow: cross sectional area at end expiration in cm, in brackets percentage airway lumen collapse
between end-inspiratory and end-expiratory imaging

with increasing age. Our study shows that in non- In addition to management of the respiratory symp-
neuronopathic MPSII patients aged 30 years or older, toms, knowledge of airway form and function in
pulmonary function is more severely compromised than MPSII patients is important for planning surgical pro-
in younger patients and that this is mainly due to pro- cedures. Pre-anesthesia airway evaluation should in-
gression of the obstructive component of the airway dis- clude fibroscopic inspection of the upper airway and
ease. The cause of this progression is thought to be due PFTs. Based on this study we also recommend to per-
to the increasing tracheal and bronchial obstruction and form (dynamic) airway imaging by chest CT scan to
collapse. assess airway morphology. In this manner a compre-
The observed severe expiratory collapse of the trachea hensive multidisciplinary approach to peri-operative
and main bronchi can explain the high rate of deaths airway management can be achieved. Possible con-
caused by airway impairment in adult MPSII patients cerns related to radiation exposure deriving by the
[2]. In one of our patients (patient 3), there was almost use of CT is likely overcome by the severity of the
complete closure of the trachea upon expiration central airway obstruction. Moreover, thanks to mag-
(Table 3). The clinically most severely affected patients netic resonance imaging (MRI), this limitation might
(patient 3 and 4) were the patients with by far the smal- be resolved, as shown in a recent study in pediatric
lest expiratory diameter of the trachea at the level of the patients with tracheobronchomalacia [16].
aortic arch and 2 cm above the carina (Table 3). Respiratory pathology in MPS is thought to arise
In patient 3, nightly bilevel positive airway pressure from the accumulation of GAGs at different levels of
(BiPAP) was started when respiratory insufficiency was de- the airway. Histopathological studies in MPS II have
tected (mean transcutaneous CO2 8.5 KPa) resulting in shown GAG accumulation in adenoidal and supraglot-
improvement of symptoms and normalisation of the tic tissues [17], but accumulation in tracheal tissues
pCO2 levels. In patient 4 there were progressive respira- has, to our knowledge, only been shown in MPS I
tory symptoms despite early antibiotic treatment in case and mucolipidosis patients [18]. Collapsibility of the
of suspected pulmonary infection, oral steroid therapy to trachea has not been studied in other forms of MPS
reduce airway inflammation and inhaled bronchodilator then MPS II. Gross histopathological examination of
therapy. Because of progressive airway obstruction due to tracheas of MPSII patients showed flattening of the
severe tracheobronchial collapse together with increased tracheal cartilage with loss of the anterioposterior
sputum production due to reduced mucocilliary clearance, diameter [5]. Whereas in most sites involved in
nightly CPAP therapy was started with a significant reduc- MPSII GAG accumulation results in stiffness and re-
tion in work of breathing and improvement in respiratory duced mobility (e.g. cardiac valves, joints, larynx,
symptoms. In this patient, placement of a tracheostomy or skin) in the trachea the result is softening and weak-
tracheal stent was discussed, but not pursued because of ness of the supporting cartilage, resulting in airway
the severity and extensiveness of the airway obstruction, collapse. A factor that might be responsible for this
involving the entire trachea and main bronchi. loss of structural integrity of the cartilage could be
There is an additional value of airway imaging com- inflammation. In a rodent model for MPS VI, in
pared to PFTs alone in the assessment of respiratory which full collapse of the trachea usually occurs by
symptoms in MPSII patients. For example, in patient 3 9 months of age, two forms of anti-inflammatory
standard lung function tests could not explain his severe treatment resulted in an increased tracheal lumen and
respiratory symptoms. Additional body plethysmography a thicker tracheal wall compared to untreated rats
suggested obstructive airway disease and trapped air that [19, 20]. As such, anti-inflammatory therapy may be
was confirmed by CT scanning. Thus, the combination of value in the treatment of the severe tracheabronch-
of these tests was necessary to correctly identify the ori- omalacia, since ERT does not seem to prevent the oc-
gin of the severe respiratory symptoms. currence of this life-threatening disease manifestation.
Rutten et al. Orphanet Journal of Rare Diseases (2016) 11:50 Page 6 of 6

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Competing interests
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The authors declare that they have no competing interests.
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manuscript, ML participated in the design and coordinated the study, Anti-TNF-alpha therapy enhances the effects of enzyme replacement
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Author details
1
Department of Pulmonology, Erasmus University Medical Center, Rotterdam,
The Netherlands. 2Department of Radiology, Erasmus University Medical
Center, Rotterdam, The Netherlands. 3Department of Paediatric Pulmonology,
Sophia Children’s Hospital, Erasmus University Medical Center, Rotterdam,
The Netherlands. 4Center for Lysosomal and Metabolic Diseases, Erasmus Submit your next manuscript to BioMed Central
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1. Holt JB, Poe MD, Escolar ML. Natural progression of neurological disease in
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mucopolysaccharidosis type II. Pediatrics. 2011;127(5):e1258–65. doi:10.1542/
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