SHORT COMMUNICATION
INT J TUBERC LUNG DIS 18(8):995–997 Q 2014 The Union http://dx.doi.org/10.5588/ijtld.13.0763 E-published ahead of print 27 May 2014
The prevalence of bronchiectasis in patients with Marfan syndrome H. S. Hwang,* C. A. Yi,* H. Yoo,† J. H. Yang,‡ D-K. Kim,‡ W-J. Koh† *Department of Radiology, †Division of Pulmonary and Critical Care Medicine and ‡Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea SUMMARY
An association has been suggested between Marfan syndrome (MFS) and the nodular bronchiectatic form of lung disease caused by non-tuberculous mycobacteria (NTM). We evaluated the prevalence of bronchiectasis in 79 adult patients with MFS using computed tomography (CT) imaging. Airway dilation indicative of bronchiectasis (22/79, 28%) and bronchioloectasis
(10/79, 13%) were relatively common, although the extent of dilation was not severe and was frequently confined to a single lobe. However, bronchiolitis was evident in only three patients (4%), and no patient was diagnosed with NTM lung disease. K E Y W O R D S : bronchiectasis; Marfan syndrome; nontuberculous mycobacteria
LUNG DISEASE caused by non-tuberculous mycobacteria (NTM) has been increasingly noted in elderly women with bronchiectasis, a nodular bronchiectatic form of NTM lung disease. Such patients have a distinct body morphotype, including a thin body habitus, scoliosis, pectus excavatum and mitral valve prolapse.1,2 Such individuals are often described as having Marfanoid features.3 Marfan syndrome (MFS) is an autosomal-dominant systemic disorder of connective tissue caused by the mutation of the gene encoding the extracellular matrix protein fibrillin-1 (FBN-1).4 The lungs are uncommonly involved, the most common manifestations being the development of spontaneous pneumothorax and apical blebs.4 Any association between bronchiectasis and MFS remains unclear. A previous examination of chest radiographs (CXR) of 100 MFS patients showed that only two had bronchiectasis.5 The aim of the present study was to analyse the prevalence of bronchiectasis in a cohort of MFS patients using multidetector computed tomographic (MDCT) angiographic imaging.6,7
were treated between January 1995 and June 2010 at the Marfan Clinic of Samsung Medical Center, Seoul, Korea.6,7 All patients were of Korean origin, and 30 (35.7%) had a family history of MFS.7 As all patients fulfilled the revised Ghent nosological diagnostic criteria for MFS, our patients were deemed to have MFS rather than Marfanoid features.6,7 Seventy-nine patients diagnosed with MFS underwent MDCT angiography and were examined for airway disease. This study protocol was approved by the institutional review board of the Samsung Medical Center, Seoul, Korea. Informed consent was waived due to the retrospective nature of the study. MDCT angiography was performed using a 64slice scanner (Aquilion 64; Toshiba Medical Systems, Tokyo, Japan). The scanning parameters were 120 kV; automatic exposure control (min: 150 mA, max: 400 mA) at a fixed noise index of 8 HU; collimation of 64 3 0.5 mm; increment of 0.4 mm; a pitch of 0.828; and a tube rotation time of 0.6 s. MDCT scans were reviewed by two chest radiologists (HSH and CAY) with respectively 5 and 11 years of experience, and final conclusions were reached by consensus. The lungs were divided into six segments (right upper, middle and lower lobes; the left upper lobe; the lingular segment; and the left lower lobe) and each lobe or segment was evaluated for the presence or absence of bronchiectasis, bronchioloectasis and bronchiolitis (evidenced by the presence of centrilobular nodules and a tree-in-bud appearance).8
METHODS We reviewed the Marfan database and gathered data on 84 consecutive adult patients aged 720 years who HSH and CAY contributed equally to this work.
Correspondence to: Won-Jung Koh, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea. Tel: (þ82) 2 3410 3429. Fax: (þ82) 2 3410 3849. e-mail: [email protected] Article submitted 17 October 2013. Final version accepted 26 March 2014.
996
The International Journal of Tuberculosis and Lung Disease
Table 79)
Characteristics of patients with Marfan syndrome (n ¼ n (%)
Male sex
47 (60)
Age, years, median [IQR]
38 [31-45]
Smoking status: current or ex-smoker
16 (20)
History of pulmonary tuberculosis CT findings*
4 (5)
frequently involved only a single lobe. Bronchiolitis was present in only three patients (4%), with underlying bronchiectasis or bronchioloectasis. Bronchiectasis or bronchioloectasis was commonly seen in addition to convexity of the aorta, a thoracic cage deformity, cardiomegaly or fibrotic sequelae of TB (Figure).
Bronchiectasis Single lobe/multi-lobe
22 (28) 14/8
DISCUSSION
Bronchioloectasis Single lobe/multi-lobe
10 (13) 7/3
This is the first study to evaluate the prevalence of bronchiectasis in MFS patients with the aid of chest CT images. Plain CXR is inadequately sensitive when used to diagnose bronchiectasis, but CT detects airway abnormalities characteristic of the condition.8 We found that the prevalence of airway dilation caused by bronchiectasis (28%) or bronchioloectasis (13%) was higher than in a previous study employing CXR,5 although the extent of airway dilation was not severe and dilation was frequently confined to a single lobe. In addition, bronchiolitis, suggestive of a combined mycobacterial infection, was uncommon (4% of patients). NTM were cultured from only one patient and the infection was considered to be clinically insignificant. Thoracic abnormalities, including pectus excavatum, scoliosis and mitral valve prolapse, are frequently noted in patients with NTM lung disease.1,2 Such patients have therefore been considered to have a low-level form of MFS.3 MFS is caused by mutation
Bronchiolitis with bronchiectasis or bronchioloectasis
3 (4)
* Lungs were divided into six regions (right upper, middle and lower lobes; left upper lobe; lingular segment; and left lower lobe). IQR ¼ interquartile range; CT ¼computed tomography.
RESULTS A total of 79 patients (47 males and 32 females; median age 38 years, interquartile range [IQR] 3145) with MFS were included in the present study (Table). Four patients (5%) had previous histories of treatment of pulmonary tuberculosis (PTB). During the median follow-up of 65 months (IQR 47-122), one patient was diagnosed with culture-confirmed PTB and one had culture-positive but smear-negative sputum for an NTM. CT findings are summarised in the Table. Of the 79 MFS patients, bronchiectasis was evident in 22 (28%) and bronchioloectasis in 10 (13%); airway dilation
Figure A 27-year-old woman with Marfan syndrome and a severe thoracic cage deformity. Computed tomography revealed bronchiectasis in the right middle and lower lobes in regions adjacent to the displaced descending aorta in the narrow thoracic cage (arrow). A small amount of pneumothorax (arrowhead) was evident in the left hemithorax.
Bronchiectasis and Marfan syndrome
in the FBN-1 gene, causing tissue levels of transforming growth factor-beta (TGF-b) to become elevated. Such high levels are the core feature of MFS pathogenesis.4 A recent study found that the TGF-b expression level was increased in patients with NTM lung disease.9 In addition, NTM lung disease was described in an adult patient with congenital contractual arachnodactyly,10 an autosomal-dominant disorder caused by mutation gene encoding fibrilline2 (FBN-2); the phenotype of the condition overlaps with that of MFS. It was suggested that mutation in the fibrilline-encoding gene was associated with abnormal TGF-b metabolism and increased susceptibility to NTM infection.10 A possible association between MFS and the nodular bronchiectatic form of NTM lung disease was therefore worthy of investigation. We failed to find convincing evidence that NTM lung disease was common in a large cohort of MFS patients, although we frequently identified bronchiectasis and bronchioloectasis in such patients. However, we evaluated CT scans taken at the time of referral to our hospital; follow-up CT scans were not available for many patients and sputum testing for NTM was not routinely performed. As the median age of our patients was only 38 years, long-term follow-up would be useful to evaluate the possible association between MFS and the nodular bronchiectatic form of NTM lung disease, as NTM lung disease is most common among elderly individuals. Acknowledgements This study was supported by a grant from the Korean Health
997
Technology R&D Project, Ministry for Health & Welfare, Seoul, Republic of Korea (A120647). Conflict of interest: none declared.
References 1 Kim R D, Greenberg D E, Ehrmantraut M E, et al. Pulmonary non-tuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome. Am J Respir Crit Care Med 2008; 178: 1066-1074. 2 Kartalija M, Ovrutsky A R, Bryan C L, et al. Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes. Am J Respir Crit Care Med 2013; 187: 197-205. 3 Chan E D, Iseman M D. Underlying host risk factors for nontuberculous mycobacterial lung disease. Semin Respir Crit Care Med 2013; 34: 110-123. 4 Judge D P, Dietz H C. Marfan’s syndrome. Lancet 2005; 366: 1965-1976. 5 Wood J R, Bellamy D, Child A H, Citron K M. Pulmonary disease in patients with Marfan syndrome. Thorax 1984; 39: 780-784. 6 Sohn G H, Jang S Y, Moon J R, et al. The usefulness of multidetector computed tomographic angiography for the diagnosis of Marfan syndrome by Ghent criteria. Int J Cardiovasc Imaging 2011; 27: 679-688. 7 Yang J H, Han H, Jang S Y, et al. A comparison of the Ghent and revised Ghent nosologies for the diagnosis of Marfan syndrome in an adult Korean population. Am J Med Genet A 2012; 158A: 989-995. 8 Bonavita J, Naidich D P. Imaging of bronchiectasis. Clin Chest Med 2012; 33: 233-248. 9 Ovrutsky A R, Merkel P A, Schonteich E, et al. Patients with non-tuberculous mycobacterial lung disease have elevated transforming growth factor-beta following ex vivo stimulation of blood with live Mycobacterium intracellulare. Scand J Infect Dis 2013; 45: 711-714. 10 Paulson M L, Olivier K N, Holland S M. Pulmonary nontuberculous mycobacterial infection in congenital contractural arachnodactyly. Int J Tuberc Lung Dis 2012; 16: 561-563.
Bronchiectasis and Marfan syndrome
i
RESUME
Une association a e´ t´e sugg´er´ee entre le syndrome de Marfan (MFS) et la forme bronchectasique nodulaire de la maladie pulmonaire due a` des mycobact´eries nontuberculeuses (NTM). Nous avons e´ valu´e la pr´evalence des bronchectasies chez 79 patients adultes porteurs de MFS grace ˆ a` une imagerie en tomodensitom´etrie. Une dilatation des voies ae´ riennes indiquant une
bronchectasie (22/79, 28%) et les bronchectasies proprement dites (10/79, 13%) e´ taient relativement fr´equentes, bien que le degr´e de dilatation ne fut ˆ pas grave et fr´equemment limit´e a` un seul lobe. Cependant, une bronchiolite n’´etait e´ vidente que chez trois patients (4%) et aucun n’a eu un diagnostic de maladie pulmonaire a` NTM. RESUMEN
Se ha comunicado una asociacion ´ entre el s´ındrome de Marfa´ n (MFS) y la enfermedad nodular con bronquiectasias causada por las micobacterias at´ıpicas (NTM). Se evaluo´ la prevalencia de bronquiectasias en 79 pacientes adultos con MFS, mediante la tomograf´ıa axial computarizada. Se observo´ con relativa frecuencia la presencia de dilataciones de las v´ıas respiratorias
indicativas de bronquiectasias (22/79 pacientes, 28%) y de ectasia bronquiolar (10/79, 13%), pero la amplitud de la dilatacion ´ no era grave y las lesiones sol´ıan circunscribirse a un lobulo. ´ Sin embargo, solo se encontro´ bronquiolitis en tres pacientes (4%) y en ningun ´ caso se diagnostico´ micobacteriosis pulmonar por NTM.
INT J TUBERC LUNG DIS 18(8):995–997 Q 2014 The Union http://dx.doi.org/10.5588/ijtld.13.0763 E-published ahead of print 27 May 2014
The prevalence of bronchiectasis in patients with Marfan syndrome H. S. Hwang,* C. A. Yi,* H. Yoo,† J. H. Yang,‡ D-K. Kim,‡ W-J. Koh† *Department of Radiology, †Division of Pulmonary and Critical Care Medicine and ‡Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea SUMMARY
An association has been suggested between Marfan syndrome (MFS) and the nodular bronchiectatic form of lung disease caused by non-tuberculous mycobacteria (NTM). We evaluated the prevalence of bronchiectasis in 79 adult patients with MFS using computed tomography (CT) imaging. Airway dilation indicative of bronchiectasis (22/79, 28%) and bronchioloectasis
(10/79, 13%) were relatively common, although the extent of dilation was not severe and was frequently confined to a single lobe. However, bronchiolitis was evident in only three patients (4%), and no patient was diagnosed with NTM lung disease. K E Y W O R D S : bronchiectasis; Marfan syndrome; nontuberculous mycobacteria
LUNG DISEASE caused by non-tuberculous mycobacteria (NTM) has been increasingly noted in elderly women with bronchiectasis, a nodular bronchiectatic form of NTM lung disease. Such patients have a distinct body morphotype, including a thin body habitus, scoliosis, pectus excavatum and mitral valve prolapse.1,2 Such individuals are often described as having Marfanoid features.3 Marfan syndrome (MFS) is an autosomal-dominant systemic disorder of connective tissue caused by the mutation of the gene encoding the extracellular matrix protein fibrillin-1 (FBN-1).4 The lungs are uncommonly involved, the most common manifestations being the development of spontaneous pneumothorax and apical blebs.4 Any association between bronchiectasis and MFS remains unclear. A previous examination of chest radiographs (CXR) of 100 MFS patients showed that only two had bronchiectasis.5 The aim of the present study was to analyse the prevalence of bronchiectasis in a cohort of MFS patients using multidetector computed tomographic (MDCT) angiographic imaging.6,7
were treated between January 1995 and June 2010 at the Marfan Clinic of Samsung Medical Center, Seoul, Korea.6,7 All patients were of Korean origin, and 30 (35.7%) had a family history of MFS.7 As all patients fulfilled the revised Ghent nosological diagnostic criteria for MFS, our patients were deemed to have MFS rather than Marfanoid features.6,7 Seventy-nine patients diagnosed with MFS underwent MDCT angiography and were examined for airway disease. This study protocol was approved by the institutional review board of the Samsung Medical Center, Seoul, Korea. Informed consent was waived due to the retrospective nature of the study. MDCT angiography was performed using a 64slice scanner (Aquilion 64; Toshiba Medical Systems, Tokyo, Japan). The scanning parameters were 120 kV; automatic exposure control (min: 150 mA, max: 400 mA) at a fixed noise index of 8 HU; collimation of 64 3 0.5 mm; increment of 0.4 mm; a pitch of 0.828; and a tube rotation time of 0.6 s. MDCT scans were reviewed by two chest radiologists (HSH and CAY) with respectively 5 and 11 years of experience, and final conclusions were reached by consensus. The lungs were divided into six segments (right upper, middle and lower lobes; the left upper lobe; the lingular segment; and the left lower lobe) and each lobe or segment was evaluated for the presence or absence of bronchiectasis, bronchioloectasis and bronchiolitis (evidenced by the presence of centrilobular nodules and a tree-in-bud appearance).8
METHODS We reviewed the Marfan database and gathered data on 84 consecutive adult patients aged 720 years who HSH and CAY contributed equally to this work.
Correspondence to: Won-Jung Koh, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea. Tel: (þ82) 2 3410 3429. Fax: (þ82) 2 3410 3849. e-mail: [email protected] Article submitted 17 October 2013. Final version accepted 26 March 2014.
996
The International Journal of Tuberculosis and Lung Disease
Table 79)
Characteristics of patients with Marfan syndrome (n ¼ n (%)
Male sex
47 (60)
Age, years, median [IQR]
38 [31-45]
Smoking status: current or ex-smoker
16 (20)
History of pulmonary tuberculosis CT findings*
4 (5)
frequently involved only a single lobe. Bronchiolitis was present in only three patients (4%), with underlying bronchiectasis or bronchioloectasis. Bronchiectasis or bronchioloectasis was commonly seen in addition to convexity of the aorta, a thoracic cage deformity, cardiomegaly or fibrotic sequelae of TB (Figure).
Bronchiectasis Single lobe/multi-lobe
22 (28) 14/8
DISCUSSION
Bronchioloectasis Single lobe/multi-lobe
10 (13) 7/3
This is the first study to evaluate the prevalence of bronchiectasis in MFS patients with the aid of chest CT images. Plain CXR is inadequately sensitive when used to diagnose bronchiectasis, but CT detects airway abnormalities characteristic of the condition.8 We found that the prevalence of airway dilation caused by bronchiectasis (28%) or bronchioloectasis (13%) was higher than in a previous study employing CXR,5 although the extent of airway dilation was not severe and dilation was frequently confined to a single lobe. In addition, bronchiolitis, suggestive of a combined mycobacterial infection, was uncommon (4% of patients). NTM were cultured from only one patient and the infection was considered to be clinically insignificant. Thoracic abnormalities, including pectus excavatum, scoliosis and mitral valve prolapse, are frequently noted in patients with NTM lung disease.1,2 Such patients have therefore been considered to have a low-level form of MFS.3 MFS is caused by mutation
Bronchiolitis with bronchiectasis or bronchioloectasis
3 (4)
* Lungs were divided into six regions (right upper, middle and lower lobes; left upper lobe; lingular segment; and left lower lobe). IQR ¼ interquartile range; CT ¼computed tomography.
RESULTS A total of 79 patients (47 males and 32 females; median age 38 years, interquartile range [IQR] 3145) with MFS were included in the present study (Table). Four patients (5%) had previous histories of treatment of pulmonary tuberculosis (PTB). During the median follow-up of 65 months (IQR 47-122), one patient was diagnosed with culture-confirmed PTB and one had culture-positive but smear-negative sputum for an NTM. CT findings are summarised in the Table. Of the 79 MFS patients, bronchiectasis was evident in 22 (28%) and bronchioloectasis in 10 (13%); airway dilation
Figure A 27-year-old woman with Marfan syndrome and a severe thoracic cage deformity. Computed tomography revealed bronchiectasis in the right middle and lower lobes in regions adjacent to the displaced descending aorta in the narrow thoracic cage (arrow). A small amount of pneumothorax (arrowhead) was evident in the left hemithorax.
Bronchiectasis and Marfan syndrome
in the FBN-1 gene, causing tissue levels of transforming growth factor-beta (TGF-b) to become elevated. Such high levels are the core feature of MFS pathogenesis.4 A recent study found that the TGF-b expression level was increased in patients with NTM lung disease.9 In addition, NTM lung disease was described in an adult patient with congenital contractual arachnodactyly,10 an autosomal-dominant disorder caused by mutation gene encoding fibrilline2 (FBN-2); the phenotype of the condition overlaps with that of MFS. It was suggested that mutation in the fibrilline-encoding gene was associated with abnormal TGF-b metabolism and increased susceptibility to NTM infection.10 A possible association between MFS and the nodular bronchiectatic form of NTM lung disease was therefore worthy of investigation. We failed to find convincing evidence that NTM lung disease was common in a large cohort of MFS patients, although we frequently identified bronchiectasis and bronchioloectasis in such patients. However, we evaluated CT scans taken at the time of referral to our hospital; follow-up CT scans were not available for many patients and sputum testing for NTM was not routinely performed. As the median age of our patients was only 38 years, long-term follow-up would be useful to evaluate the possible association between MFS and the nodular bronchiectatic form of NTM lung disease, as NTM lung disease is most common among elderly individuals. Acknowledgements This study was supported by a grant from the Korean Health
997
Technology R&D Project, Ministry for Health & Welfare, Seoul, Republic of Korea (A120647). Conflict of interest: none declared.
References 1 Kim R D, Greenberg D E, Ehrmantraut M E, et al. Pulmonary non-tuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome. Am J Respir Crit Care Med 2008; 178: 1066-1074. 2 Kartalija M, Ovrutsky A R, Bryan C L, et al. Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes. Am J Respir Crit Care Med 2013; 187: 197-205. 3 Chan E D, Iseman M D. Underlying host risk factors for nontuberculous mycobacterial lung disease. Semin Respir Crit Care Med 2013; 34: 110-123. 4 Judge D P, Dietz H C. Marfan’s syndrome. Lancet 2005; 366: 1965-1976. 5 Wood J R, Bellamy D, Child A H, Citron K M. Pulmonary disease in patients with Marfan syndrome. Thorax 1984; 39: 780-784. 6 Sohn G H, Jang S Y, Moon J R, et al. The usefulness of multidetector computed tomographic angiography for the diagnosis of Marfan syndrome by Ghent criteria. Int J Cardiovasc Imaging 2011; 27: 679-688. 7 Yang J H, Han H, Jang S Y, et al. A comparison of the Ghent and revised Ghent nosologies for the diagnosis of Marfan syndrome in an adult Korean population. Am J Med Genet A 2012; 158A: 989-995. 8 Bonavita J, Naidich D P. Imaging of bronchiectasis. Clin Chest Med 2012; 33: 233-248. 9 Ovrutsky A R, Merkel P A, Schonteich E, et al. Patients with non-tuberculous mycobacterial lung disease have elevated transforming growth factor-beta following ex vivo stimulation of blood with live Mycobacterium intracellulare. Scand J Infect Dis 2013; 45: 711-714. 10 Paulson M L, Olivier K N, Holland S M. Pulmonary nontuberculous mycobacterial infection in congenital contractural arachnodactyly. Int J Tuberc Lung Dis 2012; 16: 561-563.
Bronchiectasis and Marfan syndrome
i
RESUME
Une association a e´ t´e sugg´er´ee entre le syndrome de Marfan (MFS) et la forme bronchectasique nodulaire de la maladie pulmonaire due a` des mycobact´eries nontuberculeuses (NTM). Nous avons e´ valu´e la pr´evalence des bronchectasies chez 79 patients adultes porteurs de MFS grace ˆ a` une imagerie en tomodensitom´etrie. Une dilatation des voies ae´ riennes indiquant une
bronchectasie (22/79, 28%) et les bronchectasies proprement dites (10/79, 13%) e´ taient relativement fr´equentes, bien que le degr´e de dilatation ne fut ˆ pas grave et fr´equemment limit´e a` un seul lobe. Cependant, une bronchiolite n’´etait e´ vidente que chez trois patients (4%) et aucun n’a eu un diagnostic de maladie pulmonaire a` NTM. RESUMEN
Se ha comunicado una asociacion ´ entre el s´ındrome de Marfa´ n (MFS) y la enfermedad nodular con bronquiectasias causada por las micobacterias at´ıpicas (NTM). Se evaluo´ la prevalencia de bronquiectasias en 79 pacientes adultos con MFS, mediante la tomograf´ıa axial computarizada. Se observo´ con relativa frecuencia la presencia de dilataciones de las v´ıas respiratorias
indicativas de bronquiectasias (22/79 pacientes, 28%) y de ectasia bronquiolar (10/79, 13%), pero la amplitud de la dilatacion ´ no era grave y las lesiones sol´ıan circunscribirse a un lobulo. ´ Sin embargo, solo se encontro´ bronquiolitis en tres pacientes (4%) y en ningun ´ caso se diagnostico´ micobacteriosis pulmonar por NTM.
