Diffuse panbronchiolitis: not just an Asian disease: Australian case series and review of the literature
1Department of Medical Imaging, John Hunter Hospital, Newcastle, Australia
2Department of Respiratory Medicine, John Hunter Hospital, Newcastle, Australia
Diffuse panbronchiolitis is a disease of obscure aetiology
that is traditionally associated with Asian ethnicity. We propose that this
disease also occurs in Caucasians and the incidence in this population is
greater than currently recognised. We further propose that high resolution
computed tomography (HRCT) and response to macrolide therapy should be relied
upon to make this diagnosis without verification by lung biopsy. In most circumstances,
obtaining a biopsy for histopathology is not practical, and the disease may
then be mistaken for other more common airway diseases. Accuracy of diagnosis
is important as untreated disease is associated with a poor prognosis, and
effective treatment is available. We report four out of a series of cases as
evidence that DPB is in fact more common in the Western population than is
currently understood. � 2009 Biomedical Imaging and Intervention Journal.
All rights reserved.
Keywords: Diffuse panbronchiolitis; high resolution computed
tomography; small airways disease; erythromycin; macrolide
First described in 1969, diffuse panbronchiolitis (DPB) is
a chronic inflammatory disease of the distal airways [1,2]. Patients present
with a history of cough, large volume sputum production similar to
bronchiectasis, exertional dyspnoea, and chronic sinusitis. Physical signs
include rales and rhonchi. Lung function tests demonstrate a mixed
obstructive/restrictive pattern. Chest radiograph features may be non-specific,
with the presence of ill-defined small nodular shadows, hyperinflation, and in
later stages, bronchiectasis. HRCT features classically include small
centrilobular nodules and branching linear opacities � the �tree-in-bud� (TIB)
appearance. Treatment consists of macrolide antibiotic in low dosage for 3 to 6
A 64-year-old Caucasian female non-smoker presented in
June 2004 with a 20-year history of non-productive cough. There was no
significant past medical or exposure history. Previous therapeutic trials of a
combination inhaler containing budesonide and efermoterol, and omeprazole had
Clinical examination, spirometry and flow volume loop were
normal. Forced expiratory volume in 1 second (FEV1) was 96% predicted, and
forced vital capacity (FVC) was 125% predicted. A bronchial provocation with
hypertonic saline challenge revealed a PD20 greater than 20 milli-litres (normal).
Serum immunoglobulin levels were normal.
HRCT demonstrated mild bronchiectasis in the lower lobes,
and diffuse centrilobular nodules. There was a scattered TIB appearance.
There was complete resolution of symptoms when treated
with erythromycin 250mg twice daily for three months.
A 16-year-old Caucasian Australian-born boy presented in
March 2004 with a chronic cough productive of yellow sputum. The cough began in
early childhood and was initially intermittent but became more severe and
persistent around the age of 11 years. There was no associated wheeze or
breathlessness. The severity of the cough gradually increased. His symptoms
were attributed to asthma and he received asthma therapy including intermittent
oral steroids without benefit for several years. There was no history of
smoking, dust nor fume exposure.
He had a barrel chest, and had widespread bilateral
crackles. There were no signs of pulmonary hypertension, and no clubbing.
Spirometry showed mixed restrictive and obstructive change
with an FEV1/FVC of 2.4/3.34 litres without acute reversibility (predicted
3.93/4.26). Sputum cultures grew haemophilus influenzae. No acid fast
bacili was grown from repeated sputum cultures. There was a mild elevation in
white cell count, but other blood tests were normal.
HRCT demonstrated bilateral bronchiectasis, and diffuse
centrilobular nodules predominantly affecting the mid and lower zones. There
was diffuse TIB appearance.
No improvement in symptoms resulted when treated with
augmentin. A 6-week trial of erythromycin 250mg twice daily led to resolution
of symptoms. There was an approximately 80% clearance of the above-mentioned
HRCT findings on repeat examination. Spirometry improved to an FEV1/FVC of
A 65-year-old Caucasian Australian-born man presented in
October 2004 with a 6-year history of cough productive of mucoid sputum,
wheeze, breathlessness and worsening pan-sinusitis. There was a history of hay
fever and gastro-oesophageal reflux. He had experienced short-term improvement
with a number of courses of antibiotics relapsing after each was complete.
There was no history of smoking, occupational dust or fume exposure. Presenting
symptoms had been attributed to asthma but had not responded to asthma therapy.
Clinical examination revealed generalised wheezing, but no
other abnormality was detected.
Spirometry showed mild airflow obstruction with
improvement post bronchodilator. FEV1/FVC pre bronchodilator 1.96/3.0 litres,
and 2.28/3.82 litres post bronchodilator (predicted 2.85/3.64 litres).
HRCT demonstrated mild basal bronchiectasis and basal TIB.
There was an improvement in spirometry (FEV1/FVC =
2.68/3.75 without bronchodilator response) and complete resolution of his
symptoms after a 3-month course of erythromycin 250mg twice daily.
A 73-year-old Caucasian Australian-born woman presented in
August 2003 with 6 months of cough productive of mucopurulent sputum, but no
systemic symptoms. There was no significant past medical history, and no
history of environmental exposures or of smoking. The cough had not responded
to several courses of oral antibiotics including ciprofloxacin.
Clinical examination and spirometry was normal (FEV1 129 %
predicted, FVC 130% predicted). Sputum cultures grew Pseudomonas aeruginosa
and Mycobacterium avium complex (MAC) in 1 out of 3 samples.
Bronchoscopic samples grew Pseudomonas aeruginosa only. There was no
The chest x-ray demonstrated changes of right middle and
lower lobe bronchiectasis and large lung volumes. HRCT showed bronchiectasis in
the middle and lower lobes, and some atelectasis. There were diffuse
centrilobular nodules. The left lower lobe also demonstrated TIB appearance.���������
A 2-week course of ciprofloxacin and prednisone did not
improve her symptoms. A 3-month course of erythromycin 250mg twice daily led to
resolution of her cough.
DPB is a chronic inflammatory disease of obscure aetiology
affecting the distal airways, predominantly at the transition zone between the
respiratory bronchioles and alveoli [1,2].
The disease typically occurs in the 2nd to 5th
decade of life (average onset 40 years). The male: female ratio is 1.4:2.1.
Two-thirds of patients are non-smokers and patients have no particular history
of inhalation of toxic fumes . Whilst initially almost exclusively reported
in Japan  there have now been sporadic cases reported in every continent
. The pathogenesis is still unclear, and thought to be related to both genetic
and environmental factors. Sugiyama et al.  showed that 63% of
patients possessed the HLA-Bw54 antigen. She et al. demonstrated
increased frequency of class I HLA-A11. HLA-associated major histocompatibility
genes are thought to be located in the HLA class I region between the HLA-A and
HLA-B loci on chromosome 6p21.3 [6, 7].
DPB is often confused with other airway diseases characterised
by chronic productive cough , including bronchiectasis, chronic bronchitis,
and cystic fibrosis . Due to this confusion and the importance of an
accurate diagnosis, the diagnosis of DPB has often relied upon histopathologic
confirmation. Pathologic criteria include 1) diffuse, bilateral, chronic
inflammatory airway disease; 2) predominant involvement of the walls of
respiratory bronchioles and adjacent centrilobular regions; and 3) interstitial
accumulation of foamy macrophages . Typical features seen include
thickening of the walls of the respiratory bronchioles, transmural and
peribronchial infiltration by lymphocytes, plasma cells, and histocytes . The
inflammatory infiltrate destroys the bronchiolar epithelium and extends to
peribronchiolar spaces, but most of the alveoli are unaffected . The
characteristic �unit lesion� of DPB described by Kitaichi 
incorporates some of these features, and is considered to histologically
distinguish DPB from a number of other entities including chronic bronchitis,
cystic fibrosis, Mycoplasma pneumonia and cryptogenic organising pneumonia
There are obvious restraints in the ability to always
obtain a biopsy for diagnosis and an increasing reliance on clinical and radiologic
findings should be encouraged. A plain chest X-Ray (CXR) reveals bilateral,
diffuse, small (<5mm) nodular shadows predominantly in the lower field of
the lung with hyperinflation. In advanced cases, ring-shaped or tram-line
shadows appear, indicating bronchiectasis.
By contrast, the HRCT features of diffuse panbronchiolitis
� given the appropriate clinical setting � can be near pathognomonic , and
are more representative of the pathologic process . In advanced stages,
multiple cystic lesions predominate in the lower lung fields and are
accompanied by dilated proximal bronchi showing the appearance of extensive
bronchiectasis. These findings extend from the respiratory bronchioles to the
proximal airways . Nodular shadows are distributed in a centrilobular
fashion, often extending to small, branching linear areas of attenuation (�TIB�
pattern). Peripheral air trapping is usually confirmed in expiratory films.
Dilatation of airways and bronchial wall thickening are present. Mosaic
oligoemia is usually absent .
The natural history of DPB is progressive respiratory
failure marked by chronic and/or frequent episodes of superimposed bacterial
infection. The capacity for gas exchange is reduced, which causes progression
of hypoxaemia, and later, hypercapnia. Pulmonary hypertension develops and is
associated with the development of cor pulmonale and ultimately death within 5
years for up to 20% of patients . However, the cases described above may
lead to the conclusion that the disease is less severe in Caucasians . These
patients had persistent symptoms for several years without serious impairment
of lung function.
Appropriate management with a low-dose macrolide
antibiotic such as erythromycin (200-600mg daily), is well recognised to
significantly alter the course of the disease , resulting in improved
symptoms and pulmonary function tests, reduced hypoxaemia, improved radiographic
appearances, and usually cure and improved survival . It has been found
that both serum and sputum erythromycin levels with treatment are actually
below the minimum inhibitory concentration for the common superinfecting
organisms, and it is postulated that the mechanism of action of erythromycin is
related to anti-inflammatory and immunomodulatory effects [20, 21], rather than
to its antimicrobial properties .
Nishimaki et al. propose that anti-inflammatory
effects, including the inhibition of GM-CSF production from monocytes, lung
fibroblasts and bronchial epithelial cells and the acceleration of neutrophil
apoptosis by the action of macrolide therapy, is what leads to improved
survival . Studies show an interference with neutrophil chemotaxis by
erythromycin, and resultant lower neutrophil levels in broncho-alveolar lavage
fluid samples. In addition, macrolides reduce the presence of activated
T-lymphocytes at the site of inflammation, promoting T-cell apoptosis via the
down-regulation of anti-apoptotic Bcl-2 protein family in DPB which are present
in high levels in such patients .
A lack of familiarity with the diagnosis of DPB in Western
countries has led to under-diagnosis and failure to treat such cases [25, 26].
In view of the dramatic effectiveness of treatment, and that the treatment
itself is very specific, the diagnostic features of DPB need to be recognised
early. Fitzgerald et al.  suggest that if the appropriate clinical,
physiologic, and radiological features are present, then lung biopsy is usually
unnecessary, and a therapeutic trial of a macrolide antibiotic is appropriate.
The reported cases illustrate that this approach is successful. These cases
also highlight that, in Caucasians, the disease may be less severe. However,
treatment can lead to symptom control. Improved awareness of the disease should
lead to higher rates of diagnosis and, therefore, improved treatment of such
- DPB ����� diffuse panbronchiolitis
- HRCT��� high resolution computed tomography
- TIB�������� tree in bud
- FEV1����� forced expiratory volume in 1 second
- FVC ������ forced vital capacity
- CXR������ chest X-Ray
Figure 1 HRCT images of the lower chest in a 16 year-old boy (Case 2) at presentation (A), and 8 weeks later after a 6-week course of erythromycin 250mg twice daily. The bilateral bronchiectasis and prominent centri-lobular nodules with a tree-in-bud pattern shows marked improvement on the follow-up scan.
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|Received 5 April 2009; received in revised form 1 May 2009;
accepted 1 May 2009
Correspondence: John Hunter Hospital, Lookout Rd, New Lambton, NSW Australia. E-mail: Please contact Managing Editor
Please cite as: Anthony M-P, Singham S, Soans B, Tyler G,
Diffuse panbronchiolitis: not just an Asian disease: Australian case series and review of the literature, Biomed Imaging Interv J 2009; 5(4):e19