Case 1 -
Philip T. Cagle
Baylor College of Medicine
Click on each slide thumbnail image for an enlarged view
The patient was a 16 year old girl who developed a nonproductive cough and intermittent wheezing in
the absence of any viral illness. She failed to respond to antibiotics and bronchodilators and
progressively worsened over three months with severe exertional dyspnea. Pulmonary function tests showed
severe airflow obstruction with no response to bronchodilators:
| PFT ||Initial visit ||1 month ||3 months ||1 year|
|FEV1/FVC ||32% ||37% ||36% ||39%|
She failed to respond to B-agonist inhalation and oral and intravenous theophylline and prednisone.
No evidence of alpha-1-antitrypsin disease, cystic fibrosis or aspiration was found on clinical,
radiologic or serologic evaluations. She had a weakly positive rheumatoid factor, but other work-up for
collagen vascular disease was negative. A clinical diagnosis of bronchiolitis obliterans was made. She
underwent a left thoracotomy and a diagnosis of "consistent with bronchiolitis obliterans" was made. She
required intubation and mechanical ventilation on several occasions and was eventually transferred to The
Methodist Hospital for lung transplantation.
Case 1 - Figure 1 - Gross cut surface of the explanted lung shows scattered small yellow nodules.
Case 1 - Figure 2 - Low power view of a bronchiole with mural infiltrates of foam cells and chronic inflammatory cells with exfoliation of foamy macrophages into the bronchiolar lumen.
Case 1 - Figure 3 - Low power of bronchiole with intramural foam cells.
Case 1 - Figure 7 - Constrictive bronchiolitis with fibrous obliteration of the bronchiolar lumen.
Case 1 - Figure 8 - A tremendous number of foam cells fill the wall of this bronchiole.
The patient underwent transplantation of her heart and both lungs. Case 1 Figure 1 shows the gross
cut surface of one of her native lungs. The remaining figures show microscopic views of sections taken
from her native lungs. Figures 3, 4 and 5 are consecutively higher powers of one lesion.
Diagnosis: Diffuse Panbronchiolitis
The patient was originally diagnosed with xanthomatous bronchiolitis obliterans.  Her
histopathology/clinical features are those of an obstructive or constrictive bronchiolitis due to
accumulation of foamy macrophages. The histopathologic features are suggestive of diffuse
panbronchiolitis (DPB), a disease in which there is inflammation and foam cell infiltration of
bronchioles. As noted below, DPB had not been recognized as arising in non-Japanese patients in North
America at the time of her diagnosis in 1985. A number of pulmonary diseases can have small airway
histopathology that is superficially similar to DPB, including variable inflammation and foam cell
infiltration of bronchioles, and should be considered in the differential diagnosis.
This case of xanthomatous brocnhiolitis obliterans was reported in the Archives
of Pathology and Laboratory Medicine in 1988.  The etiology of this patient's airway
disease was not determined. Detailed studies of blood lipids did not reveal a hyperlipidemia other than
a very mild nonspecific elevation of cholesterol and did not suggest a storage disease. Other underlying
disease such as chronic infection, exposure to fumes, drug history or collagen vascular disease was not
On cut surface, the lungs showed numerous punctate yellow nodules. The histopathology consists of
narrowing of bronchiolar lumens by foamy, lipid-laden macrophages within the walls of bronchioles. Most
of these are membranous (terminal) bronchioles and some of the small bronchi are similarly involved. The
lumens of occasional bronchioles are completely obliterated by mature fibrous scar. The foam cells
occasionally extend into adjacent interstitial spaces. Focal ulceration of bronchiolar and bronchial
mucosa results in exfoliation of lipid-laden macrophages into bronchiolar and bronchial lumens. There is
also extra-cellular lipid material and a lipid/cholesterol pneumonia probably representing a
post-obstructive lipoid pneumonia observed on some slides.
The differential diagnosis for the histopathologic findings in this unusual case includes:
(1) Diffuse pan-bronchiolitis (DPB)
DPB is a distinctive, idiopathic sinobronchial syndrome characterized by progressive obstructive and
suppurative airway disease.
Patients have chronic sinusitis in most cases, dyspnea on
exertion, cough and eventually purulent sputum production, obstructive pattern on pulmonary function
tests, bilateral small nodular opacities on chest x-ray and centrilobular lesions on HRCT. Patients
typically have highly elevated serum cold agglutinins. Most cases occur in Japan, although it has been
increasingly reported in other locations around the world, both in patients of Japanese and non-Japanese
An association with HLA-Bw54 has been reported in Japan and it has been proposed
that HLA alleles or closely linked genes contribute to a genetic predisposition to DPB which may partly
explain why this disorder is found primarily in Asians.
There is a slight male
predominance and patients span a wide age range with a mean of 50 years. Colonization with Haemophilus
influenzae or Pseudomonas aeruginosa is commonly observed and Pseudomonas infection may develop and is
associated with poor prognosis. If untreated, DPB progresses to bronchiectasis and respiratory failure.
Patients often have prolonged survival with chronic low-dose macrolide therapy, presumably as a result of
non-specific anti-inflammatory effects of these antibiotics since they are effective even in the absence
of Pseudomonas or other infection. [26-31] Baz et al  reported recurrence of DPB in
a patient who underwent lung transplantation.
Grossly, the cut surfaces of the lungs show scattered 1 to 4 mm yellow nodules and may show findings
of bronchiectasis and/or pneumonia. DPB is histopathologically characterized by:
lymphoplasmacytic infiltrates throughout the full thickness of the walls of the respiratory
bronchioles and their adjacent alveolar ducts and alveoli.  Involvement of the distal
centrilobular conducting/gas exchange unit in DPB has been called the "PB unit lesion" and is the
defining histopathologic feature of DPB.  Membranous bronchioles may be involved and may be
ectatic. Follicular bronchiolitis, intraluminal acute inflammation, superimposed acute or organizing
pneumonia, post-obstructive lipoid pneumonia and/or bronchiectasis may be present.
- diffuse, bilateral chronic airway inflammation,
- bronchiolocentric, centrilobular chronic interstitial inflammation and
- accumulation of foam cells and
(2) Rheumatoid arthritis-associated bronchiolar disease (RA-BD)/DPB in rheumatoid arthritis
Although rheumatoid factor is often elevated in patients with DPB, relatively few patients have overt
rheumatoid disease. However, several authors have reported DPB lesions in patients with rheumatoid
Hayakawa et al  reported lesions that they referred to as RA-BD.
RA-BD lesions differed from DPB in that:
DPB or pulmonary lesions resembling DPB have also been described in association with microscopic
polyangiitis,  Lambert-Eaton myasthenic syndrome and idiopathic thrombocytopenic
purpura,  ulcerative colitis,  Churg-Strauss syndrome,  Sjogren's
syndrome with malignant thymoma  and thymoma. 
- panbronchiolitis lesions were more common in DPB (68%
- bronchiolar obliteration occurred at more proximal sites in RA-BD,
- long-term macrolide
therapy had less effect in RA-BD and
- HLA-B was more frequent in DPB (50% versus 22.2%)
(3) Human T-cell lymphotropic virus type 1 (HTLV-1)-associated bronchiolitis and DPB
Patients with HTLV-1 have occasionally been reported to have clinical and histopathologic findings of
A study by Kadota et al  compared 15 cases of HTLV-1-associated
bronchiolitis to 43 cases of DPB. HTLV-1-associated bronchiolitis was reported to have histopathologic
features similar to DPB, but HTLV-1-assoicated bronchiolitis had a higher ratio of interleukin-2 receptor
expression in T cells from BAL and did not respond as well to chronic macrolide therapy.
DPB or DPB-like lesions have been reported in patients with adult T-cell leukemia  and
non-Hodgkin's lymphoma. 
(4) Pulmonary diseases with centrilobular interstitial foam cell accumulations
In 1994, Masatoshi Iwata, Tom Colby and Masanori Kitaichi published a classic paper on DPB and
pulmonary diseases with centrilobular interstitial foam cell accumulations.  In this study,
the authors found PB-like lesions in 20 of 1,336 wedge biopsies, resections or autopsies of various lung
diseases that involve airways.
Although histopathologically resembling the PB unit lesions of DPB, the authors observed differences
in their 20 cases and referred to the lesions in these cases as PB-like lesions. Therefore, similar to
our case of xanthomatous bronchiolitis obliterans, these cases resembled DPB but using established
criteria could be differentiated from DPB. Foam cells were found in the walls of alveolar ducts and, to
a lesser extent, respiratory bronchioles. Membranous bronchioles or small bronchi showed the greatest
accumulation of foam cells in cases of constrictive bronchiolitis, follicular bronchiolitis,
bronchiectasis and cystic fibrosis typically associated with lymphoid hyperplasia and scarring. Other
diseases showed focal poorly-developed PB-like lesions or occasional foci of interstitial foam cells
associated with acute inflammation and intraluminal granulation tissue. A summary of these other lung
diseases with PB-like lesions based on Iwata et al  is given below:
(5) Idiopathic bronchiolitis clinically mimicking DPB
Poletti et al
screened all their patients presenting with clinical, pathophysiologic
and radiologic pattern compatible with DPB and found 4 cases of DPB over a ten-year period. They also
found 5 cases of idiopathic bronchiolitis that had clinical symptoms and HCT findings indistinguishable
from those of DPB but lacking the typical histopathologic features of DPB.
(6) Eosinophilic bronchiolitis clinically mimicking DPB
Takayanagi et al  reported a patient who carried a diagnosis of DPB without response to
erythromycin for 3 years. A diagnosis of eosinophilic bronchiolitis was eventually made on wedge biopsy
of the lung tissue.
This case of xanthomatous bronchiolitis obliterans has some clinical, gross and histopathologic
features that suggest a diagnosis of DPB. DPB was first described in Japan in 1969  and
studied in a large nation-wide survey in Japan in 1983  but was not recognized in North
American patients until several years later.  Our patient underwent lung transplant and was
diagnosed with xanthomatous bronchiolitis obliterans in 1985, a number of years before the disease was
recognized as occurring in North America. Although treatment of patients with macrolide antibiotics for
infections began in 1983, Kudoh et al reported that chronic low-dose macrolide antibiotic
therapy improved the course of DPB through mechanisms not related to treatment of infection. Therefore,
it is not surprising that our patient did not receive macrolide therapy even if a diagnosis of DPB had
been suspected in 1985.
This patient did not have any of the conditions mentioned above that are associated with PB-like
lesions. Indeed, the accumulation of foamy macrophages in bronchiolar walls is very dramatic in some of
the bronchioles in sections of her lung tissue and would not likely represent the more modest foam cell
accumulations secondary to other conditions.
This case may be best considered a variant of classic DPB. In addition to an absence of some of the
expected clinical features, this case differs from classic DPB in that:
These differences may be related to the short course of the disease in a young patient, since
most studied cases represent long-standing disease in middle-aged to older adults. Disease variations
due to geoethnic differences may also be factors.
- The membranous bronchioles and
small airways are more involved by the foam cell infiltrates than expected in DPB and
- The relative
amount of both mural chronic inflammation and intra-luminal acute inflammation are less than is typical
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