Interstitial Lung Disease Other than UIP
Moderators: Brian Chiu and William D. Travis
Section 5 -
Hypersensitivity Pneumonitis – Recently Recognized Variants
Armando E. Fraire
University of Massachusetts
Worcester, MA, USA
"The throat, lungs and eyes are keenly aware of serious damage" wrote Ramazzini in the early 1700's,
calling attention to a malady affecting grain sifters in his native Italy. Nearly a century later
Palsson, in Iceland described debilitating fevers, cough and shortness of breath in "those who work with
badly harvested moldy hay". These are but two of early seminal observations that in present day
terminology would be regarded as hypersensitivity states, attributable to work place conditions. As the
Academy approaches its 100th anniversary it is fitting to acknowledge contributions made by
such early workers, and others who more recently (Campbell, Pepys, Higgins) have made significant
contributions that expand our understanding of hypersensitivity reactions affecting the lungs.
Offending agents currently known to affect individuals in and outside the work place are legion. They
include the common place (bird feathers, excreta) as well as the esoteric (cork dust mold, animal pelts,
bat droppings). Recent years have seen "newer" forms of hypersensitivity states and by now there may
well be over 200 reported agents capable of eliciting pulmonary hypersensitivity. This brief review is
primarily focused on 3 relatively new ( variants of the old ? ) hypersensitivity states, which are
colloquially known as popcorn workers lung, nylon flock lung and hot tub lung and secondarily to one
recently recognized but less well known pulmonary condition: respiratory disease associated with
exposure to metal working fluid. The mechanism of injury to the lung in these conditions is poorly
understood but in some instances, in addition to hypersensitivity there may be an associated non
allergic, irritant mediated response to inhaled agents. In the case of popcorn lung, the evidence for
hypersensitivity is limited, resting primarily on the occurrence of epithelioid granulomas in some of the
patients. In the case of hot tub lung, the role of direct infection with mycobacteria versus
hypersensitivity has not been completely elucidated. In the case of flock lung and metal-working fluid
exposure, the role of hypersensitivity is well supported by available clinical and histopathological
Respiratory Disease Related to Metal Working Fluids
Initial knowledge on this condition is derived primarily from
work by Bernstein and associates and subsequent reports by Kreiss and Cox-Gaenser. A typical
presentation is exemplified in the following case reported by Becket et al. The patient, a man in his
50's, had operated for several years a machine that cut metal parts, continuously lubricated by a metal
working fluid (MWF) that was collected and recycled through large tanks holding more than 1,000 gallons
of fluid. His initial symptoms consisted of dyspnea, cough and fatigue. He was afebrile and had no
digital clubbing. A chest radiograph showed bilateral increased interstitial markings, and he was
treated empirically with antibiotics. Symptoms were worse after work, and occupational asthma was
suspected, but a trial with bronchodilators was not effective in relieving symptoms. Later, a
thin-section CT scan of the chest showed "ground glass" opacities indicating interstitial lung disease
and mild bronchiectasis. Bronchoalveolar lavage showed 90% lymphocytes with a negative smear and culture
for mycobacteria and fungi. A transbronchial lung biopsy showed interstitial chronic inflammation and
epithelioid cells suggestive of granulomas with negative stains for acid-fast bacilli and fungi.
MWF's are widely used, particularly in the automotive industry. MWFs are fluids used during machining
and grinding of metal parts to prolong the life of the tool, carry away metal chips and other machining
debris, and to protect the surface of work pieces. These fluids reduce friction between the cutting tool
and the work piece, reduce wear, and dissipate heat generated by the machining process. In the US alone
more than a million workers are potentially exposed. While there is no doubt MWF exert an adverse effect
on human airways, there is little data concerning dose-effect relationships. The histopathology of the
case above described and others in the literature does suggest a hypersensitivity
type of reaction to MWF fluids. Bona fide cases of occupational asthma have also been reported in
A 46 year old woman employed for 18 months at a US microwave popcorn production plant developed
shortness of breath and cough. A CT scan of the chest showed pulmonary interstitial changes. A
thoracoscopic lung biopsy showed focal bronchiolar fibrosis and fibroblastic proliferation compressing
bronchiolar lumina consistent with constrictive bronchiolitis. She did not respond to steroids but
showed symptomatic relief to a 3 month course of cyclophosphamide. Later, she was accepted for a lung
transplant. In May 2000, the above cited index patient and seven other former workers at the microwave
popcorn production plant were recognized as having clinical evidence of severe bronchiolitis obliterans.
All but one of the eight workers were non-smokers. The suspected offending agent appeared to be a work
What is the responsible agent(s) for the airway damage ? As
noted below, non-necrotizing granulomas have been described in lung tissues of popcorn workers disease
suggesting a possible role of hypersensitivity. However, more obvious agents responsible for the disease
are the vapors of butter flavoring employed in the manufacturing of
popcorn. To test the hypothesis that these vapors are noxious agents to the lung, Hubbs and associates
exposed rats to heated butter flavorings. Rats were exposed for 6 hours by inhalation and autopsied a
day later. By gas chromatography, the vapors had major peaks corresponding to diacetyl (2,3
butanedione), acetic acid, acetone and butiryc acid. In the lung, vapors containing containing 285-370
ppm diacetyl caused multifocal necrotizing bronchiolitis.
How is the diagnosis made ? Clearly, history of current or
past exposure to vapors of butter flavoring is critical. Most cases reported thus far have been
diagnosed as bronchiolitis on basis of clinical, spirometric and radiographic findings. Histopathologic
responses described thus far include 1) non necrotizing granulomas, 2) constrictive bronchiolitis and 3)
focal bronchiolar fibrosis and fibroblastic proliferation compressing bronchiolar lumina. The case
illustrated in this session (contributed by Bill Travis) showed findings of constrictive bronchiolitis.
Overall, the evidence suggests a toxic effect of diacetyl but an element of hypersensitivity has not been ruled out.
A 26 year old man first presented with increasing shortness of
breath associated and a persistent dry cough. His O2 saturation at rest was 97% but decreased
to 93% upon walking 1200 ft in 5 minutes. The chest X ray showed patchy densities bilaterally in the
upper lung fields. A high resolution CT of the chest showed a pattern consistent with bronchiolitis,
most prominent in the upper lobes. The clinical differential diagnoses included hypersensitivity
pneumonitis, bronchial asthma, idiopathic interstitial pneumonitis and an infectious process. He was a
machine operator at a Massachusetts synthetic flock factory and was primarily responsible for mixing and
loading machines with raw flock material. He denied smoking or family history of tuberculosis. Therapy
with a short course of prednisone provided only temporary relief of his symptoms. An open, video
assisted open lung biopsy was performed.
Kern and associates first called attention to the occurrence
of chronic interstitial lung disease among workers in the nylon flocking industry. Flocking is a
process in which continuous synthetic fibers (mainly nylon) are chopped into short segments and then
applied to an adhesive-coated backing fabric to produce a plush finish such as in fabrics used to
upholster seating in the automotive industry. Although the cut fibers, or flock, are of non-respirable
size, smaller respirable nylon shards may be produced during processing Two other men employed at a
nylon flocking plant in Rhode Island developed interstitial lung disease of unknown etiology. This led
to identification of four additional cases for a total of seven cases. In six of seven patients who had
a biopsy, a picture of non specific interstitial pneumonitis was noted. The seventh had bronchiolitis
obliterans organizing pneumonia. All seven had peribronchovascular interstitial lymphoid nodules, some
with germinal centers and most had lymphocytic bronchiolitis and interstitial fibrosis.
To investigate the problem, the National Institute of Occupational Safety and Health
(NIOSH) Branch of the Centers for Disease Control hosted a clinical-pathological workshop to review
additional accumulated case load of patients with interstitial lung disease associated with the flocking
industry. In all, biopsies from fifteen patients (eight open, seven transbronchial) were reviewed at the
workshop by a panel of pathologists led by Tom Colby. In this group of flock workers, the main
histopathologic findings was a peribronchiolar lymphocytic interstitial inflammation with associated
lymphoid hyperplasia, a finding that is most consistent with hypersensitivity pneumonitis. The
histopathologic features in the group of 15 cases were classified as prominent or variable. Prominent features included peribronchiolar lymphocyte hyperplasia; bronchiolar
mural lymphocytic inflammation and peribronchiolar alveolar macrophages. Variable
features included Type II hyperplasia; non-lymphocytic interstitial inflammatory cells,
bronchiolar mural fibrosis and organizing air space processes such as BOOP. Despite the absence of
granulomas these histopathologic changes suggest hypersensitivity.
Hot Tub Lung
Although more recreational than occupational, hot tub lung use was included as one of "top ten
conditions in occupational pulmonary diseases" for 2004. Hot tub lung is but one of several hazards that
have been linked to hot tub bathing. Other hazards are pseudomonas folliculitis, reactive airways
dysfunction syndrome secondary to water bromination and hypersensitivity to cladosporium and other fungal
and bacterial agents. As presently understood however, the term hot tub lung is commonly reserved for
cases of hypersensitivity associated with non tuberculous mycobacteria of the M. avium complex (MAC)
occurring in hot tub users. Less typical cases occur in individuals exposed to contaminated household
water and in one instance, contaminated water in a steam iron water
reservoir. An unusual case of hot tub lung recently seen at our institution was reported by
Angelis and associates as "Hot tub lung sine Hot tub". This occurred in a
52 year man with a preexisting bronchogenic cyst containing MAC organisms. We believe the cyst acted as
an internal or "built in" reservoir for mycobacteria in a sauna-like fashion similar to that resulting
from bathing in external hot tubs. Whether hot tub lung is secondary to infection with MAC or
hypersensitivity to MAC is a matter of much discussion and it may well be that both mechanisms may be
operational in hot tub lung. Regardless of its actual etiopathogenesis, hot tub lung can be described as
an acute pulmonary illness characterized by fever, shortness of breath and interstitial nodular
Another case seen at our institution exemplifies the clinical presentation. A 49 year old female
beautician developed a 38.9°C fever and chills. A high resolution CT of chest showed reticulonodular
infiltrates in both lung fields. She had purchased and used a hot tub for her salon and although she
cleaned the tub on a regular basis, the water and filter were found to be strongly MAC positive. An open
lung biopsy revealed bronchiolocentric granulomatous lung disease but mycobacteria could not be
identified in lung tissue.
An informative, comprehensive review of hot tub lung was provided by Hanak et al at the Mayo Clinic.
In their series of 21 patients, 9 were men and 12 were women with a mean age of 46. All 21 patients had
had exposure to hot tubs and the most common initial diagnoses were asthma, bronchitis and sarcoidosis.
Dyspnea and cough were present in all patients and 10 of the 21 had hypoxemia. High resolution CT of
chest showed centrilobular nodules and / or ground opacities in 20 of 20 cases in which HR-CT was done.
MAC was isolated from hot tub water, respiratory secretions or lung tissue in all patients.
Transbronchial lung biopsies or open surgical biopsies showed bronchiolocentric granulomatous
inflammation as the most prominent histopathologic finding in 18 of 18 patients in whom biopsies were
performed. These findings suggest a state of hypersensitivity.
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