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 data. 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 exposed individuals. Popcorn Lung 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 place toxin. 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. Flock Lung 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 infiltrates. 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. References Rammazini B. Morbis Artificum Diatriba, 1713. Translation by W.C. Wright. The University of Chicago Press. 1940, reprinted by the Classics of Medicine,Gryphon editions; 1983;337-351. Eliasson O. Farmer's Lung Disease: A New Historical Perspective from Iceland. J History Med Allied Sci 1982;37:440-3. Campbell J. Acute symptoms following work with hay. Br Med J 1932;2:1143-4. Pepys JRR, KM Citron, YM Clayton. Precipitins against extracts of hay and moulds in the serum of patients with farmer's lung, aspergillosis, asthma and sarcoidosis. Thorax 1962;17:366-74. Yi ES. Hypersensitivity pneumonitis. Crit Rev Clin Lab Sci 2002;39(6):581-629. Metal Working Fluids Bernstein D, Lummus Z, Santilli G, Siskosky J, Bernstein I. A hypersensitivity pneumonitis disorder associated with exposure to metal working fluid aerosols. Chest 1995; 108:626-641. Beckett W, Kallay m, Sood A et al. Respiratory symptoms associated with occupational exposure to metal working fluid. ATS web site, http:11.thoracic.org. sections/clinical-information/environmental-and-occupational/clin. Kreiss K, Cox-Gaenser J. Metalworking fluid-associated hypersensitivity pneumonitis: a workshop summary. Am J Indust Med 1997;32:423-43. Bracker A, Storey E, Yang C, Hodgson MJ. An outbreak of hypersensitivity pneumonitis at a metal working plant. Appl. Occup Environ Hyg 2003;18:96-108. Popcorn Workers Kreiss K, Gomma A, Kullman G et al. Clinical bronchiolitis obliterans at a microwave popcorn plant. NEJM 347:330-338, 2002. Parmet AJ and Von Essen S. Rapidly progressive fixed airway obstructive disease in popcorn workers: a new occupational pulmonary illness ? J. Occup Environ Med 44:216-218, 2002. Akpinar-Elci M, Kanwall R and Kreiss K. Bronchiolitis obliterans syndrome in popcorn plant workers. Amer J Resp Crit care Med 163:A526, 2002. Hubbs AF, Batteli LA, Goldsmith WT et al. Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicol and Applied Pharmacol 185:128-135, 2002. Flock Lung Kern DG, Durand KTH, Crausman RS, et al. Nonspecific interstitial pneumonia in the synthetic textile industry. Am J of Respir & Crit Care Med 155:A810, 1997. Kern DG, Crausman RS, Durand KTH, et al. Flock Worker's Lung: Chronic Interstitial Lung Disease in the Nylon Flocking Industry. Annals of Internal Medicine 129;261-272, 1998. Eschenbacher WL, Kreiss K, Lougheed MD, Pransky GS, Castellan RM. Clinical Pathology Workshop Summary on Nylon-Flock Associated Interstitial Pneumonitis. Amer Rev. Resp. Crit Care Med 159:2003-2008, 1998. Boag AH, Colby TV, Fraire AE, Kuhn CH, Roggli, VL, Travis WD and Vallyathan V. The pathology of interstitial lung disease in nylon flock workers. Amer J Surg Path 23:1539-1545, 1999. Kern DG, Kuhn C, Wesley E, Pransky GS, Mello CJ, Fraire AE and Muller J. Flock workers lung, broadening the spectrum of clinico-pathology, narrowing the spectrum of suspected etiologies. Chest 117:251-259, 2000. Hot Tub Lung Kahana LM, Kay JM. Pneumonitis due to Mycobacterium avium complex in hot tub water: infection or hypersensitivity? Chest 1997;112:1713-1714. Marras TK, Wallace RJ, Jr., Koth LL, et al. Hypersensitivity pneumonitis reaction to Mycobacterium avium in household water. Chest 2005; 127:664-671. Patel AM, Ryu JH, Reed CE. Hypersensitivity pneumonitis: current concepts and future questions. J Allergy Clin Immunol 2001; 108:661-670. Cappelluti E, Fraire AE, Schaefer O. A case of hot tub lung due to mycobacterium avium complex in an immunocompetent host. Arch Intern Med 2003;163:845-848. Smith DD. Top ten list in occupational pulmonary disease. Chest 2004;126:1360-1363. Angelis SM, Fraire AE, McNamee C, Kiebara , Libraty DH. Hot tub lung sine hot tub: an immunopathology study (submitted for publication). Hanak V, Kalra S, Aksamit TR, et al. Hot tub lung: Presenting features and clinical course of 21 patients. Respir Med 2005 2006; 100:610-615.