Case ReR~o~rts~ _

Hypersensitivity Pneumonitis and Exposure to Zirconium

Silicate in a Young Ceramic nle Worker
KARl K. LlIPPO, SISKO L. ANTTILA, OLAVI TAIKINA-AHO, EEVA-LiISA RUOKONEN, SAULI T. TOIVONEN,
and TIMO TUOMI
Department of Diseases of the Chest, Turku University Central Hospital, and Department of Forensic Medicine, University of Turku;
Institute of Occupational Health, Helsinki; and Institute of Electron Optics, University of Oulu, Oulu, Finland

We describe a nonsmoking ceramic tile worker 25 yr of age who developed a worsening dry cough and
dyspnea after 3.5 yr as a sorter and glazer of tiles. Open lung biopsy revealed an intense granulomatous
interstitial pneumonia with mild fibrosis, compatible with hypersensitivity pneumonitis, and numerous very
small birefringent crystals around the terminal airways and occasionally in granulomas. Pulmonary parti-
cle analysis revealed an inhaled dust burden nearly 100-fold the normal background level, mainly consist-
ing of clay minerals and zirconium silicate. The patient had no history or clinical or laboratory findings sug-
gesting any organic etiologic agent. A sarcoid granulomatosis type of chronic pulmonary hypersensitivity
reaction is known after long-term exposure to zirconium, but this case demonstrates that zirconium can
also cause an acute and fulminant allergic alveolitislike hypersensitivity reaction. Liippo KK, Anttila SL,
Taikina-Aho 0, Ruokonen E-L, Toivonen ST, Tuomi T. Hypersensitivity pneumonitis and exposure to
zirconium silicate in a young ceramic tile worker. Am Rev Respir Dis 1993; 148:1089-92.

Zirconium compounds are used as opacifiers in ceramic enamels,
glasses, and glazes because of their resistance to acid and to
thermal shock. Zirconium has been considered fairly inert in the
human lungs, and there are few reports of granulomatous or fibrotic
lung disease in humans (1, 2). However, hypersensitivity granu-
lomas are familiar in the skin of both experimental animal and
human subjects (3).
A sarcoid granulomatosis type of pulmonary hypersensitivity
reaction has been reported recently in a nuclear reactor industry
worker after long-term exposure to zirconium (2). We describe a
young ceramic tile glazer who developed a fulminant allergic al-
veolitis type of granulomatous interstitial pneumonia after a short
but intense exposure to zirconium silicate.
CASE REPORT
In August 1990, a nonsmoking woman 25 yr of age presented with two
months of dry cough and shortness of breath on exertion. She had a previ-
ous history of atopic dermatitis and, at 13 yr of age, a pneumonia. Her
only regular medication was oral contraceptives. At presentation coarse
crepitations were heard on both lungs, and in the chest radiograph bilateral
interstitial fibrosis and small discrete nodules were noted (figure 1). The
respiratory function was markedly decreased: FEV., 1.2 L (32% of
predicted); FVC, 1.4 L (34% of predicted); peak expiratory flow rate, 435
Umin (90% of predicted). Single-breath CO diffusing capacity was 2.87
(Received in original form December 10, 1992 and in revised form May 4, 1993)
Supported by a grant from the Finnish Antituberculosis Association.
Correspondence and requests for reprints should be addressed to Kari Liippo,
M.D., Department of the Diseases of the Chest, University of Turku, Paimio
Hospital, FIN-21540, Preitila, Finland.
Am Rev Respir Dis Vol 148. pp 1089-1092, 1993
mmol/min/kPa (36% of predicted). In October 1983, both the chest radio-
graph and the FEV. (3.1 L, 88% of predicted) had been normal. All tests
of sputum and serum for bacterial and viral infection were negative. Fiberop-
tic bronchoscopy was normal, and in the bronchoalveolar lavage (SAL)
the total number of cells was 495 x 106/L; lymphocytes, 29%; neutro-
phils, 18%; eosinophils, 10%. There was no history of exposure to inhaled
organic substances usually linked with allergic alveolitis, and no antibod-
ies against Aspergillus fumicatus, Micropolyspora faeni, or Thermoac-
tinornyces vulgaris were found. An allergic skin reaction to nickel, cobalt,
and colophony had been verified in the hands during her employment
as a glazer.
Until August 1990, she had worked altogether for 3.5 yr in a ceramic
tile factory: 1.5 yr as a glazer, 2 yr as a sorter, and about 1 month in the
manufacture of special shaped ceramics. She had not used respiratory
protective devices regularly, and exposure to dusts of clay, quartz, wol-
lastonite, and zirconium silicate was apparent. In the glazing material zir-
conium silicate constituted 10 to 30% by weight. It was mixed with water
and sprayed manually on the tiles with a compressed air aerosol under
local exhaust ventilation. Dust concentrations during manual glazing were
0.8 to 5.8 mg/m3 • Elsewhere in the factory total dust concentrations were
0.5 to 2.6 mg/m 3 during the manufacture of shaped ceramics and in sort-
ing, and somewhat higher, as much as 8.6 mg/m 3 , in plate pressing work.
The amount of respirable quartz dust in air samples taken at the press-
ing site was about 15%. Scanning electron microscopy and radiographic
microanalysis revealed various types of silicate particles, containing also
zinc, used as a pigment in the glaze. When 1 mg/kg prednisolone given
orally for 9 months gave no significant clinical improvement, an open lung
biopsy was made to explore the etiology of the lung process. One week
after the biopsy her dyspnea and nausea increased; cardiac arrest,
hemothorax, contralateral pneumothorax, and massive intra-abdominal
bleeding were diagnosed. Despite reoperation, she died.
In autopsy the main pathologic findings were in the lungs. The vol-
ume of the lungs was considerably smaller and the consistency was firmer
than normal. There was slight nodularity and a fibrinous cover on the
pleural surfaces. The cutting surface was also firm, with dense, diffuse
1090 AMERICAN REVIEW OF RESPIRATORY DISEASE VOL 148 1993

Figure 1. Chest radiograph of the patient at presentation, showing bilateral

interstitial opacities and small discrete nodules.

patchy infiltration. The histologic picture was similar to that in the open
lung biopsy. The severity of fibrosis varied from slight to early honeycomb-
ing in the upper lobes. There were no signs of systemic disorders such
as collagen vascular diseases in the different organs. A hypersensitivity
pneumonitis caused by inhalation of zirconium silicate was considered
to be the underlying cause of death. The open lung biopsy had been com-
plicated by pneumothorax, which presumably resulted in a prompt rise
in polmonary arterial pressure and an acute failure of the right side of
the heart. Severe stasis of the liver and the spleen followed, with a proba-
ble rupture of the spleen and massive intra-abdominal hemorrhage, which
was the immediate cause of death . Figure2. Light micrograph of the open lung biopsy, showing granuloma-
Light microscopy showed diffuse interstitial inflammation, with patchy tous interstitial pneumonia . The wall of a terminal bronchiolus (Br) is partly
areas of consolidation varying with preserved alveolar structures. Fibro- destroyed , and two large granulomas are seen in the proximity (arrows)
sis of the alveolar walls was seen in small areas, but advanced fibrosis (Movat's pentachrome stain; magnification x120).
was not found in the biopsy specimen. The areas of the worst inflamma-
tion did not follow any regular intralobular distribution. The alveolar walls
were widened, with inflammatory cell infiltrate composed of lymphocytes
with' some eosinophils and a few plasma cells and neutrophils. There was c/es, 1.8 mm 3, and 14,000 mm 2 of mineral dust , respectively, per gram
an intense inflammation also in the walls of the terminal and respiratory dry weight (table 1). Because the mean zirconium particle diameter was
bronchioli, with ulceration of the epithelium. Close to the airway lumen, 0.5 urn, most of the particles were undetectable by light microscopy.
there were frequent non-necrotizing granulomas of various sizes of the
"hypersensitivity type," with epithelioid cells and a few multinucleated gi- DISCUSSION
ant Langhans cells, surrounded by lymphocytes. Granulomas were lo-
The patient's exposure to inorganic dusts was relatively brief in
cated randomly also in the alveolar parenchyma. Inflammatory exudate
with some macrophages and lymphocytes was seen in the alveolar lu- relation to her clinical condition, the changes found on the chest
mina. Movat's pentachrome stain revealed no structures suggesting radiograph, and the respiratory deterioration. Clinical and chest
microbial material. Black granular inhaled material (abundant very small radiographic examinations of five other employees with equal ex-
crystals, birefringent in polarizing light) was found around the vascular posure were normal. Rapid disease progression is usually indic-
structures and terminal airways and sometimes in the granulomas. The ative of very high exposure to harmful inhaled substances. Heavy
morphologic picture was of an intense, mainly lymphocytic, interstitial in- quartz exposure in ceramic workers has been connected with al-
flammation with mild fibrosis and significant granulomatous inflammation- veolar proteinosis (5), but our patient's disease more closely resem-
features compatible with hypersensitivity pneumonitis (figure 2).
bled fibrosing alveolitis; furthermore, industrial hygienic measure-
A tissue sample for particle analysis was digested in 5% potassium
ments showed far lower exposure to quartz than the level usually
hydroxide for 20 h, and it was further prepared as described in detail else-
where (4). Altogether 2fJl particles (> 0.1 1J1T1) were identified by scanning
preceding acute silicoproteinosis.
transmission electron microscopy with an energy-dispersive spectrome- However, inorganic dusts had heavily invaded the lungs rela-
ter and electron difftraction. Approximate volumes and surface areas for tively quickly, for the amount of dust in the lungs was almost 100-
various particle types were calculated (4). The number, volume, and sur- fold compared with unexposed patients. The transmission elec-
face area of the pulmonary particle burden totaled 4,400 million parti- tron microscopy used can disclose a burden between tens and
Case Report 1091

TABLE 1 patient's granulomas were not of the foreign-body type, and inter-
PULMONARY PARTICLE BURDEN OF A 25-YR-OLD CERAMIC stitial inflammation was heavy. Granulomatous pulmonary reac-
TILE WORKER WITH GRANULOMATOUS tion has been described from occupational exposure to alunite
INTERSTITIAL PNEUMONIA
(12) and aluminum welding fumes (13), but not from common
Number Total Total Total Surface aluminum-containing minerals like those in our patient's lungs.
(milJion/g Number Volume Area An allergic skin reaction to cobalt had been verified in our pa-
Particle dry weight) (%) (%) (%)
tient previously, but allergy to zinc, chromium, or zirconium had
Clay 1,600 37 33 42 not been tested. Cobalt is considered the etiologic factor in hard-
Zirconium 1,300 30 19 17 metal pneumoconiosis, which histologically is a giant cell inter-
K-feldspar 500 11 18 14
stitial pneumonia. Features common to our patient and to patients
Quartz 400 9 17 13
Titanium 200 5 3 3 with typical hard-metal pneumoconiosis are that they are young,
Mica 150 3 5 5 nonsmoking, sometimes atopic, and develop the disease after rel-
Plagioclase 50 1 2 1 atively short exposure, suggesting the significance of a possible
Talc 25 <1 < 1 <1 sensitization (14).
Barium 25 <1 < 1 <1 Zirconium is an interesting candidate as a causal factor for
Calcium 25 <1 < 1 <1
Chromium 25 <1 1 <1 hypersensitivity pneumonitis. Human skin granulomas that de-
Various 80 2 < 1 1 veloped after the use of deodorant sticks containing zirconium
salts were believed to be attributable to zirconium hypersensitiv-
ity (15-17). Epstein and coworkers (18) sensitized several hundred
hundreds of million particles per gram of dried lung after lifelong human subjects experimentally with intradermal injections of zir-
trivial accumulation of inhaled dust (4, 6), and from hundreds to conium lactate; in five subjects the healing injection sites flared
thousands of millions after years in dusty occupations. The main up after 6 wk to 6 months. The lesion enlarged and became more
pulmonary mineral content consisted of clay minerals such as kao- inflamed, and the histologic picture showed collections of lym-
lin and zirconium silicate, with minor amounts of feldspar and phocytes and epithelioid cell granulomas different from the foreign-
quartz, corresponding fairly closely to the composition of the ce- body response (18).
ramic glazing material. In addition, the patient had been exposed There is increasing evidence for the ability of zirconium to cause
to pigments containing titanium, zinc, cadmium, cobalt, and a pulmonary granulomatous lesion. In a few animal experiments
chromium. with. zirconium compounds, interstitial pneumonia, fibrosis, and
Open lung biopsy revealed a hypersensitivity pneumonitis and foreign-body or histiocytic granulomas have been reported (19-21),
extensive inhaled particulate material. The patient had no history but other experiments have given negative results. There is one
of exposure to moldy hay or other organic dusts that can cause report of a chemical engineer who developed pulmonary sarcoid
hypersensitivity pneumonia, and no precipitating antibodies granulomatosis after 7 years of exposure in a zirconium and haf-
against fungi were detected. Also, the patient's condition did not nium processing plant; because comparable lesions did not oc-
respond to the steroid treatment during sick leave, which is not cur in any other employees, the condition was considered sar-
typical of a hypersensitivity pneumonitis caused by organic dust. coidosis or attributable to previous exposure to beryllium (22).
The histologic features did not correspond to sarcoidosis or beryl- Abraham (23) analyzed lung tissue from 33 patients with differ-
liosis, and the patient had no history of exposure to beryllium, ent granulomatous lung lesions and detected zirconium-containing
which is a well-known inorganic etiologic agent of the sarcoid particles in association with hypersensitiVity pneumonitis in a ce-
granulomatosis type of hypersensitivity reaction. There were no ramic worker who probably had been involved in enamel spray-
clinical, histopathologic, or laboratory data indicative of infectious ing. End-stage fibrosis without any granulomatous features was
granulomatous pulmonary diseases. described in a grinder of glass lenses who had been exposed to
No previous evidence suggests that any of the particle types zirconium powder for years (1), and sarcoid granulomatosis type
found in her lung tissue could provoke this kind of radiographic of pulmonary lesion in a nuclear reactor industry worker after long-
changes or granulomatous interstitial pneumonia. Clay minerals term exposure to zirconium (2). The cases in the literature possi-
can cause simple pneumoconiosis (histologically, dust macules bly associated with exposure to zirconium are shown in table 2.
with minimal fibrosis [7]); also, silicates such as clay, mica, or talc The present case shows that zirconium can cause a fulminant
may lead to a pneumoconiosis typified by foreign-body granulomas allergic alveolitislike interstitial pneumonia in addition to a chronic
with or without interstitial inflammation and fibrosis (8-11). Our sarcoid granulomatosis type of hypersensitivity reaction.

TABLE 2
CASES IN THE LITERATURE POSSIBLY ASSOCIATED WITH EXPOSURE TO ZIRCONIUM

Patient Work Time Pulmonary

Reference (sex/age) Type of Work (yr) Reaction Type

Reed, 1956 (22) M/NA Production of 7 Sarcoid granulomatosis

Zr metal
Abraham, 1980 (23) M/NA Ceramic sprayer NA Granulomatous interstitial
pneumonia
Bartter and colleagues, 1991 (1) M/62 Grinder of glass lenses 39 End-stage fibrosis
Kotter and Zieger, 1992 (2) F/50 Nuclear reactor industry 16 Sarcoid granulomatosis
worker
Present case F/25 Ceramic glazer 3.5 Granulomatous interstitial
pneumonia

Definition of abbreviations: NA = not available.

1092
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