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(Chest. 2003;124:1145-1152.)
© 2003 American College of Chest Physicians

Suberosis*

Clinical Study and New Etiologic Agents in a Series of Eight Patients

Ferran Morell, PhD; Àlex Roger, MD; María-Jesús Cruz, BS; Xavier Muñoz, PhD and María-José Rodrigo, PhD

* From Servei de Pneumologia (Drs. Morell, Roger, Muñoz, and Ms. Cruz), Unitat d’Investigació en Pneumologia & Laboratoris Clinics-Unitat Immunologia (Dr. Rodrigo), Hospital Universitari Vall d’Hebron, Barcelona, Spain.

Correspondence to: Ferran Morell, PhD, Servei de Pneumologia, Hospital General Vall d’Hebron, Passeig Vall d’Hebron, 119-129, 08035 Barcelona, Spain; e-mail: fmorell{at}hg.vhebron.es


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Penicillium frequentans is considered to be the causal agent of suberosis, hypersensitivity pneumonitis due to cork dust inhalation. Nevertheless, other fungi can colonize cork during its storage period in humid conditions. The aims of the study were to assess the etiologic role of several fungi and cork itself in the genesis of suberosis, and to review the clinical characteristics of patients with this disease.

Methods: Eight patients with suberosis were studied. Chest radiography, high-resolution chest CT, pulmonary function testing, bronchofibroscopy with BAL and transbronchial biopsy, and delayed cutaneous hypersensitivity tests were performed. Fungal and suberin (cork that is culture negative for fungi) antigens were used for serum determination of specific IgG antibodies, immediate hypersensitivity specific skin tests, and specific bronchial challenge tests.

Results: Serum specific IgG antibody determinations and specific skin tests against Aspergillus fumigatus and suberin demonstrated the capacity of both these antigenic extracts to induce an immunologic response. Positive specific bronchial challenge tests performed not only with P frequentans but also with A fumigatus, and cork itself were recorded in some patients for the first time in this disease. Dyspnea and cough were the most frequent symptoms. Clinical and functional improvement occurred after antigen avoidance.

Conclusions: In addition to P frequentans, A fumigatus and cork dust itself may contribute to the development of suberosis.

Key Words: Aspergillus fumigatus • hypersensitivity pneumonitis • suberosis


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cork is a light, porous, impermeable material extracted from the bark of some trees. The most widely used cork is obtained from the cork tree (Quercus suber), owing to its greater thickness. The processes used in the manufacture of cork depend on the end product to be obtained. "Natural" stoppers (wine bottle corks) are made from bark that is boiled, stored under dark humid conditions until moldy, sliced, punched, and polished. Cork compounds made from ground bark are used as parquet flooring, wallpaper, wall coverings, shoe soles, life belts, champagne corks, and panels for industrial soundproofing, etc. During the manufacturing process, workers are exposed to an environment that is heavily contaminated with cork dust. The world production of cork is centered in the south of Europe, with Spain being the second most important producer after Portugal.

Suberosis was first described in 1955 by Cancella d’Abreu.1 In any event, different respiratory and occupational diseases ranging from bronchial asthma to chronic bronchitis2 3 4 have been related to cork dust exposure and associated microbial contaminants. Suberosis is the term applied to hypersensitivity pneumonitis due to cork dust inhalation. It is the most well-known respiratory disease attributable to cork exposure in Spain. Despite the importance of the Spanish cork industry, there are few epidemiologic5 or sporadic studies6 7 on this subject, particularly as compared to those published by Portuguese authors.3

In early works, researchers2 3 4 5 6 7 8 detected precipitins to cork dust and later to Penicillium frequentans in serum of cork workers. Since that time, this microorganism has been considered the causal agent of suberosis.1 2 8 9 During its storage period in humid conditions, however, cork is frequently colonized by other fungi such as Aspergillus fumigatus or Mucor sp; therefore, these microorganisms and even the cork dust itself may also play an etiologic role in the genesis of the disease.

The aims of this study were to assess the etiologic role of several fungi and cork in the genesis of suberosis, and to review the clinical and epidemiologic characteristics of a series of eight patients with this disease. For the first time in an study of this entity, specific skin tests, quantitative determination of specific serum antibodies by enzyme-linked immunosorbent assay (ELISA), and specific bronchial challenge tests against various fungi and/or antigenic cork extract uncontaminated by fungi have all been performed. Because of the small number of series described in the literature and the limited challenge test data, we believe that the results presented may be of interest to researchers working in this field.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
Eight patients (five women) with a mean age (± SD) of 36.8 ± 9 years (range, 26 to 57 years) who fulfilled diagnostic criteria for suberosis10 were retrospectively studied. All but one of the patients received a diagnosis at our occupational respiratory disease unit between 1982 and 2000. The other patient (case 6) received a diagnosis in 1982.6 At the time of diagnosis, all patients were actively working in cork manufacturing industries in the province of Gerona (Catalonia) and all presented acute symptoms of hypersensitivity pneumonitis. Mean exposure time to cork dust prior to diagnosis was 9.6 years (range, 1 to 18 years). The following data were retrospectively reviewed: medical history, physical examination, general analyses, chest radiography, high-resolution chest CT scans, pulmonary function testing (spirometry, pulmonary volumes, and diffusion), bronchofibroscopy with BAL and transbronchial biopsy (TBB), delayed cutaneous hypersensitivity tests, serum determination of specific IgG antibodies (ELISA), specific immediate hyper-sensitivity skin tests against fungal and suberin (cork culture-negative for fungi) antigens and, finally, specific bronchial challenge tests performed with these same antigens.

Antigen Extract Preparation
Cork antigenic extract (suberin) was prepared from Sabouraud culture-negative cork. Soluble proteins were extracted with ammonium bicarbonate buffer 0.2 mol/L (pH 7.9) overnight at 4°C. The solution was centrifuged and the supernatant dialyzed at 4°C against distilled water using a 3,500-d pore-size membrane (Spectra/Por; Spectrum Medical Industries; Los Angeles, CA). The material obtained from the dialysate was lyophilized and the protein concentration determined by the bicinchoninic acid method (Pierce; Rockford, IL). Commercialized extracts (Bial-Aristegui; Bilbao, Spain) from P frequentans, A fumigatus, Mucor mucedo, and Rhizopus nigricans were used to study fungi.

Specific Skin Tests
Skin tests were performed by intradermal injection in the forearm of 0.1 mL of solutions (1/100 weight/volume) of the following extracts: P frequentans, A fumigatus, and suberin. Based on the role of IgG in the mediation of immediate hypersensitivity,11 the appearance of a papule with a maximum diameter > 10 mm at 15 min (immediate reading) was the criterion defining a positive test result.12 13 Specific skin testing against P frequentans, A fumigatus, and suberin were also performed in 12 healthy individuals serving as a control group.

Determination of Specific IgG Antibodies to P frequentans, A fumigatus, M mucedo, R nigricans,and Suberin
Specific IgG antibodies to fungi and suberin were determined by an ELISA technique based on the modified method of Metzger et al.14 Concentrations of 2 µg protein/well in Na2CO3/NaHCO3 buffer (pH 9.6) were placed in high-affinity microtiter plates (Costar; Cambridge, MA) and incubated for 16 h at 4°C. Results were expressed as absorbance units at 450 nm. Values above the mean plus 2 SDs of the results obtained in a control population of 30 healthy individuals previously studied in our laboratory were considered positive.

Delayed Cutaneous Hypersensitivity Tests
Delayed cutaneous hypersensitivity tests were performed by intradermal injection in the forearm of 0.1 mL of each of the following antigen extracts solutions: candidine 1/100 weight/volume (Lab. Leti; Madrid, Spain), tuberculin (PPD Evans RT-23; Evans Medical España; Madrid, Spain), 0.1 mL = 2 tuberculin units (Medeva-Pharma S.A.; Leatherhead, Surrey, UK), tricophyton mentagrophytes 100 µg/mL (Lab. Leti), and varidase-streptokinase 40 IU/mL/streptodornase 10 IU/mL (Lab. Lederle; Madrid, Spain). Development of a papule with a maximum diameter > 5 mm by 48 h after extract injection was considered positive.15 16

Pulmonary Function Tests
Forced spirometry, static pulmonary volumes, and diffusion capacity of the lung for carbon monoxide (DLCO) were performed in eight patients, four patients, and six patients, respectively, using a MasterLab apparatus (MasterLab; Jaeger; Würzburg, Germany). All tests were performed following European Respiratory Society guidelines.17 18 Static pulmonary volumes were measured using the plethysmography method, and transfer factor was measured using the single breath-hold method.19 The theoretical values proposed by Roca et al20 for the Mediterranean population were applied for spirometry, and values proposed by the European Respiratory Society for static pulmonary volumes and DLCO testing.17 18

Specific Bronchial Challenge Tests
Specific bronchial challenge tests were always performed in the hospital setting and after obtaining the patient’s written consent. Total blood count, chest radiography, spirometry, DLCO, and oxygen saturation determination by pulsed oximetry were performed prior to the challenge tests.

Using a De Vilbiss 646 nebulizer (De Vilbiss; Somerset, PA) and a Mefar MB3 dosimeter (Mefar, Ele H2O; Medicali; Brescia, Italy), which releases the solution during the first second of each inspiration, the patient was requested to inhale 2 mL of the suspected antigen at a dilution of 1/100 (0.01 mg/mL).21 FVC, FEV1, DLCO, and the patient’s temperature were recorded at 20 min after the inhalation and every hour for the following 8 h thereafter. New blood counts, chest radiographs, and oxygen saturation measurements were performed 8 h after inhalation.

The test result was considered positive when any of the following responses was elicited: (1) FVC decrease > 15% or DLCO decrease > 20% as compared with basal values; (2) 10 to 15% FVC decrease plus the appearance of at least one of the following criteria with respect to clinical status and basal analytic values22 23 : (A) WBC increase >= 20%, (B) 3% decrease in oxygen saturation, (C) significant radiologic changes, (D) rise in body temperature > 0.5°C, and (E) evident clinical symptoms (cough, dyspnea, ...); and (3) FVC decrease < 10% but with evidence of three or more of the previously mentioned clinical and analytic criteria.21 When the test result proved negative, inhalation of a new antigen dilution of 1/10 (0.1 mg/mL) following the same procedure was performed the next day.

Since these patients were later followed up at our center, it was also possible to collect data on their long-term clinical evolution. Similarly, control spirometry was performed to ascertain functional evolution in the five patients followed up for > 1 year.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical Data and Test Results
Clinical data and test results are shown in Table 1 . At the time of diagnosis, the patients had presented symptoms for a mean of 2.6 years (range, 0.5 to 5 years). Characteristically, symptoms began halfway through the working day or at the end of the evening shift and remitted or improved at weekends or during holidays. Evolution was highly favorable in all patients after a mean antigen avoidance period of 14.2 months (range, 4 to 26 months); 50% of patients (cases 1, 4, 6, and 8) remained asymptomatic, and 50% of patients (cases 2, 3, 5, and 7) had dyspnea only on extreme exertion. Chest radiography showed a slight interstitial pattern predominantly affecting the lower lobes in only four patients; however, high-resolution chest CT performed in seven of the eight patients revealed parenchymal changes in six patients (Fig 1 ).


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  		Table 1.. Clinical, Analytical, and Radiologic Characteristics of Eight Patients With Suberosis*

 


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  		Figure 1.. High-resolution chest CT in case 3. Patchy airtrapping (mosaic pattern) is seen on expiratory scan.

 
Pulmonary function studies showed decreased FVC (< 80%) in three patients and slightly decreased DLCO (< 80%) in two patients (this was the only functional impairment detected in case 5). In case 2, pulmonary function tests were performed after 1 year of antigen avoidance. None of the patients showed obstruction or airtrapping. Functional evolution was recorded in five patients (cases 2 to 5, and case 7) after a mean period of 17.2 months (range, 13 to 26 months) without workplace exposure. Cases 2 and 4, with initially normal respiratory function, showed no changes, whereas cases 3, 5, and 7, with initially decreased FVC and DLCO, showed normal values (FVC > 80% and DLCO > 80%) for these parameters (Fig 2 ).



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  		Figure 2.. A 24% decrease in DLCO and a 15% decrease in FVC is observed between the fifth and sixth hours after inhalation of the A fumigatus extract in case 2. TEMP = temperature in degrees Celsius.

 
BAL and TBB were performed in six patients and five patients, respectively, although one patient (case 2) underwent bronchofibroscopy after 1 year of antigen avoidance. BAL cell count obtained in the other five patients revealed lymphocytosis > 20% in four patients. The common characteristic of TBB (cases 2 to 5, and case 8) was the presence of an interstitial lymphohistiocytic infiltrate; neither granulomas nor bronchiolitis were detected in any case.

Specific Skin Tests
The specific skin test for P frequentans proved positive in three of the four patients in whom it was performed. The cork extract skin test was positive in four of five patients. A fumigatus tested positive in the only patient (case 7) in whom it was performed (Table 2 ).


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  		Table 2.. Immunologic Test Responses to Various Antigens in the Eight Patients With Suberosis and Results of Cultures of Cork From the Workplace*

 
In the control group, the mean maximum diameter of response was 1.4 mm (range, 0 to 7 mm), 2.6 mm (range, 0 to 12 mm), and 6.1 mm (range, 0 to 11 mm) for P frequentans, A fumigatus, and suberin, respectively. One positive result was obtained for A fumigatus, and one for suberin in two different healthy individuals.

Determination of Specific IgG Antibodies to P frequentans, A fumigatus, M mucedo, R nigricans,and Suberin
Specific IgG antibodies to the fungal antigens studied were determined in seven patients (Table 2) , and positive results were obtained against P frequentans in six patients. Precipitins to this same microorganism were detected in the patient in whom specific IgG had not been determined by ELISA (case 6). Specific IgG to A fumigatus was positive in four of seven patients. Five patients presented specific IgG antibodies to more than one fungal antigen. Positive specific IgG antibodies against suberin antigen extract were obtained in four of six patients (Table 2) .

Specific Bronchial Challenge Tests
Specific bronchial challenge tests (Table 2) against different antigens were performed in seven patients according to clinical suspicion, results obtained in specific skin tests and serum determinations of specific IgG antibodies, and antigenic extract availability at the hospital laboratory. P frequentans was positive in three of the four patients tested with this antigen. In another patient (case 6), P frequentans was isolated in cork from his workplace and was used to perform his challenge test, with positive results. Positive results were also obtained in two of four of the challenge tests performed against clean cork and in the only test performed with A fumigatus (after testing against P frequentans had proved negative). In this last patient (case 2), A fumigatus was isolated in culture of the cork that had triggered the patient’s symptoms.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present work describes the clinical, analytic, and radiologic features, as well as immunologic test responses of a well-characterized group of patients with suberosis, and is one of very few articles published to date on this subject. The study shows that besides P frequentans, A fumigatus, and cork itself, uncontaminated by fungi, may participate in the etiopathogenesis of suberosis in some patients.

The etiology of cork dust-induced hypersensitivity pneumonitis has been attributed to the antigenic capacity of P frequentans.1 2 8 9 Its known causative role in this disease is confirmed in the present study by positive specific skin test results, specific serum IgG antibody analyses, and specific bronchial challenge tests—considered to be the "gold standard" diagnostic procedure22 —against this antigen. However, other fungi, such as A fumigatus, Mucor sp, or Rhizopus sp, can also be isolated in cultures of cork sheets or compounds from the work place, as occurred with A fumigatus in our case 2. In view of this culture result and the positive specific IgG serum determinations to these fungi, we suggest that cork workers may be exposed to various antigenic sources during the workday, and that each of these may contribute to the etiology of the disease. This concept is further supported by positive specific IgG serum antibody determinations and specific skin test results against clean cork, as well as positive skin test results against A fumigatus found in some patients. Additionally, and for the first time, this study presents positive results of two specific bronchial challenge tests performed against clean cork extract (cases 1 and 5) and one against A fumigatus (case 2), which appear to confirm the etiologic role of these agents in the development of suberosis. It is noteworthy that the functional impairment observed in the bronchial challenge tests was a drop in FVC and/or DLCO 6 to 8 h after antigen extract inhalation, which is characteristic of an immune complex-mediated late reaction but not of an IgE-mediated one. In fact, no specific IgE antibodies to fungi were detected in any patient.

The positive bronchial challenge test against A fumigatus does not seem to be the result of cross-reactions between common antigens of different fungi. Case 2, despite presenting specific IgG antibodies to P frequentans and A fumigatus, had a negative specific bronchial challenge test result to P frequentans. In contrast, bronchial challenge was positive to both A fumigatus and cork colonized by Aspergillus sp in this patient.

The findings in case 5 provide particular evidence to support the participation of cork, itself, in the etiology of suberosis. This patient had positive specific skin and bronchial challenge test results against suberin, but did not show specific serum antibodies against P frequentans or A fumigatus. We verified the antigenicity of suberin extract in a previous study of 73 cork dust-exposed workers in whom significant specific IgG serum antibody levels against suberin were detected in 70% of cases. The 97.5% percentile of values obtained in 33 nonexposed control subjects (unpublished data) was considered the cut-off of positivity.

With regard to clinical management, the prolonged latency period and late onset of symptoms after exposure to the causal agent can hinder the diagnosis of suberosis.24 Thus, diagnosis may depend on a high rate of suspicion. The first and most important therapeutic approach for a patient with hypersensitivity pneumonitis is avoidance of the antigen.25 26 Treatment with corticosteroids has proved successful in controlling clinical symptoms during acute episodes of the disease; however, long-term results are not guaranteed.27 In the present series, the response to antigen avoidance was markedly favorable. Pulmonary function returned to normal in patients with initial impairment (although 75% presented dyspnea on extreme effort), and there was significant clinical improvement in all patients at the end of follow-up. Early diagnosis of the disease is of paramount importance so that antigen avoidance measures can be adopted as soon as possible, since prolonged persistence of symptoms in other types of hypersensitivity pneumonitis has proved to be a factor of poor prognosis.26

Pulmonary function tests at the time of diagnosis showed a tendency toward decreased FVC and/or impaired DLCO. These findings are consistent with the presence of an interstitial lung pattern that was not always detected on chest radiography. The usefulness of chest CT28 to detect pulmonary parenchymal changes such as areas of expiratory airtrapping29 was evident in this series. BAL and TBB results were not always specific for hypersensitivity pneumonitis, but consistent findings, together with highly suggestive clinical symptoms, were frequently helpful to establish the diagnosis.

Cellular immunity is known to be depressed during the acute phase of sarcoidosis30 and in some forms of hypersensitivity pneumonitis,15 which differentiates these entities from other types of interstitial lung disease.31 Among the three patients who underwent delayed cutaneous hypersensitivity tests in the present study, results were almost completely negative during the acute phase of the disease (Table 1) , and there was a change to positive in one patient after antigenic avoidance, suggesting that the same phenomenon also occurs in suberosis.

Quantification of serum-specific IgG antibodies by ELISA and immediate specific skin tests are markers of exposure but are not specific for disease; nevertheless, these test permit a better etiologic approach to the diagnosis of suberosis, particularly when high clinical suspicion has been established. In any event, specific bronchial challenge testing confirmed the diagnosis in many cases and, together with other diagnostic techniques, proved that antigens other than P frequentans can participate in causing the disease. In conclusion, apart from P frequentans, A fumigatus and cork dust itself may play an etiologic role in the development of suberosis.


   Acknowledgements
 
We thank Christine O’Hara for English translation of the manuscript, and María-Dolores Untoria, a member of the nursing staff, for laboratory analysis.


   Footnotes
 
Abbreviations: DLCO = diffusion capacity of the lung for carbon monoxide; ELISA = enzyme-linked immunosorbent assay; TBB = transbronchial biopsy

This study was financed in part by grant FISS 90/0941, and Red Respira (Instituto Carlos III. Fis RTYC-C03/11), SEPAR.

Received for publication July 16, 2002. Accepted for publication January 27, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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