Use of Immunologic Technology in the Diagnosis of Environmental and Occupational Immunologic Lung Disease

Use of Immunologic Technology Environmental and Occupational Disease*

in the Diagnosis of Immunologic Lung

Roy lbtterson, M.D., F.C.C.P.; Leslie C. Grammer; M.D., F.C.C.P.; C. Raymond Zeiss, M.D.; Kathleen E. Harris, B.S.; and Martha A. Shaughnessy, B.S.

F = formalde~ TDI=toluene ••

NIH= N ationa I Institutes of Health; anate; TMA=trimellitic anhydride

.t irway and interstitial lung diseases may be the result of

11

immunopathogenetic mechanisms. In such diseases, the immunoreactants include antigenic substances and the biologic response reactants of the host. Antigenic substances in these diseases are generally inhaled, and the host responses may include antibodies of all of the immunoglobulin isotypes and specific lymphocyte responses. Measurement of these immune responses in a defined clinical syndrome with known environmental antigen exposure may be of great value in determining a diagnosis in an individual with pulmonary disease. Alternatively, the absence of antibodies in certain diseases may exclude an environmental exposure as etiologic in an individual case of lung disease. For example, the absence of specific lgE excludes cat asthma or allergic bronchopulmonary aspergillosis. Finally, immunologic techniques may be used inappropriately for financial gain with resultant psychic trauma and social and occupational turmoil. We present an overview of the usefulness and uncertainties of immunoassays in environmental and occupational lung diseases. IMMUNOASSAYS OF POTENTIAL DIAGNOSTIC VALUE IN IMMUNOLOGIC LUNG DISEASES

Table 1 lists examples of established immunologic lung diseases due to inhaled substances. A variety of inhaled materials may result in immunologic lung diseases; examples of these are listed in Thble 2. A variety of immunoassays may be of value in demonstrating relevant antibodies ('Iable 3). It cannot be emphasized too strongly that the demonstration of antibody by any technique does not make a diagnosis. Variables to be considered include the antigen, the antibody isotype, the concentration of antibody, the nature of exposure, the type of symptoms, the nature of the disease, and, most important, the correlation of all these factors by an experienced clinician. As a simple example, patients may have IgE antibody against plant pollens too heavy to be airborne. These pollens do not cause allergic rhinitis except in unusual exposure conditions.

recognized and understood for years (such as animal dander asthma), airway diseases due to inhaled reactive chemicals constitute a newer and far more complex group of clinical occupational and immunologic problems. The most clearly understood occupational lung diseases in this group are those that result from inhalation of trimellitic anhydride (TMA) ('Iable 4). In order to demonstrate that these TMA diseases were actually due to TMA and to define the proposed immunologic mechanisms, these diseases should be able to be established in animals and passively transferred Table 1-Emmpl.e. of Lung DileGaa due to

Inhaled Agenta

Disease

Agent

Mechanism

Cat asthma

Cat protein

Pigeon breeder's disease

Pigeon dropping proteins

Immunologic hemorrhagic pneumonia Allergic bronchopulmonary aspergillosis

Trimellitic anhydride

IgE antibody-mast cell system' Toxic antigen-antibody complexes Lymphocyte reactivity" IgG antibody'

Spores of

AapergUlw fumigatus

Antigen-lgG (and other isotype) antibody complexes"

Environmental Substance

Example

Disease

Foreign protein Bacteria Fungal spores Example 1 Example2 Example3

Cat dander

Asthma"

Mlcropolyapora foeni

Farmer's lung•

AltemariD AspergillUB jlaCUB Afumigatus

Asthma" Farmer's lung" Allergic bronchopulmonary aspergillosis•,.. .. Asthma 13

LUNG DISEASE DUE TO REACTIVE CHEMICALS

Although many immunologic lung diseases have been *From the Sections of Allergy-Immunology and Occupational Medicine, Department of Medicine, Northwestern University Medical School, Cnicago Reprint requeata: Dr. ltJtterBon, Northweatem University Medical School, J03 Eaat Chicogo Avenue, Chicogo, 60611

IgE antibody-mast cell mediators'

Reactive chemicals

Trimellitic anhydride Diphenylmethane diisocyanate Trimellitic anhydride

Hypersensitivity pneumonitis.. Hemorrhagic pneumonia'

Table 5-Animal Models Uaed 1b Confirm the lmmunopathogenea. ofTMA Pulmonary lMetMe Immunoassay

Immunoreactant IgE antibody

Species

Skin test (immediate type) Radioimmunoassay'" EUSA•• Precipitin reaction" Radioimmunosorbent assay'" EUSA'" In oitro stimulation of lymphocytes•• 13

IgG antibody

Specific lymphocyte reactivity

to other animals with serum or passively transferred with human serum to animals (Thble 5). Despite the complexity of the problem of TMA (which also serves as an irritant to the airway) and the need for further study of various basic and clinical questions, TMA serves as the model of occupational immunologic lung disease. The strong base of knowledge was derived from cooperative efforts of academia, both industry and workers, and initial NIH funding. No less important and even more complex problems relate to various isocyanates. Immunologic asthma, irritant asthma, and asthma of unknown mechanism in humans due to TDI have been reported, 13 as bas hypersensitivity pneumonitis due to other isocyanates..... Animal models of various types and varying relativity to human diseases have been described.17• The complexity of the issues of isocyanate immunologic and nonimmunologic airway disease is such that further review is not possible here. The evaluation of clinical and laboratory analyses of formaldehyde airway responses presents a contrast to the TMA syndromes. Formaldehyde is clearly an airway irritant above certain threshold levels• and can induce an immune response to F-conjugated host proteins. 30 Various studies have attempted to demonstrate immunologically mediated F asthma analogous to TMA asthma or some cases ofTDI asthma, but neither human nor animal immunologic asthma due to gaseous F has been conclusively demonstrated. With continued investigation and failure to document immunologic F asthma,31-31 the conclusion will eventually be that it does not exist or is so rare that further search for any case is of doubtful value. The current state of knowledge relative to environmental and occupational immunologic lung disease can expand, Table 4-Imtnunologic lAmg lMetMe due to Bet1Ctive Inhaled Clremical.: 7nmellitic Anhydride oa the Model Immunologic Mechanism

Disease

Antigen

Asthma

TMA-self protein-new antigenic determinant complex Same

IgE antibody

Same

IgG, IgM antibody

Late respiratory systemic syndrome

(hypersensitivity pneumonitis) Hemorrhagic pneumonia

IgG, IgM antibody

Transfer of IgE-triggered asthma Induction of hemorrhagic pneumonia Transfer of hemorrhagic pneumonia

Immunoreactant

Rhesus monkey

Rats

lgG"'

Rats

JgGII

Table 6-fi.lcton Belated to Antigen and Hat or Cohort* Factors Related to Antigen

Factors Related to Host or Cohort

1. Antigen also an irritant 2. Antigen cannot be measured in environment 3. Antigen present in workplace and home

1. Cigarette smoking 2. Presence of irreversible obstructive lung disease 3. Coincidental allergic or nonallergic asthma 4. Misinformation, fear 5. Compensation neurosis

*Exposure to an antigen and the occurrence of asthma may be cause and ell"ect. Alternatively, these two events may have no relation except a coincidental relation. There are complicating variables that make establishment of asthma as an immunologic disease difficult. This is applicable to individual patients or exposed cohorts.

since the knowledge and technology in the expanding field of immunology are increasing. This situation affords increased opportunity for understanding and controlling diseases already described and new diseases that will occur due to chemical agents just being developed. A major point requiring repeated emphasis is that, in most individual cases or in groups of exposed individuals, an immunologic test does not make a diagnosis. The correlation of clinical and serologic data by physicians is required for establishment of the diagnosis. When this is not carried out, the outcome may be the misuse of immunologic techniques. Examples of such misuse are (I) application of techniques irrelevant to exposure or disease, (2) .no titers of relevance (IgG
1 Gutman AA. Allergens and other factors important in atopic disease. In: Patterson R, ed. Allergic diseases: diagnosis and management, 3rd ed. Philadelphia: JB Lippincott, 1985:123-75 2 Salvaggio JE. Hypersensitivity pneumonitis. J Allergy Clin Immunol1987; 79:558-71 3 Patterson R, Addington W. Banner AS, Byron GE, FrancoM, Herbert FA, et al. Antihapten antibodies in workers exposed to trimellitic anhydride fumes: a potential immunopathogenetic mechanism for the trimellitic anhydride pulmonary dise~ anemia syndrome. Am Rev Respir Dis 1979; 120:1259-67 4 McCarthy DS, Pepys J. Allergic bronchopulmonary aspergilloCHEST I 98 I 5 I NOVEMBER, 1990 I SUpplement

207S

5

6

7

8 9

10 11

12 13

14

15

16

17

18

sis. Clinical immunology 2: skin, nasal and bronchial tests. Clin Allergy 1971; 1:415-32 Greenberger PA. Allergic bronchopulmonary aspergillosis. In: Middleton E, Jr, Reed CE, Ellis EF, Adkinson NF, Yunginger Jw. eds. Allergy: principles and practice, 3rd ed. StLouis: CV Mosby, 1988:1219-36 Van Metre TE, Jr, Marsh DG, Adkinson NF, Fish JE, KageySobotlca A, Norman PS, et al. Dose of cat (Felis domeatictu) allergen 1 (Fel d 1) that induces asthma. J Allergy Clin Immunol 1986; 78:62-75 Dickie HA, Rankin J. Farmer's lung: an acute granulomatous interstitial pneumonitis occurring in agricultural workers. JAMA 1958; 167:1069-76 Reed CE. Asthma. In: Kaplan AP, ed. Allergy. New York: Churchill Livingston, 1985:367-416 Patterson R, Sommers H, Fink JN. Farmer's lung following inhalation of Aapergillus ftaous growing in mouldy com. Clin Allergy 1974; 4:79-86 · Pepys J. Hypersensitivity diseases of the lung due to fungi and organic dusts. New York: S Karger, 1969 Hinson KFw, Moon AJ, Plummer NS. Bronchopulmonary aspergillosis: a review and report of eight new cases. Thorax 1952; 73:317-33 Golbert TM, Patterson R. Pulmonary allergic aspergillosis. Ann Intern Med 1970; 72:395-403 Zeiss CR, Patterson R, Pruzansky JJ, Miller MM. Rosenberg M, Levitz D. Trimellitic anhydride (TMA)-induced airway syndromes: clinical and immunologic studies. J Allergy Clin Immunol1977; 60:96-103 Zeiss CR, Kanellakes TM, Bellone JD, Levitz D, Pruzansky JJ. Immunoglobulin E-mediated asthma and hypersensitivity pneumonitis with precipitating anti-hapten antibodies due to diphenylmethane diisocyanate (MDI) exposure. J Allergy Clin lmmunol1980; 65:34&52 Zeiss CR, Pruzansky JJ, Patterson R, Roberts M. A solid phase radioimmunoassay for the quantification of human reaginic antibody against ragweed antigen E. J lmmunol1973; 110:41421 Bernstein Dl, Patterson R, Zeiss CR. Clinical and immunologic evaluation of trimellitic anhydride and phthalic anhydrideexposed workers using a questionnaire with comparative analysis of enzyme-linked immunosorbent and radioimmunoassay studies. J Allergy Clin Immunol1982; 69:311-18 Fink JN. Hypersensitivity pneumonitis. In: Patterson R, ed. Allergic diseases: diagnosis and management, 3rd ed. PhiJadelphia: JB Lippincott, 1985:679-90 Lidd D, Farr RS. Primary interaction between 1311-labeled ragweed pollen and antibodies in the sera of humans and rabbits. J Allergy 1962; 33:45-58

19 Maluish AE, Strong DM. Lymphocyte proliferation. In: Rose NR, Friedman H, Fahey JL, eds. Manual of clinical laboratory immunology, 3rd ed. Washington, DC: American Society for Microbiology, 1986:274-81 20 Dykewicz MS, Patterson R, Harris ICE. Induction of antigen specific bronchial reactivity to trimellityl-human serum albumin by passive transfer of serum from man to rhesus monkey. J Lab Clin Med 1988; 111:459-65 21 Zeiss CR, Leach CL, Smith LJ, Levitz D, Hatoum NS, Garvin PJ, et al. A serial immunologic and histopathologic study of lung injury induced by trimellitic anhydride. Am Rev Respir Dis 1988; 137:191-96 22 Leach CL, Hatoum NS, Ratajczak UV, Zeiss CR, Garvin PJ. Evidence of immunologic control of lung injury induced by trimellitic anhydride. Am Rev Respir Dis 1988; 137:186-91 23 Bernstein IL. Isocyanate-induced pulmonary diseases: a current perspective. J Allergy Clin Immunol1982; 70:24-31 24 Malo J-L, Zeiss CR. Occupational hypersensitivity pneumonitis after exposure to diphenylmethane diisocyanate. Am Rev Respir Dis 1982; 125:113-16 25 Charles J, Bernstein A, Jones B, Jones OJ, Edwards JH, Seal RM, et al. Hypersensitivity pneumonitis after exposure to isocyanates. Thorax 1976; 31:127-36 26 Walker CL, Grammer LC, Shaughnessy MA, Duffy M, StotlztUs VD, Patterson R. Dipbenylmethane diisocyanate hypersensitivity pneumonitis: a serologic evaluation. J Occup Med 1989; 31: 315-19 27 Karol MH, Dixon C, Brady M, Alarie Y. Immunologic sensiti· zation and pulmonary hypersensitivity by repeated inhalation of aromatic isocyanates. Toxicol Appl Pharmacol 1980; 53:26067 28 Patterson R, Harris KE, Zeiss CR. Antibodies against toluene diisocyanate protein conjugates: three methods of measurement. J Allergy Clin Immunol1983; 72:676-80 29 Barrow CS, Steinhagen WH, ChangJCF. FOrmaldehyde sensory irritation. In: Gibson JE, ed. FOrmaldehyde toxicity. Washington, DC: Hemisphere Publishing Corp, 1983:16-25 30 Patterson R, Harris ICE, Grammer LC. Canine antibodies against formaldehyde dog serum albumin conjugates: induction, measurement and specificity. J Lab Clin Med 1985; 106:93-100 31 Patterson R, Dykewicz MS, Grammer LC, Pruzanslty JJ, Zeiss CR, Harris ICE. FOrmaldehyde reactions and the burden of proof[editorial]. J Allergy Clin lmmunol1987; 79:705-06 32 Patterson R, Dykewicz MS, Grammer LC, Greenberger PA, Harris ICE, Lawrence I, et al. Immunoglobulin G (IgG) antibody against formaldehyde human serum proteins: a comparison with other IgG antibodies against inhalant proteins and reactive chemicals. J Allergy Clin Immunol1989; 84:359-66