Serum therapy for tuberculosis revisited: Reappraisal of the role of antibody-mediated immunity against Mycobacterium tuberculosis

Clinical Microbiology Reviews

Volumn 11, Issue 3, 1998, Pages 514-532

  Glatman Freedman, Aharona ^a   Casadevall, Arturo ^a  

^a ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BACTERIUM ANTIBODY; BCG VACCINE;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ANTIBIOTIC RESISTANCE; ANTIBODY RESPONSE; BACTERIAL IMMUNITY; BCG VACCINATION; HUMAN; MYCOBACTERIUM TUBERCULOSIS; REVIEW; TUBERCULOSIS;

EID: 0031818673     PISSN: 08938512     EISSN: None     Source Type: Journal    
DOI: 10.1128/cmr.11.3.514     Document Type: Review

References (125)

1. Andersen, A. B., and P. J. Brennan. 1994. Proteins and antigens of Mycobacterium tuberculosis, p. 307-332. In B. R. Bloom (ed.), Tuerculosis. Pathogenesis, protection and control. ASM Press, Washington, D.C.
2. Andersen, P. 1997. Host responses and antigens involved in protective immunity to Mycobacterium tuberculosis. Scand. J. Immunol. 45:115-131.
3. Anonymous. 1894. The results obtained by Dr. Viquerat in his treatment of tuberculosis. Lancet ii:756-757.
4. Armstrong, J. A., and P. D. Hart. 1975. Phagosome-lysosome interactions in cultured macrophages infected with virulent tubercle bacilli. J. Exp. Med. 142:1-16.
5. Band, H., S. Sinha, and G. P. Talwar. 1987. Inhibition of interaction of mycobacteria with Schwann cells by antimycobacterial antibodies. J. Neuroimmunol. 14:235-239.
6. Barrera, L., I. de Kantor, V. Ritacco, A. Reniero, B. Lapez, J. Benetucci, M. Beltran, O. Libonatti, E. Padula, J. Castagnino, and L. Gonzalez Montaner. 1992. Humoral response to Mycobacterium tuberculosis in patients with human immunodeficiency virus infection. Tubercle Lung Dis. 73:187-191.
7. Bassano, H. F. 1905. Five cases of tuberculosis treated with Dr. Marmorek's serum. Lancet ii:760-762.
8. Beretta, C. 1891. On the use of dog's serum in the treatment of tuberculosis. Br. Med. J. ii:1041-1042.
9. Bluhm, I. 1952. The influence of immune and normal human serum on the respiration of tubercle bacilli. Acta Med. Scand. Suppl. 275:1-28.
10. Boyden, S, V. 1951. The adsorption of proteins on erythrocytes treated with tannic acid and subsequent hemagglutination by antiprotein sera. J. Exp. Med. 93:107-120.
11. British Medical Research Council. 1948. Streptomycin treatment of pulmonary tuberculosis. A Medical Research Council investigation. Br. Med. J. ii:769-782.
12. British Medical Research Council. 1952. The treatment of pulmonary tuberculosis with isoniazide. An interim report to the Medical Research Council by their Tuberculosis Chemotherapy Trials Committee. Br. Med. J. ii:735-746.
13. Bulmer, G. S., M. D. Sans, and C. M. Gunn. 1967. Cryptococcus neoformans. I. Nonencapsulated mutants. J. Bacteriol. 94:1475-1479.
14. Calmette, A. 1923. Passive immunity: attempts at antituberculous serotherapy, p. 603-623. In Tubercle bacillus infection and tuberculosis in man and animals. The Williams & Wilkins Co., Baltimore, Md.
15. Carlucci, F. 1896. Pulmonary tuberculosis treated with Maragliano serum. Med. Rec. N. Y. 49:515-516.
16. Casadevall, A. 1995. Antibody immunity and invasive fungal infections. Infect. Immun. 63:4211-4218.
17. Casadevall, A. 1998. Antibody-mediated protection against intracellular pathogens. Trends Microbiol. 6:102-107.
18. Casadevall, A., and M. D. Scharff. 1994. Serum therapy revisited: animal models of infection and development of passive antibody therapy. Antimicrob. Agents Chemother. 38:1695-1702.
19. Casadevall, A., and M. D. Scharff. 1995. Return to the past: the case for antibody-based therapies in infectious diseases. Clin. Infect. Dis. 21:150-161.
20. Chan, J., X. Fan, S. W. Hunter, P. J. Brennan, and B. R. Bloom. 1991. Lipoarabinomannan, a possible virulence factor involved in persistence of Mycobacterium tuberculosis within macrophages. Infect. Immun. 59:1755-1761.
21. Choucroun, N. 1949. Precipitin test for carbohydrate antibodies in human tuberculosis. Am. Rev. Tuberc. 59:710-712.
22. Choudhury, A., N. F. Mistry, and N. H. Antia. 1989. Blocking of Mycobacterium leprae adherence to dissociated schwann cells by anti-mycobacterial antibodies. Scand. J. Immunol. 30:505-509.
23. Clawson, B. J. 1936. The destruction of tubercle bacilli within phagocytes in vitro. J. Infect. Dis. 58:64-69.
24. Cole, L. R., and C. B. Favour. 1955. Correlations between plasma protein fractions, antibody titers, and the passive transfer of delayed and immediate cutaneous reactivity to tuberculin PPD and tuberculopolysaccharides. J. Exp. Med. 101:391-420.
25. Collins, F. M. 1991. Antituberculous immunity: new solutions to an old problem. Rev. Infect. Dis. 13:940-950.
26. Cornet, G. 1905. Therapy of pulmonary tuberculosis, p. 587-597. In W. B. James (ed.), Tuberculosis: acute general miliary tuberculosis. Nothnagel's encyclopedia of practical medicine. The W. B. Saunders Co., Philadelphia, Pa.
27. Costello, A. M., A. Kumar, V. Narayan, M. S. Akbar, S. Ahmed, C. Abou-Zeid, G. A. W. Rook, J. Stanford, and C. Moreno. 1992. Does antibody to mycobacterial antigens, including lipoarabinomannan, limit dissemination in childhood tuberculosis? Trans. R. Soc. Trop. Med. Hyg. 86:686-692.
28. Cummins, S. L. 1922. The Spahlinger treatment. Lancet i:98-99.
29. Da Costa, C. T. K. A., S. Khanolkar-Young, A. M. Elliott, K. M. A. Wasunna, and K. P. W. J. McAdam. 1993. Immunoglobulin G subclass responses to mycobacterial lipoarabinomannan in HIV-infected and noninfected patients with tuberculosis. Clin. Exp. Immunol. 91:25-29.
30. Daniel, T. M., M. J. Oxtoby, E. M. Pinto, and E. S. Moreno. 1981. The immune spectrum in patients with pulmonary tuberculosis. Am. Rev. Respir. Dis. 123:556-559.
31. Denison, C. 1898. The antitoxin treatment of tuberculosis. JAMA 30:290-294.
32. De Schweinitz, E. A., and M. Dorset. 1897. Some products of the tuberculosis bacillus and the treatment of experimental tuberculosis with antitoxic serum. N. Y. Med. J. 66:105-111.
33. Devi, S. J. N. 1996. Preclinical efficacy of glucuronoxylomannan-tetanus toxoid conjugate vaccine of Cryptococcus neoformans in a murine model. Vaccine 14:841-844.
34. Drexhage, H. A., B. M. E. Blomberg-Flier, and W. B. Berg. 1980. Studies on the effect of mycobacterial antibodies on skin-test reactivity to M. tuberculosis. Br. J. Exp. Pathol. 61:186-194.
35. Dromer, F., J. Charreire, A. Contrepois, C. Carbon, and P. Yeni. 1987. Protection of mice against experimental cryptococcosis by anti-Cryptococcus neoformans monoclonal antibody. Infect. Immun. 55:749-752.
36. Dunlap, N. E., and D. E. Briles. 1993. Immunology of tuberculosis. Med. Clin. North Am. 77:1235-1251.
37. Emmart, E. W., and F. B. Seibert. 1945. The effect of tuberculous and sensitized sera and serum fractions on the development of tubercles in the chorio-allantoic membrane of the chick. J. Immunol. 50:143-160.
38. Fisch, C. 1897. The antitoxic and bactericidal properties of the serum of horses treated with Koch's new tuberculin. JAMA 29:882-889.
39. Flick, L. F. 1905. Serum treatment in tuberculosis. Rep. Henry Phipps Inst. 1905:87-102.
40. Fong, J., D. Chin, H. J. Akiyama, and S. S. Elberg. 1959. Studies on tubercle bacillus-monocyte relationship. III. Conditions affecting the action of serum and cells. Modification of bacilli in an immune system. J. Exp. Med. 109: 523-543.
41. Fong, J., P. Schneider, and S. S. Elberg. 1956. Studies on tubercle bacillus-monocyte relationship. I. Quantitative analysis of effect of serum of animals vaccinated with BCG upon bacterium-monocyte system. J. Exp. Med. 104: 455-465.
42. Fong, J., P. Schneider, and S. S. Elberg. 1957. Studies on tubercle bacillus-monocyte relationship. II. Induction of monocyte degeneration by bacteria and culture filtrate: specificity of serum and monocyte effects on resistance to degeneration. J. Exp. Med. 105:25-37.
43. Forget, A., J. C. Benoit, R. Turcotte, and N. Gusew-Chartrand. 1976. Enhancement activity of anti-mycobacterial sera in experimental Mycobacterium bovis (BCG) infection in mice. Infect. Immun. 13:1301-1306.
44. Gamgee, A. 1894. Dr. Viquerat's treatment of tuberculosis. Lancet ii:811-813.
45. Gaussel, M. 1913. Traitment de la tuberculose pulmonaire par le serum de Marmorek. Montpellier Med. 36:561-566.
46. Gheorghiu, M., D. Mouton, H. Lecoeur, M. Lagranderie, J. C. Mevel, and G. Biozzi. 1985. Resistance of high and low antibody responder lines of mice to the growth of avirulent (BCG) and virulent (H37Rv) strains of mycobacteria. Clin. Exp. Immunol. 59:177-184.
47. Gigliotti, F., and W. T. Hughes. 1988. Passive immunoprophylaxis with specific monoclonal antibody confers partial protection against Pneumocystis carinü pneumonitis in animal models. J. Clin. Invest. 81:1666-1668.
48. Haas, D. W., and R. M. Des Prez. 1995. Mycobacterium tuberculosis, p. 2213-2243. In G. L. Mandell, J. E. Bennett, and R. Dolin (ed.), Principal and practice of infectious diseases. Churchill Livingstone, Inc., New York, N.Y.
49. Han, Y., and J. E. Cutler. 1995. Antibody response that protects against disseminated candidiasis. Infect. Immun. 63:2714-2719.
50. Hanks, J. H., and E. Brockenbrough. 1940. The action of serum cells and blood on acid-fast bacteria in vitro. I. Absence of in vitro bactericidal power against human tubercle bacilli or Timothy bacilli in the serum-leucocyte mixtures or the blood of normal and immunized rabbits. Am. Rev. Tuberc. 41:605-619.
51. Hanson, R. 1936. Report on therapeutic tests in certain forms of tuberculosis with an antituberculosis serum prepared by J. Reenstierna. Acta Med. Scand. Suppl. 73:1-88.
52. Hayden, A. M. 1896. Report of results and recoveries obtained by the use of anti-tubercle serum. JAMA 26:965-966.
53. Hemsted, H. 1909. A case of disseminated tuberculosis treated with Marmorek's serum. Br. Med. J. ii:1337-1338.
54. Holmes, A. M. 1899. A further report on the use of "anti-phthisic serum T.R." (Fisch) in tuberculosis. JAMA 33:886-888.
55. Ingraham, C. W. 1895. Serum therapy in pulmonary tuberculosis, with an explanation of secondary symptoms following the administration of anti-toxin. JAMA 24:661-662.
56. Josset, A. 1924. Les conditions de succès de la sérotherapie antituberculeuse chez l'homme. Bull. Mem. Soc. Med. Hop. Paris 40:923-939.
57. Josset, A. 1924. Resultats experimentaux de la sérotherapie antituberculeuse. Bull. Mem. Soc. Hop. Paris 40:826-831.
58. Josset, A. 1924. Seize années de sérotherapie antituberculeuse. Bull. Mem. Soc. Med. Hop. Paris 40:777-781.
59. Kardito, T., and J. M. Grange. 1980. Immunological and clinical features of smear-positive pulmonary tuberculosis in East Java. Tubercle 61:231-238.
60. Koch, R. 1891. Weitere Mitteilung über das Tuberkulin. Dtsch. Med. Wochenschr. 17:1189-1192.
61. Kreidler, W. A., and C. W. Nissler. 1939. Bacteriostatic power of serum in pulmonary tuberculosis. Am. Rev. Tuberc. 40:604-606.
62. Latham, A. 1904. On the use of Dr. Marmorek's antituberculous serum. Lancet i:979-981.
63. Lehmann, J. 1946. Para-aminosalicylic acid in the treatment of tuberculosis. Lancet i:15-16.
64. Lemen, J. R. 1898. Three years of serum therapy in tuberculosis. N. Y. Med. J. 67:672-677.
65. Lenzini, L., P. Rottoli, and L. Rottoli. 1977. The spectrum of human tuberculosis. Clin. Exp. Immunol. 27:230-237.
66. Loeb, H. W. 1895. Experience with Paquin's antitubercle serum in the treatment of laryngeal tuberculosis. N. Y. Med. J. 62:425-430.
67. Lurie, M. B. 1942. Studies on the mechanism of immunity in tuberculosis. The fate of tubercle bacilli injested by mononuclear phagocytes derived from normal and immunized animals. J. Exp. Med. 75:247-267.
68. Lurie, M. B., and P. Zappasodi. 1941. III. Experimental study of certain factors related to hereditary constitutional resistance to tuberculosis. Am. Rev. Tuberc. 44(Suppl. 3):80-111.
69. Lurie, M. B. 1941. IV. Hereditary constitution and tuberculosis. Summary and discussion. Am. Rev. Tuberc. 44(Suppl. 3):112-125.
70. Maragliano, C. 1896. Le sérum antituberculeux et son antitoxine. Rev. Tuberc. 1896:131-138.
71. Maragliano, E. 1896. Première statistique du traîtement de la tuberculose par la sérum Maragliano. Rev. Tuberc. 1896:156-157.
72. Marmorek, A. 1903. Antituberculous serum and "vaccine." Lancet ii:1642-1645.
73. Mazanec, M. B., C. S. Kaetzel, M. E. Lamm, and D. Fletcher. 1992. Intracellular neutralization of virus by immunoglobulin A antibodies. Proc. Natl. Acad. Sci. USA 89:6901-6905.
74. Middlebrook, G., and R. J. Dubos. 1948. Specific serum agglutination of erythrocytes sensitized with extracts of tubercle bacilli. J. Exp. Med. 88: 521-528.
75. Mineo, J. R., I. A. Khan, and L. H. Kasper. 1994. Toxoplasma gondii: a monoclonal antibody that inhibits intracellular replication. Exp. Parasitol. 79:351-361.
76. Mitchell, J. P. 1912. Clinical trials with Marmorek's antituberculous serum. Br. Med. J. i:299.
77. Mukherjee, J., G. Nussbaum, M. D. Scharff, and A. Casadevall. 1995. Protective and nonprotective monoclonal antibodies to Cryptococcus neoformans originating from one B cell. J. Exp. Med. 181:405-409.
78. Mukherjee, J., M. D. Scharff, and A. Casadevall. 1992. Protective murine monoclonal antibodies to Cryptococcus neoformans. Infect. Immun. 60: 4534-4541.
79. Mukherjee, S., S. C. Lee, and A. Casadevall. 1995. Antibodies to Cryptococcus neoformans glucuronoxylomannan enhance antifungal activity of murine macrophages. Infect. Immun. 63:573-579.
80. Musher, D. M. 1995. Streptococcus pneumoniae, p. 1811-1826. In G. L. Mandell, J. E. Bennett, and R. Dolin (ed.), Principles and practice of infectious diseases. Churchill Livingstone, Inc., New York, N.Y.
81. Nussbaum, G., W. Cleare, A. Casadevall, M. D. Scharff, and P. Valdom. 1997. Epitope location in the Cryptococcus neoformans capsule is a determinant of antibody efficacy. J. Exp. Med. 185:685-694.
82. Nussbaum, G., R. Yuan, A. Casadevall, and M. D. Scharff. 1996. Immunoglobulin G3 blocking antibodies to the fungal pathogen Cryptococcus neoformans. J. Exp. Med. 183:1905-1909.
83. Orme, I. M. 1995. Prospects for new vaccines against tuberculosis. Trends Microbiol. 3:401-404.
84. Paquin, P. 1895. Anti tubercle serum. JAMA 24:341-346.
85. Paquin, P. 1895. The treatment of tuberculosis by injections of immunized blood serum. JAMA 24:842-845.
86. Paquin, P. 1897. Further report of cases treated with anti-tubercle serum. JAMA 29:98-99.
87. Paquin, P. 1898. How we treat consumption today. JAMA 30:294-299.
88. Peterson, J. C., R. Langercranz, S. I. Rollof, and J. Lind. 1952. Tuberculin hemagglutination studies in active tuberculosis infections, benign and virulent. Acta Paediatr. 41:57-73.
89. Pirofski, L., and A. Casadevall. 1996. Cryptococcus neoformans: paradigm for the role of antibody immunity against fungi? Zentbl. Bakteriol. 284: 475-495.
90. Prioleau, W. H. 1898. Antitubercle serum (Paquin) in tuberculosis. JAMA 31:687-688.
91. Raffel, S. 1946. The relationship of acquired resistance, allergy, antibodies and tissue reactivities to the components of the tubercle bacillus. Am. Rev. Tuberc. 54:564-573.
92. Raviglione, M. C., D. E. Snider, Jr., and A. Kochi. 1995. Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic. JAMA 273:220-226.
93. Reggiardo, Z., and G. Middlebrook. 1974. Failure of passive serum transfer of immunity against aerogenic tuberculosis in rabbits. Proc. Soc. Exp. Biol. Med. 145:173-175.
94. Reiss, F., G. Szilagyi, and E. Mayer. 1975. Immunological studies of anti-cryptococcal factor of normal human serum. Mycopathologia 55:175-178.
95. Richer, A. J. 1905. The therapeutic value of Marmorek's antituberculous serum. N. Y. Med. J. 81:1158-1159.
96. Robbins, J. B., R. Schneerson, and S. C. Szu. 1996. Hypothesis: how licenced vaccines confer protective immunity. Adv. Exp. Med. Biol. 397:169-182.
97. Sanford, J. E., D. M. Lupan, A. M. Schlageter, and T. R. Kozel. 1990. Passive immunization against Cryptococcus neofomans with an isotype-switch family of monoclonal antibodies reactive with cryptococcal polysaccharide. Infect. Immun. 58:1919-1923.
98. Schlesinger, L. S., and M. A. Horwitz. 1990. Phagocytosis of leprosy bacilli is mediated by complement receptors CR1 and CR3 on human monocytes and complement component C3 in serum. J. Clin. Invest. 85:1304-1314.
99. Schlesinger, L. S., and M. A. Horwitz. 1994. A role for natural antibody in the pathogenesis of leprosy: antibody in nonimmune serum mediates C3 fixation to the Mycobacterium leprae surface and hence phagocytosis by human mononuclear phagocytes. Infect. Immun. 62:280-289.
100. Schlesinger, L. S., S. R. Hull, and T. M. Kaufman. 1994. Binding of the terminal mannosyl units of lipoarabinomannan from a virulent strain of Mycobacterium tuberculosis to human macrophages. J. Immunol. 152:4070-4079.
101. Seibert, F. B. 1956. The significance of antigen-antibody reactions in tuberculosis. J. Infect. Dis. 99:76-83.
102. Seibert, F. B. 1958. The interplay of an immune substance with tuberculopolysaccharide and it's antibody in tuberculosis. J. Infect. Dis. 103:52-60.
103. Seibert, F. B., E. E. Miller, U. Buseman, M. V. Seibert, E. Soto-Figueroa, and L. Fry. 1956. The significance of antibodies to tuberculoprotein and polysaccharide in resistance to tuberculosis. Am. Rev. Tuberc. Pulm. Dis. 73:547-562.
104. Seibert, F. B., and J. W. Nelson. 1943. Proteins of tuberculin. J. Am. Chem. Soc. 65:272-278.
105. Seibert, F. B., and M. V. Seibert. 1957. Relationship between immunity and circulating antibodies, complement and tuberculopolysaccharide in tuberculosis. J. Infect. Dis. 101:109-118.
106. Shropshire, L. L. 1896. A limited experience with the Paul Paquin antitubercle serum. N. Y. Med. J. 63:15-16.
107. Smith, D. T., and N. B. Scott. 1950. Clinical interpretation of the middle-brook-Dubos hemagglutination test. Am. Rev. Tuberc. 62:121-127.
108. Snider, D. E. J., M. Raviglione, and A. Kochi. 1994. Global burden of tuberculosis, p. 3-11. In B. R. Barry (ed.), Tuberculosis. Pathogenesis, protection, and control. ASM Press, Washington, D.C.
109. Spahlinger, H. 1922. Note on the treatment of tuberculosis. Lancet i:5-8.
110. Stephani, T., and B. Hudson. 1925. Pulmonary tuberculosis treated by Spahlinger's serum. Br. Med. J. i:43.
111. Stubbert, J. E. 1898. Some statistics upon sero-therapy in tuberculosis. Trans. Am. Climatol. Assoc. 14:214-230.
112. Suter, E. 1953. Multiplication of tubercle bacilli within mononuclear phagocytes in tissue cultures derived from normal animals and animals vaccinated with BCG. J. Exp. Med. 97:235-245.
113. Trudeau, E. L., and E. R. Baldwin. 1898. Experimental studies on the preparation and effects of antitoxins for tuberculosis. Am. J. Med. Sci. 116:692-707.
114. Trudeau, E. L., and E. R. Baldwin. 1899. Experimental studies on the preparation and effects of antitoxins for tuberculosis. Am. J. Med. Sci. 117:56-76.
115. Tsuji, S, K. Ito, and S. Oshima. 1957. The role of humoral factors in native and acquired resistance to tuberculosis. Am. Rev. Tuberc. Pulm. Dis. 76: 90-102.
116. Vallée, H. 1909. Sur le proprietés du sérum du cheval hyperimmunisé contre la tuberculose à l'aide de bacilles humains virulents. C. R. Seance Soc. Biol. 67:700-702.
117. Vallée, H., and G. Finzi. 1910. Sur le précipito-diagnostic de la tuberculose et les proprietés du serum du cheval hyperimmun contre cette infection. C. R. Seance Soc. Biol. 68:259-260.
118. Venisse, A., J. J. Fournié, and G. Puzo. 1995. Mannosylated lipoarabinomannan interacts with phagocytes. Eur. J. Biochem. 231:440-447.
119. Vordermeier, H. M., N. Venkataprasad, D. P. Harris, and J. Ivanyi. 1996. Increase of tuberculous infection in the organs of B cell-deficient mice. Clin. Exp. Immunol. 106:312-316.
120. Waxham, F. E. 1898. Report of cases of tuberculosis treated with antiphthisic serum T.R. (Fisch). JAMA 30:643-646.
121. Yuan, R., A. Casadevall, J. Oh, and M. D. Scharff. 1997. T cells cooperate with passive antibody to modify Cryptococcus neoformans infection in mice. Proc. Natl. Acad. Sci. USA 94:2483-2488.
122. Yuan, R., A. Casadevall, G. Spira, and M. D. Scharff. 1995. Isotype switching from IgG3 to IgG1 converts a nonprotective murine antibody to Cryptococcus neoformans into a protective antibody. J. Immunol. 154:1810-1816.
123. Zaheer, S. A., K. R. Beena, H. K. Kar, A. K. Sharma, R. S. Misra, A. Mukherjee, R. Mukherjee, H. Kaur, R. M. Pandey, R. Walia, et al. 1995. Addition of immunotherapy with Mycobacterium w vaccine to multi drug therapy benefits multibacillary leprosy patients. Vaccine 13:1102-1110.
124. Zebedee, S. L., R. K. Koduri, J. Mukherjee, S. Mukherjee, S. Lee, D. F. Sauer, M. D. Scharff, and A. Casadevall. 1994. Mouse-human immunoglobulin G1 chimeric antibodies with activities against Cryptococcus neoformans. Antimicrob. Agents Chemother. 38:1507-1514.
125. Zitrin, C. M., and O. Wasz-Höckert. 1957. Preliminary experiments on passive transfer of protective humoral antibodies in tuberculosis. Am. Rev. Tuberc. Pulm. Dis. 76:256-262.