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Profound interferon gamma deficiency in patients with chronic pulmonary nontuberculous mycobacteriosis
BRIEF OBSERVATION
Profound Interferon Gamma Deficiency in Patients with Chronic Pulmonary Nontuberculous Mycobacteriosis Amar Safdar, MD, Dorothy A. White, MD, Diane Stover, MD, Donald Armstrong, MD, Henry W. Murray, MD
C
hronic pulmonary nontuberculous mycobacteriosis, or “Lady Windermere syndrome” (which was inappropriately named after a supposedly fastidious character in an Oscar Wilde play), was originally described in middle-aged women with rib-cage abnormalities who presented with central bronchiectasis involving the lingula and right middle lobe (1,2). Voluntary cough suppression was initially associated with suboptimal drainage of the lower respiratory tract, leading to stasis and infection due to environmental mycobacteria (3). It may be that structural abnormalities of the thorax predispose elderly patients to localized infection and irreversible lung damage (4,5), or that an unrecognized immune deficiency is involved. We evaluated 5 patients with persistent nontuberculous mycobacterial lung infection, focusing on interferon gamma (IFN-␥) secretion, since IFN-␥ is important in host antimycobacterial defenses (6 –9).
PATIENTS AND METHODS Five adult patients who were seronegative for human immunodeficiency virus (HIV) were evaluated during 1997 to 1999 at Memorial Sloan-Kettering Cancer Center because of persistent pulmonary nontuberculous mycobacterial infection. All had some degree of scoliosis or pectus excavatum (2,3); none had any apparent immunologic defect. Isolation and species identification of acid-fast bacilli from respiratory tract specimens and antibiotic susceptibility testing were performed using National Committee for Clinical Laboratory Standards methods. Persistent (refractory) infection was defined as the presence of symptoms and a positive sputum and/or bronchial culture for ⬎6 months despite treatment. Infection involving two or more noncontiguous body sites was considered disseminated. All participants gave informed consent. 756
©2002 by Excerpta Medica Inc. All rights reserved.
Peripheral blood was collected before the start of antimycobacterial therapy, and in 2 patients after treatment response. Peripheral blood mononuclear cells were separated (10), and T-cell population was typed by FACScan Sorter cytofluoroscopy (Becton Dickinson, Mountain View, California) using anti-CD3, anti-CD4, and antiCD8. T-cell proliferation assays were performed after 72 hours of mitogen stimulation (11). For cytokine release, cells were stimulated with phytohemagglutinin-HA16 (5 g for 2 ⫻ 106 final cell concentration) and phorbal 12myristate 13-acetate (5 ng for 2 ⫻ 106 final cell concentration), or with murine hybridoma anti-human CD3 (1 ⫻ 106 for 2 ⫻ 106 final cell concentration). After 48 hours of incubation of 2 million cells per mL in 10% pooled normal human serum, culture supernatants were collected. Extracellular cytokines were measured by enzyme-linked immunosorbent assay. The limit of detection was 8.0 pg/mL for IFN-␥ and 7.0 pg/mL for interleukin (IL)-2. Median (⫾ SD) laboratory values from 46 healthy controls with no known disease or infection (age range, 22 to 55 years; male-to-female ratio of 1:2) were used for comparison.
Statistical Analysis We compared categorical variables between median values for cytokines in patients and controls using the chisquared test. A P value of ⬍0.05 (two-sided) was considered significant.
RESULTS Patient characteristics at initial presentation are summarized in Table 1. Four patients were white and 1 was of Filipino descent; none were leukopenic (median white blood cell count, 8.5 ⫾ 2.1 ⫻ 103/mm3). All 5 patients had multilobar central bronchiectasis, with involvement of the lingula and the right middle lobe. In response to mitogen stimulation, the median (⫾ SD) IFN-␥ level for the 5 patients was 43-fold lower than that for 35 controls (450 ⫾ 3401 pg/mL vs. 19,400 ⫾ 14,482 pg/mL, P ⫽ 0.001) (Table 2). Similarly, IFN-␥– producing capacity after predominant stimulation of lymphocytes by anti-human CD3 was suppressed in patients by 71-fold compared with controls (250 ⫾ 5552 pg/mL vs. 17,800 ⫾ 13,967 pg/mL, P ⫽ 0.001). In 3 patients after stimulation with mitogens (1300 ⫾ 794 pg/ mL) or anti-human CD3 (340 ⫾ 501 pg/mL), IL-2 levels were reduced by six- to eightfold compared with controls. These differences, however, were not significant (P ⬎0.5). Pulmonary mycobacterial infection resolved in patients 2 and 3 following 12 to 18 months of treatment with clarithromycin plus ciprofloxacin (patient 2) and 0002-9343/02/$–see front matter PII S0002-9343(02)01313-X
azithromycin, clofazimine, cycloserine, and inhaled kanamycin (patient 3) (Table 2). Before therapy, their lymphocytes showed relatively intact in-vitro mitogenrelated proliferation (patient 2: 5565 cpm; patient 3: 59,264 cpm; range in controls: 69,354 to 290,891 cpm). Preserved T-cell proliferation was also seen following anti-CD3 stimulation (patient 2: 27,795 cpm; patient 3: 41,724 cpm; range in controls: 50,931 to 294,724 cpm). Before treatment, IFN-␥ secretion in these patients was markedly suppressed; however, there was no significant improvement in cytokine secretion following treatment. Suppressed helper T-cell type 1 cytokine release (IFN-␥ and IL-2) was not associated with changes in CD4 cell count after treatment, which had doubled in patient 2 but remained unchanged in patient 3.
M. avium
Multiple relapses over 10 years (refractory disease) Multiple relapses over 10 years Persistent infection Mycobacterium simiae
Bilateral diffuse reticulonodular consolidation Bilateral reticulonodular consolidation, severe bronchiectasis
Breast cancer, in remission None
DISCUSSION
82/F
74/F
4
5
F ⫽ female; M ⫽ male.
51/F 3
Cough, anorexia, fatigue, depression Cough, fatigue, cachexia, depression
71/M 2
Fever, night sweats, cough, emaciation, depression
M. avium
Multiple relapses over 25 years (refractory disease) M. avium
Adenocarcinoma of prostate and renal oncocytoma, both in remission None Bilateral lower lobe bronchiectasis, multicentric peribronchial infiltrates
Multiple relapses over 10 years Mycobacterium avium None
Diffuse bilateral reticulonodular consolidation, noncalcified granulomas Bilateral cystic bronchiectasis, peribronchial consolidation 1
Fever, night sweats, anorexia, cough, emaciation, depression Cough, emaciation, depression 70/F
Patient
Clinical Presentation
Findings from Computed Tomographic Scan of Chest Age (years)/ Sex
Table 1. Characteristics of the 5 Patients at Initial Presentation
Underlying Disease
Mycobacterium Species
Response to Prior Antimycobacterial Therapy
Interferon Gamma Deficiency in Refractory Mycobacterial Infection/Safdar et al
Pulmonary infection due to opportunistic low-virulence mycobacteria such as Mycobacterium avium develops in patients who have preexisting lung disease, such as advanced chronic obstructive pulmonary disease (12,13), or those with profound CD4⫹ cell depletion due to HIV infection (14). There have been several cases of M. avium–Mycobacterium intracellulare pulmonary infection in women aged ⬎60 years with no known risk factors, who present with insidious focal infection involving progressive structural lung damage and multicentric bronchiectasis (15). Failure to respond to treatment, or relapse following apparently successful antimicrobial therapy, is common (1,16), as was observed in our patients. Some also had multiple relapses and persistent isolated pulmonary mycobacteriosis accompanied by permanent destruction of lung architecture. Interferon gamma is important in antimycobacterial host defense, through containment and eradication of intracellular organisms via macrophage activation (6 –9). Granuloma formation at infected tissue sites, which is thought to be critical in this setting, also involves IFN-␥ (17). The 5 patients in our study had a profound defect in IFN-␥ secretion that may have resulted from one of several mechanisms, including suboptimal generation of primary inducers such as IL-2, IL-12, and IL-18 (9); the persistent presence of suppressive cytokines such as IL-4, IL-10, and IL-13; failure in the lung to shift from a dominant down-regulating helper T-cell type 2 cell–associated response to a predominant activating helper T-cell type 1 cell–associated response (18,19); macrophage deactivation (20); or low CD4 T-cell counts. We suspect that this defect in patients with chronic pulmonary mycobacteriosis may predispose to persistent nontuberculous mycobacterial infections (8,21). Dysfunction in the lymphocyte-cytokine-macrophage axis may be independent of the prolonged pulmonary suppurative process,
December 15, 2002
THE AMERICAN JOURNAL OF MEDICINE威
Volume 113 757
Interferon Gamma Deficiency in Refractory Mycobacterial Infection/Safdar et al
Table 2. Extracellular Cytokine Profile by ELISA after Mitogen and Anti-Human CD3 Stimulation of the Peripheral Blood Mononuclear Cells Phytohemagglutinin ⫹ Phorbal 12-Myristate 13-Acetate
Anti-Human CD3 Antibodies
CD4 T Cells (cells/mm3 [%])
Interferon Gamma (pg/mL)
Interleukin 2 (pg/mL)
Interferon Gamma (pg/mL)
Interleukin 2 (pg/mL)
70 768 ⫾ 248
35 19,400 ⫾ 14,482
41 11,272 ⫾ 6509
39 17,800 ⫾ 13,967
46 1998 ⫾ 1378
NA 236 [55] 559 [56] 499 [41] 436 [42] 295 [17] 593 [39]
450 125 125 380 1900 3800 8000
NA 1300 125 1000 1000 NA 2500
8800 125 125 250 460 11,500 120
NA 325 180 1200 1200 NA 340
Healthy controls (n) Median value ⫾ SD Patients 1 2 4 months post-treatment 3 8 months post-treatment 4 5
ELISA ⫽ enzyme-linked immunosorbent assay; NA ⫽ not available.
since cytokine deficiency persisted despite a clinical response to antimicrobial therapy, or may be independent of deficient CD4 cells, since the number of cells was not invariably low in IFN-␥– deficient patients before or after treatment. Holland et al. (22) reported clinical improvement following IFN-␥ treatment in 7 patients with disseminated, multiorgan disease due to M. avium complex and Mycobacterium kansasii. There was a notable decrease in IFN-␥– generating capacity in all patients, most likely related to an IL-12 deficiency (23), and the favorable clinical response was induced by adjuvant recombinant cytokine and antimicrobial therapy (22). Thus, adjuvant cytokine therapy using either IFN-␥ or its inducers, such as IL-2, IL-12, or IL-18, may be beneficial in patients with chronic pulmonary nontuberculous mycobacteriosis.
ACKNOWLEDGMENT We acknowledge the generous help of Katherine M. Smith and the staff of the Cellular Immunology Laboratory, Department of Clinical Laboratories, Memorial Sloan-Kettering Cancer Center, New York, New York.
REFERENCES 1. Prince DS, Peterson DD, Steiner RM, et al. Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med. 1989;321:863–868. 2. Reich JM, Johnson RE. Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern. The Lady Windermere syndrome. Chest. 1992;101:1605–1609. 3. Dhillon SS, Watanakunakorn C. Lady Windermere syndrome: middle lobe bronchiectasis and Mycobacterium avium complex infection due to voluntary cough suppression. Clin Infect Dis. 2000; 30:572–575. 758
December 15, 2002
THE AMERICAN JOURNAL OF MEDICINE威
4. Iseman MD, Buschman DL, Ackerson LM. Pectus excavatum and scoliosis: thoracic anomalies associated with pulmonary disease due to M. avium complex. Am Rev Respir Dis. 1991;144:914 –916. 5. Iseman MD. That’s no lady [letter]. Chest. 1996;109:1411–1412. 6. Remus N, Reichenbach J, Picard C, et al. Impaired interferon gamma-mediated and susceptibility to mycobacterial infection in childhood. Pediatr Res. 2001;50:8 –13. 7. Ehlers S, Richter E. Differential requirement for interferon-gamma to restrict the growth of or eliminate some recently identified species of nontuberculous mycobacteria in vitro. Clin Exp Immunol. 2001;124:229 –238. 8. Greinert U, Schlaak M, Rusch-Gerdes S, et al. Low in vitro production of interferon-gamma and tumor necrosis factor-alpha in HIVseronegative patients with pulmonary disease caused by nontuberculous mycobacteria. J Clin Immunol. 2000;20:445–452. 9. Holland SM. Immunotherapy of mycobacterial infection. Semin Respir Infect. 2001;16:47–59. 10. Lucas KG, Small TN, Heller G, et al. The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation. Blood. 1996;87:2594 –2603. 11. Goldbach-Mansky R, King PD, Taylor AP, Dupont B. A co-stimulatory role for CD28 in the activation of CD4⫹ T lymphocytes by staphylococcal enterotoxin B. Int Immunol. 1992;4:1351–1360. 12. Engbaek HC, Vermann B, Bentzon MW. Lung disease caused by Mycobacterium avium/Mycobacterium intracellulare: an analysis of Danish patients during the period 1962–1976. Eur J Respir Dis. 1981;62:72–76. 13. Teirstein AS, Damsker B, Kirschner PA, et al. Pulmonary infection with Mycobacterium avium-intracellulare: diagnosis, clinical patterns, treatment. Mt Sinai J Med. 1990;57:209 –215. 14. Horsburgh CRJ. Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N Engl J Med. 1991;324: 1332–1338. 15. Kubo K, Yamazaki Y, Hachiya T, et al. Mycobacterium avium-intracellulare pulmonary infection in patients without known predisposing lung disease. Lung. 1998;176:381–391. 16. Huang JH, Kao PN, Adi V, Ruoss SJ. Mycobacterium avium-intracellulare pulmonary infection in HIV-negative patients without preexisting lung disease: diagnosis and management limitations. Chest. 1999;115:1033–1040.
Volume 113
Interferon Gamma Deficiency in Refractory Mycobacterial Infection/Safdar et al 17. Hansch HC, Smith DA, Mielke ME, et al. Mechanism of granuloma formation in murine Mycobacterium avium infection: the contribution of CD4⫹ T cells. Int Immunol. 1996;8:1299 –1310. 18. Heurlin N, Bratel T, Andersson J, et al. Lack of T-helper lymphocytes in BAL fluid from a HIV-negative patient with recurrent nontuberculous mycobacterial lung infection. Scand J Infect Dis. 1996; 28:625–628. 19. Heurlin N, Bergstrom SE, Andersson SE, et al. Lack of T-lymphocytosis and poor interferon gamma production in BAL fluid from HIV-negative immunocompetent patients with pulmonary nontuberculous mycobacteriosis. Scand J Infect Dis. 1998;30:339 –343. 20. Gomez-Flores R, Tamez-Guerra R, Tucker SD, et al. Bidirectional effect of IFN-gamma on growth of Mycobacterium avium complex in murine peritoneal macrophages. J Interferon Cytokine Res. 1997; 17:331–336. 21. Vankayalapati R, Wizel B, Samten B, et al. Cytokine profiles in immunocompetent persons infected with Mycobacterium avium complex. J Infect Dis. 2001;183:478 –484. 22. Holland SM, Eisenstein EM, Kuhns DB, et al. Treatment of refrac-
tory disseminated nontuberculous Mycobacterial infection with interferon gamma. N Engl J Med. 1994;330:1348 –1355. 23. Greinert U, Ernst M, Schlaak M, Entzian P. Interleukin-12 as successful adjuvant in tuberculosis treatment. Eur Res J. 2001;17: 1049 –1051.
From the Infectious Diseases Service (AS, DA) and Pulmonary Service (DAW, DS), Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; and the Infectious Diseases Service (AS, DA) and Pulmonary Service (DAW, DS), Department of Medicine (HWM), Weill Medical College of Cornell University, New York, New York. Dr. Safdar is now with the Division of Infectious Diseases, Department of Medicine, University of South Carolina School of Medicine, Columbia, South Carolina. Requests for reprints should be addressed to Amar Safdar, MD, Department of Medicine, Division of Infectious Diseases, University of South Carolina School of Medicine, Two Medical Park, Suite 502, Columbia, South Carolina 29206, or [email protected]. Manuscript submitted March 6, 2002, and accepted in revised form August 5, 2002.
December 15, 2002
THE AMERICAN JOURNAL OF MEDICINE威
Volume 113 759
Profound Interferon Gamma Deficiency in Patients with Chronic Pulmonary Nontuberculous Mycobacteriosis Amar Safdar, MD, Dorothy A. White, MD, Diane Stover, MD, Donald Armstrong, MD, Henry W. Murray, MD
C
hronic pulmonary nontuberculous mycobacteriosis, or “Lady Windermere syndrome” (which was inappropriately named after a supposedly fastidious character in an Oscar Wilde play), was originally described in middle-aged women with rib-cage abnormalities who presented with central bronchiectasis involving the lingula and right middle lobe (1,2). Voluntary cough suppression was initially associated with suboptimal drainage of the lower respiratory tract, leading to stasis and infection due to environmental mycobacteria (3). It may be that structural abnormalities of the thorax predispose elderly patients to localized infection and irreversible lung damage (4,5), or that an unrecognized immune deficiency is involved. We evaluated 5 patients with persistent nontuberculous mycobacterial lung infection, focusing on interferon gamma (IFN-␥) secretion, since IFN-␥ is important in host antimycobacterial defenses (6 –9).
PATIENTS AND METHODS Five adult patients who were seronegative for human immunodeficiency virus (HIV) were evaluated during 1997 to 1999 at Memorial Sloan-Kettering Cancer Center because of persistent pulmonary nontuberculous mycobacterial infection. All had some degree of scoliosis or pectus excavatum (2,3); none had any apparent immunologic defect. Isolation and species identification of acid-fast bacilli from respiratory tract specimens and antibiotic susceptibility testing were performed using National Committee for Clinical Laboratory Standards methods. Persistent (refractory) infection was defined as the presence of symptoms and a positive sputum and/or bronchial culture for ⬎6 months despite treatment. Infection involving two or more noncontiguous body sites was considered disseminated. All participants gave informed consent. 756
©2002 by Excerpta Medica Inc. All rights reserved.
Peripheral blood was collected before the start of antimycobacterial therapy, and in 2 patients after treatment response. Peripheral blood mononuclear cells were separated (10), and T-cell population was typed by FACScan Sorter cytofluoroscopy (Becton Dickinson, Mountain View, California) using anti-CD3, anti-CD4, and antiCD8. T-cell proliferation assays were performed after 72 hours of mitogen stimulation (11). For cytokine release, cells were stimulated with phytohemagglutinin-HA16 (5 g for 2 ⫻ 106 final cell concentration) and phorbal 12myristate 13-acetate (5 ng for 2 ⫻ 106 final cell concentration), or with murine hybridoma anti-human CD3 (1 ⫻ 106 for 2 ⫻ 106 final cell concentration). After 48 hours of incubation of 2 million cells per mL in 10% pooled normal human serum, culture supernatants were collected. Extracellular cytokines were measured by enzyme-linked immunosorbent assay. The limit of detection was 8.0 pg/mL for IFN-␥ and 7.0 pg/mL for interleukin (IL)-2. Median (⫾ SD) laboratory values from 46 healthy controls with no known disease or infection (age range, 22 to 55 years; male-to-female ratio of 1:2) were used for comparison.
Statistical Analysis We compared categorical variables between median values for cytokines in patients and controls using the chisquared test. A P value of ⬍0.05 (two-sided) was considered significant.
RESULTS Patient characteristics at initial presentation are summarized in Table 1. Four patients were white and 1 was of Filipino descent; none were leukopenic (median white blood cell count, 8.5 ⫾ 2.1 ⫻ 103/mm3). All 5 patients had multilobar central bronchiectasis, with involvement of the lingula and the right middle lobe. In response to mitogen stimulation, the median (⫾ SD) IFN-␥ level for the 5 patients was 43-fold lower than that for 35 controls (450 ⫾ 3401 pg/mL vs. 19,400 ⫾ 14,482 pg/mL, P ⫽ 0.001) (Table 2). Similarly, IFN-␥– producing capacity after predominant stimulation of lymphocytes by anti-human CD3 was suppressed in patients by 71-fold compared with controls (250 ⫾ 5552 pg/mL vs. 17,800 ⫾ 13,967 pg/mL, P ⫽ 0.001). In 3 patients after stimulation with mitogens (1300 ⫾ 794 pg/ mL) or anti-human CD3 (340 ⫾ 501 pg/mL), IL-2 levels were reduced by six- to eightfold compared with controls. These differences, however, were not significant (P ⬎0.5). Pulmonary mycobacterial infection resolved in patients 2 and 3 following 12 to 18 months of treatment with clarithromycin plus ciprofloxacin (patient 2) and 0002-9343/02/$–see front matter PII S0002-9343(02)01313-X
azithromycin, clofazimine, cycloserine, and inhaled kanamycin (patient 3) (Table 2). Before therapy, their lymphocytes showed relatively intact in-vitro mitogenrelated proliferation (patient 2: 5565 cpm; patient 3: 59,264 cpm; range in controls: 69,354 to 290,891 cpm). Preserved T-cell proliferation was also seen following anti-CD3 stimulation (patient 2: 27,795 cpm; patient 3: 41,724 cpm; range in controls: 50,931 to 294,724 cpm). Before treatment, IFN-␥ secretion in these patients was markedly suppressed; however, there was no significant improvement in cytokine secretion following treatment. Suppressed helper T-cell type 1 cytokine release (IFN-␥ and IL-2) was not associated with changes in CD4 cell count after treatment, which had doubled in patient 2 but remained unchanged in patient 3.
M. avium
Multiple relapses over 10 years (refractory disease) Multiple relapses over 10 years Persistent infection Mycobacterium simiae
Bilateral diffuse reticulonodular consolidation Bilateral reticulonodular consolidation, severe bronchiectasis
Breast cancer, in remission None
DISCUSSION
82/F
74/F
4
5
F ⫽ female; M ⫽ male.
51/F 3
Cough, anorexia, fatigue, depression Cough, fatigue, cachexia, depression
71/M 2
Fever, night sweats, cough, emaciation, depression
M. avium
Multiple relapses over 25 years (refractory disease) M. avium
Adenocarcinoma of prostate and renal oncocytoma, both in remission None Bilateral lower lobe bronchiectasis, multicentric peribronchial infiltrates
Multiple relapses over 10 years Mycobacterium avium None
Diffuse bilateral reticulonodular consolidation, noncalcified granulomas Bilateral cystic bronchiectasis, peribronchial consolidation 1
Fever, night sweats, anorexia, cough, emaciation, depression Cough, emaciation, depression 70/F
Patient
Clinical Presentation
Findings from Computed Tomographic Scan of Chest Age (years)/ Sex
Table 1. Characteristics of the 5 Patients at Initial Presentation
Underlying Disease
Mycobacterium Species
Response to Prior Antimycobacterial Therapy
Interferon Gamma Deficiency in Refractory Mycobacterial Infection/Safdar et al
Pulmonary infection due to opportunistic low-virulence mycobacteria such as Mycobacterium avium develops in patients who have preexisting lung disease, such as advanced chronic obstructive pulmonary disease (12,13), or those with profound CD4⫹ cell depletion due to HIV infection (14). There have been several cases of M. avium–Mycobacterium intracellulare pulmonary infection in women aged ⬎60 years with no known risk factors, who present with insidious focal infection involving progressive structural lung damage and multicentric bronchiectasis (15). Failure to respond to treatment, or relapse following apparently successful antimicrobial therapy, is common (1,16), as was observed in our patients. Some also had multiple relapses and persistent isolated pulmonary mycobacteriosis accompanied by permanent destruction of lung architecture. Interferon gamma is important in antimycobacterial host defense, through containment and eradication of intracellular organisms via macrophage activation (6 –9). Granuloma formation at infected tissue sites, which is thought to be critical in this setting, also involves IFN-␥ (17). The 5 patients in our study had a profound defect in IFN-␥ secretion that may have resulted from one of several mechanisms, including suboptimal generation of primary inducers such as IL-2, IL-12, and IL-18 (9); the persistent presence of suppressive cytokines such as IL-4, IL-10, and IL-13; failure in the lung to shift from a dominant down-regulating helper T-cell type 2 cell–associated response to a predominant activating helper T-cell type 1 cell–associated response (18,19); macrophage deactivation (20); or low CD4 T-cell counts. We suspect that this defect in patients with chronic pulmonary mycobacteriosis may predispose to persistent nontuberculous mycobacterial infections (8,21). Dysfunction in the lymphocyte-cytokine-macrophage axis may be independent of the prolonged pulmonary suppurative process,
December 15, 2002
THE AMERICAN JOURNAL OF MEDICINE威
Volume 113 757
Interferon Gamma Deficiency in Refractory Mycobacterial Infection/Safdar et al
Table 2. Extracellular Cytokine Profile by ELISA after Mitogen and Anti-Human CD3 Stimulation of the Peripheral Blood Mononuclear Cells Phytohemagglutinin ⫹ Phorbal 12-Myristate 13-Acetate
Anti-Human CD3 Antibodies
CD4 T Cells (cells/mm3 [%])
Interferon Gamma (pg/mL)
Interleukin 2 (pg/mL)
Interferon Gamma (pg/mL)
Interleukin 2 (pg/mL)
70 768 ⫾ 248
35 19,400 ⫾ 14,482
41 11,272 ⫾ 6509
39 17,800 ⫾ 13,967
46 1998 ⫾ 1378
NA 236 [55] 559 [56] 499 [41] 436 [42] 295 [17] 593 [39]
450 125 125 380 1900 3800 8000
NA 1300 125 1000 1000 NA 2500
8800 125 125 250 460 11,500 120
NA 325 180 1200 1200 NA 340
Healthy controls (n) Median value ⫾ SD Patients 1 2 4 months post-treatment 3 8 months post-treatment 4 5
ELISA ⫽ enzyme-linked immunosorbent assay; NA ⫽ not available.
since cytokine deficiency persisted despite a clinical response to antimicrobial therapy, or may be independent of deficient CD4 cells, since the number of cells was not invariably low in IFN-␥– deficient patients before or after treatment. Holland et al. (22) reported clinical improvement following IFN-␥ treatment in 7 patients with disseminated, multiorgan disease due to M. avium complex and Mycobacterium kansasii. There was a notable decrease in IFN-␥– generating capacity in all patients, most likely related to an IL-12 deficiency (23), and the favorable clinical response was induced by adjuvant recombinant cytokine and antimicrobial therapy (22). Thus, adjuvant cytokine therapy using either IFN-␥ or its inducers, such as IL-2, IL-12, or IL-18, may be beneficial in patients with chronic pulmonary nontuberculous mycobacteriosis.
ACKNOWLEDGMENT We acknowledge the generous help of Katherine M. Smith and the staff of the Cellular Immunology Laboratory, Department of Clinical Laboratories, Memorial Sloan-Kettering Cancer Center, New York, New York.
REFERENCES 1. Prince DS, Peterson DD, Steiner RM, et al. Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med. 1989;321:863–868. 2. Reich JM, Johnson RE. Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern. The Lady Windermere syndrome. Chest. 1992;101:1605–1609. 3. Dhillon SS, Watanakunakorn C. Lady Windermere syndrome: middle lobe bronchiectasis and Mycobacterium avium complex infection due to voluntary cough suppression. Clin Infect Dis. 2000; 30:572–575. 758
December 15, 2002
THE AMERICAN JOURNAL OF MEDICINE威
4. Iseman MD, Buschman DL, Ackerson LM. Pectus excavatum and scoliosis: thoracic anomalies associated with pulmonary disease due to M. avium complex. Am Rev Respir Dis. 1991;144:914 –916. 5. Iseman MD. That’s no lady [letter]. Chest. 1996;109:1411–1412. 6. Remus N, Reichenbach J, Picard C, et al. Impaired interferon gamma-mediated and susceptibility to mycobacterial infection in childhood. Pediatr Res. 2001;50:8 –13. 7. Ehlers S, Richter E. Differential requirement for interferon-gamma to restrict the growth of or eliminate some recently identified species of nontuberculous mycobacteria in vitro. Clin Exp Immunol. 2001;124:229 –238. 8. Greinert U, Schlaak M, Rusch-Gerdes S, et al. Low in vitro production of interferon-gamma and tumor necrosis factor-alpha in HIVseronegative patients with pulmonary disease caused by nontuberculous mycobacteria. J Clin Immunol. 2000;20:445–452. 9. Holland SM. Immunotherapy of mycobacterial infection. Semin Respir Infect. 2001;16:47–59. 10. Lucas KG, Small TN, Heller G, et al. The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation. Blood. 1996;87:2594 –2603. 11. Goldbach-Mansky R, King PD, Taylor AP, Dupont B. A co-stimulatory role for CD28 in the activation of CD4⫹ T lymphocytes by staphylococcal enterotoxin B. Int Immunol. 1992;4:1351–1360. 12. Engbaek HC, Vermann B, Bentzon MW. Lung disease caused by Mycobacterium avium/Mycobacterium intracellulare: an analysis of Danish patients during the period 1962–1976. Eur J Respir Dis. 1981;62:72–76. 13. Teirstein AS, Damsker B, Kirschner PA, et al. Pulmonary infection with Mycobacterium avium-intracellulare: diagnosis, clinical patterns, treatment. Mt Sinai J Med. 1990;57:209 –215. 14. Horsburgh CRJ. Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N Engl J Med. 1991;324: 1332–1338. 15. Kubo K, Yamazaki Y, Hachiya T, et al. Mycobacterium avium-intracellulare pulmonary infection in patients without known predisposing lung disease. Lung. 1998;176:381–391. 16. Huang JH, Kao PN, Adi V, Ruoss SJ. Mycobacterium avium-intracellulare pulmonary infection in HIV-negative patients without preexisting lung disease: diagnosis and management limitations. Chest. 1999;115:1033–1040.
Volume 113
Interferon Gamma Deficiency in Refractory Mycobacterial Infection/Safdar et al 17. Hansch HC, Smith DA, Mielke ME, et al. Mechanism of granuloma formation in murine Mycobacterium avium infection: the contribution of CD4⫹ T cells. Int Immunol. 1996;8:1299 –1310. 18. Heurlin N, Bratel T, Andersson J, et al. Lack of T-helper lymphocytes in BAL fluid from a HIV-negative patient with recurrent nontuberculous mycobacterial lung infection. Scand J Infect Dis. 1996; 28:625–628. 19. Heurlin N, Bergstrom SE, Andersson SE, et al. Lack of T-lymphocytosis and poor interferon gamma production in BAL fluid from HIV-negative immunocompetent patients with pulmonary nontuberculous mycobacteriosis. Scand J Infect Dis. 1998;30:339 –343. 20. Gomez-Flores R, Tamez-Guerra R, Tucker SD, et al. Bidirectional effect of IFN-gamma on growth of Mycobacterium avium complex in murine peritoneal macrophages. J Interferon Cytokine Res. 1997; 17:331–336. 21. Vankayalapati R, Wizel B, Samten B, et al. Cytokine profiles in immunocompetent persons infected with Mycobacterium avium complex. J Infect Dis. 2001;183:478 –484. 22. Holland SM, Eisenstein EM, Kuhns DB, et al. Treatment of refrac-
tory disseminated nontuberculous Mycobacterial infection with interferon gamma. N Engl J Med. 1994;330:1348 –1355. 23. Greinert U, Ernst M, Schlaak M, Entzian P. Interleukin-12 as successful adjuvant in tuberculosis treatment. Eur Res J. 2001;17: 1049 –1051.
From the Infectious Diseases Service (AS, DA) and Pulmonary Service (DAW, DS), Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; and the Infectious Diseases Service (AS, DA) and Pulmonary Service (DAW, DS), Department of Medicine (HWM), Weill Medical College of Cornell University, New York, New York. Dr. Safdar is now with the Division of Infectious Diseases, Department of Medicine, University of South Carolina School of Medicine, Columbia, South Carolina. Requests for reprints should be addressed to Amar Safdar, MD, Department of Medicine, Division of Infectious Diseases, University of South Carolina School of Medicine, Two Medical Park, Suite 502, Columbia, South Carolina 29206, or [email protected]. Manuscript submitted March 6, 2002, and accepted in revised form August 5, 2002.
December 15, 2002
THE AMERICAN JOURNAL OF MEDICINE威
Volume 113 759