Reply to Tham et al
TO THE EDITOR—Tham et al report 3 patients with nontuberculous mycobacteria (NTM) infections and varying levels of neutralizing anti-interferon-gamma (IFNγ) autoantibodies, highlighting the complex and nonlinear relationship between autoantibody levels and clinical disease [1]. These relationships are quite similar to those we reported previously [2]. It is important to reiterate that the majority of cases of disseminated NTM with anti-IFNγ autoantibodies do not require treatment with rituximab. However, for those with treatment refractory disease who have
persistently high anti-IFNγ neutralizing immunoglobulin G levels, rituximab has been effective [2, 3]. In those settings, the fall and rise of intra-individual titers appear to be good correlates for therapeutic response [2]. Important factors that affect the biologic impact of anti-IFNγ autoantibodies include the antibody type and subclass, the targeted epitope and the binding avidity. In addition, we fully agree that cofactors extrinsic to anti-IFNγ autoantibodies likely influence host susceptibility, such as virulence of the infecting organisms, as well as the patient’s background genetics, nutrition, smoking
CORRESPONDENCE
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CID 2016:63 (15 August)
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status, and general health. However, what virtually all the cases of anti-IFNγ autoantibodies have in common, including those of Tham et al, is precisely the cytokine neutralization that leads to a phenocopy of genetic defects in the IFNγ/ interleukin 12 pathway, suggesting that this is a unifying pathogenic mechanism. Our patient had disseminated, drugsensitive tuberculosis, associated with anti-IFNγ autoantibodies, yet still developed a severe paradoxical immune reaction [4]. This suggests that intact IFNγ signaling is dispensable for the tuberculosis paradoxical reaction. Similar observations have been made with hemophagocytic lymphohistiocytosis in patients with defects in the IFNγ receptor [5]. In summary, we agree with Tham et al that there are likely to be unappreciated
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CID 2016:63 (15 August)
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cofactors, both host and microbial, which determine what level of IFNγ neutralization is required to permit severe infection in any given individual. Those factors and permissive antibody titers vary from person to person, but once it has occurred, the titer is a reasonable longitudinal marker of neutralization severity [2]. Note Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Yingda L. Xie,1 Ray Y. Chen,1 Irini Sereti,2 Christa S. Zerbe,1 Steven M. Holland,1 and Sarah K. Browne3 Laboratory of Clinical Infectious Diseases, 2Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, and 3Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland 1
CORRESPONDENCE
References 1. Tham EH, Huang CH, Soh JY, et al. Neutralizing anti-interferon autoantibody levels may not correlate with clinical course of disease. Clin Infect Dis 2016; 63:572–3. 2. Browne SK, Zaman R, Sampaio EP, et al. Anti-CD20 (rituximab) therapy for anti-IFN-gamma autoantibody-associated nontuberculous mycobacterial infection. Blood 2012; 119:3933–9. 3. Browne SK, Burbelo PD, Chetchotisakd P, et al. Adult-onset immunodeficiency in Thailand and Taiwan. N Engl J Med 2012; 367:725–34. 4. Xie YL, Rosen LB, Sereti I, et al. Severe paradoxical reaction during treatment of disseminated tuberculosis in a patient with neutralizing anti-γ autoantibodies. Clin Infect Dis 2016; 62:770–3. 5. Tesi B, Sieni E, Neves C, et al. Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFNgamma receptor deficiency. J Allergy Clin Immunol 2015; 135:1638–41. Correspondence: S. M. Holland, CRC B3-4141 MSC 1684 Bethesda, MD 20892-1684 ([email protected]). Clinical Infectious Diseases® 2016;63(4):573–4 Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/cid/ciw352
TO THE EDITOR—Tham et al report 3 patients with nontuberculous mycobacteria (NTM) infections and varying levels of neutralizing anti-interferon-gamma (IFNγ) autoantibodies, highlighting the complex and nonlinear relationship between autoantibody levels and clinical disease [1]. These relationships are quite similar to those we reported previously [2]. It is important to reiterate that the majority of cases of disseminated NTM with anti-IFNγ autoantibodies do not require treatment with rituximab. However, for those with treatment refractory disease who have
persistently high anti-IFNγ neutralizing immunoglobulin G levels, rituximab has been effective [2, 3]. In those settings, the fall and rise of intra-individual titers appear to be good correlates for therapeutic response [2]. Important factors that affect the biologic impact of anti-IFNγ autoantibodies include the antibody type and subclass, the targeted epitope and the binding avidity. In addition, we fully agree that cofactors extrinsic to anti-IFNγ autoantibodies likely influence host susceptibility, such as virulence of the infecting organisms, as well as the patient’s background genetics, nutrition, smoking
CORRESPONDENCE
•
CID 2016:63 (15 August)
•
573
status, and general health. However, what virtually all the cases of anti-IFNγ autoantibodies have in common, including those of Tham et al, is precisely the cytokine neutralization that leads to a phenocopy of genetic defects in the IFNγ/ interleukin 12 pathway, suggesting that this is a unifying pathogenic mechanism. Our patient had disseminated, drugsensitive tuberculosis, associated with anti-IFNγ autoantibodies, yet still developed a severe paradoxical immune reaction [4]. This suggests that intact IFNγ signaling is dispensable for the tuberculosis paradoxical reaction. Similar observations have been made with hemophagocytic lymphohistiocytosis in patients with defects in the IFNγ receptor [5]. In summary, we agree with Tham et al that there are likely to be unappreciated
574
•
CID 2016:63 (15 August)
•
cofactors, both host and microbial, which determine what level of IFNγ neutralization is required to permit severe infection in any given individual. Those factors and permissive antibody titers vary from person to person, but once it has occurred, the titer is a reasonable longitudinal marker of neutralization severity [2]. Note Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Yingda L. Xie,1 Ray Y. Chen,1 Irini Sereti,2 Christa S. Zerbe,1 Steven M. Holland,1 and Sarah K. Browne3 Laboratory of Clinical Infectious Diseases, 2Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, and 3Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland 1
CORRESPONDENCE
References 1. Tham EH, Huang CH, Soh JY, et al. Neutralizing anti-interferon autoantibody levels may not correlate with clinical course of disease. Clin Infect Dis 2016; 63:572–3. 2. Browne SK, Zaman R, Sampaio EP, et al. Anti-CD20 (rituximab) therapy for anti-IFN-gamma autoantibody-associated nontuberculous mycobacterial infection. Blood 2012; 119:3933–9. 3. Browne SK, Burbelo PD, Chetchotisakd P, et al. Adult-onset immunodeficiency in Thailand and Taiwan. N Engl J Med 2012; 367:725–34. 4. Xie YL, Rosen LB, Sereti I, et al. Severe paradoxical reaction during treatment of disseminated tuberculosis in a patient with neutralizing anti-γ autoantibodies. Clin Infect Dis 2016; 62:770–3. 5. Tesi B, Sieni E, Neves C, et al. Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFNgamma receptor deficiency. J Allergy Clin Immunol 2015; 135:1638–41. Correspondence: S. M. Holland, CRC B3-4141 MSC 1684 Bethesda, MD 20892-1684 ([email protected]). Clinical Infectious Diseases® 2016;63(4):573–4 Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/cid/ciw352
