Mycobacterial and Opportunistic Infections in HIV-Negative Thai and Taiwanese Patients Associated With Autoantibodies to Interferon-gamma

Condition(s) targeted: Immunodeficiency; Mycobacterial Infection; Opportunistic Infection

Phase: N/A

Status: Recruiting

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Overall contact:
Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov

Opportunistic infections are caused by bacteria, mycobacteria, fungi or viruses that do not normally cause infections in people with healthy immune systems. Some of these infections can cause public health concerns, especially in areas with limited access to treatment. People who acquire opportunistic infections usually have diseases that affect their immune systems, such as human immunodeficiency virus (HIV), or do not have enough white blood cells to fight the infection. However, some people acquire opportunistic infections even though they have normal amounts of white blood cells and are free from known diseases that harm their immune systems. This study will investigate some of the reasons that otherwise healthy people get opportunistic infections to learn more about why some people are more likely to have them.

This study will include up to 210 HIV-negative males and females older than 18 years of age who have opportunistic infections. The patients will be drawn from multiple sites in Thailand and Taiwan including Khon Kaen University Hospital, Siriraj Hospital, Ramathibodi Hospital, National Taiwan University Hospital, National Cheng-Kung University Hospital

Patients will undergo an initial evaluation that will include a physical examination, medical history, and blood and urine testing. Additional tests will be conducted if the researchers consider that the tests are medically necessary to treat the opportunistic infection; the results of the tests will be reviewed and saved for study purposes. Depending on the severity of the infection, the initial evaluation may take more than 1 day to complete.

After the evaluation, patients will be given standard and appropriate medicines to treat the infections.

Patients will return for follow-up visits to allow researchers to monitor their condition and to assess how well the patient is responding to the treatment. Patients will be evaluated by the study researchers at least once a year for 2 years following the initial treatment.

Official title: Mycobacterial and Opportunistic Infections in HIV-Negative Thai Patients Associated With Autoantibodies to Interferon-gamma

Study design: Prospective

Detailed description: The acquisition of opportunistic infections has been causally linked to innate and acquired immunodeficiencies. We have recently identified a population of Asian women with autoantibodies to interferon gamma (IFNg), all of whom were diagnosed by virtue of nontuberculous mycobacterial infections. Similar patient populations have been reported from Thailand and Taiwan, and we have found similar autoantibodies in anonymous serum samples from there. In addition, many of the patients who have disseminated or lymphatic nontuberculous infections have had other opportunistic infections (OI), such as salmonella, penicilliosis, and histoplasmosis. Recently, patients who are clinically similar to our Thai population were described in Taiwan. Two of these cases have been diagnosed with IFNG) autoantibodies (unpublished data). The described patients have normal lymphocyte counts and are human immunodeficiency virus (HIV) negative. Therefore, the identification of autoantibodies to a critical cytokine, the occurrence of opportunistic infections, and the lack of other common explanations suggests that this is an important population to study. We propose to enroll patients in a natural history study of non-HIV opportunistic infections to explore the presence of autoantibodies to cytokines, and to examine potential immunogenetic factors influencing the development of this disease. Plasma, cells, and DNA samples will be obtained and stored for use in this study. This study will accrue up to 210 patients over 3 years as per the groups described.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

- INCLUSION CRITERIA:

Patients must meet all of the following criteria at the time of evaluation to be eligible for enrollment into the study cohorts:

Group 1 (NTM alone):

1. Past or current infection with NTM proven by culture or specific DNA detection in the presence of a compatible clinical picture as judged by the responsible clinician and PI on site.

2. HIV negative within 3 months either prior to the diagnosis of OI, or prior to enrollment in this study, if HIV status was unknown at the time of OI

3. No evidence of active malignancy

4. No systemic corticosteroids at time of diagnosis of OI (defined as greater than 4 weeks at a dose greater than 10 mg per day of prednisone within 3 months prior to diagnosis of the NTM)

5. No previously identified immune deficiency

Group 2 (non-NTM OI with or without NTM):

1. Patients must have or have had proven infection with one or more of the following organisms: NTM, disseminated Salmonella, Listeria, Penicillium, Burkholderia pseudomallei, Cryptococcus, Histoplasma, Herpes zoster involving 2 or more non-contiguous dermatomes, or extradermal involvement or other opportunistic infections not listed above, but relevant, as determined by the PI.

2. HIV-negative within 3 months either prior to the diagnosis of OI, or prior to enrollment in this study, if HIV status was unknown at the time of OI diagnosis

3. No evidence of active malignancy

4. No systemic corticosteroids at time of diagnosis of OI (defined as greater than 4 weeks at a dose greater than 10 mg per day of prednisone within 3 months prior to diagnosis of the NTM)

5. No previously identified immune deficiency

Group 3 (diseased control with pulmonary MTB):

1. Active pulmonary MTB, i. e. patients who are AFB positive and responding to therapy for MTB.

2. Diagnosed with the past 6 months.

3. No concurrent infections due to NTM or OI listed under above inclusion criteria for study subjects

4. HIV negative within 3 months either prior to the diagnosis of MTB, or prior to enrollment in this study, if HIV status was unknown at the time of MTB diagnosis

Group 4 (diseased control with disseminated MTB):

Disseminated MTB includes infections involving greater than 2 noncontiguous sites, one of which may include pulmonary disease or greater than 2 separate groups of lymph nodes.

1. Active disseminated MTB or cured disseminated MTB

2. No concurrent infections due to NTM or OI listed under above inclusion criteria for study subjects

3. HIV negative within 3 months either prior to the diagnosis of MTB, or prior to enrollment in this study, if HIV status was unknown at the time of MTB diagnosis

Group 5 (healthy control, anonymous blood bank donors):

Eligibility criteria not applicable.

EXCLUSION CRITERIA:

Patients will be excluded for the following reasons:

1. HIV-positive serostatus

2. Active malignancy

3. Medical conditions requiring immune modulating therapy

4. Any other medical conditions unsuitable for this study as determined by the principal investigator

5. Age less than 18 years

Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov

Srinagarind Hospital, Khon Kaen 40002, Thailand; Recruiting

Related publications:

Dorman SE, Holland SM. Interferon-gamma and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev. 2000 Dec;11(4):321-33. Review.

Patel SY, Ding L, Brown MR, Lantz L, Gay T, Cohen S, Martyak LA, Kubak B, Holland SM. Anti-IFN-gamma autoantibodies in disseminated nontuberculous mycobacterial infections. J Immunol. 2005 Oct 1;175(7):4769-76.

Kampmann B, Hemingway C, Stephens A, Davidson R, Goodsall A, Anderson S, Nicol M, Schölvinck E, Relman D, Waddell S, Langford P, Sheehan B, Semple L, Wilkinson KA, Wilkinson RJ, Ress S, Hibberd M, Levin M. Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-gamma. J Clin Invest. 2005 Sep;115(9):2480-8. Epub 2005 Aug 25.

Starting date: December 2008
Last updated: August 24, 2009