Disseminated Nontuberculous Mycobacterial Disease

Disseminated Nontuberculous Mycobacterial Disease

Disseminated nontuberculous mycobacterial (NTM) disease refers to the infections caused by nontuberculous mycobacteria in the blood, bone marrow, or two or more non-contiguous organs that are normally sterile. These are opportunistic infections occurring in individuals with underlying immunodeficiency conditions such as HIV infection; those undergoing steroid or biological therapy for underlying diseases, post-organ transplantation; and those with congenital immunodeficiencies (such as Mendelian susceptibility to mycobacterial disease and GATA2 deficiency). Recent years have witnessed an increased research interest in anti-IFNγ neutralizing antibody-positive disseminated NTM disease, an acquired immunodeficiency disorder affecting previously healthy adults.

Anti-IFNγ Neutralizing Antibodies and Adult-onset Immunodeficiency (AOID)

The interferon (IFN)/interleukin (IL)-12 pathway is a crucial immune mechanism against intracellular pathogens, including mycobacteria. Adult-onset immunodeficiency (AOID) refers to a condition where acquired neutralizing autoantibodies against IFNγ lead to immunodeficiency, with disseminated NTM disease being a representative phenotype. In 2000, disseminated NTM disease caused by rapidly growing mycobacteria in an immunocompetent host was reported from Thailand, although the neutralizing antibodies had not been discovered at that time and the condition was described as “a previously unrecognized clinical entity.”⁽¹⁾ Anti-IFNγ neutralizing antibodies were discovered in 2004, and the first cases of disseminated NTM disease due to AOID were reported that same year in Germany ⁽²⁾ and the UK ⁽³⁾. The first case in Japan was reported in 2007 by Kyoto University ⁽⁴⁾, with the second reported in 2009 by Niigata University ⁽⁵⁾. In 2012, the National Institutes of Health (NIH) proposed the concept of AOID, which has since gained widespread recognition ⁽⁶⁾. There has been an increase in reported cases, particularly from East and Southeast Asia, including Thailand, Taiwan, Japan, and China. To date, approximately 100 cases have been diagnosed in Japan, making it an extremely rare disease.

Characteristics of Disseminated NTM due to AOID

Disseminated NTM disease has been reported to occur in previously healthy adults, with a majority of cases involving individuals of Asian descent. The NTM species involved included M. abscessus and Mycobacterium avium complex (MAC); the causative species varied depending on the country of origin and region of residence ⁽⁷⁾,⁽⁸⁾. In Japan, MAC is the most common causative species, accounting for approximately 70% of cases ⁽⁹⁾. In addition to NTM disease, infections caused by intracellular pathogens, such as tuberculosis, salmonella, and cryptococcus, have been reported.

Although NTM disease primarily presents as a disseminated infection, blood cultures are not always positive, and lesions are often found in the lungs, lymph nodes, and bones. Consequently, symptoms are non-specific, such as fever, joint pain, and lymphadenopathy, and the initial diagnosis often suspects cancer or malignant lymphoma. Furthermore, the absence of mycobacterial infection findings in pathology or culture can lead to a delayed diagnosis.

In a Japanese cohort study, most cases were controlled with multidrug antimicrobial therapy, and the prognosis was relatively good. However, a high likelihood of relapse exists if NTM treatment is discontinued. For refractory cases, surgical drainage and therapies such as rituximab (an anti-CD20 monoclonal antibody) or cyclophosphamide have been reported as useful, although these are considered off-label treatments in Japan. In addition, cases of developing malignant lymphoma during the course of the disease have been observed ⁽¹⁰⁾.

Approximately, 80% of previously healthy individuals with disseminated NTM disease exhibit anti-IFNγ autoantibodies ⁽⁶⁾,⁽⁹⁾, and the antibody titer may fluctuate depending on the disease activity ⁽¹¹⁾. The QuantiFERON-TB Gold (QFT) test, one of the antigen-specific IFNγ release assays, is useful for screening these antibodies ⁽¹²⁾. Unlike the T-SPOT assay, which isolates lymphocytes from blood, QFT uses whole blood. Anti-IFNγ autoantibodies neutralize IFNγ secreted by lymphocytes in the patient’s serum upon stimulation with the mitogen. Thus, the positive control is less than 0.5 IU/mL, resulting in “indeterminate.” A research project is currently being conducted at Kumamoto University, Japan, to quantify anti-IFNγ autoantibodies ⁽¹³⁾.