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 Table of Contents  
Year : 2020  |  Volume : 9  |  Issue : 1  |  Page : 91-94

Disseminated Mycobacterium scrofulaceum Infection in a Patient with Anti-Interferon-γ Autoantibodies: A Case Report and Review of the Literature

Division of Infectious Diseases, Faculty of Medicine, Thammasat University, Khlong Nueng, Pathumthani, Thailand

Date of Submission22-Nov-2019
Date of Decision07-Dec-2019
Date of Acceptance01-May-2020
Date of Web Publication6-Mar-2020

Correspondence Address:
Suttichai Visuttichaikit
Division of Infectious Diseases, Faculty of Medicine, Thammasat University, Khlong Nueng, Pathumthani, 12120
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmy.ijmy_182_19

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Mycobacterium scrofulaceum is an environmental mycobacterial species rarely reported to cause disseminated infection in adults. We report the case of a disseminated M. scrofulaceum infection in a 55-year-old nonhuman immunodeficiency virus-infected Thai man with anti-interferon-γ autoantibodies. The clinical signs of the infection improved after the induction regimen with amikacin, rifampicin, ethambutol, and clarithromycin, followed by the consolidation regimen with ethambutol, clarithromycin, and trimethoprim/sulfamethoxazole. Our review of previous reported cases of this infection indicates its association with immune deficiency, complex treatment, and a high rate of unfavorable outcomes.

Keywords: Anti-interferon-γ autoantibodies, disseminated infection, Mycobacterium scrofulaceum, Thai

How to cite this article:
Chaononghin S, Visuttichaikit S, Apisarnthanarak A, Khawcharoenporn T. Disseminated Mycobacterium scrofulaceum Infection in a Patient with Anti-Interferon-γ Autoantibodies: A Case Report and Review of the Literature. Int J Mycobacteriol 2020;9:91-4

How to cite this URL:
Chaononghin S, Visuttichaikit S, Apisarnthanarak A, Khawcharoenporn T. Disseminated Mycobacterium scrofulaceum Infection in a Patient with Anti-Interferon-γ Autoantibodies: A Case Report and Review of the Literature. Int J Mycobacteriol [serial online] 2020 [cited 2021 Oct 28];9:91-4. Available from: https://www.ijmyco.org/text.asp?2020/9/1/91/280140

  Introduction Top

Nontuberculous mycobacterial (NTM) species are environmental pathogens. Slow-growing mycobacterial species are relatively uncommon and have been reported less than rapid-growing mycobacterial species. Mycobacterium scrofulaceum is a slow-growing Runyon II mycobacterial species distributed across a wide range of environments.[1] It is an opportunistic pathogen that has been often associated with lymphadenitis in children. Other clinical diseases caused by M. scrofulaceum were rarely documented. We herein report the case of disseminated M. scrofulaceum infection in a patient with anti-interferon (IFN)-γ autoantibodies presenting with recurrent axillary lymphadenopathy.

  Case Report Top

A 55-year-old Thai man with no known underlying disease presented with a 5-month history of a progressively enlarged left axillary mass, low-grade intermittent fever, anorexia, and significant weight loss. Three months later, the patient came to our hospital, underwent incision and drainage of the mass, and received a 1-week course of oral dicloxacillin. However, 2 weeks later, the left axilla mass recurred, and the patient developed a dry cough.

The physical examination showed normal vital signs. Multiple small cervical lymph nodes, multiple small inguinal lymph nodes, and one left axilla mass (3 cm in diameter with redness, warmth, irregular surface, rubbery consistency, and fixed with the skin underneath) were palpated. Liver function tests were normal except for albumin of 2.9 g/dL and alkaline phosphatase level of 758 U/L. A fourth-generation human immunodeficiency virus (HIV) antibody assay was nonreactive. Sputum examination for acid-fast bacilli was negative three times.

Computed tomography of the chest revealed multifocal mixed irregular subpleural consolidation, fibroreticular opacities, and multiple small centrilobular nodules with tree-in-bud appearance scattered in both lungs [Figure 1]a and [Figure 1]b. Computed tomography of the abdomen revealed a slightly prominent liver and spleen without focal lesion [Figure 1]c, and there were also multiple enlarged nodes [Figure 1]d. Left axillary lymph node biopsy was performed, and tissue pathology showed acute noncaseous granulomatous inflammation which was negative for acid-fast, Grocott's methenamine silver, and periodic acid-Schiff staining. The mycobacterial blood culture subsequently grew M. scrofulaceum.
Figure 1: (a and b) Chest computed tomography revealed multifocal subpleural consolidation, fibroreticular opacities, and multiple centrilobular nodules with tree-in-bud appearance scattered in both lungs. (c and d) Abdominal computed tomography revealed slightly hepatosplenomegaly and multiple enlarged nodes

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The clinical and laboratory data supported the diagnosis of disseminated M. scrofulaceum infection. This isolate was susceptible to amikacin, rifabutin, clarithromycin, linezolid, and trimethoprim/sulfamethoxazole. Intramuscular amikacin plus rifampicin, ethambutol, and clarithromycin were initiated as the induction regimen for 2 months followed by the consolidation regimen of ethambutol plus clarithromycin and trimethoprim/sulfamethoxazole. Given the patient's clinical presentation with NTM infection, a cellular-mediated immune defect other than that caused by HIV infection was suspected. A final diagnosis of anti-IFN-γ autoantibodies was confirmed based on a positive anti-IFN-γ antibody assay. The level of anti-IFN-γ autoantibodies titer was 1:200,000 (reference range <1:100). After 1 month of the antimicrobial treatment, the patient became afebrile and had gained 2 kg of weight. The left axillary lymph node and other lymph nodes had gradually shrunk. The follow-up mycobacterial blood culture result became negative at 4 months after antimicrobial therapy. After 5 months of antimicrobial therapy, immunosuppressive therapy with rituximab was initiated for the treatment of anti-IFN-γ autoantibody along with antimicrobial agents. The patient was doing well at the 6-month follow-up visit.

  Discussion Top

Anti-IFN-γ autoantibody is the cause of adult-onset immunodeficiency syndrome. The disease is commonly found in Southeast Asia. Anti-IFN-γ autoantibodies were detected in 88% of Asian adults with multiple opportunistic infections and caused by adult-onset immunodeficiency akin to that of advanced HIV infection.[2] The sex distribution of this syndrome in Asia is equal, but outside Asia, most patients are female. The association of the disease with HLA-DRB1 and DQB1 alleles, especially HLA-DRB1_15:01, DRB1_16:02, DQB1_05:01, and DQB1_05:02 suggests that this disease is associated with both genetic and environmental factors.[3] In Thailand, the presence of anti-IFN-γ autoantibodies is associated with disseminated NTM diseases manifesting as generalized lymphadenitis and reactive skin lesions.

IFN-γ, cytokines in the cell-mediated immune cascade, produced in response to the infection of an intracellular pathogen. It is mainly secreted by natural killer (NK) cells and T-cells to activate macrophages that can kill the intracellular pathogen.[4] The pathogenesis of anti-IFN-γ autoantibodies is associated with interfering with IFN-γ-interleukin (IL)-12 axis. Anti-IFN-γ autoantibodies can neutralize IFN-γ, resulting in the reduction of IFN-γ to activate macrophages. In addition, a high titer of anti-IFN-γ autoantibodies also inhibits IL-12 production, resulting in decreased stimulation of T-cells and NK cells to produce IFN-γ.

From the literature review, only eight cases, including this case, with detailed descriptions of disseminated M. scrofulaceum infection are reported in [Table 1].[5],[6],[7],[8],[9],[10],[11] In regards to the five adult cases, one patient each had AIDS and leukemia, while no underlying disease was reported in the other two cases.[7],[8],[9],[11] To the best of our knowledge, this is the first reported case of disseminated M. scrofulaceum infection associated with anti-IFN-γ autoantibodies in adults. The reported organ involvement of this infection included the skin (six cases), bone marrow (four cases), lung (six cases), lymph node (four cases), and liver (three cases).
Table 1: Summarized reported cases of disseminated Mycobacterium scrofulaceum infection

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In general, treatment for M. scrofulaceum lymphadenitis is excision of the lymph nodes, but no standard treatment is recommended, and no prospective study was conducted for other forms of infections due to M. scrofulaceum, including disseminated infection. Drug susceptibility testing should be used to guide the treatment regimen which usually comprises three or four active agents. Furthermore, the required treatment periods for disseminated M. scrofulaceum infection are unknown but usually guided by the clinical responses to both infection and underlying diseases.

In-depth study in pulmonary tuberculosis (TB) patients to assess the association of plasma cytokines (IL-2,-4,-6,-10, tumor necrosis factor-α, and IFN-γ) with radiological recovery revealed significantly high IL-2 and -4 at baseline (P =0.001) in slow responders.[12] A recent cross-sectional study of immune profile of pulmonary TB patients revealed significant differences in CD3dim/CD56+ NKT among TB patients with significantly low levels in healthy controls and after treatment completion (P < 0.0001).[13] In addition, the percentage of human regulatory T-cell (Treg) was higher in TB patients than healthy controls. The results of these studies may be useful for targeted immune interventions for disease control in patients with mycobacterial infection.

Various adjunctive therapies have been used to treat patients with anti-IFN-γ autoantibodies, including B-cell depletion therapy with rituximab, which has attracted much attention.[14] Rituximab, a monoclonal antibody, targets CD20 on the surface of B-cell has been used as an adjunct treatment in NTM-infected patients with anti-IFN-γ autoantibodies. Browne et al. reported four patients with refractory NTM infection who were treated with rituximab, resulting in the reduction of autoantibody titer and sustained disease remission.[15]

In our case, immunosuppressive therapy had not been administered until 5 months after initiating antimicrobial therapy. To date, there is no standard guideline or published literature to guide the optimal timing of immunosuppressive agents initiation. Due to the possible harmful effects of immunosuppressive agents, we decided to start rituximab therapy after the clinical symptoms and signs of infection are completely resolved. Our case report and review of the literature suggest that a high index of suspicion should be made for disseminated M. scrofulaceum infection among individuals with anti-IFN-γ autoantibodies. Close monitoring for clinical responses is needed due to the complex treatment regimens and the high rate of an unfavorable outcome.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images, and other clinical information to be reported in the journal. The patient understands that name and initials will not be published, and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367-416.  Back to cited text no. 1
Browne SK. Anticytokine autoantibody-associated immunodeficiency. Annu Rev Immunol 2014;32:635-57.  Back to cited text no. 2
Pithukpakorn M, Roothumnong E, Angkasekwinai N, Suktitipat B, Assawamakin A, Luangwedchakarn V, et al. HLA-DRB1 and HLA-DQB1 are associated with adult-onset immunodeficiency with acquired anti-interferon-gamma autoantibodies. PLoS One 2015;10:e0128481.  Back to cited text no. 3
Wongkulab P, Wipasa J, Chaiwarith R, Supparatpinyo K. Autoantibody to interferon-gamma associated with adult-onset immunodeficiency in non-HIV individuals in Northern Thailand. PLoS One 2013;8:e76371.  Back to cited text no. 4
Lincoln EM, Gilbert LA. Disease in children due to mycobacteria other than Mycobacterium tuberculosis. Am Rev Respir Dis 1972;105:683-714.  Back to cited text no. 5
Dustin P, Demol P, Derks-Jacobovitz D, Cremer N, Vis H. Generalized fatal chronic infection by Mycobacterium scrofulaceum with severe amyloidosis in a child. Pathol Res Pract 1980;168:237-48.  Back to cited text no. 6
Gallo JH, Young GA, Forrest PR, Vincent PC, Jennis F. Disseminated atypical mycobacterial infection in hairy cell leukemia. Pathology 1983;15:241-5.  Back to cited text no. 7
Sanders JW, Walsh AD, Snider RL, Sahn EE. Disseminated Mycobacterium scrofulaceum infection: A potentially treatable complication of AIDS. Clin Infect Dis 1995;20:549.  Back to cited text no. 8
Takemoto Y, Tokuyasu H, Ikeuchi T, Nakazaki H, Nakamatsu S, Kakite S, et al. Disseminated Mycobacterium scrofulaceum infection in an immunocompetent host. Intern Med 2017;56:1931-5.  Back to cited text no. 9
Marazzi MG, Chapgier A, Defilippi AC, Pistoia V, Mangini S, Savioli C, et al. Disseminated Mycobacterium scrofulaceum infection in a child with interferon-gamma receptor 1 deficiency. Int J Infect Dis 2010;14:e167-70.  Back to cited text no. 10
Hsueh PR, Hsiue TR, Jarn JJ, Ho SW, Hsieh WC. Disseminated infection due to Mycobacterium scrofulaceum in an immunocompetent host. Clin Infect Dis 1996;22:159-61.  Back to cited text no. 11
Iqbal NT, Hussain R, Shahid F, Dawood G. Association of plasma cytokines with radiological recovery in pulmonary tuberculosis patients. Int J Mycobacteriol 2016;5:111-9.  Back to cited text no. 12
  [Full text]  
Pandey P, Bhatnagar AK, Mohan A, Sachdeva KS, Vajpayee M, Das BK, et al. Insights in tuberculosis immunology: Role of NKT and T regulatory cells. Int J Mycobacteriol 2019;8:333-40.  Back to cited text no. 13
[PUBMED]  [Full text]  
Chetchotisakd P, Anunnatsiri S, Nanagara R, Nithichanon A, Lertmemongkolchai G. Intravenous Cyclophosphamide therapy for antiIFNgamma autoantibodyassociated Mycobacterium abscessus infection. J Immunol Res 2018;3:1-7.  Back to cited text no. 14
Browne SK, Zaman R, Sampaio EP, Jutivorakool K, Rosen LB, Ding L, et al. Anti-CD20 (rituximab) therapy for anti-IFN-γ autoantibody-associated nontuberculous mycobacterial infection. Blood 2012;119:3933-9.  Back to cited text no. 15


  [Figure 1]

  [Table 1]


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