Non-tuberculous mycobacterial infection and reactive dermatosis associated with adult-onset immunodeficiency due to anti–interferon-gamma autoantibodies

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Editor: Maya Saranathan. The skin is affected most commonly, followed by the lymph nodes and blood [6] . We describe an anti-IFN-g autoantibodypositive patient with NTM infection and intractable reactive dermatosis.

Case report
A 69-year-old Chinese man presented with a 2-month history of pruritic skin lesions on his forearms, trunk, and legs in October 2017. The lesions showed thickening, erythema, and desquamation (Fig. 1A). From June 2015 to April 2017, he had intermittent fever and was diagnosed with five opportunistic infections without conventional immunosuppression-associated factors through culture or tissue biopsy (Salmonella typhi, Mycobacterium sp., Candida sp., Burkholderia cepacia, and Talaromyces marneffei; Table 1). The patient received chemotherapy for tuberculosis from October 2015 to October 2017, but the foci showed no absorption.
The patient's white blood cell count was normal (21.8% eosinophils; absolute eosinophil count, 1.70 Â 10 9 /L). Immunological testing revealed elevated immunoglobulin (Ig)E (622.5 IU/ mL) and IgG (30.2 g/L) levels, and reduced total T lymphocyte (49.70%) and CD8 cell (15.0%) concentrations. Ultrasound showed bilateral cervical, axillary, and inguinal lymphadenopathy. Chest computed tomography (CT) revealed patchy shadows in the apical and posterior left upper lobe, and enlarged mediastinal lymph nodes ( Fig. 2A, B). Testing for parasites and human immunodeficiency virus (HIV) antibodies, and radionuclide bone imaging, yielded unremarkable findings. Bronchoscopic, lymph-node, and bone-marrow biopsies revealed no cancer or infection. Skin pathological examination showed nonspecific inflammation with lymphocyte infiltration and a few eosinophils in the edematous dermis, but no evidence of a pathogen (Fig. 3A, B). The patient was anti-IFN-g autoantibody positive, as determined by enzyme-linked immunosorbent assay (see Text, Supplementary Method, Available at: http://links.lww. com/MD/E756 which explains details for measuring anti-IFN-g autoantibody levels).
The case was highly suspicious for NTM infection due to the patient's previous Mycobacterium positivity, the poor effects of anti-tuberculosis treatment, and the patient's anti-IFN-g autoantibody positivity, which conferred a high susceptibility to NTM infection. Moxifloxacin (0.4 g/d) and clarithromycin (0.5 g/d) treatment was initiated, combined with antihistamines for eczematous dermatitis. The skin invasion had improved somewhat 10 days later. The patient continued the anti-NTM treatment for 2 months, and then elected to stop it. In the subsequent 3 months, he complained repeatedly of pruritis and erythematous edema, with persistent elevated IgE level and eosinophil count. Oral prednisone (30 mg/d) was initiated for reactive dermatitis due to anti-IFN-g autoantibody positivity, and the skin symptoms improved dramatically (Fig. 1B). One month after initiation of prednisone treatment, the patient developed enlargement of the cervical lymph nodes and pain, and was restarted on anti-NTM treatment consisting of moxifloxacin and clarithromycin. Glucocorticoids were reduced gradually and stopped 8 weeks later, but the skin symptoms relapsed readily thereafter. Thus, corticosteroid treatment was resumed and adjusted according to these symptoms.
During 2 years of follow-up, the patient was hospitalized twice during glucocorticoid use for cough and worsening of lung lesions (visualized by CT, Fig. 2C, D). He had elected to discontinue the anti-NTM treatment before being admitted to hospital. To improve his skin symptoms and reduce the risk of infection, the anti-NTM and glucocorticoid regimens were maintained after discharge. Compound sulfamethoxazole and ethambutol were added, according to the patient's clinical condition. Thereafter, the patient's clinical condition remained  stable, without opportunistic infection and with reduction of the IgE level and eosinophil count, largely steady autoantibody levels ( Table 2) and lung lesions absorption (Fig. 2E, F)

Discussion
Adult-onset immunodeficiency due to anti-IFN-g autoantibodies is associated with opportunistic infections, commonly NTM infection and others [3][4][5] . Despite the lack of culture evidence, our patient's previous Mycobacterium positivity, susceptibility to NTM infection due to anti-IFN-g autoantibody positivity, lung involvement, and therapeutic response support the diagnosis of NTM infection. Thus, we consider that this suspected diagnosis is credible. The patient required long-term anti-NTM treatment to prevent the development of lung lesions on progression. We highlights that clinicians should be vigilant for NTM infection in patients with anti-IFN-g autoantibodies, even when culture results are negative. Skin involvement, classified as reactive or infective dermatosis, is common in patients with anti-IFN-g autoantibodies [6] . We considered our case to represent nonspecific reactive dermatosis, given the absence of histological evidence of infection. Persistent IgE elevation and eosinophilia were the patient's prominent characteristics. Absolute eosinophil counts were found to be significantly higher in patients with anti-IFN-g autoantibodies with reactive skin lesions than in those with no reactive skin disease [6] . Given the skin biopsy evidence of eosinophil infiltration and the release of IgE-inducing histamine, proteases, and other mediators [7] , we suggest that the skin lesions were associated with IgE and eosinophil elevation. Some previous cases also showed remarkable elevated IgG [5,8] . Thus we guess that immunoglobulin elevation may be immune disorder associated with presence of anti-IFN-g autoantibody. Reactive dermatosis treatment guidelines are lacking; corticosteroid was used in some cases to improve skin symptoms [2,6] . As our patient's skin symptoms relapsed readily after corticosteroid discontinuation, we consider that corticosteroids effectively suppress skin inflammation in patients with reactive dermatosis. However, more attention should be paid to balancing of the benefits of corticosteroid treatment and infection risk. Our patient underwent long-term anti-NTM and corticosteroid maintenance treatment, which improved his skin symptoms and minimized infection.
In summary, we reported the case of an HIV-negative man with anti-IFN-g autoantibody who developed NTM infection