Disseminated <i>Mycobacterium abscessus</i> secondary to adult onset immunodeficiency syndrome due to anti‐interferon gamma autoantibodies

A 34year-old female living in Ireland but originally from rural Cambodia presented to a district general hospital in March 2018 with ahistory of dry cough, headaches and photophobia. She also described otalgia and tinnitus during her inpatient admission. Her past medical history was not significant although her sister was known to be living with an autoimmune disorder of unknown etiology. HIV testing returned negative. Lumbar puncture at the time of presentation demonstrated a lymphocytic pleocytosis and cervical lymph node biopsy demonstrated a granulomatous reaction with areas of caseous necrosis. The patient was transferred to a tertiary referral center. She was commenced on treatment for presumptive disseminated multidrug-resistant TB meningitis based on her epidemiological risk factors with rifampicin, isoniazid, pyrazinamide, ethambutol, amikacin, and moxifloxacin. High-dose steroids were also given. On review by the Ophthalmology team, the patient had evidence of features in keeping with TB papillitis and uveitis. She was discharged from the hospital following recovery from her initial illness on a tapering course of steroids. Shortly after discharge, she deteriorated clinically with the development of bilateral tender nodules on both lower limbs and increasing cervical lymphadenopathy. She was readmitted to the hospital and steroids were restarted when she developed an airway compromise. A repeat biopsy of submental glandular tissue demonstrated a densely lymphocytic infiltrate of a reactive nature with prominent eosinophils. She also had evidence of new but persistent eosinophilia in serum sampling. A focal rash on her face soon became evident and after demonstrating positive toxocara serology, she was treated with albendazole for visceral erythema migrans with symptomatic relief. The facial rash remained however and worsened over a 3-month period. In June 2018, three months after the first presentation, sputum cultures sent for Mycobacterium species flagged positive and were later identified as Mycobacterium abscessus. The patient began a prolonged and complex anti-mycobacterial course of therapy complicated by multiple DDIs, side effects, and secondary bacterial infections. The patient was admitted with relapsing neurological symptoms nearly 3 years after the initial diagnosis and required recommencement of therapy again. Following specialist advice, interferon-gamma (IFN-y) assays were sent for analysis to the United Kingdom. A rare and complex diagnosis of IFN-y auto-antibody syndrome was diagnosed. A decision was made to commence rituximab therapy in an effort to neutralize autoantibodies to IFN-y. The patient has received six cycles of treatment with a plan to continue until autoantibody levels are neutralized. This has led to a good clinical response and allowed for IV antimycobacterial therapy to be stopped in April 2023. She was switched to a daily oral maintenance dose of azithromycin and is reviewed on a 3-monthly basis at the Infectious Diseases outpatient clinic. She has remained clinically stable. This case demonstrates the diagnostic complexity of patients with non-tuberculous mycobacterial (NTM) presentations and the many challenges faced by clinicians in treating such patients. NTM consists of over 200 species and subspecies,1 many of which are pathogenic to humans at both pulmonary and extra-pulmonary sites.2 They are diverse and ubiquitous in the environment and remain notoriously difficult to treat due to the intrinsic resistance of these bacteria to commonly available antibiotics. M. abscessus is defined as one of the rapidly growing NTMs along with subspecies massiliense and bolletii, and poses as a potentially life-threatening infection in a human host, with a complex multi-drug treatment regimen required for treatment.3 This includes the recommendation of macrolide therapy, even in disease caused by strains with inducible or mutational macrolide resistance, for immunomodulatory properties, although the macrolide is not counted as an active drug within the regimen.2 M. abscessus isolates display in vitro resistance to most oral antibiotics and are generally susceptible to a limited number of parenteral agents including tigecycline, imipenem, cefoxitin, and amikacin. No current guidelines exist internationally for the management of disseminated or extrapulmonary NTM infections, with most anti-mycobacterial regimens based on current best evidence for pulmonary NTM infections.3 These regimens are complex and depend largely on macrolide susceptibility to the erm gene with induction treatment phases consisting of a 3–5 drug regimen for several months and further continuation phase lasting anywhere from 12 months or longer, with or without surgical debridement for source control depending on the site of infection.4, 5 This case also highlights the difficulty in elucidating the diagnosis of acquired adult-onset immunodeficiency syndromes such as autoantibodies to IFN-y and the need for further research into targeted immunomodulator therapies for such syndromes.6 Autoantibodies against IFN-γ are associated with severe disseminated opportunistic infection and are increasingly described in the literature, particularly affecting subjects of East Asian ethnicity.7 The control of infection with mycobacteria and salmonella depends on the integrity of the IFN-γ, interleukin-12, and tumor necrosis factor-α pathways.8 Patients with genetic defects tend to present early in life, whereas patients with therapeutic antibody-associated disease have clear risk factors and tend to present in adulthood.9 Given that our patient was of East Asian origin and to date this syndrome is described predominantly in this population, it may be important to ascertain the rates of autoantibodies to IFN-y in Asian diaspora born outside of Asia. Since 2004, there has been an increase in the number of disseminated nontuberculous mycobacterial and other opportunistic infections involving neutralizing anti–IFN-γ autoantibodies described in the literature of adults without human immunodeficiency virus infection and of East Asian origin.10 There is a paucity of data on other cohorts similarly affected outside of East Asia and current literature suggests the possibility that NTM infections in these patients may be only one manifestation of this apparently acquired cellular immunodeficiency syndrome not yet described or observed in other population groups. Finally, this case highlights the need for a dynamic and team-based approach to patient care.11 Our patient required interpreter services, weekly access to outpatient services, liaison with international specialists, and access to the national outpatient parenteral antimicrobial therapy service in an area of Ireland in which it had not been previously available. The cost of a tailor-made individual treatment course to date is also an important factor to consider in an already overburdened public health care system and one which we may see more of going forward. Rhea O'Regan prepared and wrote the initial draft. Eavan G. Muldoon revised and edited the final draft. Both were involved in the clinical care of the patient. The data that support the findings of this study are available from the corresponding author upon reasonable request.