Mendelian susceptibility to mycobacterial is a clinical syndrome, first described in 1951, that predisposes apparently healthy individuals to infections caused by weakly virulent mycobacteria, such as BCG and EM. However, these patients are also susceptible to infections by more virulent Mycobacterium tuberculosis [3]. These diseases are caused due to a defect in the IL-12/IL-23/ISG15-Interferon-γ axis, which is the principal immunological pathway for intra-macrophagic pathogens. The defect in Interferon γ (IFN γ) - mediated signalling is characterized by decreased production or reduced response to IFN γ.
IL12Rß1 deficiency is the most common cause of MSMD and accounts for 44% of the known genetic etiologies. Mycobacterial infections are the most common infections observed in patients with IL-12Rβ1 deficiency (BCG, M.avium, M. avium intracellulare complex, M. chelonae, M. fortuitum etc.) [1]. Vaccination with BCG is known to protect against subsequent infections with EM and recurrent infections with BCG were reported to be relatively rare in these patients. Among the patients who were BCG-vaccinated, 78% patients developed BCG disease [4]. The time period between the BCG vaccination and the development of lymphadenitis in a case series of 10 patients was found to be 2 to 22 months [5]. Index case was vaccinated with BCG at birth and presented at 4 months with enlarged left axillary lymph node diagnosed to be tubercular in origin, possibly BCG lymphadenitis.
IL12 pathway is also involved in protection against Salmonella species, and non-typhoid salmonellosis is the second most common infection described in patients with IL12Rß1 deficiency [6]. A recent study of patients with IL-12Rβ1 deficiency reported salmonellosis in 33.3% of the patients [7]. Staretz-Haham, et al described a case who had six episodes of asymptomatic Salmonella bacteremia who was treated with ceftriaxone on all occasions except for the last episode in which ciprofloxacin was added for 6 weeks [8]. Another case report of a young girl with 4 episodes of salmonella gastroenteritis was treated with third generation cephalosporins during each episode and duration of therapy ranged from 7–14 days. During the fourth episode a course of ciprofloxacin was given for 4 weeks followed by prophylaxis with trimethoprim & sulfamethoxazole [6]. Salmonella bacilli was isolated from the lymph node biopsy in our patient who presented only with low grade fever and lymphadenopathy in the absence of gastrointestinal symptoms. He was treated with third generation cephalosporins for a prolonged duration of 8 weeks and stool culture done prior to discontinuing antibiotics was reported sterile.
Interestingly, there are a few reports of patients with salmonella enteritidis infection who had skin biopsy proven leukocytoclastic vasculitis that responded to antibiotic therapy [4, 9, 10]. Index case presented with intermittent rashes over the face and trunk responsive to topical steroids, possibly a form of cutaneous vasculitis.
Previous case series have reported varied clinical spectrum in patients with IL-12Rβ1 deficiency. Infections with various other intracellular organisms like Nocardia, Klebsiella, Candida, Cryptococcus, Paracoccidiomycosis etc have also been reported in these patients [4, 5, 11]. The profile of previously reported patients with IL-12Rβ1 deficiency has been tabulated in Table S2.
Prognosis of patients with IL-12Rβ1 deficiency is variable and cannot be completely attributed to the underlying immune deficiency. The overall mortality in these patients is 26% and is dependent on several factors such as the age of presentation, the infectious agent and the therapeutics used. Early age of presentation was found to be associated with poorer prognosis compared to patients presenting at a later age. Infection with Salmonella species was found to be associated with a higher mortality rate up to 52% compared to infections with EM (7%) [1]. Individuals with IL-12Rβ1 deficiency treated with prolonged courses of antibiotics and exogenous IFN γ were less likely to undergo surgical resection of the affected areas. Hematopoietic Stem Cell transplantation (HSCT) though a curative option, is not indicated in all patients and be considered in selected cases, especially in those in which there is an HLA-compatible donor available within the family and in settings where IFN γ treatment is not readily available [1, 12]. It must be noted that IFN γ therapy is not readily accessible in resource-limited settings like ours and the index case is doing well on azithromycin prophylaxis.