Effective anti-mycobacterial treatment for BCG disease in patients with Mendelian Susceptibility to Mycobacterial Disease (MSMD): a case series

Abstract

Background Post-vaccination BCG disease typically attests to underlying inborn errors of immunity (IEIs), with the highest rates of complications in patients with Mendelian susceptibility to mycobacterial disease (MSMD). However, therapeutic protocols for the management of BCG-osis (disseminated) and persistent BCG-itis (localized) are still controversial. Methods Twenty-four Iranian patients with MSMD (BCG-osis or BCG-itis), followed from 2009 to 2020 in Tehran, were included in the study. Their medical records were retrospectively reviewed for demographics, clinical features, laboratory findings, and molecular diagnosis. The therapeutic protocol sheets were prepared to contain the types and duration of anti-mycobacterial agents. Results BCG disease either as BCG-itis (33.3%) or BCG-osis (66.7%) was confirmed in all patients by positive gastric washing test (54.2%), microbial smear and culture (58.3%), or purified protein derivative (PPD) test (4.2%). The duration between BCG-osis onset and MSMD diagnosis was 21.6 months. All except three patients were initiated on second-line anti-mycobacterial agents with either a fluoroquinolone (levofloxacin: 15 mg/kg/day, ciprofloxacin: 20 mg/kg/day, ofloxacin: 15 mg/kg/day), aminoglycoside (amikacin: 10–15 mg/kg/day, streptomycin: 15 mg/kg/day), and/or macrolide (clarithromycin: 15 mg/kg/day) along with oral rifampin (10 mg/kg/day), isoniazid (15 mg/kg/day), and ethambutol (20 mg/kg/day). Three patients showed a clinical response to rifampin, despite in vitro resistance. Fourteen (58.3%) patients received also adjuvant subcutaneous IFN-γ therapy, 50 µ/m2 every other day. At the end of survey, most patients (n = 22, 91.7%) were alive and two patients died following BCG-osis and respiratory failure. Conclusions We recommend the early instigation of second-line anti-mycobacterial agents in MSMD patients with BCG disease.

A Novel Homozygous Stop Mutation in IL23R Causes Mendelian Susceptibility to Mycobacterial Disease

“…The connection of IL-23 signaling to mycobacterial disease is based on the observation that IL23a −/− mice have impaired long-term control of pulmonary Mycobacterium tuberculosis infection [ 12 ], the fact that exogenous IL-23 can complement IL-12 deficiency for restoring mycobacterial immunity in mice [ 13 ], the association of a partial LOF variant c.1142G > A (R381Q) with active pulmonary tuberculosis [ 8 ] and the report of a kindred with MSMD harboring a homozygous complete LOF mutation in IL23R [ 7 ]. In addition, a second patient with MSMD and a splice homozygous splice site mutation, c.367 + 1G > A, at the exon 3 of IL23R is reported but the effect of this variant on IL23R expression and signaling was not reported [ 14 ].…”

Ly6G+Granulocytes-derived IL-17 limits protective host responses and promotes tuberculosis pathogenesis

“…These patients develop severe diseases even upon exposure to BCG and respond poorly to anti-TB treatment (Casanova et al, 1995;Mahdaviani et al, 2022). We believe the MSMD phenotype could be a manifestation of the IL-17-neutrophil axis observed in IFNg -/animals.…”

“…A relatively small fraction, but a sizeable number of TB cases, belong to a category known as Mendelian Susceptibility to Tubercular Diseases or MSMD, which typically is caused by a mutation in the IFNγ/IL12p70 pathway, which also acts via regulating IFNγ (Filipe-Santos et al, 2006; Kerner et al, 2020; Levin et al, 1995). These patients develop serious diseases even upon exposure to BCG and respond poorly to anti-TB treatment (Casanova et al, 1995; Mahdaviani et al, 2022). We believe the MSMD phenotype could be a manifestation of the IL-17-PMN axis observed in IFNγ -/- animals.…”

Host-directed immunotherapy to fight infectious diseases

“…While some forms of MSMD are marked by inability to produce IFN-g in response to mycobacteria, others are characterized by a diminished but not absent capacity to respond to it (i.e., partial deficiency). Because the ultimate defect in both of these categories is insufficient activation of IFN-gmediated intracellular killing of mycobacteria, patients in either of these categories usually respond well when antimycobacterial therapy is complemented with recombinant human IFN-g (e.g., 50-200 mg/square meter of body surface area, subcutaneously, three times weekly [42][43][44], or by nebulization [45]). As expected, adjunctive IFN-g is ineffective in patients who have mutations conferring complete deficiency (i.e., absence of function) in their capacity to respond to it.…”