Current Status of the Management of Mendelian Susceptibility to Mycobacterial Disease in Mainland China

Ying, Wenjing; Liu, Danru; Dong, Xinxin; Wang, Wenjie; Hui, Xiaoying; Hou, Jia‐Woei; Yao, Haili; Zhou, Qinhua; Sun, Bijun; Sun, Jinqiao; Wang, Xiaochuan

doi:10.1007/s10875-019-00672-x

Cited by 21 publications

(24 citation statements)

References 37 publications

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“…The risk of MSMD in STAT1 LOF patients with osteomyelitis was 6.77 times higher than that in those without osteomyelitis (Figure 7). A recent study found that IFN-γ plays a role in inhibiting osteoclastogenesis in human cells, and that this inhibition is weaker in osteoclasts from patients with STAT1 deficiency (38). Another study shows that anti-IFNγ antibodies induce osteoclast formation, probably mediated by RANKL-induced activation of the NF-κB signaling pathway (39).…”

Section: Discussionmentioning

confidence: 99%

Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review

et al. 2021

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Background: Germline mutations in signal transducer and activator of transcription 1 (STAT1), which lead to primary immunodeficiency, are classified as defects in intrinsic and innate immunity. To date, no comprehensive overview comparing GOF with LOF in early-onset immunodeficiency has been compiled.Objective: To collect and systematically review all studies reporting STAT1 GOF and LOF cases, and to describe the clinical, diagnostic, molecular, and therapeutic characteristics of all the conditions.Methods: A systematic review of the PubMed, EMBASE, Web of Science, Scopus, and Cochrane to identify articles published before May 23, 2020. Data pertaining to patients with a genetic diagnosis of STAT1 GOF or LOF germline mutations, along with detailed clinical data, were reviewed.Results: The search identified 108 publications describing 442 unique patients with STAT1 GOF mutations. The patients documented with chronic mucocutaneous candidiasis (CMC; 410/442), lower respiratory tract infections (210/442), and autoimmune thyroid disease (102/442). Th17 cytopenia was identified in 87.8% of those with GOF mutations. Twenty-five patients with GOF mutations received hematopoietic stem cell transplantation (HSCT), and 10 died several months later. Twelve of 20 patients who received JAK inhibitor therapy showed improved symptoms. Twenty-one publications described 39 unique patients with STAT1 LOF mutations. The most common manifestations were Mendelian susceptibility to mycobacterial diseases (MSMD) (29/39), followed by osteomyelitis (16/39), and lymphadenopathy (9/39). Missense, indel, and frameshift mutations were identified as LOF mutations. There were no obvious defects in lymphocyte subsets or immunoglobulin levels. Eighteen patients required antimycobacterial treatment. Three patients received HSCT, and one of the three died from fulminant EBV infection.Conclusions: STAT1 GOF syndrome is a clinical entity to consider when confronted with a patient with early-onset CMC, bacterial respiratory tract infections, or autoimmune thyroid disease as well as Th17 cytopenia and humoral immunodeficiency. HSCT is still not a reasonable therapeutic choice. Immunoglobulin replacement therapy and JAK inhibitors are an attractive alternative. STAT1 LOF deficiency is a more complicated underlying cause of early-onset MSMD, osteomyelitis, respiratory tract infections, and Herpesviridae infection. Anti-mycobacterial treatment is the main therapeutic choice. More trials are needed to assess the utility of HSCT.

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Section: Discussionmentioning

confidence: 99%

Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review

et al. 2021

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“…Hematopoietic stem cell transplantation (HSCT) is the only known curative treatment for patients with complete AR IFNGR1 deficiency, for which IFNGR1 is not expressed, and IFN-γ is not produced. Some patients recover well after HSCT (12,19). However, a high prevalence of graft rejection (even for transplants from a relative with an identical human leukocyte antigen) has been observed due to a high serum level of IFN-γ (19,20).…”

Section: Discussionmentioning

confidence: 99%

“…Some patients recover well after HSCT (12,19). However, a high prevalence of graft rejection (even for transplants from a relative with an identical human leukocyte antigen) has been observed due to a high serum level of IFN-γ (19,20).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Disseminated Mycobacterium intracellulare Infection With More Than 1-Year Follow-Up in a Young Boy With IFNGR1 Deficiency

et al. 2022

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All members of the genus Mycobacterium are collectively labeled as “non-tuberculous mycobacterium” (NTM), with the exception of the Mycobacterium tuberculosis complex and M. leprae. Recently, the incidence of NTM infection and number of cases have been increasing, but their identification remains difficult in some countries. Usually, NTM infections and diseases are associated with primary immunodeficiency diseases (PIDs), and their prognoses can be improved with a timely diagnosis and appropriate treatment. Here, we report a case of a 3-year-old boy with disseminated NTM disease (Mycobacterium intracellulare) and interferon-γ receptor 1 (IFNGR1) deficiency. He presented with skin and soft-tissue disease, disseminated osteomyelitis, and pulmonary disease. Initially, we suspected an infection due to the Bacillus Calmette–Guérin vaccine but later suspected Langerhans cell histiocytosis. Following oral treatment of azithromycin, rifampicin, and ethambutol, his condition improved progressively according to clinical and imaging manifestations. This case highlights the importance of early identification of the pathogen in a timely prescription of specific treatments in PIDs patients. We also discuss our experience of treatment of M. intracellulare disease in patients with IFNGR1 deficiency.

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“…However, they did not receive it regularly and we could not assess its e cacy. Adjuvant IFN-γ therapy can restore macrophage function and provide better control of BCG-osis in patients with CGD and MSMD [24], which seems to particularly improve the prognosis for patients with IL-12Rb1 de ciency [25]. However, it is ineffective in the absence of functional surface receptors observed in autosomal recessive complete IFN-gR1 and IFN-gR2 de ciency [14].…”

Section: Discussionmentioning

confidence: 99%

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

Mahdaviani¹,

Fallahi²,

Jamee³

et al. 2021

Preprint

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Background/purpose: 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. Conclusion: We recommend the early instigation of second-line anti-mycobacterial agents in MSMD patients with BCG disease.

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Current Status of the Management of Mendelian Susceptibility to Mycobacterial Disease in Mainland China

Cited by 21 publications

References 37 publications

Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review

Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review

Case Report: Disseminated Mycobacterium intracellulare Infection With More Than 1-Year Follow-Up in a Young Boy With IFNGR1 Deficiency

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

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