Mendelian Susceptibility to Mycobacterial Disease: Retrospective Clinical and Genetic Study in Mexico

Abstract

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disorder characterized by impaired immunity against intracellular pathogens, such as mycobacteria, attenuated Mycobacterium bovis -Bacillus Calmette–Guérin (BCG) vaccine strains, and environmental mycobacteria in otherwise healthy individuals. Retrospective study reviewed the clinical, immunological, and genetic characteristics of patients with MSMD in Mexico. Overall, 22 patients diagnosed with MSMD from 2006 to 2021 were enrolled: 14 males (64%) and eight females. After BCG vaccination, 12 patients (70%) developed BCG infection. Furthermore, 6 (22%) patients developed bacterial infections mainly caused by Salmonella , as what is described next in the text is fungal infections, particularly Histoplasma. Seven patients died of disseminated BCG disease. Thirteen different pathogenic variants were identified in IL12RB1 ( n = 13), IFNGR1 ( n = 3), and IFNGR2 ( n = 1) genes. Interleukin-12Rβ1 deficiency is the leading cause of MSMD in our cohort. Morbidity and mortality were primarily due to BCG infection. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-022-01357-8.

Impact of SARS-CoV-2 infection and COVID-19 on patients with inborn errors of immunity

“…First, the age of affected IEI patients was markedly younger than the general population (∼28 years vs ∼50-plus years). 16 , 44 , 79 , 81 , 84 , 89 , 91 , 93 , 94 , 95 , 100 , 102 , 103 , 104 , 108 , 109 , 110 , 115 There were also differences in age at infection for different IEI. Thus, SARS-CoV-2–infected patients with CVID, periodic fevers, or complement defects were generally older, and patients with defects in innate immune cell signaling due to pathogenic variants in IRAK4, MYD88, or IFNAR1 / IFNAR2 were generally younger, than the entire cohort of published IEI patients ( Fig 1 , A ).…”

“…Over the past 2 years, outcomes of SARS-CoV-2 infection have been reported for ∼1330 individuals with IEI. These studies range from reports of single cases or small numbers of patients 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 to cohort studies from Iran, 89 , 90 , 91 Turkey, 92 , 93 , 94 Brazil, 95 , 96 Israel, 97 Italy, 98 , 99 , 100 , 101 Spain, 102 the United Kingdom, 15 , 103 , 104 Mexico, 105 Denmark, 106 , 107 Poland, 108 …”

“… 91 , 99 , 103 , 115 Consequently, the overall average age at death due to SARS-CoV-2 infection in IEI patients is much younger than the general population ( Fig 2 ; ∼50 years vs ∼80 years). 16 , 44 , 79 , 81 , 84 , 89 , 91 , 93 , 94 , 95 , 100 , 102 , 103 , 104 , 109 , 110 , 115 Thus, in addition to IEI patients’ generally presenting with COVID-19 at a younger age and a greater proportion requiring admission to ICU than the general population, the mortality rate of SARS-CoV-2 infection is greater in IEI, especially at ages where SARS-CoV-2 has a very low—even negligible—CFR in the general population ( Fig 2 ). 16 , 91 , 99 , 103 , 115 …”

Of Mycelium and Men: Inherent Human Susceptibility to Fungal Diseases

“…Most of these fall in the collection of disorders referred to as Mendelian Susceptibility to Mycobacterial Disease (MSMD) [ 147 , 148 , 149 ]. While MSMDs were initially recognized for their distinct susceptibility to mycobacteria (particularly non-tuberculous (NTM) and occasionally M. tuberculosis ) and Salmonella (predisposing victims to extra-intestinal salmonellosis) [ 38 , 39 , 150 , 151 , 152 , 153 , 154 ], they were also subsequently found in patients with otherwise unexplained disseminated TDEF infection, including histoplasmosis (IL12RB1 [ 153 , 155 , 156 , 157 ]; IFNGR1 [ 158 ]), coccidioidomycosis (IFNGR1 [ 159 ] and IL12RB1 [ 160 ]), and paracoccidioidomycosis (IL12RB1 [ 161 ]). These findings provided the framework of human immunity to TDEF, which was followed by the identification of other IEI congruent with defective IFN-γ-mediated immunity, including CD40L deficiency [ 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 ] (discussed further in the section on “Pneumocystis”), GATA2 deficiency [ 171 ], and STAT1 GOF [ 168 , 169 , 172 , 173 ].…”

Disseminated Mycobacterial Infection With Reactive Polyarthritis (Poncet’s Disease) During Immune-suppressive Treatment Including Ustekinumab for Pediatric Crohn’s Disease

“…To assess the presence of genetic predisposing factors for TB, we searched for variants (frequency <1%) in more than 1400 genes associated with immune system abnormalities included in the human phenotype ontology database, with a focus on those related to Mendelian susceptibility to MI (complete gene list in Supplemental Digital Content 1, http://links.lww.com/INF/F426). [14][15][16][17] No significant variations were identified in the patient by whole-exome sequencing with in silico gene panel analysis (methods reported in Supplemental Digital Content 2, http://links.lww.com/INF/F427).…”