Manish Butte

Pediatrics. 2021 Aug 20:e2021050351. doi: 10.1542/peds.2021-050351. Online ahead of print.

ABSTRACT

STAT3 hyper-immunoglobulin E syndrome (STAT3-HIES) is a rare primary immunodeficiency syndrome characterized by elevated serum immunoglobulin E levels, eczema, recurrent skin and respiratory tract infections, and several gastrointestinal (GI) problems. GI manifestations, such as gastroesophageal reflux disease, dysphagia, abdominal pain, gut dysmotility, bowel perforation, eosinophilic esophagitis, and diarrhea, have been reported in 60% of patients. Until now, there was no efficient treatment that could effectively manage all aspects of the syndrome. In this report, we present the case of a 21-year-old man who suffered from undetectable pathogenic refractory diarrhea that persisted >21 days despite aggressive antibiotic and steroid treatment since he was 2 years old. STAT3 Int10(–2)A > G splicing mutation-caused STAT3-HIES was diagnosed by next-generation sequencing. The patient had suffered recurrent intestinal and colon perforations since he was 10 years old. He had received multiple surgeries and continuous systemic intravenous immunoglobulin therapy to manage his GI symptoms. However, refractory diarrhea occurring >5 to 6 times per day with severe eczematous dermatitis and frequent abscess formation remained threats to his life. Dupilumab 300 mg every 3 weeks was prescribed to control his skin problems, but the patient’s diarrhea also completely subsided. As such, it appears that dupilumab may not only effectively treat the skin inflammation but also the GI manifestation-related inflammation of STAT3-HIES refractory to traditional immunomodulators.

PMID:34417287 | DOI:10.1542/peds.2021-050351

Front Immunol. 2021 Aug 3;12:696268. doi: 10.3389/fimmu.2021.696268. eCollection 2021.

ABSTRACT

CONTEXT: Disseminated infections due to Mycobacterium bovis Bacillus Calmette-Guérin (BCG) are unusual and occur mostly in patients with inborn error of immunity (IEI) or acquired immunodeficiency. However, cases of secondary BCGosis due to intravesical BCG instillation have been described. Herein, we present a case of severe BCGosis occurring in an unusual situation.

CASE DESCRIPTION: We report one case of severe disseminated BCG disease occurring after hematological malignancy in a 48-year-old man without BCG instillation and previously vaccinated in infancy with no complication. Laboratory investigations demonstrated that he was not affected by any known or candidate gene of IEI or intrinsic cellular defect involving IFNγ pathway. Whole genome sequencing of the BCG strain showed that it was most closely related to the M. bovis BCG Tice strain, suggesting an unexpected relationship between the secondary immunodeficiency of the patient and the acquired BCG infection.

CONCLUSION: This case highlights the fact that, in addition to the IEI, physicians, as well as microbiologists and pharmacists should be aware of possible acquired disseminated BCG disease in secondary immunocompromised patients treated in centers that administrate BCG for bladder cancers.

PMID:34413849 | PMC:PMC8369751 | DOI:10.3389/fimmu.2021.696268

Sci Immunol. 2021 Aug 19;6(62):eabl4348. doi: 10.1126/sciimmunol.abl4348.

ABSTRACT

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10^-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10^-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients’ blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.

PMID:34413140 | DOI:10.1126/sciimmunol.abl4348

Pediatr Transplant. 2021 Aug 19:e14120. doi: 10.1111/petr.14120. Online ahead of print.

ABSTRACT

BACKGROUND: Haploidentical HSCT is a good option for children with PIDs lacking an HLA-matched donor. Co-transplantation of MSCs during haploidentical HSCT in patients with PIDs may enhance engraftment, decrease the risk of GVHD, and ensure stable donor chimerism.

METHODS: Twenty-seven pediatric patients (median age, 1.4 years; range, .3-10.9) with PIDs undergoing thirty haploidentical HSCT with TCR αβ depletion and co-transplantation of MSCs were enrolled to study. Most patients (73.3%) received myeloablative conditioning consisting of treosulfan or busulfan, fludarabine, and thiotepa. The median duration of follow-up was 14.3 months (range, 1-69 months).

RESULTS: Acute GVHD occurred in 7 patients (grade I-II n = 5, grade III-IV n = 2). Chronic GVHD was observed in only one patient. Twenty-one patients (70.2%) had 100% donor chimerism in all cell lines including T-cell and B-cell lineages. Primary graft failure was observed in 7 patients (25.9%). The cumulative incidences of TRM were 20% at day 100, and 26.7% at one year and five years. Probabilities of OS were 80% at day 100, and 71.9% at 1 year and 5 years. Infants transplanted younger than 6 months of age had the highest 5-year survival rate (85.7%).

CONCLUSION: We conclude that use of TCR αβ depleted haploidentical transplantation with MSCs may ensure a rapid engraftment rate, low incidence of significant acute and chronic GVHD, and acceptable post-transplantation morbidity, especially in patients diagnosed with SCID and may be considered in children with PIDs. In younger patients (≤6 months), survival is comparable between HLA-matched graft and CD3+ TCRαβ depleted HLA-mismatched graft recipients.

PMID:34409718 | DOI:10.1111/petr.14120

Front Immunol. 2021 Aug 2;12:712915. doi: 10.3389/fimmu.2021.712915. eCollection 2021.

ABSTRACT

Common variable immunodeficiency (CVID) is the most common symptomatic primary antibody immunodeficiency, characterized by reduced serum levels of IgG, IgA, and/or IgM. The vast majority of CVID patients have polygenic inheritance. Immune dysfunction in CVID can frequently involve the gastrointestinal tract and lung. Few studies have started to investigate the gut microbiota profile in CVID patients. Overall, the results suggest that in CVID patients there is a reduction of alpha and beta diversity compared to controls. In addition, these patients can exhibit increased plasma levels of lipopolysaccharide (LPS) and markers (sCD14 and sCD25) of systemic immune cell activation. CVID patients with enteropathy exhibit decreased IgA expression in duodenal tissue. Mouse models for CVID unsatisfactorily recapitulate the polygenic causes of human CVID. The molecular pathways by which gut microbiota contribute to systemic inflammation and possibly tumorigenesis in CVID patients remain poorly understood. Several fundamental questions concerning the relationships between gut microbiota and the development of chronic inflammatory conditions, autoimmune disorders or cancer in CVID patients remain unanswered. Moreover, it is unknown whether it is possible to modify the microbiome and the outcome of CVID patients through specific therapeutic interventions.

PMID:34408753 | PMC:PMC8366412 | DOI:10.3389/fimmu.2021.712915

Pediatr Allergy Immunol. 2021 Aug 18. doi: 10.1111/pai.13653. Online ahead of print.

ABSTRACT

Interferon gamma receptor-1 (IFNγR1) deficiency is a rare inborn error of immunity. It can be inherited as an autosomal recessive (AR), partial or complete, or autosomal dominant (AD) trait and exhibits high allelic variability. Biallelic deleterious recessive variants of IFNGR1 that result in absent expression or defective downstream signaling of IFNγR1, cause failure to activate macrophages in response to interferon-gamma (IFN-γ), rendering innate immunity ineffective in clearing intracellular pathogens.

PMID:34407251 | DOI:10.1111/pai.13653

Clin Immunol. 2021 Aug 12:108821. doi: 10.1016/j.clim.2021.108821. Online ahead of print.

ABSTRACT

BACKGROUND: Information regarding inborn error of immunity (IEI) as a risk factor for severe COVID-19 is scarce. We aimed to determine if paediatric patients with moderate/severe IEI got COVID-19 at the same level as the general population, and to describe COVID-19 expression.

MATERIAL AND METHODS: We included patients with moderate/severe IEI aged 0-21 years old: cross-sectional study (June2020) to determine the prevalence of COVID-19; prospective study (January2020-January2021) including IEI patients with COVID-19. Assays used: nasopharyngeal swab SARS-CoV-2 PCR and SARS-CoV-2-specific immunoglobulins.

RESULTS: Seven from sixty-five patients tested positive (prevalence: 10.7% (7%-13%)) after the first SARS-COV-2 wave and 13/15 patients diagnosed with COVID-19 had an asymptomatic/mild course.

CONCLUSIONS: In our area, prevalence of COVID-19 in moderate/severe IEI paediatric patients after the first wave was slightly higher than in the general population. The majority of patients presented a benign course, suggesting a possible protective factor related with age despite IEI.

PMID:34391937 | DOI:10.1016/j.clim.2021.108821

BMC Genomics. 2021 Aug 15;22(1):618. doi: 10.1186/s12864-021-07909-3.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEI) are a group of genetic disorders that impair the immune system, with over 400 genes described so far, and hundreds more to be discovered. To facilitate the search for new genes, we need a way to prioritize among all the genes in the genome those most likely to play an important role in immunity.

RESULTS: Here we identify a new list of genes by linking known IEI genes to new ones by using open-source databases of protein-protein interactions, post-translational modifications, and transcriptional regulation. We analyze this new set of 2,530 IEI-related genes for their tolerance of genetic variation and by their expression levels in various immune cell types.

CONCLUSIONS: By merging genes derived from protein interactions of known IEI genes with transcriptional data, we offer a new list of candidate genes that may play a role in as-yet undiscovered IEIs.

PMID:34391382 | DOI:10.1186/s12864-021-07909-3

J Clin Immunol. 2021 Aug 14. doi: 10.1007/s10875-021-01086-4. Online ahead of print.

ABSTRACT

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers.

PMID:34390440 | DOI:10.1007/s10875-021-01086-4

Pediatr Rheumatol Online J. 2021 Aug 13;19(1):121. doi: 10.1186/s12969-021-00623-0.

ABSTRACT

BACKGROUND: Mendelian susceptibility to mycobacterial disease (MSMD) is an inborn error of immunity, resulting in susceptibility to weakly virulent mycobacteria and other intramacrophagic pathogens. Rheumatologic manifestations and vasculitis are considered rare manifestations in MSMD patients.

CASE PRESENTATION: In this study, we reported a 20-year-old female who was presented with recurrent lymphadenitis following bacillus Calmette-Guérin (BCG) vaccination and a history of recurrent disseminated rash diagnosed as leukocytoclastic vasculitis (LCV). A slight reduction in lymphocyte subsets including CD4+, CD19+, and CD 16 + 56 T-cell count, as well as an elevation in immunoglobulins level (IgG, IgA, IgM, IgE), were observed in the patient. Whole exome sequencing revealed a homozygous Indel-frameshift mutation, c.527_528delCT (p. S176Cfs*12), at the exon 5 of the IL12B gene. She experienced symptom resolution after treatment with anti-mycobacterial agents and subcutaneous IFN-γ. We conducted a manual literature search for MSMD patients reported with vasculitis in PubMed, Web of Science, and Scopus databases. A total of 18 MSMD patients were found to be affected by a variety of vasculitis phenotypes mainly including LCV and Henoch-Schönlein purpura (HSP) with often skin involvement. Patients were all involved with vasculitis at the median age of 6.8 (2.6-7.7) years, nearly 6.1 years after the initial presentations. Sixteen patients (88.9%) had IL12RB1 defects and concurrent Salmonella infection was reported in 15 (88.2%) patients.

CONCLUSION: The lack of IL-12 and IL-23 signaling/activity/function and salmonella infection may be triggering factors for the development of leukocytoclastic vasculitis. IL12B or IL12RB1 deficiency and salmonellosis should be considered in MSMD patients with vasculitis.

PMID:34389021 | DOI:10.1186/s12969-021-00623-0