Manish Butte

J Clin Immunol. 2022 Jun 28. doi: 10.1007/s10875-022-01303-8. Online ahead of print.

ABSTRACT

Disorders of the long arm of chromosome 11 (11q) are rare and involve various chromosomal regions. Patients with 11q disorders, including Jacobsen syndrome, often present with a susceptibility for bacterial and prolonged viral and fungal infections partially explained by hypogammaglobulinemia. Additional T lymphocyte or granular neutrophil dysfunction may also be present. In order to evaluate infectious burden and immunological function in patients with 11q disorders, we studied a cohort of 14 patients with 11q deletions and duplications. Clinically, 12 patients exhibited prolonged and repetitive respiratory tract infections, frequently requiring (prophylactic) antibiotic treatment (n = 7), ear-tube placement (n = 9), or use of inhalers (n = 5). Complicated varicella infections (n = 5), chronic eczema (n = 6), warts (n = 2), and chronic fungal infections (n = 4) were reported. Six patients were on immunoglobulin replacement therapy. We observed a high prevalence of low B lymphocyte counts (n = 8), decreased T lymphocyte counts (n = 5) and abnormal T lymphocyte function (n = 12). Granulocyte function was abnormal in 29% without a clinical phenotype. Immunodeficiency was found in patients with terminal and interstitial 11q deletions and in one patient with terminal 11q duplication. Genetically, FLI1 and ETS1 are seen as causative for the immunodeficiency, but these genes were deleted nor duplicated in 4 of our 14 patients. Alternative candidate genes on 11q may have a role in immune dysregulation. In conclusion, we present evidence that inborn errors of immunity are present in patients with 11q disorders leading to clinically relevant infections. Therefore, broad immunological screening and necessary treatment is of importance in this patient group.

PMID:35763218 | DOI:10.1007/s10875-022-01303-8

Zhongguo Dang Dai Er Ke Za Zhi. 2022 Jun 15;24(6):635-642. doi: 10.7499/j.issn.1008-8830.2112098.

ABSTRACT

OBJECTIVES: To evaluate the clinical effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with hyper-IgM syndrome (HIGM).

METHODS: A retrospective analysis was performed on the medical data of 17 children with HIGM who received allo-HSCT. The Kaplan Meier method was used for the survival analysis of the children with HIGM after allo-HSCT.

RESULTS: After allo-HSCT, 16 children were diagnosed with sepsis; 14 tested positive for virus within 100 days after allo-HSCT, among whom 11 were positive for Epstein-Barr virus, 7 were positive for cytomegalovirus, and 2 were positive for JC virus; 9 children were found to have invasive fungal disease. There were 6 children with acute graft-versus-host disease and 3 children with chronic graft-versus-host disease. The median follow-up time was about 2 years, and 3 children died in the early stage after allo-HSCT. The children had an overall survival (OS) rate of 82.35%, an event-free survival (EFS) rate of 70.59%, and a disease-free survival (DFS) rate of 76.47%. The univariate analysis showed that the children receiving HLA-matched allo-HSCT had a significantly higher EFS rate than those receiving HLA-mismatched allo-HSCT (P=0.019) and that the children receiving HLA-matched unrelated allo-HSCT had significantly higher OS, EFS, and DFS rates than those receiving HLA-mismatched unrelated allo-HSCT (P<0.05). Compared with the children with fungal infection after allo-HSCT, the children without fungal infection had significantly higher EFS rate (P=0.02) and DFS rate (P=0.04).

CONCLUSIONS: Allo-HSCT is an effective treatment method for children with HIGM. HLA-matched allo-HSCT and active prevention and treatment of fungal infection and opportunistic infection may help to improve the prognosis of such children.

PMID:35762429 | DOI:10.7499/j.issn.1008-8830.2112098

Front Immunol. 2022 Jun 10;13:906540. doi: 10.3389/fimmu.2022.906540. eCollection 2022.

ABSTRACT

Genetic disorders that impair the immune system, known as Primary Immunodeficiencies (PI), include over 450 single-gene inborn errors of immunity. Timely and appropriate diagnosis and treatment is vital to quality of life (QOL) and sometimes survival, as patients are susceptible to frequent, persistent, severe, and sometimes life-threatening infections or autoimmunity. Suspected PI patients that do not have a genetic diagnosis often endure a prolonged, onerous, inefficient, and expensive experience, known as a diagnostic odyssey. The resulting diagnostic delay prohibits proper disease management and treatment, causing unnecessary distress and diminished QOL. Next-generation sequencing (NGS) offers relief from the distress of the diagnostic odyssey, but because of cost and barriers to access, it is regularly unobtainable. The Jeffrey Modell Foundation (JMF) introduced “Jeffrey’s Insights”, a no-charge genetic sequencing pilot program, in January 2019 for patients within the Jeffrey Modell Centers Network (JMCN) with an underlying PI, but no genetic diagnosis. Building on the success of the pilot program, JMF expanded it globally to more than 400 Centers in the JMCN in early 2020. The most current version of Invitae’s PI Panel available was used for this program. All participating clinicians were invited to complete a brief questionnaire assessing prior impediments to access and post-sequencing alterations in disease management and treatment. A total of 1,398 patients were tested, with 20.3% receiving a molecular diagnosis and many more receiving helpful diagnostic leads. Results obtained from genetic sequencing led to an alteration of clinical diagnosis, disease management, treatment, and genetic counseling in 39%, 38%, 35%, and 53% of patients, respectively. The global expansion of this program further underscores the crucial need for NGS for PI, along with its efficiency and potential cost savings. The results of this program to date further define rationale for the availability of comprehensive diagnostic NGS for patients with PI when requisitioned by an expert immunologist.

PMID:35757720 | PMC:PMC9226364 | DOI:10.3389/fimmu.2022.906540

Front Pediatr. 2022 Jun 10;10:855445. doi: 10.3389/fped.2022.855445. eCollection 2022.

ABSTRACT

Patients with inborn errors of immunity (IEI) are susceptible to developing a severe infection-related clinical phenotype, but the clinical consequences of immune dysregulation, expressed with autoimmunity, atopy, and lymphoproliferation could represent the first sign in a significant percentage of patients. Therefore, during the diagnostic work-up patients with IEI are frequently addressed to different specialists, including endocrinologists, rheumatologists, and allergologists, often resulting in a delayed diagnosis. In this paper, the most relevant non-infectious manifestations of IEI are discussed. Particularly, we will focus on the potential presentation of IEI with autoimmune cytopenia, non-malignant lymphoproliferation, severe eczema or erythroderma, autoimmune endocrinopathy, enteropathy, and rheumatologic manifestations, including vasculitis and systemic lupus erythematosus. This paper aims to identify new warning signs to suspect IEI and help in the identification of patients presenting with atypical/non-infectious manifestations.

PMID:35757131 | PMC:PMC9226481 | DOI:10.3389/fped.2022.855445

Front Genet. 2022 Jun 9;13:873635. doi: 10.3389/fgene.2022.873635. eCollection 2022.

ABSTRACT

Variants in the MSN gene were recently reported as the cause of a primary immunodeficiency disease called X-linked moesin-associated immunodeficiency (X-MAID). Hitherto, only 10 patients were reported worldwide. Here, we report a boy who presented with recurrent high fever, oral ulcers, abdominal pain, and hematochezia for over 2 weeks. His serum inflammatory markers were elevated, and colonoscopy showed multiple colon ulcers and terminal ileum ulcers which resemble colitis caused by inflammatory bowel disease. A novel heterozygous variant c.934G>T(p.Glu312Ter) in the MSN gene was identified using whole exome sequencing (WES) and trio analysis. Intestinal ulcers were almost healed after inducing therapy with steroids and maintenance treatment of anti-TNFα therapy. We summarized the genotype and phenotype of reported X-MAID patients and presented the patient’s unique phenotype in this study. This study also expanded the spectrum of MSN mutation-caused immunodeficiency.

PMID:35754805 | PMC:PMC9224403 | DOI:10.3389/fgene.2022.873635

Pediatr Allergy Immunol. 2022 Jun;33(6):e13805. doi: 10.1111/pai.13805.

NO ABSTRACT

PMID:35754127 | DOI:10.1111/pai.13805

Sr Care Pharm. 2022 Jul 1;37(7):284-292. doi: 10.4140/TCP.n.2022.284.

ABSTRACT

Objectives To evaluate the efficacy and safety of megestrol for off-label use in older patients with weight loss. Design Retrospective, nonblinded cohort study. Setting Upstate University Hospital is a 420-bed facility and academic medical center with a level 1 trauma center. Upstate Community Hospital is a 314-bed acute care/hospital/ambulatory care center and long-term care hospital that also provides teaching services. Participants Patients 65 years of age and older without malignancy or acquired immunodeficiency syndrome who were initiated and continued megestrol therapy at the Upstate University hospitals for at least two weeks were included. Of the 1,290 patients initially screened, 16 patients on megestrol were evaluated. An age- and gender-matched control group of 16 patients was utilized for comparison of changes in weight and other variables. Interventions Patients in the megestrol group have received daily doses of megestrol between 160 mg to 800 mg for an average duration of 19 days. Patients in the control group had no history or current use of megestrol utilization. Main Outcome Measurements The primary outcome was an increase in weight. Secondary outcome measures included albumin and thromboembolic events. Changes in weight and albumin were also compared with the control group. Results At a mean duration of 19 days, there was no significant difference in weight gain (0.95 kg, OR = 1.33 [95% CI -1.615-3.527]). Albumin decreased by (0.4 g/dL OR = 0.916 [95% CI 0.12-0.78]) and none of the patients developed a thromboembolic event. Conclusion In older hospitalized patients, megestrol did not increase weight, and did not improve albumin. No thromboembolic events were observed, but this may be because of a limited duration of observation of therapy and the routine use of anticoagulation prophylaxis in the inpatient setting.

PMID:35752918 | DOI:10.4140/TCP.n.2022.284

Clin Immunol. 2022 Jun 21:109067. doi: 10.1016/j.clim.2022.109067. Online ahead of print.

ABSTRACT

BACKGROUND: Severe combined immunodeficiency (SCID) is characterized by severe, early-onset infection in infants. B-cell lymphoma/leukemia (BCL) 10 defects causing SCID have been reported previously in two patients.

MATERIAL & METHODS: A seven-month-old female infant was admitted with bilateral pneumonia requiring ventilatory support. She had a history of recurrent infections starting from four months of age. The patient was investigated for primary immunodeficiency.

RESULTS: Immunological investigations revealed hypogammaglobulinemia with normal CD4 and CD8 lymphocyte counts, while a lymphocyte proliferation assay showed absent response to phytohemagglutinin stimulation, thereby establishing the diagnosis of an atypical form of SCID. Genetic testing revealed a homozygous mutation in the BCL10 gene, with both parents demonstrating a heterozygous state (NM_003921.5:c.271A>C:p.[Thr91Pro]). The patient died before bone marrow transplantation due to severe disseminated adenovirus disease. Conclusion We report the first patient from the Middle East with a novel homozygous mutation in the BCL10 gene causing SCID.

PMID:35750252 | DOI:10.1016/j.clim.2022.109067

J Allergy Clin Immunol. 2022 Jun 21:S0091-6749(22)00837-5. doi: 10.1016/j.jaci.2022.06.007. Online ahead of print.

ABSTRACT

BACKGROUND: Germline mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for two distinct human diseases: autosomal-dominant hyper-immunoglobulin E syndrome (AD-HIES) caused by STAT3 loss-of-function (STAT3-LOF) mutations and STAT3 gain-of-function (STAT3-GOF) disease. So far, these entities have been regarded as antithetic, with AD-HIES mainly associated with characteristic infections and a connective tissue phenotype and STAT3-GOF characterized by lymphoproliferation and poly-autoimmunity. The R335W substitution in the DNA binding domain of STAT3 was initially described in 2 patients with typical AD-HIES, but paradoxically, recent functional analysis demonstrated a GOF effect of this variant.

OBJECTIVE: We describe a patient with Sjögren syndrome and features of AD-HIES with this mutation and further characterize its molecular consequences.

METHODS: We provide a clinical and immunological description of the patient. We studied STAT phosphorylation in primary patient cells and used A4 cells transfected with the patient allele to study phosphorylation kinetics, transcriptional activity and target-gene induction.

RESULTS: The hybrid clinical features of the patient were associated with normal Th17 cells. We observed enhanced and prolonged STAT3 phosphorylation, an increased STAT3 driven luciferase reporter activity upon interleukin-6 stimulation, but reduced IL-6 induced SOCS3 production.

CONCLUSION: The germline R335W-STAT3 variant displays a mixed behavior in vitro that mainly shows gain-of-function, but also loss-of-function features. This is matched by an ambiguous clinical and immunological phenotype which dismantles the classical antithetic dualism of gain- versus loss-of-function. Germline STAT3 mutation related-disease represents a pathological spectrum with the p.R335W associated phenotype locating between the two recognized clinical disease patterns.

PMID:35750105 | DOI:10.1016/j.jaci.2022.06.007

J Clin Immunol. 2022 Jun 24. doi: 10.1007/s10875-022-01289-3. Online ahead of print.

ABSTRACT

We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.

PMID:35748970 | DOI:10.1007/s10875-022-01289-3