Manish Butte

Tomography. 2023 Apr 23;9(3):894-900. doi: 10.3390/tomography9030073.

ABSTRACT

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in serum immunoglobulins and early-onset infections. Coronavirus Disease-2019 (COVID-19) pneumonia in immunocompromised patients presents clinical and radiological peculiarities which have not yet been completely understood. Very few cases of agammaglobulinemic patients with COVID-19 have been reported since the beginning of the pandemic in February 2020. We report two cases of migrant COVID-19 pneumonia in XLA patients.

PMID:37218933 | DOI:10.3390/tomography9030073

Adv Rheumatol. 2023 May 22;63(1):23. doi: 10.1186/s42358-023-00303-5.

ABSTRACT

INTRODUCTION: The deficiency of ADA2 (DADA2) is a rare autoinflammatory disease provoked by mutations in the ADA2 gene inherited in a recessive fashion. Up to this moment there is no consensus for the treatment of DADA2 and anti-TNF is the therapy of choice for chronic management whereas bone marrow transplantation is considered for refractory or severe phenotypes. Data from Brazil is scarce and this multicentric study reports 18 patients with DADA2 from Brazil.

PATIENTS AND METHODS: This is a multicentric study proposed by the Center for Rare and Immunological Disorders of the Hospital 9 de Julho – DASA, São Paulo – Brazil. Patients of any age with a confirmed diagnosis of DADA2 were eligible for this project and data on clinical, laboratory, genetics and treatment were collected.

RESULTS: Eighteen patients from 10 different centers are reported here. All patients had disease onset at the pediatric age (median of 5 years) and most of them from the state of São Paulo. Vasculopathy with recurrent stroke was the most common phenotype but atypical phenotypes compatible with ALPS-like and Common Variable Immunodeficiency (CVID) was also found. All patients carried pathogenic mutations in the ADA2 gene. Acute management of vasculitis was not satisfactory with steroids in many patients and all those who used anti-TNF had favorable responses.

CONCLUSION: The low number of patients diagnosed with DADA2 in Brazil reinforces the need for disease awareness for this condition. Moreover, the absence of guidelines for diagnosis and management is also necessary (t).

PMID:37217999 | DOI:10.1186/s42358-023-00303-5

Front Immunol. 2023 May 5;14:1172004. doi: 10.3389/fimmu.2023.1172004. eCollection 2023.

ABSTRACT

PURPOSE: Though copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI.

METHODS: We performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings.

RESULTS: Of the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one participant with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone.

CONCLUSION: Pairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.

PMID:37215141 | PMC:PMC10196392 | DOI:10.3389/fimmu.2023.1172004

J Allergy Clin Immunol. 2023 May 19:S0091-6749(23)00605-X. doi: 10.1016/j.jaci.2023.04.020. Online ahead of print.

ABSTRACT

BACKGROUND: Inborn errors affecting components of the T-cell receptor signaling cascade cause combined immunodeficiency with various degrees of severity. Recently, homozygous variants in LCP2 were reported to cause pediatric onset of severe combined immunodeficiency with neutrophil, platelet and T- and B-cell defects.

OBJECTIVE: To unravel the genetic cause of combined immunodeficiency and early onset immune dysregulation in a 26-year-old male who presented since early childhood with specific antibody deficiency, autoimmunity and inflammatory bowel disease.

METHODS: The patient was subjected to whole exome sequencing of genomic DNA and examination of blood neutrophils, platelets, T and B cells. Expression levels of SH2 domain-containing leukocyte protein 76kD (SLP76) and tonic and ligand-induced PI3K signaling were evaluated by flowcytometric detection of phosphorylated S6 in B- and T-cells.

RESULTS: Compound heterozygous missense variants were identified in LCP2, affecting the proline rich repeat domain of SLP76 (p.P190R and p.R204W). The patients’ total B- and T-cell numbers were within the normal range, as was platelet function. However, neutrophil function, numbers of unswitched and class switched memory B cells, and serum IgA were decreased. Moreover, intracellular SLP76 protein levels were reduced in patient CD4⁺ T, CD8⁺ T, B-, and NK cells. Tonic and ligand-induced levels of phosphorylated S6, and ligand-induced phospho- PLC-γ1 were decreased in patient CD4⁺ T, CD8⁺ T and B cells.

CONCLUSIONS: Biallelic variants in LCP2 impair neutrophil function and T-cell and B-cell antigen-receptor signaling, and can cause combined immunodeficiency with early onset immune dysregulation, even in the absence of platelet defects.

PMID:37211057 | DOI:10.1016/j.jaci.2023.04.020

J Allergy Clin Immunol. 2023 May 18:S0091-6749(23)00606-1. doi: 10.1016/j.jaci.2023.05.006. Online ahead of print.

ABSTRACT

BACKGROUND: – Primary immunodeficiencies (PID) are a heterogeneous group of rare inborn immunity defects. As management has greatly improved, morbi-mortality is reduced in this population, while our knowledge on pregnancy unfolding and outcome remains scarce.

OBJECTIVE: We conducted a retrospective monocentric study to study pregnancy outcomes in women with PID.

METHODS: The study cohort consisted of women over 18 included in the national registry for PID (CEREDIH), living in the greater Paris area, reporting ≥1 pregnancy. Data were collected through a standardized questionnaire and medical records. We analyzed PID features, pregnancy course and outcome, and neonatal features (NCT04581460).

RESULTS: We studied 93 women with PID (27 combined immunodeficiencies, 51 predominantly antibody deficiencies, and 15 innate immunodeficiencies) and their 222 pregnancies (67, 119 and 36 in each ID group respectively). One hundred and fifty four out of 222 (69%) pregnancies led to 157 live births including 4 severe preterm births (3%), in the range of pregnancy outcome in French general population. In a multivariate model, poor obstetrical outcome (fetal loss or pregnancy termination) was associated with history of severe infection (adjusted Odds Ratio of 0.28, [95% confidence interval 0.11-0.67], p=0.005). Only 59% pregnancies were led with optimal anti-infective prophylaxis; severe infections were reported in only 2 pregnancies (1%). One infant died during the neonatal period.

CONCLUSION: Pregnancy is achievable in women with a wide group of PID. Prematurity is increased and history of severe infection is associated with significant increase of fetal loss/pregnancy termination. Adjustment of care during pregnancy needs to be better delivered.

PMID:37210041 | DOI:10.1016/j.jaci.2023.05.006

J Crit Care. 2023 May 17;77:154300. doi: 10.1016/j.jcrc.2023.154300. Online ahead of print.

ABSTRACT

PURPOSE: Infectious encephalitis (IE) is a severe disease which requires intensive care unit (ICU) admission in up to 50% of cases. We aimed to describe characteristics, management and outcomes of IE patients who required ICU admission.

MATERIALS AND METHODS: Ancillary study focusing on patients with ICU admission within the ENCEIF cohort, a French prospective observational multicentre study. The primary criteria for outcome was the functional status at hospital discharge, categorized using the Glasgow outcome scale (GOS). Logistic regression model was used to identify risk factors for poor outcome, defined as a GOS ≤ 3.

RESULTS: We enrolled 198 ICU patients with IE. HSV was the primary cause (n = 72, 36% of all IE, 53% of IE with microbiological documentation). Fifty-two patients (26%) had poor outcome at hospital discharge, including 22 deaths (11%). Immunodeficiency, supratentorial focal signs on admission, lower cerebrospinal fluid (CSF) white cells count (<75/mm3), abnormal brain imaging, and time from symptoms onset to acyclovir start >2 days were independent predictors of poor outcome.

CONCLUSION: HSV is the primary cause of IE requiring ICU admission. IE patients admitted in ICU have a poor prognosis with 11% of in-hospital mortality and 15% of severe disabilities in survivors at discharge.

PMID:37207520 | DOI:10.1016/j.jcrc.2023.154300

JPGN Rep. 2021 Jul 12;2(3):e102. doi: 10.1097/PG9.0000000000000102. eCollection 2021 Aug.

ABSTRACT

X-linked lymphoproliferative syndrome type 2 (XLP2) is a rare genetic primary immunodeficiency disease caused by mutations in the XIAP gene that lead to deficiency of the X-linked inhibitor of apoptosis protein. XLP2 is characterized by dysregulated immune responses and can result in an inflammatory bowel disease (IBD)-like phenotype, a form of monogenic IBD. Patients with XLP2 often succumb to fulminant hemophagocytic lymphohistiocytosis or Epstein-Barr virus infections. Hematopoietic stem cell transplantation (HSCT) is currently the only definitive treatment for XLP2. We report an adolescent with a delayed diagnosis of XLP2 in the setting of severe Crohn’s disease diagnosed at age 9 years and recurrent skin infections. He is under evaluation for HSCT. Gastroenterologists must recognize monogenic IBD in patients of all ages with severe disease and signs of an underlying primary immunodeficiency disease. Patients with suspected monogenic IBD should undergo immunologic and genetic analysis at diagnosis to initiate potentially life-saving treatment.

PMID:37205951 | PMC:PMC10191492 | DOI:10.1097/PG9.0000000000000102

Paediatr Child Health. 2023 Mar 28;28(3):145-150. doi: 10.1093/pch/pxac076. eCollection 2023 Jun.

ABSTRACT

Cow’s milk allergy (CMA) is one of the most common food allergies in the first years of life, with worldwide prevalence estimated to range from 2% to 5%. While the majority of children with CMA will eventually develop tolerance to cow’s milk proteins (it is estimated that >75% of children with CMA develop tolerance to cow’s milk proteins by the age of 3 years, and >90% develop tolerance by the age of 6 years), the selection of an appropriate cow’s milk (CM) alternative for those with CMA is vital to ensure adequate growth and development during childhood. The increasing number of CM alternative products on the commercial market with markedly different nutritional content and micronutrient fortification adds a layer of complexity that can be challenging for both families and clinicians to navigate. This article aims to provide guidance and clarity to Canadian paediatricians and primary care clinicians on recommending the most appropriate, safe, and nutritionally optimal CM alternatives for individuals with CMA, and beyond.

PMID:37205135 | PMC:PMC10186100 | DOI:10.1093/pch/pxac076

J Clin Immunol. 2023 May 19. doi: 10.1007/s10875-023-01503-w. Online ahead of print.

ABSTRACT

PURPOSE: Diarrhea lasting longer than 14 days which fails to respond to conventional management is defined as severe and protracted diarrhea and might overlap with inflammatory bowel disease (IBD).

METHODS: The prevalence, associated pathogens, and prognosis of severe and protracted diarrhea without IBD (SD) and with monogenetic IBD (mono-IBD) in primary immunodeficiency patients (PID) were investigated in Taiwan.

RESULTS: A total of 301 patients were enrolled between 2003 and 2022, with predominantly pediatric-onset PID. Of these, 24 PID patients developed the SD phenotype before prophylactic treatment, including Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG1 (one each), CVID (two), and SCID (one) without identified mutations. The most detectable pathogens were pseudomonas and salmonella (six each), and all patients improved after approximately 2 weeks of antibiotic and/or IVIG treatments. Six (25.0%) mortalities without HSCT implementation were due to respiratory failure from interstitial pneumonia (3 SCID and 1 CGD), intracranial hemorrhage (WAS), and lymphoma (HIGM). In the mono-IBD group, seventeen patients with mutant TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), LRBA (1), TTC37 (3), IL10RA (1), STAT1 (1), ZAP70 (1), PIK3CD (1), and PIK3R1 (1) genes failed to respond to aggressive treatments. Nine mono-IBD patients with TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), and LRBA (1) mutations were fatal in the absence of HSCT. The mono-IBD group had a significantly earlier age of diarrhea onset (1.7 vs 33.3 months, p = 0.0056), a longer TPN duration (34.2 vs 7.0 months, p < 0.0001), a shorter follow-up period (41.6 vs 132.6 months, p = 0.007), and a higher mortality rate (58.9 vs 25.0%, p = 0.012) compared with the SD group.

CONCLUSION: When compared to those with the SD phenotype, the mono-IBD patients had significant early-onset and poor responses to empiric antibiotics, IVIG, and steroids. Anti-inflammatory biologics and suitable HSCT still have the potential to control or even cure the mono-IBD phenotype.

PMID:37202577 | DOI:10.1007/s10875-023-01503-w

Rev Med Inst Mex Seguro Soc. 2023 Mar 1;61(2):189-195.

ABSTRACT

The autoimmune diseases include many in which the immune system is directed against the host, leading to life-threatening destruction of organs. The origin of autoimmune disorders can be multifactorial and, there are no specific therapy for these diseases. Primary immunodeficiencies are a group of immune disorders that affect different components of the innate and adaptive responses. Interestingly, patients with primary immunodeficiencies have an increased susceptibility to infectious diseases and non-infectious complications including allergies, malignancies, and autoimmune diseases. The molecular mechanism for development of autoimmunity in immunodeficiencies is unclear. The study of the complex immune regulatory and signaling mechanisms is revealing the relationships between primary immunodeficiency syndromes and autoimmune diseases. Newly, it has been demonstrated that a deficient maturation of immune cells; the deficiency of proteins important for T and B lymphocyte function and impaired signally pathways that include key molecules in regulation and activation of immune cells are associated with the development of autoimmunity in patients with primary immunodeficiencies. The aim of the present work is to review the evidence available to date regarding the cellular and molecular mechanisms involved in the development of autoimmunity in patients with primary immunodeficiencies.

PMID:37200522