Manish Butte

Front Immunol. 2022 Jul 7;13:932385. doi: 10.3389/fimmu.2022.932385. eCollection 2022.

ABSTRACT

Deficiency of adenosine deaminase 2 (DADA2) is an inherited autosomal recessive disease characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages, end organ vasculitis), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure. Allogeneic hematopoietic cell transplantation (HCT) is curative for DADA2 as it reverses the hematological, immune and vascular phenotype of DADA2. The primary goal of HCT in DADA2, like in other non-malignant diseases, is engraftment with the establishment of normal hematopoiesis and normal immune function. Strategies in selecting a preparative regimen should take into consideration the specific vulnerabilities to endothelial dysfunction and liver toxicity in DADA2 patients. Overcoming an increased risk of graft rejection while minimizing organ toxicity, graft-versus-host disease, and infections can be particularly challenging in DADA2 patients. This review will discuss approaches to HCT in DADA2 patients including disease-specific considerations, barriers to successful engraftment, post-HCT complications, and clinical outcomes of published patients with DADA2 who have undergone HCT to date.

PMID:35911698 | PMC:PMC9336546 | DOI:10.3389/fimmu.2022.932385

Qatar Med J. 2022 Mar 28;2022(2):29. doi: 10.5339/qmj.2022.fqac.29. eCollection 2022.

ABSTRACT

BACKGROUND: Intravenous immunoglobulin (IVIG) therapy has been used as antibody replacement therapy in primary immunodeficiency diseases (PID) for more than 50 years. In this study, we aimed to define IVIG usage and adverse reactions and complications in PID and explain how subcutaneous immunoglobulin (SCIG) replacement therapy is an alternative that improves the patient experience. In addition, the additional nursing responsibilities associated with this service were also identified.

METHODS: Data and service satisfaction surveys for the last 10 years were reviewed from the Allergy and Immunology Division log registry for those on IVIG and SCIG.

RESULTS: IVIG practice: Most patients currently on IVIG in our unit have PID. Adverse reactions occur during the initial 30 to 60 minutes of the infusion and are mild and self-limited. Infusion reactions are more likely to occur in patients receiving IVIG for the first time. Infusion-related complications included pyrogenic reactions, allergic reactions, and vasomotor symptoms. Complications reported in the literature such as the transmission of blood-borne pathogens and other serious complications, including thrombotic events, renal adverse events, and aseptic meningitis were never reported. Pyrogenic reactions occurred at a rate ≥ 100 mL/hr in at least 3 patients, and a slower infusion rate of ≤ 75 mL/hr mitigated this rate-related complication. SCIG program: This program started in Qatar in 2017. Usually, the clinician assesses and evaluates several factors to help select candidates for this therapy, including the perceptions of inconvenience and/or pain of IV infusions, presence of difficult vein access, and other relevant clinical and social factors. Once training in the appropriate techniques has been accomplished (3-6 sessions), it is most often self-administered in the home setting by the patient or a parent for a child. Table 1 summarizes patients on SCIG. Additional nursing responsibilities: The nursing role in subcutaneous IgG administration is primarily that of an educator and to help the patient/family become independent. This can be achieved by the assessment of appropriate patient selection for self-administration. Determining which patients are suitable include adequate patient education with return demonstration of the necessary skill set, monitoring parameters, educating patients about their medication, and providing educational resources and support.

CONCLUSION: SCIG administration can be a convenient alternative for patients with PID receiving long-term IVIG.

PMID:35909401 | PMC:PMC9284658 | DOI:10.5339/qmj.2022.fqac.29

J Crohns Colitis. 2022 Jul 30:jjac103. doi: 10.1093/ecco-jcc/jjac103. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD) have a complex polygenic aetiology. Rare genetic variants can cause monogenic intestinal inflammation. The impact of chromosomal aberrations and large structural abnormalities on IBD susceptibility is not clear. We aimed to comprehensively characterise the phenotype and prevalence of patients with IBD who possess rare numeric and structural chromosomal abnormalities.

METHODS: We performed a systematic literature search of databases PubMed and Embase; analysed gnomAD, Clinvar, the 100,000 Genomes Project and DECIPHER databases. Further we analysed international paediatric IBD cohorts to investigate the role of IL2RA duplications in IBD susceptibility.

RESULTS: A meta-analysis suggests that monosomy X (Turner syndrome) is associated with increased expressivity of IBD that exceeds the population baseline (1.86%, 95% CI 1.48-2.34%) and causes a younger age of IBD onset. There is little evidence that Klinefelter Syndrome, Trisomy 21, Trisomy 18, mosaic Trisomy 9 and 16, or partial trisomies contribute to IBD susceptibility. Copy number analysis studies suggest inconsistent results. Monoallelic loss of X-linked or haploinsufficient genes is associated with IBD by hemizygous or heterozygous deletions, respectively. However, haploinsufficient gene deletions are detected in healthy reference populations, suggesting that the expressivity of IBD might be overestimated. One duplication that has previously been identified as potentially contributing to IBD risk involves the IL2RA/IL15R loci. Here we provide additional evidence that a microduplication of this locus may predispose to very-early-onset IBD by identifying a second case in a distinct kindred. However, the penetrance of intestinal inflammation in this genetic aberration is low (<2.6%).

CONCLUSIONS: Turner Syndrome is associated with increased susceptibility to intestinal inflammation. Duplication of the IL2RA/IL15R loci may contribute to disease risk.

PMID:35907265 | DOI:10.1093/ecco-jcc/jjac103

J Clin Immunol. 2022 Jul 30. doi: 10.1007/s10875-022-01302-9. Online ahead of print.

ABSTRACT

OBJECTIVE: The Bacille Calmette-Guérin (BCG) vaccine is routinely applied in Brazil. Adverse events (AE) may occur in patients with inborn or acquired immunodeficiencies, varying between local (BCGitis) or disseminated (BCGosis) reactions. We evaluated 53 individuals with local or disseminated adverse events to BCG vaccination to assess if they had inborn errors of immunity (IEI).

METHODS: Patients diagnosed with an adverse event following BCG vaccination between 2014 and 2017 were included in the study. We collected clinical data, immunophenotyped T and B lymphocytes, and natural killer cells (NK), assessed oxidative function of neutrophils through dihydrorhodamine (DHR) 123 testing, and genotyped 361 genes related to IEI through targeted (panel) sequencing.

RESULTS: The median age of the 53 individuals was four months (IQ 1.5-12), and 52.8% were male. Forty-eight (90.6%) individuals presented only locoregional AE and five (9.4%) presented both locoregional and disseminated AE. Nine (16.9%) patients were diagnosed with an IEI. Four of them presented BCGitis and five presented BCGosis after BCG vaccination. Clinically, four presented chronic granulomatous disease (CGD), three Mendelian susceptibility to mycobacterial disease (MSMD), and two severe combined immunodeficiency (SCID). Patients with IEI had a higher frequency of systemic symptomatology (p = 0.002), history of other infections (p < 0.001), parental consanguinity (p = 0.01), familial history of sick siblings (p < 0.001), or early deaths in the family (p < 0.01).

CONCLUSION: There is a high frequency of IEI in patients with locoregional and disseminated adverse events to BCG vaccination, revealing the need for the investigation of IEI accompanied by clinical and familial inquiry.

PMID:35907101 | DOI:10.1007/s10875-022-01302-9

Ther Umsch. 2022 Aug;79(6):279-283. doi: 10.1024/0040-5930/a001361.

ABSTRACT

Antibodydeficiencies Epidemiology, Clinical manifestation, Diagnostics and Therapy Abstract. Primary Immune Deficiencies (PID) are caused by a genetically induced malformation/dysfunction of the immune system. Leading symptoms include susceptibility to infection, autoimmune diseases, lymphoproliferative, allergic as well as malignant diseases. They can be divided into ten main groups, including the primary antibody deficiency syndromes (PAD) in adults. The most well-known PADs include the variable immunodeficiency syndrome (CVID), Bruton’s agammaglobulinaemia, IgG subclass deficiencies, immunoglobulin A deficiency, Antibody deficiency and transient childhood hypogammaglobulinaemia. Secondary hypogammaglobulinaemia by medicinal products, haematological diseases, malignancies and infections should be excluded. Delayed diagnosis of CVID is associated with a significant increase in morbidity and an increase in mortality. In addition to vaccinations, immunoglobulin replacement therapy is used therapeutically.

PMID:35903831 | DOI:10.1024/0040-5930/a001361

Ther Umsch. 2022 Aug;79(6):301-306. doi: 10.1024/0040-5930/a001365.

ABSTRACT

Treatment of Patients with Immunodeficiency Abstract. Primary, genetically determined immunodeficiencies (PID) are caused by dysfunction of the innate and/or adaptive immune system. The majority of PID present with antibody deficiency, clinically associated with increased susceptibility to airway infections. Infections and pulmonary complications can be reduced by immunoglobulin substitution. The main practical issues of the clinical use of immunoglobulin replacement therapy are discussed here. Molecular dissection of PID is increasingly possible using next generation sequencing, enabling targeted immune modulation and immune reconstitution. This personalized immune modulation is discussed here as a seminal addition to the treatment options in patients with PID.

PMID:35903828 | DOI:10.1024/0040-5930/a001365

Ther Umsch. 2022 Aug;79(6):307-311. doi: 10.1024/0040-5930/a001366.

ABSTRACT

Vaccination and Vaccination Response in Immunodeficiency Abstract. Vaccination of patients with immunodeficiencies is challenging. A lack of increase in vaccine antibody titers or vaccine-induced infections may indicate primary immunodeficiency. All vaccines against SARS-CoV-2 licensed in Switzerland can be administered to immunocompromised patients.

PMID:35903827 | DOI:10.1024/0040-5930/a001366

J Clin Immunol. 2022 Jul 28. doi: 10.1007/s10875-022-01335-0. Online ahead of print.

ABSTRACT

PURPOSE: The aim of this study is to evaluate the usefulness of T cell receptor excision circle (TREC) and/or kappa-deleting recombination excision circle (KREC) measurements integrated with diagnostic next-generation sequencing (NGS) analysis using a severe combined immunodeficiency (SCID) newborn screening (NBS) program.

METHODS: TREC and/or KREC values were measured in 137,484 newborns between April 2017 and December 2021 using EnLite TREC (n = 80,791) or TREC/KREC kits (n = 56,693). For newborns with positive screening results, diagnostic NGS analysis was performed with a 349-gene panel to detect genetic mutations associated with primary immunodeficiencies (PIDs).

RESULTS: A total of 145 newborns (0.11%) had abnormal TREC and/or KREC values, and a genetic diagnosis was established in 2 patients with SCID (1 in 68,742 newborns) (IL2RG-SCID and reticular dysgenesis) and 10 with non-SCID PIDs with T and/or B cell deficiencies (1 in 13,748 newborns) using NGS analysis. Furthermore, TREC values of 2849 newborns were measured and confirmed the significant correlation between the results of both TREC and TREC/KREC kits (P < 0.001) and naïve T cell counts.

CONCLUSIONS: We performed the first large-scale TREC and TREC/KREC NBS programs in Japan. Our NBS programs followed by the diagnostic NGS analysis for newborns with abnormal TREC and/or KREC values are useful for the early identification and rapid molecular evaluation of not only SCID but also different non-SCID PIDs.

PMID:35902420 | DOI:10.1007/s10875-022-01335-0

Open Forum Infect Dis. 2022 Jul 5;9(7):ofac330. doi: 10.1093/ofid/ofac330. eCollection 2022 Jul.

ABSTRACT

BACKGROUND: Invasive disease caused by airway pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Moraxella catarrhalis, has high morbidity and mortality worldwide, with immunodeficiency being a known association with recurrent disease. The study aimed to describe the frequency of known immunodeficiency and predisposing factors in adult patients presenting with invasive infections and determine the frequency of screening for and detection of immunodeficiency.

METHODS: A retrospective analysis was conducted at a large tertiary Australian health service, comprising multiple centers. Patients aged 18 years or older, in whom the above pathogens were isolated from sterile sites, were included as identified through a microbiology database, between 2015 and 2020. Using electronic medical records, patient demographics, medical history, outcomes of admission, and pathology results were captured and reviewed to address the aims.

RESULTS: In 252 patients, S pneumoniae was the most common culprit, isolated in 73% (185/252), compared to 14.3% (36/252) and 11.5% (29/252) of infections caused by H influenzae and N meningitidis, respectively. Known diagnoses of secondary immunodeficiency were common (31% of patients). Of those presenting with invasive pneumococcal disease, 78% had at least 1 predisposing condition, though only 9 patients (6%) had previously received pneumococcal vaccination. Despite poor screening for immunodeficiency, 12 new diagnoses were made. While the commonest immunodeficiency was secondary, due to hematological and solid organ malignancies, 3 new primary immunodeficiency diagnoses were made.

CONCLUSIONS: Immunodeficiency is common in this patient population. Screening should be undertaken to ensure timely diagnosis and treatment of the underlying condition to avoid future morbidity and mortality.

PMID:35899285 | PMC:PMC9314888 | DOI:10.1093/ofid/ofac330

J Med Case Rep. 2022 Jul 27;16(1):301. doi: 10.1186/s13256-022-03517-1.

ABSTRACT

INTRODUCTION: Wiskott-Aldrich syndrome is a rare X-linked primary immunodeficiency that mostly presents with a classic triad of eczema, microthrombocytopenia, recurrent infections, and increased risk of autoimmunity/malignancies.

CASE PRESENTATION: We present an 8-month-old African male, born from nonconsanguineous parents and who presented with a history of eczematous skin rash since day 9 of life, with recurrent sinus infections, otitis media, and skin abscesses. An elder male sibling who had similar symptoms passed away during infancy. Investigations were consistent with microthrombocytopenia and significantly raised immunoglobulin E, while immunoglobulin A and immunoglobulin G were moderately elevated with normal immunoglobulin M. Genetic testing revealed the patient to be hemizygous for a pathogenic Wiskott-Aldrich syndrome gene variant (NM_000377.2:c.403C>T). He was managed conservatively with supportive treatment until he died a year later.

CONCLUSION: Despite Wiskott-Aldrich syndrome being a rare disease, it should be considered as a differential in any male child who presents with microthrombocytopenia and recurrent infections, especially in low-resource settings where genetic testing is not routinely available.

PMID:35897083 | DOI:10.1186/s13256-022-03517-1