Blog

Medicine (Baltimore). 2024 Feb 2;103(5):e37198. doi: 10.1097/MD.0000000000037198.

ABSTRACT

INTRODUCTION: X-linked recessive chronic granulomatous disease (XR-CGD) is a severe primary immunodeficiency principally caused by a CYBB (OMIM: 300481) gene variant. Recurrent fatal bacterial or fungal infections are the main clinical manifestations of XR-CGD.

PATIENT CONCERNS: In the current case, in vitro fertilization (IVF) associated with preimplantation genetic testing for monogenic disorder (PGT-M) was applied for a Chinese couple who had given birth to a boy with XR-CGD.

DIAGNOSIS: Next-generation sequencing-based SNP haplotyping and Sanger-sequencing were used to detect the CYBB gene variant (c.804 + 2T>C, splicing) in this family.

INTERVENTIONS: The patient was treated with IVF and PGT-M successively.

OUTCOMES: In this IVF cycle, 7 embryos were obtained, and 2 of them were euploid and lacked the CYBB gene variant (c.804 + 2T>C). The PGT results were verified by prenatal diagnosis after successful pregnancy, and a healthy girl was eventually born.

CONCLUSION: PGT-M is an effective method for helping families with these fatal and rare inherited diseases to have healthy offspring. It can availably block the transmission of disease-causing loci to descendant.

PMID:38306523 | PMC:PMC10843245 | DOI:10.1097/MD.0000000000037198

Clin Exp Immunol. 2024 Feb 2:uxae008. doi: 10.1093/cei/uxae008. Online ahead of print.

ABSTRACT

Selective IgA deficiency (sIgAD) and Common Variable Immunodeficiency (CVID) and Transient Hypogammaglobulinemia of Infancy (THI) are the most frequent forms of primary antibody deficiencies. Difficulties in initial diagnosis, especially in the early childhood, the familiar occurrence of these diseases, as well as the possibility of progression to each other suggest common cellular and molecular patomechanism and a similar genetic background. In this review, we discuss both similarities and differences of these three humoral immunodeficiencies, focusing on current and novel therapeutic approaches. We summarize immunoglobulin substitution, antibiotic prophylaxis, treatment of autoimmune diseases and other common complications, i.e. cytopenias, gastrointestinal complications, and granulomatous disease. We discuss novel therapeutic approaches such as allogenic stem cell transplantation and therapies targeting specific proteins, dependant on the patient’s genetic defect. The diversity of possible therapeutics models result from a great heterogeneity of the disease variants, implying the need of personalized medicine approach as a future of primary humoral immunodeficiencies treatment.

PMID:38306460 | DOI:10.1093/cei/uxae008

Trends Immunol. 2024 Feb;45(2):113-126. doi: 10.1016/j.it.2023.12.006. Epub 2024 Jan 31.

ABSTRACT

New discoveries in the field of human monogenic immune diseases highlight critical genes and pathways governing immune responses. Here, I describe how the ~500 currently defined human inborn errors of immunity help shape what I propose is an ‘adaptive arsenal model of rapid defenses’, emphasizing the set of immunological defenses poised for rapid responses in the natural environment. This arsenal blurs the lines between innate and adaptive immunity and is established through molecular relays between cell types, often traversing from sensors (pathogen detection) to intermediates to executioners (pathogen clearance) via soluble factors. Predictions and missing information based on the adaptive arsenal model are discussed, as are emergent and outstanding questions fundamental to advances in the field.

PMID:38302340 | DOI:10.1016/j.it.2023.12.006

N Engl J Med. 2024 Feb 1;390(5):432-441. doi: 10.1056/NEJMoa2309149.

ABSTRACT

BACKGROUND: Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1), with the goal of lifelong control of angioedema attacks after a single dose.

METHODS: In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks.

RESULTS: Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%.

CONCLUSIONS: In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).

PMID:38294975 | DOI:10.1056/NEJMoa2309149

Pediatr Allergy Immunol. 2024 Jan;35(1):e14074. doi: 10.1111/pai.14074.

NO ABSTRACT

PMID:38284921 | DOI:10.1111/pai.14074

Pediatr Allergy Immunol. 2024 Jan;35(1):e14068. doi: 10.1111/pai.14068.

ABSTRACT

BACKGROUND: Primary immune deficiencies (PID) encompasses genetic disorders that result in recurrent infections and immune dysregulation, often increasing the risk of malignancies. The aim of this study is to determine the quality of life, depression, and anxiety in parents of children with PID.

METHODS: Various validated assessment tools, including the Beck Depression Inventory (BDI), State and Trait Anxiety Inventory (STAI), the 36-item Short Form Survey (SF-36), and a demographic form, were employed to gather data from 85 parents of 64 PID patients and 85 parents of 75 healthy children.

RESULTS: The findings reveal that parents of PID patients exhibited higher BDI, STAI-S, STAI-T, and fatigue subdomain of SF-36 (p = .013, p = .013, p = .027, p = .000). Both parents had lower energy levels than the normal population, but mothers experienced higher levels of anxiety and depression. PID mothers’ had higher scores than fathers of PID patients with healthy children in BDI, STAI-S, and STAI-T (p = .002, p = .010, p = .001). Mothers of PID patients reported lower scores in RLEP, E/F, EWB, P, and GH compared to fathers (p = .009, p = .005, p = .034, p = .001, p = .003). Additionally, the study found that STAI-T influenced all subdimensions of HRQOL. These results highlight the substantial emotional and psychological burden placed on parents caring for children with PID.

CONCLUSION: The study underscores the importance of supporting caregivers to enhance the overall well-being of both parents and children with PID. Such support can potentially alleviate depression and anxiety levels among parents, ultimately improving their quality of life and aiding in the management of children with PID.

PMID:38284917 | DOI:10.1111/pai.14068

Front Immunol. 2024 Jan 12;14:1308305. doi: 10.3389/fimmu.2023.1308305. eCollection 2023.

ABSTRACT

BACKGROUND: Primary Immunodeficiency Disease (PID), also known as Inborn Errors of Immunity (IEI), comprises a group of rare genetic disorders that impair the body’s immune responses. These conditions result from monogenic germline mutations that affect the function of genes governing the innate and adaptive immune system. Therefore, individuals with PID are more susceptible to infectious diseases, allergies, and autoimmune and autoinflammatory conditions. The prevalence of PID has been on the rise, with the number of classified diseases reaching 404, and 430 genetic defects reported to cause these conditions. However, in Malaysia, genetic testing for PID is currently limited and needs to be outsourced to overseas laboratories, posing financial challenges for families. Moreover, limited research has focused on the knowledge and awareness of genetic testing among parents of children with PID in Malaysia. This study aims to address this gap and provide valuable insights into the knowledge, awareness, and perception of genetic testing among this specific population.

METHOD: This qualitative cross-sectional study utilised online open-ended, semi-structured focus group interviews to explore the perceptions and experiences of parents of children with Primary Immunodeficiency (PID). Participants were recruited through convenience sampling from the Malaysian Patient Organisation for Primary Immunodeficiencies (MyPOPI), a non-governmental organisation dedicated to providing support and raising awareness about PID. The study spanned from May 2023 to July 2023 and included participants from diverse regions of Malaysia who had undergone different diagnostic journeys in various hospitals.

RESULT: The focus group discussions yielded 11 sub-themes that highlighted the experiences, understanding and challenges of the participants regarding genetic testing based on the semi-structured questions. These sub-themes were then grouped into four main themes that are awareness and understanding of genetic testing, the journey towards diagnosis and treatment, emotional impact and psychological factors, and the importance of medical experts in diagnosing and managing PID, as well as public perception and awareness.

CONCLUSION: In conclusion, this study highlights the diverse knowledge, awareness, and perception surrounding genetic testing for PID. Factors such as access to services, family history, and personal circumstances shape individuals’ understanding of genetic testing. The importance of healthcare professionals, along with the need for improved accessibility and targeted communication strategies, is underscored to enhance understanding and reduce stigma surrounding genetic testing for rare diseases like PID.

PMID:38283358 | PMC:PMC10811462 | DOI:10.3389/fimmu.2023.1308305

Clin Exp Med. 2024 Jan 27;24(1):17. doi: 10.1007/s10238-023-01259-y.

ABSTRACT

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. Despite available treatments, survival for individuals with APDS appears to be shortened from the average lifespan. A Kaplan-Meier survival analysis for APDS showed the conditional survival rate at the age of 20 years was 87%, age of 30 years was 74%, and ages of 40 and 50 years were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The overall mortality rate for HSCT in APDS1 and APDS2 cases was 15.6%, while the mortality rate for lymphoma was 47.6%. This survival and mortality data illustrate that new treatments are needed to mitigate the risk of death from lymphoma and other cancers as well as infection. These analyses based on real-world evidence gathered from the medical literature comprise the largest study of survival and mortality for APDS to date.

PMID:38280023 | PMC:PMC10821986 | DOI:10.1007/s10238-023-01259-y

J Pediatric Infect Dis Soc. 2024 Jan 27:piae004. doi: 10.1093/jpids/piae004. Online ahead of print.

ABSTRACT

BACKGROUND: Palivizumab is recommended for prevention of severe respiratory syncytial virus (RSV) disease in immunocompromised children, despite a lack of strong supporting evidence. The recent approval of substitute RSV-neutralizing monoclonal antibodies against RSV, offers an opportunity to synthesize the most current evidence supporting the palivizumab standard of care.

OBJECTIVE: To evaluate the efficacy of palivizumab in preventing acute respiratory tract infection- or RSV-related hospitalization, or mortality in immunocompromised children.

METHODS: We searched Ovid MEDLINE and EMBASE for published clinical studies that investigated outcomes of palivizumab use in children. We included clinical trials, cohort studies, and case-control studies. The primary outcomes were RSV-related or respiratory viral infection-related hospitalizations, or RSV-related mortality. This systematic review was registered in PROSPERO (ID CRD42021248619) and is reported in accordance with the PRISMA guidelines.

RESULTS: From the 1993 records, 6 studies were eligible and included, for a total of 625 immunocompromised children with an heterogenous composition of primary and acquired immunodeficiencies enrolled from palivizumab programs. There were no intervention studies. None of the studies included a control group. RSV hospitalizations were infrequent (0 to 3.1% of children). Most children included received palivizumab, although one study (N = 56) did not specify how many received palivizumab. RSV mortality was neither observed, in three studies, nor reported, in three other studies.

CONCLUSIONS: The evidence supporting the use of palivizumab for prevention of severe RSV disease in immunocompromised children remains extremely limited and appears insufficient to justify prioritizing this intervention as the current standard of care over alternative interventions.

PMID:38279954 | DOI:10.1093/jpids/piae004

J Allergy Clin Immunol. 2024 Jan 24:S0091-6749(24)00078-2. doi: 10.1016/j.jaci.2024.01.011. Online ahead of print.

ABSTRACT

BACKGROUND: The 10 Warning Signs (WS) of Primary Immunodeficiency were created 30 years ago to advance recognition of inborn-errors of immunity (IEI). However, no population-level assessment of their utility applied to electronic health record (EHR) data has been conducted.

OBJECTIVE: We sought to quantify the value of having 2+ WS towards diagnosing IEI using a highly representative real-world US cohort. A secondary goal was estimating the US prevalence of IEI.

METHODS: In this cohort study, we accessed normalized and de-identified EHR data on 152 million US lives. An IEI cohort (n=41,080) was defined by having at least 1 verifiable IEI diagnosis placed ≥2 times in their record and compared to a matched set of controls (n=250,262). WS were encoded along with relevant diagnoses, relative weights were calculated and the proportion of IEI vs controls with 2+ WS was compared.

RESULTS: The proportion of IEI patients with 2+ warning signs significantly differed from controls (0.33 vs. 0.031; p < 0.0005 ChiSq). We also estimated a US IEI prevalence of 6:10,000 individuals (41,080/73,165,655; 0.056%). Warning signs 9 (2+deep-seated infections), 7(fungal infections), 5(failure to thrive) and 4(2+pneumonias in 1 year) were the most heavily weighted among the IEI cohort.

CONCLUSIONS: From this nationally representative US-based cohort study, we note that WS presence, and associated clinical diagnoses, can facilitate IEI patient identification from EHR data. In addition, we estimate that 6 in 10,000 or approximately 150-200,00 persons are affected by IEI across the US.

PMID:38278184 | DOI:10.1016/j.jaci.2024.01.011