Research

Cureus. 2022 Jun 2;14(6):e25594. doi: 10.7759/cureus.25594. eCollection 2022 Jun.

ABSTRACT

Common variable immunodeficiency (CVID) or acquired hypogammaglobulinemia is one of the common forms of primary immunodeficiency, which primarily affects the respiratory tract, but is often associated with gastrointestinal complications. The pathophysiology is not fully understood, making a diagnosis of CVID difficult. The low levels of IgG and IgA and defective B cells make intravenous immunoglobulin (IVIG) therapy the mainstay of management. The present article describes the journey of a 41-year-old male suffering from CVID and severe recurrent uncontrollable gastrointestinal infections requiring Intravenous immunoglobulin therapy, which was successfully substituted with an alternative oral Hyperimmune Bovine Colostrum and Zinc combination for long term gastrointestinal disease control in a more affordable manner. Keywords: Common variable immunodeficiency, Hypogammaglobulinemia, Primary Immunodeficiency, Gastrointestinal infection, Intravenous Immunoglobulin Therapy, Bovine Colostrum.

PMID:35664290 | PMC:PMC9161369 | DOI:10.7759/cureus.25594

Front Pediatr. 2022 May 19;10:839111. doi: 10.3389/fped.2022.839111. eCollection 2022.

ABSTRACT

OBJECTIVE: We aimed to assess BCG (Bacillus Calmette-Guérin) complications in patients with Inborn Errors of Immunity (IEI), according to the inherited disorders and associated immunological defects, as well as the different BCG substrains.

MATERIAL: We studied adverse reactions to the locally-produced BCG Moreau vaccine, analyzed in patients with IEI diagnosed between 1980 and 2020 in the Department of Immunology, Children’s Memorial Health Institute (CMHI), Warsaw. These results were compared with previously published studies.

RESULTS: Significantly fewer disseminated BCG infections (BCGosis) were found in 11 of 72 (15%) SCID (Severe Combined Immunodeficiency) NK (Natural Killer)-phenotype patients, when compared with the 119 out of 349 (34%) (p = 0.0012) patients with SCID with BCG in other countries. Significantly fewer deaths caused by BCGosis were observed (p = 0.0402). A significantly higher number of hematopoietic stem cell transplantations (HSCTs) were performed in the CMHI study (p = 0.00001). BCGosis was found in six patients with Mendelian susceptibility to mycobacterial diseases (MSMD). Other patients with IEI prone to BCG complications, such as CGD (Chronic Granulomatous Disease), showed no case of BCGosis.

CONCLUSION: The BCG Moreau substrain vaccine, produced in Poland since 1955, showed genetic differences with its parental Brazilian substrain together with a superior clinical safety profile in comparison with the other BCG substrains, with no BCGosis in patients with IEI other than SCID and MSMD. Our data also confirmed significantly fewer cases of BCGosis and deaths caused by BCG infection in patients with SCID with this vaccine substrain. Finally, they confirmed the protecting role of NK cells, probably via their production of IFN-γ.

PMID:35664873 | PMC:PMC9161164 | DOI:10.3389/fped.2022.839111

Stem Cell Res. 2022 May 31;62:102822. doi: 10.1016/j.scr.2022.102822. Online ahead of print.

ABSTRACT

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a rare autosomal dominant primary immunodeficiency disease (PID) which was caused by the acquired mutation of PIK3CD gene. In this study, we generated a human induced pluripotent stem cell (hiPSC) line CHCMUi001-A from the peripheral blood mononuclear cells (PBMCs) of a APDS patient, who has a heterozygous mutation (c.3061 G > A) in the PIK3CD gene. This iPSC line presented a normal karyotype and exhibited characteristics of pluripotent stem cells. This iPSC line can be very useful for not only studying disease mechanisms but also developing new potential clinical treatments for APDS patients.

PMID:35660815 | DOI:10.1016/j.scr.2022.102822

Sci Immunol. 2022 Jun 3;7(72):eabn2888. doi: 10.1126/sciimmunol.abn2888. Epub 2022 Jun 3.

ABSTRACT

The SKIV2L RNA exosome is an evolutionarily conserved RNA degradation complex in the eukaryotes. Mutations in the SKIV2L gene are associated with a severe inherited disorder, trichohepatoenteric syndrome (THES), with multisystem involvement but unknown disease mechanism. Here, we reported a THES patient with SKIV2L mutations showing severe primary B cell immunodeficiency, hypogammaglobulinemia, and kappa-restricted plasma cell dyscrasia but normal T cell and NK cell function. To corroborate these findings, we made B cell-specific Skiv2l knockout mice (Skiv2l^fl/flCd79a-Cre), which lacked both conventional B-2 and innate-like B-1 B cells in the periphery and secondary lymphoid organs. This was linked to a requirement of SKIV2L RNA exosome activity in the bone marrow during early B cell development at the pro-B cell to large pre-B cell transition. Mechanistically, Skiv2l-deficient pro-B cells exhibited cell cycle arrest and DNA damage. Furthermore, loss of Skiv2l led to substantial out-of-frame V(D)J rearrangement of immunoglobulin heavy chain and severely reduced surface expression of μH, both of which are crucial for pre-BCR signaling and proliferative burst during early B cell development. Together, our data demonstrated a crucial role for SKIV2L RNA exosome in early B cell development in both human and mice by ensuring proper V(D)J recombination and Igh expression, which serves as the molecular basis for immunodeficiency associated with THES.

PMID:35658009 | DOI:10.1126/sciimmunol.abn2888

Allergy Asthma Clin Immunol. 2022 Jun 2;18(1):45. doi: 10.1186/s13223-022-00688-w.

ABSTRACT

BACKGROUND: Human inborn errors of immunity (IEI) are a group of inherited genetic disorders of the immune system. IEI Patients suffer from severe repeated infections, autoimmunity, lymphadenopathy and/or increased susceptibility to malignancies. IEI are due to absence, disproportion, or loss of function of immune cells; mostly inherited in autosomal recessive manner, hence are more common in countries with high rate of consanguinity. Definite diagnosis of IEI is achieved by genetic analysis, however it is not always available.

AIM: to report on different IEI categories and impact of expanding the use of flow cytometry (FCM) in diagnosis, categorization and follow up of IEI patients in a highly consanguineous population.

METHODS: Retrospective chart review on different IEI categories diagnosed at the primary immunodeficiency center in Cairo University Specialized Pediatric hospital from 2011 to 2021 based on expanding the use of FCM.

RESULTS: 1510 IEI patients were diagnosed; 480 were diagnosed genetically with FMF, 11 with cystic fibrosis and 1019 patients were diagnosed with other IEI disorders. Phagocytic defects were the commonest (30%) followed by severe combined immunodeficiency (22%) and combined immunodeficiency (18.3%). FCM testing properly diagnosed and categorized 73% of the cases.

CONCLUSION: Using multi-color FCM to evaluate immune cells populations, subpopulations, functions, and intracellular proteins expression is proved a useful cost-effective method for screening, categorization and follow up of IEI patients. FCM can improve the diagnosis of IEI significantly when tests are properly targeted and well designed. This study presents a 10-year experience in diagnosis of IEI using FCM at a tertiary referral center in a setting of limited resources and yet high prevalence of IEI.

PMID:35655284 | DOI:10.1186/s13223-022-00688-w

Pediatr Pulmonol. 2022 Jun 2. doi: 10.1002/ppul.26027. Online ahead of print.

ABSTRACT

Numerous publications on wheezing disorders in children younger than 6 years have appeared in the medical literature over the last decades with the aim of shedding light on the mechanistic pathways (endotypes) and treatment. Nevertheless, there is yet no consensus as to the appropriate way to manage preschool wheeze mainly because of the lack of a clear definition of “preschool asthma” and the paucity of scientific evidence concerning its underlying endotypes. A symptom-based approach is inadequate since the human airway can respond to external stimuli with a limited range of symptoms and signs, including cough and wheeze, and these manifestations represent the final expression of many clinical entities with potentially different pathophysiologies requiring different individualized treatments. Hence, new studies challenge the symptom-based approach and promote the importance of managing the wheezy child based on the “airway phenotype”. This will enable the clinician to identify not only the child with a serious underlying pathology (e.g. a structural airway disorder or immunodeficiency) who is in need of prompt and specific treatment but also increase the specificity of treatment for the child with symptoms suggestive of an “asthma” syndrome. In the latter case, focus should be given to the identification of treatable traits. This review summarizes the current understanding in management of preschool wheezing and highlights the unmet need for further research. This article is protected by copyright. All rights reserved.

PMID:35652262 | DOI:10.1002/ppul.26027

Clin Rev Allergy Immunol. 2022 Jun 1. doi: 10.1007/s12016-022-08942-0. Online ahead of print.

ABSTRACT

Primary immunodeficiency (PID) may impact any component of the immune system. The number of PID and immune dysregulation disorders is growing steadily with advancing genetic detection methods. These expansive recognition methods have changed the way we characterize PID. While PID were once characterized by their susceptibility to infection, the increase in genetic analysis has elucidated the intertwined relationship between PID and non-infectious manifestations including autoimmunity. The defects permitting opportunistic infections to take hold may also lead the way to the development of autoimmune disease. In some cases, it is the non-infectious complications that may be the presenting sign of PID autoimmune diseases, such as autoimmune cytopenia, enteropathy, endocrinopathies, and arthritis among others, have been reported in PID. While autoimmunity may occur with any PID, this review will look at certain immunodeficiencies most often associated with autoimmunity, as well as their diagnosis and management strategies.

PMID:35648371 | DOI:10.1007/s12016-022-08942-0

Int J Neonatal Screen. 2022 May 10;8(2):33. doi: 10.3390/ijns8020033.

ABSTRACT

Screening for severe combined immunodeficiency (SCID) was added to the New Zealand national newborn screening programme in December 2017. Documentation pertaining to the application to add SCID to the panel and screening results over the first three years were reviewed. Screening evaluation metrics were shown to differ according to site of collection (babies in a neonatal intensive care unit vs. the community), definition of a positive test (out-of-range result vs. result leading to a further action on baby), and screening target/case definition (primary SCID vs. non-SCID T-cell lymphopenia). Our experience demonstrates both the value of close clinical involvement during the implementation phase of SCID screening and that the use of standard definitions will facilitate international comparison.

PMID:35645287 | DOI:10.3390/ijns8020033

J Allergy Clin Immunol Pract. 2022 May 25:S2213-2198(22)00505-0. doi: 10.1016/j.jaip.2022.05.017. Online ahead of print.

ABSTRACT

Genetic testing is a state-of-the-art and readily accessible diagnostic tool and is increasingly indicated in the evaluation process when relevant and possible, although incorporation of this modality into the daily practice of allergists-immunologists in both academic and nonacademic or community settings is still a challenge. Educational sessions and resources support the use of genetic testing in the diagnosis and management of Primary Immunodeficiency (PID) by both the American Academy of Allergy, Asthma and Immunology, as well as the Clinical Immunology Society. Genetic testing for PID has become much more convenient and affordable over the past decade; allergist-immunologists in private practice are now able to offer patients high-quality and comprehensive genetic testing panels to help diagnose or characterize underlying immune abnormalities among patients with recurrent infections, and even patients with allergic disorder and non-infectious complications. Though genetic testing has not been a commonplace consideration in day-to-day practice for many non-academic specialists, a shift toward adopting this into our standard toolkit should be taking place. Most of the commercial genetic testing is aiming for a panel of genes ranging anywhere from just a few to several hundred, so the specialist can feel comfortable clearly interpreting the data. As the panels are analyzing data from next generation sequencing (NGS) and deletion/duplication assays, this evaluation may need to be repeated when panels expand and include new relevant genes. Ultimately, for undiagnosed cases, whole exome and genome sequencing can be the next step, however, involvement of genetic counsellors may be needed to interpret the data. The value of genetic testing is that it may bring the clinician closer to an accurate diagnosis, therefore we can keep treating our patients more accurately and effectively, which may result in less frequent follow-ups for unresolved or recurrent problems. Additionally, we can then provide patients and their families with important information about the root-cause of their disease state, risks to other family members, and offer genetic counseling services. Genetic testing results may also aid in recognizing when a referral to expert colleagues for more advanced and specialized treatments is indicated.

PMID:35643275 | DOI:10.1016/j.jaip.2022.05.017

Pediatr Dermatol. 2022 May 29. doi: 10.1111/pde.15032. Online ahead of print.

ABSTRACT

Granulomatous skin disease is known to be associated with various primary immunodeficiencies, including ataxia telangiectasia (AT). Recent reports of persistence of live vaccine strain rubella within such cutaneous granulomas have raised concern regarding the safety of vaccination. Here we report a case of cutaneous granuloma in association with AT, demonstrating wild type, rather than vaccine strain rubella. This supports the persistence of rubella as a causative mechanism, but suggests it is not vaccine strain-specific, and thus may impact the decision of those considering not vaccinating this subset of children.

PMID:35644916 | DOI:10.1111/pde.15032