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Summary: Background: Immunocompromised patients with primary and secondary immunodeficiencies have shown impaired responses to SARS-CoV-2 mRNA vaccines, necessitating recommendations for additional booster doses. However, longitudinal data reflecting the real-world impact of such recommendations remains limited. Methods: This study represents a two-year follow-up of the COVAXID clinical trial, where 364 of the original 539 subjects consented to participate. 355 individuals provided blood samples for evaluation of binding antibody (Ab) titers and pseudo-neutralisation capacity against both the ancestral SARS-CoV-2 strain and prevalent Omicron variants. T cell responses were assessed in a subset of these individuals. A multivariate analysis determined the correlation between Ab responses and the number of vaccine doses received, documented infection events, immunoglobulin replacement therapy (IGRT), and specific immunosuppressive drugs. The original COVAXID clinical trial was registered in EudraCT (2021-000175-37) and clinicaltrials.gov (NCT04780659). Findings: Several of the patient groups that responded poorly to the initial primary vaccine schedule and early booster doses presented with stronger immunogenicity-related responses including binding Ab titres and pseudo-neutralisation at the 18- and 24-month sampling time point. Responses correlated positively with the number of vaccine doses and infection. The vaccine response was blunted by an immunosuppressive state due to the underlying specific disease and/or to specific immunosuppressive treatment. Interpretation: The study results highlight the importance of continuous SARS-CoV-2 vaccine booster doses in building up and sustaining Ab responses in specific immunocompromised patient populations. Funding: The present studies were supported by the European Research Council, Karolinska Institutet, Knut and Alice Wallenberg Foundation, Nordstjernan AB, Region Stockholm, and the Swedish Research Council.

Background: The relationship between inborn errors of immunity (IEIs) and COVID-19 severity and incidence rates remains unclear due to limited and diverse data. This study aimed to address this gap by identifying specific IEIs associated with an increased risk of severe COVID-19 or a predisposition to severe disease before vaccination. Materials and Methods: Data were collected from the medical records of 15 patients with various IEIs, supplemented by interviews with individuals from an IEIs registry who had experienced COVID-19 before vaccination. Results: Among the participants, only three patients (20%) experienced severe-prolonged COVID-19. Notably, this severity was predominantly observed in two male patients with Bruton’s disease (BD) and one female patient with autosomal recessive hypogammaglobinemia. Moderate and severe COVID-19 cases were equally distributed (13.33%). In the female subgroup, one patient with common variable immunodeficiency and another with combined immunodeficiency experienced moderate and severe COVID-19, respectively. Conversely, both male patients with moderate and severe COVID-19 had BD. Conclusion: Despite the limited number of severe cases, the absence of cytokine storm manifestation suggests potential protective mechanisms, possibly due to intravenous immunoglobulin therapy and inherent deficiencies within cytokine-producing cells (B and T cells). While IEIs may not be significant risk factors for COVID-19, they offer promising avenues for further research into therapeutic strategies targeting specific immune system components to mitigate severe COVID-19.

Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is a rare, combined immunodeficiency disease predominantly caused by gain-of-function variants in the CXCR4 gene that typically results in truncation of the carboxyl terminus of C-X-C chemokine receptor type 4 (CXCR4) leading to impaired leukocyte egress from bone marrow to peripheral blood. Diagnosis of WHIM syndrome continues to be challenging and is often made through clinical observations and/or genetic testing. Detection of a pathogenic CXCR4 variant in an affected individual supports the diagnosis of WHIM syndrome but relies on an appropriate annotation of disease-causing variants. Understanding the genotypic-phenotypic associations in WHIM syndrome has the potential to improve time to diagnosis and guide appropriate clinical management, resulting in a true example of precision medicine. This article provides an overview of the spectrum of CXCR4 variants in WHIM syndrome and summarizes the various lines of clinical and functional evidence that can support interpretation of newly identified variants.

BackgroundTumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant disorder with a low incidence in Asia. The most frequent clinical manifestations include fever, rash, myalgia, joint pain and abdominal pain. Misdiagnosis rates are high because of the clinical and genetic variability of the disease. The pathogenesis of TRAPS is complex and yet to be fully defined. Early genetic diagnosis is the key to precise treatment.MethodsIn this study, a Chinese family with suspected TRAPS were analyzed by genome-wide SNP genotyping, linkage analysis and targeted sequencing for identification of mutations in causative genes. To study the pathogenicity of the identified gene mutation, we performed a conservation analysis of the mutation site and protein structure analysis. Flow cytometry was used to detect TNFRSF1A shedding and quantitative real-time PCR were used to assess the activation of unfolded protein response (UPR) in the mutation carriers and healthy individuals.ResultsA typical TRAPS family history, with a pattern of autosomal dominant inheritance, led to the identification of a rare mutation in the TNFRSF1A gene (c.G374A [p.Cys125Tyr]) with unknown significance. The patient responded well to corticosteroids, and long-term therapy with colchicine effectively reduced the inflammatory attacks. No amyloid complications occurred during the 6-year follow-up. In silico protein analysis showed that the mutation site is highly conversed and the mutation prevents the formation of intrachain disulfide bonds in the protein. Despite a normal shedding of the TNFRSF1A protein from stimulated monocytes in the TRAPS patients with p.C125Y mutation, the expression of CHOP and the splicing of XBP1 was significantly higher than healthy controls, suggesting the presence of an activation UPR.ConclusionThis is the first report of a Chinese family with the rare p.C125Y mutation in TNFRSF1A. The p.C125Y mutation does not result in aberrant receptor shedding, but instead is associated with an activated UPR in these TRAPS patients, which may provide new insights into the pathogenesis of this rare mutation in TRAPS.

IntroductionAccording to the PRISMA criteria, a systematic review has been conducted to investigate the clinical relevance between patients with severe congenital neutropenia (SCN) and cyclic congenital neutropenia (CyN) induced by ELANE mutations.MethodsWe have searched PubMed, EMBASE, Web of Science, Scopus, Cochrane, CNKI, Wanfang Medicine, and VIP for ELANE mutation related literature published from 1997 to 2022. Using Microsoft Excel collect and organize data, SPSS 25, GraphPad Prism 8.0.1, and Omap analyze and plot statistical. Compare the gender, age, geography, mutation sites, infection characteristics, treatment, and other factors of SCN and CyN patients induced by ELANE mutations, with a focus on exploring the relationship between genotype and clinical characteristics, genotype and prognosis.ResultsThis study has included a total of 467 patients with SCN and 90 patients with CyN. The onset age of SCN and CyN are both less than 1 year old, and the onset and diagnosis age of SCN are both younger than CyN. The mutation of ELANE gene is mainly missense mutation, and hot spot mutations include S126L, P139L, G214R, c.597+1G>A. The high-frequency mutations with severe outcomes are A57V, L121H, L121P, c.597+1G>A, c.597+1G>T, S126L, C151Y, C151S, G214R, C223X. Respiratory tract, skin and mucosa are the most common infection sites, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli are the most common.DiscussionPatients with refractory G-CSF are more likely to develop severe outcomes. The commonly used pre-treatment schemes for transplantation are Bu-Cy-ATG and Flu-Bu-ATG. The prognosis of transplantation is mostly good, but the risk of GVHD is high.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/. PROSPERO, identifier CRD42023434656.

BackgroundPrimary 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.MethodThis 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.ResultThe 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.ConclusionIn 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.

Background: Schimke immune-osseous dysplasia (SIOD) is an ultra-rare multisystemic, monogenic, and autosomal recessive inherited disease caused by biallelic mutations in the SMARCAL1 gene. Approximately 100 cases have been reported worldwide. The disease is characterized by skeletal, renal, and immunological abnormalities. Case description: This is a 6-year-old female patient who debuted with nephrotic syndrome at five years of age, with a switch to corticosteroid resistance and poor response to immunosuppressive treatment received. The patient was admitted and referred to our institution due to convulsive status. During her hospitalization, thrombosis was found in the left renal vein, and a renal biopsy report of Collapsing Focal and Segmental Glomerulosclerosis (FSGS) was obtained. The patient had multiple infections during hospitalization, with T lymphocyte lymphopenia and severe IgG hypogammaglobulinemia. Additionally, given dysmorphic facies, delayed weight-height development, and spondyloepiphyseal dysplasia, exome sequencing was performed, finding an homozygous pathogenic variant c.1933C > T p.Arg645Cys in SMARCAL1, compatible with the diagnosis of SIOD. Discussion: We present the case of a patient that exhibited a severe phenotype of the disease, with skeletal, renal, severe combined immunological compromise and cerebrovascular involvement during follow-up, and the available proposed mechanisms of the disease focused on the clinical manifestations of this patient. It is the first case of SIOD reported in Colombia and the first comprehensive characterization reported in the literature of a patient with homozygosity of the known variant c.1933C > T p.Arg645Cys. Conclusion: A severe phenotype of the disease with cerebrovascular involvement by homozygosity of the known variant c.1933C > T p.Arg645Cys in the SMARCAL1 gene can be expected.

Summary: Background: Immunocompromised patients have varying responses to SARS-CoV-2 mRNA vaccination. However, there is limited information available from prospective clinical trial cohorts with respect to long-term immunogenicity-related responses in these patient groups following three or four vaccine doses, and in applicable cases infection. Methods: In a real-world setting, we assessed the long-term immunogenicity-related responses in patients with primary and secondary immunodeficiencies from the prospective open-label clinical trial COVAXID. The original clinical trial protocol included two vaccine doses given on days 0 and 21, with antibody titres measured at six different timepoints over six months. The study cohort has subsequently been followed for one year with antibody responses evaluated in relation to the third and fourth vaccine dose, and in applicable cases SARS-CoV-2 infection. In total 356/539 patients were included in the extended cohort. Blood samples were analysed for binding antibody titres and neutralisation against the Spike protein for all SARS-CoV-2 variants prevailing during the study period, including Omicron subvariants. SARS-CoV-2 infections that did not require hospital care were recorded through quarterly in-person, or phone-, interviews and assessment of IgG antibody titres against SARS-CoV-2 Nucleocapsid. The original clinical trial was registered in EudraCT (2021-000175-37) and clinicaltrials.gov (NCT04780659). Findings: The third vaccine dose significantly increased Spike IgG titres against all the SARS-CoV-2 variants analysed in all immunocompromised patient groups. Similarly, neutralisation also increased against all variants studied, except for Omicron. Omicron-specific neutralisation, however, increased after a fourth dose as well as after three doses and infection in many of the patient subgroups. Noteworthy, however, while many patient groups mounted strong serological responses after three and four vaccine doses, comparably weak responders were found among patient subgroups with specific primary immunodeficiencies and subgroups with immunosuppressive medication. Interpretation: The study identifies particularly affected patient groups in terms of development of long-term immunity among a larger group of immunocompromised patients. In particular, the results highlight poor vaccine-elicited neutralising responses towards Omicron subvariants in specific subgroups. The results provide additional knowledge of relevance for future vaccination strategies. Funding: The present studies were supported by grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Nordstjernan AB, Region Stockholm, and Karolinska Institutet.

Background: Primary (PID) or secondary (SID) immunodeficiencies are diseases caused by quantitative and/or functional alterations of the different mechanisms involved in the innate and adaptive immune response. This economic evaluation was conducted to compare the cost of treatment of HYQVIA® (hyaluronidase-facilitated subcutaneous infusion of immunoglobulin, fSCIG) compared to intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG), currently reimbursed in Italy, in the treatment of PIDs or SIDs. Methods: A cost-minimisation analysis was carried out, considering the hospital’s perspective. The direct medical costs (cost of immunoglobulins and cost of administration) were assessed. The analysis was conducted considering one year (52 weeks) time horizon. The reference population included adult patients with PID with impaired antibody production or adult patients with SID with severe or recurrent infections, ineffective antimicrobial treatment and documented specific antibody defect (PSAF) or serum IgG level < 4 g/L. Results: In the maintenance treatment of PID, HYQVIA® (€ 20,020.00) was the therapeutic alternative with the lowest mean annual cost compared to HIZENTRA® (€ 22,165.19) and VENITAL® (€ 24,967.68). Moreover, in the maintenance treatment of SIDs, HYQVIA® (€ 17,160.00) was the cost-saving therapeutic alternative compared to VENITAL® (€ 22,107.68). A sensitivity analysis confirmed the base case results. Conclusion: Due to lower costs of administration and different scheme of administration, HYQVIA® was a cost-saving alternative to SCIG e IVIG in the treatment of PID and to IVIG in the treatment of SID

BackgroundAdult antibody deficiency remains under-recognised and under-studied – especially among Asian populations. Patterns of immunoglobulin use and the feasibility of subcutaneous immunoglobulin (SCIg) replacement among Chinese patients remains unclear.ObjectiveTo investigate the trends of immunoglobulin use, burden of adult antibody deficiency and the outcomes of patients on SCIg compared to intravenous immunoglobulin (IVIg) replacement in Hong Kong through a retrospective observational study.MethodsPopulation-wide data of immunoglobulin recipients in Hong Kong between 2012 and 2021, and longitudinal clinical data of adult immunodeficiency patients at Queen Mary Hospital were collected and analysed.ResultsTotal immunoglobulin consumption and recurrent immunoglobulin recipients increased continuously from 175,512g to 298,514g (ρ=0.99, p

BackgroundImmune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder of the immune regulatory system caused by forkhead box P3 (FOXP3) mutations. Abnormal numbers or functions of regulatory T (Treg) cells account for the various autoimmune symptoms. We aimed to explore the molecular genetics and phenotypic spectra of patients with atypical IPEX syndrome in China.MethodsWe analyzed the molecular, clinical and immune phenotype characteristics of five Chinese patients with FOXP3 mutations.ResultsWe summarized the molecular and phenotypic features of five patients with FOXP3 mutations, including two novel mutations. Four of the five patients displayed atypical phenotypes, and one developed immune-related peripheral neuropathy. Three of the five patients showed normal frequencies of Treg cells, but the proportions of subsets of Treg cells, CD4+ T cells and B cells were out of balance.ConclusionsOur report broadens the understanding of the clinical features of atypical IPEX syndrome. Our detailed analyses of the immunological characteristics of these patients enhance the understanding of the possible mechanisms underlying the clinical manifestations.

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.

Abstract Background Loss-of-function (LOF) mutations in signal transducer and activator of transcription 3 (STAT3) is one of the causes of STAT3 hyperimmunoglobulin E (IgE) syndrome (STAT3-HIES), while gain-of-function (GOF) mutations in STAT3 lead to immune dysregulation diseases. We retrospectively analyzed the age, common clinical symptoms, immunologic and molecular manifestations in 11 patients with LOF STAT3 mutations and 1 patient with a GOF STAT3 mutation. Methods Twelve patients were enrolled in our study. Serum immunoglobulin measurements, lymphocyte subset detection and whole-exome sequencing were performed. Results The median age at diagnosis of STAT3-HIES patients was 4.74 years. Eczema, recurrent respiratory infections, fevers, abscesses and Staphylococcus aureus infections were the classic manifestations. Elevated serum IgE levels are not always observed in conjunction with high eosinophil counts. A moderate viral DNA load was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common mutation site, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients achieved notable improvement after receiving intravenous immunoglobulin. Conclusion We updated the current knowledge of this topic. We found an earlier median age at diagnosis, a higher survival rate, and a general lack of nonimmunological abnormalities; we also described the treatment details and novel mutations involve in STAT3-HIES and compared STAT3 LOF and GOF mutations.

DNA ligase IV (LIG4) deficiency is an extremely rare autosomal recessive primary immunodeficiency disease caused by mutations in LIG4. Patients suffer from a broad spectrum of clinical problems, including microcephaly, growth retardation, developmental delay, dysmorphic facial features, combined immunodeficiency, and a predisposition to autoimmune diseases and malignancy. In this study, the clinical, molecular, and immunological characteristics of 15 Chinese patients with LIG4 deficiency are summarized in detail. p.R278L (c.833G>T) is a unique mutation site present in the majority of Chinese cases. We conducted pedigree and haplotype analyses to examine the founder effect of this mutation site in China. This suggests that implementation of protocols for genetic diagnosis and for genetic counseling of affected pedigrees is essential. Also, the search might help determine the migration pathways of populations with Asian ancestry.

BackgroundInfections are the major cause of morbidity and mortality in patients with primary immunodeficiency disease (PID). Timely and accurate microbiological diagnosis is particularly important in these patients. Metagenomic next-generation sequencing (mNGS) has been used for pathogen detection recently. However, few reports describe the use of mNGS for pathogen identification in patients with PID.ObjectiveTo evaluate the utility of mNGS for detecting pathogens in patients with PID, and to compare it with conventional microbiological tests (CMT).MethodsThis single center retrospective study investigated the diagnostic performance of mNGS for pathogens detection in PID patients and compared it with CMT. Sixteen PID patients with suspected infection were enrolled, and medical records were analyzed to extract detailed clinical characteristics such as gene variation, immune status, microbial distribution, time-consuming of mNGS and CMT, treatment, and outcomes.ResultsmNGS identified pathogenic microbe in 93.75% samples, compared to 31.25% for culture and 68.75% for conventional methods, and detected an extra 18 pathogenic microorganisms including rare opportunistic pathogens and Mycobacterium tuberculosis. Pathogen identification by mNGS required 48 hours, compared with bacterial culture for 3-7 days and even longer for fungus and Mycobacterium tuberculosis culture.ConclusionsmNGS has marked advantages over conventional methods for pathogenic diagnosis, particularly opportunistic pathogens and mixed infections, in patients with PID. This method might enable clinicians to make more timely and targeted therapeutic decisions, thereby improving the prognosis of these patients.

Abstract Background Primary immunodeficiency disease (PID) is a disorder caused by an inherited flaw in the immune system that increases the susceptibility to infections. Methods In this study, 112 children with PID were diagnosed and classified based on the 2017 criteria presented by the International Union of Immunological Societies (IUIC) in a single tertiary care center from January 2013 to November 2018. We retrospectively studied the clinical features of those PID children and followed-up them as well. Results It was revealed that male/female ratio was 6:1. The most frequent diagnosed PID was severe combined immunodeficiency (SCID) (28.6%) and hyper-IgM (HIGM) syndrome (24.1%), followed by predominantly antibody deficiencies (17.8%). Combined immunodeficiencies with associated or syndromic features (12.5%) and congenital defects of phagocyte number, function, or both (10.7%) were less common in our center compared with SCID and HIGM syndrome. Besides, we found that 20 children (17.8%) had a positive family history of PID, and almost all cases (97.3%) had a history of recurrent infection. Recurrent respiratory tract infection was among the most common symptoms, followed by the bacterial infection of the skin and mucous membranes and diarrhea. Additionally, adverse event following immunization (AEFI) was found in 20.5% of the patients, and immune disorder was commonly observed in PID patients. In the present study, 47 patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), and 2-year overall survival (OS) rate for these patients was 78.7% (37/47). It is noteworthy that OS widely differed among PID patients with different phenotypes who underwent allo-HSCT. The 2-year OS rate for SCID, HIGM syndrome, and the remaining of PID patients who underwent allo-HSCT was 14.3, 83.3, and 100%, respectively. Conclusions PID typically emerges at early age. Recurrent infection and serious infection were the most common clinical manifestations. Allo-HSCT is a relatively effective therapeutic strategy for PID patients.

Abstract Background The atopic syndrome consists of heterogeneous manifestations, in which multiple associated genetic loci have recently been identified. It is hypothesized that immune dysregulation plays a role in the pathogenesis. In primary immunodeficiency diseases (PIDs), which are often monogenic immunodysregulation disorders, the atopic syndrome is a frequently occurring comorbidity. Based on the genetic defects in PIDs, novel gene/pathway-targeted therapies have been evaluated, which could be relevant in the atopic syndrome as well. Therefore, we aimed to define subclasses within the atopic syndrome based on the expression profiles of immune cell lineages of healthy mice. Methods Overlap between known atopy-related genes as described in the Human Gene Mutation Database and disease-causing genes of monogenic PIDs was evaluated. Clusters of atopy-related genes were based on the overlap in their co-expressed genes using the gene expression profiles of immune cell lineages of healthy mice from the Immunological Genome Project. We analyzed pathways involved in the atopic syndrome using Ingenuity Pathway Analysis. Results Twenty-two (5.3%) genes were overlapping between the atopy-related genes (n = 160) and PID-related genes (n = 278). We identified seven distinct clusters of atopy-related genes. Functional pathway analysis of all atopy-related genes showed relevance of T helper cell-mediated pathways. Conclusions This study shows a model to define clusters within the atopic syndrome based on gene expression profiles of immune cell lineages. Our results support the hypothesis that both genetic mechanisms and immune dysregulation play a role in the pathogenesis. It also opens up the possibility for novel therapeutic targets and a more tailored approach towards personalized medicine.

Primary immunodeficiency diseases (PIDD) are inherited disorders resulting from defects in diverse elements of the human immune system. Currently, more than 330 PIDDs have been described, and the molecular (genetic) bases for more than 320 of them are known. PIDD can be divided into nine different groups, including antibody (humoral) deficiencies, innate/intrinsic deficiencies, phagocytic system deficiencies, complement component deficiencies, combined (T and B cells) immunodeficiencies, syndromic combined immunodeficiencies, immune dysregulation disorders, autoinflammatory diseases and phenocopies of PIDD. In the PIDD group, primary antibody deficiencies are the most common group, and approximately 50% of patients with PIDD fall into this group of deficiencies. Congenital primary immunodeficiencies typically appear early in life, although late onset is gradually more identified. Affected patients usually present clinically with recurrent/ severe infections, or clinical pictures resembling various autoimmune or other diseases. An early diagnosis of congenital immunodeficiencies is necessary for transfer to specialized medical centers, and prompt commencement of the optimal treatment, including transplantation and enhanced outcomes. In this review, a general approach is described for the investigation of the most common groups of PIDD, outlining the most appropriate laboratory investigations when the clinician comes across typical clinical pictures and/or infections suggesting immunodeficiency.

We report here the results of a phase 3 study to assess the efficacy, safety, and tolerability of GC5107, a new 10% liquid intravenous immunoglobulin (IVIG) in preventing serious bacterial infections in patients with primary immunodeficiency (ClinicalTrials.gov: NCT02783482). Over a 12-month study period, 49 patients aged 3 to 70 years with a confirmed diagnosis of primary immunodeficiency received GC5107 at doses ranging from 319 to 881 mg/kg body weight every 21 or 28 days, according to their previous IVIG maintenance therapy. A total of 667 infusions of GC5107 were administered comprising a total of 45.86 patient-years of treatment. A single acute serious bacterial infection occurred during the study, resulting in an incidence of 0.02 events per patient-year (upper 99% one-sided confidence interval limit: 0.21), meeting the prespecified primary efficacy endpoint. The mean incidence of infections other than acute serious bacterial infections was 2.9 infections per patient-year. Efficacy was also demonstrated by the low mean annualized rate of hospitalizations due to infection (0.1 day) and the mean annualized duration of hospitalizations (0.1 day). The mean rate of intravenous and oral antibiotic use was 0.1 day and 13.2 days, respectively. There was a mean of 7.1 days of missed work, school, or daycare days. The proportion of infusions with temporally associated adverse events (TAAEs) occurring during or within 72 hours after GC5107 infusion was 0.24 (upper 95% one-sided confidence interval limit: 0.31), meeting the pre-specified primary safety endpoint. Overall, 149 of 667 infusions (22%) were associated with TAAEs. The most common TAAE was headache, reported by 49% of patients. More than 98% (731/743) of all adverse events that occurred throughout the 12-month study period were mild or moderate. More than 98% of infusions were completed without discontinuation, interruption or rate reduction. There were no treatment-emergent serious adverse events related to GC5107 or study discontinuations due to an adverse event. Overall, pharmacokinetic parameters for GC5107 were within the range of those reported in studies of other marketed IVIG products. Results of the present study demonstrate that GC5107 is an effective, safe and well-tolerated treatment for patients with primary immunodeficiency.

Patients with primary immunodeficiency disease (PID) are not only vulnerable to mycobacterial disease, but are also more likely to develop adverse events following BCG vaccination. These events can range from regional disease (BCGitis) to disseminated disease (BCGosis). Chronic granulomatous disease (CGD), which is characterized by impaired leukocyte phagocytic function, is one of the many inherited PIDs that increase the body’s susceptibility to recurrent bacterial and fungal infections. Here, we report a 6-year-old boy with no significant past medical history who presented with progressive lymphadenopathy six years after BCG vaccination. He was later diagnosed with CGD on further evaluation.

Individuals with Primary Immunodeficiency Disease (PID) have increased risk for infection, autoimmune conditions, and inflammatory disorders. Cognitive impairment, also referred to as brain fog, has been recognized in other medical conditions and as a side-effect of treatments; however, it has not been previously reported in individuals with PID. The phenomenon of brain fog is recognized in other autoimmune or inflammatory conditions, including lupus, multiple sclerosis, chronic fatigue syndrome, and has resulted from chemotherapy treatment for cancer. This research investigates the self-reported memory function of individuals with a diagnosis of PID. Respondents completed a survey which used reliable and valid questionnaires: Memory Functioning Questionnaire, Beck’s Depression Inventory II, and Beck’s Anxiety Inventory. Of the 292 completed surveys, 133 did not report any comorbid neurological diagnosis or incident of concussion (both of which could influence perceived memory function). When compared to normative scores, the respondents in this study were found to have significantly greater perceived memory impairment. The respondents had a significant higher score for anxiety and depression as compared to non-anxious and non-depressed normative values. This study finds that individuals with a diagnosis of PID have a greater degree of perceived memory impairment, or brain fog, in addition to greater levels of anxiety and depression. Individuals with a diagnosis of PID would benefit from prospective surveillance through a comprehensive neuropsychological assessment to track cognitive status and implement corrective measures, should any decline be identified.

Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs. Flow cytometry can evaluate specific cell populations and subpopulations, cell surface, intracellular and intranuclear proteins, biologic effects associated with specific immune defects, and certain functional immune characteristics, each being useful for the diagnosis and evaluation of PIDs. Flow cytometry effectively identifies major forms of PIDs, including severe combined immunodeficiency, X-linked agammaglobulinemia, hyper IgM syndromes, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, familial hemophagocytic lymphohistiocytosis, autoimmune lymphoproliferative syndrome, IPEX syndrome, CTLA 4 haploinsufficiency and LRBA deficiency, IRAK4 and MyD88 deficiencies, Mendelian susceptibility to mycobacterial disease, chronic mucocuneous candidiasis, and chronic granulomatous disease. While genetic analysis is the definitive approach to establish specific diagnoses of PIDs, flow cytometry provides a tool to effectively evaluate patients with PIDs at relatively low cost.

The marketing approval of genetically engineered hematopoietic stem cells (HSCs) as the first-line therapy for the treatment of severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) is a tribute to the substantial progress that has been made regarding HSC engineering in the past decade. Reproducible manufacturing of high-quality, clinical-grade, genetically engineered HSCs is the foundation for broadening the application of this technology. Herein, the current state-of-the-art manufacturing platforms to genetically engineer HSCs as well as the challenges pertaining to production standardization and product characterization are addressed in the context of primary immunodeficiency diseases (PIDs) and other monogenic disorders.

X-linked agammaglobulinemia (XLA), caused by a mutation in the Bruton's tyrosine kinase (BTK) gene, is rarely reported in patients with recurrent hemophagocytic lymphohistiocytosis (HLH). This mutation leads to significantly reduced numbers of circulatory B cells and serum immunoglobulins in patients. Therefore, they exhibit repetitive bacterial infections since infancy, and immunoglobulin (Ig) replacement therapy is the primary treatment. HLH is a life-threatening condition with manifestations of non-remitting fever, hepatosplenomegaly, cytopenias, coagulopathy, lipid disorder, and multiple organ failure. It is caused by the immune dysregulation between cytotoxic T cells, NK cells, and histiocytes. The treatment is based on HLH-2004 protocol including immunotherapy, chemotherapy, supportive therapy, and stem cell transplantation. However, as we know more about the classification and pathophysiology of HLH, the treatment is modified. T-cell-directed immunotherapy is effective in patients with primary HLH, and strong immunosuppression is contraindicated in patients with severe ongoing infections or some primary immunodeficiency diseases (PIDs). Here, we report the case of a 7-year-old boy who presented with ecthyma gangrenosum and several episodes of pyogenic infections during childhood. At the age of 5 years, he exhibited cyclic HLH every 2–3 months. The remission of HLH episodes finally achieved after he received monthly Ig replacement therapy (400 mg/kg) at the 4th HLH. However, transient elevation of IgM was incidentally discovered after 6 cycles of monthly Ig replacement therapy. IgM-secreting multiple myeloma, Waldenström's macroglobulinemia, and lymphoma were excluded. The IgM levels then declined and returned to the normal range within a year. The patient and his parents received whole-genome sequencing analysis. It revealed a novel hemizygous c.1632-1G>A mutation in the BTK gene and XLA was diagnosed. XLA exhibits a spectrum of clinical and immunological presentations in patients. The identification of the mutation in the BTK gene contribute to an accurate diagnosis. Ig replacement therapy is the primary treatment for HLH in patients with XLA.

Behcet’s disease (BD) is a chronic inflammatory disease with multisystemic involvement. Its etiology is considered to involve complex environmental and genetic factors. Several susceptibility genes for BD, such as human leukocyte antigen (HLA)-A26, IL23R-IL12RB2, IL10 and ERAP1, in addition to the well-studied HLA-B51, were mainly identified by genome-wide association studies. A heterozygous mutation in TNFAIP3, which leads to A20 haploinsufficiency, was found to cause an early-onset autoinflammatory disease resembling BD in 2016. Several monogenic diseases associated with primary immunodeficiency disease and trisomy 8 have recently been reported to display BD-like phenotypes. Among the genes causing these diseases, TNFAIP3, NEMO, RELA, NFKB1 and TNFRSF1A are involved in the NF-κB (nuclear factor κ light-chain enhancer of activated B cells) signaling pathway, indicating that this pathway plays an important role in the pathogenesis of BD. Because appropriate treatment may vary depending on the disease, analyzing the genetic background of patients with such diseases is expected to help elucidate the etiology of pediatric BD and assist with its treatment. Here, we summarize recently emerging knowledge about genetic predisposition to BD.

X-linked lymphoproliferative disease (XLP) was first described in the 1970s as a fatal lymphoproliferative syndrome associated with infection with Epstein–Barr virus (EBV). Features include hemophagocytic lymphohistiocytosis (HLH), lymphomas, and dysgammaglobulinemias. Molecular cloning of the causative gene, SH2D1A, has provided insight into the nature of disease, as well as helped characterize multiple features of normal immune cell function. Although XLP type 1 (XLP1) provides an example of a primary immunodeficiency in which patients have problems clearing primarily one infectious agent, it is clear that XLP1 is also a disease of severe immune dysregulation, even independent of EBV infection. Here, we describe clinical features of XLP1, how molecular and biological studies of the gene product, SAP, and the associated signaling lymphocyte activation molecule family receptors have provided insight into disease pathogenesis including specific immune cell defects, and current therapeutic approaches including the potential use of gene therapy. Together, these studies have helped change the outcome of this once almost uniformly fatal disease.

Stephen Jolles Department of Immunology, University Hospital of Wales, Cardiff, UK Abstract: Immunoglobulin (Ig)-replacement therapy represents the mainstay of treatment for patients with primary antibody deficiency and is administered either intravenously (IVIg) or subcutaneously (SCIg). While hyaluronidase has been used in clinical practice for over 50 years, the development of a high-purity recombinant form of this enzyme (recombinant human hyaluronidase PH20) has recently enabled the study of repeated and more prolonged use of hyaluronidase in facilitating the delivery of SC medicines. It has been used in a wide range of clinical settings to give antibiotics, local anesthetics, insulin, morphine, fluid replacement, and larger molecules, such as antibodies. Hyaluronidase has been used to help overcome the limitations on the maximum volume that can be delivered into the SC space by enabling dispersion of SCIg and its absorption into lymphatics. The rate of facilitated SCIg (fSCIg) infusion is equivalent to that of IVIg, and the volume administered at a single site can be greater than 700 mL, a huge increase over conventional SCIg, at 20–40 mL. The use of fSCIg avoids the higher incidence of systemic side effects of IVIg, and it has higher bioavailability than SCIg. Data on the long-term safety of this approach are currently lacking, as fSCIg has only recently become available. fSCIg may help several areas of patient management in primary antibody deficiency, and the extent to which it may be used in future will depend on long-term safety data and cost–benefit analysis. Keywords: enzyme facilitated IgG infusion, recombinant human hyaluronidase PH20, subcutaneous immunoglobulin, intravenous immunoglobulin, primary immunodeficiency disease

Primary immunodeficiency diseases (PID) include over 250 diverse disorders. The current study assessed management of PID by family practice physicians. The American Academy of Allergy, Asthma, and Immunology Primary Immunodeficiency Committee and the Immune Deficiency Foundation conducted an incentivized mail survey of family practice physician members of the American Medical Association and the American Osteopathic Association in direct patient care. Responses were compared with subspecialist immunologist responses from a similar survey. Surveys were returned by 528 (of 4500 surveys mailed) family practice physicians, of whom 44% reported following ≥1 patient with a PID. Selective immunoglobulin A (IgA), deficiency (21%), and chronic granulomatous disease (11%) were most common and were followed by significantly more subspecialist immunologists (P

Epstein-Barr virus (EBV) was discovered 50 years ago from an African Burkitt lymphoma cell line. EBV-associated lymphoproliferative disorders (LPDs) are life-threatening diseases, especially in children. In this article, we review EBV-associated LPDs, especially in the area of primary immunodeficiency disease (PID). We searched PubMed for publications with key words including EBV infection, lymphoma, LPDs and PID, and selected the manuscripts written in English that we judged to be relevant to the topic of this review. On the basis of the data in the literature, we grouped the EBV-associated LPDs into four categories: nonmalignant disease, malignant disease, acquired immunodeficiency disease and PID. Each category has its own risk factor for LPD development. EBV-associated LPD is a complex disease, creating new challenges for diagnosis and treatment.