Gastroenterological disorders in inborn errors of immunity. Part 2 A. Overview of selected diseases.

Infectious diseases and inborn errors of immunity

World Health Organisation recommends the practice of BCG vaccination at birth in countries which have a high incidence of tuberculosis and/or high leprosy burden. The BCG vaccination is considered safe for a competent immune system. However, in children with weakened immune systems cause of which can be primary or secondary, the vaccine may lead to side effects which can be localized or disseminated. In this study, we report a spectrum of inborn errors of immunity (IEI) commonly referred to as primary immunodeficiency disorders (PIDs) diagnosed in a large cohort of patients presenting with complications to BCG vaccination from India. Retrospective data analysis of patients referred to ICMR- National Institute of Immunohematology (ICMR-NIIH) for IEI workup between 2007 and 2019 was done. IEI was identified in n=52/90 (57.7%) patients presenting with BCG complications. Of these, n=13(14.4%) patients were diagnosed with severe combined immune deficiency, n=15(16.7%) with chronic granulomatous disease, n=19(21.1%) with Inborn errors of IFN-γ immunity, n=4(4.4%) with Combined immunodeficiency and n=1(1.1%) with Leucocyte Adhesion Deficiency type1. Majority of cases with BCGosis (88%) had an underlying IEI. This study strongly highlights the need for evaluation of patients with BCG complications for underlying IEI. While disseminated BCGosis strongly predicts underlying IEI, even localized persistent adenitis may be a warning sign of underlying IEI. It is also strongly recommended to record a family history of previous sibling death prior to administration of this live vaccine and deferring live vaccine till the diagnosis of IEI is ruled out in cases with a positive family history.

The gastrointestinal (GI) tract is frequently affected by inborn errors of immunity (IEI), and GI manifestations can be present in IEI patients before a diagnosis is confirmed. We aimed to investigate clinical features, endoscopic and histopathologic findings in IEI patients. This was a retrospective cohort study conducted from 1995 to 2020. Eligible patients were diagnosed with IEI and had GI manifestations that were enough to require endoscopies. IEI was classified according to the International Union of Immunological Societies classification. Of 165 patients with IEI, 55 (33.3%) had GI manifestations, and 19 (11.5%) underwent endoscopy. Among those 19 patients, nine (47.4%) initially presented with GI manifestations. Thirteen patients (68.4%) were male, and the mean age of patients 11.5 ± 7.9 years (range, 0.6 – 26.6) when they were consulted and evaluated with endoscopy. The most common type of IEI with severe GI symptoms was “Disease of immune dysregulation” (31.6%) followed by “Phagocyte defects” (26.3%), according to the International Union of Immunological Societies classification criteria. Patients had variable GI symptoms such as chronic diarrhea (68.4%), hematochezia (36.8%), abdominal pain (31.6%), perianal disease (10.5%), and recurrent oral ulcers (10.5%). During the follow-up period, three patients developed GI tract neoplasms (early gastric carcinoma, mucosa associated lymphoid tissue lymphoma of colon, and colonic tubular adenoma, 15.8%), and 12 patients (63.2%) were diagnosed with inflammatory bowel disease (IBD)-like colitis. Investigating immunodeficiency in patients with atypical GI symptoms can provide an opportunity for correct diagnosis and appropriate disease-specific therapy. Gastroenterologists and immunologists should consider endoscopy when atypical GI manifestations appear in IEI patients to determine if IBD-like colitis or neoplasms including premalignant and malignant lesions have developed. Also, if physicians in various fields are better educated about IEI-specific complications, early diagnosis and disease-specific treatment for IEI will be made possible.

To describe SARS-CoV-2 infection outcome in unvaccinated children and young adults with inborn errors of immunity (IEI) and to compare their specific acute and long-term immune responses with a sex-, age-, and severity-matched healthy population (HC). Unvaccinated IEI patients up to 22 years old infected with SARS-CoV-2 were recruited along with a cohort of HC. SARS-CoV-2 serology and ELISpot were performed in the acute phase of infection (up to 6 weeks) and at 3, 6, 9, and 12 months. Twenty-five IEI patients (median age 14.3 years, min.-max. range 4.5-22.8; 15/25 males; syndromic combined immunodeficiencies: 48.0%, antibody deficiencies: 16.0%) and 17 HC (median age 15.3 years, min.-max. range 5.4-20.0; 6/17 males, 35.3%) were included. Pneumonia occurred in 4/25 IEI patients. In the acute phase SARS-CoV-2 specific immunoglobulins were positive in all HC but in only half of IEI in whom it could be measured (n=17/25): IgG+ 58.8% (10/17) (p=0.009); IgM+ 41.2% (7/17)(p<0.001); IgA+ 52.9% (9/17)(p=0.003). Quantitative response (index) was also lower compared with HC: IgG IEI (3.1 ± 4.4) vs. HC (3.5 ± 1.5)(p=0.06); IgM IEI (1.9 ± 2.4) vs. HC (3.9 ± 2.4)(p=0.007); IgA IEI (3.3 ± 4.7) vs. HC (4.6 ± 2.5)(p=0.04). ELISpots positivity was qualitatively lower in IEI vs. HC (S-ELISpot IEI: 3/11, 27.3% vs. HC: 10/11, 90.9%; p=0.008; N-ELISpot IEI: 3/9, 33.3% vs. HC: 11/11, 100%; p=0.002) and also quantitatively lower (S-ELISpot IEI: mean index 3.2 ± 5.0 vs. HC 21.2 ± 17.0; p=0.001; N-ELISpot IEI: mean index 9.3 ± 16.6 vs. HC: 39.1 ± 23.7; p=0.004). As for long term response, SARS-CoV-2-IgM+ at 6 months was qualitatively lower in IEI(3/8, 37.5% vs. 9/10 HC: 90.0%; p=0.043), and quantitatively lower in all serologies IgG, M, and A (IEI n=9, 1.1 ± 0.9 vs. HC n=10, 2.1 ± 0.9, p=0.03; IEI n=9, 1.3 ± 1.5 vs. HC n=10, 2.9 ± 2.8, p=0.02; and IEI n=9, 0.6 ± 0.5 vs. HC n=10, 1.7 ± 0.8, p=0.002 -respectively) but there were no differences at remaining time points. Our IEI pediatric cohort had a higher COVID-19 pneumonia rate than the general age-range population, with lower humoral and cellular responses in the acute phase (even lower compared to the reported IEI serological response after SARS-CoV-2 vaccination), and weaker humoral responses at 6 months after infection compared with HC.

BackgroundImmune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia (AIN) are disorders characterized by immune‐mediated destruction of hematopoietic cell lineages. A link between pediatric immune cytopenias and inborn errors of immunity (IEI) was established in particular in the combined and chronic forms.ObjectiveAim of this study is to provide clinical‐immunological parameters to hematologists useful for a prompt identification of children with immune cytopenias deserving a deeper immunological and genetic evaluation.MethodsWe retrospectively collected 47 pediatric patients with at least one hematological disorder among which persistent/chronic ITP, AIHA, and AIN, aged 0–18 years at onset of immune cytopenias and/or immune‐dysregulation. The cohort was divided into two groups (IEI+ and IEI−), based on the presence/absence of underlying IEI diagnosis. IEI+ group, formed by 19/47 individuals, included: common variable immune deficiency (CVID; 9/19), autoimmune lymphoproliferative syndrome (ALPS; 4/19), DiGeorge syndrome (1/19), and unclassified IEI (5/19).ResultsIEI prevalence among patients with ITP, AIHA, AIN, and Evans Syndrome was respectively of 42%, 64%, 36%, and 62%. In IEI+ group the extended immunophenotyping identified the presence of statistically significant (p < .05) specific characteristics, namely T/B lymphopenia, decrease in naїve T‐cells%, switched memory B‐cells%, plasmablasts%, and/or immunoglobulins, increase in effector/central memory T‐cells% and CD21low B‐cells%. Except for DiGeorge and three ALPS patients, only 2/9 CVID patients had a molecular diagnosis for IEI: one carrying the pathogenic variant CR2:c.826delT, the likely pathogenic variant PRF1:c.272C> and the compound heterozygous TNFRSF13B variants p.Ser144Ter (pathogenic) and p.Cys193Arg (variant of uncertain significance), the other one carrying the likely pathogenic monoallelic variant TNFRSF13B:p.Ile87Asn.ConclusionThe synergy between hematologists and immunologists can improve and fasten diagnosis and management of patients with immune cytopenias through a wide focused clinical/immunophenotypical characterization, which identifies children worthy of IEI‐related molecular analysis, favouring a genetic IEI diagnosis and potentially unveiling new targeted‐gene variants responsible for IEI phenotype.

BackgroundHuman 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.MethodsRetrospective 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.Results1510 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.ConclusionUsing 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.

The heuristic concept of "inborn errors of metabolism" was introduced more then 70 years ago and by analogy has prompted the more recent introduction of the term "inborn errors of immunity". It is now well recognized that many inborn errors of immunity can be considered inborn errors of metabolism. Typically, many forms of severe combined immunodeficiency result from adenosine deaminase deficiency, i.e., an inborn error of purine metabolism. On the other hand, errors of immunity are often associated with "errors of morphogenesis", resulting from an intrinsically abnormal developmental process (malformation), a secondary or extrinsic interference with originally normal development (disruption), or an abnormal organization of cells into tissues (dysplasia). Twenty years after the original description, the DiGeorge anomaly should be considered an inborn error of morphogenesis and immunity due either to disruption or less frequently to malformation. In other immunodeficiencies, such as ataxia telangiectasia, the morphologic and immunologic errors result from a dyshistogenesis, i.e., dysplasia. Also, true malformation syndromes, such as Down's syndrome, are consistently associated with immunodeficiency.

BackgroundAlthough viral infections are one of the common clinical manifestations in patients with inborn errors of immunity (IEIs), little is known about the epidemiology, susceptibility genes, and clinical status of viral infections in patients with IEIs.MethodsThe demographic information, clinical diagnoses, and laboratory findings of 931 IEI patients who underwent viral testing from January 2016 to December 2022 were collected and analyzed.ResultsIn total, 47.15% (439/931) patients with IEI tested positive for at least one virus during hospitalization. There were a total of 640 viral infections during the study period, mainly from EBV 131 (20.47%), HRV 102(15.94%), CMV 100(15.63%), and RV 84(13.13%). CMV and RV infections were more common in the combined immunodeficiencies (IEI_I) group during the infant stage, whereas EBV infection was more common in the immune dysregulation (IEI_IV) group during the preschool stage. Mutations in SH2D1A (57.14%), PIK3CD (56.41%) and LRBA (50%) make individuals susceptible to EBV infection; mutations in WAS (30%) make individuals susceptible to CMV infection; and mutations in IL2RG (56.52%) and RAG1 (37.5%) make individuals susceptible to RV infection. Joinpoint analysis revealed trends in viral positivity in different years.ConclusionThese data suggest that it is possible to target the prevention, treatment, and management of IEI patients who are infected with a virus by accounting for the age at infection, type of IEI, and mutant genes, but special attention needs to be paid to viral infections in IEI_I and IEI_IV patients during the infant stage.

Simple SummaryInborn Errors of Immunity (IEI) are a heterogeneous group of disorders characterized by a defect in the function of at least one, and often more, components of the immune system. The overall risk for cancer in children with IEI ranges from 4 to 25%. Several factors, namely, age of the patient, viral infection status and IEI type can influence the development of different cancer types. Immunologists and oncologists should interact to monitor and promptly diagnose the potential development of cancer in known IEI patients, as well as an underlying IEI in newly diagnosed cancers with suggestive medical history or high rate of therapy-related toxicity. The creation of an international registry of IEI cases with detailed information on the occurrence of cancer is fundamental to optimizing the diagnostic process and to evaluating the outcomes of new therapeutic options, with the aim of improving prognosis and reducing comorbidities. Inborn Errors of Immunity (IEI) are a heterogeneous group of disorders characterized by a defect in the function of at least one, and often more, components of the immune system. The aim of this narrative review is to discuss the epidemiology, the pathogenesis and the correct management of tumours in patients with IEI. PubMed was used to search for all of the studies published over the last 20 years using the keywords: “inborn errors of immunity” or “primary immunodeficiency” and “cancer” or “tumour” or “malignancy”. Literature analysis showed that the overall risk for cancer in children with IEI ranges from 4 to 25%. Several factors, namely, age of the patient, viral infection status and IEI type can influence the development of different cancer types. The knowledge of a specific tumour risk in the presence of IEI highlights the importance of a synergistic effort by immunologists and oncologists in tracking down the potential development of cancer in known IEI patients, as well as an underlying IEI in patients with newly diagnosed cancers. In the current genomic era, the creation of an international registry of IEI cases integrated with malignancies occurrence information is fundamental to optimizing the diagnostic process and to evaluating the outcomes of new therapeutic options, with the hope to obtain a better prognosis for these patients.

Inborn errors of immunity (IEI) are a group of rare heterogeneous diseases. Currently, more than 400 monogenetic IEI have been identified and increasingly a genetic diagnosis can be made in patients with an immune deficiency disorder [1]. Patients may present with a variety of clinical symptoms including a broad spectrum of infections, inflammatory manifestations, auto-immune phenomena and malignant diseases. Treatment by hematopoietic stem cell transplantation (HSCT) is increasingly successful [2–10] and the joint EBMT/ESID Inborn Errors Working Party (IEWP) has played a pivotal role designing and developing common HSCT guidelines, which have contributed to this success. The wide clinical heterogeneity of patients, together with the fact that outcome data are based on observational rather than prospective studies, means that it is not yet possible to recommend strictly defined protocols for transplanting IEI patients. The current guidelines provide recommendations based on published data, center experience and expert opinions. Whenever possible, the individual transplant protocol should follow these guidelines, but modifications may be necessary according to the particular variant of the IEI and/or the patient’s clinical condition. For all these reasons the IEWP strongly recommends that all patients with primary immunodeficiency are transplanted in an experienced center that regularly transplants such patients, and also actively participates in the IEWP, as only in this way continuous improvement in outcomes can be achieved. The prognosis of survival for some patients with IEI extends for years and even decades with conservative therapy alone. In those, the decision in favor or against HSCT or other cellular therapies can be extremely challenging. This decision needs to consider multiple factors such as clinical presentation, past and current infections, immunophenotype, genotype, autoimmune manifestations, current and anticipated future organ damage, family history and family experience with the disease, psychological and social factors such as quality of life and fertility, and informed consent not only of caregivers but also patients themselves. In case of a decision for a conservative treatment strategy, this should be re-evaluated on a regular basis by a team, which is informed about and experienced in all currently available therapeutic options. Centers are strongly advised to register their transplanted patients in the EBMT, ESID, and SCETIDE registries, which will allow continuous evaluation of the outcomes in transplanted IEI patients treated in line with IEWP guidelines. Patients with IEI frequently present with or develop autoimmune or inflammatory complications eg, autoimmune cytopenias and inflammatory bowel disease as their sole clinical phenotype [11]. In recent years, monogenetic defects are increasingly identified in patients with primary immune regulation disorders (PIRD [12]). Awareness of the possibility that a monogenetic IEI may be the underlying defect in patients with aforementioned disease manifestations is pivotal in their clinical management and may provide the rationale for allogeneic HSCT as a curative approach [13]. In recent years, stem cell gene addition therapy (GT) has been explored for a limited number of IEI, including ADA-SCID, X-linked SCID, XL-CGD, and WAS. A retroviral ADA GT product (Strimvelis®) is licensed by the European Medicines Agency, and recently excellent results have been reported with lentiviral-based ADA GT [14]. There are ongoing clinical studies in a variety of other IEI [15]. GT offers the potential advantage of avoiding the negative consequences of alloreactivity (GVHD), but concerns remain about the curative potential of a mixed chimeric state in non-SCID IEI, which is inherent to current GT approaches, and the possible risk for insertional mutagenesis (although no vector related adverse events have been reported with lentiviral vectors). However, in the absence of comparative studies it is extremely difficult to make firm recommendations on the hierarchial position of GT in comparison to conventional HSCT. It has to be considered that: (a) long-term safety and efficacy data of GT are still limited, and (b) comparing outcome data from prospective single- or oligocentre studies (as is the case for GT) with retrospective multi-center studies (as most of the evidence for HSCT) does not meet the scientific standard and is therefore suboptimal. Currently, participation in a GT study may be considered for patients lacking a matched donor and able to travel to a respective study center. The IEWP guidelines are reviewed periodically and retrospective studies are regularly performed on behalf of IEWP to evaluate and compare clinical outcomes of patients with specific disease entities treated according to these guidelines [3, 9, 16]. These studies are instrumental to periodically revise and update the guidelines for specific conditions.

Background/Objectives: Cutaneous manifestations of inborn errors of immunity (IEI) are among the most common and often early signs of these disorders, estimated to affect about 40% of patients with IEI, and in some cases, they provide the first diagnostic clue. Skin findings in IEI are heterogeneous and include recurrent skin infections, severe atopic dermatitis, autoimmune manifestations, as well as atypical granulomatous dermatoses, neoplastic lesions, pigmentation disorders, and changes involving hair and nails. Early recognition of these manifestations and linking them to the appropriate immunologic defect is crucial for establishing the diagnosis and initiating targeted therapy. Methods: This paper reviews the dermatologic phenotypes associated with IEI, with particular emphasis on a tabular classification of skin lesions corresponding to specific immunologic defects. Relevant literature was analyzed to summarize characteristic cutaneous presentations and current diagnostic approaches, highlighting the importance of interdisciplinary evaluation. Results: Cutaneous findings in IEI encompass a wide spectrum of infectious, inflammatory, autoimmune, and neoplastic manifestations. Systematic classification of these lesions facilitates earlier recognition of underlying immune defects and supports differential diagnosis. Dermatologic signs frequently precede systemic manifestations, making them valuable early clinical indicators of IEI. Conclusions: Recognition of dermatologic manifestations is critical for early diagnosis of IEI. Interdisciplinary collaboration between dermatologists, immunologists, and other specialists improves diagnostic accuracy and patient management. Current therapeutic strategies range from symptomatic treatment to targeted therapies, and personalized approaches improve prognosis and quality of life in patients with IEI.

Background and objectivesSafety and effectiveness concerns may preclude physicians from recommending vaccination in mild/moderate inborn errors of immunity (IEI). This study describes attitudes and practices regarding vaccination among physicians who care for patients with mild/moderate B cell or mild/moderate combined immunodeficiencies (CID) and vaccination completeness among patients diagnosed with IEIs.MethodsCanadian physicians caring for children with IEI were surveyed about attitudes and practices regarding vaccination in mild/moderate IEI. Following informed consent, immunization records of pediatric patients with IEI evaluated before 7 years of age were reviewed. Vaccine completeness was defined at age 2 years as 4 doses of diphtheria-tetanus-pertussis (DTaP), 3 doses pneumococcal conjugate (PCV), and 1 dose measles-mumps-rubella (MMR) vaccines. At 7 years 5 doses of DTP and 2 doses MMR were required.ResultsForty-five physicians from 8 provinces completed the survey. Most recommended inactivated vaccines for B cell deficiency: (84% (38/45) and CID (73% (33/45). Fewer recommended live attenuated vaccines (B cell: 53% (24/45), CID 31% (14/45)). Of 96 patients with IEI recruited across 7 centers, vaccination completeness at age 2 was 25/43 (58%) for predominantly antibody, 3/13 (23%) for CID, 7/35 (20%) for CID with syndromic features, and 4/4 (100%) for innate/phagocyte defects. Completeness at age 7 was 15%, 17%, 5%, and 33%, respectively.ConclusionMost physicians surveyed recommended inactivated vaccines in children with mild to moderate IEI. Vaccine completeness for all IEI was low, particularly at age 7. Further studies should address the reasons for low vaccine uptake among children with IEI and whether those with mild-moderate IEI, where vaccination is recommended, eventually receive all indicated vaccines.

Conflicts of Interests: EYW receives consulting and speaker fees from Pharming Healthcare, Inc. regarding their work on the medication leniolisib approved for activated PI3 kinase delta syndrome (APDS). The remaining authors AHS and MK declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The number of inborn errors of immunity (IEI) is growing rapidly (1). They can be challenging to diagnose given the expanding and variable clinical phenotypes (2,3). Specifically, there is an increasing recognition that immune dysregulation can be an initial or predominant manifestation of a substantive portion of IEIs (4,5). Immune dysregulation can also have a large impact on disease treatment, monitoring, and outcomes. Significant progress has been made in the elucidation of molecular and cellular mechanisms underlying the immune dysregulation of IEIs. Tremendous improvement has also been made in the management of IEIs with availability of therapies expanding to include biologics and small molecular inhibitors. Despite progress, more understanding is needed to tailor the use of immunomodulatory therapy in IEIs. This Research Topic "Immune Dysregulation in Inborn Errors of Immunity" highlights recent advances in the understanding of the prevalence, mechanisms, spectrum of manifestations, and management of immune dysregulation in IEIs. Gagne et al. provide a concise review of how Mendelian type I interferonopathies can masquerade as non-Mendelian autoimmune disorders like systemic lupus erythematosus (SLE) and dermatomyositis, which are also associated with increased type I interferon (IFN) expression. Similarly, Hetrick et al. described how autoinflammatory bone disorders characterized by sterile osteomyelitis can be seen with both monogenic forms including Majeed syndrome and deficiency of the interleukin-1 antagonist (DIRA) and the more common sporadic form chronic nonbacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO). Other autoimmune manifestations of IEIs include, but are not limited to, autoimmune cytopenia, endocrinopathies, inflammatory bowel disease, neutrophilic dermatoses, arthritis, and vasculitis as illustrated by the case of activated phosphoinositide 3-kinase delta (PI3Kd) syndrome (APDS) from Sood et al.The highly variable clinical manifestations of IEIs can contribute to diagnostic delays, which in turn, can lead to poorer outcomes. Autoimmunity and autoinflammation can negatively impact morbidity and mortality and are an independent prognostic factor for death among individuals with IEIs (5). Immune dysregulation may also contribute to the increased risk of malignancy observed in IEIs as with the APDS case presented by Sood et al.Improving awareness and early recognition of IEIs is also critical because making a diagnosis can impact treatment and surveillance. There may be disease-specific treatments available like leniolisib, an oral selective PI3Kd inhibitor, for APDS as discussed by Sood et al. Because type 1 IFN work through the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, Gagne et al. also consider the increasing use of JAK inhibition in autoinflammatory IFN-mediated monogenic diseases. The study by Berrueco et al. showed mycophenolate mofetil may be an effective and safe treatment for pediatric patients with autoimmune cytopenia and IEI, even cases of autoimmune cytopenia refractory to first-line therapies like corticosteroids and intravenous immunoglobulin (IVIG).These articles also nicely illustrate the need for a multidisciplinary approach to the immune dysregulatory manifestations in IEIs as there are contributions from Rheumatology (inteferonopathies and pediatric autoinflammatory bone disorders), Hematology (autoimmune cytopenias), and Allergy/Immunology (APDS). The conditions covered in this topic represent only a fraction of disordered immune conditions in IEIs and should be considered in more detail in the future.The recognition of immune dysregulation in IEIs continues to increase as the number of patients impacted expands. There is a clear need for ongoing investigation into the epidemiology and pathophysiology for clinical manifestations and the risk factors for developing immune dysregulation as well as a collaborative multidisciplinary approach to improve diagnosis and management of this population. Our hope is that this topic has piqued the interest of researchers and clinicians in this area to provide better understanding, care, and outcomes to these patients.Lastly, we would like to thank the reviewers for their time and valuable assessments. This important collection of articles would not be possible without their contributions.

Introduction The term inborn errors of immunity (IEIs) refers to the rapidly expanding group of genetic disorders causing dysregulation of the immune system. With improved genetic testing in recent years, the number of defined IEIs and their range of phenotypic presentations have grown vastly, with more than 480 IEIs now described. This review outlines common IEIs with a focus on clinical presentations across different specialties, including guidelines regarding when an underlying IEI should be considered. Method We conducted a comprehensive review of peer-reviewed articles, registries, and case series describing systemic manifestations in IEIs, focusing on clinical and biochemical diagnostic features. Results IEIs cause diverse clinical manifestations, including infection, autoimmunity, lymphoproliferation, allergy, and malignancy, with initial manifestations often appearing long before the diagnosis of an IEI is made. Furthermore, IEIs are increasingly diagnosed in adulthood, and a family history of disease is not always apparent. Physicians in all specialties are likely to encounter patients with IEIs, often before a formal diagnosis of an IEI is made or immunology consultation sought. Early diagnosis of an IEI improves patient outcomes through access to specialist immunology services and the potential for more specific, targeted treatment options. Conclusion Early diagnosis of IEIs remains a challenge due to the wide array of clinical manifestations. All physicians need an understanding of IEIs and presenting manifestations to facilitate timely diagnosis, immunologist referral, and potential access to targeted therapies.

Introduction Little is known about nutritional management in inborn errors of immunity (IEIs), including clinician and service delivery needs. This is the first study internationally to explore the service and clinician needs for the nutritional management of people living with IEIs. This study aimed to explore the knowledge, perceptions, and needs of dietetic staff involved in the care of people with IEIs and the dietetic services provided to this group in Australian tertiary health care settings. Method A cross-sectional study was developed to evaluate the knowledge, perceptions, dietetic input, and needs of dietitians and dietetic managers who are involved in the care of people with an IEI. Participants were recruited via an invitation email through the dietitian’s network group associated with the Australian Society of Clinical Immunology and Allergy (ASCIA) and via heads of department of nutrition and dietetics in tertiary services across Australia. Data were analysed descriptively. Results Nine tertiary dietitians completed the survey. Our findings revealed few dietitians working with this group across adult and paediatric populations (full-time equivalent [FTE] ranging from 0 to 0.2 FTE), with greater service delivery focus on allergy and oncology. Faltering growth, malnutrition, gastrointestinal complications (diarrhoea, gut failure), nutritional deficiencies, disordered eating behaviours, malabsorption, and impaired bone mineral density were common presenting nutrition-related symptoms for people with IEIs. Dietitians reported a high willingness to work with people with IEIs and that appropriate nutrition is a high priority for this group. However, inadequate staffing and training and high caseload were barriers. Identified needs included the availability of evidence-based nutrition guidelines, resources for both patients and healthcare professionals, and professional communities of practice. Conclusion Our exploratory study identified a range of nutrition-related symptoms impacting people with IEIs and high willingness among dietitians to engage with this group. However, inadequate staffing, limited knowledge, and lack of standardised guidelines were barriers to working with IEIs. The development of evidence-based nutrition guidelines to support clinicians in working with IEI is a priority.