Diagnosis Of Primary Immunodeficiency Disorders Research Articles

General Population Awareness of Primary Immune Deficiency Disease in Children in the Arar Region, Saudi Arabia.

Background Primary immunodeficiency disorders (PIDD) are of various types and severities, and they are associated with a delay in diagnosis. Early diagnosis of PIDD helps to improve the quality of life of affected children and prevent permanent consequences such as organ damage. Hence, awareness of PIDD is a must in the community to aid in early detection. Objectives The study aims to investigate the general population's awareness of PIDD in children in Arar, Northern Saudi Arabia. Methods A cross-sectional design was utilized to determine the awareness of PIDD in children in Arar, Northern Saudi Arabia. The participants were selected through an online self-administered questionnaire. The collected data was analyzed using descriptive and inferential statistics. Results A total of528 participants were involved in the current study. The majority of the sample population falls within the 20-30 age range. 9.1% of respondents know a child with primary immunodeficiency. Additionally, participants were aware of certain symptoms, such as delayed growth and chronic diarrhea, with rates of 47.0% and 34.1%, respectively. On the other hand, symptoms like otitis media and sinusitis have lower awareness rates of 25.8% and 33.3%, respectively. Conclusion This study can help in developing targeted awareness campaigns and educational programs to improve the understanding of primary immune deficiency disease among the general population in Saudi Arabia. This, in turn, can lead to earlier diagnosis and better management of the disease in children, ultimately improving their quality of life.

Primary immunodeficiency disorders imitating inflammatory bowel diseases: clinical aspects and problems of the differential diagnosis

From the beginning of 2000s, there has been a significant increase in the incidence of inflammatory bowel diseases (IBD) and primary immunodeficiency disorders (PIDs) in adults and children in many countries around the world. The aim of the review is to summarize the state-of-the-art on diverse clinical types of PIDs with gastrointestinal manifestations and their differential diagnostic algorithms.
 Atypical PIDs with “blunted” clinical manifestations are challenging for the timely diagnosis. Some types of PIDs with gastrointestinal involvement are also difficult to differentiate with classical IBDs. Molecular genetic studies have allowed for selection of a specific group of monogenic IBD-like diseases, represented mainly by PIDs. The authors discuss current classification of PIDs and their main clinical types imitating IBD, with important clinical and laboratory aspects. High level of information and awareness of practicing specialists working with IBD patients would be helpful in the selection of a patient cohort with possible PIDs and in the performance of extended laboratory assessment or referring for genetic tests. Timely diagnosis of PIDs would ensure quick administration of target therapy or hematopoietic stem cell transplantation, which in most cases would allow for the achievement of the disease remission, improvement of quality and duration of life.

Assessment of Sleep Disturbances and Sleep Disordered Breathing in Primary Immunodeficiency Disorders

IntroductionPatients with primary immunodeficiency disorders (PIDD) have lower health related quality of life (HRQoL) compared to the general population. Fatigue is a predominant symptom for PIDD patients and previous publications have demonstrated increased self-reported measures of fatigue in this population, including PROMIS-29 scores. Fatigue is also seen in patients with sleep related disorders including sleep disordered breathing (SDB). Thus, we examined the prevalence of sleep disturbances and SDB in patients with PIDD. MethodsPatients from our institution with a physician-confirmed diagnosis of PIDD were recruited for this IRB-approved study. Patients under 18 years of age, currently pregnant, or with previous diagnosis of SDB were excluded. Patients completed the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS), and Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires via REDCap. Patients then completed a home sleep apnea test (HSAT) using the Watch-PAT One device. ResultsA total of 24 patients with PIDD were enrolled in the study. Median age was 49.4 (range: 22.5–68.7) years, 18/24 (75%) patients were female. 22 out of 24 patients completed the questionnaires. Median values for PSQI, ESS, and FSS were 9.0 (2–18), 7.5 (0–20), and 4.9 (1.0–7.0), respectively. The median PROMIS Fatigue score was 57.9 (33.7–75.8). 14 out of 24 patients completed HSATs at the time of abstract submission. Sleep disordered breathing was defined as having an apnea-hypopnea index (AHI) of 5 events/hour or greater. For patients who completed HSATs, 10 (71%) met the threshold for having SDB. Based on guidelines established by the American Academy of Sleep Medicine, 6 (43%) had mild SDB, 3 (21%) had moderate SDB, and 1 (7%) had severe SDB. ConclusionPatients with an established diagnosis of PIDD, without previously diagnosed SDB, show a higher burden of poor sleep quality, daytime sleepiness, and fatigue based on scoring of self-reported questionnaires as compared to the general population. Overall, these patients were also noted to have a higher burden of sleep disordered breathing. These results provide preliminary evidence that undiagnosed sleep disturbances and SDB may contribute to the increased burden of fatigue in patients with PIDD.

A horse or a zebra? Unusual manifestations of common cutaneous infections in primary immunodeficiency pediatric patients.

Patients with primary immunodeficiency disorders (PIDs) often suffer from recurrent infections because of their inappropriate immune response to both common and less common pathogens. These patients may present with unique and severe cutaneous infectious manifestations that are not common in healthy individuals and may be more challenging to diagnose and treat. To describe a cohort of patients with PIDs with atypical presentations of skin infections, who posed a diagnostic and/or therapeutic challenge. This is a retrospective study of pediatric patients with PID with atypical presentations of infections, who were treated at the immunodeficiency specialty clinic and the pediatric dermatology clinic at the Sheba Medical Center between September 2012 and August 2022. Epidemiologic data, PID diagnosis, infectious etiology, presentation, course, and treatment were recorded. Eight children with a diagnosis of PID were included, five of whom were boys. The average age at PID diagnosis was 1.7 (±SD 3.2) years. The average age of cutaneous infection was 6.9 (±SD 5.9) years. Three patients were born to consanguineous parents. The PIDs included the following: common variable immunodeficiency, severe combined immunodeficiency, DOCK8 deficiency, ataxia telangiectasia, CARD11 deficiency, MALT1 deficiency, chronic granulomatous disease, and a combined cellular and humoral immunodeficiency syndrome of unknown etiology. The infections included the following: ulcerative-hemorrhagic varicella-zoster virus (two cases) atypical fungal and bacterial infections, resistant Norwegian scabies, giant perianal verrucae (two cases), and diffuse molluscum contagiosum. In this case series, we present unusual manifestations of infectious skin diseases in pediatric patients with PID. In some of the cases, recognition of the infectious process prompted life-saving treatment. Increasing familiarity with these dermatological manifestations, as well as keeping a high index of suspicion, is important to enabling early diagnosis of cutaneous infections in PIDs and initiation of prompt suitable treatment.

Investigating Biomarkers for Primary Immunodeficiency Disorders in Patients with Autoimmune Cytopenia

Introduction: Autoimmune cytopenias (AICs) occur in the setting of immune dysregulation and autoimmunity. AICs are known to precede the classical presentation and subsequent diagnosis of primary immunodeficiency disorders (PIDs) in some cases, with a PID spectrum involving B, T, and Treg dysregulation. Conversely, PID patients are also at a markedly increased risk of AICs and patients co-diagnosed with AICs and PIDs face higher mortality rates likely due to delayed diagnosis or improper/delayed therapy. Further, co-diagnosed patients are often refractory to standard treatment. Early screening and diagnosis of PIDs in the setting of AICs could lead to more targeted therapies and potentially better patient outcomes. We intend to investigate biomarkers that differentiate immune dysregulation among those with or without PID in the setting of AIC. Methods: A retrospective analysis comparing clinical history, including symptoms, presence of PID, genetic testing and diagnosis and treatment outcomes was performed on AIC patients in our hospital from 2016 to 2019. We also performed extensive immune phenotyping by flow cytometric analysis. Patients with expansion of CD19hi CD21lo B cells were further evaluated for Tbet+ CD11chi features for potential autoreactivity. Results: Our original cohort of 103 AIC patients included patients who were diagnosed with AIC only (n=52) or co-diagnosed with AIC-PID (n=51). From this cohort, a total of 43 were evaluated for further immune phenotyping, including 35 AIC-PID patients and 8 AIC only patients. Of the AIC-PID patients, 23 (65.7%) had a genetically coded PID, including pathogenic variants in CTLA4, NFKB1, PI3K or partial DiGeorge, while 12 (34.3%) were diagnosed with CVID/CID. Flow cytometry analysis revealed significantly increased T-follicular helper cell (Tfh) population in the AIC-PID group compared to AIC only (p=0.03) and healthy donor (HD) (p=0.004). We saw a similar expansion of CD19hi CD21lo B cells within the AIC-PID group. Conversely, patients with AIC-PID had decreased percentage of T-regulatory cells (Tregs) when compared to AIC only and HD groups. These differences were amplified within the genetically coded AIC-PID patients in Treg and Tfh populations and maintained in CD19hi CD21lo B cells. Further investigation of clinical history within the symptomatic, genetically coded AIC-PID group yielded 3 (33.3%) patients responsive to treatment and 6 (66.7%) patients unresponsive or partially responsive to therapy. Interestingly, nonresponsive patients showed an increased percentage of CD19hi CD21lo B cells. Conclusions: Our analysis demonstrates the potential utility of biomarkers, notably CD19hi CD21lo B cells and their immunological function for detecting underlying PIDs within the setting of AIC patients. Though this B cell population needs further assessment regarding Tbet and CD11c expression, with studies ongoing, these biomarkers may lead to a screening methodology to increase clinical visibility and detection as well as hasten diagnosis of underlying PID and potentially predict response to therapy, therefore increasing effective treatment outcomes for patients co-diagnosed with AIC PID.

Clinical and laboratory spectrum of inborn errors of immunity in Egypt: Five years of experience at a tertiary care university hospital.

The recognition and diagnosis of primary immunodeficiency disorders (PIDs) is challenging in developing countries. This study aimed to describe the features of PID patients in a tertiary care setting in Egypt and analyse the distribution, clinical features and outcome of PID among paediatric patients. This cross-sectional retrospective study was conducted between January 2016 and January 2021, to evaluate all paediatric patients aged below 18 years with PID that were diagnosed according to the International Union of Immunological Societies 2017 classification. We retrospectively studied the clinical features, diagnostic spectrum, laboratory investigations and relevant immunological workup, and treatment options. A total of 61 PID patients were enrolled in the current study. The median age at diagnosis was 22 months. The overall consanguinity rate was 49.2%, and the family history of PID was 19.7%. Among all PIDs, the combined immunodeficiency with syndromic features predominates with 17 cases, accounting for 27.9% of all cases of PIDs. The predominant antibody deficiency was the second common PID that was diagnosed in 14 patients (23%). Recurrent pneumonia was the most common initial presentation, occurring in 77% of patients, followed by failure to thrive (63.9%), and recurrent otitis media (55.7%). The total deaths were 18 patients (29.5%). Paediatric patients with PIDs are not uncommon in Egypt. There is a need to improve PID diagnosis and treatment, for better estimation of PID and to decrease morbidity and mortality.

Role of T-B-NK cell with naive and memory cell markers in the diagnosis of primary immunodeficiency disorders in a tertiary care hospital

Role of T-B-NK cell with naive and memory cell markers in the diagnosis of primary immunodeficiency disorders in a tertiary care hospital

Impact of the J Project on progress of primary immunodeficiency care in Ukraine.

The J Project is a Central-Eastern European collaborative program in the field of physician education and clinical research aimed at improving the clinical care and diagnosis of primary immunodeficiency disorders (PIDs). Ukraine was one of the first to participate in the project, which allowed us to join the whole European PID community. Since 2004, the country has been holding annual J Project meetings with the involvement of new regions. The spread of the J Project impact has contributed to significantly improved early PID diagnosis in Ukraine. Progress has been made not only in identifying patients but also in arranging the treatment. The assistance in genetic diagnosis made it possible to detect PIDs, study their features, and improve approaches to the management. This also gave an impetus to the development of regional PID centers and participation in scientific research. Of utmost importance is the cooperation with colleagues from Poland, Hungary, and Belarus, who are active members of the J Project.

Clinical and Laboratory Characteristics of Primary Immunodeficiency Patients from a Tertiary Care Center in Pakistan.

The aim of this study was to describe and identify clinical presentation of primary immunodeficiency disorders (PIDs). Characteristic quantitative and qualitative immunological abnormalities have been described which help in establishing a definitive PID diagnosis. This was a cross sectional study conducted in the Immunology department of the Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from Jan 2016 to Dec 2018. Sixty patients of different PIDs including humoral defects, combined immunodeficiency, phagocytic defects and other miscellaneous disorders, were diagnosed over a period of 3 years in our institute. Their clinical presentation and laboratory data are presented in this study. In 3 years, 40 (66%) males and 20 (33%) females were diagnosed, with 13 (21.6%) patients of humoral deficiency, 22 (36.6%) of severe combined immunodeficiency, 18 (30%) of phagocytic defects and 7 (11.6%) of other miscellaneous disorders. Maximum patients belonged to Punjab province, i.e., 23 (38.3%). Their mean age for initiation of symptoms was 7±12.6 months, while diagnosis was made at mean age of 26±39.28 months, in all groups combined. Respiratory infections were commonest presentation, in 46 (76.6%) patients. Also 46 (76.6%) patients had consanguineous parents. Presence of family history of PID in 27 (45%) patients was not associated with an earlier diagnosis (p 0.955). Each group of patients carried characteristic laboratory findings. PIDs should be suspected in offsprings with warning signs coming from consanguineous parents. There is a need to introduce genetic diagnosis of PIDs in order to timely diagnose less characteristic PID presentations.

High frequency of variants in genes associated with primary immunodeficiencies in patients with rheumatic diseases with secondary hypogammaglobulinaemia

ObjectivesTreatment of rheumatic diseases requires immunomodulatory agents which can compromise antibody production. However, even in case of agents directly targeting B cells, a minority of patients develop hypogammaglobulinaemia, suggesting a...

National Survey about awareness of Primary Immunodeficiency Disorders among Primary Care Physicians in Saudi Arabia: Protocol and Challenges.

Introduction:Primary Health Care Centers (PHCC) are the first contact health facility to which patients in Saudi Arabia can go to seek help. Primary Immunodeficiency Disorders (PIDD) are of various types and severities, and they are associated with a delay in diagnosis. Early diagnosis of PIDD helps to improve the quality of life of affected children and prevent permanent consequences such as organ damage and disability. In this study, we present a protocol of a national survey that assesses awareness among PHCC physicians about diagnosing PIDD and the challenges associated with the execution of this protocol.Methods:This cross-sectional survey used stratified multistage sampling and systematic random selection of PHCC from a list of PHCC affiliated centers under the Ministry of Health (MOH) in Saudi Arabia. The survey was conducted through phone calls to the selected physicians. Data collection started in April 2020, and it is still ongoing.Conclusion:In Saudi Arabia, this study will provide baseline data about PHCC physicians’ levels of awareness of the diagnosis of PIDD. This will help policy-makers in designing educational courses or programs to increase awareness levels among physicians. The protocol could be used to study other health outcomes at a national level.

Primary Immunodeficiency Disorders Among North Indian Children.

To report the distribution pattern of various categories of primary immunodeficiency disorders (PIDs) in children from North India, frequency of warning signs and critical parameters for evaluation. In this retrospective study, 528 children below 18 y of age after clinical assessment and presentation suggestive of PID were further screened by immunophenotyping for immune cell markers by flow cytometry. A total of 120 (23%) children were diagnosed with PID with median age at diagnosis being 2.5 y in males and 3.5 y in females and an average delay in diagnosis from onset of symptoms being approximately 5 y. Chronic lower respiratory tract infections, gastrointestinal symptoms like persistent diarrhea and failure to thrive were amongst the most common warning signs in these patients. PIDs were classified according to the International Union of Immunological Societies' (IUIS) criteria. The diagnosis of index study subjects included combined humoral and cellular immunodeficiency (29%), phagocytic defects (29%), followed by predominantly antibody deficiency (18%), innate immunity and dysregulation (17%) and other well-defined syndromes (7%). A family history of PID (23%), consanguineous marriage (8%) and previous sibling death (23%) were observed as major clinical predictors/clues for underlying PID. All children received prophylactic antibiotics and/or antifungals in addition to specific therapy for underlying immune deficiency. The field of PIDs in India remains largely unexplored and we are faced with various challenges in the diagnosis of PIDs due to lack of awareness as well as absence of equipped immunological laboratory support. The authors propose a methodical step-wise laboratory diagnostic approach that can facilitate early diagnosis and timely intervention of these mis/underdiagnosed disorders.

Targeted high-throughput sequencing technique for the molecular diagnosis of primary immunodeficiency disorders.

The aim of this study was to investigate the usefulness of targeted high-throughput sequencing (HTS) for the molecular diagnosis of primary immunodeficiency diseases (PID).A total of 56 clinically diagnosed or suspected PID patients were divided into 4 groups according to the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015 and their chief clinical presentations. Patients and their biological family members were examined by targeted HTS, which sequenced the exons and ±10 bp flanking introns of 171 PID-related genes panel. All significant variants were confirmed by PCR-Sanger sequencing. Pathogenicity of the variants was evaluated by using bioinformatics.A total of 117 variants in 73 genes were found in 56 patients. Accurate molecular diagnosis of PID was made in 13 (23.2%) patients, and 12 novel mutations were detected in these patients. Twenty-seven patients carried heterozygous variants that are probably pathogenic in ≥2 genes; 16 patients had only 1 missense variant, or had several variants but not >1 variant was deleterious as evaluated by bioinformatics. The meaning of the targeted HTS results of these patients remains to be studied.Targeted HTS can make a precise molecular diagnosis of PID and detect more novel pathogenic mutations. More and more variations with ambiguous significance are discovered and explanation of these variations is a challenge to the clinicians.

457 - Challenges of Haematopoietic Stem Cell Transplantation in Primary Immunodeficiency Disorders in a Developing Country

Hematopoietic stem cell transplant (HSCT) is required in a subset of patients with primary immunodeficiency disorders (PID). The diagnosis of PID is often delayed in a developing country, and active infections and delay in transplantation may lead to poorer outcomes in this setting. This is a retrospective analysis of allogeneic HSCTs carried out from January 1998 to August 2017 in patients with PID in a tertiary care centre in India. Thirty-two patients with a median age 36 months (Range 6 months to 18 years) underwent allogeneic HSCT. The two most common disorders were Wiskott Aldrich syndrome (n = 8) and severe combined immunodeficiency (n = 7). Six patients had active infection at the time of transplant (1 patient with tuberculosis, 2 with nocardiosis and tuberculosis, 1 patient with fungal pneumonia and 2 with skin/soft tissue infection). Haploidentical transplants were carried out in 12 (37.5%) patients, matched sibling donor (MSD) in 10 (31.2%), matched family donor (MFD) and matched unrelated donor (MUD) in 5 (15.6%) each. Stem cells were derived from peripheral blood in 19 (59.3%) patients, bone marrow in 12 (37.5%) and cord blood in one (3.1%). Median CD34+ cell dose infused was 10.4 × 106/kg. Conditioning regimes used were busulfan based in 9 (28.1%) patients and treosulfan based in 22 (68.8%). One patient did not receive conditioning. Six patients expired prior to engraftment due to infectious complications. Of the remaining patients, all except one engrafted. Grade 3-4 acute GVHD occurred in 8 (25%) patients. Bacterial, viral and fungal infections were noted in 22 (68.8%), 19 (59.3%) and 11 (34.3%) patients respectively in peri-transplant period. Seven (21.8%) patients had chronic GVHD. The 2 year OS and EFS in MSD was 88.9 ± 10.5%, with a significantly lower OS in MUD/MFD and Haplo-identical transplants, 33.3 ± 17.2% and 40.0 ± 14.6% respectively (P = .033), and EFS 33.3 ± 17.2% and 33.3 ± 13.6% respectively (P = .022) (Figure 1). Outcomes in matched sibling donor HSCT is comparable to data in the West, however there are significant challenges associated with haplo-identical transplants in the Indian setting, with a significant mortality secondary to infections.

Evaluation of Clinical and Immunological Characteristics of Children with Common Variable Immunodeficiency.

Background Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder (PID) that typically presents with hypogammaglobulinemia and impaired antibody production. Objectives This study aimed to promote the awareness of CVID, whose clinical spectrum is quite broad. Methods The demographic, clinical, and laboratory characteristics of 12 children (seven males and five females) with CVID were analyzed retrospectively. The patients were diagnosed using the diagnostic criteria of the European Society for Primary Immunodeficiencies. Results The median disease onset age was 7.2 ± 4.1 years, and the mean diagnosis age was 11.6 ± 3.7 years. The diagnosis delay was 4.3 ± 2.6 years, and the parental consanguinity rate was 75%. Most patients presented with recurrent infections, including upper respiratory tract infections (n = 8), lower respiratory tract infections (n = 9), and gastroenteritis (n = 5). In addition, growth retardation (n = 9) and bronchiectasis (n = 5) were common comorbidities. Two patients presented with autoimmune thrombocytopenia and anemia, and one patient exhibited lung empyema. All the patients had immunoglobulin G deficiencies. Conclusion CVID is a heterogeneous disease, so the diagnosis is frequently delayed. In the CVID patients with pulmonary complications, relationships were seen with the diagnosis delay, symptom onset age, and lung infection prevalence. Overall, the early diagnosis and treatment of PIDs can preclude life-threatening complications.

Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency.

Primary immunodeficiency disorders (PIDs) render patients vulnerable to infection with a wide range of microorganisms and thus provide good in vivo models for the assessment of immune responses during infectious challenges. Priming of the immune system, especially in infancy, depends on different environmental exposures and medical practices. This may determine the timing and phenotype of clinical appearance of immune deficits as exemplified with early exposure to Bacillus Calmette-Guérin (BCG) vaccination and dissemination in combined immunodeficiencies. Varied phenotype expression poses a challenge to identification of the putative immune deficit. Without the availability of genomic diagnosis and data analysis resources and with limited capacity for functional definition of immune pathways, it is difficult to establish a definitive diagnosis and to decide on appropriate treatment. This study describes the use of exome sequencing to identify a homozygous recessive variant in MAP3K14, NIKVal345Met, in a patient with combined immunodeficiency, disseminated BCG-osis, and paradoxically elevated lymphocytes. Laboratory testing confirmed hypogammaglobulinemia with normal CD19, but failed to confirm a definitive diagnosis for targeted treatment decisions. NIKVal345Met is predicted to be deleterious and pathogenic by two in silico prediction tools and is situated in a gene crucial for effective functioning of the non-canonical nuclear factor-kappa B signaling pathway. Functional analysis of NIKVal345Met- versus NIKWT-transfected human embryonic kidney-293T cells showed that this mutation significantly affects the kinase activity of NIK leading to decreased levels of phosphorylated IkappaB kinase-alpha (IKKα), the target of NIK. BCG-stimulated RAW264.7 cells transfected with NIKVal345Met also presented with reduced levels of phosphorylated IKKα, significantly increased p100 levels and significantly decreased p52 levels compared to cells transfected with NIKWT. Ideally, these experiments would have been conducted in patient-derived immune cells, but we were unable to source these cells from the patient. The functional analysis described in this paper supports previous illustrations of the importance of NIK in human immune responses and demonstrates the involvement of function-altering mutations in MAP3K14 in PIDs. The genomic approach used for this patient demonstrates its value in the diagnosis of an unusual PID and as a tool for detecting rarer mutations to help guide treatment approaches.

Surveillance of Primary Immunodeficiency Disorders in Mofid Children's Hospital: A 10-year retrospective experience

Background: Primary immunodeficiency disorders comprise a heterogeneous group of diseases in which there is a defect in the development or function of the immune system. Clinical presentation of these disorders is highly variable. The aim of this study was to determine the frequency and type of primary immunodeficiency disorders, diagnostic delay, common pathogenic microorganisms, and infectious complications in patients, admitted to Mofid Children’s hospital in the past decade (2004 - 2014). Methods: The data of patients with a diagnosis of primary immunodeficiency disorder, admitted to Mofid Children’s hospital from 2004 to 2014, were reviewed. The frequency, diagnostic delay, pathogenic microorganisms, and their sequelae were determined. Results: In 32 patients (20 males and 12 females) admitted to Mofid hospital in the past decade, chronic granulomatous disease was the most frequent primary immunodeficiency disorder (22%). Other immunodeficiency disorders in these patients included X-linked agammaglobulinemia, hyper IgM syndrome, common variable immunodeficiency, severe combined immunodeficiency, ataxia-telangiectasia syndrome, transient hypogammaglobulinemia of infancy, leukocyte adhesion deficiency, and Kostmann syndrome. The mean age at onset of these disorders was 15 months, and the mean delay in diagnosis was 20 months. Pneumonia was the most common infectious manifestation (53%), and Acinetobacter was the most common isolated microorganism. Conclusions: Diagnostic delay is a major concern in patients with primary immunodeficiency disorders. Ethnic and geographical differences may significantly influence the frequency and presentation of these disorders. Therefore, local epidemiological data are always necessary and useful in the management of primary immunodeficiency disorders.

Primary immunodeficiencies associated with eosinophilia.

BackgroundEosinophilia is not an uncommon clinical finding. However, diagnosis of its cause can be a dilemma once common culprits, namely infection, allergy and reactive causes are excluded. Primary immunodeficiency disorders (PID) are among known differentials of eosinophilia. However, the list of PIDs typically reported with eosinophilia is small and the literature lacks an inclusive list of PIDs which have been reported with eosinophilia. This motivated us to review the literature for all PIDs which have been described to have elevated eosinophils as this may contribute to an earlier diagnosis of PID and further the understanding of eosinophilia.MethodsA retrospective PubMed, and Google Scholar search using the terms “eosinophilia” and “every individual PID” as classified by Expert Committee of the International Union of Immunological Societies with the limit of the English language was performed. Results were assessed to capture case(s) which reported eosinophilia in the context of PID conditions. Absolute eosinophil counts (AEC) were retrieved from manuscripts whenever reported.ResultsIn addition to the typical PID conditions described with eosinophilia, we document that MHC class II deficiency, CD3γ deficiency, STAT1 deficiency (AD form), Kostmann disease, cyclic neutropenia, TCRα deficiency, Papillon-Lefevre syndrome, CD40 deficiency, CD40L deficiency, anhidrotic ectodermal dysplasia with immune deficiency, ataxia-telangiectasia, common variable immunodeficiency disorders (CVID), Blau syndrome, CARD9 deficiency, neonatal onset multisystem inflammatory disease or chronic infantile neurologic cutaneous and articular syndrome (NOMID/CINCA), chronic granulomatous disease, MALT1 deficiency and Roifman syndrome have been noted to have elevated eosinophils. Severe eosinophilia (>5.0 × 109/L) was reported in Omenn syndrome, Wiskott Aldrich syndrome, ADA deficiency, autoimmune lymphoproliferative syndrome, immunodysregulation polyendocrinopathy enteropathy X-linked, STAT3 deficiency, DOCK8 deficiency, CD40 deficiency, MHC II deficiency, Kostmann disease, Papillon-Lefevre syndrome, and CVID.ConclusionsThis literature review shows that there is an extensive list of PIDs which have been reported with eosinophilia. This list helps clinicians to consider an extended differential diagnoses when tasked with exclusion of PID as a cause for eosinophilia.Electronic supplementary materialThe online version of this article (doi:10.1186/s13223-016-0130-4) contains supplementary material, which is available to authorized users.

7th International Immunoglobulin Conference: Immunodeficiencies.

Most primary immunodeficiency disorders (PID) are the result of single gene defects. Based on this fact, more than 240 different entities have been identified. Those PIDs with predominant antibody deficiency are treated with immunoglobulin (Ig) replacement therapy. This review focuses on the diagnosis, clinical characteristics and treatment of patients suffering from PID, or secondary immunodeficiency disorders (SID) caused, for instance, by irradiation, immunosuppressive drugs or thymectomy. Common variable immunodeficiency (CVID) is the most commonly diagnosed and least understood form of PID, with a heterogeneous range of symptoms and genotypes, requiring individualized treatment plans. This includes adjusting the dose and treatment interval, administrating Ig by intravenous or subcutaneous injection by either pump or push, and finally deciding which treatment options are best for a given patient. Ig therapy can also be used to treat immunodeficiencies resulting from lymphoproliferative and autoimmune diseases or immunosuppression following organ transplantation; however, there is an urgent need for research in this field. Accurate and early diagnosis of PID is important to ensure that optimal treatment is started early to maintain the patient's health. Detailed patient registries have been established to increase awareness of PID, as well as provide a valuable resource for further research.

The Spread of the J Project

The J Project physician education and clinical research collaboration program was launched in 2004 in Eastern and Central Europe (ECE). In less than 10 years, it has achieved remarkable success. This project aims to increase knowledge in the field of primary immunodeficiency disorders (PID), and to improve the diagnosis and treatment of patients worldwide, particularly in countries with limited economic resources, which currently report fewer such patients than expected. In most ECE countries, gene sequencing, which can provide a definitive diagnosis of PID, still remains unavailable. By contrast, such technology is used elsewhere to detect the more than 200 PID-causing genes that have been discovered in the last three decades. Thus, PID awareness programs like the J Project remain critically important, to improve diagnostic facilities and treatment and to promote clinical research collaboration. This paper highlights the achievements of the J Project and the spread of its concepts and spirit to the countries of Western Asia.