Diagnosis Of Primary Immunodeficiency Diseases Research Articles

Assessment of the Presence of Predominantly Antibody Deficiency among Pediatric Patients with Interstitial Lung Disease

Abstract Background Predominantly antibody deficiencies (PADs) are frequent primary immunodeficiency diseases (PIDs) that have different etiologies. PAD patients present with various clinical manifestations, including infections and non-infectious disorders such as interstitial lung disease (ILD). The determination of serum Igs (IgG, IgM, IgA) is the first step in the evaluation of humoral immunity, and will help diagnose or at least point to a suspicion of quantitative Ig deficiencies. Lung disease is a frequent clinical manifestation in people living with primary immunodeficiency diseases, the most prevalent of which are common variable immunodeficiency disorders (CVID). Aim of Work Screening for Predominantly Antibody Deficiency (PAD) among pediatric patients diagnosed with primary interstitial lung disease. Patients and Methods This was a pilot study that was conducted on 30 children diagnosed with primary interstitial lung disease (ILD) following up in the Pediatric chest clinic, Children’s hospital, Ain Shams University in the period from September 2022 to February 2023, their ages ranged between 9-180 months and They were 16 (53.3%) males and 14 (46.7%) females. Tools of assessment included detailed clinical history with stress on history of respiratory symptoms, history of ten warning signs of immunedeficiency, general and chest examination and immunoglobulins (IgA, IgM, IgG) level by ELISA. Results There were 2 (6.7%) children with low levels of IgG, As regard IgM 2(6.7%) children had low levels, and 1(3.3%) child had high level. While 5 (16.7%) children had low levels of IgA. based on the criteria of Europian Society For Immunodeficiencies (ESID) 2 children were probable to be Commom Variable Immundeficiency (CVID) and 3 children were possible to be CVID. Conclusion Predominantly antibody deficiencies (PADs) may be presented as ILD and ILD may be the first presentation even before PID diagnosis.

FSCIG 10% in pediatric primary immunodeficiency diseases: a European post-authorization safety study

BackgroundThe safety, tolerability, and immunogenicity of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% (dual-vial unit of human immunoglobulin 10% and recombinant human hyaluronidase [rHuPH20]) were assessed in children with primary immunodeficiency diseases (PIDs).MethodsThis phase 4, post-authorization, prospective, interventional, multicenter study (NCT03116347) conducted in the European Economic Area, enrolled patients aged 2 to < 18 years with a documented PID diagnosis who had received immunoglobulin therapy for ≥ 3 months before enrollment. New fSCIG 10% starters underwent fSCIG 10% dose ramp-up for ≤ 6 weeks (epoch 1) before receiving fSCIG 10% for ≤ 3 years (epoch 2); patients pretreated with fSCIG 10% entered epoch 2 directly. The primary outcome was the number and rate (per infusion) of all noninfectious treatment-related serious and severe adverse events (AEs).ResultsIn total, 42 patients were enrolled and dosed (median [range] age: 11.5 [3–17] years; 81% male; 23 new starters; 19 pretreated). Overall, 49 related noninfectious, treatment-emergent AEs (TEAEs) were reported in 15 patients; most were mild in severity (87.8%). No treatment-related serious TEAEs were reported. Two TEAEs (infusion site pain and emotional distress) were reported as severe and treatment-related in a single new fSCIG 10% starter. The rate of local TEAEs was lower in pretreated patients (0.1 event/patient-year) versus new starters (1.3 events/patient-year). No patients tested positive for binding anti-rHuPH20 antibodies (titer of ≥ 1:160).ConclusionsNo safety signals were identified, and the incidence of local AEs declined over the duration of fSCIG 10% treatment. This study supports fSCIG 10% long-term safety in children with PIDs.Trial registration number (ClinicalTrials.gov)NCT03116347.

Paving the way in implementation of SCID newborn screening in developing nations: feasibility study and strategies to move forward in Malaysia.

Early diagnosis and effective management of Primary immunodeficiency diseases (PIDs), particularly severe combined immunodeficiency (SCID), play a crucial role in minimizing associated morbidities and mortality. Newborn screening (NBS) serves as a valuable tool in facilitating these efforts. Timely detection and diagnosis are essential for swiftly implementing isolation measures and ensuring prompt referral for definitive treatment, such as allogeneic hematopoietic stem cell transplantation. The utilization of comprehensive protocols and screening assays, including T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC), is essential in facilitating early diagnosis of SCID and other PIDs, but their successful application requires clinical expertise and proper implementation strategy. Unfortunately, a notable challenge arises from insufficient funding for the treatment of PIDs. To address these issues, a collaborative approach is imperative, involving advancements in technology, a well-functioning healthcare system, and active engagement from stakeholders. The integration of these elements is essential for overcoming the existing challenges in NBS for PIDs. By fostering synergy between technology providers, healthcare professionals, and governmental stakeholders, we can enhance the efficiency and effectiveness of early diagnosis and intervention, ultimately improving outcomes for individuals with PIDs.

Diagnosis of primary immunodeficiency diseases by flow cytometry: Experience from Bangladesh

Abstract BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and immunologically diverse and require a wide array of clinical and laboratory modalities to make specific diagnosis. Serum immunoglobulin levels and T cell, B cell and NK (Natural killer) cell immunophenotyping are routine laboratory investigations advised to diagnose the PIDD cases in Bangladesh. Along with T-B-NK markers, use of Naïve (CD45RA+) and memory (CD45RO+) T cell, switched memory B cell (CD27+IgD-) markers, detection of intracellular BTK (Bruton’s tyrosine kinase), LRBA (Lipopolysaccharide-responsive beige-like anchor), DOCK8 (Dedicator of cytokinesis 8) protein expression and DHR123 (Dihydro-rhodamine 123) assay of neutrophil can increase the PIDD cases detection in Bangladesh. METHODS: The study was conducted in the Department of Microbiology and Immunology, Bangabandhu Sheikh Mujib Medical University (BSMMU) during the time period of March, 2021 to February, 2022. Seventy clinically suspected PIDD cases were enrolled in this study on the basis of clinical findings and peripheral venous blood was collected from all patients to perform immunophenotyping. Routine T-B-NK cell, naïve and memory T cell with switched memory B cell markers were detected by flow-cytometry. Serum immunoglobulins (IgG, IgM, IgA &amp; IgE) were estimated by Nephelometry and by Chemiluminescence. Intracellular BTK, LRBA and DOCK8 protein expression was detected by flow-cytometry in suspected X-linked agammaglobulinemia (XLA), LRBA and DOCK8 deficiency patients respectively. DHR123 assay was performed in suspected Chronic granulomatous disease (CGD) patients. RESULTS: Among the 70 clinically suspected PIDD cases, 9 (12.9%) were diagnosed as patients of PIDDs on the basis of laboratory evidence. Five (55.55%) cases were diagnosed as predominantly antibody deficiencies (PADs), 3 (33.33%) were patients of combined immunodeficiency (CID) and 1 (11.11%) was CGD patient. Among the diagnosed PIDD cases, 2 (22.22%) were diagnosed by T-B-NK cell immunophenotyping with serum immunoglobulin levels and 7 (77.77%) cases were diagnosed by additional CD45RA+, CD45RO+, CD27+IgD- markers, BTK protein expression detection and DHR123 assay. LRBA and DOCK8 deficiency cases could not found in this study. CONCLUSION: The use of additional markers (CD45RA+, CD45RO+, CD27+IgD-) with BTK, LRBA, DOCK8 intracellular protein expression evaluation and DHR123 assay by flow-cytometry can increase rate of specific diagnosis of the PIDD cases in Bangladeshi paediatric population.

Long-term safety of facilitated subcutaneous immunoglobulin 10% treatment in patients with primary immunodeficiency diseases: final analysis from a post-authorization safety study conducted in the USA

IntroductionFacilitated subcutaneous immunoglobulin (fSCIG) 10% is an immunoglobulin replacement therapy that utilizes recombinant human hyaluronidase (rHuPH20) to enhance immunoglobulin dispersion and absorption. fSCIG 10% is approved in the USA for adult patients with primary immunodeficiency diseases (PIDDs). This study aimed to assess the long-term safety of fSCIG 10% in routine clinical practice. MethodsThis prospective, non-interventional, open-label, multicenter, post-authorization safety study (NCT02593188) was conducted in the USA from Nov-2015 to Aug-2022. Patients with PIDD, aged ≥16 years, prescribed or receiving fSCIG 10% were enrolled. Treatment regimens were planned by the attending physician in accordance with routine clinical practice. Adverse event (AE) data were collected from enrollment to study completion or discontinuation and the presence of anti-rHuPH20 antibodies was evaluated on a voluntary basis. ResultsIn total, 253 patients were enrolled and included in the full analysis set (mean age [standard deviation] 54.3 years [15.6]; 79.1% female). The most common PIDD diagnosis was common variable immunodeficiency (71.9%). Patients received fSCIG 10% treatment for a median (interquartile range) duration of 10.0 (3.7–11.8) months, with most infusions administered every 4 weeks (54.4% [1197 of 2201 infusions]) at home (62.6% [1395 of 2230 infusions]). Overall, 98.5% of infusions were administered without a rate reduction, interruption, or discontinuation due to AEs. Treatment-related, non-serious AEs were experienced by 52 patients (20.6%, 284 events). Two patients (0.8%) each experienced one treatment-related serious AE (aseptic meningitis and deep vein thrombosis). Two fatal AEs (0.8%) were reported; neither were treatment-related. Of 196 patients tested, 14 (7.1%) were positive for treatment-emergent binding anti-rHuPH20 antibodies (titer ≥1:160; maximum titer 10 240); no neutralizing antibodies were detected. There was no relationship between anti-rHuPH20 antibody positivity and the occurrence of treatment-related serious or non-serious AEs. ConclusionsLong-term, repeated, self-administration of fSCIG 10% is well-tolerated in US clinical practice by patients with PIDD. Development of non-neutralizing antibodies against rHuPH20 was uncommon and did not correlate with treatment-related AEs.Baxalta US Inc., a Takeda company, funded this study. Takeda Pharmaceuticals International AG funded writing support.

REAL-WORLD UTILIZATION OF IMMUNE GLOBULIN SUBCUTANEOUS 16.5% IN TREATMENT-NAÏVE PRIMARY IMMUNODEFICIENT PATIENTS

<h3>Introduction</h3> Immune Globulin Subcutaneous (Human) 16.5% (IGSC 16.5%) is a subcutaneous immunoglobulin (IG) approved for the treatment of primary immunodeficiency diseases (PIDD) in adults and pediatric patients ≥2 years old. We evaluated clinical outcomes in IG treatment-naïve patients with PIDD who utilized IGSC 16.5% as initial therapy. <h3>Methods</h3> A retrospective review was conducted in IG treatment-naïve patients who received 24 weeks of IGSC 16.5% from 5/2019-4/2022. Data included demographics, IGSC 16.5% utilization, adverse reactions, respiratory tract infections (RTIs), and treatment adherence defined as self-administering within two days of the scheduled treatment. <h3>Results</h3> Thirty-five IG treatment-naïve patients (mean age 49±11.8 years, 94% female) utilized IGSC 16.5% during the study period. The predominant PIDD diagnosis was common variable immunodeficiency (40%). All patients infused weekly, with a mean dose of 122±31.8 mg/kg/week. The initial infusion rate was 26.5±6.9 mL/hr/all sites, and the maximum rate was 55.7±19.9 mL/hr/all sites (min 22.1, max 86.1). During infusions 1-24, local reactions were reported in 27 patients (77%), most commonly swelling, redness and itching. Local reactions were highest at infusion 1 and decreased significantly over time (p<0.01). Systemic reactions were reported in 15 patients (43%), most commonly fatigue and headache. Systemic reactions also diminished significantly over time (p<0.05). Seventeen bacterial RTIs occurred in 13 patients (33%); none were serious. Patients were adherent in 833/840 infusions (99% adherence rate). <h3>Conclusion</h3> Our real-world study confirmed effectiveness and excellent adherence with IGSC 16.5% in IG treatment-naïve patients with PIDD. Local and systemic reactions were highest at treatment initiation and then decreased significantly over time.

Early Diagnosis of Primary Immunodeficiency Disease Using Clinical Data and Machine Learning

Primary immunodeficiency diseases (PIDD) are a group of immune-related disorders that have a current median delay of diagnosis between 6 and 9 years. Early diagnosis and treatment of PIDD has been associated with improved patient outcomes. To develop a machine learning model using elements within the electronic health record data that are related to prior symptomatic treatment to predict PIDD. We conducted a retrospective study of patients with PIDD identified using inclusion criteria of PIDD-related diagnoses, immunodeficiency-specific medications, and low immunoglobulin levels. We constructed a control group of age-,sex-, and race-matched patients with asthma. The primary outcome was the diagnosis of PIDD. We considered comorbidities, laboratory tests, medications, and radiological orders as features, all before diagnosis and indicative of symptom-related treatment. Features were presented sequentially to logistic regression, elastic net, and random forest classifiers, which were trained using a nested cross-validation approach. Our cohort consisted of 6422 patients, of whom 247 (4%) were diagnosed with PIDD. Our logistic regression model with comorbidities demonstrated good discrimination between patients with PIDD and those with asthma (c-statistic: 0.62 [0.58-0.65]). Adding laboratory results, medications, and radiological orders improved discrimination (c-statistic: 0.70 vs 0.62, P < .001), sensitivity, and specificity. Extending to the advanced machine learning models did not improve performance. We developed a prediction model for early diagnosis of PIDD using historical data that are related to symptomatic care, which has potential to fill an important need in reducing the time to diagnose PIDD, leading to better outcomes for immunodeficient patients.

Diagnosis of primary immunodeficiency diseases in pediatric patients hospitalized for recurrent, severe, or unusual infections.

Primary immunodeficiency diseases (PID) usually presents itself with recurrent, severe, and unusual infections, along with autoimmunity and various other malignancies. But, the diversity of PID often makes the diagnosis of patients difficult for physicians other than clinical immunologists. This study aimed to describe the characteristics of patients diagnosed with PIDs during the inpatient treatment for infectious diseases, and to highlight the cases in which a PID diagnosis should be considered. The clinical, immunological, and molecular features of 81 pediatric patients treated for infectious diseases, who were diagnosed with a PID during hospitalization was retrospectively analyzed. The diagnosis was based on the PID criteria of the International Union of Immunological Societies. The five main PID sub-types were identified. Predominantly, antibody deficiencies were the most common (61.7%) group. The average delay in diagnosis was 34.6 months, and the positive family history rate was 24.7%, while the consanguineous marriage rate was 45.7%. Around thirty-five (43%) patients were found to have mutated PID-related genes. While lower respiratory tract infections were the most common symptom, a fever of unknown origin was another remarkable diagnosis. Eight (9.9%) patients underwent allogeneic hematopoietic stem cell transplantation. Clinicians should consider a PID diagnosis, especially in the cases of recurrent, severe, or atypical infections. Increased knowledge of the alarm features of PID can promote early diagnosis.

Respiratory Infections in Patients with Primary Immunodeficiency

Recurrent and life-threatening respiratory infections are nearly universal in patients with primary immunodeficiency diseases (PIDD). Early recognition, aggressive treatment, and prophylaxis with antimicrobials and immunoglobulin replacement have been the mainstays of management and will be reviewed here with an emphasis on respiratory infections. Genetic discoveries have allowed direct translation of research to clinical practice, improving our understanding of clinical patterns of pathogen susceptibilities and guiding prophylaxis. The recent identification of inborn errors in type I interferon signaling as a basis for life-threatening viral infections in otherwise healthy individuals suggests another targetable pathway for treatment and/or prophylaxis. The future of PIDD diagnosis will certainly involve early genetic identification by newborn screening before onset of infections, with early treatment offering the potential of preventing disease complications such as chronic lung changes. Gene editing approaches offer tremendous therapeutic potential, with rapidly emerging delivery systems. Antiviral therapies are desperately needed, and specific cellular therapies show promise in patients requiring hematopoietic stem cell transplantation. The introduction of approved therapies for clinical use in PIDDislimited by the difficulty of studying outcomes in rarepatients/conditions with conventional clinical trials.

Experience of Autoimmune and autoinflammatory diseases in a Turkish pediatric cohort with primary immunodeficiencies.

Primary immunodeficiency diseases (PID) are the diseases characterized by a dysfunction of the immune system. Affected patients share a different phenotype such as chronic infections, allergy, autoimmunity, and autoinflammation. In all, 433 children with PID were enrolled in this study. Clinical, laboratory, and demographic data of patients were reviewed retrospectively to investigate autoimmune and autoinflammatory complications. Autoinflammation in all patients with inflammation was confirmed by genetic analysis after excluding infectious etiology. Clinical features of 433 PID patients were evaluated retrospectively with long-term follow-up. Autoimmune disorders were identified in 69 (15.9%) patients with PID; 31 (45%) patients had a history of autoimmune disease before diagnosis of PID. The frequency of autoimmunity in immune dysregulation subgroup (76.6%) was higher than other forms of PID. The most common autoimmune manifestations were reported to be Addison's disease, hypoparathyroidism, and autoimmune hemolytic anemia. Autoinflammation were identified in 22 of the 433 (5.1%) patients with PID, including hyper immunoglobulin D syndrome (n = 9), Aicardi-Goutieres syndrome 1 (n = 6), adenosine deaminase 2 deficiency (n = 3), Blau syndrome (n = 2), tumor necrosis factor (TNF) receptor-associated periodic syndrome (n = 1), and auto-inflammation and phospholipase Cγ2-associated antibody deficiency and immune dysregulation syndrome (n = 1). It is important to recognize association between autoimmunity, autoinflammation, and PID, which in the future could be useful for increased awareness and early diagnosis for these diseases.

Differential diagnosis of primary immunodeficiency in patients with BCGitis and BCGosis: A single-centre study.

BCG infections occur more frequently in patients with underlying primary immunodeficiency disease (PIDD). In this study, we aimed to evaluate the ratio of PIDD in the patients with BCG infections. Patients with BCG infections were analyzed in a tertiary referral centre in the 2015-2020 period. Forty-seven patients with BCGitis/BCGosis were evaluated; thirty-four (72.3%) had BCGitis, and 13 (27.7%) had BCGosis. Common tissue and organs affected are lymph nodes (57.4%), skin and subcutaneous tissue (48.9%), lungs (23.4%) and liver (17%). PIDD was shown in 26 patients (55.3%), including 92.3% of patients with BCGosis and 41.2% of patients with BCGitis. Ten patients had Mendelian susceptibility to Mycobacterial disease (MSMD) (21.2%), six had predominantly antibody deficiency (PAD) (12.7%), five had severe combined immunodeficiency (SCID) (10.6%), three had CGD (6.3%), and two had CID (4.2%). Mortality was reported in two patients (4.2%) with CID (ZAP70 deficiency (n=1) and PIK3R1 deficiency (n=1)). Parental consanguinity (84%), axillary lymphadenopathy (65%), mycobacterial lung disease (42%), hepatomegaly (30%) and growth retardation (19%) were significantly high in patients with PIDD diagnosis. Isolated vaccination site infection was also recorded in patients with PIDD (CID (n=1), SCID (n=1), PAD (n=5)). BCG vaccination should be planned with caution for the cases with suspected PIDD. This study indicates that almost all patients (92.3%) with BCGosis and one in every two patients (41.2%) with BCGitis have an underlying PIDD. Parental consanguinity, axillary lymphadenopathy, mycobacterial lung disease, hepatomegaly and growth retardation (19%) are important clinical features in the differential diagnosis of PIDD.

Living with primary immunodeficiency disease during the Covid-19 pandemic.

AimThe purpose of this survey study was to investigate the impact of Covid-19 on the lives of individuals living with primary immunodeficiency disease (PID). Subject and methods An online survey was distributed through social media to individuals with a diagnosis of PID to investigate behaviors and concerns during the Covid-19 pandemic. ResultsFive hundred and fifty seven responses were collected, of which 495 surveys were 100% complete; partial responses were analyzed. Respondents have been extremely cautious and have minimized their potential Covid-19 exposure risk. In this study, 56.6% (n = 289) participated in telehealth visits with the physician responsible for managing their PID during the Covid-19 pandemic. Respondents reported they would be somewhat comfortable with returning to normal activities if there was widespread herd immunity (40.9%, n = 209), an effective vaccine (46.0%. n = 235), or public health protections (44.0%, n = 225). The majority of respondents were extremely concerned (57.3%, n = 293) about additional waves of Covid-19 cases when their state or country reopens.ConclusionThe PID community is aware of the health risks posed by this public health crisis, and have done as much as possible to minimize their risk to community exposure. This pandemic has highlighted the importance of continuous medical care for a vulnerable population through the use of telemedicine. Healthcare providers should be aware of the emotional burden and increased psychiatric distress, often presenting as fear, anxiety, or depression, in patients with a chronic medical condition during a public health crisis such as the Covid-19 pandemic.

Genetic Panel Testing for Primary Immunodeficiency Diseases

Advances in genetic testing have allowed for increased diagnosis of primary immunodeficiency diseases (PIDDs). Over 400 PIDDs have been recognized with the majority being monogenic defects. We aimed to examine the demographics and outcome of genetic testing for PIDD at a large pediatric tertiary hospital.

Primary immunodeficiency diseases treated with immunoglobulin and associated comorbidities.

Background: Primary immunodeficiency diseases (PIDD) consist of a heterogeneous group of disorders characterized by various aspects of immune dysregulation. Although the most universally recognized manifestation of PIDD is an increased susceptibility to infections, there is a growing body of evidence that patients with PIDD often have a higher incidence of lung disease, autoimmunity, autoinflammatory disorders, and malignancy. Objective: The purpose of this study was to better understand the noninfectious complications of PIDD by determining the comorbid disease prevalence across various age groups, genders, and immunoglobulin replacement types compared with the general population. Methods: A large U.S. insurance claims database was retrospectively analyzed for patients who had a diagnosis of PIDD and who had received intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG). The prevalences of 31 different comorbid conditions in the Elixhauser comorbidity index were compared among the 3125 patients in the PIDD population to > 37 million controls separated by gender and by 10-year age cohorts. Results: In the PIDD population, statistically significantly higher comorbid diagnoses included chronic obstructive pulmonary disease-asthma in 51.5%, rheumatoid disease in 14%, deficiency anemia in 11.8%, hypothyroidism in 21.2%, lymphoma in 16.7%, neurologic disorders in 9.7%, arrhythmias in 19.9%, electrolyte disorders in 23.6%, coagulopathies in 16.9%, and weight loss in 8.4%. Conclusion: PIDD that require immunoglobulin replacement are associated with an increased risk of numerous comorbid conditions that affect morbidity and mortality. Recognition and increased awareness of these noninfectious complications can allow for better monitoring, care coordination, targeted treatments, and improved prognosis.

Investigation of causative genetic defects in patients with primary immunodeficiency by next generation sequencing

Aim: Inborn errors of immunity are rare diseases presented with a broad range of clinical symptoms. There are more than 450 causative genetic defects and the genetic diagnosis is very important for the patients. Use of next generation sequencing facilitated the molecular and genetic identification of these diseases for last 10 years. We aimed to search disease-causing defects in patients with primary immunodeficiencies (PIDs) by next generation sequencing. Materials and Methods: The study included 12 PID patients without genetic diagnosis. We performed whole exome sequencing for the investigation of genetic defects and Sanger sequencing for variant validation.Results: We found seven different disease-causing mutations in 6 patients with a diagnosis rate of 50%. There were three known pathogenic variants in CYBA, SBDS and RAG2 genes. We identified two additional new causative variants in NCF2 and SBDS genes and two novel mutations in PGM3 and SAMD9L genes.Conclusion: The result revealed that NGS-based methods especially whole exome sequencing can be used efficiently for genetic diagnosis of primary immunodeficiency diseases.

Primary Immunodeficiencies in India: Molecular Diagnosis and the Role of Next-Generation Sequencing.

Primary immunodeficiency diseases (PIDs) are a group of clinically and genetically heterogeneous disorders showing ethnic and geographic diversities. Next-generation sequencing (NGS) is a comprehensive tool to diagnose PID. Although PID is common in India, data on the genetic spectrum of PIDs are limited due to financial restrictions. The study aims to characterize the clinical and genetic spectrum of PID patients in India and highlight the importance of a cost-effective targeted gene panel sequencing approach for PID in a resource-limited setting. The study includes 229 patients with clinical and laboratory features suggestive of PIDs. Mutation analysis was done by Sanger sequencing and NGS targeting a customized panel of genes. Pathogenic variants were identified in 97 patients involving 42 different genes with BTK and IL12RB1 being the most common mutated genes. Autosomal recessive and X-linked recessive inheritance were seen in 51.6% and 23.7% of patients. Mendelian susceptibility to mycobacterial diseases (MSMD) and IL12RB1 mutations was more common in our population compared to the Western world and the Middle East. Two patients with hypomorphic RAG1 mutations and one female with skewed CYBB mutation were also identified. Another 40 patients had variants classified as variants of uncertain significance (VUS). The study shows that targeted NGS is an effective diagnostic strategy for PIDs in countries with limited diagnostic resources. Molecular diagnosis of PID helps in genetic counseling and to make therapeutic decisions including the need for a stem cell transplantation.

Self-reported cognitive impairment in individuals with Primary Immunodeficiency Disease

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.

Newborn Screening for SCID and Other Severe Primary Immunodeficiency in the Polish-German Transborder Area: Experience From the First 14 Months of Collaboration.

In 2017, in the Polish-German transborder area of West Pomerania, Mecklenburg-Western Pomerania, and Brandenburg, in collaboration with two centers in Warsaw, a partnership in the field of newborn screening (NBS) for severe primary immunodeficiency diseases (PID), mainly severe combined immunodeficiency (SCID), was initiated. SCID, but also some other severe PID, is a group of disorders characterized by the absence of T and/or B and NK cells. Affected infants are susceptible to life-threatening infections, but early detection gives a chance for effective treatment. The prevalence of SCID in the Polish and German populations is unknown but can be comparable to other countries (1:50,000–100,000). SCID NBS tests are based on real-time polymerase chain reaction (qPCR) and the measurement of a number of T cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and beta-actin (ACTB) as a quality marker of DNA. This method can also be effective in NBS for other severe PID with T- and/or B-cell lymphopenia, including combined immunodeficiency (CID) or agammaglobulinemia. During the 14 months of collaboration, 44,287 newborns were screened according to the ImmunoIVD protocol. Within 65 positive samples, seven were classified to immediate recall and 58 requested a second sample. Examination of the 58 second samples resulted in recalling one newborn. Confirmatory tests included immunophenotyping of lymphocyte subsets with extension to TCR repertoire, lymphoproliferation tests, radiosensitivity tests, maternal engraftment assays, and molecular tests. Final diagnosis included: one case of T-BlowNK+ SCID, one case of atypical Tlow BlowNK+ CID, one case of autosomal recessive agammaglobulinemia, and one case of Nijmegen breakage syndrome. Among four other positive results, three infants presented with T- and/or B-cell lymphopenia due to either the mother's immunosuppression, prematurity, or unknown reasons, which resolved or almost normalized in the first months of life. One newborn was classified as truly false positive. The overall positive predictive value (PPV) for the diagnosis of severe PID was 50.0%. This is the first population screening study that allowed identification of newborns with T and/or B immunodeficiency in Central and Eastern Europe.

Nocardiosis Associated with Primary Immunodeficiencies (Nocar-DIP): an International Retrospective Study and Literature Review.

Nocardiosis is a life-threatening infectious disease. We aimed at describing nocardiosis in patients with primary immunodeficiency diseases (PID). This international retrospective cohort included patients with PID and nocardiosis diagnosed and/or published from Jan 1, 2000, to Dec 31, 2016. To identify nocardiosis cases, we analyzed PID databases from the French National Reference Center for PID (Paris, France) and the National Institute of Health (NIH, United States of America) and we performed a literature review on PubMed. Forty-nine cases of nocardiosis associated with PID were included: median age at diagnosis of nocardiosis was 19 (0-56)years and most cases were observed among chronic granulomatous disease (CGD) patients (87.8%). Median time from symptoms to diagnosis of Nocardia infection was 20 (2-257)days. Most frequent clinical nocardiosis presentation was pneumonia (86.7%). Twelve-month mortality rate was 4.2%, and 11.9% of patients experienced a possible recurrence of infection. Nocardiosis more frequently led to the diagnosis of PID among non-CGD patients than in CGD patients. Non-CGD patients experienced more cerebral nocardiosis and more disseminated infections, but mortality and recurrence rates were similar. Highest incidences of nocardiosis among PID cohorts were observed among CGD patients (0.0057 and 0.0044 cases/patient-year in the USA and in France, respectively), followed by IL-12p40 deficiency. Among 49 cases of nocardiosis associated with PID, most patients had CGD and lung involvement. Both mortality and recurrence rates were low.

Establishing Simultaneous T Cell Receptor Excision Circles (TREC) and K-Deleting Recombination Excision Circles (KREC) Quantification Assays and Laboratory Reference Intervals in Healthy Individuals of Different Age Groups in Hong Kong.

The clinical experience gathered throughout the years has raised awareness of primary immunodeficiency diseases (PIDD). T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) assays for thymic and bone marrow outputs measurement have been widely implemented in newborn screening (NBS) programs for Severe Combined Immunodeficiency. The potential applications of combined TREC and KREC assay in PIDD diagnosis and immune reconstitution monitoring in non-neonatal patients have been suggested. Given that ethnicity, gender, and age can contribute to variations in immunity, defining the reference intervals of TREC and KREC levels in the local population is crucial for setting up cut-offs for PIDD diagnosis. In this retrospective study, 479 healthy Chinese sibling donors (240 males and 239 females; age range: 1 month−74 years) from Hong Kong were tested for TREC and KREC levels using a simultaneous quantitative real-time PCR assay. Age-specific 5th–95th percentile reference intervals of TREC and KREC levels (expressed in copies per μL blood and copies per 106 cells) were established in both pediatric and adult age groups. Significant inverse correlations between age and both TREC and KREC levels were observed in the pediatric age group. A significant higher KREC level was observed in females than males after 9–12 years of age but not for TREC. Low TREC or KREC levels were detected in patients diagnosed with mild or severe PIDD. This assay with the established local reference intervals would allow accurate diagnosis of PIDD, and potentially monitoring immune reconstitution following haematopoietic stem cell transplantation or highly active anti-retroviral therapy in the future.