Diagnosis Of Primary Immunodeficiencies Research Articles

Primary immunodeficiency as a cause of immune-mediated kidney diseases.

Primary immunodeficiency (PID) is no longer defined by infections alone, and autoimmunity is an accompanying manifestation of PID. Recurrent infections may trigger autoimmunity through molecular mimicry, bystander activation, or superantigens. The diagnosis of PID is still challenging, but genetic analysis reveals the underlying link between PID and autoimmunity. Mutations in relevant genes affecting central and peripheral immune tolerance, regulatory T-cell function, expansion of autoreactive lymphocytes, antigen clearance, hyperactivation of type I interferon, and NF-κB pathways have all been implicated in triggering autoimmunity in PID. Autoimmunity in PID leads to chronic inflammation, tissue damage, and organ failure and increases the mortality of patients with PID. The kidneys are inextricably linked with the immune system, and kidney diseases can be mediated by both infection and autoimmunity/inflammation in PID patients. The manifestations of kidney involvement in PID patients are very heterogeneous and include lupus nephritis, C3 glomerulopathy, kidney thrombotic microangiopathy, vasculitis, and interstitial nephritis.Patients with PID-caused kidney diseases have defined immune function defects and may benefit from pathway-based biologics, stem cell transplantation, or gene therapy. Early diagnosis and appropriate treatment of PID are crucial for reducing the mortality rate and improving organ function and quality of life.

Inborn errors of immunity: features of epidemiology and continuity of medical care in the Republic of Tatarstan

BACKGROUND: Currently, inborn errors of immunity represent one of the most interesting problems in clinical immunology. The data obtained in the field of studying pathogenetic mechanisms and clinical manifestations, expanding diagnostic capabilities, including molecular genetic methods, formed the basis for revising the classification and introducing new modern treatment methods. The study of regional characteristics of inborn errors of immunity is important because it allows us to determine epidemiological indicators, clinical features of diseases and evaluate the therapy being carried out.
 AIM: To assess the effectiveness and level of continuity of medical care in the Republic of Tatarstan based on an epidemiological analysis of a group of patients diagnosed with primary immunodeficiency.
 MATERIALS AND METHODS: analysis of the register of patients living in the Republic of Tatarstan with an established diagnosis of primary immunodeficiency, observed from 1994 to 2023. A total of 240 patients were included in the study.
 RESULTS: An epidemiological analysis of inborn errors of immunity in the Republic of Tatarstan revealed an overall prevalence of 6.0 per 100,000 population, with the status "alive" ― 4.98 per 100,000 population, excluding patients with selective IgA deficiency ― 5.3 and 4.4 per 100,000 population, respectively, with a high proportion of patients over 18 years of age (53%), with the largest group of patients having defects in antibody production (42%).
 CONCLUSION: The increasing relevance of the problem of primary immunodeficiency requires special attention to the organization of medical care for patients with primary immunodeficiency, increasing continuity between specialized pediatric services and the adult network, as well as developing issues of interdisciplinary interaction.

Disseminated nocardiosis and anti-GM-CSF antibodies.

Infections that are unusually severe or caused by opportunistic pathogens are a hallmark of primary immunodeficiency (PID). Anti-cytokine autoantibodies (ACA) are an emerging cause of acquired immunodeficiency mimicking PID. Nocardia spp. are Gram-positive bacteria generally inducing disseminated infections in immunocompromised patients, but seldom also occurring in apparently immunocompetent hosts. Anti-GM-CSF autoantibodies are associated with autoimmune pulmonary alveolar proteinosis (PAP). In those patients, an increased incidence of disseminated nocardiosis and cryptococcosis has been observed. It is unclear whether the PAP or the autoantibodies predispose to the infection. We report an apparently immunocompetent woman presenting with disseminated nocardiosis without any evidence of PAP. Clinical data and radiological images were retrospectively collected. Lymphocyte populations were analyzed by flow cytometry. Anti-GM-CSF autoantibodies were measured by ELISA. A 55-year-old otherwise healthy woman presented with cerebral and pulmonary abscesses. Personal and familial history of infections or autoimmunity were negative. After extensive examinations, a final diagnosis of disseminated nocardiosis was made. Immunologic investigations including neutrophilic function and IFN-γ/IL-12 circuitry failed to identify a PID. Whole-exome sequencing did not find pathogenic variants associated with immunodeficiency. Serum anti-GM-CSF autoantibodies were positive. There were no clinical or instrumental signs of PAP. Trimethoprim-sulfamethoxazole and imipenem were administered, with progressive improvement and recovery of the infectious complication. We identified anti-GM-CSF autoantibodies as the cause of disseminated nocardiosis in a previously healthy and apparently immunocompetent adult. This case emphasizes the importance of including ACA in the differential diagnosis of PID, especially in previously healthy adults. Importantly, anti-GM-CSF autoantibodies can present with disseminated nocardiosis without PAP.

Very high immunoglobulin E levels in children: when from pediatrician to immunologist?

Total serum immunoglobulin E (IgE) is increased in many situations such as allergic diseases, primary immunodeficiencies (PID), parasitosis, infections and malignancies. When IgE levels are >1000 kU/L PIDs are suspected by pediatricians. We tried to define some clinical and laboratory parameters to distinguish PID from the others. We evaluated 158 children between 1.7-17 years (mean: 6.6±3.4) for allergic diseases, PID, parasitosis and others. Total IgE, specific IgE, immunoglobulin levels and skin prick tests were performed to all patients. Parasite investigations, viral serological tests and detailed immunologic tests were analyzed in only patients who had suspected complaints. Hyper IgE syndrome (HIES) scoring sheet was filled out for all patients. Among all patients, 114 were diagnosed as bronchial asthma, allergic rhino-conjunctivitis or atopic dermatitis. PID diagnosis was established in totally 32 patients. Immunological evaluations were normal in 126 patients. Eleven patients were accepted as parasitosis. Median HIES score was 18 (5-44 points). Pediatricians may use HIES scoring sheet when they suspect a patient with PID. If the patient has very low points, they may follow the patient. If there are about 18-20 points, they should get an opinion from an immunologist for detailed immunologic tests.

Evaluation of the Effectiveness of the 6 Warning Signs of the European Society for Immunodeficiencies for Primary Immunodeficiencies in Older Adults

Introduction: Diagnostic delay in cases of primary immunodeficiency (PID) is a significant problem for clinicians, and most do not have sufficient awareness of this uncommon disorder. The European Society for Immunodeficiencies (ESID) has developed 6 warning signs to increase awareness of adult PIDs. The aim of this study was to determine the prevalence of PID in older adults regardless of the reason for presentation and to evaluate the effectiveness of the 6 warning signs of ESID in the diagnosis of PIDs. Methods: The study included 1,331 patients aged ≥65 years who presented at our clinic for any reason and were questioned about the ESID 6 warning signs for PIDs. After the exclusion of reasons for secondary immunodeficiency (SID), all the patients underwent immunological evaluation for the diagnosis of potential underlying PIDs. Results: After excluding 6 patients diagnosed with SID, PID was diagnosed in 16 (1.2%) of 1,325 older adults using ESID warning signs. The most common reasons for presentation were infection (69%) in the PID group and urticaria and/or angioedema (41.5%) in the non-PID group. The most common PID subgroup was common variable immunodeficiency (50%). In 12 of the patients diagnosed with PID, there was at least 1 positive ESID warning sign. In 4 patients, PID was determined despite negative ESID warning signs. The patients diagnosed with PID showed a significant, minimal level of agreement with questions 1 and 4 of the ESID warning signs (p < 0.001, ĸ = 0.204, p = 0.005, ĸ = 0.208, respectively). Conclusion: The ESID warning signs do not encompass all the symptoms and findings of PIDs. There is a need for more infection-centered questions to determine PIDs in older adults. Therefore, the ESID warning signs should be further developed.

MAURIVAX: A Vaccination Campaign Project in a Hospital Environment for Patients Affected by Autoimmune Diseases and Adult Primary Immunodeficiencies.

Background: Patients with autoimmune diseases (ADs) and primary immunodeficiencies (PIDs) are characterized by an increased risk of noninvasive and widespread infections as they are considered frail patients. In addition, many flares of the underlying disease are reported after routine vaccinations. To date, the vaccination rate in these two populations is suboptimal. According to the latest guidelines, targeted interventions are needed, such as strengthening the network of vaccination activities. Our project aimed to propose a pilot network for carrying out the recommended vaccinations in frail patients. Methods: The Allergy and Immunology Center of the Mauriziano Hospital in Turin, Italy started the "Maurivax" project, a facilitated pathway for frail patients to administer the recommended vaccinations in the setting of a dedicated structure where they could be properly followed up. Results: From June 2022 to February 2023, 49 patients underwent a vaccination consultation: 45 of them (91.8%) were subsequently vaccinated. Among these, 36 subjects (80%) were affected by an active AD and were already in treatment with immunosuppressive therapy or about to start it. Seven patients (15.5%) had a confirmed diagnosis of PID or showed a clinical presentation that was highly suggestive of that condition. Overall, twenty-seven patients (60%) showed a high-grade immunosuppression and six (13.3%) had a low-grade immunosuppression. No patients had a disease flare within 30 days from vaccination and no severe reactions after vaccination was observed. Conclusions: Adherence and vaccination safety at our immunology hospital vaccine clinic dedicated to patients with ADs and PIDs were high. We propose an effective model for managing vaccinations in frail patients in a specialist hospital setting.

Cutaneous findings in Inborn Errors of Immunity: An immunologist`s perspective.

Cutaneous manifestations are common in patients with inborn errors of immunity (IEI)/primary immunodeficiency (PID) and could be due to infections, immune dysregulation, or lymphoproliferative/malign diseases. Immunologists accept some as warning signs for underlying inborn errors of immunity. Herein, we include noninfectious/infectious cutaneous manifestations that we come across in rare IEI cases in our clinic and provide a comprehensive literature review. For several skin diseases, the diagnosis is challenging and differential diagnosis is necessary. Detailed disease history and examination play a vital role in reaching a diagnosis, especially if there is a potential underlying IEI. A skin biopsy is sometimes necessary, especially if we need to rule out inflammatory, infectious, lymphoproliferative, and malignant conditions. Specific and immunohistochemical stainings are particularly important when diagnosing granuloma, amyloidosis, malignancies, and infections like HHV6, HHV8, HPV, and orf. Elucidation of mechanisms of IEIs has improved our understanding of their relation to cutaneous findings. In challenging cases, the immunological evaluation may lead the approach when there is a specific PID diagnosis or at least help to reduce the number of differential diagnoses. On the other hand, the response to therapy may provide conclusive evidence for some conditions. This review will raise awareness of concomitant lesions and expand the scope of the differential diagnosis of IEI and the spectrum of skin disease therapy by highlighting frequent forms of IEI-associated cutaneous manifestations. The manifestations given here will guide clinicians to plan for alternative use of diverse therapeutics in a multidisciplinary way for skin diseases.

Combined deficient response to polysaccharide-based and protein-based vaccines predicts a severe clinical phenotype.

Antibody response on polysaccharide- and protein-based vaccines is useful to test Bcell functionality. As only few studies have explored the value of studying immune response to both vaccines, we evaluated the clinical value of anti-polysaccharide and anti-protein Luminex-based multiplex assays in context of primary immunodeficiency (PID) diagnosis. A 10-plex Luminex-based assay detecting antibodies to ten pneumococcal polysaccharide (PnPS) serotypes [present in unconjugated Pneumovax, not in 13-valent pneumococcal conjugated vaccine (PCV)] and a 5-plex assay detecting antibodies to five protein antigens (present in DTap/Tdap) were clinically validated in healthy individuals (n=99) and in retrospective (n=399) and prospective (n=108) patient cohorts. Clinical features of individuals with impaired response to PnPS and/or proteins were compared to those with normal response. Antigen-specific antibody thresholds were determined in healthy individuals. Individuals with impaired anti-PnPS responses and deficient immunoglobulin levels suffered more from autoimmune diseases and had lower Bcell levels compared to individuals with impaired anti-PnPS response with normal immunoglobulin levels. Individuals with combined impaired response to PnPS and proteins showed more severe clinical manifestations compared to individuals with isolated impaired response to PnPS or proteins. Eight of the 11 individuals with severely impaired responses to both PnPS and proteins had common variable immunodeficiency. Evaluation of the anti-PnPS response to four serotypes not contained in 20-valent PCV was comparable to evaluation to ten serotypes not contained in 13-valent PCV. Multiplexed assessment of anti-PnPS and anti-protein responses combined with immunoglobulin quantification provides useful clinical information to support PID diagnosis.

T cell exocytosis testing provides superior sensitivity for the diagnosis of familial HLH

The rapid diagnosis of primary immunodeficiencies (PID) affecting cytotoxic lymphocyte granule exocytosis is commonly performed by evaluating NK cell surface CD107a expression after K562 challenge. NK cell exocytosis can also be induced by stimulating NK cells with P815 and anti-CD16 antibody. We have previously described how these NK tests can be adapted to study cytotoxic T cell CD107a exocytosis by gating CD3+CD8 +CD57+ cells after TCR engagement with P815 and anti-CD3 antibody. Here we present data comparing 92 patients with variants in genes affecting exocytosis function against 58 other PID patients diagnosed over 10 years from one center. NK and cytotoxic T cell exocytosis was tested on all patient samples. The anti-CD3T cell test returns superior sensitivity and specificity of 97.8% and 94.7% while the K562 NK test a sensitivity of 86.7% and specificity of 96.1%. The anti-CD 16 NK test was found comparable to the T cell test with values of 97.8% and 93.4%. The data was additionally juxtaposed against 63 patients with secondary HLH, 198 healthy adult donors, and 84 transport controls, all giving similar results of high accuracy. We further stratified the data by time taken between venipuncture and arrival at the testing laboratory and found that control samples up to 36 hours old showed comparable function to < 24 hours old samples. This is important as transporting samples from remote primary care centers often cannot be accomplished within 24 hours.While all three exocytosis tests return superior diagnostic sensitivity, we find the anti-CD3 antibody induced exocytosis of T cells and the anti-CD16 antibody induced exocytosis of NK cells more accurate than the current standard K562 cell stimulation for the diagnosis of PIDs affecting cytotoxic lymphocyte exocytosis. Evaluating T cells alongside NK cells acts as a confirmatory test and buffers against technical failures and the lack of NK cells which can be seen in lymphopenic patients. These assays with improved sensitivity may help us better understand PIDs that partially impair exocytosis.

Screening diagnosis of primary immunodeficiencies in the practice of an allergist-immunologist

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Flow-cytometry as an auxiliary in the diagnosis of primary humoral immunodeficiencies.

Antibody deficiencies encompass a wide spectrum of pathologies and constitute approximately 50 % of primary immunodeficiencies; with cytometry, it is possible to evaluate the immune status rapidly, effectively and at low cost. To assess, by means of flow cytometry, the cells of patients with three types of primary humoral immunodeficiencies. Using flow cytometry, blood samples from patients and healthy subjects were analyzed with different monoclonal antibodies. Using various stains, a severe decrease in B lymphocytes was shown in patients with X-linked agammaglobulinemia, as well as a lack of CD154 expression in patients with hyper-immunoglobulin M syndrome, and heterogeneity of B lymphocyte subpopulations in patients with common variable immunodeficiency. Flow cytometry enables early diagnosis of primary immunodeficiencies with a high level of confidence and, in many cases, identification of the genes involved.

An emerging new respiratory pathogen, Lophomonas blattarum, found in bronchoalveolar lavage in an immunodeficient patient with asthma

Infections with unusual organisms are frequently found in patients with primary and acquired immunodeficiency. It is estimated that 1 in 1200 individuals in the United States have a diagnosis of primary immunodeficiency, with common variable immunodeficiency (CVID) accounting for approximately 35% of the cases. 1 Boyle JM Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol. 2007; 27: 497-502 Crossref PubMed Scopus (317) Google Scholar CVID is a heterogeneous disorder that is primarily a defect of the humoral immune system, although approximately 50% of patients have T cell defects as well. Patients with CVID have increased susceptibility to infections, particularly of the upper and lower respiratory tract, and increased incidence of autoimmune diseases and neoplasms. 2 Bonilla FA Kahn DA Ballas ZK Chinen J Frank MM Hsu JT et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015; 136 (1186-1205.e1-e78) Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar Common pathogens causing respiratory tract infections in CVID include Streptococcus pneumoniae, Haemophilus influenza, and Staphylococcus aureus.2 Bonilla FA Kahn DA Ballas ZK Chinen J Frank MM Hsu JT et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015; 136 (1186-1205.e1-e78) Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar Although parasitic infections can occur, the most often described is Giardia infection of the gastrointestinal tract. 2 Bonilla FA Kahn DA Ballas ZK Chinen J Frank MM Hsu JT et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015; 136 (1186-1205.e1-e78) Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar Infections with other parasites particularly of the respiratory tract have rarely been described. Lophomonas blattarum is a flagellated protozoa found in the gut of cockroaches and termites which has been found to cause rare bronchopulmonary infections, although there are no published cases in the United States to date. 3 Martinez-Girón R Cornelis van Woerden H. Lophomonas blattarum and bronchopulmonary disease. J Med Microbiol. 2013; 62: 1641-1648 Crossref Scopus (35) Google Scholar ,4 Chaudhury A Parija SC. Lophomonas blattarum: a new flagellate causing respiratory tract infections. Trop Parasitol. 2020; 10: 7-11 Google Scholar The most often reported symptoms of L blattarum infection are fever and productive cough. The infection is usually responsive to treatment with metronidazole. 3 Martinez-Girón R Cornelis van Woerden H. Lophomonas blattarum and bronchopulmonary disease. J Med Microbiol. 2013; 62: 1641-1648 Crossref Scopus (35) Google Scholar ,4 Chaudhury A Parija SC. Lophomonas blattarum: a new flagellate causing respiratory tract infections. Trop Parasitol. 2020; 10: 7-11 Google Scholar

Treatment of lymphoid malignancies in patients with primary immunodeficiencies associated with DNA repair defects

Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia (AT; Louis–Bar syndrome) are primary immunodeficiencies (PID) associated with chromosome instability and DNA repair defects that predispose individuals to an increased risk of various malignancies. In our study, we retrospectively analyzed clinical characteristics and outcomes of 28 cancer cases in 14 patients with AT and 10 patients with NBS who had been treated at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology between January 2007 and December 2022. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The most common type of malignancy was mature B-cell non-Hodgkin lymphoma (B-NHL) (42%), with diffuse large B-cell lymphoma (DLBCL) accounting for 91% of all B-NHL cases. Other cases included T-cell acute lymphoblastic leukemia (ALL) (n = 3), B-cell ALL (n = 2), Hodgkin lymphoma (n = 3), NK/T-cell lymphoma (n = 1), T-cell lymphoblastic lymphoma (n = 1), peripheral T- cell lymphoma (n = 2), medulloblastoma (n = 1) epithelioid rhabdomyosarcoma (n = 1), T-cell prolymphocytic leukemia (n = 2). A total of 4 patients were diagnosed with second malignancies (2 children with AT and 2 children with NBS. The diagnosis of PID was suspected or confirmed before the initiation of cancer therapy in 62% of AT patients and in 100% of NBS patients. Treatment was given in accordance with standard protocols with chemotherapy dose modifications. A total of 93% of patients with AT and 80% of patients with NBS required dose reduction. The level of response was quite high: 81% of patients with AT and 58% of patients with NBS achieved complete remission. According to our data, the use of reduced-dose chemotherapy regimens helps to achieve an acceptable toxicity profile without reducing the overall effectiveness of treatment.

The examination of family functioning in immunodeficiency patients in the context of McMaster family therapy in Turkey

ABSTRACT Immunodeficiency diseases associated with the absence or dysfunction of any of the components that make up the immune system. These diseases may create difficulties for family functionality. The study aims to examine family functionality in the context of McMaster Family Therapy in families with immunodeficiency patients. The study include 153 family members from Immunodeficiency Patients Solidarity Platform in Turkey. The sociodemographic questionnaire and McMaster Family Assessment Device were used to collect data with respect to problem solving, communication, roles, affective responsiveness and involvement, behaviour control, and general functioning. The majority of the participants are married, females, university graduates and low income. Most of them have nuclear families and a diagnosis of primary immunodeficiency in children. Areas of non-healthy family functionality include affective involvement and behaviour control. Also, problem-solving, roles, and communication create risks in terms of dysfunction.

Autoinflammatory undifferentiated syndrome

Identification of primary immunodeficiencies (PID), distinction of their nosological forms and timely admoinistered therapy for this disorders frepresent topical problems of modern immunology. According to the PID registry of the National Association of Experts in the Field of Primary Immunodeficiencies (NAEPID), as of 2021, 3617 cases of this disease were diagnosed in Russian Federation (RF). The prevalence of PID in Russian Federation is 2.48 per 100,000 population. Currently, autoinflammatory syndromes (AIS) comprise rare, genetically determined disorders. According to the NAEPID registry data, of the PID register, 541 cases of autoinflammatory syndrome (AIS) were registered in the Russian Federation (2021). Timely diagnosis of AIS is especially important in young children who have similar phenotypic signs, in order to reduce the number of deaths and prevent disability. According to the PID registry, the median diagnostic delay in Russia is 27 months. The purpose of this work is to update information about the autoinflammatory syndrome that clinicians may encounter, e.g., pediatricians, rheumatologists, hematologists and other specialists. This syndrome requires a complex differential diagnostic algorithm for clinicians and is often subject to multidisciplinary approach, involving specialists of different profile. This article describes a clinical case of a 3-year-old child S. with a diagnosis of Primary immunodeficiency: autoinflammatory syndrome, undifferentiated. The patient was diagnosed since the age of 5 months, when periodic rises in body temperature to febrile values were registered once a month. Later on, the fever episodes were observed 2 times a month. The diagnosis was made at the place of residence as secondary immunodeficiency virus-associated state (CMV infection). CMV viremia was canceled against the background of ongoing treatment, but the inflammatory attacks persisted. Molecular genetic studies did not reveal any defects. In view of poor response to NSAID therapy and prednisone prescribed at a dose of 1-1.5 mg/kg/day, he was admitted to the Dmitry Rogachev Research Medical Cemter. The child was finally diagnosed with PID, and therapy was initiated with a selective competitive inhibitor of TNFa etanercept at a dose of 0.8 mg/kg/day once a week. Hence, the autoinflammatory syndrome in children is difficult to diagnose and select therapy, and it may be unfavorable prognostically.

Physician awareness and understanding of primary immunodeficiency disorders: a web-based study in Japan

Primary immunodeficiencies (PIDs)/Inborn errors of immunity (IEI) consist of a complex genetic group of disorders that cause susceptibility to infections, inflammation, immune dysregulation, autoimmunity, and malignancy. One of the key steps to reach an early diagnosis is improving knowledge of PID among the medical community. In this study, a web-based survey was conducted among 355 Japanese physicians, consisting of 121 pediatricians, 116 hematologists, and 118 general internal medicine physicians, to assess their awareness and knowledge about the diagnostic flow of PID. One of the major problems this study identified was the unawareness of optimal IgG trough levels among the physicians, while around half the physicians knew about the symptoms of PID. Results from the hypothetical case study revealed that over 70% of physicians considered PID after obtaining the past medical history of patients and 75.2% of physicians showed interest in gaining more knowledge about PID. The survey findings revealed that proper questioning to understand the exact medical history of patients may lead to basic immunological examination. There is a need to improve knowledge about PID, e.g., the ‘10 warning signs of PID’ and ‘4 stages of testing for PID’, and to motivate physicians to ensure earlier diagnosis of PID.

A validated artificial intelligence-based pipeline for population-wide primary immunodeficiency screening

Identification of patients with underlying inborn errors of immunity and inherent susceptibility to infection remains challenging. The ensuing protracted diagnostic odyssey for such patients often results in greater morbidity and suboptimal outcomes, underscoring a need to develop systematic methods for improving diagnostic rates. The principal aim of this study is to build and validate a generalizable analytical pipeline for population-wide detection of infection susceptibility and risk of primary immunodeficiency. This prospective, longitudinal cohort study coupled weighted rules with a machine learning classifier for risk stratification. Claims data were analyzed from a diverse population (n= 427,110) iteratively over 30 months. Cohort outcomes were enumerated for new diagnoses, hospitalizations, and acute care visits. This study followed TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) standards. Cohort members initially identified as high risk were proportionally more likely to receive a diagnosis of primary immunodeficiency compared to those at low-medium risk or those without claims of interest respectively (9% vs 1.5% vs 0.2%; P< .001, chi-square test). Subsequent machine learning stratification enabled an annualized individual snapshot of complexity for triaging referrals. This study's top-performing machine learning model for visit-level prediction used a single dense layer neural network architecture (area under the receiver-operator characteristic curve= 0.98; F1 score= 0.98). A 2-step analytical pipeline can facilitate identification of individuals with primary immunodeficiency and accurately quantify clinical risk.

Role of innate errors of immunity in the group of children with fatal outcomes during the first year of life

In the modern world, inborn errors of immunity (IEIs), or primary immunodeficiencies (PIDs), are among of the main causes of childhood disability and mortality, determining the demographic state of mankind not only at present, but also in the future. In the Sverdlovsk Region over the past 5 years, there were about 30% of children who died from severe combined primary immunodeficiency. This retrospective study is devoted to the study of the nosological profile of mortality in the children with immune-dependent disorders in the Sverdlovsk Region, as well as to assess information significance of extrachromosomal circular DNA molecules (TREC and KREC) analysis. Some anamnestic data on the course of prenatal period in the current and previous pregnancies were considered the signs of suggested diagnosis of primary immunodeficiencies, i.e., threats of pregnancy loss at the early terms, documented cases of early childhood death, persistent viral and bacterial infections in the mother, complicated course of pregnancy in the mother, as well as some clinical manifestations, including fungal-bacterial sepsis, generalized viral infection, repair disorders, reduced physiological tolerance accompanied by autoimmune organ damage and uncontrolled systemic inflammation. The study demonstrated a wide range of nosological entities of innate errors of immunity in the structure of early childhood mortality, including both classical forms of primary immunodeficiencies and the disorders not directly related to innate errors of immunity, but those showing phenotypically pronounced immunodeficiency and their immediate role in statistical deviations. Among the main criteria that may presume possible presence of an immune-dependent pathology in the early neonatal period we considered the molecular markers of naive T and B cells (TREC and KREC, respectively) revealed in 70% of the cases studied, with, at least, one of these indexes found to be reduced. It is important to understand that primary immunodeficiencies are not as rare as previously thought. Therefore, it is necessary to carry out timely and high-quality diagnostics, in order to avoid unavoidable deaths.

Missed Opportunities? A Retrospective Study Into Adults Hospitalized With Invasive Infection From Airway Pathogens.

BackgroundInvasive disease caused by airway pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Moraxella catarrhalis, has high morbidity and mortality worldwide, with immunodeficiency being a known association with recurrent disease. The study aimed to describe the frequency of known immunodeficiency and predisposing factors in adult patients presenting with invasive infections and determine the frequency of screening for and detection of immunodeficiency.MethodsA retrospective analysis was conducted at a large tertiary Australian health service, comprising multiple centers. Patients aged 18 years or older, in whom the above pathogens were isolated from sterile sites, were included as identified through a microbiology database, between 2015 and 2020. Using electronic medical records, patient demographics, medical history, outcomes of admission, and pathology results were captured and reviewed to address the aims.ResultsIn 252 patients, S pneumoniae was the most common culprit, isolated in 73% (185/252), compared to 14.3% (36/252) and 11.5% (29/252) of infections caused by H influenzae and N meningitidis, respectively. Known diagnoses of secondary immunodeficiency were common (31% of patients). Of those presenting with invasive pneumococcal disease, 78% had at least 1 predisposing condition, though only 9 patients (6%) had previously received pneumococcal vaccination. Despite poor screening for immunodeficiency, 12 new diagnoses were made. While the commonest immunodeficiency was secondary, due to hematological and solid organ malignancies, 3 new primary immunodeficiency diagnoses were made.ConclusionsImmunodeficiency is common in this patient population. Screening should be undertaken to ensure timely diagnosis and treatment of the underlying condition to avoid future morbidity and mortality.

Antimycobacterial prophylaxis regarding Bacillus Calmette-Guérin -associated complications in children with primary immunodeficiency

ObjectiveBacillus Calmette-Guérin (BCG) vaccine derived from Mycobacterium bovis can cause BCG vaccine associated complications (BCG-VAC) especially in patients with primary immunodeficiencies (PID). No consensus exists for antimycobacterial prophylactic therapy for patients with PID who receive the BCG vaccine. AimThis study aimed to define the risk factors in the development of BCG-VAC and effect of antimycobacterial prophylaxis in PID patients vaccinated with BCG. MethodsThis is a retrospective cohort study. 104 patients diagnosed with PID who received the BCG vaccination were referred to pediatric pulmonology in a single center were enrolled. The demographic characteristics, type, dosage and duration of antimycobacterial prophylaxis regimen, treatment modalities for BCG-VAC were documented. Regression analysis was performed to evaluate the effect of covariates for predicting BCG-VAC in patients with PIDs. ResultsAmong 104 patients 21 (21.2%) developed BCG-VAC. The frequency of BCG-VAC was highest in patients with Mendelian susceptibility to mycobacterial disease (46.2%) followed by patients with severe combined immunodeficiency (22.4%) and those with chronic granulomatous disease (9.5%). Prophylactic therapy against mycobacterium was initiated for 72 patients (69.2%). Among patients who received the antimycobacterial prophylaxis, BCG-VAC developed in only four patients (5.6%), whereas 17 patients (53.1%) developed BCG-VAC in the non-prophylaxis group and this difference was statistically significant (p < 0.001). Multivariable regression analysis with age at diagnosis, type of PID, receiving antimycobacterial prophylaxis, median T cell number at the time of PID diagnosis and HSCT status showed that not receiving antimycobacterial prophylaxis and lower median T cell number were predictors, with antimycobacterial prophylaxis having the highest odds ratio for BCG-VAC prediction in patients with PIDs (p:<0.001, R2:0.64). ConclusionThe lower frequency of BCG-VAC in our cohort can be explained by two main reasons; relatively late BCG vaccination schedule and receiving antimycobacterial prophylaxis.It is reasonable to begin antimycobacterial prophylaxis in patients with PIDs who are susceptible to BCG-VAC.