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The European internet-based patient and research database for primary immunodeficiencies: results 2006–2008
Abstract
Primary immunodeficiencies (PID) are rare diseases; therefore transnational studies are essential to maximize the scientific outcome and to improve diagnosis and therapy. In order to estimate the prevalence of PID in Europe as well as to establish and evaluate harmonized guidelines for the diagnosis and treatment of PID, the European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This database is a platform for epidemiological analyses as well as the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. Within 4 years, 7430 patients from 39 countries have been documented in the ESID database. Common variable immunodeficiency (CVID) represents the most common entity, with 1540 patients or 20.7% of all entries, followed by isolated immunoglobulin (Ig)G subclass deficiency (546 patients, 7.4%). Evaluations show that the average life expectancy for PID patients varies from 1 to 49 years (median), depending on the type of PID. The prevalence and incidence of PID remains a key question to be answered. As the registration progress is far from finished we can only calculate minimum values for PID, with e.g. France currently showing a minimum prevalence of 3.72 patients per 100,000 inhabitants. The most frequently documented permanent treatment is immunoglobulin replacement; 2819 patients (42% of all patients alive) currently receive this form of treatment.
... The majority of IEI patients suffer from predominantly antibody deficiencies (PAD), which are generally not immediately life-threatening. PADs can be subdivided into the rare, more severe, agammaglobulinemias and hyper-IgM syndromes, and the less rare hypogammaglobulinemias [2]. The latter may remain undiagnosed for years [2][3][4][5]; however, also these can ultimately lead to important morbidity, irreversible organ damage and reduced lifespan when they are not recognized and adequately treated in time [6][7][8]. ...
... PADs can be subdivided into the rare, more severe, agammaglobulinemias and hyper-IgM syndromes, and the less rare hypogammaglobulinemias [2]. The latter may remain undiagnosed for years [2][3][4][5]; however, also these can ultimately lead to important morbidity, irreversible organ damage and reduced lifespan when they are not recognized and adequately treated in time [6][7][8]. ...
... However, even for CVID, expert opinion varies as to which patients with decreased IgG and disturbed specific antibody responses should be classified under this diagnosis, some considering combination with decreased IgA or decreased IgM sufficient, and others diagnosing CVID only in case IgA is decreased (± decreased IgM) [12]. Many more patients suffer from less-well described and understood forms of hypogammaglobulinemia: decreased total IgG, IgG-subclass(es), IgM, IgA and/or specific antibodies, alone, or in combination(s) [2]. The International Union of Immunological Societies (IUIS) has grouped these cases together in the 'predominantly antibody deficiencies' section as 'isotype/light chain/functional deficiencies' (with a subdivision based on immunological laboratory values; Table 1) [3]; in the European Society for Immunodeficiencies (ESID) Clinical Working Definitions they are divided in separate entities which overlap in part with the IUIS subdivisions (Table 2) [13]. ...
Background
Primary antibody deficiencies (PADs) without an identified monogenetic origin form the largest and most heterogeneous group of primary immunodeficiencies. These patients often remain undiagnosed for years and many present to medical attention in adulthood after several infections risking structural complications. Not much is known about their treatment, comorbidities, or prognosis, nor whether the various immunological forms (decreased total IgG, IgG subclass(es), IgM, IgA, specific antibody responses, alone or in combination(s)) should be considered as separate, clearly definable subgroups. The unclassified primary antibody deficiency (unPAD) study aims to describe in detail all PAD patients without an identified specific monogenetic defect regarding their demographical, clinical, and immunological characteristics at presentation and during follow-up. In constructing these patterns, the unPAD study aims to reduce the number of missed and unidentified PAD patients in the future. In addition, this study will focus on subclassifying unPAD to support the identification of patients at higher risk for infection or immune dysregulation related complications, enabling the development of personalized follow-up and treatment plans.
Methods and analysis
We present a protocol for a multicenter observational cohort study using the ESID online Registry. Patients of all ages who have given informed consent for participation in the ESID online Registry and fulfill the ESID Clinical Working Definitions for ‘unclassified antibody deficiency’, ‘deficiency of specific IgG’, ‘IgA with IgG subclass deficiency’, ‘isolated IgG subclass deficiency’, ‘selective IgM deficiency’, ‘selective IgA deficiency’ or ‘common variable immunodeficiency’ will be included. For all patients, basic characteristics can be registered at first registration and yearly thereafter in level 1 forms. Detailed characteristics of the patients can be registered in level 2 forms. Consecutive follow-up forms can be added indefinitely. To ensure the quality of the collected data, all data will be fully monitored before they are exported from the ESID online Registry for analysis. Outcomes will be the clinical and immunological characteristics of unPAD at presentation and during follow-up. Subgroup analyses will be made based on demographical, clinical and immunological characteristics.
... Complex medical features and the necessity for lifelong and resource-consuming treatments in many patients underscores the importance of qualified epidemiological data in decision making and PID management. Although epidemiological research in this field faces a variety of difficulties due to the novelty of PID and its rarity [5], national and international collaborations help to advance translational research and improve the management and therapeutic strategies [6,7]. ...
... Most of the prevalence estimations have been based on selected populations such as tertiary hospitals, or single-center registries. Reports from several PID registries in different countries show a prevalence of 1:8500 to 1:100000 for symptomatic patients [5,[8][9][10][11][12][13][14]. However, it has been generally accepted that PID is under-diagnosed and under-reported. ...
... equity, freedom of science, social rights, the duty of the society to promote public health), following the principle of proportionality [99]. Comparison with other European countries suggests that on average 5:100000 is a reasonable estimation for the PID prevalence in Europe as a whole [5,10,100,101]. ...
Introduction
During the last 4 decades, registration of patients with primary immunodeficiencies (PID) has played an essential role in different aspects of these diseases worldwide including epidemiological indexes, policymaking, quality controls of care/life, facilitation of genetic studies and clinical trials as well as improving our understanding about the natural history of the disease and the immune system function. However, due to the limitation of sustainable resources supporting these registries, inconsistency in diagnostic criteria and lack of molecular diagnosis as well as difficulties in the documentation and designing any universal platform, the global perspective of these diseases remains unclear.
Areas covered
Published and unpublished studies from January 1981 to June 2020 were systematically reviewed on PubMed, Web of Science and Scopus Additionally, the reference list of all studies was hand-searched for additional studies. The authors summarized currently available experiences from different countries regarding the registration of PID patients to more accurately determine the PID prevalence and emphasize better the current burden of these diseases worldwide. This effort identified a total of 104614 registered patients and suggests identification of at least 10590 additional PID patients, mainly from countries located in Asia and Africa. Molecular defects in genes known to cause PID were identified and reported in 13852 (13.2% of all registered) patients.
Expert opinion
Although these data suggest some progress in the identification and documentation of PID patients during the last 40 years worldwide, achieving the basic requirement for the global PID burden estimation and registration of undiagnosed patients will require more reinforcement of the progress, involving both improved diagnostic facilities and neonatal screening.
... Selective IgA deficiency was the most common type in this class similar to registries in Spain (12) , Latin America (13) , Saudia Arabia (14) and contrary to registries in Ain Shams University (5) , Iran (15) , USA (16) , Europe (17) where CVID was the predominant type. Bruton agammaglobulinemia was the predominant in Chinese children (18) . ...
... The incidence of phagocytic disorders and immune dysregulation was lower than Ain Shams university (12%, 3%) (5) , china (10%,3%) (18) , Europe (12%, 1.3%) (17) . ...
... Results from other studies suggested that PIDs were no longer considered pediatric diseases, which was further convinced by surveys conducted in Europe and USA. It was shown that only 67.71% of the patients were below 20 in Europe (17) and about a quarter (26%) was below 18 in USA (16) . In different countries, average onset ages were mostly under 15 months .In our study the median age was 7 months and 36% of patients were above 3 years. ...
Aim of study: To identify and report various type of primary immunodeficiency disorders in children at Zagazig university hospitals, and their characteristic features, clinical manifestations and laboratory profiles. Patients and methods; patients with history,clinical findings and laboratory findings matching with any of eight classes of primary immunodeficiency were included in this study, also we used ten warning signs,immunodediciency disease related score in evaluation of patients. Results: Fifty patients were diagnosed with different primary immunodeficiency disorders in Pediatric department, Zagazig University Hospital during period from July 2011 to July 2013. The spectrum of PIDs in our center was as follow: predominantly antibody deficiency was the most common category (46%) followed by combined immunodeficiency (22%) then well defined syndromes (20%), auto inflammatory disorders (8%), complement disorders (4%). No cases were diagnosed in any category of phagocytic disorders, innate immunity or immune dysregulation. Selective IgA deficiency was the most frequent disease type. Median age of onset of symptoms was 7 months, the median age of diagnosis lag was 24 months.Pneumonia was the most common presentation. Consanguinity rate was 60%. Mortality rate was 20% mostly duo to bronchopneumonia. Conclusion: primary immunodeficiency disorders are not rare in our center ,but under diagnosed.
... [10] CVID was reported as the commonest antibody deficiency disorder in Europe, representing 21.01% of PIDD cases. [34] Selective IgM deficiency (11.11%) was diagnosed based on age-specific serum Ig levels in this study. In Bangladesh, a study reported 7.14% of cases of SIgMD among PIDD cases, which finding is lower than that of the present study. ...
... times more in males than females in other studies. [34] The present study showed that the predominantly antibody deficiency (55.55%) patients were in around the 6-9 years age group and one patient of SCID was < 12 months of age. These findings are consistent with the study done in Sri Lanka that showed predominantly antibody deficiency disorders were predominant in 5 to < 12 years age group and all SCID patients were in < 12 months of age. ...
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.
... CVID was reported as the commonest antibody deficiency disorder in Europe representing 21.01% of PIDD cases [34]. Selective IgM deficiency (11.11%) was diagnosed based on age specific serum Immunoglobulin levels in this study. ...
... The male to female ratio was 1.25:1 in the confirmed PIDD cases in this study. Since the pattern of inheritance of some primary immunodeficiency diseases is gender related, the overall incidence of PIDDs was reported 1.4 to 2.3 times more in males than females in other studies [34]. ...
Primary immunodeficiency disorders (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-B-NK 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 T cell (CD45RO+), switched memory B cell (CD27 + IgD-) markers, detection of intracellular BTK, LRBA, DOCK8 protein expression and DHR123 (Dihydro-rhodamine 123) assay of neutrophil can increase the PIDD cases detection in Bangladesh.
The study was conducted in the Department of Microbiology and Immunology, Bangabandhu Sheikh Mujib Medical University (BSMMU) during the time period of August, 2021 to July, 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 & 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.
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 deficiency disorders (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 + and IgD- markers, BTK protein expression detection and DHR123 assay. LRBA and DOCK8 deficiency cases could not found in this study.
The use of additional markers (CD45RA, CD45RO, CD27 and 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.
... Ранее считалось, что ПИД встречаются редко, однако, результаты применения современных методов диагностики свидетельствуют, что частота этих состояний существенно недооценивалась. Распространенность ПИД, по-видимому, составляет не менее 1:10 000 рождений (1,4-10,1 на 100 000 новорожденных) [4,5]. Хотя традиционно к основным проявлениям ПИД относятся тяжелые и/или необычно частые эпизоды инфекций, клиника может осложняться развитием аутоиммунных заболева-ний, а также опухолей. ...
... Хотя традиционно к основным проявлениям ПИД относятся тяжелые и/или необычно частые эпизоды инфекций, клиника может осложняться развитием аутоиммунных заболева-ний, а также опухолей. В настоящее время наиболее эффективным способом диагностики наследственных дефектов иммунной системы является молекулярно-генетическое исследование, результаты которого оцениваются в совокупности с данными клинико-лабораторных исследований [5,6,7]. Современные технологии высокопроизводительного секвенирования позволяют одномоментно проанализировать кодирующую последовательность всех известных генов, кодирующих факторы иммунной защиты. ...
Currently, the most effective way to diagnose hereditary defects of the immune system is molecular genetic research, the results of which are evaluated in conjunction with the data of clinical and laboratory studies.
Aims of the sudy: to evaluate the frequency and spectrum of rare genetic variants associated with the development of primary immunodeficiency (PID) in children with recurrent infections.
Materials and methods: DNA samples from 113 children with recurrent infections were analyzed by targeted multigene sequencing of 338 PID-associated genes. Results: Pathogenic variants appropriate to the potential diagnosis of PID were identified in 8% of patients. Interestingly, 47.8% of children had variants associated with auto-inflammatory disorders.
... Predominantly (primary) antibody deficiencies (PADs) are a typical example of such difficult-to-recognize rare diseases [3]. Hypogammaglobulinemias are by far the most common forms of PAD, comprising nearly half of all primary immunodeficiency (PID) diagnoses [4][5][6]. Affected persons commonly develop recurrent otitis media, sinusitis, and pneumonia. Recurrent pneumonias can lead to bronchiectasis, which serves as a negative factor for long-term morbidity and mortality. ...
... The burden of infections was perceived to be susceptible to change. Participants pointed out that they experienced positive as well as negative fluctuations in the burden of infections due to weather conditions: four patients reported being sick throughout the year (1,2,4,8); three patients were almost never ill during the summer (5,6,9). ...
Background
Patients with predominantly (primary) antibody deficiencies (PADs) commonly develop recurrent respiratory infections which can lead to bronchiectasis, long-term morbidity and increased mortality. Recognizing symptoms and making a diagnosis is vital to enable timely treatment. Studies on disease presentation have mainly been conducted using medical files rather than direct contact with PAD patients. Our study aims to analyze how patients appraised their symptoms and which factors were involved in a decision to seek medical care.
Methods
14 PAD-patients (11 women; median 44, range 16-68 years) were analyzed using semi-structured interviews until saturation of key emergent themes was achieved.
Results
Being always ill featured in all participant stories. Often from childhood onwards periods of illness were felt to be too numerous, too bad, too long-lasting, or antibiotics were always needed to get better. Recurrent or persistent respiratory infections were the main triggers for patients to seek care. All participants developed an extreme fatigue, described as a feeling of physical and mental exhaustion and thus an extreme burden on daily life that was not solved by taking rest. Despite this, participants tended to normalize their symptoms and carry on with usual activities. Non-immunologists, as well as patients, misattributed the presenting signs and symptoms to common, self-limiting illnesses or other ‘innocent’ explanations. Participants in a way understood the long diagnostic delay. They know that the disease is rare and that doctors have to cover a broad medical area. But they were more critical about the way the doctors communicate with them. They feel that doctors often don’t listen very well to their patients. The participants’ symptoms as well as the interpretation of these symptoms by their social environment and doctors had a major emotional impact on the participants and a negative influence on their future perspectives.
Conclusions
To timely identify PAD, ‘pattern recognition’ should not only focus on the medical ‘red flags’, but also on less differentiating symptoms, such as ‘being always ill’ and ‘worn out’ and the way patients cope with these problems. And, most important, making time to really listen to the patient remains the key.
... Due to the limited number of registries, inconsistency in diagnostic criteria, different clinical phenotypes, and lack of molecular diagnosis, the global perspective of these diseases remains unclear. Reports from several PID registries in different countries show a prevalence of 1:8500 to 1:100000 for symptomatic patients [44][45][46]. Predominantly B-cell deficiencies encompass the main category of PIDs. Although the exact data about the frequency is lacking, a great number of immune deficiencies are known to be associated with mild or severe neutropenia as a result of close interactions both in their ontogeny and during their functional life of myeloid and lymphoid cells. ...
... Severe combined immunodeficiency (SCID) syndromes are characterized by a block in T lymphocyte differentiation that is variably associated with abnormal development of other lymphocyte lineages (B and/or natural killer [NK] cells), leading to death early in life unless treated urgently by hematopoietic stem cell transplantation. The overall frequency is estimated to 1 in 75 000-100 000 births [44,57]. Reticular dysgenesis, caused by a mutation in the adenylate kinase 2 (AK2) gene is an autosomal recessive disease with granulocytopenia as well as pancytopenia, lack of innate and adaptive immune responses, and sensorineural deafness [1,57]. ...
Phagocytes including neutrophil granulocytes and macrophages are important cells of the innate immune system whose primary function is to ingest and destroy microorganisms. Neutrophils help their host fight infections by phagocytosis, degranulation, and neutrophil extracellular traps. Neutrophils are the most common type of circulating white blood cells and the principal cell type in acute inflammatory reactions. A total absence of neutrophils or a significant decrease in their number leads to severe immunodeficiency that renders patients vulnerable to recurrent infections by Staphylococcus aureus and Gram-negative bacteria being the most life-threatening. Neutropenia may be classified as mild, moderate or severe in terms of numbers in the peripheral blood, and intermittent, cyclic, or chronic in terms of duration. Besides well-known classic severe congenital neutropenia, chronic neutropenia appears to be associated with an increasing number of primary immunodeficiency diseases (PIDs), including those of myeloid and lymphoid lineage. A comprehensive overview of the diverse clinical presenting symptoms, classification, aetiological and genetic etiologies of chronic isolated and syndromic neutropenia is aimed to be reviewed.
... Our study demonstrates a high mortality rate in the Russian PID cohort-as high as 9.8%-as compared with the most recently published German and Swiss registry. Yet it is comparable to the 8.6% (641/7,430) in the previously published ESID registry (18) and the 8% (2,232/27,550) provided by the online ESID reporting website 2 . Significantly, half of reported PID deaths occur within the first 5 years of life. ...
... Comparing this data to other registries-where patients over 18 years old represent up to 55% of all PID (4), 2 (18)we can conclude that adults with PID are the most underdiagnosed category in Russia. This statement is confirmed by the low proportion of PAD defects in the Russian registry (21 vs. 56% in the ESID registry) (9), 2 (18,21). This, in turn, reflects low numbers of patients with CVID, the main PID affecting adults worldwide. ...
Introduction: Primary immunodeficiencies (PID) are a group of rare genetic disorders with a multitude of clinical symptoms. Characterization of epidemiological and clinical data via national registries has proven to be a valuable tool of studying these diseases. Materials and Methods: The Russian PID registry was set up in 2017, by the National Association of Experts in PID (NAEPID). It is a secure, internet-based database that includes detailed clinical, laboratory, and therapeutic data on PID patients of all ages. Results: The registry contained information on 2,728 patients (60% males, 40% females), from all Federal Districts of the Russian Federation. 1,851/2,728 (68%) were alive, 1,426/1,851 (77%) were children and 425/1,851 (23%) were adults. PID was diagnosed before the age of 18 in 2,192 patients (88%). Antibody defects (699; 26%) and syndromic PID (591; 22%) were the most common groups of PID. The minimum overall PID prevalence in the Russian population was 1.3:100,000 people; the estimated PID birth rate is 5.7 per 100,000 live births. The number of newly diagnosed patients per year increased dramatically, reaching the maximum of 331 patients in 2018. The overall mortality rate was 9.8%. Genetic testing has been performed in 1,740 patients and genetic defects were identified in 1,344 of them (77.2%). The median diagnostic delay was 2 years; this varied from 4 months to 11 years, depending on the PID category. The shortest time to diagnosis was noted in the combined PIDs-in WAS, DGS, and CGD. The longest delay was observed in AT, NBS, and in the most prevalent adult PID: HAE and CVID. Of the patients, 1,622 had symptomatic treatment information: 843 (52%) received IG treatment, mainly IVIG (96%), and 414 (25%) patients were treated with biological drugs. HSCT has been performed in 342/2,728 (16%) patients, of whom 67% are currently alive, 17% deceased, and 16% lost to follow-up. Three patients underwent gene therapy for WAS; all are currently alive. Conclusions: Here, we describe our first analysis of the epidemiological features of PID in Russia, allowing us to highlight the main challenges around PID diagnosis and treatment.
... Inborn error of immunity (IEI), historically known as primary immunodeficiency (PID), is a heterogeneous group of disorders caused by genetic defects in the cells of the immune system [1]. It has a prevalence of 1:1200 to 1:25,000 depending on the population being studied [2][3][4][5][6][7][8]. The most common and clinically significant type of PID, which accounts for 50 to 70% of them, is the predominantly antibody deficiency (PAD) [6,9,10]. ...
... Although the subcutaneous route is gaining popularity, the intravenous route of administering IgG is still the most common mode of IgG replacement therapy [7,11]. Intravenous immunoglobulin G (IVIG) replacement doses of 300-800 mg/kg is given every 3-4 weekly at an infusion rate of 0.01-0.08 ...
PurposeWe conducted a systematic review and meta-regression analysis to evaluate the impact of increasing immunoglobulin G (IgG) trough levels on the clinical outcomes in patients with PID receiving intravenous immunoglobulin G (IVIG) treatment.Methods
Systematic search was conducted in PubMed and Cochrane. Other relevant articles were searched by reviewing the references of the reviewed article. All clinical trials with documented IgG trough levels and clinical outcome of interest in patients receiving IVIG treatment were eligible to be included in this review. Meta-regression analysis was conducted using Comprehensive Meta-analysis Software. Additional sensitivity analyses were undertaken to evaluate the robustness of the overall results.ResultsTwenty-eight clinical studies with 1218 patients reported from year 2001 to 2018 were included. The mean IVIG dose used ranges from 387 to 560 mg/kg every 3 to 4 weekly, and mean IgG trough obtained ranges from 660 to 1280 mg/dL. Random-effects meta-regression slope shows that IgG trough level increases significantly by 73 mg/dL with every increase of 100 mg/kg dose of IVIG (p < 0.05). Overall infection rates reduced significantly by 13% with every increment of 100 mg/dL of IgG trough up to 960 mg/dL (p < 0.05).Conclusion
This meta-analysis concludes that titrating the IgG trough levels up to 960 mg/dL progressively reduces the rate of infections, and there is less additional benefit beyond that. Further studies to validate this result are required before it can be used in clinical practice.
... The rates both for all evaluable infections and for the severe or serious infections were more than twice as high in the group with lower IgG trough lev- Figure 2. Serum IgG trough levels (A; g/L; mean + SD) and infection rates (B; mean) in the group with lower IgG trough levels (≤ 5.0 g/L) and in the group with higher IgG trough levels (> 5.0 g/L); rates were calculated using the evaluable treatment periods as illustrated in Figure 1; p-value for group comparison: 0.038 (negative binomial regression model for all infections requiring antimicrobial treatment). The lower margin of reference range for serum IgG in adults is given as 7 g/L [31,32]. els than in the group with higher IgG trough levels (10.3 vs. 4.4 and 2.5 vs. 1.0 infections per 10 patient years) ( Figure 2B). ...
OBJECTIVE: To investigate the association between serum immunoglobulin G (IgG) concentrations and the incidence of infections in patients with chronic lymphocytic leukemia (CLL) and secondary immunodeficiency receiving treatment with Privigen.
MATERIALS AND METHODS: Data was analyzed from a non-interventional study conducted in 31 centers in Germany and 1 in Austria. Adult CLL patients with hypogammaglobulinemia and recurrent infections were allowed to enter the study upon signing informed consent, if a prior decision for treatment with Privigen had been made. All infections requiring an antimicrobial treatment were subject to analysis. Patients were stratified according to their mean post-baseline serum IgG trough levels in a group with lower IgG trough levels (≤ 5.0 g/L), and a group with higher IgG trough levels (> 5.0 g/L).
RESULTS: Overall, 89 patients and 840 treatment cycles were analyzed. Up to 11 treatment cycles (average duration 29 days) were documented in each patient. In the group with higher IgG trough levels (> 5.0 g/L, N = 72), significantly fewer infections were observed than in the group with lower IgG trough levels (≤ 5.0 g/L, N = 17), including fewer severe and serious infections. The Privigen dosage was a major determinant of the post-baseline serum IgG levels. Overall tolerability of Privigen was assessed as very good or good in 91% of patients.
CONCLUSION: This analysis confirms the association of serum IgG trough levels with the incidence of infections and highlights the importance of careful monitoring of IgG levels during treatment of secondary immunodeficiencies in CLL patients.
... Since both the innate and adaptive immune responses are essential in deterring the virus, patients with various types of immunodeficiencies are afflicted (5). A mass vaccination policy is a reasonable approach to counteracting the effects of the disease on the general population and IEI patients (6). Nevertheless, there is insufficient conclusive data regarding the effects of COVID-19 and its vaccination on patients with IEI. ...
Background:
Few studies have evaluated COVID-19 vaccine efficacy in patients with inborn errors of immunity (IEI).
Objective:
To evaluate the levels of antibody (Ab) production and function after COVID-19 vaccination in IEI patients with phagocytic, complement, and Ab deficiencies and their comparison with healthy controls.
Methods:
Serum samples were collected from 41 patients and 32 healthy controls at least one month after the second dose of vaccination, while clinical evaluations continued until the end of the third dose. Levels of specific anti-receptor-binding domain (RBD) IgG and anti-RBD neutralizing antibodies were measured using EUROIMMUN and ChemoBind kits, respectively. Conventional SARS-CoV-2 neutralization test (cVNT) was also performed. Cutoff values of ≤20, 20-80, and ≥80 (for cVNT and Chemobined) and 0.8-4.2, 4.2-8.5, and ≥8.5 (for EUROIMMUN) were defined as negative/weak, positive/moderate, and positive/significant, respectively.
Results:
A considerable distinction was observed between the Ab-deficient patients and the controls for Ab concentration (EUROIMMUN, p<0.01) and neutralization (ChemoBind, p<0.001). However, there was no significant difference compared with the other patient groups. A near-zero cVNT in Ab-deficient patients was found compared to the controls (p<0.01). A significant correlation between the two kits was found using the whole data (R2=0.82, p<0.0001).
Conclusion:
Despite varying degrees of Ab production, all Ab deficient patients, as well as almost half of those with complement and phagocytic defects, did not effectively neutralize the virus (cVNT). In light of the decreased production and efficiency of the vaccine, a revised immunization plan may be needed in IEI.
... The onset of PADs is diverse, potentially arising from defects in early B-cell development, immunoglobulin (Ig) class-switch recombination, or terminal B-cell differentiation [43]; disease severity for PADs can be loosely classified as mild (IgG subclass deficiency, specific antibody deficiency, or primary hypogammaglobulinemia), moderate (uncomplicated common variable immunodeficiency disorders [CVIDs]), or severe (complicated PAD, often with an underlying monogenic cause) [30]. In populations with PADs, the most frequently diagnosed symptomatic PID is the CVID phenotype [44]. Although the exact genetic defect underlying CVID is unknown, it is generally identified by the reduction in at least 2 serum Ig isotypes and, in some cases, defects in T-cell immunity, consequently leading to increased susceptibility to infection [2,45]. ...
Primary immunodeficiencies (PIDs) are heterogeneous, rare disorders that increase susceptibility to infection and/or immune dysregulation. Individuals with certain PIDs are at high risk of severe or fatal outcomes from SARS-CoV-2 infections (the causative agent of COVID-19), either due to the underlying PID and/or due to the presence of comorbidities such as severe lung and liver disease. Vaccination remains the primary strategy to protect individuals with PID from COVID-19. However, populations with PID exhibit variable vaccine seroresponse rates, antibody titers, and neutralization activity depending on the type of PID and/or COVID-19 vaccine, and consequently, are at an elevated risk of severe disease. In this article, we review the COVID-19 burden in patients with PIDs and focus in-depth on findings from patients with predominantly antibody deficiencies or combined immunodeficiencies. We conclude by providing COVID-19 vaccination recommendations for this population.
... Patients have a profound reduction in serum IgG, with decreased serum IgM and/or IgA, that is at least two standard deviations below the age-corrected mean values [2]. Estimated to affect 1:25,000 to 1:100,000 individuals of European descent, CVID is the most prevalent group of symptomatic IEI in older children and adults [3][4][5]. Remarkably, up to 60-70% of CVID patients display one or more non-infectious complications (simultaneously or sequentially over their disease course) that significantly increase their morbidity and mortality. These complications include (i) autoimmunity (cytopenias, thyroiditis, rheumatoid arthritis, etc.); (ii) lymphoma (majority non-Hodgkin's) and other malignancy; (iii) enteropathy; (iv) chronic liver disease due to granulomas, nodular hyperplasia, primary sclerosing/biliary cholangitis; (v) chronic pulmonary disease such as lymphoid interstitial pneumonia (LIP), granulomatous and lymphocytic interstitial lung disease (GLILD); and (vi) other nonmalignant lymphoid hyperplasia [6][7][8][9][10][11]. ...
Purpose
A subset of common variable immunodeficiency (CVID) patients either presents with or develops autoimmune and lymphoproliferative complications, such as granulomatous lymphocytic interstitial lung disease (GLILD), a major cause of morbidity and mortality in CVID. While a myriad of phenotypic lymphocyte derangements has been associated with and described in GLILD, defects in T and B cell antigen receptor (TCR/BCR) signaling in CVID and CVID with GLILD (CVID/GLILD) remain undefined, hindering discovery of biomarkers for disease monitoring, prognostic prediction, and personalized medicine approaches.
Methods
To identify perturbations of immune cell subsets and TCR/BCR signal transduction, we applied mass cytometry analysis to peripheral blood mononuclear cells (PBMCs) from healthy control participants (HC), CVID, and CVID/GLILD patients.
Results
Patients with CVID, regardless of GLILD status, had increased frequency of HLADR⁺CD4⁺ T cells, CD57⁺CD8⁺ T cells, and CD21lo B cells when compared to healthy controls. Within these cellular populations in CVID/GLILD patients only, engagement of T or B cell antigen receptors resulted in discordant downstream signaling responses compared to CVID. In CVID/GLILD patients, CD21lo B cells showed perturbed BCR-mediated phospholipase C gamma and extracellular signal-regulated kinase activation, while HLADR⁺CD4⁺ T cells and CD57⁺CD8⁺ T cells displayed disrupted TCR-mediated activation of kinases most proximal to the receptor.
Conclusion
Both CVID and CVID/GLILD patients demonstrate an activated T and B cell phenotype compared to HC. However, only CVID/GLILD patients exhibit altered TCR/BCR signaling in the activated lymphocyte subsets. These findings contribute to our understanding of the mechanisms of immune dysregulation in CVID with GLILD.
... Before the diagnosis of cancer, a small percentage of patients can be diagnosed with immunodeficiency diseases (IDDs) containing primary or secondary immunodeficiencies. In the general population, primary immunodeficiencies are quite rare in incidence, and the prevalence can range from 1/500 to 1/500,000 [14] of which 30% had common variable immunodeficiency (CVID) in a European internet-based database [15]. Of note, previous studies indicated that primary immunodeficiencies have a high risk of solid tumors and hematological malignancies [16,17]. ...
Background:
Immunodeficiency diseases (IDDs) are associated with an increased proportion of cancer-related morbidity. However, the relationship between IDDs and malignancy readmissions has not been well described. Understanding this relationship could help us to develop a more reasonable discharge plan in the special tumor population.
Methods:
Using the Nationwide Readmissions Database, we established a retrospective cohort study that included patients with the 16 most common malignancies, and we defined two groups: non-immunodeficiency diseases (NOIDDs) and IDDs.
Results:
To identify whether the presence or absence of IDDs was associated with readmission, we identified 603,831 patients with malignancies at their time of readmission in which 0.8% had IDDs and in which readmission occurred in 47.3%. Compared with NOIDDs, patients with IDDs had a higher risk of 30-day (hazard ratio (HR) of 1.32; 95% CI of 1.25-1.40), 90-day (HR of 1.27; 95% CI of 1.21-1.34) and 180-day readmission (HR of 1.28; 95% CI of 1.22-1.35). More than one third (37.9%) of patients with IDDs had readmissions that occurred within 30 days and most (82.4%) of them were UPRs. An IDD was an independent risk factor for readmission in patients with colorectal cancer (HR of 1.32; 95% CI of 1.01-1.72), lung cancer (HR of 1.23; 95% CI of 1.02-1.48), non-Hodgkin's lymphoma (NHL) (HR of 1.16; 95% CI of 1.04-1.28), prostate cancer (HR of 1.45; 95% CI of 1.07-1.96) or stomach cancer (HR of 2.34; 95% CI of 1.33-4.14). Anemia (44.2%), bacterial infections (28.6%) and pneumonia (13.9%) were the 30-day UPR causes in these populations. (4) Conclusions: IDDs were independently associated with higher readmission risks for some malignant tumors. Strategies should be considered to prevent the causes of readmission as a post discharge plan.
... и 2,105 на 100 тыс. населения соответственно [9,10,11]. ...
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.
... Common variable immunodeficiency is a large group of genetic disorders that result in severe IgG immunodeficiency combined with IgA or IgM deficiency. In primary immunodeficiency registries, common variable immunodeficiency is the most common diagnosis and is reported in 20% of patients registered [30,31]. The rate of hospital admissions increased in common variable immunodeficiency by 3.45 fold. ...
Background
Non-malignant hematologic and immune disorders-related hospitalization trends are unstudied despite their importance from a public health standpoint. Therefore, this study aimed to define the hospitalization trends of the International Statistical Classification of Diseases-10 (ICD-10) category diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism (B&ID).
Methods
We conducted an ecologic study to analyze hospital admission data obtained from England's Hospital Episode Statistics database and Wales' Patient Episode Database. Hospital admissions data for non-malignant hematologic disorders and immune disorders were extracted for the period from April 1999 to March 2019. We used the Poisson model to assess trends in hospital admissions.
Results
The total annual B&ID-related hospital admission (RHA) rate for all categories increased by 137.9% between 1999 and 2019 (p<0.01). Females accounted for 54% of all B&ID-RHA. Around 37% of B&ID-RHA were seen in the age group of 15-59 years and 29% in the age group of 75 years and above. The most common causes of B&ID-RHA were aplastic and other anemias and other bone marrow failure syndromes, ICD-10 category (33%) and nutritional anemias category (28%). Certain disorders involving the immune mechanism category accounted for the least number of B&ID-RHA (8.4%). The highest increase in B&ID-RHA was seen in the nutritional anemias category (3.86 fold), followed by certain disorders involving the immune mechanism (1.28 fold). Iron deficiency anemia accounted for 95.1% of all hospitalizations secondary to nutritional anemias. Around half of all, hemolytic anemia category hospitalizations were secondary to the sickle cell anemia subcategory.
Conclusions
Hospital admissions trends in non-malignant hematologic and immune disorders changed dynamically among age groups and gender in England and Wales over the last two decades. Understanding these changes has important implications for public health planning.
... Predominantly antibody deficiency (PAD) is the most common primary immunodeficiency (PID), and it accounts for more than 50% of the total PID cases and up to 78% as reported in some studies. [1][2][3][4][5][6] Symptomatic patients with these disorders are at a high risk of acquiring other infections and selected neoplastic diseases, autoimmune diseases, and allergies. [7][8][9][10] Lack of correct and timely diagnosis in most patients is a notable problem. ...
The majority of primary immunodeficiencies (PIDs) are antibody deficiencies (PADs), and not all of them are rare diseases; As an example, Caucasian individuals suffer from selective IgA deficiency at a frequency of 1:500.
In addition to infections, symptomatic patients with PAD are more likely to develop neoplastic, autoimmune, and allergic diseases. In the event that PAD is neglected or delayed for more than ten years, complications develop, eventually resulting in death. No studies have been conducted to devise and report detailed ready-to-use protocols for managing PAD to date.
This study aimed to propose protocols and guidelines for the adult PAD patients’ standard care. Preparing the protocol, we considered the frequency and type of laboratory tests, imaging, endoscopic examinations, specialist consultations, and standardized recommendations for further care in the place of residence.
As a result of the proposed monitoring scheme, patients can be provided with complete care in terms of their underlying conditions and comorbidities, as well as early detection of complications. This protocol will serve as a guide for physicians dealing with these patients and enable comparisons of patient groups across a variety of treatment centers, even far away from each other. A national consultant in the field of clinical immunology verified the protocol mainly developed by Polish experts from reference immunology centres for adults.
... If the patient presents two or more of the following signs, this should suggest the presence of innate errors of the immune system: (1) four or more ear infections within 1 year, (2) two or more serious sinus infections within 1 year, (3) two or more episodes of ineffective response to antibiotic management, (4) two or more episodes of pneumonia within 1 year, (5) failure to grow normally, (6) recurrent skin abscesses or abscesses in organs, (7) persistent canker sores in the mouth or fungal infection on the skin, (8) need for intravenous antibiotics to eradicate infections, (9) two or more systemic or deep infections, and (10) the presence of a family history of PIDs. 9 Different countries in Europe and Asia report prevalence of innate errors of the immune system between 1:8500 and 1:100,000, which is higher in populations where inbreeding is common. [10][11][12][13][14] In the United States, prevalence between 29.1 and 50.5 patients has been reported for each 100,000 inhabitants. 11 In Latin America, a regional database was created in 2009 by the Latin American Society for Primary Immunodeficiencies (Society for Immunodeficiencies Database or LASID). ...
Introduction:
In recent decades, there has been a growing increase in the diagnosis of patients with inborn errors of the immune system, formerly known as primary immunodeficiency disorders (PIDs). Timely diagnosis remains a challenge due to low clinical suspicion and poor education on the subject. It is estimated that between 70% and 90% of these pathologies remain underdiagnosed in our environment.
Objective:
The objective of this study is to characterize the demographic and clinical presentation of pediatric group patients with inborn errors of the immune system in a Colombian tertiary hospital.
Methods:
Retrospective descriptive study of 306 patients with a diagnosis of innate errors of the immune system who consulted the PID clinic between 2011 and 2018 in a high-complexity institution in Cali, Colombia.
Results:
Three-hundred and six patients were included. The median age was 4 years (IQR 2.3-7.7 years), and 59.5% of the patients were male. According to the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency classification for inborn errors of the immune system, the most common group was antibody deficiency in 74.8% (n˂229), especially in the age group between 1 and 5 years. The least frequent in our population was complement deficiency. Of the warning signs stipulated for these pathologies, the most frequent were the (1) need for intravenous antibiotics (32%), (2) difficulty growing (15.7%), (3) four or more episodes of ear infection (10.8%), and (4) abscesses in organs or cutaneous abscesses (12.7%). No patient reported two or more episodes of pneumonia or sinusitis, and only 5.8% of the patients received a bone marrow transplant.
Conclusions:
Innate errors of the immune system require an early diagnosis with follow-up from an early age to ensure adequate management and follow-up in order to reduce morbidity and mortality. It is imperative to sensitize the medical population about the existence of these pathologies so that early intervention can be carried out, which improves the quality of life of patients and their families.
... Males (64.4%) were predominantly affected in this study. A similar trend was reported by centers in Europe [9], India [10,11], and Sri Lanka [12]. Interestingly, in our cohort males were frequently affected even if X-linked diseases were excluded. ...
Primary immune deficiencies better known as Inborn Errors of Immunity (IEI) are a heterogeneous group of disorders that predispose affected individuals to infections, allergy, autoimmunity, autoinflammation, and malignancies.. Inborn Errors of Immunity are increasingly being recognized in the Indian subcontinent. Two hundred and eight patients diagnosed with an IEI during February 2017 to November 2021 at a tertiary care centre in South India were included in the study. The clinical features, laboratory findings including microbiologic and genetic data, treatment & outcome details were analyzed. The diagnosis of IEI was confirmed in a total of 208 patients (198 kindreds) based on relevant immunological tests and/or genetic tests. The male to female ratio was 1.8:1. The most common IEI in our cohort was SCID (17.7%) followed by CGD (12.9%) and CVID (9.1%). We also had a significant proportion of patients with DOCK8 deficiency (7.2%), LAD (6.2%), and six patients (2.8%) with autoinflammatory diseases. Autoimmunity was noted in forty-six (22%) patients during the course of their illness. Molecular testing was performed in 152 patients by exome sequencing on NGS platform and a genetic variant was reported in 132 cases. Twenty-nine children underwent 34 HSCT, and 135 patients remain on supportive therapy such as immunoglobulin replacement and/or antimicrobial prophylaxis. Fifty-nine (28.3%) patients died during the study period and infections were the predominant cause of mortality. Seven families underwent prenatal testing in the subsequent pregnancy. We describe the profile of 208 patients with IEI and to the best of our knowledge, this represents the largest data on IEI from the Indian subcontinent reported so far.
... By the secondary questionnaire, we found that predominantly antibody deficiency was the most common (40%), followed by congenital defects of phagocyte number, function or both (19%) among the PID disease categories. Bruton's tyrosine kinase (BTK) deficiency was found to be the most common PID in Japan, and accounted for a higher rate (14.7%) than in European countries (5.9%) (7). On the other hand, the prevalence of common variable immunodeficiency (CVID) was low (11.0%). ...
Primary immunodeficiency (PID) is primarily characterized by susceptibility to infectious diseases. In addition, patients with some type of PID are prone to develop autoimmune, autoinflammatory, or malignant diseases. Therefore, the term, inborn errors of immunity (IEI), has been more used rather than PID. In recent years, the number of diseases which belong to PID has been increasing. There were approximately 110 diseases in the report of International Union of Immunological Societies in 1999. Since then, the number increased to 430 diseases in the latest IUIS report in 2019. We conducted PID nationwide survey in Japan for 3 times in the last 15 years. These studies were focused on incidence and complications of PID, the clinical course of viral infection, and methods to prevent infectious diseases in PID patients. For the awareness of PID, it is essential to know the general and fundamental information of PID patients. Needless to say, we need it to offer appropriate medical services for PID patients. Moreover, chances to provide answers to the questionnaires and seeing the results of the analysis should contribute to the awareness of PID among doctors. In this review, I am going to summarize the results of 3 nationwide survey in Japan, and pick up interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency as an example for creating awareness for its appropriate management.
... Although CVID is a heterogeneous disease and many patients lack a genetic diagnosis, our results may reflect a growing recognition of IEI among non-pediatric physicians, since many patients with CVID are diagnosed in adulthood [23]. However, the number of CVID patients was still smaller than those reported from Europe [24] or the USA [25]. This may be due to the low questionnaire response rate from non-pediatric departments since the majority of CVID patients in this study were reported from pediatric departments. ...
We conducted a nationwide survey of inborn errors of immunity (IEI) in Japan for the second time in 10 years, focusing on protective measures for IEI patients against infectious diseases. Questionnaires were sent to various medical departments nationwide, and a total of 1307 patients were reported. The prevalence of IEI was 2.2 patients per 100,000 population, which was comparable with the previous nationwide study. The most common disease category was autoinflammatory disorders (25%), followed by antibody deficiencies (24%) and congenital defects of phagocyte number or function (16%). We found that a significant number of patients received contraindicated vaccines, principally because the patients were not diagnosed with IEI by the time of the vaccination. Regarding diseases for which BCG vaccination is contraindicated, 43% of patients had actually received BCG, of which 14% developed BCG-related infections. BCG-related infections were mainly observed among patients with CGD and MSMD. In order to prevent IEI patients from receiving inadequate vaccines, continuous education to parents and physicians is needed, along with the expansion of newborn screening, but efforts to screen IEI at the site of vaccination also remain important.
... As shown in Figure 4, compared with the NC group, the serum concentrations of IgA, IgG, and IgM in the MC, MP, and LP groups were significantly or immensely significantly increased (P < 0.05 or P < 0.001), but they were significantly decreased (P < 0. Immune deficiencies appear to exhibit antibody production deficiencies [33]. In some cases, Ig replacement treatment is the most effective treatment in primary immunodeficiency diseases [34][35][36]. ...
The purpose of this study was to investigate whether the Dictyophora echinovolvata spore polysaccharides (DESP) affect the immunity in immunocompromised mice induced by cyclophosphamide (CTX). The healthy female Kunming mice were randomly divided into six groups, including a normal control (NC) group, a positive control group, a model control (MC) group, and three groups treated with low-, intermediate-, and high-dose polysaccharide, respectively. A series of immunoregulatory properties were determined, including humoral and cellular immunity, immune function, and immune factors of mononuclear macrophages. Compared with NC and MC groups, treatment with DESP significantly increased the spleen index and decreased the thymus index; increased the serum concentrations of immunoglobulin (Ig)A, IgG, IgM, hemolysin, IL-1β, and IL-2; delayed the allergic reaction; and improved the splenic lymphocyte transformation ability; and enhanced the phagocytosis of macrophages and the ability to secrete IL-6, TNF-α, caspase-1, and NO with DESP supplementation. These results indicated that DESP might have a good regulatory effect on CTX-induced immunodeficiency in mice, adjust the body’s immune imbalance, and improve the symptoms of low immunity.
... This is the first comprehensive report on the clinical and immunological features of SCID patients from Morocco. SCID accounts for 11% of all PID cases in Morocco, a proportion higher than the 3.06% for the European registry [7], but much lower than that reported for Saudi Arabia [8].The incidence and prevalence of SCID vary around the world, and are higher in countries with high consanguinity rates. In Saudi Arabia, the reported incidence of SCID is 1/2906 live births [9], 20 times higher than from the incidence of 1/58,000 live births reported by the USA NBS programs [10].Taking these data and the high rate of consanguinity in the general population of Morocco (22%) [11] into account, the number of patients collected in our cohort over the two decades considered remains very low, suggesting that many SCID cases were probably missed and died without diagnosis. ...
Severe combined immunodeficiency (SCID) is a heterogeneous group of primary immunodeficiency diseases (PIDs) characterized by a lack of autologous T lymphocytes. This severe PID is rare, but has a higher prevalence in populations with high rates of consanguinity. The epidemiological, clinical, and immunological features of SCIDs in Moroccan patients have never been reported. The aim of this study was to provide a clinical and immunological description of SCID in Morocco and to assess changes in the care of SCID patients over time. This cross-sectional retrospective study included 96 Moroccan patients referred to the national PID reference center at Casablanca Children’s Hospital for SCID over two decades, from 1998 to 2019. The case definition for this study was age < 2 years, with a clinical phenotype suggestive of SCID, and lymphopenia, with very low numbers of autologous T cells, according to the IUIS Inborn Errors of Immunity classification. Our sample included 50 male patients, and 66% of the patients were born to consanguineous parents. The median age at onset and diagnosis were 3.3 and 6.5 months, respectively. The clinical manifestations commonly observed in these patients were recurrent respiratory tract infection (82%), chronic diarrhea (69%), oral candidiasis (61%), and failure to thrive (65%). The distribution of SCID phenotypes was as follows: T−B−NK+ in 44.5%, T−B−NK− in 32%, T−B+NK− in 18.5%, and T−B+NK+ in 5%. An Omenn syndrome phenotype was observed in 15 patients. SCID was fatal in 84% in the patients in our cohort, due to the difficulties involved in obtaining urgent access to hematopoietic stem cell transplantation, which, nevertheless, saved 16% of the patients. The autosomal recessive forms of the clinical and immunological phenotypes of SCID, including the T−B−NK+ phenotype in particular, were more frequent than those in Western countries. A marked improvement in the early detection of SCID cases over the last decade was noted. Despite recent progress in SCID diagnosis, additional efforts are required, for genetic confirmation and particularly for HSCT.
... The presentation of PIDD is highly variable because different components of the immune system and nearly every organ system can be affected. [1][2][3][4][5][6][7] Common treatment for PIDD that involves humoral immunodeficiency consists of immunoglobulin replacement. This study included patients with PIDD who were on intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG), which primarily captured individuals with PIDD who had humoral defects. ...
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.
... [1][2][3][4] The prevalence of PAD has been reported at a ratio of 1:25 000 worldwide, ranging from 1:15 000 to 1:30 000. [5][6][7][8] Examples of PAD include common variable immune deficiency (CVID), X-linked agammaglobulinaemia (XLA), selected IgA deficiency, unclassified hypogammaglobulinemia and IgG subclass deficiency. 1,3 Although it is a rare disease, it is considered a serious medical condition due to its tendency to cause serious and fatal infection in affected patients. ...
Aims
There is considerable interpatient variability in the pharmacokinetics (PK) of intravenous immunoglobulin G (IVIG), causing difficulty in optimizing individual dosage regimen. This study aims to estimate the population PK parameters of IVIG and to investigate the impact of genetic polymorphism of the FcRn gene and clinical variability on the PK of IVIG in patients with predominantly antibody deficiencies.
Methods
Patients were recruited from four hospitals. Clinical data were recorded and blood samples were taken for PK and genetic studies. Population PK parameters were estimated by nonlinear mixed‐effects modelling in Monolix®. Models were evaluated using the difference in objective function value, goodness‐of‐fit plots, visual predictive check and bootstrap analysis. Monte Carlo simulation was conducted to evaluate different dosing regimens for IVIG.
Results
A total of 30 blood samples were analysed from 10 patients. The immunoglobulin G concentration data were best described by a one‐compartment model with linear elimination. The final model included both volume of distribution (Vd) and clearance (CL) based on patient's individual weight. Goodness‐of‐fit plots indicated that the model fit the data adequately, with minor model mis‐specification. Genetic polymorphism of the FcRn gene and the presence of bronchiectasis did not affect the PK of IVIG. Simulation showed that 3–4‐weekly dosing intervals were sufficient to maintain IgG levels of 5 g L⁻¹, with more frequent intervals needed to achieve higher trough levels.
Conclusions
Body weight significantly affects the PK parameters of IVIG. Genetic and other clinical factors investigated did not affect the disposition of IVIG.
... живонароджених [11], Франції -16,5 на 100 тис. народжених живими [12]. Найвища частота зареєстрована в деяких етнічних групах Туреччини -24 на 100 тис. ...
Первинні імунодефіцити (ПІД) являють собою групу рідкісних вроджених захворювань системи імунітету. Виявлення ПІД, підрахунок їх кількості й ідентифікація нозологічних форм є надзвичайно актуальною проблемою педіатрії, оскільки це важливо для розробки заходів щодо діагностики та лікування. Метою роботи було вивчення частоти ПІД в Україні та їх нозологічних форм шляхом створення реєстру пацієнтів. У 27 адміністративних центрах України була зібрана інформація про всіх пацієнтів із ПІД, діагностованих протягом 1995–2014 рр. На початок 2015 р. у реєстр включено 814 пацієнтів, із них 684 — живі, серед яких 561 дітина та 123 пацієнти віком понад 18 років. Мінімальна частота ПІД становить 1,23 живого пацієнта на 100 тис. населення, мінімальна частота народження дитини із ПІД — 9,94 на 100 тис. народжених живими. Структура ПІД за ланкою ураження імунної системи в Україні близька до структури у світі, основні групи ПІД представлені 39 нозологічними формами. Отримані дані свідчать про недостатнє виявлення ПІД в Україні, тому залишається актуальним питання підвищення настороженості лікарів різних спеціальностей стосовно ПІД і своєчасного направлення пацієнтів на консультацію до дитячого імунолога.
... Predominantly antibody deficiency (PAD) comprises the largest group of patients (~70%) with a primary immunodeficiency disorder (PID). [1][2][3][4][5] Patients are defined by an impaired antibody (Ab) response to antigen stimulation. [6][7][8] Within the group of PAD patients, those with a complete absence of serum immunoglobulin (Ig) and of circulating B cells are defined as having agammaglobulinemia. ...
Background
Annual influenza vaccination is recommended to all individuals over 6 months of age, including predominantly antibody deficiency (PAD) patients. Vaccination responses are typically evaluated by serology, and because PAD patients are by definition impaired in generating IgG and receive immunoglobulin replacement therapy (IgRT), it remains unclear whether they can mount an antigen‐specific response.
Objective
To quantify and characterise the antigen‐specific memory B (Bmem) cell compartment in healthy controls and PAD patients following an influenza booster vaccination.
Methods
Recombinant hemagglutinin (HA) from the A/Michigan/2015 H1N1 (AM15) strain with an AviTag was generated in a mammalian cell line, and following targeted biotinylation, was tetramerised with BUV395 or BUV737 streptavidin conjugates. Multicolour flow cytometry was applied on blood samples before and 28 days after booster influenza vaccination in 16 healthy controls and five PAD patients with circulating Bmem cells.
Results
Recombinant HA tetramers were specifically recognised by 0.5–1% of B cells in previously vaccinated healthy adults. HA‐specific Bmem cell numbers were significantly increased following booster vaccination and predominantly expressed IgG1. Similarly, PAD patients carried HA‐specific Bmem cells, predominantly expressing IgG1. However, these numbers were lower than in controls and did not increase following booster vaccination.
Conclusion
We have successfully identified AM15‐specific Bmem cells in healthy controls and PAD patients. The presence of antigen‐specific Bmem cells could offer an additional diagnostic tool to aid in the clinical diagnosis of PAD. Furthermore, alterations in the number or immunophenotype of HA‐specific Bmem cells post‐booster vaccination could assist in the evaluation of immune responses in individuals receiving IgRT.
... 14 Similar to many countries, Saudi Arabia has developed its own registries for PIDD. 13,15 The registry, housed at King Faisal Specialist Hospital and Research Centre (KFSH&RC), started in 2010 and includes over 820 patients. 16 Using a national survey, we assessed the abilities of primary care physicians throughout the Kingdom of Saudi Arabia to demonstrate sufficient awareness of PIDD and to diagnose and refer PIDD patients for proper treatment. ...
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.
... CVID was defined with markedly decreased levels of IgG, IgA, and/or IgM (2 standard deviations (SDs) below the mean for age) and low immune response to a PNA vaccine [7,13,14]. IgG deficiency was assigned if IgG levels were lower than 2 SD below the mean for age without meeting the criteria for CVID [5,11,15]. IgG2 deficiency was assigned if IgG subclass 2 levels were lower than 2 SD below the mean of age, with normal levels of total IgG and other IgG subclasses [16][17][18]. ...
PurposeAlthough common variable immunodeficiency (CVID) is considered the most prevalent symptomatic primary antibody deficiency (PAD), there is a population with symptomatic PADs that do not meet criteria for CVID. We analyzed clinical and immunological profiles of patients with different PADs to better understand the differences and similarities between CVID and other PADs.Methods
We extracted clinical and laboratory data of patients with PADs from electronic medical records. Patients were categorized into CVID, IgG subclass 2 deficiency (IgG2D), IgG deficiency (IgGD), and specific antibody deficiency (sAbD) based on basal immunoglobulin levels and pneumococcal vaccine responses. We compared clinical and immunological characteristics in these groups.ResultsAll patients, regardless of PAD types, showed similar frequencies of infections, bronchiectasis, and interstitial lung disease (ILD). Hematopoietic malignancies were more frequently found in the CVID than in the IgG2D, IgGD, and sAbD groups, while the latter groups trended towards an increased frequency of connective tissue diseases (CTD). Low counts of natural killer (NK) cells were associated with malignancy, autoimmunity, and ILD in CVID but not in other PAD groups.Conclusions
Higher frequency of hematopoietic malignancy in CVID than in the other PADs and association of lower NK cell counts with non-infectious complications in CVID suggest a relationship between immune alterations and the development of non-infectious manifestations in PADs.
... Primary immunodeficiencies (PID) are a group of more than 350 rare diseases, which are characterised by a variety of clinical symptoms and are difficult to diagnose [1]. The delay from initial symptoms to PID diagnosis is more than four years [2,3]. ...
Introduction: Primary immunodeficiencies (PID) are a group of more than 350 rare diseases, which are char-acterised by a variety of clinical symptoms and are difficult to diagnose. Early diagnosis is very important for improvement of quality of life of the children with PID. The aim of the study was to evaluate the warning signs of PID, taking into account the regional features of PID prevalence to improve early verification of these disorders. Material and methods: Overall, 107 children aged between two months and 18 years with warning signs of PID, developed by the Jeffrey Modell Foundation Medical Advisory Board, as well as with other warning signs of PID, developed by the Ukrainian Association of Pediatric Immunology, were enrolled in the study. The patients were referred to immunologists by primary care physicians or hospital specialists during the implementation of physician education and a public awareness program of early diagnosis and management of PID. Results: Among 107 children with warning signs, PID was diagnosed in 19 (17.8%) patients. Chronic diarrhoea with malabsorption was present more frequently in the patients with definable PID (p = 0.0048). Dys-morphic features and/or microcephaly were also more common in the patients with PID (p = 0.0456). More significant differences were found when microcephaly was combined with dysmorphic features (p = 0.0004). Congenital heart disease occurred only in the patients with PID (p = 0.0437), in particular with DiGeorge (22q11.2 deletion) syndrome. Conclusions: For early detection of PID, it is necessary to take into account regional features of the prevalence of certain PID. Our study has established that such warning signs as chronic diarrhoea with malabsorption, dysmorphic features and microcephaly, and congenital heart disease with/or without seizures with underlying hypocalcaemia were important for PID diagnosis in the studied region.
... This process plays a pivotal role in the development of humoral immunity, and its deficiency leads to immune-related pathologies. Among primary immune deficiencies, antibody production-related diseases are the most frequent and clinically relevant [1]. Communication between immune cells coordinates an effective immune response to eliminate pathogens while maintaining physiological homeostasis. ...
Intercellular communication orchestrates effective immune responses against disease-causing agents. Extracellular vesicles (EVs) are potent mediators of cell-cell communication. EVs carry bioactive molecules, including microRNAs, which modulate gene expression and function in the recipient cell. Here, we show that formation of cognate primary T-B lymphocyte immune contacts promotes transfer of a very restricted set of T-cell EV-microRNAs (mmu-miR20-a-5p, mmu-miR-25-3p, and mmu-miR-155-3p) to the B cell. Transferred EV-microRNAs target key genes that control B-cell function, including pro-apoptotic BIM and the cell cycle regulator PTEN. EV-microRNAs transferred during T-B cognate interactions also promote survival, proliferation, and antibody class switching. Using mouse chimeras with Rab27KO EV-deficient T cells, we demonstrate that the transfer of small EVs is required for germinal center reaction and antibody production in vivo, revealing a mechanism that controls B-cell responses via the transfer of EV-microRNAs of T-cell origin. These findings also provide mechanistic insight into the Griscelli syndrome, associated with a mutation in the Rab27a gene, and might explain antibody defects observed in this pathogenesis and other immune-related and inflammatory disorders.
... Predominantly antibody deficiency (PAD) represents the largest group of primary immunodeficiencies (PIDs) and includes up to 70% of all patients (1)(2)(3)(4)(5). The hallmark of PAD is a history of severe and recurrent sinopulmonary infections and poor vaccination responses underpinned by impaired B-cell differentiation and antibody production. ...
... 16 In addition to the clinical phenotypes of SCID, distribution and absolute count of T, B, and NK cell subsets can provide clues regarding the extent to which the immune system is affected. 17 The most common form affecting approximately 30%-60% of the patients is X-linked SCID caused by mutations in the gene encoding the common γc of the IL-2R 18,19 which is mostly presented as T-B+ NK− SCID. Similarly, in our study the IL2RG mutation was found in 3 patients, who were subjected to genetic tests and were almost devoid of CD3+ T-cells (0%-3.2%) ...
Purpose:
While there is an urgent need for diagnosis and therapeutic intervention in patients with primary immunodeficiency diseases (PIDs), current genetic tests have drawbacks. We retrospectively reviewed the usefulness of flow cytometry (FCM) as a quick tool for immunophenotyping and functional assays in patients suspected to have PIDs at a single tertiary care institute.
Methods:
Between January 2001 and June 2018, patients suspected of having PIDs were subjected to FCM tests, including lymphocyte subset analysis, detection of surface- or intracellular-target proteins, and functional analysis of immune cells, at Samsung Medical Center, Seoul, Korea. The genetic diagnosis was performed using Sanger or diagnostic exome sequencing.
Results:
Of 60 patients diagnosed with definite or probable PID according to the European Society of Immune Deficiencies criteria, 24 patients were provided with useful information about immunological dysfunction after initial FCM testing. In 10 patients, the PID diagnosis was based on abnormal findings in FCM testing without genetic tests. The FCM findings provided strong evidence for the diagnosis of severe combined immunodeficiency (n = 6), X-linked chronic granulomatous diseases (CGD) (n = 6), leukocyte adhesion deficiency type 1 (n = 3), X-linked agammaglobulinemia (n = 11), autoimmune lymphoproliferative syndrome-FASLG (n = 1), and familial hemophagocytic lymphohistiocytosis type 2 (n = 1), and probable evidence for autosomal recessive-CGD (n = 2), autosomal dominant-hyper-immunoglobulin E (IgE)-syndrome (n = 1), and STAT1 gain-of-function mutation (n = 1). In PIDs derived from PIK3CD (n = 2), LRBA (n = 2), and CTLA4 mutations (n = 3), the FCM test provided useful evidence of immune abnormalities and a tool for treatment monitoring.
Conclusions:
The initial application of FCM, particularly with known protein targets on immune cells, would facilitate the timely diagnosis of PIDs and thus would support clinical decisions and improve the clinical outcome.
... Most knowledge about B cell development in BM came from mouse studies; however, detailed insight into normal human BCP development is important to identify and unravel pathophysiological processes in hematological malignancies and primary immunodeficiencies (PID), caused by genetic defects (16). In turn, BCP analysis in genetically-defined PID can help elucidating the role of specific genes in BCP development (13,17), because absence (or dysfunction) of essential proteins cause a full or incomplete block of maturation at specific developmental stages (18)(19)(20). ...
B-cell precursors (BCP) arise from hematopoietic stem cells in bone marrow (BM). Identification and characterization of the different BCP subsets has contributed to the understanding of normal B-cell development. BCP first rearrange their immunoglobulin (Ig) heavy chain (IGH) genes to form the pre-B-cell receptor (pre-BCR) complex together with surrogate light chains. Appropriate signaling via this pre-BCR complex is followed by rearrangement of the Ig light chain genes, resulting in the formation, and selection of functional BCR molecules. Consecutive production, expression, and functional selection of the pre-BCR and BCR complexes guide the BCP differentiation process that coincides with corresponding immunophenotypic changes. We studied BCP differentiation in human BM samples from healthy controls and patients with a known genetic defect in V(D)J recombination or pre-BCR signaling to unravel normal immunophenotypic changes and to determine the effect of differentiation blocks caused by the specific genetic defects. Accordingly, we designed a 10-color antibody panel to study human BCP development in BM by flow cytometry, which allows identification of classical preB-I, preB-II, and mature B-cells as defined via BCR-related markers with further characterization by additional markers. We observed heterogeneous phenotypes associated with more than one B-cell maturation pathway, particularly for the preB-I and preB-II stages in which V(D)J recombination takes place, with asynchronous marker expression patterns. Next Generation Sequencing of complete IGH gene rearrangements in sorted BCP subsets unraveled their rearrangement status, indicating that BCP differentiation does not follow a single linear pathway. In conclusion, B-cell development in human BM is not a linear process, but a rather complex network of parallel pathways dictated by V(D)J-recombination-driven checkpoints and pre-BCR/BCR mediated-signaling occurring during B-cell production and selection. It can also be described as asynchronous, because precursor B-cells do not differentiate as full population between the different stages, but rather transit as a continuum, which seems influenced (in part) by V-D-J recombination-driven checkpoints.
Primary immune deficiencies or inborn errors of immunity (IEI) are a heterogeneous group of disorders that predispose affected individuals to infections, allergy, autoimmunity, autoinflammation and malignancies. IEIs are increasingly being recognized in the Indian subcontinent. Two hundred and eight patients diagnosed with an IEI during February 2017 to November 2021 at a tertiary care center in South India were included in the study. The clinical features, laboratory findings including microbiologic and genetic data, and treatment and outcome details were analyzed. The diagnosis of IEI was confirmed in a total of 208 patients (198 kindreds) based on relevant immunological tests and/or genetic tests. The male-to-female ratio was 1.8:1. Of the 208 patients, 72 (34.6%) were < 1 yr, 112 (53.8%) were 1–18 years, and 24 (11.5%) were above 18 years. The most common IEI in our cohort was SCID (17.7%) followed by CGD (12.9%) and CVID (9.1%). We also had a significant proportion of patients with DOCK8 deficiency (7.2%), LAD (6.2%) and six patients (2.8%) with autoinflammatory diseases. Autoimmunity was noted in forty-six (22%) patients. Molecular testing was performed in 152 patients by exome sequencing on the NGS platform, and a genetic variant was reported in 132 cases. Twenty-nine children underwent 34 HSCT, and 135 patients remain on supportive therapy such as immunoglobulin replacement and/or antimicrobial prophylaxis. Fifty-nine (28.3%) patients died during the study period, and infections were the predominant cause of mortality. Seven families underwent prenatal testing in the subsequent pregnancy. We describe the profile of 208 patients with IEI, and to the best of our knowledge, this represents the largest data on IEI from the Indian subcontinent reported so far.
Inborn errors of immunity (IEI) are multifaced diseases which can present with a variety of phenotypes, ranging from infections to autoimmunity, lymphoproliferation, and neoplasms. In recent decades, research has investigated the relationship between autoimmunity and IEI. Autoimmunity is more prevalent in primary humoral immunodeficiencies than in most other IEI and it can even be their first manifestation. Among these, the two most common primary immunodeficiencies are selective IgA deficiency and common variable immunodeficiency. More than half of the patients with these conditions develop non-infectious complications due to immune dysregulation: autoimmune, autoinflammatory, allergic disorders, and malignancies. Around 30% of these patients present with autoimmune phenomena, such as cytopenia, gastrointestinal and respiratory complications, and endocrine and dermatologic features. Complex alterations of the central and peripheral mechanisms of tolerance are involved, affecting mainly B lymphocytes but also T cells and cytokines. Not only the immunophenotype but also advances in genetics allow us to diagnose monogenic variants of these diseases and to investigate the pathogenetic basis of the immune dysregulation. The diagnosis and therapy of the primary humoral immunodeficiencies has been mostly focused on the infectious complications, while patients with predominant features of immune dysregulation and autoimmunity still present a challenge for the clinician and an opportunity for pathogenetic and therapeutic research.
The article presents the analytical review of literature on the evaluation and diagnostics of primary immunodefi ciency (PID) in children. In 2015, there was published the updated classifi cation of primary immunodefi ciencies compiled by the Primary Expert Committee of Immunodefi ciency (PID EC) and the International Union of Immunological Societies (IUIS). The new version contains 34 new gene defects. The most common types are defi ciency of production of antibodies, combined defi ciency of B-cell and T-cell elements, defi ciency of the system of complement and phagocytic element of the immune system. Children with these diseases often have atypical, unusually severe, recurrent infections, and infections badly responding to etiotropic therapy.
Bronchiectasis is a significant cause of morbidity and mortality. It is the end point of a pathological process. We should be aiming to identify at risk patients before they develop bronchiectasis and treat them aggressively to prevent disease progression. With improved social conditions and health care, infective causes of bronchiectasis have diminished in higher-income countries, and genetic causes are therefore relatively more common. The underlying cause of bronchiectasis should always be sought and readdressed, for example as discoveries of innate immune defects are made. ‘Idiopathic bronchiectasis’ should be a diagnosis of last resort. This chapter reviews potential genetic causes of bronchiectasis and suggests a plan for investigating the underlying aetiology. Management is discussed but it is important to note that suggested treatment strategies are often extrapolated from evidence in bronchiectasis associated with cystic fibrosis; this is likely to be inappropriate in diseases of differing pathophysiology. Rare lung diseases need to be moved out of the ‘orphan’ category by instigating multi-centre, multi-national clinical trials and producing disease-specific evidence-based guidelines.KeywordsBronchiectasisGeneticCystic fibrosisPrimary ciliary dyskinesiaPrimary immunodeficiencyDiagnosisManagementPathophysiology
Some studies have found increased coronavirus disease-19 (COVID-19)-related morbidity and mortality in patients with primary antibody deficiencies. Immunization against COVID-19 may, therefore, be particularly important in these patients. However, the durability of the immune response remains unclear in such patients. In this study, we evaluated the cellular and humoral response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in a cross-sectional study of 32 patients with primary antibody deficiency (n = 17 with common variable immunodeficiency (CVID) and n = 15 with selective IgA deficiency) and 15 healthy controls. Serological and cellular responses were determined using enzyme-linked immunosorbent assay and interferon-gamma release assays. The subsets of B and T lymphocytes were measured using flow cytometry. Of the 32 patients, 28 had completed the vaccination regimen with a median time after vaccination of 173 days (IQR = 142): 27 patients showed a positive spike-peptide-specific antibody response, and 26 patients showed a positive spike-peptide-specific T-cell response. The median level of antibody response in CVID patients (5.47 ratio (IQR = 4.08)) was lower compared to healthy controls (9.43 ratio (IQR = 2.13)). No difference in anti-spike T-cell response was found between the groups. The results of this study indicate that markers of the sustained SARS-CoV-2 spike-specific immune response are detectable several months after vaccination in patients with primary antibody deficiencies comparable to controls.
One gene, the immunoglobulin heavy chain (IgH) gene, is responsible for the expression of all the different antibody isotypes. Transcriptional regulation of the IgH gene is complex and involves several regulatory elements including a large element at the 3’ end of the IgH gene locus (3’RR). Animal models have demonstrated an essential role of the 3’RR in the ability of B cells to express high affinity antibodies and to express different antibody classes. Additionally, environmental chemicals such as aryl hydrocarbon receptor (AhR) ligands modulate mouse 3’RR activity that mirrors the effects of these chemicals on antibody production and immunocompetence in mouse models. Although first discovered as a mediator of the toxicity induced by the high affinity ligand 2,3,7,8-tetracholordibenzo-p-dioxin (dioxin), understanding of the AhR has expanded to a physiological role in preserving homeostasis and maintaining immunocompetence. We posit that the AhR also plays a role in human antibody production and that the 3’RR is not only an IgH regulatory node but also an environmental sensor receiving signals through intrinsic and extrinsic pathways, including the AhR. This review will 1) highlight the emerging role of the AhR as a key transducer between environmental signals and altered immune function; 2) examine the current state of knowledge regarding IgH gene regulation and the role of the AhR in modulation of Ig production; 3) describe the evolution of the IgH gene that resulted in species and population differences; and 4) explore the evidence supporting the environmental sensing capacity of the 3’RR and the AhR as a transducer of these cues. This review will also underscore the need for studies focused on human models due to the premise that understanding genetic differences in the human population and the signaling pathways that converge at the 3’RR will provide valuable insight into individual sensitivities to environmental factors and antibody-mediated disease conditions, including emerging infections such as SARS-CoV-2.
Non-cystic fibrosis bronchiectasis (NCFB) may be caused by several different systemic diseases that also have pulmonary manifestations. This is not unexpected since bronchiectasis is not a single disease but a condition that can be the result of many different diseases and pathological processes. Awareness of these diseases is critical. First, physicians who primarily care for those systemic diseases need to be aware of bronchiectasis as a possible complication. Second, pulmonologists who see patients with these systemic diseases need to have an appropriate index of suspicion so they can monitor for and diagnose bronchiectasis at an early timepoint and initiate treatments such as airway clearance early. Lastly, pulmonologists caring for bronchiectasis patients also need to be aware since some of those systemic diseases’ initial manifestations may be through pulmonary complications such as bronchiectasis and can help diagnose previously unappreciated systemic diseases.In this chapter, we will review the major systemic diseases that can lead to bronchiectasis with a focus on pathological basis for bronchiectasis development, key epidemiology, and demographics of the systemic disease to help raise awareness of the previously undiagnosed patient with said systemic disease, and unique considerations in the management of bronchiectasis for patients with that systemic disease.KeywordsPrimary ciliary dyskinesiaPrimary immunodeficienciesRheumatoid arthritisSjogren’s syndromeRelapsing polychondritisFibrillinopathiesSarcoidosisAlpha one antitrypsin deficiency
A 35-year-old male presented with fatigue for 1 month and was found to have megaloblastic anaemia. Further evaluation showed low globulin levels and pan hypogammaglobulinemia. Past history was significant for chronic small bowel diarrhoea and bilateral genu valgum deformity from childhood. Hence, a malabsorption syndrome with a probable antibody deficiency was suspected. An upper gastrointestinal (GI) endoscopy was done, which revealed chronic atrophic gastritis with Helicobacter pylori infection, dysplasia and subtotal villous atrophy with a paucity of plasma cells, which was suggestive of common variable immunodeficiency (CVID)-related enteropathy. CVID can present with predominantly autoimmune GI manifestations without any history of recurrent infections. The risk of gastric dysplasia and malignancy is high in CVID and needs close monitoring.
Background
Inborn errors of immunity (IEI) predispose patients to various infectious and non-infectious complications. Thanks to the development and expanding use of flow cytometry and increased awareness, the diagnostic rate of IEI has markedly increased in Algeria the last decade.AimThis study aimed to describe a large cohort of Algerian patients with probable IEI and to determine their clinical characteristics and outcomes.Methods
We collected and analyzed retrospectively the demographic data, clinical manifestations, immunologic, genetic data, and outcome of Algerian IEI patients - diagnosed in the department of medical immunology of Beni Messous university hospital center, Algiers, from 2008 to 2021.ResultsEight hundred and seven patients with IEI (482 males and 325 females) were enrolled, 9.7% of whom were adults. Consanguinity was reported in 50.3% of the cases and a positive family history in 32.34%. The medium age at disease onset was 8 months and at diagnosis was 36 months. The median delay in diagnosis was 16 months. Combined immunodeficiencies were the most frequent (33.8%), followed by antibody deficiencies (24.5%) and well-defined syndromes with immunodeficiency (24%). Among 287 patients tested for genetic disorders, 129 patients carried pathogenic mutations; 102 having biallelic variants mostly in a homozygous state (autosomal recessive disorders). The highest mortality rate was observed in patients with combined immunodeficiency (70.1%), especially in patients with severe combined immunodeficiency (SCID), Omenn syndrome, or Major Histocompatibility Complex (MHC) class II deficiency.Conclusion
The spectrum of IEI in Algeria is similar to that seen in most countries of the Middle East and North Africa (MENA) region, notably regarding the frequency of autosomal recessive and/or combined immunodeficiencies.
Bacterial respiratory tract infections are the hallmark of primary antibody deficiencies (PADs). Because they are also among the most common infections in healthy individuals, PADs are usually overlooked in these patients. Careful evaluation of the history, including frequency, chronicity, and presence of other infections, would help suspect PADs. This review will focus on infections in relatively common PADs, discussing diagnostic challenges, and some management strategies to prevent infections.
Predominantly antibody deficiency (PAD) is the most prevalent form of primary immunodeficiency, and is characterized by broad clinical, immunological and genetic heterogeneity. Utilizing the current gold standard of whole exome sequencing for diagnosis, pathogenic gene variants are only identified in less than 20% of patients. While elucidation of the causal genes underlying PAD has provided many insights into the cellular and molecular mechanisms underpinning disease pathogenesis, many other genes may remain as yet undefined to enable definitive diagnosis, prognostic monitoring and targeted therapy of patients. Considering that many patients display a relatively late onset of disease presentation in their 2nd or 3rd decade of life, it is questionable whether a single genetic lesion underlies disease in all patients. Potentially, combined effects of other gene variants and/or non-genetic factors, including specific infections can drive disease presentation. In this review, we define (1) the clinical and immunological variability of PAD, (2) consider how genetic defects identified in PAD have given insight into B-cell immunobiology, (3) address recent technological advances in genomics and the challenges associated with identifying causal variants, and (4) discuss how functional validation of variants of unknown significance could potentially be translated into increased diagnostic rates, improved prognostic monitoring and personalized medicine for PAD patients. A multidisciplinary approach will be the key to curtailing the early mortality and high morbidity rates in this immune disorder.
Knowledge of the range of non-neoplastic and benign mediastinal and thymic lesions is indispensable due to their morphological similarity to their neoplastic counterparts. Therefore, non-neoplastic lesions should always be included in the differential diagnosis during diagnostic workup of any mediastinal mass. Clinically and radiologically, these lesions often closely mimic mediastinal malignancies and tissue diagnosis is usually necessary for definitive diagnosis. Consideration of the age of the patient, symptomatology, laboratory results, as well as the exact topography of the lesion diagnosis or even resection of the entire lesion is often is usually necessary for definitive diagnosis. Important for correct diagnosis of thymic lesions is also Consideration of the age of the patient, symptomatology, laboratory results, as well as the exact topography of the lesion are other important factors in the evaluation of mediastinal lesions. Another crucial parameter in the assessment of thymic pathology is the size and weight of the thymus in relation to an age-specific reference range.
Introduction
The prevalence of undiagnosed primary immunodeficiency diseases is remarkably high and contributes to increasing the rate of morbidity and mortality among this group of patients.
Objective
To examine the 10 warning sign scoring system in patients suspected of primary immune deficiency and also estimate the diagnostic delay in patients with proven disease.
Methods
This descriptive cross-sectional study was carried out during the years 2015–2016 in Ali Asghar (AS) Clinic and Hospital. Two hundred patients with suspected primary immune deficiency disease were eligible for inclusion in the study. Multivariable logistic regression analysis was used to determine the relation between findings.
Results
In this study, the majority of suspected cases of immunodeficiency were males (57%) with a mean age of 3.33 ± 2.89 years. Twenty-one (10.5%) patients were diagnosed with immunodeficiency disease. The mean diagnostic delay among primary immune deficient patients was 2.05 ± 1.7 years. There was a significant relationship between having parental consanguinity (OR = 2.68, 95% CI: 1.07–6.70), allergies (OR = 5.03, 95% CI: 1.13–22.31), vaccine adverse effects (OR = 9.31, 95% CI: 1.24–69.96) and primary immune deficiency diagnosis. No association was observed between age (OR = 0.98, 95% CI: 0.84–1.14), gender (OR = 0.99, 95% CI: 0.39–2.47), immune deficiency scoring (OR = 0.68, 95% CI: 0.31–1.45) and primary immune deficiency diagnosis.
Conclusion
Ten warning sign scoring system is of less value to consider a patient suspected of having primary immune deficiency. There is a meaningful delay in diagnosis of primary immune deficiencies especially in antibody deficiency defects which seeks further upgrading of knowledge in physicians.
Aim:
To determine the frequency of sinopulmonary infections, detect changes in the respiratory system, and measure functional capacity of the lungs in our patients with humoral immunodeficiency.
Material and methods:
Fifty-six patients with humoral immunodeficiency were enrolled in this study. The clinical, laboratory, and radiologic data, and pulmonary function tests of the subjects were evaluated from their file records, retrospectively.
Results:
The distribution of our patients was as follows: 25 patients had common variable immune deficiency, three patients had X-linked agammaglobulinemia, five patients had hyper immunoglobulin M syndrome, 19 patients had deficiency of immunoglobulin G subset, and four patients had selective immunoglobulin A deficiency. The most common symptom of the patients was chronic cough (n=47, 83.9%). The most common pathologies on high-resolution computed tomography of the chest were atelectasis and bronchiectasis (27.7%). The most common pathology in pulmonary function tests was the presence of moderate obstructive patterns along with restrictive patterns (n=6,12.5%). The FEV 1, FVC, and FEF 25-75 values were significantly lower in patients with common variable immunodeficiency compared with the patients who had IgG subset deficiencies (p=0.001, p=0.01, p=0.01). Among the patients who were treated with intravenous immunoglobulin, the age at the diagnosis of immunodeficiency was higher in patients with bronchiectasis (14.2±8.4 years) compared with those without bronchiectasis (10.1±11.4 years) (p=0.04).
Conclusion:
Clinical findings are not sufficient to monitor the structural and functional changes in the respiratory system, and patients should be evaluated using high-resolution computed tomography of the chest and pulmonary function tests.
Unlabelled:
Primary immunodeficiencies (PIDs) belong to the group of rare diseases. The European Society for Immunodeficiencies (ESID), is establishing an innovative European patient and research database network for continuous long-term documentation of patients, in order to improve the diagnosis, classification, prognosis and therapy of PIDs. The ESID Online Database is a web-based system aimed at data storage, data entry, reporting and the import of pre-existing data sources in an enterprise business-to-business integration (B2B). The online database is based on Java 2 Enterprise System (J2EE) with high-standard security features, which comply with data protection laws and the demands of a modern research platform.
Availability:
The ESID Online Database is accessible via the official website (http://www.esid.org/).
Supplementary information:
Supplementary data are available at Bioinformatics online.
Primary immunodeficiency disorders are heterogeneous group of illnesses that predispose patients to serious complications. Registries for these disorders have provided important epidemiological data and shown both racial and geographical variations. The clinical features of 76 patients with primary immunodeficiency disorders registered in Kuwait National Primary Immunodeficiency Registry from 2004 to 2006 were recorded. Ninety-eight percent of the patients presented in childhood. The prevalence of these disorders in children was 11.98 in 100,000 children with an incidence of 10.06 in 100,000 children. The distribution of these patients according to each primary immunodeficiency category is: combined T and B cell immunodeficiencies (21%), predominantly antibody immunodeficiency (30%), other well defined immunodeficiencies (30%), diseases of immune dysregulation (7%), congenital defects of phagocyte number, function or both (8%), and complement deficiencies (4%). The consanguinity rate within the registered patients was 77%. The patients had a wide range of clinical features affecting different body systems. Primary immunodeficiency disorders are prevalent in Kuwait and have a significant impact into the health system.
Primary Immunodeficiency Diseases presents discussions of gene identification, mutation detection, and clinical and research applications for over 100 genetic immune disorders - disorders featuring an increased susceptibility to infections and, in, certain conditions, an increased rate of malignancies and autoimmune disorders. This resource proudly documents the tremendous pace of progress in dissecting the complex immunologic networks responsible for protecting individuals from these disorders.
Common variable immunodeficiency (CVI) is a het erogenous immunodeficiency syndrome characterized by hypogammaglob ulinemia, recurrent bacterial infec tions, and various immunologic abnormalities. In addi tion to recurrent infections, patients with this syndrome also have an increased incidence of autoimmune dis ease and malignancy. Because the spectrum of asso ciated diseases is broad, patients with CVI are seen by various medical specialists. This review discusses the pathogenesis, clinical manifestations, diagnosis, and treatment of CVI.
Immunoglobulins (IgG) as replacement therapy in primary antibody deficiencies can be given as intramuscular injections, or as intravenous or subcutaneous infusions. Our aims were to obtain information on the frequency of adverse systemic reactions during subcutaneous therapy, the occurrence and intensity of tissue reactions at the infusion sites, and serum IgG changes. Furthermore, we compared costs between the different replacement regimes. Our study included 165 patients (69 women, 96 men, aged 13-76 years) with primary hypogammaglobulinaemia or IgG-subclass deficiencies. Data were compiled from questionnaires filled in by the patients and from their medical records. 33,168 subcutaneous infusions (27,030 in home therapy) had been given. 106 (of which 16 were at home) adverse systemic reactions (100 mild, 6 moderate) were recorded in 28 patients (17%). No severe or anaphylactoid reactions occurred. Despite large immunoglobulin volumes given during 434 patient years (28,480 infusions), no signs have been found that indicate the transmission of hepatitis virus. Transient tissue reactions occurred at the infusion sites but were not troublesome to most patients and we found significant increases in mean serum IgG. The use of subcutaneous instead of intravenous infusions at home would reduce the yearly cost per patient for the health-care sector by US $10,100 in Sweden alone. We conclude that subcutaneous administration of IgG is a safe and convenient method of providing immunoglobulins. We were able to reach serum IgG concentrations similar to those by the intravenous therapy and we found that the method could also be used successfully in patients with previous severe or anaphylactoid reactions to intramuscular injections.
Common variable immunodeficiency (CVI) is a heterogenous immunodeficiency syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections, and various immunologic abnormalities. In addition to recurrent infections, patients with this syndrome also have an increased incidence of autoimmune disease and malignancy. Because the spectrum of associated diseases is broad, patients with CVI are seen by various medical specialists. This review discusses the pathogenesis, clinical manifestations, diagnosis, and treatment of CVI.
The Spanish Registry for Primary Immunodeficiency Diseases (REDIP) was organized in 1993. One thousand sixty-nine cases of primary immunodeficiency diseases (PID) were registered in patients diagnosed between January 1980 and December 1995. PID diagnosis was made according to the World Health Organization criteria. The most frequent disorders were IgA deficiency (n = 394) and common variable immunodeficiency (n = 213), followed by severe combined immunodeficiency (n = 61), C1 inhibitor deficiency (n = 52), X-linked agammaglobulinemia (n = 49), IgG subclass deficiency (n = 48), and chronic granulomatous disease (n = 32). A comparative study between REDIP and data recently obtained from the European registry (ESID Report, 1995) revealed important differences between phagocytic disorders and complement deficiencies reported in both registries, 4.9 vs 8.7 and 6.0 vs 3.6, while percentages of predominantly antibody deficiencies and T cell and combined deficiencies concurred with those reported in the European registry, 69.3 vs 64.7 and 14.7 vs 20.2, respectively. The heterogeneous nature of the geographical distribution of cases submitted may indicate underdiagnosis of PID in some country areas; surprisingly, the interval between the onset of clinical symptoms and diagnosis was significant, even in immunodeficiency diseases, such as IgA deficiency, which are easy to diagnose.
This study represents the first national epidemiological survey of primary immunodeficiency diseases in Norway. Uniform questionnaires were sent out in April 1998 to all hospital departments considered relevant. As of February 1999, a total of 372 patients have been registered, of whom 69 patients are deceased. With a population of 4.45 million people, the total prevalence of primary immunodeficiency diseases in Norway February 1, 1999 is 6.82 per 100000 inhabitants. Distribution between the main immunodeficiency diagnoses is (a) antibody deficiencies 50.8%, (b) combined deficiencies included other immunodeficiency syndromes 12.4%, (c) complement deficiencies 21.0%, (d) phagocytic disorders 6.7%, (e) and immunodeficiency associated with other congenital diseases 9. 1%. Compared to previous reports from other European countries, there is a smaller proportion of antibody deficiencies due to few IgA deficiencies registered and a large proportion of complement deficiencies due to many patients with hereditary angioedema.
Although relatively rare, primary immunodeficiency diseases (PIDs) provide an excellent window into the functioning of the immune system. In the late 1960s, observations on these diseases, with their associated infections and genetics, bisected the immune system into humoral immunity and cell-mediated immunity. These diseases also represent a challenge in their diagnosis and treatment. Beginning in 1970, a unified nomenclature for the then-known PIDs was created by a committee convoked by the World Health Organization. Since then, and later under the aegis of the International Union of Immunological Societies, an international committee of experts has met every 2 to 3 years to update the classification of PIDs. During the past 15 years, the molecular basis of more than 120 PIDs has been elucidated. This update results from the latest meeting of this committee in Budapest, Hungary, in June 2005, which followed 2 1/2 days of scientific discussions. As a result of this work, new entities have been included, and the nomenclature of some PIDs (specifically of the various forms of class-switch recombination defects, previously known as hyper-IgM syndromes) has been changed.
Because primary immunodeficiencies (PID) are rare diseases, transnational studies are essential to maximize the scientific outcome and lead to improved diagnosis and therapy. Immunologists in Europe have united to determine the prevalence of PID in Europe and to establish and evaluate harmonized guidelines for the diagnosis and treatment of PID as well as to improve the awareness of PID in Europe. In order to achieve this aim we have developed an internet-based database for clinical and research data on patients with PID. This database forms the platform for studies of demographics, the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. The database is completely secure, while providing access to researchers via a standard browser using password and encrypted log-in sessions and conforms to all European and national ethics and data protection guidelines. So far 2386 patients have been documented by 35 documenting centres in 20 countries. Common variable immunodeficiency (CVID) is the most common entity, accounting for almost 30% of all entries. First statistical analyses on the quality of life of patients show the advantages of immunoglobulin replacement therapy, at the same time revealing a mean diagnostic delay of over 4 years. First studies on specific questions on selected PID are now under way. The platform of this database can be used for any type of medical condition.
Despite rapid developments in the science of primary immunodeficiency diseases (PID), population characteristics and the burden of disease are poorly characterized. Aggregated data on PID via patient registries are a key component of the public health response. The web-enabled Australasian Society of Clinical Immunology and Allergy PID Register was designed and implemented to address gaps in knowledge of PID.
The register provided a cumulative, cross-sectional survey of PID patients in Australia and New Zealand via an online, single time point, center-based, voluntarily recalled, and patient-consented questionnaire.
Eighty-eight centers reported 1,209 patients across 56 separate PID syndromes. The study prevalence (cases per 100,000 population) was 5.6 for Australia, 12.4 for the state of South Australia, and 4.9 for Australia and New Zealand combined. Predominately antibody deficiency syndromes accounted for 77% of patients. Common variable immunodeficiency was the most common diagnosis. Patients were geographically dispersed with 80% of centers reporting caseloads of less than 20 patients. Potentially preventable complications of disease were common. Immunoglobulin replacement therapy was used in 30 conditions with 26.5% of the total recipients having antibody deficiency disorders with normal serum IgG.
PID in Australia and New Zealand are prevalent, clinically diverse, geographically dispersed, and are characterized by high rates of potentially preventable morbidity and resource utilization. A public health focus on PID is required, including strategies to correct disparities in access to care, improve molecular diagnostics and reduce preventable complications of disease. Further studies in antibody deficiency syndromes with normal serum IgG are required.
Primary immunodeficiency diseases (PIDs) are a genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system, such as neutrophils, macrophages, dendritic cells, complement proteins, natural killer cells, and T and B lymphocytes. The study of these diseases has provided essential insights into the functioning of the immune system. More than 120 distinct genes have been identified, whose abnormalities account for more than 150 different forms of PID. The complexity of the genetic,immunologic, and clinical features of PID has prompted the need for their classification, with the ultimate goal of facilitating diagnosis and treatment. To serve this goal, an international committee of experts has met every 2 years since 1970. In its last meeting in Jackson Hole, Wyo, after 3 days of intense scientific presentations and discussions, the committee has updated the classification of PID, as reported in this article.
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