Primary Immunodeficiency Registry Research Articles

Long term longitudinal follow-up of an AD-HIES cohort: the impact of early diagnosis and enrollment to IPINet centers on the natural history of Job’s syndrome

Job’s syndrome, or autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES, STAT3-Dominant Negative), is a rare inborn error of immunity (IEI) with multi-organ involvement and long-life post-infective damage. Longitudinal registries are of primary importance in improving our knowledge of the natural history and management of these rare disorders. This study aimed to describe the natural history of 30 Italian patients with AD-HIES recorded in the Italian network for primary immunodeficiency (IPINet) registry. This study shows the incidence of manifestations present at the time of diagnosis versus those that arose during follow up at a referral center for IEI. The mean time of diagnostic delay was 13.7 years, while the age of disease onset was < 12 months in 66.7% of patients. Respiratory complications, namely bronchiectasis and pneumatoceles, were present at diagnosis in 46.7% and 43.3% of patients, respectively. Antimicrobial prophylaxis resulted in a decrease in the incidence of pneumonia from 76.7% to 46.7%. At the time of diagnosis, skin involvement was present in 93.3% of the patients, including eczema (80.8%) and abscesses (66.7%). At the time of follow-up, under therapy, the prevalence of complications decreased: eczema and skin abscesses reduced to 63.3% and 56.7%, respectively. Antifungal prophylaxis decreased the incidence of mucocutaneous candidiasis from 70% to 56.7%. During the SARS-CoV-2 pandemic, seven patients developed COVID-19. Survival analyses showed that 27 out of 30 patients survived, while three patients died at ages of 28, 39, and 46 years as a consequence of lung bleeding, lymphoma, and sepsis, respectively. Analysis of a cumulative follow-up period of 278.7 patient-years showed that early diagnosis, adequate management at expertise centers for IEI, prophylactic antibiotics, and antifungal therapy improve outcomes and can positively influence the life expectancy of patients.

Historical Cohort of Severe Congenital Neutropenia in Iran: Clinical Course, Laboratory Evaluation, Treatment, and Survival.

Severe congenital neutropenia (SCN) is one of the primary immunodeficiency diseases developed by genetic alterations. Mutations in several genes including HAX-1 , G6PC3 , jagunal , and VPS45 account for autosomal recessive SCN. Patients with SCN registered in the Iranian Primary Immunodeficiency Registry and referred to our clinic at the Children's Medical Center were reviewed. Thirty-seven eligible patients with a mean age of 28.51 ± 24.38 months at the time of diagnosis were included. Nineteen cases had consanguineous parents and 10 cases had confirmed or unconfirmed positive family history. The most prevalent infectious symptoms were oral infections followed by respiratory infections. We identified HAX-1 mutation in 4, ELANE mutation in 4 cases, G6PC3 mutation in 1, and WHIM syndrome in 1 case. Other patients remained genetically unclassified. After the median follow-up of 36 months from the time of diagnosis, the overall survival was 88.88%. The mean event-free survival was 185.84 months (95% CI: 161.02, 210.66). Autosomal recessive SCN is more common in countries with high rates of consanguinity like Iran. The genetic classification was possible only for a few patients in our study. This might suggest that there are other autosomal recessive genes causative of neutropenia that have yet to be described.

Allogeneic Hematopoietic Stem Cell Transplantation Activity in Inborn Errors of Immunity in Russian Federation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is an established therapy for many inborn errors of immunity (IEI). The indications for HSCT have expanded over the last decade. The study aimed to collect and analyze the data on HSCT activity in IEI in Russia. The data were collected from the Russian Primary Immunodeficiency Registry and complemented with information from five Russian pediatric transplant centers. Patients diagnosed with IEI by the age of 18 years and who received allogeneic HSCT by the end of 2020 were included. From 1997 to 2020, 454 patients with IEI received 514 allogeneic HSCT. The median number of HSCTs per year has risen from 3 in 1997-2009 to 60 in 2015-2020. The most common groups of IEI were immunodeficiency affecting cellular and humoral immunity (26%), combined immunodeficiency with associated/syndromic features (28%), phagocyte defects (21%), and diseases of immune dysregulation (17%). The distribution of IEI diagnosis has changed: before 2012, the majority (65%) had severe combined immunodeficiency (SCID) and hemophagocytic lymphohistiocytosis (HLH), and after 2012, only 24% had SCID and HLH. Of 513 HSCTs, 48.5% were performed from matched-unrelated, 36.5% from mismatched-related (MMRD), and 15% from matched-related donors. In 349 transplants T-cell depletion was used: 325 TCRαβ/CD19+ depletion, 39 post-transplant cyclophosphamide, and 27 other. The proportion of MMRD has risen over the recent years. The practice of HSCT in IEI has been changing in Russia. Expanding indications to HSCT and SCID newborn screening implementation may necessitate additional transplant beds for IEI in Russia.

Autoinflammatory undifferentiated syndrome

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

Cardiac Complications in Patients with Common Variable Immune Deficiency: A Longitudinal Study

Background: The common variable immune deficiency (CVID) is known as the most prevalent symptomatic primary immune deficiency (PID) diseases, which is characterized by hypogammaglobulinemia with variable infectious and noninfectious manifestations. In this study, the researchers aimed to evaluate the frequency of cardiac disorders and investigate its association with other manifestations in CVID patients.&#x0D; Method: A total of 337 CVID patients registered in the Iranian Primary Immunodeficiency Registry were evaluated in this study. The questionnaire was completed for all patients to collect the participants’ demographic data, clinical manifestations and laboratory finding. The analysis was performed between the two groups of the study including CVID patients with cardiac manifestation and those without it.&#x0D; Results: The prevalence rate of cardiac manifestation was calculated to be 9.1%. pericardial and myocardial diseases and pulmonary hypertension were the most prevalent complications. CVID patients with a history of cardiac problem had significantly higher prevalence rates of otitis media, lymphoproliferative disorders, splenomegaly, hepatomegaly, failure to thrive and lower numbers of CD8+ T cells and CD19+ B cells compared to the patients without cardiac disorders. Notably, no significant differences were observed in immunoglobulins serum levels, CD3+ and CD4+ T cells between the patients with and without cardiac manifestation.&#x0D; Conclusion: Regular echocardiographic evaluation and of CVID patients for cardiac complications especially for inflammatory cardiac disease, heart failure and pulmonary hypertension, is critical to reduce the risk of heart disease.

Peripheral-blood cytopenia, an early indicator of inborn errors of immunity.

SummaryInborn errors of immunity (IEI) are inherited monogenic disorders resulting in defective immune response. Non‐infectious presentations are increasingly more apparent. Widely available, cost‐effective early indicators are needed. Peripheral‐blood cytopenia may be a presenting laboratory feature or an observed secondary phenomenon. This retrospective review of the South African Primary Immunodeficiency Registry (SAPIDR) aimed to assess the haematological indices at presentation and their association with the International Union of Immunological Societies (IUIS) 2019 IEI classification and mortality. Of 396 patients on the SAPIDR, 66% (n = 257) had available haematological results. Sixty percent were males and 85% under 18 years. A majority (53%) had predominantly antibody deficiency. At presentation, infection was prominent (86%) followed by cytopenia (62%). Neutropenia was associated with IUIS III [odds ratio (OR) 3.65, confidence interval (CI) 1.44–9.25], thrombocytopenia with IUIS II (OR 14.39, CI 2.89–71.57), lymphopenia with IUIS I (OR 12.16, CI 2.75–53.73) and pancytopenia with IUSI I (OR 12.24, CI 3.82–39.05) and IUIS II (OR 5.99, CI 2.80–12.76). Cytopenia showed shorter overall survival (OR 2.81, CI 1.288–4.16). Cytopenias that are severe, persistent, unusual and/or recurrent should prompt further investigation for IEI. The full blood count and leucocyte differential may facilitate earlier identification and serve as an adjunct to definitive molecular classification.

Comparison of Demographic and Clinical Characteristics Among X-Linked and Autosomal Recessive Agammaglobulinemia

Background: Congenital agammaglobulinemia is an inborn error of immunity, resulting in the impairment of effective antibody production. Agammaglobulinemia may be due to X-linked or autosomal genetic abnormalities. The primary defect in X-Linked agammaglobulinemia (XLA) and autosomal recessive agammaglobulinemia (ARAG) is the B cell precursors’ failure to mature B-lymphocytes and, ultimately, plasma cells. This study aims to evaluate the differences in clinical and paraclinical characteristics of XLA and ARAG patients. Method: A total of 58 patients were enrolled in this retrospective study. The data were extracted from the Iranian primary immunodeficiency registry (IPIDR). Forty-eight of the patients were diagnosed with XLA, while the other ten were diagnosed with ARAG. Measures including demographic data, clinical manifestations, and laboratory data of the patients were compared between the groups. Results: Patients with ARAG, presented manifestations at an earlier age and had a lower diagnosis delay compared to XLA patients. However, the mortality rate was not significantly affected. The pattern of organ involvement also differed between the two groups, as patients with ARAG showed manifestations that are more chronic in nature (e.g., autoimmunity, lymphoproliferation, and allergy). In contrast, XLA patients were more prone to infections and other associated complications (e.g., meningitis, sinusitis, diarrhea, and bronchiectasis). Meningitis was exclusively observed in the XLA group. The number of CD19+ B cells was significantly higher in the ARAG group (P=0.002), While the level of IgM was significantly higher in the XLA group (P=0.045). Conclusion: Identifying the clinical presentations of XLA and ARAG, may assist clinicians in early diagnosis in the setting of limited available genetic studies.

Respiratory System Involvement in Patients with IgA Deficiency

Background: Selective IgA deficiency (SIgAD), is known as the most common antibody deficiency. This study, investigated the respiratory disorders among these patients. Method: In this retrospective descriptive study, the data of patients with SIgAD in “Iranian Primary Immunodeficiency Registry” were extracted. Then, demographic characteristics, frequency and type of respiratory disorders, in addition to immunologic findings were gathered and analyzed by SPSS software. Results: One hundred and twenty three patients with SIgAD (78 males/45 females), with the mean age of 18± 9.6 years old were investigated. Respiratory complications (recurrent cold, chronic cough and pneumonia), were the first presentation in 45% of the patients, and respiratory system involvement was detected among 66 patients (54.1%). The prevalence of pneumonia, otitis media and sinusitis, were 33.3%, 12.5% and 20.7%; respectively; which were significantly reduced after the diagnosis (PV&lt;0.05). Bronchiectasis had also been found in five patients (4.1%). Conclusion: Respiratory problems were shown to be common presenting disorders in SIgAD. Early diagnosis and appropriate therapy could be crucial for better protection, and avoidance of severe respiratory complications in these patients.

Immunoglobulin replacement therapy in patients with primary immunodeficiency diseases in Russia

According to the data from Russian primary immunodeficiencies (PID) registry 71% of registered patients were treated with immunoglobulins (IG). Regular immunoglobulin substitutions were reported in 90% of patients with primary antibody deficiencies (PAD), 86% - with syndromic PID and 91% of patients with combined T and B cell defects. The study was supported by Academic Council of Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology and approved by Local Ethical Committee within the Russian PID registry. Regular IG substitution was analyzed in the representative cohort of 235 PID patients from 12 Russian regions. Of these 121 were children, 114 – adults. In 78% cases IG treatment has been started during the first 10 years of life. 80% patients were treated with highly safe products (Octagam 5% and 10%, Privigen, IG VENA, Gamunex) reaching therapeutic median pre-infusion level of serum IgG of 7 g/l. Significantly lower levels of pre-infusion serum IgG were observed in patients treated with Gabreglobin-IgG. Irregular treatment was observed in 61% of patients mainly due to the poor drug supply (lack of medication in the health care centers). Infections were reported in 90% percent of patients with irregular treatment. Unscheduled hospitalizations were two times more frequent in the group of patients with irregular IVIG treatment. Additionally, we assessed quality of life of patients with regular IVIG treatment, which significantly improved in comparison with the pretreatment period and became comparable to the group of healthy controls.

ТЕЧЕНИЕ ИНФЕКЦИИ COVID-19 У ПАЦИЕНТОВ С ПЕРВИЧНЫМИ ИММУНОДЕФИЦИТНЫМИ СОСТОЯНИЯМИ

The article presents data on the features of COVID-19 infection in patients with primary immunodeficiencies (PIDs) in the Russian Federation, obtained through the National association of experts in PID (NAEPID) registry. Materials and methods: from March 1, 2020 to October 15, 2020, 15 cases of close intrafamilial contact between PIDs patients and COVID-19 patients without reliable infection of the first and 23 cases of COVID-19 infection in PIDs patients were reported. Results: 6/23 infected people had asymptomatic course of infection, 9/23 patients – mild form, 8/23 – moderate form of disease, one patient had a severe course with a fatal outcome. 19/23 patients were under 18 years of age, which corresponds with the age data of the national Russia PID registry. Conclusion: perhaps this age composition partially explains the milder course of COVID-19 in PIDs patients compared to the European data. Other possible reasons for a milder course may be the lower pathogenicity of the coronavirus strain circulating in the Russian Federation.

Primary Immunodeficiencies in Russia: Data From the National Registry.

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.

Clinical and Mutation Description of the First Iranian Cohort of Infantile Inflammatory Bowel Disease: The Iranian Primary Immunodeficiency Registry (IPIDR)

ABSTRACT We describe a cohort of 25 Iranian patients with infantile inflammatory bowel disease (IBD), 14 (56%) of whom had monogenic defects. After proper screening, patients were referred for whole exome sequencing (WES). Four patients had missense mutations in the IL10 RA, and one had a large deletion in the IL10 RB. Four patients had mutations in genes implicated in host:microbiome homeostasis, including TTC7A deficiency, and two patients with novel mutations in the TTC37 and NOX1. We found a novel homozygous mutation in the SRP54 in a deceased patient and the heterozygous variant in his sibling with a milder phenotype. Three patients had combined immunodeficiency: one with ZAP-70 deficiency (T+B+NK−), and two with atypical SCID due to mutations in RAG1 and LIG4. One patient had a G6PC3 mutation without neutropenia. Eleven of the 14 patients with monogenic defects were results of consanguinity and only 4 of them were alive to this date.

Monogenic Primary Immunodeficiency Disorder Associated with Common Variable Immunodeficiency and Autoimmunity

Background: Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency disorder mainly characterized by recurrent bacterial infections besides other immunological defects including loss of or dysfunction of B cells and decreased immunoglobulin levels. In this study, our aim is to evaluate clinical, immunological, and molecular data of patients with a primary clinical diagnosis of CVID and autoimmune phenotype with a confirmed genetic diagnosis. Methods: Among 297 patients with CVID, who were registered in the Iranian Primary Immunodeficiency Registry at Children’s Medical Center Hospital in Iran, 83 patients have been genetically examined and 27 patients with autoimmunity and confirmed genetic mutations were selected for analysis. Whole-exome sequencing and confirmatory Sanger sequencing methods were used for the study population. A questionnaire was retrospectively filled for all patients to evaluate demographic, laboratory, clinical, and genetic data. Results: In the 27 studied patients, 11 different genetic defects were identified, and the most common mutated gene was LRBA, reported in 17 (63.0%) patients. Two patients (7.7%) showed autoimmune complications as the first presentation of immunodeficiency. Eleven patients (40.7%) developed one type of autoimmunity, and 16 patients (59.3%) progressed to poly-autoimmunity. Most of the patients with mono-autoimmunity (n = 9, 90.0%) primarily developed infectious complications, while in patients with poly-autoimmunity, the most common first presentation was enteropathy (n = 6, 37.6%). In 13 patients (61.9%), the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency. The most frequent autoimmune manifestations were hematologic (40.7%), gastrointestinal (48.1%), rheumatologic (25.9%), and dermatologic (22.2%) disorders. Patients with poly-autoimmunity had lower regulatory T cells than patients with mono-autoimmunity. Conclusion: In our cohort, the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency in most patients. This association highlights the fact that patients referring with autoimmune manifestations should be evaluated for humoral immunity.

Frequency and Manifestations of Autoimmunity Among Children Registered in the Kuwait National Primary Immunodeficiency Registry.

Objectives: To present a prospective report on the characteristics of autoimmune manifestations in patients with primary immunodeficient children registered in the Kuwait National PIDs Registry (KNPIDR).Methods: The data were obtained from the Kuwait National Primary Immunodeficiency Disorders Registry during the period of January 2004 to December 2019.Results: A total of 286 PID children were registered in KNPIDR during the study period with a predominance of immunodeficiencies affecting cellular and humoral immunity followed by combined immunodeficiencies with associated syndromic features and diseases of immune dysregulation. Fifty-seven (19.9%) patients presented with a total of 107 autoimmune manifestations. There was no significant statistical association between autoimmune manifestations and gender. Patients with autoimmune manifestations were older at onset of PID symptoms compared to those with no such manifestations, but this did not reach level of significance. The diagnosis delay was longer in patients with autoimmune manifestations compared to those with no such manifestations (p = 0.038). Forty-seven percent of these manifestations were among the presenting symptoms while 53% were documented later during the course of the disease. Fifty-seven percent of the patients developed 1 autoimmune manifestation, 30% developed 2 such manifestations, and 16% had ≥3 autoimmune manifestations. The most common autoimmune manifestation was cytopenia, followed by gastrointestinal manifestations and manifestations of the skin, hair, and nails. Autoimmune cytopenia were more common in patients with immune dysregulation syndromes, while gastrointestinal and skin manifestations predominate in patients with immunodeficiencies affecting cellular and humoral immunity and endocrine manifestations were more common in immune dysregulation syndromes. There were significant statistical associations between developing autoimmune manifestations and death as well as PID categories, being more common in patients with immune dysregulation. The frequency of autoimmunity was high among patients with RAG, WAS, STAT5b, NF-κB2, Fas, FasL, LRBA, APECED, IL-10, and C4 deficiencies.Conclusions: Autoimmunity is frequent in patients with PIDs in Kuwait. This should prompt the suspicion of a PID in patients who present initially with autoimmunity, especially autoimmune cytopenia. Such patients should be managed with extra care since they are at a higher risk of death.

Factors Beyond Lack of Antibody Govern Pulmonary Complications in Primary Antibody Deficiency.

Pulmonary complications occur frequently in primary antibody deficiency (PAD). While the impact of antibody deficiency may appear implicit for certain respiratory infections, immunoglobulin replacement therapy does not completely ameliorate pulmonary complications in PAD. Thus, there may be antibody-independent factors influencing susceptibility to respiratory disease in PAD, but these remain incompletely defined. We harnessed the multicenter US Immunodeficiency Network primary immunodeficiency registry to compare prevalence of asthma, bronchiectasis, interstitial lung disease (ILD), and respiratory infections between two forms of PAD: common variable immunodeficiency (CVID) and x-linked agammaglobulinemia (XLA). We also defined the clinical and immunological characteristics associated with ILD and asthma in CVID. Asthma, bronchiectasis, ILD, pneumonia, and upper respiratory infections were more prevalent in CVID than XLA. ILD was associated with autoimmunity, bronchiectasis, and pneumonia as well as fewer B and T cells in CVID. Asthma was the most common chronic pulmonary complication and associated with lower IgA and IgM in CVID. Age of symptom onset or CVID diagnosis was unrelated with ILD or asthma. Despite having less severe immunoglobulin deficiency than XLA, respiratory infections, ILD, and asthma were more common in CVID. Among CVID patients, ILD was associated with autoimmunity and reduced lymphocytes and asthma with lower immunoglobulins. Though our results are tempered by registry limitations, they provide evidence that factors beyond lack of antibody promote pulmonary complications in PAD. Efforts to understand how genetic etiology, nature of concurrent T cell deficiency, and propensity for autoimmunity shape pulmonary disease may improve treatment of PAD.

The United Kingdom Primary Immune Deficiency (UKPID) registry 2012 to 2017.

This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well-established registry.

Gene therapy in rare diseases: the benefits and challenges of developing a patient-centric registry for Strimvelis in ADA-SCID

BackgroundStrimvelis (autologous CD34+ cells transduced to express adenosine deaminase [ADA]) is the first ex vivo stem cell gene therapy approved by the European Medicines Agency (EMA), indicated as a single treatment for patients with ADA-severe combined immunodeficiency (ADA-SCID) who lack a suitable matched related bone marrow donor. Existing primary immunodeficiency registries are tailored to transplantation outcomes and do not capture the breadth of safety and efficacy endpoints required by the EMA for the long-term monitoring of gene therapies. Furthermore, for extended monitoring of Strimvelis, the young age of children treated, small patient numbers, and broad geographic distribution of patients all increase the risk of loss to follow-up before sufficient data have been collected. Establishing individual investigator sites would be impractical and uneconomical owing to the small number of patients from each location receiving Strimvelis.ResultsAn observational registry has been established to monitor the safety and effectiveness of Strimvelis in up to 50 patients over a minimum of 15 years. To address the potential challenges highlighted above, data will be collected by a single investigator site at Ospedale San Raffaele (OSR), Milan, Italy, and entered into the registry via a central electronic platform. Patients/families and the patient’s local physician will also be able to submit healthcare information directly to the registry using a uniquely designed electronic platform. Data entry will be monitored by a Gene Therapy Registry Centre (funded by GlaxoSmithKline) who will ensure that necessary information is collected and flows between OSR, the patient/family and the patient’s local healthcare provider.ConclusionThe Strimvelis registry sets a precedent for the safety monitoring of future gene therapies. A unique, patient-focused design has been implemented to address the challenges of long-term follow-up of patients treated with gene therapy for a rare disease. Strategies to ensure data completeness and patient retention in the registry will help fulfil pharmacovigilance requirements. Collaboration with partners is being sought to expand from a treatment registry into a disease registry. Using practical and cost-efficient approaches, the Strimvelis registry is hoped to encourage further innovation in registry design within orphan drug development.

Burden of Poor Health Conditions and Quality of Life in 656 Children with Primary Immunodeficiency

To gain insight into how primary immunodeficiencies (PIDs) affect children's health status and quality of life. The French Reference Center for PIDs conducted a prospective multicenter cohort that enrolled participants who met all criteria: patients included in the French Reference Center for PIDs registry, children younger than18 years, and living in France. Participants were asked to complete both a health questionnaire and a health-related quality of life (HR-QoL) questionnaire. A severity score was assigned to each health condition: grade 1 (mild) to grade 4 (life-threatening). HR-QoL in children was compared with age- and sex-matched French norms. Among 1047 eligible children, 656 were included in the study, and 117 had undergone hematopoietic stem cell transplantation; 40% experienced at least one grade 4 condition, and 83% experienced at least one grade 3 or 4 condition. Compared with the French norms, children with PID scored significantly lower for most HR-QoL domains. Low HR-QoL scores were associated strongly with burden of poor conditions. Our results quantify the magnitude of conditions in children with PID and demonstrate that the deleterious health effects borne by patients already are evident in childhood. These results emphasize the need to closely monitor this vulnerable population and establish multidisciplinary healthcare teams from childhood. ClinicalTrials.gov: NCT02868333 and EudraCT 2012-A0033-35.

A homozygous mutation in the stem II domain of RNU4ATAC causes typical Roifman syndrome

Roifman syndrome (OMIM# 616651) is a complex syndrome encompassing skeletal dysplasia, immunodeficiency, retinal dystrophy and developmental delay, and is caused by compound heterozygous mutations involving the Stem II region and one of the other domains of the RNU4ATAC gene. This small nuclear RNA gene is essential for minor intron splicing. The Canadian Centre for Primary Immunodeficiency Registry and Repository were used to derive patient information as well as tissues. Utilising RNA sequencing methodologies, we analysed samples from patients with Roifman syndrome and assessed intron retention. We demonstrate that a homozygous mutation in Stem II is sufficient to cause the full spectrum of features associated with typical Roifman syndrome. Further, we demonstrate the same pattern of aberration in minor intron retention as found in cases with compound heterozygous mutations.

Chronic Granulomatous Disease in Patients Reaching Adulthood: A Nationwide Study in France.

Although prognosis of Chronic Granulomatous Disease (CGD) has greatly improved, few studies have focused on its long-term outcome. We studied the clinical course and sequelae of CGD patients diagnosed before age 16, at various adult time points. Cross-sectional French nationwide retrospective study of patients screened through the National Reference Center for Primary Immunodeficiencies (CEREDIH) registry. Eighty CGD patients (71 males [88.7%], 59 X-linked [73.7%], median age 23.9 years [minimum, 16.6; maximum, 59.9]) were included, Median ages at diagnosis and last follow-up were 2.52 and 23.9 years, respectively. Seven patients underwent hematopoietic stem cell transplantation. A total of 553 infections requiring hospitalization occurred in 2017 patient-years. The most common site of infection was pulmonary (31%). Aspergillus spp. (17%) and Staphylococcus aureus (10.7%) were the commonest pathogens. A total of 224 inflammatory episodes occurred in 71 patients, mainly digestive (50%). Their characteristics as well as their annual frequency did not vary before and after age 16. Main sequelae were a small adult height and weight and mild chronic restrictive respiratory failure. At age 16, only 53% of patients were in high school. After age 30 years, 9/13 patients were working. Ten patients died during adulthood. Adult CGD patients displayed similar characteristics and rates of severe infections and inflammatory episodes that those of childhood. The high rate of handicap has become a matter of medical and social consideration. Careful follow-up in centers of expertise is strongly recommended and an extended indication of curative treatment by HSCT should be considered.