Haematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is an inborn error of immunity due to defects in the transport or function of subunits of nicotinamide adenine dinucleotide phosphate oxidase, the enzyme that generates the phagocyte respiratory burst responsible for intracellular killing of engulfed micro-organisms. Patients present with infectious or inflammatory complications. Common bacterial pathogens include Staphylococcus aureus and Burkholderia cepacia complex. Fungal pathogens include Aspergillus species, particularly Aspergillus fumigatus. Inflammatory complications most commonly manifest as inflammatory bowel disease or lung disease. Granulomata are the distinguishing histological feature. Haematopoietic stem cell transplantation (HSCT) was first considered for CGD in the early 1970's. Since then, refinements in transplant technique, donor selection, conditioning regimens, and graft engineering have widened the option of HSCT to most patients with CGD. This review charts the progress made in HSCT for CGD.

T-lymphocyte depleted transplants for inborn errors of immunity.

INTRODUCTION: Hematopoietic stem cell transplantation is a curative treatment for many inborn errors of immunity (IEI). Incremental improvements and advances in care have led to high rates of >85% survival and cure in many of these diseases. Improvements in HLA-classification and matching have led to increased survival using HLA-matched donors, but survival using T-lymphocyte-depleted mismatched grafts remained significantly worse until fairly recently. Advances in T-lymphocyte depletion methods and graft engineering, although not specific to IEI, have been widely adopted and instrumental in changing the landscape of donor selection, such that a donor should now be possible for every patient. AREAS COVERED: A literature review focusing on T-lymphocyte depletion methodologies and treatment results was performed. The importance of early T-lymphocyte immunoreconstitution to protect against viral infection is reviewed. Two main platforms now dominate the field - immune-magnetic selection of specific cell types and post-transplant chemotherapeutic targeting of rapidly proliferating allo-reactive T-lymphocytes - the emerging literature on these reports, focusing on IEI, is explored, as well as the impact of serotherapy on early immunoreconstitution. EXPERT OPINION: Pharmacokinetic monitoring of serotherapy agents, and use of co-stimulatory molecule blockade are likely to become more widespread. Post-transplant cyclophosphamide or TCR depletion strategies are likely to become the dominant methods of transplantation for nonmalignant diseases.

Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

European dermatology forum: Updated guidelines on the use of extracorporeal photopheresis 2020 - Part 2.

BACKGROUND: Following the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma published in 1983, this technology has received continued use and further recognition for additional earlier as well as refractory forms. After the publication of the first guidelines for this technology in the JEADV in 2014, this technology has maintained additional promise in the treatment of other severe and refractory conditions in a multidisciplinary setting. It has confirmed recognition in well-known documented conditions such as graft-vs.-host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection including lung, heart and liver and to a lesser extent inflammatory bowel disease. MATERIALS AND METHODS: In order to further provide recognized expert practical guidelines for the use of this technology for all indications, the European Dermatology Forum (EDF) again proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. All authors had the opportunity to review each contribution as it was added. RESULTS AND CONCLUSION: These updated 2020 guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion. The guidelines were divided into two parts: PART I covers Cutaneous T-cell lymphoma, chronic graft-vs.-host disease and acute graft-vs.-host disease, while PART II will cover scleroderma, solid organ transplantation, Crohn's disease, use of ECP in paediatric patients, atopic dermatitis, type 1 diabetes, pemphigus, epidermolysis bullosa acquisita and erosive oral lichen planus.

European dermatology forum - updated guidelines on the use of extracorporeal photopheresis 2020 - part 1.

BACKGROUND: Following the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma published in 1983, this technology has received continued use and further recognition for additional earlier as well as refractory forms. After the publication of the first guidelines for this technology in the JEADV in 2014, this technology has maintained additional promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. It has confirmed recognition in well-known documented conditions such as graft-versus-host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection including lung, heart and liver and to a lesser extent inflammatory bowel disease. MATERIALS AND METHODS: In order to further provide recognized expert practical guidelines for the use of this technology for all indications, the European Dermatology Forum (EDF) again proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. All authors had the opportunity to review each contribution as it was added. RESULTS AND CONCLUSION: These updated 2020 guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion. The guidelines are divided in two parts: PART I covers cutaneous T-cell lymphoma, chronic graft-versus-host disease and acute graft-versus-host disease while PART II will cover scleroderma, solid organ transplantation, Crohn's disease, use of ECP in paediatrics practice, atopic dermatitis, type 1 diabetes, pemphigus, epidermolysis bullosa acquisita and erosive oral lichen planus.

The challenges presented by haematopoietic stem cell transplantation in children with primary immunodeficiency.

INTRODUCTION OR BACKGROUND: For many primary immunodeficiencies (PIDs), haematopoietic stem cell transplantation (HSCT) offers treatment to cure disease. However, patients with PID present a unique set of challenges when considering HSCT. SOURCES OF DATA: Review of recent literature. AREAS OF AGREEMENT: The most significant recent impact on successful outcome is introduction of newborn screening programmes for diagnosis of severe combined immunodeficiency-wider adoption of screening in an increasing number of countries will see further improvements. Other PIDs have better outcomes when treated earlier, before development of co-morbidities-early referral for consideration of HSCT is important. Evolution of conditioning regimens is improving short- and long-term toxicities-targeted busulfan and low-toxicity myeloablative treosulfan regimens deliver good survival with reduced short-term toxicities. AREAS OF CONTROVERSY: The most radical development, still in clinical trials, is the use of mono-antibody-based conditioning, which eliminates the requirement for chemotherapy and is likely to become much more important in HSCT for non-malignant disease in the future. GROWING POINTS: Multidisciplinary working for optimum care is essential. AREAS TIMELY FOR DEVELOPING RESEARCH: International collaborations are important to learn about rare presentations and complications, and to formulate the most effective and safe treatment strategies.

Conditioning Regimens for Hematopoietic Cell Transplantation in Primary Immunodeficiency.

PURPOSE OF REVIEW: Hematopoietic cell transplantation (HCT) is an established curative treatment for children with primary immunodeficiencies. This article reviews the latest developments in conditioning regimens for primary immunodeficiency (PID). It focuses on data regarding transplant outcomes according to newer reduced toxicity conditioning regimens used in HCT for PID. RECENT FINDINGS: Conventional myeloablative conditioning regimens are associated with significant acute toxicities, transplant-related mortality, and late effects such as infertility. Reduced toxicity conditioning regimens have had significant positive impacts on HCT outcome, and there are now well-established strategies in children with PID. Treosulfan has emerged as a promising preparative agent. Use of a peripheral stem cell source has been shown to be associated with better donor chimerism in patients receiving reduced toxicity conditioning. Minimal conditioning regimens using monoclonal antibodies are in clinical trials with promising results thus far. Reduced toxicity conditioning has emerged as standard of care for PID and has resulted in improved transplant survival for patients with significant comorbidities.

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 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 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.

Thymopoiesis following HSCT; a retrospective review comparing interventions for aGVHD in a pediatric cohort.

Acute graft-versus-host disease (aGVHD) complicates allogeneic hematopoietic stem cell transplantation (HSCT), and is treated with topical and/or systemic corticosteroids. Systemic corticosteroids and aGVHD damage thymic tissue. We compared thymopoietic effect of topical steroid therapy, corticosteroids and extracorporeal photopheresis (ECP) in 102 pediatric allogeneic HSCT patients. We categorized patients into 4 groups: - no aGVHD, aGVHD treated with topical or systemic steroid, or ECP. Naïve CD4+CD45RA+CD27+ T-lymphocyte values at 3, 6, 9, 12months post-HSCT were recorded: for ECP patients, values were recorded at 3, 6, 9, 12months during ECP. Differences were compared using the Kruskal-Wallis test. 41 patients had no aGVHD, 23 had aGVHD treated topically or systemically (25), 13 received ECP. Rate of thymopoiesis was significantly different between all groups at all time-points post-transplant (p=0.002, p<0.001, p<0.001, p=0.001 respectively). Even mild aGVHD impairs thymopoiesis. Worst recovery was in ECP patients. Earlier institution of ECP may speed thymic recovery.

Treosulfan-based conditioning regimens for allogeneic haematopoietic stem cell transplantation in children with non-malignant diseases.

An increasing number of children with non-malignant diseases can be cured by allogeneic haematopoietic stem cell transplantation (HSCT). Treosulfan (L-treitol-1,4-bis-methanesulfonate) is being used more frequently for conditioning, owing to its' lower toxicity profile compared with conventional myeloablative regimens. A retrospective analysis was performed of children registered in the EBMT database, who received treosulfan before HSCT between January 2005 and 2010, to identify possible dose-related toxicity and determine the incidence of engraftment, treatment-related mortality and overall survival (OS). Results from 316 transplants from 11 different countries are presented. Ninety-five (30%) were under 1 year of age at the time of transplant. OS was 83% and event-free survival was 76%; 3-year OS and event-free survival of infants below 1 year were 79% and 73%, respectively. No association was found with age at transplant, dose of treosulfan given, other agents used in combination with treosulfan, donor type, stem cell source, or second or subsequent transplant. In this report of the largest number of children to date receiving treosulfan for non-malignant diseases, treosulfan is shown to be a safe and effective agent even for those under 1 year of age at the time of transplant. Further prospective studies are needed using precisely defined protocols with pharmacokinetic monitoring and detailed chimerism analysis. In addition, long-term studies will be vital to determine long-term effects, for example, on fertility in comparison with other regimens.

The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years' activity 2008-2012.

This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (www.ukpin.org.uk). Twenty-seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.

Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease.

Chronic Granulomatous Disease (CGD) is a rare primary immunodeficiency due to a defect in one of the NADPH oxidase complex subunits; 70 % of cases are X-linked, due to a CYBB mutation, resulting in defective production of gp91PHOX. Female carriers of X-linked CGD have previously been considered to be unaffected. It is increasingly recognized that they may suffer from similar problems to CGD patients. This review will examine the literature about clinical manifestations of disease in X-linked carriers of CGD.

Impact of the 7-valent pneumococcal conjugate vaccine on the incidence of childhood pneumonia.

In September 2006, the 7-valent pneumococcal conjugate vaccine (PCV7) was added to the UK immunization programme. We aimed to evaluate the impact of PCV7 on the incidence of all-cause community-acquired pneumonia (CAP) in children. A prospective survey was undertaken in 2008-2009 at 11 hospitals in North East England of children aged 0-16 years with radiologically confirmed pneumonia. Data were compared to those from a similar survey undertaken in the same hospitals in 2001-2002. A total of 542 children were enrolled, of which 74% were aged <5 years. PCV7 uptake was 90∙7%. The incidence of pneumonia was 11∙8/10,000 [95% confidence interval (CI) 10∙9-12∙9], and the hospitalization rate was 9∙9/10,000 (95% CI 9∙0-10∙9). Compared to 2001, there was a 19% (95% CI 8-29) reduction in the rate of CAP in those aged <5 years, and in those <2 years a 33∙1% (95% CI 20-45) reduction in the incidence of CAP and 38∙1% (95% CI 24-50) reduction in hospitalization rates. However, for those unvaccinated aged ≥5 years, there was no difference in the incidence of CAP and hospitalization rate between both surveys. Since 2001, the overall reduction in incidence was 17∙7% (95% CI 8-26) and for hospitalization 18∙5% (95% CI 8-28). For the <5 years age group there was a lower incidence of CAP in PCV7-vaccinated children (25∙2/10,000, 95% CI 22∙6-28∙2) than in those that were not vaccinated (37∙4/10,000, 95% CI 29∙2-47∙1). In conclusion, PCV7 has reduced both incidence and rate of hospitalization of pneumonia in children, particularly in the <2 years age group.

Outcome of children requiring intensive care following haematopoietic SCT for primary immunodeficiency and other non-malignant disorders.

Haematopoietic SCT (HSCT) is curative for many children with primary immunodeficiencies or other non-malignant conditions. Outcome for those admitted to intensive care following HSCT for oncology diagnoses has historically been very poor. There is no literature available specifically regarding the outcome for children with primary immunodeficiency requiring intensive care following HSCT. We reviewed our post-HSCT admission to intensive care over a 5-year period. A total of 111 children underwent HSCT. Median age at transplant was 1 year 4 months. The most common diagnosis was SCID. In all, 35% had at least one intensive care admission and 44% survived to be discharged from intensive care. Also, 73% of admission episodes requiring invasive ventilation but no inotropes or renal replacement therapy resulted in survival to discharge. Children undergoing HSCT for immunological diagnoses had a high rate of admission to intensive care. No factors were identified that could predict the need for admission. Invasive ventilation alone has a much better outcome than that in historical series. However, the need for multi-organ system support was still associated with a poor outcome. This information is useful when counselling families of children that have deteriorated and been admitted to intensive care during the HSCT procedure.

Immunological aspects of 22q11.2 deletion syndrome.

Chromosome 22q11 deletion is the most common chromosomal deletion syndrome and is found in the majority of patients with DiGeorge syndrome and velo-cardio-facial syndrome. Patients with CHARGE syndrome may share similar features. Cardiac malformations, speech delay, and immunodeficiency are the most common manifestations. The immunological phenotype may vary widely between patients. Severe T lymphocyte immunodeficiency is rare-thymic transplantation offers a new approach to treatment, as well as insights into thymic physiology and central tolerance. Combined partial immunodeficiency is more common, leading to recurrent sinopulmonary infection in early childhood. Autoimmunity is an increasingly recognized complication. New insights into pathophysiology are reviewed.

Flow cytometric analysis of TCR Vß repertoire in patients with 22q11.2 deletion syndrome.

In 22q11.2 deletion patients, the normal decrease in T lymphocyte counts after 1-2 years is blunted such that relatively T lymphocyte numbers increase over early childhood, probably via post-thymic expansion of peripheral lymphocytes. This may leave less T lymphocyte receptor (TCR) diversity than when derived from naive thymic emigrants. We analysed TCR Vß repertoire on 27 22q11.2 chromosome deletion patients. No patient had infection at sampling. CD3(+) CD4(+) recent thymic emigrants (RTEs) were identified by CD45RA and CD31 expression. TCR Vß repertoire was determined using four-colour flow cytometry. Patients and controls showed significant TCR Vß family usage differences between CD3(+) CD4(+) and CD3(+) CD4(-) T lymphocyte subpopulations. Vß family abnormalities (±3 SD of controls) were identified in 18/27 (67%) patients and 12/47 (25%) controls. In patients, the magnitude of expansions was increased, with some Vß families representing 37% of the cells present in the subpopulations. There was a significant increase in frequency of abnormalities in CD3(+) CD4(+) (P < 0.001) and CD3(+) CD4(-) T lymphocytes (P < 0.05) in patients. A total of 11/16 patients had an abnormal CD4(+) CD25(Bright) TCR Vß repertoire. There was no difference in expansions/contractions between CD4(+) CD25(Bright) and CD4(+) T lymphocyte repertoires (P = 0.575) for individual patients but significant differences in expansions/contractions between CD4(+) CD25(Bright) and CD8(+) T lymphocytes repertoires (P = 0.011). There was bias in Vß usage between CD3(+) CD4(+) and CD3(+) CD4(-) T lymphocyte subsets. A total of 67% patients had TCR Vß repertoire abnormalities, with a trend towards increased repertoire abnormalities with fewer RTEs, suggesting thymic output plays an important role in TCR repertoire diversity. There was no correlation between skewed repertoire and symptoms of infection or autoimmunity.

Responses to a conjugate pneumococcal vaccine in preterm infants immunized at 2, 3, and 4 months of age.

Preterm infants are at an increased risk of invasive pneumococcal disease infection and, additionally, have a diminished response to Haemophilus influenzae type b (Hib) conjugate vaccines. There are little data examining the response of preterm infants to a seven-valent pneumococcal conjugate vaccine (PCV7). We examined the responses of preterm infants immunized at 2, 3, and 4 months of age to PCV7. A total of 133 preterm and 54 term infants were immunized with PCV7 and the Neisseria meningitidis group C (MCC), diphtheria, tetanus, pertussis, polio, and Hib vaccines. Pneumococcal serotype-specific IgG was measured by enzyme-linked immunosorbent assay (ELISA) pre- and postimmunization and at 12 months or following a booster of PCV7. Term and preterm responses were compared using linear and logistic regression analyses. Term infants had higher preimmunization geometric mean concentrations (GMCs) for all serotypes. Preterm infants had lower postimmunization GMCs for serotype 23F. Gestational age affected postimmunization GMCs for serotypes 4, 6B, and 23F. Preterm infants were as likely to have levels of ≥0.35 µg/ml as term infants for all serotypes except 23F. The proportions of infants with titers of ≥0.35 µg/ml for all 7 serotypes were comparable between groups. A total of 28 of 29 term infants who received a booster had levels of ≥0.35 µg/ml for all serotypes. One infant had undetectable levels for serotype 6B. Of the 32 preterm infants boosted, 9 had levels of <0.35 µg/ml for 1 serotype, and 1 had levels of <0.35 µg/ml for 2 serotypes. In nonboosted infants, GMCs for all serotypes except 6B had fallen by 12 months of age. These results support the need for a booster dose in the second year of life.

Association between hypoparathyroidism and defective T cell immunity in 22q11.2 deletion syndrome.

AIMS: Although poor thymic function leading to viral and fungal infections can be a feature of chromosome 22q11.2 deletion syndrome, most patients have relatively normal immunity. The aim of this study was to investigate which clinical and laboratory parameters best predict the likelihood of serious or recurrent infections in patients with this syndrome. METHODS: Clinical and laboratory parameters from 64 patients with 22q11.2 deletion syndrome referred to two immunology centres in the north of England were studied retrospectively. RESULTS: 31 (48%) patients had no problems with infection, 21 (33%) had bacterial infections, and 12 (19%) had recurrent or persistent thrush and/or viral enteritis and bronchiolitis, the latter suggestive of a significant T cell immunodeficiency. Patients with a history of thrush/viral infections, but not those with bacterial infections, had significantly lower CD4+ and CD8+ T lymphocyte numbers (relative risk (95% CI) 0.3 (0.1 to 0.8)) and phytohaemagglutinin mitogen responses (0.4 (0.2 to 0.8)) adjusted for age at testing. Hypoparathyroidism was associated with low T lymphocyte numbers and function (p<0.05) as well as an increased risk of thrush/viral infections (p<0.0001) after adjusting for age at testing. CONCLUSIONS: 22q11.2 syndrome patients with hypoparathyroidism are more likely to have a clinically significant T cell immunodeficiency and lower laboratory parameters of T cell function, with a higher risk of thrush and viral bronchiolitis and enteritis. Measurement of absolute CD3 count is a simple and accurate predictor of fungal/viral infection risk, with phytohaemagglutinin mitogen responses providing little or no further value in most patients.