Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. RESULTS: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.

Improving current immunoglobulin therapy for patients with primary immunodeficiency: quality of life and views on treatment.

BACKGROUND: Subcutaneous or intravenous immunoglobulin replacement is the mainstay of treatment for most patients with primary immunodeficiency disease (PID). The purpose of this study was to gain an understanding of how existing PID therapies affect patient lives and to identify desired improvements to immunoglobulin treatments. METHODS: An online questionnaire was made available through the International Patient Organisation for Primary Immunodeficiencies to patients with PID and their caregivers regarding current treatment satisfaction, living with PID, and patient preferences using a conjoint approach. Health-related quality of life was canvassed via questionnaires using the Short Form 12 Health Survey and EuroQoL 5 Dimensions. RESULTS: A total of 300 responded to the survey (72% patients with PID and 28% caregivers) from across 21 countries, mostly the UK, Sweden, Canada, France, Germany, and Spain. Fifty-three percent and 45% of patients received intravenous and subcutaneous therapy, respectively. Most respondents (76%) were satisfied with their current treatment, reflecting the benefits that immunoglobulin therapy provides for patient health and well-being. However, patients remained below the physical and mental well-being norms for health-related quality of life as determined by the questionnaire. All respondents expressed a desire for 4-weekly infusions, the ability to administer these at home, self-administration, shorter duration of administration, and fewer needle sticks. CONCLUSION: The results of this survey highlight the importance of providing access to different treatment options and modes of administration to ensure individual patient needs are best met.

Primary immune deficiencies - principles of care.

Primary immune deficiencies (PIDs) are a growing group of over 230 different disorders caused by ineffective, absent or an increasing number of gain of function mutations in immune components, mainly cells and proteins. Once recognized, these rare disorders are treatable and in some cases curable. Otherwise untreated PIDs are often chronic, serious, or even fatal. The diagnosis of PIDs can be difficult due to lack of awareness or facilities for diagnosis, and management of PIDs is complex. This document was prepared by a worldwide multi-disciplinary team of specialists; it aims to set out comprehensive principles of care for PIDs. These include the role of specialized centers, the importance of registries, the need for multinational research, the role of patient organizations, management and treatment options, the requirement for sustained access to all treatments including immunoglobulin therapies and hematopoietic stem cell transplantation, important considerations for developing countries and suggestions for implementation. A range of healthcare policies and services have to be put into place by government agencies and healthcare providers, to ensure that PID patients worldwide have access to appropriate and sustainable medical and support services.

Han canviat el diagnòstic, el tractament i el pronòstic de la infecció per VIH en els darrers anys? / No disponible

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X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options.

A large proportion of patients with mutations in the Wiskott-Aldrich syndrome (WAS) protein gene exhibit the milder phenotype termed X-linked thrombocytopenia (XLT). Whereas stem cell transplantation at an early age is the treatment of choice for patients with WAS, therapeutic options for patients with XLT are controversial. In a retrospective multicenter study we defined the clinical phenotype of XLT and determined the probability of severe disease-related complications in patients older than 2 years with documented WAS gene mutations and mild-to-moderate eczema or mild, infrequent infections. Enrolled were 173 patients (median age, 11.5 years) from 12 countries spanning 2830 patient-years. Serious bleeding episodes occurred in 13.9%, life-threatening infections in 6.9%, autoimmunity in 12.1%, and malignancy in 5.2% of patients. Overall and event-free survival probabilities were not significantly influenced by the type of mutation or intravenous immunoglobulin or antibiotic prophylaxis. Splenectomy resulted in increased risk of severe infections. This analysis of the clinical outcome and molecular basis of patients with XLT shows excellent long-term survival but also a high probability of severe disease-related complications. These observations will allow better decision making when considering treatment options for individual patients with XLT.

Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome.

BACKGROUND: The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues. Recently, HIES has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T(H)17 cells. OBJECTIVE: To determine whether there is a correlation between the genotype and the phenotype of patients with HIES and to establish diagnostic criteria to distinguish between STAT3 mutated and STAT3 wild-type patients. METHODS: We collected clinical data, determined T(H)17 cell numbers, and sequenced STAT3 in 100 patients with a strong clinical suspicion of HIES and serum IgE >1000 IU/mL. We explored diagnostic criteria by using a machine-learning approach to identify which features best predict a STAT3 mutation. RESULTS: In 64 patients, we identified 31 different STAT3 mutations, 18 of which were novel. These included mutations at splice sites and outside the previously implicated DNA-binding and Src homology 2 domains. A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy. T(H)17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (<1%) T(H)17 cells but were distinct by markedly reduced IFN-gamma-producing CD4(+)T cells. CONCLUSION: We propose the following diagnostic guidelines for STAT3-deficient HIES. Possible: IgE >1000IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate. Probable: These characteristics plus lack of T(H)17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.

Visceral leishmaniasis associated hemophagocytic syndrome in patients with chronic granulomatous disease.

Visceral leishmaniasis is a severe form of infection caused by a parasite endemic along the Mediterranean coast. Complications such as infection-associated hemophagocytic syndrome can occur despite correct therapy. We report visceral leishmaniasis-associated infection-associated hemophagocytic syndrome in 3 patients with chronic granulomatous disease.

Chronic granulomatous disease: the European experience.

CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a "respiratory burst", essential for the clearance of phagocytosed micro-organisms. CGD patients lack this mechanism, which leads to life-threatening infections and granuloma formation. However, a clear picture of the clinical course of CGD is hampered by its low prevalence (approximately 1:250,000). Therefore, extensive clinical data from 429 European patients were collected and analyzed. Of these patients 351 were males and 78 were females. X-linked (XL) CGD (gp91(phox) deficient) accounted for 67% of the cases, autosomal recessive (AR) inheritance for 33%. AR-CGD was diagnosed later in life, and the mean survival time was significantly better in AR patients (49.6 years) than in XL CGD (37.8 years), suggesting a milder disease course in AR patients. The disease manifested itself most frequently in the lungs (66% of patients), skin (53%), lymph nodes (50%), gastrointestinal tract (48%) and liver (32%). The most frequently cultured micro-organisms per episode were Staphylococcus aureus (30%), Aspergillus spp. (26%), and Salmonella spp. (16%). Surprisingly, Pseudomonas spp. (2%) and Burkholderia cepacia (<1%) were found only sporadically. Lesions induced by inoculation with BCG occurred in 8% of the patients. Only 71% of the patients received antibiotic maintenance therapy, and 53% antifungal prophylaxis. 33% were treated with gamma-interferon. 24 patients (6%) had received a stem cell transplantation. The most prominent reason of death was pneumonia and pulmonary abscess (18/84 cases), septicemia (16/84) and brain abscess (4/84). These data provide further insight in the clinical course of CGD in Europe and hopefully can help to increase awareness and optimize the treatment of these patients.

The Wiskott-Aldrich syndrome protein is required for iNKT cell maturation and function.

The Wiskott-Aldrich syndrome (WAS) protein (WASp) is a regulator of actin cytoskeleton in hematopoietic cells. Mutations of the WASp gene cause WAS. Although WASp is involved in various immune cell functions, its role in invariant natural killer T (iNKT) cells has never been investigated. Defects of iNKT cells could indeed contribute to several WAS features, such as recurrent infections and high tumor incidence. We found a profound reduction of circulating iNKT cells in WAS patients, directly correlating with the severity of clinical phenotype. To better characterize iNKT cell defect in the absence of WASp, we analyzed was(-/-) mice. iNKT cell numbers were significantly reduced in the thymus and periphery of was(-/-) mice as compared with wild-type controls. Moreover analysis of was(-/-) iNKT cell maturation revealed a complete arrest at the CD44(+) NK1.1(-) intermediate stage. Notably, generation of BM chimeras demonstrated a was(-/-) iNKT cell-autonomous developmental defect. was(-/-) iNKT cells were also functionally impaired, as suggested by the reduced secretion of interleukin 4 and interferon gamma upon in vivo activation. Altogether, these results demonstrate the relevance of WASp in integrating signals critical for development and functional differentiation of iNKT cells and suggest that defects in these cells may play a role in WAS pathology.

Common variable immunodeficiency: 20-yr experience at a single centre.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. It can present at any age in patients with a history of recurrent bacterial infections, with or without a family history of other primary immunodeficiencies (PID), and shows a wide range of clinical manifestations and immunological data. Diagnosis is based on low IgG, IgM and/or IgA levels. Delayed diagnosis and therapy can lead to bronchiectasis and malabsorption. The aim of this study was to describe a paediatric population diagnosed of CVID and its evolution in the population. Memory B-cell (MB) classification carried out in these patients was correlated with clinical manifestations and outcome. Clinical and immunological data of 22 CVID children under 18 yr treated at our centre between 1985 and 2005 are presented. Immunological studies included those for diagnosis and MB quantification. Differences in form of presentation, familial incidence and MB classification were reviewed. A statistical descriptive analysis was made. Infections were the commonest manifestation, affecting mainly respiratory (19/22) and gastrointestinal (10/22) tracts. Bronchiectasis was present in seven cases, and detected prior to CVID diagnosis in five. Replacement therapy led to a significant reduction in the number of infections. Severe complications appeared mostly in patients without MB. Patients of the same family share the same MB group. Family members had also been diagnosed of CVID in seven cases. Early diagnosis and therapy are essential to improve outcome in these patients. MB studies are useful in children to orient prognosis and further genetic studies.

An update on treatment strategies for common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a primary immunological disease with variable severity, ranging from mild forms of infections to chronic progressive complications. The hallmark of this disorder is hypogammaglobulinemia due to an unknown molecular defect in immune regulation. The primary clinical manifestations are recurrent infections that may lead to structural damage of affected organs. Adequate intravenous immunoglobulin (Ig) therapy has dramatically changed the prognosis of this disorder, and the advent of home subcutaneous Ig therapy has further improved the quality of life of these patients. Aberrant T-cell functions predispose to autoimmune, inflammatory and lymphoproliferative complications, as well as malignancies in a variable percentage of CVID patients. Immunosuppressive anti-inflammatory therapies and chemotherapy are used, although always in conjunction with adequate replacement Ig therapy and adjunct antimicrobial prophylaxis. Any organ can be involved and therefore a multidisciplinary approach to the management of this disorder is essential.

Progression of selective IgA deficiency to common variable immunodeficiency.

Selective IgA deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. Although it is often asymptomatic, selected patients show an increased frequency of infections, allergies and autoimmune manifestations. Common variable immunodeficiency (CVID) is a primary antibody deficiency disease that shares many clinical features with IgAD. A common genetic basis for IgAD and CVID has been suggested based on their occurrence in members of the same family and the similarity of the underlying B cell defects. Progression from IgAD to CVID has also been reported in several cases. Here we present 4 patients with IgAD and autoimmune features who subsequently developed CVID. All symptomatic IgAD patients, especially those with associated IgG subclass deficiency or autoimmune features, should be monitored for evolution to CVID. Early diagnosis of this conversion and institution of immunoglobulin therapy is effective in preventing severe bacterial infections and pulmonary insufficiency.

Toll-like receptor stimulation induces higher TNF-alpha secretion in peripheral blood mononuclear cells from patients with hyper IgE syndrome.

Hyper IgE syndromes (HIES) are primary immunodeficiency disorders of unknown pathogenesis. Patients are typically affected with 'cold' abscesses of the skin, recurrent cyst-forming pneumonia, chronic mucocutaneous candidiasis and other less frequent features such as progressive skeletal abnormalities. Defective signaling in the Toll-like receptor (TLR) pathways has been suggested as a responsible pathologic mechanism, however, in previous reports, 10 patients revealed no defect in inflammatory cytokine responses to different TLR ligands. Here, we report the increase in pro-inflammatory cytokines TNF-alpha and IL-8, following TLR2 and TLR4 stimulation in a larger cohort of 25 additional patients with HIES, and provide a meta-analysis of the TLR data in HIES.

The EUROclass trial: defining subgroups in common variable immunodeficiency.

The heterogeneity of common variable immunodeficiency (CVID) calls for a classification addressing pathogenic mechanisms as well as clinical relevance. This European multicenter trial was initiated to develop a consensus of 2 existing classification schemes based on flowcytometric B-cell phenotyping and the clinical course. The clinical evaluation of 303 patients with the established diagnosis of CVID demonstrated a significant coincidence of granulomatous disease, autoimmune cytopenia, and splenomegaly. Phenotyping of B-cell subpopulations confirmed a severe reduction of switched memory B cells in most of the patients that was associated with a higher risk for splenomegaly and granulomatous disease. An expansion of CD21(low) B cells marked patients with splenomegaly. Lymphadenopathy was significantly linked with transitional B-cell expansion. Based on these findings and pathogenic consideration of B-cell differentiation, we suggest an improved classification for CVID (EUROclass), separating patients with nearly absent B cells (less than 1%), severely reduced switched memory B cells (less than 2%), and expansion of transitional (more than 9%) or CD21(low) B cells (more than 10%). Whereas the first group contains all patients with severe defects of early B-cell differentiation, severely reduced switched memory B cells indicate a defective germinal center development as found in inducible constimulator (ICOS) or CD40L deficiency. The underlying defects of expanded transitional or CD21(low) B cells remain to be elucidated. This trial is re-gistered at http://www.uniklinik-freiburg.de/zks/live/uklregister/Oeffentlich.html as UKF000308.

Congenital rubella syndrome, hyper-IgM syndrome and autoimmunity in an 18-year-old girl.

Congenital rubella syndrome can be associated with disgammaglobulinaemia and autoimmune phenomena in adult and paediatric population. The aim of this article is to present the association between a congenital rubella syndrome with hypogammaglobulinaemia and hyper IgM diagnosed at the age of 8 months and autoimmune manifestations in an 18-year-old girl. A medical chart review of this patient since admission at our institution at 8 months of age was carried out. During infancy she presented the classical manifestations of a rubella syndrome (sensorineural deafness and brain calcifications in basal ganglia) with respiratory and gastrointestinal infections. She was also diagnosed of localised scleroderma and thyroiditis. She has been on intravenous immunoglobulin since diagnosis, with rapid normalisation of IgG and IgM levels, decreased incidence of infectious processes, but with persistent autoimmune phenomena. At 18 years of age she was admitted because of a thyroid mass. Fine needle aspiration biopsy was not conclusive and thyroidectomy was performed. Pathology studies showed no malignancy. She is now on replacement therapy with thyroid hormones. Our aim is to emphasise the importance of the association between autoimmune phenomena in patients with immunodeficiencies, even secondary to some infections, and the increased frequency of malignancies owing to the persistent immunologic defect in this syndrome.

Common variable immunodeficiency: association between memory B cells and lung diseases.

BACKGROUND: Malabsorption syndrome often develops in patients with common variable immunodeficiency (CVID). Why structural damages appear in some CVID patients and not in others is not fully understood. Memory B cells (MBs) are responsible for the production of specific antibodies, and their defects have previously been related to autoimmune, granulomatous, and lymphoproliferative complications of CVID. The objective of this study was to ascertain whether a relationship exists between MB defects and the clinical outcome of respiratory and intestinal involvement in these patients. METHODS: Forty-one CVID patients were grouped as follows, according to the quantification of peripheral MBs: the MB2 group (n = 7) included patients with normal MBs; the MB1 group (n = 16) included patients with low switched MBs; and the MB0 group (n = 18) included patients with absent/low MBs. The clinical outcome of respiratory and intestinal involvement of patients was then compared among the three groups. RESULTS: In the MB0 group, chronic lung disease (ie, bronchiectasis and diminished FVC and/or FEV1) developed in 50% of patients vs 13% in the MB1 group and 0% in the MB2 group (p < 0.05). In the MB0 group, malabsorption syndrome or chronic noninfectious diarrhea developed in 50% of patients vs 19% in the MB1 group and 0% in the MB2 group (p < 0.05). No differences were found among the three groups for age at onset of symptoms, delay in diagnosis/treatment, months of follow-up/treatment, and prediagnostic serum IgG concentration. CONCLUSIONS: Alterations in MB count appear to be associated with a severe clinical outcome of respiratory and intestinal involvement in CVID. The MB count could be a useful laboratory parameter for orienting the prognosis and management of CVID patients.

Més de 20 anys de SIDA pediàtrica / No disponible

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Inmunomoduladores e inmunosupresores en inmunodeficiencias / No disponible

La modulación de la respuesta inmune se ha empleado durante muchos años para aumentar la respuesta, por ejemplo con el uso de vacunas, o para disminuirla o suprimirla, con el uso de fármacos específicos. Las inmunodeficiencias pueden ser primarias, como resultado de un defecto congénito molecular, generalmente transmitido genéticamente, o secundarias a infección, fármacos, malnutrición, etc. En el grupo de las primarias se usan ampliamente diversos tipos de terapia de sustitución, sobre todo gammaglobulinas (G.G), citocinas y trasplante de médula ósea. En algunos pacientes con linfoproliferación dañina puede requerirse el uso de inmunosupresores (CyA y corticoides) para controlar la enfermedad gastrointestinal o pulmonar. Las inmunodeficiencias secundarias se pueden modular en relación a su etiología, por ejemplo, uso de G.G en algunas infecciones. Sin embargo la indicación más frecuente de inmunosupresión es el control de enfermedades proliferativas malignas, o por contraste, para evitar la respuesta inmune “normal” en los trasplantes. El extenso uso de estas terapias en muy variadas situaciones (fallo renal, hepático, respiratorio, etc.) está dando lugar a una larga lista de nuevos productos, sobre todo anticuerpos monoclonales con dianas específicas y sus ulteriores aplicaciones a otras enfermedades inmunológicas (AU)

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