Vincent Barlogis

Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP-deficiency) versus type 2 (XLP-2/XIAP-deficiency)

X-linked lymphoproliferative syndromes (XLP) are primary immunodeficiencies characterized by a particular vulnerability toward Epstein-Barr virus infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP type 1 (XLP-1) is caused by mutations in the gene SH2D1A (also named SAP), whereas mutations in the gene XIAP underlie XLP type 2 (XLP-2). Here, a comparison of the clinical phenotypes associated with XLP-1 and XLP-2 was performed in cohorts of 33 and 30 patients, respectively. HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups. Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of HLH (XLP-1, 92%; XLP-2, 83%). Survival rates and mean ages at the first HLH episode did not differ for both groups, but HLH was more severe with lethal outcome in XLP-1 (XLP-1, 61%; XLP-2, 23%). Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients (17%) had chronic hemorrhagic colitis as documented by histopathology. Recurrent splenomegaly often associated with cytopenia and fever was preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably represents minimal forms of HLH as documented by histopathology. This first phenotypic comparison of XLP subtypes should help to improve the diagnosis and the care of patients with XLP conditions.

Neutrophil depletion impairs natural killer cell maturation, function, and homeostasis

Neutropenia in mice and humans results in the generation of NK cells with an immature and hyporesponsive phenotype.

Epidemiology and outcome of invasive fungal diseases in patients with chronic granulomatous disease: a multicenter study in France.

Background: Chronic granulomatous disease (CGD) is a rare inherited phagocytic disorder resulting in an increased susceptibility to infections including invasive fungal diseases (IFDs) and inflammatory complications. This study is aimed at assessing the incidence, prevalence, and outcome of IFDs among CGD patients followed in France. Methods: CGD patients were identified through the French national registry for primary immunodeficiencies (PID) held by the French national reference Centre of PID (Centre de Référence Déficits Immunitaires Héréditaires), which comprises a total of 3083 patients including 155 with CGD followed between 1976 and 2008. A questionnaire was filled out for each episode of IFD. Information retrieved included a description of the IFD using the 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group IFD definition criteria. Results: Of CGD patients, 42.6% (66/155) developed at least 1 episode of IFD. Overall incidence of IFD was 0.040/patient-years (1862 patient-years of total follow-up). IFD incidence was found to be significant while receiving itraconazole prophylaxis compared with no prophylaxis (0.027 vs. 0.053 IFD/patient-years; P < 0.01). Median age at IFD diagnosis was 6.5 years (3.3–11.3). The most common fungal genus was Aspergillus sp. accounting for 40% of all IFDs. Of the IFDs, 42.5% were proven, 30.0% probable, and 27.5% possible. Of all IFD episodes, 52.5% were treated by antifungal monotherapy, mostly by amphotericin B. Survival was reduced in IFD patients compared with those without it (log-rank = 0.04). Conclusions: IFDs are a frequent and life-threatening complication in CGD patients. Itraconazole significantly reduces its incidence and should be recommended in absence of better alternatives.

Successful allogeneic hematopoietic stem cell transplantation for DOCK8 deficiency

with an asymptomatic cohort of HDI-exposed workers. Significant associations between genotype and occupational asthma were found only after adjustment for work-relevant diisocyanate exposure (ie, HDI vs TDI, MDI). The reason for restriction of this finding to the HDI-exposed population is unknown and may be an artifact of the greater numbers of HDI-exposed subjects available for statistical analysis. This study used a case-control design with a candidate gene approach. The rarity of diisocyanate asthma and the relatively small numbers of subjects able to be recruited compared with genetic studies of nonoccupational asthma are limitations of this study and hindrances to future replication studies. However, the issue of small group sizes could be counterbalanced by the ability to define theDA phenotype precisely by using objective SIC testswithwork-relevant diisocyanate chemicals. The role of these genotype combinations in the pathogenesis of DA is unknown and awaits functional characterization. Nevertheless, susceptibility genes associated with TH2cell differentiation (eg, IL4RA, IL13) and innate immunity (CD14) have been extensively investigated in nonoccupational asthma. The IL13 (R110Q) SNP has been associated with asthma and airway hyperresponsiveness, and IL4RAvariant Vand R alleles (I50Vand Q551R, respectively) have been associated with asthma and atopy.No suchassociationswere detected in the current study of workers not enriched with atopic subjects. In summary, we have confirmed a previous observation in expanded groups of workers: a reported association between genotype combinations associated with TH2 and innate immunity and diisocyanate-induced asthma caused by HDI. Replication of these results in other background populations will be necessary to define the possible value of these genetic markers for risk assessment. David I. Bernstein, MD Grace E. Kissling, PhD Gurjit Khurana Hershey, MD, PhD Berran Yucesoy, PhD Victor J. Johnson, PhD Andr e Cartier, MD Denyse Gautrin, PhD Joaquin Sastre, MD Louis-Philippe Boulet, MD Jean-Luc Malo, MD Santiago Quirce, MD Susan M. Tarlo, MBBS Stacy Langmeyer, MS Michael I. Luster, PhD Zana L. Lummus, PhD

Complications and treatment of patients with β-thalassemia in France: results of the National Registry

Background β-thalassemia is a rare disease in France, encountered mainly in patients originating from Italy and North Africa. In the setting of the recent French plan for rare diseases, a National Registry for thalassemia has been developed since 2005. Epidemiological and clinical data have been collected on living patients with β-thalassemia major or intermedia, including those who underwent hematopoietic stem cell transplantation. Design and Methods A standardized questionnaire was sent to clinicians throughout the national professional networks involved in the management of thalassemic patients and data were updated every 18 months. A cross-sectional study was performed in February 2009. Results Data on 378 patients (267 with thalassemia major) with a median age of 20 were recorded. Hematopoietic stem cell transplantation was performed in 52 patients. Stature, rates of parenthood, splenectomy, and cholecystectomy were no different between non-transplanted thalassemia major and thalassemia intermedia patients, after adjustment for age. Among the 215 non-transplanted thalassemia major patients, the median serum ferritin level was 1240 ng/mL and the rates of iron-related complications were 10%, 6%, 10% and 48% for cardiac failure, diabetes, hypothyroidism, and hypogonadism, respectively. From 2005 to 2008, a dramatic switch in chelation treatment, from deferoxamine to deferasirox, was observed. Conclusions The rates of complications of iron overload in French thalassemia major patients appeared similar to those reported in other developed countries in which this condition is not endemic. There were no significant differences in height and parenthood rates between patients with the major and the intermedia forms of the disease, underlining the progress in clinical care. Future developments will focus on mortality and morbidity under oral chelation treatment.

Lymphocyte subset reconstitution after unrelated cord blood or bone marrow transplantation in children

We report the post‐transplant lymphocyte subset recovery of 226 children treated with Unrelated Cord Blood transplant (UCBT) (n = 112) or Unrelated Bone Marrow Transplant (UBMT) (n = 114) for malignant or non‐malignant diseases. Absolute numbers of natural killer (NK), B and T cells were monitored by flow cytometry up to 5 years post‐transplant. Immunological endpoints were: time to achieve a CD3+ cell count >0·5 and 1·5 × 109/l, CD4+ > 0·2 and 0·5 × 109/l, CD8+ > 0·25 × 109/l, CD19+ > 0·2 × 109/l, NK > 0·1 × 109/l. These endpoints were analysed through the use of cumulative incidence curves in the context of competing risks. CD8+ T cell recovery was delayed after UCBT with a median time to reach CD8+ T cells > 0·25 × 109/l of 7·7 months whereas it was 2·8 months in UBMT (P < 0·001). B cell recovery was better in UCBT, with a median time to reach CD19+ cells > 0·2 × 109/l of 3·2 months in UCBT and 6·4 months in UBMT (P = 0·03). Median time for CD4+ T cell and NK cell recovery was similar in UCBT and UBMT. CD4+ T cells recovery was negatively correlated to age (better reconstitution in younger patients, P = 0·002). CD8+ T cells recovery was shorter in recipients with a positive cytomegalovirus serology (P = 0·001).

A Novel Leukocyte Adhesion Deficiency III Variant: Kindlin-3 Deficiency Results in Integrin- and Nonintegrin-Related Defects in Different Steps of Leukocyte Adhesion

Leukocyte adhesion deficiency type III is a recently described condition involving a Glanzmann-type bleeding syndrome and leukocyte adhesion deficiency. This was ascribed to a defect of the FERMT3 gene resulting in abnormal expression of kindlin-3, a protein expressed in hematopoietic cells with a major role in the regulation of integrin activation. In this article, we describe a patient with a new mutation of FERMT3 and lack of kindlin-3 expression in platelets and leukocytes. We assayed quantitatively the first steps of kindlin-3–defective leukocyte adhesion, namely, initial bond formation, bond strengthening, and early spreading. Initial bond formation was readily stimulated with neutrophils stimulated by fMLF, and neutrophils and lymphocytes stimulated by a phorbol ester or Mn2+. In contrast, attachment strengthening was defective in the patient’s lymphocytes treated with PMA or Mn2+, or fMLF-stimulated neutrophils. However, attachment strengthening was normal in patient’s neutrophils treated with phorbol ester or Mn2+. In addition, the patient’s T lymphocytes displayed defective integrin-mediated spreading and a moderate but significant decrease of spreading on anti-CD3–coated surfaces. Patient’s neutrophils displayed a drastic alteration of integrin-mediated spreading after fMLF or PMA stimulation, whereas signaling-independent Mn2+ allowed significant spreading. In conclusion, the consequences of kindlin-3 deficiency on β2 integrin function depend on both cell type and the stimulus used for integrin activation. Our results suggest looking for a possible kindlin-3 involvement in membrane dynamical event independent of integrin-mediated adhesion.

Frequent and Widespread Vascular Abnormalities in Human Signal Transducer and Activator of Transcription 3 Deficiency

Background —STAT3 deficiency is responsible for autosomal dominant hyper-IgE syndrome characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyper-IgE and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics and etiology of these features have yet to be described. Methods and Results —We prospectively screened 21 adult STAT3-deficient patients (median age: 26 years; range 17 - 44) for vascular abnormalities. They were explored with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography and echo-tracking-based imaging of the carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, murine models of aortic aneurysm were studied in the presence and absence of inhibitors of STAT3-dependent signaling. Brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, atrophy) were found in 95% of patients. Peripheral and brain artery abnormalities were reported in 84% of patients, whereas coronary artery abnormalities were detected in 50%. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models. Conclusions —Vascular abnormalities are highly prevalent in STAT3-deficient patients. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.Background— Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described. Methods and Results— We prospectively screened 21 adult patients with STAT3 deficiency (median age, 26 years; range, 17 to 44) for vascular abnormalities. We explored the carotid arteries with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography, and echo-tracking–based imaging. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, we studied murine models of aortic aneurysm in the presence and absence of inhibitors of STAT3-dependent signaling. Ninety-five percent of patients showed brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, and atrophy). We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress, indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models. Conclusions— Vascular abnormalities are highly prevalent in patients with STAT3 deficiency. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.

Prevention of Infections During Primary Immunodeficiency

Because infectious diseases are a major source of morbidity and mortality in the majority of patients with primary immunodeficiencies (PIDs), the application of a prophylactic regimen is often necessary. However, because of the variety of PIDs and pathogens involved, and because evidence is scarce, practices are heterogeneous. To homogenize practices among centers, the French National Reference Center for PIDs aimed at elaborating recommendations for anti-infectious prophylaxis for the most common PIDs. We performed a literature review of infectious complications and prophylactic regimens associated with the most frequent PIDs. Then, a working group including different specialists systematically debated about chemoprophylaxis, immunotherapy, immunization, and recommendations for patients. Grading of prophylaxis was done using strength of recommendations (decreasing from A to D) and evidence level (decreasing from I to III). These might help infectious diseases specialists in the management of PIDs and improving the outcome of patients with PIDs.

A French Cohort of Childhood Leukemia Survivors: Impact of Hematopoietic Stem Cell Transplantation on Health Status and Quality of Life

The late effects and quality of life (QoL) in childhood acute leukemia survivors were compared between hematopoietic stem cell transplantation (HSCT) recipients and patients who underwent conventional therapy. The study included 943 patients, 256 of whom underwent HSCT (27.1%). Medical visits were conducted to detect the occurrence of physical late effects. Based on patient age, different questionnaires were used to assess QoL. To evaluate the association between HSCT and each type of late effect or QoL dimension, the appropriate multivariate regressions were performed. QoL mean scores were compared with those obtained for age- and sex-matched French control subjects. Of all the survivors, 674 (71.5%) had at least 1 late effect, with the risk being 5.0 CI95 (3.0-8.6) times higher for transplantation survivors. For child survivors, scoring of QoL showed no significant differences between the treatment groups. The adult HSCT survivors reported lower physical dimension QoL scores than chemotherapy survivors. Compared with French norms, the survivor group reported a significantly lower mental composite score; however, the physical composite score showed no significant difference. Thus, transplanted survivors have a high risk of developing late effects, resulting in a decreased physical well-being in adulthood. However, long after treatment completion, childhood leukemia survivors report that effects on psychological well-being are more important than they are in physical QoL dimensions.