World human neutrophil antigens investigation survey.

BACKGROUND AND OBJECTIVES: Human neutrophil antigens (HNAs) are categorized into five systems: HNA-1 to HNA-5. Given the importance of neutrophils in immunity, we sought to create awareness of the role of HNA diagnostic services in managing immune neutropenia and transfusion-related acute lung injury. To provide health communities all around the world with access to these services, we conducted a survey to create a directory of these HNA diagnostic services. MATERIALS AND METHODS: An Excel table-based survey was created to capture information on the laboratory's location and was emailed to 55 individuals with known or possible HNA investigation activity. The collected data were then summarized and analysed. RESULTS: Of contacted laboratories, the surveys were returned from 23 (38.2%) laboratories; 17 have already established HNA diagnostic (of them 12 were regular participants of the International Granulocyte Immunobiology Workshop [ISBT-IGIW]), 4 laboratories were in the process of establishing their HNA investigation and the remaining 2 responder laboratories, did not conduct HNA investigations. In established laboratories, investigation for autoimmune neutropenia (infancies and adults) was the most frequently requested, and antibodies against HNA-1a and HNA-1b were the most commonly detected. CONCLUSION: The directory of survey respondents provides a resource for health professionals wanting to access HNA diagnostic services. The present study offers a comprehensive picture of HNA diagnostics (typing and serology), identifying weak points and areas for improvement for the first time. Identifying more laboratories involved in HNA diagnostics with limited access to international societies in the field will globally improve HNA diagnostics.

Antiphospholipid syndrome in patients over 65 years: A comparative study of clinical and biological features and thrombotic relapses.

OBJECTIVE: The aim of the study was to describe clinical and biological characteristics and thrombotic relapses of patients diagnosed with antiphospholipid syndrome (APS) after the age of 65 years, in comparison with patients diagnosed with APS before 65. METHODS: This retrospective multicenter study was performed to 2005 from 2017 and included patients diagnosed with APS after the age of 65 years, in accordance with Sydney criteria. We compared these patients with APS patients diagnosed before the age of 65 years, and with control thrombotic patients older than 65 years. RESULTS: Fifty-eight APS patients over the age of 65 years were compared to 127 APS patients aged less than 65 and to 58 controls. In elderly APS versus younger APS, there was a male predominance (58.6% vs 36.2% p = .001); myocardial infarction and lower limb deep vein thrombosis (LLDVT) were more frequent in elderly, respectively, 12.1% versus 1.6% (p = .005), and 44.8% versus 29.9% (p = .048). Anticardiolipin antibody (aCL) IgM was more frequently found in old patients compared to younger patients (33.9% vs 18.1%, p = .02), contrary to lupus anticoagulant (LAC) (52.8% vs 66.9%, p = .02). Older patients were more often diagnosed with single positive APS (82.8% vs 59.8% p = .002). The thrombotic relapse free survival was lower in elderly APS patients (p = .044) compared to younger APS. Elderly APS patients had more recurrent arterial and venous thrombosis (p = .03) and had poorer overall survival (p = .004) than elderly controls. CONCLUSION: In this study, APS was different in patients aged more than 65 years, with a male predominance and more myocardial infarctions and LLDVT at diagnosis. Single antiphopholipid positivity and aCL IgM were more frequent in older patients. Older patient with APS had more thrombotic recurrence during follow-up. Compared to elderly controls, elderly APS patients had more thrombosis recurrences and poorer survival.

Clinical and economic aspects of newborn screening for severe combined immunodeficiency: DEPISTREC study results.

PURPOSE: Severe combined immunodeficiency (SCID) refers to a group of genetic disorders characterized by greatly compromised cellular and humoral immunity. Children with SCID are asymptomatic at birth, but they die from infections within the first months of life if not treated. Quantification of T-cell receptor excision circles is an extremely sensitive screening method for detecting newborns who may have SCID.The goal of the DEPISTREC study was to evaluate the feasibility of nationwide newborn screening for severe T-cell lymphopenia in France as well as its economic and clinical utility. METHODS: The test universally used for neonatal screening for SCID was the quantification of TRECs on Guthrie cards. We compared a group of 190,517 babies from 48 maternities across the country who underwent newborn SCID screening with a control group of 1.4 million babies out of whom 28 were diagnosed with SCID without such screening during the course of the study. RESULTS: Within the screening group, 62 babies were found to be lymphopenic, including three with SCID. The cost of screening ranged from 4.7€ to €8.15 per newborn. The average 18-month cost was €257,574 vs €204,697 in the control group. CONCLUSIONS: In this large-scale study, we demonstrate that routine SCID screening is feasible and effective. This screening offers the additional benefit of aiding in the diagnosis of non-SCID lymphopenia. Economic evaluation allowed us to calculate the cost per test. Newborn screening may also prevent death by SCID before any curative treatment can be administered. The difference in cost between screened and control children could not be ascertained because of the very low numbers and death of one of the children tested.

Severe Transitory Neonatal Neutropenia Associated with Maternal Autoimmune or Idiopathic Neutropenia.

PURPOSE: Neonatal immune neutropenia is observed in rare cases in newborns from mothers with idiopathic or autoimmune neutropenia, secondary to passive transfer of maternal granulocyte auto-antibodies. METHODS: We performed a literature review and report four supplementary cases from the French registry of neutropenia. RESULTS: Only 14 cases (11 mothers, 14 newborns) have been reported. Granulocyte aggregation (GAT) and granulocyte indirect immunofluorescence test (GIFT) are the recommended laboratory procedures for antibody detection. Monoclonal antibody-specific immobilization of granulocyte antigens (MAIGA)-confirmed antibody specificity. Antibody detection in newborns is not generally possible owing to extreme neutropenia. In half of the cases autoantibodies against neutrophils (AAN) were positive in maternal sera (7 out of 11). In some newborns tested, IgG+ AAN were also positive, with disappearance in parallel of spontaneous neutrophil count improvement. No correlation between maternal type of AAN and titer and neonatal neutropenia can be established. Neutropenia resolved spontaneously between 2 weeks and 4 months. Infections in newborns were observed in 43% of cases, with no deaths reported. Granulocyte colony-stimulating factor (G-CSF) was administered to some newborns (5 out of 14) in the case of infections. Low-dose G-CSF administered to childbearing women during pregnancy could be proposed to prevent neutropenia in newborns. CONCLUSIONS: From the few cases reported so far it is impossible to draw any conclusions regarding frequency, risk factors, and outcome, but the overall prognosis for newborns seems good. Because it can be associated with potentially severe neonatal infections, autoimmune neutropenia in childbearing mothers should be closely monitored in collaboration with gynecologists and pediatricians.

[Treatment of high-risk leukaemia: allograft and immunotherapy]. / Traitement des leucémies à haut risque : allogreffe et immunothérapie.

Leukaemia results from a malignant proliferation of cells in the bone marrow. The prognosis is defined by the disease's biological characteristics. Treatment is based on chemotherapy. In cases of high-risk leukaemia, an allograft may be proposed. The arrival of targeted therapies and immunotherapy has revolutionised the prognosis of the disease. The challenge of the next few years will be to define the place of these therapies.

Newborn Screening for Severe Combined Immunodeficiency: Analytic and Clinical Performance of the T Cell Receptor Excision Circle Assay in France (DEPISTREC Study).

Severe combined immunodeficiency (SCID) is characterized by a major T cell deficiency. Infants with SCID are asymptomatic at birth but die from infections in the first year of life if not treated. Survival rates are better for early treatment. SCID therefore meets criteria for newborn screening (NBS). T cell receptor excision circle (TREC) quantification is a reliable marker of T cell deficiency and can be performed using Guthrie cards. The DEPISTREC project was designed to study the feasibility, clinical utility, and cost-effectiveness of generalized SCID screening in France. About 200,000 babies from all over the country were screened at birth with a commercial kit. We determined assay performance and proposed a cutoff for classification of results. Our findings suggest that, given clearly established validation rules and decision-making procedures, the TREC assay is a suitably specific and sensitive method for high-throughput SCID screening. Clinical Trials: NCT02244450.

T-Cell Receptor Excision Circles in HIV-Exposed, Uninfected Newborns Measured During a National Newborn Screening Program for Severe Combined Immunodeficiency.

Severe combined immunodeficiency screening by measuring T-receptor excision circles at birth allows evaluation of the impact of various maternal conditions on newborn immunity. The slight decrease observed in a French cohort of newborns to HIV-infected mothers can be explained by the confounding factors of prematurity and African descent.

Severe chronic primary neutropenia in adults: report on a series of 108 patients.

Severe chronic primary neutropenia (CPN) is a rare entity, and long-term outcome and risk factors for infections in severe CPN adults have not been described to date. We report the characteristics and outcomes of 108 severe adult CPN patients enrolled in a multi-institutional observational study. Severe CPN adults were mostly female (78%), and median age at diagnosis was 28.3 years. Diagnosis was fortuitous in 62% of cases. The median absolute neutrophil count (ANC) at diagnosis was 0.4 × 10(9)/L, and median ANC without granulocyte colony-stimulating factor (G-CSF) during follow-up was 0.5 × 10(9)/L. Twenty-three of 66 (34.8%) evaluable patients had neutrophil autoantibodies, and 6 of 47 (12.8%) a T-cell clone. The presence of neutrophil autoantibodies or T-cell clone was not associated with any specific clinical or biological characteristics. No death or hematologic malignancies occurred, and 44 severe bacterial infections were reported in 27 patients with a median follow-up of 8.3 years. Fifty patients received G-CSF either sporadically (n = 24) or continuously (n = 26) and responded (96%). Nineteen patients received immunosuppressive therapies: overall response (OR) was 41%, and median duration of response was 3 months. At diagnosis, the only predictive factor for the occurrence of severe bacterial infections was an ANC count below 0.2 × 10(9)/L (OR, 0.76). Severe CPN in adults is characterized by a female predominance and a benign outcome with a low rate of severe bacterial infections and no secondary malignancies. G-CSF is efficient and well tolerated but is not required in a majority of patients.

Systematic neonatal screening for severe combined immunodeficiency and severe T-cell lymphopenia: Analysis of cost-effectiveness based on French real field data.

BACKGROUND: The inclusion of severe combined immunodeficiency (SCID) in a Europe-wide screening program is currently debated. OBJECTIVE: In making a case for inclusion in the French newborn screening program, we explored the costs incurred and potentially saved by early management of SCID. METHODS: For test costs, a microcosting study documented the resources used in a laboratory piloting a newborn screening test on Guthrie cards using the T-cell receptor excision circle quantification method. For treatment costs, patients with SCID admitted to the national reference center for primary immunodeficiency in France between 2006 and 2010 were included. Costs of admission were estimated from actual national production costs. We estimated the costs for patients who underwent early versus delayed hematopoietic stem cell transplantation (HSCT; age, ≤3 vs. >3 months, respectively). RESULTS: The unit cost of the test varied between €4.69 and €6.79 for 33,800 samples per year, depending on equipment use and saturation. Of the 30 patients included, 27 underwent HSCT after age 3 months. At 1 year after HSCT, 10 of these had died, and all 3 patients undergoing early transplantation survived. The medical costs for HSCT after 3 months were €195,776 (interquartile range, €165,884-€257,160) versus €86,179 (range, €59,014-€272,577) when performed before 3 months of age. In patients undergoing late transplantation, active infection contributed to high cost and poor outcome. CONCLUSION: Early detection of SCID could reduce the cost of treatment by €50,000-100,000 per case. Assuming a €5 unit cost per test, the incidence required to break even is 1:20,000; however, if the survival advantage of HSCT before 3 months is confirmed, universal screening is likely to be cost-effective.

SYK expression endows human ZAP70-deficient CD8 T cells with residual TCR signaling.

Autosomal recessive human ZAP70 deficiency is a rare cause of combined immunodeficiency (CID) characterized by defective CD4 T cells and profound CD8 T cell lymphopenia. Herein, we report two novel patients that extend the molecular genetics, the clinical and functional phenotypes associated with the ZAP70 deficiency. The patients presented as infant-onset CID with severe infections caused by varicella zoster virus and live vaccines. Retrospective TCR excision circle newborn screening was normal in both patients. One patient carried a novel non-sense mutation (p.A495fsX75); the other a previously described misense mutation (p.A507V). In contrast to CD4 T cells, the majority of the few CD8 T cells showed expression of the ZAP70-related tyrosine kinase SYK that correlated with residual TCR signaling including calcium flux and degranulation. Our findings highlight the differential requirements of ZAP70 and SYK during thymic development, peripheral homeostasis as well as effector functions of CD4 and CD8 T cells.

Early and irreversible recurrence MPO-ANCA-positive glomerulonephritis after renal transplantation.

Kidney transplantation (KTx) is the treatment of choice for eligible patients suffering from anti-neutrophil cytoplasmic antibody(ANCA)-associated vasculitis (AAV) who are in clinical remission, regardless of ANCA status. With current immunosuppressive protocols, the recurrence rate of this primary disease in the kidney graft is low and is generally observed after the 1st year of transplantation, with a favorable outcome following conventional treatment. We report here two unusual observations of early (diagnosed within 2 weeks) and aggressive (graft failure despite therapy) recurrences in the kidney graft. These observations suggest that systematic induction by depleting antibodies and antibiotic prophylaxis may help prevent this rare but severe condition. In addition, we monitored these patients for the anti- lysosomal membrane protein-2 antibody (LAMP2ab) titers, but we found that LAMP2ab titers were not a surrogate marker of early recurrence if the LAMP2ab concentration was higher in AVV recipients before KTx. Finally, we must keep in mind that rare cases of early and aggressive recurrence ANCA-associated vasculitis on kidney graft are a challenge for early diagnosis and treatment.

Use of interferon gamma release assays in clinical practice: review of QuantiFERON-TB prescription in a French university hospital.

BACKGROUND: In recent years, the clinical use of interferon gamma release assays (IGRAs) has increased exponentially, while their indications remain controversial given difficulties in interpretation. Four indications were recommended by the French National Authority for Health (HAS) in 2006. We evaluated the utilization of the QuantiFERON-TB Gold In-Tube (QFT-IT) test over a 1-y period in a French university hospital and the impact of IGRA results in particular. METHODS: The QFT-IT tests requested in 2009 were analysed retrospectively, excluding those from the Occupational Health Department, the Regional Tuberculosis Centre, and rheumatology consultations for which the indications were clearly defined. RESULTS: Three hundred and sixty QFT-IT tests were analysed. The interpretation was frequently problematic given the inclusion of a significant proportion of patients over 80 y of age (11%), immunocompromised patients (43%), and patients with a known history of tuberculosis (6%). The indications failed to comply with HAS recommendations in 42% of cases (151/360), i.e. 14% of all QFT-IT tests in 2009. Thirty-seven percent of request forms were related to suspected pulmonary tuberculosis. In the case of a positive QFT-IT test, the clinical decision-making was changed in 58% of cases when the indications met the HAS recommendations, compared with only 16% if they did not (p < 0.005). CONCLUSION: When the indications do not meet the health authority recommendations, the diagnostic value of the IGRA remains limited.

Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study.

Extranodal NK/T-cell lymphoma, nasal type, is a rare and highly aggressive disease with a grim prognosis. No therapeutic strategy is currently identified in relapsing patients. We report the results of a French prospective phase II trial of an L-asparaginase-containing regimen in 19 patients with relapsed or refractory disease treated in 13 centers. Eleven patients were in relapse and 8 patients were refractory to their first line of treatment. L-Asparaginase-based treatment yielded objective responses in 14 of the 18 evaluable patients after 3 cycles. Eleven patients entered complete remission (61%), and only 4 of them relapsed. The median overall survival time was 1 year, with a median response duration of 12 months. The main adverse events were hepatitis, cytopenia, and allergy. The absence of antiasparaginase antibodies and the disappearance of Epstein-Barr virus serum DNA were significantly associated with a better outcome. These data confirm the excellent activity of L-asparaginase-containing regimens in extranodal NK/T-cell lymphoma. L-Asparaginase-based treatment should thus be considered for salvage therapy, especially in patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma warrants evaluation in prospective trials. This trial is registered at www.clinicaltrials.gov as #NCT00283985.

Autoimmune neutropenia in children: analysis of 116 cases.

Diagnosis of autoimmune neutropenia (AIN) in infants is important, because it allows the exclusion of more severe forms of neutropenia that have an increased risk for leukemia. AIN is characterized by chronic neutropenia, which spontaneously resolves within several months to a few years, and mild infections. Diagnosis is confirmed by the presence of antibodies directed against neutrophil antigens. The human neutrophil antigen (HNA) system is a polymorphic system, which includes five antigen groups with different polymorphisms. In AIN, antibodies are mostly directed against HNA-1 (or against a specific allele of HNA-1) and HNA-4. Here, we present a series of 116 infants with AIN. We observed that anti-neutrophil antibodies were present in 60% cases; directed against HNA-1a in 73% of cases. In addition, we showed there was a bias in the HNA allele distribution in these infants because the frequency of the HNA-1a allele was greater in comparison with controls.

Neonatal Screening for SCID: The French Experience.

After it was demonstrated in 2005 that T cell receptor excision circle (TREC) quantification for dried blood spot (DBS) samples on Guthrie cards is an effective means of SCID screening and following several pilot studies, the practice was formally recommended in the US in 2010. More and more countries have adopted it since then. In France, before the health authorities could recommend adding SCID to the list of five diseases that were routinely screened for, feasibility and cost-effectiveness studies had to be conducted with a sufficiently large cohort of neonates. We carried out three such studies: The first sought to verify the effectiveness of the assay. The second, DEPISTREC, evaluated the feasibility of universal SCID screening in France and assessed the clinical benefit and economic advantage it would provide. Through the third study, NeoSKID, still under way and to continue until recommendations are issued, we have been offering SCID screening in the Pays de la Loire region of France. This review briefly describes routine newborn screening (NBS) and management of primary immunodeficiency diseases (PIDs) in France, and then considers the lessons from our studies and the status of SCID screening implementation within the country.

Chronic neutropenia: how best to assess severity and approach management?

INTRODUCTION: Neutropenia is a relatively common finding in medical practice and the medical approach requires a gradual and pertinent diagnostic procedure as well as adapted management. AREAS COVERED: The area of chronic neutropenia remains fragmented between diverse diseases or situations. Here physicians involved in different aspects of chronic neutropenia gather both the data from medical literature till the end of May 2021 and their experience to offer a global approach for the diagnosis of chronic neutropenia as well as their medical care. EXPERT OPINION: In most cases, the neutropenia is transient, frequently related to a viral infection, and not harmful. However, neutropenia can be chronic (i.e. >3 months) and related to a number of etiologies, some clinically benign, such as so-called 'ethnic' neutropenia. Autoimmune neutropenia is the common form in young children, whereas idiopathic/immune neutropenia is a frequent etiology in young females. Inherited neutropenia (or congenital neutropenia) is exceptional, with approximately 30 new cases per 106 births and 30 known subtypes. Such patients have a high risk of invasive bacterial infections, and oral infections. Supportive therapy, which is primarily based on daily administration of an antibiotic prophylaxis and/or treatment with granulocyte-colony stimulating factor (G-CSF), contributes to avoiding recurrent infections.

Phase I study of bromohydrin pyrophosphate (BrHPP, IPH 1101), a Vgamma9Vdelta2 T lymphocyte agonist in patients with solid tumors.

PURPOSE: Vgamma9Vdelta2 (gammadelta) T lymphocytes, a critical peripheral blood lymphocyte subset, are directly cytotoxic against many solid and hematologic tumor types. Vgamma9Vdelta2 T lymphocytes can be selectively expanded in vivo with BrHPP (IPH1101) and IL-2. The present phase I trial was conducted with the aim of determining the maximum-tolerated dose (MTD) and safety of IPH1101 combined with a low dose of IL-2 in patients with solid tumors. EXPERIMENTAL DESIGN: A 1-h intravenous infusion of IPH11 was administered alone at cycle 1, combined with a low dose of SC IL-2 (1 MIU/M(2) d1 to d7) in the subsequent cycles (day 1 every 3 weeks). The dose of IPH1101 was escalated from 200 to 1,800 mg/m(2). RESULTS: As much as 28 patients with solid tumors underwent a total of 109 treatment cycles. Pharmacodynamics data demonstrate that gammadelta T lymphocyte amplification in humans requires the co-administration of IL-2 and is dependent on IPH 1101 dose. Dose-limiting toxicity occurred in two patients at a dose of 1,800 mg/m(2): one grade 3 fever (1 patient) and one grade 3 hypotension (1 patient) suggesting cytokine release syndrome immediately following the first infusion. At lower doses the treatment was well tolerated; the most frequent adverse events were mild fever, chills and abdominal pain, without exacerbation in the IL-2 combined cycles. CONCLUSION: IPH1101 in combination with SC low-dose IL-2 is safe, well tolerated and induces a potent gammadelta T lymphocyte expansion in patients. Its clinical activity will be evaluated in phase II clinical trials.

Clinical manifestations of anti-synthetase syndrome positive for anti-alanyl-tRNA synthetase (anti-PL12) antibodies: a retrospective study of 17 cases.

OBJECTIVE: To describe the clinical manifestations of the anti-synthetase syndrome (ASS) specifically associated with anti-alanyl-tRNA (anti-PL12) synthetase antibodies. METHODS: In a retrospective study, 17 patients (eight males, nine females, mean age = 60.3 years) with ASS symptoms confirmed by two consecutive tests (cyto-dot and/or immunoblot, or both), with positive results for anti-PL12 antibodies, were included. RESULTS: All patients presented with interstitial lung disease (ILD), which was associated with mild myositis in 41% of the cases. RP and general impairment were common, whereas rheumatic and dermatological symptoms were uncommon. Four patients suffered from SS, and four others had an atypical oesophageal involvement. The long-term course was assessable for 10 patients (follow-up of 41.1 months). Five patients required immunosuppressive drugs. Two patients are waiting for a lung transplant because of disproportionate and refractory pulmonary hypertension. CONCLUSION: The severity of anti-PL12 ASS varied because of the constant pulmonary involvement. ILD was the predominant prognosis factor, which was notable in cases associated with pulmonary hypertension.

Granulocyte antibody screening: evaluation of a bead-based assay in comparison with classical methods.

BACKGROUND: Granulocyte antibodies have been implicated in allo- and autoimmune neutropenia and in transfusion reactions. STUDY DESIGN AND METHODS: Fifty-one sera from suspected alloimmune neutropenia or transfusion-related acute lung injury (TRALI) and 40 sera from suspected autoimmune neutropenia were tested for granulocyte antibodies using LABScreen MULTI (One Lambda, Inc.), compared with classical tests (flow cytometry [FC] and granulocyte agglutination [GAT] followed by monoclonal antibody-specific immobilization of granulocyte antigens [MAIGA]). RESULTS: In alloimmune situations, 48 sera were concordant (94%), two sera positive for HNA with LABScreen MULTI were negative by FC/GAT and/or MAIGA, and one serum sample negative for HNA with LABScreen MULTI was positive by classical tests. In autoimmune neutropenia, 30 sera were concordant (75%), four sera positive for HNA with LABScreen MULTI were negative by FC/GAT and/or MAIGA, and six sera negative for HNA with LABScreen MULTI were positive by FC/GAT and/or MAIGA. For detection of autoantibodies, the LABScreen MULTI was less concordant. However, with the exception of one case, the discrepancies were observed in sera that did not show a clear specificity. CONCLUSIONS: LABScreen MULTI correlated well with our classical methods for HNA-1 and HNA-2a antibody screening. It can be used for screening blood donors or patients suspected of TRALI, but GAT is still needed for HNA-3a antibody screening.