Patients with primary immunodeficiencies are a reservoir of poliovirus and a risk to polio eradication

ABSTARCT: Immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) have been isolated from primary immunodeficiency (PID) patients exposed to oral poliovirus vaccine (OPV). Patients may excrete poliovirus strains for months or years; the excreted viruses are frequently highly divergent from the parental OPV and have been shown to be as neurovirulent as wild virus. Thus, these patients represent a potential reservoir for transmission of neurovirulent polioviruses in the post-eradication era. In support of WHO recommendations to better estimate the prevalence of poliovirus excreters among PIDs and characterize genetic evolution of these strains, 635 patients including 570 with primary antibody deficiencies and 65 combined immunodeficiencies were studied from 13 OPV-using countries. Two stool samples were collected over 4 days, tested for enterovirus, and the poliovirus positive samples were sequenced. Thirteen patients (2%) excreted polioviruses, most for less than 2 months following identification of infection. Five (0.8%) were classified as iVDPVs (only in combined immunodeficiencies and mostly poliovirus serotype 2). Non-polio enteroviruses were detected in 30 patients (4.7%). Patients with combined immunodeficiencies had increased risk of delayed poliovirus clearance compared to primary antibody deficiencies. Usually, iVDPV was detected in subjects with combined immunodeficiencies in a short period of time after OPV exposure, most for less than 6 months. Surveillance for poliovirus excretion among PID patients should be reinforced until polio eradication is certified and the use of OPV is stopped. Survival rates among PID patients are improving in lower and middle income countries, and iVDPV excreters are identified more frequently. Antivirals or enhanced immunotherapies presently in development represent the only potential means to manage the treatment of prolonged excreters and the risk they present to the polio endgame. Keywords: Poliovirus eradication, Immunodeficiency-associated vaccine-derived polioviruses, Oral poliovirus vaccine, Humoral immunodeficiency, Combined immunodeficiency, Primary immunodeficienc

Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score

Background: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant.Objective: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant.Method: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices.Results: Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome.Conclusion: The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.Transplantation and immunomodulatio

Hematopoietic stem cell transplantation for CD40 ligand deficiency: results from an EBMT/ESID-IEWP-SCETIDE-PIDTC Study

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) were 78.2%, 58.1% and 72.3% 5 years post-HSCT. Results were better in transplants performed ≥2000 and in children <10 years old at HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT ≤2 years from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC) and bone marrow-derived stem cells. Most rejections occurred after reduced intensity or non-myeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was ≥50% donor in 85.2%. CONCLUSION: HSCT is curative in CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS and DFS. Prospective studies are required to compare risks of HSCT with those of life-long supportive therapy

Use of coherent spectrum analysis methods to assess influence of distribution channel on signal parameters

Приведены результаты теоретического анализа влияния условий распространения на амплитудные и фазовые искажения радиосигнала, передаваемого сигнала по приемному каналу связи. Предложена мера количественных искажений параметров, вносимых приземной атмосферой (тропосферой). Даны практические рекомендации по использованию полученных результатов в целях учета влияния искажений, обусловленных средой распространения на амплитуду и фазу передаваемого по радиоканалу информационного сигнала.Наведено результати теоретичного аналізу впливу умов поширення на амплітудні і фазові спотворення радіосигналу, переданого сигналу по приймальному каналу зв'язку. Запропонована міра кількісних спотворень параметрів, внесених приземною атмосферою (тропосферою). Приведені практичні рекомендації щодо використання отриманих результатів з метою врахування впливу спотворень, зумовлених середовищем поширення, на амплітуду і фазу, передається по радіоканалу інформаційного сигналу.The theoretical analysis results of propagation effects on the amplitude and phase distortions of radio receiver signal are cited. The ratio of numerical distortion parameters caused by the surface atmosphere (troposphere) is offered. The recommendations on practical application of the achieved results to help take into account the impact of the propagation medium distortions on amplitude and phase of the transmitted information radio signal are given