Journal articles on the topic 'Screening immunodeficienza congenita'
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Burnusuzov, Hasan, Ivan Yankov, Kostadin Ketev, and Mariana Murdjeva. "Primary immunodeficiency screening in an infant with cytomegalovirus disease reveals HIV infection." Folia Medica 65, no. 1 (February 28, 2023): 166–70. http://dx.doi.org/10.3897/folmed.65.e72203.
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Cytomegalovirus is widely spread worldwide, and it is not uncommon for it to complicate the congenital human immunodeficiency virus (HIV) disease as an acquired or congenital coinfection. However, the association of the two infections is not common amongst infants with primary immune deficiencies. We describe a case of a 6-month-old infant with acquired cytomegalovirus and HIV infections, diagnosed in the course of the patient’s clinical and laboratory workup for a presumed primary immunodeficiency. To date, this is the first reported case of such a combination in a child from Bulgaria.
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Verbsky, James, and John Routes. "Screening for and Treatments of Congenital Immunodeficiency Diseases." Clinics in Perinatology 41, no. 4 (December 2014): 1001–15. http://dx.doi.org/10.1016/j.clp.2014.08.017.
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Qiao, Luxi, Celina M. Turchi Martelli, Amber I. Raja, Nuria Sanchez Clemente, Thalia Velho Barreto de Araùjo, Ricardo Arraes de Alencar Ximenes, Demócrito de Barros Miranda-Filho, Anna Ramond, and Elizabeth B. Brickley. "Epidemic preparedness: Prenatal Zika virus screening during the next epidemic." BMJ Global Health 6, no. 6 (June 2021): e005332. http://dx.doi.org/10.1136/bmjgh-2021-005332.
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Zika virus (ZIKV) is a vectorborne infectious agent of global public health significance due to its potential to cause severe teratogenic outcomes. The question of whether health systems should consider adopting screening programmes for ZIKV infections during pregnancy warrants consideration. In this analysis, we apply the Wilson-Jungner framework to appraise the potential utility of a prenatal ZIKV screening programme, outline potential screening strategies within the case-finding pathway, and consider other epidemiological factors that may influence the planning of such a screening programme. Our evaluation of a potential prenatal ZIKV screening programme highlights factors affirming its usefulness, including the importance of Congenital Zika Syndrome as a public health problem and the existence of analogous congenital prenatal screening programmes for STORCH agents (syphilis, toxoplasmosis, others (eg, human immunodeficiency virus, varicella-zoster virus, parvovirus B19), rubella, cytomegalovirus, and herpes simplex virus). However, our assessment also reveals key barriers to implementation, such as the need for more accurate diagnostic tests, effective antiviral treatments, increased social service capacity, and surveillance. Given that the reemergence of ZIKV is likely, we provide a guiding framework for policymakers and public health leaders that can be further elaborated and adapted to different contexts in order to reduce the burden of adverse ZIKV-related birth outcomes during future outbreaks.
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Chee, Siew-Yin, Jiun-Wen Guo, Chi-Jung Huang, Yin-Hsiu Chien, Yu-Chin Lee, and Wen-Kan Feng. "Rare Concurrence of Two Congenital Disorders: Miller-Dieker Syndrome and T-Cell Lymphopenia." Cytogenetic and Genome Research 157, no. 4 (2019): 227–30. http://dx.doi.org/10.1159/000499956.
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Miller-Dieker syndrome (MDS; OMIM 247200) is a rare contiguous gene deletion syndrome associated with lissencephaly and characteristic facial dysmorphism. T-cell lymphopenia is an immunodeficiency disorder which can be early detected by newborn blood screening, and all live vaccines should be avoided. We report a 2.32-Mb microdeletion at chromosome 17p13.3p13.2 and T-cell lymphopenia in a 6-month-old male infant with MDS. This is, to our knowledge, the first description of these 2 conditions co-occurring in the same patient.
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Muramatsu, Hideki, Daiei Kojima, Yusuke Okuno, Shinsuke Kataoka, Yoko Nakajima, Tetsuya Ito, Ikuya Tsuge, et al. "Combination of TREC Measurement and Next-Generation Sequencing in Newborn Screening for Severe Combined Immunodeficiency: A Pilot Program in Japan." Blood 132, Supplement 1 (November 29, 2018): 3717. http://dx.doi.org/10.1182/blood-2018-99-118261.
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Abstract INTRODUCTION Severe combined immunodeficiency disease (SCID) is the most severe form of primary immunodeficiency disorders (PIDs). Impaired cellular and humoral immunity renders the affected infants susceptible to various infections and results in death within the first 2 years of life. Affected infants are asymptomatic at birth, untreated disease leads to death, and prompt treatment (i.e., hematopoietic stem cell transplantation, gene therapy, or enzyme replacement therapy) is linked to significant improvement in outcome. Thus, SCID meets the disease criteria for newborn screening (NBS). The T-cell receptor excision circle (TREC) is an excellent marker of recently formed T cells, and quantitative PCR-based measurement of TREC is an excellent tool in population-based NBS for SCID. Recent progress in next-generation sequencing (NGS) has enabled the simultaneous sequencing of numerous nucleic acids, detecting single nucleotide changes as well as copy number variants. We launched a pilot newborn optional screening program for SCID, combining the measurement of TREC and NGS in Japan. PATIENTS AND METHODS We measured TREC copy number using the Enlite™ Neonatal TREC assay (Perkin Elmer, Turku, Finland), which utilizes the duplex amplification of TREC and beta-actin in the same reaction for each specimen. We used TREC negative cutoffs as follows: TREC copy number of <30 copies/μL and beta-actin copy number of ≥50 copies/μL. In patients with TREC negative results, genomic DNA was subjected to DNA capture designed using SureDesign (Agilent, Santa Clara, USA), covering a total of 349 genes associated with PIDs, inherited bone marrow failure syndromes, and the 22q11.2 region. Target capture, enrichment, and indexing were performed according to the manufacturer's instructions. Generated libraries were sequenced using a HiSeq 2500 platform (Illumina, San Diego, USA). This study was approved by the ethical committees of the Nagoya University Graduate School of Medicine and Fujita Health University. RESULTS From April 2017 to March 2018, we screened a total of 22,865 newborns, covering 57% of the total number of births in the Aichi prefecture, Japan. We identified 48 (0.21%) newborns with TREC negative results. These newborns were referred to the Nagoya University Hospital or Fujita Health University Hospital and received thorough immunological examination, including target capture sequencing. Among them, 12 (25%) newborns had background diseases, including Down syndrome (n = 4), gastrointestinal defects (n = 3), congenital diaphragmatic hernia (n = 2), congenital chylothorax (n = 2), and severe congenital heart anomaly (n = 1). Immunological assessment identified 11 (23%) infants with lymphocytopenia (<1500 /μL). These infants avoided live vaccines and received appropriate interventions to prevent infection. Using target sequencing analyses, we identified four patients with PIDs, including 22q11.2 deletion syndrome (n = 2), Wiskott‒Aldrich syndrome (n = 1), and combined immunodeficiency with an unknown causative gene (n = 1). CONCLUSION We successfully launched a pilot newborn optional screening program for SCID, combining the measurement of TREC and NGS in Japan. We did not identify typical SCID patients probably because of the relatively small sample size. However, this newborn screening program, incorporating an NGS assay as a second test, achieved early accurate diagnoses of patients with other PIDs with TREC negative results. Consequently, this program may facilitate patient management and optimize treatment outcomes. Disclosures No relevant conflicts of interest to declare.
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Gjerset, GF, MJ Clements, RB Counts, AS Halvorsen, and AR Thompson. "Treatment type and amount influenced human immunodeficiency virus seroprevalence of patients with congenital bleeding disorders." Blood 78, no. 6 (September 15, 1991): 1623–27. http://dx.doi.org/10.1182/blood.v78.6.1623.bloodjournal7861623.
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Two hundred and eighty-two patients with congenital bleeding disorders received blood component replacement therapy between January 1979 and April 1985, were followed-up by the Puget Sound Blood Center's Hemophilia Care Program, and were tested for antibody to human immunodeficiency virus (HIV). Serologic results were obtained at least 1 year after the last exposure to volunteer donor products that were prepared before donor HIV screening or after the last exposure to concentrates produced before the manufacturer's use of treatment methods for inactivation of HIV. In all, 106 patients were anti-HIV positive. The risk of HIV infection was greater in patients with more severe bleeding tendencies, greater exposure to components, and exposure to lyophilized concentrates from large pools of donors. Of 100 patients with hemophilia A who only received cryoprecipitate from volunteer donors from Washington State (during the 6.3-year period), 14% had become anti-HIV positive. Of 27 patients receiving mostly cryoprecipitate but also being exposed to a single lot of concentrate during the same period, 13 (48%) were positive. Of 49 patients treated predominantly or solely with factor VIII concentrates during this period, 43 (88%) were anti-HIV positive. Of 29 patients with von Willebrand disease, four were anti-HIV positive, including 2 of 26 receiving only cryoprecipitate and two of three who had received a single dose of factor VIII concentrate. Of 19 patients who were treated solely with volunteer donor plasma, all remained anti-HIV negative. Of 47 patients exposed to factor IX concentrate, 28 (60%) were positive. Data relevant to the risk of HIV transmission subsequent to screening of the volunteer donor population were also obtained. Treatment records of 55 hemophilia A patients who have remained anti-HIV negative through at least June 1990 showed exposure to 71,173 screened donors from May 1985 through December 1989, and all 55 patients have remained anti-HIV negative.
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Scott, Ori, Jenny Garkaby, Jessica Willett-Pachul, Amarilla B. Mandola, and Yehonatan Pasternak. "A novel splice site variant in FOXN1 in a patient with abnormal newborn screening for severe combined immunodeficiency and congenital lymphopenia." LymphoSign Journal 8, no. 1 (March 1, 2021): 1–4. http://dx.doi.org/10.14785/lymphosign-2021-0013.
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Background: The Forkhead box protein N1 (FOXN1) is a key regulator of thymic epithelial development, and its complete deficiency leads to a nude-severe combined immunodeficiency (SCID) phenotype. More recently, heterozygous mutations in FOXN1 have been linked with a syndrome of congenital lymphopenia and a wide clinical spectrum, with most cases being caused by missense mutations. Aim: To broaden the genotypic and phenotypic spectrum of heterozygous FOXN1 deficiency. Methods: Case report of a patient with FOXN1 haploinsufficiency due to a novel splice-site mutation. Results: Our patient was identified at 3 weeks of life given an abnormal newborn screen (NBS) for SCID, and was found to have congenital lymphopenia preferentially affecting CD8+ T-cells. Her cellular and humoral function were both excellent, and she has remained entirely asymptomatic and thriving for the first 3 years of her life. The patient was found on whole exome sequencing to carry a heterozygous splice-site mutation in the FOXN1 gene, affecting the Forkhead domain. The mutation was also identified in her asymptomatic mother. Conclusion: Heterozygous FOXN1 mutations are an increasingly-recognized cause of congenital lymphopenia. Our experience suggests most patients remain clinically well, with main manifestation including T-lymphopenia, mostly affecting CD8+ cells. Identification of the same variant in an asymptomatic parent suggests age-dependent improvement in T-cell counts and an overall benign course, while provides impetus for diligent conservative management with regular follow-up. Statement of novelty: Heterozygous FOXN1 deficiency is a relatively new entity, attributed in most cases to missense mutations in FOXN1. To further expand the knowledge basis regarding this emerging disorder, as well as its genotypic repertoire, we herein report a case of heterozygous FOXN1 deficiency caused by a splice site mutation.
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Titman, Penny, Elizabeth Pink, Emily Skucek, Katherine O'Hanlon, Tim J. Cole, Jane Gaspar, JinHua Xu-Bayford, et al. "Cognitive and behavioral abnormalities in children after hematopoietic stem cell transplantation for severe congenital immunodeficiencies." Blood 112, no. 9 (November 1, 2008): 3907–13. http://dx.doi.org/10.1182/blood-2008-04-151332.
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Hematopoietic stem cell transplantation (HSCT) is a highly successful treatment for severe congenital immunodeficiencies. However, some studies have suggested that children may experience cognitive difficulties after HSCT. This large-scale study assessed cognitive and behavioral function for the cohort of children treated by HSCT at one center between 1979 and 2003 to determine the frequency and severity of problems and to identify risk factors. A total of 105 patients were assessed on standardized measures of cognitive and emotional and behavioral function together with a control group of unaffected siblings. The average IQ for the cohort was 85 (95% confidence interval, 81-90), significantly lower than both the population average of 100 (P < .001) and unaffected siblings. Multivariate analysis indicated that the underlying genetic defect, diagnosis of adenosine deaminase-deficient severe combined immunodeficiency, and consanguinity were associated with worse outcome but that age at transplantation and chemotherapy conditioning were not. Children treated by HSCT for severe immunodeficiency have an increased risk of long-term cognitive difficulties and associated emotional and behavioral difficulties. The specific genetic diagnosis, consanguinity, and severe clinical course are associated with poor outcome. Long-term follow-up of these patients should include screening to identify and manage these problems more effectively.
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Gjerset, GF, MJ Clements, RB Counts, AS Halvorsen, and AR Thompson. "Treatment type and amount influenced human immunodeficiency virus seroprevalence of patients with congenital bleeding disorders." Blood 78, no. 6 (September 15, 1991): 1623–27. http://dx.doi.org/10.1182/blood.v78.6.1623.1623.
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Abstract Two hundred and eighty-two patients with congenital bleeding disorders received blood component replacement therapy between January 1979 and April 1985, were followed-up by the Puget Sound Blood Center's Hemophilia Care Program, and were tested for antibody to human immunodeficiency virus (HIV). Serologic results were obtained at least 1 year after the last exposure to volunteer donor products that were prepared before donor HIV screening or after the last exposure to concentrates produced before the manufacturer's use of treatment methods for inactivation of HIV. In all, 106 patients were anti-HIV positive. The risk of HIV infection was greater in patients with more severe bleeding tendencies, greater exposure to components, and exposure to lyophilized concentrates from large pools of donors. Of 100 patients with hemophilia A who only received cryoprecipitate from volunteer donors from Washington State (during the 6.3-year period), 14% had become anti-HIV positive. Of 27 patients receiving mostly cryoprecipitate but also being exposed to a single lot of concentrate during the same period, 13 (48%) were positive. Of 49 patients treated predominantly or solely with factor VIII concentrates during this period, 43 (88%) were anti-HIV positive. Of 29 patients with von Willebrand disease, four were anti-HIV positive, including 2 of 26 receiving only cryoprecipitate and two of three who had received a single dose of factor VIII concentrate. Of 19 patients who were treated solely with volunteer donor plasma, all remained anti-HIV negative. Of 47 patients exposed to factor IX concentrate, 28 (60%) were positive. Data relevant to the risk of HIV transmission subsequent to screening of the volunteer donor population were also obtained. Treatment records of 55 hemophilia A patients who have remained anti-HIV negative through at least June 1990 showed exposure to 71,173 screened donors from May 1985 through December 1989, and all 55 patients have remained anti-HIV negative.
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Klass, Perri E., Elizabeth R. Brown, and Stephen I. Pelton. "The Incidence of Prenatal Syphilis at The Boston City Hospital: A Comparison Across Four Decades." Pediatrics 94, no. 1 (July 1, 1994): 24–28. http://dx.doi.org/10.1542/peds.94.1.24.
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Objective. To examine the incidence and epidemiologic correlates of congenital syphilis at an inner-city Boston hospital, and draw comparisons with the situation at the same hospital 40 years ago. Design. Chart review and comparison with data collected in 1951. Setting. Maternity and pediatric services at Boston City Hospital. Methods. A study conducted in 1951 on the maternity service of Boston City Hospital in which demographic data were collected on all women admitted in labor over a 5-month period was replicated. Serologic testing for syphilis was carried out on these women, and the demographic and medical correlates of positive maternal syphilis serology were examined. This study was repeated exactly 40 years later, using the cord blood screening for syphilis done routinely at delivery and a review of prenatal records. Results. From a group made up largely of married white women in 1951, the study population shifted in 1991 to a group made up mostly of minority women, with 75% unmarried. In 1951, 24 patients were diagnosed with syphilis either before or during the pregnancy, giving a prevalence rate of 2.4%. In 1991, 25 of 647 women were diagnosed with syphilis, for a prevalence rate of 3.9%. The women with positive cord blood serologies had a higher rate of other sexually transmitted diseases and substance abuse. No symptomatic cases of congenital syphilis were seen in 1951 or in 1991, although at least 11 of the 26 infants born to mothers with positive serologies in 1991 received intravenous penicillin therapy. Conclusions. The continued prevalence of diagnosed syphilis in women at delivery reflects an inner-city epidemic of congenital syphilis that is tied to substance abuse, human immunodeficiency virus, and changing social patterns, as well to older problems of serologic screening, prenatal care, treatment failures, and maternal reinfection. It is essential that screening programs be maintained and improved in this high-risk population, and that infants born to mothers with positive serologies receive full and adequate treatment if there is any doubt at all about their infection status.
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Karim, AKM Rezaul, Afiqul Islam, Choudhury Yakub Jamal, Abdul Matin, Md Monir Hossain, Mohammad Shafiullah, and Rehnuma Urmi. "Seroprevalence of Hepatitis B, Hepatitis C and Human Immunodeficiency Virus Among Multitransfused Thalassaemic Children in Dhaka, Bangladesh." Bangladesh Journal of Child Health 37, no. 3 (April 18, 2014): 146–53. http://dx.doi.org/10.3329/bjch.v37i3.18618.
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Background: Thalassaemia is a congenital hemolytic disease caused by defective globin chain synthesis of haemoglobin and largely treated by repeated blood transfusions. Transfusion-transmitted infections still make a great challenge in the management of patients with thalassaemia major. The most important worldwide transfusion transmitted infections (TTI) are hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Despite concern about a possible increase in the incidence of these infections there are no recent data about the prevalence of HBV, HCV and HIV from Bangladesh. Objectives: To evaluate the prevalence of hepatitis B, hepatitis C and human immunodeficiency virus in multi-transfused thalassaemia patients (MTP), to identify the possible risk factors and to evaluate the effect of compulsory screening of blood to prevent these infections. Methodology: This cross-sectional study was conducted during 2011 to 2012 on 100 consecutive multi-transfused thalassaemic patients who were interviewed using a structured questionnaire and tested for serological markers of hepatitis B virus (HBsAg), hepatitis C virus (Anti-HCV) and human immunodeficiency virus (Anti-HIV 1+2). Results: The overall prevalence of HCV, HBV, HIV and co-infection among (MTP) were 31%, 3%, 0% and 1%, respectively. Children who developed infection had a higher incidence of receiving transfusion from professional donors or unknown donors than the non-infected ones. Infected children had a higher frequency of receiving transfusions without screening and receiving more number of transfusions than their counterpart. Other non-transfusion related (NTR) risk factors such as surgical operation, dental procedures, needle stick injury were significantly higher in patients who acquired transfusion transmitted infections (TTI). Conclusions: HCV infection was the most prevalent transfusion transmitted infection (TTI) among multi-transfused thalassaemia patients (MTP) and remains a major health problem for these patients. Children who received transfusion from professional donors and received unscreened blood had more chance of getting infection with transfusion transmitted infection. DOI: http://dx.doi.org/10.3329/bjch.v37i3.18618 Bangladesh J Child Health 2013; Vol.37(3): 146-153
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R, Gadepalli. "Transfusion Transmitted Infections in Patients with Haemophilia, a Study from Western Rajasthan, India." Haematology International Journal 4, no. 2 (2020): 1–3. http://dx.doi.org/10.23880/hij-16000165.
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Introduction: Haemophilia is one of the predominant congenital coagulation disorder and a disease without ethnic or geographic limitations with incidence approximately 20 per 100 000 male births. Haemophilic patients are in regular need of blood and blood products and prone to risk of acquiring infections such as hepatitis B, C (HBV, HCV) and human immunodeficiency virus (HIV). Materials and methods: In this descriptive study, 98 haemophilic patients were selected for screening of HIV I and II, HBV, and HCV through the rapid immunochromatographic test method. Positive cases were confirmed by third generation enzyme linked immunosorbent assay (ELISA). Results: In this study, prevalence of hepatitis B among haemophilia patient was zero and prevalence of hepatitis C and HIV was 1.02% each. Conclusion: Prevalence of transfusion transmitted infections is much lower in this study than previous studies. The use of advanced methods, more sensitive tests, and virally inactivated factor concentrates might contribute to this reduction of viral infections in these patients.
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Rolles, Benjamin, Alla Bulashevska, Michele Proietti, Sigune Goldacker, Klaus Warnatz, Nadezhda Camacho-Ordonez, Margherita Vieri, et al. "Common Variable Immunodeficiency (CVID) in Adults As First Manifestation of (cryptic) Dyskeratosis Congenita." Blood 134, Supplement_1 (November 13, 2019): 1217. http://dx.doi.org/10.1182/blood-2019-128915.
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Introduction: Dyskeratosis Congenita (DKC) is caused by mutations in genes related to telomere maintenance resulting in prematurely shortened telomeres. Clinically, classical DKC is characterized by mucocutaneous abnormalities, bone marrow failure and other variable features such as lung or liver fibrosis. In adults, mono- or oligosymptomatic DKC is typically presenting with a clinically more heterogeneous and often cryptic picture without classical symptoms of DKC. Data on immunodeficiency as a predominant symptom in DKC patients is limited. The common variable immunodeficiency (CVID) represents a heterogenous group of disease with no universally accepted definition. Typically, patients show hypogammaglobulinaemia and impaired vaccine response. In most cases the genetic basis of CVID remains unknown and to date, the disease is primarily via exclusion of other reasons for hypogammaglobulinaemia. In this study, we aimed to retrospectively analyze the frequency and characteristics of adult patients with altered telomere maintenance (manifesting themselves as "cryptic DKC") within a well-defined cohort of patients with clinical findings of CVID. Materials and Methods: 200 patients of the Freiburg registry of adult CVID patients underwent whole-exome sequencing (WES). Diagnosis of CVID was established based on the recommendations of the European Society of Immune Deficiencies. Retrospectively, all patients were screened for mutations/variants in the following DKC causing genes: TERT, RTEL1, DKC1, NHP2, TERC, NOP10, TCAB1, TIN2 and CTC1. Screening identified 23 patients (age: 45 +/- 13 years; mean +/- S.D.) with mutations/polymorphisms in these genes. All identified variants were heterozygous. One patient showed polymorphisms in three different genes. To analyze the functional consequences on telomere maintenance, telomere length (TL) of peripheral blood mononuclear cells (PBMCs) were analyzed via MM-Q-PCR in all 23 patients. Furthermore, Flow-FISH analysis of lymphocytes as well as granulocytes was carried out in 22 and 14 patients, respectively. Results: TL analysis measured with MM-Q-PCR showed in most of the 23 patients shortened TL compared to an age-matched control group. We measured premature TL shortening below the 1% percentile in 44% (10/23) and below the 10% percentile in 52% (12/23). TL determined via flow-FISH showed TL in lymphocytes below the 10% percentile in 64% (14/22) and below 1% in 27% (6/22). WES revealed 24 polymorphisms/mutations in RTEL1 (n=5), TERT (n=3), NHP2 (n=6), DKC1 (n=8) and CTC1 (n=2). Based on bioinformatic prediction, 78 % (19/24) of all polymorphisms were classified as likely benign variants. Two patients with pathogenic mutations were identified: One 30 year old patient with previously described pathogenic TERT mutation (c.1234C>T, p.His412Tyr) was identified showing lymphocyte and granulocyte TL with flow-FISH between the 1% and 10% percentile and below the 1% percentile using MM-Q-PCR. One 23 year old patient with a bioinformatic predicted pathogenic mutation in RTEL1 (c.2313_2315delAGA, p.Glu771del) showed TL in flow-FISH and MM-Q-PCR below the 1% percentile. Of note, this patient developed few years after initial CVID diagnosis severe interstitial lung disease. Three patients were identified with possible DKC showing variants of unknown significance in the RTEL1 (41 years: c.380G>A, p.Arg127Gln) and TERT (65 years: c.3257G>A, p.Arg1086His and 42 years: c.1843G>A, p.Ala615Thr) gene having both TL in lymphocytes/granulocytes (flow-FISH) and leukocytes (MM-Q-PCR) below the 5% percentile. Conclusions: Clinical signs of immunodeficiency can be a rare first manifestation of cryptic/late-onset DKC in adult patients. We found out that at least 1% of all patients with CVID syndrome is caused by mutations typically found in DKC. Our data adds a further important clinical manifestation to the broad clinical spectrum of cryptic DKC. In return, awareness of CVID as a possible first manifestation of cryptic DKC can improve patient management. TL analysis in addition to genetic work-up provides a valuable tool to identify DKC as underlying disease of CVID and other disorders characterized by impaired replicative potential. Disclosures Brümmendorf: Ariad: Consultancy; Merck: Consultancy; University Hospital of the RWTH Aachen: Employment; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy. Beier:Novartis: Honoraria; Repeat Dx: Other: Partner.
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Di Marco, Vito, Maria Rumi, and Massimo Colombo. "Management of HCV-Related Liver Disease in Hemophilia and Thalassemia." Seminars in Liver Disease 38, no. 02 (May 2018): 112–20. http://dx.doi.org/10.1055/s-0038-1655774.
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AbstractChronic infection with the hepatitis C virus (HCV) has long been the dominant complication of substitution therapy in patients with inherited blood disorders and the cause of anticipated death due to end-stage liver disease. In hemophilia, transmission of HCV with clotting factors concentrates started to be curbed in the mid-1980s following the adoption of procedures of virus inactivation of concentrates based on heat, whereas in the 1990s treatment of HCV infection with interferon monotherapy was attempted, however, with little success. The advent of combination therapy of interferon with ribavirin led to a substantial improvement of treatment outcome (40% rate of cure), that however was still of limited efficacy in patients with advanced liver disease, those with high load of HCV genotype 1, and patients coinfected with the human immunodeficiency virus. In this latter population, while the course of hepatitis C was accelerated as a consequence of immunodeficiency, the advent of highly active antiretroviral therapy led acquired immunodeficiency syndrome (AIDS) to decline and hepatitis C to progressively emerge as a dominant cause of mortality, in parallel. In patients with thalassemia, transfusion-related transmission of HCV was efficiently interrupted in 1992 with the advent of sensitive screening tests for testing donors for HCV, whereas treatment with interferon and ribavirin of infected thalassemics was constrained by an increased risk of anemia due to the hemolytic properties of ribavirin coupled with interferon-induced bone marrow suppression. The advent of safe and potent regimens based on the oral administration of direct antiviral agents has revolutionized therapy of HCV in patients with congenital blood diseases, providing substantial clinical benefits and making elimination of infection in these populations, possible.
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Movahedi, Mahshid, Mahnaz Jamee, Hosseinali Ghaffaripour, Farzad Noori, Mehdi Ghaini, Shabnam Eskandarzadeh, Javad Enayat, et al. "Pulmonary manifestations in a cohort of patients with inborn errors of immunity: an 8-year follow-up study." Allergologia et Immunopathologia 50, no. 1 (January 1, 2022): 80–84. http://dx.doi.org/10.15586/aei.v50i1.388.
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Background: Inborn errors of immunity (IEIs) are a group of congenital diseases caused by genetic defects in the development and function of the immune system. The involvement of the respiratory tract is one of the most common presentations in IEIs.Methods: Overall, 117 patients with diagnosed IEIs were followed-up within 8 years at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD). Demographic, clinical, and laboratory data were collected in a questionnaire. Pulmonary function test (PFT), chest X-ray (CXR), and high-resolution computed tomography (HRCT) scans were obtained where applicable.Results: Our study population consisted of 48 (41%) patients with predominantly antibody deficiencies (PADs), 39 (32%) patients with congenital defects of phagocytes, 14 (11.9%) patients with combined immunodeficiency (CID), and 16 (14%) patients with Mendelian susceptibility to mycobacterial diseases (MSMD). . Recurrent pneumonia was the most common manifestation, while productive cough appeared to be the most common symptom in almost all diseases. PFT showed an obstructive pattern in patients with PAD, a restrictive pattern in patients with CID, and a mixed pattern in patients with CGD. HRCT findings were consistent with bronchiectasis in most PAD patients, whereas consolidation and mediastinal lesions were more common in the other groups.Conclusions: Pulmonary manifestations vary among different groups of IEIs. The screening for lung complications should be performed regularly to reveal respiratory pathologies in early stages and follow-up on already existing abnormalities.
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Puck, Jennifer. "Diagnostic Challenges in the Era of Genomic Sequencing and Newborn Screening." Blood 130, Suppl_1 (December 7, 2017): SCI—30—SCI—30. http://dx.doi.org/10.1182/blood.v130.suppl_1.sci-30.sci-30.
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Abstract Early diagnosis of rare immune disorders is important for clinical care and of great interest for the study of immune pathways. Severe combined immunodeficiency (SCID) is a collective term for the most profound inherited defects of T cell development combined with B cell defects or dysfunction. While fatal without treatment, SCID is treatable by allogeneic hematopoietic cell transplantation, or in certain genotypes by enzyme or gene therapy. Avoidance of life-threatening infections to provide optimal treatment and outcomes for affected infants has led to population-based SCID newborn screening (NBS). Infants with SCID fail to generate a diverse repertoire of functional T cells, and consequently have very low numbers of T cells and T cell receptor excision circles (TRECs), DNA byproducts of T cell receptor gene rearrangement. TRECs are readily measured in DNA isolated from newborn dried blood spots (DBS) collected for population based screening. Thus newborn screening for insufficient TRECs identifies SCID before infections occur. As SCID NBS has become widespread, new disease definitions are required for healthy-appearing affected infants without failure to thrive or opportunistic infections. Typical SCID cases have <300 autologous T cells/uL, <10% of the lower range of normal proliferation to the mitogen phytohemmaglutinin A, and/or detectable maternal T cell engraftment, most often with deleterious mutations in recognized SCID genes. One fourth of all SCID cases are "leaky" due to hypomorphic SCID gene mutations; these cases are also detected by TREC testing; they may have >300 T cells/uL, but have impaired T cell function and lack naïve CD4 T cells expressing CD45RA. A subset of infants with leaky SCID have Omenn syndrome, with expansion of oligoclonal, dysregulated T cells leading to adenopathy, erythroderma, hepatosplenomegaly, eosinophilia, and elevated IgE. In addition to these primary target disorders of population screening for SCID, the TREC test identifies infants with additional conditions due to either impaired production or increased loss of T cells. Non-SCID congenital syndromes with variable degrees of T cell lymphopenia (TCL) include DiGeorge syndrome/22q11.2 deletion, CHARGE syndrome, trisomy 21, and ataxia telangiectasia, among others. TREC NBS also finds infants with secondary TCL, in which T cell generating capacity is intrinsically normal, but circulating T cells are diminished as a consequence of other factors, including hydrops, congenital heart disease, chylothorax, neonatal leukemia, maternal immunosuppressive medications taken during pregnancy, or extreme preterm birth. The T cells of these infants normalize once their primary problems resolve. A particularly challenging group of infants are those with abnormal TREC screen results and non-SCID TCL, but no immediate diagnosis. About half of these have syndromes, such as DiGeorge/22q deletion, but with mild or initially unapparent features; others experience resolution of TCL over time, while still others prove to have previously unknown immune disorders that may be diagnosed after deep sequencing and research functional studies. It is important to remember that many serious disorders of T cells are not identified by TREC screening if the block in T cell development or function occurs at a later stage than T cell receptor rearrangement; combined immunodeficiencies (CIDs) with TRECs that are often normal include Zap-70 deficiency and MHC class I and II non-expression. Thus, while virtually completely sensitive and highly specific for the intended target, SCID, population based TREC screening leaves us with both diagnostic dilemmas presented by non-symptomatic infants with low T cells and inability to capture individuals with the >300 non-SCID primary immunodeficiency disorders that would also benefit from early intervention. Deep sequencing is not yet clinically useful, not only due to cost, turnaround time and technical limitations, but primarily due to problems of interpretation, given the extraordinary number of genomic variants of uncertain significance. Disclosures Puck: InVitae, a clinical DNA sequencing company: Other: Spouse employment and stock options; UpToDate: Patents & Royalties: Recieve royalties to write and edit entries on primary immune disorders.
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Zhu, Q., M. Zhang, RM Blaese, JM Derry, A. Junker, U. Francke, SH Chen, and HD Ochs. "The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene." Blood 86, no. 10 (November 15, 1995): 3797–804. http://dx.doi.org/10.1182/blood.v86.10.3797.bloodjournal86103797.
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The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, and immunodeficiency. Besides the classic WAS phenotype, there is a group of patients with congenital X-linked thrombocytopenia (XLT) who have small platelets but only transient eczema, if any, and minimal immune deficiency. Because the gene responsible for WAS has been sequenced, it was possible to correlate the WAS phenotypes with WAS gene mutations. Using a fingerprinting screening technique, we determined the approximate location of the mutation in 13 unrelated WAS patients with mild to severe clinical symptoms. Direct sequence analysis of cDNA and genomic DNA obtained from patient-derived cell lines showed 12 unique mutations distributed throughout the WAS gene, including insertions, deletions, and point mutations resulting in amino acid substitutions, termination, exon skipping, or splicing defects. Of 4 unrelated patients with the XLT phenotype, 3 had missense mutations affecting exon 2 and 1 had a splice-site mutation affecting exon 9. Patients with classic WAS had more complex mutations, resulting in termination codons, frameshift, and early termination. These findings provide direct evidence that XLT and WAS are caused by mutations of the same gene and suggest that severe clinical phenotypes are associated with complex mutations.
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Бегларян, С. А. "Analysis of Clinical Manifestations of Primary Immunodeficiencies in Children: Prediction of Suspected Congenital Immune Pathology Using an Improved Online Test." Педиатрия. Восточная Европа, no. 2 (June 17, 2021): 233–43. http://dx.doi.org/10.34883/pi.2021.9.2.008.
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Введение. На сегодня существует более 400 описанных первичных иммунодефицитов, которые относятся к группе орфанных болезней. Выявление этих врожденных заболеваний зависит от наличия неонатального скрининга, налаженности иммунологической службы и настороженности врачей. При раннем установлении диагноза возможна терапия первичных иммунодефицитов с возможностью полноценной жизни, а иногда и полного выздоровления. Информационные технологии могут дать возможность оценки клинической истории и решить вопрос о раннем направлении к детскому иммунологу как родителям пациентов, так и врачам разных специальностей.Цель. Усовершенствовать разработанный нами ранее иммунологический онлайн-тест с помощью расчета прогностических коэффициентов для отдельных клинических признаков в разных возрастных группах детей с подтвержденными первичными иммунодефицитами.Материалы и методы. Анализ клинического анамнеза 163 детей с различными нозологиями первичного иммунодефицита, помесячное сопоставление их клинических проявлений с возрастом с использованием мультиноминальной логистической регрессии. Внедрение полученных коэффициентов с использованием регрессии Кокса для усовершенствования иммунологического онлайн-теста.Результаты. Полученные коэффициенты каждого клинического маркера показали неоднородную динамику рисков по выявлению первичного иммунодефицита в разном возрасте. Отдельные проявления являются достаточно важными, даже патогномоничными. Однако большинство клинических проявлений развиваются с возрастом постепенно, что затрудняет возможность обнаружения этих редких заболеваний в более раннем возрасте. Эти коэффициенты использованы для усовершенствования существующего иммунологического онлайн-теста, а именно замены использованных ранее эмпирических алгоритмов на полученные уточненные данные.Заключение. Мы оценили клинические признаки за возрастной динамикой у детей, которые уже имели диагноз первичного иммунодефицита. Усовершенствованный на основании этих данных иммунологический онлайн-тест сможет вычислить приблизительные риски наличия той или иной нозологии врожденного иммунодефицита согласно введенному пользователем клиническому анамнезу ребенка. Introduction. Today, there are more than 400 described primary immunodeficiencies that belong to the group of orphan diseases. Detection of these congenital diseases depends on the presence of neonatal screening, coordination of the immunological service, and the doctors’ vigilance. In early diagnostics, treatment of primary immunodeficiencies is possible with full life and even complete recovery in some cases. Information technology can enable the assessment of clinical history and solve the issue of early referral to a pediatric immunologist for both parents of patients and doctors of different specialties.Purpose. To improve our previously developed online immunological test by calculating prognostic coefficients for separate clinical signs in different age groups of children with confirmed primary immunodeficiencies.Materials and methods. Analysis of the clinical history of 163 children with various nosologies of primary immunodeficiency, monthly comparison of their clinical manifestations with age using multinominal logistic regression were conducted. Implementation of the derived coefficients using Cox regression was conducted to improve the online immunological test.Results. The coefficients obtained for each clinical marker showed heterogeneous risk dynamics on detection of primary immunodeficiency at different ages. Certain manifestations are quite important, even pathognomonic. However, most clinical manifestations develop gradually with age, making it difficult to detect these rare diseases at earlier age. These coefficients were used to improve the existing online immunological test, namely to replace the empirical algorithms used previously with the updated obtained data.Conclusion. We evaluated the clinical signs by age dynamics in children, who were already diagnosed with primary immunodeficiency. The improved immunological online test will be able to calculate the approximate risks of the presence of a particular congenital immunodeficiency nosology, according to the clinical history of the child. The test will even be able to predict some diagnoses, if there is a high risk probability.
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Tereshchenko, S. Yu, and M. V. Smolnikova. "Congenitally impaired pattern-recognition receptors in pathogenesis of pediatric invasive and recurrent pneumococcal infection." Russian Journal of Infection and Immunity 9, no. 2 (July 12, 2019): 229–38. http://dx.doi.org/10.15789/2220-7619-2019-2-229-238.
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Here we review currently available data showing that innate immune signs predisposing to recurrent and invasive pneumococcal infections were identified in children. Streptococcus pneumoniae (pneumococcus) belongs to Grampositive bacteria being the major cause of morbidity and mortality in infants, especially in developing countries and in communities with low socioeconomic status. Due to the lack of anti-pneumococcal vaccination, the significant proportion of pneumococcus carriers develop non-invasive (pneumonia, otitis media, sinusitis) and severe invasive (bacteremia/septicemia, meningitis) pneumococcal infection. A great deal of diverse factors related to pneumococcus biological features (virulence factors) as well individualized host-specific immunity are implicated in efficient bacterial penetration across the mucous membranes. The TLR signaling system plays a crucial role in the human nonspecific defense upon the first encounter with the pathogen. Various TLRs comprise the first pattern recognition receptor fami ly ever described which sense ligands derived from the outer bacterial wall. The complement system is the ancient innate immunity component mainly involved in intravascular elimination of bacterial agents. In addition, the complement proteins serve as a bridge between innate and adaptive immunity, ensuring optimal conditions for B- and T-cell maturation and differentiation. Because pneumococcus secretes the IgA protease, a local protective effects related to IgA antibodies might not be so prominent. Therefore, B-cell immunodeficiency and impaired complement system hold a lead place among congenital causes resulting in severe and recurrent pneumococcal infections in children. Thus, based on available data, we concluded that impaired B-cell function, the complement components deficiency as well as receptor-recognition receptors (TLR-2, -9, -4, MYD88 adapter protein, TLR cascade enzymes: IRAK4, NEMO, NOD-like receptors: NOD2, NLRP3; C-type lectins: MBL, Dextin-2, and, possibly, ficoline) play the most important role among congenital immunodeficiencies predisposing to invasive and recurrent pneumococcal infections play the most important role among congenital immunodeficiencies predisposing to invasive and recurrent pneumococcal infections, and should be used as a rationale for immunological surveillance and organizing immunogenetics screening in these patients.
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Gavril, Eva-Cristiana, Alina Costina Luca, Alexandrina-Stefania Curpan, Roxana Popescu, Irina Resmerita, Monica Cristina Panzaru, Lacramioara Ionela Butnariu, Eusebiu Vlad Gorduza, Mihaela Gramescu, and Cristina Rusu. "Wolf-Hirschhorn Syndrome: Clinical and Genetic Study of 7 New Cases, and Mini Review." Children 8, no. 9 (August 30, 2021): 751. http://dx.doi.org/10.3390/children8090751.
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Wolf–Hirschhorn syndrome (WHS), a rare disorder determined by distal 4p deletion, is characterized by a pre and postnatal growth retardation, hypotonia, intellectual disability, epilepsy, craniofacial dysmorphism, and congenital fusion anomalies. The clinical aspects are dependent on the deletion’ size. Our aim was to identify rare specific characteristics in a cohort of seven cases with 4p deletion and to assess the utility of Multiplex ligation-dependent probe amplification (MLPA) (cheap and sensitive test)—combined kits—as a diagnostic test and selection tool for cases that require other investigations (chromosomal microarray analysis—CMA, karyotype). For all cases we conducted a clinical examination with the main features identified: facial dysmorphism, intellectual disability, postnatal development delay, cardiac defects and hypotonia. In some cases, we observed seizures, structural brain abnormalities, immunodeficiencies, and renal anomalies. Prenatal growth retardation was detected in a relatively small number of cases, but postnatal growth failure was a constant feature. In all cases, the clinical diagnosis was confirmed by genetic analyses: karyotype and/or MLPA. In conclusion, renal and brain defects, as well as immunodeficiency are rare manifestations and should be looked for. Although CMA is the standard test, in our experience, MLPA is also a reliable screening method as the identified cases were either confirmed by MLPA or selected for further investigations.
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Korsunsky, I. A., D. A. Kudlay, A. P. Prodeus, A. Yu Shcherbina, and A. G. Rumyantsev. "NEONATAL SCREENING FOR PRIMARY IMMUNODEFICIENCY AND Т-/B- CELL LYMPHOPENIA AS THE BASIS FOR THE FORMATION OF RISK GROUPS FOR CHILDREN WITH CONGENITAL PATHOLOGIES." Pediatria. Journal named after G.N. Speransky 99, no. 2 (April 13, 2020): 8–15. http://dx.doi.org/10.24110/0031-403x-2020-99-2-8-15.
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Wakamatsu, Manabu, Hideki Muramatsu, Shinsuke Kataoka, Yusuke Okuno, Sakai Yoshimi, Yoko Nakajima, Tetsuya Ito, Ikuya Tsuge, Seiji Kojima, and Yoshiyuki Takahashi. "Utility of Newborn Screening for Severe Combined Immunodeficiency and X-Linked Agammaglobulinemia Using TREC and KREC Assays." Blood 134, Supplement_1 (November 13, 2019): 3604. http://dx.doi.org/10.1182/blood-2019-126669.
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Background Severe combined immune deficiency (SCID) is a potentially fatal primary immunodeficiency due to the absence of T and B lymphocyte function. Early intervention for patients with SCID results in a higher survival rate. From 2017, we launched the first optional newborn screening (NBS) for SCID in Japan based on the detection of T-cell receptor excision circles (TREC). However, NBS for severe B-cell lymphopenia, such as X-linked agammaglobulinemia (XLA), has not been a standard screening test because of a high false-positive rate of Kappa-deleting recombination excision circles (KREC), which reflects the replication of B cells. XLA is characterized by severe B-cell lymphopenia and marked reduction of all classes of serum immunoglobulins. Patients with XLA require early diagnosis and immunoglobulin replacement therapy to prevent the development of bronchiectasis caused by recurrent infections. This study aimed to analyze the results of NBS for SCID and elucidate the utility of NBS for SCID and XLA using the TREC/KREC assay. Patients and Methods We enrolled infants who received NBS for SCID (n = 29,447) between April 2017 and June 2018. Using the EnLiteTM TREC kit, we measured TRECA and β-actin, which are used as controls for monitoring sample amplification. Samples with less than 30 copies/µL and adequate β-actin were defined as positive TRECA. All infants with positive TRECA were followed up for at least 12 months. We measured TRECB and KREC using the EnLiteTM TREC/KREC kit in these infants. As positive controls, we used TRECB and KREC in patients with SCID and XLA, respectively. Furthermore, all infants with positive TRECA were evaluated using flow cytometric analysis and target capture-based next-generation sequencing (NGS) analysis covering 349 primary immunodeficiency- and bone marrow failure-related genes to evaluate CD4+CD45RA+ T-cell counts and identify diagnostic variants. This study was approved by the institutional review board of Nagoya University Graduate School of Medicine. Results Of the infants who underwent NBS for SCID, 43 (0.15%) infants showed positive TRECA. All 43 infants were followed up in Nagoya University for at least 12 months. Of these, we identified one case with DiGeorge syndrome showing severe lymphopenia but did not identify typical SCID. TRECB and KREC were measured in 43 infants with positive TRECA. To determine which kit is more useful to detect T-cell lymphopenia, we compared TRECA with TRECB in 1454 infants with normal TRECA and 43 with positive TRECA. All healthy infants with normal TRECA showed TRECB with more than 30 copies/µL but nine patients with SCID showed extremely low TRECB (median [range], 0 [0-3] copies/µL). Only 6 of 43 (14%) infants showed TRECB with less than 30 copies/µL. Moreover, we analyzed the correlation between CD4+CD45RA+ T-cell counts and TRECB. Compared with 37 infants with normal TRECB, 6 infants with positive TRECB demonstrated significantly lower CD4+CD45RA+ T-cell counts (P = 0.026). However, target capture-based NGS did not identify any diagnostic variants among them. This finding suggested that using this kit, false-positive rates might be decreased from 0.15% (43/29,447) to 0.02% (6/29,447). Using this kit, we assessed KREC in 1454 infants with normal TRECA and 43 with positive TRECA. Of these, we identified one case with less than 30 copies/µL KREC who was diagnosed with congenital asplenia. As positive controls, all six patients with XLA showed quite low KREC (0 [0-9] copies/µL). Compared with previously reported KREC assay, this kit may result in lower false-positive rates. Furthermore, to demonstrate whether KREC reflects the replication of B cells, we analyzed the correlation with CD19+ B-cell counts and KREC. Among 43 infants with positive TRECA, infants with less than 500/µL CD19+ B cells showed significantly lower KREC than those with more than 500/µL CD19+ B cells (P = 0.014). Conclusion We conducted the first large-scale study to evaluate the utility of the newly released EnLiteTM TREC/KREC kit. This kit may be more useful than the current TREC kit to identify infants with T-cell lymphopenia and to avoid unnecessary follow up. Compared with previous NBS for XLA, the false-positive rate of this assay was within an acceptable range. Furthermore, TRECB and KREC were assessed with almost the same screening cost and labor. Therefore, we are considering switching from the current TREC kit to this TREC/KREC kit. Disclosures No relevant conflicts of interest to declare.
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Giannelou, Angeliki, Hongying Wang, Qing Zhou, Yong Hwan Park, Mones S. Abu-Asab, Kris Ylaya, Deborah L. Stone, et al. "Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors." Annals of the Rheumatic Diseases 77, no. 4 (January 22, 2018): 612–19. http://dx.doi.org/10.1136/annrheumdis-2017-212401.
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ObjectivesTo characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype.MethodsWe studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients’ primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM).ResultsWe identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients’ fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth.ConclusionsMutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.
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Jalas, Chaim, Anastasia Fedick, Bari J. Ballew, Blanche P. Alter, Neelam Giri, Simon Boulton, Kenneth Offit, John Petrini, Nathan Treff, and Sharon A. Savage. "Higher Than Expected Carrier Frequency Of The Dyskeratosis Congenita RTEL1 p.Arg1264His recessive Founder In Individuals Of Ashkenazi Jewish Ancestry." Blood 122, no. 21 (November 15, 2013): 1228. http://dx.doi.org/10.1182/blood.v122.21.1228.1228.
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Abstract Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure syndrome (IBMFS) in which germline mutations in telomere biology genes account for approximately 70% of known families. DC is clinically diagnosed by the presence of the triad of nail dysplasia, lacy skin pigmentation, and oral leukoplakia. However, not all patients have the triad and multiple other medical problems may include, stenosis of the esophagus, urethra and/or lacrimal ducts, avascular necrosis of the hips or shoulders, developmental delay, head and neck squamous cell cancer, and/or leukemia. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients have features of DC but also have microcephaly, cerebellar hypoplasia, and intrauterine growth retardation, and may present with severe immunodeficiency and enteropathy. Telomere lengths (in blood leukocyte subsets analyzed by flow FISH) less than the 1st percentile for age are diagnostic of any form of DC, including HH. We identified a germline autosomal recessive (AR) mutation (p.Arg1264His) in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The minor allele frequency of this variant is ∼0.0001 in public databases of 9600 individuals. The affected individuals in these families are homozygous for this mutation, which affects three isoforms of RTEL1. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In both families, each parent was a healthy, heterozygous carrier of one mutant allele. Haplotypes were reconstructed from twelve common SNPs based on allele sharing in the unaffected siblings and parents. No recombinants were seen in either family and the segregating risk haplotype was identical in affected individuals from both families. Thus, p.Arg1264His is carried on a common haplotype, likely from a common AJ founder. We determined the carrier frequency of the p.Arg1264His mutation, as well as three other mutations, p.Gly763Val, p.Met516Ile and p.Arg998Ter, which were recently reported and possibly found in individuals of AJ ancestry. DNA was derived from 1,048 self-described AJ individuals enrolled in the Dor Yeshorim program. Consent form information included that patient material would be used for clinical testing and that excess material would be de-identified and used for research purposes. The mutations were genotyped by TaqMan assays and heterozygous carrier samples were confirmed by Sanger sequencing with stringent quality control. No individuals in this study carried the p.Gly763Val or p.Arg998Ter minor alleles. Two individuals (0.19%) were carriers of the p.Met516Ile mutation. Notably, 1% (10 of 1,032) of AJ individuals in this study were carriers of the p.Arg1264His mutation in RTEL1. This carrier frequency of 1 in 100 is similar to that of the FANCC AJ mutation and many other FA founder populations, such as FANCA in South African Afrikaners, Spanish Gypsies, Brazilians, Tunisians, and Moroccans, as well as FANCG in Sub-Saharan Blacks, and BRCA2 (FANCD1) in the US general population. A carrier frequency of 1 in 100 is similar to that of genetic disorders found in the AJ population recommended for screening by the American College of Medical Genetics. Based on this, we suggest that genetic counseling and RTEL1 p.Arg1264His carrier screening for the HH variant of DC be offered to individuals of AJ ancestry. Disclosures: No relevant conflicts of interest to declare.
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Nadiminti, Kalyan, Abhishek A. Mangaonkar, Kimberly J. Langer, Shakila P. Khan, Vilmarie Rodriguez, Naseema Gangat, Michelle A. Elliott, et al. "Survival Outcomes Following Allogeneic Stem Cell Transplantation for Inherited Bone Marrow Failure and Myeloid Germline Predisposition Syndromes." Blood 134, Supplement_1 (November 13, 2019): 3300. http://dx.doi.org/10.1182/blood-2019-121742.
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Introduction: Allogeneic stem cell transplant (HCT) is the only potential curative option for patients with inherited marrow failure (iBMF) and myeloid germline predisposition syndromes (GPD). HCT outcomes are influenced by inherent disease specific-nuances such as alkylating agent and radio-sensitivity, immune deregulation, and higher risks for graft failure and GVHD; factors contributing to transplant related mortality (TRM) and morbidity. We carried out this retrospective study to assess survival outcomes and long term complications (LTC) in patients with IBMF and GPD that underwent HCT. Patients and methods: We queried our institutional database and identified patients with iBMF and GPD as defined by the 2016 WHO classification. These included Fanconi anemia (FA), short telomere syndromes (STS), Diamond-Blackfan anemia (DBA), GATA2 and RUNX1 haploinsufficiency, congenital amegakaryocytic thrombocytopenia (CAMT), deficiency of adenosine deaminase 2 (DADA2), among others. Patients with acquired causes of BMF were excluded. Statistical analyses were performed using SAS (JMP v14.1). Results: Twenty eight patients, median age 10 years (1 month-63 years), 46% males, were included in the study (table 1). Fanconi anemia Seven (25%) patients with FA underwent HCT, 5 (71%) without myeloid transformation and 2 after transformation to MDS/AML. Five (71%) patients received a RIC, 4 (57%) prior to transformation. At a median follow up (FU) of 126 m, the median OS was 194 m (95% CI 34m; NR) and 10 year survival was 64%. Grade 1 aGVHD was seen in four (57%) and 3 (42%) developed mild cGVHD, while 1 developed a donor derived AML (sibling not tested for FA). LTC included second primary malignancy (SPM) - squamous cell cancer (SCC) of skin and muscle invasive bladder cancer (MIBC) in 1(14%) and SCC of head/neck and anogenital region in 3 patients (43%), psychosocial complications (PS) in 6(85%), premature ovarian failure (POF) in 3(43%), and avascular necrosis (AVN) in 4(57%) patients. Short Telomere Syndromes (STS) Seven patients with STS underwent HCT, 2 (28%) after transformation to MDS. Five (71%) received RIC, including both the transformed patients. At a median FU of 67m, median OS was NR (95% CI 2m; NR) and 5 year survival was 47%. One (14%) patient developed grade 2 aGVHD and mild cGVHD of skin. Three (43%) developed SPM - skin cancers in 2 and MIBC in 1. PS was noted in 1(15%), and AVN in 3(43%). Three (43%) patients had concomitant mild IPF/restrictive lung disease. GATA2 haploinsufficiency : Seven patients with GATA2 haploinsufficiency underwent HCT; 2(28.5%) after transformation to MDS and 3(43%) to AML, of which 2(40%) received MAC. At a median FU of 57m, median OS was NR (95% CI 7m; NR) and 5 year survival was 71%. Three (50%) developed grade 2 aGVHD of skin and GI tract and 2(33%) developed mild cGVHD. LTC include PTLD, AVN and POF in 1 patient each. Ribosomopathies : One patient (13y) with DBA underwent RIC HCT and developed grade 2 aGVHD, secondary iron overload, and died at 10 months due to severe fungal infection. Others : Identical twins with CAMT underwent HCT (at 4y and 5y) from the same unrelated donor and at last FU (74m and 87m, respectively) remain 100% donor without GVHD. Two children with primary immunodeficiency and marrow failure underwent HCT (at 2y and 7y), one after transformation to MDS. The non-transformed patient is currently alive (120m), while the patient with transformation died 1month after HCT from disseminated cytomegalovirus infection. One patient with germline RUNX1 deletion developed CMML and underwent a RIC HCT and is alive at a FU of 4 months, with no GVHD. One patient with DADA2 (n=1) underwent RIC HCT without LTC. Due to the smaller cohort size, we compared OS in transformed and non-transformed patients for the IBMF and GATA2 patients only (n=24, 9 with transformation) (figure1). At a median FU of 74m, the median OS of transformed vs non-transformed patients was 108m(95% CI 1;108m) and 163m(95% CI 67m; NR), respectively (p=0.033). Conclusions: Our study demonstrates that HCT remains an important intervention for IBMF and GPD, with the maximum impact being gained prior to transformation. While only mild chronic GVHD was noted (37%), inherent syndromic issues resulted in a high rate of SPM (FA/STS) and organ failure (STS- IPF). Notably, one FA patient who received an MRD HCT developed donor derived AML, underlining the importance of genetic screening in asymptomatic related individuals. Disclosures Kenderian: Lentigen: Research Funding; Kite/Gilead: Research Funding; Morphosys: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.
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Fazi, C., L. Lodi, L. Magi, C. Canessa, M. Giovannini, C. Pelosi, F. Pochiero, et al. "Case Report: Zellweger Syndrome and Humoral Immunodeficiency: The Relevance of Newborn Screening for Primary Immunodeficiency." Frontiers in Pediatrics 10 (March 25, 2022). http://dx.doi.org/10.3389/fped.2022.852943.
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BackgroundZellweger syndrome (ZS) is a congenital autosomal recessive disease within the spectrum of peroxisome biogenesis disorders, characterized by the impairment of peroxisome assembly. The presence of peroxisome enzyme deficiencies leads to complex developmental sequelae, progressive disabilities, and multiorgan damage, due to intracellular accumulation of very-long-chain fatty acids (VLCFAs).Case PresentationWe report the case of an infant affected by ZS in which agammaglobulinemia, detected through neonatal screening of congenital immunodeficiencies, appeared as a peculiar trait standing out among all the other classical characteristics of the syndrome. The exome analysis through next-generation sequencing (NGS), which had previously confirmed the diagnostic suspicion of ZS, was repeated, but no mutations causative of inborn error of immunity (humoral defect) were detected.ConclusionIn this case, no genetic variants accountable for the abovementioned agammaglobulinemia were detected. Given that the scientific literature reports the involvement of peroxisomes in the activation of Nuclear Factor κ-light-chain-enhancer of activated B cells (NF-κB) pathway, which is crucial for B-cell survival, with this work, we hypothesize the existence of a link between ZS and humoral immunodeficiencies. Further studies are required to confirm this hypothesis.
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Ye, Xiuling, Xin Quan, Xu Guo, Zhidong Wang, and Hao Wu. "Idiopathic non-cirrhotic portal hypertension in a patient with Talaromyces marneffei infection: a case report." BMC Infectious Diseases 23, no. 1 (March 1, 2023). http://dx.doi.org/10.1186/s12879-023-08090-6.
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Abstract Background The etiopathogenesis of idiopathic non-cirrhotic portal hypertension (INCPH) is so far poorly understood. Altered immunity, blood diseases, infections, congenital defects and drug exposure have been documented in a part of patients with INCPH owing to increased recognition of the disorder in patients with HIV, or various haematological disorders or autoimmune diseases. We aim to discuss the possible etiopathogenesis of INCPH. Case presentation We reported that a patient with intestinal infection of T. Marneffei and hyper-IgE syndrome, a group of rare primary immunodeficiency disorders, was finally diagnosed with INCPH for gastroesophageal variceal bleeding. The diagnosis was mainly based on histopathological features. Transjugular intrahepatic portosystemic shunt was performed and there was no recurrence of melena during the six-month follow-up. Conclusion In the context of immunodeficiency, INCPH may associated with intestinal infections. Thus, screening for enterogenic infection and immunological disorders in patients with unexplained portal hypertension is necessary.
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Sukwa, Nsofwa, Michelo Simuyandi, Masuzyo Chirwa, Yvonne Mutombo Kumwimba, Obvious N. Chilyabanyama, Natasha Laban, Aybüke Koyuncu, and Roma Chilengi. "Clinical presentation of congenital syphilis in a rotavirus vaccine cohort study in Lusaka: a case series." Journal of Medical Case Reports 15, no. 1 (April 1, 2021). http://dx.doi.org/10.1186/s13256-021-02745-1.
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Abstract Background Despite an otherwise robust national antenatal clinic program, maternal and congenital syphilis remains an important public health issue in Zambia. This case series reports the clinical presentation of seven infants diagnosed with congenital syphilis in Lusaka, Zambia. Case presentations The cases in this series were incidental findings from a cohort of infants enrolled in a rotavirus vaccine immunogenicity study recruiting infants at 6 weeks of age. As part of clinical care for enrolled participants, we screened mothers of children who presented with adverse events of (i) repeated upper respiratory tract infections/coryza, (ii) skin lesions, and (iii) poor weight gain, for syphilis using rapid plasma reagin test. From a cohort of 214 mother–infant pairs enrolled between September and December 2018, a total of 115 (44.4%) of the mothers reported to have not been screened during antenatal care. Of these, four (3.5%) reported to have tested positive; and only two received treatment. Seven out of 57 (26.6%) children meeting the screening criteria had a positive rapid plasma reagin test result. The mean age at diagnosis was 4.5 months (1.3 months standard deviation), and the common presenting features included coryza (6/7), skin lesions (4/7), conjunctivitis (3/7), pallor/anemia (5/7), wasting (2/7), and underweight (5/7). Three of the seven infants were exposed to human immunodeficiency virus. Following diagnosis, all seven cases received standard treatment according to national treatment guidelines. That is, 6/7 cases received inpatient care with benzylpenicillin for 10 days, while 1/7 was treated as an outpatient and received daily procaine penicillin for 10 days. Conclusion These findings suggest that, though screening for syphilis is part of the standard antenatal care in Zambia, it is not offered optimally. There is urgent need to address programmatic shortcomings in syphilis screening and treatment to avoid long-term sequelae. Additionally, clinicians need to raise their index of suspicion and rule out syphilis when confronted with these clinical symptoms, regardless of the mother’s human immunodeficiency virus status.
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Teutsch, Suzy M., Carlos A. Nunez, Anne Morris, Guy D. Eslick, Angela Berkhout, Daniel Novakovic, Julia ML Brotherton, et al. "Australian Paediatric Surveillance Unit (APSU) Annual Surveillance Report 2021." Communicable Diseases Intelligence 46 (October 20, 2022). http://dx.doi.org/10.33321/cdi.2022.46.66.
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The Australian Paediatric Surveillance Unit (APSU) has been conducting surveillance of rare communicable and non-communicable conditions in children since its inception in 1993. In this report, the results are described of surveillance of ten communicable diseases (and complications) for 2021, including the numbers of cases and incidence estimates; demographics; clinical features; and management and short-term outcomes. The included diseases are: acute flaccid paralysis (AFP); congenital cytomegalovirus (CMV); neonatal herpes simplex virus (HSV) infection; paediatric human immunodeficiency virus (HIV) infection; perinatal exposure to HIV; severe complications from influenza; juvenile-onset respiratory papillomatosis (JoRRP); congenital rubella syndrome; congenital varicella syndrome; and neonatal varicella infection. In 2021, cases of JoRRP were reported to the APSU for the first time since 2017, indicating potential gaps in HPV vaccination. AFP surveillance by APSU again contributed to Australia achieving a minimum target incidence of one AFP case per 100,000 children aged < 15 years. There were no cases of children with severe complications of influenza. No cases of varicella or congenital rubella were reported; however, at-risk populations, especially young migrant and refugee women from countries without universal vaccination programs, need to be screened and prioritised for vaccination prior to pregnancy. Cases of perinatal exposure to HIV continue to increase; however, the rate of mother-to-child-transmission remains at low levels due to the use of effective intervention strategies. Case numbers of congenital CMV and neonatal HSV remain steady in the absence of vaccines, prompting the need for greater awareness and education, with recent calls for target screening of at-risk infants for congenital CMV.
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Speckmann, Carsten, Uta Nennstiel, Manfred Hönig, Michael H. Albert, Sujal Ghosh, Catharina Schuetz, Inken Brockow, et al. "Prospective Newborn Screening for SCID in Germany: A First Analysis by the Pediatric Immunology Working Group (API)." Journal of Clinical Immunology, February 27, 2023. http://dx.doi.org/10.1007/s10875-023-01450-6.
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Abstract Backgr ound T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019. Methods Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years. Results Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn syndrome (OS)/idiopathic T-cell lymphocytopenia, and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in utero onset OS and died after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result. Conclusion The German TREC-NBS represents the largest European SCID screening at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54,000, very similar to previous observations from North American and European regions and countries where TREC-NBS was implemented. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe.
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Oszer, Aleksandra, Katarzyna Bąbol-Pokora, Sylwia Kołtan, Agata Pastorczak, and Wojciech Młynarski. "Germline 3p22.1 microdeletion encompassing RPSA gene is an ultra-rare cause of isolated asplenia." Molecular Cytogenetics 14, no. 1 (November 15, 2021). http://dx.doi.org/10.1186/s13039-021-00571-0.
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Abstract Background Isolated Congenital Asplenia (ICA, OMIM #271400) is a rare, life-threatening abnormality causing immunodeficiency, which is characterized by the absence of a spleen. Diagnosis should be completed in early childhood and antibiotic prophylaxis applied with additional vaccinations. Case presentation We report the case of a six-month old girl with hematologic abnormalities and asplenia documented in imaging, with Howell-Jolly bodies in peripheral blood smear. Targeted Next Generation Sequencing screening did not reveal any pathogenic variant in genes associated with congenital asplenia. Since absence of the spleen was found by imaging, high-resolution copy number variations detection was also performed using genomic Single Nucleotide Polymorphism microarray: a heterozygous 337.2 kb deletion encompassing the RPSA gene was observed, together with SLC25A38, SNORA6, SNORA62 and MOBP genes. Despite haploinsufficiency of SLC25A38, SNORA6, SNORA62 and MOBP, no change in the clinical picture was observed. A search of available CNV databases found that a deletion of the RPSA locus seems to be unique and only duplications were found in this region with the frequency of less than 0.02%. Conclusions Copy number variations in RPSA gene locus are ultrarare cause of isolated asplenia. Furthermore, since the patient does not present any concomitant clinical features, it would appear that haploinsufficiency of SLC25A38, SNORA6, SNORA62 and MOBP genes does not affect the phenotype of patients. However, to confirm this thesis a longer follow-up of the patient’s development is needed.
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Cerda, Rodrigo, Freddy Perez, Rosa Maria S. M. Domingues, Paula M. Luz, Beatriz Grinsztejn, Valdilea G. Veloso, Sonja Caffe, Jordan A. Francke, Kenneth A. Freedberg, and Andrea L. Ciaranello. "Prenatal Transmission of Syphilis and Human Immunodeficiency Virus in Brazil: Achieving Regional Targets for Elimination." Open Forum Infectious Diseases 2, no. 2 (2015). http://dx.doi.org/10.1093/ofid/ofv073.
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Abstract Background. The Pan-American Health Organization has called for reducing (1) human immunodeficiency virus (HIV) mother-to-child transmission (MTCT) to ≤0.30 infections/1000 live births (LB), (2) HIV MTCT risk to ≤2.0%, and (3) congenital syphilis (CS) incidence to ≤0.50/1000 LB in the Americas by 2015. Methods. Using published Brazilian data in a mathematical model, we simulated a cohort of pregnant women from antenatal care (ANC) through birth. We investigated 2 scenarios: “current access” (89.1% receive one ANC syphilis test and 41.1% receive 2; 81.7% receive one ANC HIV test and 18.9% receive birth testing; if diagnosed, 81.0% are treated for syphilis and 87.5% are treated for HIV) and “ideal access” (95% of women undergo 2 HIV and syphilis screenings; 95% receive appropriate treatment). We conducted univariate and multivariate sensitivity analyses on key inputs. Results. With current access, we projected 2.95 CS cases/1000 LB, 0.29 HIV infections/1000 LB, 7.1% HIV MTCT risk, and 11.11 intrauterine fetal demises (IUFD)/1000 pregnancies, with significant regional variation. With ideal access, we projected improved outcomes: 1.00 CS cases/1000 LB, 0.10 HIV infections/1000 LB, HIV MTCT risk of 2.4%, and 10.65 IUFD/1000 pregnancies. Increased testing drove the greatest improvements. Even with ideal access, only HIV infections/1000 LB met elimination goals. Achieving all targets required testing and treatment >95% and reductions in prevalence and incidence of HIV and syphilis. Conclusions. Increasing access to care and HIV and syphilis antenatal testing will substantially reduce HIV and syphilis MTCT in Brazil. In addition, regionally tailored interventions reducing syphilis incidence and prevalence and supporting HIV treatment adherence are necessary to completely meet elimination goals.
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Wang, Zhouhan, Hao Xu, Beiqing Gu, Yanqi Jin, Tianyuan Wang, Jindi Ma, Yingfeng Lu, Xiaopeng Yu, Beiwen Zheng, and Yimin Zhang. "Flavorubredoxin, a Candidate Trigger Related to Thrombotic Thrombocytopenic Purpura: Screening of the Complete Genome of a Salmonella enterica Serovar Typhimurium Isolate From an AIDS Case." Frontiers in Cellular and Infection Microbiology 12 (June 10, 2022). http://dx.doi.org/10.3389/fcimb.2022.864087.
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Thrombotic thrombocytopenic purpura (TTP) is one of the two classic thrombotic microangiopathy (TMA) diseases which could be induced by infections. To the best of our knowledge, this is the first report of an acquired immunodeficiency syndrome (AIDS) patient with acquired TTP induced by infection with Salmonella enterica serovar Typhimurium (hereafter, S. Typhimurium) isolate, S. Typhimurium_zhang, which was confirmed by serology and genetic taxonomy. The literature review identified 17 TMA-related genes encoding the candidate triggers, which were searched in the annotated genome sequence of S. Typhimurium_zhang. Anaerobic nitric oxide reductase flavorubredoxin (FlRd), encoded by norV which is related to another TMA, haemolytic uraemic syndrome (HUS), was found in S. Typhimurium_zhang. Basic local alignment search tool (BLAST) analysis revealed that norV and FlRd in S. Typhimurium_zhang, as well as eight S. Typhimurium type strains, have high identity with HUS-related Escherichia coli O157:H7 strain TW14359. Similar results were obtained from the BLAST analysis of 73 S. enterica isolates for congenital TTP which was also previously reported to be triggered by S. enterica. Phylogenetic analysis and amino acid sequence alignment revealed that FlRd was functional and highly conservative on 69 Enterobacteriaceae, including S. Typimurium_zhang and TW14359. In brief, we found norV in the genome of a S. Typhimurium clinical isolate that induced TTP in an AIDS patient. FlRd, the protein encoded by norV, probably triggered the TTP and was highly conservative, functional, and widespread in S. enterica and Enterobacteriaceae. More in vitro and in vivo studies are required to confirm our findings and determine the underlying mechanism.
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Guisasola Cienfuegos, M., J. Nuche, A. Lareo, S. Alonso, F. Arribas-Ynsaurriaga, P. Escribano Subias, and C. Jimenez Lopez-Guarch. "Usefulness of transthoracic echocardiography for pulmonary artery aneurysm screening in patients with pulmonary arterial hypertension." European Heart Journal 42, Supplement_1 (October 1, 2021). http://dx.doi.org/10.1093/eurheartj/ehab724.1973.
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Abstract Background/Introduction Pulmonary artery aneurysm (PAA), defined as a pulmonary artery (PA) diameter >40 mm, is a common finding among pulmonary arterial hypertension (PAH) patients. Although often asymptomatic, PAA may lead to life-threatening complications such as left main coronary artery compression or PA dissection. Transthoracic echocardiography (TTE) is regularly employed for risk assessment in PAH patients. However, TTE accuracy for PA measurement has not been evaluated, and current practice guidelines lack formal recommendations for PAA screening and follow-up. We aim to determine whether TTE is an appropriate tool for PA diameter measurement and determine an optimal cut-off point to diagnose a PAA through TTE. Methods We retrospectively analyzed a cohort of 657 PAH patients followed up at a national referral centre. For this analysis, we selected those patients who had undergone at least one TTE and one computed tomography (CT) or magnetic resonance (MR) within six months before or after the TTE. We performed an agreement analysis between CT/MR-based and TTE-based PA diameter using the Passing–Bablok method. Furthermore, we calculated the area under the curve for the identification of a PAA with a TTE (compared to CT/MR). Results We analyzed 281 simultaneous CT/MR and TTE of a total of 178 PAH patients (71% women). Median age at diagnosis was 42.1 (32.2–58.0) years. PAH etiology was idiopathic or familial in 67 (38%), associated with congenital heart disease in 28 (16%) and associated with connective tissue disease in 36 (20%) patients. In 46 (26%) patients PAH was associated with other entities, such as human immunodeficiency virus, pulmonary veno-occlusive disease, drugs or portal hypertension. We found a significant correlation between PA diameter measured in TTE and CT/CMR (Lin's concordance correlation coefficient = 0.851) (Figure 1). The area under the curve for the detection of PAA was 0.91 (95% CI 0.88–0.95, p=0.018) (Figure 2). We selected a TTE-based PA diameter 37 mm as the optimal cut-off point for PAA identification. This diameter correctly classified 85.4% of measurements with a sensitivity and a specificity of 83.2% and 87.2%, respectively. Conclusion Our study demonstrates that TTE is an adequate tool for PA diameter quantification with a strong correlation with CT/MR. This good correlation makes TTE an excellent tool for PAA screening among PAH patients, avoiding unnecessary CT or MR scan and helping to identify those patients in whom close follow-up is advisable. Based on these results, we recommend the inclusion of PA diameter measurement in TTE acquisition protocols for PAH patients. Funding Acknowledgement Type of funding sources: None. Figure 1. Passing–Bablok regression lineFigure 2. ROC curve for PAA detection with TTE
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Menon, Sonia, Lenka Benova, and Hillary Mabeya. "Epilepsy management in pregnant HIV+ women in sub-Saharan Africa, clinical aspects to consider: a scoping review." BMC Medicine 18, no. 1 (November 17, 2020). http://dx.doi.org/10.1186/s12916-020-01799-0.
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Abstract Background Since the introduction of highly active antiretroviral therapy (HAART), acquired immune deficiency syndrome (AIDS) related mortality has markedly declined. As HAART is becoming increasingly available, the infection with human immunodeficiency virus (HIV+) in sub-Saharan Africa (SSA) is becoming a chronic condition. While pregnancy in HIV+ women in SSA has always been considered a challenging event for the mother and the fetus, for pregnant HIV+ women also diagnosed with epilepsy (WWE), there are additional risks as HIV increases the odds of developing seizures due to the vulnerability of the central nervous system to other infections, immune dysfunction, and overall metabolic disturbances. In light of a growing proportion of HIV+ WWE on HAART and an increasing number of pregnant women accessing mother-to-child transmission of HIV programs through provision of HAART in SSA, there is a need to develop contextualized and evidenced-based clinical strategies for the management of epilepsy in this population. In this study, we conduct a literature scoping review to identify issues that warrant consideration for clinical management. Result Twenty-three articles were retained after screening, which covered six overarching clinical aspects: status epilepticus (SE), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), dyslipidemia, congenital malformation (CM), chronic kidney disease (CKD), and neurological development. No studies for our population of interest were identified, highlighting the need for a cautionary approach to be employed when extrapolating findings. Conclusion High risks of CM and drug interactions with first-line antiepileptic drugs (AEDs) warrant measures to increase the accessibility and choices of safer second-line AEDs. To ensure evidence-based management of epilepsy within this population, the potential high prevalence of SE, CKD, dyslipidemia, and SJS/TEN and the cumulative effect of drug-drug interactions should be considered. Further understanding of the intersections between pregnancy and drug-drug interactions in SSA is needed to ensure evidenced-based management of epilepsy in pregnant HIV+ WWE. To prevent SE, the barriers for AED treatment adherence in pregnant HIV+ women should be explored. Our review underscores the need to conduct cohort studies of HIV+ WWE in reproductive age over time and across pregnancies to capture the cumulative effect of HAART and AED to inform clinical management.
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Lim, Sung Min, Je Hee Shin, Jee Yeon Baek, Ji Young Lee, Ji-Man Kang, and Jong Gyun Ahn. "572. Adverse Events Following Live Immunization in Patients with DiGeorge Syndrome: A Retrospective, Single Center Study in Korea." Open Forum Infectious Diseases 9, Supplement_2 (December 1, 2022). http://dx.doi.org/10.1093/ofid/ofac492.625.
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Abstract Background DiGeorge syndrome (DGS) is a syndrome accompanied by congenital heart defect, hypoparathyroidism and immunodeficiency of varying severity. Live vaccination is generally contraindicated in patients with DGS. However, in real clinical practice, there are cases in which live vaccines are immunized before the diagnosis of DGS or are incidentally immunized. We collected these cases and investigated adverse events (AEs), especially infections caused by the vaccine strains. Methods This retrospective study included all patients diagnosed with DGS at Severance Hospital Seoul, Korea, between November 2005 and June 2021. We extracted patients with ICD-10 code (D82.1) and then excluded subjects without genetic confirm. According to the immune status, subjects were categorized into three groups: group A [CD3 < 500 or CD8 < 200 (cells/mm3)], group B [CD3 ≥500 and CD8 ≥ 200 (cells/mm3)] and group C (unknown). Results Of a total 94 DGS patients, approximately 40% of subjects (38/94) underwent immunological test, of which 21% (8/38) belonged to group A and 79% (30/38) were in group B. Approximately 80% of study subjects (73/94) had a record of at least one live vaccination. By vaccine type, measles-mumps-rubella accounted for the most at 70% (66/94), followed by varicella, bacillus Calmette–Guérin, rotavirus, and live-attenuated Japanese encephalitis virus vaccine. A total of 50 AEs were observed (Figure 1): fever (n=29), URI (n=9), diarrhea (n=4), rash (n=3), thrombocytopenia (n=3), injection site pus (n=1) and febrile convulsion (n=1). Among them 26% (13/50) occurred in group A and no significant difference in the incidence rate of AEs between group A and B was observed (P = 0.14). Six cases of them turned out to be consistent with live vaccination by WHO 2009 causality analysis. Moreover, there were no serious reactions, including ICU hospitalization or death, and there was no emergence of disease caused by vaccine strains. Conclusion Our data show that live vaccines were often given without immunologic screening and generally well tolerated in our study population. Disclosures All Authors: No reported disclosures.