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BACKGROUND: Newborn screening (NBS) programs for severe combined immunodeficiency facilitate early diagnosis of severe combined immunodeficiency and promote early treatment with hematopoietic stem cell transplantation, resulting in improved clinical outcomes. Infants with congenital athymia are also identified through NBS because of severe T-cell lymphopenia. With the expanding introduction of NBS programs, referrals of athymic patients for treatment with thymus transplantation have recently increased at Great Ormond Street Hospital (GOSH) (London, United Kingdom). OBJECTIVE: We studied the impact of NBS on timely diagnosis and treatment of athymic infants with thymus transplantation at GOSH. METHODS: We compared age at referral and complications between athymic infants diagnosed after clinical presentation (n = 25) and infants identified through NBS (n = 19) who were referred for thymus transplantation at GOSH between October 2019 and February 2023. We assessed whether age at time of treatment influences thymic output at 6 and 12 months after transplantation. RESULTS: The infants referred after identification through NBS were significantly younger and had fewer complications, in particular fewer infections. All deaths occurred in the group of those who did not undergo NBS, including 6 patients before and 2 after thymus transplantation because of preexisting infections. In the absence of significant comorbidities or diagnostic uncertainties, timely treatment was achieved more frequently after NBS. Treatment when younger than age 4 months was associated with higher thymic output at 6 and 12 months after transplantation. CONCLUSION: NBS contributes to earlier recognition of congenital athymia, promoting referral of athymic patients for thymus transplantation before they acquire infections or other complications and facilitating treatment at a younger age, thus playing an important role in improving their outcomes.
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Síndromes de Imunodeficiência , Imunodeficiência Combinada Severa , Lactente , Recém-Nascido , Humanos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia , Triagem Neonatal , TimoRESUMO
BACKGROUND: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care. OBJECTIVE: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients. METHODS: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data. RESULTS: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home. CONCLUSIONS: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.
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Angioedemas Hereditários , Humanos , Feminino , Masculino , Angioedemas Hereditários/epidemiologia , Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/uso terapêutico , Danazol/uso terapêutico , Reino Unido/epidemiologia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.
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Doenças do Sistema Imunitário , Síndromes de Imunodeficiência , Criança , Humanos , Autoimunidade/genética , Estudos de Coortes , Mutação com Ganho de Função , Síndromes de Imunodeficiência/genética , Mutação , Fator de Transcrição STAT3/genética , Proliferação de Células , LinfócitosRESUMO
BACKGROUND: Terminal complement pathway deficiencies often present with severe and recurrent infections. There is a lack of good-quality data on these rare conditions. This study investigated the clinical outcome and genetic variation in a large UK multi-center cohort with primary and secondary terminal complement deficiencies. METHODS: Clinicians from seven UK centers provided anonymised demographic, clinical, and laboratory data on patients with terminal complement deficiencies, which were collated and analysed. RESULTS: Forty patients, median age 19 (range 3-62) years, were identified with terminal complement deficiencies. Ten (62%) of 16 patients with low serum C5 concentrations had underlying pathogenic CFH or CFI gene variants. Two-thirds were from consanguineous Asian families, and 80% had an affected family member. The median age of the first infection was 9 years. Forty-three percent suffered meningococcal serotype B and 43% serotype Y infections. Nine (22%) were treated in intensive care for meningococcal septicaemia. Two patients had died, one from intercurrent COVID-19. Twenty-one (52%) were asymptomatic and diagnosed based on family history. All but one patient had received booster meningococcal vaccines and 70% were taking prophylactic antibiotics. DISCUSSION: The genetic etiology and clinical course of patients with primary and secondary terminal complement deficiency are variable. Patients with low antigenic C5 concentrations require genetic testing, as the low level may reflect consumption secondary to regulatory defects in the pathway. Screening of siblings is important. Only half of the patients develop septicaemia, but all should have a clear management plan.
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COVID-19 , Infecções Meningocócicas , Sepse , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Proteínas do Sistema Complemento/genética , Doenças da Deficiência Hereditária de Complemento , Humanos , Infecções Meningocócicas/genética , Pessoa de Meia-Idade , Reino Unido/epidemiologia , Adulto JovemRESUMO
The formation of mammalian dendritic cells (DCs) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 exerts a differential effect on DC subsets, including plasmacytoid DCs (pDCs) and the classical DC lineages cDC1 and cDC2. In humans, cDC2-related subsets have been described including AXL+SIGLEC6+ pre-DC, DC2 and DC3. The origin of this heterogeneity is unknown. Using high-dimensional analysis, in vitro differentiation, and an allelic series of human IRF8 deficiency, we demonstrated that cDC2 (CD1c+DC) heterogeneity originates from two distinct pathways of development. The lymphoid-primed IRF8hi pathway, marked by CD123 and BTLA, carried pDC, cDC1, and DC2 trajectories, while the common myeloid IRF8lo pathway, expressing SIRPA, formed DC3s and monocytes. We traced distinct trajectories through the granulocyte-macrophage progenitor (GMP) compartment showing that AXL+SIGLEC6+ pre-DCs mapped exclusively to the DC2 pathway. In keeping with their lower requirement for IRF8, DC3s expand to replace DC2s in human partial IRF8 deficiency.
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Antígenos CD34/metabolismo , Células Dendríticas/citologia , Hematopoese/fisiologia , Fatores Reguladores de Interferon/metabolismo , Animais , Antígenos CD1/metabolismo , Linhagem Celular , Linhagem da Célula/imunologia , Células Dendríticas/imunologia , Glicoproteínas/metabolismo , Células-Tronco Hematopoéticas/citologia , Humanos , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Camundongos , Receptores Imunológicos/metabolismoRESUMO
Germline STAT3 gain-of-function (GOF) mutations have been linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance. Here we studied the impact of 17 different STAT3 GOF mutations on the canonical STAT3 signaling pathway and correlated the molecular results with clinical manifestations. The mutations clustered in three groups. Group 1 mutants showed altered STAT3 phosphorylation kinetics and strong basal transcriptional activity. They were associated with the highest penetrance of lymphoproliferation and autoimmunity. Group 2 mutants showed a strongly inducible transcriptional reporter activity and were clinically less penetrant. Group 3 mutants were mostly located in the DNA binding domain and showed the strongest DNA binding affinity despite a poor transcriptional reporter response. Thus, the GOF effect of STAT3 mutations is determined by a heterogeneous response pattern at the molecular level. The correlation of response pattern and clinical penetrance indicates a significant contribution of mutation-determined effects on disease manifestations.
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Mutação com Ganho de Função/genética , Linfócitos/imunologia , Fator de Transcrição STAT3/genética , Autoimunidade/genética , Proliferação de Células , Feminino , Humanos , Masculino , Família Multigênica , Penetrância , Fosforilação , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genéticaRESUMO
For children under 12 years of age who have chronic hepatitis C virus (HCV) infection, there are currently no approved treatments with direct-acting antiviral agents. We therefore evaluated the safety and efficacy of ledipasvir-sofosbuvir in HCV-infected children aged 3 to <6 years. In an open-label study, patients 3 to <6 years old chronically infected with HCV genotype 1 (n = 33) or 4 (n = 1) received weight-based doses of combined ledipasvir-sofosbuvir as granules (33.75 mg/150 mg for weights <17 kg or 45 mg/200 mg for weights ≥17 kg) for 12 weeks. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12). For the first 14 patients, intensive pharmacokinetic sampling was done on day 10 of treatment. All patients had been infected through perinatal transmission and were treatment naïve. No patients had known cirrhosis. Ten patients (29%) weighed <17 kg. SVR12 was achieved in 97% of patients (33 of 34); the patient who did not achieve SVR12 was 3 years old and discontinued treatment after 5 days because of an adverse event "abnormal drug taste." The most common adverse events were vomiting (24% of patients), cough (21%), and pyrexia (21%). No patients experienced a serious adverse event. Intensive pharmacokinetic analysis of 13 patients for whom data were evaluable confirmed that the doses selected were appropriate. Conclusion: Ledipasvir-sofosbuvir was well tolerated and highly effective in children 3 to <6 years old with chronic HCV infection.
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Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Fluorenos/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Uridina Monofosfato/análogos & derivados , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Criança , Pré-Escolar , Feminino , Fluorenos/efeitos adversos , Humanos , Masculino , Sofosbuvir , Resposta Viral Sustentada , Fatores de Tempo , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/efeitos adversosRESUMO
[This corrects the article DOI: 10.3389/fimmu.2019.00568.].
RESUMO
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency. Patients with CVID are prone to recurrent bacterial infection due to the failure of adequate immunoglobulin production. Monogenetic defects have been identified in ~25% of CVID patients. Recently, mutations in IKZF1, encoding the zinc-finger transcription factor IKAROS which is broadly expressed in hematopoietic cells, have been associated with a CVID-like phenotype. Herein we describe 11 patients with heterozygous IKZF1 variants from eight different families with autosomal dominant CVID and two siblings with an IKZF1 variant presenting with inflammatory bowel disease (IBD). This study shows that mutations affecting the DNA binding domain of IKAROS can impair the interaction with the target DNA sequence thereby preventing heterochromatin and pericentromeric localization (HC-PC) of the protein. Our results also indicate an impairment of pericentromeric localization of IKAROS by overexpression of a truncated variant, caused by an immature stop codon in IKZF1. We also describe an additional variant in TNFSF10, encoding Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), additionally presented in individuals of Family A. Our results indicate that this variant may impair the TRAIL-induced apoptosis in target cell lines and prohibit the NFκB activation by TRAIL and may act as a modifier in Family A.
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Imunodeficiência de Variável Comum/genética , Fator de Transcrição Ikaros/genética , Mutação , Infecções Respiratórias/genética , Dedos de Zinco , Adulto , Animais , Anticorpos/imunologia , Sítios de Ligação/genética , Núcleo Celular/metabolismo , Centrômero/metabolismo , Estudos de Coortes , Imunodeficiência de Variável Comum/imunologia , DNA/metabolismo , Análise Mutacional de DNA , Feminino , Células HEK293 , Heterozigoto , Humanos , Fator de Transcrição Ikaros/metabolismo , Doenças Inflamatórias Intestinais/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Células NIH 3T3 , Linhagem , Fenótipo , Infecções Respiratórias/imunologiaRESUMO
Low or absent immunoglobulin A (IgA) levels are frequently found in children in whom immunodeficiency is not suspected. IgA deficiency is the most common primary immunodeficiency disorder in the UK affecting approximately 1 in 600 people. Isolated IgA deficiency is often identified coincidentally when investigating a child for conditions such as coeliac disease. The aim of this article is to provide a structured approach to the history, investigation and management of an isolated IgA deficiency.
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Deficiência de IgA/diagnóstico , Achados Incidentais , Doenças Assintomáticas , Criança , Humanos , Deficiência de IgA/etiologia , Reação TransfusionalRESUMO
BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.
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Classe I de Fosfatidilinositol 3-Quinases/genética , Síndromes de Imunodeficiência/genética , Transtornos Linfoproliferativos/genética , Mutação/genética , Infecções Respiratórias/genética , Adolescente , Adulto , Animais , Antibioticoprofilaxia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Estudos de Coortes , Inibidores Enzimáticos/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/mortalidade , Infecções por Herpesviridae/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/terapia , Lactente , Cooperação Internacional , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/terapia , Masculino , Camundongos , Pessoa de Meia-Idade , Recidiva , Infecções Respiratórias/mortalidade , Infecções Respiratórias/terapia , Inquéritos e Questionários , Análise de Sobrevida , Adulto JovemRESUMO
This paper describes a voluntary anonymous survey to investigate the seroprevalence of Hepatitis C (HCV) in children in Glasgow, UK attending a Dental Hospital and the proportion of HCV positive mothers who have a child who is HCV seropositive. The study was undertaken among children and accompanying parents and household contacts attending a general anaesthetic assessment clinic at Glasgow Dental Hospital and School. Children were asked to provide an oral fluid specimen for HCV testing. Accompanying adults were asked to provide demographic data on the child and information on familial risk factors for HCV infection using a standardised questionnaire. Birth mothers were also asked to provide an oral fluid specimen. Specimens and questionnaires were linked by a unique anonymous study number. Between June 2009 and December 2011, samples were collected from 2141 children and 1698 mothers. None of the samples from the children were HCV seropositive but 16 (0.9%, 95% CI 0.6-1.5%) of the specimens from mothers were HCV antibody positive. In summary, the prevalence of HCV seropositivity in the birth mothers of the children was similar to that estimated in the general population served by the hospital and showed no evidence of mother-to-child transmission of HCV.
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Anticorpos Anti-Hepatite C/análise , Hepatite C/epidemiologia , Saliva/química , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Escócia/epidemiologia , Estudos Soroepidemiológicos , Inquéritos e QuestionáriosRESUMO
Most illnesses associated with fever are self-limiting and children recover with no specific treatment. However, fever can also be the presenting feature of serious illness, which may be life threatening if not diagnosed and treated appropriately. It is important to establish whether the temperature has been measured and, if so, how. The height of the temperature should be recorded, and always enquire what device has been used, as a reading from a forehead thermometer may not be accurate. While many families will use a thermometer the impression of the child being hot to touch without formal measurement should still be taken seriously. Check whether the child is still feeding or taking fluids adequately. Any child may be irritable when their temperature is high, but a constantly irritable or inconsolable child, or one who is extremely lethargic, drowsy or difficult to rouse is a cause for concern. Ask about any skin changes or rashes the parent may have noticed. Find out what measures the parent may already have taken to manage the fever, and in particular, whether, and at what time, antipyretics have been given. Enquire about contact with infectious illnesses, and foreign travel. Other vital signs, including heart rate, respiratory rate and capillary refill time should also be recorded. The child should be examined for focal signs indicating the site of infection, and hydration should be assessed. Posture, tone, fontanelle (if patent), presence of a rash, neck stiffness and level of consciousness should also be assessed. If the diagnosis is unclear, potentially serious, and specific treatment may be needed to prevent deterioration, the child should be referred.
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Febre , Criança , Febre/diagnóstico , Febre/etiologia , Febre/terapia , HumanosRESUMO
PURPOSE: Adenosine deaminase (ADA) deficiency is a systemic disorder of purine metabolism. Deficiency of the purine salvage enzyme ADA leads to the build-up of the toxic metabolites, deoxyadenosine triphosphate and deoxyadenosine. ADA is ubiquitously expressed in all tissues of the body but most profoundly affects lymphocyte development and function leading to severe combined immunodeficiency (SCID). Unlike most other forms of SCID, ADA deficiency also results in non-immunologic manifestations. Associations between ADA deficiency and sensorineural hearing loss, behavioural abnormalities, non-infectious pulmonary disease and skeletal dysplasia are all recognised, and affect the long term outcome for these patients. Identification of new non-immunological manifestations and clinical presentations of ADA deficiency is essential to allow early optimisation of supportive care. METHODS AND RESULTS: Here we report four patients with ADA deficiency whose presenting feature was haemolytic uremic syndrome (HUS). 3 of 4 patients were diagnosed with ADA deficiency only after developing HUS, and one diagnosis was made post mortem, after a sibling was diagnosed with SCID. Shiga-toxigenic organisms were not isolated from any of the patients. 2 patients made a good recovery from their HUS with supportive treatment and initiation of PEG-ADA. Both remain well on enzyme replacement with mild or no residual renal impairment. CONCLUSIONS: Clinicians should be aware of this previously unreported non-immunologic manifestation of ADA deficiency.
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Adenosina Desaminase/deficiência , Agamaglobulinemia/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Imunodeficiência Combinada Severa/diagnóstico , Adenosina Desaminase/genética , Agamaglobulinemia/tratamento farmacológico , Criança , Diagnóstico Diferencial , Evolução Fatal , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação , Imunodeficiência Combinada Severa/tratamento farmacológicoRESUMO
Neisseria meningitidis is an encapsulated Gram-negative diplococcus which colonises the upper respiratory tract without causing symptoms in up to 25% of the population. At least 13 different serogroups cause invasive meningococcal disease (IND). In the UK serogroup B causes more than 80% of cases of invasive disease. More than 75% of cases occur in the under 5s, reflecting the lack of ability of the immature immune system to mount an effective response to the polysaccharide capsule of the organism. There is also a peak around adolescence. Meningococcal disease can present with features of septicaemia, fever, purpura, and rapidly progressive shock, or with meningitis which can occur without a rash. Many cases have a mixed picture. Young infants with meningitis may not display the classical signs, but appear unwell, lethargic and floppy Petechiae which start to spread, become purpuric, occur in association with signs of shock or meningitis, or in any child who appears ill should always be treated as IMD until proven otherwise. Any child with symptoms and signs suggestive of IMD and a non-blanching rash should be transferred to hospital as an emergency immediately. IM (or IV) benzylpenicillin (or ceftriaxone) should be given at the earliest opportunity, but treatment should not delay transfer. if the child does not have features suggestive of IMD at the time of initial assessment it is important to give parents advice regarding symptoms and signs which may suggest deterioration.
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Infecções Meningocócicas/diagnóstico , Antibacterianos/uso terapêutico , Ceftriaxona/uso terapêutico , Criança , Humanos , Infecções Meningocócicas/tratamento farmacológico , Infecções Meningocócicas/prevenção & controle , Vacinas Meningocócicas/uso terapêutico , Penicilina G/uso terapêuticoRESUMO
We report a case of Epstein-Barr virus infection with the subsequent development of haemophagocytic lymphohistiocytosis in a teenage Crohn's disease patient treated with azathioprine. We found that the early introduction of the anti-B cell monoclonal antibody rituximab precipitated a rapid fall in circulating B-cells and EBV viral load, resulting in a prompt and sustained recovery from what is a potentially fatal complication of azathioprine therapy in Crohn's disease patients.
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Anticorpos Monoclonais Murinos/uso terapêutico , Azatioprina/efeitos adversos , Doença de Crohn/tratamento farmacológico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Adolescente , Azatioprina/uso terapêutico , Doença de Crohn/complicações , Doença de Crohn/imunologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/virologia , RituximabRESUMO
We investigated oral fluid (OF) as an alternative to sampling of rashes for varicella zoster virus (VZV) genotyping and further characterized VZV clade prevalence in the United Kingdom and Europe. VZV was detected in up to 91% of OF specimens. Paired OF and vesicle fluid samples contained identical VZV clades. While clades 1 and 3 were the most prevalent across the United Kingdom and Europe, in Western Europe, clade 5 viruses were circulating. Viruses from the same outbreak belonged to different clades, but no clade was associated with a severe-disease phenotype. OF is suitable and convenient for large-scale molecular epidemiological studies of VZV.
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Varicela/epidemiologia , Herpes Zoster/epidemiologia , Herpesvirus Humano 3/genética , Epidemiologia Molecular , Polimorfismo de Nucleotídeo Único , Saliva/virologia , Varicela/virologia , Europa (Continente)/epidemiologia , Genótipo , Herpes Zoster/virologia , Herpesvirus Humano 3/isolamento & purificação , Humanos , Boca/virologia , Prevalência , Sensibilidade e Especificidade , Pele/patologia , Pele/virologia , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Determination of the genetic defect in patients with a congenital disorder of glycosylation (CDG) is challenging because of the wide clinical presentation, the large number of gene products involved, and the occurrence of secondary causes of underglycosylation. Transferrin isoelectric focusing has been the method of choice for CDG screening; however, improved methods are required for the molecular diagnosis of patients with CDG type II. METHODS: Plasma samples with a typical transferrin isofocusing profile were analyzed. N-glycans were released from these samples by PNGase F [peptide-N4-(acetyl-ß-glucosaminyl)-asparagine amidase] digestion, permethylated and purified, and measured on a MALDI linear ion trap mass spectrometer. A set of 38 glycans was used for quantitative comparison and to establish reference intervals for such glycan features as the number of antennae, the level of truncation, and fucosylation. Plasma N-glycans from control individuals, patients with known CDG type II defects, and patients with a secondary cause of underglycosylation were analyzed. RESULTS: CDGs due to mannosyl (α-1,6-)-glycoprotein ß-1,2-N-acetylglucosaminyltransferase (MGAT2), ß-1,4-galactosyltransferase 1 (B4GALT1), and SLC35C1 (a GDP-fucose transporter) defects could be diagnosed directly from the N-glycan profile. CDGs due to defects in proteins involved in Golgi trafficking, such as subunit 7 of the conserved oligomeric Golgi complex (COG7) and subunit V0 a2 of the lysosomal H(+)-transporting ATPase (ATP6V0A2) caused a loss of triantennary N-glycans and an increase of truncated structures. Secondary causes with liver involvement were characterized by increased fucosylation, whereas the presence of plasma sialidase produced isolated undersialylation. CONCLUSIONS: MALDI ion trap analysis of plasma N-glycans documents features that discriminate between primary and secondary causes of underglycosylation and should be applied as the first step in the diagnostic track of all patients with an unsolved CDG type II.