RESUMO
The tissue microenvironment is a major driver in imprinting tissue-specific macrophage functions in various mammalian tissues. As monocytes are recruited into the gastrointestinal (GI) tract at steady state and inflammation, they rapidly adopt a tissue-specific and distinct transcriptome. However, the GI tract varies significantly along its length, yet most studies of intestinal macrophages do not directly compare the phenotype and function of these macrophages in the small and large intestine, thus leading to disparities in data interpretations. This review highlights differences along the GI tract that are likely to influence macrophage function, with a specific focus on diet and microbiota. This analysis may fuel further investigation regarding the interplay between the intestinal immune system and GI tissue microenvironments, ideally providing unique therapeutic targets to modulate specific intestinal macrophage populations and/or functions.
Assuntos
Trato Gastrointestinal , Microbiota , Animais , Intestinos , Macrófagos , MonócitosRESUMO
Over 100 genes are associated with monogenic forms of inflammatory bowel disease (IBD). These genes affect the epithelial barrier function, innate and adaptive immunity in the intestine, and immune tolerance. We provide an overview of newly discovered monogenic IBD genes and illustrate how a recently proposed taxonomy model can integrate phenotypes and shared pathways. We discuss how functional understanding of genetic disorders and clinical genomics supports personalised medicine for patients with monogenic IBD.
Assuntos
Doenças Inflamatórias Intestinais , Medicina de Precisão , Humanos , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , Intestinos , FenótipoRESUMO
Phosphomannomutase 2 (PMM2) deficiency causes Congenital Disorder of Glycosylation (PMM2-CDG), but does not have a recognised association with Inflammatory Bowel Disease (IBD). A distinct clinical syndrome of hyperinsulinism and autosomal recessive polycystic kidney disease (HIPKD) arises in the context of a specific variant in the PMM2 promotor, either in homozygosity, or compound heterozygous with a deleterious PMM2 variant. Here, we describe the development of IBD in three patients with PMM2-HIPKD, with onset of IBD at 0, 6, and 10 years of age. In each case, intestinal inflammation coincided with the unusual finding of gastric antral foveolar hyperplasia. IBD disease was of variable severity at onset but well controlled with conventional and first-line biologic treatment approaches. The organ-level pattern of disease manifestations in PMM2-HIPKD-IBD may reflect a loss of cis-acting regulatory control by hepatocyte nuclear factor 4 alpha (HNF4A). Analysis of published transcriptomic data suggests that IBD most likely arises due to an impact on epithelial cellular function. We identify a specific pattern of variation in PMM2 as a novel association of early-onset IBD with distinctive gastric pathology.
Assuntos
Defeitos Congênitos da Glicosilação , Hiperinsulinismo , Doenças Inflamatórias Intestinais , Doenças Renais Policísticas , Humanos , Hiperplasia/genéticaRESUMO
The commonest cause of rickets worldwide is vitamin D deficiency, but studies from sub-Saharan Africa describe an endemic vitamin D-independent form that responds to dietary calcium enrichment. The extent to which calcium-deficiency rickets is the dominant form across sub-Saharan Africa and in other low-latitude areas is unknown. We aimed to characterise the clinical and biochemical features of young children with rickets in a densely populated urban informal settlement in Kenya. Because malnutrition may mask the clinical features of rickets, we also looked for biochemical indices of risk in children with varying degrees of acute malnutrition. Twenty one children with rickets, aged 3 to 24 months, were identified on the basis of clinical and radiologic features, along with 22 community controls, and 41 children with either severe or moderate acute malnutrition. Most children with rickets had wrist widening (100%) and rachitic rosary (90%), as opposed to lower limb features (19%). Developmental delay (52%), acute malnutrition (71%), and stunting (62%) were common. Compared to controls, there were no differences in calcium intake, but most (71%) had serum 25-hydroxyvitamin D levels below 30 nmol/L. These results suggest that rickets in young children in urban Kenya is usually driven by vitamin D deficiency, and vitamin D supplementation is likely to be required for full recovery. Wasting was associated with lower calcium (p = .001), phosphate (p < .001), 25-hydroxyvitamin D (p = .049), and 1,25-dihydroxyvitamin D (p = 0.022) levels, the clinical significance of which remain unclear.
Assuntos
Desnutrição/complicações , Raquitismo/etiologia , Deficiência de Vitamina D/complicações , Cálcio/sangue , Cálcio/deficiência , Cálcio da Dieta/administração & dosagem , Pré-Escolar , Suplementos Nutricionais , Feminino , Humanos , Lactente , Quênia , Masculino , Fosfatos/sangue , Fosfatos/deficiência , Raquitismo/diagnóstico , Raquitismo/tratamento farmacológico , População Urbana , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Síndrome de Emaciação/sangue , Síndrome de Emaciação/etiologiaRESUMO
BACKGROUND: Hyperbilirubinaemia is a major cause of neonatal morbidity. Early identification of those infants most at risk might allow the development of targeted primary preventative therapy and follow-up. The objective of this study was to assess whether arterial umbilical cord bilirubin (aUCB) level at delivery predicts the development of neonatal jaundice in term deliveries. METHODS: Retrospective analysis of hospital biochemistry records identified term deliveries with recorded aUCB. Infant medical records were reviewed to identify those who developed neonatal hyperbilirubinaemia (requiring treatment according to UK NICE guidelines) with/without a positive direct antiglobulin test (DAT). RESULTS: Of 1411 term deliveries with a clearly recorded aUCB, 30 infants developed clinically-significant jaundice (2.7%), of whom 8 were DAT + ve (0.6%) mostly due to ABO incompatibility. aUCB strongly predicted the development of DAT + ve jaundice (area under the ROC curve = 0.996), as well as all-cause jaundice (area under the ROC curve = 0.74). However, this effect was critically dependent on maternal blood group. Amongst infants at risk of ABO incompatibility (maternal blood groups O + ve/O-ve, 39.7%) the predictive value of aUCB for all cause jaundice was strengthened (area under the ROC curve = 0.88). Amongst those not at risk (defined maternal blood group not O + ve/O-ve, 51.0%) it disappeared completely (area under the ROC curve = 0.46). A cutoff of 35 µmol/l for mothers with blood group O + ve/O-ve increased the pre-test probability for all-cause jaundice of 4% to a post-test probability of 30%. CONCLUSIONS: For infants of mothers with blood group O, aUCB predicts development of neonatal jaundice. There was no evident utility for infants of mothers with other blood groups. Estimation of aUCB should be considered as a strategy for early identification of those at risk of neonatal haemolytic jaundice.
Assuntos
Bilirrubina/sangue , Sangue Fetal/metabolismo , Icterícia Neonatal/diagnóstico , Biomarcadores/sangue , Feminino , Humanos , Recém-Nascido , Icterícia Neonatal/sangue , Modelos Logísticos , Masculino , Curva ROC , Estudos RetrospectivosRESUMO
BACKGROUND: Ready-to-use therapeutic foods (RUTF) are lipid-based pastes widely used in the treatment of acute malnutrition. Current specifications for RUTF permit a high n-6 polyunsaturated fatty acid (PUFA) content and low n-3 PUFA, with no stipulated requirements for preformed long-chain n-3 PUFA. The objective of this study was to develop an RUTF with elevated short-chain n-3 PUFA and measure its impact, with and without fish oil supplementation, on children's PUFA status during treatment of severe acute malnutrition. METHODS: This randomized controlled trial in children with severe acute malnutrition in rural Kenya included 60 children aged 6 to 50 months who were randomized to receive i) RUTF with standard composition; ii) RUTF with elevated short chain n-3 PUFA; or iii) RUTF with elevated short chain n-3 PUFA plus fish oil capsules. Participants were followed-up for 3 months. The primary outcome was erythrocyte PUFA composition. RESULTS: Erythrocyte docosahexaenoic acid (DHA) content declined from baseline in the two arms not receiving fish oil. Erythrocyte long-chain n-3 PUFA content following treatment was significantly higher for participants in the arm receiving fish oil than for those in the arms receiving RUTF with elevated short chain n-3 PUFA or standard RUTF alone: 3 months after enrollment, DHA content was 6.3% (interquartile range 6.0-7.3), 4.5% (3.9-4.9), and 3.9% (2.4-5.7) of total erythrocyte fatty acids (P <0.001), respectively, while eicosapentaenoic acid (EPA) content was 2.0% (1.5-2.6), 0.7% (0.6-0.8), and 0.4% (0.3-0.5) (P <0.001). RUTF with elevated short chain n-3 PUFA and fish oil capsules were acceptable to participants and carers, and there were no significant differences in safety outcomes. CONCLUSIONS: PUFA requirements of children with SAM are not met by current formulations of RUTF, or by an RUTF with elevated short-chain n-3 PUFA without additional preformed long-chain n-3 PUFA. Clinical and growth implications of revised formulations need to be addressed in large clinical trials. TRIAL REGISTRATION: Clinicaltrials.gov NCT01593969. Registered 4 May 2012.
Assuntos
Suplementos Nutricionais , Fast Foods , Ácidos Graxos Ômega-3/administração & dosagem , Óleos de Peixe/administração & dosagem , Desnutrição/dietoterapia , Doença Aguda , Pré-Escolar , Ácidos Docosa-Hexaenoicos , Método Duplo-Cego , Ácido Eicosapentaenoico , Ácidos Graxos Insaturados/sangue , Feminino , Humanos , Lactente , Quênia , Lipídeos/sangue , MasculinoRESUMO
BACKGROUND: Environmental enteric dysfunction (EED) refers to an incompletely defined syndrome of inflammation, reduced absorptive capacity, and reduced barrier function in the small intestine. It is widespread among children and adults in low- and middle-income countries. Understanding of EED and its possible consequences for health is currently limited. OBJECTIVE: A narrative review of the current understanding of EED: epidemiology, pathogenesis, therapies, and relevance to child health. METHODS: Searches for key papers and ongoing trials were conducted using PUBMED 1966-June 2014; ClinicalTrials.gov; the WHO Clinical Trials Registry; the Cochrane Library; hand searches of the references of retrieved literature; discussions with experts; and personal experience from the field. RESULTS: EED is established during infancy and is associated with poor sanitation, certain gut infections, and micronutrient deficiencies. Helicobacter pylori infection, small intestinal bacterial overgrowth (SIBO), abnormal gut microbiota, undernutrition, and toxins may all play a role. EED is usually asymptomatic, but it is important due to its association with stunting. Diagnosis is frequently by the dual sugar absorption test, although other biomarkers are emerging. EED may partly explain the reduced efficacy of oral vaccines in low- and middle-income countries and the increased risk of serious infection seen in children with undernutrition. CONCLUSIONS: Despite its potentially significant impacts, it is currently unclear exactly what causes EED and how it can be treated or prevented. Ongoing trials involve nutritional supplements, water and sanitation interventions, and immunomodulators. Further research is needed to better understand this condition, which is of likely crucial importance for child health and development in low- and middle-income settings.
Assuntos
Meio Ambiente , Inflamação , Enteropatias/fisiopatologia , Síndromes de Malabsorção/fisiopatologia , Adulto , Infecções Bacterianas , Síndrome da Alça Cega , Pré-Escolar , Transtornos do Crescimento/etiologia , Humanos , Lactente , Enteropatias/epidemiologia , Enteropatias/etiologia , Intestinos/microbiologia , Síndromes de Malabsorção/epidemiologia , Síndromes de Malabsorção/etiologia , Pobreza , SaneamentoRESUMO
BACKGROUND: Environmental enteric dysfunction (EED) is an acquired syndrome of impaired gastrointestinal mucosal barrier function that is thought to play a key role in the pathogenesis of stunting in early life. It has been conceptualized as an adaptive response to excess environmental pathogen exposure. However, it is clinically similar to other inflammatory enteropathies, which result from both host and environmental triggers, and for which immunomodulation is a cornerstone of therapy. METHODS: In this pilot double-blind randomized placebo-controlled trial, 44 children with severe acute malnutrition and evidence of EED were assigned to treatment with mesalazine or placebo for 28 days during nutritional rehabilitation. Primary outcomes were safety and acceptability of the intervention. RESULTS: Treatment with mesalazine was safe: there was no excess of adverse events, evidence of deterioration in intestinal barrier integrity or impact on nutritional recovery. There were modest reductions in several inflammatory markers with mesalazine compared to placebo. Depression of the growth hormone--insulin-like growth factor-1 axis was evident at enrollment and associated with inflammatory activation. Increases in the former and decreases in the latter correlated with linear growth. CONCLUSIONS: Intestinal inflammation in EED is non-essential for mucosal homeostasis and is at least partly maladaptive. Further trials of gut-specific immunomodulatory therapies targeting host inflammatory activation in order to optimize the growth benefits of nutritional rehabilitation and to address stunting are warranted. Funded by The Wellcome Trust. TRIAL REGISTRATION: Registered at Clinicaltrials.gov NCT01841099.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Doenças Inflamatórias Intestinais , Desnutrição/tratamento farmacológico , Mesalamina/administração & dosagem , Serviços de Saúde da Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Habitação , Humanos , Lactente , Masculino , Desnutrição/patologia , Projetos Piloto , Pobreza , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
We compared the blood RNA transcriptome of children hospitalized with influenza A H1N1/09, respiratory syncytial virus (RSV) or bacterial infection, and healthy controls. Compared to controls, H1N1/09 patients showed increased expression of inflammatory pathway genes and reduced expression of adaptive immune pathway genes. This was validated on an independent cohort. The most significant function distinguishing H1N1/09 patients from controls was protein synthesis, with reduced gene expression. Reduced expression of protein synthesis genes also characterized the H1N1/09 expression profile compared to children with RSV and bacterial infection, suggesting that this is a key component of the pathophysiological response in children hospitalized with H1N1/09 infection.
Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/genética , Biossíntese de Proteínas/genética , Adolescente , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Infecções Bacterianas/metabolismo , Criança , Análise por Conglomerados , Humanos , Influenza Humana/imunologia , Influenza Humana/metabolismo , Reprodutibilidade dos Testes , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/metabolismo , Vírus Sincicial Respiratório Humano , Transdução de SinaisRESUMO
BACKGROUND AND AIMS: Inflammatory bowel diseases [IBD] have a complex polygenic aetiology. Rare genetic variants can cause monogenic intestinal inflammation. The impact of chromosomal aberrations and large structural abnormalities on IBD susceptibility is not clear. We aimed to comprehensively characterise the phenotype and prevalence of patients with IBD who possess rare numerical and structural chromosomal abnormalities. METHODS: We performed a systematic literature search of databases PubMed and Embase; and analysed gnomAD, Clinvar, the 100 000 Genomes Project, and DECIPHER databases. Further, we analysed international paediatric IBD cohorts to investigate the role of IL2RA duplications in IBD susceptibility. RESULTS: A meta-analysis suggests that monosomy X [Turner syndrome] is associated with increased expressivity of IBD that exceeds the population baseline (1.86%, 95% confidence interval [CI] 1.48 to 2.34%) and causes a younger age of IBD onset. There is little evidence that Klinefelter syndrome, Trisomy 21, Trisomy 18, mosaic Trisomy 9 and 16, or partial trisomies contribute to IBD susceptibility. Copy number analysis studies suggest inconsistent results. Monoallelic loss of X-linked or haploinsufficient genes is associated with IBD by hemizygous or heterozygous deletions, respectively. However, haploinsufficient gene deletions are detected in healthy reference populations, suggesting that the expressivity of IBD might be overestimated. One duplication that has previously been identified as potentially contributing to IBD risk involves the IL2RA/IL15R loci. Here we provide additional evidence that a microduplication of this locus may predispose to very-early-onset IBD by identifying a second case in a distinct kindred. However, the penetrance of intestinal inflammation in this genetic aberration is low [<2.6%]. CONCLUSIONS: Turner syndrome is associated with increased susceptibility to intestinal inflammation. Duplication of the IL2RA/IL15R loci may contribute to disease risk.
Assuntos
Doenças Inflamatórias Intestinais , Síndrome de Turner , Humanos , Variações do Número de Cópias de DNA , Síndrome de Turner/complicações , Doenças Inflamatórias Intestinais/genética , Aberrações Cromossômicas , Inflamação/complicaçõesRESUMO
BACKGROUND: Therapeutic options for paediatric inflammatory bowel disease (IBD) are limited, especially for younger children. Unlike in adults, vedolizumab and ustekinumab are not licensed for paediatric use in the UK. We aimed to understand the real-world access to, and use of, these therapies in the paediatric population. METHODS: We surveyed UK IBD centres to assess the incident use of vedolizumab and ustekinumab from 1 January 2021 to 31 December 2021. We collected information on funding, dose escalations and therapeutic drug monitoring. RESULTS: 18 of 21 centres responded, covering an estimated 5260 patients. One hundred and thirteen were started on vedolizumab, prescription incidence 2.2%, median prescriptions per centre was 4 (range 1-20). Considering ustekinumab, 73 patients were commenced, prescription incidence 1.4%. Median prescription per centre was 3.5 (range 1-13). Prescription rates at each centre were not predicted by patient number cared for at that centre (p=0.2). Dose escalation was common in vedolizumab (66.7% centres) and ustekinumab (55.5%).Funding strategies varied substantially, and multiple funding sources were used; 12 of 18 centres (66.7%) reported funding through routine National Health Service (NHS) England/Scottish arrangements. There was local NHS trust funding in 8 of 18 centres (44.4%). Individual funding requests (IFRs) were used in 5 of 18 (27.8%), although IFRs are reserved for patients with unique additional characteristics. Four centres were unable to achieve funding in pre-pubescent children. CONCLUSIONS: There is widespread use of vedolizumab and ustekinumab across the UK, although practice is highly variable. Access to therapy appeared to differ substantially. There is a growing disparity between international guidelines and real-world practice. Establishing early and effective therapy in all patients remains a priority.
Assuntos
Doenças Inflamatórias Intestinais , Ustekinumab , Adulto , Humanos , Criança , Ustekinumab/uso terapêutico , Medicina Estatal , Doenças Inflamatórias Intestinais/tratamento farmacológico , Inglaterra/epidemiologia , Resultado do Tratamento , Estudos RetrospectivosRESUMO
Genomic medicine enables the identification of patients with rare or ultra-rare monogenic forms of inflammatory bowel disease (IBD) and supports clinical decision making. Patients with monogenic IBD frequently experience extremely early onset of treatment-refractory disease, with complex extraintestinal disease typical of immunodeficiency. Since more than 100 monogenic disorders can present with IBD, new genetic disorders and variants are being discovered every year, and as phenotypic expression of the gene defects is variable, adaptive genomic technologies are required. Monogenic IBD has become a key area to establish the concept of precision medicine. Clear guidance and standardised, affordable applications of genomic technologies are needed to implement exome or genome sequencing in clinical practice. This joint British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition guideline aims to ensure that testing resources are appropriately applied to maximise the benefit to patients on a national scale, minimise health-care disparities in accessing genomic technologies, and optimise resource use. We set out the structural requirements for genomic medicine as part of a multidisciplinary team approach. Initiation of genomic diagnostics should be guided by diagnostic criteria for the individual patient, in particular the age of IBD onset and the patient's history, and potential implications for future therapies. We outline the diagnostic care pathway for paediatric and adult patients. This guideline considers how to handle clinically actionable findings in research studies and the impact of consumer-based genomics for monogenic IBD. This document was developed by multiple stakeholders, including UK paediatric and adult gastroenterology physicians, immunologists, transplant specialists, clinical geneticists, scientists, and research leads of UK genetic programmes, in partnership with patient representatives of several IBD and rare disease charities.
Assuntos
Gastroenterologia , Doenças Inflamatórias Intestinais , Humanos , Criança , Adulto , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/terapia , Estado Nutricional , GenômicaRESUMO
BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.
Assuntos
Doenças Inflamatórias Intestinais , Inibidores do Fator de Necrose Tumoral , Adalimumab/uso terapêutico , Anticorpos , Terapia Biológica , Monitoramento de Medicamentos , Humanos , Fatores Imunológicos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Estudos Retrospectivos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfaRESUMO
Epidemiological data provide strong evidence for a relationship between undernutrition and life-threatening infection in infants and children. However, the mechanisms that underlie this relationship are poorly understood. Through foetal life, infancy and childhood, the immune system undergoes a process of functional maturation. The adequacy of this process is dependent on environmental factors, and there is accumulating evidence of the impact of pre- and post-natal nutrition in this regard. This review outlines the impact of nutrition during foetal and infant development on the capacity to mount immune responses to infection. It provides an overview of the epidemiologic evidence for such a role and discusses the possible mechanisms involved.
Assuntos
Desenvolvimento Fetal , Transtornos da Nutrição Fetal/imunologia , Imunidade Materno-Adquirida , Imunidade , Infecções/imunologia , Feminino , Transtornos da Nutrição Fetal/epidemiologia , Humanos , Recém-Nascido , Infecções/epidemiologia , Troca Materno-Fetal , Fenômenos Fisiológicos da Nutrição/fisiologia , Assistência Perinatal , GravidezRESUMO
Undernutrition affects millions of children in low- and middle-income countries (LMIC) and underlies almost half of all deaths among children under 5 years old. The growth deficits that characterize childhood undernutrition (stunting and wasting) result from simultaneous underlying defects in multiple physiological processes, and current treatment regimens do not completely normalize these pathways. Most deaths among undernourished children are due to infections, indicating that their anti-pathogen immune responses are impaired. Defects in the body's first-line-of-defense against pathogens, the innate immune system, is a plausible yet understudied pathway that could contribute to this increased infection risk. In this review, we discuss the evidence for innate immune cell dysfunction from cohort studies of childhood undernutrition in LMIC, highlighting knowledge gaps in almost all innate immune cell types. We supplement these gaps with insights from relevant experimental models and make recommendations for how human and animal studies could be improved. A better understanding of innate immune function could inform future tractable immune-targeted interventions for childhood undernutrition to reduce mortality and improve long-term health, growth and development.
Assuntos
Transtornos da Nutrição Infantil/imunologia , Imunidade Inata , Animais , Biomarcadores , Criança , Transtornos da Nutrição Infantil/complicações , Transtornos da Nutrição Infantil/dietoterapia , Transtornos da Nutrição Infantil/microbiologia , Pré-Escolar , Estudos de Coortes , Países em Desenvolvimento , Disbiose/etiologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Microbioma Gastrointestinal , Transtornos do Crescimento/etiologia , Infecções por HIV/complicações , Infecções por HIV/imunologia , Humanos , Hospedeiro Imunocomprometido , Memória Imunológica , Renda , Lactente , Infecções/etiologia , Infecções/imunologia , Inflamação , Mucosa Intestinal/patologia , Subpopulações de Linfócitos/imunologia , Modelos Animais , Células Mieloides/imunologia , Síndrome de Emaciação/etiologia , Síndrome de Emaciação/imunologiaRESUMO
The extensively drug-resistant tuberculosis (XDR-TB) categorisation has been developed as a phenotypic description of those TB strains that are resistant to most conventional anti-TB drugs. While widely accepted to have significant incidence in those areas, such as Eastern Europe, that have high levels of multidrug resistance, recent reports have described a cluster of XDR-TB cases in the KwaZulu-Natal province of South Africa. With very high case-fatality rates in this setting and a paucity of potential treatment options, concerns have grown about the possibility of an outbreak of highly lethal TB occurring in areas where TB prevalence, generally, is at its highest. In this article, we review previously documented case series of XDR-TB, and examine questions around the likelihood of rapid XDR-TB expansion in sub-Saharan Africa. We analyse how current TB control measures in the area might cope with such a challenge, and identify new areas for focus within the research and development community.
Assuntos
Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , África Subsaariana/epidemiologia , Antituberculosos/uso terapêutico , Farmacorresistência Bacteriana , Tuberculose Extensivamente Resistente a Medicamentos/prevenção & controle , Humanos , Testes de Sensibilidade Microbiana/métodos , Mycobacterium tuberculosis/efeitos dos fármacosRESUMO
Intestinal failure is a recognized complication of surgically-managed necrotizing enterocolitis (NEC). Functional adaptation of remaining bowel means that many children are eventually able to achieve enteral autonomy. Integrated multidisciplinary care in the early post-operative phase is key to long-term success. The objective of this review is to outline a clinical approach to management of intestinal and nutritional complications experienced by children following intestinal resection for NEC.
Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Enterocolite Necrosante/cirurgia , Fenômenos Fisiológicos da Nutrição do Lactente , Complicações Pós-Operatórias/terapia , Enterocolite Necrosante/complicações , Enterocolite Necrosante/reabilitação , Humanos , Recém-Nascido , Complicações Pós-Operatórias/etiologiaRESUMO
BACKGROUND: Children with complicated severe acute malnutrition (SAM) have a greatly increased risk of mortality from infections while in hospital and after discharge. In HIV-infected children, mortality and admission to hospital are prevented by daily co-trimoxazole prophylaxis, despite locally reported bacterial resistance to co-trimoxazole. We aimed to assess the efficacy of daily co-trimoxazole prophylaxis on survival in children without HIV being treated for complicated SAM. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled study in four hospitals in Kenya (two rural hospitals in Kilifi and Malindi, and two urban hospitals in Mombasa and Nairobi) with children aged 60 days to 59 months without HIV admitted to hospital and diagnosed with SAM. We randomly assigned eligible participants (1:1) to 6 months of either daily oral co-trimoxazole prophylaxis (given as water-dispersible tablets; 120 mg per day for age <6 months, 240 mg per day for age 6 months to 5 years) or matching placebo. Assignment was done with computer-generated randomisation in permuted blocks of 20, stratified by centre and age younger or older than 6 months. Treatment allocation was concealed in opaque, sealed envelopes and patients, their families, and all trial staff were masked to treatment assignment. Children were given recommended medical care and feeding, and followed up for 12 months. The primary endpoint was mortality, assessed each month for the first 6 months, then every 2 months for the second 6 months. Secondary endpoints were nutritional recovery, readmission to hospital, and illness episodes treated as an outpatient. Analysis was by intention to treat. This trial was registered at ClinicalTrials.gov, number NCT00934492. FINDINGS: Between Nov 20, 2009, and March 14, 2013, we recruited and assigned 1778 eligible children to treatment (887 to co-trimoxazole prophylaxis and 891 to placebo). Median age was 11 months (IQR 7-16 months), 306 (17%) were younger than 6 months, 300 (17%) had oedematous malnutrition (kwashiorkor), and 1221 (69%) were stunted (length-for-age Z score <-2). During 1527 child-years of observation, 122 (14%) of 887 children in the co-trimoxazole group died, compared with 135 (15%) of 891 in the placebo group (unadjusted hazard ratio [HR] 0·90, 95% CI 0·71-1·16, p=0·429; 16·0 vs 17·7 events per 100 child-years observed (CYO); difference -1·7 events per 100 CYO, 95% CI -5·8 to 2·4]). In the first 6 months of the study (while participants received study medication), 63 suspected grade 3 or 4 associated adverse events were recorded among 57 (3%) children; 31 (2%) in the co-trimoxazole group and 32 (2%) in the placebo group (incidence rate ratio 0·98, 95% CI 0·58-1·65). The most common adverse events of these grades were urticarial rash (grade 3, equally common in both groups), neutropenia (grade 4, more common in the co-trimoxazole group), and anaemia (both grades equally common in both groups). One child in the placebo group had fatal toxic epidermal necrolysis with concurrent Pseudomonas aeruginosa bacteraemia. INTERPRETATION: Daily co-trimoxazole prophylaxis did not reduce mortality in children with complicated SAM without HIV. Other strategies need to be tested in clinical trials to reduce deaths in this population. FUNDING: Wellcome Trust, UK.