Dataset Information

Molecular Evidence for Differential Long-term Outcomes of Early Life Severe Acute Malnutrition.

ABSTRACT:

Background

Severe acute malnutrition (SAM) in infants may present as one of two distinct syndromic forms: non-edematous (marasmus), with severe wasting and no nutritional edema; or edematous (kwashiorkor) with moderately severe wasting. These differences may be related to developmental changes prior to the exposure to SAM and phenotypic changes appear to persist into adulthood with differences between the two groups. We examined whether the different response to SAM and subsequent trajectories may be explained by developmentally-induced epigenetic differences.

Methods

We extracted genomic DNA from muscle biopsies obtained from adult survivors of kwashiorkor (n=21) or marasmus (n=23) and compared epigenetic profiles (CpG methylation) between the two groups using the Infinium® 450K BeadChip array.

Findings

We found significant differences in methylation of CpG sites from 63 genes in skeletal muscle DNA. Gene ontology studies showed significant differential methylation of genes in immune, body composition, metabolic, musculoskeletal growth, neuronal function and cardiovascular pathways, pathways compatible with the differences in the pathophysiology of adult survivors of SAM.

Interpretation

These findings suggest persistent developmental influences on adult physiology in survivors of SAM. Since children who develop marasmus have lower birth weights and after rehabilitation have different intermediary metabolism, these studies provide further support for persistent developmentally-induced phenomena mediated by epigenetic processes affecting both the infant response to acute malnutrition and later life consequences.

Funding

Supported by a Grant from the Bill and Melinda Gates Foundation (Global Health OPP1066846), Grand Challenge "Discover New Ways to Achieve Healthy Growth."

Evidence before this study

Previous research has shown that infants who develop either kwashiorkor or marasmus in response to SAM differ in birth weight and subsequently have different metabolic patterns in both infancy and adulthood.

Added value of this study

This study demonstrates epigenetic differences in the skeletal muscle of adult survivors of marasmus versus kwashiorkor and these differences are in genes that may underlie the longer-term consequences.

Implications of all the available evidence

These data are compatible with the different clinical responses to SAM arising from developmentally-induced epigenetic changes laid down largely before birth and provide evidence for the predictive adaptive response model operating in human development.

SUBMITTER: Sheppard A

PROVIDER: S-EPMC5405153 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular Evidence for Differential Long-term Outcomes of Early Life Severe Acute Malnutrition.

Sheppard Allan A Ngo Sherry S Li Xiaoling X Boyne Michael M Thompson Debbie D Pleasants Anthony A Gluckman Peter P Forrester Terrence T

EBioMedicine 20170308

<h4>Background</h4>Severe acute malnutrition (SAM) in infants may present as one of two distinct syndromic forms: non-edematous (marasmus), with severe wasting and no nutritional edema; or edematous (kwashiorkor) with moderately severe wasting. These differences may be related to developmental changes prior to the exposure to SAM and phenotypic changes appear to persist into adulthood with differences between the two groups. We examined whether the different response to SAM and subsequent trajec ...[more]

PMID: 28330812

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Project description:ImportanceApproximately 23 700 US children undergo invasive mechanical ventilation for acute respiratory failure annually, with unknown long-term effects on neurocognitive function.ObjectiveTo evaluate neurocognitive outcomes of children who survive pediatric intensive care unit (PICU) hospitalization for acute respiratory failure compared with their biological siblings.Design, setting, and participantsProspective sibling-matched cohort study conducted at 31 US PICUs and associated neuropsychology testing centers. Patients were 8 years or younger with a Pediatric Cerebral Performance Category score of 1 (normal) before PICU admission and less than or equal to 3 (no worse than moderate neurocognitive dysfunction) at PICU discharge, excluding patients with a history of neurocognitive deficits or who were readmitted and underwent mechanical ventilation. Biological siblings were aged 4 to 16 years at testing, with Pediatric Cerebral Performance Category score of 1 and no history of mechanical ventilation or general anesthesia. A total of 121 sibling pairs were enrolled from September 2, 2014, to December 13, 2017, and underwent neurocognitive testing starting March 14, 2015. The date of the final follow-up was November 6, 2018.ExposuresCritical illness and PICU treatment for acute respiratory failure.Main outcomes and measuresThe primary outcome was IQ, estimated by the age-appropriate Vocabulary and Block Design subtests of the Wechsler Intelligence Scale. Secondary outcomes included measures of attention, processing speed, learning and memory, visuospatial skills, motor skills, language, and executive function. Evaluations occurred 3 to 8 years after hospital discharge.ResultsPatients (n = 121; 55 [45%] female patients) underwent PICU care at a median (IQR) age of 1.0 (0.2-3.2) years, received a median (IQR) of 5.5 (3.1-7.7) days of invasive mechanical ventilation, and were tested at a median (IQR) age of 6.6 (5.4-9.1) years. Matched siblings (n = 121; 72 [60%] female siblings) were tested at a median (IQR) age of 8.4 (7.0-10.2) years. Patients had a lower mean estimated IQ than matched siblings (101.5 vs 104.3; mean difference, -2.8 [95% CI, -5.4 to -0.2]). Among secondary outcomes, patients had significantly lower scores than matched siblings on nonverbal memory (mean difference, -0.9 [95% CI, -1.6 to -0.3]), visuospatial skills (mean difference, -0.9 [95% CI, -1.8 to -0.1]), and fine motor control (mean difference, -3.1 [95% CI, -4.9 to -1.4]) and significantly higher scores on processing speed (mean difference, 4.4 [95% CI, 0.2-8.5]). There were no significant differences in the remaining secondary outcomes, including attention, verbal memory, expressive language, and executive function.Conclusions and relevanceAmong children, survival of PICU hospitalization for respiratory failure and discharge without severe cognitive dysfunction was associated with significantly lower subsequent IQ scores compared with matched siblings. However, the magnitude of the difference was small and of uncertain clinical importance.

Project description:Severe acute malnutrition (SAM) affects over 16.6 million children worldwide. The integrated Community Case Management (iCCM) strategy seeks to improve essential health by means of nonmedical community health workers (CHWs) who treat the deadliest infectious diseases in remote rural areas where there is no nearby health center. The objective of this study was to assess whether SAM treatment delivered by CHWs close to families' locations may improve the early identification of cases compared to outpatient treatment at health facilities (HFs), with a decreased number complicated cases referred to stabilization centers, increased anthropometric measurements at admission (closer to the admission threshold) and similarity in clinical outcomes (cure, death, and default). The study included 930 children aged 6 to 59 months suffering from SAM in the Kita district of the Kayes Region in Mali; 552 children were treated by trained CHWs. Anthropometric measurements, the presence of edema, and other medical signs were recorded at admission, and the length of stay and clinical outcomes were recorded at discharge. The results showed fewer children with edema at admission in the CHW group than in the HF group (0.4% vs. 3.7%; OR = 10.585 [2.222-50.416], p = 0.003). Anthropometric measurements at admission were higher in the CHW group, with fewer children falling into the lowest quartiles of both weight-for-height z-scores (20.2% vs. 31.5%; p = 0.002) and mid-upper arm circumference (18.0% vs. 32.4%; p<0.001), than in the HF group. There was no difference in the length of stay. More children in the CHW group were cured (95.9% vs. 88.7%; RR = 3.311 [1.772-6.185]; p<0.001), and there were fewer defaulters (3.7% vs. 9.8%; RR = 3.345 [1.702-6.577]; p<0.001) than in the HF group. Regression analyses demonstrated that less severe anthropometric measurements at admission resulted in an increased probability of cure at discharge. The study results also showed that CHWs provided more integrated care, as they diagnosed and treated significantly more cases of infectious diseases than HFs (diarrhea: 36.0% vs. 18.3%, p<0.001; malaria: 41.7% vs. 19.8%, p<0.001; acute respiratory infection: 34.8% vs. 25.2%, p = 0.007). The addition of SAM treatment in the curative tasks that the CHWs provided to the families resulted in earlier admission and more integrated care for children than those associated with HFs. CHW treatment also achieved better discharge outcomes than standard community treatment.

Project description:BackgroundTackling severe acute malnutrition (SAM) is a global health priority. Heightened risk of non-communicable diseases (NCD) in children exposed to SAM at around 2 years of age is plausible in view of previously described consequences of other early nutritional insults. By applying developmental origins of health and disease (DOHaD) theory to this group, we aimed to explore the long-term effects of SAM.MethodsWe followed up 352 Malawian children (median age 9·3 years) who were still alive following SAM inpatient treatment between July 12, 2006, and March 7, 2007, (median age 24 months) and compared them with 217 sibling controls and 184 age-and-sex matched community controls. Our outcomes of interest were anthropometry, body composition, lung function, physical capacity (hand grip, step test, and physical activity), and blood markers of NCD risk. For comparisons of all outcomes, we used multivariable linear regression, adjusted for age, sex, HIV status, and socioeconomic status. We also adjusted for puberty in the body composition regression model.FindingsCompared with controls, children who had survived SAM had lower height-for-age Z scores (adjusted difference vs community controls 0·4, 95% CI 0·6 to 0·2, p=0·001; adjusted difference vs sibling controls 0·2, 0·0 to 0·4, p=0·04), although they showed evidence of catch-up growth. These children also had shorter leg length (adjusted difference vs community controls 2·0 cm, 1·0 to 3·0, p<0·0001; adjusted difference vs sibling controls 1·4 cm, 0·5 to 2·3, p=0·002), smaller mid-upper arm circumference (adjusted difference vs community controls 5·6 mm, 1·9 to 9·4, p=0·001; adjusted difference vs sibling controls 5·7 mm, 2·3 to 9·1, p=0·02), calf circumference (adjusted difference vs community controls 0·49 cm, 0·1 to 0·9, p=0·01; adjusted difference vs sibling controls 0·62 cm, 0·2 to 1·0, p=0·001), and hip circumference (adjusted difference vs community controls 1·56 cm, 0·5 to 2·7, p=0·01; adjusted difference vs sibling controls 1·83 cm, 0·8 to 2·8, p<0·0001), and less lean mass (adjusted difference vs community controls -24·5, -43 to -5·5, p=0·01; adjusted difference vs sibling controls -11·5, -29 to -6, p=0·19) than did either sibling or community controls. Survivors of SAM had functional deficits consisting of weaker hand grip (adjusted difference vs community controls -1·7 kg, 95% CI -2·4 to -0·9, p<0·0001; adjusted difference vs sibling controls 1·01 kg, 0·3 to 1·7, p=0·005,)) and fewer minutes completed of an exercise test (sibling odds ratio [OR] 1·59, 95% CI 1·0 to 2·5, p=0·04; community OR 1·59, 95% CI 1·0 to 2·5, p=0·05). We did not detect significant differences between cases and controls in terms of lung function, lipid profile, glucose tolerance, glycated haemoglobin A1c, salivary cortisol, sitting height, and head circumference.InterpretationOur results suggest that SAM has long-term adverse effects. Survivors show patterns of so-called thrifty growth, which is associated with future cardiovascular and metabolic disease. The evidence of catch-up growth and largely preserved cardiometabolic and pulmonary functions suggest the potential for near-full rehabilitation. Future follow-up should try to establish the effects of puberty and later dietary or social transitions on these parameters, as well as explore how best to optimise recovery and quality of life for survivors.FundingThe Wellcome Trust.

Dataset Information

Molecular Evidence for Differential Long-term Outcomes of Early Life Severe Acute Malnutrition.

Background

Methods

Findings

Interpretation

Funding

Evidence before this study

Added value of this study

Implications of all the available evidence

Publications

Molecular Evidence for Differential Long-term Outcomes of Early Life Severe Acute Malnutrition.

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