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Ultrasound signs of NEC(Necrotizing Enterocolitis) indicated by the arrows. (a) Portal vein gas. (b) Portal vein gas. (c) Pneumatosis intestinalis
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Studies on necrotizing enterocolitis (NEC) have not largely focused on enteric viruses. In order to demonstrate the association between enteric viruses and NEC, stool specimens of 51 neonates with NEC and 39 “normal” neonates were collected to detect rotavirus (RV), astrovirus (ASV), sapovirus, enterovirus (EV), adenovirus (ADV), Epstein-Barr virus...
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Citations
... Numerous studies have shown an association between NEC and the intestinal microbiota (6). The presence of Epstein-Barr virus and adenovirus may be related to the severity of NEC (7). The association between human coronavirus infection and neonatal NEC has also been reported in several studies (8)(9)(10). ...
Background
The impact of the coronavirus disease 2019 (COVID-19) pandemic on neonatal necrotizing enterocolitis (NEC) is not well characterised. This cross-sectional study evaluated the potential effects of pandemic-related measures on NEC morbidity in premature infants in a neonatal ward during the COVID-19 pandemic.
Methods
This was a retrospective study conducted in a tertiary neonatal ward in eastern and central China over 6 consecutive years (2017, 2018, 2019, 2020, 2021 and 2022). The medical records of 189 premature infants with stage II or III NEC were reviewed for clinical manifestations and aetiologies. The data were analysed and compared between the prepandemic period (2017, 2018, and 2019) and the pandemic period (2020, 2021 and 2022).
Results
A total of 9,903 infants with gestational age (GA) < 37 weeks were enrolled, including 5,382 in the prepandemic period and 4,521 in the pandemic period. A reduction in stage II or III NEC morbidity was observed in infants with GA < 37 weeks, with an average annual morbidity of 2.29% (123/5,382) (95% CI, 1.89%–2.68%) in the prepandemic period and 1.46% (66/4,521) (95% CI, 1.11%–1.81%) in the pandemic period. NEC morbidity showed resurgent characteristics in 2021. When prepandemic coinfections were excluded, most cases of NEC with bloodstream infections in the prepandemic period were attributable to Gram-negative bacteria (27/32, 84.38%), mainly Klebsiella pneumoniae, while in the pandemic period they were attributable to Gram-positive bacteria (10/18, 55.56%), mainly Staphylococcus aureus. Antimicrobial susceptibility testing revealed that Klebsiella pneumoniae was 100% sensitive to meropenem, imipenem, ciprofloxacin and levofloxacin and 100% resistant to ampicillin. Staphylococcus capitis was 100% sensitive to vancomycin, linezolid, tetracycline, cotrimoxazole and cefoxitin and 100% resistant to penicillin and benzathine.
Conclusions
COVID-19 pandemic-related interventions can reduce the morbidity of NEC and change the pathogen spectrum in patients with bloodstream infections. We need to understand the exact factors leading to these changes.
... The abundance and diversity of eukaryotic viruses in the gut are scarce in early life but gradually increase. Astroviruses are most commonly found in preterm infants [14,15]. Phages are generally classified into lytic or temperate. ...
... Eukaryotic viruses like echovirus, coronavirus, norovirus, and rotavirus play key etiological roles in NEC outbreaks [37][38][39][40]. Other viruses such as human astrovirus, adenovirus, torovirus, and cytomegalovirus have been detected in sporadic NEC [14,[41][42][43][44]. A meta-analysis of 24 studies with 4356 infants demonstrated that viral infection is linked to increased risk of NEC in newborns, especially infection with rotavirus, cytomegalovirus, norovirus, and astrovirus [7]. ...
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in neonates, particularly preterm infants. Many factors can lead to NEC, but microbial dysbiosis is one of the most important risk factors that can induce this disease. Given the major role of the gut virome in shaping bacterial homeostasis, virome research is a fledgling but rapidly evolving area in the field of microbiome that is increasingly connected to human diseases, including NEC. This review provides an overview of the development of the gut virome in newborns, discusses its emerging role in NEC, and explores promising therapeutic applications, including phage therapy and fecal virome transplantation.
... Shortly after birth, the virome is mainly composed of prokaryotic viruses (bacteriophages, or phages for short) infecting bacteria and to a lesser extent eukaryotic viruses infecting mammalian cells [11,12]. Sporadic case reports link NEC outbreaks to speci c eukaryotic viruses but again no single organism has been consistently associated with NEC [13,14]. ...
Background: Fecal filtrate transfer (FFT, i.e. “sterile filtered” fecal matter) is gaining increasing attention as a safer alternative to traditional fecal microbiota transplantation (FMT) for treating gastrointestinal (GI) complications. Indeed, in the case of necrotizing enterocolitis (NEC), a life-threatening GI emergency occurring in preterm infants, FFT is superior to FMT in terms of both safety and efficacy when investigated in preterm piglets. Since fecal filtrate is virtually devoid of bacteria, prokaryotic viruses (bacteriophages) are assumed to mediate the beneficial effects by modulating the recipient gut microbiota. However, this assumption remains unproven.
Results: To address this gap, we isolated the virome of donor feces from the residual postbiotic fluid with no loss of bacteriophage infective potential or bacteriophage spillover to the residual fluid. We then compared clinical and gut microbiota responses to these fractions with the parent FFT solution after transferring to NEC-susceptible preterm piglets. Importantly, transfer of isolated donor virome was equally effective as FFT in reducing the severity of NEC-like pathology, whereas the residual postbiotic fraction was ineffective. The bacterial compositional data corroborated clinical findings as virome transfer reduced the relative abundance of several NEC-associated pathogens e.g. Klebsiella pneumoniae and Clostridium perfringens. A viral metagenomics analysis indicated enrichment and diversification of recipient gut viral communities with concomitant constraining effect on bacterial composition in accordance with lytic phage predation of resident bacteria. Surprisingly, virome transfer but not residual postbiotic fluid was associated with suspected viral gastroenteritis as indicated by diarrhea, intestinal atrophy, and weight loss. Although virome sequencing did not reveal any obvious causative agent, we suggest that unidentified eukaryotic viruses are candidates responsible for these side effects.
Conclusion: Using NEC as a relevant case for microbiota-directed therapy, we show that transfer of isolated fecal virome is sufficient to reduce pathogenic bacterial load and overall disease burden. However, we also highlight that receiving exogenous virome increases the risk of enteric virus infection. Despite diarrhea being a minor concern in the human infant context, future work should identify ways of eliminating eukaryotic viruses without losing treatment efficacy.
... During NEC, some viruses, such as enterovirus and human bocavirus, are speci cally present in infants with NEC, and the presence of adenovirus and Epstein-Barr virus has been observed to be associated with NEC severity. [10] To restore the balance of the gut bacteriome and reduce the severity of NEC using the gut virome, Brunse et al [11] used a piglet model and showed that orogastric administration of fecal ltrate (containing pure and virus-like particles but not bacteria) could completely prevent NEC, with an increase in the diversity of virome in both mucosal and luminal compartments as well as the relative abundance of Streptococcus genus. Although this study could not rule out the potential in uence of the microbial metabolites in the fecal ltrate, this evidence highlights the potential intermediate role of the gut virome between NEC and gut bacteriome, and further investigation is necessary for more insight in this regard. ...
... 6,7 Most studies on this topic were limited by a small sample size, preventing us from drawing definitive conclusions. 8 We aimed to resolve this ambiguity by summarizing evidence in a systematic review and meta-analysis of the studies evaluating viral infections in NEC. Our review's primary objective was to determine whether infection with viral pathogens is associated with the occurrence of NEC in preterm and term infants compared with those without viral infection. ...
... The PRISMA flow diagram of the search process is shown in Fig 1. Included studies and their baseline characteristics are summarized in Table 1. 7,8, Excluded studies and the reasons for exclusion are presented in Supplemental Table 3. Twenty-one studies were published after the year 2000, and 41% were published in the last 12 years (Supplemental Fig 5A). The included studies were done Fig 5B). ...
... The column chart shows the Newcastle Ottawa scale scores along the x-axis divided into 3 groups high risk of bias (0-3), moderate risk of bias, 4-6 and low risk of bias. [7][8][9] The number of studies included in the review with those scores on the y-axis. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. were analyzed, a significant association between viral infection and occurrence of NEC (OR, 3.62, 95% CI: 1.63-8.03, ...
Context:
Necrotizing enterocolitis (NEC) is a devastating intestinal disease affecting preterm infants. Studies implicate viral infections in etiopathogenesis.
Objective:
To summarize the association of viral infections with NEC by systematic review and meta-analysis.
Data sources:
We searched Ovid-Medline, Embase, Web of Science, and Cochrane databases in November 2022.
Study selection:
We included observational studies that examined the association between viral infections and NEC in newborn infants.
Data extraction:
We extracted data regarding the methodology, participant characteristics, and outcome measures.
Results:
We included 29 and 24 studies in the qualitative review and meta-analysis, respectively. The meta-analysis demonstrated a significant association between viral infections and NEC (odds ratio [OR], 3.81, 95% confidence interval: 1.99-7.30, 24 studies). The association remained significant after excluding the outliers (OR, 2.89 [1.56-5.36], 22 studies) and studies with poor methodology (OR, 3.33 [1.73-6.43], 22 studies). In subgroup analysis based on participants' birth weight, studies including very low birth weight infants only (OR, 3.62 [1.63-8.03], 8 studies) and non-very low birth weight infants only (OR, 5.28 [1.69-16.54], 6 studies) showed a significant association. In subgroup analysis based on specific viruses, infection with rotavirus (OR, 3.96 [1.12-13.95], 10 studies), cytomegalovirus (OR, 3.50 [1.60-7.65], 5 studies), norovirus (OR, 11.95 [2.05-69.84], 2 studies), and astrovirus (OR, 6.32 [2.49-16.02], 2 studies) was significantly associated with NEC.
Limitations:
Heterogeneity of the included studies.
Conclusions:
Viral infection is associated with an increased risk of NEC in newborn infants. We need methodologically sound prospective studies to assess the effect of preventing or treating viral infections on NEC incidence.
... However, microbiota comprising the human microbiome also include eukaryotic fungi and protozoa, archae, and viruses [13,51,52], and omission of these critical microbial components of the preterm intestinal community when reporting microbiome outcomes paints an incomplete and biased picture of community roles and health [53,54]. Very few studies report nonbacterial microbial components of the preterm infant microbiome, with the majority indicating an association with NEC pathogenesis [54][55][56][57][58][59]. However, nonbacterial microbiota are healthy components of term infant [60], as well as adult [51], microbial communities. ...
... Postnatal viral diversity is initially low, especially in comparison to that of adults, but slowly increases in complexity in line with bacterial diversity [197]. Specifically, eukaryotic viruses are found in low abundance and richness at birth and increase over time [209][210][211], with astrovirus (ASV) becoming the most commonly detected enteric virus among preterm infants [55], while phages, particularly, Caudovirales [212], are highly abundant at birth and decrease as the bacterial microbiome stabilizes around 2 y [209]. However, infant viral diversity is likely significantly underestimated due to the sheer number of unidentified viral sequences. ...
... Enteric viruses have been detected in preterm infants at the time of NEC development [226][227][228][229], and several, including Coxsackie B2, CMV, and Staphylococcus phage 363_30 [230][231][232][233][234][235], have been associated, in isolation, with disease development. However, despite differences in prevalence of some enteric viruses in NEC and control infants [55], no causal role for enteric viruses has yet been identified in NEC pathogenesis [236,237]. Interestingly, CMV is both present in a small percentage of NEC cases [238], but also may present similarly to NEC, with diarrhea, fever, and generalized intestinal inflammation [239,240]. ...
The intestinal microbiome is frequently implicated in necrotizing enterocolitis (NEC) pathogenesis. While no particular organism has been associated with NEC development, a general reduction in bacterial diversity and increase in pathobiont abundance has been noted preceding disease onset. However, nearly all evaluations of the preterm infant microbiome focus exclusively on the bacterial constituents, completely ignoring any fungi, protozoa, archaea, and viruses present. The abundance, diversity, and function of these nonbacterial microbes within the preterm intestinal ecosystem are largely unknown. Here, we review findings on the role of fungi and viruses, including bacteriophages, in preterm intestinal development and neonatal intestinal inflammation, with potential roles in NEC pathogenesis yet to be determined. In addition, we highlight the importance of host and environmental influences, interkingdom interactions, and the role of human milk in shaping fungal and viral abundance, diversity, and function within the preterm intestinal ecosystem.
... Food-protein induced enterocolitis, a non-IgE-mediated gastrointestinal inflammatory disease have similar clinical presentations to NEC (77) and RNA viruses, such as Astroviridae, Caliciviridae, and Picornaviridae have also been detected in the human intestine (53). They can also have a radiologic finding of PI and PVG and make it easily misdiagnosed as NEC (78)(79)(80)(81). Therefore, PI and PVG cannot be absolute evidence for NEC, and those patients without these two signs will have a missed diagnosis. ...
... NEC is associated with lymphocytosis and often occurs in specific clusters, sporadic cases, united by a common space-time framework based primarily on viral etiology. It should be noted that the clinical differentiation of NEC associated with the virus and NEC exclusively bacterial etiology is currently difficult [7]. ...
Coxsackieviruses-induced infections, particularly in infants and young children, are one of the most important public health issues in low- and middle-income countries, where the surveillance system varies substantially, and these manifestations have been disregarded. They are widespread throughout the world and are responsible for a broad spectrum of human diseases, from mildly symptomatic conditions to severe acute and chronic disorders. Coxsackieviruses (CV) have been found to have 27 identified genotypes, with overlaps in clinical phenotypes between genotypes. In this review, we present a concise overview of the most recent studies and findings of coxsackieviruses-associated disorders, along with epidemiological data that provides comprehensive details on the distribution, variability, and clinical manifestations of different CV types. We also highlight the significant roles that CV infections play in the emergence of neurodegenerative illnesses and their effects on neurocognition. The current role of CVs in oncolytic virotherapy is also mentioned. This review provides readers with a better understanding of coxsackieviruses-associated disorders and pointing the impact that CV infections can have on different organs with variable pathogenicity. A deeper knowledge of these infections could have implications in designing current surveillance and prevention strategies related to severe CVs-caused infections, as well as encourage studies to identify the emergence of more pathogenic types and the etiology of the most common and most severe disorders associated with coxsackievirus infection.
Necrotizing enterocolitis (NEC) is a devastating, multifactorial disease mainly affecting the intestine of premature infants. Recent discoveries have significantly enhanced our understanding of risk factors, as well as, cellular and genetic mechanisms of this complex disease. Despite these advancements, no essential, single risk factor, nor the mechanism by which each risk factor affects NEC has been elucidated. Nonetheless, recent research indicates that maternal factors, antibiotic exposure, feeding, hypoxia, and altered gut microbiota pose a threat to the underdeveloped immunity of preterm infants. Here we review predisposing factors, status of unwarranted immune responses, and microbial pathogenesis in NEC based on currently available scientific evidence. We additionally discuss novel techniques and models used to study NEC and how this research translates from the bench to the bedside into potential treatment strategies.
