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ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 3  |  Page : 192-198

Evaluation of cachectin level in preterm neonates as an indicator of necrotizing enterocolitis


Department of Pediatrics, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

Date of Submission10-Oct-2020
Date of Decision01-Feb-2021
Date of Acceptance15-Apr-2021
Date of Web Publication28-Jul-2021

Correspondence Address:
Abdelmoneim Khashana
Associate professor of Pediatrics and Neonatology, Pediatrics and Neonatology, Faculty of Medicine, Suez Canal University, Ismailia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.jcn_166_20

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  Abstract 


Background: Necrotizing enterocolitis (NEC) is an inflammatory disorder that affects the gastrointestinal system of the preterm infants (gestational age less than 37 weeks). Cachectin is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. Aim: To evaluate the level of blood cachectin (TNF-α) in preterm neonates as an indicator for NEC. Material and Methods: The present study was designed as an analytical cross-sectional study that included two groups: i) preterm neonates with necrotizing enterocolitis (NEC) admitted at neonatal intensive care unit (NICU) in Suez Canal University Hospital (n = 25), and ii) healthy preterm neonates (n = 25) who served as a normal control group. All neonates subjected to prenatal, natal and postnatal history, Physical examination, and blood samples were taken from cases once diagnosed as suspected NEC, proven NEC, or advanced NEC and from healthy preterm neonates when taking full oral feeding as a control. Then, measurement of cachectin level was done by ELISA kits. Results: It was found that neonates with necrotizing enterocolitis had significantly higher cachectin level (365.91 ± 260.76 ng/L) than healthy controls (83.92 ± 44.01 ng/L) (P < 0.001) and was also found that cachectin (TNF-α) levels are higher in NEC patients with complications. It was also found that cachectin (TNF-α) level of 116.6 was the best cut-off points with sensitivity of 92% and specificity of 90% for prediction of NEC among preterm neonates. Conclusion: The level of serum cachectin is higher in neonates with NEC than in healthy preterm neonates and it can be used as an indicator for early diagnosis of NEC.

Keywords: Cachectin (tumor necrosis factor alpha), necrotizing enterocolitis, preterm neonates


How to cite this article:
Abdel-Wahab A, Khalil M, Omar H, Khashana A. Evaluation of cachectin level in preterm neonates as an indicator of necrotizing enterocolitis. J Clin Neonatol 2021;10:192-8

How to cite this URL:
Abdel-Wahab A, Khalil M, Omar H, Khashana A. Evaluation of cachectin level in preterm neonates as an indicator of necrotizing enterocolitis. J Clin Neonatol [serial online] 2021 [cited 2021 Dec 2];10:192-8. Available from: https://www.jcnonweb.com/text.asp?2021/10/3/192/322526




  Introduction Top


Necrotizing enterocolitis (NEC) is an inflammatory disorder that affects the gastrointestinal system of the neonates.[1] It is considered the most critical gastrointestinal disease in preterm infants and the most common single cause of death in extremely preterm infants. NEC mainly affects the preterm neonates less than 32 weeks' gestational age and the frequency is inversely proportional to the gestational age. The incidence of NEC is also inversely proportional to the birth weight being more common in extremely low birth weight infants.[2]

The prevalence of NEC in preterm neonates is from 5% to 7% in the U. S. A. with a mortality rate about 20%–30% of patients.[3] About one-third to one-half of patients require surgical intervention which may lead to long-term consequences including intestinal stricture, short gut syndrome, and neurodevelopmental delay.[4]

The main etiology of NEC remains incompletely understood. Multiple factors are thought to contribute to the pathogenesis of NEC including intestinal immaturity, feeding, ischemia, infectious organisms, and inflammatory mediators.[5] Other risk factors for NEC include small for gestational age, premature rupture of membrane, sepsis, assisted ventilation, and hypotension.[6] It is hypothesized that NEC occurs when intestinal ischemia affects impaired or immature gut exposed to the infectious agent along with mediating cytokines in a susceptible host.[7]

Although the etiology of NEC is still unclear, it appears to be occurred due to pro-inflammatory cytokine response. Cytokines have direct effects on the intestine and may initiate NEC.[4] Increased expression of the toll-like receptors (TLR4) in the intestine of the preterm infants is an important factor of pathogenesis of NEC. Activation of TLR4 by bacterial endotoxins leads to initiation of intestinal inflammatory response. The inflammatory mediators include interleukin 1 (IL1), cachectin, IL6, and IL8. The combination of these cellular responses along with TLR4 signaling leads to profound inflammatory response and subsequent NEC.[8]

Necrosis starts in the mucosa and may progress to involve the whole thickness of the intestine leading to perforation and subsequent peritonitis and free intra-abdominal air. Sepsis occurs in 33% of patients.[9]

Diagnosis of NEC depends on history, physical examination, laboratory and radiographic findings. Signs and symptoms of NEC are variable and can be confused with those of sepsis.[10] Laboratory finding that can be seen in NEC include thrombocytopenia, hyponatremia, metabolic acidosis, neutropenia, and leukocytosis but they are non-specific. Anteroposterior and lateral abdominal radiograph is used for diagnosis but it is undiagnostic in early phases of NEC.[4]

The relative nonspecificity of the available clinical, laboratory, and radiographic tests suggest the need for additional markers to improve the early diagnosis of NEC in preterm infants. There are some molecules that are detected in blood and are assessed for their value in diagnosing NEC and they show considerable promise, but more studies are still needed. These include acute phase reactant as C-reactive protein and inflammatory cytokines as IL6, IL8, and cachectin.[11],[12],[13] Cachectin is also known as tumor necrosis factor-alpha (TNF-α) and it is associated with the pathogenesis of NEC.[8] There is a study showed that cytokine profile is higher in neonates with surgical NEC than in neonates with spontaneous intestinal perforation.[14] Fecal calprotectin level increased significantly in neonates with feeding intolerance and NEC.[15],[16]

Early diagnosis of NEC is important to avoid short- and long-term consequences of the disease.[4] Therefore, in this study, we will evaluate blood cachectin level in preterm neonates to be used as an indicator for early diagnosis of NEC.


  Methods Top


A case–control prospective study aims to evaluate the level of serum cachectin in preterm neonates as an indicator for NEC to compare the difference of serum cachectin levels between healthy preterm neonates and preterm neonates with NEC. The study was conducted in the neonatal intensive care unit (NICU) in Suez Canal University Hospital in the period from February 2018 to January 2020.

This study was done on blood specimen taken from healthy preterm and preterm neonates with NEC.

Inclusion criteria; Preterm neonates (born <37 weeks gestational age), symptoms and signs of suspected NEC including abdominal distension, vomiting, and gastric residuals, and healthy Preterm neonates matched as a control group.

Exclusion criteria; Term and post-term neonates, neonates with congenital infection,[14] neonates with major congenital anomalies.[14]

The sample was calculated according to the following formula:



Where: n = required sample size, Zα/2 = 1.96 (The critical value that divides the central 95% of the Z distribution from the 5% in the tail), Zβ = 0.84 (The critical value that separates the lower 20% of the Z distribution from the upper 80%), σ is the estimate of the standard deviation in the study group = 1141,[14] μ1 = mean of cachectin in the preterm with NEC group = 2258,[14] μ2 = mean of cachectin in the healthy preterm group = 1275 (14). Hence, the total number of neonates in each group was 21 infants. With the calculation of nonresponse rate (10%), the total number of neonate in each group was 25. Sample framing; 25 healthy preterm neonates and 25 preterm neonates with NEC were included.

All cases were subjected to the following: Prenatal, natal and postnatal history including mother's illness and medications during pregnancy, premature rupture of membranes, mode of delivery, congenital infections, congenital anomalies and gestational age, physical examination including general examination of baby' activity, color and reflexes, vital signs, abdominal examination, chest and heart examination, blood samples were taken from cases once diagnosed as suspected NEC, proven NEC, or advanced NEC and from healthy preterm neonates when taking full oral feeding as a control.

Investigations: Measurement of cachectin level: Plasma was separated from plain tube blood samples by centrifuging in 2700 g for 10 min and stored at −80°C until analyzed. Serum cachectin level was determined by enzyme-linked immunosorbent assay kits (Biokit company, China).

All statistical analysis are carried out using statistical package for social sciences (SPSS) for windows version 20.0 (SPSS, Chicago, IL, USA) and R (version 2.15.1). The t-test is used to compare the means of the groups. Comparisons between groups with respect to numerical data are done using one analysis of variance of Kruskal-Wallis test for non-normal distributed variables. Comparisons between categorical data are performed using the Chi-square test. P <0.05 is considered statistically significant. Results of analysis of infant's characteristics are described by mean values and standard deviation. The results are presented in the appropriate form of tables and graphs using Microsoft Excel.

Ethical considerations: Administrative approval from the head of the NICU, Suez Canal University hospital. Written informed consent was obtained from parents of all subjects before enrollment in the study. In addition, ensuring the right of withdrawal at any time without giving reasons and without negative consequences.


  Results Top


The present study was designed as an analytical cross-sectional study that included two groups: (i) preterm neonates with NEC admitted at NICU in Suez Canal University Hospital (n = 25), and (ii) healthy preterm neonates (n = 25) who served as a normal control group. This study aims at assessing the possible correlation between the level of blood cachectin and the incidence of NEC in preterm neonates, besides identifying the difference of serum cachectin between preterm neonates with NEC and their healthy counterparts.

Characteristics of the studied neonates are described in [Table 1]. The mean gestational age of the sample was 34 ± 1.69 weeks. Males represented 54% of the neonates while 46% of them were females. There was no statistically significant difference between cases with NEC and healthy controls in any of their baseline variables.
Table 1: Baseline characteristics of the studied sample (n=50)

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Neonates with NEC were found to have significantly higher cachectin level (365.91 ± 260.76 ng/L) than healthy controls (83.92 ± 44.01 ng/L) (P < 0.001) [Table 2] and [Figure 1].
Table 2: Comparison of cachectin level between necrotizing enterocolitis neonates and healthy controls

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Figure 1: Cachectin blood level among NEC neonates and healthy controls

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The prenatal characteristics of the studied sample. Pregnancy illness was found in 32% of the mothers of the cases and 24% of the mothers of the controls (P = 0.53). More than 80% of the mothers in both groups had administered medications during pregnancy. Premature rapture of membrane occurred in 32% of the mothers of the cases and 28% of the mothers of the controls (P = 0.46).

Neonates with NEC had significantly higher incidence of hypoactivity (P < 0.001) and oxygen supplementation (P = 0.004). On assessing baby's color; about half of the patients (48%) with NEC were pale while 36% of them had icteric color. Moreover, all healthy preterms had normal neonatal reflexes whereas preterms with NEC had either weak or absent reflexes (P < 0.001).

The systemic manifestations of preterm neonates with NEC. Seventy-six percent of the patients had bradycardia whereas only 20% had developed hypotension. Moreover, about 64% of the patients had apneic events with mean cachectin level of 441 ± 252.77 which was significantly higher than cachectin level of those who did not have apnea (P = 0.012). All neonates had temperature instability and all cases had poor feeding and lethargy.

Almost all patients developed occult blood in stool (96%), however almost half of them had gross blood in stool. Moreover, 60% of them had absent bowel sounds and abdominal tenderness was manifested in 20% of them. There is significant relationship between intestinal manifestations regarding occult blood in stool, gross blood in stool, absent bowel sound, abdominal tenderness, abdominal cellulitis and cachectin level.

The relationship between radiological signs of NEC of the preterm neonates and cachectin level. 60% of the patients had developed ileus with mean cachectin level of 502.82 ± 248.19 which was significantly higher than cachectin level of those who did not have ileus (P < 0.001). Moreover, about 36% of the patients had developed pneumatosis intestinalis with mean cachectin level of 657.09 ± 192.32 which was significantly higher than cachectin level of those who did not have pneumatosis intestinalis (P < 0.001). Similarly, NEC patients with portal vein gas (16%) had significantly higher cachectin level than those who did not (84%) (P < 0.001). There were no reported cases with ascites or pneumoperitoneum.

[Figure 2] shows the ROC curve analysis of cachectin level for the prediction of NEC among preterm neonates, where the areas under the curve (AUC) were 0.936 (0.864 – 1) [Table 3].
Figure 2: Receiver–operating characteristics curves for prediction of necrotizing enterocolitis among preterm neonates using Cachectin level

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Table 3: Area under the curve for analysis of cachectin level for prediction of necrotizing enterocolitis among preterm neonates

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[Table 4] shows the diagnostic accuracy of cachectin level for prediction of NEC among preterm neonates. It was found that cachectin level of 116.6 was the best cut off points with sensitivity of 92% and specificity of 90% for prediction of NEC among preterm neonates.
Table 4: Sensitivity, specificity, and diagnostic accuracy of different cachectin level for prediction of necrotizing enterocolitis among preterm neonates

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  Discussion Top


This study aims at assessing the possible correlation between the level of blood cachectin and the incidence of NEC in preterm neonates, besides identifying the difference of serum cachectin between preterm with NEC and their healthy counterparts.

The mean gestational age of the sample was 34 ± 1.69 weeks. Males represented 54% of the neonates while 46% of them were females. There was no statistically significant difference between cases with NEC and healthy controls in any of their baseline variables.

In the present study, it was found that neonates with NEC had significantly higher cachectin level (365.91 ± 260.76 ng/L) than healthy controls (83.92 ± 44.01 ng/L).

In the same line, initial reports of cachectin (TNF-α) infusion into animal models describe the occurrence of shock and tissue injury that looked similar to neonatal NEC. Subsequent studies showed that intravenous administration of cachectin (TNF-α) and LPS concurrently resulted in significant bowel necrosis in animal models, and the production of platelet-activating factor, a phospholipid pro-inflammatory mediator also associated with NEC. Confirmatory studies in human neonates with NEC identified significantly elevated plasma levels of cachectin (TNF-α) compared with controls.[18]

Furthermore, elevated cachectin (TNF-α) has been detected in full-thickness, resected bowel specimens of NEC intestine and in the plasma of babies with NEC.[19]

It was found that pregnancy illness was found in 32% of the mothers of the cases and 24% of the mothers of the controls. More than 80% of the mothers in both groups had administered medications during pregnancy. Premature rapture of membrane occurred in 32% of the mothers of the cases and 28% of the mothers of the controls.

These results show that however there is a difference between cases and controls regarding maternal illness during pregnancy, the difference is still insignificant. Similarly, March et al., studied the maternal risk factors for neonatal NEC and reported that there was an increased risk of any hypertensive disorder as well as a diagnosis of severe preeclampsia or HELLP syndrome in the cases compared with the controls, but these differences did not reach statistical significance. The cases and controls had similar other maternal complications of pregnancy such as diabetes, preterm labor, preterm premature rupture of membranes, placental complications, and chorioamnionitis.[20]

March et al.,[20] also reported that No maternal medication exposure was found to increase the risk of NEC, including indomethacin or other tocolytics, magnesium sulfate, anti-hypertensives, betamethasone, induction agents, or antibiotics.

In the present study, it was found that neonates with NEC had significantly higher incidence of hypoactivity and need of oxygen supplementation. Moreover, Patients with NEC had bad general condition compared to controls which was reflected by their decreased heart rate, paler color and hypoactivity.

In the present study, the systemic manifestations of preterm neonates with NEC, 76% of the patients had bradycardia whereas only 20% had developed hypotension. Moreover, about 64% of the patients had apneic events with cachectin (TNF-α) level which was significantly higher than of those who did not have apnea. All neonates had temperature instability and all cases had poor feeding and lethargy. Similarly, Gephart et al.[21] reported that clinical signs and symptoms are nonspecific and include temperature instability, bradycardia, and apnea, hypotension like those occur in critically ill neonates with sepsis or adrenal insufficiency.[22],[23],[24],[25],[26]

In the present study, almost all patients developed occult blood in stool (96%), however almost half of them had gross blood in stool. Moreover, 60% of them had absent bowel sounds and abdominal tenderness was manifested in 20% of them. There is a significant relationship between intestinal manifestations regarding occult blood in stool, gross blood in stool, absent bowel sound, abdominal tenderness, abdominal cellulitis, and cachectin (TNF-α) level.

Similarly, Gephart et al.,[21] reported that abdominal wall erythema, increased gastric residuals, abdominal distention, emesis, blood in the stool, absent bowel sounds, abdominal tenderness, and occasionally a right lower quadrant mass.

Moreover, Schnabl et al.,[19] reported that NEC affects the gastrointestinal tract and, in severe cases, may have a profound systemic impact. Initial symptoms may be subtle and can include feeding intolerance (gastric residuals, bilious vomiting), bloody diarrhea, temperature instability, lethargy, apnea, bradycardia, decreased peripheral perfusion, delayed gastric emptying, ileus, abdominal distension, or tenderness and respiratory stress.

In the present study, 60% of the patients had developed ileus with mean cachectin (TNF-α) level of 502.82 ± 248.19 which was significantly higher than cachectin (TNF-α) level of those who did not have ileus. The ileum and proximal colon are the most commonly affected sites in NEC although any segment of the gastrointestinal tract can be involved including the stomach.[19]

Moreover, about 36% of the patients had developed pneumatosis intestinalis with mean cachectin (TNF-α) level of 657.09 ± 192.32 which was significantly higher than cachectin (TNF-α) level of those who did not have pneumatosis intestinalis. Similarly, NEC patients with portal vein gas (16%) had significantly higher cachectin (TNF-α) level than those who did not (84%). There were no reported cases with ascites or pneumoperitoneum.

In the current study, it was found that cachectin (TNF-α) levels were higher in patients with complications such as Ileus, pneumatosis intestinalis, portal vein gas than in patients without these complications.

NEC leads to hypoperfusion, which in turn induces blood to shunt away from the bowels towards critical organs, which may cause alterations in the mucosal barrier. These alterations, in combination with pathogenic microbiological intestinal flora proliferation exaggerated by feeding and antibacterial use, result in mucosal and/or transmural necrosis. The bacterial translocation and production of hydrogen gas into the bowel wall cause pneumatosis intestinalis, which can be seen radiographically as linear or circular lucencies within the intestinal wall. As a consequence, the gas can embolize from the bowel wall through the mesenteric veins to the portal venous system and the non-dependent parts of the liver, particularly the left lobe and anterior segment of the right lobe (Abboud et al., 2009).

This explain increased incidence of pneumatosis intestinalis, Portal vein gas, however, the elevated levels of cachectin (TNF-α) in these complications may be explained by the fact that the inflammatory process is further stimulated in these conditions which lead to increased levels of cachectin (TNF-α).

It was also found that cachectin (TNF-α) level of 116.6 is the best cut off point with sensitivity of 92% and specificity of 90% for prediction of NEC among preterm neonates.

The study had some limitations. First, the lack of previous similar studies, which made it difficult to compare the results with other previous studies. Second, the small sample size and rarity of the disease.

In conclusion, to our knowledge, this is the first study to assess levels of cachectin (TNF-α) in preterm neonates as an indicator of NEC. It was found that cachectin (TNF-α) levels are higher in patients with NEC. It was also found that cachectin (TNF-α) levels are higher in NEC patients with complications.

In conclusion, in the present study, we found that neonates with NEC had significantly higher cachectin (TNF-α) level (365.91 ± 260.76 ng/L) than healthy controls (83.92 ± 44.01 ng/L) (P < 0.001). It was also found that cachectin (TNF-α) levels are higher in NEC patients with complications. It was also found that cachectin (TNF-α) level of 116.6 ng/L is the best cut off point with sensitivity of 92% and specificity of 90% for the prediction of NEC among preterm neonates.

In the light of the results of the current study, we recommend the use of serum cachectin level for early diagnosis and prediction of complications of NEC in preterm neonates to improve the outcome of these patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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