Predictive value of combined serum IL-6 with UREA on severity of neonatal pneumonia: an observational study

Introduction

Neonatal pneumonia is responsible for 10 % of all child deaths in the world, with mortality rates in underdeveloped countries as high as 15 to 49 million infant deaths from pneumonia annually [1, 2]. Neonatal pneumonia has a rapid onset and more complications than adult pneumonia. Newborn growth and development are severely compromised if treatment is not timely and thorough. Severe neonatal pneumonia presents with symptoms such as respiratory failure and various organ dysfunctions, which are more dangerous to the health of neonates and may even be life-threatening [3]. However, the neonatal organs are immature, the immune system is underdeveloped, and there are not enough clear and consistent clinical signs to track disease progression. As a result, it is extremely difficult for clinicians to determine in a timely manner whether neonatal pneumonia has progressed to a serious and dangerous condition.

As an inflammatory marker, IL-6 plays a role in the initiation and progression of inflammation and is associated with the severity of the disease’s clinical manifestations [4]. It has been reported that the addition of serum IL-6 to the A2DS2 score could significantly enhance the area under curve of predicting stroke-associated pneumonia in acute ischemic stroke patients from the medical ward [5]. A solid reference for the late treatment of neonatal pneumonia has also been suggested by the combination of color Doppler flow imaging, serum C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) levels [6]. In addition to inflammatory indicators, we are focusing on other potential biomarkers. Urea nitrogen (UREA) is formed in the liver from ammonia molecules and amino acids. It is a common indicator of glomerular filtration function in clinical practice and the major nitrogenous end product of protein degradation. The literature has identified the blood urea nitrogen to serum albumin ratio as a straightforward and possibly practical predictive indicator for death in patients with aspiration pneumonia [7]. In patients with severe pneumonia, a higher urea-to-albumin ratio at admission may be independently related with an increased risk of in-hospital mortality [8]. However, there is limited evidence on the relationship between severe neonatal pneumonia and UREA levels. Therefore, the aim of this study was to investigate the association between severe neonatal pneumonia and serum levels of IL-6 and UREA. May provide reference for differentiate of severe neonatal pneumonia.

Materials and methods

Results

Analysis of receiver operating characteristic curve

Receiver operating characteristic (ROC) curve analysis was used to evaluate the efficacy of IL-6 combined with UREA in predicting the severity of neonatal pneumonia. Area under the curve (AUC) results revealed that IL-6 and UREA together had a more significant ability to discriminate than either IL-6 or UREA alone (AUC=0.809, 95 % CI 0.711–0.894, p<0.001) (Figure 1). The ROC curve showed that IL-6 had a sensitivity and specificity of 68.97 and 65.79 %, respectively, in predicting the severity of neonatal pneumonia. UREA had a 55.17 % sensitivity and 85.53 % specificity for predicting the severity of neonatal pneumonia, respectively. Binary logistic regression analysis was performed with IL-6 and UREA as independent variables to obtain a logistic regression model: Logit (p)=0.861 + 0.002 IL-6 + 0.350 UREA. The sensitivity of IL-6 combined with UREA in predicting the severity of neonatal pneumonia was 72.41 % and the specificity was 77.63 % when the cut-off value was 0.28 (Table 4).

Figure 1:

ROC curves for IL-6 and UREA separately and in combination to predict the severity of neonatal pneumonia.

Table 4:

The efficacy of IL-6, UREA alone and combined detection in predicting the severity of neonatal pneumonia.

Variables	AUC	95 % CI	Cut-off	Sensitivity, %	Specificity, %	p-Value
IL-6	0.683a	0.572–0.794	42.24 pg/mL	68.97	65.79	0.004
UREA	0.695b	0.577–0.814	4.05 mmol/L	55.17	85.53	0.002
Combined	0.809	0.711–0.894	0.28	72.41	77.63	＜0.001

1. ^ap<0.05 for IL-6 vs. combined. ^bp<0.05 for UREA vs. combined. IL-6, interleukin-6; UREA, urea nitrogen.

Discussion

Neonatal pneumonia is the most common severe respiratory disease in the newborn period. It is characterized by diffuse pulmonary lesions and atypical clinical manifestations. It is one of the major causes of neonatal death [10]. In western China, about 34.5 % of newborns die from neonatal pneumonia [11]. Unlike pneumonia in older children, neonatal pneumonia is atypical, occasionally accompanied by coughing, and temperature may not rise, the main symptoms are purple around the lips, foaming at the mouth, dyspnea, discomfort, and refusal to drink milk [12]. Therefore, it is of great importance to find biomarkers with high sensitivity and specificity to monitor the progression of neonatal pneumonia, so that we can judge whether it is necessary to turn into a severe and critical illness, and then take appropriate treatment measures.

IL-6 is a lymphokine produced by activated T cells and fibroblasts. It can promote the differentiation of primitive bone marrow cells and enhance the lysis of NK cells [13]. In innate immunity, IL-6 directs the trafficking and activation of leukocytes and induces acute phase reaction proteins in hepatocytes [14]. Therefore, IL-6 will also appear earlier than various acute phase reaction proteins. It is more suitable as a monitor for the progression of neonatal pneumonia. According to research by Zhou et al., Agiostrongylus cantonensis larvae can cause deadly pneumonia in mice in the acute and early stages of infection, significantly activate Stat3/IL-6 signaling, and enrich bone marrow cells. Additionally, in the early stage of the disease, Stat3/IL-6 inhibitors can significantly reduce the progression of severe pneumonia [15]. This supports our observation that serum IL-6 levels were markedly higher in severe pneumonia compared to mild to moderate pneumonia. In addition, increased levels of IL-6 were also discovered to be an independent risk factor for the severity of neonatal pneumonia.

On the other hand, serum UREA is a common clinical indicator of glomerular filtration function. According to our results, serum UREA level in the severe pneumonia was significantly higher than that in the mild to moderate pneumonia, and increased levels of UREA was an independent risk factor for the severity of neonatal pneumonia. UREA is an indirect marker of the metabolic pathway [16]. An elevated serum UREA level is considered to indicate protein catabolism. Dehydration and hyperosmotic conditions are common in neonatal pneumonia, which raise UREA concentrations. In addition, Pierluigi et al. noted that acute kidney damage prevalence was higher in children with severe compared to non-severe pneumonia in the study of acute renal injury in children hospitalized for community acquired pneumonia [17]. UREA is mostly eliminated by the kidney, thus if a patient has impaired renal function, UREA levels may be raised, which is probable in neonates.

The ROC curve also revealed that the AUC for IL-6 was 0.968, for UREA it was 0.683, and for IL-6 + UREA it was 0.809. This demonstrates that IL-6 and UREA detection in combination had a much greater ability to discriminate the severity of neonatal pneumonia than IL-6 or UREA alone. Additionally, the combined detection of IL-6 and UREA had a better sensitivity than either IL-6 or UREA by themselves. Previous research has concentrated on the use of distinct acute phase reactants to distinguish the origin and/or severity of CAP [18], [19], [20], [21]. Our combination detection covers both the glomerular filtration function test index UREA and the inflammation-associated cytokines IL-6, which makes it easier to observe newborn pneumonia illness progression from many angles. Additionally, it has been documented that IL-6 results in lung damage following acute kidney injury [22]. IL-6 inhibitors may be administered more frequently in COVID-19 patients with acute renal damage, according to Yasar et al. The inhibition of oxidative stress and apoptosis in kidney tissue by IL-6 inhibitors may be related to blocking nuclear factor kappa B activation [23]. We infer from the literature at hand that IL-6 and kidney damage are related, and more research is required to determine their processes in newborn pneumonia.

However, our study still has some limitations, such as the small sample size and the lack of follow-up on the future clinical outcomes of this study. Furthermore, IL-6 and UREA were measured at only one time point, and if these two biomarkers were measured consecutively at multiple stages of neonatal pneumonia, it would be useful to further explore their predictive value for the severity of neonatal pneumonia disease.

Conclusions

The severity of neonatal pneumonia was positively and independently linked with higher serum IL-6 and UREA levels. The levels of serum IL-6 combined with UREA can be used as a reference index to assess the progress of neonatal pneumonia. The combined detection of the two biomarkers has a good predictive value for severe neonatal pneumonia.