Catheter-related bloodstream infections in children with intestinal failure: a 6-year review from an intestinal rehabilitation center in China

Yi Cao · Wei-Hui Yan · Li-Na Lu · Yi-Jing Tao · Hai-Xia Feng · Qing-Qing Wu · Yi-Jing Chu · Wei Cai ,2,3 ·Ying Wang

Abstract

Keywords Enteric pathogens · Fecal examination · Gastrointestinal symptoms

Introduction

Intestinal failure (IF) is defined as the reduction of functional gut mass below the minimal amount that is necessary for digestion and absorption [ 1], which is not adequate to satisfy the nutrients and fluid requirements for maintenance in adults or growth in children [ 1]. Some of the main causes of IF include surgical short bowel syndrome (SBS), gastrointestinal dysmotility, and congenital enterocyte disorders [ 2].

Patients with IF require support through long-term parenteral nutrition (PN); therefore, placement of central venous catheters (CVCs) is necessary before initiating PN.However, alterations in the gut microbiota, small intestinal bacterial overgrowth, and intestinal mucosal inflammation are observed in children with IF, which may increase their risk of catheter-related bloodstream infections (CRBSIs) [ 3,4]. CRBSIs contribute to a large portion of morbidity and mortality among children with IF [ 5]. Despite the risk of CRBSIs, these children require nutritional support through PN for survival.

Enteric Gram-negative pathogens are reported to predominantly occur in CRBSIs in IF [ 6], which differs from children with CVCs for other diseases. Based on this information, this retrospective study analyzed fecal examinations to further confirm nearly half of the pathogens of CRBSIs in children with IF originated in the intestine. In addition, it focused on fever/gastrointestinal symptoms and laboratory inflammatory indicators at the onset of CRBSIs to identify the early signs for CRBSIs.

Methods

This study was approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (XHEC-C-2020-073). A retrospective review was conducted among children diagnosed with IF who were under PN support through CVCs from April 2014 to April 2020.

Inclusion criteria

Patients were diagnosed with IF when the patient had ＜ 25%of the expected length of small bowel for gestational age and/or were receiving PN for ＞ 42 days because of intestinal dysmotility or bowel resection [ 2]. In our study, the inclusion criteria included the presence of a peripherally inserted central catheter (PICC) or a CVC for the administration of PN. The age of the patients ranged from 1 day to 6 years old, due to most of our patients with IF were in the age group and CRBSIs were more common in young group compared to the older in our institution. Any patient who was over 6 years old or using CVCs without PN were excluded from this study. In all cases, radiography was performed to confirm whether the catheter was placed in the appropriate position. Heparin was used to lock the catheters when they were not in use.

Diagnosis of catheter-related bloodstream infections

A diagnosis of CRBSIs was made according to the guidelines from the European Society for Paediatric Gastroenterology Hepatology and Nutrition [ 7].

Any child with IF and an indwelling CVC is at significant risk for CRBSI and, accordingly, any fever (temperature ＞ 38.5 or rise ＞ 1 °C), or change in clinical or laboratory parameters should rise the suspicion of CLABSI until proven otherwise[ 7]. When symptoms or indicators relieved after catheters blocked or removed, they had been considered as suspected cases. Based on the information given above, CRBSI could be confirmed when a positive culture was obtained from CVCdrawn blood, peripheral venous catheter-drawn blood, or both.

Data collection from intestinal failure children with catheter-related bloodstream infections

Data on demographic characteristics, type of IF, and the length of small bowel after resection were recorded. Further data were collected on symptoms at the time of the initial positive blood culture (fever and gastrointestinal symptoms) and data on procalcitonin (PCT), C-reactive protein (CRP), white blood cell (WBC), absolute neutrophil count, platelet count were recorded within 24 hours of the initial positive culture,fecal bacterium/fungus cultures, and the fate of the CVCs.

Considering blood infection from bowel in IF patients,the calorie of enteral nutrition (EN) and PN within 24 hours before CRBSIs, fecal cultures (the presence of bacterium/fungus), and fecal routines including WBC count, occult blood and fat droplets were checked within 1 week since the positive blood culture was recorded.

Fecal culture was a qualitative test and generally reported only dominant bacteria. Its specific process was that stool inoculated blood plate and McConkey plate and observed the colony growth on the plate after 24 and 48 hours, respectively. If there was colony growth, single colony will be selected for identification by MALDI TOF MS, which is a mass spectrometer, and then the identification results will be reported.

Statistical analysis

All statistical analyses were performed using IBM SPSS Statistics 19.0 for Windows. Descriptive analyses were performed to catalog the characteristics of the patients and catheters. All data were reported as median or mean, with ranges and categorical data reported as frequency and percentages.According to the recommendation by the Centers for Disease Control and Prevention, CRBSI rates were expressed as the number of infections per 1000 catheter days. Chi-squared tests were used to determine the association between independent predictors and the situation in which PICC had to be removed. We set the

P

value ＜ 0.05 to indicate significant differences.

Results

Characteristics of patients

In total, 212 IF patients were identified during the 6-year study period. Of 212 patients, 50 met the study criteria and had a total of 87 CRBSIs, which comprised 17 suspected and 70 confirmed cases (Table 1). Of the 212 patients, 23%had a bloodstream infection. The rate of CRBSIs was 5.95 per 1000 catheter days.

The etiology of IF was classified into three categories: SBS (

n

= 31), pediatric intestinal pseudo-obstruction(

n

= 15), and chronic diarrhea (

n

= 4). Of the 50 patients, 15 were admitted for initial symptoms of abdominal distension and 35 for diarrhea being the major problem. The median length of the remaining small intestine in SBS patients with massive small bowel resection (in the latest surgery as measured from the ligament of Treitz) was 50 cm [interquartile range (IQR) 40-70 cm].

The median age of patients presenting with CRBSIs was 7 months (IQR 4-15 months), and 64% of patients were male. Median patient weight was 3.7 kg (IQR 3.0-6.5 kg).Their CVCs were placed for a mean of 35.9 days (range 5-138 days). The median days of a PICC was 48.7 (IQR 22-67), and the median days of a CVC was 15.1 (IQR 11.7-19.2).

Episodes of positive blood cultures

In total, 87 CRBSIs included 17 suspected and 70 confirmed cases. Of the 17 suspected cases, 11 cases had no blood culture and 6 had negative culture, while symptoms were relieved in the patients when the catheter was removed or blocked.

Seventy positive blood cultures were obtained during the period. Of all CRBSIs, 63% (44/70) were caused by a single Gram-positive organism, 23% (16/70) were caused by a single Gram-negative organism, 11% (8/70) were caused bya single fungal organism and 2.8% (2/70) were caused by polymicrobial.

Table 1 Patient characteristics ( = 50)

short bowel syndrome, interquartile range, catheterrelated bloodstream infection, central venous catheter, peripherally inserted central catheter

Variables Values Etiology of intestinal failure, n (%)Short bowel syndrome 31 (62)Pediatric intestinal pseudo-obstruction 15 (30)Chronic diarrhea 4 (8)Abdominal distention as initial symptoms, n (%) 15 (30)Diarrhea as initial symptoms, n (%) 35 (70)Median length of remaining small bowel in SBS(cm), median (IQR)50 (40-70)Males, n (%) 32 (64)Median mon of CRBSI, median (IQR) 7 (4-15)Median weight of CRBSI (kg), median (IQR) 3.7 (3.0-6.5)Mean d of CVCs 35.9 (5-138)Median d of PICC, median (IQR) 48.7 (22-67)Median d of CVC, median (IQR) 15.1 (11.7-19.2)

A total of 72 pathogens were isolated from the 70 positive blood cultures: 48.6% (35/72) were enteric organisms;the most common bacterial pathogens were

Enterococcus faecalis

(14/72),

Staphylococcus epidermidis

(11/72), and

Klebsiella pneumoniae

(8/72); all fungal organisms were

Candida

species and accounted for 11.1% (8/72) of all isolates. Pathogen types are listed in Table 2.

Fecal sample examination

We performed 82 routines, 36 bacterial cultures, and 34 fungal cultures of stool samples obtained from the patient within 1 week before and after CRBSIs (Table 3).

The results of 46% (38/82) fecal routines showed abnormalities associated with intestinal barrier, such as increased WBC count (16/82) or occult blood positive (26/82). Meanwhile, the results of 19% (16/82) routines showed the presence of fat droplets in the stool.

Table 2 Organisms cultured from positive blood cultures ( = 72)

Total blood culture pathogens n (%)Gram-positive bacterial species 48 (66.7)Staphylococcus epidermidis 11 (15.3)Staphylococcus haemolyticus 2 (2.8)Staphylococcus hominis 7 (9.7)Staphylococcus caprae 1 (1.4)Staphylococcus cohnii 1 (1.4)Staphylococcus aureus 1 (1.4)Staphylococcus warneri 1 (1.4)Lactococcus garvieae 1 (1.4)Leuconostoc lactis 1 (1.4)Enterococcus faecalis 14 (19.4)Enterococcus faecium 6 (8.3)Micrococcus luteus 1 (1.4)Streptococcus mitis 1 (1.4)Gram-negative bacterial species 16 (22.2)Klebsiella pneumoniae 8 (11.1)Escherichia coli 2 (2.8)Enterobacter aerogenes 2 (2.8)Acinetobacter lwoffii 1 (1.4)Citrobacter freundii 1 (1.4)Acinetobacter baumannii 1 (1.4)Corynebacterium afermentans 1 (1.4)Fungal species 8 (11.1)Candida parapsilosis 5 (6.9)Candida tropicalis 2 (2.8)Candida glabrata 1 (1.4)Candida guilliermondii 1 (1.4)Enteric organisms 35 (48.6)

Moreover, 92% (33/36) fecal bacterial cultures were positive.

Klebsiella pneumoniae

(18/36),

Enterococcus

(12/36), and

Escherichia coli

(13/36) were the most frequently encountered bacteria in fecal cultures. It was worth mentioning that 47% (17/36) of bacterial pathogens were consistent with those of blood cultures obtained during the same period.Fecal fungal culture results were mostly negative, and only 11% (5/34) were positive, mainly for

Candida

species. None of those were consistent with those found in blood cultures.

Symptoms and signs at the onset of catheter-related bloodstream infections

Symptoms at the time of diagnosis of CRBSIs included fever [84 (97%)]. The initial temperature was 38.3 (IQR 37.9-38.8 °C), and the highest temperature was 38.9 (IQR 38.2-39.2 °C).

Gastrointestinal symptoms at the initial time of CRBSIs were found in 71% patients. The symptoms included abdominal distension (

n

= 17), increased stool output (

n

= 41), or both (

n

= 4).

Laboratory findings with catheter-related bloodstream infections

Table 3 Fecal examination

Variables n (%)Total bacterium cultures ( n = 36)Consistent with blood culture 17 (47.2)Enterococcus faecalis 5 (16.7)Klebsiella pneumoniae 5 (16.7)Enterococcus faecium 1 (3.3)Escherichia coli 1 (3.3)Citrobacter freundii 1 (3.3)Enterobacter aerogenes 1 (3.3)Staphylococcus epidermidis 1 (3.3)Enterobacter aerogenes 1 (3.3)Lactococcus garvieae 1 (3.3)Total fecal routines ( n = 82)Occult blood 26 (31.7)White blood cells 16 (19.5)Fat droplets 16 (19.5)

Seventy-five percent (65/86) CRP and 48% (31/64) PCT of IF patients with CRBSIs were above their normative value.

As shown in Table 4, the median of CRP (16.5 mg/L;IQR 8.7-44.7) was elevated compared to normative value(CRP ≤ 8 mg/L). When compared with normative value(PCT ≤ 0.5 ng/mL), the median of PCT (0.48 ng/mL; IQR 0.2-1.76) showed an increasing trend.

Enteral/parenteral nutrition

The median total calorie in 24 hours before bloodstream infection was 103 kcal/kg/day (IQR 79.9-121.8). Total calorie comprised EN 56 kcal/kg/day (IQR 25.2-80.2) and PN 50 kcal/kg/day (IQR 33.6-65.1). The median proportion of the EN calorie in the total calorie was 51% (IQR 31.2-66.6%).

Table 4 Presenting symptoms and laboratory indicators of catheter-related bloodstream infections

interquartile range, C-reactive protein, white blood cell, absolute neutrophil count, procalcitonin

Variables Values Total, n (%) 87 (100)Fever ＞ 38.5 or rise ＞ 1 °C, n (%) 84 (97)Initial temperature (°C), median (IQR) 38.3 (37.9-38.8)Highest temperature ( C), median (IQR) 38.9 (38.2-39.2)Gastrointestinal symptoms, n (%) 62 (71)Abdominal distension 17 (19)Increased stool 41 (47)Both 4 (5)Laboratory indicators, median (IQR) Normative values CRP (mg/L) 16.5 (8.7-44.7) ≤ 8 WBC count (10 9 /L) 8.1 (5.7-12.8) 4.0-10.0 ANC 3.9 (1.9-7.1) 1.4-6.5 Platelet count (10 9 /L) 251 (142-337) 100-300 PCT (ng/mL) 0.48 (0.2-1.76) ≤ 0.5

In 11% (10/87) of episodes, children with IF were in a fasting state in the 24 hours before bloodstream infection.

Fate of the central venous catheters

CVCs including 27 PICC and three CVC were successfully retained in 30 episodes. The catheter salvage rate was 16(33%) of 48 infections due to Gram-positive organisms, 7(44%) of 16 infections due to Gram-negative organisms and 2 (25%) of eight fungal infections.

CVCs, which were all PICCs, were initially retained but then removed before the bacteremia cleared in 13 cases.CVCs, including 29 PICC and 15 CVC, were removed without any attempt to save when infection occurred in 44 episodes. Combining all episodes in cases that had CVC removal, the catheter salvage failure rate was 32 (67%) of 48 infections due to Gram-positive organisms, 9 (56%) of 16 infections due to Gram-negative organisms and 6 (75%)of 8 fungal infections.

Eighty-seven CRBSIs comprised 18 cases of CVC and 69 cases of PICC. The PICC salvage rate of 39% was higher than the CVC salvage rate of 16%.

Microbiology culture of the central venous catheters

In total, 57 catheters were removed for obtaining catheterdrawn blood culture, while the positive rate (25/57) was lower than that of blood culture (70/76).

Cultures of catheter-drawn blood, wherein the catheter was initially retained but then removed, were mostly negative, while only one culture (1/13) showed fungal infection.CVCs removed without salvage showed a higher positive rate (24/44).

The reason for the lower positive rate may be that antibiotics had been used empirically when clinical symptoms appeared. The catheters were usually removed after blood culture had a positive result. Empirical use of antibiotics may be the reason for the low positive rate.

Discussion

Our study showed that IF children had a high rate of CRBSIs, of which larger proportions were caused by Gram-positive and enteric organisms. The rate of CRBSIs in children with IF receiving long-term PN was 5.95 per 1000 catheter days. As reported in recent studies, the CRBSI rate in children with other causes ranges from 0.93 to 2.8/1000 catheter days [ 8, 9], while the pediatric IF population, it ranges from 4.4 to 13.9/1000 catheter days [ 10- 12]. This suggests that children with IF compared to children with other diseases are more likely to experience CRBSIs.

In our study, Gram-positive bacteria were the predominant isolated pathogens, accounting for 63% of CRBSIs.

Staphylococcus

as the major part of pathogens was mostly coagulase-negative staphylococci. Similar to previous studies, most CRBSIs were caused by coagulase-negative staphylococci [ 13, 14], which represents one of the major hospital-acquired pathogens and its presence is highly associated with the use of intravascular devices [ 15]. They are normal skin flora at the catheter exit site and the hub connections of the catheter [ 16]. It is now common practice that heparin is used to lock the catheters when the CVC is not in use, and there is no exception in our division. The rate of CRBSIs was highest with the use of heparin when compared with the use of 70% ethanol locks, catheter lock solutions, or taurolidine-citrate-heparin locks [ 17- 19]. This suggests that improving CVC care is important to reduce infection rates.In addition to the presence of

Staphylococcus

among Gram-positive bacteria, the high proportion of

Enterococcus faecalis

and

Enterococcus faecium

should also not be ignored, which was attributed to the intestinal flora. Notably,48.6% of CRBSIs were due to enteric organisms. The high incidence of bloodstream infections due to enteric organisms was characteristic of IF in children [ 6]. This is also characteristic of patients with IF and CRBSIs. This finding may support the theory of chronic inflammation of the gut and gut bacterial translocation in IF [ 20]. Based on this information, we retrospectively studied the results of fecal culture and routine examination in the same period. Interestingly,47.2% fecal pathogens were consistent with those of blood cultures. We further confirmed the possibility of intestinal bacterial translocation. Forty-six percent of fecal routine examination results showed mild abnormalities such as several WBCs or a little occult blood, which were associated with intestinal barrier impairment. This may suggest that children with IF are more likely to develop enterogenic catheter infections because of intestinal inflammation, requiring regular examination of fecal routine, use of drugs to repair intestinal mucosal, and intestinal antibiotics circulated to clean intestinal flora.A study found that patients with IF and/or receipt of TPN were at increased risk for the development of

Candida

related CRBSIs [ 21]. Fungal infections accounted for 11.1%(8/72) of the CRBSIs caused by pathogens. Of the eight fungal infections, three occurred in an infant with SBS who experienced five CRBSIs and each infection interval was for more than 2 months; one occurred in a child with congenital intestinal cluster disease who experienced 10 CRBSIs; two occurred in two patients with intestinal pseudo-obstruction,both of whom experienced two CRBSIs; the remaining two occurred in two infants, each with 3-5 operations. All the children had long-term feeding difficulties. It seems that children with IF who have ever experienced CRBSIs are more susceptible to fungal infections.Since the occurrence of CRBSIs in patients with IF was closely associated with intestine, this study is the first to focus on gastrointestinal symptoms at the onset of CRBSIs.There were 62 cases with different degrees of gastrointestinal symptoms when CRBSIs occurred, including 17 cases of abdominal distension, 41 cases of increased stool, or both(

n

= 4). In addition, almost all children had fever with CRBSIs, which was thought to be a common symptom when CRBSIs occurred [ 22]. According to this information, when fever is accompanied by different degrees of gastrointestinal signs in children with IF, and there is no obvious abnormality in stool routine, the possibility of CRBSIs should be considered and relevant examination should be conducted.We overviewed laboratory indicators within 24 hours of the onset of CRBSIs. Among all the indicators associated with infection, CRP and PCT appeared to be sensitive markers,which increased obviously at the occurrence of CRBSIs.

Studies were mostly focused on the effects of PN on CRBSIs. It is worth mentioning that the proportion of EN was nearly half when CRBSIs occurred in our study.Another study among critically ill patients suggested that the use of EN could decrease the incidence of bloodstream infections but was associated with increased risk of gastrointestinal complications [ 23]. In children with IF, EN sometimes maybe a burden on the gastrointestinal region and may aggravate intestinal damage, perhaps indicated through positive occult blood and fat droplets in the fecal test. Nevertheless, if EN was insufficient for a long time, then it would be difficult for children with IF to eliminate PN, which was a significant risk factor for CRBSIs [ 24]. This suggested that the addition of drugs to promote repair of the intestinal mucosa is necessary and may attribute to reduction in the rate of CRBSIs in children with IF.

Considering that the pathogens of CRBSIs in IF were mostly Gram-positive and enteric organisms, the empirical antibiotic therapy should usually include coverage for Gram-positive coagulase-negative or -positive staphylococci and Gram-negative bacilli [ 7], which had been referred in our clinical treatment.

Candida

-related CRBSI were usually prevented from the preservation of the CVCs in this study.As

Candida

CRBSI caused high mortality [ 25], it required immediate removal of the infected CVC and a defined course of systemic antibiotic therapy, except in rare circumstances when no alternate venous access was available [ 7, 26]. The improvement of CVC care and oral intestinal antibiotics circulated to clean intestinal flora are important to reduce CRBSIs rate. Empirical antibiotic treatment prior to blood culture results may be help to avoid removal of CVCs.

In conclusion, pediatric patients with IF and CVCs had a high rate of CRBSIs, of which larger proportions of infections were caused by Gram-positive and enteric organisms.Improvement in catheter care will be required to reduce infection rates.

Author contributions

WY and CW equally contributed to the conception and design of the research. CY contributed to the design of the research and drafted the manuscript. YWH, LLN, and TYJ contributed to the acquisition and analysis of the data. FHX, WQQ, and CYJ contributed to the interpretation of the data. All authors critically revised the manuscript, agreed to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript.

Funding

This study is supported by National Natural Science Foundation of China (Nos. 81974066, 81630039), Foundation of Shanghai Municipal Health Commission (Key Weak Discipline Construction Project, 2019ZB0101), Foundation of Shanghai Municipal Health Commission (No. shslczdzk05702), Foundation of Science and Technology Commission of Shanghai Municipality (No.19495810500) and Foundation of Clinical Research Plan of SHDC(No. SHDC2020CR2010A).

Data availability

We re-uploaded the original data through Springer Nature website and the data https:// doi. org/ 10. 11922/ scien cedb. 01531(unregistered). Data private access link https:// www. scidb. cn/ en/s/eiiUvm .

Declarations

Ethical approval

This study was approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (XHEC-C-2020-073).

Conflict of interest

No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. Author CW is a member of the Editorial Board for

World Journal of Pediatrics

. The paper was handled by the other Editor and has undergone rigorous peer review process. Author CW was not involved in the journal's review of, or decisions related to,this manuscript.