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Abstract

BACKGROUND:

Although the success rate of resuscitation in preterm infants is increasing, the long length of hospital stay in preterm infants and the need for more invasive operations, coupled with the widespread use of empirical antibiotics, have increased the prevalence of fungal infections in preterm infants in neonatal intensive care units (NICUs) year on year.

OBJECTIVE:

The present study aims to explore the risk factors of invasive fungal infections (IFI) in preterm infants and to identify some prevention strategies.

METHODS:

A total of 202 preterm infants with a gestational age of 26 weeks to 36 ${}^{+6}$ weeks and a birth weight of less than 2,000 g, admitted to our neonatal unit during the 5-year period from January 2014 to December 2018, were selected for the study. Among these preterm infants, six cases that developed fungal infections during hospitalization were enrolled as the study group, and the remaining 196 infants who did not develop fungal infections during hospitalization were the control group. The gestational age, length of hospital stay, duration of antibiotic therapy, duration of invasive mechanical ventilation, indwelling duration of the central venous catheter, and duration of intravenous nutrition of the two groups were compared and analyzed.

RESULTS:

There were statistically significant differences between the two groups in the gestational age, length of hospital stay, and duration of antibiotic therapy.

CONCLUSION:

A small gestational age, a lengthy hospital stay, and long-term use of broad-spectrum antibiotics are the high-risk factors for fungal infections in preterm infants. Medical and nursing measures to address the high-risk factors might reduce the incidence of fungal infections and improve the prognosis in preterm infants.

Keywords

Preterm infant fungal infection high-risk factors

1. Introduction

Preterm infants are those who are delivered before 37 weeks of gestational age. Preterm infants have immature organ functions and face more risks than full-term infants after birth. Although the success rate of resuscitation in preterm infants is increasing with the rapid development of perinatal medicine and the continuous progress of neonatal emergency and intensive care techniques, the long length of hospital stay in preterm infants and the need for more invasive operations, such as tracheal intubation and central venous catheterization, coupled with the widespread use of empirical antibiotics, especially broad-spectrum antibiotics, have increased the prevalence of fungal infections in preterm infants in neonatal intensive care units (NICUs) year on year. Fungal infection has become the third cause of late-onset sepsis in preterm infants [1], making it a serious threat to the life and health of newborns and one of the major causes of increased morbidity and mortality in preterm infants. Moreover, survivors are often left with severe neurobehavioral developmental disorders, which can seriously affect the quality of their survival.

In the present study, a total of 202 preterm infants with a gestational age of 26 weeks to 36 ${}^{+6}$ weeks were analyzed in the neonatal department of Kunming Children’s Hospital over a period of five years from January 2014 to December 2018.

2. Material and methods

2.1 Inclusion criteria

Preterm infants with a gestational age $<$ 37 weeks, birth weight $<$ 2,000 g, and length of hospital stay $>$ 7 days.

2.2 Diagnostic criteria

(1) There were high risk factors for fungal infection, such as gestational age less than 32 weeks, long-term indentured tracheal catheter or peripherally inserted central catheter (PICC), use of intravenous nutrition (TPN), and long-term antibiotic exposure. (2) During hospitalization, apnea, feeding intolerance, and other nonspecific manifestations suddenly presented, accompanied by elevated white blood cells, thrombocytopenia, elevated calcitonin and other laboratory abnormalities. (3) Abnormal elevation of 1, 3-beta-glucan may be associated with fungal infection. Fungal infection has been confirmed by blood culture, cerebrospinal fluid culture and other tests that indicated certain fungal growth [2, 3].

2.3 NICU basic information

The NICU where the author works is affiliated to the Children’s Hospital Affiliated to Kunming Medical University. The department has 22 beds, 12 physicians, and 30 nurses who have received intensive care training. Our department mainly treats respiratory failure, heart failure, severe infection, shock and other critical conditions. Among premature infants living in our department, approximately 1/3 are less than 34 weeks of gestational age.

All staff in the NICU strictly implement hand hygiene and disinfection and isolation systems, use disposable milk utensils, and strictly distinguish infected and non-infected areas in the ward. The infected area is divided into different treatment units according to the pathogen, all of which are in charge of specially assigned personnel. Warm containers in NICU should be replaced and disinfected every week, and dried thoroughly before being used again. The PICC, UVC, and other pipes should be managed in accordance with the relevant guidelines.

2.4 Methods

The clinical data of 202 preterm infants admitted to our neonatal department between January 2014 and December 2018 were retrospectively analyzed. The data included gender, gestational age, admission age, length of hospital stay, whether there was a diagnosis of invasive fungal infection (IFI), use of invasive mechanical ventilation, placement of a PICC and use of broad-spectrum antibiotics, especially the duration of use of restricted-grade antibiotics, duration of intravenous nutrition, and data from laboratory tests. Reference was made to Practical Neonatology, 5th edition, for the diagnosis of relevant diseases.

In the present study, blood culture was conducted in 130 males and 72 females on the day of admission, and a 1, 3-beta-D-glucan test was assayed on the seventh day of admission. The blood culture and fungal D-glucan were reexamined when there was a suspicion of fungal infection during hospitalization. The preterm infants who developed IFI during hospitalization were enrolled as the study group, and those who did not were included in the control group. The gestational age, length of hospital stay, duration of antibiotic therapy, duration of invasive mechanical ventilation, indwelling duration of a central venous catheter, and duration of intravenous nutrition of the two groups were compared and analyzed.

2.5 Statistical analysis

SPSS 22.0 software was used for data processing. A $t$ -test was used for data that were normally distributed, while a rank-sum test was used for data that did not have a normal distribution.

3. Results

In the present study, the blood cultures taken on the day of admission did not indicate a fungal infection in any of the infants. During hospitalization, the 1, 3-beta-D-glucan test, and blood and cerebrospinal fluid cultures were repeated when there were symptoms of suspected fungal infection present, and six cases with IFI were confirmed, an incidence of 2.9%, comprising five cases with a Candida albicans infection and one case with a Candida glabrata infection.

3.1 The length of hospital stay and the duration of antibiotic therapy

Among the six infants with fungal infections, the earliest onset was on the 16th day of hospitalization, the latest onset was on the 44th day of hospitalization, and the length of hospital stay ranged from 36 to 88 days. There were 196 cases in the control group with the length of hospital stay ranging from 7 to 73 days. All six infants had been on cephalosporin III antibiotics or restricted-grade antibiotics, such as meropenem or vancomycin, before the onset of IFI, and the duration of antibiotic therapy ranged from 7 to 88 days. A comparison of the length of hospital stay and duration of antibiotic therapy between the study group and the control group can be found in Table 1.

Table 1
Comparison of the length of hospital stay and the application duration of antibiotics between the study group and the control group

	Study group ( $n=$ 6)	Control group ( $n=$ 196)	$T$ value	$P$ value
Length of hospital stay (days)	62 (36, 88)	43.5 (7, 73)	2.776	0.006
Application duration of antibiotics (days)	47.5 (7, 88)	10.5 (7, 14)	2.604	0.010

$P<$ 0.01, with statistically significant difference between the study group and control group.

3.2 Gestational age

In the study group, the gestational age in 6 cases was 26 weeks, 28 ${}^{+6}$ weeks, 31 $+$ 3 weeks, 31 ${}^{+5}$ weeks, 35 ${}^{+1}$ weeks, and 36 ${}^{+4}$ weeks, and the average gestational age was 31.2 weeks. In the control group, there were 196 cases consisting of 49 cases with a gestational age of 28–30 weeks, 127 cases with a gestational age of 30 ${}^{+1}$ –35 weeks, and 26 cases with a gestational age of 35 ${}^{+1}$ –36 ${}^{+6}$ weeks. The data on the occurrence of fungal infections in the gestational age group of 28–30 weeks and the gestational age group of 30 ${}^{+1}$ –35 weeks were non-normally distributed and tested by the rank-sum test. The results showed $p=$ 0.006 $<$ 0.01, suggesting a statistically significant difference between the two groups, with a higher incidence in the former than in the latter.

3.3 The duration of tracheal intubation

A total of 25 cases (12.3%) with a duration of tracheal intubation greater than three days were included in the present study, including 1 case with a fungal infection. The data were non-normally distributed and tested by rank-sum test. The results showed $p=$ 0.590 $>$ 0.05, suggesting that there was no statistically significant difference in the duration of tracheal intubation between the study group and the control group.

3.4 The duration of use of an indwelling central venous catheter

A total of 20 cases (9.9%) used a PICC, with a maximum indwelling duration of 43 days, 4 cases of which developed fungal infections. The data were non-normally distributed and tested by a rank-sum test. The results showed $p=$ 0.894 $>$ 0.05, suggesting that there was no statistically significant difference in the indwelling duration of a PICC between the study group and the control group.

3.5 The duration of parenteral nutrition

Parenteral nutrition was administered in a total of 177 cases (87.6%) in the present study population, with a maximum duration of 54 days, and 4 cases developed fungal infections. The data were non-normally distributed and tested by the rank-sum test. The results showed $p=$ 0.823 $>$ 0.05, indicating that there was no statistically significant difference in the duration of parenteral nutrition between the study group and the control group. The clinical characteristics of the study group and the control group are shown in Table 2.

Table 2
Comparison of clinical characteristics between the study group and the control group

Clinical characteristics ( $n=$ 202)	Control group ( $n=$ 196)	Study group ( $n=$ 6)
Gender
Male ( $n$ )	126	4
Female ( $n$ )	70	2
Gestational age (weeks)	30 ${}^{+1}$ –35	26–36 ${}^{+4}$
Birth weight (g)	980–2000	720–1980
Clinical feature ( $n$ )
Fever or lack of rising body temperature	20	6
Feeding intolerance	46	6
Apnea	30	6
Increased heart rate	11	6
Hyporesponsiveness	43	6
Length of stay (days)	7–73	36–88
Laboratory examination ( $n$ )
Leukocytosis	87	6
Thrombocytopenia	65	3
Blood culture is positive for fungi	0	6
Indenture PICC $>$ 2 weeks ( $n=$ 20)	16	4
Indwelling tracheal catheter for more than 7 days ( $n=$ 25)	24	1
Duration of antibiotic use (days)	7–14	7–88

4. Discussion

Fungal infections in preterm infants include superficial skin infections and IFI, the former being mostly superficial infections of the skin and mucous membranes, which are easy to diagnose and treat and do not cause serious adverse consequences. However, the latter are fungal infections that invade the deep tissues, viscera, and the whole body [4] and lack specificity. They also have a rapid progression and high mortality rate, and survivors usually have severe neurological sequelae. Currently, the third cause of late-onset sepsis in preterm infants is IFI. There are many risk factors for IFI in preterm infants, which have been studied at home and abroad, including antibiotic exposure (100%), parenteral nutrition support (95%), low birth weight (77%), invasive ventilation (67%), and PICC (20%) [5].

In the present retrospective case analysis, the average gestational age of the six children with IFI was 31.2 weeks, which was consistent with the results of national and international studies [6]; in other words, the younger the gestational age, the higher the fungal susceptibility. The reasons for this are that, firstly, preterm infants have immature T and B lymphocyte function, imperfect thymus function, and an insufficient number of total T cells and subpopulations of cells, so the cellular immune function is low. Secondly, the younger the gestational age, the less immunoglobulin G (IgG) is obtained from the mother at delivery, and even if there is a sufficient concentration of IgG, the conditioning and complement function in preterm infants are not perfect, thus the humoral immune function is low [7]. Lastly, the epithelial barrier function in preterm infants is not yet mature, and the skin and mucous membrane barriers are easily destroyed, which results in less protection. Therefore, preterm infants are more prone to IFI than full-term ones.

In the present retrospective case analysis, it was found that all six preterm infants with confirmed IFI were hospital-acquired infections, and the lengths of hospital stay (36–88 days) were significantly longer than those in the non-infected infants. In addition, the onset of the IFI all started two weeks after admission, suggesting that the longer the hospital stay, the greater the chance of fungal infections. Preterm infants may have prolonged hospitalization due to severe bacterial infections, feeding intolerance, necrotizing small bowel colitis, or severe jaundice, for example. Therefore, they may receive more invasive examinations, treatments, and antibiotics, and so the rate of fungal colonization increases and at the same time the chance of cross-infection increases. Therefore, prolonged hospitalization might be one of the high-risk factors for IFI in preterm infants.

The present retrospective analysis revealed that all six preterm infants with IFI had been given broad-spectrum antibiotics (mainly cephalosporin III) before the onset of the disease, and five of them had had meropenem and vancomycin. This was significantly different when compared to the non-infected infants. Regarding the relationship between the use of broad-spectrum antibiotics and IFI, the previous view was that no single antibiotic was responsible for the development of fungal infections, but 40% of researchers in one survey in England and Ireland still considered cephalosporin III to be a significant pathogenic factor for the development of fungal infections [8, 9]. Since one of the main causes of preterm birth is intrauterine infection, preterm infants are given prophylactic anti-infection treatment after birth, but prolonged administration of broad-spectrum antibiotics will lead to dysbacteriosis in the body and can even kill some beneficial flora, thus increasing the susceptibility to fungi [10]. Therefore, the prolonged administration of broad-spectrum antibiotics might be considered to be one of the high-risk factors for the development of IFI in preterm infants.

The present study has a number of limitations. It was found that there was no statistical difference between the two groups in terms of the indwelling duration of a deep venous catheter and the duration of parenteral nutrition and tracheal intubation. However, these findings differ from previous reports [11, 12]. The bias of the comparison results could be correlated with the small number of cases receiving these three treatments in the present data, and thus an expansion of the sample size is needed for further comparison.

This was a single-center study and the NICU where the authors worked only began to treat premature infants less than 32 weeks of gestational age in 2014. The diagnosis and treatment of late-onset fungal septicemia in these children was insufficient, and PICC technology was not routinely carried out. Therefore, some possible fungal infection cases were not included in this study. In addition, late-onset sepsis and very late-onset sepsis are not strictly distinguished, and we will improve this area in future studies.

5. Conclusion

Small gestational age, prolonged hospitalization, and prolonged use of broad-spectrum antibiotics were found to be high-risk factors for the development of IFI in preterm infants in the present study.

For invasive Candida infections in preterm infants, the key is prevention, and the following prevention strategies are proposed in the context of the present study: 1) Improve the level of comprehensive management of preterm infants, strengthen the training of medical and nursing staff concerning knowledge related to hospital infections, strictly implement hand hygiene and disinfection and isolation systems, strengthen monitoring and early warning of hospital infection, and implement protective isolation for preterm infants with small gestational age, low birth mass, or those with a high risk of infection; 2) Understand clearly the indications for the use of antibiotics, reduce the use of non-essential antibiotics [13], and use antifungal therapy prophylactically when necessary. The 2016 guidelines for the management of Candida proposed by the Infectious Diseases Society of America recommend the application of fluconazole for the prevention of Candida infections in preterm infants with a birth weight $<$ 1,000 g at a dose of 3–6 mg/Kg twice weekly for six consecutive weeks if the incidence of IFI in the NICU is $>$ 10% [14, 15, 16, 17]; 3) Carry out family participatory nursing and other training to improve the parents’ ability to care for preterm babies, thereby shortening the hospital stay to a certain extent and reducing the chance of fungal infections; and 4) existing studies have shown that central venous catheterization, tracheal intubation, and long-term application of intravenous nutrition are also high-risk factors for fungal infections in preterm infants [18]. Therefore, it is necessary to increase the breastfeeding rate, realize total enteral feeding as soon as possible, and shorten the indwelling duration of central venous catheters and duration of venous nutrition. In the future, perhaps artificial intelligence could be used to predict and diagnose infections [19, 20, 21, 22]. Such measures, along with strict control of the indications of invasive mechanical ventilation and shortening the time of invasive mechanical ventilation, will help reduce the rate of fungal infection in preterm infants.

Footnotes

Conflict of interest

None to report.

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An analysis of the risk factors for invasive fungal infections in preterm infants and a discussion of prevention strategies

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Material and methods

2.1 Inclusion criteria

2.2 Diagnostic criteria

2.3 NICU basic information

2.4 Methods

2.5 Statistical analysis

3. Results

3.1 The length of hospital stay and the duration of antibiotic therapy

Table 1 Comparison of the length of hospital stay and the application duration of antibiotics between the study group and the control group

3.3 The duration of tracheal intubation

3.4 The duration of use of an indwelling central venous catheter

3.5 The duration of parenteral nutrition

Table 2 Comparison of clinical characteristics between the study group and the control group

5. Conclusion

Footnotes

Conflict of interest

References

Table 1
Comparison of the length of hospital stay and the application duration of antibiotics between the study group and the control group

Table 2
Comparison of clinical characteristics between the study group and the control group