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Nosocomial viral infections in the neonatal intensive care unit

Nosocomial viral infections in the neonatal intensive care unit
Author:
Leonard E Weisman, MD
Section Editors:
Steven A Abrams, MD
Morven S Edwards, MD
Deputy Editor:
Carrie Armsby, MD, MPH
Literature review current through: Apr 2022. | This topic last updated: Mar 10, 2021.

INTRODUCTION — Nosocomial viral infections are less common than bacterial infections among neonates cared for in the neonatal intensive care unit (NICU). However, nosocomial viral infections in the NICU population can be associated with considerable mortality and morbidity.

This topic will review the epidemiology of nosocomial viral infections in the NICU setting, including a summary of some of the more common viral pathogens in this setting and their clinical manifestations in neonates. Additional details on specific viral pathogens are presented in separate topic reviews:

Respiratory syncytial virus (RSV) (see "Respiratory syncytial virus infection: Clinical features and diagnosis")

Parainfluenza virus (PIV) (see "Parainfluenza viruses in children")

Influenza virus (see "Seasonal influenza in children: Clinical features and diagnosis")

Rhinovirus (see "Epidemiology, clinical manifestations, and pathogenesis of rhinovirus infections")

Adenovirus (see "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection")

Rotavirus (see "Clinical manifestations and diagnosis of rotavirus infection")

Enterovirus and parechovirus (see "Enterovirus and parechovirus infections: Epidemiology and pathogenesis" and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention")

Cytomegalovirus (CMV) (see "Overview of cytomegalovirus infections in children")

EPIDEMIOLOGY

Incidence — The incidence of neonatal nosocomial viral infections has probably been underestimated because most NICUs do not routinely screen for viral infections.

Incidence of viral infections in the NICU setting – Estimates of the incidence of viral infections in this population vary depending on how data were collected:

Retrospective studies – In retrospective studies, reported incidence rates of nosocomial viral infection in the NICU setting range from <1 to 5 percent [1,2]. In one study of nearly 5400 neonates admitted to a single NICU from 1992 to 2003, the overall incidence of nosocomial viral infection was 0.9 percent [2]. The most common viral pathogens were enterovirus and parechovirus (n = 20), respiratory syncytial virus (RSV; n = 15), rotavirus (n = 5), parainfluenza virus (PIV; n = 2), adenovirus (n = 2), and rhinovirus (n = 1).

Prospective surveillance studies – In prospective surveillance studies (ie, studies in which routine viral testing was performed in all neonates admitted to the NICU), reported rates of detection vary considerably [3-6]. Some studies reported that as many as 30 to 50 percent of neonates were found to have a viral infection at some point during the NICU stay [3,5], while other studies reported rates as low as 3 to 7 percent [4,6]. The variability in these estimates may be accounted for by differences in the screening protocol (eg, frequency of testing, type of test) and variation in infection control practices in the individual NICUs.

Frequency of viral infections among neonates undergoing sepsis evaluation – Prospective data demonstrate that viral infections are identified in 6 to 10 percent of neonates undergoing evaluation for suspected sepsis [7,8]. In a prospective study of 100 neonates who underwent sepsis evaluation between 2012 and 2013, a respiratory viral infection was identified in 6 percent [7]. Viruses detected included enterovirus (n=2), rhinovirus (n = 2), rhinovirus (n = 4), coronaviruses (n = 2), and PIV (n = 3). Some neonates had more than one viral pathogen identified.

Outbreaks – Outbreaks of viral infections in NICUs are not uncommon. In an analysis of a worldwide database of health care-associated outbreaks, approximately two-thirds of reported neonatal viral outbreaks occurred in NICUs [9]. The viruses that most commonly caused outbreaks were rotavirus (23 percent), RSV (18 percent), and enterovirus (16 percent).

Transmission — Neonatal nosocomial viral infections are generally dependent upon the following methods of viral transmission:

Droplet spread from the respiratory tract of infected adults or infants

Carriage of the organism from the hands of hospital personnel from infected individuals

Contaminated medical equipment or supplies including blood products, which can transmit cytomegalovirus (CMV), hepatitis B and C, and HIV

Breast milk from infected mothers may transmit CMV, HIV, herpes simplex virus, and human T cell lymphotropic virus type 1 and 2

Of note, HIV, hepatitis B and C, CMV, herpes simplex virus, varicella zoster, parvovirus, and rubella can be transmitted vertically from an infected mother either in utero or during delivery, as discussed separately. (See "Diagnostic testing for HIV infection in infants and children younger than 18 months" and "Hepatitis viruses and the newborn: Clinical manifestations and treatment" and "Overview of cytomegalovirus infections in children" and "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Epidemiology and transmission' and "Varicella-zoster infection in the newborn" and "Parvovirus B19 infection during pregnancy", section on 'Maternal-fetal effects' and "Congenital rubella".)

ETIOLOGY AND CLINICAL MANIFESTATIONS — A large number of viral pathogens cause infections in patients admitted to the NICU. These can categorized according to the type of illness they typically cause:

Respiratory disease – Viruses that commonly cause neonatal respiratory disease include respiratory syncytial virus (RSV), parainfluenza virus (PIV), influenza, adenovirus, rhinovirus, and coronavirus. The clinical manifestations of these viruses vary, ranging from mild upper respiratory tract disease (ie, coughing, rhinorrhea, or sneezing) to severe lower respiratory tract disease (eg, pneumonia), which may require mechanical ventilation. In some cases, these viruses will present as a sepsis-like illness, which may result in significant morbidity and mortality. (See 'Respiratory viruses' below.)

Gastrointestinal disease – Rotavirus is the primary viral pathogen that causes gastroenteritis in the newborn. Enterovirus and adenovirus are less frequently reported causes of neonatal enteric infections. Infected infants may be asymptomatic or have varying clinical manifestations that range from increased stool frequency to watery, hemorrhagic diarrhea. Serious complications including necrotizing enterocolitis (NEC) may occur. (See 'Gastrointestinal viruses' below.)

Systemic disease – Enterovirus and parechovirus may present as a severe and fulminant sepsis-like illness or as meningitis/encephalitis. (See 'Sepsis-like illness and meningitis/encephalitis' below.)

The neonatal clinical manifestations of the more common viruses will be reviewed here. For each of these viruses, a more extensive discussion of the clinical manifestations in older patients, diagnosis, microbiology, and treatment is found separately.

Respiratory viruses

Respiratory syncytial virus — RSV is one of the most common respiratory infections in the neonate [2,10,11]. It is a single-stranded, negative-sense RNA virus and a member of the Paramyxoviridae family. Two subtypes, A and B, are simultaneously present in most outbreaks, with subtype A typically causing more severe disease. (See "Respiratory syncytial virus infection: Clinical features and diagnosis", section on 'Microbiology'.)

The neonatal clinical manifestations vary from mild upper respiratory symptoms of rhinorrhea, congestion, and cough to severe lower tract disease, including pneumonia, that may require mechanical ventilation or result in death [10,12,13].

In the previously mentioned retrospective study, 15 neonates acquired RSV after admission to the NICU, of whom the majority were preterm infants. The median age of onset of symptoms was 21 days of age, and 12 of the infants required mechanical ventilation [2]. Smaller case series have reported similar outcomes of increased risk of severe respiratory disease in preterm infants, generally requiring mechanical ventilation [10,12-14].

Isolated outbreaks of RSV have been reported in the NICU setting, which do not appear to correspond with the seasonal variation of RSV seen in the community [10,12-15]. In one report, concurrent outbreaks of RSV and echovirus 7 infections occurred [16].

Transmission of RSV is primarily by inoculation of nasopharyngeal or ocular mucous membranes after contact with virus-containing secretions or fomites. RSV can survive for several hours on the hands and fomites. Hand washing and contact precautions are therefore important measures to prevent nosocomial RSV infection [10]. Prompt diagnosis of RSV by rapid diagnostic immunofluorescent testing can allow implementation of infection control measures to prevent further spread of RSV in the NICU [10,15]. (See "Respiratory syncytial virus infection: Clinical features and diagnosis", section on 'Transmission and incubation period' and "Respiratory syncytial virus infection: Clinical features and diagnosis", section on 'Diagnosis'.)

After discharge, infants with a history of prematurity, congenital heart disease, chronic lung disease or bronchopulmonary disease, and/or immunodeficiencies are at increased risk of developing severe RSV infections (ie, lower respiratory tract disease) and should receive immunoprophylaxis. This issue is discussed separately. (See "Respiratory syncytial virus infection: Prevention in infants and children", section on 'Palivizumab immunoprophylaxis'.)

Parainfluenza virus — Both sporadic cases and outbreaks of PIV have been reported in infants cared for in the NICU [2,17-19]. PIV is a single-stranded, enveloped RNA virus belonging to the genus Paramyxovirus in the Paramyxoviridae family. Although there are four major serologic types that cause disease in humans, parainfluenza type 3 is the type most often implicated in neonatal nosocomial infection [17,18,20-23]. It closely mimics RSV in clinical manifestations and is the second most common viral cause of pneumonia and bronchiolitis in infants and young children. (See "Parainfluenza viruses in children", section on 'Clinical presentation'.)

The clinical manifestations are based upon reports of parainfluenza type 3 outbreaks that have occurred in NICUs as well as intermediate care and normal nursery settings. They vary from mild upper respiratory tract symptoms (cough and coryza) to severe lower respiratory tract disease and apnea [17,18,20]. Preterm infants have an atypical course and often present with recurrent apneic episode, sepsis-like illness, or unexplained worsening of bronchopulmonary dysplasia with an increasing oxygen requirement and wheezing [17,22]. Newborn infants with severe lower respiratory tract disease may also require mechanical ventilation [17,20,21]. PIV type 3 infection prolongs the duration of oxygen requirement in preterm infants with bronchopulmonary dysplasia and the length of hospitalization [24].

A concomitant outbreak of PIV type 3 and RSV was reported in one newborn nursery that affected 20 of 34 infants over a three-week time period [20]. In 14 of the 20 symptomatic infants, RSV alone was isolated in seven patients, PIV type 3 alone in five, and both viruses in two. There were no differences in symptoms (which included rhinorrhea, cough, apnea, pneumonia, and fever) among the three groups of infants.

The epidemiology, pathogenesis, and clinical manifestations in older infants and children with parainfluenza viral infection are discussed in greater detail separately. (See "Parainfluenza viruses in children", section on 'Clinical presentation'.)

Influenza virus — Influenza viruses are orthomyxoviruses with three types (A, B, and C). Influenza virus type A has been reported as a cause of nosocomial respiratory infection in outbreaks in the NICU [25-30].

In neonates, the clinical manifestations of influenza type A generally present with mild to moderate signs and symptoms that are primarily due to upper rather than lower respiratory tract disease [25-29]. Other findings may include apnea, fever, and gastrointestinal symptoms.

Clinical findings are illustrated in a large case series of 30 neonates with nosocomial influenza A infection identified from a cohort of 95 newborns during two outbreaks of influenza A in a Spanish NICU [27]. Patients were detected by a positive indirect immunofluorescence antibody screen of nasopharyngeal secretions. The following findings were noted:

Clinical symptoms were noted in 22 infants, and eight were asymptomatic. Twenty-eight of the patients were preterm, and, in 14 patients, the gestational age was less than 32 weeks.

Respiratory symptoms were seen in 19 patients. Mild upper respiratory symptoms (cough, sneezing, and rhinorrhea) were seen in eight patients that remitted in two to three days. Eleven patients had mild respiratory distress that required supplementary oxygen or an increase in oxygen concentration. In these patients, the mean duration of symptoms was eight days (range 3 to 10 days).

Four patients had gastrointestinal findings, which included poor feeding, vomiting, and/or abdominal distension. There was no evidence of NEC.

There were no deaths or long-term complications related to the infection.

Infants who developed infections had lower birth weight and shorter gestational age than did the noninfected group.

Two parents and one nurse were identified as possible sources of the outbreak.

Rhinovirus — Rhinovirus can cause severe respiratory symptoms in preterm infants [31-33]. A prospective study from an Austrian neonatal care facility identified rhinovirus as the causative viral pathogen for suspected respiratory infection in 16 of 106 preterm infants who were screened for viral infection by polymerase chain reaction [32]. Other viruses included in the screening were influenza A and B, influenza H1N1, RSV, human metapneumovirus (hMPV), and adenovirus. Clinical findings of the infants with rhinoviral infection were nasal discharge, congestion, and increased work of breathing. Twelve patients received respiratory support (ie, supplemental oxygen, nasal continuous positive airway pressure, or mechanical ventilation). (See "Epidemiology, clinical manifestations, and pathogenesis of rhinovirus infections".)

Adenovirus — Adenoviruses are double-stranded DNA viruses with over 50 serotypes that cause disease in humans. Adenoviruses cause 5 to 10 percent of all febrile illnesses in infants and young children. Most individuals have serologic evidence of a prior adenoviral infection by the age of 10 years. (See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection".)

Outbreaks of adenovirus infection in the NICU have been reported that present with either new or worsening respiratory disease or keratoconjunctivitis. In one reported NICU outbreak of adenovirus type 8, 7 of 11 infected neonates had onset of new respiratory symptoms or required increased respiratory support [34]. Two patients had conjunctivitis.

In another report, 21 of 333 infants cared for in a NICU were infected with adenovirus type 30, of whom seven developed pneumonia, seven developed conjunctivitis, one had both pneumonia and conjunctivitis, another had only upper respiratory symptoms, and five were asymptomatic [35]. Six patients died. Patients with severe bronchopulmonary dysplasia requiring mechanical ventilation were more likely to develop pneumonia and die.

Other outbreaks have reported only eye involvement [36,37].

Other respiratory viruses

Coronavirus – Coronaviruses are large, enveloped, positive-stranded RNA viruses whose name is derived from their characteristic crown-like appearance in electron micrographs. Coronaviruses are important human pathogens and are associated with up to one-third of community-acquired upper respiratory infections. (See "Coronaviruses".)

In a prospective study of 40 infants in a NICU, immunofluorescence antibody screening of tracheal or nasopharyngeal specimens for viral infections was positive for coronavirus, influenza, and adenovirus in 10, 2, and 1 samples, respectively [38]. Symptoms in patients infected with coronavirus included bradycardia, apnea, hypoxia, fever, or abdominal distension. In two cases, chest radiography demonstrated diffuse infiltrates. The authors concluded that testing for coronavirus should be included in infants with respiratory symptoms because this virus appears to be a common cause of neonatal nosocomial infections.

hMPV – Since its discovery in 2001, hMPV has been shown to be a frequent and important cause of respiratory infection in children. However, there are few reports of nosocomial hMPV infection in the NICU setting [39]. (See "Human metapneumovirus infections".)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – Neonatal SARS-CoV-2 infection has been described [40]. Most of the reported cases have been community-acquired, though vertical transmission can occur [40]. The risk of nosocomial infection appears to be low if appropriate infection control measures are used [41]. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

The evaluation and management of neonates born to mothers with suspected or confirmed COVID-19 are discussed separately. (See "COVID-19: Intrapartum and postpartum issues", section on 'Care of newborns of infected mothers'.)

Gastrointestinal viruses — Rotavirus is responsible for the vast majority of viral nosocomial gastrointestinal infections in the newborn [1]. Other viruses that commonly cause gastroenteritis in other settings (eg, enterovirus, adenovirus, and norovirus) rarely cause nosocomial viral gastroenteritis in the NICU [34,35,42-44].

Enteric viruses are spread rapidly among hospitalized infants generally via the fecal-oral route. The principal mode of transmission is through health care workers, contaminated equipment, and/or fomites [45,46].

Rotavirus — Rotavirus is a double-stranded RNA virus, which belongs to the Reoviridae family. It is the primary viral pathogen that causes nosocomial gastroenteritis in the neonate. In the previously mentioned survey by the National Nosocomial Infections Surveillance System, rotavirus was isolated in 96 percent of cases of viral enteric infections of infants cared for in high-risk nurseries [1]. Neonatal rotavirus infection has been reported as a frequent occurrence worldwide. The incidence of detected virus is particularly high in developing countries. As an example, the reported incidence of rotavirus in Indian nurseries ranged from 43 to 78 percent [47,48].

The incidence of neonatal rotavirus infection increases when the virus is epidemic in the community. This was illustrated in one study that demonstrated an increase in the rate of rotavirus detected in stools from 11 percent at baseline to 21 percent during periods of community epidemics [49].

In the neonate, rotavirus infection is often mild or asymptomatic [46,48,50,51]. Gastrointestinal symptoms range from increased frequency of stools [49] to watery, mucoid, and/or hemorrhagic diarrhea [52]. Other findings include the presence of gastric residuals, abdominal distention, intestinal dilation, ileus, and emesis [51]. In severe cases of infection, dehydration, electrolyte abnormalities, and acidosis may occur [45]. Reported complications include NEC, bowel perforation, and death [50,52-55]. Although preterm infants and those with immunodeficiencies are at increased risk for severe disease and complications [56], NEC has been linked to rotavirus infections in otherwise healthy term infants [57,58].

Transplacental antibody from previously infected mothers appears to provide some protection to the neonate. This may contribute to the mild or asymptomatic presentation of infected infants who are identified by positive antigen screening of their stools. Preterm infants are at the greatest risk of severe infection because of the decrease in maternal antibody transmission [59-61]. Recurrent infections are usually mild or asymptomatic because of protective immunity following the initial infection. Infected infants who are fed human milk tend to have milder disease compared with formula-fed infants [62-64]. In one study, none of the breastfed infants who contracted rotavirus developed symptomatic diarrheal illness [62].

Rotavirus vaccination is highly effective in preventing rotavirus gastroenteritis and can be given to premature infants who are clinically stable, at least six weeks old, and are going to be or have been discharged from the nursery. This is discussed separately. (See "Rotavirus vaccines for infants", section on 'Preterm infants'.)

Sepsis-like illness and meningitis/encephalitis

Enterovirus — Some enterovirus serotypes produce a fulminant, sepsis-like illness and/or meningitis/encephalitis in the newborn infant that may be fatal. In a single-center study, 20 cases of enteroviral infection were identified among 5396 neonates admitted to the NICU [2]. All cases were severe, presenting with a sepsis-like illness, and there was a high rate of mortality (10 percent) and morbidity, including poor neurodevelopmental outcome and heart or liver failure. Early intravenous immune globulin therapy may be beneficial in severe neonatal enteroviral infections [65]. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Neonates'.)

Parechovirus — The human parechoviruses (HPeVs) belong to the Picornaviridae family. They share many of the same biologic, clinical, and epidemiologic characteristics with the enteroviruses but differ sufficiently in genomic sequence to be classified as a separate genus. Among the growing number of genotypes identified, HPeV-3 appears to cause severe illness, especially in young infants (eg, sepsis, meningitis, encephalitis) [66-68]. However, parechoviruses are also found in the central nervous system (CNS) without CNS symptoms or pleocytosis. A characteristic rash on the palms and soles (picture 1) can help distinguish HPeV infection from other systemic infections in neonates [69]. In a prospective study of 84 neonates undergoing evaluation for suspected late-onset sepsis, HPeV was detected in 13 percent [66].

Making the diagnosis of HPeV might prevent unnecessary antibiotic therapy and shorten hospital stay; however, commercially available methods for rapid laboratory diagnosis of HPeV are lacking. Real-time polymerase chain reaction testing (of the stool, respiratory secretions, cerebrospinal fluid, or blood) is the most sensitive method to diagnose HPeV and is available through the Centers for Disease Control and Prevention.

A more complete description of neonatal enterovirus and parechovirus infections is discussed separately. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Neonates'.)

Cytomegalovirus — Early postnatal cytomegalovirus (CMV) infection can occur from breast milk ingestion or from blood transfusions. Preterm infants and infants with very low birth weight (birth weight <1500 g) are especially vulnerable to severe CMV disease. A sepsis-like syndrome can occur with associated hepatosplenomegaly, pneumonitis, and abnormalities of blood counts (including lymphopenia, neutropenia, and/or thrombocytopenia) and liver function tests.

Preventive measures to reduce transmission of CMV to neonates include:

Use of CMV-seronegative or leukocyte-reduced blood for extremely preterm infants

Treatment of maternal breast milk by freezing/thawing or pasteurization

Early postnatal CMV infection in neonates is discussed in greater detail separately. (See "Overview of cytomegalovirus infections in children", section on 'Early postnatal infection'.)

SUMMARY

Nosocomial viral infections are reported to occur in 1 percent of all infants admitted to the neonatal intensive care unit (NICU), resulting in significant neonatal morbidity and mortality. However, this is likely an underestimation since most NICUs do not routinely screen for viral infections. (See 'Epidemiology' above.)

Neonatal nosocomial viral infections are primarily dependent upon transmission of the organisms through droplet spread, direct transmission of the organism from infected adults or the contaminated hands of health care providers, or contaminated medical equipment or supplies. (See 'Transmission' above.)

Viral pathogens that cause infections in neonates can be categorized according to the type of illness they typically present with (see 'Etiology and clinical manifestations' above):

Respiratory illness – Viruses that cause neonatal respiratory disease include respiratory syncytial virus (RSV; the most common of the respiratory viruses), parainfluenza virus (PIV), influenza virus, adenovirus, and coronavirus. The clinical manifestations of neonatal viral respiratory infections range from mild upper respiratory illness (ie, coughing, rhinorrhea, or sneezing) to severe lower respiratory tract disease, which may require mechanical ventilation. In some cases, these viruses will present as a sepsis-like syndrome. Preterm infants are at increased risk for severe respiratory illness. Infants with respiratory failure or systemic disease are more likely to have significant morbidity and mortality. (See 'Respiratory viruses' above.)

Gastrointestinal illness – Rotavirus is responsible for most nosocomial viral enteric infections in the newborn. Neonatal rotavirus infection is often mild or asymptomatic. Gastrointestinal symptoms range from increased frequency of stools to watery, mucoid, and/or hemorrhagic diarrhea. Preterm and immunodeficient infants are more likely to have severe disease and complications, such as intestinal dilation, ileus, fluid and electrolyte abnormalities, acidosis, necrotizing enterocolitis (NEC), bowel perforation, and death. (See 'Gastrointestinal viruses' above.)

Sepsis-like illness – Enterovirus and parechovirus infections may produce a fulminant, sepsis-like illness and/or meningitis/encephalitis in the newborn infant that is frequently fatal. (See 'Enterovirus' above and 'Parechovirus' above and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Neonates'.)

Postnatal cytomegalovirus (CMV) infection can occur from breast milk ingestion or from blood transfusions. Preterm infants and infants with very low birth weight (birth weight <1500 g) are especially vulnerable to severe CMV disease. A sepsis-like syndrome can occur with associated hepatosplenomegaly, pneumonitis, and abnormalities of blood counts (including lymphopenia, neutropenia, and/or thrombocytopenia) and liver function tests. (See 'Cytomegalovirus' above and "Overview of cytomegalovirus infections in children", section on 'Early postnatal infection'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jenny L Ravenscroft, MD, who contributed to an earlier version of this topic review.

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