Infection control in paediatrics by JOSE LUIS CONSTANTINO

Review

Infection control in paediatrics Klara M Posfay-Barbe, Danielle M Zerr, Didier Pittet

Infection control has a particularly important role in paediatric hospitals and must take into account the specificity of the needs and environment of the paediatric patient. Children are susceptible to infections that are prevented in older patients by vaccination or previous natural exposure. Consequently, the nosocomial pathogens and most common health-care-associated infection sites in children differ from those observed among adults. The immunological naivety of young children, especially neonates, translates into an enhanced susceptibility to many infections with important health consequences as well as higher rates and longer duration of microorganism shedding. In particular, respiratory virus infections, rotavirus, varicella zoster virus, and pertussis represent persistent challenges in children’s hospitals. Specific factors such as the use of breastmilk, toys, or therapy animals are associated with an increased risk for health-care-associated infections. We review the emergence of antimicrobial-resistant organisms and strategies to prevent health-care-associated infections in the paediatric setting.

Introduction The history of infection control is closely linked to the paediatric population. Ignácz Semmelweis not only made the association between hand hygiene and puerperal fever in women, but also noted its relation with perinatal infection rates.1 In response to the high incidence of infectious diseases on paediatric wards over the past century, several infection control measures have been implemented and tested in child-care settings before application to adult environments.2 In both adults and children, certain patients are particularly at risk of health-care-associated infections (HAI); among these are neutropenic patients and those in intensive care with indwelling devices. Other risk factors for HAI, such as close physical contact with health-care workers or stay in environments where antibiotic-resistant organisms are endemic, are common to adult and paediatric patients. Because of young age and the immaturity of their immune systems (figure 1), children are susceptible to infections that are prevented in older patients through vaccination or a more robust, innate immune response. Therefore, the nosocomial pathogens and most common HAI sites in children differ from those reported among adults. Children have fewer chronic or degenerative organ system disorders than adults,3 but present more often with congenital or acquired immune deficiencies as well as congenital syndromes. Close physical contact between children in communal rooms or play areas, between children and visitors such as parents and siblings, and uncontrolled fluids and bodily secretions also provide ample opportunities for infection spread. Specific aspects of children’s hospitals, such as shared rooms in general paediatric intensive care units (PICUs) instead of separate medical and surgical ICUs as for adults, toy-sharing, pet-visiting, and partial ambulatory care, also contribute to nosocomial infection risk.4 Infection control has a particularly important role in paediatric hospitals and is not a simple transposition of adult recommendations; it must take into account the specificity of the paediatric patients’ needs and environment. This Review addresses issues that characterise infection control in paediatrics with a http://infection.thelancet.com Vol 8 January 2008

particular focus on some important diﬀerences with adults.

Epidemiology Surveillance for HAI in paediatric populations usually depends on institutional or public-health requirements and commitment, and the available resources. Several studies have shown the benefit of surveillance through early detection and intervention during outbreaks, and also identification of centre-specific risk factors for HAI. Most paediatric institutions in developed countries use the US Centers for Disease Control and Prevention (CDC) definitions for nosocomial infections.5 These are generally defined by experts as infections occurring after more than 48 h hospital treatment of a patient who was admitted for a problem likely not related to the microbial pathogen. However, these definitions have been developed for the adult population and their adaptation for use in the paediatric setting is needed.6,7 For example, bloodstream infection requires either hyperthermia or hypothermia as a diagnostic criterion, but in neonatology where patients are often artificially controlled thermically through the

Lancet Infect Dis 2008; 8: 19–31 Children’s Hospital of Geneva, University of Geneva Hospitals, Geneva, Switzerland (K M Posfay-Barbe MD); Department of Pediatrics, Children’s Hospital and Regional Medical Center, Seattle, WA, USA (Prof D M Zerr MD); and Infection Control Programme, University of Geneva Hospitals and Faculty of Medicine, Geneva, Switzerland (Prof D Pittet MD) Correspondence to: Prof Didier Pittet, Infection Control Programme, University of Geneva Hospitals and Faculty of Medicine, 24 Rue Micheli-duCrest, 1211 Geneva 14, Switzerland. Tel +41 22 372 9828; fax +41 22 372 3987; didier.pittet@hcuge.ch

Figure 1: Neonate in intensive care unit

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incubator environment, temperature instabilities are seen.8 New definitions for pneumonia in children under 1 year of age include temperature instability with no other recognised cause as a criterion.9 Paediatric-specific definitions by Gastmeier and colleagues10 for central-line-associated primary bloodstream infection and

ventilator-associated pneumonia combine clinical findings with haematological and microbiological results. At present, there are no widely accepted definitions for health-care-associated viral infections. Some research studies required a negative sample on the first day of hospital admission to define nosocomial acquisition.

Study

Country

Type of unit

Age-range

Type of study Overall infection rate

Bloodstream infections

Pulmonary infections

Gray (2004)17

Paediatric hospital

Median 2 years (mean 4·2 years)

Prospective surveillance

7·1 per 1000 admissions

Muhlemann et al (2004)18

Switzerland

Seven paediatric Neonates to hospitals 18 years old

Prevalence survey

6·7% (range 1·4–11·8)

2·5 per 100 patients

Urrea et al (2004)19

Spain

Haematology/ oncology

Mean 8·2 years (SD 5·2)

Prospective surveillance

23·5%; 1·77 per 100 patient-days; 55·5% 13·3 per 100 admissions

5·5%

Urrea et al (2005)20

Spain

Trauma

Mean 10·6 years (SD 5·0)

Prospective surveillance

33%; 1·1 per 100 patient-days; 9·9 per 100 admissions

32 per 1000 CVC-days

16 per 1000 ventilator-days

Urrea et al (2003)16

Spain

NICU

0–28 days of age

Observational 24·2% prospective

56·8%

10·2%

Urrea et al (2003)21

Spain

PICU

Mean 7·5 years (SD 6·1)

Observational 15.1%; 1·5 per 100 patient-days prospective

51·7%

19%

Simon et al (2000)22

Germany

Haematologyoncology

0–19 years

Prospective surveillance

10·8 per 1000 patient-days

7·4 per 1000 CVC-days

Gastmeier et al (2002)23

Germany

Burn unit

Mean 3·8 years (range 0 years to <14 years)

Prospective cohort

59·7 per 1000 patient-days

8·9 per 1000 CVC-days

55·2 per 1000 ventilator-days

Van der Zwet et al (2005)8

Netherlands NICU

Neonates (ages not Prospective speciﬁed) surveillance

26% neonates infected; 28·6 per 1000 patient-days

14·9 (range 12·5–17·4) per 1000 patient-days

7·5 (5·7–9·2) per 1000 patientdays; or 6·3 patients with pneumonia per 1000 patient-days

Almuneef et al (2004)24

Saudi Arabia

PICU

Neonates until 12 years old

Prospective surveillance

20·06 per 1000 CVC-days

8·87 per 1000 ventilator-days

Frank et al (2005)25

Israel

Paediatric hospital

1 month to 18 years

Prospective surveillance

5·3 per 1000 patients

Wisplinghoﬀ et al (2003)26

USA

49 paediatric hospitals

Mean 2 years (range 0–24 years)

Prospective surveillance

Primary: 62% of all HAI; secondary (catheter-related): 23%

NNIS (2004)27 USA

>50 paediatric hospitals

Children (ages not speciﬁed)

Prospective surveillance

6·6 pooled mean*

2·9 pooled mean†

Stover et al (2001)28

USA

NICU, PICU (50 paediatric hospitals)

Neonates to 18 years

Retrospective study

NICU: 8·9 (range 4·6–18·1) per 1000 patient-days; PICU: 13·9 (range 1·1–31·4) per 1000 patient-days

NICU: 8·6 (range 0–16·2) per 1000 CVC-days; PICU: 8·5 (range 0–18·5) per 1000 CVC-days

NICU: 2·5 (range 0–18·1) per 1000 ventilator-days; PICU: 3·7 (range 0–10·1) per 1000 ventilator-days

Yogaraj et al (2002)29

USA

Paediatric hospital

Mean 5·5 years (range 0·18 years)

Prospective cohort

13·8 per 1000 CVC-days

Lopes et al (2002)30

Brazil

Paediatric hospital

Children (ages not speciﬁed)

Prospective surveillance

8·9 per 1000 patient-days; Laboratory-conﬁrmed: 4·4% of PICU: 16·4 per 1000 patient-days all infections; clinical sepsis: 3·8% of all infections

PICU: 6·3 per 1000 ventilatordays

Pessoa-Silva et al (2004)31

Brazil

Seven NICUs

Neonates (ages not Prospective speciﬁed) surveillance

24·9 per 1000 patient-days

Range 17·3–34·9 per 1000 CVCdays

Range 7–9·2 per 1000 ventilatordays

Tullu et al (2000)32

India

PICU

Mean 2·95 (range 1 month to 11 years)

Prospective surveillance

32·20%; 89·2 per 1000 ventilator days; 36·5 per 1000 patient-days

Deep et al (2004)33

India

PICU

Mean 3·83 years

Prospective surveillance

27·3%; 162 per 1000 patientdays

10·52% of all HAI

Duerink et al (2006)34

Indonesia

General hospital 0–87 years old

Crosssectional

13·9%

Tseng et al (2002)35

Taiwan

NICU

4·4 per 1000 patient-days

Neonates (ages not Retrospective speciﬁed) study

Data on overall infection rate, bloodstream infections, and pulmonary infections are reported here in the format used in each original study. ..=not reported. CVC=central venous catheter. HAI=health-careassociated infection. NICU=neonatal intensive care unit. PICU=paediatric intensive care unit. *Pooled mean calculated by (number of central-line associated bloodstream infections/number of central-linedays)×1000.†Pooled mean calculated by (number of ventilator-associated pneumonia/number ventilator-days)×1000.

Table 1: Health-care-associated infection in paediatrics: overall, bloodstream, and pulmonary infections

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40 Bloodstream infection Pneumonia Urinary tract infection Lower respiratory tract infection (other than pneumonia)

Percentage of nosocomial infections (%)

35 30

Surgical site infection Eye, ear, nose, or throat infection Others*

25 20 15 10 5 0 ≤2 months (n=1145)

>2 months to ≤5 years (n=3482)

>5 years to ≤12 years (n=935)

>12 years (n=728)

Figure 2: Site distribution of health-care-associated infections in paediatric intensive care units by age-group *Refers to gastrointestinal infection, skin or soft tissue infection, cardiovascular infection, miscellaneous infections. Adapted from reference 3.

80 Gram-positive Gram-negative

70 Percentage of bloodstream infections (%)

However, we do not believe that this is routine practice in clinical settings. Initial negative laboratory sample in a non-research setting is also very costly and incomplete since most laboratories can only detect a small number of viruses on one sample. For this reason, it is currently not recommended routinely. CDC recommendations to monitor the incidence and distribution of HAI include: (1) prospective surveillance on a regular basis by a trained infection control professional; (2) regular analysis of HAI rates; (3) use of data for decision-making; and (4) availability of a hospital epidemiologist for infection control strategies and policies. However, because of relatively low rates of HAI and the smaller size of paediatric hospitals, many institutions prefer to report incidence rates together with other paediatric centres. The accuracy of reported data varies by infection site and according to the efforts made for surveillance and data collection. To our knowledge, no major study has been done on the incidence and distribution of HAI in a paediatric setting.11 In the USA, the National Association of Children’s Hospitals and Related Institutions (NACHRI) established a Paediatric Prevention Network in partnership with the CDC. This network groups 194 children’s hospitals and focuses on data collection for specific infections.12,13 In 2006, one of the NACHRI studies, entitled the Eradicating Catheter-associated Bloodstream Infections Initiative, set a goal to decrease bloodstream infection rates in 27 participating hospitals. Results showed a 41% decrease in catheter-related bloodstream infection rates. A new phase with more centres is about to begin. Other large groups, such as the US National Nosocomial Infections Surveillance (NNIS) system, also include paediatric subdivisions. Currently, more than 65 US PICUs share HAI data with NNIS. The UK Neonatal Staffing Study Group includes 54 randomly selected neonatal ICUs (NICUs) and measures nosocomial bloodstream infection rates.14 Created in 1996, the German nosocomial infection surveillance system also includes paediatric patients.15 Since 1999, the Spanish Programme for Surveillance of Nosocomial Infections has recorded data from over 100 hospitals, but does not use specific paediatric definitions for intrinsic risk factors.16 In recent years, several groups around the world have reported HAI rates using CDC definitions (see table 1). Some share in-house policies focusing on particular patient categories, such as PICU, NICU, or surgical patients,3,36,37 or restrict surveillance to outbreaks only,38,39 whereas others prefer to undertake country-wide prevalence surveys,18 or focus on specific infections or individual pathogens.18,29,40 Very little information is available on the incidence of HAIs in developing countries.31,41–43 In India, information on neonatal infections is collected prospectively.44 In 2000, the National Neonatal Perinatal Database reported an incidence of 38 episodes of HAI per 1000 live births, which is probably an underestimate of the true rate.

Fungi Other

60 50 40 30 20 10 0 Overall

NICU

<1 year

1–5 years

>5 years

Figure 3: Distribution of bloodstream infection pathogens by age NICU=neonatal intensive care unit. Adapted from reference 47.

Infection control activities are challenging to implement in developing countries where resources are limited; however, the importance of these activities for patient safety and ultimately resource savings have been well documented.41,45,46

Different pathogens, different infections HAIs among children differ from those seen among adults in several respects. Site and pathogen distribution vary according to age-group and setting (figure 2 and figure 3). Of note, the type of predominant pathogen in the neonatal setting has changed over time. Gram-negative organisms are major contributors to HAI in developing countries (figure 4).24,35,41,48 By contrast, particularly in neonates,3,49 the

For more information on the National Association of Children’s Hospitals and Related Institutions (NACHRI) see http:// www.childrenshospitals.net For more information on NACHRI’s Eradicating Catheterassociated Bloodstream Infections Initiative see http:// www.childrenshospitals.net/AM/ Template.cfm?Section=Blood_ Stream_Infections_Project For more information on the Spanish Programme for Surveillance of Nosocomial Infections see http://www. mpsp.org

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young, encounter common pathogens such as respiratory syncytial virus (RSV) and rotavirus, it is often their first encounter. This immunological naivety not only affects the likelihood of infection but it can also affect the severity of infection and duration of microorganism shedding. Beyond naivety, the immune system of the infant, especially the premature infant, has limitations of both innate and adaptive immunity.59 Finally, normal child development, in terms of behavioural and emotional needs, affects the risk of infection in important ways, which we discuss in more detail later.

70 Gram-positive Gram-negative

Percentage of nosocomial infections (%)

Fungi Other

Eﬀect of infection on length of stay, morbidity, and mortality

0 HAI NICU

HAI PICU

HAI NICU in developing countries

Figure 4: Distribution of pathogens in health-care-associated infections in diﬀerent settings HAI=health-care-associated infection. NICU=neonatal intensive care unit. PICU=paediatric intensive care unit. Adapted from references 20, 32, 41, and 42.

proportion of infections caused by coagulase-negative staphylococci has increased substantially in developed countries over the past two decades, mostly because of an increase in the incidence of bloodstream infection and the improved survival of infants with very low birthweight.50 Candidal infections have also increased notably in all infection sites and Candida spp have become major pathogens among immunocompromised and critically ill children, including premature infants.25,26,47,51–54 Rates of ventilator-associated pneumonia and catheter-associated urinary tract infections are lower in PICUs than in adult medical ICUs: 21% versus 27%, and 15% versus 31%, respectively.3 One risk factor for these infections in neonatal settings is birthweight: the smaller the infant, the higher the risk (figure 5). However, as estimated by the number of (umbilical and) central line-associated bloodstream infection episodes divided by the number of (umbilical and) central-line days, the incidence of line-associated bloodstream infection is higher in children than in adults (pooled mean 7·3 vs 3·1, respectively).3 Of interest, device use in PICUs is similar to that in adult ICUs,3 apart from a less frequent use of urinary catheters. Finally, it should be emphasised that viral infections, particularly common causes of transmissible infections in children, are most certainly under-reported because appropriate cultures are not done and infections are poorly identified or not identified at all.55–58

Risk factors for infection Paediatric and adult patients share common risk factors for HAIs, including exposure to intravascular devices, hyperalimentation, mechanical ventilation, and comorbidities, such as immune-compromising conditions. There are, however, additional risk factors inherent to children. When children, especially the 22

As in adult medicine, the cost and impact of paediatric HAI depends largely on the type of infection and the patient’s underlying condition. In general, bloodstream infection carries the highest morbidity and mortality and neonates are the age-group at highest risk for poor outcome (table 2). For example, whereas bloodstream infection has an estimated attributable mortality of 3% in paediatric patients,17 the estimate is 11% among neonates with very low birthweight: crude mortality was 18% in infected cases versus 7% in uninfected controls.64 Crude mortality was even higher in babies infected with Gram-negative organisms (36%) or fungi (32%).66 Candidaemia results in prolonged hospital stay in children under 5 years old—as much as 23–25 days longer than controls.66 Furthermore, extremely low birthweight infants with systemic Candida spp infections (sepsis or meningoencephalitis) had higher rates of chronic lung disease, periventricular leucomalacia, severe retinopathy of prematurity, and adverse neurological outcomes than uninfected controls.69

Special microorganisms Certain organisms have a special role in paediatric infection control, either because they induce more pronounced disease in children or because of issues around acquisition and transmission. For example, children are often admitted to hospital with infections causing community epidemics such as respiratory and gastrointestinal viral infections.70 As a result, the hospitalised child serves as a potential source for the nosocomial transmission of typically community-associated pathogens in the setting of a highly susceptible patient population.

Respiratory virus infections Because of immunological naivety, young children are highly susceptible to respiratory viral infections. These infections have the ability to cause substantial morbidity and mortality, especially among premature infants and children with chronic cardiac or pulmonary conditions. Outbreaks of respiratory viruses in the NICU are frequently reported and attack rates over 30% have been documented in this setting.71–74 Mortality rates can also be very high; during an outbreak of infections caused by adenovirus, six http://infection.thelancet.com Vol 8 January 2008

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Rotavirus is a leading cause of nosocomial gastroenteritis in children.77 Prospective studies of hospitalised children have shown nosocomial infection rates as high as 27%.40 Such high rates are likely caused by the fact that patients with rotavirus gastroenteritis excrete high amounts of the virus in stools, and because the virus is capable of surviving on hands and surfaces for long periods of time. Thus, both the environment and the hands of health-care workers have the potential to become contaminated and serve as reservoirs for the virus. Health-care workers may also exhibit asymptomatic excretion of rotavirus, which was associated with HAI in paediatric patients in a study showing shared serotypes between health-care workers and patients.78 Although rotavirus may manifest as an asymptomatic infection, in particular among older children, it can also cause severe infection and even mortality in young children, especially those with comorbidities. A study describing the impact of nosocomial rotavirus infection on paediatric patients estimated the excess length of hospital stay to be 4·9 days.79

Central-line-associated BSI per 1000 central-line-days

Rotavirus

35 30·9

25 20 15 11·0 10

Pertussis Bordetella pertussis is highly contagious and can cause severe disease and mortality in young, under-immunised infants. The incidence of pertussis is increasing in the USA and there have been several reports of hospital outbreaks.82,83 These outbreaks demonstrate that pertussis http://infection.thelancet.com Vol 8 January 2008

4·3

B 25

19·7

14·4

10 7·1 5·8 5

Varicella zoster virus Primary infection with varicella zoster virus (VZV; chicken pox) is historically a childhood disease and for the most part has a benign course. However, VZV can cause severe disease and mortality in immunocompromised populations. Given that the index case is often a child and that children are a highly susceptible population, inadvertent exposures are quite frequent in children’s hospitals. By contrast with household settings where secondary infection of susceptible individuals is almost a certainty, attack rates in hospitals appear to be substantially lower. In one study of 89 exposed susceptible patients, four (4·5%) acquired infection, although 15 patients had received varicella zoster immune globulins.80 It is hoped that varicella vaccine will reduce the opportunities for hospital exposure. However, the breakthrough infection rate of approximately 15% and the resulting possibility of transmission from vaccinated cases81 requires infection control departments to revisit the issue of VZV immunity.

28·7

Ventilator-associated pneumonia per 1000 ventilator-days

of 21 infected infants died.72 The impact of respiratory viruses can also extend outside the NICU. A study in South Africa reported a mortality rate of 13% from health-care-associated RSV among children with comorbidities.75 Nosocomial RSV causes more severe lower respiratory tract infections in children with congenital heart disease compared with those without, as determined by duration of hospital stay and oxygen therapy.76

<1000

1000–1499

1500–2499

>2500

Birthweight (g)

Figure 5: Incidence of invasive infections in neonates by birthweight (A) Incidence of central line-associated bloodstream infection in neonates stratiﬁed by birthweight. (B) Incidence of ventilator-associated pneumonia in neonates stratiﬁed by birthweight. Adapted from reference 8.

can be transmitted between patients and health-care workers, and that hundreds of individuals can be exposed in the hospital setting. A very large investment in infection control resources for contact tracing and antimicrobial prophylaxis to prevent transmission to high-risk patients is therefore required.

Tuberculosis Although children with tuberculosis are less likely to be infectious than adults, transmission from young children has been documented. Additionally, parents and household contacts accompanying the child to the hospital are often the source of a paediatric patient’s tuberculosis. Thus, the approaches recommended for adult patients to prevent tuberculosis transmission in the health-care setting are similarly recommended for children.84 Since parents are often the source of contamination, it is important that they are screened and isolated along with their child until tuberculosis is ruled out to prevent health-care-associated transmission. This point is illustrated by an infant/mother pair with tuberculosis who exposed 16 paediatric patients 23

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development requires close contact with care-givers, including parents and health-care workers, as well as other family members, particularly siblings. This level of contact results in a potentially greater risk of transmission of both health-care-associated and community pathogens. Paediatric populations at higher risk for HAI include patients receiving intensive care, patients with cancer, solid organ transplant and haematopoietic cell transplantation recipients, and neonates. In many ways, these subpopulations are similar to their adult counterparts, with the exception of neonates.

and 293 health-care workers before diagnosis.85 In this event, tuberculin skin test conversion occurred in 6·7% of patients and 1·9% of health-care workers. Congenital tuberculosis is another potential source of health-care-associated transmission. Mouchet and colleagues86 reported the case of a premature infant diagnosed at 102 days of age with congenital tuberculosis. In this case, 97 infants, 139 health-care workers, and 180 visitors were potentially exposed and tuberculin skin test conversions occurred in six (19%) of 32 primary-care nurses and doctors. Although the most frequently reported method in the literature, assessing tuberculosis spread by tuberculin skin test only leads to underestimation. The test is also diﬃcult to interpret in infants previously vaccinated with BCG.

Neonates Neonates in intensive care are highly susceptible to infection and when infection occurs they are less able than older children to contain it. This vulnerability is likely caused by several factors, including a naive and functionally limited immune system, a gastrointestinal tract that intrinsically lacks acidity (a condition worsened by continuous feeding), and fragile, thin, and easily damaged skin (figure 1). Additionally, neonates are born with no protective microbial flora and an abnormal flora that can include potential pathogens is established in the intensive care setting. Neonates are also exposed before

Speciﬁc subpopulations Several issues related mainly to maturation of the immune system and normal child development are very relevant to paediatric infection control. The immunological naivety of children translates into an enhanced susceptibility to many infections with important health consequences as well as higher rates and longer duration of microorganism shedding. Child Study

Country

Population

Attributable length of stay and other morbidity*

Attributable mortality

Mahieu et al (2001)60

Belgium

NICU

24 days

Urrea et al (2003)21

Spain

PICU

Median excess LOS 14 days

Grohskopf et al (2002)61

USA (multicentre) PICU

Median excess LOS 6 days

Age-adjusted risk of death within 4 weeks 3·4 (95% CI 1·7–6·5)

Onen et al (2002)62

Turkey

Surgical

7 days

Gray (2004)17

Tertiary referral centre

Payne et al (2004)63

USA (multicentre) NICU, birthweight 401–1500 g Adjusted mean excess LOS: 4–7 days; crude mean excess LOS: 13–17 days

All infections

Bloodstream infection 3% ..

Stoll et al (2002)64

USA (multicentre) NICU, birthweight 401–1500 g 19 days

11%

Yogaraj et al (2002)29

USA

Fanaroﬀ et al (1998)65

USA (multicentre) NICU, birthweight 501–1500 g

PICU

28 days

40 days; increased frequency: intraventricular 12% haemorrhage, bronchopulmonary dysplasia

Gram-negative bacteraemia Stoll et al (2002)64

USA (multicentre) NICU, birthweight 401–1500 g ..

29%

Candidal or fungal bloodstream infection Morgan et al (2005)66 USA Stoll et al (2002)64

<5 years

Excess LOS 23–25 days

USA (multicentre) NICU, birthweight 401–1500 g ..

25%

Ventilator-associated pneumonia Almuneef et al (2004)24

Saudi Arabia

Apisarnthanarak et al USA (2003)67

Elward et al (2002)68

USA

PICU

19 days

NICU, birthweight ≤2000 g, <28 weeks’ gestation

56 days

Adjusted odds ratio for mortality 3·4 (95% CI 1·2–12·3); for patients hospitalised ≥30 days: attributable mortality 37%

PICU

38 days

13%

..=not reported. LOS=length of stay. NICU=neonatal intensive care unit. PICU=paediatric intensive care unit. *Excess mean length of stay reported unless otherwise stated.

Table 2: Attributable morbidity and mortality of health-care-associated infections in paediatric populations

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birth or during labour to organisms shed by the mother that in other settings have little impact. An unusual example is pneumonia caused by Ureaplasma urealyticum in preterm infants, which is associated with bronchopulmonary dysplasia.87 Finally, like other intensive care populations, neonates undergo invasive procedures that breech natural barriers to infection. As many as 31% of infants who survive more than 48 h in a high-risk nursery acquire an HAI.88 In 1999, the US Paediatric Prevention Network organised a survey to determine the point prevalence of HAI in 29 high-risk nurseries.89 Of the 827 patients involved, 94 (11·4%) had an active nosocomial infection on the day of the survey. Bloodstream and lower respiratory tract infections were the most frequent infections, and coagulase-negative staphylococci were the most common pathogens. Birthweight was identiﬁed as an important risk factor for infection. Importantly, low birthweight increases the risk of bloodstream infections and ventilator-associated pneumonia even after adjusting for exposure to central-line and ventilator use.49 It is likely that birthweight serves as a surrogate marker for the actual determinants of risk, such as immune system immaturity and other comorbidities associated with prematurity. However, birthweight is a readily available and objective means of risk categorisation and experts recommend stratifying by birthweight when analysing infection surveillance, particularly for bloodstream infection. Recently, Schelonka and colleagues90 showed that an infection control intervention consisting mostly of nurse and physician education (in particular, hand hygiene) and improved vascular access care had a sustained impact on coagulase-negative staphylococci infection rates among neonates (46% fall in coagulase-negative staphylococci infection rate, p<0·001). Furthermore, several studies have described the clonal nature of coagulase-negative staphylococci in outbreaks in NICUs. These ﬁndings prove that cross-infection through health-care workers’ hands does occur and that it could be prevented by reinforcing adherence to infection control recommendations.91–94

Immunosuppressed patients Care of paediatric solid organ and stem cell recipients must take into account the increased risk for HAI caused by drug-resistant organisms. An increasing number of transplant centres are becoming endemic for meticillin-resistant Staphylococcus aureus (MRSA), extended-spectrum beta-lactamases (ESBLs), or even vancomycin-resistant enterococci.95–98

Environment As previously discussed, the developmental status of the paediatric patient has a crucial role in HAI acquisition risk. As part of normal development, children interact http://infection.thelancet.com Vol 8 January 2008

Figure 6: Child and toy Toys are associated with an increased risk of health-care-associated infection.

closely with their environment and this poses unique risks for infection. For instance, chewing can present a risk when practised by the babies on dialysis catheters.99 Some speciﬁc paediatric environmental concerns are addressed below.

Emergency departments Emergency departments are often crowded, especially during the winter season when viral respiratory and gastrointestinal pathogens are at their peak. Transmission of microorganisms between patients has been described in this context, particularly viruses such as RSV, rotavirus, and measles.100 Although some level of cohorting in emergency settings and paediatricians’ waiting rooms would be helpful to limit transmission between patients, lack of space, erroneous or tedious diagnostic tools, as well as asymptomatic but infectious carriers, make implementation challenging.

Milk Several studies have shown the value of human breastmilk for infants from both nutritional and infection prevention perspectives. Breastmilk can, however, also be a source of HAI and it has speciﬁcally been linked to bacterial101 and cytomegalovirus infections.102,103 Pumping, collection, and storage of breastmilk create opportunities for bacterial contamination and opportunities for cross-infection if equipment is shared between mothers. To ensure the safety of expressed milk, mothers should be instructed on hygienic methods for collecting milk as well as for the cleaning and disinfection of breast pumps. The alternative to breastmilk is infant formula. Although bottled formulas are sterile, powder formulas are not. Appropriate preparation and storage practices decrease the risk of microorganism proliferation after preparation. After the recall of a product linked to Enterobacter sakazakii 25

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infections, the CDC, the US Food and Drug Administration, and the American Dietetic Association issued updated recommendations on the safe preparation and administration of commercial formula.104

Toys There are several published reports on likely fomite transmission of HAI. Toys are viewed by many as an indispensable component of the environment for hospitalised children (figure 6). Unfortunately, toys frequently become contaminated with potential pathogens; a study showed the presence of coliforms on three (14%) of 22 hard toys and nine (90%) of ten soft toys in a waiting room.105 Using molecular techniques, bath toys were shown to be linked to an outbreak of Pseudomonas aeruginosa infections, including bacteraemia, on a paediatric oncology ward.106 A before/after pilot study of toy elimination in an NICU showed a decrease in HAI rates, although the difference was not significant.107 Guidelines have been developed to address the cleansing and disinfection of toys in health-care settings.108

Animals Therapy animals are used to provide motivation and recreation to help meet the emotional and physical needs of patients, whereas service animals are trained to do tasks for the beneﬁt of a person with a disability. Many children’s hospitals not only welcome both service and therapy animals, but also more exotic visitors such as penguins and donkeys. It is an undisputed fact that animals have the potential to transmit infections to human beings. Two studies have shown that health-care workers have been the intermediary between their pets and transmission of Microsporum canis109 and Malassezia pachydermatis110 in neonatal populations, and animals have been shown to carry common human pathogens, such as MRSA.111 Concern about zoonotic infections has prompted guidelines to address the safe use of animals in the health-care setting.112,113

patients, the most commonly used antimicrobials were gentamicin, ampicillin, and vancomycin. The epidemiology of antimicrobial resistance in children’s hospitals is usually reported during outbreaks or as single institution reviews.118 However, two studies put into perspective the problem of antimicrobial resistance in paediatrics. In a prospective paediatric surveillance study in the USA, MRSA represented 16% of bloodstream infection isolates (17·9% in ICUs, 10·6% in non-ICUs), and 11% of Enterococcus faecium and 1% of Enterococcus faecalis were resistant to vancomycin.26 By contrast, data collected from 17 European hospitals in eight countries showed a slightly higher incidence of MRSA (18%), and also major resistance problems with ESBL-producing enterobacteriacae.119 Similar to the situation in adults, resistance is more common in PICUs and NICUs than on general paediatric wards, and resistant Gram-negative rods are particularly common in haematology and oncology units.120 The reported increase in non-albicans Candida species in NICUs carries the risk of increasing resistance to azole antifungal agents.52,121–125 Two additional issues that might be key problems in future paediatric infection control are the remarkable increase of community-acquired MRSA,126–129 and the equally worrying increase of penicillin-resistant or carbapenem-non-susceptible Streptococcus pneumoniae, with its potential effect on antibiotic selection at the time of admission.130,131 Interventions to prevent or at least reduce the spread of antimicrobial-resistant microorganisms can be divided in two groups: (1) improvement of infection control measures such as hand hygiene, appropriate glove use, and cohorting to avoid transmission; and (2) modification of antimicrobial use to impact on the emergence and selection of resistant organisms.118,120,132–134 These measures also have an important effect on direct and indirect costs of HAI.135,136 The increase in antimicrobial resistance has also reached alarming levels in developing countries.41

Prevention of health-care-associated infections

Antimicrobial drug resistance in paediatrics

Hand hygiene

The emergence and dissemination of antimicrobialresistant organisms is a crucial concern in paediatrics and is closely related to the use of antimicrobial agents, as in the adult setting.114,115 The Intensive Care Antimicrobial Resistance Epidemiology project and the NNIS data that report on the use of these agents in participating adult and paediatric ICUs in the USA have shown that third-generation cephalosporins are by far the most commonly used antimicrobials, followed by parenteral vancomycin, first-generation cephalosporins, and ampicillin (or amoxicillin).27,116 The Pediatric Preventive Network surveying 2647 paediatric patients in 31 hospitals recently published similar findings: first-generation and third-generation cephalosporins and vancomycin were the most frequently prescribed antibiotics in PICUs because cefazolin was used as perioperative prophylaxis.117 In NICU

Hand hygiene is considered the simplest and most effective measure to prevent cross-transmission of microorganisms and HAI.46,137 Many reports have documented the transmission of viruses or bacteria in paediatric hospitals by health-care workers.138 Unfortunately, professionals appear to have difficulties in performing hand hygiene procedures and compliance below 50% has been repeatedly reported.139 Non-compliance with hand hygiene practices and the effect of promotional programmes have often been studied in paediatric settings.94,140–142 Agents and effects on the skin of hand hygiene formulations have been reviewed elsewhere,139,143,144 as well as the impact of successful and sustained hand hygiene promotion strategies on overall HAI rates.145,146 In brief, the use of an alcohol-based handrub solution is now considered as the http://infection.thelancet.com Vol 8 January 2008

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gold standard for hand hygiene.144 The addition of a long-acting agent such as chlorhexidine gluconate to the formulation, thus combining the fast antimicrobial activity of alcohol to the prolonged effect, needs further evaluation in paediatric settings.147–149 It should be emphasised that when contact with body fluids is anticipated, gloves should be worn. Indications for hand hygiene in paediatrics follow the usual recommendations.143,144 However, the very practical problem of health-care workers unable to undertake a hand hygiene procedure between two different body sites in a very small infant is not resolved at this point: the hand can touch “dirty” and “clean” regions at the same time, resulting in cross-contamination.150 In neonates, current ongoing research focuses on reducing contaminating periods (eg, less handling of neonates), and on sequencing types of infant care (eg, moving from clean to dirty sites during infant handling, or grouping one type of infant care to one handling period).94,150 Moreover, some barriers to hand hygiene can be overcome when role models promoting the procedure are clearly identified, as shown recently in an NICU151 and as previously suggested by studies among doctors.152,153

Standard precautions Standard precautions5 in children are similar to those applied for adults. However, because of the large proportion of viral infections in hospitalised children, especially during the winter season, droplet precautions and “respiratory etiquette” are frequently required. Almost all paediatric hospitals around the world are facing a similar problem: how to separate children during seasonal epidemics? Therefore, overcrowding and lack of cohorting are frequently reported as causes of nosocomial outbreaks in paediatric settings.154,155 Particular recommendations for infection control have recently been provided for patients with cystic fibrosis,156,157 which summarise the evidence-based conclusions of a panel of international experts. The risk of cross-transmission with highly resistant organisms such as MRSA, multiresistant P aeruginosa, or Burkholderia cepacia complex is not only very high between cystic fibrosis patients, but also between cystic fibrosis and non-cystic fibrosis patients.158 It is therefore suggested to separate cystic fibrosis patients in hospital settings, both during ambulatory and inpatient care. In particular, a reduction of time in waiting areas and communal rooms, and a decrease in opportunities for contact are strongly advised, considering the long-term individual risk for the acquisition of multiresistant organisms.

Vaccination A very simple and effective means to prevent the spread of some HAIs in children is to ensure vaccination according to recommendations.159,160 As an example, pertussis, influenza, Haemophilus influenza type B, hepatitis A and B, and rotavirus can be prevented by immunisation, especially http://infection.thelancet.com Vol 8 January 2008

Figure 7: Example of a hand-hygiene promotional poster

among at-risk patients, such as candidates for transplantation or immunosuppressed children. Even infants with very low birthweight can be vaccinated during hospital stay with few side-effects and the possibility of considerable benefit.161 In recent years, new vaccines have been made available (eg, a vaccine against varicella) and new recommendations for routine vaccination have been implemented (eg, pertussis booster in teenagers, influenza vaccine and rotavirus vaccine in young children, second dose for measles vaccine) in many countries. These vaccines could potentially decrease the risk of HAI related to the targeted agents. Unfortunately, recurring controversies on vaccine safety have an effect on vaccine coverage. Parental attitude towards vaccination depends on knowledge of the preventable disease, the anxiety the illness conveys, and trust in the child’s health-care provider.162–165

Visitor screening Visitor screening policies for family visits diﬀer between hospitals to take into account cultural habits and the eventual role of the visitor as care-provider. In many developing countries, children would be poorly cared for if the family or close relatives were not available to help the severely understaﬀed health-care workers in the routine nursing. Therefore, screening is often associated with education of the visitor to ensure that he or she does not transmit pathogens to his or her child or to other 27

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Search strategy and selection criteria Data for this Review were identified by searches of PubMed, Medline, the authors’ own databases, and references from relevant articles using the search terms “infection control”, “p(a)ediatric”, “cross infection”, or “nosocomial infection”, and the following: “neonate”, “children”, “drug resistance”, “drug therapy”, “varicella zoster virus”, “tuberculosis”, “pertussis”, “influenza virus”, “respiratory syncytial virus”, “parainfluenza”, “adenovirus”, “rotavirus”, “hand hygiene”, “handwashing”, “hand antisepsis”, “formula”, “breast milk”, “animal”, and “toy”. Some references (ie, unpublished data about prevalence) were taken from authors’ own files. We reviewed all articles in English, French, and German languages published between January, 1996, and January, 2006.

children in the hospital. In most countries, it is currently recommended to promote visitors’ self-assessment of risk and education via leaﬂets, posters, and health-care workers (ﬁgure 7).

6 7

Conclusion Infection control has a particularly important role in paediatric hospitals and there is a pressing need to develop guidelines and preventive measures targeted speciﬁcally at the paediatric setting. Paradoxically, the challenges for the future are linked to the evolution of modern medicine. Over the past decade, the development of sophisticated life-support technology has resulted in a substantial increase of extremely low birthweight premature infants at high risk for nosocomial infection and this will certainly increase further in years to come. Current advances in transplantation management have resulted in improved survival rates and medical outcomes for child recipients, thus increasing the number of immunosuppressed children. Additionally, conditions that have become more prevalent in adults, such as HIV, have resulted in an increase in children with congenital illnesses. As medicine advances, it also brings a new complexity to infection risk and control in paediatrics. Devising and implementing strategies to meet the needs of this population at high risk for HAI is a unique challenge.

Conﬂicts of interest We declare that we have no conﬂicts of interest.

Acknowledgments We thank Nicolas Bornand (Paediatric Department, University of Geneva Hospitals, Geneva, Switzerland), for having kindly provided ﬁgures 1 and 6. We thank Rosemary Sudan for editorial assistance. References 1 Semmelweis I. The etiology, concept and prophylaxis of childbed fever. Madison: University of Wisconsin Press, 1983. 2 Harries EH. Infection and its control in children’s wards. Lancet 1935; 2: 173–78. 3 Richards MJ, Edwards JR, Culver DH, Gaynes RP. Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections Surveillance System. Crit Care Med 1999; 27: 887–92. 4 Winterberg DH, Wever PC, Rheenen-Verberg C, et al. A boy with nosocomial malaria tropica contracted in a Dutch hospital. Pediatr Infect Dis J 2005; 24: 89–91.

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