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Experience with the use of palivizumab together with infection control measures to prevent respiratory syncytial virus outbreaks in neonatal intensive care units
Journal of Hospital Infection (2008) 70, 246e252
Available online at www.sciencedirect.com
www.elsevierhealth.com/journals/jhin
Experience with the use of palivizumab together with infection control measures to prevent respiratory syncytial virus outbreaks in neonatal intensive care units H. Kurz a,*, K. Herbich b, O. Janata b, W. Sterniste a, K. Bauer c a
Department of Paediatrics, SMZ Ost Danube Hospital, Vienna, Austria Department of Hygiene, SMZ Ost Danube Hospital, Vienna, Austria c Institute of Laboratory Medicine, SMZ Ost Danube Hospital, Vienna, Austria b
Received 24 November 2007; accepted 18 July 2008 Available online 16 September 2008
KEYWORDS Respiratory syncytial virus; Outbreak; Palivizumab
Summary Respiratory syncytial virus (RSV) frequently causes nosocomial outbreaks in general paediatric wards and occasionally in neonatal intensive care units (NICUs). Conventional infection control measures often fail to prevent the spread of RSV, and it can cause significant morbidity especially in preterm and young infants. We report our experience in preventing an outbreak on a NICU after RSV had been detected in a premature infant. The index case was a 34-day-old premature infant who presented with clinical infection and RSV was detected in a clinical specimen. There were 11 patients in the ward at the time including the index case. The RSV-positive patient was isolated, the ward closed to admissions and infection control measures were implemented. Two patients were transferred to another hospital. Palivizumab 15 mg/kg i.m. was given to all patients and no further cases occurred. All subsequent RSV tests on nasal secretions were negative. Palivizumab combined with conventional infection control measures appeared to prevent the spread of RSV in this NICU. Strategies for the prevention of RSV outbreaks on NICUs all recommend the reinforcement of routine infection control measures. Recommendations concerning the use of palivizumab range
* Corresponding author. Address: Department of Paediatrics, SMZ Ost Danube Hospital A-1220 Vienna, Austria. Tel.: þ43 1 288020; fax: þ43 1 28802 4380. E-mail address: [email protected] 0195-6701/$ - see front matter ª 2008 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jhin.2008.07.013
Prevention of RSV outbreak in a NICU
247
from monthly prophylaxis to all infants at risk, to prophylaxis of selected cases only. Currently there are no guidelines for the use of palivizumab in NICUs or for the control of RSV outbreaks. ª 2008 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction Respiratory syncytial virus (RSV) is the main cause of bronchiolitis and pneumonia in infants and is responsible for significant morbidity and mortality. Patients in neonatal intensive care units (NICUs), with a history of prematurity, chronic lung disease (CLD) or congenital heart disease (CHD) have the highest risk for severe morbidity and death due to RSV infection.1,2 RSV causes frequent nosocomial outbreaks in general paediatric wards.3 Outbreaks in NICUs are less common but if they do occur, they can lead to severe morbidity and mortality in preterm infants and result in increased costs.4e7 The transmission of RSV occurs directly by infectious secretions that are transferred by hand contact or indirectly by contaminated objects or by droplet spread. Infection control measures have been effective in controlling RSV transmission in healthcare facilities and are recommended to prevent spread.8 Emphasis is placed on hand washing, the use of gloves and gowns and cohorting. The exact role of each of these measures in preventing the spread of RSV has not been determined. There are no such data available from NICUs.9 Palivizumab is a humanised IgG monoclonal antibody directed against an epitope in the A antigenic site of the fusion protein of RSV which neutralises RSV highly effectively. Palivizumab is widely used as RSV prophylaxis in preterm infants, infants with chronic lung and congenital heart disease.10e12 The monoclonal antibody is administered once a month i.m. during the RSV season and has proven to be effective in preventing hospitalisation due to RSV.11,12 Currently there are no guidelines for the use of palivizumab in NICUs or for the control of RSV outbreaks. Different approaches to the administration of palivizumab have been used. These include the administration of palivizumab prophylaxis to all infants in a NICU during the RSV season, prophylaxis only to infants at increased risk of RSV, prophylaxis to patients on a NICU after rapid testing for RSV
and the restriction of prophylaxis to infants at high risk.6
Methods Neonatal intensive care unit and patients The NICU is part of a tertiary care perinatal centre at a municipal hospital in Vienna, Austria. The unit has about 200 admissions per year admitted from the obstetric department of the centre, which in turn has about 2000 births per year. The NICU has three rooms. One room has six incubators, and the other two rooms may nurse up to three infants each. During the day, one nurse cares for two infants. During the night shift, one nurse cares for three infants. A family-centred model of patient care is provided which allows parents to remain on the ward all day and which encourages them to have physical contact with their babies. Older brothers and sisters are occasionally allowed to visit siblings for a short time if they are apparently healthy.
Index case, testing and infection control measures In January 2007, during an RSV epidemic and while several RSV-infected children were patients in the general paediatric ward, one of the infants on the NICU clinically deteriorated and was found to be RSV positive. The NOW RSV Test Kit (Inverness Medical, Binax, Inc., Scarborough, ME, USA) was used to test clinical specimens.13 At the time of RSV detection in the index patient, there were 11 infants in the NICU. The characteristics of the patients on the ward at the time of the RSV outbreak are shown in Table I. Two infants were transferred to another hospital on the day of RSV detection. On the same day the NICU was closed to elective admissions and gloves, masks and gowns were used in the care of all patients. Visits were restricted to the mothers, who also had to wear masks and gloves when in contact with their infants. The head of the ward assured compliance with the implemented measures Table II.
HMD, hyaline membrane disease; n-CPAP, nasal continuous positive airway pressure; IVH, intraventricular haemorrhage; PDA, patent ductus arteriosus; PFC, persistent fetal circulation; PROM, premature rupture of membranes; GA, gestational age.
Yes 2 26 F 11
1380
1654
30 þ 2
0
Yes Yes Yes Yes Yes 1 2 3 3 2 2 49 1 12 26 F F F M F 6 7 8 9 10
1800 420 4340 2260 1350
1780 958 4340 2224 1676
34 þ 4 28 þ 2 40 þ 0 34 þ 0 30 þ 2
n-CPAP Ventilated Ventilated 0 0
Yes Yes Yes Yes Yes 1 1 1 1 1 34 27 27 6 5 M F M F F 1 2 3 4 5
965 1390 678 1690 1046
1588 1702 854 1538 1122
28 þ 4 29 þ 6 24 þ 1 31 þ 2 30 þ 4
n-CPAP 0 Ventilated 0 0
Incubator Room Breathing/ ventilation Age (days) GA (weeks þ days) Weight (g) at date of investigation Birthweight (g) Sex Patient no.
Characteristics of the patients in neonatal intensive care units during the investigation Table I
Prematurity, RSV infection Prematurity Prematurity IVH, PDA Prematurity, PROM Prematurity, feto-fetal transfusion syndrome Prematurity Prematurity, HMD PFC Malformation syndrome Prematurity, PROM, infection Prematurity, PROM, infection
H. Kurz et al.
Diagnosis
248
Use of palivizumab All patients received palivizumab 15 mg/kg i.m. Daily RSV testing of nasal secretions was performed in all patients during the following 7 days. This procedure was also followed by the other hospital which had received the two transferred infants.
Literature review A review of recent literature concerning the use of palivizumab in RSV outbreaks was performed (Table II).
Results The index infant was a 34-day-old, 28-week gestational age (GA) male infant with a birthweight of 965 g. He had been born spontaneously after premature rupture of the membranes and had needed nasal continuous positive airway pressure (CPAP) for 23 days for mild respiratory distress syndrome, parenteral nutrition and phototherapy. Otherwise his clinical course had been without complications. During the days before his clinical deterioration he was stable, with normal breathing without the need for any additional oxygen. He had reached a weight of 1588 g. On the 34th day he was pale and suffered from frequent apnoeas and desaturations. Despite treatment with theophylline, CPAP had to be commenced because of dyspnoea, tachypnoea, coughing and an elevated oxygen demand. Apnoeas with deep desaturations and bradycardias were treated with doxapram. A chest X-ray was normal, C-reactive protein and white blood cells were not raised, and there was a mild thrombocytosis. Cultures for bacteria had been negative. RSV was detected in his nasal secretions. He was isolated in one of the small rooms with a designated nurse looking after him during each shift. His clinical condition improved and he was gradually weaned off CPAP 10 days after the detection of the RSV infection. The infant recovered completely from the RSV infection, and on the 55th day he was discharged from the hospital on palivizumab prophylaxis. Nosocomial RSV infection had resulted in a prolonged hospital stay of w10 days. The source of the infection was not known. Both parents were tested for RSV and were found to be negative. No sibling had visited the index case. There were no staff members complaining of symptoms of a respiratory infection working on the unit.
No. of beds
NG
Literature review of similar cases Unit level of care (no. of NICU beds if stated)
Location
Time of outbreak
No. of infants on the ward at the time of the outbreak
No. of No. of infants deaths infected with RSV
Palivizumab administered
Reference
Chapel Hill, NC, USA
Feb 1998
NG
3
1
No
Not stated
Heerens et al. (2002)6
Apr 1998
NG
6
1
No
Not stated
Heerens et al. (2002)6
Nov 1998
NG
3
0
No
NG
Neonatal Critical Care Center (NCCC) NCCC
26
NICU
Chapel Hill, NC, USA Lisbon, Portugal
18
NICU
Kettering, UK
Nov/Dec 1999
17
7
1
8 high risk infants
26
NICU
Lisbon, Portugal
March 1999
19
8
1
77
Barcelona, Spain
Jan 2000
56
4
Nashville, TN, USA
Not stated
Not stated
20
NICU (17) Intermediate care (15) Minimal care (45) NICU (37) Intermediate care (19) NICU (20)
2001
12
NICU
Riyadh, Saudi Arabia Vienna, Austria
Jan 2007
56
No. of RSV No. of days infections palivizumab after administered administration after first case of palivizumab
0 0
Prevention of RSV outbreak in a NICU
Table II
Abadesso et al. (2004)17 Cox et al. (2001)5
All infants
42 after first case, 6 after 4 cases Not stated
0
0
All infants
Not stated
0
Abadesso et al. (2004)17 Salcedo et al. (2000)18
9
0
All not infected infants
9
0
Halasa et al. (2005)7
20
8
1
All infants
Not stated
0
Kilani et al. (2002)19
11
1
0
All infants
3
0
This study
NICU, neonatal intensive care unit; RSV, respiratory syncytial virus.
249
250 After the implementation of the infection control measures and the application of palivizumab, none of the other children in the NICU suffered from clinical signs suggesting a viral respiratory infection. RSV tests were negative in all infants during the seven days of testing (including the two transferred infants). The index infant remained RSV positive during the following three days, became RSV negative on the fourth day and remained negative. Infection control measures were discontinued and the NICU was reopened for admissions 10 days after the detection of RSV from the index patient.
Discussion RSV outbreaks in NICUs can lead to severe morbidity and death in affected infants. In the outbreak reported by Cox et al. the index infant died.5 In the episode reported here the index case suffered a clinical deterioration and required respiratory support. The strategy of immediate testing of an infant suspected to be infected with RSV followed by the immediate administration of palivizumab and infection control measures seemed effective in preventing an outbreak in this episode. This strategy will be continued at our institution. The time interval between onset of symptoms, the availability of RSV test results and the start of interventions is crucial for the prevention of spread of RSV. The time interval in the episode described here was three days. We used the NOW RSV Test Kit; and the results were available from the laboratory after 4 h. This is a rapid immunochromatographic membrane assay for the qualitative detection of RSV fusion protein antigen in nasal wash and nasopharyngeal swab specimens. The sensitivity of the test has been found to be 91.1% in neonates, with a specificity of 93.2%.13 Increased awareness and earlier testing in suspected cases during the RSV season could further shorten this time interval. As well as the use of palivizumab, infection control procedures should be implemented. Palivizumab is not optimally effective immediately and reaches its maximum serum level on the second day after administration, in common with other IgG preparations.14 Several infection control measures are recommended in healthcare-associated RSV infection including hand decontamination, gloves, gowns, masks and eye protectors as well as cohorting affected patients. Cohorting of personnel, exclusion of healthcare personnel who have symptoms
H. Kurz et al. of respiratory tract infection, limiting visitors and postponing elective admissions are also recommended. The exact role of each of these measures in the prevention of the spread of RSV is unknown.9 Compliance with infection control measures is crucial. An improvement in hand hygiene compliance achieved by a multimodal intervention programme has been associated with a reduction in the rate of healthcare-associated infection in a neonatal intensive care unit.15 In our institution healthcare personnel are trained to implement infection control measures for any suspected viral infection, especially for those in whom respiratory symptoms are present, and to obtain nasal secretions for laboratory testing as early as possible. Requests for RSV tests are performed from 07:00 until 21:00 every day. In several outbreaks of RSV infection in NICUs, conventional infection control measures alone were insufficient to prevent the spread of the virus.4e7 Palivizumab is indicated for RSV prophylaxis. The IMPACT study group trial of palivizumab demonstrated a 55% reduction in RSV-associated hospitalisations when palivizumab was administered as a monthly i.m. injection to infants born at <35 weeks gestational age and with bronchopulmonary dysplasia.11 According to the recommendations of the Austrian Society of Paediatrics, in line with international recommendations, the first dose of palivizumab is routinely given to all high risk infants before discharge from hospital.10 In addition to its prophylactic effect, the immediate administration of palivizumab may also have a therapeutic effect. It is known that virus shedding may last up to four weeks in the course of RSV infection.16 In the episode reported here, the index infant became RSV negative after four days. This could be attributed to the therapeutic effect of palivizumab which binds RSV. Our review of the recent literature showed that only a few descriptions of RSV outbreaks are documented (see Table II). One report analysed two RSV outbreaks in a large (26 beds) NICU.17 Standard infection control measures were effective in the first outbreak (three cases). In the second outbreak palivizumab was given to all infants on the NICU after the fifth case was identified. The cumulative incidence, secondary attack rate (SAR) and risk ratio of infection both fell to zero after the administration of palivizumab. Cox et al. described an outbreak of RSV infection that affected seven preterm infants in an 18-bed special care baby unit.5 Infection control measures failed to prevent spread. Palivizumab was given to eight high risk infants. There were no further cases
Prevention of RSV outbreak in a NICU of RSV on the unit. Halasa et al. analysed the medical and economic impact of an RSV outbreak in a 56-bed NICU with 37 intensive care unit beds.7 Nine infants were infected with RSV and five infants required intubation. Infection control measures as well as the administration of palivizumab to all infants on the NICU were implemented. There was a delay of RSV diagnosis of nine days which was much longer than that reported in this outbreak. Salcedo et al. described an RSV outbreak with four infected infants.18 After the administration of palivizumab to all patients in the unit (56 infants), no more cases of colonisation or infection with RSV were detected. Kilani et al. reported an outbreak affecting eight out of 20 infants in a NICU.19 Palivizumab together with infection control measures were successful in preventing the further spread of RSV. However, four infants required mechanical ventilation and one died. In their commentary Heerens et al. describe their experience of RSV in the newborn critical care centre at the University of North Carolina Hospitals.6 Several outbreaks occurred in this unit. After reviewing them, the authors report the sporadic nature of RSV with up to nine cases in one season and zero cases in the following season, which is in contrast to the usual endemic nature of RSV infection in the community and hospital ward setting. They state that very low birthweight infants have a higher rate of complications in cases of RSV infection and that such cases should be the main target for prophylaxis. A more family-centred model for patient care may increase the incidence of RSV on NICUs. They recommend monthly prophylaxis during the RSV season for infants at the highest risk of infection and a heightened awareness of RSV infection in the NICU. This approach would mean administering palivizumab monthly to all very low birthweight infants, infants with CLD, with CHD and ventilator-dependent infants on the NICU during the RSV season. Given the sporadic appearance of RSV in our NICU (no cases during the last two years) we recommend the immediate testing of all infants suspected to be infected followed by the immediate administration of palivizumab and the implementation of conventional infection control measures. For prophylaxis on the NICU we recommend that high risk infants should receive their first dose of palivizumab in the NICU before discharge home, followed by monthly administration of palivizumab for the duration of the RSV season, in line with current recommendations.10 This study supports the need for vigilance for RSV infection, the need for rapid testing for RSV and the use of palivizumab in all infants admitted to a NICU together with the implementation of
251 conventional infection control measures. We note that different approaches are described in the literature. Controlled trials are necessary to investigate the effectiveness of the various approaches to the use of palivizumab. It is unlikely that such trials will be performed, given the practical and ethical considerations involved. Therefore, detailed descriptions of cases, outbreaks and preventative measures as reported here will help to expand knowledge on optimal management of RSV infection. Conflict of interest statement None declared. Funding sources None.
References 1. Groothuis JR, Gutierrez KM, Lauer BA. Respiratory syncytial virus infection in children with bronchopulmonary dysplasia. Pediatrics 1988;82:199e203. 2. MacDonald NE, Hall CB, Suffin SC, Alexson C, Harris PJ, Manning JA. Respiratory syncytial virus infection in infants with congenital heart disease. N Engl J Med 1982;307: 397e400. 3. Hall CB, Douglas RG, Geiman JM, Messner MK. Nosocomial respiratory syncytial virus infections. N Engl J Med 1975; 293:1343e1346. 4. Garcia Perez A, Caritg Bosch J, Junconsa Morros T, Krauel Vidal J. Outbreak of respiratory syncytial virus in a neonatal unit. An Esp Pediatr 1989;30:480e482. 5. Cox RA, Rao P, Brandon-Cox C. The use of palivizumab monoclonal antibody to control an outbreak of respiratory syncytial virus infection in a special care baby unit. J Hosp Infect 2001;48:186e192. 6. Heerens AT, Marshall DD, Bose CL. Nosocomial respiratory syncytial virus: a threat in the modern neonatal intensive care unit. J Perinatol 2002;22:306e307. 7. Halasa NB, Williams JV, Wilson GJ, Walsch WF, Scaffner W, Wright PF. Medical and economic impact of a respiratory syncytial virus outbreak in a neonatal intensive care unit. Pediatr Infect Dis J 2005;24:1040e1044. 8. Leclaire JM, Freeman J, Sullivan BG, Crowley CM, Goldmann DA. Prevention of nososcomial respiratory syncytial virus infections through compliance with glove and gown isolation precautions. N Engl J Med 1987;317:329e334. 9. Healthcare Infection Control Practices Advisory Committee, Centers for Disease Control and Prevention (US). Guidelines for preventing health-care-associated pneumonia, 2003 recommendations of the CDC and the Healthcare Infection Control Practices Advisory Committee. Respir Care 2004; 49:926e939. 10. Resch B, Berger A, Urlesberger B, Mu ¨ller WD. Empfehlungen zur Respiratory syncytial virus e prophylaxe bei Fru ¨hgeborenen mit Palivizumab (Synagis) e update 2003. Knsuspapier der arbeitsgruppe neonatologie und pa ¨diatrische intensivmedizin der o ¨sterreichischen gesellschaft fu ¨r kinder und jugendheilkunde. Monatsschr Kinderheilkd 2004;152: 223e224.
252 11. Impact-RSV study group. Palivizumab, a humanized respiratoy syncytial virus monoclonal antibody, reduces hospitalization for respiratory syncytial virus in high-risk infants. Pediatrics 1998;102:531e537. 12. Feltes TF, Cabalka AK, Meissner HC, et al. Cardiac Synagis Study Group. palivizumab prophylxis reduces hospitalization due to respiratory syncytial virus infection in a high-risk hospitalized population in young children with hemodynamically significant congenital heart disease. J Pediatr 2003; 143:532e540. 13. Cruz AT, Cazacu AC, Greer JM, Demmler GJ. Performance of a rapid assay (Binax NOW) for detection of respiratory syncytial virus at a children’s hospital over a 3-year period. J Clin Microbiol 2007;45:1993e1995. 14. Saez-Llorens X, Castano E, Null D, et al. Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia.
H. Kurz et al.
15.
16. 17.
18.
19.
The MEDI-493 study group. Pediatr Infect Dis J 1998;17: 787e791. Lam BCC, Lee J, Lau YL. Hand hygiene practices in a neonatal intensive care unit: a multimodal intervention and impact on nosocomial infection. Pediatrics 2004;114:565e571. Hall CB. Respiratory syncytial virus: its transmission in the hospital environment. Yale J Biol Med 1982;55:219e223. Abadesso C, Almeida HI, Verella D, Carreiro MH, Machado MC. Use of palivizumab to control an outbreak of syncytial respiratory virus in a neonatal intensive care unit. J Hosp Infect 2004;58:38e41. Salcedo S, Vinzo J, Calico I, et al. Administration of palivizumab during a nosocomial outbreak in a neonatal unit. Abstract P241, presented at the XVII European Congress of Perinatal Medicine, Porto Portugal. Prenatal Neonatal Med 2000;5:180. Kilani RA. Respiratory syncytial virus (RSV) outbreak in the NICU: description of eight cases. J Trop Pediatr 2002;48:118e122.
Available online at www.sciencedirect.com
www.elsevierhealth.com/journals/jhin
Experience with the use of palivizumab together with infection control measures to prevent respiratory syncytial virus outbreaks in neonatal intensive care units H. Kurz a,*, K. Herbich b, O. Janata b, W. Sterniste a, K. Bauer c a
Department of Paediatrics, SMZ Ost Danube Hospital, Vienna, Austria Department of Hygiene, SMZ Ost Danube Hospital, Vienna, Austria c Institute of Laboratory Medicine, SMZ Ost Danube Hospital, Vienna, Austria b
Received 24 November 2007; accepted 18 July 2008 Available online 16 September 2008
KEYWORDS Respiratory syncytial virus; Outbreak; Palivizumab
Summary Respiratory syncytial virus (RSV) frequently causes nosocomial outbreaks in general paediatric wards and occasionally in neonatal intensive care units (NICUs). Conventional infection control measures often fail to prevent the spread of RSV, and it can cause significant morbidity especially in preterm and young infants. We report our experience in preventing an outbreak on a NICU after RSV had been detected in a premature infant. The index case was a 34-day-old premature infant who presented with clinical infection and RSV was detected in a clinical specimen. There were 11 patients in the ward at the time including the index case. The RSV-positive patient was isolated, the ward closed to admissions and infection control measures were implemented. Two patients were transferred to another hospital. Palivizumab 15 mg/kg i.m. was given to all patients and no further cases occurred. All subsequent RSV tests on nasal secretions were negative. Palivizumab combined with conventional infection control measures appeared to prevent the spread of RSV in this NICU. Strategies for the prevention of RSV outbreaks on NICUs all recommend the reinforcement of routine infection control measures. Recommendations concerning the use of palivizumab range
* Corresponding author. Address: Department of Paediatrics, SMZ Ost Danube Hospital A-1220 Vienna, Austria. Tel.: þ43 1 288020; fax: þ43 1 28802 4380. E-mail address: [email protected] 0195-6701/$ - see front matter ª 2008 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jhin.2008.07.013
Prevention of RSV outbreak in a NICU
247
from monthly prophylaxis to all infants at risk, to prophylaxis of selected cases only. Currently there are no guidelines for the use of palivizumab in NICUs or for the control of RSV outbreaks. ª 2008 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction Respiratory syncytial virus (RSV) is the main cause of bronchiolitis and pneumonia in infants and is responsible for significant morbidity and mortality. Patients in neonatal intensive care units (NICUs), with a history of prematurity, chronic lung disease (CLD) or congenital heart disease (CHD) have the highest risk for severe morbidity and death due to RSV infection.1,2 RSV causes frequent nosocomial outbreaks in general paediatric wards.3 Outbreaks in NICUs are less common but if they do occur, they can lead to severe morbidity and mortality in preterm infants and result in increased costs.4e7 The transmission of RSV occurs directly by infectious secretions that are transferred by hand contact or indirectly by contaminated objects or by droplet spread. Infection control measures have been effective in controlling RSV transmission in healthcare facilities and are recommended to prevent spread.8 Emphasis is placed on hand washing, the use of gloves and gowns and cohorting. The exact role of each of these measures in preventing the spread of RSV has not been determined. There are no such data available from NICUs.9 Palivizumab is a humanised IgG monoclonal antibody directed against an epitope in the A antigenic site of the fusion protein of RSV which neutralises RSV highly effectively. Palivizumab is widely used as RSV prophylaxis in preterm infants, infants with chronic lung and congenital heart disease.10e12 The monoclonal antibody is administered once a month i.m. during the RSV season and has proven to be effective in preventing hospitalisation due to RSV.11,12 Currently there are no guidelines for the use of palivizumab in NICUs or for the control of RSV outbreaks. Different approaches to the administration of palivizumab have been used. These include the administration of palivizumab prophylaxis to all infants in a NICU during the RSV season, prophylaxis only to infants at increased risk of RSV, prophylaxis to patients on a NICU after rapid testing for RSV
and the restriction of prophylaxis to infants at high risk.6
Methods Neonatal intensive care unit and patients The NICU is part of a tertiary care perinatal centre at a municipal hospital in Vienna, Austria. The unit has about 200 admissions per year admitted from the obstetric department of the centre, which in turn has about 2000 births per year. The NICU has three rooms. One room has six incubators, and the other two rooms may nurse up to three infants each. During the day, one nurse cares for two infants. During the night shift, one nurse cares for three infants. A family-centred model of patient care is provided which allows parents to remain on the ward all day and which encourages them to have physical contact with their babies. Older brothers and sisters are occasionally allowed to visit siblings for a short time if they are apparently healthy.
Index case, testing and infection control measures In January 2007, during an RSV epidemic and while several RSV-infected children were patients in the general paediatric ward, one of the infants on the NICU clinically deteriorated and was found to be RSV positive. The NOW RSV Test Kit (Inverness Medical, Binax, Inc., Scarborough, ME, USA) was used to test clinical specimens.13 At the time of RSV detection in the index patient, there were 11 infants in the NICU. The characteristics of the patients on the ward at the time of the RSV outbreak are shown in Table I. Two infants were transferred to another hospital on the day of RSV detection. On the same day the NICU was closed to elective admissions and gloves, masks and gowns were used in the care of all patients. Visits were restricted to the mothers, who also had to wear masks and gloves when in contact with their infants. The head of the ward assured compliance with the implemented measures Table II.
HMD, hyaline membrane disease; n-CPAP, nasal continuous positive airway pressure; IVH, intraventricular haemorrhage; PDA, patent ductus arteriosus; PFC, persistent fetal circulation; PROM, premature rupture of membranes; GA, gestational age.
Yes 2 26 F 11
1380
1654
30 þ 2
0
Yes Yes Yes Yes Yes 1 2 3 3 2 2 49 1 12 26 F F F M F 6 7 8 9 10
1800 420 4340 2260 1350
1780 958 4340 2224 1676
34 þ 4 28 þ 2 40 þ 0 34 þ 0 30 þ 2
n-CPAP Ventilated Ventilated 0 0
Yes Yes Yes Yes Yes 1 1 1 1 1 34 27 27 6 5 M F M F F 1 2 3 4 5
965 1390 678 1690 1046
1588 1702 854 1538 1122
28 þ 4 29 þ 6 24 þ 1 31 þ 2 30 þ 4
n-CPAP 0 Ventilated 0 0
Incubator Room Breathing/ ventilation Age (days) GA (weeks þ days) Weight (g) at date of investigation Birthweight (g) Sex Patient no.
Characteristics of the patients in neonatal intensive care units during the investigation Table I
Prematurity, RSV infection Prematurity Prematurity IVH, PDA Prematurity, PROM Prematurity, feto-fetal transfusion syndrome Prematurity Prematurity, HMD PFC Malformation syndrome Prematurity, PROM, infection Prematurity, PROM, infection
H. Kurz et al.
Diagnosis
248
Use of palivizumab All patients received palivizumab 15 mg/kg i.m. Daily RSV testing of nasal secretions was performed in all patients during the following 7 days. This procedure was also followed by the other hospital which had received the two transferred infants.
Literature review A review of recent literature concerning the use of palivizumab in RSV outbreaks was performed (Table II).
Results The index infant was a 34-day-old, 28-week gestational age (GA) male infant with a birthweight of 965 g. He had been born spontaneously after premature rupture of the membranes and had needed nasal continuous positive airway pressure (CPAP) for 23 days for mild respiratory distress syndrome, parenteral nutrition and phototherapy. Otherwise his clinical course had been without complications. During the days before his clinical deterioration he was stable, with normal breathing without the need for any additional oxygen. He had reached a weight of 1588 g. On the 34th day he was pale and suffered from frequent apnoeas and desaturations. Despite treatment with theophylline, CPAP had to be commenced because of dyspnoea, tachypnoea, coughing and an elevated oxygen demand. Apnoeas with deep desaturations and bradycardias were treated with doxapram. A chest X-ray was normal, C-reactive protein and white blood cells were not raised, and there was a mild thrombocytosis. Cultures for bacteria had been negative. RSV was detected in his nasal secretions. He was isolated in one of the small rooms with a designated nurse looking after him during each shift. His clinical condition improved and he was gradually weaned off CPAP 10 days after the detection of the RSV infection. The infant recovered completely from the RSV infection, and on the 55th day he was discharged from the hospital on palivizumab prophylaxis. Nosocomial RSV infection had resulted in a prolonged hospital stay of w10 days. The source of the infection was not known. Both parents were tested for RSV and were found to be negative. No sibling had visited the index case. There were no staff members complaining of symptoms of a respiratory infection working on the unit.
No. of beds
NG
Literature review of similar cases Unit level of care (no. of NICU beds if stated)
Location
Time of outbreak
No. of infants on the ward at the time of the outbreak
No. of No. of infants deaths infected with RSV
Palivizumab administered
Reference
Chapel Hill, NC, USA
Feb 1998
NG
3
1
No
Not stated
Heerens et al. (2002)6
Apr 1998
NG
6
1
No
Not stated
Heerens et al. (2002)6
Nov 1998
NG
3
0
No
NG
Neonatal Critical Care Center (NCCC) NCCC
26
NICU
Chapel Hill, NC, USA Lisbon, Portugal
18
NICU
Kettering, UK
Nov/Dec 1999
17
7
1
8 high risk infants
26
NICU
Lisbon, Portugal
March 1999
19
8
1
77
Barcelona, Spain
Jan 2000
56
4
Nashville, TN, USA
Not stated
Not stated
20
NICU (17) Intermediate care (15) Minimal care (45) NICU (37) Intermediate care (19) NICU (20)
2001
12
NICU
Riyadh, Saudi Arabia Vienna, Austria
Jan 2007
56
No. of RSV No. of days infections palivizumab after administered administration after first case of palivizumab
0 0
Prevention of RSV outbreak in a NICU
Table II
Abadesso et al. (2004)17 Cox et al. (2001)5
All infants
42 after first case, 6 after 4 cases Not stated
0
0
All infants
Not stated
0
Abadesso et al. (2004)17 Salcedo et al. (2000)18
9
0
All not infected infants
9
0
Halasa et al. (2005)7
20
8
1
All infants
Not stated
0
Kilani et al. (2002)19
11
1
0
All infants
3
0
This study
NICU, neonatal intensive care unit; RSV, respiratory syncytial virus.
249
250 After the implementation of the infection control measures and the application of palivizumab, none of the other children in the NICU suffered from clinical signs suggesting a viral respiratory infection. RSV tests were negative in all infants during the seven days of testing (including the two transferred infants). The index infant remained RSV positive during the following three days, became RSV negative on the fourth day and remained negative. Infection control measures were discontinued and the NICU was reopened for admissions 10 days after the detection of RSV from the index patient.
Discussion RSV outbreaks in NICUs can lead to severe morbidity and death in affected infants. In the outbreak reported by Cox et al. the index infant died.5 In the episode reported here the index case suffered a clinical deterioration and required respiratory support. The strategy of immediate testing of an infant suspected to be infected with RSV followed by the immediate administration of palivizumab and infection control measures seemed effective in preventing an outbreak in this episode. This strategy will be continued at our institution. The time interval between onset of symptoms, the availability of RSV test results and the start of interventions is crucial for the prevention of spread of RSV. The time interval in the episode described here was three days. We used the NOW RSV Test Kit; and the results were available from the laboratory after 4 h. This is a rapid immunochromatographic membrane assay for the qualitative detection of RSV fusion protein antigen in nasal wash and nasopharyngeal swab specimens. The sensitivity of the test has been found to be 91.1% in neonates, with a specificity of 93.2%.13 Increased awareness and earlier testing in suspected cases during the RSV season could further shorten this time interval. As well as the use of palivizumab, infection control procedures should be implemented. Palivizumab is not optimally effective immediately and reaches its maximum serum level on the second day after administration, in common with other IgG preparations.14 Several infection control measures are recommended in healthcare-associated RSV infection including hand decontamination, gloves, gowns, masks and eye protectors as well as cohorting affected patients. Cohorting of personnel, exclusion of healthcare personnel who have symptoms
H. Kurz et al. of respiratory tract infection, limiting visitors and postponing elective admissions are also recommended. The exact role of each of these measures in the prevention of the spread of RSV is unknown.9 Compliance with infection control measures is crucial. An improvement in hand hygiene compliance achieved by a multimodal intervention programme has been associated with a reduction in the rate of healthcare-associated infection in a neonatal intensive care unit.15 In our institution healthcare personnel are trained to implement infection control measures for any suspected viral infection, especially for those in whom respiratory symptoms are present, and to obtain nasal secretions for laboratory testing as early as possible. Requests for RSV tests are performed from 07:00 until 21:00 every day. In several outbreaks of RSV infection in NICUs, conventional infection control measures alone were insufficient to prevent the spread of the virus.4e7 Palivizumab is indicated for RSV prophylaxis. The IMPACT study group trial of palivizumab demonstrated a 55% reduction in RSV-associated hospitalisations when palivizumab was administered as a monthly i.m. injection to infants born at <35 weeks gestational age and with bronchopulmonary dysplasia.11 According to the recommendations of the Austrian Society of Paediatrics, in line with international recommendations, the first dose of palivizumab is routinely given to all high risk infants before discharge from hospital.10 In addition to its prophylactic effect, the immediate administration of palivizumab may also have a therapeutic effect. It is known that virus shedding may last up to four weeks in the course of RSV infection.16 In the episode reported here, the index infant became RSV negative after four days. This could be attributed to the therapeutic effect of palivizumab which binds RSV. Our review of the recent literature showed that only a few descriptions of RSV outbreaks are documented (see Table II). One report analysed two RSV outbreaks in a large (26 beds) NICU.17 Standard infection control measures were effective in the first outbreak (three cases). In the second outbreak palivizumab was given to all infants on the NICU after the fifth case was identified. The cumulative incidence, secondary attack rate (SAR) and risk ratio of infection both fell to zero after the administration of palivizumab. Cox et al. described an outbreak of RSV infection that affected seven preterm infants in an 18-bed special care baby unit.5 Infection control measures failed to prevent spread. Palivizumab was given to eight high risk infants. There were no further cases
Prevention of RSV outbreak in a NICU of RSV on the unit. Halasa et al. analysed the medical and economic impact of an RSV outbreak in a 56-bed NICU with 37 intensive care unit beds.7 Nine infants were infected with RSV and five infants required intubation. Infection control measures as well as the administration of palivizumab to all infants on the NICU were implemented. There was a delay of RSV diagnosis of nine days which was much longer than that reported in this outbreak. Salcedo et al. described an RSV outbreak with four infected infants.18 After the administration of palivizumab to all patients in the unit (56 infants), no more cases of colonisation or infection with RSV were detected. Kilani et al. reported an outbreak affecting eight out of 20 infants in a NICU.19 Palivizumab together with infection control measures were successful in preventing the further spread of RSV. However, four infants required mechanical ventilation and one died. In their commentary Heerens et al. describe their experience of RSV in the newborn critical care centre at the University of North Carolina Hospitals.6 Several outbreaks occurred in this unit. After reviewing them, the authors report the sporadic nature of RSV with up to nine cases in one season and zero cases in the following season, which is in contrast to the usual endemic nature of RSV infection in the community and hospital ward setting. They state that very low birthweight infants have a higher rate of complications in cases of RSV infection and that such cases should be the main target for prophylaxis. A more family-centred model for patient care may increase the incidence of RSV on NICUs. They recommend monthly prophylaxis during the RSV season for infants at the highest risk of infection and a heightened awareness of RSV infection in the NICU. This approach would mean administering palivizumab monthly to all very low birthweight infants, infants with CLD, with CHD and ventilator-dependent infants on the NICU during the RSV season. Given the sporadic appearance of RSV in our NICU (no cases during the last two years) we recommend the immediate testing of all infants suspected to be infected followed by the immediate administration of palivizumab and the implementation of conventional infection control measures. For prophylaxis on the NICU we recommend that high risk infants should receive their first dose of palivizumab in the NICU before discharge home, followed by monthly administration of palivizumab for the duration of the RSV season, in line with current recommendations.10 This study supports the need for vigilance for RSV infection, the need for rapid testing for RSV and the use of palivizumab in all infants admitted to a NICU together with the implementation of
251 conventional infection control measures. We note that different approaches are described in the literature. Controlled trials are necessary to investigate the effectiveness of the various approaches to the use of palivizumab. It is unlikely that such trials will be performed, given the practical and ethical considerations involved. Therefore, detailed descriptions of cases, outbreaks and preventative measures as reported here will help to expand knowledge on optimal management of RSV infection. Conflict of interest statement None declared. Funding sources None.
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