Successful prevention of respiratory syncytial virus ... - Nature

Bone Marrow Transplantation (2011) 46, 137–142 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11

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ORIGINAL ARTICLE

Successful prevention of respiratory syncytial virus nosocomial transmission following an enhanced seasonal infection control program V Lavergne1,2, M Ghannoum3, K Weiss2,4, J Roy5 and C Be´liveau2,4 1 Department of Microbiology and Infectious Diseases, Hoˆpital Sacre´-Coeur de Montreál, Montreál, Que´bec, Canada; 2Department of Immunology and Microbiology, University of Montreal, Montreal, Que´bec, Canada; 3Department of Medicine, Hoˆpital de Verdun, Montreál, Que´bec, Canada; 4Department of Microbiology and Infectious Diseases, Hoˆpital Maisonneuve-Rosemont Montreál, Que´bec, Canada and 5Department of Hematology and Oncology, Hoˆpital Maisonneuve-Rosemont Montreál, Que´bec, Canada

Respiratory syncytial virus (RSV) infections can be serious in severely immunocompromised patients. Use of a targeted infection control program (TICP) has been shown to reduce RSV nosocomial transmission. We evaluated the impact of an enhanced seasonal infection control program (ESICP) vs standard TICP in a hematology–oncology ward. TICP was applied from 1999 to 2001 and ESICP applied from 2001 to 2003. ESICP consisted of strict isolation for all patients admitted on the ward during the RSV season. We prospectively evaluated the incidence, related morbidity and mortality of nosocomial RSV in both field interventions. A total of 40 hospitalized RSV infections were documented. The cumulative incidence of nosocomial RSV during TICP and ESICP was respectively of 42.8 and 3.9 cases/1000 admissions (relative risk ¼ 0.09). ESICP needed to be implemented on 26 admitted patients on our ward to prevent one RSV nosocomial case. Furthermore, implementation of ESICP prevented four pneumonias and two deaths per RSV season. We conclude that ESICP is significantly more efficient than TICP to reduce the occurrence of nosocomial RSV infections and its related morbidity and mortality in patients with hematological malignancy and recipients of hematopoietic SCT. Bone Marrow Transplantation (2011) 46, 137–142; doi:10.1038/bmt.2010.67; published online 12 April 2010 Keywords: nosocomial transmission; preventive measures; immunocompromised host; hematopoietic SCT; ribavirin.

with hematological malignancies and recipients of hematopoietic SCT (HSCT). RSV is a well established cause of respiratory infections and significant morbidity in the HSCT population. Classically, RSV initially presents as an acute upper respiratory tract infection (URTI), which can progress to pneumonia in a third of cases. Reported mortality rates vary widely. A more severe clinical course has been associated with early occurrence post-transplantation, chronic GVHD, persistant lymphopenia and allogeneic HSCT.1–8 As preemptive therapy and treatment with aerosolized ribavirin and anti-RSV antibodies offer only modest benefits1,8–14 and no effective vaccine is currently available, recent strategies have focused on RSV infection prevention. RSV nosocomial transmission usually follows community outbreaks. Up to 70% of hospitalized RSV infections on hematology–oncology wards are considered nosocomial.15–17 Strict infection control precautions are considered critical to prevent spread within a hospital ward. Among the different prophylactic measures recommended during the RSV season are isolation of infected patients, hand washing before and after contact with patients, as well as educational efforts targeted at health care personnel and family members.14 This multifaceted targeted infection control program (TICP) has been reported to be efficacious in controlling outbreaks and reducing RSV nosocomial transmission in the hematology– oncology population but has failed to eliminate RSV-related morbidity and mortality.18–21 We therefore questioned whether an enhanced seasonal infection control program (ESICP) applied systematically to all patients during RSV season could provide superior protection against RSV nosocomial transmission.

Introduction In the 1980s and 1990s, respiratory syncytial virus (RSV) was identified as an emerging pathogen in the adult immunocompromised population, particularly in patients

Correspondence: Dr V Lavergne, Department of Medical Microbiology and Infectious Diseases, Hopital Sacre´-Coeur de Montreál, 5400, boulevard Gouin Ouest, Montreal, Quebec, Canada H4J 1C5. E-mail: [email protected] Received 14 May 2009; revised 4 February 2010; accepted 7 February 2010; published online 12 April 2010

Objectives Our primary goal was to evaluate the impact of the ESICP on the incidence of nosocomial-acquired RSV and its consequences on related pneumonias and mortality.

Materials and methods The study was carried out at Maisonneuve-Rosemont Hospital, a 732-bed tertiary referral center specialized in

Infection Control for Respiratory Syncytial Virus V Lavergne et al

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hematological malignancies, autologous and allogeneic HSCT. The hemato–oncology (HO) unit receives approximately 490 admissions and 125 HSCT yearly. Our study was conducted between 1 July 1999 and 30 June 2003. Until 30 June 2001, we applied TICP on the hematology– oncology ward, as recommended by the CDC.22,23 From 1 June 2001 until the end of the study, ESICP was implemented during the declared RSV season.

Measures applied The unit is a designated ward localized in a confined area within the hospital and contains 28 private rooms. The ward consists of two separate wings, with one mostly dedicated to allogeneic HSCT recipients and the second for other hematological malignancies (leukemia, lymphoma and multiple myeloma) and autologous HSCT. At all times, hand washing was mandatory before and after each visit. The head nurse’s assistant, located at the entrance, screened everyone entering the ward for respiratory symptoms. Access was forbidden to all children under the age of 12 years old as well as hospital staff or visitors presenting respiratory symptoms. This screening was applied all year round during the entire course of the study. Throughout both study periods, the following procedures remained the same: each patient was admitted to a private room with an anteroom, a central HEPA-filtered air supply and positive pressure ventilation. Once admitted, patients were forbidden to leave their room except for examinations that needed to be done outside the unit. Gown, mask and gloves were mandatory for everyone visiting an isolated patient and for every isolated patient leaving their room. Patients were never asked to wear a mask inside their room. RSV-infected patients were moved to a negative pressure room outside the unit for ribavirin treatment and sent back to their regular isolation room after completing antiviral therapy and stabilization of their respiratory condition. In the TICP period (before 2001), isolation was applied only to patients with severe neutropenia (o500/mm3) or presenting symptoms of upper and/or lower respiratory tract infection as recommended by the CDC.23 In the ESICP period (from 1 July 2001 to 30 June 2003), all patients hospitalized on the unit during the RSV season were isolated until discharge. The beginning of the RSV season was defined as the day of the first documented RSV case in our hospital (which also includes a large pediatric population) and ended 3 weeks after the last RSV-positive specimen was reported by our virology laboratory. Between declared RSV seasons, TICP was reinstituted as described previously. Incidence To evaluate the incidence of RSV on our ward, we identified the RSV cases from the virology lab archives. We also assessed the RSV incidence in the general population by consulting the Canadian national surveillance database of respiratory viruses (Public Health Agency of Canada). Data from the HSCT and hematology– oncology program were consulted and medical charts of all RSV cases were reviewed. Bone Marrow Transplantation

Definitions Pneumonia was defined as the presence of an acute respiratory illness, characterized by either symptoms (cough, sputum or dyspnea) or signs (respiratory rate over 30/minute or oxygen requirement), in association with radiographic infiltrates. URTI was defined as symptoms such as headache, nasal congestion and rhinorrhea without evidence of pneumonia. The mode of transmission was classified as nosocomial if symptoms were observed after 5 days of admission.18 RSV was identified by direct immunofluorescence on respiratory specimens (nasopharyngeal aspirates and/or bronchoalveolar lavages). Calculations RSV cumulative incidence was calculated per 1000 admissions and incidence rate per 10 000 person-days. Relative risk (risk ratio and incidence rate ratio) and absolute risk (risk difference) were calculated with their 95% confidence intervals (95% CI). Numbers needed to prevent were calculated per number of patients admitted and per isolation days on the ward. To compare variables of the two periods, two-sided P-values were calculated as follows: Wilcoxon’s rank sum test for median time to nosocomial RSV diagnosis and w2-test (or Fisher’s exact test when appropriate) for proportions, RSV cumulative incidences and incidence rate. P-value was considered statistically significant if o0.05 (SAS 9.1, Cary, NC, USA).

Results Population description and outcome Throughout the studied period, criteria for admission to the unit as well as indications for HSCT remained the same. When comparing ESICP to the TICP period, the total number of admissions on the ward and the total number of hospitalized patient-days remained constant (see Table 1). However, we observed an increase in the total number of HSCT/year, total number of HSCT recipients followed and in the total hospitalized patient-days related to HSCT. Moreover, the proportion of patient-days attributable to transplantation increased significantly from 47% in the TICP period to 55% in the ESCIP (Po0.0001). The proportion of allogeneic vs autologous HSCT, as well as the related hospitalized patient-days, remained comparable during the two periods (P ¼ 0.72 and P ¼ 0.27, respectively). Globally, 1 year mortality rate remained constant: 30% for recipients of unrelated allogeneic HSCT, 12% for matched sibling allogeneic HSCT and 2% for autologous HSCT. Time to diagnosis of nosocomial RSV infection was comparable in both studied periods (1.9 days during 1999–2001 period, and 1.5 days during 2001–2003 period (P ¼ 0.79)). RSV distribution The declared RSV seasons, as described previously, were as follows: November 1999 to May 2000, November 2000 to June 2001, November 2001 to April 2002 and November 2002 to May 2003 (Table 2). During the 1999–2001 period, RSV cases in our studied population occurred exclusively


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between January and May with a bimodal distribution: a first wave of community-acquired cases in January followed by a second wave of predominantly nosocomial cases in spring months. From 2001 to 2003, all RSV cases occurred between December and February and there was no second wave observed.

Province of Quebec (Po0.0001) and was similar in the Greater Montreal area (P ¼ 0.06). In our population, the cumulative incidence of community-acquired RSV remained comparable (P ¼ 0.40). RSV cumulative incidence in hospitalized patients during the four declared RSV seasons of 1999–2003 was 20.5 cases/1000 admissions (see Table 3). Nosocomial RSV cumulative incidence during RSV seasons with TICP was 42.8 cases/1000 admissions compared with 3.9 cases/1000 admissions with ESICP. The relative risk of acquiring nosocomial RSV with ESICP compared with TICP was 0.09, 95% CI (0.02, 0.38). During ESICP, there was a reduction of the RSV incidence rate by 23 cases per 10 000 patient-days, 95% CI (0.0033, 0.0013). ESICP needed to be implemented on 26 admitted patients, or during 15.6 days on our ward, to prevent one nosocomial RSV case.

RSV Incidence From the 1999–2001 to the 2001–2003 periods, the RSV incidence in the general population increased in the Table 1

Characteristics of hospitalized patients TICP

Number of admissions

ESICP

1999– 2000

2000– 2001

2001– 2002

2002– 2003

418

581

508

447

Number of patients followed HSCT recipients Hematological malignancies

105 110

107 119

126 84

123 123

Hospitalized person-days HSCT recipients Allogeneic Autologous Hematological malignancies

3905 2686 1219 4465

4208 2501 1707 4676

5271 3546 1725 3530

4577 2828 1749 4544

67 38

63 48

79 56

84 59

Number of HSCT Allogeneic Autologous

Mean time to diagnosis of NA RSV Median days 2.0

1.0

1.5

RSV cases and outcome From 1999 to 2003, 44 RSV infections were diagnosed in our population. Four patients with benign communityacquired RSV were not hospitalized and were not treated with antiviral agents or immunoglobulin and had a favorable outcome. Demographics of the 40 hospitalized patients diagnosed with a RSV-related illness are presented in Table 4. Two thirds of hospitalized RSV cases were considered nosocomial. All community-acquired RSV cases developed symptoms either before admission or during the first 3 days of hospitalization. The majority of infected patients (82.5%) received both aerosolized ribavirin and RSV-specific immunoglobulin for 5 days. Sixteen out of the 40 patients developed pneumonia, 10 of which were nosocomially acquired: nine in the TICP period, compared with one in the ESICP period. It is interesting to note that 5 of the 16 pneumonias were polymicrobial: Aspergillus fumigatus (n ¼ 1), CMV (n ¼ 1), Candida albicans and

—

Abbreviations: HSCT ¼ hematopoietic stem cell transplantation; NA ¼ nosocomially-acquired; RSV ¼ respiratory syncitial virus; ESICP ¼ enhanced seasonal infection control program; TICP ¼ targeted infection control program.

Table 2

RSV distribution in our population 1999–2000

Transmission mode

2000–2001

2001–2002

2002–2003

CA

NA

CA

NA

CA

NA

CA

NA

Number of RSV cases

5

13

4

14

4

2

2

0

Site of RSV diagnosis Outpatient Inpatient

0 5

0 13

0 4

0 14

3 1

0 2

1 1

0 0

Months of RSV diagnostic November 0 December 0 January 2 February 2 March 0 April 0 May 1 June 0

0 0 0 2 5 6 0 0

0 0 2 1 0 0 1 0

0 0 2 3 1 2 6 0

0 1 3 0 0 0 0 0

0 0 1a 1 0 0 0 0

0 0 1 1 0 0 0 0

0 0 0 0 0 0 0 0

Declared RSV season in our hospital Beginning November End May

November June

November April

November May

Abbreviations: CA ¼ community-acquired; NA ¼ nosocomially-acquired; RSV ¼ respiratory syncitial virus. a One nosocomial case was acquired during previous admission on another ward where only TICP was applied. Bone Marrow Transplantation


140 Table 3

Cumulative incidence and incidence rate of RSV infections TICP

P-valuea

ESICP

1999–2000

2000–2001

2001–2002

2002–2003

Province of Quebec Number of RSV cases CI per 10 000 persons

1981 2.7

1912 2.6

2480 3.4

2428 3.4

o0.0001

Greater Montreal area Number of RSV cases CI per 10 000 persons

1105 5.1

1261 5.8

1163 5.3

1113 5.1

0.06

CA RSV in our population Number of CA RSV CI per 100 followed patients

5 2.3

4 1.8

4 1.9

2 0.8

0.40

NA RSV in our population Number of NA cases CI per 1000 admissions IR per 10 000 person-days

13 53.3 26.6

14 36.1 23.6

2b 7.9 4.5

0 0 0

o0.0001 o0.0001

Abbreviations: CA ¼ community-acquired; CI ¼ cumulative incidence; ESICP ¼ seasonal enhanced infection control program; HSCT ¼ hematopoietic stem cell transplantation; IR ¼ incidence rate; NA ¼ nosocomially-acquired; RSV ¼ respiratory syncitial virus; TICP ¼ targeted infection control program. a P-value comparing incidence TICP vs ESICP. b One nosocomial case was acquired during previous admission on another ward where only TICP was applied.

glabrata (n ¼ 1), Moraxella catarrhalis, Staphylococcus aureus and CMV (n ¼ 1), and Klebsiella spp, Pseudomonas aeruginosa and Aspergillus fumigatus (n ¼ 1). Among these five coinfected patients, there were two deaths. The 30-day RSV-related mortality rate among the 40 cases was 15%. All deaths occurred in the TICP period, four of which were nosocomially-acquired cases. In summary, per season, there were four more pneumonias and two more deaths related to nosocomial RSV during the TICP period compared to ESICP.

Discussion RSV is a common winter virus with increased activity in the community from November through April. In a vulnerable population, RSV infection causes significant morbidity such as progression to pneumonia, prolonged hospital stay, long-term airflow obstruction and increased mortality. RSV outbreaks with nosocomial transmission have been reported in hematology–oncology wards as well as in outpatient clinics following patients with hematological malignancies and HSCT recipients.24 Several infectious control strategies have been studied to reduce nosocomial RSV transmission, mostly in pediatric populations. Nosocomial RSV incidence rate was reduced by 4.9–12.9 fold with strict handwashing and patient cohorting,25 by 2–7.2 fold with rapid screening and cohorting of patients on admission,26,27 and by a 2.1 fold with gloves and gowns alone.27,28 A multifaceted infection control program including rapid diagnosis, adequate handwashing and patient cohorting is considered to be the minimally acceptable strategy to prevent nosocomial RSV transmission.29 Other less studied measures are often added, such as use of masks, goggles and visit restriction for family members with URTI. In these cases, the potential advantages have to be weighed against unnecessary barriers between patient and caregivers. Bone Marrow Transplantation

These infection control strategies can also be applied in the HSCT population. Garcia et al.18 reported the first intervention field study on the prevention and control of nosocomial RSV on two dedicated HSCT wards from December to March. The program included rapid diagnosis (antigen detection), adequate handwashing and patient cohorting of documented RSV infection (transfer to another unit, cohort and contact isolation precautions with gloves, gowns and masks). Additional measures were also instituted: mandatory masks and gloves for all close contacts with HSCT recipients, screening of visitors and access restriction to children under 12 years old, visitors and staff with URTI, a surveillance program of nosocomial RSV and an educational program for the staff. This global strategy reduced the nosocomial RSV infection incidence on the ward by 4.4 fold. A similar strategy was shown to be efficient at controlling RSV outbreaks by Jones et al.19 This prompted the CDC to adopt these preventive strategies, adding URTI screening in visitors and health care workers, as well as a daily surveillance of upper and lower respiratory tract infection signs and symptoms in patients.23 The TICP applied in our unit until 2001 was comparable with the measures adopted by Garcia et al.,18 with the significant differences being that TICP was applied all year round, reverse isolation was applied only in neutropenic patients (rather than in all HSCT recipients) and we did not cohort infected patients because each was already in a private room. Despite rigorous implementation and high compliance to TICP, we still observed occasional nosocomial transmission of RSV with dismal consequence for the infected patient. Hence, although TICP was generally effective in our unit, we decided to evaluate if the implementation of ESICP during the declared RSV season would further reduce RSV transmission compared with standard TICP. The incidence of RSV infections and related complications were dramatically reduced after implementation of


141 Table 4

Demographic data of RSV-infected inpatients Number of patients

Characteristics Age (years; mean (95% CI))

(n ¼ 40) (%)a 45.3 (41.7; 49.0)

Sex (male)

28 (70.0)

Diagnosis Acute myelogenous leukemia Non Hodgkin’s lymphoma Multiple myeloma Chronic myelogenous leukemia Acute lymphoblastic leukemia Othersb

12 10 6 5 4 3

HSCT recipients More than one HSCT Last HSCT Allogeneic Autologous

(30.0) (25.0) (15.0) (12.5) (10.0) (7.5)

30 (75.0) 4 (10.0) 20 (50.0) 10 (25.0)

Time to last HSCT Pre-engraftment Post-engraftment o1 month 1–3 months 43 months

13 (32.5) 4 (10.0) 11 (27.5)

GVHD

11 (27.5)

Chemotherapy Received in the last 3 months

33 (82.5) 27 (67.5)

White cell count Neutrophil count o500/mm3 Lymphopenia

13 (32.5) 31 (77.5)

Length of hospitalization (days; mean (95% CI))

2 (5.0)

49.6 (37.0; 62.1)

Nosocomial RSV

29 (72.5)

Complications Pneumonia Coinfection 30-days mortality

16 (40) 5 (12.5) 6 (15)

Abbreviations: CI ¼ confidence interval; HSCT ¼ hematopoietic stem cell transplantation; RSV ¼ respiratory syncytial virus. a For age and length of hospitalization, the means are shown with the 95% confidence interval given in parenthesis. For all other data, percentages are relative to the total number of patients. b Others: myelodysplastic syndrome (n ¼ 1), lymphomatoid granulomatosis (n ¼ 1), and acute myelogenous leukemia with simultaneous multiple myeloma (n ¼ 1).

ESICP. Cumulative nosocomial RSV incidence decreased from 42.8 to 3.9 cases per 1000 admissions, an 11-fold decrease. ESICP significantly reduced the risk of nosocomial RSV pneumonia and essentially eliminated its attributable mortality. This occurred despite unchanged RSV incidence in the greater Montreal area. Interestingly, one of the two nosocomial cases occurring during the ESICP period was actually acquired from another ward where only standard TICP was applied (the patient developed symptoms 3 days after being transferred). Therefore, we could postulate that ESICP was even more efficient to prevent RSV transmission. There are numerous reasons to postulate why ESICP would be preferable to TICP at reducing the burden of RSV transmission:

(1) Reduction of time to isolation of a RSV-infected patient: classical RSV symptoms may be absent or atypical in immunocompromised patients. Furthermore, daily assessment of upper and lower respiratory symptoms is subjective and dependent on patient, nursing and physician awareness. This can produce unavoidable delays in isolating contagious patients in TICP. In contrast, an ESICP isolates all patients, irrespective of symptoms. (2) Prolonged protective isolation: available literature suggests that immunocompromised patients can shed the virus for a prolonged period. ESICP therefore insures definite protection that cannot be possible with TICP. (3) Prevention of other respiratory viruses’ transmission: we can postulate that ESICP might also be effective against other respiratory viruses sharing RSV seasonal and transmission modes, such as adenovirus, parainfluenza virus, human metapneumovirus, influenza virus and other emerging respiratory viruses. On the other hand, there are also inevitable drawbacks to an ESICP: (1) Patient isolation with ESICP increases the burden already imposed by disease and hospitalization. This adds a supplementary barrier between patient and family/caregivers. (2) ESICP increases the work load for health-care personnel and inevitably makes strict adherence less likely. Recurrent teaching and prompting therefore need to be reinforced. (3) The cost of implementing the ESICP measures is substantial, but so is current treatment for RSV disease. A proper cost-effectiveness analysis should be undertaken. Evidently, there are limitations to our study: the study design is a field intervention over a period of 4 years. Although there were no changes in criteria for admission on the ward nor in HSCT indications, our population changed with time: global increase of HSCT, HSCT recipients and days of hospitalization related to HSCT. These data suggest that our population was more immunocompromised in the ESICP period. There might also be unmeasured differences in the standard of care (type of chemotherapy for example) between the two periods, which may have influenced occurrence of nosocomial RSV. Perhaps a randomized controlled study, randomizing wards to either TICP or ESICP and studied during the same RSV season might have been preferable. Another limitation is that our population is not strictly a closed cohort; rarely, patients may have been initially admitted to other wards having lesser infection control measures. In conclusion, we observed that ESICP was clearly superior to standard TICP recommended by the CDC in patients with hematological malignancies or HSCT in our HO unit, and was highly efficient to prevent the occurrence of nosocomial RSV infections. As there is no vaccination available and treatment of RSV has modest efficacy, we believe that prevention by an enhanced seasonal infection control program, if confirmed by further studies, is the most efficient way of preventing nosocomial RSV Bone Marrow Transplantation


142

transmission and its related morbidity and mortality in this population.

Conflict of interest The authors declare no conflict of interest.

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