Description of the condition
Healthcare workers, such as doctors, nurses, other health professionals, cleaners and porters may have substantial rates of clinical and sub-clinical influenza during influenza seasons (Elder 1996; Ruel 2002), but there are no reliable data on rates of laboratory-proven influenza in healthcare workers and whether they differ from those of the general population (Jefferson 2009). Laboratory-proven influenza in the general population on average accounts for 7% to 10% of influenza-like illnesses, and is based on biased or incomplete samples. Data from the control arms of randomised controlled trials (RCTs) could provide data on laboratory-proven influenza rates but is also biased.
Healthcare workers often continue to work when infected with influenza, increasing the likelihood of transmitting influenza to those in their care (Coles 1992; Weingarten 1989; Yassi 1993). Elderly people (aged 60 or older) in institutions such as long-stay hospital wards and nursing homes are at risk of influenza and its complications, especially if affected with multiple pathologies (Fune 1999; Jackson 1992; Muder 1998; Nicolle 1984).
Description of the intervention
One way to prevent the spread of influenza to elderly residents in long-term care facilities may be to vaccinate healthcare workers. The Centers for Disease Control (CDC) Advisory Committee on Immunization Practices (ACIP) recommends vaccination of all healthcare workers (Harper 2004). However, only 36% of healthcare workers in the US (CDC 2003) and 35% of staff in long-term care facilities in Canada were vaccinated in 1999 (Stevenson 2001). Nurses and (in some institutions) physicians, tend to have lower influenza vaccination rates than other healthcare workers. This relatively low uptake may partly be a reflection of doubts as to the vaccine's effectiveness (its ability to prevent influenza-like illness (ILI) and efficacy (its ability to prevent influenza) (Ballada 1994; Campos 2002-3; Ludwig-Beymer 2002; Martinello 2003; Quereshi 2004). The design and execution of campaigns to increase vaccination rates are also important (Doebbeling 1997; NFID 2004; Russell 2003a; Russell 2003b), in order to provide an intervention at minimal risk of bias from inadequate randomisation, concealment of allocation, blinding, attrition, incomplete reporting and inappropriate statistical analysis.
How the intervention might work
Healthcare workers are the key group who enter nursing and long-term care facilities on a daily basis. Immune systems of the elderly are less responsive to vaccination, and vaccinating healthcare workers should reduce the exposure of elderly people to influenza.
Why it is important to do this review
Previous systematic reviews of the effects of influenza vaccines in the elderly are now out of date or do not include all relevant studies. The Gross 1995 review is 14 years old and its conclusions are affected by the exclusion of recent evidence. The Vu 2002 review has methodological weaknesses (excluding studies with denominators smaller than 30 and quantitative pooling of studies with different designs), which are likely to undermine the conclusions. A systematic review by Jordan 2004 of the effects of vaccinating healthcare workers against influenza on high-risk elderly reports significantly lower mortality in the elderly (13.6% versus 22.4%, odds ratio (OR) 0.58, 95% confidence interval (CI) 0.4 to 0.84) but does not include the latest studies. The Burls 2006 systematic review of effects on elderly people only identified the RCTs by Potter 1997 and Carman 2000, and Anikeeva 2009 does not include the studies by Lemaitre 2009 and Oshitani 2000. It is important to provide accurate information for policy makers, and highlight the need for high quality trials to test combinations of interventions, including healthcare worker vaccination.
There are Cochrane systematic reviews assessing the effects of influenza vaccines in children (Jefferson 2008), the elderly (Rivetti 2006), healthy adults (Demicheli 2007), people affected with chronic obstructive pulmonary disease (Poole 2009), asthma (Cates 2003) and cystic fibrosis (Dharmaraj 2009), and reviews of children (Jefferson 2005a) and the elderly (Jefferson 2005b). The first publication of this review (Thomas 2006) needed updating to search for and assess new literature.
To identify all randomised controlled trials (RCTs) and non-RCTs assessing the effects of vaccinating healthcare workers on the incidence of influenza, influenza-like-illness (ILI) and its complications in elderly residents in long-term care facilities.
Criteria for considering studies for this review
Types of studies
RCTs and non-RCTs (cohort or case-control studies) reporting exposure and outcomes by vaccine status.
Types of participants
Healthcare workers (nurses, doctors, nursing and medical students, other health professionals, cleaners, porters and volunteers who have regular contact with the elderly) of all ages, caring for elderly residents (aged 60 years or older) in institutions such as nursing homes, long-term care facilities or hospital wards.
Types of interventions
Vaccination of healthcare workers with any influenza vaccine given alone or with other vaccines, in any dose, preparation, or time schedule, compared with placebo or with no intervention. Studies on vaccinated elderly are included in reviews looking at the effects of influenza vaccines in the elderly (Jefferson 2005b; Rivetti 2006). The review by Demicheli et al (Demicheli 2007) looked at the effects of vaccination in healthy adults such as healthcare workers.
Types of outcome measures
Outcomes for the elderly - specific outcome measures for influenza
- Cases of influenza confirmed by viral isolation and/or serological supporting evidence, plus a list of likely respiratory symptoms.
- Cases of influenza admitted to hospital.
- Deaths caused by influenza or its complications.
Studies reporting only serological outcomes in the absence of symptoms were excluded. Outcomes for healthcare workers were not considered.
Non-specific outcome measures related to influenza-like illness and all-cause mortality
- Cases of influenza-like illness clinically defined from a list of likely respiratory and systemic signs and symptoms within the epidemic period (the six-month winter period if not better specified).
- Cases of influenza-like illness admitted to hospital.
- Deaths from all causes.
- Any other direct or indirect indicator of disease impact (days of illness, resources consumption, complications).
Search methods for identification of studies
For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 3), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register and the Database of Abstracts of Reviews of Effects (DARE); MEDLINE (January 1966 to Week 3, September 2009); EMBASE (1974 to September 2009); Biological Abstracts (1969 to December 2005) and Science Citation Index-Expanded (1974 to September 2009), which included Science Citation Index-Expanded, Biosis Previews and Current Contents. See Appendix 1 for details of previous searches. There were no language restrictions.
We searched MEDLINE, MEDLINE in-process and CENTRAL using the following search strategy. We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity-maximising version (2008 revision); Ovid format (Lefebvre 2008). We adapted the search strategy to search EMBASE (Appendix 2) and Web of Science (Appendix 3).
We also combined the following search strategy with the SIGN filter (SIGN 2009) for identifying observational studies and ran the searches in MEDLINE and adapted them for EMBASE and Web of Science (see Appendix 4).
1 Influenza Vaccines/
2 Influenza, Human/
3 exp Influenzavirus A/
4 exp Influenzavirus B/
8 exp Vaccines/
11 exp Immunization/
12 (immuniz* or immunis*).tw.
14 7 and 13
15 1 or 14
16 exp Health Personnel/
17 ((health or health care or healthcare) adj2 (personnel or worker* or provider* or employee* or staff)).tw.
18 ((medical or hospital) adj2 (staff or employee* or personnel or worker*)).tw.
19 (doctor* or physician* or clinician*).tw.
20 (allied health adj2 (staff or personnel or worker*)).tw.
23 (nursing adj2 (staff or personnel or auxiliar*)).tw.
24 exp Hospitals/
25 Long-Term Care/
26 exp Residential Facilities/
27 nursing home*.tw.
28 (institution* adj3 elderly).tw.
29 aged care.tw.
31 30 and 15
Searching other resources
We searched bibliographies of retrieved articles and contacted trial authors for further details, if required.
Data collection and analysis
Selection of studies
Two review authors (TJL, RET) independently reviewed the abstracts by using the following inclusion criteria.
- Elderly people 60 years or older.
- Long-term care facilities or hospitals.
- Healthcare workers.
- Influenza vaccination.
- Morbidity and mortality of residents.
Disagreements were resolved by a third review author (TOJ).
Data extraction and management
Two review authors (RET, TJL) applied the inclusion criteria to all identified and retrieved articles, and extracted data from included studies into standard Cochrane Vaccines Field forms. We extracted the following data in duplicate.
Methods: purpose; design; period study conducted and statistics.
Participants: country or countries of study; setting; eligible participants; age and gender.
Interventions and exposure: in intervention group and control group.
- cases of influenza confirmed by viral isolation and/or serological supporting evidence plus a list of likely respiratory symptoms;
- cases of influenza admitted to hospital;
- cases of influenza-like illness clinically defined from a list of likely respiratory and systemic signs and symptoms within the epidemic period (the six-month winter period if not better specified);
- cases of influenza-like illness admitted to hospital;
- deaths from all causes;
- deaths caused by influenza or its complications;
- any other direct or indirect indicator of disease impact (days of illness, resources consumption, complications).
Two review authors (RET, TJL) independently checked data extraction, and disagreements were resolved by third review author (TOJ).
Assessment of risk of bias in included studies
Assessment of methodological quality for RCTs was carried out using the Cochrane Collaboration's 'Risk of bias' tool (Higgins 2008a). We assessed the quality of non-RCTs in relation to the presence of potential confounders using the appropriate Newcastle-Ottawa Scales (NOS) (Wells 2005). The NOS asks whether all possible precautions against confounding have been taken by the study designers, and links study quality to the answer. We translated the number of inadequately reported or conducted items into categories of risk of bias. We used quality at the analysis stage as a means of interpreting the results. The review authors resolved disagreements on inclusion or methodological quality of studies by discussion. Two review authors (RET, TOJ) checked quality assessment.
We looked for details of formal ethics approval and informed consent of participants.
Measures of treatment effect
Only the last primary outcome measure (that is, any other direct or indirect indicator of disease impact (days of illness, resources consumption, complications)) allowed a comparison with two studies; for each of the remaining outcomes only data from one study were available. Efficacy (against influenza) and effectiveness (against influenza-like illness) (effects) estimates were summarised as risk ratio (RR) or odds ratio (OR) within 95% confidence intervals (CI). For Hayward 2006 we analysed the data as mean differences of rates. Absolute vaccine efficacy (VE) was expressed as a percentage using the formula: VE = 1 - RR whenever significant. When statistical significance was not achieved we reported the relevant RR or OR.
Unit of analysis issues
All four RCTs were cluster-RCTs. Carman 2000 did not control for clustering and we were not able to adjust his data to do so. We adjusted the precision of the study estimates for the cluster-RCTs based on standard Cochrane Handbook for Systematic Reviews of Interventions advice (Higgins 2008b). We contacted trial authors to ascertain the intra-cluster correlation coefficient (ICC), and to confirm statistical analyses.
Dealing with missing data
We did not use any strategies to impute missing outcome data, and recorded missing data in the 'Risk of bias' table. We attributed an ICC to two studies (Carman 2000; Potter 1997), from an assumed intra-cluster variance of 2.3% in Hayward 2006.
Assessment of heterogeneity
We used the X
Assessment of reporting biases
We reviewed an additional 554 abstracts for potential RCTs and 251 for non-RCTs, and 312 citations from the systematic review by Jefferson 2005b. We identified only four cluster-RCTS and one cohort study. The funnel plot for all-cause mortality (Figure 1), for example, contains only three cluster-RCTs and it is difficult to draw conclusions about bias from such a small number.
|Figure 1. Funnel plot of comparison: 1 HCWs offered vaccination versus HCWs offered no vaccination: experimental design, outcome: 1.7 Deaths from all causes.|
We meta-analysed RCTs when the I
Subgroup analysis and investigation of heterogeneity
We structured two comparisons: studies with an experimental design and studies without an experimental design. Whenever data presented in the study allowed it, we carried out subgroup analysis according to elderly residents' vaccination status. We assessed the following outcomes which arose during the influenza season.
- Influenza-like illness.
- Laboratory-proven influenza infections (by paired serology, nasal swabs, reverse-transcriptase polymerase chain reaction (RT-PCR), or tissue culture).
- GP consultations for influenza-like illness.
- Lower respiratory tract infections.
- Deaths from pneumonia.
- All-cause mortality.
With only four cluster-RCTs, a sensitivity analysis was not feasible.
Description of studies
Results of the search
This updated search retrieved a total of 554 records in the search for RCTs and 251 records in the search for observational studies. In the first publication of this review we also examined 312 reports for detailed assessment from the review on the effects of influenza vaccines in the elderly (Rivetti 2006).
Due to the comprehensive nature of the Cochrane Review on the effects of influenza vaccines in the elderly (Rivetti 2006), we carried out a review with a very focused study question and benefited from extensive searches which generated a large number of 'hits' but a relatively low yield of studies to include.
Only four cluster-RCTs were found. The funnel plot (Figure 1) does not suggest publication bias, but the number of studies is small.
We excluded 22 studies. The abstract appeared appropriate, but after examining the full text, the studies were excluded because they either did not have influenza vaccination outcome data for the elderly or healthcare workers or both, or reported only influenza antibody levels.
Risk of bias in included studies
|Figure 2. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.|
|Figure 3. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.|
Oshitani 2000 was assessed (Appendix 5) using the 'Newcastle-Ottawa scale for assessment of quality of non-randomised studies' and the entries in the 'Risk of bias' table for sequence generation and allocation concealment do not apply to this non-RCT.
There was adequate sequence generation in three studies (Carman 2000 and Hayward 2006 by a random number table; and Lemaitre 2009 by centralised random-number generator) but uncertainty in one study (Potter 1997 "Hospital sites were stratified by unit policy for vaccination, then randomized for their healthcare workers to be routinely offered either influenza vaccination and patients unvaccinated..."). There was allocation concealment in one study (Hayward 2006 by a researcher blinded to the homes' identity and characteristics).
No RCT used blinding of participants or study personnel. In Carman 2000, Potter 1997 and Hayward 2006 there is no statement that any researcher, assessor, data analyst, healthcare worker or participant was blinded. In Hayward 2006 lead nurses "were trained to promote influenza vaccination to staff". In Carman 2000 the study nurses "took additional opportunistic nose and throat swabs from non-randomised patients who the ward nurses thought had an influenza-like illness". In Potter 1997 ward nurses paged the research nurses "if any patients under their care developed clinical symptoms suggestive of upper respiratory tract viral illness, influenza, or lower respiratory tract infection," and in Lemaitre 2009 "Influenza vaccination was further recommended during face-to-face interviews with each member of staff ... The study team individually met all administrative staff, technicians, and caregivers to invite them to participate, and volunteers were vaccinated at the end of the interview."
Incomplete outcome data
No study appeared to report results selectively.
Other potential sources of bias
For Potter 1997 potential sources of bias were as follows.
- Selection bias: the total number of long-term care hospitals in West and Central Scotland is not stated. There were inconsistencies in outcome gradients (see Table 1). In the population under observation, Potter 1997 reported 216 cases of suspected viral illness, 64 cases of influenza-like illness, 55 cases of pneumonia, 72 deaths from pneumonia and 148 deaths from all causes; in the sub-population of both vaccinated staff and patients, Potter 1997 reported 24 cases of suspected viral illness, two cases of influenza-like illness, seven cases of pneumonia, 10 deaths from pneumonia and 25 deaths from all causes. As these gradients are not plausible (one would expect a greater proportion of cases of influenza-like illness to be caused by influenza during a period of high viral activity), the effect on all-cause mortality is likely to reflect a selection bias rather than a real effect of vaccination.
- Performance bias: 67% of staff in active arm 1 and 43% in active arm 2 were vaccinated.
- There is no description of the vaccines administered, vaccine matching or background influenza epidemiology.
For Carman 2000 potential sources of bias were as follows.
- Selection bias: the total number of long-term care hospitals in West and Central Scotland is not stated. In the long-term care hospitals in which healthcare workers were offered vaccination, residents had higher Barthel scores.
- Performance bias: only 51% of healthcare workers in the Lemaitre 2009 arm received vaccine in the long-term care hospitals where vaccine was offered, and 4.8% where it was not; 48% of patients received vaccine in the arm where healthcare workers were offered vaccination, and 33% in the arm where healthcare workers were not.
- Statistical bias: the analysis was not corrected for clustering, unlike the Potter 1997 pilot; in the long-term care hospitals where healthcare workers were offered vaccination, the patients had significantly higher Barthel scores and were more likely to receive influenza vaccine (no significance level stated), and due to missing data these differences could not be adjusted for other than by estimation. Statistical power may also have been a problem as the detection rate of 6.7% was lower than the estimated rate of 25% used in the power calculation.
The Potter 1997 and Carman 2000 cluster-RCTs can be regarded as investigations in the same geographical area with a modest possible but unknown overlap of staff and residents. Only three of the long-term care hospitals in the Potter study (Potter 1997) were included in the Carman cluster-RCT (Carman 2000) because some of the homes were closed down (e-mail communication from Dr. Stott), but the continuity of staff between the institutions is unknown.
- Selection: lack of clear definition of vaccine coverage rates among healthcare workers, and unclear ascertainment of vaccination status and comparability of hemicohorts (the government mandated surveys but there is no description of the surveys, how they were administered or completeness).
- Comparability: there was no ascertainment of health status or co-morbidities in the hemicohorts, and the study mixed two types of healthcare facilities, one which is for elderly patients and the other for elderly with severe health conditions. Also, facilities with higher vaccination rates might have practised other preventive measures, such as hand washing, limitation of visitors during influenza epidemics or isolation of patients. These practices may have had an impact on the outcome but are not reported.
- Outcomes: demographic inconsistencies in reporting of denominators, differential criteria for diagnosing influenza-like illness, and the lack of laboratory confirmation.
Ethics approval: Carman 2000, Hayward 2006, Lemaitre 2009 and Potter 1997 received formal ethics approval. Carman 2000 and Potter 1997 obtained written informed consent from healthcare workers and witnessed verbal consent from participants for nose swabs to be taken and Potter 1997 for blood samples. The long-term care facilities already had policies for opting in or opting out of influenza vaccination. Lemaitre 2009 obtained face-to-face informed consent from healthcare workers and Hayward 2006 trained nurses to promote vaccination to healthcare workers, and neither had an intervention for the elderly.
Effects of interventions
The data analysis tables show two pieces of information for each study: (1) the average (central tendency of the results) as a diamond (if only one study is in the group) and as a box (if more than one study is in the group), and (2) the possible range or dispersion of the results. The convention is to show the 95% confidence interval (CI) as a horizontal bar, and the interpretation is that it shows the maximum range of results statistically possible in 95 experiments if the study were repeated 100 times, and thus 2.5% of times the result could be lower than the lower end and 2.5% of times higher then the upper end of the CI bar. For an entire set of studies the average is shown by a diamond. The legend at the bottom of each graph shows whether the placement of the boxes and diamonds favours the intervention or the control group.
Specific effects of interventions
Effects of healthcare worker vaccination on influenza
Carman 2000 reported data on influenza cases among vaccinated and unvaccinated patients combined (OR 0.80, 95% CI 0.39 to 1.64, P = 0.54). Potter 1997 reported outcomes only for unvaccinated patients (OR 1.37, 95% CI 0.22 to 8.36, P = 0.73). We were able to pool the results and we computed an overall OR of 0.86 (95% CI 0.44 to 1.68, P = 0.66). The pooled OR which was adjusted for clustering was 0.87 (95% CI 0.38 to 1.99, P = 0.74).
Effects of healthcare worker vaccination on pneumonia
The Potter 1997 study reported data separately for vaccinated patients and for vaccinated we computed an OR of 0.59 (95% CI 0.25 to 1.40, Z = 1.20, P = 0.23) and for unvaccinated we computed OR 0.78 (95% CI 0.40 to 1.54, P = 0.47). For vaccinated we computed an adjusted OR of 0.59 (95% CI 0.13 to 2.63), Z = 0.69 (P = 0.49) and for unvaccinated an adjusted OR of 0.78 (95% CI 0.26 to 2.33), Z = 0.45 (P = 0.66). The combined adjusted OR was 0.71 (0.29 to 1.71), Z = 0.77 (P = 0.44).
Effects of healthcare worker vaccination on deaths from pneumonia
Potter 1997 reported data separately for vaccinated patients and we computed OR 0.56 (95% CI 0.27 to 1.14, Z = 1.59, P = 0.11) and for unvaccinated we computed OR 0.65 (95% CI 0.35 to 1.23, Z = 1.32, P = 0.19). Lemaitre 2009 reported results for vaccinated and unvaccinated patients combined and we computed OR 1.54 (95% CI 0.75 to 3.17, Z = 1.18, P = 0.24). We were able to pool the results (Tau
Non-specific effects of interventions
Effects of healthcare worker vaccination on influenza-like illness
Potter 1997, Hayward 2006 and Lemaitre 2009 defined influenza-like illness from a list of likely respiratory and systemic signs and symptoms.
Potter 1997 reported the data separately for vaccinated patients (RR 0.14, 95% CI 0.03 to 0.60, P = 0.008) and unvaccinated patients (RR 0.87, 95% CI 0.49 to 1.55, P = 0.64).
Hayward 2006 and Lemaitre 2009 reported results for vaccinated and unvaccinated patients combined. We were able to pool the results for Hayward 2006, Lemaitre 2009 and Potter 1997, which favoured vaccination (RR 0.71, 95% CI 0.55 to 0.90, P = 0.005, I
Oshitani 2000 did not define influenza-like illness. His cohort study shows a significant effect apart from the vaccination of residents (overall vaccine efficacy (VE) 61%, 95% CI 54% to 68%), but the study had a high risk of bias.
Effects of healthcare worker vaccination on GP consultations for influenza-like illness
Hayward 2006 provided data and we computed an adjusted OR of 0.48 (95% CI 0.33 to 0.69, Z = 3.98, P < 0.0001).
Effects of healthcare worker vaccination on deaths from influenza-like illness
Hayward 2006 provided data and we computed an adjusted OR of 0.72 (95% CI 0.31 to 1.70, Z = 0.75, P = 0.45).
Effects of healthcare worker vaccination on admissions to hospital
Hayward 2006 and Lemaitre 2009 provided data, and we were able to pool their data (X
Effects of healthcare worker vaccination on deaths from all causes
Potter 1997 reported outcomes separately for vaccinated patients and we computed OR 0.55 (95% CI 0.33 to 0.91, Z = 2.32, P = 0.02) and for unvaccinated patients we computed OR 0.55 (95% CI 0.33 to 0.94, Z = 2.19, P = 0.03). Carman 2000, Hayward 2006 and Lemaitre 2009 reported data for vaccinated and unvaccinated patients combined. We were able to pool the results (Tau
We were able to pool the results for Carman 2000, Hayward 2006, Lemaitre 2009 and Potter 1997 (Tau
We identified four cluster-RCTs and one cohort study to answer the question of whether vaccinating healthcare workers against influenza protects elderly residents in long-term care facilities. For the four cluster-RCTs adequate allocation was achieved in three, concealment of allocation in one, blinding in none and incomplete data were addressed in one. Carman 2000 and Oshitani 2000 did not adjust results for the effect of clustering.
Pooled data from three cluster-RCTs (Hayward 2006; Lemaitre 2009; Potter 1997) showed no effect on specific outcomes: laboratory-proven influenza, lower respiratory tract infections, admissions to hospital and deaths from pneumonia, with the 95% CI in each case including unity. Pooled data from three cluster-RCTs (Hayward 2006; Lemaitre 2009; Potter 1997) showed for non-specific outcomes that vaccination of healthcare workers reduced influenza-like illness and resident all-cause mortality; and data from one RCT (Hayward 2006) showed that healthcare worker vaccination reduced GP consultations for influenza-like illness.
A survey of 301 nursing home directors in one chain of nursing homes in the US found that homes with more than 55% of staff and more than 89% of residents vaccinated had a 60% lower risk of influenza-like illness clusters than all others.
One question is what is the maximum contribution that influenza vaccination of elderly people could make in reducing total annual mortality. A population study by Simonsen 2006 used data from the US national multiple-cause-of-death databases from 1968 to 2001 and found that for those aged 65 years or older, the mortality attributable to pneumonia or influenza never exceeded 10% of all deaths during those winters. The study by Vila-Córcoles 2007 of 11,240 Spanish community-dwelling elderly, conducted between January 2002 to April 2005 found the attributable mortality risk in individuals not vaccinated against influenza was 24 deaths/100,000 person-weeks within influenza periods. Vaccination prevented 14% of these deaths for the population, and one death was prevented for every 239 annual vaccinations (ranging from 144 in winter 2005 to 1748 in winter 2002). It should be noted that these data are not for residents of long-term care facilities. A mathematical model (van den Dool 2008) predicted that for a 30-bed unit, an increase in healthcare worker vaccination rates from 0% to 100% would decrease resident influenza infections by 60%.
Summary of main results
We identified four cluster-RCTs. Pooled data from three cluster-RCTs (Hayward 2006; Lemaitre 2009; Potter 1997) showed that there was no effect on laboratory-proven influenza, lower respiratory tract infections, admissions to hospital and deaths from pneumonia, with the 95% CI in each case including unity. Pooled data from three cluster-RCTs (Hayward 2006; Lemaitre 2009; Potter 1997) showed that vaccination of healthcare workers reduced influenza-like illness; data from one cluster-RCT (Hayward 2006) showed that healthcare worker vaccination reduced GP consultations for influenza-like illness; pooled data from three cluster-RCTs (Hayward 2006; Lemaitre 2009; Potter 1997) showed a reduction in resident all-cause mortality. Pooled data from two cluster-RCTs, Hayward 2006 and Lemaitre 2009, did not show an effect on hospital admissions.
Overall completeness and applicability of evidence
The four cluster-RCTs focused directly on the question of the effect of healthcare worker vaccination on the mortality and morbidity of long-term care facility residents aged 60 years or older. The four cluster-RCTs contributed data from a total of 10,137 participants, and the cohort study by Oshitani 2000 contributed data from 12,742 participants.
Quality of the evidence
The Cochrane Collaboration recommends assessment of study quality by independent assessment by two authors of six risks of bias. We found the following.
(1) Adequate sequence generation in three studies (Carman 2000 and Hayward 2006 by a random number table; and Lemaitre 2009 by centralised random-number generator) but uncertainty in one study (Potter 1997 "Hospital sites were stratified by unit policy for vaccination, then randomized for their healthcare workers to be routinely offered either influenza vaccination and patients unvaccinated...").
(2) Allocation concealment in one study (Hayward 2006 by a researcher blinded to the homes' identity and characteristics).
(3) No RCT used blinding of participants or study personnel. In Carman 2000, Potter 1997 and Hayward 2006 there is no statement that any researcher, assessor, data analyst, healthcare worker or participant was blinded. In Hayward 2006 lead nurses "were trained to promote influenza vaccination to staff." In Carman 2000 the study nurses "took additional opportunistic nose and throat swabs from non-randomised patients who the ward nurses thought had an influenza-like illness." In Potter 1997 ward nurses paged the research nurses "if any patients under their care developed clinical symptoms suggestive of upper respiratory tract viral illness, influenza, or lower respiratory tract infection," and in Lemaitre 2009 "Influenza vaccination was further recommended during face-to-face interviews with each member of staff ... The study team individually met all administrative staff, technicians, and caregivers to invite them to participate, and volunteers were vaccinated at the end of the interview.
In cluster-RCTs where the intervention is delivered to a group and there is an attempt to change both individual attitudes and behaviour and group perceptions and willingness to participate, it is a good question how much blinding can be achieved. Blinding is intended to avoid effects of interventions other than the study intervention, but when sharing of ideas and motivations is a key idea in the intervention then blinding is not achievable.
(4) Incomplete data were not addressed in four studies: Carman 2000, Hayward 2006, Oshitani 2000 and Potter 1997. Nursing homes vary in the numbers of admissions and departures both of residents and staff, and a complete account of the sample requires maintaining a flow-sheet of resident admissions and discharges and staff arrivals and departures. Only Lemaitre 2009 made a full inventory of residents: "The analyses included all residents who were present on at least one day in a participating nursing home between the beginning and end of the primary study period." In Hayward 2006 "The rates were measures based on person time where the denominator was the average number of residents during the period of interest (calculated as the number of occupied bed days during the period divided by the number of days in the period) and the numerator was the number of events in these residents during the period." Potter 1997 noted that "many patients refused a blood sample, and paired samples were only available from survivors..."
(5) None were selective in reporting data.
(b) All four cluster-RCTs and Oshitani 2000 were at risk of performance bias, with inadequate provision of influenza vaccine to some or all participants. In Carman 2000, in the long-term care facilities where vaccination was offered 48% of patients (range 0% to 94% for 10 long-term care facilities) and 50.9% of healthcare workers were vaccinated, and in those where it was not offered 33% of patients (range 0% to 70% for 10 long-term care facilities) and 4.9% of healthcare workers were vaccinated. The results for healthcare workers were based on the questionnaire data for nurses (with a 68% return rate in hospitals that offered vaccine to 49% in hospitals which did not offer vaccine). In Potter 1997, in the arm where both healthcare workers and participants were offered vaccination, 67% of the healthcare workers and 88.8% of the patients were vaccinated. In the arm where only healthcare workers were offered vaccination, 57% of the healthcare workers and 0.4% of the patients were vaccinated. In the arm where only patients were offered vaccination, 91.9% of participants were vaccinated and the percentage of healthcare workers was not stated. Lastly, in the arm where neither were offered vaccination, 0% of patients were vaccinated and the percentage for healthcare workers was not stated.
In Hayward 2006 78.2% of patients in intervention homes were vaccinated in 2003 to 2004 (70.5% in 2004 to 2005), and 71.4% in control homes in 2003 to 2004 (71.1% in 2004 to 2005). For healthcare workers in intervention homes 48.2% were vaccinated in 2003 to 2004 and 43.2% in 2004 to 2005, compared to 5.9% and 3.5% in control homes. In Lemaitre 2009 the average patient vaccination rate was 84.3% in the intervention and 82.5% in the control arm; and the staff vaccination rate was 69.9% (range 48.4% to 89.5% for 20 homes) in the intervention arm and 31.8% (range 0% to 69% for 20 homes) in the control arm. Thus the vaccination rates and the ranges of vaccination rates between homes vary widely, and this varying and incomplete uptake affects the conclusions that can be drawn, as clearly the interventions had no or minimal effect on vaccination rates in some homes.
Pooled data from three cluster-RCTs showed no effect on the key specific outcomes of laboratory-proven influenza, pneumonia and deaths from pneumonia, with the 95% confidence interval (CI) in each case including unity. For the non-specific outcomes pooled data from three cluster-RCTs showed that vaccination of healthcare workers reduced influenza-like illness; data from one cluster-RCT revealed that healthcare worker vaccination reduced GP consultations for influenza-like illness; pooled data from three cluster-RCTs showed a reduction in resident all-cause mortality, and pooled data from two cluster-RCTs showed no effect on hospital admissions.
Potential biases in the review process
We imposed no language restrictions on the search, and all studies were independently assessed by two review authors. The intra-cluster correlation coefficients (ICCs) we used for two of the four studies were based on the estimate provided by Hayward 2006. Although the recalculation of the standard errors was done in accordance with recommended procedures (Higgins 2008a), we have assumed that the adjustment required is the same across the outcomes extracted for each study. Rather than increase uncertainty around the pooled effect size, adjustment of the standard errors for the studies reduced the statistical heterogeneity between the study effect estimates. If the ICCs we used as the basis for these calculations were too large, our adjusted analyses may underestimate the true amount of variation between the study results.
Agreements and disagreements with other studies or reviews
Other reviews addressing similar study questions do not include all the studies that we found.
Implications for practice
All five studies are at high risk of bias. Pooled data from three cluster-randomised controlled trials (cluster-RCTs) (Hayward 2006; Lemaitre 2009; Potter 1997) found no effect on the outcomes of direct interest, namely laboratory-proven influenza, lower respiratory tract infections, admissions to hospital and deaths from pneumonia, with the 95% confidence interval (CI) in each case including unity. Pooled data from three cluster-RCTs (Hayward 2006; Lemaitre 2009; Potter 1997) showed that vaccination of healthcare workers reduced influenza-like illness and resident all-cause mortality; and data from one RCT (Hayward 2006) showed that healthcare worker vaccination reduced GP consultations for influenza-like illness. However, there was no effect on the outcomes of direct interest, namely laboratory-proven influenza, lower respiratory tract infections, admissions to hospital and deaths from pneumonia, with the 95% CI in each case including unity, and we conclude that there is an absence of high quality evidence to guide medical care and public health practitioners to mandate influenza vaccination for healthcare workers who care for the elderly in long-term care facilities. Because influenza-like illness encompasses many pathogens other than influenza, and because winter influenza contributes to less than 10% of all-cause mortality in the elderly, the most likely explanation for our findings is residual confounding from pathogens other than influenza, differential uptake of vaccine affected by socio-economic status, and varying belief on the part of healthcare workers regarding vulnerability to influenza, vaccine effectiveness and side effects. We conclude that there is no evidence from this research that vaccinating healthcare workers against influenza protects elderly people in their care.
Implications for research
There are currently only four cluster-RCTS providing data about the impact on elderly residents of vaccinating their healthcare workers against influenza, all at high risk of bias. RCTs are needed with minimal risk of bias from allocation, failure to conceal allocation, selection, performance, attrition and detection and these should be adequately powered for the key outcomes of laboratory-proven influenza, hospitalisation for pneumonia and death from pneumonia. They should carefully define and measure outcomes including influenza-like illness, laboratory-proven influenza, cause of hospitalisation, deaths from pneumonia and all-cause mortality. They should carefully consider the degree to which they must, to adequately assess outcomes, obtain proof of diagnosis for all participants by laboratory testing all participants with appropriate symptoms for influenza and all other likely viruses, performing blood cultures, white blood cell counts and other laboratory investigations and chest X-rays if pneumonia is suspected, and following the course of all hospitalised patients by scrutinising individual records so that they can definitively assess all outcomes and co-morbidities.
The area of interest is the elderly in long-term care facilities, therefore if the existing long-term care facilities' organisational structure is to be used to implement the interventions, these will need to be given to clusters of elderly residents and healthcare workers, which will make blinding difficult. An important ethical issue is informed consent by the elderly and healthcare workers. It is not ethical to blind participants or healthcare workers, but the researchers, data assessors and statisticians could all be blinded.
The elderly are much keener to be vaccinated than healthcare workers, and there is an extensive literature about the group of healthcare workers who say they do not feel vulnerable to influenza, do not believe the vaccine is effective and are afraid of side effects, and some of these do not perceive risk for their patients. Persistence of these beliefs may limit uptake by healthcare workers, and make it difficult to test conclusively the effect of very high levels of healthcare worker influenza vaccination.
Professor David J. Stott, Academic Section of Geriatric Medicine, Glasgow Royal Infirmary, UK provided supplementary information on the Potter 1997 and Carman 2000 studies. Dr Magali Lemaitre confirmed the ICC for Lemaitre 2009, and Dr Andrew Hayward provided information regarding the analysis of data for Hayward 2006.
We acknowledge the contributions of Vittorio Demicheli (previously responsible for design of the review and responsible for the final draft); Daniela Rivetti who was responsible for the previous searches; and Sarah Thorning, who conducted the searches for this 2009 update.
The authors wish to thank the following people for commenting on this updated draft Amy Zelmer, Laila Tata, Amir Shroufi, Rob Ware and John Holden.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Appendix 1. Previous search
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Systematic Reviews and the NHS Database of Abstracts of Reviews of Effects (DARE) (The Cochrane Library 2006, issue 1); MEDLINE (January 1966 to Week 1, February 2006); EMBASE (1974 to March 2006); Biological Abstracts (1969 to December 2005) and Science Citation Index-Expanded (1974 to March 2006).
MEDLINE was searched using the following search terms in combination with stages I, II and III of the highly sensitive search strategy defined by the Cochrane Collaboration and detailed in Appendix 5b of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2005).
1 exp INFLUENZA/
4 exp VACCINES/
5 exp VACCINATION/
6 (immuniz$ or immunis$).mp.
9 3 and 8
10 exp Influenza Vaccine/
11 (influenz$ adj (vaccin$ or immun$)).mp.
13 9 or 12
14 exp Health Personnel/
15 (health personnel or healthcare personnel or health care personnel).mp.
16 (health worker$ or healthcare worker$ or health care worker$).mp.
17 (healthcare provider$ or health care provider$).mp.
18 (health practitioner$ or healthcare practitioner$ or health care practitioner$).mp.
19 health employee$.mp.
20 medical staff.mp.
21 (doctor$ or physician$).mp.
22 (allied health adj (staff or personnel)).mp.
24 nursing staff.mp.
26 nursing auxiliar$.mp.
27 hospital personnel.mp.
28 hospital staff.mp.
29 hospital worker$.mp.
30 exp HOSPITALS/
31 exp Long-Term Care/
32 exp Residential Facilities/
33 nursing home$.mp.
34 (institution$ adj3 elderly).mp.
36 13 and 35
This strategy was adapted to search the other electronic databases. See below for the EMBASE search strategy. There were no language or publication restrictions. The search of CENTRAL included trial reports identified in the systematic search by hand of the journal Vaccine. To identify additional published and unpublished studies the Science Citation Index-Expanded was used to identify articles that cite the relevant studies. The relevant studies were also keyed into PubMed and the Related Articles feature used.
Bibliographies of all relevant articles were obtained, and any published review and proceedings from relevant conferences were assessed for additional studies. We explored Internet sources in December 2005: NHS National Research Register (http://www.update-software.com/national/); the metaRegister of Clinical Trials (http://www.controlled-trials.com/) the digital dissertations website (http://wwwlib.umi.com/dissertations). The Vaccine Adverse Event Reporting System website was searched (http://www.vaers.org). We contacted first or corresponding authors of relevant studies to identify further published or unpublished trials.
#1 explode 'influenza-' / all subheadings in DEM,DER,DRM,DRR
#2 (influenza in ti) or (influenza in ab)
#3 #1 or #2
#4 explode 'vaccine-' / all subheadings in DEM,DER,DRM,DRR
#5 explode 'vaccination-' / all subheadings in DEM,DER,DRM,DRR
#6 (immuniz* in ti) or (immuniz* in ab)
#7 (immunis* in ti) or (immunis* in ab)
#8 (vaccin* in ti) or (vaccin* in ab)
#9 #4 or #5 or #6 or #7 or #8
#10 #3 and #9
#11 explode 'influenza-vaccine' / all subheadings in DEM,DER,DRM,DRR
#12 explode 'influenza-vaccination' / all subheadings in DEM,DER,DRM,DRR
#13 (influenz* adj (vaccin* or immun*)) in ti
#14 (influenz* adj (vaccin* or immun*)) in ab
#15 #10 or #11 or #12 or #13 or #14
#16 explode 'health-care-personnel' / all subheadings in DEM,DER,DRM,DRR
#17 (health personnel or healthcare personnel or health care personnel) in ti
#18 (health personnel or healthcare personnel or health care personnel) in ab
#19 (health worker* or healthcare worker* or health care worker*) in ti
#20 (healthcare provider* or health care provider*) in ti
#21 (healthcare provider* or health care provider*) in ab
#22 (health practitioner* or healthcare practitioner* or health care practitioner*) in ti
#23 (health practitioner* or healthcare practitioner* or health care practitioner*) in ab
#24 (health employee* in ti) or (health employee* in ab)
#25 explode 'hospital-personnel' / all subheadings in DEM,DER,DRM,DRR
#26 explode 'hospital-physician' / all subheadings in DEM,DER,DRM,DRR
#27 explode 'medical-personnel' / all subheadings in DEM,DER,DRM,DRR
#28 (medical staff in ti) or (medical staff in ab)
#29 explode 'physician-' / all subheadings in DEM,DER,DRM,DRR
#30 (doctor* or physician*) in ti
#31 (doctor* or physician*) in ab
#32 (allied health adj (staff or personnel)) in ti
#33 explode 'paramedical-personnel' / all subheadings in DEM,DER,DRM,DRR
#34 ( paramedic* in ti) or ( paramedic* in ab)
#35 explode 'nursing-staff' / all subheadings in DEM,DER,DRM,DRR
#36 ( nursing staff in ti) or ( nursing staff in ab)
#37 ( nurse* in ti) or ( nurse* in ab)
#38 ( nursing auxiliar* in ti) or ( nursing auxiliar* in ab)
#39 (hospital staff in ti) or (hospital staff in ab)
#40 (hospital worker* in ti) or (hospital worker* in ab)
#41 explode 'hospital-' / all subheadings in DEM,DER,DRM,DRR
#42 explode 'long-term-care' / all subheadings in DEM,DER,DRM,DRR
#43 explode 'residential-care' / all subheadings in DEM,DER,DRM,DRR
#44 explode 'residential-home' / all subheadings in DEM,DER,DRM,DRR
#45 (nursing home* in ti) or (nursing home* in ab)
#46 (institution* adj elderly) in ti
#47 (institution* adj elderly) in ab
#48 #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47
#49 #15 and #48
Appendix 2. EMBASE search strategy
27. #23 AND #26
26. #24 OR #25
25. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*;ti,ab OR ((singl* OR doubl*) NEAR/2 (blind* OR mask*)):ab,ti
24. 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR
23. #11 AND #22
22. #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21
21. 'aged care':ab,ti OR 'nursing home':ab,ti OR 'nursing homes':ab,ti
20. (institution* NEAR/3 elderly):ab,ti
19. 'hospice'/exp OR 'assisted living facility'/exp OR 'hospital'/exp OR 'nursing home'/exp OR 'residential home'/exp
18. (nursing NEAR/2 (staff OR personnel OR auxiliar* OR assistant*)):ab,ti
17. paramedic*:ab,ti OR nurse*:ab,ti
16. 'allied health staff':ab,ti OR 'allied health personnel':ab,ti OR 'allied health worker':ab,ti OR 'allied health workers':ab,ti
15. doctor*:ab,ti OR physician*:ab,ti OR clinician*:ab,ti
14. (medical OR hospital) NEAR/2 (staff OR employee* OR personnel OR worker*)
13. ((health OR healthcare) NEAR/3 (personnel OR worker* OR provider* OR employee* OR staff)):ab,ti
12. 'health care personnel'/exp
11. #1 OR #10
10. #6 AND #9
9. #7 OR #8
8. vaccin*:ab,ti OR immunis*:ab,ti OR immuniz*:ab,ti
7. 'vaccine'/exp OR 'vaccination'/exp OR 'immunization'/exp
6. #2 OR #3 OR #4 OR #5
5. influenza:ab,ti OR flu:ab,ti
4. 'influenza virus b'/exp
3. 'influenza virus a'/exp
1. 'influenza vaccine'/exp
Appendix 3. Web of Science search strategy
Appendix 4. SIGN search strategy for observational studies
1 epidemiologic studies/
2 exp case-control studies/
3 exp Cohort Studies/
4 case control.tw.
5 (cohort adj (study or studies)).tw.
6 cohort analy*.tw.
7 (follow up adj (study or studies)).tw.
8 (observational adj (study or studies)).tw.
11 cross sectional.tw.
12 Cross-Sectional Studies/
Appendix 5. Assessment of Oshitani 2000 using the Newcastle-Ottawa Scale for non-RCTs (Wells 2005)
- Representativeness of the exposed cohort:
- truly representative of the average Long Term Care Facilities in Niigata Prefecture and City (mandatory surveys of influenza vaccination status and influenza-like illness occurrence every 2 weeks January to March 1999) in the community
- somewhat representative of the average ___________ in the community
- selected group of users (e.g. nurses, volunteers)
- no description of the derivation of the cohort
- Selection of the non-exposed cohort:
- drawn from the same community as the exposed cohort
- drawn from a different source
- no description of the derivation of the non-exposed cohort
- Ascertainment of exposure to influenza vaccine:
- secure record (e.g. surgical records)
- structured interview. “Mandatory survey.” “Influenza vaccine had been given to 3933 residents (30.8%). No resident had received vaccine in 75 facilities (50.3%). Vaccines had also been given to 1532 of 7459 staff, and 10 or more staff had been vaccinated in 47 facilities (31.5%).” No description of survey or how administered or how completeness ascertained.
- written self-report
- no description
- Demonstration that outcome of interest was not present at start of study:
- yes “An influenza outbreak was defined when the number of ILI per week exceeded 10% of the residents”
- Comparability of cohorts on the basis of the design or analysis:
- study controls for differences in demographic characteristics and co-morbidities of residents who were vaccinated, and characteristics of homes where residents received vaccination (select the most important factor) No
- study controls for any additional factor: geriatric health services facilities compared to special nursing homes for those with more severe conditions (this criteria could be modified to indicate specific control for a second important factor) No
- Assessment of outcome:
- independent blind assessment
- record linkage
- self-report “Mandatory survey every 2 weeks January to March 1999”
- no description
- Was follow up long enough for outcomes to occur (select an adequate follow-up period for outcome of interest):
- yes - January to March 1999
- Adequacy of follow up of cohorts:
- complete follow up - all subjects accounted for
- subjects lost to follow up unlikely to introduce bias - small number lost (> ___ % (select an adequate %) follow up, or description of those lost))
- follow-up rate < ___% (select an adequate %) and no description of those lost
- no statement No statement of admissions, deaths or separations from homes during study period. Total number of residents in Table 2 in homes where < 10 staff vaccinated is listed as 8699 but subcategories add to 8669, and in homes where ≥ 10 staff vaccinated listed as 4085 but subcategories add to 4073
Influenza vaccination for healthcare workers who work with the elderly, 5 May 2008
Feedback: The below is not an article in Journal of Infectious Diseases 1997; 175 (1) as cited. Indeed I've not been able to locate the the study in any other journal, though the study has been cited many times in other studies as well.
Potter J, Stott DJ, Roberts MA, Elder AG, O'Donnell B, Knight PV, et al. Influenza vaccination of health care workers in long-term-care hospitals reduces the mortality of elderly patients. Journal of Infectious Diseases 1997;175(1):1-6
Submitter agrees with default conflict of interest statement:
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.
We thank Thomas Kristiansen for his comment. The article was in fact published in the Journal of Infectious Diseases (volume 175), issue 1 in 1997. It is available for purchase or download at: http://www.jstor.org/pss/30129986.
Thomas Birk Kristiansen
Feedback comment added 21 June 2008
Influenza vaccination for healthcare workers who work with the elderly, 1 December 2009
In the table and list of included studies, you have reported Hayward 2006 (BMJ Des 2006), but this study is not included in the analyses or mentioned in the text. The outcomes of this study do not seem to be adequately reported in the table.
Submitter agrees with default conflict of interest statement: I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.
We thank Signe Flottorp for his comment, which we received as we were updating the review. His comment has now been addressed.
Last assessed as up-to-date: 27 September 2009.
Protocol first published: Issue 2, 2005
Review first published: Issue 3, 2006
Contributions of authors
Responsible for the design of the review: Roger Thomas (RET), Tom Jefferson (TOJ).
Responsible for data extraction: all authors.
Responsible for the assessment of study quality and outcomes: RET and TOJ.
Responsible for the first draft: RET.
Responsible for the final draft: RET, TOJ, TJL (Toby Lasserson).
Declarations of interest
TOJ received fees for consultancies, research and speaking engagements from Glaxo SmithKline Ltd., Roche Ltd., Chiron Ltd. and Sanofi Synthelabo Ltd.
Sources of support
- No sources of support supplied
- National Institute for Health Research (NIHR), UK.Competitive grant awarded through the Cochrane Collaboration
- National Health and Medical Research Council (NHMRC), Australia.Competitive grant to Chris Del Mar and Tom Jefferson, 2009
Medical Subject Headings (MeSH)
*Health Personnel; Homes for the Aged; Infectious Disease Transmission, Professional-to-Patient [*prevention & control]; Influenza Vaccines [*administration & dosage]; Influenza, Human [prevention & control; *transmission]; Randomized Controlled Trials as Topic; Vaccines, Inactivated [administration & dosage]
MeSH check words
Adult; Aged; Humans; Middle Aged