Download Influenza in the acute hospital setting

Review
Nosocomial influenza
Influenza in the acute hospital setting
Cassandra D Salgado, Barry M Farr, Keri K Hall, and Frederick G Hayden
Influenza poses special hazards inside
healthcare facilities and can cause
explosive outbreaks of illness. Healthcare
workers are at risk of acquiring influenza
and thus serve as an important reservoir
for patients under their care. Annual
influenza immunisation of high-risk
persons and their contacts, including
healthcare workers, is the primary means
of preventing nosocomial influenza.
Despite influenza vaccine effectiveness,
it is substantially underused by healthcare providers. Influenza can be
diagnosed by culturing the virus from
respiratory secretions and by rapid
antigen detection kits; recognition of
a nosocomial outbreak is important
in order to employ infection-control
efforts. Optimal control of influenza in
the acute-care setting should focus upon
reducing potential influenza reservoirs
in the hospital, including: isolating
patients with suspected or documented
influenza, sending home healthcare
providers or staff who exhibit typical
symptoms of influenza, and discouraging
persons with febrile respiratory illness
from visiting the hospital during a
known influenza outbreak in the
community. (Note: influenza and other
respiratory viruses can cause non- Figure 1. Poster displayed at University of Virginia showing proportion of UVA healthcare
febrile illness but are still transmissible.) workers receiving influenza vaccine.
The antiviral M2 protein inhibitors
Healthcare workers have increased risk of acquiring
(amantadine, rimantadine) and neuraminidase
inhibitors (zanamivir, oseltamivir) have proven influenza during known outbreaks since they are exposed to
efficacy in treating and preventing influenza illness; infected individuals in the community as well as hospitalised
however, their role in the prevention and control of patients with influenza. Whether infected at work or in the
influenza in the acute hospital setting remains to be community, healthcare workers may become an important
more fully studied.
source of influenza for their patients.4,6,7 For example, a
Lancet Infectious Diseases 2002; 2: 145–55
An important cause of morbidity and often mortality in
most communities every winter, influenza poses special
hazards inside healthcare facilities. Because of its short
incubation period and efficient respiratory spread from
person to person, it can cause explosive outbreaks of febrile
respiratory illness. The hospital patient population has
serious underlying illnesses, making influenza more lethal in
this setting.1–5
THE LANCET Infectious Diseases Vol 2 March 2002
serological study in the UK, where healthcare worker
immunisation had not been the standard of care, found that
up to 23% of healthcare workers contracted clinical or subclinical influenza during community outbreaks.8 Up to
CDS and KKH are infectious diseases fellows, BMF is hospital
epidemiologist and FGH is professor of medicine and pathology at
the University of Virginia Health System, Charlottesville, VA, USA.
Correspondence: Professor Frederick G Hayden, Box 800473,
University of Virginia Health System, Charlottesville, VA 22908, USA.
Tel +1 434 924 5059; fax +1 434 924 9065; email [email protected]
http://infection.thelancet.com
145
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review
Nosocomial influenza
impact, its modes of transmission and
reservoirs of infectivity, and methods of
nosocomial influenza detection, control,
and prevention.
Active surveillance within medical
facilities is necessary to identify
nosocomial outbreaks and
prevent spread within the facility.
All patients with suspected
influenza should be tested,
isolated under droplet
precautions, and reported
to infection control.
Epidemiology of nosocomial
influenza in the acute care
setting
Any patient who develops a
flu-like illness 72 h after
admission should be considered
a nosocomial case.
Hospital admissions
The annual number of influenza cases
and subsequent influenza-associated
hospital admissions, complications, and
deaths in the community are dependent
upon the pattern of disease and
circulating viral strains. Annual
Influenza testing should be
When a nosocomial outbreak
influenza epidemics typically affect
instituted when influenza is
is suspected, infected patients
5–10% of the adults in the community
detected during surveillance,
should be isolated. In extreme
and result in hospitalisation rates of
especially when a documented
situations, cohorting of patients
2–4/10 000 in otherwise young healthy
nosocomial case occurs, or a
on a ward staffed by designated
adults.10,11 However, hospitalisation rates
cluster (3) of cases of
vaccinated personnel may
suspected nosocomial influenza
are much higher among infants and
be necessary.
occur on the same ward during
young children, the elderly and certain
a short (48–72 h) period.
high-risk populations.12–14 In influenza
epidemics from 1968–1997 in the
USA, the number of disease-related
hospital admissions
ranged from
Once a nosocomial case is
16 000–220 000 per epidemic with over
confirmed, daily monitoring
for flu-like illnesses should be
half of these hospitalisations occurring
done, especially on
in those 65 years of age.12–15 Many of
wards with high-risk patients.
those hospitalised are considered to
have exacerbations of underlying disease
and are not always recognised as having
All healthcare personnel with
intercurrent influenza infection, so they
flu-like illness should be tested
may serve as potential sources of spread.
and excluded from patient care
Influenza-associated deaths are often
pending results.
the result of pneumonia or exacerbations
of cardiopulmonary conditions, and the
elderly population currently accounts for
In addition, influenza antivirals
approximately 90% of all influenzashould be considered to treat
related deaths.16 Excess influenza-related
infected patients and for
deaths occurred in 19 of 23 influenza
prophylaxis of exposed patients,
epidemics with rates ranging from
unvaccinated personnel, and
30–150/100 000 persons in those older
those vaccinated <2 weeks
before exposure.
than 65 years in the USA.15 Of note,
epidemics of influenza A H3N2 subtype
viruses have been associated with greater
Figure 2. Infection control measures for documented or suspected outbreaks. Adapted from
hospitalisation and mortality rates. In
www.cdc.gov/ncidod/hip/INFECT/flu_acute.htm
addition
to
causing
substantial
morbidity and mortality, epidemics
three-quarters of healthcare workers with influenza-like often have a deleterious, sometimes overwhelming, effect on
illness have continued to work while ill9 and thus may healthcare delivery and cause marked increases in healthcare
perpetuate transmission and foster outbreaks. Illness in costs. This results not only from a sudden surge in the
healthcare workers may also disrupt patient care and result number of hospital admissions over a relatively short period
in higher hospital expenditures.
of time, but also disruption of services due to an increased
Optimal prevention of nosocomial influenza should number of ill caregivers.15,17 Medical cost-containment
involve multiple strategies that focus upon reducing efforts, resulting in decreased numbers of available beds and
potential influenza reservoirs in the hospital. For example, staff, could exacerbate this problem and lead to shortages of
campaigns encouraging healthcare workers to get vaccinated acute care hospital beds during epidemics.
An even more dramatic and devastating effect on the
is one way forward (figure 1).We will review relevant aspects
of influenza epidemiology in the acute-care setting, its healthcare system has been described with pandemic
146
THE LANCET Infectious Diseases Vol 2 March 2002
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review
Nosocomial influenza
influenza. The pandemic of 1918–1919 was responsible for
nearly 40 million deaths and over 500 million infections
worldwide.18 It disrupted essential community services
including healthcare delivery in many communities.19 The
world-wide cumulative number of deaths in the 1957 Asian
and 1968 Hong Kong pandemics was estimated at nearly 6
million.18 Furthermore, pandemics are associated with
excess hospitalisations and mortality in adults below the age
of 65 years.16 One of the first well-documented descriptions
of nosocomial influenza involved a severe outbreak on a
general medical service during the 1957 pandemic.20
Estimates indicate that the next pandemic will cause
between 89 000 and 207 000 deaths and between 314 000
and 734 000 hospitalisations in the USA alone.21
Nosocomial impact
During periods of increased influenza activity in the
community and subsequent higher numbers of patients with
influenza in hospitals, the risk for nosocomial transmission
from infected patients increases. In addition, nosocomial
influenza may be acquired from healthcare workers, other
hospital employees, and visitors. Influenza can cause
sporadic or epidemic disease in hospitalised patients, and
nosocomial outbreaks have been described in regular
hospital wards, neonatal and adult intensive care units,
transplant centres, and in nursing homes and other chronic
care facilities.
Nosocomial influenza outbreaks are not uncommon but
are likely substantially under-reported. Outbreaks usually
occur during periods of community influenza activity and
are associated with notable morbidity, increased cost of care,
and excess mortality.1–5,17 In a review of 12 nosocomial
influenza outbreaks2-4,6,7,22-29(table), the outbreak duration
ranged from 2–69 days (median 7 days) and reported
patient attack rates ranged from 3–50% on epidemic wards
and 0·7–20% throughout the hospital. Healthcare worker
attack rates were infrequently reported but ranged from
11–59% among those caring for patients with influenza.
Much lower healthcare worker infection rates have been
documented at our hospital (less than 2% in any season
during the past decade) where workers have been
encouraged to be vaccinated, to report febrile respiratory
illness, to be screened for influenza, and sent home when ill
to prevent spread of infection to patients.30 Most nosocomial
outbreaks are caused by influenza A with nosocomial
influenza B infections occurring primarily in hospitalised
children; however, influenza B adult outbreaks have been
reported and one outbreak affected 20% of hospitalised
adults, whose average age was over 60 years.4 Although
valuable information is gained from review of these
outbreak investigations, most were not prospective studies
and may not be representative of all hospital experience with
influenza.
Mortality rates during nosocomial outbreaks vary
according to the affected patient population and circulating
strain. In neonatal ICU outbreaks, mortality may be low,
except for deaths occurring in babies with severe underlying
cardiopulmonary disease.24 In acute-care facilities, and
geriatric hospitals, median mortality has been 16%,2,4,6
whereas in specialised populations such as transplant
THE LANCET Infectious Diseases Vol 2 March 2002
or ICU patients, the mortality can be 33–60%.3,29 The
immunocompromised population including transplant
recipients, those receiving chemotherapy for malignancies,
and those with advanced HIV disease deserve special
consideration as illness secondary to influenza is often
severe. Up to 70% of influenza infections in
immunocompromised transplant and acute leukaemia
patients have been nosocomial in origin in several
studies.31–33 Pneumonia and death are common
complications of influenza in immunosuppressed children,
bone-marrow-transplant recipients, and those receiving
chemotherapy for acute leukaemia.33–37 Patients at greatest
risk of these complications seem to be those with the highest
degree of immunosuppression.36
Information regarding the economic impact of
nosocomial influenza is limited, but the financial burden
can be substantial, in part because of prolongation of
hospital stay and additional diagnostic and therapeutic
interventions for affected patients. Excess hospital costs are
also due in part to absenteeism of healthcare workers who
become ill during an influenza outbreak, since hospitals
must cover the salaries of the ill workers in addition to their
replacements.17 One study estimated a mean excess hospital
cost of over $7500 per episode of nosocomially acquired
influenza.17
Transmission
General principles
The influenza virus spreads from person to person by
respiratory droplets. When a person coughs or sneezes,
particles of varying sizes are created ranging from large
particle droplets that are filtered by the nose and pharynx
to small particle droplets that reach the alveolus. The
observation that influenza can be induced by intranasal
drops38 suggests a role for direct contact spread, but several
lines of evidence indicate more efficient transmission via
smaller particle aerosols. In experimentally infected
volunteers, the human infectious dose is at least 10–100
fold lower with inhalation of small particle aerosols
delivered to the lower respiratory tract than with direct
instillation of nasal drops.39 Further, intranasally
administered influenza virus uncommonly causes cough or
lower respiratory tract manifestations in experimentally
infected volunteers,40 whereas early onset and protracted
cough indicative of tracheobronchitis is characteristic of
natural influenza.41
Studies of differing routes of administering antiviral
drugs also suggest that intranasal inoculation is not the
usual route of natural transmission of influenza. Intranasal
zanamivir and intranasal interferon are protective against
intranasally introduced influenza under experimental
conditions, but both fail to prevent natural influenza in
ambulatory persons.42–44 By contrast, inhaled zanamivir is
protective against natural influenza in household and
nursing home contacts.45 Because of the range in natural
respiratory droplet particle size and a resulting gradient in
where particles land in the respiratory tract between the
nasopharynx and the alveolus, it is possible, however, that
droplets of intermediate size (ie, those capable of passing
the nose but not able to reach those more than about 5 feet
http://infection.thelancet.com
147
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review
Nosocomial influenza
Table 1. Description of reported nosocomial outbreaks in the acute-care setting
Author
Outbreak population
Muchmore6 Neurology ward
Duration of outbreak
Virus type
Number of patients affected (attack rate)
1 month
Influenza A2 “Asian Flu”
77 (50% on epidemic ward,
9% entire hospital)
Bauer7
Neonatal intensive care unit
Kapila2
Acute-care hospital ward
1 week
Influenza A2
9 (30% on epidemic ward)
Hall23
Acute-care infant ward
*1 month
Influenza A and B
12 (not stated, total number
exposed not known)
One week
Influenza A/Victoria/3/75
(H3N2)
8 infants affected, 5 with
documented infection
(total number exposed not known)
1 month
Influenza B/Singapore/222/
79-like
28 (33% on epidemic ward;
hospital attack rate for first 2 weeks
20%, 12% for last 2 weeks)
Meibalane28 Neonatal ICU
Not stated, but all cases occurred Influenza A/
within hours of each other
Hong Kong/1/68 (H3N2)
3 (not stated, total number exposed
not known)
Van-Voris4
Acute-care hospital
Malavaud25
Solid organ transplant unit
4 days
Influenza A (H3N2)
4 (33·3%)
CDC3
Medical-surgical ICU
Not stated
Influenza A
3 affected (total number exposed not
stated)
1 week
Influenza A (H3N2) Sydney
7 (25·9%)
4 (26·7%)
Weinstock29 Adult bone marrow
transplant unit
Munoz24
Neonatal ICU
5 days
Influenza A (H3N2)
Adal26
Acute-care hospital
69 days
Influenza A (H3N2)
10 (total number exposed not known)
Gowda22
Geriatric unit (rehabilitation and 1 month
admission wards)
Influenza A (resembling A/
Victoria/3/75)
19 (30%)
*Description of nosocomial influenza infections during a 1 month period of increased influenza activity in the community
Table continues on page 149
from the coughing individual) could have an important
role in influenza transmission. Of note, influenza viruses
retain infectiousness after aerosolisation for at least 24 h at
room temperature under conditions of low relative
humidity.46
Some epidemiological observations also point to
transmission through the air. One point source outbreak
due to an infected passenger on a delayed aeroplane with a
non-functioning ventilation system found a 72% clinical
attack rate for people throughout the passenger cabin over
the following 4 days; the risk of illness was dependent upon
the amount of time spent on board during the repairs of
the system.47 This outbreak is often used as evidence of
smaller particle droplet transmission, although it remains
possible that large particle droplet spread also had a role in
transmission during this outbreak as passengers moved
freely about the passenger compartment.47,48 Such
observations suggest that most naturally occurring
influenza infections occur by inhalation of droplets or
droplet nuclei rather than direct intranasal inoculation (eg,
from contaminated fingers).
Nosocomial aspects
In general, hospitalised patients with influenza are
maintained in private rooms but are not placed into
negative pressure isolation. Despite this, only rare
instances of spread outside the isolation room have been
recognised. For example, we have not recognised timespace clusters of cases of nosocomial influenza during the
past 15 influenza seasons at the University of Virginia
despite putting most cases of influenza into private,
positive pressure ventilation rooms. However, when
susceptible patients or groups are cohorted with an
148
infected index case, spread through the air seems to be
responsible for some transmission. One study assessed
influenza virus cross-infection during an influenza season
in paediatric wards and found that patients admitted to
wards with a greater proportion of beds in an open area
were more likely to acquire nosocomial influenza than
those who were admitted to wards with a greater
proportion of private beds.49 While this suggested spread
through the air, the data cannot clearly distinguish
between large and small particle droplet spread because of
lack of information about the spacing of the beds and any
time-space clustering of the illnesses. Furthermore, one of
the four wards in the group with more nosocomial
infections had 100% private rooms, which accounted for
29% of all of the infections in this group.49
The rapid onset and explosive nature of nosocomial
influenza outbreaks with secondary cases often occurring
within hours of each other have been used to suggest that
smaller particle aerosol transmission must be involved.7,24
In one of these outbreaks, two culture-proven and one
suspected nosocomial case occurred within hours of
one another, but each patient had been cared for by a
healthcare worker with influenza.7 In the other outbreak
four infants developed illness over a 4-day period; two
of the babies’ cribs were adjacent to one another
suggesting possible transmission. However, four neonatal
ICU nurses were sent home just before onset of the cases
for flu-like illness, although they had reportedly not
worked with the affected infants.24 While the sources and
transmission modes of influenza are unclear in such
reports, they implicate healthcare workers.7,24 Influenza
viruses can retain infectiousness on non-porous surfaces
for 24–48 h and for at least 5 min on hands,50 and one
THE LANCET Infectious Diseases Vol 2 March 2002
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review
Nosocomial influenza
Table, continued
Author
Presenting symptoms
Muchmore6 Headache, chills, muscle
aches, and fever
Healthcare worker attack rate
Patient mortality rate
3 healthcare workers
affected (total number
with patient contact not known)
3 deaths occurred (all with
Inter-ward transfers discontinued and
underlying pulmonary disease) afebrile patients discharged to
epidemic ward 16% hospital 4% decrease crowding
Control efforts employed
Bauer7
Fever, nasal drainage,
2 ill healthcare workers
tachypnoea, raised white blood (total number with patient
cell count
contact not known); both
were symptomatic and cared
for infants before their diagnosis
0%
Not stated
Kapila2
Fever, bronchopulmonary
No ill healthcare
symptoms, and chest radioworkers reported
graph findings of basilar infiltrates
67%. All patients had
underlying illness.
Not stated
Hall23
Fever, dry cough, lethargy,
irritability, white blood cell
count, anorexia, and pulmonary
infiltrates
One physician caring for infants 0%
affected (documented); however,
4 of 9 (44%) other medical
personnel possibly affected
but not tested
Careful handwashing and gown use
when handling affected infants
Meibalane28 Lethargy, poor feeding, mottling,
apnoea, fever, cough,
pulmonaryinfiltrates. Duration of
illness ranged from 4–11 days.
Not stated but immediately before 0%
the outbreak several patients
and nursing staff had fever
with upper respiratory symptoms
Parents were not allowed to visit
and nursing staff was sent home
Van-Voris4
Malaise, chills, fever
(0–8 days), cough,
Excess hospital duration
of 3·2 days.
Excess hospital cost of
$458 per patient infected
59% on epidemic ward
0%
Patients clinically ill with influenza placed
into cohorts, elective admissions limited,
visitors limited, and ill workers sent home
Malavaud25
Fever, headache, myalgias,
cough, pulmonary infiltrates
on chest x-ray
11·1%
0%
Respiratory isolation of infected patients.
CDC3
Not stated
1 healthcare worker affected; total 33%
number exposed not known
Not stated
Weinstock29 Radiographic evidence
of pneumonia
5 healthcare worker affected but 60%
total number exposed not known
15 step infection control programme
Munoz24
Rhinorrhea, cough, tachypnoea, Not stated
fever, mild WBC elevation,
and hypoxaemia
25%. All patients had
underlying cardiac or
pulmonary disease
Adal26
Specific symptoms not stated
10%. Patient had underlying
pulmonary illness
Gowda22
Not stated
Fever, tachycardia, hypotension, Not stated
mental status changes, and
patchy consolidation on chest
15·8%
Respiratory isolation for ill patients and
use of a mask, gown, and gloves for care.
Potentially exposed infants cohorted
Suspected cases placed into
respiratory isolation, symptomatic
visitors discouraged from entering
hospital
Not stated
radiograph.
ICU= intensive care unit; WBC=white blood cells; HCW=healthcare workers
*Description of nosocomial influenza infections during a 1 month period of increased influenza activity in the community
nursing home outbreak implicated transmission by the
hands of healthcare providers.51 It seems reasonable to
assume that multiple routes of nosocomial transmission
are possible.
Duration of contagiousness
An important issue in acute-care settings is the type
and duration of isolation for patients with documented
or suspected influenza. The principal reservoir of
human influenza is the respiratory tract, particularly
nasopharyngeal secretions and sputum of infected people.
The period of communicability is estimated by the duration
of recovery of infectious virus from respiratory tract samples
but is likely to be heavily influenced by the presence of
THE LANCET Infectious Diseases Vol 2 March 2002
symptoms that generate infectious aerosols (eg, coughing).
Viral shedding may begin at least 1 day before clinical illness
and the duration of shedding depends on the age and
immune status of the affected person. Outpatient children
commonly shed for 7 days or longer, whereas nonhospitalised immunocompetent adults may shed for 4–5
days after symptom onset.52 Institutionalised elderly adults
have shown more prolonged virus recovery (for up to 7
days),53 and nosocomially infected infants shed virus for up
to 21 days.23
Immunosuppressed patients often also shed for
prolonged periods of time. For example, one 7-year-old girl
with advanced HIV disease had nasopharyngeal shedding of
influenza for at least 9 weeks54 and among influenza-infected
http://infection.thelancet.com
149
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review
Nosocomial influenza
adult bone-marrow-transplant or leukaemia patients, the
median duration of shedding was 7 days but ranged up to 44
days.55,56 Of note, among rimantadine recipients, 83% of
those shedding virus for 3 days or more had resistant
variants. The duration of virus recovery is not well
characterised in hospitalised adults but many have
detectable virus in upper-respiratory-tract samples at 5 days
after admission.57 The duration of viral replication in the
lower respiratory tract has not been studied rigorously, nor
has the effect of antiviral therapy on viral recovery
been critically assessed in hospitalised patients. Prolonged
shedding has important implications for nosocomial
spread, in that such patients may serve as reservoirs of
influenza virus, including drug-resistant variants. Sequential
virological monitoring of patients at high risk for protracted
viral excretion may be necessary.
Detection and diagnosis
Recognition of an outbreak is essential in order to employ
control efforts such as isolation of patients suspected of
having influenza, discouraging visits by those with suspected
influenza, and sending home ill healthcare workers. The
development of unexplained fever and/or respiratory illness
in a hospitalised patient should raise the possibility of
nosocomial influenza during influenza season. Hospitalised
elderly adults may exhibit atypical features including
gastrointestinal manifestations and altered cognition. In
infants, a sepsis syndrome may occur with apnoea, lethargy,
and poor feeding.28 Influenza may occur sometimes outside
the usual seasonal patterns, so outbreaks of unexplained
febrile illness during summer months warrant appropriate
diagnostic studies.
Influenza can be diagnosed by culturing the virus from
respiratory secretions (nasal swabs, throat swabs, or nasal
washes), or by more rapid influenza diagnostic tests
for antigen (immunoassay or immunofluoresence),
neuraminidase enzymatic activity, or viral RNA by reverse
transcription PCR. The performance of one enzyme
immunoassay, Directigen FLU-A (Becton Dickinson
Microbiology Systems, Cockeysville, MD) and a direct
immunofluorescence test, IFA, were compared with culture
isolation of influenza A in geriatric patients.58 Directigen
FLU-A had a sensitivity of 86·8% and a specificity of 99·1%,
and IFA had a sensitivity of 92·5% and a specificity of
97·2%.58 By providing same-day diagnosis, rapid testing
allows for early detection of nosocomial influenza outbreaks
and enables infection control departments to institute
appropriate containment measures throughout the hospital
to prevent further spread. However, sending specimens for
viral culture is important because only culture isolates can
provide information regarding influenza subtypes and
strains and potential drug resistance. Furthermore, the
available rapid diagnostic tests vary in their performance
characteristics according to assay type, sample type, time of
sample collection, and age of the patient. When compared
with influenza isolation, immunofluorescence assays are
50–90% sensitive for viral detection58–61 and enzyme
immunoassays are 50–80% sensitive.62–65 In general, the
sensitivity of rapid diagnostic tests is higher in children than
adults and higher for nasal samples than throat specimens.59
150
False-positive results occur with some commercial antigen
assays and have resulted in incorrect diagnosis of influenza
as a cause of several outbreaks of respiratory illness. The
positive predictive value of these tests outside known
influenza epidemics may be low.60–63
Annual prospective surveillance of influenza activity in
the community helps to define the period of risk for
hospitalised patients. Passive surveillance by employee
health services may not be helpful as the only method of
community influenza surveillance because it often
underestimates the amount of active influenza illness in the
community. Once influenza is known to be circulating in
the community, we recommend routine influenza testing in
patients presenting to hospitals for admission with an acute
febrile respiratory illness. Hospitalised patients who develop
symptoms compatible with influenza during a known
outbreak in the community should also be tested. Pseudooutbreaks due to laboratory contamination should be
considered when unusual isolates or recovery from persons
with atypical illness occur.66
Prevention and control
Interrupting transmission of virus
Effective control of outbreaks in acute-care facilities is
challenging since several reservoirs for transmission exist,
including patients, providers, staff, and visitors. Once a
community outbreak has been recognised, patients
presenting for hospital admission with febrile respiratory
illness should be tested for influenza and placed into
droplet precautions (private room, mask for healthcare
workers and for patients when they leave the room) until
their influenza status is known (figure 2). Similarly,
droplet precautions should be employed for hospitalised
patients with documented or suspected influenza.15 As
influenza rapid antigen tests are relatively insensitive,
patients with suspected influenza and a negative rapid
antigen test should remain in droplet precautions for at
least 5 days pending results of influenza cultures before
removal from isolation. When appropriate, it is also
important to consider and screen for alternative diagnoses,
such as respiratory synctial virus, adenovirus, Mycoplasma
pneumoniae, and others. Rapid tests may be useful in
situations where patient cohorting becomes necessary.
Patients with documented influenza of the same type may
be placed in the same room or cohort ward. To prevent
further spread, visitors with fever and respiratory
symptoms should be discouraged from entering the
hospital. This can be accomplished by public service
announcements in local newspapers, on television news,
over radio broadcasts, and on memos posted around
hospital entrances. Another nosocomial reservoir is
healthcare providers and other hospital employees who
have patient contact. Sending home of these workers when
they exhibit symptoms typical of influenza becomes an
important control measure. Illness in healthcare workers is
likely to be under-reported because these people are highly
motivated and typically do not want to burden co-workers,
consider their roles important, and may not feel “ill
enough” to stay home. In addition, many paid healthcare
workers may avoid using sick leave days that are combined
THE LANCET Infectious Diseases Vol 2 March 2002
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review
Nosocomial influenza
with vacation time. Educational efforts explaining the
seriousness of illness caused by influenza, its mode of
transmission and nosocomial spread, as well as ways they
can participate in control and prevention activities may be
necessary to gain compliance with furlough of infected
workers.
Immunisation
Annual influenza immunisation of high-risk persons and
their contacts, including healthcare providers, is the
primary means of preventing nosocomial influenza;
however, vaccination has been substantially underused,
particularly by healthcare workers.15
acceptance by healthcare workers continues to be below
recommended levels. One survey during the1986–87
season at a large acute-care hospital found that among
healthcare workers, immunisation rates were less than
10%.9 Also, 35% developed influenza-like illness during
that influenza season, and 77% took care of patients while
ill.9 Even in the setting of community-wide epidemics,
several studies have reported that one-third or fewer
hospital workers accepted influenza vaccine,73,74 and some
studies have found lower rates of healthcare worker
acceptance than among non-medical employees in such
institutions.75 More recent surveys in the USA have found
that approximately 30% of healthcare workers receive
influenza immunisations.76
Inactivated influenza vaccine in patients
Increasing rates of pre-season immunisation among people
in the community and healthcare providers would lessen
the impact of influenza on the healthcare environment.
Prevention of influenza has been hampered by inadequate
vaccine use and by the fact that many high-risk patients
do not develop a protective antibody response after
immunisation. The Advisory Committee on Immunisation
Practices (ACIP) of the Centers for Disease Control and
Prevention (CDC) recommends annual immunisation
vaccination of high-risk patients and their contacts.15 Highrisk is currently defined as age 50 years or more, residence
in a nursing home or other long-term care facility, chronic
pulmonary or cardiovascular disorders, underlying illness
that requires regular medical follow-up or hospitalisation,
long-term aspirin therapy, and pregnancy entering its
second or third trimester during an influenza season.
Generally, in healthy young adults, influenza vaccine
efficacy has ranged from 70–90% depending upon seasonal
virus circulation.67 Among the US population over the age
of 65, influenza vaccination rates have increased from 33%
in 198968 to 63% in 1998.69 The greatest proportion of those
vaccinated are non-Hispanic whites, and rates are lower
among blacks and Hispanics.69 According to CDC, only
23% of adults younger than 50 years with high-risk
conditions were vaccinated last year in the USA, far short
of the 60% goal.15
The effectiveness of vaccine in preventing influenza
among the institutionalised elderly and those with chronic
illness may be as low as 30–40%, but can be effective for
reducing hospitalisations, complications, and deaths.70,71
One recent study suggested that an increased influenza
vaccination rate among elderly patients in the community
(to 65%) could have had an important effect (along with a
significant increase in healthcare worker vaccination
compliance rate) on risk for nosocomial influenza among
patients in the local hospital.30
Inactivated influenza vaccine in healthcare workers
ACIP has also recommended annual influenza
immunisation for healthcare workers since 1981 and has
targeted providers in both hospitals and outpatient care
settings as a high priority group since 1986.72 The goals of
this strategy are to reduce the risk of patient influenza
exposure and to ensure provision of essential community
services, so that patient care is not disrupted. Vaccine
THE LANCET Infectious Diseases Vol 2 March 2002
Vaccine acceptance among healthcare workers
Surveys of healthcare workers have identified various
reasons for a lack of vaccine acceptance including
inconvenience, necessity of obtaining written informed
consent, concerns about vaccine effectiveness, concerns
about vaccine side-effects including misconceptions that
vaccine may cause influenza, and lack of understanding
of the risks of acquiring infection and transmitting it to
high-risk patients. One study found that the most
frequently cited reasons for non-acceptance were fear of
side-effects (35%), avoidance of medications (33%),
reaction to vaccine in the past (24%), impression of
low risk of acquiring influenza (18%), and dislike of
shots (18%).75
Specific occupational groups have different concerns,
which remain to be fully elucidated. Better understanding
of epidemiological risk factors and barriers to influenza
immunisation should translate into better acceptance of
vaccine. For example, a study at the University of Iowa74
found that physicians were significantly more likely to
accept the vaccine than other occupational groups.
Advancing age, prior absenteeism (as surrogate marker for
underlying illness), higher socioeconomic status (salary
level), and marriage were associated with increased vaccine
uptake in various target groups.74 Another study found
that the predictors of acceptance were prior receipt of
influenza vaccine, age of at least 50 years, and knowledge
that vaccine does not cause influenza.75
Vaccine efforts need to be directed at all healthcare
workers and other staff who deal directly with sick people.
In this regard, the Iowa study concluded that professional
support staff with patient contact, younger workers,
those recently employed, and lower paid workers should
be considered for targeted efforts at increasing
immunisation.74 To maximise convenience and minimise
disruption of usual clinical activities, the ACIP
recommends using a mobile cart to deliver vaccine onsite
to healthcare workers in the workplace, increased
availability after hours, and follow-up immunisation
programmes early in the course of recognised community
outbreaks.15 At the University of Virginia, use of a chart,
showing updated healthcare worker compliance rates with
influenza vaccine, posted in frequented areas of the
hospital, was partly responsible for increasing vaccination
acceptance rates to nearly 70% (figure 1).30
http://infection.thelancet.com
151
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review
Nosocomial influenza
number of reported febrile days exceeded the number of
work absence days suggested that the affected healthcare
providers reported for work during febrile illness82
(figure 3). Inactivated influenza vaccine is highly effective
in preventing influenza infection in younger healthcare
workers, reduces days of illness, and probably days of
absenteeism.82
Vaccine efficacy
Convincing evidence that influenza immunisation of
healthcare workers would prevent nosocomial crossinfection would be a compelling argument in favour of
healthcare worker immunisation. Two studies conducted in
Scottish geriatric hospitals, one retrospective and the other
prospective, provided evidence that healthcare worker
immunisation was associated with reduced mortality during
influenza season in the resident patients.8,77 However, it was
unclear whether the reduction in mortality was due to
prevention of influenza, since no data were presented
regarding specific rates of influenza-related illness or
pneumonia in patients or workdays lost in healthcare
providers.8 Another study from the University of Virginia
documented an association between a significant
improvement in vaccine compliance among hospital
employees and a significant decrease in nosocomial
influenza among hospital patients over the same period.30
Questions remain regarding the cost benefit of
vaccinating healthy working adults because cost-benefit
studies have not been consistent.78–81 A recent assessment of
the societal economic impact of annual influenza
vaccination of healthy working adults was conducted by
Nichol.78 A mathematical model estimated that,
vaccination prevented an average of 12 workday
absenteeisms and three physician visits per 100 persons
vaccinated per year. Vaccination also resulted in a net
savings of almost $14 for each person vaccinated and was
cost effective 95% of the time.78
Few studies have focused specifically on healthcare
workers. One double-blind, placebo-controlled trial found
that vaccine efficacy based on serological evidence of
infection was high in healthcare workers, mostly resident
physicians and medical students.82 Compared with the
cumulative influenza attack rate of 14% in the control
group, protection against laboratory-documented
influenza infection averaged approximately 90% for both
influenza A and B virus infections. Reductions in days of
reported febrile illness or days of absence were observed in
vaccine recipients, but these were not statistically
significant, perhaps due to relatively small samples sizes,
intercurrent non-influenza illness, and a high degree of
motivation to return to work. The finding that the mean
Live-attenuated, intranasal influenza vaccine
A live-attenuated, cold-adapted influenza vaccine (CAIV)
administered intranasally is under active consideration by
the United States Food and Drug Administration
(USFDA) for use in adults younger than 65 years and
children. One question regarding CAIV is whether it is as
efficacious as the injected inactivated vaccine in adults.
A 5-year controlled, blinded trial involving 5210 healthy
adult, over 80% of whom were aged 18–65 years,
compared the efficacy of inactivated vaccine to attenuated
intranasal CAIV formulations containing two influenza A
viruses. For H1N1 infection, the efficacy of intranasal
vaccine was 85% in preventing culture-positive illness
compared with 76% for injected vaccine. For H3N2
infection the efficacies were 58% and 76%, respectively.
Inactivated vaccine significantly increased serum
haemagglutination-inhibiting (HAI) antibody titres and
appeared to be more protective against seroconversion and
reported illness.83 However, this trial was limited by
use of a ten-fold lower dose of CAIV virus than current
formulations, administration by drops instead of spray
(perhaps more effective), and, unlike the situation for
injected vaccine components, by lack of frequent
intranasal CAIV virus updates to assure a good antigenic
match with the circulating strains of influenza. A recent
study in experimental intranasally induced human
influenza A and B found that the efficacy of a trivalent
CAIV in preventing influenza following wild-type
challenge was higher with CAIV-T (85%) than with
trivalent inactivated vaccine (71%).84 A related question is
whether vaccine recipients, symptomatic or not, are at risk
of transmitting vaccine virus infection to hospitalised
patients. In immunised adults the titres of recoverable
virus in the nasal secretions have usually been much lower
than those needed to induce infection in seronegative
children (103 50% tissue culture
infectious doses [TCID50]/mL)
or adults (105 TCID50/mL). Very
rare instances of transmission of
CAIV have been recognised from
immunised children.
% serological influenza
Days of absence per 100 persons
Antiviral chemoprophylaxis
Amantadine and rimantadine
Days of febrile respiratory
illness per 100 persons
Trivalent influenza vaccine
Control
0
10
20
Figure 3. Influenza vaccine in healthcare workers: cumulative outcomes.82
152
30
40
50
Two classes of antiviral agents,
the M2 ion-channel inhibitors
(amantadine
and
rimantadine)
and the neuraminidase inhibitors
(oseltamivir and zanamivir) have
proven efficacy in preventing
influenza illness and infection. The
first reported trial demonstrating the
THE LANCET Infectious Diseases Vol 2 March 2002
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review
Nosocomial influenza
efficacy of antiviral chemoprophylaxis
for hospital-acquired influenza was
Clinical
conducted in 197285 (figure 4). The
influenza A
trial was a non-blinded randomised
comparison of oral amantadine with no
Subclinical
treatment among patients admitted to
influenza A
either a general medicine or neurology
ward during a recognised community
epidemic of influenza A. Amantadine
Total
infection
was given in a dose of 100 mg twice
daily for the duration of hospitalisation.
Four patients were admitted with active
0
5
10
15
20
25
influenza. The efficacy of amantadine in
%
of
patients
preventing influenza illness was 100%
compared with an attack rate of 11% in
No treatment (n=61)
Amantadine (n=50)
the group receiving no treatment.
Almost all of the infections occurred in Figure 4. Prevention of nosocomial influenza with amantadine.
those with a low admission HI titre
(less than or equal to 1/20) and only a few patients had Oseltamivir and zanamivir
The neuraminidase inhibitors (zanamivir and oseltamivir)
received vaccine.85
Emergence and transmission of drug-resistant influenza have demonstrated safety and efficacy in prevention of
may occur rapidly with use of amantadine or rimantadine, both influenza A and B in community and family-based
specifically in institutions and households. Up to one-third studies.45,91 Oseltamivir may be given orally; however,
of patients may shed resistant strains by 2–5 days after because of poor bioavailablity, zanamivir must be given by
starting treatment for influenza56,86,87 Of note, among inhalation. One controlled trial of inhaled zanamivir for
immunocompromised rimantadine recipients, 83% of those prevention of influenza in families with an index case of
shedding virus for 3 days or more had resistant variants.56 illness demonstrated that zanamivir provided protection
Failures of drug prophylaxis and at least one case of fatal against influenza A and B with a 79% reduction in the
influenza due to probable nosocomial transmission of proportion of families with at least one affected contact.45
Also, importantly, no zanamivir-resistant variants were
resistant virus have occurred in nursing home residents.88
The optimal duration of antiviral chemoprophylaxis for a recovered among index cases who received zanamivir. The
nosocomial outbreak is not certain. Randomised trials in protective efficacy of long-term use of oseltamivir during
nursing home populations, which employed short-term or an influenza season was 74% for influenza-like illness and
long-term amantadine prophylaxis found that administration 87% for culture-proven disease.91 When used for postfor 14 days, and 7 days beyond the last confirmed illness on exposure prophylaxis in families, oseltamivir (75 mg once
the unit, appeared to be adequate.88 The duration of antiviral daily for 7 days) was 90% effective.92 Clinical isolates with
prophylaxis should be guided by ongoing surveillance on the reduced susceptibility to zanamivir and oseltamivir after
specific ward or facility. Once drug use has been initiated, treatment have been reported uncommonly;{Roche
virologic testing of any new illnesses is helpful in guiding Laboratories 2000 70 /id} but data are limited regarding
duration and to look for other nosocomial pathogens (eg, possible transmission of these strains and their ultimate
respiratory syncitial virus [RSV]). Persistent isolations of virus clinical impact.
with new cases suggest circulation of drug-resistant variants or
The use of zanamivir and oseltamivir during acute-care
new introductions. For example, in nursing homes, outbreaks outbreaks of influenza has not been reported, but evidence
of parainfluenza virus, RSV, and influenza B virus have been exists regarding effective influenza prevention in other
documented during periods of community influenza A institutional settings. One randomised, unblinded study
activity or there have been out-of-season outbreaks not
temporally associated with community activity.89
Search strategy and selection criteria
Amantadine and rimantadine can cause central nervous
Medline searches of English language publications from
system (CNS) and gastrointestinal side-effects. The incidence
1966–2001 on the major topic headings: influenza, cross
of CNS side-effects seems to be greater for those taking
infection, nosocomial influenza, morbidity, mortality,
amantadine. One nursing home study evaluated CNS toxicity
death, patient outcome, influenza vaccine, infection control,
among patients receiving amantadine or rimantadine for
cost, cost benefit analysis, prevention, and treatment (and
influenza A prophylaxis during the 1997–1998 influenza
combinations thereof) as well as personal Reference
season.90 Amantadine was associated with a significantly
Manager files and bibliography lists of textbook chapters
higher rate of CNS toxicity than rimantadine (18·6% vs 1·9%,
were used as the database for this review. References were
p<0·01) and more patients discontinued amantadine (17·3%
selected for use if they addressed the impact, transmission,
vs 1·9%, p<0·001). Confusion was the predominant symptom
prevention, or control of influenza in the acute-care
associated with CNS toxicity and after multivariate analysis,
hospital, or the efficacy and recommendations for influenza
male sex, reduced creatinine clearance, and amantadine use
vaccine and chemoprophylaxis.
were all significant risk factors for CNS toxicity.90
85
THE LANCET Infectious Diseases Vol 2 March 2002
http://infection.thelancet.com
153
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review
Nosocomial influenza
compared zanamivir chemoprophylaxis with rimantadine
during an influenza A nursing home outbreak and to no
prophylaxis during a subsequent influenza B outbreak.93
During the prophylaxis period for the influenza A outbreak,
only one laboratory-confirmed case of influenza A occurred
in a volunteer taking rimantadine and during the
prophylaxis period for the influenza B outbreak, only one
laboratory- confirmed case of influenza B occurred in a
volunteer not receiving prophylaxis.93 Even though this
study was small with a low overall influenza attack rate, it
demonstrated that zanamivir was comparable to the
standard of care at the time. A follow-up, blinded trial
study compared 2-week prophylaxis with oral rimantadine
(100 mg daily) with inhaled zanamivir (10 mg daily in
nursing homes with documented influenza A outbreaks)
and found that zanamivir was associated with 61%
additional protective efficacy compared with rimantadine,
References
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Weingarten S, Friedlander M, Rascon, Ault M,
Morgan M, Meyer R. Influenza surveillance in an
acute-care hospital. Arch Intern Med 1988; 148:
113–16.
Kapila R, Lintz D, Tecson F, Ziskin L, Louria D. A
nosocomial outbreak of influenza A. Chest 1977; 71:
576–9.
Anonymous, Centers for Disease Control and
Prevention. Suspected nosocomial influenza cases in
an intensive care unit. Morb Mortal Wkly Rep 1988;
37: 3–4.
Van-Voris L, Belshe R, Shaffer J. Nosocomial
influenza B virus infection in the elderly. Ann Intern
Med 1982; 96: 153–8.
Bean B, Rhame F, Hughes R, Weiler M, Peterson L,
Gerding D. Influenza B: hospital activity during a
community epidemic. Diag Microbiol Infect Dis 1983;
1: 177–83.
Muchmore H, Felton F, Scott L. A confirmed hospital
epidemic of Asian influenza. J Oklahoma State Med
Assoc 1960; 53: 142–5.
Bauer C, Elie K, Spence L, Stern L. Hong Kong
influenza in a neonatal unit. JAMA 1973; 223:
1233–35.
Elder A, O’Donnell B, McCruden E, Symington I,
Carman W. Incidence and recall of influenza in a
cohort of Glasgow healthcare workers during the
1993-4 epidemic: results of serum testing and
questionnaire. BMJ 1996; 313: 1241–42.
Weingarten S, Riedinger M, Bolton L, Miles P,
Ault M. Barriers to influenza vaccine acceptance: a
survey of physicians and nurses. Am J Infect Control
1989; 17: 201–207.
Barker W, Mullooly J. Impact of epidemic type A
influenza in a defined adult population. Am J
Epidemiol 1980; 112: 798–811.
Neuzil K, Reed G, Mitchel E, et al. Influenzaassociated morbidity and mortality in young and
middle aged women. JAMA 1999; 281: 901–907.
Simonsen L, Fukuda K, Schonberger L, Cox N.
Impact of influenza epidemics on hospitalisations.
J Pediatr 2000; 181: 831–37.
Noble G. Epidemiological and clinical aspects of
influenza. In: Beare A, editor. Basic and applied
influenza research. 1 ed. Boca Raton, FL: CRC Press,
1982: 27–38.
Lui K, Kendal A. Impact on influenza epidemics on
mortality in the United States from October 1972 to
May 1985. Am J Public Health 1987; 77: 712–16.
Anonymous. Prevention and control of influenza;
recommendations of the Advisory Committee on
Immunisation Practices (ACIP). Morb Mortal Wkly
Rep 2001; 50: 1–44.
Simonsen L, Clarke M, Schonberger L, Arden N,
Cox N, Fukuda K. Pandemic versus epidemic
influenza mortality: a pattern of changing age
distribution. J Infect Dis 1998; 178: 53–60.
Serwint J, Miller R. Why diagnose influenza infections
in hospitalised pediatric patients? Pediatr Infect Dis J
1993; 12: 200–4.
Oxford J. Influenza A pandemics of the 20th century
with special reference to 1918: virology, pathology,
and epidemiology. Rev Med Virol 2000; 10: 119–33.
Schoch-Spana M. Implications of pandemic influenza
154
in part because of failures of rimantadine prophylaxis
due to drug-resistant strains.48 In a highly immunised
nursing home population, seasonal prophylaxis with oral
oseltamivir 75 mg once daily was well-tolerated and
92% preventive against influenza compared with placebo.94
These newer antiviral agents are highly effective for
prevention but more expensive than M2 inhibitors, and
other than documented influenza B outbreaks, their role
in prevention of nosocomial outbreaks in acute-care
hospitals remains to be determined. Given the significant
healthcare effects associated with nosocomial influenza
outbreaks, CDC recommends that institutions consider
prophylaxis for exposed patients, unvaccinated personnel,
and those vaccinated less than 2 weeks before exposure.
When choosing which antiviral to use for prophylaxis, sideeffects, cost, and influenza strain and susceptibility pattern
should be considered.
for bioterrorism response. Clin Infect Dis 2000; 31:
1409–13.
20 Blumenfeld H, Kilbourne E, Louria D, Rogers D.
Studies on influenza in the pandemic of 1957-58: I.
An epidemiologic, clinical, and serologic investigation
of an intrahospital epidemic, with a note on vaccine
efficacy. J Clin Invest 1959; 38: 199–212.
21 Meltzer M, Cox N, Fukuda K. The economic impact
of pandemic influenza in the United States: priorities
for intervention. Emerg Infect Dis 1999; 5: 659–71.
22 Gowda H. Influenza in a geriatric unit. Postgrad Med J
1979; 55: 188–91.
23 Hall C, Douglas R. Nosocomial influenza infection as
a cause of intercurrent fevers in infants. Paediatrics
1975; 55: 673–7.
24 Munoz F, Campbell J, Atmar R, Garcia-Prats J,
Baxter D, Johnson L, et al. Influenza A virus outbreak
in a neonatal intensive care unit. Paediatr Infect Dis J
1999; 18: 811–15.
25 Malavaud S, Malavaud B, Sandres, Durand D, Marty
N, Icart J, et al. Nosocomial outbreak of influenza
virus A (H3N2) infection in a solid organ transplant
department. Transplantation 2001; 72: 535–37.
26 Adal K, Flowers R, Anglim A, Hayden F, Titus M,
Coyner B, et al. Prevention of nosocomial influenza.
Infect Control Hosp Epidemiol 1996; 17: 641–48.
27 Glezen W, Falcao O, Cate T, Mintz A. Nosocomial
influenza in a general hospital for indigent patients.
Can J Infect Control 1991; 6: 65–67.
28 Meibalane R, Sedmak G, Sasidharan P, Garg P,
Grausz J. Outbreak of influenza in a neonatal
intensive care unit. J Pediatr 1997; 91: 974–76.
29 Weinstock D, Eagan J, Malak S, Rogers M, Wallace H,
Kiehn T et al. Control of influenza A on a bone
marrow transplant unit. Infect Control Hosp Epidemiol
2000; 21:730–32.
30 Salgado C, Giannetta E, Hayden F, Farr B. Preventing
nosocomial influenza by improving clinicians’ vaccine
acceptance. Abstracts of the 11th Annual Scientific
Meeting of the Society for Healthcare Epidemiology
of America; Toronto, Canada; 2001; 271. 97.
31 Aschan J, Ringdien O, Ljungman, Andersson J,
Lewensohn-Fuchs I, Forsgren M. Influenza B in
transplant patients. Scand J Infect Dis 1989; 21:
349–50.
32 Mauch T, Bratton S, Myers, Krane E, Gentry S,
Kashtan C. Influenza B virus infection in pediatric
solid organ transplant recipients. Paediatrics 1994; 94:
225–29.
33 Whimbey E, Elting L, Couch R, et al. Influenza A
virus infections among hospitalised adult bone
marrow recipients. Bone Marrow Transplant 1994; 13:
440.
34 Kempe A, Hall C, MacDonald N, et al. Influenza in
children with cancer. J Paediatr 1989; 115: 33–9.
35 Hirschhorn L, McIntosh K, Anderson K, Dermody T.
Influenzal pneumonia as a complication of
autologous bone marrow transplantation. Clin Infect
Dis 1992; 14: 786–87.
36 Yousuf H, Englund J, Couch R, et al. Influenza among
hospitalised adults with leukemia. Clin Infect Dis
1997; 24: 1095–99.
37 Lin J, Nichol K. Excess mortality due to pneumonia
or influenza during influenza seasons among persons
with acquired immunodeficiency syndrome. Arch
Intern Med 2001; 161: 441–46.
38 Couch R, Cate T, Douglas R, Gerone P, Knight V.
Effect of route of inoculation on experimental
respiratory viral disease in volunteers and evidence of
airborne transmission. Bacteriol Rev 1966; 30: 517–29.
39 Alford R, Kasel J, Gerone P, Knight V. Human
influenza resulting from aerosol inhalation. Proc Soc
Exp Biol Med 1966; 122: 800–804.
40 Treanor J, Hayden F. Volunteer challenge studies. In:
Nicholson K, Webster R, Hay A, editors. Textbook of
Influenza. 1 ed. Malden, MA: Blackwell Science Ltd,
1998: 517–37.
41 Nicholson K. Human influenza. In: Nicholson K,
Webster R, Hay A, editors. Textbook of Influenza.
1 ed. Malden, MA: Blackwell Science Ltd.; 1998. p.
219–64.
42 Calfee D, Peng A, Hussey E, Lobo M, Hayden F.
Safety and efficacy of once daily intranasal zanamivir
in preventing experimental human influenza A
infection. Antiviral Therapy 1999; 4: 143–49.
43 Tannock G, Gillett S, Gillett R, Barry R, Hensley M,
Herd R, et al. A study of intranasally administered
interferon A (rIFN-a2A) for the seasonal prophylaxis
of natural viral infections of the upper respiratory
tract in healthy volunteers. Epidemiol Infect 1988; 101:
611–21.
44 Kaiser L, Henry D, Flack N, Keene O, Hayden F.
Short-term treatment with zanamivir to prevent
influenza: results of a placebo-controlled study.
Clin Infect Dis 2000; 30: 587–89.
45 Hayden F, Gubareva L, Monto A, Klein T, Elliot M,
Hammond J, et al. Inhaled zanamivir for the
prevention of influenza in families. Zanamivir Family
Study Group. N Engl J Med 2000; 343: 1282–89.
46 Hemmes J, Winkler K, Kool S. Virus survival as a
seasonal factor in influenza and poliomyelitis. Nature
1960; 4748: 430–31.
47 Moser M, Bender T, Margolis H, Ritter D, Noble G,
Kendal A, et al. An outbreak of influenza aboard
a commercial airliner. Am J Epidemiol 1979;
110: 1–6.
48 Gravenstein S, Drinka P, Osterweil D, Schilling M,
McElhaney J, Elliot M, et al. A multicenter
prospective double-blind randomized controlled trial
comparing the relative safety and efficacy of
zanamivir to rimantidine for nursing home influenza
outbreak control. Abstracts of the 40th Interscience
Conference on Antimicrobial Agents and
Chemotherapy; Toronto, Canada; 2000. 1155: 270.
49 Gardner P, Court S, Brocklebank J, Downham M,
Weightman D. Virus cross-infection in pediatric
wards. BMJ 1973; 9: 571–75.
50 Bean B, Moore B, Sterner B, Peterson L, Gerding D,
Balfour H. Survival of influenza on environmental
surfaces. J Infect Dis 1982; 146: 47–51.
51 Morens D, Rash V. Lessons from a nursing home
outbreak of influenza A. Infect Control Hosp Epidemiol
1995; 16: 275–80.
52 Frank A, Taber L, Wells C, Wells J, Glezen W, Paredes
A. Patterns of shedding of myxoviruses and
paramyxoviruses in children. J Infect Dis 1981; 144:
433–41.
53 Betts R, Treanor J, Graman P, Bentley D,
Dolin R. Antiviral agents to prevent or treat
influenza in the elderly. J Resp Dis 1987; Supplement:
S56-S59.
THE LANCET Infectious Diseases Vol 2 March 2002
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review
Nosocomial influenza
54 Evans K, Kline M. Prolonged influenza A infection
responsive to rimantadine therapy in a human
immunodeficiency virus-infected child. Pediatr Infect
Dis J 1995; 14: 332–4.
55 Englund J, Champlin R, Wyde P, Kantarjian H,
Atmar R, Tarrand J, et al. Common emergence of
amantadine- and rimantadine-resistant influenza A
viruses in symptomatic immunocomprimised adults.
Clin Infect Dis 1998; 26: 1418–24.
56 Klimov A, Rocha E, Hayden F, Shult P, Roumillat L,
Cox N. Prolonged shedding of amantadine-resistant
influenza A viruses by immunodeficient patients:
detection by polymerase chain reaction-restriction
analysis. J Infect Dis 1995; 172: 1352–5.
57 Ison MG, Gnann J, Treanor J, et al. Phase II study of
the safety and efficacy of nebulized zanamivir in
patients with serious influenza virus infections.
Abstracts of the 41st Interscience Conference on
Antimicrobial Agents and Chemotherapy, Chicago,
IL, 2001: 289
58 Leonardi G, Leib H, Birkhead G, Smith C, Costello P,
Conron W. Comparison of rapid detection methods
for influenza A virus and their value in health-care
management of institutionalized geriatric patients.
J Clin Microbiol 1994; 32: 70–4.
59 Waner JL, Todd SJ, Shalaby H, Murphy P, Wall LV.
Comparison of Directigen FLU-A with viral isolation
and direct immunofluorescence for the rapid
detection and identification of influenza A virus.
J Clin Microbiol 1991; 29: 479–82.
60 Dominguez EA, Taber LH, Couch RB. Comparison of
rapid diagnostic techniques for respiratory syncytial
and influenza A virus respiratory infections in young
children. J Clin Microbiol 1993; 31: 2286–90.
61 Claas EC, van Milaan AJ, Sprenger MJ, et al.
Prospective application of reverse transcriptase
polymerase chain reaction for diagnosing influenza
infections in respiratory samples from a children’s
hospital. J Clin Microbiol 1993; 31: 2218–21.
62 Duverlie G, Houbart L, Visse B, et al. A nylon
membrane enzyme immunoassay for rapid diagnosis
of influenza A infection. J Virolog Methods 1992; 40:
77–84.
63 Kok T, Mickan LD, Burrell CJ. Routine diagnosis of
seven respiratory viruses and Mycoplasma
pneumoniae by enzyme immunoassay. J Virolog
Methods 1994; 50: 87–100.
64 Chomel JJ, Remilleux MF, Marchand P, Aymard M.
Rapid diagnosis of influenza A. Comparison with
ELISA immunocapture and culture. J Virol Methods
1992; 37: 337–43.
65 Atmar RL, Baxter BD. Typing and subtyping clinical
isolates of influenza virus using reverse transcriptionpolymerase chain reaction. Clin Diagn Virology 1996;
7: 77–84.
66 Budnick L, Moll M, Hull H, Mann J, Kendal A. A
pseudo-outbreak of influenza A associated with the
use of laboratory stock strain. Am J Public Health
1984; 74: 607–9.
67 Palache A. Influenza vaccines: a reappraisal of their
use. Drugs 1997; 54: 841–56.
68 Centers for Disease Control and Prevention.
Influenza and pneumococcal vaccination coverage
levels among persons aged 65 years, United States,
1973-93. Morb Mortal Wkly Rep 1995; 44: 506–7.
69 Singelton J, Lu P. Influenza vaccination levels in the
United States, 1998. Abstracts of the 35th National
Immunisation Conference; Atlanta, GA; 2001 (in
press).
70 Dorrell L, Hassan L, Marshall S, Chakraverty P,
Ong E. Clinical and serologic response to an
inactivated influenza vaccine in adults with HIV
infection, diabetes, obstructive airways disease, elderly
adults, and healthy volunteers. Int J STD AIDS 1997;
8: 776–79.
71 Gross P, Hermogenes A, Sacks H, Lau J,
Levandowski R. The efficacy of influenza vaccine in
elderly persons. A meta-analysis and review of the
literature. Ann Intern Med 1995; 123: 518–27.
72 Anonymous. Recommendations for prevention and
control of influenza. Recommendations of the
Immunisation Practices Advisory Committee. Ann
Intern Med 1986; 105: 399–404.
73 Watanakunakorn C, Ellis G, Gemmel D. Attitude of
healthcare personnel regarding influenza
immunisation. Infect Control Hosp Epidemiol 1993;
14: 17–20.
74 Doebbeling B, Edmond M, Davis C, Woodin J,
Zeitler R. Influenza vaccination of health care
workers: evaluation of factors that are important in
acceptance. Preventive Med 1997; 26: 68–77.
75 Heimberger T, Chang H, Shaikh M, Crotty L,
Morse D, Birkhead G. Knowledge and attitudes of
healthcare workers about influenza: why are they not
getting vaccinated? Infect Control Hosp Epidemiol
1995; 16: 412–15.
76 Walker F, Singleton J, Strikas. National Immunisation
Programme CAG: are U.S. health care workers
receiving annual influenza vaccinations? Abstracts of
the 39th Interscience Conference on Antimicrobial
Agents and Chemotherapy; San Fransisco, CA; 1999.
752: 606.
77 Potter J, Stott D, Roberts M, Elder A, O’Donnell B,
Knight P, et al. Influenza vaccination of health care
workers in long-term care hospitals reduces the
mortality of elderly patients. J Infect Dis 1997; 175:
1–6.
78 Nichol K. Cost-benefit analysis of a strategy to
vaccinate healthy working adults against influenza.
Arch Intern Med 2001; 161: 749–59.
79 Bridges C, Thompson W, Meltzer M, Reeve G,
Talamonti W, Cox N, et al. Effectiveness and costbenefit of influenza vaccination of healthy working
adults: A randomized controlled trial. JAMA 2000;
284: 1655–63.
80 Campbell D, Rumley M. Cost-effectiveness of the
influenza vaccine in a healthy, working-age
population. J Occup Environ Med 1997; 39: 408–14.
81 Kumpulainen V, Makela M. Influenza vaccination
among healthy employees: a cost benefit analysis.
THE LANCET Infectious Diseases Vol 2 March 2002
http://infection.thelancet.com
Scand J Infect Dis 1997; 29: 181–85.
82 Wilde J, McMillan J, Serwint J, Butta J, O’Riordan
M, Steinhoff M. Effectiveness of influenza vaccine in
health care professionals: a randomized trial. JAMA
1999; 281: 908–13.
83 Edwards K, Dupont W, Westrich M, Plummer W,
Palmer P, Wright P. A randomized controlled trial
of cold-adapted and inactivated vaccines for the
prevention of influenza A disease. J Infect Dis 1994;
169: 68–76.
84 Treanor J, Kotloff K, Betts R, Belshe R, Newman F,
Iacuzio D, et al. Evaluation of trivalent, live, coldadapted (CAIV-T) and inactivated (TIV) influenza
vaccines in prevention of virus infection and illness
following challenge of adults with wild-type
influenza A (H1N1), A (H3N2), and B viruses.
Vaccine 1999; 18: 899–906.
85 O’Donoghue J, Ray C, Terry D, Beaty H. Prevention
of nosocomial influenza infection with amantadine.
Am J Epidemiol 1973; 97: 1616–20.
86 Hayden F, Belshe R, Clover R, Hay A, Oakes M,
Soo W. Emergence and apparent transmission of
rimantadine-resistant influenza A virus in families.
New Engl J Med 1989; 321: 1696–702.
87 Mast E, Harmon M, Gravenstein, et al. Emergence
and possible transmission of amantadine-resistant
viruses during nursing home outbreaks of influenza
A (H3N2). Am J Epidemiol 1991; 134: 988–97.
88 Drinka P, Gravenstein S, Schilling M, Krause P,
Miller B, Shult P. Duration of antiviral prophylaxis
during nursing home outbreaks of influenza A: a
comparison of 2 protocols. Arch Intern Med 1998;
158: 2155–59.
89 Drinka P, Gravenstein S, Krause P, Langer E,
Barthels L, Dissing M, et al. Non-influenza
respiratory viruses may overlap and obscure
influenza activity. J Am Geriatr Soc 1999; 47:
1087–93.
90 Keyser L, Karl M, Nafziger A, Bertino J. Comparison
of central nervous system adverse effects of
amantadine and rimantadine used as sequential
prophylaxis of influenza A in elderly nursing home
patients. Arch Intern Med 2000; 160: 1485–88.
91 Hayden F, Atmar R, Schilling M, Johnson C,
Poretz D, Parr D, et al. Use of the selective oral
neuraminidase inhibitor oseltamivir to prevent
influenza. N Engl J Med 1999; 341: 1336–43.
92 Welliver R, Monto A, Carewicz O, Schatteman E,
Hassman M, Hedrick J, et al. Effectiveness of
oseltamivir in preventing influenza in household
contacts. JAMA 2001; 285: 748–54.
93 Schilling M, Povinellit L, Krause O, Gravenstein M,
Ambrozaitis A, Jones H, et al. Efficacy of zanamivir
for chemoprophylaxis of nursing home influenza
outbreaks. Vaccine 1998; 16: 1771–74.
94 Peters P, Gravenstein S, Norwood P, DeBock V,
Van Couter A, Gibbens M et al. Long-term use of
oseltamivir for the prophylaxis of influenza in a
vaccinated frail older population. J Am Geriatr Soc
2001; 49: 1–7.
155
For personal use. Only reproduce with permission from The Lancet Publishing Group.