Influenza-Associated Pediatric Mortality in the United States: Increase of Staphylococcus aureus Coinfection

Article (PDF Available)inPEDIATRICS 122(4):805-11 · November 2008with27 Reads
DOI: 10.1542/peds.2008-1336 · Source: PubMed
Abstract
Pediatric influenza-associated death became a nationally notifiable condition in the United States during 2004. We describe influenza-associated pediatric mortality from 2004 to 2007, including an increase of Staphylococcus aureus coinfections. Influenza-associated pediatric death is defined as a death of a child who is younger than 18 years and has laboratory-confirmed influenza. State and local health departments report to the Centers for Disease Control and Prevention demographic, clinical, and laboratory data on influenza-associated pediatric deaths. During the 2004-2007 influenza seasons, 166 influenza-associated pediatric deaths were reported (n = 47, 46, and 73, respectively). Median age of the children was 5 years. Children often progressed rapidly to death; 45% died within 72 hours of onset, including 43% who died at home or in an emergency department. Of 90 children who were recommended for influenza vaccination, only 5 (6%) were fully vaccinated. Reports of bacterial coinfection increased substantially from 2004-2005 to 2006-2007 (6%, 15%, and 34%, respectively). S aureus was isolated from a sterile site or endotracheal tube culture in 1 case in 2004-2005, 3 cases in 2005-2006, and 22 cases in 2006-2007; 64% were methicillin-resistant S aureus. Children with S aureus coinfection were significantly older and more likely to have pneumonia and acute respiratory distress syndrome than those who were not coinfected. Influenza-associated pediatric mortality is rare, but the proportion of S aureus coinfection identified increased fivefold over the past 3 seasons. Research is needed to identify risk factors for influenza coinfection with invasive bacteria and to determine the impact of influenza vaccination and antiviral agents in preventing pediatric mortality.
ARTICLE
Influenza-Associated Pediatric Mortality in the
United States: Increase of Staphylococcus
aureus Coinfection
Lyn Finelli, DrPH
a
, Anthony Fiore, MD
a
, Rosaline Dhara, MPH
a
, Lynnette Brammer, MPH
a
, David K. Shay, MD
a
, Laurie Kamimoto, MD
a
,
Alicia Fry, MD
a
, Jeffrey Hageman, MPH
b
, Rachel Gorwitz, MD
b
, Joseph Bresee, MD
a
, Timothy Uyeki, MD
a
a
Influenza Division, National Center for Immunization and Respiratory Diseases, and
b
Division of Healthcare Quality Promotion, National Center for Preparedness,
Detection, and Control of Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
The authors have indicated they have no financial relationships relevant to this article to disclose.
What’s Known on This Subject
Influenza-associated S aureuspneumonia was described as a cause of mortality and severe
illness during the 1918 and 1957 influenza pandemics, but high rates of influenza–S aureus
coinfection–related mortality have not been seen before in children in seasonal influenza
epidemics.
What This Study Adds
Reports of influenza-related death complicated by bacterial coinfection increased sub-
stantially from 2004 –2005 to 2006 –2007, and S aureus was isolated from 2% of cases in
2004 –2005, 6% of cases in 2005–2006, and 30% of cases in 2006 –2007; 64% were
MRSA.
ABSTRACT
OBJECTIVE. Pediatric influenza-associated death became a nationally notifiable condi-
tion in the United States during 2004. We describe influenza-associated pediatric
mortality from 2004 to 2007, including an increase of Staphylococcus aureus coinfec-
tions.
METHODS. Influenza-associated pediatric death is defined as a death of a child who is
younger than 18 years and has laboratory-confirmed influenza. State and local
health departments report to the Centers for Disease Control and Prevention demo-
graphic, clinical, and laboratory data on influenza-associated pediatric deaths.
RESULTS. During the 2004 –2007 influenza seasons, 166 influenza-associated pediatric
deaths were reported (n 47, 46, and 73, respectively). Median age of the children
was 5 years. Children often progressed rapidly to death; 45% died within 72 hours
of onset, including 43% who died at home or in an emergency department. Of 90
children who were recommended for influenza vaccination, only 5 (6%) were fully
vaccinated. Reports of bacterial coinfection increased substantially from 2004 –2005
to 2006 –2007 (6%, 15%, and 34%, respectively). S aureus was isolated from a sterile
site or endotracheal tube culture in 1 case in 2004 –2005, 3 cases in 2005–2006, and
22 cases in 2006 –2007; 64% were methicillin-resistant S aureus. Children with S
aureus coinfection were significantly older and more likely to have pneumonia and
acute respiratory distress syndrome than those who were not coinfected.
CONCLUSIONS. Influenza-associated pediatric mortality is rare, but the proportion of S
aureus coinfection identified increased fivefold over the past 3 seasons. Research is
needed to identify risk factors for influenza coinfection with invasive bacteria and to determine the impact of
influenza vaccination and antiviral agents in preventing pediatric mortality. Pediatrics 2008;122:805–811
I
N THE UNITED States, seasonal influenza epidemics result in an estimated average of 226 000 hospitalizations and
36 000 deaths each year.
1,2
Influenza virus infection can cause severe morbidity and mortality in all ages, but the
highest rates of severe complications from influenza are observed among children who are younger than 2 years,
adults who are older than 65 years, and those with chronic medical conditions.
1–5
Although influenza virus infection alone can lead to death, most influenza-related deaths are the result of either
exacerbation of underlying medical conditions or invasive coinfection with another infectious pathogen.
1,2
Severe,
sometimes fatal, bacterial pneumonia after influenza has been observed in many studies and is thought to have been
a major cause of increased mortality during influenza pandemics.
6–8
More than 90% of estimated influenza-
attributable deaths occur among people who are 65 years of age in the United States.
2
Data are limited on mortality
associated with influenza in children. One study that modeled death certificate and influenza surveillance data
estimated that a range of 28 to 92 influenza-associated deaths occurred per year in children who were younger than
5 years in the United States between 1990 and 1999.
2
www.pediatrics.org/cgi/doi/10.1542/
peds.2008-1336
doi:10.1542/peds.2008-1336
Key Words
influenza, influenza vaccine, mortality
rates, Staphylococcus aureus
Abbreviations
CDC—Centers for Disease Control and
Prevention
ACIP—Advisory Committee on
Immunization Practices
MRSA—methicillin-resistant
Staphylococcus aureus
Accepted for publication Jul 1, 2008
Address correspondence to Lyn Finelli, DrPH,
Centers for Disease Control and Prevention,
Influenza Division, 1600 Clifton Rd, NE, MS
A-32, Atlanta, GA 30333. E-mail: lfinelli@cdc.
gov
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275); published in the public
domain by the American Academy of
Pediatrics
PEDIATRICS Volume 122, Number 4, October 2008 805
Influenza-associated pediatric mortality is a nation-
ally notifiable condition in the United States. National
surveillance for influenza-associated pediatric mortality
was implemented in October 2004, which followed a
severe influenza season when 153 pediatric influenza-
associated deaths were reported.
9
During early 2007, the
Centers for Disease Control and Prevention (CDC) noted
an increase in the number of reports of influenza-asso-
ciated pediatric deaths associated with Staphylococcus au-
reus coinfection compared with previous seasons. In this
report, we describe influenza-associated pediatric mor-
tality from 2004 to 2007 and the increase in reports of S
aureus coinfection during the 2006 –2007 season.
METHODS
An influenza-associated pediatric death is defined as
death in a child who is younger than 18 years and has a
clinically compatible illness and laboratory-confirmed
influenza. Confirmation of influenza virus infection may
occur before or after death and requires a positive find-
ing for influenza A or B on at least 1 of the following
laboratory methods: a rapid influenza virus diagnostic
test or enzyme immunoassay, viral isolation in tissue cell
culture, fluorescent antibody staining, reverse transcrip-
tion polymerase chain reaction, or immunohistochemi-
cal staining of tissue samples. Most specimens were
tested for influenza at hospital, local, or state health
department laboratories, and some influenza A viruses
were subtyped.
For influenza surveillance purposes, an influenza sea-
son is defined as October 1 to September 30 of the
subsequent year. State and local health departments
report cases of influenza-associated pediatric mortality to
the CDC by using a standardized case report form that
includes demographic information, date and location of
death, laboratory test results, health history, influenza
vaccination status, medical care received related to the
illness, and bacterial or fungal coinfection from sterile
sites. The case report form contained a comment field
where information could be noted on cultures from
nonsterile sites and other relevant clinical information.
Children with chronic medical conditions recognized by
the Advisory Committee on Immunization Practices
(ACIP) as an indication for influenza vaccination were
considered to have an ACIP-defined high-risk condi-
tion.
10
* For the 2004 –2005 influenza season, annual
influenza vaccination was recommended for all children
who were 6 to 23 months of age; beginning with the
2006 –2007 season, all children who were aged 6 to 59
months were recommended for influenza vaccination.
ACIP recommends that children who are younger than 9
years receive 2 doses of influenza vaccine in the first
season they are vaccinated. A child was considered to be
fully vaccinated when documentation was available to
verify that he or she had received influenza vaccine in
the appropriate number of doses at least 14 days before
the onset of illness. Children were categorized as fully
vaccinated when they had documentation that they had
received influenza vaccine in the appropriate number of
doses at least 14 days before the onset of illness. In
addition, children who were younger than 9 years were
classified as fully vaccinated by the aforementioned
definition, fully vaccinated by history when they had
a current influenza vaccination documented at least
14 days before the onset of illness and had vaccination
in the previous year by history but no documentation,
partially vaccinated when they had a current influ-
enza vaccination at least 14 days before the onset of
illness and no previous vaccination, and partially vac-
cinated with missing information when they had a
current influenza vaccination at least 14 days before
the onset of illness and missing information on previ-
ous vaccination.
Data were entered into Microsoft Access 2002 (Red-
mond, WA) and analyzed in SPSS 15 (SPSS, Inc, Chi-
cago, IL). A
2
test was used to evaluate statistically
significant differences between proportions for 2
groups. Yates correction for continuity was used to pre-
vent overestimation of statistical significance for cell size
data when indicated. All comparisons were 2-sided, and
P .05 was considered significant.
RESULTS
A total of 166 influenza-associated pediatric deaths were
reported from October 1, 2004, to September 30, 2007,
by 41 reporting jurisdictions (39 state and 2 local health
departments). The numbers of deaths were approxi-
mately equal during the first 2 seasons of surveillance
and increased in the third season (n 47, 46, and 73,
respectively; Table 1). Slightly more than half of the
decedents were male, and most were white, black, or
Hispanic. The median age in years varied by season and
was highest (7 years) in the 2006 –2007 season. The
median number of days between onset of influenza to
death ranged from 3 to 4 days, and 75% of deaths
occurred within 7 days (Fig 1). Forty-four percent of
children died at home or in the emergency department.
Over 3 seasons, 74 (45%) children had an ACIP-defined
high-risk condition (26, 22, and 26 children, respec-
tively, in these seasons). The proportion of children with
an underlying chronic high-risk condition declined from
55% in the 2004–2005 influenza season to 35% in
2006 –2007. The most common high-risk conditions re-
ported were asthma (n 23), seizure disorder (n 16),
and neuromuscular disorder including cerebral palsy
(n 15). Some children had 1 high-risk condition.
Few children with an indication for influenza vacci-
nation had received vaccination during the season in
which they died. Of 90 children with an age-related or
ACIP-defined high-risk condition recommended for vac-
cination, 18 (20%) were at least partially vaccinated
14 days before illness onset per season, respectively;
Table 1). One child who was partially vaccinated did not
have either an age-related or ACIP-defined high-risk
condition recommended for vaccination. Data on com-
plications of influenza were available for 73 children; the
*Children with ACIP-defined high-risk conditions include those who are receiving long-term
aspirin therapy or have chronic pulmonary (including asthma), cardiovascular (except hyper-
tension), renal, hepatic, hematologic, or metabolic disorders (including diabetes mellitus); im-
munosuppression; or any condition (eg, cognitive dysfunction, spinal cord injuries, seizure
disorders, other neuromuscular disorders) that can compromise respiratory function or the
handling of respiratory secretions or that can increase the risk for aspiration.
806 FINELLI et al
most common complications were pneumonia (n 59),
invasive bacterial coinfection (n 36), acute respiratory
distress syndrome (n 30), seizures (n 23), enceph-
alopathy (n 18), and shock (n 16). Information on
antiviral treatment was not available. Both influenza A
and B virus infections were associated with pediatric
deaths. No predominant influenza virus type was iden-
tified among the decedents, and the distribution of in-
fluenza virus types was not different among cases in the
3 seasons (Table 2).
Bacterial coinfection increased substantially over the
3 influenza seasons (6%, 15%, and 35%, respectively).
S aureus was the most commonly identified bacterial
pathogen and accounted for a large proportion of the
increase in bacterial coinfection in 2006 –2007 compared
with the previous 2 seasons (Table 2). S aureus was
isolated from a sterile site in 1 (2%) child in 2004 –2005,
2 (4%) children in 2005–2006, and 18 (25%) children in
2006 –2007 (Table 2). S aureus was isolated from an
endotracheal tube culture in 1 (2%) child in 2005–2006
and in 4 (6%) children in 2006 –2007. Overall, S aureus
FIGURE 1
Number of days from influenza onset until influenza-associated death: United States, 2004 –2007.
TABLE 1 Characteristics of Influenza-Associated Pediatric Deaths:
United States, 2004–2007
Characteristic Season
a
2004–2005
(N 47)
2005–2006
(N 46)
2006–2007
(N 73)
Male, n (%) 26 (55) 26 (57) 41 (56)
Race/ethnicity, n (%)
White 22 (47) 10 (22) 38 (52)
Black 7 (15) 11 (24) 13 (18)
Asian/Pacific Islander 2 (4) 7 (15) 3 (4)
Hispanic 12 (25) 13 (28) 12 (17)
Native American/Alaska Native 0 (0) 1 (2) 1 (1)
Unknown 4 (9) 4 (9) 6 (8)
Age group, n (%)
b
0–5 mo 8 (17) 8 (17) 11 (15)
6–23 mo 4 (8) 13 (28) 10 (14)
24–59 mo 9 (20) 5 (10) 10 (14)
5–8 y 10 (22) 9 (19) 15 (21)
9–12 y 7 (15) 6 (13) 15 (21)
13–17 y 8 (17) 5 (10) 12 (16)
Age, median (range), y 5 (0–17) 3 (0–17) 7 (0–17)
Time from onset to death,
median (range), d
4 (0–69) 3 (0–33) 4 (0–37)
Died in emergency department
or at home, n (%)
16 (34) 23 (50) 32 (44)
ACIP-defined high-risk condition,
n (%)
26 (55) 22 (48) 26 (35)
1 influenza vaccination this
season for children with age
or medical indication for
vaccination, n/N (%)
c
9/27 (33) 5/29 (24) 4/34 (9)
a
Season defined as October 1 to September 30 of the following year.
b
One case missing age in 2004 –2005 season.
c
Of 18 children vaccinated, 5 were fully vaccinated, 6 were fully vaccinated by history, 3 were
partially vaccinated, and 4 were partially vaccinated with missing information.
TABLE 2 Influenza Type and Bacterial Coinfections Among
Children With Influenza-Associated Death: United
States 2004 –2007
Parameter Season, n (%)
2004–2005
(N 47)
2005–2006
(N 46)
2006–2007
(N 73)
Influenza type
Influenza A 27 (57) 29 (63) 51 (70)
Influenza B 18 (38) 12 (26) 17 (23)
Type not distinguished 2 (4) 5 (11) 5 (7)
Bacteria isolated from sterile site
a
3 (6) 7 (15) 26 (36)
S aureus isolated from sterile site 1 (2) 2 (4) 18 (25)
Bacteria isolated from nonsterile site
b
1 (2) 2 (4) 4 (5)
S aureus sterile or nonsterile site
c
1 (2) 3 (6) 22 (30)
a
Sterile site is defined as blood, cerebrospinal fluid, pleural, pericardial, peritoneal, bone, joint,
or internal body site.
b
Includes endotracheal tube and postmortem lung biopsy.
c
Endotracheal tube.
PEDIATRICS Volume 122, Number 4, October 2008 807
was isolated from a sterile site or endotracheal tube
culture in 1 child in 2004 –2005, 3 children in 2005–
2006, and 22 children in 2006 –2007 (Table 2). Of all 26
S aureus infections identified, 15 (60%) were methicillin-
resistant S aureus (MRSA), 6 were methicillin-susceptible
S aureus (MSSA), and 5 had S aureus with susceptibility
unknown (Table 3). Information on the date of the
bacterial culture was not collected, and whether S aureus
coinfection was community-associated or hospital-asso-
ciated could not be determined.
Characteristics of children with and without S aureus-
influenza coinfection were evaluated for the 2006 –2007
influenza season (Table 4). Children with coinfection
were significantly older and more likely to have radio-
logically confirmed pneumonia or acute respiratory dis-
tress syndrome. The proportion of children with an
ACIP-defined high-risk condition or who had received
influenza vaccination (Table 4) was similar regardless of
the presence of S aureus coinfection.
DISCUSSION
This report describes 166 cases of laboratory-confirmed,
influenza-associated deaths that occurred during the
2004 –2005, 2005–2006, and 2006–2007 influenza sea-
sons and were reported to the CDC. Several character-
istics of children who died from influenza-associated
complications are notable. Influenza was often rapidly
fatal with almost half of children dying within 72 hours
of the onset of symptoms and 75% dying within 7 days;
almost half died at home or in the emergency depart-
ment. The number of bacterial coinfections increased
substantially in 2006 –2007 with most infections caused
by S aureus, primarily MRSA. Finally, many deaths oc-
curred among children without a condition or age that
would make them recommended to receive vaccination.
Even so, of deaths among children with an indication for
influenza vaccination, only 21% had been vaccinated
during the season in which they died. This increase in
pediatric death and in bacterial coinfection occurred in
the context of relatively mild influenza seasons in 2005–
2006 and 2006 –2007.
Rapid progression to death among many of the chil-
dren in this study is consistent with pediatric deaths
caused by influenza reported in the 2003–2004 influ-
enza season, in which almost half of the influenza-
associated deaths occurred outside the hospital setting or
in the emergency department.
9
In both studies, the ma-
jority of deaths occurred in previously healthy children
without an underlying medical condition, and few of
those children with an indication for influenza vaccina-
tion were vaccinated.
9
The children in our study expe-
rienced a wide range of complications similar to those
previously associated with severe influenza, including
pneumonia, bacterial coinfection, acute respiratory dis-
tress syndrome, seizures, encephalopathy, and shock.
11,12
The mechanisms of these influenza-associated deaths
are unknown, but some could include an abnormal host
inflammatory response to influenza virus infection. In-
fluenza and influenza-like illness have also been associ-
ated with S aureus toxic shock syndrome
13
; however,
clinical criteria for S aureus toxic shock syndrome were
not collected in our study to determine the presence of
toxic shock syndrome.
There are several hypothesized mechanisms by
which influenza virus infections increase the risk for
subsequent bacterial coinfection. Influenza virus dam-
ages the epithelial cell layer of the tracheobronchial
tree, thereby enhancing staphylococcal adherence.
14,15
Increased adherence might be mediated by the neur-
aminidase activity of the influenza virus, which in-
creases bacterial adherence two- to fourfold in in vitro
models that used human alveolar cells.
15
Influenza
virus suppresses the respiratory burst response and
phagocytic function of neutrophils and macrophages,
which might facilitate the development of a secondary
bacterial infection.
15–18
TABLE 3 Organisms Isolated From Sterile Sites Among Children
With Influenza and Bacterial Coinfection: United States,
2004 –2007
Organism Season Total
(N 166)
2004–2005
(N 47)
2005–2006
(N 46)
2006–2007
(N 73)
S aureus (methicillin
susceptible)
0145
S aureus (methicillin
resistant)
1 0 13 14
S aureus susceptibility
unknown
0112
Group A Streptococcus 1135
Viridans streptococci 0 2 0 2
Haemophilus influenzae
(non–type B)
0011
Enterobacter cloacae 0011
Klebsiella pneumoniae 0011
Pseudomonas aeruginosa 0101
Acinetobacter 1001
Nocardia 0011
Gram-negative bacteria,
not identified
0112
Missing 5 3 4 12
None 39 36 43 118
TABLE 4 Characteristics of Children With Influenza-Associated
Death According to Presence of S aureus Coinfection:
United States, 2006–2007
Characteristic S aureus Infection
(N 22)
No S aureus
Infection
(N 51)
Age, median (range), y
a
10 (0–16) 5 (0–17)
Radiologically confirmed pneumonia,
n/N (%)
a
14/22 (64) 14/51 (28)
Acute respiratory distress syndrome, n/N
(%)
a
10/22 (45) 5/51 (10)
ACIP-defined indication for vaccination,
n/N (%)
8/22 (36) 27/51 (53)
1 Influenza vaccination this season for
children with age or medical
indication for vaccination, n/N (%)
0/8 (0) 4/26 (15)
a
P .01.
808 FINELLI et al
The proportion of children with bacterial coinfection
increased more than fivefold between the 2004 –2005
and 2006–2007 influenza seasons, with nearly all of the
increase attributable to S aureus coinfections. Bhat et al
9
found that 24 of 102 children who had data available
and died from influenza-associated complications during
the 2003–2004 influenza season had evidence of bacte-
rial coinfection, including 6 patients who had coinfec-
tion with MRSA and 5 with methicillin-susceptible S
aureus or S aureus with unknown sensitivity. Influenza-
associated S aureus pneumonia and sepsis among previ-
ously healthy children and adults has been reported
for the past century.
7,8
Influenza-associated S aureus
pneumonia with antecedent staphylococcal soft tissue
infection was described during the 1957 pandemic.
19
Overwhelming sepsis caused by S aureus has been
reported in infants
20
and older children,
21
and several
studies have shown that a recent history of staphylo-
coccal soft tissue infection in the case patient or a
family member often precedes the invasive infection,
and family clusters of invasive staphylococcal infec-
tion have been described.
20,22–25
Approximately 30% to 40% of children are colonized
with S aureus; colonization prevalence is highest among
children who are 6 to 11 years of age.
26–28
Whereas
frequencies of S aureus nasal carriage have not increased
significantly, MRSA nasal carriage has increased. In
2001, data from a nationally representative carriage sur-
vey indicated that 0.8% of the US population was colo-
nized by MRSA
26
; 2003–2004 data from the same study
indicated that 1.5% of the US population were colo-
nized.
29
In 2001, data from a large pediatric primary care
practice in Tennessee demonstrated colonization rates of
0.8%.
30
In 2005, a repeat survey in the same Tennessee
pediatric primary care practice found that MRSA nasal
carriage exceeded 9%.
30
Nasal carriage with MRSA has
been reported to be as high as 22% among new admis-
sions to a pediatric hospital; 92% of children with MRSA
were not known previously to be MRSA carriers, al-
though some children had risk factors for MRSA coloni-
zation.
28,31–33
In addition to antimicrobial resistance,
there is recent evidence that many of these MRSA iso-
lates are the USA300 strain,
20,33
which has been associ-
ated with the Panton-Valentine leukicidin toxin, an impor-
tant virulence factor linked with necrotizing pneumonia
and necrotic skin lesions.
34
As MRSA nasal carriage in-
creases, there is a potential for increasing coinfection with
MRSA and influenza virus, resulting in severe morbidity
and mortality in children.
Influenza vaccination remains the major prevention
strategy for influenza and its associated complications.
Currently, all children who are aged 6 to 59 months and
those with certain chronic underlying conditions should
receive annual influenza vaccination; however, only
21% of the cases recommended for annual vaccination
had received influenza vaccine. Notably, 46% of the
cases did not meet current criteria for targeted influenza
vaccination, but vaccination might have been indicated
for some children as household contacts of people at
high risk for influenza complications. Influenza vaccina-
tion coverage levels among children at high risk for
influenza complications remain very low. Only 21% of
children aged 6 to 23 months were fully vaccinated
against influenza during the 2005–2006 influenza sea-
son,
35
and immunization registry data indicate that cov-
erage for the 2006 –2007 season was similar.
36
This sug-
gests that substantial efforts must be made to increase
influenza vaccination coverage among target groups. In-
fluenza vaccination can reduce complications of influ-
enza, such as acute otitis media and pneumonia, in
young children and adults.
37–39
By reducing the risk for
influenza, invasive bacterial infections that are facilitated
by disruptions in host defenses during influenza virus
infection could also presumably be reduced.
Several studies have demonstrated the effectiveness
of influenza antiviral treatment to prevent secondary
complications. Early treatment with the neuraminidase
inhibitor oseltamivir reduced the development of otitis
media in children by 44%
40
and reduced the develop-
ment of various secondary bacterial complications (si-
nusitis, bronchitis, or pneumonia) that required antibi-
otics in previously healthy adults.
41
The mechanism by
which neuraminidase inhibitors reduce secondary bac-
terial complications is unknown but might be associated
with inactivation of viral neuraminidase and elimination
of its ability to facilitate bacterial adherence.
15,42,43
On the
basis of preclinical studies, it has been proposed that
even delayed treatment with neuraminidase inhibitors
could prevent influenza-associated bacterial complica-
tions, although the course of influenza virus infection
may not be altered.
15,42
A recent study of the effective-
ness of oseltamivir treatment of hospitalized adult pa-
tients demonstrated a reduction in influenza complica-
tions and mortality even when treatment was initiated
after 2 days of illness onset.
44
Our findings are subject to several potential limita-
tions that could result in an underestimation of influ-
enza deaths in children and bacterial coinfections. Influ-
enza-associated pediatric mortality case reports varied in
completeness and were less complete for children who
had not been hospitalized. Influenza-associated pediatric
deaths are likely underreported, because influenza-asso-
ciated pediatric mortality became a nationally notifiable
condition only in 2004. State-level reporting require-
ments have been implemented incrementally over the
past 3 years, with 42 states requiring reporting currently;
however, incremental increases in reporting would af-
fect the total number of reports submitted but should not
affect the proportion of cases with bacterial coinfection.
Low levels of influenza testing in children might also con-
tribute to underreporting. Despite the availability and util-
ity of influenza tests, influenza testing is not currently
routinely incorporated in the diagnostic workup of most
children who are seen in primary care or emergency de-
partment settings with influenza-like illness.
45
Further-
more, physicians may not order influenza diagnostic
testing in severe cases, and clinical data are limited for
patients who die at home or in an emergency depart-
ment. Of those who die outside the hospital, not all cases
are referred for postmortem examination. Even when
referred for postmortem examination, not all cases have
routine influenza or staphylococcal diagnostic testing on
PEDIATRICS Volume 122, Number 4, October 2008 809
autopsy tissue specimens.
46
We did not systematically
collect information on bacterial isolates from nonsterile
sites (eg, endotracheal tube), and this information if
collected might have captured additional cases of bacte-
rial pneumonia among children with fatal influenza vi-
rus infection; therefore, we may have underascertained
the proportion of cases with bacterial coinfections, in-
cluding S aureus. Also, our findings are an underestima-
tion of severe MRSA and influenza because we did not
include severe nonfatal cases.
Influenza-associated pediatric mortality is rare, but
the proportion of cases in which S aureus was identified
has increased fivefold over the past 3 influenza seasons.
Increasing rates of MRSA nasal carriage may increase the
potential for coinfection with MRSA and influenza virus,
resulting in severe morbidity and mortality in children.
Influenza vaccination remains the primary prevention
strategy for influenza. Although vaccination efforts
should be focused on children at highest risk for severe
disease and complications, any child who wants (or
whose parents want) to reduce his or her risk of influ-
enza infection should be vaccinated. Furthermore, chil-
dren who are household contacts of people who are at
high risk for influenza complications should be vacci-
nated. In February 2008, the ACIP recommended an-
nual influenza vaccination for all children from 6
months to 18 years of age with incremental implemen-
tation over the next 2 years.
47
CONCLUSIONS
Children who are at risk for influenza complications or
healthy children with moderate to severe respiratory
illness should be tested for influenza and, when infected,
treated with oseltamivir or zanamivir.
48
Physicians
should consider treating children with suspected S aureus
pneumonia during influenza season with vancomycin or
other antibiotic to treat MRSA when they reside in areas
where MRSA is prevalent
24
or have risk factors for
MRSA infection (eg, underlying conditions, history of
MRSA colonization or infection). Additional studies are
needed to evaluate risk factors for coinfection with in-
fluenza and bacterial pathogens, to assess increasing in-
fluenza vaccination in children, and to determine the
role of influenza vaccination and antiviral agents in pre-
venting severe morbidity and mortality that are caused
by influenza among children.
REFERENCES
1. Thompson W, Shay D, Weintraub E, et al. Influenza-associated
hospitalizations in the United States. JAMA. 2004;292(11):
1333–1400
2. Thompson W, Shay D, Weintraub E, et al. Mortality associated
with influenza and respiratory syncytial virus in the United
States. JAMA. 2003;289(2):179–186
3. Izurieta HS, Thompson WW, Kramarz P, et al. Influenza and
the rates of hospitalization for respiratory disease among in-
fants and young children. N Engl J Med. 2000;342(4):232–239
4. Mullooly JP, Bridges CB, Thompson WW, et al. Influenza and
RSV-associated hospitalizations among adults. Vaccine. 2007;
25(5):846 855
5. O’Brien MA, Uyeki, TM, Shay DK, et al. Incidence of outpa-
tient visits and hospitalizations related to infants and young
children. Pediatrics. 2004;113(3 pt 1):585–593
6. McCullers JA. Insights into the interaction between influenza
virus and Pneumococcus. Clin Microbiol Rev. 2006;19(3):571–582
7. Chickering HT, Park JH. Staphylococcus aureus pneumonia.
JAMA. 1919;72:617–626
8. Louria DB, Blumenfeld HL, Ellis JT, Kilbourne ED, Rogers DE.
Studies on influenza in the pandemic of 1957–1958. II. Pul-
monary complications of influenza. J Clin Invest. 1959;38(1 pt
2):213–265
9. Bhat, N, Wright JG, Broder KR, et al. Influenza-associated
deaths among children in the United States, 2003–2004. N Engl
J Med. 2005;353(24):2559–2567
10. Fiore AE, Shay DK, Haber P, et al. Prevention and control of
influenza: recommendations of the Advisory Committee on
Immunization Practices. MMWR Recomm Rep. 2007;56(RR-6):
1–54
11. Podewils LJ, Liedtke LA, McDonald C, et al. A national survey
of severe influenza-associated complications among children
and adults, 2003–2004. Clin Infect Dis. 2005;40(11):1693–1696
12. Coffin SE, Zaoudis TE, Rosenquist AB, et al. Incidence, com-
plications, and risk factors for prolonged stay in children hos-
pitalized with community-acquired influenza. Pediatrics. 2007;
119(4):740 –748
13. MacDonald KL, Osterholm MT, Hedberg CW, et al. Toxic shock
syndrome: a newly recognized complication of influenza and
influenza-like illness. JAMA. 1987;257(8):1053–1058
14. Hers JF, Masurel N, Mulder J. Bacteriology and histopathology
of the respiratory tract and lungs of fatal Asian influenza.
Lancet. 1958;2(7057):1164–1165
15. Peltola VT, McCullers JA. Respiratory viruses predisposing to
bacterial infections: role of neuraminidase. Pediatr Infect Dis J.
2004;23(1 suppl):S87–S97
16. Abramson JS, Lewis JC, Lyles DS, Heller KA, Mills EL, Bass DA.
Inhibition of neutrophil lysosome-phagosome fusion associ-
ated with influenza virus infection in vitro: role in depressed
bactericidal activity. J Clin Invest. 1982;69(6):1393–1397
17. Nickerson CL, Jakab GJ. Pulmonary antibacterial defenses dur-
ing mild and severe influenza virus infection. Infect Immun.
1990;58(9):2809 –2814
18. Jakab GJ. Immune impairment of alveolar macrophage phago-
cytosis during influenza virus pneumonia. Am Rev Respir Dis.
1982;126(5):778 –782
19. Goslings WR, Mulder J, Djajadiningrat J, Masurel N. Staphy-
lococcal pneumonia in influenza in relation to antecedent
staphylococcal skin infection. Lancet. 1959;2(7100):428 430
20. Fortunov RM, Hulten KG, Hammerman WA, Mason EO Jr,
Kaplan SL. Community-acquired Staphylococcus aureus infec-
tions in term and near-term previously healthy neonates. Pe-
diatrics. 2006;118(3):874 881
21. Adem PV, Montgomery CP, Husain AN, et al. Staphylococcus
aureus sepsis and the Waterhouse-Friderichsen syndrome in
children. N Engl J Med. 2005;353(12):1245–1251
22. Hageman JC, Uyeki TM, Francis JS, et al. Severe community-
acquired pneumonia due to Staphylococcus aureus, 2003– 04 in-
fluenza season. Emerg Infect Dis. 2006;12(6):894 899
23. Adam H, McGeer A, Simor A. Fatal case of post-influenza,
community-associated MRSA pneumonia in an Ontario teen-
ager with subsequent familial transmission. Can Commun Dis
Rep. 2007;33(4):45–48
24. Centers for Disease Control and Prevention (CDC). Severe
methicillin-resistant Staphylococcus aureus community-acquired
pneumonia associated with influenza—Louisiana and Georgia,
December 2006 –January 2007. MMWR Morb Mortal Wkly Rep.
2007;56(14):325–339
25. Jones TF, Creech CB, Erwin P, Baird SG, Woron AM, Schaffner
W. Family outbreaks of invasive community-associated methi-
810 FINELLI et al
cillin-resistant Staphylococcus aureus infection. Clin Infect Dis.
2006;42(9):e76 e78
26. Kuehnert MJ, Kruszon-Moran D, Hill HA, et al. Prevalence of
Staphylococcus aureus nasal colonization in the United States,
2001–2002. J Infect Dis. 2006;193(2):172–179
27. Nakamura MM, Rohling KL, Shashaty M, Lu H, Tang YW,
Edwards KM. Prevalence of methicillin-resistant Staphylococcus
aureus nasal carriage in the community pediatric population.
Pediatr Infect Dis J. 2002;21(10):917–922
28. Fergie J, Purcell K. The epidemic of methicillin-resistant Staph-
ylococcus aureus colonization and infection in children: effects
on the community, health systems, and physician practices.
Pediatr Ann. 2007;36(7):404 412
29. Gorwitz RJ, Kruszon-Moran D, McAllister SK, et al. Changes in
Staphylococcus aureus nasal colonization in the United States,
2001–2004. J Infect Dis. 2008;197(9):1226 –1234
30. Creech CB 2nd, Kernodle DS, Alsentzer A, Wilson C, Edwards
KM. Increasing rates of nasal carriage of methicillin-resistant
Staphylococcus aureus in healthy children. Pediatr Infect Dis J.
2005;24(7):617– 621
31. Alfaro C, Mascher-Denen M, Fergie J, Purcell K. Prevalence of
methicillin-resistant Staphylococcus aureus nasal carriage in pa-
tients admitted to Driscoll Children’s Hospital. Pediatr Infect Dis
J. 2006;25(5):459 461
32. King MD, Humphrey BJ, Wang YF, Kourbatova EV, Ray SM,
Blumberg HM. Emergence of community-acquired methicil-
lin-resistant Staphylococcus aureus USA 300 clone as the pre-
dominant cause of skin and soft-tissue infections. Ann Intern
Med. 2006;144(5):309–317
33. Daum RS. Clinical practice: skin and soft-tissue infections
caused by methicillin-resistant Staphylococcus aureus. N Engl
J Med. 2007;357(4):380–390
34. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-
resistant S. aureus infections among patients in the emergency
department. N Engl J Med. 2006;355(7):666 674
35. Centers for Disease Control and Prevention. Influenza vacci-
nation coverage among children aged 6 –23 months—United
States, 2005– 06 influenza season. MMWR Morb Mortal Wkly
Rep. 2007;56(37):959–963
36. Centers for Disease Control and Prevention. Influenza vacci-
nation coverage among children aged 6 –59 months: six im-
munization information system sentinel sites, United States,
2006 07 influenza season. MMWR Morb Mortal Wkly Rep. 2007;
56(37):963–965
37. Clements DA, Langdon L, Bland C, Walter E. Influenza A
vaccine decreases the incidence of otitis media in 6- to 30-
month-old children in day care. Arch Pediatr Adolesc Med. 1995;
149(10):1113–1117
38. Ozgur SK, Beyazova U, Kemaloglu YK, et al. Effectiveness of
inactivated influenza vaccine for prevention of otitis media in
children. Pediatr Infect Dis J. 2006;25(5):401– 404
39. Nichol KL, Wuorenma J, von Sternberg T. Benefits of influenza
vaccination for low-, intermediate-, and high-risk senior citi-
zens. Arch Intern Med. 1998;158(16):1769 –1776
40. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir
treatment of influenza in children. Pediatr Infect Dis J. 2001;
20(2):127–133
41. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety
of the oral neuraminidase inhibitor oseltamivir in treating
acute influenza: a randomized controlled trial: US Oral Neur-
aminidase Study Group. JAMA. 2000;283(8):1016 –1024
42. McCullers JA, Bartmess KC. Role of neuraminidase in lethal
synergism between influenza and Streptococcus pneumoniae. J In-
fect Dis. 2003;187(6):1000–1009
43. Peltola VT, Murti KG, McCullers JA. Influenza virus neuramin-
idase contributes to secondary bacterial pneumonia. J Infect Dis.
2005;192(2):249 –257
44. McGeer A, Green KA, Plevneshi A, et al. Antiviral therapy and
outcomes of influenza requiring hospitalization in Ontario,
Canada. Clin Infect Dis. 2007;45(12):1568 –1575
45. Bonner AB, Monroe KW, Talley LI, Klasner AE, Kimberlin
DW. Impact of rapid diagnosis of influenza on physician deci-
sion-making and patient management in the pediatric emer-
gency department: results of a randomized, prospective, con-
trolled trial. Pediatrics. 2003;112(2):363–367
46. Guarner J, Paddock CD, Shieh WJ, et al. Histopathologic and
immunohistochemical features of fatal influenza virus infec-
tion in children during the 2003–2004 season. Clin Infect Dis.
2006;43(2):132–140
47. Fiore AE, Shay DK, Haber P, et al. Prevention and control of
influenza: recommendations of the Advisory Committee on
Immunization Practices. MMWR Recomm Rep. 2008;57(RR-7):3
48. American Academy of Pediatrics Committee on Infectious Dis-
eases. Antiviral therapy and prophylaxis for influenza in chil-
dren. Pediatrics. 2007;119(4):852–860
RECENT LOW BIRTH WEIGHT RATE HIGHEST IN 40 YEARS
“The low birth weight rate in 2005 was 8.2%, the highest percentage since
1968, according to the Annie E. Casey Foundation’s 2008 Kids Count report.
The state with the highest percentage of infants with low birth rates was
Mississippi, at 11.8%. Among all states surveyed, 13.6% of all black infants
were reported to have low birth weights, while 7.3% of whites and 6.9% of
Hispanics had low birth weights. The report also collected data on other
indicators of child wellness and found no change in infant mortality.”
Merriman J. Contemporary Pediatrics. July 2008
Noted by JFL, MD
PEDIATRICS Volume 122, Number 4, October 2008 811
    • "Bacterial pathogens associated with CIRD include Bordetella bronchiseptica, Streptococcus equi subspecies zooepidemicus and Mycoplasma [7]. In humans, Staphylococcal species are frequently identified as the cause of bacterial pneumonia [8, 9]. A study from our group showed that Staphylococcus pseudintermedius (Sp) was the most frequently isolated bacterial pathogen (24/40) from respiratory cases (unpublished data). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Canine influenza virus (CIV) and Staphylococcus pseudintermedius (Sp) are pathogens that cause respiratory disease in dogs. Considering bacterial infections following influenza are a leading cause of illness and death, it is of particular meaning to investigate the interaction between these two pathogens. In this study, BALB/c mice were used as a mouse model to assess whether inoculation with CIV H3N2 followed by S. pseudintermedius 72 h later resulted in exacerbation of disease. Disease was characterized by assessment of body weight loss, titration of virus and bacteria, histopathology, and cytokine production. Results: There was a significantly greater decrease in body weight in the co-infected group compared with the CIV-only and SP-only groups. CIV inoculation increased bacterial colonization, whereas secondary infection with S. pseudintermedius elevated the viral RNA load of CIV in tissues. The histological lesions in the brain, spleen and lung were more severe in the CIV/Sp group than in the singly treated groups. Infection with CIV alone, Sp alone or coinfection stimulated a significantly higher release of cytokines, such as interferon-gamma (IFN)-γ, interleukin 6 (IL)-6, tumor necrosis factor (TNF-α) and lymphotactin (Lptn), than was observed in the mock-infected group (PBS). Moreover, the levels of IFN-γ in the spleen and lung were higher in the CIV/Sp group compared with the CIV-only and Sp-only groups. Conclusion: Our findings provide the first demonstration that the secondary infection of mice with Sp leads to increased clinical signs and lesions during canine influenza.
    Full-text · Article · Dec 2016
    • "(MRSA) [2]. A potential complication of influenza is superinfection with Aspergillus species. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Invasive aspergillosis may occur in the setting of severe influenza infections due to viral-induced respiratory epithelium disruption and impaired immune effects, but data are limited. Methods A retrospective study was conducted among severe influenza cases requiring medical ICU admission at an academic center during the 2015-2016 season. Data collected included respiratory cultures; medical conditions and immunosuppressants; laboratory and radiographic data; and outcomes. A systematic literature review (PubMed; January 1963 - March 2016) of published cases in the English language of aspergillosis complicating influenza was conducted. Results Six (75%) of 8 ICU influenza cases had Aspergillus isolated; five were classified as invasive disease. No ICU patient testing negative for influenza infection developed aspergillosis during the study period. Among cases with invasive aspergillosis, influenza infection was type A (H1N1) (n=2) and influenza B (n=3). Published and current cases yielded n=57 (EORTC/MSG criteria: 37% proven, 25% probable, and 39% possible cases). An increasing number of cases were reported since 2010. Sixty-five percent of cases lacked classic underlying conditions at admission for aspergillosis, 86% had lymphopenia, and 46% died. Conclusions Aspergillosis may occur in the setting of severe influenza infections even among immunocompetent hosts. Risks may include influenza A (H1N1) or B infections and viral-induced lymphopenia, although further studies are needed. Prompt diagnosis and antifungal therapy are recommended given high mortality rates.
    Full-text · Article · Aug 2016
    • "Severe disease and complications due to influenza infection, including hospitalization and death, generally occur in elderly, very young, and individuals with underlying medical conditions [6]. Although influenza virus infection alone can lead to death, most of influenza-related deaths are the result of either exacerbation of underlying medical conditions or invasive coinfection with another infectious pathogen, particularly secondary bacterial infections [5]. In Nepal, ARI is most common cause of death in children less than 5 years old [7], but data are limited on mortality associated with influenza. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Acute respiratory infections (ARIs) represent one of the major causes of childhood mortality and morbidity in Nepal. The Influenza virus is one of the common causes of viral ARIs and bacterial infection secondary to influenza contributes to majority of childhood death worldwide. However, the diagnosis of influenza virus infection is not routinely suggested in Nepal even for children clinically presenting with influenza like illness (ILI). Methods: With an aim to describe the status of viral influenza in Nepalese children with ILI, a throat swab and a nasal swab specimen were collected from each pediatric ILI patients visiting to the outpatient department of Kanti Children's Hospital (KCH). Viral influenza was diagnosed by rapid antigen detection test and further confirmed by reverse transcription-polymerase chain reaction (RT-PCR). Results: Among 200 ILI cases analyzed, 20 (10.0%) cases were confirmed as influenza A and 5 (2.5%) were confirmed as influenza B by rapid antigen detection test. Among 20 influenza A cases diagnosed by rapid test, 16 (80.0 %) were confirmed as A/H3 type and one was identified as pdm H1N109 by RT-PCR. Similarly, 3 out of 5 influenza B positive cases in rapid test were confirmed as influenza B by RT-PCR. Conclusion: Though, our study does not represent whole year data, this finding suggests routine influenza testing of all pediatric ILI cases.
    Full-text · Article · Jul 2016
Show more

    Recommended publications

    Discover more