Pandemic H1N1 influenza-associated hospitalizations in children in Madrid, Spain.

Abstract

To describe the epidemiological and clinical characteristics of children hospitalized with 2009 pandemic influenza (pH1N1) in Madrid, Spain.
We included patients less than 14 years of age admitted to one of 18 hospitals in Madrid, Spain, between May 1 and November 30, 2009 and diagnosed with pH1N1 by polymerase chain reaction. A retrospective chart review was conducted and data were compared by age, presence of high-risk medical conditions, and pediatric intensive care unit (PICU) admission.
A total of 517 pH1N1 cases were included for final analysis. One hundred and forty-two patients (27·5%) had predisposing underlying illnesses, with immunosuppression (36 children, 7%) and moderate persistent asthma (34, 6·6%) being the most common ones. Patients with underlying medical conditions had longer hospital stays [median 5, interquartile range (IQR) 3-8 days, versus median 4, IQR 3-6, P < 0·001] and required intensive care (20·4% versus 5·9%, P < 0·001) and mechanical ventilation more frequently than previously healthy children. Globally, intensive care was required for 51 patients (10%) and invasive mechanical ventilation for 12 (2%). Pediatric intensive care unit admission was significantly associated with abnormal initial chest X-ray [Odds Ratio (OR) 3·5, 95% confidence interval (CI) 1·5-8·5], underlying neurological condition (OR 3·1, CI 1·2-7·5) and immunosuppression (OR 2·9, 1·2-6·8). Five patients (0·9%) died; two with severe neurological disease, two with leukemia, and one with a malignant solid tumor.
Children with underlying medical conditions experienced more severe pH1N1 disease. Risk factors for admission to the PICU included underlying neurological conditions, immunosuppression and abnormal initial chest X-ray.

Full text

Page 1

Pandemic H1N1 influenza-associated hospitalizations in
children in Madrid, Spain
Teresa del Rosal,aFernando Baquero-Artigao,bCristina Calvo,cMarı ´a J. Mellado,dJuan C. Molina,e
Marı ´a del Mar Santos,fMarı ´a J. Cilleruelo,gMercedes Bueno,hPilar Storch de Gracia,eCovadonga
Terol,iMiguel A´. Roa,iRoi Pin ˜eiro,gMilagros Garcı ´a Lo ´pez-Hortelano,dMarı ´a L. Garcı ´a-Garcı ´a,cSonia
Rodrı ´guez,jMarı ´a Penı ´n,jAlejandro Zarauza,bFrancisco Alvarado,kAna de Blas,lEnrique Otheo,l
Alfonso Rodrı ´guez,mMarı ´a L. Herreros,nAlfredo Tagarro,nLuis Grande,oJose ´ T. Ramos,oIrene Mate ´,p
Cristina Mun ˜oz,qMiguel A´. Zafra,rMarı ´a P. Romero-Go ´mez,sElia Pe ´rez-Ferna ´ndez,tAlberto Delgado,u
Inmaculada Casas,vMarı ´a E. Cabezasw
aPediatrics Department, Hospital Infanta Elena, Valdemoro, Madrid, Spain.bPediatric Infectious Diseases Unit, Hospital La Paz, Madrid, Spain.
cPediatrics Department, Hospital Severo Ochoa, Legane ´s, Madrid, Spain.dPediatric Infectious Diseases and Tropical Medicine Unit, Hospital
Carlos III, Madrid, Spain.eEmergency Department, Hospital Infantil Universitario Nin ˜o Jesu ´s, Madrid, Spain.fPediatric Infectious Diseases Unit,
Hospital Gregorio Maran ˜o ´n, Madrid, Spain.gPediatrics Department, Hospital Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain.
hPediatrics Department, Hospital Fundacio ´n Alcorco ´n, Alcorco ´n, Madrid, Spain.iPediatrics Department, Hospital de Mo ´stoles, Mo ´stoles, Madrid,
Spain.jPediatrics Department, Hospital Prı ´ncipe de Asturias, Alcala ´ de Henares, Madrid, Spain.kPediatric Intensive Care Unit, Hospital La Paz,
Madrid, Spain.lPediatrics Department, Hospital Ramo ´n y Cajal, Madrid, Spain.mPediatrics Department, Hospital del Sureste, Arganda del Rey,
Madrid, Spain.nPediatrics Department, Hospital Infanta Sofı ´a, San Sebastia ´n de los Reyes, Madrid, Spain.oPediatrics Department, Hospital de
Getafe, Getafe, Madrid, Spain.pPediatrics Department, Hospital del Henares, Coslada, Madrid, Spain.qPediatrics Department, Hospital Infanta
Leonor, Madrid, Spain.rPediatrics Department, Hospital de Fuenlabrada, Fuelabrada, Madrid, Spain.sMicrobiology Department, Hospital La Paz,
Madrid, Spain.tBiostatistics Unit, Hospital La Paz, IdiPaz, Madrid, Spain.uMicrobiology Department, Hospital Fundacio ´n Alcorco ´n, Alcorco ´n,
Madrid, Spain.vInfluenza and Respiratory Viruses Laboratory, National Centre for Microbiology, Intituto de Sauld Carlos III, Madrid, Spain.
wPediatrics Department, Hospital del Tajo, Aranjuez, Madrid, Spain.
Correspondence: Teresa del Rosal, Pediatrics Department, Hospital Infanta Elena, Avenida Reyes Cato ´licos 21, 28342 Valdemoro, Madrid, Spain.
E-mail: teredelrosal@yahoo.es
Accepted 17 May 2011. Published Online 20 July 2011.
Objective To describe the epidemiological and clinical
characteristics of children hospitalized with 2009 pandemic
influenza (pH1N1) in Madrid, Spain.
Patients ⁄Methods We included patients less than 14 years of age
admitted to one of 18 hospitals in Madrid, Spain, between May 1
and November 30, 2009 and diagnosed with pH1N1 by
polymerase chain reaction. A retrospective chart review was
conducted and data were compared by age, presence of high-risk
medical conditions, and pediatric intensive care unit (PICU)
admission.
Results A total of 517 pH1N1 cases were included for final
analysis. One hundred and forty-two patients (27Æ5%) had
predisposing underlying illnesses, with immunosuppression (36
children, 7%) and moderate persistent asthma (34, 6Æ6%) being
the most common ones. Patients with underlying medical
conditions had longer hospital stays [median 5, interquartile range
(IQR) 3–8 days, versus median 4, IQR 3–6, P < 0Æ001] and
required intensive care (20Æ4% versus 5Æ9%, P < 0Æ001) and
mechanical ventilation more frequently than previously healthy
children. Globally, intensive care was required for 51 patients
(10%) and invasive mechanical ventilation for 12 (2%). Pediatric
intensive care unit admission was significantly associated with
abnormal initial chest X-ray [Odds Ratio (OR) 3Æ5, 95%
confidence interval (CI) 1Æ5–8Æ5], underlying neurological
condition (OR 3Æ1, CI 1Æ2–7Æ5) and immunosuppression (OR 2Æ9,
1Æ2–6Æ8). Five patients (0Æ9%) died; two with severe neurological
disease, two with leukemia, and one with a malignant solid
tumor.
Conclusions Children with underlying medical conditions
experienced more severe pH1N1 disease. Risk factors for
admission to the PICU included underlying neurological
conditions, immunosuppression and abnormal initial chest X-ray.
Keywords 2009 pandemic influenza A (H1N1), hospitalizations,
pediatric influenza, pH1N1.
Please cite this paper as: del Rosal et al. (2011) Pandemic H1N1 influenza-associated hospitalizations in children in Madrid, Spain. Influenza and Other
Respiratory Viruses 5(6), e544–e551.
DOI:10.1111/j.1750-2659.2011.00272.x
www.influenzajournal.com
Original Article
e544
ª 2011 Blackwell Publishing Ltd, Influenza and Other Respiratory Viruses, 5, e544–e551

Page 2

Introduction
In April 2009, the first cases of infection by a novel influ-
enza A H1N1 virus (pandemic H1N1 or pH1N1) were reg-
istered in Mexico.1Since then, the virus spread worldwide
causing significant morbidity. The first cases of the new
virus in Spain were detected by the end of April 2009.2
The highest incidence in Madrid occurred in week 43
(October 25–31, 2009), with 375 cases⁄100 000 inhabit-
ants.3
Most infected children had a mild clinical picture, but
pH1N1 resulted in an unusually high number of serious
cases among young people.4Children with underlying
health conditions appear to be at higher risk for severe
infection.5,6This risk for severe clinical course is highest
among children with underlying neurological diseases.7,8
Asthma has been described as one of the most common
medical conditions among hospitalized children,7,9but to
our knowledge, pH1N1 severity has not been analyzed
across different asthma severity levels.
The objectives of our study were as follows: (i) to
describe the clinical and epidemiological features of hospi-
talized children with pH1N1; (ii) to compare the character-
istics of ward and pediatric intensive care unit (PICU)
patients; and (iii) to evaluate the influence of underlying
medical conditions on disease course.
Patients and methods
Patients and samples
Children £14 years with confirmed pH1N1 by reverse-
transcriptase polymerase chain reaction (RT-PCR) and
admittedto one of 18
in Madrid during a 7-month period (May–November
2009) were included in the study. Older children and
those referred from other cities of Spain to PICU in
Madrid were excluded from the analysis. All centers rou-
tinely tested for pH1N1 every child admitted with fever
and respiratory symptoms up to December 2009, as
pH1N1 activity markedly declined afterwards in Spain.
Up to May 22nd, all positive children were admitted to
hospital for isolation purposes. After this date, they were
only admitted if the clinical picture recommended to do
so.10
Samples were collected according to the protocol that
the Health Department of the Madrid Government set up
at the beginning of the pandemic. They were sent to one
of the Influenza Laboratories Network of Madrid and
processed within 24 hours of collection.11The diagnosis
of pH1N1 was made with the World Health Organisation
approved real-time PCR A H1N1 assay in all laborato-
ries.12
publicpediatric hospitals
Clinical assessment
A retrospective chart review was conducted using a stan-
dardized questionnaire, collecting data concerning demo-
graphics, health status, clinical manifestations, laboratory
tests and chest X-ray results, complications, and outcome.
There was at least one pediatrician in charge of collecting
the data at each participating hospital.
Underlying health conditions for influenza-related com-
plications were defined according to the recommendations
of the Spanish Association of Pediatrics: respiratory diseases
(cystic fibrosis, moderate or severe persistent asthma, and
bronchopulmonary dysplasia), hemodynamically significant
heart diseases, metabolic diseases (diabetes mellitus, morbid
obesity), immunosuppression, neurological and neuromus-
cular diseases, chronic renal failure, and hemoglobinopa-
thies.13Morbid obesity was defined as body mass index at
or above the 99th percentile for the child’s age. Asthma
severity was established according to the classification of
the Spanish Society for Pediatric Pulmonology: children
with infrequent intermittent and frequent intermittent
asthma had less than five and eight exacerbations per year,
respectively, remaining completely asymptomatic between
them. In contrast, patients with moderate persistent asthma
had wheezing episodes at least each 4–5 weeks, with mild
symptoms between exacerbations and nocturnal symptoms
up to two nights per week. Children with severe persistent
asthma had frequent exacerbations with symptoms between
them, wheezing with minimal physical efforts and noctur-
nal symptoms more than two nights per week.14
Complications among patients hospitalized with con-
firmed pH1N1 were identified by using data from the dis-
chargesummariesand medical
insufficiency was defined as the need for mechanical venti-
lation (invasive or non-invasive) in patients without
asthma. Children who were admitted to PICU because of
asthma exacerbation were considered as having severe
bronchospasm. We identified patients with suspected or
confirmed bacterial pneumonia taking into account the
data regarding blood tests, chest X-ray (focal infiltrates or
consolidation, pleural effusion), blood cultures, and clinical
course.Patients whohad
‡24 hours were categorized as having encephalopathy.
records. Respiratory
alteredmental statusfor
Statistical analysis
We described the characteristics of children with pH1N1
who were admitted to hospital. Clinical features and out-
comes were compared according to age and the presence of
underlying health conditions. We also compared PICU and
ward patients to identify potential risk factors for a more
severe clinical course.
Data analysis was performed at the Biostatistics Unit of
Hospital La Paz, using SPSS statistical software, version 9.0
Pediatric hospitalizations due to H1N1 influenza
ª 2011 Blackwell Publishing Ltd, Influenza and Other Respiratory Viruses, 5, e544–e551
e545

Page 3

(SPSS Inc., Chicago, IL, USA). Continuous variables were
described with mean and standard deviation or median
and interquartile range.
described with absolute and relative frequencies.
The association of possible risk factors and PICU admis-
sion was studied using Chi-square test and Fisher’s exact
test in categorical variables and Student’s t and Mann–
Whitney U tests in continuous variables. The area under
the ROC curve was estimated to evaluate the discriminat-
ing capacity of lymphocyte count, choosing 1840 cells⁄mm3
as the cut-off that maximized sensitivity (76Æ2%, 95% CI:
61Æ5–86Æ5) and specificity (49Æ6%, 95% CI: 44Æ8–54Æ5).
Finally, all factors that had a significant association
(P < 0Æ05) with PICU admission were put into a full model
for multiple logistic regression analysis. To estimate the
predictive capacity of the model, the area under the ROC
curve was calculated.
A two-tailed P value < 0Æ05 was considered statistically
significant.
Categoricalvariableswere
Results
Clinical and demographic characteristics
During the study period, 517 children with confirmed
pH1N1 infection were hospitalized. The first pediatric case
was confirmed on the 20th of May and hospitalizations for
pH1N1 peaked at the end of October. Cases included in
this review represent 90% of confirmed hospitalized paedi-
atric cases in Madrid, according to data from the regional
epidemiologic bulletin.10
Main characteristics of the total study group are pre-
sented in Table 1. Mean age was 4Æ7 ± 3Æ9 years and 59Æ8%
patients were less than 5 years. Median time to consulta-
tion from the beginning of symptoms was 3 days (inter-
quartile range, IQR: 1–5). The most frequent reasons for
hospital admission were high fever and respiratory distress.
Mean maximal temperature
38Æ9?C ± 0.7?C.
One hundred and forty-two patients (27Æ5%) had high-
risk medical conditions, with immunosuppression, moder-
ate persistent asthma, and neurological disease being the
most common ones. There were 163 patients (31Æ5%) with
asthma: 87 had infrequent intermittent asthma, 41 frequent
intermittent, 34 moderate persistent, and 1 severe persistent
asthma. Patients with underlying health conditions were
significantly older than those previously healthy (mean age
5Æ5 ± 3Æ8 years versus 4Æ3 ± 3Æ9 years, P < 0Æ01).
before admissionwas
Radiological, laboratory, and microbiological
studies
Chest radiograph was performed on admission in 432 chil-
dren (84%). Abnormal chest radiographs were significantly
more frequent in children that required PICU admission
Table 1. Characteristics of children hospitalized with pandemic
H1N1 influenza, Madrid, 2009
Number
of cases Percentage
Gender
Female
Male
205
312
40
60
Age group
<1 year
1–5 years
5–11 years
11–14 years
9919
41
30
10
210
155
53
Clinical signs and symptoms
Fever 50097
Upper respiratory tract manifestations
Cough
Rhinorrhea
Odynophagia
455
369
62
88
72
12
Breathing difficulty25850
General symptoms
Headache
Myalgias
Irritability⁄malaise
54
43
11
9
19638
Gastrointestinal symptoms
Vomiting
Diarrhea
144
69
28
14
Chest radiograph
Interstitial pneumonia
Lobar or segmental consolidation
Other radiologic findings
(atelectasis, pleural effusion)
Normal
432
187
94
19
84
43
22
4
13231
Treatment
Oseltamivir
Antibiotics
Bronchodilators
Oxygen supplementation
Intravenous fluid therapy
389
264
244
221
204
76
52
48
43
40
Underlying health conditions*
Moderate or severe persistent
asthma
Other chronic lung disorders
(e.g., cystic fibrosis,
bronchopulmonary dysplasia,
obliterant bronchiolitis)
Immunosuppression (because of
underlying disease
and⁄or therapy) or immunodeficiency
142
35
27Æ5
6Æ8
193Æ7
367
del Rosal et al.
e546
ª 2011 Blackwell Publishing Ltd, Influenza and Other Respiratory Viruses, 5, e544–e551

Page 4

than in ward patients (88% versus 67%, P < 0Æ01). Blood
was collected and analyzed for 462 children (89%). Pediat-
ric intensive care unit patients had lower lymphocyte
counts (1590 ± 1298 versus 2702 ± 2868, P < 0Æ001). We
observed no differences between PICU and ward patients
regarding white blood cell count, neutrophils, and C-reac-
tive protein.
Blood cultures were performed in 341 children (66%),
but they were positive only in seven patients (excluding
bacterial contaminations). The most frequent isolate was
Streptococcus pneumoniae (six cases). Streptococcus pyogenes
was identified in one case. There were no infections by
Staphylococcus aureus.
Antiviral treatment, clinical course, and
complications
Antiviral use was reported in 389 children (76%), oseltami-
vir being the only drug prescribed. Oseltamivir use was
more frequent in PICU than in ward patients (86% versus
74Æ9%, P = 0Æ08) and significantly lower in infants <1 year
compared with older children (59Æ6% versus 79Æ9%,
P < 0Æ001). There were no major adverse effects associated
with oseltamivir therapy.
The median length of hospital stay was 4 days (IQR: 3–
6). Complications were registered in 132 patients (26%), as
listed in Table 1. The most frequent one was suspected or
confirmed bacterial pneumonia, which occurred in 72
patients (14Æ5%), followed by severe bronchospasm requir-
ing PICU admission (16 patients, 3Æ1%).
When comparing infants less than 1 year of age with
older children, we found no differences regarding hospital
stay [median(IQR)4 days
P = 0Æ59], PICU admission (11% versus 10%, P = 0Æ71),
and invasive mechanical ventilation (3% versus 2%,
P = 0Æ39). Underlying medical conditions (14Æ1% versus
30Æ6%, P = 0Æ001) and complications (17Æ2% versus 27Æ5%,
P = 0Æ04) were less frequent in infants.
As for patients with high-risk medical conditions, they
had longer hospital stay [5 days (3–8) versus 4 (3–6),
P < 0Æ001] and required PICU admission (20Æ4% versus
5Æ9%, P < 0Æ001) and invasive mechanical ventilation (6Æ3%
versus 0Æ8%, P < 0Æ01) more frequently than previously
healthy children.
However, the presence or severity of asthma was not sig-
nificantly associated with PICU admission or mechanical
ventilation. Pediatric intensive care unit admission and
invasive mechanical ventilation proportions were respec-
tively 6Æ9% and 1Æ1% in patients with infrequent intermit-
tent asthma (n = 87), 12Æ2% and 2Æ4% in patients with
frequent intermittent asthma (n = 41), and 11Æ8% and
2Æ9% in patients with moderate persistent asthma (n = 34).
There was only one patient with severe persistent asthma,
who required PICU admission but not invasive mechanical
ventilation. Amongnon-asthmatic
9Æ9% required PICU admission and 2Æ5% invasive mechani-
cal ventilation (P = 0Æ51 for PICU admission and 0Æ82 for
mechanical ventilation, when comparing non-asthmatic
and asthmatic children across the different asthma severity
levels).
(3–6) forboth groups,
children(n = 354),
Risk factors for PICU admission
Intensive care was required for 51 patients (10%), breath-
ing difficulty being the most frequent reason for admission
at the PICU. Comparison of ward versus PICU patients is
showed in Table 2.
Thirty-one patients (6%) received non-invasive ventila-
tion and 12 (2%) invasive mechanical ventilation. Of the
12 patients who required invasive mechanical ventilation,
nine (75%) had underlying medical conditions and four
died. The most frequent underlying medical conditions
in these patients were neurological or neuromuscular dis-
ordersand immunosuppression
each).
(four patients,33%
Table 1. (Continued)
Number
of cases Percentage
Neurological or neuromuscular disorders
Heart disease
Diabetes mellitus
Chronic renal disease
Morbid obesity
Hemoglobinopathy
30
27
5Æ8
5Æ2
5
4
3
3
1
0Æ8
0Æ6
0Æ6
Complications?
Confirmed or suspected
bacterial pneumonia
Severe bronchospasm
Respiratory insufficiency
Seizures
Acute otitis media
Clinical sepsis
Encephalopathy
Other?
132
72
26
14Æ5
16
12
3Æ1
2Æ3
1Æ4
1Æ4
0Æ8
0Æ6
3Æ7
7
7
4
3
19
*Children may have had more than one of the conditions listed;
percentage represents the number with each condition over the
total number of children (n = 517).
?Children may have had more than one of the complications listed;
percentage represents the number with each condition over the
total number of children (n = 517).
?Severe laryngitis (2), decompensation of heart disease (2), bactere-
mia (2), hepatitis (2), hemolytic crises (1), Stevens–Johnson syn-
drome (1), urinary tract infection (1), acute tonsillopharyngitis (1),
erosive gastritis (1), dehydration (1), hyponatremia (1), incomplete
Kawasaki disease (1), myositis (1), pneumothorax (1), and interstitial
lung disease (1).
Pediatric hospitalizations due to H1N1 influenza
ª 2011 Blackwell Publishing Ltd, Influenza and Other Respiratory Viruses, 5, e544–e551
e547

Page 5

Table 2. Comparison of characteristics of ward versus pediatric intensive care unit (PICU) patients
Ward patients
n = 466
Number (%)
PICU patients
n = 51
Number (%)P*
Male sex
Mean age (years)
283 (60Æ7) 29 (56Æ9)0Æ59
0Æ64Æ7 ± 3Æ94Æ4 ± 3Æ7
Clinical signs and symptoms
Fever452 (97Æ2)48 (94Æ1)0Æ23
Upper respiratory tract manifestations
Cough
Rhinorrhea
Odynophagia
413 (88Æ8)
335 (72)
57 (12Æ4)
42 (82Æ4%)
34 (69Æ4)
5 (10Æ9)
0Æ17
0Æ69
0Æ76
Breathing difficulty219 (47Æ2) 39 (78)
<0Æ001
General symptoms
Headache
Myalgias
Irritability⁄malaise
53 (11Æ6)
42 (9Æ2)
178 (38Æ4)
1 (2Æ2)
1 (2Æ2)
18 (38Æ3)
0Æ07
0Æ16
0Æ98
Gastrointestinal symptoms
Vomiting
Diarrhea
136 (29Æ4)
67 (14Æ4)
8 (16Æ3)
2 (4Æ1)
0Æ05
0Æ04
Mean time from symptom onset to
hospital admission (days)
4Æ1 ± 10Æ72Æ5 ± 1Æ70Æ3
Abnormal chest radiograph67% 88%
<0Æ01
Blood test results
White blood cell count (cells⁄mm3)
Lymphocytes (cells⁄mm3)
Neutrophils (cells⁄mm3)
C-reactive protein (mg⁄l)
9994 ± 5988
2702 ± 2868
6026 ± 4970
34Æ3 ± 52Æ7
9430 ± 6537
1590 ± 1298
6804 ± 5981
45 ± 68Æ6
0Æ57
<0Æ001
0Æ41
0Æ31
Treatment
Oseltamivir
Antibiotics
Bronchodilators
Oxygen supplementation
Intravenous fluid therapy
346 (74Æ9)
223 (49Æ2)
215 (46Æ6)
173 (37Æ7)
161 (35Æ2)
43 (86)
41 (80Æ4)
29 (58)
48 (94Æ1)
43 (87Æ8)
0Æ08
<0Æ0001
0Æ12
<0Æ0001
<0Æ0001
Underlying health conditions
Any
Moderate or severe persistent asthma
Other chronic lung disorders (e.g. cystic fibrosis,
bronchopulmonary dysplasia, obliterant bronchiolitis)
Immunosuppression (because of underlying disease
and⁄or therapy) or immunodeficiency
Neurological or neuromuscular disorders
Heart disease
113 (24Æ2)
30 (6Æ4)
15 (3Æ2)
29 (56Æ9)
5 (9Æ8)
4 (7Æ8)
<0Æ001
0Æ36
0Æ11
28 (6)8 (15Æ7)
<0Æ01
22 (4Æ7)
23 (4Æ9)
8 (15Æ7)
4 (7Æ8)
<0Æ01
0Æ33
Complications
Any
Confirmed or suspected bacterial pneumonia
85 (18Æ2)
52 (11Æ1)
47 (92Æ2)
20 (39Æ2)
<0Æ0001
<0Æ0001
Statistically significant differences are shown in bold.
del Rosal et al.
e548
ª 2011 Blackwell Publishing Ltd, Influenza and Other Respiratory Viruses, 5, e544–e551

Page 6

In a multivariable model that included underlying medi-
cal conditions, lymphocyte count and chest radiograph
result, we identified four statistically significant risk factors
associated with PICU admission: underlying neurological
or neuromuscular disease [P = 0Æ006, Odds Ratio (OR) 4Æ2,
95% CI 1Æ5–11Æ3], immunosuppression (P = 0Æ008, OR 4Æ4,
95% CI 1Æ5–13Æ2), abnormal initial chest X-ray (P = 0Æ005,
OR 5Æ2, 95% CI 1Æ7–16Æ5), and lymphocytes under
1840 cells⁄mm3(P = 0Æ006, OR 2Æ9, 1Æ3–6Æ2). The estimated
effects in this model were similar to those estimated in the
previous univariate analysis. The area under the ROC curve
was 0Æ720 (95% CI 0Æ66–0Æ80).
Mortality
Five patients (0Æ9%) died, all of them suffering of underly-
ing health conditions. Two children (both 4 years old) had
leukemia with severe pancytopenia and developed acute
respiratory distress with refractory hypoxemia. A 10-year-
old patient had a malignant peripheral nerve sheath tumor
with cerebral metastasis. He developed bronchopneumonia
and acute respiratory distress syndrome with progressive
worsening, and limitation of therapeutic effort was decided.
A 3-month-old infant with Edwards’ syndrome developed
respiratory insufficiency with severe hypoxemia, and limita-
tion of therapeutic effort was decided. The last patient was
4 years old and had a severe encephalopathy with cerebral
palsy and a seizure disorder. Her chest radiograph showed
a large pleural effusion and developed severe breathing dif-
ficulty and refractory hypoxemia. Four out of five of these
patients, the exception being the one affected by Edwards’
syndrome, received oseltamivir, were admitted to PICU
and put on mechanical ventilation.
Discussion
Children hospitalized for pH1N1 infections in Madrid had
a wide spectrum of clinical pictures, ranging from mild
respiratory symptoms and fever to severe illness and death.
The majority of children in our study were less than
5 years of age. Presenting features and median length of
hospital stay were similar to those described in other ser-
ies.5,15,16Underlying medical conditions were frequent,
mainly asthma, immunosuppression, and neurological dis-
ease. Patients with underlying health conditions were older
than previously healthy children. Abnormal chest radio-
graph, low lymphocytes, and underlying health conditions
were associated with PICU admission, while asthma was
not.
Infants less than1 year
increased risk for influenza-related complications only on
the basis of age and had the highest hospitalization rates at
the beginning of the pandemic.17In our study, the clinical
course was similar in this age group than in older children,
havebeen consideredat
which could be related to a higher hospitalization rate
among infants (even when presenting with mild symptoms)
and to the fact that the majority of infants were previously
healthy. Perhaps, children less than 1 year did not yet have
the opportunity to be diagnosed with some of the high-risk
medical conditions that increase the risk for severe disease.
A recent pediatric study showed that older hospitalized
children with pH1N1 were significantly more likely to
require PICU admission than hospitalized children <2 years
of age.7Besides, previous studies of seasonal influenza in
Spain did not find more complications among hospitalized
infants younger than 6 months.18,19Notably, there was only
one death in the infant group, and the patient suffered
from Edwards’ syndrome. Oseltamivir treatment was signif-
icantly less likely in infants less than 1 year of age, although
an Emergency Use Authorization was issued temporarily
allowing its use in infants during the H1N1 pandemic.
However, some pediatricians may have been reluctant to
use oseltamivir because of the limited data in patients
younger than 1 year of age.
Overall, asthma was the most frequent underlying health
condition (31Æ5% of cases, including intermittent asthma),
as other authors have reported.5,14,20It seems that children
admitted to hospital with pH1N1 are more likely to have
asthma than those with seasonal influenza.7,21To our
knowledge, there are no published data assessing the sever-
ity of pH1N1 infection across different asthma severity lev-
els. In our case series, most hospitalized children with
asthma and no other health conditions had intermittent
asthma (79%), suggesting that children with intermittent
asthma are at risk of pH1N1 infection requiring hospital
admission, which is in accordance with other pediatric ser-
ies.20,21However, when analyzing severity of pH1N1 in
patients with asthma in our series (PICU admission,
death), it was similar to that of children without underly-
ing medical conditions, and also similar in each asthma
severity level. Nevertheless, only one child suffered from
severe persistent asthma, and this may limit the validity of
our results in this group of patients.
PICU admission rates range from 5Æ4 to 27% in the liter-
ature.5,7,15,16,21–23Our rate of 10% is similar to that of sea-
sonal influenza.21,24–26As it has been previously reported,
PICU admission and mechanical ventilation have occurred
mainly in children with known comorbidities.27,28The pro-
portion of high-risk medical conditions among patients
admitted to intensive care units is similar to that reported
for adults in our country. However, for adults, the most
common underlying medical condition was obesity.29In
our series, immunosuppression and neurological disorders
were the most common underlying medical conditions
among PICU patients, and they were significantly associ-
ated with PICU admission. Several reports on seasonal
influenza had previously shown the importance of neuro-
Pediatric hospitalizations due to H1N1 influenza
ª 2011 Blackwell Publishing Ltd, Influenza and Other Respiratory Viruses, 5, e544–e551
e549

Page 7

logical and neuromuscular conditions as a predisposing risk
factor for severe disease.30–32As for pH1N1 influenza, it
seems that these patients are also at higher risk for compli-
cations and PICU admission, mainly those children with
multiple developmental diagnoses and⁄or comorbid pul-
monary conditions.7,8,22,33,34The underlying mechanisms of
vulnerability in these children may include problems with
muscle tone, weakness, inadequate clearance of respiratory
tract secretions, and susceptibility to recurrent respiratory
infections.32,33
Complicated cases among children are
mostly attributable to secondary bacterial infection, which
is more common in children than in adults.35The inci-
dence of suspected bacterial pneumonia was similar to the
one reported for seasonal influenza.31,36The low rate of
confirmed bacterial coinfections in our study is similar to
that observed in other pH1N1 case series,9,33in which
S. pneumoniae has also been the most frequent isolated
pathogen.5,15However, bacterial diagnostic tests were not
performed in all cases, and many patients received antibiot-
ics around the time of culture collection, which could have
reduced the diagnostic sensitivity.33In hospitalized patients
with seasonal influenza, culture-proven bacterial infection
is also rare, and S. aureus and S. pneumoniae are the pre-
dominant pathogens isolated.24Notably, there were no
S. aureus infections in our series. In Spain, community-
acquired staphylococcal pneumonia is rare, but infections
caused by methicillin-resistant S. aureus are emerging.37A
coinfection by methicillin-resistant S. aureus and pandemic
influenza H1N1 was recently documented in a child in our
country.38
During the 2009 influenza H1N1 pandemic, global hos-
pitalization rates have been higher for children less than
the age of 5 years, but the need for mechanical ventilation
and the overall case fatality rate among hospitalized
patientsappearsto be
dren.20,22,29,33,35,39,40Mortality proportions among hospital-
ized children with pH1N1 show marked differences; from
021,28to 5%.15Most pediatric deaths have affected patients
with underlying medical conditions.5,15,27,34Our mortality
data are comparable to seasonal influenza, with the likely
exception of the 2003–2004 H3N2 season, which was asso-
ciated with increased mortality and morbidity.30,31,36
There are several limitations in our study. First, although
data recording was standardized, observations may have
differed among hospitals or healthcare providers, and not
all information was collected for all patients. Second, rou-
tine diagnostic testing recommended by public health
authorities for hospitalized children with fever and respira-
tory symptoms may have led to a greater number of con-
firmed cases than in previous influenza seasons. Third,
admission criteria may have not been the same in all the
hospitals that participated in the study.
lowest amongchil-
However, we provide global information from a large
sample, not only from tertiary care pediatric hospitals but
also from local hospitals. Diagnostic methods were the
same among all centers and during the whole study period.
In conclusion, pH1N1 in hospitalized children in Madrid
(Spain) has affected mainly children less than 5 years of
age, and asthma was the most common underlying medical
condition. Children less than 1 year were less likely to have
high-risk health conditions and develop complications.
Patients with predisposing health conditions, especially
those with neurological disease, were more likely to experi-
ence severe pH1N1 infection. Therefore, this group of chil-
dren should be carefully assessed for early recognition and
adequate follow-up and treatment of pH1N1 infection. As
for asthmatic patients, although they did not experience
more severe disease, it seems that even children with inter-
mittent asthma are at risk of pH1N1 infection requiring
hospital admission and should therefore receive vaccination
and be considered for early antiviral therapy.
Addendum
This is a multicentric study conducted in 18 different hos-
pitals by a Study Group. In each hospital, there was at least
one investigator (depending on the number of cases), who
collected data and contributed to their interpretation. All
authors have revised the intellectual content of the manu-
script.
Conflicts of interest
The authors declare to have no conflicts of interest.
References
1 Echevarrı ´a-Zuno S, Mejı ´a Arangure ´ JM, Mar-Obeso AJ et al. Infec-
tion and death from influenza A H1N1 virus in Mexico: a retrospec-
tive analysis. Lancet 2009; 374:2072–2079.
2 Editorial Team. Pandemic phase level 4: human cases of the novel
influenza A⁄H1N1 strain confirmed in Scotland and Spain. Euro Sur-
veill 2009; 14:19185.
3 Comunidad de Madrid. Informe semanal de gripe. Temporada
2009–2010 [portal de sanidad de la Comunidad de Madrid]. Avail-
able at http://www.madrid.org/sanidad/profesional/informacio ´ntec-
nica/saludpublica/vigilanciaepid/vigilanciadelagripe/incidenciaseman-
aldegripe (Accessed 31 March 2010).
4 European Centre for Disease Prevention and Control. The 2009
A(H1N1) Pandemic in Europe. Stockholm: ECDC, 2010.
5 Bettinger JA, Sauve ´ LJ, Scheifele DW et al. Pandemic influenza in
Canadian children: a summary of hospitalized pediatric cases. Vac-
cine 2010; 28:3180–3184.
6 Hackett S, Hill L, Patel J et al. Clinical characteristics of paediatric
H1N1 admissions in Birmingham, UK. Lancet 2009; 374:605.
7 Bagdure R, Curtis DJ, Dobyns E, Glode ´ MP, Dominguez SR. Hospi-
talized children with 2009 pandemic influenza A (H1N1): compari-
del Rosal et al.
e550
ª 2011 Blackwell Publishing Ltd, Influenza and Other Respiratory Viruses, 5, e544–e551

Page 8

son to seasonal influenza and risk factors for admission to the PICU.
PLoS One 2010; 5:e15173.
8 Stein M, Tasher D, Glikman D et al. Hospitalization of children with
influenza A (H1N1) virus in Israel during the 2009 outbreak in Israel:
a multicenter survey. Arch Pediatr Adolesc Med 2010; 164:1015–
1022.
9 Launay E, Ovetchkine P, Saint-Jean M et al. Novel influenza A
(H1N1): clinical features of pediatric hospitalizations in two succes-
sive waves. Int J Infect Dis 2011; 15:e122–e130.
10 Comunidad de Madrid. Boletı ´n Epidemiolo ´gico de la Comunidad de
Madrid 2010;2:3–56. Available
Satellite?c=PTSA_Generico_FA&cid=1142593584355&language=es&
pageid=1142336590538&pagename=PortalSalud%2FPTSA_Generico_
FA%2FPTSA_pintarGenericoIndice&pv=1142336587119&vest=11563
29914017 (Accessed 7 January 2011).
11 Comunidad de Madrid. Criterios para la toma de muestras de gripe
A (H1N1)[portal de sanidad de la Comunidad de Madrid]. 2009.
Available at http://www.madrid.org/cs/Satellite?cid=114254872
3512&language=es&pagename=PortalSalud%2FPage%2FPTSA_pin-
tarContenidoFinal&vest=1156329914017
2010).
12 CDC. CDC protocol of real-time RT-PCR for influenza A H1N1.
2009.
13 Mare `s J, Rogrigo C, Moreno-Pe ´rez D et al. Recomendaciones sobre
el tratamiento de la gripe en pediatrı ´a (2009–2010). An Pediatr
(Barc) 2010; 72:144.e1–144.e12.
14 GEMA 2009. Guı ´a espan ˜ola para el manejo del asma. 2009. Avail-
able at http://www.gemasma.com (Accessed 15 February 2011).
15 Libster R, Bugna J, Coviello S et al. Pediatric hospitalizations associ-
ated with 2009 pandemic influenza A (H1N1) in Argentina. N Engl
J Med 2010; 362:45–55.
16 Kumar S, Havens PL, Chusid MJ, Willoughby RE, Simpson P, Hen-
rickson KJ. Clinical and epidemiological characteristics of children
hospitalized with 2009 pandemic H1N1 influenza A infection. Pedi-
atr Infect Dis J 2010; 29:591–594.
17 Domı ´nguez-Cherit G, Lapinsky SE, Macı ´as AE et al. Critically ill
patients with 2009 influenza A(H1N1) in Mexico. JAMA 2009;
302:1880–1887.
18 Aro ´stegi Kareaga N, Montes M, Pe ´rez-Yarza EG, Sardo ´n O, Vicente
D, Cilla G. Caracterı ´sticas clı ´nicas de los nin ˜os hospitalizados por in-
feccio ´n por virus influenza. An Pediatr (Barc) 2005; 62:5–12.
19 Calvo Rey C, Garcı ´a Garcı ´a ML, Casas Flecha I, Martı ´n del Valle
F, Centeno Jime ´nez M, Pe ´rez-Bren ˜a P. Infecciones por virus de la
gripe en menores de dos an ˜os. An Pediatr (Barc) 2005; 63:22–
28.
20 Nguyen-Van-Tam JS, Openshaw PJM, Hashim A et al. Risk factors
for hospitalisation and poor outcome with pandemic A⁄H1N1 influ-
enza: United Kingdom first wave (May–September 2009). Thorax
2010; 65:645–651.
21 O’Riordan S, Barton M, Yau Y, Read SE, Allen U, Tran D. Risk fac-
tors and outcomes among children admitted to hospital with pan-
demic H1N1 influenza. CMAJ 2009; 182:39–44.
22 Kumar A, Zarychanski R, Pinto R et al. Critically ill patients with
2009 influenzaA(H1N1) infection
302:1872–1879.
23 Louie JK, Gavali S, Acosta M et al. Children hospitalized with 2009
novel influenza A(H1N1) in California. Arch Pediatr Adolesc Med
2010; 164:1023–1031.
at http://www.madrid.org/cs/
(Accessed 10October
inCanada.JAMA 2009;
24 Schrag SJ, Shay DK, Gershman K et al. Multistate surveillance for
laboratory-confirmed, influenza-associated hospitalizations in chil-
dren: 2003–2004. Pediatr Infect Dis J 2006; 25:395–400.
25 Burton C, Vaudry W, Moore DL et al. Children hospitalized
with influenza during the 2006–2007 season: a report from the
Canadian Immunization Monitoring Program, Active (IMPACT). Can
Commun Dis Rep 2008; 34:17–32.
26 Wooton S, Scheifele DW, Mozel M et al. The epidemiology of influ-
enza in children hospitalized in Canada, 2004–2005, in Immuniza-
tion Monitoring Program Active (IMPACT) centres. Can Commun
Dis Rep 2006; 32:65–74.
27 Lister P, Reynolds F, Parslow R et al. Swine-origin influenza virus
H1N1, seasonal influenza virus, and critical illness in children. Lancet
2009; 374:605–607.
28 Lockman JL, Fischer WA, Perl T, Valsamakis A, Nichols DG. The criti-
cally ill child with novel H1N1 influenza A: a case series. Pediatr Crit
Care Med 2010; 11:173–178.
29 Rello J, Rodrı ´guez A, Iba ´n ˜ez P et al. Intensive care adult patients
with severe respiratory failure caused by influenza A (H1N1)v in
Spain. Crit Care 2009; 13:R148.
30 Bhat N, Wright JG, Broder KR et al. Influenza-associated deaths
among children in the United States, 2003–2004. N Engl J Med
2005; 353:2559–2567.
31 Coffin SE, Zaoutis TE, Wheeler AB et al. Incidence, complications,
and risk factors for prolonged stay in children hospitalized with
community-acquired influenza. Pediatrics 2007; 119:740–748.
32 Keren R, Zaoutis TE, Bridges CB et al. Neurological and neuromus-
cular disease as a risk factor for respiratory failure in children hospi-
talized with influenza infection. JAMA 2005; 294:2188–2194.
33 Jain S, Kamimoto L, Bramley AM et al. Hospitalized patients with
2009 H1N1 influenza in the United States, April–June 2009. N Engl
J Med 2009; 361:1935–1944.
34 CDC. Surveillance for pediatric deaths associated with 2009 pan-
demic influenza A (H1N1) virus infection – United States, April–
August 2009. MMWR Morb Mortal Wkly Rep 2009; 58:941–947.
35 Rothberg MB, Haessler SD. Complications of seasonal and pan-
demic influenza. Crit Care Med 2010; 38:e91–e97.
36 Ampofo K, Gesteland PH, Bender J et al. Epidemiology, complica-
tions, and cost of hospitalization in children with laboratory-con-
firmed influenza infection. Pediatrics 2006; 118:2409–2417.
37 Broseta A, Chaves F, Rojo P, Otero JR. Emergencia de un clon de
Staphylococcus aureus resistente a meticilina de origen comunitario
en la poblacio ´n pedia ´trica del sur de Madrid. Enferm Infecc Micro-
biol Clin 2006; 24:31–35.
38 Obando I, Valderrabanos ES, Millan JA, Neth OW. Necrotising pneu-
monia due to influenza A (H1N1) and community-acquired methicil-
lin-resistant
Staphylococcusaureus
management of the first documented paediatric case. Arch Dis
Child 2010; 95:305–306.
39 Vaillant L, La Ruche G, Tarantola A, Barboza P; for the epidemic
intelligence team at InVS. Epidemiology of fatal cases associated
with pandemic H1N1 influenza 2009. Euro Surveill 2009; 14:19309.
40 Pe ´rez-Padilla R, de la Rosa-Zamboni D, Ponce de Leo ´n S et al. Pneu-
monia and respiratory failure from swine-origin influenza A (H1N1)
in Mexico. N Engl J Med 2009; 361:680–689.
clone USA300: successful
Pediatric hospitalizations due to H1N1 influenza
ª 2011 Blackwell Publishing Ltd, Influenza and Other Respiratory Viruses, 5, e544–e551
e551