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original article
T h e n e w e ngl a nd j o u r na l o f m e dic i n e
n engl j med 361;7 nejm.org august 13, 2009680
Pneumonia and Respiratory Failure from
Swine-Origin Influenza A (H1N1) in Mexico
Rogelio Perez-Padilla, M.D., Daniela de la Rosa-Zamboni, M.D.,
Samuel Ponce de Leon, M.D., Mauricio Hernandez, M.D.,
Francisco Quiñones-Falconi, M.D., Edgar Bautista, M.D.,
Alejandra Ramirez-Venegas, M.D., Jorge Rojas-Serrano, M.D.,
Christopher E. Ormsby, M.Sc., Ariel Corrales, M.D., Anjarath Higuera, M.D.,
Edgar Mondragon, M.D., and Jose Angel Cordova-Villalobos, M.D.,
for the INER Working Group on Influenza*
From the National Institute of Respiratory
Diseases (INER) (R.P.-P., D.R.-Z., F.Q.-F.,
E.B., A.R.-V., J.R.-S., C.E.O., A.C., A.H.,
E.M.), Biologicals and Reactives of Mexi-
co (BIRMEX) (S.P.L.), and the Secretariat
of Health (M.H., J.A.C.-V.) — all in Mexi-
co City. Address reprint requests to Dr.
Perez-Padilla at Instituto Nacional de En-
fermedades Respiratorias, Tlalpan 4502,
14080 Mexico, or at perezpad@gmail.com.
*Members of the INER Working Group
on Influenza are listed in the Appendix.
This article (10.1056/NEJMoa0904252) was
published on June 29, 2009, at NEJM.org.
N Engl J Med 2009;361:680-9.
Copyright © 2009 Massachusetts Medical Society.
A bs tr ac t
Background
In late March 2009, an outbreak of a respiratory illness later proved to be caused
by novel swine-origin influenza A (H1N1) virus (S-OIV) was identified in Mexico.
We describe the clinical and epidemiologic characteristics of persons hospitalized
for pneumonia at the national tertiary hospital for respiratory illnesses in Mexico
City who had laboratory-confirmed S-OIV infection, also known as swine flu.
Methods
We used retrospective medical chart reviews to collect data on the hospitalized
patients. S-OIV infection was confirmed in specimens with the use of a real-time
reverse-transcriptase–polymerase-chain-reaction assay.
Results
From March 24 through April 24, 2009, a total of 18 cases of pneumonia and con-
firmed S-OIV infection were identified among 98 patients hospitalized for acute
respiratory illness at the National Institute of Respiratory Diseases in Mexico City.
More than half of the 18 case patients were between 13 and 47 years of age, and
only 8 had preexisting medical conditions. For 16 of the 18 patients, this was the
first hospitalization for their illness; the other 2 patients were referred from other
hospitals. All patients had fever, cough, dyspnea or respiratory distress, increased
serum lactate dehydrogenase levels, and bilateral patchy pneumonia. Other common
findings were an increased creatine kinase level (in 62% of patients) and lymphopenia
(in 61%). Twelve patients required mechanical ventilation, and seven died. Within
7 days after contact with the initial case patients, a mild or moderate influenza-like
illness developed in 22 health care workers; they were treated with oseltamivir, and
none were hospitalized.
Conclusions
S-OIV infection can cause severe illness, the acute respiratory distress syndrome,
and death in previously healthy persons who are young to middle-aged. None of the
secondary infections among health care workers were severe.
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pneumonia and Respir atory Failure from S-OIV
n engl j med 361;7 nejm.org august 13, 2009 681
In April 2009, the Mexican Secretariat of Health reported an outbreak of respiratory disease. In the affected patients, a novel swine-
origin influenza A (H1N1) virus (S-OIV) with
molecular features of North American and Eur-
asian swine, avian, and human influenza viruses1-4
was found. In the same month, the World Health
Organization (WHO) classified the global spread
of this virus as a public health event of interna-
tional concern. After documentation of human-
to-human transmission of the virus in at least
three countries of two WHO regions, the WHO
raised the pandemic level to 6.5
As of May 29, 2009, Mexico had reported 4910
confirmed cases and 85 deaths caused by S-OIV.6
Mexico has reported the greatest number of cases
of severe clinical presentations and death,1 where-
as other countries have reported predominantly
mild cases of influenza-like illness.
This case series describes the clinical and epi-
demiologic characteristics of the first 18 persons
with pneumonia and laboratory-confirmed S-OIV
infection (also known as swine flu) hospitalized
at the National Institute of Respiratory Diseases
(INER) in Mexico. We also describe apparent trans-
mission of this infection to health care workers
during the initial days of the outbreak.
Me thods
INER is the Mexican national tertiary care and
research center devoted to respiratory diseases.
The 178-bed facility provides clinical services pri-
marily for the uninsured population of Mexico
City and neighboring states. We retrospectively
reviewed medical charts and radiologic and labo-
ratory findings. This study was determined to be
exempt from the requirement of institutional re-
view, because it was conducted as part of a public
health investigation into retrospective data. All
tests and procedures were performed at the re-
quest of the physicians in charge of the patients.
All study patients had influenza-like illness with
opacities found on the chest radiograph (reveal-
ing pneumonia) and had laboratory-confirmed
S-OIV infection. We also reviewed clinical data
from a group of 21 hospitalized patients with
influenza-like illness and pneumonia but with a
negative result on reverse-transcriptase–polymer-
ase-chain-reaction (RT-PCR) testing for influenza A
(H1N1).
Microbiologic Studies
Nasopharyngeal-swab specimens were collected
at admission, and bronchial-aspirate samples were
obtained after tracheal intubation. Specimens
were placed in transport medium and kept at a
temperature from 2 to 4°C. RT-PCR testing was
done in accordance with published guidelines
from the U.S. Centers for Disease Control and
Prevention (CDC).7 Primers and probes for S-OIV
were recently developed and distributed to the
Mexican Secretariat of Health and its affiliated
national institutions by the CDC. In addition, re-
spiratory specimens from all patients were tested
with the use of a multiplex PCR assay for respira-
tory viral and atypical bacterial panels (Seagene)
for the detection of influenza A, influenza B, adeno-
virus, respiratory syncytial virus, parainfluenza
(types 1, 2, and 3), human metapneumovirus,
rhinovirus, Legionella pneumophila, Chlamydophila
pneumoniae, and Mycoplasma pneumoniae.
Statistical Analysis
Data analysis was conducted using STATA statis-
tical software.8 We compared clinical character-
istics on admission between patients positive for
S-OIV who died and those who survived and be-
tween patients who were positive for S-OIV and
those who were negative for S-OIV. The risk of
death was analyzed by means of a univariate Cox
proportional-hazards model; odds ratios were cal-
culated and Fisher’s exact test was performed for
dichotomous categorical variables. Continuous
data were tested by means of the Wilcoxon rank-
sum test. All reported P values are two-sided and
were not adjusted for multiple testing.
R esult s
Study Patients
The number of emergency room visits for pneu-
monia or influenza-like illness increased consid-
erably at the INER in Mexico City during the last
week of March 2009, peaking in late April and
decreasing during the first week of May (Fig. 1).
From March 24 through April 24, 2009, a total of
214 emergency room consultations for cases of
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T h e n e w e ngl a nd j o u r na l o f m e dic i n e
n engl j med 361;7 nejm.org august 13, 2009682
pneumonia or influenza-like illness were regis-
tered, 98 of which required hospitalization. Of
these cases, 18 confirmed cases of S-OIV infec-
tion, with pneumonia and influenza-like illness,
are the focus of this report.
Characteristics of the 18 study patients with
confirmed S-OIV infection are listed in Table 1,
and Table S1 in the Supplementary Appendix
(available with the full text of this article at
NEJM.org). The ages of the patients ranged from
9 months to 61 years (median, 38 years). More
than half the patients were between 13 and 47
years of age, and 90% were less than 52 years of
age. Nine patients (50%) were male.
All patients resided in the Mexico City greater
metropolitan area. Eight patients had preexisting
medical conditions: arterial hypertension (in three
patients), non–type 1 diabetes mellitus (in three,
one of whom also had hypertension), asthma (in
two), and obstructive sleep apnea (in one). Only
three of the patients had undergone seasonal
influenza vaccination in 2008–2009; all three
survived without requiring mechanical ventilation.
None of the patients had a history of pneumo-
coccal vaccination. Among the 14 patients whose
occupation was recorded, 6 were students, 2 were
taxi drivers, 3 were housekeepers, 1 was a lock-
smith, 1 was an employee of a billiards parlor,
and 1 was a physician who did not have clinical
duties and was not an INER employee.
The time between onset of symptoms and ad-
mission to the hospital ranged from 4 to 25 days
(median, 6) (Fig. 2). All patients had fever, with
temperatures higher than 38°C, cough, and dys-
pnea or respiratory distress. Four of the five chil-
dren (all under 14 years of age) had diarrhea, and
only two patients (11%) reported wheezing. The
median Acute Physiology and Chronic Health
Evaluation II score9 was 14 (range, 4 to 32), and
the me dian Sequential Organ Failure Assessment
score10 was 6 (range, 1 to 13); both were higher,
indicating more severe abnormalities among the
patients who died than among those who lived
(Table 2).
Twelve patients sought medical care at other
institutions as outpatients before hospitalization
at INER and were treated with one or more anti-
biotics: ceftriaxone (five patients), amikacin (three),
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AUTHOR:
FIGURE:
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AUTHOR, PLEASE NOTE:
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ARTIST: ts
360xx ISSUE:
Admission
Figure 1. Emergency Room Consultations for Pneumonia or Respiratory Infection, Including Influenza-like Illness,
at the National Institute of Respiratory Diseases of Mexico.
Patients with the reported cases were admitted between March 24 and April 24 (gray vertical lines). The Ministry of
Health issued an epidemiologic alert on April 17 and a full sanitary alert, with closing of schools and cancellation of
many public activities on April 23, after it was confirmed that the patients were infected with the novel influenza A
(H1N1) virus.
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pneumonia and Respir atory Failure from S-OIV
n engl j med 361;7 nejm.org august 13, 2009 683
azithromycin (one), amoxicillin–clavulanate (two)
or other macrolides (three), or another agent
(two). Except for two patients transferred from
other health centers, the reported hospitaliza-
tion was the first hospitalization related to the
disease.
Laboratory Results
At the time of admission, all 16 tested patients
had elevated lactate dehydrogenase levels; levels
in 10 patients exceeded 1000 IU per liter (range,
1086 to 6309). Ten of the 16 patients had increased
creatine kinase levels, which were above 1000 IU
per liter (range, 1099 to 5122) in 5 patients. Eleven
of all 18 patients (61%) had lymphopenia (<1000
lymphocytes per cubic millimeter), 2 patients had
more than 10,000 leukocytes per cubic millimeter,
and 2 patients had mild thrombocytopenia at
admission. Patient 3 had myocardial ischemia, as
revealed on electrocardiography, with myocardial
infarction documented on autopsy. Three patients
had elevated creatinine levels (1.8 to 4.6 mg per
deciliter [159 to 407 μmol per liter]) at admis-
sion. Four patients had d-dimer levels greater
than 1000 IU per liter, and 11 patients had elevated
aminotransferase levels (aspartate aminotransfer-
ase, 50 to 65 U per liter; alanine aminotransferase,
43 to 147 U per liter). Results of other routine
tests were within normal limits.
The following bacterial cultures obtained with-
in 24 hours after admission were negative: cul-
tures of blood specimens from six patients, of
bronchial aspirate samples from two patients, and
of pleural-fluid specimens from one patient. Three
of these patients had received antibiotics within
24 to 48 hours before admission. No other respi-
ratory viruses or atypical bacteria were identified
by means of PCR assay in any patient tested.
All 18 patients had radiologically confirmed
pneumonia (Fig. 3A, and Fig. S2 and S3 in the
Supplementary Appendix) with bilateral patchy
alveolar opacities (predominantly basal), affect-
ing three or four lung quadrants in 11 patients.
Also common were linear, reticular, or nodular
shadows (interstitial opacities). Findings on chest
radiographs were consistent with the acute respi-
ratory distress syndrome in all patients requir-
ing mechanical ventilation.11
Treatment
None of the patients had received oseltamivir be-
fore admission; 14 received it in the hospital, at
a dose of 75 mg twice a day for a minimum of
5 days; 11 began receiving it at admission (a mean
of 8 days after the onset of symptoms) and 3 be-
tween 2 and 10 days after admission. Four pa-
tients who survived did not receive oseltamivir.
After admission, 17 patients received ceftriaxone
and 10 received clarithromycin. Additional anti-
biotics were prescribed in several patients, on the
basis of their clinical course: three were given
levofloxacin; seven, vancomycin; five, cefepime;
five, imipenem; and two, dicloxacillin.
Clinical Course during Hospital Stay
Respiratory distress requiring intubation and me-
chanical ventilation developed in 10 patients with-
in the first 24 hours after admission. These pa-
tients had a median oxygen saturation of 71%
(interquartile range, 64 to 77) in the absence of
supplementary oxygen (2240 m above sea level),
and treatment of eight patients involved positive
end-expiratory pressure at or above 16 cm of
water. Two additional patients required mechan-
ical ventilation during their stay in the hospital
(Table S2 in the Supplementary Appendix). Dura-
tion of mechanical ventilation ranged from 7 to 30
days in patients who survived and from 4 to 17
days in patients who died. Norepinephrine infu-
sion was begun in 9 of 18 patients (50%) during
the period of hospitalization, and 5 patients re-
ceived corticosteroids (hydrocortisone at a dose of
300 mg per day or methylprednisolone at a dose
of 60 mg per day). Of the six patients in whom
renal failure developed, five died. Seven patients
had multiorgan system failure. None of the pa-
tients had disseminated intravascular coagulation
or neurologic complications. Four patients had
ventilator-associated pneumonia, each case with
a different cause: Acinetobacter baumannii, Achro-
mobacter xylosoxidans, methicillin-resistant Staphy-
lococcus aureus, or Escherichia coli.
Of the 18 patients, 7 died, and 11 recovered
and were discharged from the hospital. Patients
died within 10 to 23 days (mean, 14) after the
onset of illness and between 4 and 18 days (mean,
9 days) after admission. Figure 3B shows a lung-
tissue specimen from the autopsy of Patient 3,
a 43-year-old patient who died after a 14-day ill-
ness complicated by acute renal failure and myo-
cardial infarction. Pathological evaluation of the
lung showed diffuse alveolar damage, thick hya-
line membranes, and prominent fibroblast pro-
liferation.
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T h e n e w e ngl a nd j o u r na l o f m e dic i n e
n engl j med 361;7 nejm.org august 13, 2009684
Patients with confirmed S-OIV infection had
more severe disease, including a higher death rate
(Table S2 in the Supplementary Appendix), than
did hospitalized patients with negative test results.
The median time from illness onset to collection
of samples for viral testing was 9 days (range, 3 to
46) among the 18 patients who were positive for
S-OIV infection and 10 days (range, 3 to 27) among
those with negative test results (P = 0.50).
Clinical Infection in Contacts and Health
Care Workers
Patients identified a total of 82 family contacts,
20 of whom had respiratory symptoms within a
week after the patient was hospitalized. Of the
20, 4 required hospitalization, including 3 con-
tacts of Patient 6; 1 contact who had Down’s syn-
drome died in another hospital from respiratory
failure. Patient 2, in whom severe respiratory fail-
Table 1. Characteristics of the 18 Study Patients Who Had Confirmed Infection with Novel Swine-Origin Influenza A
(H1N1) Virus.*
Variable Value
Male sex — no./total no. (%) 9/18 (50)
Age — yr
Median 38
Range 0.75–61
All patients — no./total no. (%)
≤5 yr 3/18 (17)
>5 to ≤10 yr 1/18 (6)
>10 to ≤15 yr 1/18 (6)
>15 to ≤50 yr 11/18 (61)
>50 yr 2/18 (11)
Patients who died — no./total no.
≤5 yr 0/3
>5 to ≤10 yr 1/1
>10 to ≤15 yr 1/1
>15 to ≤50 yr 4/11
>50 yr 1/2
Symptom or outcome — no./total no. (%)
Cough 18/18 (100)
Blood in sputum 6/18 (33)
Rhinorrhea 5/18 (28)
Wheezing 2/18 (11)
Headache 4/18 (22)
Myalgia or arthralgia 8/18 (44)
Fever (temperature >38°C) 18/18 (100)
Dyspnea or respiratory distress 18/18 (100)
Diarrhea 4/18 (22)
Sudden onset of symptoms 13/18 (72)
Hypotension that did not resolve after fluid administration 9/18 (50)
Mechanical ventilation on admission 10/18 (56)
Death 7/18 (39)
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