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Inuenza A (H1N1) pneumonia:

a brief review
La polmonite da inuenza A (H1N1): una breve review
Review article / Articolo di revisione
Rassegna di Patologia dellApparato Respiratorio 2012; 27: 333-337 333
Antonello Nicolini

Catia Cilloniz*
Division of Respiratory Diseases,
General Hospital of Sestri Levante,
Sestri Levante, Italy;
Department of
Pneumology, Institut Clinic del Trax,
Hospital Clinic of Barcelona, Institut
dInvestigacions Biomdiques
August Pi i Sunyer (IDIBAPS),
University of Barcelona (UB), Ciber
de Enfermedades Respiratorias
(Ciberes) Barcelona, Spain
Key words
Inuenza A H1N1 virus
Pandemic Pneumonia
Parole chiave
Inuenza A H1N1 Pandemia
Ricevuto l8-5-2012.
Accettato il 13-9-2012.
Antonello Nicolini
UO Pneumologia
via Terzi, 43
16039 Sestri Levante (Ge)
Pandemic inuenza A (H1N1) virus emerged in Mexico during the spring of 2009 and spread rapidly and
caused signicant strain on health systems worldwide. The clinical picture of the pandemic inuenza A (H1N1)
virus ranges from a self-limiting a-febrile infection to a rapidly progressive pneumonia. The presence of less
co-morbidity, more extensive respiratory compromise, and ICU admission are key features of the clinical pre-
sentation of patients with novel H1N1-associated pneumonia compared with other viruses and in particular
seasonal inuenza pneumonia. Bacterial co-infections, particularly Streptococcus pneumoniae, increased the
severity of illness and consumption of health resources. Patients from the post-pandemic period had an unex-
pectedly high mortality rate and showed a trend towards affecting a more vulnerable population, much like
more typical seasonal viral infection. Early use of non-invasive ventilation in severe cases of acute respiratory
failure required shorter ventilation time as well as shorter ICU stay and hospital stay.
La pandemia di inuenza A (H1N1), virus apparso in Messico durante la primavera del 2009 e diffusosi rapi-
damente in tutto il mondo, ha causato un signicativo impegno di tutti i sistemi sanitari. Il quadro clinico della
pandemia inuenzale A (H1N1) varia da un infezione autolimitante a-febbrile ad una polmonite rapidamente
progressiva. Le presenza di minori comorbilit, una compromissione respiratoria pi ampia, un pi frequente
ricorso al ricovero in terapia intensiva sono le caratteristiche osservate maggiormente nei soggetti affetti da
polmonite causata da virus inuenzale H1N1 rispetto a quanto nora osservato in polmoniti causate da altri
tipi di virus, in particolare da quello dell inuenzale stagionale. La presenza di co-infezioni batteriche (in par-
ticolare da Streptococcus pneumoniae) aumenta la severit del quadro clinico e di conseguenza il consumo
di risorse. Nel periodo post-pandemico (seconda ondata) linfezione ha provocato un tasso di mortalit pi
elevata del previsto, ha mostrato una tendenza a colpire una popolazione pi vulnerabile, in linea con una
modalit pi tipica dellinuenza stagionale. Lutilizzo precoce della ventilazione non invasiva nei casi di insuf-
cienza respiratoria acuta severa ha reso il tempo di ventilazione pi breve, pi breve la degenza in terapia
intensiva, come pure la durata del ricovero ospedaliero.
From the beginning of the epidemic,
Inuenza A H1N1 infection seemed to
have a more severe course and worse
outcomes than did infection with seasonal
inuenza A. In addition, the demographic
prole of inuenza A H1N1 infection was
younger; moreover, it affected individuals
with fewer co-morbidities
.The incubation
period of H1N1 is similar to that of sea-
sonal u with some striking differences.
A quarter of all patients with pandemic
u presented with gastrointestinal symp-
toms and approximately 40% of all hos-
pitalized patients had ndings consistent
with pneumonia on initial chest X-rays. In
addition 10-30% of hospitalized patients
required admission to ICUs and mechani-
cal ventilation
The most notable difference in routine
laboratory tests is in the white blood cell
(WBC) count. In human seasonal inuenza
A, leucopenia is common and a predictor
of severity. However, in H1N1, leukocyto-
sis is the rule and is associated with fever,
dry cough, severe myalgias, otherwise
unexplained thrombocytopenia, relative
lymphopenia plus mildly elevated serum
transaminases and elevated creatine phos-
Female and individuals between 20 and
39 years of age present the highest risk of
mortality (median age of 26 years).
A. Nicolini, C. Cilloniz
Rassegna di Patologia dellApparato Respiratorio 334
V. 27 n. 06 Dicembre 2012
Complications leading to hospitalization and pos-
sibly death can occur in some of subjects, especially
those affected by underlying medical conditions in-
cluding diabetes mellitus, pulmonary, cardiovascular,
neurologic and psychiatric diseases.
A quarter of all patients with pande-
mic u presented with gastrointestinal
symptoms and approximately 40% of
all hospitalized patients had ndings
consistent with pneumonia.
Obesity (BMI 30) and morbid obesity (BMI 40)
was an independent risk factor for morbidity and
mortality from pandemic inuenza A H1N1
: a high
number of obese subjects were among the more se-
vere cases
Complications leading to hospita-
lization and possibly death can occur
in some of subjects, especially those
affected by underlying medical condi-
This particular susceptibility to respiratory infection
may be the result of a concurrence of mechanical and
hormonal factors due to the excess weight. Another
important risk factor for severe disease was preg-
. During 2009 H1N1 pandemic hospitalization
rate was signicantly higher among pregnant than non
. Maternal obesity and smoking during preg-
nancy were also associated with hospital admission
and more severe disease. Women admitted to hospital
with inuenza A H1N1 infection were more likely to de-
liver preterm
Obesity (BMI 30) and morbid obe-
sity (BMI 40) was an independent risk
factor for morbidity and mortality from
pandemic inuenza A H1N1.
A lower respiratory tract involvement was seen from
19% to 50 % of the diagnosed H1N1 virus infection
. The impact of co-infection was reported
in several studies, particularly bacterial co-infections.
Mixed respiratory viral co-infections were often less
. The most common viruses detected were
rhinovirus, enterovirus, bocavirus, coronavirus OC43
and parainuenza virus 3. Patients with viral co-infec-
tion showed a trend towards higher rates of pneumo-
nia and hospital admission. In addition, the duration
of hospitalization was signicantly longer than in those
without co-infection, possibly reecting a more se-
vere clinical course
. Bacterial co-infection has been
reported with rates between 0%
and 28%
commonest bacterial culprit was Streptococcus pneu-
, followed by Mycoplasma pneumoniae, Sta-
phylococcus aureus, Klebsiella pneumoniae, Moraxella
catarrhalis, Pseudomonas aeruginosa, Streptococcus
pyogenes and Streptococcus agalactiae
. Bacterial
co-infection was more frequent in patients aged more
than 50 years of age. The presence of underlying co-
morbidity increased the risk for bacterial co-infection.
ICU admissions, mechanical ventilation, renal im-
pairment and mortality were notably higher in patients
with bacterial co-infections. Moreover, leukocyto-
sis and neutrophilia were more common in bacterial
co-infected patients. Relative lymphopenia has been
considered a non-specic laboratory test indicator
of inuenza A H1N1 pneumonia
. Leukocytosis and
neutrophilia have been regarded markers of bacte-
rial co-infection. Lymphopenia lower than 800/ml was
associated with a worst outcome
. Invasive aspergil-
losis after infection with inuenza A H1N1 virus have
been recently described in ve patients: all the pa-
tients were admitted to intensive care unit and two of
them died
Clinical and radiological
Pneumonia is the most common complication of
inuenza A H1N1. Primary viral pneumonia is dened
in patients who presents during the acute phase of
inuenza virus illness with respiratory symptoms and
unequivocal alveolar opacication with negative res-
piratory and blood bacterial cultures
. Although
rapid antigen tests had a lower sensitivity (10% to
51%) and could not differentiate novel H1N1 from
other strains of inuenza A they were used early in the
pandemic. Consequently, negative rapid tests can-
not exclude the diagnosis
. At present,the preferred
test is RT-PCR. It has a sensitivity of 98%, a positive
predictive value of 100%, and a negative predictive
value of 98%
11 13
. Among hospitalized patients with
H1N1 pneumonia, about 26% had an inltrate limited
to one lobe on chest X ray and 22.9%-49% of this co-
hort presented rapidly progressive acute respiratory
13 14
. Inuenza A H1N1 pneumonia occurs in
about 20-70% of admitted patients. In severe cases
of H1N1 infection, dyspnea usually progresses rapidly
within 24 - 48 h with severe respiratory failure asso-
ciated with bilateral inltrates on chest radiographs.
Patients with mixed co-infections pneumonia are usu-
ally older, have higher level of procalcitonin and higher
scores of severity.
Various degrees of bilateral multifocal lesions of
ground-glass opacities associated or not with con-
solidations (Figure 1); these lesions are both bron-
chocentric and centrilobular and often multifocal
Bilateral, symmetric and multifocal areas of consoli-
dation, often associated with ground-glass opaci-
ties are the predominant ndings in pediatric patients
and are often associated with a more severe clinical
. Other rarer radiological manifestations were
atelectasis, pneumothorax, pneumomediastinum, and
subcutaneous emphysema, ascribed to ARDS
16 17
H1N1 pneumonia
Rassegna di Patologia dellApparato Respiratorio 335
V. 27 n. 06 Dicembre 2012
Small pleural effusions are common; additional ndings
include cavitation, necrosis and bronchial thickening
Aviram et al. reviewed 97 admission chest radiographs
of inuenza A H1N1 patients to determinate predict-
ing factors of clinical outcome: bilateral opacities and
involvement of multiple lung zones were common and
occurred signicantly more frequently in patients with
more severe morbidity (invasive mechanical ventilation)
and death
17 18
Among patients admitted to an ICU between 32.7%
and 62.5% had hypotension requiring vasopressors
and between 13% and 59% developed acute renal
. Patients who had refractory hypoxia and
hypotension not improving despite good therapeutic
strategies usually died from secondary multi-organ fail-
ure. Overall mortality reported was between 2.7% and
11.0% and was highest (18%-20%) in patients young-
er than 65 years
13 21
. Mortality among patients who
required mechanical ventilation was quite high (from
21.3% and 45.5%)
.Only twelve studies from eight
countries in Europe, the Americas, the western Pacic
and Asia were published concerning number of deaths
or mortality rate due to 2009 pandemic: data are not
available for Africa and southeast Asian countries. Be-
cause of the absence of global data, the number of
deaths and the mortality rate in the world has been
likely underestimated
Post-pandemic infection targeted
patients with a worse basal condition
than those of the 2009 pandemic: they
were older, had more chronic comorbi-
dities and more advanced clinical pre-
sentation on admission.
Post-pandemic infection period targeted patients
with a worse basal condition than those of the 2009
pandemic infection. Patients from the post-pandemic
(second wave) were older, had more chronic comor-
bidities, had more advanced clinical presentation on
admission, higher severity scores, increased com-
munity-acquired respiratory co-infection (particularly
Streptococcus pneumoniae), septic shock, and an
increased requirement for mechanical ventilation than
those from the pandemic period. In addition patients
from the post-pandemic received empiric antiviral
treatment less frequently and later in their hospitaliza-
tion, and had a higher mortality rate. The second wave
attacked a more vulnerable population (COPD, diabe-
tes, HIV patients), similarly to the pattern of typical sea-
sonal viral infection
Studies of patients admitted to ICU found three fac-
tors independently associated with in hospital death:
requirement of invasive ventilation, any co-existing
morbidity, and older age
. Some laboratory ndings
such as transaminases, LDH were positively correlated
with the number of pulmonary lobes involved and the
severity of the outcome
.The patients at highest risk
of developing complications include children younger
than ve years or persons 65 years or older, pregnant
women and those with chronic underlying medical
conditions (particularly asthma, but including other
pulmonary, cardiac, hematologic, hepatic, neurologic,
and metabolic diseases). Also at higher risk are immu-
nocompromised patients, residents of long-term care
facilities and obese patients
. A longer interval from
onset of symptoms to treatment, concurrent underly-
ing conditions such as pregnancy were related to the
severity of illness too
A recent study evaluated the role of community-
acquired severity scores as predictors of severity and
mortality for patients affected by Inuenza A H1N1
: the conclusions were that current com-
munity-acquired (CAP) severity scores (PSI, CRB-65,
CURB-65) fail to predict actual mortality in a signicant
number of hospitalized patients and underestimate
the severity of illness. Moreover, the authors found
that obesity and wheezing were the only novel vari-
ables associated with mortality. Traditional markers of
pneumonia severity as CAP scores, serum lactate and
Figure 1. Chest computed tomography in patient presen-
ting bilateral lobar densities.
Figure 2. Chest computed tomography in a patient with
bilateral and multifocal areas of consolidation associated
with ground-glass opacities (often associated with a more
severe clinical course).
A. Nicolini, C. Cilloniz
Rassegna di Patologia dellApparato Respiratorio 336
V. 27 n. 06 Dicembre 2012
ported high rates of NIV failure in pandemic inuenza A
H1N1 pneumoniaand early non-invasive ventilation was
strongly not recommended
. However, other authors
have more recently reported some cases demonstrating
the effectiveness of NIV in severe respiratory failure re-
lated to H1N1 pneumonia
34 35
. Early use of non-invasive
ventilation severe cases of acute respiratory failure have
achieved a success rate of up 40%.Patients success-
fully treated required shorter ventilation time, shorter ICU
and hospital stay. Their mortality rate has been similar to
those intubated at admission
Inuenza A H1N1 virus produces a higher incidence
of severe outcomes in younger people: most of them
present with pneumonia. Obesity, pregnancy and sever-
al pre-existing conditions such as respiratory, cardiovas-
cular, and immune-hematological disorders, higher lev-
els of C-protein reaction and delay in medical care were
predictive factors for pneumonia in adult patients
Younger age, less co-morbidity, more extensive respira-
tory compromise, and ICU admission are key features of
the clinical presentation of patients with novel H1N1-as-
sociated pneumonia compared with other viruses and
in particular seasonal inuenza pneumonia
. Bacterial
co-infections, particularly Streptococcus pneumoniae,
increased the severity of illness and consumption of
health resources
37 38
. Patients affected by inuenza A
H1N1 during post pandemic (second wave) period were
older, had more chronic co-morbid conditions, had
greater severity of illness and received empiric antiviral
treatment less frequently and later than rst wave pa-
tients. They had an unexpectedly higher mortality rate,
representing a more vulnerable population
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anionic gap also did not correlate with ICU admission.
There were also statistically signicant differences be-
tween survivors and non-survivors regarding the suc-
cess of non-invasive ventilation, time to conrmation of
the H1N1 virus infection after hospital admission, and
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late diagnosis, and late antiviral therapy were associ-
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Therapeutic strategies
At the present, with few exceptions, inuenza A
H1N1 virus remains susceptible to the neuraminidase
inhibitors oseltamivir and zanamivir, but resistant to the
M2 inhibitors amantadine and rimantadine
. In mild
cases oseltamivir when given early (2 days after on-
set of symptoms) can shorten the duration of symp-
toms; for high-risk patients or patients with severe
or progressive clinical illness, oseltamivir or zanamivir
should be initiated immediately or as soon as possi-
ble (ideally within 48 hours of the onset of illness)
A total of 264 oseltamivir-resistant pandemic inu-
enza A H1N1 viruses have been identied since the
end of 2010. These resistant organisms demonstrate
a H275Y mutation which causes resistance to osel-
tamivir, but not to zanamivir
. The risk of resistance
is considered higher in patients who have prolonged
illness or have received antiviral treatment for an ex-
tended duration
. Some adult cases of oseltamivir-re-
sistence have been reported in Korea and in Spain with
a single exception; they have not been fatal
. Nausea
and vomiting are the most common adverse effects to
these anti-viral agents. Less common are neuropsychi-
atric reactions
. Antimicrobial treatment should follow
the recommendations of IDSA/ATS guidelines: use a
beta-lactam agents in combination with a macrolide
or a respiratory uoroquinolone. The use of antibiotics
against MRSA (such as vancomycin or linezolid) should
be limited to patients with conrmed MRSA infection
or with a compatible clinical presentation (shock and
necrotizing pneumonia) and in patients admitted to
. Treatment of corticosteroids in patients with se-
vere H1N1 infection is still controversial and has dem-
onstrated no improvement in survival
Several types of ventilation were considered in the
most severe respiratory failure due to inuenza H1N1
. Most of the patients required invasive me-
chanical ventilation and were treated with conventional
modes of ventilation using a lung-protective strategy with
low tidal volume, plateau pressure between 30 and 35
cm H
O and optimal end-expiratory pressure. In some
cases with persistent hypoxemia alternative modes of
ventilation such as high-frequency oscillatory ventilation,
and airway pressure release ventilation
. In patients with
refractory respiratory failure in which oxygen saturation
cannot be effectively maintained over 90% by mechani-
cal ventilation treatment of extracorporeal membrane
oxygenation (ECMO) was used with good results
. In
the beginning of pandemics several authors have re-
H1N1 pneumonia
Rassegna di Patologia dellApparato Respiratorio 337
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