Professional Documents
Culture Documents
Viral pneumonia
Olli Ruuskanen, Elina Lahti, Lance C Jennings, David R Murdoch
Lancet 2011; 377: 126475
Published Online
March 23, 2011
DOI:10.1016/S01406736(10)61459-6
Department of Paediatrics,
Turku University Hospitals,
Turku, Finland
(Prof O Ruuskanen MD,
E Lahti MD); and Microbiology
Unit, Canterbury Health
Laboratories, and Department
of Pathology, University of
Otago, Christchurch,
New Zealand
(Prof D R Murdoch MD,
L C Jennings PhD)
Correspondence to:
Prof Olli Ruuskanen,
Department of Paediatrics,
Turku University Hospitals,
PL 52, 20521 Turku, Finland
olli.ruuskanen@tyks.
About 200 million cases of viral community-acquired pneumonia occur every year100 million in children and
100 million in adults. Molecular diagnostic tests have greatly increased our uwnderstanding of the role of viruses in
pneumonia, and ndings indicate that the incidence of viral pneumonia has been underestimated. In children,
respiratory syncytial virus, rhinovirus, human metapneumovirus, human bocavirus, and parainuenza viruses are
the agents identied most frequently in both developed and developing countries. Dual viral infections are common,
and a third of children have evidence of viral-bacterial co-infection. In adults, viruses are the putative causative agents
in a third of cases of community-acquired pneumonia, in particular inuenza viruses, rhinoviruses, and coronaviruses.
Bacteria continue to have a predominant role in adults with pneumonia. Presence of viral epidemics in the community,
patients age, speed of onset of illness, symptoms, biomarkers, radiographic changes, and response to treatment can
help dierentiate viral from bacterial pneumonia. However, no clinical algorithm exists that will distinguish clearly
the cause of pneumonia. No clear consensus has been reached about whether patients with obvious viral communityacquired pneumonia need to be treated with antibiotics. Apart from neuraminidase inhibitors for pneumonia caused
by inuenza viruses, there is no clear role for use of specic antivirals to treat viral community-acquired pneumonia.
Inuenza vaccines are the only available specic preventive measures. Further studies are needed to better understand
the cause and pathogenesis of community-acquired pneumonia. Furthermore, regional dierences in cause of
pneumonia should be investigated, in particular to obtain more data from developing countries.
Introduction
Pneumonia is a common illness that continues to be the
major killer of young children in developing countries
and elderly people in developed countries. Many
microorganisms are associated with pneumonia, and
now attention is turning to the importance of viruses as
pathogens. Widespread introduction of Haemophilus
inuenzae type b and pneumococcal conjugate vaccines
into immunisation programmes has led to speculation
about the growing predominance of viruses as causes of
childhood pneumonia. The emergence of severe acute
respiratory syndrome (SARS), avian inuenza A (H5N1)
virus, and the 2009 pandemic inuenza A (H1N1) virus
has re-emphasised the important role of respiratory
viruses as causes of severe pneumonia. New respiratory
virusessuch as human metapneumovirus, coronaviruses NL63 and HKU1, and human bocavirushave
been discovered during the past decade. Importantly, the
availability of molecular diagnostic assays (such as PCR)
has greatly increased our ability to detect and characterise
the epidemiology of respiratory virus infections. Findings
of previous studies, in which conventional virological
1264
Epidemiology of pneumonia
According to WHO estimates, 450 million cases of
pneumonia are recorded every year; about 4 million people
die from this illness, accounting for 7% of total mortality
of 57 million people.6,7 The highest incidences arise in
children younger than 5 years and in adults older than
75 years (gure 1).8 In developing countries, incidence
could be ve times higher than in developed regions. In
children, 156 million episodes of pneumonia are recorded
annually, of which 151 million are present in developing
countries.6,7 In 2008, 16 million children younger than
5 years died from pneumonia.9 5 million cases of childhood
community-acquired pneumonia are reported yearly in
developed countries, but mortality has declined strikingly
and is now very rare. In a Canadian study, 25 319 admissions
for childhood pneumonia took place during the 9-year
study period; 11 deaths were recorded and only one death
did not have a comorbid condition.10 Mortality of 12 per
million previously healthy young adults has been recorded
in the UK.11 In the USA alone, the economic burden of
community-acquired pneumonia has been estimated to
be more than US$17 billion annually.12
Seminar
80
Incidence (per 1000 popultion per year)
60
40
20
0
0
15
30
45
Age (years)
60
75
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Age
Adults
Epidemic situation
..
History of illness
Slow onset
Rapid onset
Clinical prole
Rhinitis, wheezing
Biomarkers
Total white-blood cell count
>60 mg/L
<01 g/L
>05 g/L
Slow or non-responsive
Rapid
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Rhinovirus
(n=580)
Respiratory syncytial
virus (n=1655)
Adenovirus
(n=902)
Parainuenza
virus 1 (n=94)
Parainuenza
virus 2 (n=49)
Parainuenza
virus 3 (n=315)
Inuenza A
virus (n=544)
Inuenza B
virus (n=139)
Pneumonia
18%
16%
8%
9%
6%
14%
9%
8%
Wheezy bronchitis
22%
12%
2%
2%
4%
8%
6%
6%
Otitis media
23%
59%
24%
27%
20%
30%
26%
19%
14%
32%
37%
27%
22%
50%
44%
53%
Bronchiolitis
3%
34%
1%
2%
10%
5%
1%
1%
Laryngitis
2%
2%
1%
37%
53%
10%
5%
4%
4%
Tonsillitis
2%
30%
1%
2%
5%
2%
1%
5%
10%
2%
1%
2%
Febrile convulsion
1%
2%
7%
4%
5%
12%
9%
44%
63%
81%
77%
76%
63%
94%
89%
Fever 38C
Rhinovirus infections are from 1987 to 2006; other respiratory virus infections are from 1980 to 1999. Modied from reference 51, with permission of John Wiley and Sons.
Table 2: Occurrence of pneumonia and other ndings in 4277 children with laboratory-conrmed viral respiratory infection at Turku University Hospital, Finland
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Research in adults
We identied ten studies of adults with communityacquired pneumonia (n=2910 episodes) in which PCR
was used to test for respiratory viruses. Evidence of viral
infection was detected in 22% of cases.19,20,7785 In most of
these studies, a comprehensive array of conventional
virological methods were also implemented to better
dene the role of viruses in adults with communityacquired pneumonia. Similar to ndings of paediatric
studies, prevalence of infection with inuenza viruses
(8%), respiratory syncytial virus (3%), parainuenza
viruses (2%), and adenovirus (2%) is comparable with
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Viral-bacterial co-infection
Interest has grown with respect to the interaction of
bacteria and viruses in the pathogenesis of pneumonia.
Evidence from cell culture, ecological, post-mortem, and
clinical studies support this area of interest. A favoured
hypothesis is that viral infection is followed by secondary
bacterial infection. Researchers who reassessed data
from the inuenza pandemics of 1918, 1957, and 1968
have suggested that most deaths during these periods
probably resulted from secondary bacterial pneumonia.114
This nding contrasts with avian H5N1-associated
pneumonia, which seems to be a primarily viral
infection.102 In patients with 2009 pandemic H1N1
infection, secondary bacterial infection developed in
424% of cases.103,106,115
Evidence of probable mixed viral-bacterial infection
has been recorded in up to 45% of cases of communityacquired pneumonia in children.21,30,4046 Not surprisingly,
the most typical combination is Streptococcus pneumoniae
with various respiratory viruses. In developing
countries, both viruses and bacteria have been detected
directly in lung aspirate samples from children with
pneumonia.22 In a study from The Gambia, 45 of
74 children had evidence of pneumococcal communityacquired pneumonia and 15 (33%) of these also had
evidence of a respiratory virus infection, shown by virus
culture or serological tests.116 In a study from Nigeria,117
virological analysis was done in 122 children with
community-acquired pneumonia. 61 (50%) had
evidence of viral infection and, of those, ten (16%) also
had blood cultures positive for bacteria, most usually
Staphylococcus aureus. Furthermore, ten (16%) of
62 cases with measles-associated community-acquired
pneumonia had bacteraemia.117
Mixed viral-bacterial infections in adults with
community-acquired pneumonia seem to be reported
less frequently than those in children.19,20,7785 In one study,
both viral and bacterial pathogens were noted in 35 (14%)
of 242 cases.84 In another investigation, evidence of mixed
viral and bacterial infections was reported in 45 (15%) of
304 patients (median age 70 years). The most frequent
combinations were rhinovirus plus Strep pneumoniae and
inuenza A plus Strep pneumoniae.19 Undoubtedly,
detection of several pathogens will be noted more
frequently as more elaborate diagnostic tests are used as
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Pathology
Post-mortem studies provide direct evidence for a viral
cause of pneumonia and descriptions of characteristics
of lung histopathology. Many dierent respiratory viruses
have been detected in lung tissue in case reports or in
larger series.
In 200 children who died from serious respiratory
infections in Brazil, use of immunohistochemical
techniques aided detection of viruses in lung tissue from
53 (34%) with bronchopneumonia and 18 (42%) with
interstitial pneumonitis, predominantly respiratory
syncytial virus, inuenza A and B viruses, adenovirus,
and parainuenza viruses types 1, 2, and 3.123 In another
study from Mexico, PCR detected respiratory syncytial
virus in lung tissue from 29 (30%) of 98 children who
died from pneumonia.124 Of archived lung tissue from
175 children who died of pneumonia in south China,
20 samples had adenovirus detected by PCR or by
immunohistochemistry.72 Rhinovirus infection of the
lung has also been shown by histopathology.125
1270
Management
Do all patients with community-acquired pneumonia,
including those with evidence of viral infection, need to
be treated with antibiotics? To date, no clear consensus
exists on this issue. Some experts recommend that all
patients with pneumonia should receive antibiotic
treatment, because exclusion of the presence of bacterial
infection is impossible. Recommendations of the British
Thoracic Society are that antibiotic treatment can be
withheld in young children with mild illness in whom
viral infection is likely.1 As far as we know, only one
randomised placebo-controlled study has been done to
investigate the need for antibiotic treatment in childhood
community-acquired pneumonia.133 In 136 children, no
clinically signicant ecacy of antibiotics was recorded.
Most study children had fairly mild disease and the
investigation was undertaken during an epidemic of
respiratory syncytial virus, so most participants probably
had pneumonia caused by this virus. Further randomised
placebo-controlled trials of antibiotic treatment
for pneumonia are unlikely to happen because of
ethical concerns.
Opportunities are currently limited in clinical practice
for use of antivirals in the treatment of pneumonia
(table 3).134 Neuraminidase inhibitors, such as oseltamivir
www.thelancet.com Vol 377 April 9, 2011
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Treatment
Prevention
Inuenza A virus
..
Palivizumab (intramuscular)
Adenovirus
Cidofovir (intravenous)
Rhinovirus
Pleconaril
Enteroviruses
Pleconaril
Human metapneumovirus
Ribavirin (intravenous)
Hantavirus
Ribavirin (intravenous)
Varicella-zoster virus
Aciclovir (intravenous)
Vaccine
*Long successful use in US military conscripts, no production now. Has been used for compassionate cases.
Table 3: Possibilities for antiviral treatment and prevention of severe viral pneumonia
Prevention
Possibilities to prevent viral community-acquired
pneumonia are limited. Inuenza vaccines have been
used since the mid 1940s and they now have an
established role in prevention of inuenza A and B virus
infections. Importantly, inactivated inuenza vaccine is
eective in young children, including those younger than
2 years.150 During the 2009 H1N1 pandemic, a monovalent
vaccine against the virus was developed.103 Its active use
could have played a part in the course of the initial
pandemic wave in some countrieseg, in Finland, only
44 fatal cases were recorded. In addition to vaccines,
inuenza A and B virus infections can be prevented by
prophylactic use of neuraminidase inhibitors.137 Severe
respiratory syncytial virus infections in high-risk neonates
have been prevented successfully with palivizumab, a
humanised monoclonal antibody, which is administered
during a respiratory syncytial virus epidemic.151 This
agent has been shown to prevent admissions related to
respiratory syncytial virus by 50% in premature infants.
Since the 1960s, several types of vaccines for respiratory
syncytial virus have been developed without success.
Live-attenuated vaccines produced by reverse genetics
are now in clinical studies.142 Pneumonia caused by
adenovirus types 4 and 7 has been prevented in military
trainees by an oral vaccine, with 95% ecacy.
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Future research
Despite many advances, further studies are still needed to
better understand the role of viruses in the cause and
pathogenesis of community-acquired pneumonia.
Increased availability of molecular diagnostic methods
enables us to evaluate our understanding of viral
pneumonia and to reassess all existing dogma. Further
clarication is needed of the role of bacterial-viral
interaction in the pathogenesis of pneumonia and of the
importance of viruses as pneumonia pathogens in the
world after widespread implementation of H inuenzae
type b and pneumococcal conjugate vaccines. Also,
examination of regional dierences in causes of pneumonia
is needed urgently, particularly to obtain additional data
from developing countries. Detailed understanding of the
viral cause of community-acquired pneumonia will guide
antiviral drug and vaccine developments.
Contributors
All authors contributed to the writing of this Seminar.
Conicts of interest
EL and DRM declare that they have no conicts of interest. OR has
been a consultant to Novartis Vaccines and Abbot. LCJ has received
grant support from Homann La-Roche and honoraria or travel
assistance from Homann La-Roche, GlaxoSmithKline, Sano Pasteur,
Baxter, Novartis, Wyeth, and CSL for participation in advisory groups
and scientic meetings.
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