www.thelancet.com Published online March 23, 2011 DOI:10.1016/S0140-6736(10)61459-6 1
March 23, 2011
Department of Paediatrics,
Turku University Hospitals,
(Prof O Ruuskanen MD,
E Lahti MD); and Microbiology
Unit, Canterbury Health
Laboratories, and Department
of Pathology, University of
(Prof D R Murdoch MD,
L C Jennings PhD)
Prof Olli Ruuskanen,
Department of Paediatrics,
Turku University Hospitals,
PL 52, 20521 Turku, Finland
Olli Ruuskanen, Elina Lahti, Lance C Jennings, David R Murdoch
About 200 million cases of viral community-acquired pneumonia occur every year—100 million in children and
100 million in adults. Molecular diagnostic tests have greatly increased our understanding of the role of viruses in
pneumonia, and fi ndings indicate that the incidence of viral pneumonia has been underestimated. In children,
respiratory syncytial virus, rhinovirus, human metapneumovirus, human bocavirus, and parainfl uenza viruses are
the agents identifi ed 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 infl uenza viruses, rhinoviruses, and coronaviruses.
Bacteria continue to have a predominant role in adults with pneumonia. Presence of viral epidemics in the community,
patient’s age, speed of onset of illness, symptoms, biomarkers, radiographic changes, and response to treatment can
help diff erentiate 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 community-
acquired pneumonia need to be treated with antibiotics. Apart from neuraminidase inhibitors for pneumonia caused
by infl uenza viruses, there is no clear role for use of specifi c antivirals to treat viral community-acquired pneumonia.
Infl uenza vaccines are the only available specifi c preventive measures. Further studies are needed to better understand
the cause and pathogenesis of community-acquired pneumonia. Furthermore, regional diff erences in cause of
pneumonia should be investigated, in particular to obtain more data from developing countries.
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
infl uenzae 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 infl uenza A (H5N1)
virus, and the 2009 pandemic infl uenza A (H1N1) virus
has re-emphasised the important role of respiratory
viruses as causes of severe pneumonia. New respiratory
viruses—such as human metapneumovirus, corona-
viruses NL63 and HKU1, and human bocavirus—have
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
diagnostic techniques were used, have most likely
underestimated the role of viruses as pneumonia
pathogens.1–5 In this Seminar, we review viral community-
acquired pneumonia in immunocompetent children and
adults, focusing on studies that have used modern
molecular diagnostic techniques.
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 (fi gure 1).8 In developing countries, incidence
could be fi 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, 1·6 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 1·2 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
Diagnosis of viral pneumonia
Laboratory diagnosis of viral pneumonia has relied on
detection of virus or viral antigen in upper-respiratory
specimens (eg, nasopharyngeal aspirates) and lower-
respiratory samples (eg, induced sputum) by culture or
immunofl uorescence microscopy, and on measurement
Search strategy and selection criteria
We searched PubMed for original research, reviews, and
commentaries, with the terms “pneumonia and children/
adults”, “pneumonia and aetiology”, “viral pneumonia”,
“pneumonia and viruses”, and names of specifi c respiratory
viruses and pneumonia. No date or language restrictions
were included. We paid special attention to reports published
since 2000 when molecular diagnostics were introduced. We
also searched our personal database of references gathered
over the past 15 years and manually scanned references from
selected reports and from selected authors.
www.thelancet.com Published online March 23, 2011 DOI:10.1016/S0140-6736(10)61459-6
of antibodies in paired serum samples. Introduction of
PCR has increased the ability to detect respiratory viruses,
including those that are diffi cult to culture. At least
26 viruses have now been associated with community-
acquired pneumonia (panel).
Despite technological advances, establishing the cause
of pneumonia remains challenging.13 Specimens from
the lower-respiratory tract can be hard to obtain, and
colonisation from infection can be diffi cult. For diagnosis
of viral pneumonia, reliance on testing of nasopharyngeal
specimens presents its own challenges; detection of a
virus in the nasopharynx could represent coincidental
prolonged shedding or
upper-respiratory infection or a pneumonia pathogen.
Measurement of background prevalence of asymptomatic
nasopharyngeal viral infection in a control group might
help to clarify the size of this diagnostic issue at a
population level, but this approach has been used only
rarely in aetiological studies. Furthermore, most research
has focused on patients admitted to hospital and,
therefore, fi ndings might not be representative of mild-
Several diff erent types of specimen from the upper and
lower airway have been used in aetiological studies of
community-acquired pneumonia, including: naso-
pharyngeal aspirates or washes; swabs from the
nasopharynx, nose, or throat; combined nasopharygeal
and throat swabs; expectorated and induced sputum;
tracheal aspirates; bronchoalveolar lavage; and lung
puncture.14,15 Recovery of virus fl uctuates according to
specimen type, which probably accounts for some of the
variability of fi ndings between studies.
Most studies of the cause of viral pneumonia have
used upper-respiratory specimens to test for viruses. In
children, nasopharyngeal aspirates are generally deemed
the specimen of choice because both nasal and
nasopharyngeal mucus samples are gathered. Respira-
tory viruses have been noted in 95% of mucus samples
obtained by nasopharyngeal aspiration from children
with respiratory infection.16 Obtaining an aspirate is,
however, unpleasant and requires a suction device.
Nasal swabs taken with a sterile cotton swab from a
depth of 2–3 cm have comparable sensitivity to
nasopharyngeal aspirates for culture of all major
respiratory viruses, except respiratory syncytial virus.17
Flocked swabs with nylon fi bres in a perpendicular
fashion are now preferred by many clinicians because
they are convenient to use and have a similar sensitivity
to nasopharyngeal aspirates for detection by PCR of
respiratory viruses.15,17,18 In adults, nasopharyngeal swabs
have a higher sensitivity than throat swabs, but they can
be less sensitive than nasopharyngeal washes.14
Transnasal nasopharyngeal fl ocked swabs also have
high virus detection rates in adults.19,20
Lower-respiratory specimens have obvious advantages
for establishing the cause of pneumonia because they
come from the site of infection. However, obtaining
reliable specimens that are not contaminated by fl ora
from the upper airway is diffi cult. Induced sputum
specimens have been used in paediatric pneumonia
studies, although assuring that the specimens are
representative of the lower-respiratory tract can be
challenging.21 High-quality specimens can be obtained by
thoracic needle aspiration, but this technique has not
been adopted widely because of safety concerns, despite
a low complication rate.22,23
In general, PCR-based methods are between two and
fi ve times more sensitive than conventional virus
diagnostic methods (culture, antigen detection, and
serological assays) for detection of respiratory viruses.
0 1530 4560 75
Incidence (per 1000 popultion per year)
Figure 1: Age-specifi c incidence of community-acquired pneumonia
Error bars=95% CIs. Modifi ed from reference 8 with permission of Oxford
Panel: Viruses linked to community-acquired pneumonia
in children and adults
• Respiratory syncytial virus
• Infl uenza A, B, and C viruses
• Human metapneumovirus
• Parainfl uenza viruses types 1, 2, 3, and 4
• Human bocavirus*
• Coronavirus types 229E, OC43, NL63, HKU1, SARS
• Varicella-zoster virus
• Epstein-Barr virus
• Human herpesvirus 6 and 7
• Herpes simplex virus
*Mostly in children. †Mostly in developing countries.
www.thelancet.com Published online March 23, 2011 DOI:10.1016/S0140-6736(10)61459-6 3
This benefi t applies particularly to adults and elderly
people, who might have a smaller nasopharyngeal viral
load than children.24,25 Moreover, some respiratory viruses
can only be detected readily by PCR. Development of
several multiplex assays has enabled simultaneous
detection of up to 15 diff erent viruses, and use of these
tests is becoming standard for identifi cation of
The ability to diff erentiate viral from bacterial
pneumonia could have important management
implications. Despite advances, diagnostic tests still
fail to identify causative agents in many aff ected
individuals.28 As a result, other variables have been
used to distinguish viral from bacterial pneumonia
(table 1). However, no clinical algorithm exists to
discern clearly the cause of pneumonia. This absence
is perhaps not surprising in view of the probable
important interaction between viruses and bacteria in
pathogenesis of pneumonia.
Respiratory viruses usually follow seasonal patterns of
activity and are most likely to cause pneumonia during
those times. Epidemics of respiratory syncytial virus
typically happen every or every other year in late autumn,
rhinovirus epidemics arise in autumn and spring,
whereas infl uenza peaks are seen during late autumn
and early winter. Several viruses can be co-circulating at
specifi c times of the year, even during the highest
epidemic peaks of one virus.29
Although viral pneumonia is being recognised
increasingly in adults, it still seems to be most typical
in children, especially in infants younger than 2 years.30
According to the British Thoracic Society, fever higher
than 38·5°C, a respiratory rate greater than 50 breaths
per min, and chest recession are suggestive of bacterial
rather than viral pneumonia; by comparison, young
age, wheezing, fever less than 38·5°C, and striking
chest recession are suggestive of a viral cause.1 However,
clinical signs and symptoms of viral and bacterial
pneumonia are highly variable and overlap; there fore,
they cannot be relied on. Importantly, typical
pneumococcal pneumonia (sudden onset, high
fever, chills, pleuritic chest pain, lobar infi ltrates,
leucocytosis) is only one part of the range of bacterial
White-blood-cell count and concentrations in serum of
C-reactive protein and procalcitonin are variables studied
widely in children and adults with community-acquired
pneumonia. In general, these biomarkers are raised
signifi cantly in individuals with bacterial pneumonia
compared with patients
(table 1),19,32–35 although none has suffi cient sensitivity or
specifi city to be used in isolation. Use of procalcitonin in
clinical practice to identify bacterial infection and help
guide antimicrobial treatment has been the focus of
many studies. This substance increases within 6–12 h
after onset of bacterial infection and halves daily when
infection is controlled.34 In the context of pneumonia,
with viral pneumonia
concentrations of procalcitonin greater than 0·5 μg/L
support bacterial infection, whereas repeatedly low
amounts suggest that bacterial infection is unlikely.
However, the exact role of procalcitonin in management
of pneumonia is still the subject of ongoing discussion
Recommendations from the American Thoracic Society
are that diagnosis of pneumonia should be made on the
basis of chest radiography.36 Interstitial infi ltrates on
chest radiographs are generally believed to suggest a viral
cause of pneumonia and alveolar infi ltrates to indicate a
Suggests viral cause Suggests bacterial cause
History of illness
Clinical profi le
Total white-blood cell count
C-reactive protein concentration in serum <20 mg/L
Procalcitonin concentration in serum
Chest radiograph fi ndings
Response to antibiotic treatment
Younger than 5 years
Ongoing viral epidemic
High fever, tachypnoea
<10×109 cells per L>15×109 cells per L
Lobar alveolar infi ltrates
Sole interstitial infi ltrates, bilaterally
Slow or non-responsive
Table 1: Variables used to distinguish viral from bacterial pneumonia
Figure 2: Chest radiographs of patients with viral pneumonia
(A) Pneumonia caused by human bocavirus in a 1-year-old girl. Chest radiograph shows alveolar infi ltrates in right
middle lobe and left lower lobe. (B) Pneumonia caused by metapneumovirus and Haemophilus infl uenzae in a
7-year-old girl. Chest radiograph shows alveolar infi ltrate in left lower lobe. (C) Pneumonia caused by rhinovirus
and Streptococcus pneumoniae in an 11-year-old girl. Chest radiograph shows alveolar infi ltrate in right lower lobe.
(D) Pneumonia caused by adenovirus in a 22-year-old man. Chest radiograph shows alveolar and interstitial
infi ltrates in right lower lobe.
www.thelancet.com Published online March 23, 2011 DOI:10.1016/S0140-6736(10)61459-6
bacterial cause (fi gure 2). However, bacteria and viruses
alone or together can induce a broad range of chest
radiographic changes, and alterations are only helpful in
specifi c cases to confi rm a microbial cause of pneumonia.
In one study, bacterial infection was noted in 97 (71%) of
137 children with alveolar infi ltrates, whereas 97 (72%) of
134 with bacterial pneumonia had alveolar infi ltrates.33 In
children with viral pneumonia, 40 (49%) had alveolar
changes. Of 85 children with bacteraemic pneumococcal
pneumonia, alveolar infi ltrates were recorded in 77 (91%)
and interstitial infi ltrates alone in eight (9%).37 Multilobe
disease in various cases of viral pneumonia was reported
in half of 88 adults with community-acquired
pneumonia.19 Thoracic CT indicated tree-bud opacities,
multifocal consolidations, and ground-glass opacities in
adults with viral pneumonia without any evidence of
possible concomitant bacterial infection; however, a viral
cause was never suggested by the radiologists.38
Intuitively, bacterial pneumonia should respond to
appropriate antibacterial treatment but viral pneumonia
should not. In a study of 153 children admitted with
community-acquired pneumonia, median duration of
fever was 14 h after onset of antibiotic treatment.39 No
diff erence was recorded between those diagnosed with
viral and bacterial pneumonia. However, children with
mixed viral and bacterial infections became afebrile over
a longer period. Undetected bacterial co-infection
probably accounts for the response to antibacterial
treatment in patients with apparent viral pneumonia.
Community-acquired pneumonia is a dynamic
situation. Biomarkers and
radiographs are only snapshots of this active state.
Findings of follow-up studies, after 12–24 h, might be
totally diff erent.
infi ltrates on chest
Causes of viral pneumonia
We identifi ed nine studies of community-acquired
pneumonia (n=4279 episodes) in which the viral cause
had been searched for by PCR. In most of these
investigations, virus culture and antigen detection were
also used.21,30,40–46 Seven studies were undertaken in
developed countries and two in developing countries.
Evidence of viral infection was recorded in 49% (range
43–67) of cases. Prevalence of community-acquired
pneumonia associated with respiratory syncytial virus
(11%), infl uenza viruses (10%), parainfl uenza viruses
(8%), and adenovirus (3%) was similar to that reported
in studies in which only conventional diagnostic
approaches were used.1,2 Exact numbers of diff erent
viruses are diffi cult to compare from one study to another
because several techniques were applied. When
serological assays alone were used, evidence of a viral
cause was obtained in 20–43% of children with
syncytial virus was dominant.47–50 PCR has increased
detection of rhinoviruses (18%) and enteroviruses (7%).
Of newly described viruses, human bocavirus was
recorded in 5% of cases and human metapneumovirus
in 8%. Coronaviruses were seen in 22 (7%) of 338 children
in one study.41 In a 3-year prospective study in Finland,
the overall probable cause of pneumonia was recorded
in 85% of children, with bacterial infection in 53% and
viral infection in 62%.30 The most comprehensive study
from a virological perspective searched for 14 viruses in
338 children with pneumonia over a 2-year period.41
Prevalence of viral infection was 67%, with respiratory
syncytial virus, rhinoviruses, human bocavirus, human
meta pneumo virus, and parainfl uenza viruses being the
most common agents.
Many researchers have focused on the role of single
respiratory viruses as a cause of childhood community-
acquired pneumonia or have studied sole virus infections
and looked for pneumonia in their clinical profi les (table 2).
Globally, respiratory syncytial virus continues to be the
major causative viral agent of pneumonia in children and
could be the predominant viral cause of severe pneumonia
in this population.52,53 With the advent of PCR techniques,
rhinoviruses have been detected increasingly in childhood
pneumonia.54 The clinical profi le of 643 rhinovirus
virus 1 (n=94)
virus 2 (n=49)
virus 3 (n=315)
Infl uenza A
Infl uenza B
Non-specifi ed acute respiratory infection
Fever without a focus
Rhinovirus infections are from 1987 to 2006; other respiratory virus infections are from 1980 to 1999. Modifi ed from reference 51, with permission of John Wiley and Sons.
Table 2: Occurrence of pneumonia and other fi ndings in 4277 children with laboratory-confi rmed viral respiratory infection at Turku University Hospital, Finland
www.thelancet.com Published online March 23, 2011 DOI:10.1016/S0140-6736(10)61459-6 5
infections in children admitted to hospital has been
reported in seven studies,55–61 and 11–53% had pneumonia.
However, the role of rhinoviruses in pneumonia is still
questioned because of the frequent detection of
rhinoviruses in asymptomatic
prevalence 15%), strikingly more than for other respiratory
viruses (prevalence 1–5%).62 Jartti and colleagues suggested
that PCR is likely to detect a true but asymptomatic
infection.62 A diffi culty with rhinoviruses is the paucity of
serological tests to verify
immunocompetent individuals, rhinoviral clearance after
symptomatic infection is rapid (average 1–3 weeks).18
Pneumonia was diagnosed in 10% of children admitted
with acute human metapneumovirus respiratory
infection,63–66 with the highest prevalence (44%) in infants
younger than 12 months.66 It has also been recorded in
11–75% of children with human bocavirus infection.67 In
a study from Thailand of infants younger than 5 years
admitted with pneumonia, human bocavirus was the
third most prevalent agent detected, after rhinovirus and
respiratory syncytial virus, accounting for 12% of all
cases.68 Although the role of human bocavirus in
pneumonia is still being clarifi ed, serological evidence
suggests it is a cause of human infection. With a novel
IgM and IgG enzyme immunoassay, 96% of children
with a high load of human bocavirus in nasopharyngeal
aspirates and 92% of wheezy children with viraemia had
diagnostic seroresponses.69 Human bocavirus was
identifi ed serologically in 12 (12%) of 101 children with
community-acquired pneumonia in Italy.70
pneumonia is fairly low (range 2–12%), this type of
infection is important to recognise because it might
induce severe and fatal necrotising pneumonia (especially
serotypes 3, 7, and 14).30,40–46,71 In China, adenovirus DNA
was detected in 9% of post-mortem pulmonary tissue
specimens from 175 children with fatal pneumonia.72 Of
note, PCR is substantially more sensitive for identifi cation
of adenovirus than is antigen detection.73
Human coronaviruses 229E and OC43, and newly
discovered types NL63 and HKU1, have been linked to
community-acquired pneumonia in children.74,75 Infection
with human coronavirus was detected in 3% of children
and adolescents in a large pneumonia study in Thailand.76
acute infection. In
Research in adults
We identifi ed ten studies of adults with community-
acquired pneumonia (n=2910 episodes) in which PCR
was used to test for respiratory viruses. Evidence of viral
infection was detected in 22% of cases.19,20,77–85 In most of
these studies, a comprehensive array of conventional
virological methods were also implemented to better
defi ne the role of viruses in adults with community-
acquired pneumonia. Similar to fi ndings of paediatric
studies, prevalence of infection with infl uenza viruses
(8%), respiratory syncytial virus (3%), parainfl uenza
viruses (2%), and adenovirus (2%) is comparable with
values recorded with conventional diagnostic methods
alone.5,36 Serological techniques only were used in four
studies; evidence of viral community-acquired pneumonia
was noted in 10–23% of patients.86–89 Use of PCR has
augmented detection of viruses that are diffi cult to
identify with conventional
rhinoviruses (6%), human coronaviruses (5%), and
human metapneumovirus (1%). As a result, overall
prevalence of respiratory viral infection in PCR studies
(15–56%) is generally higher than for studies in which
PCR was not implemented. With a full set of tests,
fi ndings of three reports suggest that a third of adult
cases of community-acquired pneumonia are associated
with viral infection.19,20,85
Other researchers have focused on the role of specifi c
respiratory viruses in adults with community-acquired
pneumonia. Respiratory syncytial virus is recognised
increasingly as a cause of illness in adults,90 and roughly
2–9% of elderly patients admitted with pneumonia in the
USA have infection associated with this virus.91 Infections
with respiratory syncytial virus are linked to substantial
mortality.92 Several outbreaks of severe respiratory disease
(including fatal pneumonia) in elderly residents of nursing
homes have been associated with rhinoviruses.93,94
Adenoviruses have been implicated in 90% of pneumonia-
related admissions in basic military trainees.95 An outbreak
of pneumonia associated with adenovirus serotype 14 has
been reported.96 When searched for systematically,
coronaviruses have been detected in samples from a small
proportion (2–6%) of adults with pneumonia.76,97 These
patients had clinical illnesses indistinguishable from those
in individuals with community-acquired pneumonia
associated with other micro organisms. 2% of asymptomatic
controls also had human coronavirus infection.76
Infections with human metapneumovirus arise
throughout adulthood. Outbreaks of this viral infection
associated with fatal outcome have been reported from
long-term care facilities.98,99 Of patients admitted with
human metapneumovirus infection, 27% had chest
radiographic infi ltrates, 12% required ventilatory support,
and 7% died.100 Human bocavirus is an uncommon cause
of pneumonia in adults. As part of a surveillance project
in Thailand, this virus was detected in fi ve (1%) of
667 adults (age 20 years or older) admitted with
pneumonia and in one of 126 (1%) controls without
febrile or respiratory illness.68
Pneumonia associated with SARS, avian infl uenza, and
2009 pandemic infl uenza
During 2002 and 2003, the SARS coronavirus caused
severe respiratory infection in more than 8000 people
and led to 774 deaths. Up to a third of patients with SARS
became critically ill. Pneumonia with lung injury arose
in about 16% of all individuals infected with the virus
and in 80% of critically ill patients. By contrast with other
viral pneumonias, children were fairly well protected
from severe illness.101
www.thelancet.com Published online March 23, 2011 DOI:10.1016/S0140-6736(10)61459-6
Since November, 2003, avian infl uenza A (H5N1) virus
has caused more than 450 human infections, with a
case-fatality proportion of about 60%. Multiorgan failure
usually develops within 1 week from onset of illness,
with lymphopenia, thrombocytopenia, and raised con-
centrations of aminotransferase and creatinine. Almost
all patients with avian infl uenza develop pneumonia.
Cause of death is most typically progressive
Since March, 2009, pandemic infl uenza A (H1N1)
virus has spread in more than 200 countries over the
world, causing about 18 000 deaths. In the USA alone,
more than 59 million people have been infected.103 In
Australia, the rate of admission was 23 per
100 000 population. Critical illness arose most commonly
in adults with a median age of 40 years and has been
rare in those older than 65 years.103–105 Half of patients
with critical illness had viral pneumonitis or acute
respiratory distress syndrome.103,106
pneumonia was diagnosed in 275 (0·7%) of
40 729 patients with pandemic H1N1 virus infection;
half of these were admitted.107 In the UK, 102 (29%) of
349 patients with chest radiographs had fi ndings
consistent with pneumonia. Median age of patients with
pneumonia was 26 years.108 Poor outcomes from H1N1
virus infection have been recorded in pregnant women,
indigenous populations, and individuals with substantial
obesity or serious comorbidities.
Chest radiographic infi ltrates in SARS, H5N1, and
H1N1 infections were most usually interstitial, patchy,
Detection of several viruses
In 1997, Drews and colleagues110 reviewed eight studies of
a total of 1341 cases of respiratory viral infection detected
mostly with conventional techniques. These researchers
noted dual viral infection in 67 (5%) cases. Detection of
several viruses in a fairly high proportion of cases has
been a feature of pneumonia aetiological studies in which
PCR was used. In particular, for childhood pneumonia,
two or three viruses have been detected in 10–20% of
children.21,30,40–46 Specifi cally, human bocavirus is detected
frequently in association with other respiratory viruses.67–69
In a Thai pneumonia study, 40 (91%) of 44 children
younger than 5 years with human bocavirus infections
had co-infection with other viruses.68 The combination of
human bocavirus and rhinovirus was the most typical
dual infection. In a comprehensive virological study of
childhood pneumonia, two or more viruses were detected
in 61 (18%) of 338 pneumonia episodes, and three viruses
were recorded in nine cases.41 Human bocavirus was
associated with other viruses in 33 (69%) of 48 episodes,
followed by infl uenza viruses (13/25; 52%) and respiratory
syncytial virus (34/67; 51%). In another study, 64% of
children with human bocavirus infection and co-infection
with another virus had serological evidence of acute
human bocavirus infection.69
The clinical relevance of detection of several viruses in
pneumonia, and the association with severe illness, is
uncertain.111–113 Viral-viral interaction in vivo is poorly
understood. Viruses might interact indirectly or directly,
resulting in complementation or inhibition. Children
with pneumonia caused by co-infection with human
bocavirus and other viruses have more wheezing than
with viral pneumonia associated with a sole pathogen.69
In one study, viral co-infections were associated with
more severe pneumonia than were single infections,
when rates of admission were looked at.41
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 infl uenza pandemics of 1918, 1957, and 1968
have suggested that most deaths during these periods
probably resulted from secondary bacterial pneumonia.114
This fi 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
4–24% of cases.103,106,115
Evidence of probable mixed viral-bacterial infection
has been recorded in up to 45% of cases of community-
acquired pneumonia in children.21,30,40–46 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 community-
acquired 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.19,20,77–85 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
infl uenza A plus Strep pneumoniae.19 Undoubtedly,
detection of several pathogens will be noted more
frequently as more elaborate diagnostic tests are used as
www.thelancet.com Published online March 23, 2011 DOI:10.1016/S0140-6736(10)61459-6 7
part of pneumonia aetiological studies. Presuming that
viral infection precedes bacterial infection, we are likely
to continue underestimating the true incidence of viral-
bacterial co-infection because of diffi culties detecting the
Evidence, albeit sparse, suggests that mixed infections
could induce a more severe infl ammatory and clinical
disease than individual bacterial or viral infections.19,84,118
Concomitant infl uenza virus and Staph aureus infection
can cause severe fatal pneumonia in children and
adults.119–121 Moreover, in one pneumonia study, half of
children with treatment failure had evidence of mixed
viral-bacterial infection.39 Similarly, in adults, rhinovirus-
pneumococcal and infl uenza-bacterial
co-infections are associated with severe pneumonia and
raised mortality.19,84,121 Detection of Strep pneumoniae in
the nasopharynx of patients with 2009 pandemic H1N1
infection predicted severe disease outcome.122
Post-mortem studies provide direct evidence for a viral
cause of pneumonia and descriptions of characteristics
of lung histopathology. Many diff erent respiratory viruses
have been detected in lung tissue in case reports or in
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, infl uenza A and B viruses, adenovirus,
and parainfl uenza 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
The nature of histopathological changes in viral
pneumonia varies, possibly an indication of diff erences
in viral infections and comorbidity. Generally,
interstitial pneumonitis with lymphocytic infi ltrations
is seen in viral pneumonitis.123 In fatal cases of
pneumonia caused by respiratory syncytial virus
infection, post-mortem evidence shows infection of
both bronchial and alveolar epithelium.126 Most cells
around the bronchioles and in the alveolar interstitium
were alveolar macrophages and monocytes, and CD3-
positive lymphocytes were also seen frequently around
bronchioles. In rhinovirus pneumonia, hyperplasia
and desquamation of alveolar-lining cells and
antigen in alveolar epithelial cells and macrophages
were seen.125 In fatal cases of human metapneumovirus
pneumonia, pathological analysis indicated bilateral
Histopathological fi ndings in fatal cases of SARS and
avian H5N1 infection are quite similar and have been
characterised by diff use alveolar damage, desquamation
of pneumocytes, oedema, and hyaline-membrane
formation.128,129 Diff use alveolar damage has also been
recorded in the lungs of people who died of 2009
pandemic H1N1 infections (fi gure 3). Furthermore,
necrotising bronchiolitis, diff use alveolar damage with
alveolar haemorrhage, alveolar septal oedema, hyaline
membranes, hyperplasia of type 2 pneumocytes, and
necrosis of bronchiolar walls have been noted.130,131
Histopathological evidence of bacterial co-infection was
reported in 29 of 100 fatal H1N1 cases.132
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 signifi cant effi cacy 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
for pneumonia are unlikely to happen because of
Opportunities are currently limited in clinical practice
for use of antivirals in the treatment of pneumonia
(table 3).134 Neuraminidase inhibitors, such as oseltamivir
of antibiotic treatment
Figure 3: Immunolocalisation of 2009 pandemic infl uenza H1N1 viral
antigen in lung tissue
Viral antigens (red staining) are present in nuclei of alveolar-lining cells.
Reprinted from reference 132 with permission of the American Society for
www.thelancet.com Published online March 23, 2011 DOI:10.1016/S0140-6736(10)61459-6
and zanamivir, were developed during the 1990s and now
have established roles in early treatment of infl uenza A
and B infections. In children and adults, neuraminidase
inhibitors reduce median time to resolution of symptoms
by 0·5–2·5 days when administered within 48 h of onset
of symptoms.135 Importantly, early use of neuraminidase
inhibitors can reduce development of complications such
as pneumonia.136 The Infectious Diseases Society of
America extends treatment
inhibitors to admitted infl uenza patients whose onset of
symptoms is more than 48 h before presentation.137
Selection of the most appropriate antiviral to treat
infl uenza should be made on the basis of relevant
susceptibility data. Before emergence of the 2009
pandemic H1N1 virus, the seasonal H1N1 virus developed
resistance to oseltamivir, and treatment with either
zanamivir or amantadine
recommended, whereas the seasonal H3N2 virus was
resistant to amantadine and rimantidine. If subtype
information is unavailable, zanamivir or a combination
of oseltamivir and rimantadine is recommended.137 The
2009 pandemic H1N1 virus remains susceptible to
neuraminidase inhibitors, and oseltamivir has been used
widely for treatment of pneumonia caused by this virus.
Although resistance to oseltamivir has been reported in
people with 2009 pandemic H1N1 virus infection, it has
been largely restricted
individuals.103 All isolates are still susceptible to zanamivir.
Intravenous use of peramivir or zanamivir could be
lifesaving in critically ill patients with infl uenza.138,139
Experience with antivirals for community-acquired
pneumonia caused by viruses other than infl uenza is
scarce, with existing knowledge mainly from case reports
and some treatment studies in immunosuppressed
patients. Ribavirin has a broad antiviral range, including
respiratory syncytial virus, human metapneumovirus,
and parainfl uenza and infl uenza viruses.140 Effi cacy of
ribavirin aerosol treatment for bronchiolitis and
pneumonia caused by respiratory syncytial virus infection
is modest at best. Intravenous ribavirin could be
considered for treatment of severe pneumonia caused by
or rimantidine was
infection with respiratory syncytial virus, human
metapneumovirus, or parainfl uenza virus, on the basis
of experience in immunosuppressed patients.141
New antiviral agents are in development for respiratory
syncytial virus infection, including small interfering
RNAs.142 In several case studies of immunocompromised
patients, clinical effi cacy of cidofovir has been shown
for severe adenovirus pneumonia.143 Cidofovir should
be considered for treatment of new adenovirus
subtype 14 pneumonia. Researchers reported successful
manage ment of human metapneumovirus pneumonia
with a combination of intravenous ribavirin and
immuno globulin.144 Varicella pneumonia should be
treated with aciclovir.145
Use of corticosteroids for treatment of viral community-
acquired pneumonia is controversial and can vary
according to the causative virus. The ineff ectiveness of
these agents for treatment of respiratory syncytial virus
infections is well established.146 For management of SARS,
inconclusive results were reported in 26 treatment studies,
and possible harm was indicated in four trials.147 High-dose
corticosteroids were administered to a third of patients
with 2009 pandemic H1N1 virus infection,148 but use of
these agents is not recommended because of prolonged
viral shedding in seasonal infl uenza and increased
mortality in avian H5N1 and, possibly, 2009 pandemic
H1N1 virus infections.103 On the other hand, some data
suggest that corticosteroids can augment outcome of
pneumonia caused by infection with varicella-zoster virus
(in combination with aciclovir) and hantavirus.149
Possibilities to prevent viral community-acquired
pneumonia are limited. Infl uenza vaccines have been
used since the mid 1940s and they now have an
established role in prevention of infl uenza A and B virus
infections. Importantly, inactivated infl uenza vaccine is
eff ective 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 countries—eg, in Finland, only
44 fatal cases were recorded. In addition to vaccines,
infl uenza 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% effi cacy.
Infl uenza A and B virusesOseltamivir (oral); zanamivir (inhalation,
intravenous); peramivir (intravenous)
Amantadine (oral); rimantadine (oral)
Ribavirin (inhalation, intravenous)
Vaccines (inactivated, live);
Vaccine for types 4 and 7*
Alfa interferon (intranasal)
Infl uenza A virus
Respiratory syncytial virus
*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
www.thelancet.com Published online March 23, 2011 DOI:10.1016/S0140-6736(10)61459-6 9
Unfortunately, confl ict over the manufacturing process
stopped production in 1996.95 Pneumococcal conjugate
vaccine was shown to prevent a third of viral pneumonia
cases in a study in South Africa, most probably by
prevention of superimposed bacterial co-infections.152
Despite many advances, further studies are still needed to
better understand the role of viruses in the cause and
pathogenesis of community-acquired
Increased availability of molecular diagnostic methods
enables us to evaluate our understanding of viral
pneumonia and to reassess all existing dogma. Further
clarifi cation 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 infl uenzae
type b and pneumococcal conjugate vaccines. Also,
examination of regional diff erences 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.
All authors contributed to the writing of this Seminar.
Confl icts of interest
EL and DRM declare that they have no confl icts of interest. OR has
been a consultant to Novartis Vaccines and Abbot. LCJ has received
grant support from Hoff mann La-Roche and honoraria or travel
assistance from Hoff mann La-Roche, GlaxoSmithKline, Sanofi Pasteur,
Baxter, Novartis, Wyeth, and CSL for participation in advisory groups
and scientifi c meetings.
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