ABSTRACT 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 findings indicate that the incidence of viral pneumonia has been underestimated. In children, respiratory syncytial virus, rhinovirus, human metapneumovirus, human bocavirus, and parainfluenza viruses are the agents identified 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 influenza 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 differentiate 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 influenza viruses, there is no clear role for use of specific antivirals to treat viral community-acquired pneumonia. Influenza vaccines are the only available specific preventive measures. Further studies are needed to better understand the cause and pathogenesis of community-acquired pneumonia. Furthermore, regional differences in cause of pneumonia should be investigated, in particular to obtain more data from developing countries.
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ABSTRACT: Background Human rhinovirus/enterovirus (HRV/ENT) infections are commonly identified in children with acute respiratory infections (ARIs), but data on their clinical severity remain limited.Objectives We compared the clinical severity of HRV/ENT to respiratory syncytial virus (RSV), influenza A/B (FLU), and other common respiratory viruses in children.Patients/Methods Retrospective study of children with ARIs and confirmed single positive viral infections on mid-turbinate swabs by molecular assays. Outcome measures included hospital admission and, for inpatients, a composite endpoint consisting of intensive care admission, hospitalization >5 days, oxygen requirements or death.ResultsA total of 116 HRV/ENT, 102 RSV, 99 FLU, and 64 other common respiratory viruses were identified. Children with single HRV/ENT infections presented with significantly higher rates of underlying immunosuppressive conditions compared to those with RSV (37·9% versus 13·6%; P < 0·001), FLU (37·9% versus 22%; P = 0·018) or any other single viral infection (37·9% versus 22·5%; P = 0·024). In multivariable analysis adjusted for underlying conditions and age, children with HRV/ENT infections had increased odds of hospitalization compared to children with RSV infections (OR 2·6; 95% CI 1·4, 4·8; P < 0·003) or FLU infections (OR 3·0; 95% CI 1·6, 5·8; <0·001) and increased odds of severe clinical disease among inpatients (OR 3·0; 95% CI 1·6,5·6; P = 0·001) when compared to those with FLU infections.Conclusions Children with HRV/ENT had a more severe clinical course than those with RSV and FLUA/B infections and often had significant comorbidities. These findings emphasize the importance of considering HRV/ENT infection in children presenting with severe acute respiratory tract infections.Influenza and Other Respiratory Viruses 05/2014; · 1.47 Impact Factor
- Clinical Infectious Diseases 04/2014; · 9.37 Impact Factor
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ABSTRACT: Background. The role of viral infections in the etiology of severe community-acquired pneumonia (SCAP) was prospectively evaluated from 2008-2012 at university-level intensive care unit. Methods. Clinical data and microbiological tests were assessed: blood cultures, urine pneumococcal and legionella antigens, Mycoplasma pneumoniae and Chlamydia pneumoniae antibodies from paired serums and respiratory virus detections by multiplex, real-time polymerase chain reaction (PCR) from nasopharyngeal swabs and lower tracheal specimens via intubation tube. Results. Of 49 mechanically ventilated SCAP patients (21 males and 28 females; median age, 54 years), the etiology was identified in 45 cases (92%). There were 21 pure bacterial infections (43%), 5 probably pure viral infections (10%), and 19 mixed bacterial-viral infections (39%), resulting in viral etiology in 24 patients (49%). Out of 26 viruses, 21 (81%) were detected from bronchial specimens and five (19%) from nasopharyngeal swabs. Rhinovirus (15 cases, 58%) and adenovirus (4 cases, 15%) were most common viral findings. The bacterial-viral etiology group had the highest peak CRP levels (median 356 [25th-75th percentiles 294-416], p=0.05), while patients with probably viral etiology had the lowest peak PCT levels (1.7 [1.6-1.7]. The clinical characteristics of pure bacterial and mixed bacterial-viral etiologies were comparable. Hospital stay was longest among bacterial group (17 vs. 14 days, p=0.02). Conclusion. Viral findings were demonstrated in almost half of the SCAP patients. Clinical characteristics were similar between the pure bacterial and mixed bacterial-viral infections groups. The frequency of viral detection depends on the availability of PCR techniques and lower respiratory specimens.Clinical Infectious Diseases 04/2014; · 9.37 Impact Factor
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 456075
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 causeSuggests 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.
1 British Thoracic Society of Standards of Care Committee. BTS
guidelines for the management of community acquired pneumonia
in childhood. Thorax 2002; 57 (suppl 1): i1–24.
2 McIntosh K. Community-acquired pneumonia in children.
N Engl J Med 2002; 346: 429–37.
3 File TM. Community-acquired pneumonia. Lancet 2003;
4 Durrington HJ, Summers C. Recent changes in the management of
community-acquired pneumonia in adults. BMJ 2008; 336: 1429–33.
5 Lim WS, Baudoin SV, George RC, et al. British Thoracic Society
guidelines for the management of community acquired pneumonia
in adults: update 2009. Thorax 2009; 64 (suppl III): iii1–55.
6 Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H.
Epidemiology and etiology of childhood pneumonia.
Bull World Health Organ 2008; 86: 408–16.
7 WHO. Revised global burden of disease 2002 estimates. 2004.
regional_2002_revised/en/ (accessed Nov 5, 2010).
8 Jokinen C, Heiskanen L, Juvonen H, et al. Incidence of community-
acquired pneumonia in the population of four municipalities in
eastern Finland. Am J Epidemiol 1993; 137: 977–88.
9 Black RE, Cousens S, Johnson HL, et al, for the Child Health
Epidemiology Reference Group of WHO and UNICEF. Global,
regional, and national causes of child mortality in 2008:
a systematic analysis. Lancet 2010; 375: 1969–87.
10 de Wals P, Robin E, Fortin E, Thibeault R, Ouakki M,
Douville-Fradet M. Pneumonia after implementation of the
pneumococcal conjugate vaccine program in the province of
Quebec, Canada. Pediatr Infect Dis J 2008; 27: 963–68.
11 Simpson JCG, Macfarlane JT, Watson J, Woodhead MA. A national
confi dential enquiry into community acquired pneumonia deaths
in young adults in England and Wales. Thorax 2000; 55: 1040–45.
12 File TM, Marrie TJ. Burden of community acquired pneumonia in
North American adults. Postgrad Med 2010; 122: 130–41.
13 Murdoch DR, O’Brien KL, Scott AG, et al. Breathing new life into
pneumonia diagnostics. J Clin Microbiol 2009; 47: 3405–08.
14 Lieberman D, Lieberman D, Shimoni A, Keren-Naus A,
Steinberg R, Shemer-Avni Y. Identifi cation of respiratory viruses in
adults: nasopharyngeal versus oropharyngeal sampling.
J Clin Microbiol 2009; 47: 3439–43.
15 Loens K, Van Heirstraeten L, Malhotra-Kumar S, Goossens H,
Ieven M. Optimal sampling sites and methods for detection of
pathogens possibly causing community-acquired lower respiratory
tract infections. J Clin Microbiol 2009; 47: 21–31.
16 Ruohola A, Waris M, Allander T, Ziegler T, Heikkinen T,
Ruuskanen O. Viral etiology of common cold in children, Finland.
Emerg Infect Dis 2009; 15: 344–46.
17 Heikkinen T, Marttila J, Salmi AA, Ruuskanen O. Nasal swab versus
nasopharyngeal aspirate for isolation of respiratory viruses.
J Clin Microbiol 2002; 40: 4337–39.
18 Peltola V, Waris M, Österback R, Susi P, Ruuskanen O, Hyypiä T.
Rhinovirus transmission within families with children: incidence of
symptomatic and asymptomatic infections. J Infect Dis 2008;
19 Jennings LC, Anderson TP, Beynon KA, et al. Incidence and
characteristics of viral community-acquired pneumonia in adults.
Thorax 2008; 63: 42–48.
20 Johansson N, Kalin M, Tiveljung-Lindell A, Giske C, Hedlund J.
Etiology of community-acquired pneumonia: increased
microbiological yield with new diagnostic methods. Clin Infect Dis
2010; 50: 202–09.
21 Lahti E, Peltola V, Waris M, et al. Induced sputum in the diagnosis
of childhood community-acquired pneumonia. Thorax 2009;
22 Adegbola RA, Falade AG, Sam BE, et al. The etiology of pneumonia
in malnourished and well-nourished Gambian children.
Pediatr Infect Dis J 1994; 13: 975–82.
23 Vuori-Holopainen E, Peltola H. Reappraisal of lung tap: review of
an old methods for better etiologic diagnosis of childhood
pneumonia. Clin Infect Dis 2001: 32: 715–26.
24 Talbot HK, Falsey AR. The diagnosis of viral respiratory disease in
older adults. Clin Infect Dis 2010: 50: 747–51.
25 She RC, Polage CR, Caram LB, et al. Performance of diagnostic
tests to detect respiratory viruses in older adults.
Diagn Microbiol Infect Dis 2010; 67: 246–50.
26 Tiveljung-Lindell A, Rotzen-Östlund M, Gupta S, et al.
Development and implementation of a molecular diagnostic
platform for daily rapid detection of 15 respiratory viruses.
J Med Virol 2009; 81: 167–75.
27 Arens MQ, Buller RS, Rankin A, et al. Comparison of the Eragen
multi-code respiratory virus panel with conventional viral testing
and real-time multiplex PCR assays for detection of respiratory
viruses. J Clin Microbiol 2010; 48: 2387–95.
28 Murdoch DR, Jennings LC, Bhat N, Anderson TP. Emerging
advances in rapid diagnostics of respiratory infections.
Infect Dis Clin North Am 2010; 24: 791–807.
29 Mäkelä MJ, Puhakka T, Ruuskanen O, et al. Viruses and bacteria
in the etiology of the common cold. J Clin Microbiol 1998;
30 Juvén T, Mertsola J, Waris M, et al. Etiology of community-acquired
pneumonia in 254 hospitalized children. Pediatr Infect Dis J 2000;
31 van der Poll T, Opal SM. Pathogenesis, treatment, and prevention of
pneumococcal pneumonia. Lancet 2009; 374: 1543–56.
32 Flood R, Badik J, Aronoff S. The utility of serum C-reactive protein
in diff erentiating bacterial from nonbacterial pneumonia in
children. Pediatr Infect Dis J 2008; 27: 95–99.
33 Virkki R, Juven T, Rikalainen H, Svedström E, Mertsola J,
Ruuskanen O. Diff erentiation of bacterial and viral pneumonia in
children. Thorax 2002; 57: 438–41.
34 Schuetz P, Albrich W, Christ-Crain M, Chastre J, Mueller B.
Procalcitonin for guidance of antibiotic therapy.
Expert Rev Anti Infect Ther 2010; 8: 575–87.
35 Gilbert DN. Use of plasma procalcitonin levels as an adjunct to
clinical microbiology. J Clin Microbiol 2010; 48: 2325–29.
www.thelancet.com Published online March 23, 2011 DOI:10.1016/S0140-6736(10)61459-6
36 Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases
Society of America/American Thoracic Society consensus guidelines
on the management of community-acquired pneumonia in adults.
Clin Infect Dis 2007; 44 (suppl 2): S27–72.
37 Toikka P, Virkki R, Mertsola J, Ashorn P, Eskola J, Ruuskanen O.
Bacteremic pneumococcal pneumonia in children. Clin Infect Dis
1999; 29: 568–72.
38 Shiley KT, van Deerlin VM, Miller WT Jr. Chest CT features of
community-acquired respiratory viral infections in adult inpatients
with lower respiratory tract infections. J Thorac Imaging 2010; 25: 68–75.
39 Juvén T, Mertsola J, Waris M, Leinonen M, Ruuskanen O. Clinical
response to antibiotic therapy for community-acquired pneumonia.
Eur J Pediatr 2004; 163: 140–44.
40 Tsolia MN, Psarras S, Bossios A, et al. Etiology of community-acquired
pneumonia in hospitalized school-age children: evidence for high
prevalence of viral infections. Clin Infect Dis 2004; 39: 681–86.
41 Cilla G, Oñate E, Perez-Yarza EG, Montes M, Vicente D,
Perez-Trallero E. Viruses in community-acquired pneumonia in
children aged less than 3 years old: high rate of viral coinfection.
J Med Virol 2008; 80: 1843–49.
42 Hamano-Hasegawa K, Morozumi M, Nakayama E, et al.
Comprehensive detection of causative pathogens using real-time
PCR to diagnose pediatric community-acquired pneumonia.
J Infect Chemother 2008; 14: 424–32.
43 Nascimento-Carvalho CM, Ribeiro CT, Cardoso MRA, et al. The role
of respiratory viral infections among children hospitalized for
community-acquired pneumonia in a developing country.
Pediatr Infect Dis J 2008; 27: 939–41.
44 Samramsamruajkit R, Hiranrat T, Chieochansin T, et al.
Prevalence, clinical presentations and complications among
hospitalized children with infl uenza pneumonia. Jpn J Infect Dis
2008; 6: 446–49.
45 Cevey-Macherel M, Galetto-Lacour A, Gervaix A, et al. Etiology of
community-acquired pneumonia in hospitalized children based on
WHO clinical guidelines. Eur J Pediatr 2009; 168: 1429–36.
46 Wolf DG, Greenberg D, Shemer-Avni Y, Givon-Lavi N, Bar-Ziv J,
Dagan R. Association of human metapneumovirus with
radiologically diagnosed community-acquired alveolar pneumonia in
young children. J Pediatr 2010; 156: 115–20.
47 Ausina V, Coll P, Sambeat M, et al. Prospective study on the etiology
of community-acquired pneumonia in children and adults in Spain.
Eur J Clin Microbiol Infect Dis 1988; 7: 343–47.
48 Claesson BA, Trollfors B, Brolin I, et al. Etiology of
community-acquired pneumonia in children based on antibody
responses to bacterial and viral antigens. Pediatr Infect Dis J 1989;
49 Heiskanen-Kosma T, Korppi M, Jokinen C, et al. Etiology of
chilhood pneumonia: serologic results of a prospective,
population-based study. Pediatr Infect Dis J 1998; 17: 986–91.
50 Don M, Fasoli L, Paldanius M, et al. Aetiology of
community-acquired pneumonia: serological results of a paediatric
survey. Scand J Infect Dis 2005; 37: 806–12.
51 Peltola V, Jartti T, Putto-Laurila A, et al. Rhinovirus infections in
children: a retrospective and prospective hospital-based study.
J Med Virol 2009; 81: 1831–38.
52 Berkley JA, Munywoki P, Ngama M, et al. Viral etiology of severe
pneumonia among Kenyan children and infants. JAMA 2010;
53 Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower
respiratory infections due to respiratory syncytial virus in young
children: a systematic review and meta-analysis. Lancet 2010;
54 Hayden FG. Rhinovirus and the lower respiratory tract.
Rev Med Virol 2004; 14: 17–31.
55 Calvo C, García-García ML, Blanco C, Pozo F, Flecha IC,
Pérez-Breña P. Role of rhinovirus in hospitalized infants with
respiratory tract infections in Spain. Pediatr Infect Dis J 2007;
56 Cheuk DKL, Tang IWH, Chan KH, Woo PCY, Peiris MJS, Chiu SS.
Rhinovirus infection in hospitalized children in Hong Kong:
a prospective study. Pediatr Infect Dis J 2007; 26: 995–1000.
57 Miller EK, Edwards KM, Weinberg GA, et al. A novel group of
rhinoviruses is associated with asthma hospitalizations.
J Allergy Clin Immunol 2009; 123: 98–104.
58 Miller EK, Lu X, Erdman DD, et al, for the New Vaccine
Surveillance Network. Rhinovirus-associated hospitalizations in
young children. J Infect Dis 2007; 195: 773–81.
59 Pierangeli A, Gentile M, Di Marco P, et al. Detection and typing by
molecular techniques of respiratory viruses in children hospitalized
for acute respiratory infection in Rome, Italy. J Med Virol 2007;
60 Renwick N, Schweiger B, Kapoor V, et al. A recently identifi ed
rhinovirus genotype is associated with severe respiratory tract
infection in children in Germany. J Infect Dis 2007; 196: 1754–60.
61 Louie JK, Roy-Burman A, Guardia-LaBar L, et al. Rhinovirus
associated with severe lower respiratory tract infections in children.
Pediatr Infect Dis J 2009; 28: 337–39.
62 Jartti T, Jartti L, Peltola V, Waris M, Ruuskanen O. Identifi cation of
respiratory viruses in asymptomatic subjects: asymptomatic
respiratory viral infections. Pediatr Infect Dis J 2008; 27: 1103–07.
63 Werno AM, Anderson TP, Jennings LC, Jackson PM, Murdoch DR.
Human metapneumovirus in children with bronchiolitis or
pneumonia. J Paediatr Child Health 2004; 40: 549–51.
64 Esper F, Boucher D, Weibel C, Martinello RA, Kahn JS.
Human metapneumovirus infection in the United States:
clinical manifestations associated with a newly emerging
respiratory infection in children. Pediatrics 2003; 111: 1407–10.
65 Williams JV, Harris PA, Tollefson SJ, et al. Human
metapneumovirus and lower respiratory tract disease in
otherwise healthy infants and children. N Engl J Med 2004;
66 Camps M, Ricart S, Dimova V, et al. Prevalence of human
metapneumovirus among hospitalized children younger than
1 year in Catalonia, Spain. J Med Virol 2008; 80: 1452–60.
67 Schildgen O, Muller A, Allander T, et al. Human bocavirus: passenger
or pathogen in acute respiratory tract infections? Clin Microbiol Rev
2008; 21: 291–304.
68 Fry AM, Lu X, Chittaganpitch M, et al. Human bocavirus: a novel
parvovirus epidemiologically associated with pneumonia requiring
hospitalization in Thailand. J Infect Dis 2007; 195: 1038–45.
69 Söderlund-Venermo M, Lahtinen A, Jartti T, et al. Clinical assessment
and improved diagnosis of bocavirus-induced wheezing in children,
Finland. Emerg Infect Dis 2009; 15: 1423–30.
70 Don M, Söderlund-Venermo M, Valent F, et al. Serologically verifi ed
human bocavirus pneumonia in children. Pediatr Pulmonol 2010;
71 Carballal G, Videla C, Misirlian A, Requeijo PV, Aguilar MC.
Adenovirus type 7 associated with severe and fatal acute lower
respiratory infections in Argentine children. BMC Pediatr 2002; 2: 6.
72 Ou Z-Y, Zeng Q-Y, Wang F-H, et al. Retrospective study of
adenovirus in autopsied pulmonary tissue of pediatric fatal
pneumonia in South China. BMC Infect Dis 2008; 8: 122.
73 Arnold JC, Singh KK, Spector SA, Sawyer MH. Undiagnosed
respiratory viruses in children. Pediatrics 2008; 121: e631–37.
74 Heugel J, Martin ET, Kuypers J, Englund JA. Coronavirus-associated
pneumonia in previously healthy children. Pediatr Infect Dis J 2007;
75 Lau SKP, Woo PCY, Yip CCY, et al. Coronavirus HKU1 and other
coronavirus infections in Hong Kong. J Clin Microbiol 2006;
76 Dare RK, Fry AM, Chittaganpitch M, Sawanpanyalert P, Olsen SJ,
Erdman DD. Human coronavirus infections in rural Thailand:
a comprehensive study using real-time reverse-transcription
polymerase chain reaction assays. J Infect Dis 2007; 96: 1321–28.
77 Templeton KE, Scheltinga SA, van den Eeden WCJFM,
Graff elman AW, van den Broek PJ, Claas ECJ. Improved diagnosis
of the etiology of community-acquired pneumonia with real-time
polymerase chain reaction. Clin Infect Dis 2005; 41: 345–51.
78 Marcos MA, Camps M, Pumarola T, et al. The role of viruses in the
aetiology of community-acquired pneumonia in adults. Antivir Ther
2006; 11: 351–59.
79 Saito A, Kohno S, Matsushima T, et al. Prospective multicenter
study of the causative organisms of community-acquired
pneumonia in adults in Japan. J Infect Chemother 2006; 12: 63–69.
80 Charles PG, Whirby M, Fuller AJ, et al. The etiology of community-
acquired pneumonia in Australia: why penicillin plus doxycycline or
a macrolide is the most appropriate therapy. Clin Infect Dis 2008;
www.thelancet.com Published online March 23, 2011 DOI:10.1016/S0140-6736(10)61459-6 11
81 Hohenthal U, Vainionpää R, Meurman O, et al. Aetiological
diagnosis of community acquired pneumonia: utility of rapid
microbiological methods with respect to disease severity.
Scand J Infect Dis 2008; 40: 131–38.
82 Hohenthal U, Vainionpää R, Nikoskelainen J, Kotilainen P. The role
of rhinovirus and enteroviruses in community acquired pneumonia
in adults. Thorax 2008; 63: 658–59.
83 Johnstone J, Majumdar SR, Fox JD, Marrie TJ. Viral infection in
adults hospitalized with community-acquired pneumonia:
prevalence, pathogens, and presentation. Chest 2008; 134: 1141–48.
84 Diederen BMW, Van Der Eerden MM, Vlaspolder F, Boersma WG,
Kluytmans JAJW, Peeters MF. Detection of respiratory viruses and
Legionella spp by real-time polymerase chain reaction in patients with
community acquired pneumonia. Scand J Infect Dis 2009; 41: 45–50.
85 Lieberman D, Shimoni A, Shemer-Avni Y, Keren-Naos A,
Shtainberg R, Lieberman D. Respiratory viruses in adults with
community-acquired pneumonia. Chest 2010; 138: 811–16.
86 Ruiz M, Ewig S, Marcos MA, et al. Etiology of community-acquired
pneumonia: impact of age, comorbidity, and severity.
Am J Respir Crit Care Med 1999; 160: 397–405.
87 Lim WS, Macfarlane JT, Boswell TCJ, et al. Study of community
acquired pneumonia aetiology (SCAPA) in adults admitted to
hospital: implications for management. Thorax 2001; 56: 296–301.
88 Lauderdale T, Chang F, Ben R, et al. Etiology of community
acquired pneumonia among adults patients requiring
hospitalization in Taiwan. Respir Med 2005; 99: 1079–86.
89 Almirall J, Boixeda R, Bolibar I, et al. Diff erences in the etiology of
community-acquired pneumonia according to site of care:
a population-based study. Respir Med 2007; 101: 2168–75.
90 Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE.
Respiratory syncytial virus infection in elderly and high-risk adults.
N Engl J Med 2005; 352: 1749–59.
91 Han LL, Alexander JP, Anderson LJ. Respiratory syncytial virus
pneumonia among the elderly: an assessment of disease burden.
J Infect Dis 1999; 179: 25–30.
92 Thompson WW, Shay DK, Weistraub E, et al. Mortality associated
with infl uenza and respiratory syncytial virus in the United States.
JAMA 2003; 289: 179–86.
93 Hicks LA, Shepard CW, Britz PH, et al. Two outbreaks of severe
respiratory disease in nursing homes associated with rhinovirus.
J Am Geriatr Soc 2006; 54: 284–89.
94 Longtin J, Marchand-Austin A, Winter A, et al. Rhinovirus
outbreaks in long-term care facilities, Ontario, Canada.
Emerg Infect Dis 2010; 16: 1463–65.
95 Tucker SN, Tingley DW, Scallan CD. Oral adenoviral-based
vaccines: historical perspective and future opportunity.
Expert Rev Vaccines 2008; 7: 25–31.
96 Esposito DH, Gardner TJ, Schneider E, et al. Outbreak of
pneumonia associated with emergent human adenovirus serotype
14: southeast Alaska, 2008. Clin Infect Dis 2010; 202: 214–22.
97 Woo PCY, Lau SKP, Tsoi H-W, et al. Clinical and molecular
epidemiological features of coronavirus HKU1-associated
community-acquired pneumonia. J Infect Dis 2005; 192: 1898–907.
98 Boivin G, De Serres G, Hamelin M-E, et al. An outbreak of severe
respiratory tract infection due to human metapneumovirus in a
long term-care facility. Clin Infect Dis 2007; 44: 1152–58.
99 Louie JK, Schnurr DP, Pan C-Y, et al. A summer outbreak of human
metapneumovirus infection in a long-term-care facility. J Infect Dis
2007; 196: 705–08.
100 Walsh EE, Peterson DR, Falsey AR. Human metapneumovirus
infections in adults: another piece of the puzzle. Arch Intern Med
2008; 168: 2489–96.
101 Levy MM, Baylor MS, Bernard GR, et al. Clinical issues and
research in respiratory failure from severe acute respiratory
syndrome. Am J Respir Crit Care Med 2005; 171: 518–26.
102 The Writing Committee of the World Health Organization (WHO)
Consultation on human infl uenza A/H5. Avian infl uenza A (H5N1)
infection in humans. N Engl J Med 2005; 353: 1374–85.
103 Writing Committee of the WHO Consultation on Clinical Aspects of
Pandemic (H1N1) 2009 Infl uenza. Clinical aspects of pandemic 2009
infl uenza A (H1N1) virus infection. N Engl J Med 2010; 362: 1708–19.
104 Bishop JF, Murnane MP, Owen R. Australia’s winter with the 2009
pandemic infl uenza A (H1N1) virus. N Engl J Med 2009;
105 Kotsimbos T, Waterer G, Jenkins C, et al, on behalf of the Thoracic
Society of Australia and New Zealand H1N1 Infl uenza 09 Task
Force. Infl uenza A/H1N1_09: Australia and New Zealand’s winter of
discontent. Am J Respir Crit Care Med 2010; 181: 300–06.
106 Louie JK, Acosta M, Winter K, et al, for the California Pandemic
(H1N1) Working Group. Factors associated with death or
hospitalization due to pandemic 2009 infl uenza A (H1N1) infection
in California. JAMA 2009; 302: 1896–902.
107 Poggensee G, Gilsdorf A, Buda S, et al. The fi rst wave of pandemic
infl uenza (H1N1) 2009 in Germany: from initiation to acceleration.
BMC Infect Dis 2010; 10: 155.
108 Nguyen-Van-Tam JS, Openshaw PJM, Hashim A, et al. Risk factors
for hospitalisation and poor outcome with pandemic A/H1N1
infl uenza: United Kingdom fi rst wave (May–September 2009).
Thorax 2010; 65: 645–51.
109 Agarwal PP, Cinti S, Kazerooni EA. Chest radiographic and CT
fi ndings in novel swine-origin infl uenza A (H1N1) virus (S-OIV)
infections. Am J Radiol 2009; 193: 1488–93.
110 Drews AL, Atmar RL, Glezen WP, Baxter BD, Piedra PA,
Greenberg SB. Dual respiratory virus infections. Clin Infect Dis
1997; 25: 1421–29.
111 Jennings LC, Anderson TP, Werno AM, Beynon KA, Murdoch DR.
Viral etiology of acute respiratory tract infections in children
presenting to hospital: role of polymerase chain reaction and
demonstration of multiple infections. Pediatr Infect Dis J 2004;
112 Calvo C, García-García ML, Blanco C, et al. Multiple simultaneous
viral infections in infants with acute respiratory tract infections in
Spain. J Clin Virol 2008; 42: 268–72.
113 Midulla F, Scagnolori C, Bonci E, et al. Respiratory syncytial virus,
human bocavirus and rhinovirus bronchiolitis in infants.
Arch Dis Child 2010; 95: 35–41.
114 Morens DM, Taubenberger JK, Fauci AS. Predominant role of
bacterial pneumonia as a cause of death in pandemic infl uenza:
implications for pandemic infl uenza preparedness. J Infect Dis
2008; 198: 962–70.
115 Kumar A, Zarychanski R, Pinto R, et al. Critically ill patients with
2009 infl uenza A (H1N1) infection in Canada. JAMA 2009;
116 Forgie IM, O’Neill KP, Lloyd-Evans N, et al. Etiology of acute lower
respiratory tract infections in Gambian children: II—acute lower
respiratory tract infections in children ages one to nine years
presenting at the hospital. Pediatr Infect Dis J 1991; 10: 42–47.
117 Johnson A-W, Osinusi K, Aderele WI, et al. Etiologic agents and
outcome determinants of community-acquired pneumonia in
urban children: a hospital-based study. J Nat Med Assoc 2008;
118 McCullers JA. Insights into the interaction between infl uenza virus
and pneumococcus. Clin Microbiol Rev 2006; 19: 571–82.
119 Finelli L, Fiore A, Dhara R, et al. Infl uenza-associated pediatric
mortality in the United States: increase of Staphylococcus aureus
coinfection. Pediatrics 2008; 122: 805–11.
120 Reed C, Kallen AJ, Patton M, et al. Infection with community-onset
Staphylococcus aureus and infl uenza virus in hospitalized children.
Pediatr Infect Dis J 2009; 28: 572–76.
121 Seki M, Kosai K, Yanagihara K, et al. Disease severity in patients
with simultaneous infl uenza and bacterial pneumonia. Intern Med
2007; 46: 953–58.
122 Palacios G, Hornig M, Cisterna D, et al. Streptococcus pneumoniae
coinfection is correlated with the severity of H1N1 pandemic
infl uenza. PloS One 2009; 4: e8540–44.
123 do Carmo Debur M, Raboni SM, Flizikowski FBZ, et al.
Immunohistochemical assessment of respiratory viruses in
necropsy samples from lethal and non-pandemic seasonal
respiratory infections. J Clin Pathol 2010; 63: 930–34.
124 Bustamante-Calvillo ME, Velázquez FR, Cabrera-Munõz L, et al.
Molecular detection of respiratory syncytial virus in postmortem
lung tissue samples from Mexican children deceased with
pneumonia. Pediatr Infect Dis J 2001; 20: 495–501.
125 Imakita M, Shiraki K, Yutani C, Ishibashi-Ueda H. Pneumonia
caused by rhinovirus. Clin Infect Dis 2000; 30: 611–12.
126 Johnson JE, Gonzales RA, Olson SJ, Wright PF, Graham BS.
The histopathology of fatal untreated human respiratory syncytial
virus infection. Mod Pathol 2007; 20: 108–19.
www.thelancet.com Published online March 23, 2011 DOI:10.1016/S0140-6736(10)61459-6
127 Donoso AF, León JA, Camacho JF, Cruces PI, Ferrés M. Fatal
hemorrhagic pneumonia caused by human metapneumovirus in an
immunocompetent child. Pediatr Intern 2008; 50: 589–91.
128 Nicholls JM, Poon LLM, Lee KC, et al. Lung pathology of fatal
severe acute respiratory syndrome. Lancet 2003; 361: 1773–78.
129 Korteweg C, Jiang G. Pathology, molecular biology, and
pathogenesis of avian infl uenza A (H5N1) infection in humans.
Am J Pathol 2008; 172: 1155–70.
130 Soto-Abraham MV, Soriano-Rosas J, Diaz-Quinonez A, et al.
Pathological changes associated with the 2009 H1N1 virus.
N Engl J Med 2009; 361: 2001–03.
131 Mauad T, Hajjar LA, Callegari GD, et al. Lung pathology in fatal
novel human infl uenza A (H1N1) infection.
Am J Respir Crit Care Med 2010; 181: 72–79.
132 Shieh W-J, Blau DM, Denison AM, et al. 2009 pandemic infl uenza
A (H1N1): pathology and pathogenesis of 100 fatal cases in the
United States. Am J Pathol 2010; 177: 166–75.
133 Friis B, Andersen P, Brenoe E, et al. Antibiotic treatment of
pneumonia and bronchiolitis. Arch Dis Child 1984; 59: 1038–45.
134 Wong SSY, Yuen K-Y. Antiviral therapy for respiratory tract
infections. Respirology 2008; 13: 950–71.
135 Shun-Shin M, Thompson M, Heneghan C, Perera R, Harnden A,
Mant D. Neuraminidase inhibitors for treatment and prophylaxis of
infl uenza in children: systematic review and meta-analysis of
randomised controlled trials. BMJ 2009; 339: 3172–80.
136 Yu H, Liao Q, Yuan Y, et al. Eff ectiveness of oseltamivir on disease
progression and viral RNA shedding in patients with mild
pandemic 2009 infl uenza A H1N1: opportunistic retrospective study
of medical charts in China. BMJ 2010; 341: c4779.
137 Harper SA, Bradley JS, Englund JA, et al. Seasonal infl uenza in
adults and children: diagnosis, treatment, chemoprophylaxis, and
institutional outbreak management—clinical practice guidelines of
the Infectious Diseases Society of America. Clin Infect Dis 2009;
138 Birnkrant D, Cox E. The emergency use authorization of peramivir
for treatment of 2009 H1N1 infl uenza. N Engl J Med 2009;
139 Härter G, Zimmermann O, Maier L, et al. Intravenous zanamivir
for patients with pneumonitis due to pandemic (H1N1) 2009
infl uenza virus. Clin Infect Dis 2010; 50: 1249–51.
140 Yin MT, Brust JCM, van Tieu H, Hammer SM. Antiherpes,
anti-hepatitis virus, and anti-respiratory virus agents. In:
Richman DD, Whitley RJ, Hayden FG, eds. Clinical virology,
3rd edn. Washington: ASM Press, 2009: 217–64.
141 Hopkins P, McNeil K, Kermeen F, et al. Human metapneumovirus
in lung transplant recipients and comparison to respiratory
syncytial virus. Am J Respir Crit Care Med 2008; 178: 876–81.
142 Empey KM, Pebbles S, Koll JK. Pharmacologic advances in the
treatment and prevention of respiratory syncytial virus.
Clin Infect Dis 2010; 50: 1258–67.
143 Doan ML, Mallory GB, Kaplan SL, et al. Treatment of adenovirus
pneumonia with cidofovir in pediatric lung transplant recipients.
J Heart Lung Transplant 2007; 26: 883–89.
144 Bonney D, Razali H, Turner A, Will A. Successful treatment of
human metapneumovirus pneumonia using combination therapy
with intravenous ribavirin and immune globulin. Br J Haematol
2009; 145: 667–69.
145 Frangites CY, Pneumatikos I. Varicella-zoster virus pneumonia in
adults: report of 14 cases and review of the literature.
Eur J Intern Med 2004; 15: 364–70.
146 Jartti T, Vanto T, Heikkinen T, Ruuskanen O. Systemic
glucocorticoids in childhood expiratory wheezing: relation between
age and viral etiology with effi cacy. Pediatr Infect Dis J 2002;
147 Stockman LJ, Bellamy R, Garner P. SARS: systematic review of
treatment eff ects. PLoS Med 2006; 3: e343.
148 Falagas ME, Vouloumanou EK, Baskouta E, Rafailidis PI, Polyzos K,
Rello J. Treatment options for 2009 H1N1 infl uenza: evaluation of
the published evidence. Int J Antimicrob Agents 2010; 35: 421–30.
149 Cheng VCC, Tang BSF, Wu AKL, Chu CM, Yuen KY. Medical
treatment of viral pneumonia including SARS in
immunocompetent adult. J Infect 2004; 49: 262–73.
150 Heinonen S, Silvennoinen H, Lehtinen P, Vainionpää R, Ziegler T,
Heikkinen T. Eff ectiveness of inactivated infl uenza vaccine in
children aged 9 months to 3 years: an observational cohort study.
Lancet Infect Dis (published online Nov 23, 2010).
151 American Academy of Pediatrics. Policy statement: modifi ed
recommendations for use of palivizumab for prevention of
respiratory syncytial virus infections. Pediatrics 2009; 124: 1694–701.
152 Madhi SA, Klugman KP, The Vaccine Trialist Group. A role for
Streptococcus pneumoniae in virus associated pneumonia. Nat Med
2004; 10: 811–13.