Seminar

Community-acquired pneumonia
Elena Prina, Otavio T Ranzani, Antoni Torres

Community-acquired pneumonia causes great mortality and morbidity and high costs worldwide. Empirical
selection of antibiotic treatment is the cornerstone of management of patients with pneumonia. To reduce the
misuse of antibiotics, antibiotic resistance, and side-eects, an empirical, eective, and individualised antibiotic
treatment is needed. Follow-up after the start of antibiotic treatment is also important, and management should
include early shifts to oral antibiotics, stewardship according to the microbiological results, and short-duration
antibiotic treatment that accounts for the clinical stability criteria. New approaches for fast clinical (lung ultrasound)
and microbiological (molecular biology) diagnoses are promising. Community-acquired pneumonia is associated
with early and late mortality and increased rates of cardiovascular events. Studies are needed that focus on the
long-term management of pneumonia.

Clinical presentation
Community-acquired pneumonia is responsible for great
mortality and morbidity and high costs. Communityacquired pneumonia was featured in Seminars in
The Lancet in 19981 and 2003.2 In this updated Seminar,
we address important topics related to communityacquired pneumonia in immunocompetent adults.
Suspected community-acquired pneumonia is defined
by acute symptoms and presence of signs of lower
respiratory tract infection (LRTI) without other obvious
cause, whereas new pulmonary infiltrate on chest
radiograph is needed for definite diagnosis.36 The most
common signs and symptoms are dyspnoea, cough, fever,
and new focal chest signs (appendix). In subgroups of
patients (eg, elderly people), clinical presentation can
have less evident symptoms (eg, an altered state of
consciousness, gastrointestinal discomfort, and fever can
be absent) and diagnosis is frequently delayed. A
prolonged time between the onset of symptoms and a
medical visit has been described for less severe
pneumonia, individuals with alcoholism, and for patients
receiving drugs such as corticosteroids, non-steroidal
anti-inflammatory drugs, and antibiotics.7 For some
pathogens, unusual clinical presentations that involve
the gradual onset of symptoms such as dry cough, the
Search strategy and selection criteria
We searched Medline, Embase, and the Cochrane Library for
papers published from inception to Jan 31, 2015. We used the
search terms community-acquired pneumonia or lower
respiratory tract infection, in combination with the terms
epidemiology, diagnosis, aetiology, pathophysiology,
risk factors, management, treatment, outcomes,
long-term, and their variations. We restricted the search
strategy to adults. We largely selected publications in the past
5 years and also searched the reference lists of articles
identified by this search strategy. We gave more weight to
randomised controlled trials and meta-analyses, as suggested
by The Lancet. Review articles and book chapters are cited to
provide readers with more details and more references. The
reference list was modified on the basis of peer-review process.

www.thelancet.com Vol 386 September 12, 2015

absence of fever, and extrapulmonary manifestations are

frequent. For example, patients with pneumonia due
to Legionella spp can present with headache, confusion,
diarrhoea, and clinical manifestations of hyponatraemia.8
Mycoplasma pneumoniae can be associated with upper
respiratory involvement (otitis, pharyngitis), skin changes
(Stevens-Johnson-like syndrome), and haemolytic
anaemia.9 Investigators have clearly shown that differentiation between typical and atypical pneumonia on
the basis of patient history and chest radiograph is not
reliable in guidance of antibiotic treatment.3,10 By contrast,
the use of validated scores for antibiotic decisions is
promising. A 2014 study11 proposed a score that can rule
out Legionella spp pneumonia with a negative predictive
value of 99%.

Dierential diagnosis

Lancet 2015; 386: 1097108

Published Online
August 13, 2015
http://dx.doi.org/10.1016/
S0140-6736(15)60733-4
Department of Pulmonology,
Hospital Clinic of Barcelona,
University of Barcelona,
Institut Dinvestigacions
August Pi I Sunyer (IDIBAPS),
Ciber de Enfermedades
Respiratorias (CIBERES),
Barcelona, Spain (E Prina MD,
Prof A Torres PhD) and
Respiratory Intensive Care
Unit, Pulmonary Division,
Heart Institute, Hospital das
Clnicas, University of
Sao Paulo, Sao Paulo, Brazil
(O T Ranzani MD)
Correspondence to:
Prof Antoni Torres, Department
of Pulmonology, Hospital Clinic
of Barcelona, University of
Barcelona, Institut
Dinvestigacions
August Pi I Sunyer (IDIBAPS),
Ciber de Enfermedades
Respiratorias (CIBERES),
Barcelona 08036, Spain
[email protected]
See Online for appendix

Many diseases and syndromes have clinical signs and

symptoms that can mimic pneumonia (appendix). When
the probability of a dierential diagnosis is high, careful
assessment is needed because delays in correct diagnoses
increase the risks of poor outcomes.12 In patients with
not-severe community-acquired pneumonia, the main
dierential diagnosis is upper respiratory infection. In
these cases, clinicians should rely on clinical evaluations
(including manifestations of LRTI, focal chest sounds,
exclusion of other possible diagnosis) and point-of-care
tests (eg, C-reactive protein [CRP]).6
Patients with severe community-acquired pneumonia
should be monitored for other life-threatening disorders.
Because dierentiation of pneumonia from noninfectious disorders such as acute heart failure is
occasionally dicult, prompt start of antibiotic treatment
is recommended. Biomarkers (eg, procalcitonin [PCT])
can help in the early dierentiation from heart failure
decompensation, avoiding antibiotic misuse.13 When the
diagnosis of pneumonia is excluded, antibiotic treatment
must be stopped. Dynamic evaluation of the patient also
helps the clinician in terms of management (eg,
pulmonary infiltrates that resolve completely after
positive pressure ventilation are probably due to heart
failure or atelectasis). In patients with recurrent
pneumonia, underlying diseases should be suspected
1097

Seminar

such as lung cancer, metastasis, tuberculosis, foreign

bodies, hypersensitivity pneumonitis, and unknown
immunosuppressed status.

Epidemiology

Worldwide incidence
The Global Burden of Disease Study14 reported that LRTI
remains the second biggest cause of deaths and years of
life lost in 2013. The age-standardised death rate was
417 (95% CI 371441) per 100 000 population for
LRTI.14 The incidence of pneumonia is estimated to be
between 15 and 140 cases per 1000 person-years.1517
This rate varies according to the region, season, and
population characteristics. In terms of age, incidence
of community-acquired pneumonia is U-shapedit is
common in children younger than 5 years and adults
older than 65 years. The incidence is also higher in men
and boys than in women and girls. Patients who do not
need admission into hospital have a mortality rate of
lower than 1%.18,19 Short-term mortality (in-hospital and
30 day mortality) for hospitalised patients ranges from
40% to 180%;17,20,21 however, for patients in intensive
care, this rate can reach 50%.22 Costs related to
community-acquired pneumonia are high,23 and few
approaches (such as reducing the length-of-stay, adequate
use of antibiotics, and the introduction of vaccines) have
reduced these costs so far.24,25

Causative pathogens
Streptococcus pneumoniae is the main pathogen that causes
community-acquired pneumonia worldwide, independent
of age.23,26,27 In Europe, nearly 35% (1268%)23 of cases are
caused by pneumococcal disease; worldwide it is about
273% (95% CI 239311).28 Other frequent causes
include Haemophilus influenzae, which accounts for 12%
(24449%) of cases23 and the so-called atypical bacteria
(including Mycoplasma, Chlamydia, and Legionella spp),
which caused 22% of cases in a large worldwide cohort.29
In recent years, the availability of molecular microbiological tests and clinical suspicion has increased
isolation of respiratory viruses in community-acquired
pneumonia.30 In adults, viruses, particularly influenza,
rhinovirus, and coronaviruses, cause a third of cases of
pneumonia.30 However, the attribution of the aetiology to
respiratory viruses is debatable because it is dicult to
define the virus as the causative agent of pneumonia.
Resistance of S pneumoniae to penicillin and macrolides
has been nearly stable in recent years.24 The introduction
of the conjugated pneumococcal vaccine in children has
decreased the incidence of the invasive penicillin-resistant
cases; however, infections with serotypes not aected by
the vaccine have increased.31 The incidence of Mycoplasma
pneumoniae resistant to macrolides varies greatly with
geography (eg, with peak of about 69% in China).32,33
Although the proportion of patients infected with
pathogens not covered by standard empirical treatment is
low, these pathogens are associated with high mortality and
1098

costs. In immunocompetent patients with communityacquired pneumonia, these pathogens are more frequently
Pseudomonas aeruginosa, Enterobacteriaceae extendedspectrum -lactamase (ESBL+), and meticillin-resistant
Staphylococcus aureus (MRSA).34,35

Pathophysiology
In healthy individuals, many microorganisms colonise
the nasopharynx and oropharynx. Microaspiration of
contaminated secretions can cause infections in the
lower airways. The glottal reflexes, the presence of
complement proteins and immunoglobulins, the
secretion of peptides with antimicrobial activities, and
the inhibition of bacteria binding all protect the lower
airways.36 The healthy microbiota of the upper airway
also exert protection eects by competing with
pathogens for nutritional resources and interacting with
cellular receptors. The use of broad-spectrum antibiotics
can modify the microbiota and predispose to infection.37
The interactions between the virulence of the pathogens,
the amount of inoculum, and the innate and adaptive
immune responses determine the development of
pneumonia.36

Risk factors and genetics

All individuals are at risk for development of pneumonia.
However, some individuals are more prone to pneumonia
than are others due to intrinsic and extrinsic factors
(appendix).38 New findings have revealed individual
genetic variability in the predisposition to the development
of pneumonia and its clinical presentation.39 For example,
specific variants of the FER gene are associated with a
reduced risk of death in patients with sepsis due to
pneumonia. Thereby, the FER gene might be a potential
target for new therapies.40 Misch and colleagues41 showed
that TLR6 polymorphism is associated with increased
risk of Legionnaires disease (odds ratio [OR] 583,
95% CI 2211639).

Diagnostic investigations
Laboratory evaluation

In patients who clinicians suspect to have communityacquired pneumonia, blood tests can provide information about the inflammatory state (ie, leucocyte cell
number and characteristics [neutrophilia] and CRP), the
associated organ damage (ie, acute renal failure), and
the severity of the disease. Biomarkers can support
clinicians in the dierentiation of bacterial pneumonia
from other disorders (eg, upper respiratory tract
disorders). A meta-analysis suggested that antibiotic
exposure can be reduced in suspected LRTI via the use
of CRP measurements in primary care (risk ratio [RR]
078 [95% CI 066092]).42 The 2014 NICE guidelines6
recommend not to oer antibiotics when CRP is lower
than 20 mg/L in primary care for patients without a
convincing clinical diagnosis of community-acquired
pneumonia.
www.thelancet.com Vol 386 September 12, 2015

Seminar

PCT had high sensitivity but moderate specificity to

dierentiate bacterial and viral infections. For outpatients,
patients in emergency departments, and inpatients, an
antibiotic is encouraged when PCT concentrations are
higher than 025 g/L and is strongly encouraged when
PCT concentrations are higher than 05 g/L; whereas
they are discouraged when concentrations are lower than
010 g/L.43 In patients admitted to intensive care,
antibiotic treatment is always strongly encouraged
with PCT concentrations higher than 025 g/L. A
meta-analysis reported that the use of PCT to guide
antibiotic treatment in pneumonia resulted in a reduction
in the exposure to antibiotics from median 8 days
[IQR 512] to 4 days [08], with an adjusted dierence of
334 days (95% CI 379 to 288) without increases in
mortality or treatment failure.44 Moreover the use of PCT
to guide antibiotic treatment reduced costs of treatment.45

Microbiological evaluation
Despite many improvements, the pathogen is not
detected in nearly half of pneumonia episodes.3
Microbiological tests are recommended in patients in
whom the probability of changing the empirical
antibiotic is high: reducing treatment failure and
preventing
antibiotic
overuse.
Microbiological
evaluations (figure 1) are recommended for higher-risk
patients such as those with severe community-acquired
pneumonia, special disorders (eg, asplenia, immunosuppression, HIV infection, and alcohol abuse), severe
sepsis or septic shock, a risk of resistant pathogens, and
failure of the initial empirical treatment.35 By contrast,
recommendations for microbiological testing remain
controversial in less severe pneumonia because such
tests are expected to have little eect on antibiotic
management due to good responses to empirical
treatment.4648 However, microbiological evaluations
could be valuable for surveillance.
Although a positive blood (or pleural fluid) culture
test definitively identifies the pathogen responsible for
pneumonia, a positive respiratory tract sample needs
clinical interpretation because the microorganism can
be present due to colonisation or be part of the healthy
flora. The main diculties are related to the need for a
high-quality sample.3 Furthermore, the collection of
any sample after the administration of antibiotics
increases the rate of false-negative results. Despite
these limitations, in patients in hospital with purulent
sputum, a sample collection for Gram stain and culture
is recommended.5,6
Urinary antigens are useful for the detection of all
serotypes of S pneumoniae and for serogroup 1 of
Legionella pneumophila (responsible for about 90%
oflegionella cases of community-acquired pneumonia).
Advantages of these tests are promptness (<15 min),
reasonable accuracy, and the ability to detect the infection
while the patient is receiving antibiotic therapy.6 The
main drawback is the absence of information about
www.thelancet.com Vol 386 September 12, 2015

resistance. The urinary antigen for S pneumoniae has a

sensitivity of 740% (95% CI 666823) and a specificity
of 972% (927998).49 For L pneumophila, sensitivity is
740% (680810) and specificity is 991% (984997).50
Two randomised controlled trials have tested empirical
versus pathogen-directed antibiotic treatment through
urinary antigen tests in patients in hospital with stable
pneumonia51,52 and shown no dierences in major
outcomes, although their conclusions were hampered by
methodological issues.
For atypical pathogens, blood serology tests are
available for Chlamydia pneumoniae, M pneumoniae,
and Legionella spp; however, their clinical usefulness is
limited by the delay in the results and diculty in
interpretation. PCR tests are available for bacterial
causes related to Mycoplasma, Chlamydia, Streptococcus,
and Legionella spp, which have to be done on
bronchoalveolar lavage fluid or nasopharyngeal swabs.
Real-time and multiplex-panel PCR aim to provide
results in a few hours and are promising methods for
fast bacterial aetiological diagnoses of communityacquired pneumonia.53 However, their cost-eectiveness
is unclear, and there are no data about resistance. PCR
tests are available for several respiratory viruses.30 In
view of the controversies about the use of antiviral
therapy, diculties related to the diagnosis of viral
pneumonia, and cost-eectiveness, clinicians should
reserve testing for viruses for special groups of patients
and within influenza season.

Imaging
Thoracic images are essential for several aspects of
pneumonia management. Chest radiograph has
diagnostic accuracies of 75% for alveolar consolidation
and 47% for pleural eusion, considering CT as the gold
standard technique.54 Performing both posteroanterior
and laterolateral projections increases its accuracy. By
contrast, chest radiograph has less accuracy in
bedridden, obese, and severely immunosuppressed
patients and in patients with previous alterations on
chest radiograph.

Outpatient

Inpatient,
low severity

Inpatient, no ICU,
moderate severity

Inpatient, ICU,
high severity

Sputum culture

None routinely

Yes

Yes

Yes

Blood culture

None routinely

None routinely

Yes

Yes

Legionella urinary antigen

None routinely

None routinely

Yes

Yes

Pneumococcal urinary antigen

None routinely

None routinely

Yes

Yes

Invasive respiratory
tract sample culture

None routinely

None routinely

None routinely

Yes

Others

None routinely

None routinely

None routinely

Yes*

Figure 1: Microbiological investigations

ICU=intensive care unit. *Others indicates fungal, tuberculosis cultures, PCR, specific serology, lung biopsy.

1099

Seminar

CT is the most accurate imaging technique for the

diagnosis of lung condensation54 and provides detailed
information about the lung parenchyma and mediastinum
and can also reveal alternative diagnoses. However, CT has
limitations that include increased cost, radiation exposure,
and the impossibility of doing CT at the bedside.54,55 For
these reasons, CT is reserved for specific situations such as
excluding the presence of other diagnoses (eg, pulmonary
embolism), when the suspicion of a fungal lung infection
is present, in patients with unclear chest radiograph (eg,
occult pneumonia in chronic obstructive pulmonary
disease), and in non-responding pneumonia for the
detection of complications (eg, lung abscesses).
Lung ultrasound is a useful method for evaluating
respiratory diseases including pneumonia.56 A recent
meta-analysis showed a sensitivity of 940% (95% CI
920960) and a specificity of 960% (940970) in the
diagnosis of pneumonia in adults.57 Compared with
previous methods, lung ultrasound has some advantages;
it is radiation-free, can be done at the bedside and on
pregnant woman, allows for dynamic evaluations, has
increased accuracy in the detection of consolidation and
pleural eusion compared with chest radiograph, and
takes less time.5658 Lung ultrasound is limited by its
learning curve, repeatability, and operator dependency.59

Acute management
Site of care

Early in the evaluation of patients with communityacquired pneumonia, two questions need to be answered:
does the patient need to be admitted in the hospital and
CAP

Severity assessment
(clinical judgment supported by severity scores)

Low risk

Moderate risk

High risk

CURB-65=0, 1
PSI=I, II, III

CURB-65=2
PSI=IV, V

CURB-65=3, 4
PSI=IV, V
Severe CAP criteria:
3 minor, or 1 major criteria

Outpatient
Inpatient
(admitted for social reasons)

Inpatient, no ICU

Inpatient, ICU

Microbiological tests

Microbiological tests

Antibiotic
Combination antibiotics
or quinolone

Antibiotic
Combination antibiotics
(-lactam plus macrolide*
or -lactam plus quinolone)

should they be treated in intensive care? These decisions

need to be made early because it has been widely shown
that late admission into intensive care is associated with
increased mortality.60 By contrast, the admission of
patients who can be treated outside the hospital is
associated with increased costs and risk of the
development of nosocomial infections.61
Clinical judgment is the main determinant of the site-ofcare decision.6 Oxygen saturation (SpO) and arterial gas
analysis can give important information about severity (eg,
SpO <92% can be considered a safer cuto than can
SpO <90% for hospital admission).62 Furthermore, scores
and biomarkers can assist the clinical judgment. The
Pneumonia Severity Index (PSI)18 and CURB-6563 are the
most frequently used scores. PSI is composed of 20 items
and classifies patients into five categories of severity that
are associated with the risk of mortality. Age and
comorbidities are highly weighted in the PSI, and for these
reasons, PSI can underestimate the severity of pneumonia
in young patients and in those without previous diseases.
CURB-65 uses five items and is practical for calculations,
although it does not account for comorbidities. Important
considerations not included in either score are
socioeconomic status and social support, both of which
can aect outcomes.64 Both PSI and CURB-65 were not
developed to predict complications associated with
community-acquired pneumonia; clinical research is
needed to develop specific scores to predict these events.
Patients should be admitted to intensive care when
they require mechanical ventilation or vasopressors (both
of which are major criteria for severe pneumonia in the
American Thoracic Society and Infectious Diseases
Society of America guidelines).3 In addition to the major
criteria, nine minor criteria are included to predict
admission into intensive care.3 A meta-analysis proposed
a simplification of the American Thoracic Society and
Infectious Diseases Society of America minor criteria
through removal of three variables (thrombocytopenia,
hypothermia, and leucopenia), which had a similar
accuracy.65 Other useful scores that are used to predict
admission into intensive care are the SMART-COP66 and
the REA-ICU for late admission.67 Some biomarkers can
increase the performance of some scores to predict ICU
admission (eg, proadrenomedullin)68 and can identify
severe community-acquired pneumonia (eg, CRP).69
Biomarkers can also identify patients who are first
admitted to the ward who might need an admission into
intensive care later.70

Selection of antibiotics
Antibiotic
Monotherapy in patients
without comorbidities
or risk factors

Figure 2: Acute management of the community-acquired pneumonia

CAP=community-acquired pneumonia. CURB-65=Confusion Urea Respiratory rate Blood pressure and age 65 year
old score. PSI=Pneumonia Severity Index. ICU=intensive care unit. *Combination with macrolide is preferred.

1100

Antibiotic treatment is typically chosen empirically

because of the absence of microbiological results upon
diagnosis. The choice of the empirical antibiotic depends
on the most likely pathogen, individual risk factors,
comorbidities, allergies, and cost-eectiveness (appendix).
Figure 2 and the table describe the management and
antibiotic treatment proposed by community-acquired
www.thelancet.com Vol 386 September 12, 2015

Seminar

pneumonia guidelines.36 Several studies have shown

reductions in mortality when these guidelines are
followed.71,72 Guidelines suggest the coverage of
S pneumoniae and atypical pathogens (eg, combination of
a -lactam plus macrolide or respiratory flouroquinolone).3,6
However, dual coverage is still debated,6,73 and three metaanalyses reported dierent results about mortality.7476
Furthermore, concerns exist about side-eects (such as an
increased risk of cardiovascular events in patients who
receive macrolides)77,78 and selective pressure for resistance
to macrolides and fluoroquinolone.
Two recent randomised controlled trials provided
important results about antibiotic treatment for people
admitted into hospital with non-severe communityacquired pneumonia. A cluster-crossover trial assessed the
non-inferiority of -lactam versus -lactam plus macrolide
versus fluoroquinolone regimens with 90 day mortality as
the primary outcome. Including 2283 patients with
clinically suspected pneumonia treated in non-intensivecare-unit wards, monotherapy with -lactam was not
inferior to the other antibiotic regimens.79 Another noninferiority, open-label trial randomly assigned 580 patients
with moderately severe community-acquired pneumonia
to receive -lactam or -lactam plus macrolide.80 The study
was unable to show non-inferiority for clinical stability
after 7 days of treatment. Nevertheless, a non-significant
trend for superiority was shown in favour of dual therapy
(between-group dierence 76%, two-sided 95% CI 08%
to 160%). For severe community-acquired pneumonia,
coverage of typical and atypical pathogens seems to be
protective of mortality and is recommended by major
guidelines.35 Macrolides seem to have additional benefits
due to their immunomodulatory eects in severe
community-acquired pneumonia.81,82
A small proportion of patients with specific pathogens
require a dierent treatment because they do not

respond to the standard empirical treatment.34 For this

reason, the 2005 American Thoracic Society and
Infectious Diseases Society of America nosocomial
pneumonia guidelines introduced a new category of
pneumonia called health-care-associated pneumonia to
help clinicians to select patients who need an extendedspectrum antibiotic due to a high probability of resistant
pathogens.83 This definition has been widely criticised
because it has many limitations, and studies have
shown it not to be accurate in the detection of at-risk
patients.84,85 Other scores have been developed and have
better accuracies; however, they also have some
limitations and still need strong external validation.34,8688
A summary of risk factors for resistant pathogens is
contained in the appendix. Because resistant pathogens
have dierent treatments, scores based on specific risk
factors for each pathogen might be more useful
methods compared with general definitions.34,35,89
Another concern is related to the treatment of patients
who are at risk for resistant pneumococcus, such as
elderly patients (age >65 years), those who have received
recent therapy with -lactams, macrolides, or
fluoroquinolones; alcohol consumption; and immunosuppression (appendix).3,90
New antibiotics are urgently needed for infections
because of the spread of resistance in some settings.
A recent phase 3 trial showed promising results for
ceftaroline fosamil, a fifth-generation cephalosporin
with activity against MRSA, in the treatment of
community-acquired pneumonia with PSI IIIIV in
Asian patients.91 Among macrolides, solithromycin is a
potential new antibiotic with activity against macrolideresistant bacteria.92
The ecacy of neuraminidase inhibitors to prevent
and treat influenza pneumonia is still controversial.93 For
patients with influenza A H1N1, a recent meta-analysis

American (IDSA/ATS)

British (NICE/BTS),

Preferred

Alternative

Preferred

Alternative

Preferred

European
Alternative

Outpatient without
Macrolide
comorbidities; low severity

Doxycycline

Amoxicillin

Macrolide or
tetracycline

Amoxicillin or
tetracycline

Macrolide

Outpatient with
comorbidities or high rate
bacterial resistance

-lactam plus
macrolide

Respiratory
fluoroquinolone

Respiratory
fluoroquinolone

Inpatient not in ICU;

moderate severity

-lactam* plus
macrolide

Respiratory
fluoroquinolone

Amoxicillin plus
macrolide

Respiratory
fluoroquinolone

Aminopenicillin
with or without
macrolide

Inpatient in ICU;
high severity

-lactam plus
macrolide

-lactam plus
respiratory
fluoroquinolone

-lactamase stable
-lactams plus
macrolide

Respiratory
fluoroquinolone

Respiratory
Third-generation
cephalosporin plus fluoroquinolone
with or without a
macrolide
third-generation
cephalosporin

Respiratory
fluoroquinolone

Local or adapted guidelines should be used to adapt for dierent epidemiology. IDS=Infectious Diseases Society of America. ATS=American Thoracic Society. NICE=National
Institute for Health and Care Excellence. BTS=British Thoracic Society. ICU=intensive care unit. *Preferred -lactam drugs include cefotaxime, ceftriaxone, and ampicillin.
Respiratory fluoroquinolone limited to situations in which other options cannot be prescribed or are ineective (eg, hepatotoxicity, skin reactions, cardiac arrhythmias, and
tendon rupture). Preferred -lactam drugs include cefotaxime, ceftriaxone, or ampicillin-sulbactam. -lactamase-stable -lactams include co-amoxiclav, cefotaxime,
ceftaroline fosamil, ceftriaxone, cefuroxime, and piperacillin-tazobactam. Third-generation cephalosporin (eg, cefotaxime, ceftriaxone).

Table: Empirical antibiotics suggested for community-acquired pneumonia

www.thelancet.com Vol 386 September 12, 2015

1101

Seminar

showed a reduction in mortality in hospitalised patients

who received neuraminidase inhibitors.94

Timing of antibiotic treatment

The first dose of antibiotics should be given as soon
as possible after diagnosis of community-acquired
pneumonia. The antibiotics should be started preferably
within the first 48 h of hospital arrival and a shorter time
to the first dose of antibiotic can be a marker of quality of
care.95 However, a meta-analysis of stable patients with
community-acquired
pneumonia
revealed
that
administration within 4 h was not associated with lower
mortality (OR 095, 95% CI 073123)96 and the pressure
for rapid antibiotic administration was associated with an
increased risk of misdiagnosis and an increased risk of
adverse eects.97 In unstable patients with severe sepsis or
septic shock, the time to the first dose is strongly associated
with a reduction in mortality, and administration in the
first hour after diagnosis is recommended.82,98

Care of pneumonia-related sepsis

Pneumonia is the main cause of sepsis worldwide, and
for severe sepsis or septic shock, the previous aspects of
care are the priority (ie, assessment of pathogens,
antibiotics, and whether early intensive care unit
admission is needed).82,98 The Surviving Sepsis Campaign
also advocates the measure of lactate concentration at
diagnosis and prompt initial expansion with 30 mL/kg of
crystalloid for hypotension or lactate concentrations of
4 mmol/L or higher.82 Results related to recommendation
of early goal-directed therapy are controversial mainly
because of insucient benefits reported in well designed
multicentre randomised controlled trials.99101 A major
concern about patients with sepsis due to pneumonia are
the risks associated with cumulative fluid balance and
blood transfusion because of worsening in respiratory
function.102,103

Respiratory support
Patients with acute respiratory failure due to pneumonia
must be assessed early for a need for respiratory
support, and oxygen saturation is an important marker
for outcome.62 Patients with severe pneumonia are
candidates for invasive mechanical ventilation, and a
delay can lead to an increased mortality.104 Patients
with moderately severe disease can be cautiously
managed with the use of non-invasive ventilation by
trained sta.105 A meta-analysis suggested that the
appropriate use of non-invasive ventilation in
pneumonia can reduce the need for endotracheal
intubation (OR 028, 95% CI 009088), intensive
care unit mortality (026, 011061), and the lengthof-stay in intensive care units (mean 100, 95% CI
205 to 005). However, this meta-analysis included
only 151 patients in three randomised trials, and
benefits were particularly evident in patients
with chronic obstructive pulmonary disease or
1102

immunosuppression.106 Non-invasive ventilation can

also be considered a palliative treatment in patients with
terminal illness.107 For mechanically ventilated patients,
protective ventilation is strongly recommended on
diagnosis of acute respiratory distress syndrome. For
less severe pneumonia, protective ventilation also
seems to prevent the progression of lung injury.3,108

Adjunctive therapy
The use of corticosteroids for community-acquired
pneumonia is debated, especially how it aects
mortality.109 Meta-analyses110,111 have reported reduced
hospital length-of-stay (mean 121 days, 95% CI
212 to 029) with use of corticosteroids. A multicentre
randomised controlled trial112 showed a shorter time to
reach clinical stability in patients with pneumonia
receiving oral prednisone (50 mg a day for 7 days) in
relation to the placebo group (30 days vs 44 days, hazard
ratio 133 95% CI 115150). Another multicentre
randomised controlled trial113 showed that methylprednisolone (05 mg/kg per 12 h for 5 days) reduced risk
for treatment failure compared with placebo (OR 034,
95% CI 014087) in patients with severe communityacquired pneumonia with high baseline concentrations
of CRP. For mortality, updated meta-analyses110,111,114116
report no conclusive results for hospitalised patients,
although corticosteroids were associated with better
survival in the subgroup with severe community-acquired
pneumonia.114117 However, trials included in the metaanalyses were small, have high heterogeneity, and
insucient power to assess mortality. No definitive data
are available for the best type and dose of corticosteroids
for patients with community-acquired pneumonia, nor
those for whether they should be given continuously or to
intermittent and tapering schemes.6 The clinician should
be aware of possible steroid-induced side-eects in
patients. In controlled settings (eg, randomised controlled
trials), only hyperglycaemia was more frequently reported
for patients with community-acquired pneumonia
receiving a corticosteroid. However, large trials including
patients with severe sepsis or septic shock with
community-acquired pneumonia as the main source of
infection, showed other steroid side-eects such as
superinfection.6,118
Investigators have proposed statins as an adjunctive
therapy in pneumonia due to their anti-inflammatory
activities and ability to reduce cardiovascular events, but
their eects are controversial.119

Long-term management

Evaluation of clinical stability

After the initial management of community-acquired
pneumonia, the subsequent days are fundamental for
good outcomes and high-quality management needs a
multidimensional approach (figure 3). The evaluation of
clinical stability (appendix) is a fundamental aspect of
community-acquired pneumonia care.120,121 Stability
www.thelancet.com Vol 386 September 12, 2015

Seminar

Stewardship
When microbiological tests become available, it is
important to re-evaluate antibiotic treatment. Antibiotics
should be adapted according to antibiogram results,
narrowed according to the identified pathogen, and
discontinued when a diagnosis of pneumonia is unlikely.25
Stewardship is fundamental to avoid the continuation of
unnecessary treatment, increasing the selective pressure
for resistance, and reducing the risks of unnecessary
complications (eg, Clostridium dicile infection).125

Severity assessment
Site of care
Microbiological tests
Empirical antibiotics
Supportive care

Clinical stability?
Check microbiological
results
Reassessment of
antibiotics:
Stewardship
Switch to oral
antibiotic
Duration

Discharge assessment
Follow-up scheduled:
Vaccination
Rehabilitation
Reintroduction of
previous drugs
Chest radiograph for some
patients

Clinical reassessment
Repeat microbiological
tests?
Change antibiotic?
Repeat chest radiograph
(or consider CT scan)?

Care

criteria oer information about antibiotic treatment (eg,

the appropriateness of such treatment, switching to oral
medication, and short antibiotic treatment durations)
and indications for hospital discharge that reduce
hospital length-of-stay.122124

Switch to oral therapy

Most patients in hospital with community-acquired
pneumonia began treatment with an intravenous
antibiotic. A switch to oral therapy should be considered
for patients who reach clinical stability. Two randomised
controlled trials25,126 have shown no dierence in mortality,
but important reductions in the length-of-stay and adverse
drug reactions, in patients who switch to oral therapy early.

Duration of therapy
5 days of treatment should be given for low-severity
pneumonia with clinical stability after 3 days of treatment,
and 7 days should be given for severe pneumonia, which
should be adapted depending on the improvements in
symptoms and stability.3,4,6,122,127 Indeed, two meta-analyses
reported similar ecacies for short-course (7 days) and
long-course (>7 days) treatments when patients with
severe pneumonia were excluded.127,128 Additionally, an
observational study with robust analyses reported similar
outcomes for short-course and long-course antibiotic
treatments for patients with severe community-acquired
pneumonia.123 Patients with extrapulmonary complications
or empyema and pneumonia due to specific pathogens
(eg, Legionella spp and MRSA) seem to have benefits from
prolonged treatments.
Biomarkers can be used to guide antibiotic duration.
One-time PCT values lower than 025 g/mL or a
decrease from the peak by 8090% are a strong indication
that antibiotics should be discontinued.4345 A randomised
controlled trial129 to compare PCT and CRP for antibiotic
guidance in patients with severe sepsis and septic shock
showed similar outcomes; however, more studies are
needed to compare cost-eectiveness among biomarkers.6

Clinical failure
Patients with community-acquired pneumonia can
present with deterioration, known as clinical failure,
which predicts mortality.130 Therefore, definition of the
causes of failure is essential. Early failure (<72 h) seems to
be related to the severity of the primary infection (eg,the
www.thelancet.com Vol 386 September 12, 2015

48 h
Normal response

72 h

Reassessment time
Time

Complicated pneumonia

Discharge time

Prolonged complicated pneumonia

Figure 3: Acute and long-term assessment of community-acquired pneumonia

development of septic shock), whereas the late failures

(>72 h) tend to be due to secondary events (eg, nosocomial
superinfection, exacerbation of comorbidities). The
development of severe sepsis is the primary reason for
failure.131 Outpatients also need an early follow-up (after
72 h) to detect development of failure.132 Non-responding
pneumonia is a dierent disorder that comprises the
persistence of pulmonary infiltrates 1 month after
symptom onset and can be due to many causes, such as
the presence of lung cancer or an underlying lung disease.3

Early rehabilitation
Patients in hospital seem to benefit from early mobilisation
and rehabilitation.133,134

Follow-up and outcomes

Readmission rate

Between 7% and 12% of patients who are admitted

into hospital for community-acquired pneumonia are
readmitted within 30 days.135,136 In more than half of cases,
comorbidities are the cause of readmission (mainly
cardiovascular, pulmonary, or neurological diseases),
whereas in other patients, a new episode of pneumonia
is the cause of readmission. The main risk factors
for readmission are initial treatment failure, clinical
instability at hospital discharge, older age, comorbidities,
and impaired functional status.135,136

Long-term mortality
Pneumonia causes much short-term and long-term
mortality. Mortality for patients with community-acquired
pneumonia is higher than for those with other infections
1103

Seminar

Panel 1: Controversies and uncertainties

1 The implementation of rapid diagnostic testing using PCR techniques for viruses and
bacteria might increase the number of microbiological diagnoses and consequently
the number of initial appropriate treatments; although some devices are able to
provide rapid diagnoses, well designed studies are needed to investigate major
outcomes and cost-eectiveness4,53
2 The real rates of dierent to treat pathogens in community-acquired pneumonia,
such as Pseudomonas aeruginosa, Enterobacteriaceae extended-spectrum -lactamase,
and meticillin-resistant Staphylococcus aureus, dier between continents and countries
(eg, the USA and Japan vs Europe); the concept of health-care-associated pneumonia
is not accurate and has resulted in the excessive administration of broad-spectrum
antibiotics;84 risk factors for these microorganisms have been described recently, but
implementation in clinical practice is still lacking34,35
3 Combination antibacterial therapy is a matter of debate; such therapy is
recommended for patients with community-acquired pneumonia who are admitted
to the intensive care unit,3,4 and in patients with bacteraemic Streptococcus
pneumoniae;82 furthermore, patients with high mortality admitted to the ward might
benefit from this treatment strategy80
4 Recent data from randomised controlled trials112,113 showed a reduction of time to
clinical stability and of treatment failure in patients with community-acquired
pneumonia receiving corticosteroids; however, data are controversial for eect on
mortality; a prematurely halted trial of severe community-acquired pneumonia
revealed an important decrease in mortality (39% vs 0%)117
5 The long-term cardiovascular complications of patients with community-acquired
pneumonia are not completely understood; but it seems that residual inflammation
might have an important role in triggering procoagulation pathways and leading to
cardiovascular complications37,138

Panel 2: Outstanding research questions

1

1104

Interventional studies are needed of microbiological testing techniques to increase

the rate of initial appropriate treatments, which would result in improved outcomes
and reduced overuse of antibiotics
Validation studies that use risk factors for dierent-to-treat microorganisms to
confirm the accuracies of these risk factors for their implementation in clinical
practice are also needed
Interventional studies should be done to assess cost-eectiveness for C-reactive
protein and procalcitonin in low-income and middle-income countries and
specific settings
A randomised controlled trial is needed in patients with severe communityacquired pneumonia who are not admitted to the intensive care unit that
compares monotherapy with respiratory quinolones and combination therapy
(-lactam plus macrolide)
Investigators should do a large randomised controlled trial in patients with
community-acquired pneumonia who are admitted to intensive care units that
assesses the administration of corticosteroids versus placebo powered to address
mortality and quality-of-life outcomes
Studies of severe community-acquired pneumonia are needed, both in animal
models and in human beings, to test new coadjutant treatments, such as enriched
immunoglobulin M, monoclonal antibodies, and molecules that can block the
endotoxins and exotoxins of the microbes
Prospective observational follow-up studies in patients with community-acquired
pneumonia are needed to better describe the clinical and biological risk factors for
cardiovascular complications to design a pharmacological randomised controlled trial

and patients who are admitted into hospital for other

reasons after adjusting for important variables.137 Several
predictors of long-term mortality have been described
and include age, comorbidities, frailty, cardiovascular
complications, inflammation and the severity of the
initial insult.137

Cardiovascular events
Community-acquired pneumonia is associated with an
increased risk of cardiovascular complications.138 Some
explanatory reasons for this include hypoxaemia,
inflammation, prothrombotic status, pathogen-specific
factors, and host characteristics.137,139 A meta-analysis for
the incidence of cardiac events within 30 days of hospital
admission for community-acquired pneumonia reported
a cumulative rate of heart failure of 14% (range 733%),
an arrhythmia rate of 5% (range 111%), and an acute
coronary syndrome rate of 5% (range 111%).140

Prevention and vaccines

Clinicians should pay attention regarding modifying
factors available to decrease the risk of a new episode of
community-acquired pneumonia (appendix). Influenza
vaccines are robustly associated with a reduced rate of
pneumonia and better outcomes.3,4 A study of
286 000 individuals older than 65 years reported a 30%
reduction in the rate of pneumonia and influenza infection
that was followed by a reduction in all-cause mortality.141
Two vaccines are available for S pneumoniae:
the pneumococcal polysaccharide vaccine and the
pneumococcal conjugate vaccine. The pneumococcal
polysaccharide vaccine contains polysaccharides for
23pneumococcal serotypes and the most recent version of
pneumococcal conjugate vaccine contains 13 serotypes. By
comparison with pneumococcal polysaccharide vaccine,
the pneumococcal conjugate vaccine seems to induce a
stronger and longer-lasting secondary immune response
with booster eect.142 Results from a recent meta-analysis
showed strong evidence for the recommendation for
pneumococcal polysaccharide vaccine-23 vaccination to
prevent invasive pneumococcal disease in adults.143
Nevertheless, there is less clear evidence for its ecacy in
the prevention of non-bacteraemic pneumonia,143 in
patients with chronic illnesses, and for the reduction of
all-cause pneumonia and mortality.143 The pneumococcal
conjugate vaccine-13 was approved for clinical use in
adults by the US and European agencies. The CAPiTA
study144 (a double-blind, randomised, placebo-controlled
clinical trial involving nearly 85 000 adults older than
65 years) showed clinical ecacy of pneumococcal
conjugate vaccine-13 in the prevention of the first episode
of vaccine-serotype pneumococcal community-acquired
pneumonia (including non-bacteraemic pneumonia and
invasive pneumococcal disease);144 however, the trial
excluded immunosuppressed patients and previously
vaccinated person. Because a substantial number of cases
of pneumonia is caused by serotypes not included in the
www.thelancet.com Vol 386 September 12, 2015

Seminar

pneumococcal conjugate vaccine-13 (38% of invasive

pneumococcal disease in the US in 2013), the US Centers
for Disease Control and Prevention recommended the
administration of both pneumococcal conjugate
vaccine-13 and pneumococcal polysaccharide vaccine-23
in series to all adults aged 65 years and older (panel 1).142
Outstanding research questions remain, which should be
addressed in future large trials (panel 2).
Contributors
All authors equally contributed in the literature search and data
interpretation, conceived, wrote, and approved the final version of the
manuscript.
Declaration of interests
AT participated in advisory boards for Merck, Pfizer (vaccines), and
Cempra. EP and OTR declare no competing interests.
References
1
Brown PD, Lerner SA. Community-acquired pneumonia. Lancet
1998; 352: 1295302.
2
File TM. Community-acquired pneumonia. Lancet 2003;
362: 19912001.
3
Mandell LA, Wunderink RG, Anzueto A, et al, for the Infectious
Diseases Society of America, and the American Thoracic Society.
Infectious Diseases Society of America/American Thoracic
Society consensus guidelines on the management of communityacquired pneumonia in adults. Clin Infect Dis 2007;
44 (suppl 2): S2772.
4
Lim WS, Baudouin SV, George RC, et al, for the Pneumonia
Guidelines Committee of the BTS Standards of Care Committee.
BTS guidelines for the management of community acquired
pneumonia in adults: update 2009. Thorax 2009;
64 (suppl 3): iii155.
5
Woodhead M, Blasi F, Ewig S, et al, for the Joint Taskforce of the
European Respiratory Society and European Society for Clinical
Microbiology and Infectious Diseases. Guidelines for the
management of adult lower respiratory tract infectionsfull version.
Clin Microbiol Infect 2011; 17 (suppl 6): E159.
6
National Institute for Health and Care Excellence. Pneumonia:
Diagnosis and management of community- and hospital-acquired
pneumonia in adults. NICE guidelines, 2014. https://www.nice.org.
uk/guidance/cg191 (accessed Jan 15, 2015).
7
Sanz F, Restrepo MI, Fernndez-Fabrellas E, et al. Does prolonged
onset of symptoms have a prognostic significance in communityacquired pneumonia? Respirology 2014; 19: 107379.
8
Arancibia F, Cortes CP, Valds M, et al. Importance of Legionella
pneumophila in the etiology of severe community-acquired
pneumonia in Santiago, Chile. Chest 2014; 145: 29096.
9
Cunha BA. The atypical pneumonias: clinical diagnosis and
importance. Clin Microbiol Infect 2006; 12 (suppl 3): 1224.
10 Bochud PY, Moser F, Erard P, et al. Community-acquired
pneumonia. A prospective outpatient study.
Medicine (Baltimore) 2001; 80: 7587.
11 Haubitz S, Hitz F, Graedel L, et al. Ruling out Legionella in
community-acquired pneumonia. Am J Med 2014; 127: 1010, e1119.
12 Metlay JP, Fine MJ. Testing strategies in the initial management
ofpatients with community-acquired pneumonia.
Ann Intern Med 2003; 138: 10918.
13 Schuetz P, Kutz A, Grolimund E, et al, for the ProHOSP Study
Group. Excluding infection through procalcitonin testing improves
outcomes of congestive heart failure patients presenting with acute
respiratory symptoms: results from the randomized ProHOSP trial.
Int J Cardiol 2014; 175: 46472.
14 GBD 2013 Mortality and Causes of Death Collaborators.
Global,regional, and national age-sex specific all-cause and
cause-specific mortality for 240 causes of death, 19902013:
asystematic analysis for the Global Burden of Disease Study 2013.
Lancet 2015; 385: 11771.
15 Millett ER, Quint JK, Smeeth L, Daniel RM, Thomas SL.
Incidenceof community-acquired lower respiratory tract
infectionsand pneumonia among older adults in the United
Kingdom: a population-based study. PLoS One 2013; 8: e75131.

www.thelancet.com Vol 386 September 12, 2015

16

17
18
19

20

21

22

23
24

25

26
27
28

29

30
31

32
33

34
35
36
37

Ochoa-Gondar O, Vila-Crcoles A, de Diego C, et al, for the

EVAN-65 Study Group. The burden of community-acquired
pneumonia in the elderly: the Spanish EVAN-65 study.
BMC Public Health 2008; 8: 222.
File TM Jr, Marrie TJ. Burden of community-acquired pneumonia
in North American adults. Postgrad Med 2010; 122: 13041.
Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify
low-risk patients with community-acquired pneumonia.
N Engl J Med 1997; 336: 24350.
Carratal J, Fernndez-Sab N, Ortega L, et al. Outpatient care
compared with hospitalization for community-acquired pneumonia:
a randomized trial in low-risk patients. Ann Intern Med 2005;
142: 16572.
Ewig S, Birkner N, Strauss R, et al. New perspectives on
community-acquired pneumonia in 388 406 patients. Results from a
nationwide mandatory performance measurement programme in
healthcare quality. Thorax 2009; 64: 106269.
Arnold FW, Wiemken TL, Peyrani P, Ramirez JA, Brock GN, for
the CAPO authors. Mortality dierences among hospitalized
patients with community-acquired pneumonia in three world
regions: results from the Community-Acquired Pneumonia
Organization (CAPO) International Cohort Study. Respir Med 2013;
107: 110111.
Woodhead M, Welch CA, Harrison DA, Bellingan G, Ayres JG.
Community-acquired pneumonia on the intensive care unit:
secondary analysis of 17,869 cases in the ICNARC Case Mix
Programme Database. Crit Care 2006; 10 (suppl 2): S1.
Welte T, Torres A, Nathwani D. Clinical and economic burden
ofcommunity-acquired pneumonia among adults in Europe.
Thorax 2012; 67: 7179.
Johnstone J, Marrie TJ, Eurich DT, Majumdar SR. Eect of
pneumococcal vaccination in hospitalized adults with
community-acquired pneumonia. Arch Intern Med 2007;
167: 193843.
Carratal J, Garcia-Vidal C, Ortega L, et al. Eect of a 3-step critical
pathway to reduce duration of intravenous antibiotic therapy and
length of stay in community-acquired pneumonia: a randomized
controlled trial. Arch Intern Med 2012; 172: 92228.
Drijkoningen JJ, Rohde GG. Pneumococcal infection in adults:
burden of disease. Clin Microbiol Infect 2014; 20 (suppl 5): 4551.
Howard LS, Sillis M, Pasteur MC, Kamath AV, Harrison BD.
Microbiological profile of community-acquired pneumonia in
adults over the last 20 years. J Infect 2005; 50: 10713.
Said MA, Johnson HL, Nonyane BA, et al, and the AGEDD Adult
Pneumococcal Burden Study Team. Estimating the burden of
pneumococcal pneumonia among adults: a systematic review and
meta-analysis of diagnostic techniques. PLoS One 2013; 8: e60273.
Arnold FW, Summersgill JT, Lajoie AS, et al, and the CommunityAcquired Pneumonia Organization (CAPO) Investigators.
Aworldwide perspective of atypical pathogens in communityacquired pneumonia. Am J Respir Crit Care Med 2007; 175: 108693.
Ruuskanen O, Lahti E, Jennings LC, Murdoch DR. Viral pneumonia.
Lancet 2011; 377: 126475.
Kyaw MH, Lynfield R, Schaner W, et al, and the Active Bacterial Core
Surveillance of the Emerging Infections Program Network. Eect of
introduction of the pneumococcal conjugate vaccine on drug-resistant
Streptococcus pneumoniae. N Engl J Med 2006; 354: 145563.
Principi N, Esposito S. Macrolide-resistant Mycoplasma pneumoniae:
its role in respiratory infection. J Antimicrob Chemother 2013;
68: 50611.
Cao B, Zhao CJ, Yin YD, et al. High prevalence of macrolide
resistance in Mycoplasma pneumoniae isolates from adult and
adolescent patients with respiratory tract infection in China.
Clin Infect Dis 2010; 51: 18994.
Webb BJ, Dascomb K, Stenehjem E, Dean N. Predicting risk
ofdrug-resistant organisms in pneumonia: moving beyond the
HCAP model. Respir Med 2015; 109: 110.
Prina E, Ranzani OT, Polverino E, et al. Risk factors associated with
potentially antibiotic-resistant pathogens in community-acquired
pneumonia. Ann Am Thorac Soc 2015; 12: 15360.
Alcn A, Fbregas N, Torres A. Pathophysiology of pneumonia.
Clin Chest Med 2005; 26: 3946.
Ubeda C, Pamer EG. Antibiotics, microbiota, and immune defense.
Trends Immunol 2012; 33: 45966.

1105

Seminar

38
39
40
41
42

43
44
45

46
47
48

49

50
51

52

53

54
55
56

57
58

1106

Torres A, Peetermans WE, Viegi G, Blasi F. Risk factors

forcommunity-acquired pneumonia in adults in Europe:
aliterature review. Thorax 2013; 68: 105765.
Wunderink RG, Waterer GW. Genetics of community-acquired
pneumonia. Semin Respir Crit Care Med 2005; 26: 55362.
Rautanen A, Mills TC, Gordon AC, et al. Genome-wide association
study of survival from sepsis due to pneumonia: an observational
cohort study. Lancet Respir Med 2015; 3: 5360.
Misch EA, Verbon A, Prins JM, Skerrett SJ, Hawn TRA. A TLR6
polymorphism is associated with increased risk of Legionnaires
disease. Genes Immun 2013; 14: 42026.
Aabenhus R, Jensen JU, Jrgensen KJ, Hrbjartsson A, Bjerrum L.
Biomarkers as point-of-care tests to guide prescription of antibiotics
in patients with acute respiratory infections in primary care.
Cochrane Database Syst Rev 2014; 11: CD010130.
Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance
of antibiotic therapy in community-acquired pneumonia:
arandomized trial. Am J Respir Crit Care Med 2006; 174: 8493.
Schuetz P, Mller B, Christ-Crain M, et al. Procalcitonin to initiate
or discontinue antibiotics in acute respiratory tract infections.
Cochrane Database Syst Rev 2012; 9: CD007498.
Schuetz P, Balk R, Briel M, et al. Economic evaluation of
procalcitonin-guided antibiotic therapy in acute respiratory
infections: a US health system perspective.
Clin Chem Lab Med 2015; 53: 58392.
Fine MJ, Orlo JJ, Arisumi D, et al. Prognosis of patients
hospitalized with community-acquired pneumonia. Am J Med 1990;
88: 1N8N.
Malcolm C, Marrie TJ. Antibiotic therapy for ambulatory patients
with community-acquired pneumonia in an emergency department
setting. Arch Intern Med 2003; 163: 797802.
Marrie TJ, Lau CY, Wheeler SL, Wong CJ, Vandervoort MK,
Feagan BG. A controlled trial of a critical pathway for treatment of
community-acquired pneumonia. CAPITAL Study Investigators.
Community-Acquired Pneumonia Intervention Trial Assessing
Levofloxacin. JAMA 2000; 283: 74955.
Sinclair A, Xie X, Teltscher M, Dendukuri N. Systematic review
andmeta-analysis of a urine-based pneumococcal antigen test
fordiagnosis of community-acquired pneumonia caused by
Streptococcus pneumoniae. J Clin Microbiol 2013; 51: 230310.
Shimada T, Noguchi Y, Jackson JL, et al. Systematic review
andmetaanalysis: urinary antigen tests for Legionellosis.
Chest2009; 136: 157685.
van der Eerden MM, Vlaspolder F, de Graa CS, et al.
Comparisonbetween pathogen directed antibiotic treatment
andempirical broad spectrum antibiotic treatment in patients
withcommunity acquired pneumonia: a prospective randomised
study. Thorax 2005; 60: 67278.
Falguera M, Ruiz-Gonzlez A, Schoenenberger JA, et al.
Prospective, randomised study to compare empirical treatment
versus targeted treatment on the basis of the urine antigen results
in hospitalised patients with community-acquired pneumonia.
Thorax 2010; 65: 10106.
Schulte B, Eickmeyer H, Heininger A, et al. Detection of
pneumonia associated pathogens using a prototype multiplexed
pneumonia test in hospitalized patients with severe pneumonia.
PLoS One 2014; 9: e110566.
Syrjl H, Broas M, Suramo I, Ojala A, Lhde S. High-resolution
computed tomography for the diagnosis of community-acquired
pneumonia. Clin Infect Dis 1998; 27: 35863.
Brenner DJ, Hall EJ. Computed tomographyan increasing source
of radiation exposure. N Engl J Med 2007; 357: 227784.
Volpicelli G, Elbarbary M, Blaivas M, et al, and the International
Liaison Committee on Lung Ultrasound (ILC-LUS) for
International Consensus Conference on Lung Ultrasound
(ICC-LUS). International evidence-based recommendations for
point-of-care lung ultrasound. Intensive Care Med 2012;
38: 57791.
Chavez MA, Shams N, Ellington LE, et al. Lung ultrasound for
thediagnosis of pneumonia in adults: a systematic review and
meta-analysis. Respir Res 2014; 15: 50.
Reissig A, Copetti R, Mathis G, et al. Lung ultrasound in the diagnosis
and follow-up of community-acquired pneumonia: aprospective,
multicenter, diagnostic accuracy study. Chest 2012; 142: 96572.

59
60

61
62

63

64

65
66

67

68

69
70
71
72
73
74

75

76

77
78
79

Ramirez P, Torres A. Should ultrasound be included in the

initialassessment of respiratory patients? Lancet Respir Med 2014;
2: 599600.
Restrepo MI, Mortensen EM, Rello J, Brody J, Anzueto A.
Lateadmission to the ICU in patients with community-acquired
pneumonia is associated with higher mortality. Chest 2010;
137: 55257.
Gonzlez-Moraleja J, Sesma P, Gonzlez C, Lpez ME, Garca JF,
Alvarez-Sala JL. What is the cost of inappropriate admission of
pneumonia patients? Arch Bronconeumol 1999; 35: 31216.
Majumdar SR, Eurich DT, Gamble JM, Senthilselvan A, Marrie TJ.
Oxygen saturations less than 92% are associated with major adverse
events in outpatients with pneumonia: a population-based cohort
study. Clin Infect Dis 2011; 52: 32531.
Lim WS, van der Eerden MM, Laing R, et al. Defining community
acquired pneumonia severity on presentation to hospital: an
international derivation and validation study. Thorax 2003;
58: 37782.
Jones B, Gundlapalli AV, Jones JP, Brown SM, Dean NC. Admission
decisions and outcomes of community-acquired pneumonia in the
homeless population: a review of 172 patients in an urban setting.
Am J Public Health 2013; 103 (suppl 2): S28993.
Salih W, Schembri S, Chalmers JD. Simplification of the IDSA/ATS
criteria for severe CAP using meta-analysis and observational data.
Eur Respir J 2014; 43: 84251.
Charles PG, Wolfe R, Whitby M, et al, for the Australian
Community-Acquired Pneumonia Study Collaboration.
SMART-COP: a tool for predicting the need for intensive
respiratory or vasopressor support in community-acquired
pneumonia. Clin Infect Dis 2008; 47: 37584.
Labarre J, Schuetz P, Renaud B, Claessens YE, Albrich W,
Mueller B. Validation of a clinical prediction model for early
admission to the intensive care unit of patients with pneumonia.
Acad Emerg Med 2012; 19: 9931003.
Renaud B, Schuetz P, Claessens YE, Labarre J, Albrich W,
Mueller B. Proadrenomedullin improves Risk of Early Admission
to ICU score for predicting early severe community-acquired
pneumonia. Chest 2012; 142: 144754.
Chalmers JD, Singanayagam A, Hill AT. C-reactive protein is
anindependent predictor of severity in community-acquired
pneumonia. Am J Med 2008; 121: 21925.
Ramrez P, Ferrer M, Mart V, et al. Inflammatory biomarkers
andprediction for intensive care unit admission in severe
community-acquired pneumonia. Crit Care Med 2011; 39: 221117.
Dean NC, Silver MP, Bateman KA, James B, Hadlock CJ, Hale D.
Decreased mortality after implementation of a treatment guideline
for community-acquired pneumonia. Am J Med 2001; 110: 45157.
Martnez R, Reyes S, Lorenzo MJ, Menndez R. Impact of guidelines
on outcome: the evidence. Semin Respir Crit Care Med 2009; 30: 17278.
File TM Jr, Marrie TJ. Does empiric therapy for atypical pathogens
improve outcomes for patients with CAP?
Infect Dis Clin North Am 2013; 27: 99114.
Nie W, Li B, Xiu Q. -Lactam/macrolide dual therapy versus
-lactam monotherapy for the treatment of community-acquired
pneumonia in adults: a systematic review and meta-analysis.
J Antimicrob Chemother 2014; 69: 144146.
Asadi L, Sligl WI, Eurich DT, et al. Macrolide-based regimens
andmortality in hospitalized patients with community-acquired
pneumonia: a systematic review and meta-analysis.
Clin Infect Dis 2012; 55: 37180.
Eliakim-Raz N, Robenshtok E, Shefet D, et al. Empiric antibiotic
coverage of atypical pathogens for community-acquired pneumonia
in hospitalized adults. Cochrane Database Syst Rev 2012;
9: CD004418.
Schembri S, Williamson PA, Short PM, et al. Cardiovascular events
after clarithromycin use in lower respiratory tract infections:
analysis of two prospective cohort studies. BMJ 2013; 346: f1235.
Mortensen EM, Halm EA, Pugh MJ, et al. Association of
azithromycin with mortality and cardiovascular events among older
patients hospitalized with pneumonia. JAMA 2014; 311: 2199208.
Postma DF, van Werkhoven CH, van Elden LJ, et al, for the
CAP-START Study Group. Antibiotic treatment strategies for
community-acquired pneumonia in adults. N Engl J Med 2015;
372: 131223.

www.thelancet.com Vol 386 September 12, 2015

Seminar

80

81

82

83

84
85
86

87

88
89
90

91

92

93
94

95

96

97
98

Garin N, Genn D, Carballo S, et al. -Lactam monotherapy vs

-lactam-macrolide combination treatment in moderately severe
community-acquired pneumonia: a randomized noninferiority trial.
JAMA Intern Med 2014; 174: 1894901.
Sligl WI, Asadi L, Eurich DT, Tjosvold L, Marrie TJ,
MajumdarSR.Macrolides and mortality in critically ill patients with
community-acquired pneumonia: a systematic review and
meta-analysis. Crit Care Med 2014; 42: 42032.
Dellinger RP, Levy MM, Rhodes A, et al, for the Surviving
SepsisCampaign Guidelines Committee including The Pediatric
Subgroup. Surviving Sepsis Campaign: international guidelines
formanagement of severe sepsis and septic shock, 2012.
Intensive Care Med 2013; 39: 165228.
American Thoracic Society, and the Infectious Diseases Society of
America. Guidelines for the management of adults with hospitalacquired, ventilator-associated, and healthcare-associated
pneumonia. Am J Respir Crit Care Med 2005; 171: 388416.
Ewig S, Welte T, Chastre J, Torres A. Rethinking the concepts of
community-acquired and health-care-associated pneumonia.
Lancet Infect Dis 2010; 10: 27987.
Dobler CC, Waterer G. Healthcare-associated pneumonia:
aUSdisease or relevant to the Asia Pacific, too? Respirology 2013;
18: 92332.
Aliberti S, Di Pasquale M, Zanaboni AM, et al. Stratifying risk
factors for multidrug-resistant pathogens in hospitalized patients
coming from the community with pneumonia. Clin Infect Dis 2012;
54: 47078.
Shorr AF, Zilberberg MD, Reichley R, et al. Validation of a clinical
score for assessing the risk of resistant pathogens in patients with
pneumonia presenting to the emergency department. Clin Infect Dis
2012; 54: 19398.
Shindo Y, Ito R, Kobayashi D, et al. Risk factors for drug-resistant
pathogens in community-acquired and healthcare-associated
pneumonia. Am J Respir Crit Care Med 2013; 188: 98595.
Wunderink RG. Community-acquired pneumonia versus
healthcare-associated pneumonia. The returning pendulum.
Am J Respir Crit Care Med 2013; 188: 89698.
Kuster SP, Rudnick W, Shigayeva A, et al, for the Toronto
Invasive Bacterial Diseases Network. Previous antibiotic exposure
and antimicrobial resistance in invasive pneumococcal disease:
results from prospective surveillance. Clin Infect Dis 2014;
59: 94452.
Zhong NS, Sun T, Zhuo C, et al. Ceftaroline fosamil versus
ceftriaxone for the treatment of Asian patients with
community-acquired pneumonia: a randomised, controlled,
double-blind, phase 3, non-inferiority with nested superiority
trial.Lancet Infect Dis 2015; 15: 16171.
Oldach D, Clark K, Schranz J, et al. Randomized, double-blind,
multicenter phase 2 study comparing the ecacy and safety of
oralsolithromycin (CEM-101) to those of oral levofloxacin in the
treatment of patients with community-acquired bacterial
pneumonia. Antimicrob Agents Chemother 2013; 57: 252634.
Jeerson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for
preventing and treating influenza in healthy adults and children.
Cochrane Database Syst Rev 2014; 4: CD008965.
Muthuri SG, Venkatesan S, Myles PR, et al, and the PRIDE
Consortium Investigators. Eectiveness of neuraminidase
inhibitors in reducing mortality in patients admitted to hospital
with influenza A H1N1pdm09 virus infection: a meta-analysis of
individual participant data. Lancet Respir Med 2014; 2: 395404.
Barlow G, Nathwani D, Williams F, et al. Reducing door-toantibiotic time in community-acquired pneumonia: controlled
before-and-after evaluation and cost-eectiveness analysis.
Thorax 2007; 62: 6774.
Yu KT, Wyer PC. Evidence-based emergency medicine/critically
appraised topic. Evidence behind the 4-hour rule for initiation
ofantibiotic therapy in community-acquired pneumonia.
Ann Emerg Med 2008; 51: 65162.
Welker JA, Huston M, McCue JD. Antibiotic timing and errors
indiagnosing pneumonia. Arch Intern Med 2008; 168: 35156.
Noritomi DT, Ranzani OT, Monteiro MB, et al. Implementation of
amultifaceted sepsis education program in an emerging country
setting: clinical outcomes and cost-eectiveness in a long-term
follow-up study. Intensive Care Med 2014; 40: 18291.

www.thelancet.com Vol 386 September 12, 2015

99
100
101
102

103
104
105
106
107
108

109
110
111
112

113

114
115
116

117
118
119
120
121

Peake SL, Delaney A, Bailey M, et al, for the ARISE Investigators,

and the ANZICS Clinical Trials Group. Goal-directed resuscitation
for patients with early septic shock. N Engl J Med 2014; 371: 1496506.
Yealy DM, Kellum JA, Huang DT, et al, for the ProCESS
Investigators. A randomized trial of protocol-based care for
earlyseptic shock. N Engl J Med 2014; 370: 168393.
Mouncey PR, Osborn TM, Power GS, et al, for the ProMISe Trial
Investigators. Trial of early, goal-directed resuscitation for septic
shock. N Engl J Med 2015; 372: 130111.
Azevedo LC, Park M, Salluh JI, et al, for the ERICC (Epidemiology
of Respiratory Insuciency in Critical Care) investigators. Clinical
outcomes of patients requiring ventilatory support in Brazilian
intensive care units: a multicenter, prospective, cohort study.
Crit Care 2013; 17: R63.
Gajic O, Rana R, Winters JL, et al. Transfusion-related acute lung
injury in the critically ill: prospective nested case-control study.
Am J Respir Crit Care Med 2007; 176: 88691.
Carrillo A, Gonzalez-Diaz G, Ferrer M, et al. Non-invasive
ventilation in community-acquired pneumonia and severe
acuterespiratory failure. Intensive Care Med 2012; 38: 45866.
Brambilla AM, Aliberti S, Prina E, et al. Helmet CPAP vs. oxygen
therapy in severe hypoxemic respiratory failure due to pneumonia.
Intensive Care Med 2014; 40: 94249.
Zhang Y, Fang C, Dong BR, Wu T, Deng JL. Oxygen therapy for
pneumonia in adults. Cochrane Database Syst Rev 2012;
3: CD006607.
Nava S, Ferrer M, Esquinas A, et al. Palliative use of non-invasive
ventilation in end-of-life patients with solid tumours: a randomised
feasibility trial. Lancet Oncol 2013; 14: 21927.
Gajic O, Frutos-Vivar F, Esteban A, Hubmayr RD, Anzueto A.
Ventilator settings as a risk factor for acute respiratory distress
syndrome in mechanically ventilated patients.
Intensive Care Med 2005; 31: 92226.
Pvoa P, Salluh JI. What is the role of steroids in pneumonia
therapy? Curr Opin Infect Dis 2012; 25: 199204.
Chen Y, Li K, Pu H, Wu T. Corticosteroids for pneumonia.
Cochrane Database Syst Rev 2011; 3: CD007720.
Shafiq M, Mansoor MS, Khan AA, Sohail MR, Murad MH.
Adjuvant steroid therapy in community-acquired pneumonia:
asystematic review and meta-analysis. J Hosp Med 2013; 8: 6875.
Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for
patients with community-acquired pneumonia: a multicentre,
double-blind, randomised, placebo-controlled trial. Lancet 2015;
385: 151118.
Torres A, Sibila O, Ferrer M, et al. Eect of corticosteroids on
treatment failure among hospitalized patients with severe
community-acquired pneumonia and high inflammatory response:
a randomized clinical trial. JAMA 2015; 313: 67786.
Nie W, Zhang Y, Cheng J, Xiu Q. Corticosteroids in the treatment
of community-acquired pneumonia in adults: a meta-analysis.
PLoS One 2012; 7: e47926.
Cheng M, Pan ZY, Yang J, Gao YD. Corticosteroid therapy for severe
community-acquired pneumonia: a meta-analysis. Respir Care 2014;
59: 55763.
Confalonieri M, Annane D, Antonaglia C, Santagiuliana M,
Borriello EM, Meduri GU. Is prolonged low-dose glucocorticoid
treatment beneficial in community-acquired pneumonia?
Curr Infect Dis Rep 2013; 15: 15866.
Confalonieri M, Urbino R, Potena A, et al. Hydrocortisone
infusionfor severe community-acquired pneumonia: a preliminary
randomized study. Am J Respir Crit Care Med 2005; 171: 24248.
Kalil AC, Sun J. Low-dose steroids for septic shock and severe
sepsis: the use of Bayesian statistics to resolve clinical trial
controversies. Intensive Care Med 2011; 37: 42029.
Khan AR, Riaz M, Bin Abdulhak AA, et al. The role of statins in
prevention and treatment of community acquired pneumonia:
asystematic review and meta-analysis. PLoS One 2013; 8: e52929.
Menndez R, Martinez R, Reyes S, et al. Stability in
community-acquired pneumonia: one step forward with markers?
Thorax 2009; 64: 98792.
Halm EA, Fine MJ, Marrie TJ, et al. Time to clinical stability in
patients hospitalized with community-acquired pneumonia:
implications for practice guidelines. JAMA 1998; 279: 145257.

1107

Seminar

122 el Moussaoui R, de Borgie CA, van den Broek P, et al.

Eectivenessof discontinuing antibiotic treatment after three days
versus eight days in mild to moderate-severe community acquired
pneumonia: randomised, double blind study. BMJ 2006; 332: 1355.
123 Choudhury G, Mandal P, Singanayagam A, Akram AR,
Chalmers JD, Hill AT. Seven-day antibiotic courses have similar
ecacy to prolonged courses in severe community-acquired
pneumoniaa propensity-adjusted analysis.
Clin Microbiol Infect 2011; 17: 185258.
124 Blasi F, Ostermann H, Racketa J, Medina J, McBride K, Garau J,
for the REACH study group. Early versus later response to
treatment in patients with community-acquired pneumonia:
analysis of the REACH study. Respir Res 2014; 15: 6.
125 Polgreen PM, Chen YY, Cavanaugh JE, et al. An outbreak of
severeClostridium dicile-associated disease possibly related to
inappropriate antimicrobial therapy for community-acquired
pneumonia. Infect Control Hosp Epidemiol 2007; 28: 21214.
126 Oosterheert JJ, Bonten MJ, Schneider MM, et al. Eectiveness
ofearly switch from intravenous to oral antibiotics in severe
community acquired pneumonia: multicentre randomised trial.
BMJ 2006; 333: 1193.
127 Li JZ, Winston LG, Moore DH, Bent S. Ecacy of short-course
antibiotic regimens for community-acquired pneumonia:
ameta-analysis. Am J Med 2007; 120: 78390.
128 Dimopoulos G, Matthaiou DK, Karageorgopoulos DE,
Grammatikos AP, Athanassa Z, Falagas ME. Short- versus
long-course antibacterial therapy for community-acquired
pneumonia: a meta-analysis. Drugs 2008; 68: 184154.
129 Oliveira CF, Botoni FA, Oliveira CR, et al. Procalcitonin
versusC-reactive protein for guiding antibiotic therapy in sepsis:
arandomized trial. Crit Care Med 2013; 41: 233643.
130 Aliberti S, Blasi F. Clinical stability versus clinical failure in patients
with community-acquired pneumonia. Semin Respir Crit Care Med
2012; 33: 28491.
131 Menndez R, Torres A, Zalacan R, et al, for the Neumofail Group.
Risk factors of treatment failure in community acquired
pneumonia: implications for disease outcome. Thorax 2004;
59: 96065.
132 Ott SR, Hauptmeier BM, Ernen C, et al. Treatment failure in
pneumonia: impact of antibiotic treatment and cost analysis.
Eur Respir J 2012; 39: 61118.
133 Mundy LM, Leet TL, Darst K, Schnitzler MA, Dunagan WC.
Earlymobilization of patients hospitalized with
community-acquired pneumonia. Chest 2003; 124: 88389.

1108

134 Stolbrink M, McGowan L, Saman H, et al. The Early Mobility

Bundle: a simple enhancement of therapy which may reduce
incidence of hospital-acquired pneumonia and length of hospital
stay. J Hosp Infect 2014; 88: 3439.
135 Jasti H, Mortensen EM, Obrosky DS, Kapoor WN, Fine MJ.
Causesand risk factors for rehospitalization of patients
hospitalized with community-acquired pneumonia.
Clin Infect Dis2008; 46: 55056.
136 Capelastegui A, Espaa Yandiola PP, Quintana JM, et al.
Predictors of short-term rehospitalization following discharge
ofpatients hospitalized with community-acquired pneumonia.
Chest 2009; 136: 107985.
137 Restrepo MI, Faverio P, Anzueto A. Long-term prognosis in
community-acquired pneumonia. Curr Opin Infect Dis 2013;
26: 15158.
138 Corrales-Medina VF, Alvarez KN, Weissfeld LA, et al.
Associationbetween hospitalization for pneumonia and
subsequent risk of cardiovascular disease. JAMA 2015; 313: 26474.
139 Yende S, DAngelo G, Kellum JA, et al, and the GenIMS
Investigators. Inflammatory markers at hospital discharge
predictsubsequent mortality after pneumonia and sepsis.
Am J Respir Crit Care Med 2008; 177: 124247.
140 Corrales-Medina VF, Suh KN, Rose G, et al. Cardiac complications
in patients with community-acquired pneumonia: a systematic
review and meta-analysis of observational studies. PLoS Med 2011;
8: e1001048.
141 Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M.
Influenza vaccination and reduction in hospitalizations for
cardiac disease and stroke among the elderly. N Engl J Med 2003;
348: 132232.
142 Tomczyk S, Bennett NM, Stoecker C, et al, and the Centers
forDisease Control and Prevention (CDC). Use of 13-valent
pneumococcal conjugate vaccine and 23-valent pneumococcal
polysaccharide vaccine among adults aged 65 years:
recommendations of the Advisory Committee on Immunization
Practices (ACIP). MMWR Morb Mortal Wkly Rep 2014; 63: 82225.
143 Moberley S, Holden J, Tatham DP, Andrews RM. Vaccines
forpreventing pneumococcal infection in adults.
Cochrane Database Syst Rev 2013; 1: CD000422.
144 Bonten MJ, Huijts SM, Bolkenbaas M, et al. Polysaccharide
conjugate vaccine against pneumococcal pneumonia in adults.
N Engl J Med 2015; 372: 111425.

www.thelancet.com Vol 386 September 12, 2015