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Epidemiology, pathogenesis, and

microbiology of community-acquired
pneumonia in adults
MICROBIOLOGY  Typical versus atypical bacteria

Topic Graphics (7)

author: Thomas M File, Jr, MD

section editor: Julio A Ramirez, MD, FACP
deputy editor: Sheila Bond, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and

our peer review process is complete.

Literature review current through: Oct 2023.

This topic last updated: Mar 03, 2023.

INTRODUCTION

Community-acquired pneumonia (CAP) is

defined as an acute infection of the pulmonary
parenchyma in a patient who has acquired the
infection in the community, as distinguished
from hospital-acquired (nosocomial)
pneumonia (HAP).

CAP is a common and potentially serious illness

[1,2]. It is associated with considerable
morbidity and mortality, particularly in older
adult patients and those with significant
comorbidities. (See "Morbidity and mortality
associated with community-acquired
pneumonia in adults".)

The epidemiology, pathogenesis, and

microbiology of CAP in adults will be reviewed
here. A variety of other important issues
related to CAP are discussed separately. These
include:

● (See "Clinical evaluation and diagnostic

testing for community-acquired
pneumonia in adults".)

● (See "Sputum cultures for the evaluation

of bacterial pneumonia".)

● (See "Community-acquired pneumonia in

adults: Assessing severity and
determining the appropriate site of care".)

● (See "Treatment of community-acquired

pneumonia in adults in the outpatient
setting".)

● (See "Treatment of community-acquired

pneumonia in adults who require
hospitalization".)

● (See "Aspiration pneumonia in adults" and

"Epidemiology of pulmonary infections in
immunocompromised patients".)

● (See "Nonresolving pneumonia".)

● (See "Morbidity and mortality associated

with community-acquired pneumonia in
adults".)

● (See "COVID-19: Epidemiology, virology,

and prevention".)

EPIDEMIOLOGY

Community-acquired pneumonia — The

overall incidence of CAP in adults is estimated
at approximately 16 to 23 cases per 1000
persons per year; the rate rises with age [3-5].
In the United States, approximately 30 percent
of patients with CAP are hospitalized, with an
incidence of approximately 5 to 7 CAP
hospitalizations per 1000 persons per year [3-
5]. There is seasonal variation, with more cases
occurring during the winter months. The rates
of pneumonia are higher for men than for
women and for Black persons compared with
White persons. The etiology of CAP varies by
geographic region; however, Streptococcus
pneumoniae is the most commonly identified
bacterial cause of CAP worldwide. Viruses are
common causes of CAP as well [6,7]. The
microbiology of CAP is discussed in greater
detail below. (See 'Microbiology' below.)

In 2005, pneumonia and influenza combined

was the eighth most common cause of death in
the United States and the seventh most
common cause of death in Canada [8,9]. There
were over 60,000 deaths due to pneumonia in
the United States. Mortality is highest for CAP
patients who require hospitalization. Data from
the Centers for Medicare and Medicaid Services
database estimate the 30-day mortality rate of
CAP patients (mostly those >65 years of age)
requiring admission to the hospital in the
United States to be approximately 12 percent
[10]. Overall mortality may also vary according
to geographic location (United States/Canada
7.3 percent; Europe 9.1 percent; Latin America
13.3 percent); however, following adjustment
for confounding variables, these differences
are often reduced [11]. All-cause mortality in
patients with CAP is as high as 28 percent
within one year. Given the aging population in
North America, it is expected that the burden
of CAP will increase. (See "Morbidity and
mortality associated with community-acquired
pneumonia in adults".)

Health care-associated pneumonia — As

noted above, community-acquired pneumonia
(CAP) is defined as an acute infection of the
pulmonary parenchyma in a patient who has
acquired the infection in the community, as
distinguished from hospital-acquired
(nosocomial) pneumonia (HAP).

A third category of pneumonia, designated

health care-associated pneumonia (HCAP), was
included in prior HAP guidelines [12] (but not
current HAP guidelines [13]) to identify patients
thought to be at increased risk for multidrug-
resistant (MDR) pathogens coming from
community settings. HCAP referred to
pneumonia acquired in health care facilities
such as nursing homes, hemodialysis centers,
and outpatient clinics or a hospitalization
within the past three months. The rationale for
the separate designation of HCAP (and its
association with HAP) was that patients with
HCAP were thought to be at higher risk for
MDR organisms. However, several studies have
shown that many patients defined as having
HCAP are not at high risk for MDR pathogens
[14-16], and that this designation is not a good
predictor of who will have an infection with an
MDR organism [17]. Furthermore, although
interaction with the health care system is
potentially a risk for MDR pathogens,
underlying patient characteristics are also
important independent determinants of risk
for MDR pathogens and mortality. It is
anticipated that patients previously designated
as HCAP will be included in the next update of
the Infectious Diseases Society of America
(IDSA)/American Thoracic Society (ATS) CAP
guidelines because patients with HCAP
frequently present from the community and
are initially cared for in emergency
departments.

PATHOGENESIS

The lungs are constantly exposed to particulate

material and microbes that are present in the
upper airways and, by microaspiration, enter
the lower respiratory tract. Contrary to
longstanding belief, the lower respiratory tract
is not sterile. Using culture-independent
techniques, investigators have shown that
healthy lower airways contain some bacterial
species that are also found in the upper
respiratory tract, such as Prevotella spp,
Veillonella spp, and Streptococcus spp [18].
However, pulmonary host defenses are
important for maintaining the microbiome at
low levels and devoid of conventional
pathogens. These host defenses can be
categorized as innate (nonspecific) or acquired
(specific). The development of community-
acquired pneumonia (CAP) indicates either a
defect in host defenses, exposure to a
particularly virulent microorganism, or an
overwhelming inoculum [19-21].

Microaspiration is the most common

mechanism through which the constituents of
the microbiota and pathogens reach the lung.
Hematogenous spread from a distant infected
site, direct spread from a contiguous focus, and
macroaspiration are other mechanisms
whereby pathogens gain access to the lung.

Local pathogen multiplication — New

understanding of the human microbiome
indicates that the lower airways and alveolar
space in the healthy lung are not free of
microorganisms, as previously considered [18].
Bacteria and viruses are part of the normal
lung microbiome. The bacteria that constitute
the normal alveolar flora are predominantly
anaerobic organisms and microaerophilic
streptococci. The pathogenesis of some cases
of CAP may involve the uncontrolled
multiplication of some of these bacteria already
present in the alveoli.

Since the common bacterial pathogens

associated with CAP are not part of the normal
alveolar microbiome, they must arrive and
multiply in the alveoli. Local multiplication may
be prevented by the killing of organisms by the
alveolar macrophage. The presence of a
normal alveolar flora may also interfere with
the local multiplication of newly arrived
pathogenic organisms. The uncontrolled
alveolar multiplication of organisms is likely
due to a combination of arrival to the alveolar
space of a particularly virulent microorganism
and abnormal host defenses. In a host prone to
aspiration, local multiplication of less virulent
bacteria, usually anaerobes from the upper
airway, may occur due to an overwhelming
inoculum (see "Aspiration pneumonia in
adults"). Tobacco use and alcohol consumption
are common host conditions that favor
development of CAP by altering the normal
host defense mechanisms.

Local inflammatory response — If the local

alveolar macrophage fails to contain the local
multiplication of the pathogenic organism, the
macrophage will produce a series of cytokines
to bring new phagocytes to the alveolar space.
Local production of cytokines will generate an
inflammatory response with increased local
microvascular permeability. This will facilitate
the movement of white blood cells (WBCs),
proteins, and fluid into the alveolar space. The
arrival of neutrophils, lymphocytes, and
antibodies will aid the macrophages in the
killing of alveolar pathogens.

Systemic inflammatory response — The

production of cytokines and chemokines by
activated cells in the alveolar space will spill
into the systemic circulation and produce a
systemic inflammatory response. The systemic
response will aid the local response primarily
by activating production of WBCs by the bone
marrow, increasing cardiac output, and
elevating body temperature. The combination
of the local and systemic inflammatory
responses can be seen as a normal or
physiologic host response to prevent the
spread of infection and to control the local
alveolar infection. The host local and systemic
inflammatory responses explain the majority of
the patient's clinical features.

Dysregulated inflammatory response — In

some patients, the initial systemic
inflammatory response can become
dysregulated. This abnormal response will be
associated with tissue injury and organ
dysfunction. The progression from a
physiologic to a dysregulated systemic
inflammatory response indicates that
pneumonia is now complicated with sepsis
[22]. Patients with CAP and sepsis are at risk of
progression to organ failure.

Virulence factors — Some microorganisms

have developed specific mechanisms to
overcome pulmonary host defenses and
establish infection [19-21]. Examples include:

● Chlamydia pneumoniae produces a

ciliostatic factor.

● Mycoplasma pneumoniae can shear off

cilia.

● Influenza virus markedly reduces tracheal

mucus velocity within hours of onset of
infection and for up to 12 weeks
postinfection.

● S. pneumoniae and Neisseria meningitidis

produce proteases that can split secretory
immunoglobulin (Ig)A. In addition, the
pneumococcus produces other virulence
factors, including the capsule that inhibits
phagocytosis, pneumolysin, a thiol-
activated cytolysin that interacts with
cholesterol in host cell membranes,
neuraminidase, and hyaluronidase.

● Mycobacterium spp, Nocardia spp, and

Legionella spp are resistant to the
microbicidal activity of phagocytes.

Predisposing host conditions — In addition to

microbial virulence factors, diseases and
conditions in the host may lead to impairment
of pulmonary defense and increased risk of
CAP ( table 1). These include [23]:

● Older age (marked increase in pneumonia

incidence among adults >65 years old)

● Chronic lung diseases and/or other

disorders that impair airway clearance:

• Chronic obstructive pulmonary disease

(COPD)
• Cystic fibrosis
• Bronchiectasis
• Heart failure
• Bronchial obstruction due to stenosis,
tumor, or foreign body
• Lung cancer
• Previous episode of pneumonia
(presumably due to scarring)
• Immotile cilia syndrome and
Kartagener syndrome (ciliary
dysfunction, situs inversus, sinusitis,
bronchiectasis)

● Conditions that increase risk of

macroaspiration of stomach contents
and/or microaspiration of upper airway
secretions:

• Any alteration in level of consciousness

(eg, stroke, seizure, anesthesia, drug
or alcohol intoxication)
• Dysphagia due to esophageal lesions
and motility problems
• Wearing dentures while sleeping [24]

● Immunocompromising conditions, such

as:

• Diabetes mellitus [25]

• HIV infection (especially for
pneumococcal pneumonia) (see
"Bacterial pulmonary infections in
patients with HIV", section on
'Community-acquired pneumonia')
• Solid organ or hematopoietic stem cell
transplantation
• Immunosuppressive medication use
(eg, tumor necrosis factor-alpha
inhibitors, chemotherapy)

● Metabolic disorders:

• Malnutrition
• Uremia
• Acidosis

● Lifestyle factors and environmental

exposures:

• Smoking tobacco
• Alcohol consumption
• Opioid use [26]
• Toxic inhalations
• Overcrowding in jails and shelters
[27,28]
• Homelessness [29]

● Instrumentation of the respiratory tract

(eg, intubation or bronchoscopy) [30]

● Viral respiratory tract infection, especially

influenza; influenza can cause viral
pneumonia and predispose patients to
bacterial pneumonia (see "Seasonal
influenza in adults: Clinical manifestations
and diagnosis", section on 'Pneumonia')

Combinations of risk factors, such as smoking,

congestive heart failure, and COPD, are
additive in terms of risk, a concept known as
risk factor stacking [29,31].

Risk factors for CAP caused by specific

pathogens are discussed separately. (See
"Microbiology, epidemiology, and pathogenesis
of Legionella infection", section on 'Risk factors'
and "Pneumonia caused by Chlamydia
pneumoniae in adults", section on
'Epidemiology' and "Mycoplasma pneumoniae
infection in adults", section on 'Epidemiology'
and "Pneumococcal pneumonia in patients
requiring hospitalization", section on
'Epidemiology'.)

Drugs

● Acid-reducing agents – Several studies

have shown an increased risk of CAP
among patients taking gastric acid–
suppressive therapy, including proton
pump inhibitors and H2 blockers. This is
discussed in detail separately. (See
"Antiulcer medications: Mechanism of
action, pharmacology, and side effects",
section on 'Adverse effects' and "Proton
pump inhibitors: Overview of use and
adverse effects in the treatment of acid
related disorders", section on
'Pneumonia'.)

● Antipsychotic drugs – Several studies

have shown an association between use
of antipsychotic drugs and CAP, although
the mechanism remains unclear. In one
case-control study, use of antipsychotic
drugs was associated with an almost 60
percent increase in the risk of pneumonia
among older persons requiring
hospitalization [32]. In another case-
control study, current use of atypical
(odds ratio [OR] 2.61, 95% CI 1.48-4.61) or
typical (OR 1.76, 95% CI 1.22-2.53)
antipsychotic use was associated with a
dose-dependent increased risk for CAP
compared with past use [33]. Atypical
antipsychotic use was also associated
with an increase in the risk of fatal CAP
(OR 5.97, 95% CI 1.49-23.98).

● ACE inhibitors – In a meta-analysis of

randomized trials and observational
studies, ACE inhibitors were associated
with a reduced risk of pneumonia [34].
However, an accompanying editorial
noted that this effect was seen only in
observational studies (but not in
randomized trials), there was a high
likelihood of reporting bias, respiratory
infection was not a primary outcome of
most of the studies, and there was
substantial heterogeneity among the
studies [35].

● Glucocorticoids – Some studies, but not

others, have suggested an association
between inhaled glucocorticoids for
chronic obstructive pulmonary disease
and pneumonia. (See "Role of inhaled
glucocorticoid therapy in stable COPD",
section on 'Adverse effects' and "Major
side effects of inhaled glucocorticoids",
section on 'Lung infection'.)

● Sedatives – Sedatives increase the risk of

aspiration pneumonia by reducing
consciousness. (See "Aspiration
pneumonia in adults", section on
'Predisposing conditions'.)

MICROBIOLOGY

Typical versus atypical bacteria — Bacteria

have traditionally been divided into two
groups, "typical" and "atypical" agents.

● "Typical" organisms include S.

pneumoniae, Haemophilus influenzae,
Staphylococcus aureus, group A
streptococci, Moraxella catarrhalis,
anaerobes, and aerobic gram-negative
bacteria.

● "Atypical" pneumonia refers to

pneumonia caused by Legionella spp, M.
pneumoniae, C. pneumoniae, and
Chlamydia psittaci; although imprecise, we
use this term because of its acceptance
among clinicians.

In the individual patient, there are no findings

from history, physical examination, or routine
laboratory studies that allow the clinician to
distinguish pneumonia caused by atypical
versus typical organisms.

Common pathogens — There are more than

100 microbes (bacteria, viruses, fungi, and
parasites) that can cause community-acquired
pneumonia (CAP). Most cases of CAP in which
an organism is identified are caused by one of
only four or five microorganisms ( figure 1
and figure 2), but the distribution of
pathogens varies with the clinical setting [36]. A
microbiologic diagnosis was confirmed in 38 to
87 percent of cases of CAP in studies that used
specialized tests to detect various pathogens
[6,7,37-41] but in a lower percentage of cases
in studies that did not used specialized tests (
table 2) [42,43]. In clinical practice, an
etiologic agent is identified even less
frequently. As an example, in a review of 17,435
cases of CAP in the Medicare database for
United States emergency departments, an
etiologic diagnosis was reported in only 7.6
percent of cases [44].

The true prevalence of the various etiologic

agents in CAP is uncertain. Studies
investigating the etiology of CAP have been
performed in different regions, in various
patient populations and clinical settings, and
using a variety of microbiologic techniques.
Because direct culture of infected lung tissue
requires invasive techniques, studies primarily
use laboratory tests that provide indirect
evidence of etiology. These indirect methods
include sputum cultures (which may be
contaminated with oropharyngeal flora), blood
cultures, polymerase chain reaction, urinary
antigen tests, and serology. Studies that used
serologic testing may have overestimated the
incidence of CAP caused by specific pathogens,
such as M. pneumoniae and C. pneumoniae [37-
40,45], since positive serologic results may
represent recent infection rather than active
infection. In addition to the use of indirect
methods, interpretation of the results is
hampered by the failure to identify an
organism in a large proportion of cases and the
frequency of mixed infections. Pneumococcal
vaccination rates also vary across regions,
limiting the extent to which prevalence studies
can be pooled or generalized from one region
to another.

Despite these problems, studies have identified

some consistent trends and conclusions
regarding the etiology of CAP in adults, which
are listed below:

● S. pneumoniae has been the most

commonly detected bacterial species in
most studies. However, the detection of S.
pneumoniae from patients with CAP in the
United States has declined significantly,
likely due in part to the use of
pneumococcal vaccines in adults and the
universal use of pneumococcal conjugate
vaccines in children (leading to herd
immunity). (See 'S. pneumoniae' below.)

● The coronavirus disease 2019 (COVID-19)

pandemic has dramatically changed the
epidemiology of CAP. And overall, there is
increasing recognition that respiratory
viruses are common causes of CAP, either
as the sole pathogen or as a coinfecting
organism. Using molecular methods,
viruses are detected in approximately
one-third of cases of CAP in adults in
nonepidemic settings. (See 'Viruses'
below.)

● The "atypical" pathogens (M. pneumoniae,

Legionella spp, C. pneumoniae, C. psittaci)
are not often identified in clinical practice
 because there are no widely available
specific, rapid, or standardized tests for
their detection with the exception of
Legionella pneumophila. Of these, M.
pneumoniae is the most commonly
identified pathogen, especially in
pneumonia treated on an ambulatory
basis. Legionella spp are less common
causes of CAP but are important because
they can cause severe CAP and can result
in outbreaks of pneumonia. C.
pneumoniae was formerly thought to be
common based upon studies that used
serologic techniques (which do not
distinguish between current and past
infection), but more recent studies that
used molecular techniques identified C.
pneumoniae in <1 percent of cases of CAP.

Atypical bacteria, chiefly M. pneumoniae

and Legionella spp, have been detected in
approximately 3 to 15 percent of patients
with CAP requiring hospitalization using
techniques other than serology (eg,
molecular techniques, Legionella urinary
antigen, Mycoplasma culture) [6,7,46].
Other studies have detected atypical
bacteria in 20 to 30 percent of cases, but
these studies may have overestimated the
incidence because serologic techniques
were used [45,47,48]. In addition, some of
the cases may have occurred as part of
sporadic outbreaks. (See 'M. pneumoniae'
below and 'C. pneumoniae' below and
'Legionella' below.)

● Staphylococcus aureus,
Enterobacteriaceae, and Pseudomonas
aeruginosa are important pathogens in
selected groups of patients (eg,
postinfluenza, prior antimicrobial
treatment, or pulmonary comorbidities)
[49,50].

● The etiology of pneumonia in a region is

dynamic, as evidenced by the emergence
of avian influenza viruses, severe acute
respiratory syndrome coronaviruses, and
Middle East respiratory syndrome
coronavirus (MERS-CoV). (See 'Influenza
viruses' below and 'Middle East
respiratory syndrome coronavirus' below
and 'Other viruses' below.)

The frequency of other etiologic agents, such

as Mycobacterium tuberculosis, C. psittaci
(psittacosis), Coxiella burnetii (Q fever),
Francisella tularensis (tularemia), and endemic
fungi (histoplasmosis, coccidioidomycosis,
blastomycosis), varies with the epidemiologic
setting. (See 'Epidemiologic clues' below.)

Pathogen detection based on illness

severity — The most commonly identified
pathogens depend in part upon the severity of
illness as judged by the site of care (outpatient
versus inpatient versus intensive care unit
[ICU]) ( table 3) [6,7,37-39,42,45,48,51].

Outpatients — Among patients treated

in the outpatient setting, the most frequently
detected pathogens are S. pneumoniae, M.
pneumoniae, and respiratory viruses (eg,
influenza, parainfluenza, respiratory syncytial
virus [RSV]) ( table 3) [39,48]. Legionella
pneumoniae and H. influenzae are less common.

Inpatients — Among patients who

require hospitalization but not admission to an
ICU, the most frequently detected pathogens
are S. pneumoniae, respiratory viruses (eg,
influenza, parainfluenza, RSV, rhinovirus), and,
less often, H. influenzae, M. pneumoniae, and
Legionella spp ( table 3) [6,7,37-39,42,45,51].
Among patients who require admission to an
ICU, S. pneumoniae is the most commonly
detected pathogen, but Legionella, enteric
gram-negative bacilli, S. aureus, H. influenzae,
and respiratory viruses are also important.

In the Etiology of Pneumonia in the Community

(EPIC) study, a prospective multicenter
population-based active surveillance study
conducted by the United States Centers for
Disease Control and Prevention (CDC) between
2010 and 2012 that included 2259 adults
requiring hospitalization for CAP that used
specialized techniques, one or more viruses
were detected in 23 percent of cases, bacteria
in 11 percent, bacteria and viruses in 3 percent,
and fungi or mycobacteria in 1 percent; an
etiology was not identified in 62 percent of
cases [7]. The most commonly identified
organisms were rhinovirus (in 9 percent),
influenza virus (in 6 percent), and S.
pneumoniae (in 5 percent). The incidences of
influenza virus and S. pneumoniae were nearly
five times as high among individuals ≥65 years
of age than among younger adults, and the
incidence of rhinovirus was nearly 10 times as
high among individuals ≥65 years of age than
among younger adults. A caveat is that
polymerase chain reactions (PCRs) for
respiratory viruses was performed from
nasopharyngeal or oropharyngeal swabs;
positive results may have represented upper
respiratory tract infection in some cases. The
majority of patients were admitted to a hospital
ward; 21 percent required ICU admission.

A study of 323 adults with CAP admitted to two

tertiary hospitals in the United Kingdom used
both bacterial cultures and comprehensive
multiplex molecular testing for bacteria and
viruses on lower respiratory tract specimens
that were collected within 48 hours of
admission [6]. Using molecular methods, a
pathogen was identified in 87 percent of cases.
Culture-based methods detected a pathogen in
only 39 percent of cases. Of 127 culture-
positive specimens, 125 (98 percent) were also
positive for the same bacterial species by PCR.
H. influenzae and S. pneumoniae were the most
common agents detected, followed by a wide
variety of typical and atypical pathogens.
Viruses were present in 30 percent of cases; 82
percent of these were detected in specimens
that also tested positive for bacteria. All
patients included in this trial were able to
produce a mucopurulent sputum specimen,
which may have led to an overestimate of
diagnostic yield. An additional caveat is that
contamination of specimens with upper
respiratory tract secretions could cause false-
positive results [52]. However, even when a
cutoff of ≥100,000 colony forming units/mL
was applied to the bacterial species that
commonly colonize the oropharynx, 72 percent
of patients were considered to have a bacterial
cause of CAP, compared with 81 percent when
no cutoff was applied [6].

Epidemiologic clues — The presenting clinical

manifestations cannot reliably differentiate
between different etiologies, but there are a
few epidemiologic and/or clinical clues that can
be helpful and must be taken into account
when considering the etiology of CAP (
table 1):

● Know the local epidemiology and the

patient's travel history (eg, endemic fungi,
such as Histoplasma, Coccidioides,
Blastomyces, and Paracoccidioides spp;
hantavirus). (See 'Fungi' below.)

● Be aware of national and international

outbreaks (eg, influenza [including avian
influenza H5N1 and H7N9], SARS, or
MERS) in the geographic region that the
patient resides in and/or has visited. (See
'Influenza viruses' below and 'Middle East
respiratory syndrome coronavirus' below
and 'Other viruses' below.)

● Be aware of local outbreaks of Legionella

spp, M. pneumoniae, or C. pneumoniae
infections. (See 'Legionella' below and 'M.
pneumoniae' below and 'C. pneumoniae'
below.)

● Elicit history of specific exposures (eg,

Histoplasma spp and bat or bird
droppings, C. psittaci and birds). (See
'Histoplasma capsulatum' below.)

● Methicillin-resistant S. aureus (MRSA) is an

important cause of severe, occasionally
necrotizing CAP. Risk factors for CAP
caused by MRSA are discussed below. (See
'S. aureus' below.)

● MRSA and multidrug-resistant gram-

negative bacilli, such as P. aeruginosa and
extended-spectrum beta-lactamase–
producing gram-negative bacilli, should
be considered in patients who have
certain comorbidities, who have recently
received antibiotics, and/or who have had
exposure to health care settings. (See
'Gram-negative bacilli' below and 'S.
aureus' below and "Epidemiology,
pathogenesis, microbiology, and
diagnosis of hospital-acquired and
ventilator-associated pneumonia in
adults", section on 'MDR risk factors'.)

● Patients who are severely ill with influenza

pneumonia should be evaluated for
secondary bacterial pneumonia, which is
most likely to be caused by S. pneumoniae,
S. aureus (including MRSA), or group A
Streptococcus. (See "Seasonal influenza in
adults: Clinical manifestations and
diagnosis".)

● Never forget M. tuberculosis as a cause of

pneumonia, particularly in patients who
reside in or have visited endemic regions.

● Pneumocystis jirovecii (formerly P. carinii) is

often forgotten as a cause of CAP now
that antiretroviral therapy has resulted in
a decrease in the number of cases of
Pneumocystis pneumonia (PCP) in HIV-
infected patients. However, it continues to
cause pneumonia in patients with risk
factors.

● Consider potential agents of bioterrorism

that can cause respiratory symptoms.
These include B. anthracis (inhalation
anthrax), Yersinia pestis (pneumonic
plague), F. tularensis (tularemia), C. burnetii
(Q fever), Legionella spp, influenza virus,
hantavirus, and ricin ( table 4). (See
'CAP and bioterrorism agents' below.)

Bacteria — In many studies of patients with

CAP, bacteria have been the most commonly
detected organisms. The true incidence of
these infections is uncertain because of the
difficulty in distinguishing colonizing organisms
from pathogens.

S. pneumoniae — S. pneumoniae has

traditionally been the most common cause of
CAP. In the preantibiotic era, S. pneumoniae was
responsible for >75 percent of cases of
pneumonia [2,53,54]. However, more recent
studies have isolated the organism in only 5 to
15 percent of cases in the United States
[7,42,55-57] but in a higher proportion of cases
in some other countries [2,6,37]. Factors that
are likely to have contributed to the decline in
S. pneumoniae as a cause of CAP in the United
States include the use of pneumococcal
vaccines in adults, the universal use of
pneumococcal conjugate vaccines in children
(leading to herd immunity), and a reduction in
cigarette smoking [2,58].

It is important to note that the rate of isolation

of S. pneumoniae increases when more invasive
methods are used for obtaining specimens,
such as transtracheal aspiration, which
eliminates contaminating oropharyngeal flora;
this method was used in the past but is no
longer used. It is believed that many culture-
negative cases are caused by pneumococcus.
One factor arguing for the predominance of S.
pneumoniae as a cause of CAP is that in
patients with CAP who have positive blood
cultures, 58 to 81 percent of bloodstream
isolates are S. pneumoniae [59,60]; however,
only 7 to 10 percent of patients with CAP have
positive blood cultures [7,59,60]. One group
has estimated that, for every case of
bacteremic pneumococcal pneumonia, there
are at least three additional cases of non-
bacteremic pneumococcal pneumonia [61]. The
data supporting this conclusion are presented
in greater detail separately.

H. influenzae — Nontypeable H. influenzae is

an important cause of pneumonia in older
adults and in patients with underlying
pulmonary disease, such as cystic fibrosis and
chronic obstructive pulmonary disease (COPD).
The clinical features are indistinguishable from
CAP caused by other organisms. (See
"Epidemiology, clinical manifestations,
diagnosis, and treatment of Haemophilus
influenzae".)

M. pneumoniae — M. pneumoniae is the most

common cause of atypical pneumonia in series
from the United States and other parts of the
world, accounting for up to 15 percent of cases
of pneumonia treated in the ambulatory
setting based mostly on serologic methods
[48]. However, studies that use serologic
techniques may overestimate the incidence.
(See 'Common pathogens' above.)

M. pneumoniae is transmitted from person to

person by infected respiratory droplets during
close contact. Infection rates are highest in
school-aged children, military recruits, and
college students. Substantial rates of macrolide
resistance have been observed in certain
regions, such as Asia [62]. (See "Mycoplasma
pneumoniae infection in adults".)

C. pneumoniae — The incidence of C.

pneumoniae in adults with CAP has varied in
different studies from 0 to 20 percent [37-
39,45], although the validity of these data is in
question due to problems with diagnostic
testing [63,64]. One problem is the use of a
serologic test in many studies, which lacks both
sensitivity and specificity for C. pneumoniae. In
addition, positive serologic results may
represent either current or past infection. More
recent studies that used molecular techniques
identified C. pneumoniae in <1 percent of cases
of CAP [6,7]. (See "Clinical evaluation and
diagnostic testing for community-acquired
pneumonia in adults", section on 'Multiplex
molecular assays' and "Pneumonia caused by
Chlamydia pneumoniae in adults", section on
'Diagnosis'.)

Transmission of the organism is thought to be

person to person and has been implicated in
outbreaks of pneumonia in residents of long-
term care facilities and military recruits [65-68].
Unlike other respiratory infections, which have
peak rates in the winter months, C. pneumoniae
infection does not vary significantly by season.
Pneumonia and bronchitis are the most
common respiratory infections associated with
C. pneumoniae. (See "Pneumonia caused by
Chlamydia pneumoniae in adults".)

Legionella — Legionella accounts for 1 to 10

percent of cases of CAP. Legionella can occur as
a sporadic infection or cause outbreaks. Travel-
associated legionellosis is becoming more
common. In most instances, Legionella is
transmitted to humans by inhalation of
aerosols containing the bacteria. Outbreaks
have been associated with exposure to a
variety of aerosol-producing devices, including
showers, a grocery store mist machine, cooling
towers of air conditioning systems, whirlpool
spas, and fountains (see "Microbiology,
epidemiology, and pathogenesis of Legionella
infection"). Sporadic legionellosis constitutes
the majority of Legionella cases and the source
for these cases is often unknown. In
Connecticut, investigators found an association
between residence of cases in proximity to
rivers and watersheds [69].

Gram-negative bacilli — Gram-negative

bacilli, especially Klebsiella pneumoniae,
Escherichia coli, Enterobacter spp, Serratia spp,
Proteus spp, P. aeruginosa, and Acinetobacter
spp, are uncommon causes of CAP except in
patients with severe pneumonia requiring
admission to an ICU where, as a group, they
are among the most commonly isolated
organisms after S. pneumoniae and in patients
with significant underlying disease ( table 3)
[70,71]. (See "Treatment of community-
acquired pneumonia in adults who require
hospitalization", section on 'Likely pathogens'.)

● Klebsiella pneumoniae – K. pneumoniae is

responsible for approximately 6 percent
of cases of CAP in Asia [45] but is less
common in other regions ( table 2). K.
pneumoniae must be considered as a
cause of severe CAP in patients who have
significant underlying disease, such as
COPD, diabetes, and alcohol abuse. In a
study of 112 immunocompetent patients
with severe CAP, multivariate analysis
found K. pneumoniae was an independent
risk factor for mortality [71]. (See "Clinical
features, diagnosis, and treatment of
Klebsiella pneumoniae infection", section
on 'Community-acquired pneumonia'.)

● Pseudomonas aeruginosa – Risk factors for

community-acquired P. aeruginosa
pneumonia include bronchiectasis (eg,
due to cystic fibrosis) and the use of
repeated antibiotic courses or prolonged
glucocorticoids in patients with other
structural lung abnormalities, such as
COPD and pulmonary fibrosis [49,50,72].
Immunocompromise (eg, neutropenia,
HIV infection, solid organ or
hematopoietic stem cell transplantation)
and previous hospitalization are other risk
factors for Pseudomonas pneumonia. (See
"Pseudomonas aeruginosa pneumonia".)

● Acinetobacter spp – Acinetobacter spp are

well recognized as pathogens causing
nosocomial pneumonia. In addition,
Acinetobacter baumannii is emerging as a
cause of severe CAP with high mortality.
Multidrug resistance is an increasing
problem with Acinetobacter infection. (See
"Acinetobacter infection: Treatment and
prevention" and "Acinetobacter infection:
Treatment and prevention", section on
'Pneumonia'.)

● Moraxella catarrhalis – Moraxella is a gram-

negative diplococcus that can cause lower
respiratory tract infections in adults with
COPD and in immunocompromised
persons. In a review of 58 patients with M.
catarrhalis bacteremia, 70 percent had
predisposing factors, such as
neutropenia, malignancy, or COPD, either
alone or in combination [73]. Many
patients with this infection are
malnourished. Not infrequently, it is a
copathogen [74].

S. aureus — In an international multicenter

study of inpatients with CAP, MRSA was
detected in 95 of 3193 patients (3 percent) who
underwent microbiologic testing within 24
hours of admission, with varying prevalence in
different continents and countries [75]. Among
all S. aureus isolates, 51 percent were MRSA and
49 percent were methicillin-susceptible S.
aureus (MSSA). In a study in the United States
of 2259 inpatients with CAP, S. aureus was
isolated from 37 patients (1.7 percent),
including 15 (0.7 percent) with MRSA and 22 (1
percent) with MSSA [76].

S. aureus pneumonia that is community

acquired is usually seen in older adults and in
younger patients who are recovering from
influenza (post-influenza pneumonia) [77-81].
However, the pneumococcus remains the most
frequent pathogen in this setting. (See
"Seasonal influenza in adults: Clinical
manifestations and diagnosis", section on
'Pneumonia'.)

During the 2003 to 2004 influenza season, 17

cases of S. aureus CAP were reported to the
CDC from nine states; 15 cases were
community-associated methicillin-resistant S.
aureus (CA-MRSA) [78]. All isolates had
community-associated genetic characteristics;
12 of 13 available S. aureus isolates had the
Panton-Valentine leukocidin (PVL) gene.
Influenza virus infection was also documented
in 12 (71 percent) of cases. All patients were
hospitalized and death occurred in five (29
percent); four of the deaths were in patients
with MRSA infection. Another outbreak of 10
cases of severe CA-MRSA pneumonia occurred
in association with influenza during the 2006 to
2007 influenza season [79]. Six of the patients
died.

In a study of 627 patients who presented to

emergency departments in 12 cities in the
United States between the winter of 2006 and
the spring of 2007 and who were hospitalized
with CAP, S. aureus was cultured from the blood
and/or respiratory tract in 24 patients (4
percent); of these S. aureus infections, 9 (2
percent) were caused by methicillin-susceptible
S. aureus and 14 (2.4 percent) were caused by
methicillin-resistant S. aureus [43]. Isolation of
MRSA (as compared with any other or no
pathogen) was associated with a patient history
of MRSA, nursing home admission in the
previous year, close contact with someone with
a skin infection during the previous month,
multiple infiltrates or cavities on chest
radiograph, and comatose state, intubation,
receipt of pressor agents, or death in the
emergency department.

CA-MRSA is often associated with severe

necrotizing pneumonia [77-79,82-86]. Several
studies suggested that the tendency to
necrotizing pneumonia may be mediated by
PVL, which is typically present in CA-MRSA
strains [77-79,83-85,87-89]. However,
subsequent reports have disproven the role of
PVL as a virulence factor in MRSA pneumonia
[90-94].

Other bacteria

● Group A Streptococcus – Group A

Streptococcus (GAS; S. pyogenes) can cause
a fulminant pneumonia with early
empyema formation even in young,
immunocompetent hosts. In a
prospective surveillance study for invasive
GAS infection, pneumonia accounted for
11 percent of cases with a mortality rate
of 38 percent compared with 26 percent
for necrotizing fasciitis and 12 percent for
the entire cohort of invasive disease [95].

The largest outbreak of GAS pneumonia

in the United States occurred in 2002
among military recruits at the recruiting
depot in San Diego [96,97]. Twenty-seven
percent of 127 cases of pneumonia were
definitely or probably due to GAS, and
another 17 percent were coinfected with
GAS and another pathogen [96,97]. The
epidemic occurred despite prophylaxis
against GAS but was ended after the
administration of additional prophylaxis
[97].

● Anaerobes – Anaerobic organisms cause

the pneumonia that sometimes develops
following aspiration and are also involved
in necrotizing polymicrobial infections
that result in lung abscess. Anaerobic
pathogens in pulmonary infections should
be suspected when there is putrid sputum
or putrid empyema fluid (diagnostic of
anaerobes), infection associated with
aspiration, which usually results in an
infiltrate in a dependent pulmonary
segment (superior segment of a lower
lobe or posterior segment of an upper
lobe), or infection-associated necrosis
(abscess or necrotizing pneumonia). Most
infections are polymicrobial with
predominance of anaerobes (eg,
Bacteroides melaninogenicus,
Fusobacterium spp, Peptostreptococcus
spp) and/or oral streptococci (eg,
Streptococcus milleri). Given the difficulty
with obtaining appropriate pretreatment
specimens and the tedious microbiology
required, most cases are treated
empirically. (See "Aspiration pneumonia in
adults" and "Lung abscess in adults".)

● Neisseria meningitidis – N. meningitidis is

an uncommon cause of CAP.
Meningococcal pneumonia has no
distinguishing clinical features compared
to other causes of CAP. However,
pneumonia due to N. meningitidis should
be reported to the health department and
prophylaxis given as for meningitis or
septicemia. (See "Clinical manifestations
of meningococcal infection".)
 ● Mycobacterium tuberculosis – M.
tuberculosis is an important cause of CAP
in developing countries and in some
regions of the United States [98,99].
Missed diagnosis is common, as
illustrated in report from Baltimore in
which 16 of 33 patients (48 percent) with
culture-confirmed pulmonary tuberculosis
(TB) were initially treated for presumed
CAP [99]. (See "Clinical manifestations and
complications of pulmonary
tuberculosis".)

● Burkholderia pseudomallei – B.
pseudomallei is an important cause of CAP
in endemic regions (South and Southeast
Asia, China, and Northern Australia).
Occurrence outside of these regions is
rare and usually linked to travel. (See
"Melioidosis: Epidemiology, clinical
manifestations, and diagnosis".)

Other bacteria that can cause CAP include F.

tularensis (tularemia), C. burnetii (Q fever), and
Bacillus anthracis (anthrax). These
microorganisms are described below. (See 'CAP
and bioterrorism agents' below.)

Viruses — The frequency of specific viral

pathogens varies with the diagnostic studies
used for detection [100]. The use of the PCR
has increased the diagnostic yield compared
with conventional tests, such as viral culture
and antigen detection assays [101-103]. As an
example, in a randomized trial that included
107 inpatients with CAP, real-time PCR
increased the diagnostic yield compared with
conventional diagnostic procedures (43
compared with 21 percent) with 26 viral
etiologies identified by PCR compared with only
16 by conventional methods [101]. In other
studies that used PCR with or without other
methods, viruses were detected in up to one-
third of cases of CAP in adults
[6,7,37,51,102,104]. Since respiratory virus can
be present in the upper airways without
causing illness, studies using multiplex PCR
may overestimate the frequency of viruses as a
cause of CAP. Using PCR, nasopharyngeal
swabs are positive for respiratory tract viruses
in 20 to 30 percent of healthy adults [105].

Influenza remains the clinically most significant

viral cause of CAP in adults; other common viral
pathogens include RSV, parainfluenza viruses,
and adenovirus ( figure 1 and figure 2)
[102]. Other viruses that have been detected in
patients with CAP include rhinoviruses,
coronaviruses, and human metapneumovirus
(hMPV) [102]. However, in a study that used
multiplex PCR, in 30 of 32 patients in whom
rhinovirus or a coronavirus was implicated,
another organism was also identified [106]. A
possible reason for this is that rhinovirus and
coronavirus were not causing the pneumonia
but impairing upper airway defenses so that
pathogens can establish themselves in the
lower respiratory tract. In another study,
bacterial coinfection was associated with
approximately 40 percent of viral respiratory
tract infections requiring hospitalization [107].
In a separate study, the rate of mixed viral-
bacterial infection was approximately 20
percent; such mixed infections have been
found to be associated with more severe CAP
and longer hospitalization than CAP caused by
bacteria alone [108].

Although viruses are commonly found in the

nasopharynx of adults with CAP, it is often
unclear whether these viruses are the sole
agents causing CAP. In addition to possibly
predisposing patients to infections with other
organisms, the presence of a respiratory virus
may also represent prolonged shedding
(especially in immunocompromised hosts),
upper respiratory tract infection, or
colonization.

However, some studies have suggested that

viruses like rhinovirus are likely to play a
pathogenic role in CAP in adults. As an
example, one study evaluated whether viruses
are detected in the nasopharynx by PCR more
commonly in patients with pneumonia than in
asymptomatic individuals sampled at the same
time and in the same geographic area [109].
Viruses were detected rarely in asymptomatic
adults but frequently in adults with CAP (2.1
versus 24.5 percent). Viruses were detected
more often in both asymptomatic children (24.4
percent) and children with CAP (68.8 percent)
compared with adults. Detection of influenza,
RSV, and hMPV were rare in asymptomatic
adults and children. Associations of rhinovirus
and adenovirus with CAP varied with age.
Asymptomatic rhinovirus detection declined
with increasing age. This led to a strong
association of rhinovirus with CAP in adults, a
more modest association in older children, and
no association in younger children. In children,
RSV and hMPV were highly associated with CAP.
Adenovirus in the nasopharynx was only
associated with CAP in children <2 years of age
but not in older children.

In a study of 259 patients with a pneumonia

syndrome, 44 viruses were detected in 42
patients: 26 (16.2 percent) had rhinovirus, 7
had coronavirus, 4 had parainfluenza virus, 3
had RSV, 1 had hMPV, and 1 had influenza [55].
A virus was the only pathogen detected in 30; 3
of 30 patients had clinical characteristics
suggestive of bacterial pneumonia. The
procalcitonin level was 0.81, significantly lower
than in patients with bacterial infection. In 28
of 42 patients (66.6 percent), there was
reasonable evidence that the viral pathogen
detected in the nasopharynx did indeed cause
the pneumonia.

Influenza viruses — Influenza A or B viruses

cause an acute respiratory illness that occurs in
outbreaks and epidemics worldwide, mainly in
the winter season. Avian influenza viruses (eg,
H5N1 and H7N9 avian influenza) have emerged
to cause disease in humans. (See "Influenza:
Epidemiology and pathogenesis" and "Avian
influenza: Epidemiology and transmission".)

Influenza viruses can cause pneumonia,

although they are far more likely to cause
upper respiratory tract infection and to
predispose to secondary pulmonary infection
by bacteria. (See "Seasonal influenza in adults:
Clinical manifestations and diagnosis", section
on 'Pneumonia'.)

Primary influenza pneumonia occurs when

influenza virus infection directly involves the
lung, typically producing a severe pneumonia.
Influenza pneumonia occurs most frequently in
certain groups of patients with underlying
chronic illnesses who are classified as "high
risk" for this infection ( table 5).

Patients who are severely ill with influenza

should be evaluated for a secondary bacterial
pneumonia, which is most likely to be caused
by S. pneumoniae, S. aureus (including MRSA), or
group A streptococci. (See "Seasonal influenza
in adults: Clinical manifestations and
diagnosis".)

The first association of avian influenza H5N1

with clinical respiratory disease occurred in
Hong Kong in 1997 when 18 human cases
occurred during a poultry outbreak of highly
pathogenic H5N1 influenza in live bird markets.
The clinical features of avian influenza are
variable, being determined in part by the
strain. In the 1997 outbreak, 58 percent of
patients had pneumonia. (See "Avian influenza:
Epidemiology and transmission".)

Another avian influenza virus, H7N9, emerged

in China in 2013 and has caused severe
pneumonia in some patients. (See "Avian
influenza: Epidemiology and transmission",
section on 'Avian influenza H7N9'.)

Severe acute respiratory syndrome

coronavirus 2 (SARS-CoV-2) — COVID-19, the
disease caused by SARS-CoV-2, is discussed
separately. (See "COVID-19: Epidemiology,
virology, and prevention".)

Parainfluenza viruses — Parainfluenza

viruses are important respiratory pathogens in
immunocompromised adults, causing
potentially life-threatening lower respiratory
tract infections. (See "Parainfluenza viruses in
adults".)

Respiratory syncytial virus — RSV causes

acute respiratory tract illness in persons of all
ages. Traditionally a viral pathogen of children,
RSV can also cause CAP in adults and can be
particularly severe in older adults and
immunocompromised individuals (eg,
hematopoietic cell transplant recipients). (See
"Respiratory syncytial virus infection: Clinical
features and diagnosis".)

Adenovirus — Adenovirus pneumonia was

first described among military recruits in whom
it causes an "atypical pneumonia." The usual
symptoms are fever, malaise, and cough (often
with substernal discomfort). Increased
peribronchial markings with patchy alveolar
infiltrates are found on chest radiography.
Pneumonia occasionally results in fatalities.
(See "Pathogenesis, epidemiology, and clinical
manifestations of adenovirus infection".)

Human metapneumovirus — HMPV was first

described in 2001 in the Netherlands. HMPV
can cause upper and lower respiratory tract
infection in patients of all age groups, but
symptomatic disease most often occurs in
young children or older adults. It is an
emerging pathogen as a cause of CAP in adults.
(See "Human metapneumovirus infections".)

Middle East respiratory syndrome

coronavirus — A novel coronavirus, Middle
East respiratory syndrome coronavirus, causing
severe respiratory illness, emerged in 2012 in
Saudi Arabia. Additional cases and clusters of
MERS-CoV infections have been detected
subsequently in Saudi Arabia, other Arabian
Peninsula countries, and other countries. MERS
should be considered in patients who have
traveled to the Arabian Peninsula within 14
days of presentation. (See "Middle East
respiratory syndrome coronavirus: Virology,
pathogenesis, and epidemiology" and "Middle
East respiratory syndrome coronavirus: Clinical
manifestations and diagnosis", section on
'Diagnosis'.)

Although most clusters of MERS have been

characterized by limited human-to-human
transmission, an outbreak of MERS in South
Korea in 2015 was associated with
superspreading events. Superspreading events
are outbreaks in which specific individuals are
responsible for a disproportionately large
number of transmission events [110]. (See
"Middle East respiratory syndrome coronavirus:
Virology, pathogenesis, and epidemiology",
section on 'Human-to-human transmission'.)

Rhinovirus — Rhinoviruses are among the

most common pathogens that affect humans
and are implicated in 30 to 50 percent of acute
respiratory tract infections [111]. The advent of
multiplex PCR for the etiologic diagnosis of CAP
has led to the current prominence of
rhinoviruses in the CAP field. As an example, a
2005 study showed that inclusion of PCR on
nasopharyngeal and oropharyngeal swabs of
patients with CAP improved the diagnostic yield
by 16 percent [106]. The most common virus
detected was rhinovirus, in 18 of 105 patients
(17 percent).

The evidence is accumulating that rhinovirus is

likely to play a role in CAP in adults.
Nevertheless, some experts have questioned
the role of rhinoviruses in the pathogenesis of
pneumonia [111,112], arguing that the
frequency of rhinovirus infections in the
population makes assessment of causal role in
pneumonia difficult [111].

In the EPIC study, a prospective multicenter

population-based active surveillance study of
2259 adults requiring hospitalization for CAP,
rhinovirus was the most commonly identified
organism (in 9 percent) [7]. The incidence of
rhinovirus was nearly 10 times as high among
CAP patients ≥65 years of age than among
younger CAP patients. A caveat is that PCR for
rhinovirus was performed from
nasopharyngeal or oropharyngeal swabs;
positive results may have represented upper
respiratory tract infection in some cases.
Nevertheless, a related study suggested that
rhinovirus is strongly associated with CAP in
adults (but not in children) [109]. Rhinovirus
was detected in 21 of 192 adults with CAP (10.9
percent) but in only 2 of 238 asymptomatic
adults (0.8 percent). (See 'Viruses' above.)

In a single-center study in Finland conducted

from June 2008 to May 2012, three
nasopharyngeal swabs and bronchoalveolar
lavage fluid were obtained from adults with
CAP who were started on mechanical
ventilation during the first 48 hours following
ICU admission [103]. Of the 49 patients
studied, a bacterium was detected in 43
percent and a virus in 49 percent; in 10 percent
of patients, a virus was the only pathogen
detected. Rhinoviruses were found in 31
percent of patients.

Other viruses

● Severe acute respiratory syndrome – In

November 2002, an outbreak of SARS
started in Guangdong Province in
southern China and spread worldwide,
affecting more than 8000 persons. SARS
was due to a novel coronavirus that
jumped the species barrier from civet cats
to man. The case-fatality rate of the 2003
Hong Kong outbreak was 11 percent, but
higher mortality was seen in older adults
(≥60 years of age) and pregnant women.
Superspreading events, which are
outbreaks in which specific individuals are
responsible for a disproportionately large
number of transmission events, likely
contributed to the SARS outbreak [110].
(See "Severe acute respiratory syndrome
(SARS)" and "Severe acute respiratory
syndrome (SARS)", section on
'Transmission'.)

● Other coronaviruses – Human

coronaviruses were first described in
association with respiratory infections in
1935 but were ignored until the advent of
SARS. HCoV-229E and HCoV-OC43 caused
upper and lower respiratory tract
infections prior to the SARS outbreaks.
Since that time, human coronaviruses
HCoV-NL63 and CoV-HKU1 have been
identified as additional etiologic agents in
CAP.

HCoV-NL63 was recovered from 19 of 525

(3.6 percent) of respiratory specimens
collected from laboratories across Canada
in 2001 and 2002 [113], primarily causing
infections of the upper respiratory tract.
In contrast, CoV-HKU1 accounted for 2.4
percent (10 of 418) of CAP cases in Hong
Kong [114]. (See "Coronaviruses".)

● Hantavirus – In May 1993, an outbreak of

severe respiratory illness caused by a
previously unknown virus, hantavirus,
occurred in the southwestern United
States. The illness was preceded by
prodromal flu-like symptoms, followed by
noncardiogenic pulmonary edema. The
virus accounting for the initial cases, Sin
Nombre virus, is spread to humans from
infected mice. Subsequently, other
hantaviruses have been found to cause
hantavirus pulmonary syndrome, and the
disease has been described in other parts
of the United States, western Canada, and
South America. It is important to
recognize that hantavirus does not cause
pneumonia but instead causes an acute
respiratory distress syndrome (ARDS)-like
picture due to the host response to this
virus. (See "Epidemiology and diagnosis of
hantavirus infections" and "Hantavirus
cardiopulmonary syndrome".)

● Varicella – Varicella pneumonia is the

most frequent complication of varicella
infection in normal healthy adults, with a
reported incidence of about 1 in 400
cases. The case-fatality rate is between 10
and 30 percent. (See "Clinical features of
varicella-zoster virus infection:
Chickenpox".)

Fungi — Fungal infection is an unusual cause

of CAP in immunocompetent patients, but
certain fungi (eg, Histoplasma capsulatum,
Coccidioides spp, Blastomyces dermatitidis) can
cause pneumonia in immunocompetent or
immunocompromised patients who reside in or
have visited endemic areas. The specific
epidemiology of some fungal infections is
therefore important as a diagnostic clue.
Fungal infection is more common in
immunocompromised patients, particularly
those with neutropenia, those receiving chronic
immunosuppressive therapy (eg, organ
transplant recipients), and those infected with
HIV.

A retrospective study examined the

microbiologic etiology of 94 cases of
community-acquired pulmonary fungal
infection hospitalized in Taiwan [115]. The
criteria for diagnosis were a lung lesion on
chest radiographs and either the presence or
isolation of fungi from a tissue biopsy, pleural
effusion, or blood. The most frequently isolated
fungi were Aspergillus species (56 percent),
followed by Cryptococcus species (31 percent),
and Candida species (4 percent).

Cryptococcus spp — Cryptococcus organisms

are found in the soil throughout the world, and
a significant percent of the population has
most likely been exposed to these organisms.
Primary infections occur in both
immunocompetent and immunocompromised
persons. In immunocompetent individuals,
primary infections are most commonly
asymptomatic and usually discovered as an
incidental finding on chest radiograph. In
contrast, cryptococcal pneumonia in
immunocompromised patients is usually
symptomatic with the most common signs and
symptoms being cough, fever, and dyspnea.
(See "Microbiology and epidemiology of
Cryptococcus neoformans infection" and
"Cryptococcus neoformans infection outside
the central nervous system".)

Histoplasma capsulatum — H. capsulatum is

found worldwide; within the United States,
infection is most common in the Midwestern
states located in the Ohio and Mississippi River
Valleys. H. capsulatum proliferates best in soil
contaminated with bird or bat droppings. Less
than 5 percent of exposed individuals develop
symptomatic disease after a low-level
exposure. However, the majority of patients
develop symptomatic infection following more
extensive exposure, as occurs with activities
that disturb heavily contaminated soil or areas
with large amounts of bird or bat droppings.

Symptomatic patients with acute

histoplasmosis generally present with a flu-like
illness with pulmonary complaints and
radiographic abnormalities, including
bronchopneumonia or signs of interstitial
pneumonitis. (See "Pathogenesis and clinical
features of pulmonary histoplasmosis".)

Coccidioides spp — Coccidioidomycosis is the

infection caused by the dimorphic fungi of the
genus Coccidioides (C. immitis and C. posadasii).
These fungi are endemic to certain deserts of
the Western Hemisphere, including southern
Arizona, central California, southwestern New
Mexico, and west Texas in the United States.
They are also found in parts of Mexico and
Central and South America. (See "Primary
pulmonary coccidioidal infection", section on
'Epidemiology' and "Primary pulmonary
coccidioidal infection", section on
'Microbiology'.)

A prospective observational study of 55 adults

with CAP in Arizona found serologic evidence
for coccidioidomycosis (valley fever) as the
etiologic agent in 16 patients (29 percent) [116].
This study suggests that valley fever is a
common cause of CAP after exposure in a
disease-endemic region and that patients
exposed in these regions that develop CAP
should undergo laboratory evaluation for this
organism.

The most common presenting symptoms of

primary coccidioidal infection are chest pain,
cough, and fever. Although initial infections
usually have a respiratory component, chest
radiographs are unremarkable in up to one-
half of all patients. Common radiographic
abnormalities include unilateral infiltrate and
ipsilateral hilar adenopathy. (See "Primary
pulmonary coccidioidal infection".)

Other fungi — Other fungi that can cause

CAP include Aspergillus spp and Pneumocystis
jirovecii (formerly P. carinii). Infection with these
fungi occurs primarily in the setting of
immunosuppression. Pulmonary aspergillosis
is particularly associated with severe
neutropenia, while P. jirovecii is particularly
associated with HIV infection and other defects
in cell-mediated immunity. (See "Epidemiology
and clinical manifestations of invasive
aspergillosis" and "Epidemiology, clinical
presentation, and diagnosis of Pneumocystis
pulmonary infection in patients with HIV" and
"Epidemiology, clinical manifestations, and
diagnosis of Pneumocystis pneumonia in
patients without HIV".)

B. dermatitidis can cause pneumonia in both

immunocompetent and immunocompromised
hosts. (See "Clinical manifestations and
diagnosis of blastomycosis", section on
'Pulmonary involvement' and "Mycology,
pathogenesis, and epidemiology of
blastomycosis", section on 'Epidemiology'.)

Mixed infections — The role of more than one

causative microorganism in CAP is difficult to
establish. A prospective study of 1511
consecutive hospitalized patients examined the
incidence of mixed respiratory pathogens in
patients with CAP [117]. Microbiologic
evaluation included sputum and blood cultures
(and pleural fluid, transbronchial aspirates,
protected specimen brush, and bronchial
alveolar lavage when available), paired
serologies (for influenza, parainfluenza,
respiratory syncytial, and adenoviruses and C.
pneumoniae, M. pneumoniae, L. pneumophila,
and C. burnetii), and urine antigen (for S.
pneumoniae and L. pneumophila). Of 610
patients in whom an etiology was identified, 82
(13 percent) had more than one
microorganism. S. pneumoniae was identified in
44 of 82 mixed infections (54 percent).

The clinical importance of mixed infections on

outcome is difficult to assess, although there is
a suggestion that patients with mixed
infections have a more severe illness as
illustrated in a prospective study of 493
patients with CAP in whom an extensive
microbiologic workup was performed [118].
Compared with patients with monomicrobial
pneumonia, patients with mixed pneumonia
were more likely to have complications of the
pneumonia (39.3 versus 18.6 percent);
however, they were also more likely to have an
underlying comorbid illness (64 versus 45
percent).

CAP and bioterrorism agents — Several

biological agents may be used for bioterrorism
and can cause a CAP syndrome. In the event of
a possible bioterrorist event, local emergency
response systems should be activated by
dialing 911 in the United States or equivalent
emergency telephone numbers in other
countries. Local and state public health
authorities should also be notified immediately.
In addition, in the United States, the local
Federal Bureau of Investigation office should
be contacted promptly. (See "Identifying and
managing casualties of biological terrorism",
section on 'Public health notification'.)

Bioterrorism agents that can cause CAP include

B. anthracis (inhalation anthrax), Yersinia pestis
(pneumonic plague), F. tularensis (tularemia), C.
burnetii (Q fever), Legionella spp, influenza
virus, and hantavirus ( table 4) [119]:

● Bacillus anthracis (anthrax) – On October

2, 2001, a 63-year-old male from Florida
 became the first case of inhalation
anthrax in the United States since 1968
and was the first due to an act of
biological terrorism. Anthrax was
deliberately spread through the postal
system by sending letters with a powder
containing B. anthracis, a gram-positive
bacillus that forms spores. Two of the 22
persons infected in the postal attack
developed inhalational anthrax. (See
"Microbiology, pathogenesis, and
epidemiology of anthrax".)

Inhalation anthrax is the deadliest form of

the disease. The incubation period
following exposure is one to six days. The
classic chest radiograph findings are
mediastinal widening with pleural
effusions. A World Health Organization
expert committee estimated that if 50 kg
of anthrax was released over an urban
population of five million, there would be
250,000 casualties, 100,000 of whom
would be expected to die without
treatment [120]. (See "Clinical
manifestations and diagnosis of
anthrax".)

● Yersinia pestis (plague) – Biological

weapons programs in the United States
and the Soviet Union following World War
II developed techniques for aerosolizing Y.
pestis, the agent of plague. The
hypothetical intentional release of
aerosolized plague would cause
widespread illness; the case-fatality rate
for primary pneumonic plague is close to
100 percent if treatment is not initiated
within 24 hours.

The time to onset of symptoms following

exposure is two to three days. The most
common chest radiograph findings are
bilateral infiltrates, often with pleural
effusions. (See "Clinical manifestations,
diagnosis, and treatment of plague
(Yersinia pestis infection)".)

● Francisella tularensis (tularemia) –

Tularemia is caused by the gram-negative
bacilli, F. tularensis. During the 1950s and
1960s, both the United States and the
Soviet Union biological weapons program
developed aerosolized F. tularensis. It has
been estimated that dispersal of 50 kg of
virulent F. tularensis over a metropolitan
area with five million people would result
in 250,000 incapacitating casualties,
including 19,000 deaths [121].

Tularemia has a longer incubation period

than either inhalation anthrax or plague.
The classic chest radiographic findings are
bilateral infiltrates with hilar adenopathy.
(See "Tularemia: Clinical manifestations,
diagnosis, treatment, and prevention".)

● C. burnetii (Q fever) – C. burnetii is the

etiologic agent of Q fever and is a CDC
category B biological agent. As a
biological warfare agent, C. burnetii can be
easily dispersed as an aerosol with a high
infectivity rate and pneumonia as the
major manifestation. Further information
regarding Q fever can be found on the
United States Centers for Disease
Control and Prevention website [122,123].

Ricin is a toxin naturally found in castor beans

that could be used as an agent of bioterrorism.
Although ricin does not cause CAP, inhalational
ricin may cause respiratory distress, fever,
cough, and pulmonary edema. (See
"Identifying and managing casualties of
biological terrorism", section on 'Toxins of
concern'.)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education

materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five
key questions a patient might have about a
given condition. These articles are best for
patients who want a general overview and who
prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer,
more sophisticated, and more detailed. These
articles are written at the 10th to 12th grade
reading level and are best for patients who
want in-depth information and are comfortable
with some medical jargon.

Here are the patient education articles that are

relevant to this topic. We encourage you to
print or e-mail these topics to your patients.
(You can also locate patient education articles
on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education:

Community-acquired pneumonia in adults
(The Basics)")

● Beyond the Basics topic (see "Patient

education: Pneumonia in adults (Beyond
the Basics)")

SUMMARY

● Community-acquired pneumonia (CAP) is

a common and potentially serious illness.
It is associated with considerable
morbidity and mortality, particularly in
older adult patients and those with
significant comorbidities. (See
'Introduction' above.)

● The overall incidence of CAP in adults is

estimated at approximately 16 to 23 cases
per 1000 persons per year; the rate rises
with age. There is seasonal variation, with
more cases occurring during the winter
months. The rates of pneumonia are
higher for men than for women and for
Black persons compared with White
persons. (See 'Epidemiology' above.)

● The lungs are constantly exposed to

particulate material and microbes that are
present in the upper airways and, by
microaspiration, enter the lower
respiratory tract. Contrary to
longstanding belief, the lower respiratory
tract is not sterile. Healthy lower airways
contain some bacterial species that are
also found in the upper respiratory tract,
such as Prevotella spp, Veillonella spp, and
Streptococcus spp. The development of
CAP indicates either a defect in host
defenses, exposure to a particularly
virulent microorganism, or an
overwhelming inoculum. (See
'Pathogenesis' above.)

● In addition to microbial virulence factors,

diseases and conditions in the host may
lead to impairment of pulmonary defense
and increased risk of CAP ( table 1). (See
'Predisposing host conditions' above.)

● The presenting clinical manifestations

cannot reliably differentiate between
different etiologies, but there are a few
epidemiologic and/or clinical clues that
can be helpful and must be taken into
account when considering the etiology of
CAP ( table 1). (See 'Epidemiologic clues'
above.)

● There are more than 100 microbes

(bacteria, viruses, fungi, and parasites)
that can cause CAP. Most cases of
pneumonia are caused by one of only four
or five microorganisms ( figure 1 and
figure 2). The most commonly
identified pathogens depend in part upon
the severity of illness as judged by the site
of care (outpatient versus inpatient versus
intensive care unit) ( table 3). (See
'Microbiology' above.)

● In many studies of patients with CAP,

bacteria have been the most commonly
detected organisms. The true incidence of
these infections is uncertain because of
the difficulty in distinguishing colonizing
organisms from pathogens. S.
pneumoniae is the most commonly
identified bacterial cause of CAP. However,
it has decreased markedly due to
pneumococcal vaccines ( table 3 and
table 2). (See 'Bacteria' above.)

● Using molecular methods, viruses are

detected in approximately one-third of
cases of CAP in adults. Influenza is the
most significant viral cause of CAP in
adults. SARS-CoV-2 is an important cause
during the pandemic. Mixed viral-bacterial
infection is relatively common. (See
'Viruses' above.)

● Fungal infection is an unusual cause of

CAP in the immunocompetent patient, but
certain fungi (eg, Histoplasma capsulatum,
Coccidioides spp) can cause pneumonia in
immunocompetent or
immunocompromised patients who
reside in or have visited endemic areas.
The specific epidemiology of some fungal
infections is therefore important as a
diagnostic clue. Fungal infection is more
common in immunocompromised
patients, particularly those with
neutropenia, those receiving chronic
immunosuppressive therapy (eg, organ
transplant recipients), and those infected
with HIV. (See 'Fungi' above.)

ACKNOWLEDGMENT

UpToDate gratefully acknowledges John G

Bartlett, MD (deceased), who contributed as
Section Editor on earlier versions of this topic
and was a founding Editor-in-Chief for
UpToDate in Infectious Diseases.

Use of UpToDate is subject to the Terms of Use.

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