64
64
Acute Pneumonia
GERALD R. DONOWITZ
I n 1901, Sir William Osler1 noted in the fourth edition of his book,
The Principles and Practice of Medicine, that “the most widespread and
fatal of all acute diseases, pneumonia, is now Captain of the Men of
Death.” Over a century later, the prominence of pneumonia as a clini-
cal entity remains. It is among the top ten most common causes of
death among all age groups in the United States, the sixth leading cause
of death in those 65 years or older, and the single most common cause
of infection-related mortality.2 The clinical challenge of treating com-
munity-acquired pneumonia is the large number of microbial agents
that can cause disease (Tables 64-1A-D), the difficulty in making a
clinical and etiologic diagnosis, and the fact that no single antimicro-
bial regimen can cover all the possible etiologies. Because a specific
etiologic diagnosis is often not possible at the time initial treatment is
begun, the clinician must decide what empiric therapy is most appro-
priate. The increasing prevalence of antibiotic resistance among many
of the most common pathogens has made this challenge more difficult.
An understanding of the pathogenesis of the disease, evaluation of
relevant data from a careful history and physical examination, recogni-
tion of common clinical patterns of infection, and information from
the microbiology laboratory all aid in narrowing down the possible
etiologic agents of pneumonia, thereby allowing reasonable therapy to
be selected empirically.
Host Defenses and Pathogenesis
The lung is constantly exposed to the mixture of gases, particulate
material, and microbes that constitute inspired air. In addition, organ-
isms from oral secretions frequently seep down from the upper airways
as a consequence of microaspiration. Yet, the lower airways usually
remain sterile because of the defense mechanisms of the respiratory
tract. The development of acute pulmonary infection indicates either
a defect in host defenses, exposure to a particularly virulent microor-
ganism, or an overwhelming inoculum. Infectious agents gain entry to
the lower respiratory tract through aspiration of upper airway resident
flora, inhalation of aerosolized material, and less frequently, metastatic
seeding of the lung from blood.
PULMONARY DEFENSE SYSTEMS
The pulmonary defense system involves both innate and adaptive
immunity, including anatomic and mechanical barriers, humoral
immunity, cell-mediated immunity, and phagocyte activity (Table
64-2).3,4 The upper airways, including the nasopharynx, oropharynx,
and larynx, are the sites first exposed to inhaled microorganisms. The
nasal mucosa contains ciliated epithelium and mucus-producing cells.
Mechanical clearance of entrapped organisms occurs through the
nasopharynx via expulsion or swallowing. In the oropharynx, the flow
of saliva, sloughing of epithelial cells, local production of complement,
and bacterial interference from resident flora serve as important
factors in local host defense. Secretory immunoglobulin A (IgA) is the
major immunoglobulin produced in the upper airways and accounts
for 10% of the total protein of nasal secretions. It possesses antibacte-
rial and antiviral activity despite being a relatively poor opsonin.
Despite some controversy, low IgA levels are probably not associated
with increased bacterial infection. IgG and IgM enter the airways pre-
dominantly via transudation from the blood. Their roles in bacterial
opsonization, complement activation, agglutination, and neutraliza-
tion activity are similar to those noted in serum.
Adherence of microorganisms to epithelial surfaces of the upper
airways is a critical initial step in colonization and subsequent infec-
tion. Changes in fibronectin secretion and in binding characteristics
of epithelium for various lectins occur as a response to underlying
diseases. This may help to explain why colonization occurs in some
clinical settings and not in others. Particles larger than 10  µm are
efficiently filtered by the hair in the anterior nares or impact onto
mucosal surfaces because of the configuration of the upper airways and
the nasal turbinates. The cough and epiglottic reflexes also keep large
particulate matter from reaching the central airways. The trachea and
conducting airways of the transbronchial tree are usually effective in
entrapping particles from 2 to 10 µm in size. The sharp angles at which
the central airways branch cause particles to impact on mucosal sur-
faces, where they are entrapped by endobronchial mucus. Once
entrapped, particles are removed by ciliated epithelium to the
oropharynx.
Epithelial cells, which line the conducting airways, submucosal
glands, and alveoli, produce airway surface liquid—a complex mixture
of proteins and peptides mixed with plasma transudate. Airway surface
liquid contains lysozyme, lactoferrin, and secretory leukocyte protein-
ase inhibitor, all of which possess microbicidal activity. Respiratory
epithelial cells produce other potent antimicrobial peptides including
cathelicidins and β-defensins. These peptides possess individual anti-
microbial activity as well as synergistic antimicrobial activity with each
other. In addition, the β-defensins may act as chemokines for memory
T cells and dendritic cells, thereby serving as a link between the innate
and adaptive immune systems.
Most bacteria are 0.5 to 2 µm in size. This size particle may reach
the terminal airways and alveoli. No mucociliary apparatus exists at
this level, yet a variety of humoral and cell-mediated host defenses
function here. The alveolar-lining fluid contains surfactant, fibronec-
tin, IgG, and complement, all of which are effective opsonins. Surfac-
tant is composed of several components (SP-A, SP-B, SP-C, SP-D) that
serve to increase the microbicidal capacity of macrophages. These
compounds may also affect free radical production and lymphocyte
activity.5 SP-A and SP-D are collectins—a family of collagenous car-
bohydrate-binding proteins. These proteins bind a variety of organ-
isms, including viruses, gram-negative and gram-positive bacteria,
mycobacteria, and fungi, which may decrease their virulence or
enhance phagocytosis by neutrophils and alveolar macrophages.6 Free
fatty acids, lysozyme, iron-binding proteins, and defensins are also
present and may be directly microbicidal.
Phagocytic cells, including macrophages and neutrophils, play a
major role in pulmonary host defense. Four distinct populations of
macrophages exist in the lung and vary in their location and function.7
The alveolar macrophage is located in the alveolar lining fluid at the
interphase between air and lung tissue. It serves as the resident phago-
cytic cell in the lower airway and is the first phagocyte encountered by
inert particles and potential pathogens entering the lung via inspired
air. Alveolar macrophages play several critical roles.3 As phagocytic
cells, they can eliminate certain organisms. If the numbers of organ-
isms increase beyond the macrophages’ capability to handle them or
if the organisms involved are particularly virulent (e.g., Pseudomonas
aeruginosa), the macrophage becomes a mediator of an inflammatory
response by producing cytokines that recruit neutrophils into the
lung.8 Interstitial macrophages are located in the lung connective tissue
and serve both as phagocytic cells and antigen-processing cells. Den-
dritic cells derive from monocytes and are located within the epithe-
lium of the trachea, conducting airways, terminal airways, alveolar
septa, pulmonary vasculature, and visceral pleura. These cells are
therefore positioned to interact with antigens in inhaled air. Dendritic
891
892 Part II  Major Clinical Syndromes

TABLE TABLE
64-1A Causative Agents of Acute Pneumonia—Bacteria 64-1C Causative Agents of Acute Pneumonia—Fungi

Common Uncommon Common

Streptococcus pneumoniae Acinetobacter var. anitratus Histoplasma capsulatum
Staphylococcus aureus Actinomyces and Arachnia spp. Coccidioides immitis
Haemophilus influenzae Bacillus spp. Agents of Mucormycosis
Mixed anaerobic bacteria Moraxella catarrhalis Rhizopus spp.
(aspiration) Campylobacter fetus Absidia spp.
Bacteroides spp. Eikenella corrodens Mucor spp.
Fusobacterium spp. Francisella tularensis Cunninghamella spp.
Peptostreptococcus spp. Neisseria meningitidis Uncommon
Peptococcus spp. Nocardia spp. Aspergillus spp.
Prevotella spp. Pasteurella multocida Candida spp.
Enterobacteriaceae Proteus spp.
Escherichia coli Pseudomonas pseudomallei
Klebsiella pneumoniae factor-α (TNF-α) and IL-I that then activate transcription factors
Salmonella spp.
Enterobacter spp.
such as mitogen-activated protein kinase, phosphoinositide 3-kinase,
Enterococcus faecalis
Serratia spp.
nuclear factor kappa B (NF-κB), and interferon-regulatory factors.
Streptococcus pyogenes
Pseudomonas aeruginosa
These transcription factors serve as a common pathway for pattern
Legionella spp. (including L.
recognition receptors and orchestrate the development of the inflam-
pneumophila and L. micdadei) matory response by mediating the transcription of chemokines,
adhesin molecules, and other cytokines. This signal cascade serves two
purposes. The first is to generate and maintain the inflammatory
cells possess an enhanced capacity to capture, process, and present response to recruit neutrophils into areas of microbial invasion. The
class II antigens. They can migrate to lymphoid tissue, where they can other goal is to activate anti-inflammatory response mediators, which
stimulate T-cell immune responses. Dendritic cells can also produce a leads to the shedding of receptors, neutralization of cytokines, and
variety of cytokines and chemokines, including interleukin (IL)-12, inhibition of macrophage recruitment. These all serve to ensure that
which serves to stimulate B-cell immune function.9 The intravascular the inflammatory response is held in check and that noninvolved areas
macrophage is located in the capillary endothelial cells. These cells are of lung are not injured. It is this balance of proinflammatory and anti-
actively phagocytic and remove foreign or damaged material entering inflammatory cytokines and effector molecules that allows for steril-
the lungs via the bloodstream. ization of an infected area of lung without gross destruction of lung
Neutrophil recruitment is crucial for the inflammatory response in tissue.
the lung. The mechanisms involved in the initial detection of organ- Other lung parenchymal cells may also help regulate the inflamma-
isms in the lung and the generation and subsequent resolution of a tory response.16 In addition to epithelial cells, interstitial macrophages,
response to them are now being more clearly delineated.10-15 Microor- and dendritic cells, endothelial cells, pulmonary smooth muscle
ganisms express molecular recognition patterns that are unique and cells, and fibroblasts produce both proinflammatory (e.g., colony-
different from those of the host. Pattern recognition receptor families stimulating factors, chemokines) and anti-inflammatory (e.g., IL-10)
such as Toll-like receptors are present on epithelioid cells, alveolar factors.
macrophages, dendritic cells as well as other cells that are located in Cell-mediated immunity is central to adaptive immune responses
strategic areas of the lung and either individually or in groups serve to in the lung and is especially important against certain pathogens,
recognize molecular patterns of invading organisms. This recognition including viruses and intracellular organisms, that can survive within
leads to the generation of early response cytokines like tumor necrosis pulmonary macrophages (e.g., Mycobacterium, Legionella). The lung
has lymphoid tissue where homing and differentiation of previously
uncommitted cells to memory T and B cells occur.17 Most of the orga-
TABLE
64-1B Causative Agents of Acute Pneumonia—Viruses nized lymphoid tissue in the lung is located in follicles along the
bronchial tree in bronchus-associated lymphoid tissues (BALT). The
Children Adults lymphoid centers are morphologically similar to Peyer’s patches in the
Common Common intestine and are similarly associated with mucosal epithelium. Inhaled
Respiratory syncytial virus Influenza A virus
Parainfluenza virus types 1, 2, 3 Influenza B virus
Influenza A virus Respiratory syncytial virus TABLE Causative Agents of Acute Pneumonia—
Uncommon Human metapneumovirus 64-1D Other Agents
Adenovirus types 1, 2, 3, 5 Adenovirus types 4 and 7 (in military Rickettsia Nontuberculous Mycobacteria
Influenza B virus recruits) Coxiella burnetii M. abscessus
Rhinovirus Uncommon Rickettsia rickettsiae M. avium complex
Coxsackievirus Rhinovirus Mycoplasma and Chlamydia M. kansasii
Echovirus Enteroviruses Mycoplasma pneumoniae M. chelonae
Measles virus Echovirus Chlamydophila psittaci M. fortuitum
Hantavirus Coxsackievirus Chlamydia trachomatis M. xenopi
Epstein-Barr virus Chlamydophila pneumoniae (TWAR) M. simiae
Cytomegalovirus Mycobacteria M. scrofulaceum
Varicella-zoster virus Mycobacterium tuberculosis M. malmoense
Parainfluenza virus Parasites
Measles virus Ascaris lumbricoides
Herpes simplex virus Pneumocystis jirovecii
Hantavirus Strongyloides stercoralis
Human herpesvirus 6 Toxoplasma gondii
Coronavirus (SARS) Paragonimus westermani
 64  Acute Pneumonia 893

TABLE
64-2 Pulmonary Host Defenses

Location Host Defense Mechanism*

Upper Airways
Nasopharynx Nasal hair
Turbinates
Anatomy of upper airways
Mucociliary apparatus
IgA secretion
Oropharynx Saliva
Sloughing of epithelial cells
Cough
Bacterial interference
Complement production
Conducting Airways
Trachea, bronchi Cough, epiglottic reflexes
Sharp-angled branching of airways
Mucociliary apparatus
Airway surface liquid (lysozyme, lactoferrin, secretory leukocyte proteinase inhibitor)
Dendritic cells†
Bronchus-associated lymphoid tissue (BALT)} } Antigen processing and presentation→
stimulation of memory and effector T cells and B cells
Immunoglobulin production (IgG, IgM, IgA)
Lower Respiratory Tract
Terminal airways, alveoli Alveolar lining fluid (surfactant, fibronectin, immunoglobulin, complement, free fatty acid, iron-binding proteins)
Alveolar macrophages
Neutrophil recruitment‡
(pattern recognition receptors→transcription factor stimulation→proinflammatory and anti-inflammatory cytokine and chemokine
production)
Dendritic cells†
Bronchus-associated lymphoid tissue (BALT)} } Antigen processing and presentation→
stimulation of memory and effector T cells and B cells
*Aspects of native and adaptive immunity play a role throughout the respiratory tract.
†
Major component of adaptive immunity and important in response to vaccines and prior infections.
‡
Major component of innate immunity.

antigens therefore are able to cross the epithelial surface and immedi-
ately encounter cells involved with antigen processing. Once these
antigens are processed and presented, it is in the BALT that B and T
lymphocytes localize and are stimulated to become memory cells and
effector cells.
Normal lung parenchyma usually contains few lymphoid cells,
which represent only 5% to 10% of the total cell population. The
lymphocytes present are memory cells located in the submucosa and
lamina propria; effector cells located between epithelial cells and in the
interstitium; and cells thought to be “preactivated,” awaiting stimula-
tion by inhaled antigens in the alveolus. The majority of lymphocytes
are T cells, with 35% to 45% representing a CD4 (helper, inducer)
phenotype, and 18% to 32% representing a CD8 (suppressor)
phenotype.18
Antigens inhaled into the alveolus and captured by antigen-present-
ing cells subsequently activate intra-alveolar lymphoid cells. These cells
can stimulate the migration of memory lymphocytes into the area,
leading to a localized accumulation of antigen-specific T and B lym-
phocytes, many of which possess effector cell function. As is true in
other anatomic areas, binding of T cells to endothelium is a critical
first step in the inflammatory process and is mediated by the interac-
tion of leukocyte function-associated antigen (LFA)-1 integrins on the
lymphocyte cell surface, with ligands exposed by endothelium in areas
of inflammation (intercellular adhesion molecules 1 and 2 and vascu-
lar cell adhesion molecule 1). Expression of these ligands on pulmo-
nary endothelium is upregulated by inflammatory mediators, such as
IL-1, interferon-γ, and TNF-α, and by bacterial lipopolysaccharides.
Pulmonary lymphocytes are thought to shuttle between two func-
tionally distinct lymphoid areas, the BALT, which can be viewed as the
afferent limb where antigens first stimulate an immune response, and
the lung parenchyma, where differentiated T and B cells participate in
the inflammatory response, which can be viewed as the efferent limb.
The increase in numbers of memory T cells after antigenic stimulation
may occur as a result of local proliferation or via migration of cells
from BALT.
Lymphocytes in the lung have three major roles: (1) antibody pro-
duction, (2) cytotoxic activity, and (3) inflammatory mediator pro-
duction. The lung contains a variety of cytotoxic T cells including
natural killer cells (antigen nonrestricted), antibody-dependent cyto-
toxic cells, and antigen-restricted cytotoxic cells. Pulmonary T cells
produce a large number of cytokines. Mouse models suggest that
unstimulated T cells produce mainly IL-2. After stimulation and con-
version to memory T cells, two distinct groupings of cytokines are
produced. The helper T cell 1 (Th1) and helper T cell 2 (Th2) pattern
of cytokine production noted in murine models occurs in humans,
although it appears to be less restrictive. Th1 cells produce interferon-γ,
IL-2, IL-6, and IL-10 and contribute to cell-mediated immunity,
whereas Th2 cells produce IL-4, IL-5, and IL-10 and contribute to
humoral immune function. Furthermore, IL-3, TNF-α, granulocyte-
macrophage colony-stimulating factor, and chemokines are secreted
by both Th1 and Th2 phenotypes. Th1 cells are involved in cell-
mediated inflammatory reactions, whereas Th2 cells stimulate anti-
body production, especially IgE, and stimulate eosinophil activity.
IMPAIRMENT OF PULMONARY DEFENSES
The defenses of the lung, when they are functioning normally, are
extremely efficient in maintaining sterility of the lower airways.
However, a number of factors are known to interfere with these
defenses and predispose the host to infection. Alterations in the level
of consciousness from any cause (stroke, seizures, drug intoxication,
anesthesia, alcohol abuse, and even normal sleep) can compromise
epiglottic closure and lead to aspiration of oropharyngeal flora into the
lower respiratory tract.19 Cigarette smoke, perhaps the most common
agent involved in compromising natural pulmonary defense mecha-
nisms, disrupts both mucociliary function and macrophage activity.20
894 Part II  Major Clinical Syndromes
Alcohol not only impairs the cough and epiglottic reflexes but also
has been associated with increased colonization of the oropharynx
with aerobic gram-negative bacilli, decreased mobilization of neutro-
phils,21 abnormal phagocyte oxidative metabolism, and abnormal che-
motaxis.22 Alcohol effectively blocks the TNF response to endotoxin,
with decreased recruitment of neutrophils to the lung. Furthermore,
alcohol enhances monocyte production of IL-10, a cytokine with anti-
inflammatory properties.23
Infections with Mycoplasma pneumoniae or Haemophilus influenzae
may interfere with normal ciliary function.24 Viruses may actually
destroy respiratory epithelium and may disrupt normal ciliary activity.
Neutrophil function, including chemotaxis, phagocytosis, and stimu-
lation of oxidative metabolism and alveolar macrophage function, may
also be inhibited by certain viral infections.25 Sepsis associated with
extrapulmonary infections may undermine lung defense mechanisms.
In animal models, exposure to lipopolysaccharide or endotoxin
decreases lung clearance of a bacterial challenge.26 Infection with
human immunodeficiency virus (HIV) compromises many of the
components of pulmonary host defense. Quantitative defects involve
the naive CD4 T cells initially, with the memory CD4 T cells depleted
more rapidly later in infection. Functional defects caused by the virus
include impaired response to remote recall antigens, inhibited response
to soluble antigen followed in time by decreased T-cell response to
alloantigens and mitogens, impaired IL-2 and interferon-γ production,
and decreased immunoglobulin production.27 In BALT, destruction of
dendritic cells and degeneration of lymphoid follicles have been noted.
Defective antigen presentation by dendritic cells has also been observed.
Abnormal chemotaxis, phagocytosis, and oxidative metabolism in
neutrophils of patients with acquired immunodeficiency syndrome
(AIDS) have been described.
Iatrogenic manipulations that bypass or interfere with the usual host
defenses of the upper airways (endotracheal tubes, nasogastric tubes,
and respiratory therapy machinery) all predispose to infection.28 A
variety of commonly prescribed drugs have been shown to inhibit host
defenses in vitro or in models, but the clinical significance of this is
uncertain. These agents include aspirin,29 erythromycin,30 aminophyl-
line,31 and proton pump inhibitors.32 A recent study documented that
the rates of pneumonia increased in hospitalized patients if proton-
pump inhibitors or histamine type 2 (H2) receptor antagonists were
used compared with hospitalized patients in whom these acid-
suppressive medications were not used (4.9% and 2.0%, respectively).32a
Other factors that impair pulmonary host defenses include hypoxemia,
acidosis, toxic inhalations,33 pulmonary edema,34 uremia, malnutri-
tion, immunosuppressive agents,35 and mechanical obstruction.
Older adults are at increased risk for the development of pneumonia
(see Chapter 314). Although numerous factors play an important role
in this regard, including an increased number and increased severity
of underlying diseases and an increased number of hospitalizations,
there are age-related impairments in host defenses.36,37 Less effective
mucociliary clearance and abnormal elastic recoil may lead to less
effective coughing and clearing of the upper airways. Some popula-
tions of elderly patients have an increased incidence of microaspira-
tion. Changes in humoral immunity and cell-mediated immune
function have been documented in older persons, though their role in
the development of infection remains unclear. Immune dysregulation
has been shown to occur in the elderly, so that low-grade inflammation
occurs in the lung in the absence of clinically detectable infection.
Recurrent episodes of bacterial pneumonia suggest the presence of
specific predisposing factors.37 In children and young adults, recurrent
pneumonia is associated with defects in host defenses, including leu-
kocyte function38 and immunoglobulin production.38-40 Congenital
defects in ciliary activity, including the immotile cilia syndrome,41
Kartagener syndrome (ciliary dysfunction, situs inversus, sinusitis,
bronchiectasis),42 Young’s syndrome (azoospermia, sinusitis, pneu-
monia), and cystic fibrosis, are other clinical entities associated with
recurrent pneumonia in young persons. Structural lung abnormalities
such as bronchiectasis and pulmonary sequestration are also impor-
tant predisposing factors for both younger and older patient popula-
tions. As more has become known about the molecular basis of the
inflammatory response, it has become clear that a variety of genetic
polymorphisms exist that are associated with predisposition for the
development of pneumonia. It is important to recognize that these
defects may be associated with a narrow range of potential pathogens
which may aid in the identification of the defect.12,15
Although most congenital defects in host defenses appear in child-
hood, common variable hypogammaglobulinemia may first appear in
adulthood with recurrent pneumonia. Acquired host defense defects
are more varied and include malignancies (lymphoma, chronic lym-
phocytic leukemia, myeloma), infection (AIDS), and iatrogenic causes
(immune suppression associated with solid organ or marrow trans-
plantation or cancer chemotherapy). Underlying respiratory tract dis-
orders, such as chronic obstructive pulmonary disease (COPD),
bronchiectasis, adult-onset cystic fibrosis, bronchopulmonary seques-
tration, and tracheobronchomegaly, may occur with pneumonia.
Bronchial obstruction due to intrinsic compression (adenocarcinoma)
or extrinsic compression (lymphadenopathy due to sarcoidosis or
malignancy) has also been associated with recurrent episodes of pneu-
monia. Underlying diseases that predispose to aspiration lead to an
increased incidence of pneumonia. These may be associated with gas-
trointestinal diseases (tracheoesophageal fistula, esophageal divertic-
ula, esophageal reflux, esophageal stricture), neuromuscular disorders
(myasthenia gravis, dementia, amyotrophic lateral sclerosis), and
cancer of the head and neck. Some systemic illnesses, including Weber-
Christian disease, chronic renal failure, diabetes, and sickle cell disease,
have been associated with pneumonia.
Clinical Evaluation
HISTORY
The history should define (1) symptoms consistent with the diagnosis
of pneumonia, (2) the clinical setting in which the pneumonia takes
place, (3) defects in host defense that could predispose to the develop-
ment of pneumonia, and (4) possible exposures to specific pathogens.
Respiratory symptoms are commonly encountered in primary care
practices but usually are not caused by pneumonia. Of over 10 million
visits reported associated with a chief complaint of cough, only 4% to
6% actually involved pneumonia.43 Although the prevalence of pneu-
monia may vary depending on the age of the patient population and
the presence of comorbid diseases, pneumonia remains only one of
many possible explanations for respiratory complaints. Therefore, a
serious effort should be made to differentiate pneumonia from other
clinical entities with which it may be confused. Although the clinical
findings of pneumonia related to the respiratory tract should be
sought, including cough, sputum production, dyspnea, and fever, it
should be recognized that nonrespiratory symptoms are commonly
present. These include fatigue, sweats, headache, nausea, and
myalgia.44,45 With increasing age, both respiratory and nonrespiratory
symptoms of pneumonia become less frequent. Unfortunately, symp-
toms at presentation elucidated by a careful history may not always be
able to distinguish pneumonia from other respiratory problems.46
Specific etiologic agents of pneumonia have been associated with
certain underlying diseases and patient populations. Mycoplasmal
pneumonia occurs more often in younger people, but it may be a cause
of pneumonia in older patients and require hospitalization.47 Gram-
negative pneumonia tends to occur in older adults, especially those
who are debilitated with comorbid diseases.48 Tuberculosis should be
suspected in the homeless, those infected with HIV, those who come
from developing countries where tuberculosis is prevalent, and those
who have been exposed to others with the disease. Staphylococcal
pneumonia classically has been noted during epidemics of influenza.
Over the past 20 years, methicillin-resistant Staphylococcus aureus
(MRSA) has grown in importance as an etiology of ventilator-
associated pneumonia (VAP). In addition, since 2002, a strain of
MRSA which carries the staphylococcal cassette chromosome (SCC)
IV and contains the gene coding for Panton-Valentine leukocidin, has
emerged as an important cause of community-acquired pneumonia.
Known as community-acquired MRSA or CA-MRSA, the organism

causes severe pneumonia with high mortality in relatively young popu-
lations without underlying comorbidities.49,50 Severe acute respiratory
syndrome (SARS) is a pneumonia syndrome caused by a coronavirus,
associated with travel to China, Taiwan, Hong Kong, Singapore,
Vietnam, and Toronto, Canada.51
Pneumonia has been noted to occur with increased frequency in
patients with a variety of underlying disorders, such as congestive heart
failure, diabetes, alcoholism, and COPD.48,52 In one series of 292
patients with pneumonia, only 18% were found to have no underlying
disease.48 Certain lifestyle factors have also been associated with an
increased risk of pneumonia. These include cigarette smoking, alcohol
use (especially in males), contact with children and pets, and living in
a household with more than 10 people.53 A history of antecedent upper
respiratory tract infection has been elicited in 36% to 50% of patients
with acute pneumonia, especially in those with pneumococcal disease.54
Recent dental manipulations, sedative overdoses, seizures, alcoholism,
or loss of consciousness for any reason should raise the suspicion of
anaerobic infection caused by aspiration of oral contents.19
Special note should be made of the relationship between pneumonia
and patients with COPD.55 Although well-controlled studies are
lacking, it does appear that patients with COPD have an increased
incidence of pneumonia. However, because the tracheobronchial tree
is often colonized with Streptococcus pneumoniae and H. influenzae, it
has been difficult to distinguish clearly between colonization and infec-
tion in many studies. Although these organisms play an important role
as etiologic agents of pneumonia in this patient population, most of
the clinical studies were carried out before it was recognized that other
less common pathogens also play a significant role in causing disease.
The roles of Moraxella catarrhalis, Legionella, Chlamydophila, and
aerobic gram-negative rods including P. aeruginosa have been estab-
lished.55-57 Cystic fibrosis is commonly associated with Pseudomonas
and staphylococcal pulmonary infections.58 Burkholderia spp. and Ste-
notrophomonas spp. are also important pulmonary pathogens in this
setting. Pulmonary alveolar proteinosis is associated with Nocardia
infection.
Patients infected with HIV are at high risk for the development of
pulmonary infections.59-61 Although Pneumocystis pneumonia remains
an important clinical entity in this patient population, prophylaxis has
reduced its incidence and importance as a cause of death.62 In consid-
ering the nature of pulmonary infection in patients infected with HIV,
geographic exposures, demographic characteristics of the patient, and
the degree of immune suppression should be considered.59,60 Although
in the past, Pneumocystis infection has been reported to be relatively
uncommon in patients with AIDS in Africa, more recent data have
suggested that the incidence is increasing. Overall, however, it is a
more common complication of HIV infection in Europe and the
United States. In many centers worldwide, Mycobacterium tuberculosis
is now viewed as the major pulmonary pathogen in patients with
AIDS.63 Though use of highly active antiretroviral therapy has led to a
decreased incidence of disease, its overall importance in AIDS as a
pulmonary pathogen remains. Because fungal infections play a major
role in this patient population, exposure in endemic areas of histoplas-
mosis, blastomycosis, and coccidioidomycosis should be considered.
The greatest risk appears to be associated with intravenous and inhaled
drug use.59,64 Common pulmonary pathogens such as S. pneumoniae,
H. influenzae, and S. aureus play an important role.60 The incidence of
invasive pneumococcal pneumonia is 100 to 300 times higher in HIV-
infected patients, and the incidence of H. influenzae infection may be
up to 100-fold higher in this population. P. aeruginosa pneumonia is
often associated with bacteremia or cavitary lung disease and is a later
complication of HIV infection, occurring with CD4 counts of less than
25 cells/µL. The infection is associated with the presence of central
venous catheters and urinary catheters and the use of steroids. Other
agents, such as Legionella, Nocardia, aerobic gram-negative bacilli, and
Rhodococcus equi, are also important causes of pneumonia.
In patients infected with HIV, the relationship between the degree
of immune suppression using the CD4 count as a marker and the
specific etiology of pneumonia deserves emphasis. Bacterial pneumo-
nia and tuberculosis usually occur when the CD4 count is less than
64  Acute Pneumonia 895
400/µL with increased risk when the count falls below 200 cells/µL.64,65
Pneumocystis and disseminated tuberculosis are associated with CD4
counts below 200 cells/µL, and disseminated nontuberculous myco-
bacterial infections and disseminated fungal infection occur with CD4
counts less than 50 to 100 cells/µL.65 Pulmonary infections in HIV-
infected patients are discussed in more detail in Chapter 122.
Pneumonia developing in hospitalized patients often involves
Enterobacteriaceae, P. aeruginosa, and S. aureus, organisms that are
unusual in community-acquired disease.66 Pneumonia in older adults,
especially those who are bedridden or who have chronic diseases, is
more often associated with gram-negative bacilli than is pneumonia
in younger populations.67 However, lack of clear definition between
colonization and true infection has made the actual role of gram-
negative organisms unclear. In general, S. pneumoniae, nontypeable
strains of H. influenzae, and M. catarrhalis are important pathogens in
older adults.
Recently, it has been recognized that patients with outpatient
contact with the health care system develop pneumonia with etiologic
agents that may be seen in both community-acquired and nosocomial
pneumonia.68-70 Increased importance of MRSA, aerobic gram-nega-
tive rods including Pseudomonas aeruginosa, and mixed aerobic/anaer-
obic organisms due to aspiration are associated with this new syndrome
of health care–associated pneumonia (see discussion in later section,
“Pneumonia Syndromes”).
Important aspects of a patient’s history that may suggest specific
potential infectious agents include occupation, exposure to animals,
travel, and sexual history (Table 64-3). The presence of noninfectious
pulmonary disease, such as tumors or pulmonary emboli, which may
masquerade as pneumonia, may also be suggested by a careful history.
TABLE Pneumonia: Etiology Suggested by Environmental
64-3 History
Infectious Agent Environmental History
Anthrax Exposure to cattle, swine, horses, goat hair, raw wool,
animal hides
Possible agent of bioterrorism
Brucellosis Exposure to cattle, goats, pigs; ingestion of
unpasteurized dairy products; employment as
abattoir worker or veterinarian
Melioidosis Travel to West Indies, Australia, Guam, Southeast
Asia, South and Central America
Plague Exposure to ground squirrels, chipmunks, rabbits,
prairie dogs, rats
Possible agent of bioterrorism
Tularemia Exposure to tissue or body fluids of infected animals
during trapping, hunting, or skinning (rabbits,
hares, foxes, squirrels) or to bites of an infected
arthropod (flies, ticks)
Handling or ingesting poorly cooked meat from an
infected animal
Possible agent of bioterrorism
Psittacosis Exposure to birds (parrots, budgerigars, cockatoos,
pigeons, turkeys)
Leptospirosis Exposure to wild rodents, dogs, cats, pigs, cattle, or
horses, or exposure to water contaminated with
animal urine
Coccidioidomycosis Residence in or travel to San Joaquin Valley, southern
California, southwestern Texas, southern Arizona,
New Mexico
Histoplasmosis Exposure to bat droppings or dust from soil enriched
with bird droppings
Q fever Exposure to infected goats, cattle, sheep, domestic
animals, and their secretions (milk, amniotic fluid,
placenta, feces)
Legionnaires’ disease Exposure to contaminated aerosols (e.g., air coolers,
hospital water supply)
Pasteurella multocida Exposure to infected dogs and cats
Hantavirus Exposure to rodent droppings, urine, saliva
SARS Travel to area of outbreaks
SARS, severe acute respiratory syndrome.
896 Part II  Major Clinical Syndromes
PHYSICAL EXAMINATION
Fever is reported to be present in 65% to 90% of patients with pneu-
monia. It may be sustained, remittent, or at times hectic. Fever patterns
per se, however, are not useful for establishing a specific diagnosis. The
temperature should be taken rectally to reduce error caused by rapid
mouth breathing. Recording of postural changes in blood pressure and
pulse rate is useful in assessing hydration and intravascular fluid
volume. The pulse usually increases by 10 beats per minute for every
degree (centigrade) of temperature elevation. A pulse–temperature
deficit (e.g., a relative bradycardia for the amount of fever) should
suggest viral infection, mycoplasmal infection, chlamydial infection,
tularemia, or infection with Legionella. Cyanosis, a rapid respiratory
rate, the use of accessory muscles of respiration, sternal retraction, and
nasal flaring suggest serious respiratory compromise.
Furuncles are rarely secondary to staphylococcal pneumonia
acquired by the respiratory route, but they may signal a source of
bacteremia with subsequent pneumonia via hematogenous spread,
although this is uncommon. Herpes labialis is seen in up to 40% of
patients with pneumococcal pneumonia.71 Bullous myringitis is an
infrequent but significant finding in mycoplasmal pneumonia. The
presence of poor dentition should suggest a mixed infection due to
aspiration of anaerobes and aerobes that colonize the oropharynx.
Although edentulous patients may develop anaerobic pneumonia as a
result of aspiration, it is uncommon.72
Examination of the thorax may reveal “splinting,” or an inspiratory
lag on the side of the lesion, that is suggestive of bacterial pneumonia.
Early in the disease process, definite signs of pulmonary involvement
may be lacking or may be manifest only as fine rales. Chest examina-
tion may reveal these early signs of pneumonia even though the chest
film is normal. Evidence of consolidation (dullness on percussion,
bronchial breath sounds, and E to A changes) is highly suggestive of
bacterial infection, but may be absent in two thirds of patients ill
enough to be hospitalized and may be absent more often in patients
treated as outpatients.73 Patients with mycoplasmal or viral infection
may exhibit few abnormalities on physical examination, despite the
presence of impressive infiltrates on the chest film.
The overall usefulness of the history and physical examination to
detect the presence of pneumonia has been questioned.46,74 A great deal
of interobserver variation exists in detecting the signs and symptoms.46
In one series, three examiners seeing the same patients could not
consistently agree on the physical examination findings. The diagnosis
of pneumonia could be made with a sensitivity of only 47% to 69%
and with a specificity of 50% to 75%.75 Rare findings such as egobron-
chophony and asymmetrical chest movements have a high predictive
value for pneumonia. Other findings are usually not helpful. The
absence of any vital sign abnormalities (i.e., respiratory rate greater
than 20 breaths/min, heart rate greater than 100 beats/min, and tem-
perature greater than 37.8° C) has been associated with a less than 1%
chance of a patient’s having pneumonia, assuming a pneumonia prev-
alence of 5% in the population under study.74 Others have questioned
the importance of any of these specific findings on detecting the pres-
ence of pneumonia.46 The probability of detecting pneumonia varies
with the patient population, the prevalence of pneumonia in that
population, the threshold values for defining a vital sign as abnormal,
and the ability of the clinician to detect abnormal physical findings.
No single physical finding is particularly helpful in making a definite
diagnosis. However, a constellation of cough, fever, tachycardia, and
crackles raises the possibility of pneumonia being present to 18% to
42%. Therefore, although variable and nondefinitive, a complete
history and physical examination may be extremely helpful in guiding
the workup of pneumonia.
DIAGNOSTIC TESTING
The presence of pneumonia is suggested by clinical features derived
from a careful history and physical examination and confirmed by
radiographic imaging of the chest that shows an infiltrate. The role of
microbiologic tests to identify the specific etiology is an important
though controversial element of care. Most empirical antibiotic regi-
mens are successful in the therapy of community-acquired pneumo-
nia, especially mild to moderates cases. Studies comparing empirical
therapy to laboratory-guided, pathogen-directed care have shown no
differences in efficacy, although increased side effects were noted in
the patients receiving empirical therapy.76 Efforts to determine the
specific etiology of community-acquired pneumonia are justified by
the fact that they (1) may enable the clinician to narrow the antibiotic
spectrum, and use fewer agents, thereby decreasing exposure of the
patient to potential side effects and potentially reducing the develop-
ment of resistance; (2) may aid in the specific antibiotic choice for an
individual patient, depending on the specific epidemiology of infection
and the specific resistance patterns of the locale; and (3) may identify
pathogens not usually suspected and therefore not usually covered by
empirical therapy. On a broader scale, identifying specific etiologies
may help define new agents, trends in antibiotic resistance in estab-
lished agents, and epidemiology of infectious outbreaks. Though even
aggressive efforts to diagnose the cause of pneumonia using some of
the most advanced techniques will yield positive results only 58% of
the time, diagnostic yields are higher in sicker patients, where the
information is most helpful.77 The most recent guidelines from the
Infectious Diseases Society of America/American Thoracic Society
(IDSA/ATS) have suggested diagnostic testing “whenever the result is
likely to change individual antibiotic management,” or in patients
where “the diagnostic yield is thought to be greatest.”78
EXAMINATION OF SPUTUM AND OTHER
RESPIRATORY TRACT SAMPLES
Microscopic examination and culture of expectorated sputum remain
the mainstays of the laboratory evaluation of pneumonia despite
ongoing controversy concerning their sensitivity and specificity. Of
patients admitted to the hospital with community-acquired pneumo-
nia, 40% to 60% will not be able to produce sputum. Of those that do,
45% to 50% of samples may be judged to be inadequate for further
study because of oropharyngeal contamination.79-81 Many patients
have received antibiotics before the studies are carried out, which
drastically reduces the diagnostic yield. A variety of organisms cannot
be detected by Gram stain, including species of Legionella, Myco-
plasma, Chlamydia, and Chlamydophila. However, in patients who
produce sputum of adequate quality to be examined (minimal or no
oropharyngeal contamination) and who have not received prior anti-
biotics, diagnostic yields of 80% for sputum Gram stain have been
reported in patients with bacteremic S. pneumoniae pneumonia.80
Despite its pitfalls, sputum Gram stain is noninvasive, can be carried
out at no risk to the patient, and under the right circumstances may
aid in the diagnosis and choice of empirical therapy in patients with
community-acquired pneumonia.82
Examination of the sputum should include observation of the color,
amount, consistency, and odor. Mucopurulent sputum is most com-
monly found with bacterial pneumonia or bronchitis. However,
sputum of a similar nature has been described in one third to one half
of patients with mycoplasma or adenovirus infections.83 Scant or
watery sputum is more often noted with these and other atypical
pneumonias. “Rusty” sputum suggests alveolar involvement and has
been most commonly (although not solely) associated with pneumo-
coccal pneumonia.84 Dark red, mucoid sputum (currant jelly sputum)
suggests Friedländer’s pneumonia caused by encapsulated Klebsiella
pneumoniae (Fig. 64-1).85 Foul-smelling sputum is associated with
mixed anaerobic infections most commonly seen with aspiration.72
To maximize the diagnostic yield of the sputum examination, only
samples with minimal oropharyngeal contamination should be
reviewed. As a guide, the number of neutrophils and epithelial cells
should be quantitated under low power (×100), with further examina-
tion reserved for samples containing 25 or more neutrophils and 10
or fewer epithelial cells. Samples with more epithelial cells and fewer
neutrophils are usually nondiagnostic and should be discarded. The

Figure 64-1  “Currant jelly” sputum associated with Klebsiella
pneumoniae pneumonia.
morphologic and staining characteristics of any bacteria seen should
be recorded and an estimate made of the predominant organisms
(Figs. 64-2 to 64-6). When no bacterial predominance exists, this
should be noted as well.
In the appropriate clinical setting, a predominance of gram-positive,
lancet-shaped diplococci should suggest pneumococcal infection (see
Fig. 64-2). When strict criteria for Gram stain positivity are used (pre-
dominant flora or more than 10 gram-positive, lancet-shaped diplo-
cocci per oil immersion field [×1000], or both), the specificity of the
Gram stain for identifying pneumococci has been shown to be 85%,
with a sensitivity of 62%.86 The diagnostic yield of the sputum exami-
nation for pneumococci can be maximized by the use of the quellung
reaction (see Fig. 64-3), although it is rarely used. Anticapsular anti-
serum reacts with capsular polysaccharide, and this may be seen as a
distinctly outlined capsule. Because pneumococci may be part of the
nasopharyngeal flora in 10% to 50% of healthy adults and often colo-
nize the lower airways in patients with chronic bronchitis, identifica-
tion of the organism does not mean that it is the cause of disease.87
However, it is our experience that the large number of pneumococci
necessary to produce a positive Gram stain or quellung reaction is
unusual in carriers. The Gram stain may reveal large numbers of
organisms in patients with bronchitis.
The sputum Gram stain is helpful to identify organisms other than
pneumococci. Small gram-negative coccobacillary organisms are char-
acteristic of H. influenzae (see Fig. 64-4). The sensitivity of the sputum
Gram stain for detecting H. influenzae is usually less than that for S.
Figure 64-2  Expectorated sputum with gram-positive, lancet-
shaped diplococci from a patient with pneumococcal pneumonia.
64  Acute Pneumonia 897
Figure 64-3  Expectorated sputum demonstrating a positive
quellung reaction in a patient with pneumococcal pneumonia.
pneumoniae but has been reported to be up to 80%. Staphylococci
appear as gram-positive cocci in tetrads and grapelike clusters (see Fig.
64-5). Organisms of mixed morphology are characteristic of anaerobic
infection. Few bacteria are seen with legionnaires’ disease, mycoplasma
pneumonia, and viral pneumonia. When the criteria for minimal oro-
pharyngeal contamination is met and when a predominant morphol-
ogy is observed, the sensitivity of the sputum Gram stain in matching
organisms found in the blood was reported to be 85% in patients with
community-acquired pneumonia. In contrast, sputum cultures posi-
tive for pneumococci are found in only 50% to 60% of patients with
pneumonia and pneumococcal bacteremia.88 In some centers, sputum
examination has been a useful means of diagnosing Pneumocystis
pneumonia in patients with AIDS. The use of commercially available
monoclonal antibodies or Giemsa’s, Gomori’s methenamine silver, or
toluidine blue O stain has led to a diagnosis in up to 50% of cases,
making more aggressive diagnostic procedures unnecessary.89 Special
sputum staining techniques are important in identifying other organ-
isms such as mycobacteria (Fig. 64-7).
Sputum culture as a means of diagnosing pneumonia is as contro-
versial as the sputum Gram stain. Not all patients with pneumonia will
produce sputum, and when they do, patients with bacteremic pneu-
mococcal pneumonia have been reported to have negative sputum
cultures in 45% to 50% of cases, even when large numbers of organ-
isms have been noted on a Gram stain.88 Similarly, 34% to 47% of
sputum cultures are negative with proven H. influenzae pneumo-
Figure 64-4  Expectorated sputum with gram-negative coccobacil-
lary forms from a patient with Haemophilus influenzae
pneumonia.
898 Part II  Major Clinical Syndromes
Figure 64-5  Expectorated sputum with clusters of gram-positive
cocci in a patient with Staphylococcus aureus pneumonia.
nia.90,91 Furthermore, sputum cultures have frequently been shown to
yield more bacterial species than more invasive methods of obtaining
respiratory tract secretions.92 Contamination with gram-negative
bacilli from the oropharynx has been noted in 32% of sputum cultures.
A lack of correlation between findings from sputum culture and find-
ings from blood cultures and serologic studies has been observed.
Several key parameters have been identified in efforts to maximize
the diagnostic yield from sputum culture. Procurement of adequate
sputum samples is an essential first step. With increasing numbers of
epithelial cells and decreasing numbers of neutrophils, an increased
amount of oropharyngeal contamination is present, as indicated by the
isolation of more bacterial species.
The presence of alveolar macrophages does not alter the bacterio-
logic findings when substantial numbers of epithelial cells are present,
indicating that otherwise adequate samples of sputum can be contami-
nated with oropharyngeal contents and thereby rendered nondiagnos-
tic. This type of initial screening has proved helpful in differentiating
adequate sputum samples from saliva, thereby increasing the diagnos-
tic yield of sputum culture. When organisms such as M. tuberculosis
(see Fig. 64-7), Legionella, and Pneumocystis are found in sputum,
clinical infection is indicated regardless of the sputum quality because
these organisms are not normal flora.
When culture of sputum is delayed, the isolation of pneumococci is
less likely because of overgrowth by oropharyngeal flora. Rapid pro-
cessing of samples is therefore another important factor leading to
Figure 64-6  Expectorated sputum with gram-negative rods in a
patient with Klebsiella pneumoniae pneumonia.
Figure 64-7  Expectorated sputum with acid-fast bacilli in a patient
with Mycobacterium tuberculosis.
higher diagnostic yield. Some reports suggest that with adequate
sputum samples and prompt culture of specimens, the diagnostic yield
of the sputum culture may be improved.
Antigen detection in respiratory secretions has been used for over 2
decades to try to maximize the diagnostic yield of sputum, especially
for infections caused by S. pneumoniae, Pneumocystis, Legionella pneu-
mophila, and a variety of respiratory viruses. The direct fluorescent
antibody assays for L. pneumophila and Pneumocystis jirovecii are the
most commonly used, with sensitivities of 25% to 75% for Legionella
and 80% for Pneumocystis. Specificities of 90% have been reported in
the assays for each pathogen. Strains of Legionella other than L. pneu-
mophila may be missed in these assays. For other organisms, such as
Chlamydophila, problems with colonization versus infection, varying
sensitivities, and cross-reactivity with nonpathogens have limited the
usefulness of the study.
Although direct fluorescent antibody tests have been used to
detect Chlamydia trachomatis, the assay is insufficiently sensitive
(varying between 20% and 60%) for detection of Chlamydophila
pneumoniae.93 On the other hand, direct fluorescent antibody assays
are over 80% sensitive and 90% specific when used for the detection
of Pneumocystis.
Detection of microbial nucleic acid in respiratory tract secretions
remains an area of ongoing study.94-97 Nucleic acid amplification
assays, especially polymerase chain reaction (PCR) are particularly
attractive because they have the capability of detecting minute amounts
of material from potential pathogens, do not appear to be influenced
by prior antibiotic therapy, and can be performed quickly. Although
a variety of PCR techniques have been described, FDA licensed assays
exist for only M. tuberculosis and Legionella species. Assays for more
commonly encountered organisms such as S. pneumoniae, H. influen-
zae, and Chlamydophila have been developed, but lack of standardiza-
tion and difficulty in determining true infection from colonization
remain problematic. False-negative results have been reported because
of the presence of natural inhibitors. Although PCR has been used to
detect P. jirovecii, published studies have detected positive results in
the setting of negative cultures and absence of clinical features of infec-
tion. Individual PCR assays as well as multiplex assays have been used
to detect viruses. It is unclear if positive results indicate upper rather
than lower respiratory tract infection, colonization, or true infection
of the lung. PCR has become a mainstay in the diagnosis of SARS.96
PCR techniques have been used to identify DNA from M. tuberculosis
in both sputum and lavage fluid. Sensitivities of 83.5% and specificities
as high as 99% have been noted. Sensitivities of 63% have been
reported in patients who were smear negative but culture positive.
However, PCR has been reported to be positive in 70% of people with
prior exposure to tuberculosis but no active disease. This problem of
false-positive results remains.

FIBER-OPTIC BRONCHOSCOPY
Although the sputum examination should always be included in the
initial evaluation of patients with pneumonia, it may be inadequate for
a presumptive diagnosis. In cases in which (1) no sputum is produced,
(2) no clear predominance of a potential pathogen exists on sputum
Gram stain or culture, (3) there has been a poor response to antibiotics
chosen on the basis of expectorated sputum, (4) gram-negative rods
or yeast forms are found in the sputum, or (5) the possibility of super-
infection exists, a more direct method of obtaining lower respiratory
tract secretions may be necessary.
Fiber-optic bronchoscopy is usually not performed in patients with
community-acquired pneumonia unless severe pneumonia, unresolv-
ing pneumonia, or a clear failure of antibiotic therapy is encountered.98
Use of the protected brush catheter and quantitative culturing of mate-
rial obtained from the procedure have both minimized the problem
of oropharyngeal contamination and helped to differentiate coloniza-
tion from true infection. Approximately 106 to 108 organisms per
milliliter (mL) are present in lung tissue involved with pneumonia.
Accounting for dilution of samples, a bacterial count of more than 103
to 104 has been used as a breakpoint for determining the clinical sig-
nificance of an isolate.
Although sensitivities of 70% to 97% and specificities of 95% to
100% have been reported in the diagnosis of community-acquired
pneumonia, bronchoscopy has proven to be less useful in some patient
groups.99 These include patients who have already received antibiotics,
patients with purulent bronchitis in whom bacterial counts greater
than 103 are noted, and patients with underlying structural disease in
whom over 50% of bronchoscopic specimens yield significant numbers
of organisms even in the absence of pneumonia.99 Gram stain of speci-
mens obtained from fiber-optic bronchoscopy has been used as a guide
to empirical therapy while cultures are pending. A positive Gram stain
predicts growth of more than 103 colony-forming units (CFU)/mL
with up to 78% sensitivity. When studied prospectively early in the
course of community-acquired pneumonia, bronchoscopy has yielded
a diagnosis in approximately 50% of patients.100
Bronchoscopy with a protected specimen brush has been shown to
have sensitivities as high as 82% to 100% and as low as 36% with
specificities as high as 60% to 77% and as low as 50%.101-103 Differences
in exclusion and inclusion criteria, different definitions of pneumonia,
and the acceptance or rejection of patients with recent antibiotic
changes may explain the different results.104 The use of antibiotics
markedly diminishes the diagnostic yield of the procedure.105 Most
bacterial species initially found by a protected specimen brush are
undetectable after 72 hours of antibiotic therapy, and the majority of
organisms found are resistant to the antibiotics given. These may have
no role in the infection. However, in a patient with ongoing pneumo-
nia despite antibiotic therapy, bronchoscopy with a protected speci-
men brush should pick up resistant organisms that may be playing a
role in infection.101
False-negative findings are seen in up to 30% to 40% of patients,
which may reflect the fact that bacterial counts may differ by fiftyfold
in areas of infected lung versus noninfected adjacent areas, making the
sampling site an important consideration. Other possible explanations
include prior antibiotic use, technique problems, and in some cases an
early stage of pneumonia where bacterial numbers are not yet high
enough to reach the breakpoint of the procedure.
Bronchoalveolar lavage (BAL), in which a segment of the lung is
washed with sterile fluid, is useful in establishing the etiologic agent of
pneumonia. Approximately 100 million alveoli are sampled, and con-
sequently a larger area of lung is evaluated than with the protected
specimen brush. A diagnostic threshold of 104 CFU/mL is used with
lavage because the procedure recovers 5 to 10 times more organisms
than brushing. The most consistent results have been seen in the diag-
nosis of Pneumocystis pneumonia in patients with AIDS. Diagnostic
yields of 89% to 98% have been reported.106 Excellent yields have been
noted in detecting cytomegalovirus in patients with AIDS as well as in
bone marrow and solid organ transplant recipients.107 Although the
64  Acute Pneumonia 899
isolation of the organism does not prove that it is the cause of the
pneumonia.
BAL has proved especially useful for diagnosing pneumonia caused
by M. tuberculosis.108 Culture of BAL material has a sensitivity of 85%,
even in the presence of negative cultures of expectorated sputum and
gastric aspirate. In patients with miliary tuberculosis in whom sputum
culture yields are low (25%), culture of M. tuberculosis from BAL fluid
approximates 100%. In addition to culture and staining, adenosine
deaminase levels and enzyme-linked immunosorbent assay (ELISA)
for antibodies to M. tuberculosis have been studied.109,110 BAL has also
been used for the diagnosis of atypical pneumonias, including those
caused by Legionella species and M. pneumoniae.
Both bronchoscopy and BAL have been used widely in patients with
ventilator-associated pneumonia (VAP).111,112 The “bacteriologic strat-
egy” used in attempting to make an etiologic diagnosis in patients with
VAP uses bronchoscopy, BAL, and endobronchial aspiration to estab-
lish the presence or absence of pulmonary infection as well as to
determine the specific etiology.69
Although the risks of bronchoscopy are relatively small, hypoxia
occurs in 13% to 28% of patients on ventilators undergoing BAL. In
patients with gram-negative pneumonia, the procedure may be fol-
lowed by a sepsis-like picture with increased temperature and decreased
mean arterial pressure.
OTHER TECHNIQUES
A variety of less invasive techniques have been used in attempts to
determine the cause of pneumonia without resorting to bronchoscopy.
Blind endotracheal suctioning with quantitative cultures has com-
pared favorably with bronchoscopic procedures in some studies.113
With a threshold of greater than 105 CFU/mL, the sensitivity for pre-
dicting ventilator-associated pneumonia was comparable to that of
lavage or protected brush procedures, although the specificity was
somewhat lower.113 Furthermore, no differences in mortality, length of
stay in the intensive care unit, or duration of mechanical ventilation
were noted when quantitative endotracheal cultures were used as the
sole means of diagnosis compared to bronchoalveolar lavage and to
protected specimen brush. Others have reported false-negative rates of
over 30% and many more organisms isolated by endotracheal suction-
ing than by brushing.114 At present, this procedure is best used when
bronchoscopy cannot be done.
The blind protected specimen brush has compared favorably with
bronchoscopically guided procedures, with 86% agreement.115 Non-
bronchoscopic bronchoalveolar lavage has been obtained in some
cases by a protected catheter to minimize contamination. Sensitivities
of 70% to 80% and specificities of 66% to 96% have been noted.116
Mortality from ventilator-associated pneumonia is unchanged inde-
pendent of whether bronchoscopic or nonbronchoscopic procedures
are used for diagnosis.117
LUNG BIOPSY
Direct means of obtaining diagnostic material in patients with pneu-
monia include percutaneous lung aspiration, transbronchial lung
biopsy, thoracoscopy, and open lung biopsy.118 These procedures are
usually reserved for cases of pneumonia in impaired hosts and in
pediatric populations, in whom sputum is not routinely available.
Biopsy procedures are rarely indicated in the previously well patient
with acute pneumonia. The indications and usefulness of these inva-
sive procedures remain controversial. Lung aspiration has provided a
diagnostic yield of 30% to 82% in adults and children, although false-
negative rates of up to 18% have been reported.119 Bleeding and pneu-
mothorax have been reported as major complications in 5% to 39%
of procedures.119 The use of transbronchial biopsy in the diagnosis of
pneumonia has been reviewed, revealing similar diagnostic yields
although somewhat lower complication rates.120
Thoracoscopy, in which the pleura and underlying lung are visual-
ized before biopsy, has been used in several series of children and
900 Part II  Major Clinical Syndromes
adults with pneumonia. Despite a diagnostic yield of over 90% and
low complication rates,121,122 there has not been extensive experience
with this procedure.
Open lung biopsy remains the definitive invasive procedure for
making an etiologic diagnosis of pneumonia in immunosuppressed
patients, with diagnostic yields of 60% to 100%.123 The incidence of
pneumothorax and bleeding is usually less than 10%, even in patients
who are thrombocytopenic.120 However, some have questioned
whether open lung biopsy provides meaningful information that sig-
nificantly affects a patient’s clinical outcome.
EXAMINATION OF PLEURAL EFFUSIONS
The characteristics of pleural effusions and their importance in the
differential diagnosis of pulmonary disease are discussed in Chapter
65. Pleural effusion or parapneumonic effusion will occur in 20% to
40% of hospitalized patients with pneumonia.124 The incidence of
pleural effusions associated with pneumonia varies with the etiologic
agent, from approximately 40% to 57% with pneumococci, to 50% to
70% with gram-negative bacilli, to up to 95% with group A strepto-
cocci.84,125 Pleural fluid cultures, when positive, are specific for the
organism causing the underlying pneumonia. Furthermore, analysis of
pleural fluid may play a major role in determining when drainage is
necessary as well as differentiating other causes of pulmonary infil-
trates that may mimic bacterial pneumonia, including tuberculosis,
tumors, pulmonary emboli, and collagen vascular diseases. If neutro-
phils are not the predominant cell type seen in the pleural space, a
diagnosis other than bacterial pneumonia should be sought. Pleural
biopsy specimens from patients with acute bacterial pneumonia
are nonspecific and are therefore of little use in the differential
diagnosis.
Parapneumonic effusions can be divided into three stages.124,125
The first stage or exudative stage is culture negative, has a pH
greater than 7.2, glucose level greater than 60  mg/dL, and an LDH
level that is less than three times normal. This stage is due to pulmo-
nary interstitial fluid entering the pleural space and increased perme-
ability of the capillaries in the pleura. These uncomplicated pleural
effusions usually resolve with therapy for the underlying disease.
Without appropriate therapy, pleural effusions become infected
with the organisms causing the underlying pneumonia and develop
into the second stage or fibropurulent stage. This is associated with
positive microbial cultures, pH less than 7.2, glucose level less than
60  mg/dL, and LDH greater than three times normal. This is now a
complicated pleural effusion which requires drainage. The most sensi-
tive finding in determining if a pleural effusion needs drainage is a
pleural fluid pH less than 7.2. This usually occurs before the other
chemical parameters associated with complicated pleural effusions
develop.124 If pH is used to determine whether an effusion is to be
drained, it must be measured with a blood gas machine and not a
pH meter or pH indicator strip, which are inaccurate. If left untreated,
fibropurulent pleural effusions will develop into stage three effusions
where a thick pleural rind is formed, restricting normal lung
expansion.
Empyema is defined as pus in the pleural space and represents a
late manifestation of complicated pleural effusions. The presence of
empyema mandates draining the pleural space.
Complicated pleural effusions will yield positive culture results over
50% of the time, making thoracentesis and culture of fluid a valuable
means of making an etiologic diagnosis of the underlying pneumo-
nia.126 Other diagnostic tools have proven useful in identifying organ-
isms associated with pleural effusions. PCR technology has been useful
in detecting M. tuberculosis in effusions with a sensitivity of approxi-
mately 70% and specificity of 100%.127 Adenosine deaminase, an
enzyme associated with lymphocytes, may also be used to detect M.
tuberculosis, with sensitivity and specificity of 93%.128,129 Detection of
the lymphocyte-related cytokine soluble IL-2 receptor may also be
useful.
BLOOD CULTURE, SEROLOGIC STUDIES, AND URINE
STUDIES, INCLUDING ANTIGEN DETECTION
Blood cultures are positive in 4 to 18 of patients hospitalized with
community-acquired pneumonia.130-134 Recent studies have suggested
that positive blood cultures add little to the management of patients
hospitalized with community-acquired pneumonia and are not pre-
dictive of increased mortality. Although some studies have suggested
that the presence or absence of bacteremia cannot be predicted, others
have shown that the presence of liver disease, hypotension, hyperther-
mia or hypothermia, tachycardia, elevated BUN, hyponatremia, and
increased or decreased WBC are independent predictors of bacteremia
and can be used to define a “high-risk” group of patients.130-132 The
presence of positive blood cultures is highly specific, may be helpful in
narrowing antibiotic use, and may identify the presence of unusual
organisms that would not be adequately covered by routine empirical
antibiotic coverage.133,135 Therefore, blood cultures should be obtained
in all patients suspected of having bacterial pneumonia who are ill
enough to be hospitalized. Further, because the etiology of pneumonia
is not always found, assessment of clinical response to initial therapy
is important. Blood cultures may be of help in patients not responding
to antibiotic therapy.133
Serologic assays have been used for decades to try to identify poten-
tial etiologies of pneumonia. Success has been limited, although recent
improvements have been made. Serum antibody assays for diagnosis
of M. pneumoniae and C. pneumoniae infection have been widely
used. The Centers for Disease Control and Prevention (CDC) and the
Laboratory Centre for Disease Control (LCDC) have established diag-
nostic standards. Microimmunofluorescence (MIF) for serum chla-
mydophilal antigens has been recommended, though enzyme immu-
noassays are also available and may be more sensitive and specific.136
An IgM titer of greater than 1 : 16 or a fourfold rise in IgG value is used
to define positivity. Use of a single IgG value is not viewed as a defini-
tive test. Because the present assays show day-to-day variation, it has
been suggested that acute and convalescent titers be assayed at the
same time.137 A fourfold rise in IgG rather than a single clinical titer is
accepted as a positive test for M. pneumoniae. Although an elevated
IgM titer suggests a recent infection, reinfection with mycoplasma
occurs frequently and a rise of IgM may not always be seen.138 Cold
agglutinins may be elevated in infections with M. pneumoniae. Titers
greater than or equal to 1 : 4 are suggestive of M. pneumoniae infection.
For both Mycoplasma and Chlamydophila infections, nucleic amplifi-
cation technologies are being examined as alternative diagnostic
modalities.
S. pneumoniae produces a variety of antigens and surface markers
that are type- or species-specific.139 Although both antigen and anti-
body detection methods in serum have been studied, none has
become clinically significant. PCR techniques have been applied to
whole blood for the detection of pneumococci, but the assays remain
experimental.140
A variety of assays have been used to detect pathogens that have
been difficult to isolate using routine culture techniques. Serologic
assays have been used to diagnose infections caused by Legionella
species, M. pneumoniae, Chlamydophila species, and Coxiella bur-
netii.141 The sensitivity and specificity of the assays vary, and their
overall usefulness in making a rapid diagnosis is limited.
PCR has also been used to detect DNA from Pneumocystis in blood
from patients with AIDS and in BAL fluid.142 PCR techniques have also
been used for detection of Legionella and can be designed to detect all
the Legionella species. DNA probes have been used to successfully
identify M. tuberculosis, Mycobacterium avium intracellulare, Mycobac-
terium kansasii, and Mycobacterium gordonae from colonies growing
in solid and liquid medium, which has reduced the time of identifica-
tion from 59 days to between 17 and 31 days.
A variety of cytokines are released into the circulation as a result
of infection.143-146 Evidence suggests that these biomarkers may be
useful adjuncts in diagnosing pneumonia and predicting severity of

disease.143-146 The calcitonin family of gene products, especially procal-
citonin, C-reactive protein (CRP), and soluble triggering receptor
expressed on myeloid cells (STREP-1), have been the markers most
often associated with pneumonia. Procalcitonin appears to be the ear-
liest marker to appear during the course of infection. Elevated levels
(greater than 0.25 to 0.5  µg/L) have been used in some studies to
decide which patients should be treated with antibiotics and, based on
whether levels fall, how long antibiotics should be continued.147,148
Procalcitonin has also been used as a gauge of pneumonia-related
mortality.149 C-reactive protein is an acute-phase reactant produced in
the liver as a response to a variety of stimuli, including infection.
Normal values of less than 10 mg/L are unusual in patients with pneu-
monia and can be used to exclude the diagnosis. Levels of 100 mg/L
or greater suggests the diagnosis of pneumonia and has been associated
with an increased 30-day mortality and a greater likelihood of need for
ventilator or vasopressor support, all associated with severe pneumo-
nia.146 In comparative trials with procalcitonin, CRP appears to have
the best diagnostic capability although definitive studies are lacking.145
Other cytokines studied include IL-6 and TNF-α, but their correla-
tions with pneumonia appear less consistent. Cortisol levels have also
been shown to predict the severity of pneumonia and the chance of
survival.150,151 Large-scale, randomized studies using biomarkers are
lacking, and therefore their role in diagnosis and severity assessment
in pneumonia has not been clearly defined. Some have felt that these
biomarkers offer little more than the severity assessment tools already
used clinically.152
Antigen detection in urine rather than blood or sputum has become
a successful means of detecting some important pulmonary pathogens.
Soluble L. pneumophila antigen can be detected in urine using a com-
mercially available enzyme immunoassay (EIA). Although it is useful
for detecting only L. pneumophila serogroup 1, this assay offers the
advantage of being rapid and noninvasive, and it has a sensitivity of
80% to 95% and a specificity estimated to be 99%.153 A relative problem
with this method is that antigenuria may persist for weeks to months
after therapy.153
An immunochromatographic membrane test has been developed to
detect the C polysaccharide cell wall antigen found in all S. pneumoniae
in urine of patients with pneumonia (Binax NOW; Binax, Inc., Scar-
borough, ME).154 This has been reported to be an extremely useful
means of diagnosing pneumococcal pneumonia. Using a variety of
standard diagnostic tests as controls, overall sensitivities of 65.5% to
A B
Figure 64-8  A, Normal chest radiograph. B, Patchy infiltrate representing bronchopneumonia in a patient with Streptococcus pneumoniae
infection.
64  Acute Pneumonia 901
100%, specificities of approximately 94% to 100%, and positive pre-
dictive values of 62% have been noted.155-159 Sensitivities have, in
general, been high in bacteremia episodes, with the yields increased
slightly by concentrating the urine. The test is not affected by the prior
use of antibiotics. Potential problems with the urinary antigen assay
include weakly positive results caused by non-pneumococcal organ-
isms, false-positive results in children with nasopharyngeal carriage
rather than true infection, and positive results lasting for weeks after
the infection has resolved.156,160 A shortfall of the test is that no organ-
ism is isolated and no antibiotic susceptibilities can be carried out.
Despite these problems, the urinary antigen test for S. pneumoniae has
become an accepted diagnostic modality and has been recommended
in the IDSA/ATS. Recently, an assay for detection of pneumolysin in
urine has been developed. Although studies are limited, sensitivity
appears lower than that of the Binax NOW assay for C polysaccharide,
but specificity appears comparable.161
RADIOLOGIC EXAMINATION
Chest radiography plays a critical role in the diagnosis of pneumonia,
and for many it represents the gold standard of making a clinical
diagnosis. The differential diagnosis of respiratory complaints and
abnormal physical findings includes upper and lower respiratory tract
infection as well as an array of noninfectious entities. Demonstration
of an abnormal chest radiograph consistent with pneumonia differen-
tiates a patient population that may benefit from antibiotic therapy
from the populations that will not. Because overuse of antibiotics for
therapy of upper respiratory infections has been documented and may
contribute to the growing problem of antibiotic resistance, identifying
patients who really should be receiving antibiotic therapy is clearly of
importance. The chest radiograph is readily available, is reasonably
reliable (despite interobserver variability),162,163 and should be obtained
in most patients suspected of having pneumonia.78,162-164 The extent
and nature of radiographic abnormalities may define patients who are
more seriously ill and may need close monitoring.
The chest film usually does not show an infiltrate pattern that is very
helpful in making a specific etiologic diagnosis (Fig. 64-8). However,
certain features may be of some diagnostic aid. Lobar consolidation,
cavitation, and large pleural effusions support a bacterial cause (Figs.
64-9 and 64-10). Most lobar pneumonias are pneumococcal, whereas
most pneumococcal pneumonias are not lobar. When bilateral diffuse
902 Part II  Major Clinical Syndromes

A B
Figure 64-9  A, Chest radiograph showing dense left lower consolidation consistent with bacterial pneumonia, in this case caused by Streptococ-
cus pneumoniae. B, Lateral radiograph of a patient with left lower lobe pneumococcal pneumonia.

involvement is noted, Pneumocystis pneumonia, Legionella pneumo-
nia, or a primary viral pneumonia should be suspected. Staphylococcal
pneumonia may result from infection metastasizing from a primary
focus unrelated to the lung. In these cases, multiple nodular infiltrates
throughout the lung may be seen. Staphylococci may cause marked
necrosis of lung tissue with ill-defined thin-walled cavities (pneuma-
toceles), bronchopleural fistulas, and empyema, especially in children
(Fig. 64-11). Although pneumatoceles are diagnostically significant
findings in staphylococcal pneumonia, they may be seen in pneumo-
nias with other causes, including K. pneumoniae, H. influenzae, S.
pneumoniae, and, more rarely, Pneumocystis. Staphylococcus aureus
producing the Panton-Valentine leukocidin, whether methicillin-

A B
Figure 64-10  Chest radiographs showing a large left pleural effusion in a patient with Klebsiella pneumoniae pneumonia.
 64  Acute Pneumonia 903

People with legionnaires’ disease may initially present with a radio-

graphic picture similar to that of mycoplasma pneumonia. A patchy
interstitial or finely nodular pattern is seen in the lower lobe.174
However, unlike the situation with mycoplasmal pneumonia, pneu-
monia with more than two-lobe involvement is commonly seen. Rapid
progression and pleural effusions are also common. Pulmonary
nodules, either single or multiple and with segmental infiltrates, may
occur with pneumonia caused by Legionella micdadei. As in pneumo-
nia caused by L. pneumophila, rapid radiologic progression of the
disease is characteristic.175
Chest radiographs are most helpful in conjunction with the clinical
history and physical examination, but, as noted previously, are often
not helpful in making a specific etiologic diagnosis. Without clinical
information, readings of radiographs correctly identify pneumonia
as bacterial only 67% of the time and as viral only 65% of the
time. Mycoplasmal pneumonia is usually incorrectly identified as
bacterial.
The usefulness of computed tomography (CT) in managing chest
Figure 64-11  Pneumatocele formation in the left upper lobe of a infections, including pneumonia, has been reviewed.176,177 In the
patient with staphylococcal pneumonia. immunocompetent host, chest CT is most helpful in evaluating recur-
rent pneumonia or infections unresponsive to therapy. Pneumonia
resistant or not, is associated with necrotizing pneumonia with multi- developing behind an obstruction caused by tumors or other masses
lobar cavitary lesions and is frequently associated with pleural effusions and lung abscess may also be better defined by CT than by routine
and empyema.165,166 Pulmonary infections due to Pseudomonas may chest radiographs. High-resolution CT has been shown to improve
cavitate. Pseudomonas and other gram-negative bacilli most com- radiographic characterization of lung infection.176 Compared with a
monly cause lower lobe pneumonia. routine chest radiograph, high-resolution CT detects lung abnormali-
Aspiration pneumonia should be considered along with gram- ties more often and does a better job in defining disease in the upper
negative and staphylococcal pneumonias as a source of necrotizing and lower lobes and in the lingula. However, exposure to more radia-
pneumonia, cavitation, and empyema. Aspiration pneumonia com- tion (the radiation from one CT scan equals that from six to seven
monly involves either the superior segment or the basilar segment of chest radiographs) and the increased expense (approximately seven
either lower lobe, or the posterior segment of the upper lobes, depend- times the cost of a chest radiograph) has limited its use as the initial
ing on whether aspiration occurred in the dependent or the upright radiographic procedure. Furthermore, it is unclear if all abnormalities
position. Chronic aspiration most commonly results in bilateral lower found on the chest CT scan truly represent pneumonia.177 In the
lobe pneumonia, although it may involve one side more than the immunocompromised host in whom infection is only one of the pos-
other. sible causes of abnormal chest radiographs, chest CT or one of its
Viral infection of the lower airway involves respiratory epithelium variations, such as spiral CT or high-resolution CT, may aid in better
and parenchyma adjacent to terminal respiratory bronchioles. Diffuse defining a “questionable” chest radiograph and may be helpful in
hemorrhagic congestion of alveolar septa may occur as well.167 The localizing involved areas of lung as a guide to biopsy procedures.
radiographic concomitants of these pathologic findings usually involve Certain infections, such as those caused by Aspergillus, M. tuberculosis,
patchy areas of peribronchial ground-glass opacity, air-space consoli-
dation, and poorly defined small nodules. Diffuse and localized
involvement with both interstitial and alveolar patterns has been noted
(Fig. 64-12).167 There is little radiologic distinction between the various
viral etiologies of pneumonia. Influenza pneumonia is associated with
poorly defined, patchy air-space consolidation with rapid confluence.
Varicella pneumonia usually involves peribronchial involvement with
nodular infiltrates. Adenovirus, which is more common in immune-
compromised hosts, may be associated with diffuse bilateral broncho-
pneumonia, areas of overinflation, atelectasis, and nodular opacities.168
Lobar or subsegmental consolidation mimicking bacterial pneumonia
may also be seen. People with hantavirus pneumonia usually present
with interstitial edema, which may progress to consolidation repre-
senting a pulmonary capillary leak syndrome. Bilateral involvement
and pleural effusion are common.167 In the majority of cases of SARS,
caused by a coronavirus, bilateral basilar infiltrates primarily involving
an interstitial pattern are present. Progression with symmetrical air-
space disease has been commonly described.169,170 A recently defined
viral pulmonary pathogen is the human metapneumovirus. Although
most cases involve upper respiratory tract infections in children, pneu-
monia in adults has been described.171,172 Multilobe infiltrates have
been noted in 50% of cases, though most disease is unilateral.
Mycoplasma pneumonia often manifests with an interstitial pattern
in a peribronchial and perivascular distribution. Consolidation is
noted in approximately 38% of patients, usually in the lower lobe.
Once this consolidation stage is reached, radiologic differentiation
between bacterial and mycoplasmal pneumonia is difficult. Cavitation
is rare, although pleural effusions may be seen in approximately 20% Figure 64-12  Bilateral involvement with a mixed interstitial-alveo-
of cases.173 lar pattern in a patient with viral pneumonia.
904 Part II  Major Clinical Syndromes
and Pneumocystis, have characteristic appearances on CT that in the
correct clinical setting may make invasive procedures unnecessary.
Techniques such as perfusion magnetic resonance imagery have been
shown to be able to differentiate pneumonia from COPD and pulmo-
nary emboli. The clinical utility of these techniques remains to be
defined.
Nuclear medicine procedures have been used to detect pneumonia.
These procedures include gallium-67 citrate scans, indium-111–
labeled granulocyte scans, and technetium-99 diethylenetriamine
penta-acetic acid aerosol clearance.178 In general, these procedures
have been used in patients with AIDS to define the presence of lung
infection in the absence of abnormal chest radiographs. In patients
with AIDS, diffuse uptake of gallium is usually seen with Pneumocystis
infection but may also be seen with infection caused by Mycobacterium
avium complex, cytomegalovirus, and Cryptococcus neoformans, and
in patients with lymphoma. Localized uptake may be associated
with bacterial disease. Focal uptake corresponding to lymph node
areas has been associated with M. avium complex, M. tuberculosis,
and lymphoma.
Pneumonia Syndromes
ACUTE COMMUNITY-ACQUIRED PNEUMONIA
A long list of bacterial, fungal, viral, and protozoal agents may cause
pneumonia. Because initial evaluation rarely results in a specific etio-
logic diagnosis, antibiotic therapy is usually begun empirically. Defin-
ing pneumonia syndromes on the basis of clinical, epidemiologic,
radiographic, and laboratory parameters, with a limited number of
organisms commonly associated with each syndrome, has helped the
clinician to select rational empirical therapy for the most likely
organisms involved. Many of the syndromes have overlapping signs
and symptoms, which at times makes clear identification of a specific
syndrome in an individual impossible.179,180 Furthermore, the charac-
teristics of the syndrome of acute community-acquired pneumonia
as defined almost 30 years ago are changing.48,180,181 Increases in the
numbers of patients living longer, more and varied comorbidities, and
expanded contact with various aspects of the health care system have
led to a wider array of presentations, etiologic agents, and strategies
for empiric therapy. Newly described microbial agents are being
recognized as potential causes of community-acquired pneumonia.
Subgrouping syndromes under the general description of community-
acquired pneumonia may be made based on patient age, severity of
illness, comorbidities, need for hospitalization, and epidemiologic
setting.
Patients with acute community-acquired pneumonia are usually in
their mid 50s to late 60s. Peak incidences of disease in midwinter and
early spring have been described, but there is no “pneumonia season,”
and disease takes place throughout the year. Most patients (58% to
89%) have one or more chronic underlying diseases. Immunosuppres-
sion related to malignancy, neutropenia, the chronic use of steroids or
myelosuppressive agents, or HIV infection may be present in up to
57% of patients.180,182
Classically, community-acquired pneumonia presents with a sudden
onset of a chill followed by fever, pleuritic chest pain, and cough that
produces mucopurulent sputum. The signs, symptoms, and physical
findings vary according to the age of the patient, therapy with antibiot-
ics before presentation, and the severity of illness. These classic find-
ings in some combination are present in approximately 81% of patients
with community-acquired pneumonia. Patients usually present after
having been ill for a mean of 6 days. Cough is noted in greater than
80% to 90% of patients and is productive in 60% to 80%.45,180,181 Chest
pain is present in 30% to 46% of cases, chills in 40% to 70%, and true
rigors in 15%.44,45,180
A variety of nonrespiratory symptoms are associated with pneumo-
nia, including fatigue (91%), anorexia (71%), sweats (69%), and
nausea (41%).44 Both respiratory and nonrespiratory findings occur
less frequently in older age groups.44
Physical examination reveals fever in 68% to 78% of patients but
may be seen less commonly in older populations. Tachypnea (respira-
tory rate greater than 24 to 30 breaths per minute) is noted in 45% to
69% of patients and may be more frequently seen in older age groups.44
Tachycardia (pulse rate greater than 100 beats/min) is noted in 45%.
Rales are noted in 78% of patients, and signs of consolidation are noted
in 29%.
Most commonly, the white blood cell count is in the range of 15,000
to 35,000/mm3, and the differential cell count reveals an increased
number of juvenile forms. Leukopenia may be noted and is a poor
prognostic sign.183 The hematocrit and the red blood cell indices are
usually normal.
Sputum is thick and purulent and may be rust colored. The sputum
Gram stain reveals numerous neutrophils and bacteria, often with a
single organism predominating. Chest films show areas of parenchymal
involvement, usually with an alveolar-filling process. There is moderate
hypoxemia due to ventilation perfusion abnormalities. Even with rig-
orous laboratory evaluation and using definitions of definite, probable,
and possible causes, a microbiologic diagnosis may be made in only 20%
to 70% of cases of community-acquired pneumonia.47,82,180
In the past, 50% to 90% of cases of acute community-acquired
pneumonia were caused by S. pneumoniae.43 More recently, some pub-
lished reports have indicated that the relative importance of the pneu-
mococcus has varied, showing this range to be from 16% to 60%.65,181
However, pneumococcus remains the leading cause of the syndrome
of acute community-acquired pneumonia in most series.
Severe pneumococcal infections, including pneumonia, have been
associated with prior splenectomy due either to trauma or to staging
for Hodgkin’s disease,184-186 abnormal immunoglobulin responses
(myeloma, lymphoma, HIV infection),187 and functional asplenia due
to systemic lupus erythematosus or marrow transplant.
An estimated 3% to 38% of cases of acute community-acquired
pneumonia are caused by H. influenzae.48,188 The true incidence of this
organism is obscured by the difficulty of isolating it from sputum and
identifying it in sputum Gram stain, and by the difficulty of distin-
guishing colonization from infection. The age of patients, presence of
underlying disease, and presentation are all similar to those of pneu-
mococcal disease. Although the use of the H. influenzae conjugate
vaccine has decreased the incidence of invasive disease caused by H.
influenzae type B, there is a strikingly increased incidence of invasive
disease including pneumonia caused by nontypeable strains. In one
series, over 50% of isolates from patients with invasive H. influenzae
disease were nontypeable.189
Classically, S. aureus has accounted for 2% to 5% of acute commu-
nity-acquired pneumonia cases190 and takes on increased importance
as a cause of pneumonia in older adults and in those with influenza.
Patients who develop postinfluenza pneumonia may be younger and
have less underlying disease than other patients with community-
acquired pneumonia. Clinical signs and symptoms of influenza are
present but appear to resolve over several days. After a variable period
of time ranging from 2 to 14 days, symptoms suddenly reappear, with
the onset of shaking chills, pleuritic chest pain, and cough that pro-
duces purulent sputum. An elevated white blood cell count with a shift
to the left, physical signs of pulmonary consolidation, and radio-
graphic evidence of focal parenchymal disease appear. The sputum
Gram stain is consistent with bacterial pneumonia. Although pneu-
mococcus still represents the most common etiologic agent, staphylo-
coccal disease occurs with a higher frequency than that noted in
non–influenza-related, community-acquired pneumonia.
As noted previously, in 2002 many cases of community-acquired
pneumonia caused by S. aureus were described in France.49,191 Patients
were young, had few if any comorbidities, usually presented after a
flulike illness with high fevers, leukopenia, tachycardia, tachypnea,
and multilobar disease on x-ray rapidly evolving into bilateral disease.
Acute respiratory distress syndrome (ARDS) was a frequent complica-
tion of infection and mortality rates were higher than in patients with
pneumonia caused by S. aureus without the Panton-Valentine leuko-
cidin. Similar disease patterns have been described in the United States

with these strains of community-acquired of MRSA, or CA-MRSA.50,192
These CA-MRSA pneumonias are associated with severe pneumonia
with mortality rates of 29% to 60%. Flulike illness precedes the onset
of disease in 75% of patients with documented influenza noted in 71%
of cases. CA-MRSA pneumonia has therefore become an important
entity to consider in the right clinical setting.
Aerobic gram-negative bacteria, exclusive of H. influenzae, and
mixed aerobic and anaerobic infections cause most of the remaining
cases of acute community-acquired pneumonia. Gram-negative rods
may cause anywhere from 7% to 18% of pneumonia cases. K. pneu-
moniae, P. aeruginosa, and Enterobacter species are the most often
isolated organisms.193 Gram-negative bacilli are particularly important
pathogens in older adults, especially those with chronic underlying
disease and those who are bedridden and recently hospitalized. Pseu-
domonas infection should be suspected in patients with pulmonary
comorbidities and recent hospital stays.
Legionella species are the most important water-related pulmonary
pathogens in the United States with regard to mortality and morbidity.
The importance of Legionella species in causing pneumonia has varied
greatly in different geographic areas, with incidences ranging from 2%
to 30%.180,194 Since 2003, an increased incidence of legionellosis has
been observed in the United States, especially on the East coast.195
Although infection may occur at any age, those aged 45 to 64 now
appear to be at greatest risk. No clinical features reliably distinguish
Legionella species pneumonia from that caused by other bacteria.196
However, the presence of a high fever (greater than 40° C), male sex,
previous β-lactam therapy, multilobar involvement, rapid progression
of radiographic abnormalities, a need for intensive care, gastrointesti-
nal and neurologic abnormalities, elevated liver enzyme levels, and
increased creatinine levels have all been associated with Legionella
pneumonia.180,194,196
Moraxella catarrhalis has also been identified as a cause of pneumo-
nia.197 The overall incidence of disease caused by this bacterium is low,
but it is an important pathogen in older adults with COPD and various
forms of immunosuppression.
COMMUNITY-ACQUIRED PNEUMONIA IN
THE OLDER ADULT
Pneumonia in the elderly has become an increasingly important clini-
cal entity as the world’s population has aged.198 Pneumonia is the
second or third most common reason for hospitalization in those 65
and older and represents a major cause of morbidity and mortality. In
some series, pneumonia represents the leading cause of death in this
population (see Chapter 314). For those older than 60 years, pneumo-
nia is a predictor of increased mortality after the specific episode has
resolved and for several years thereafter.199
The clinical presentation of pneumonia in older adults (especially
those older than 80) may be more subtle than in younger populations,
with more gradual onset of symptoms and fever and the classic signs
of pneumonia.44,180,200 Fever occurs less commonly in older adults, and
temperature elevation is muted.44,180,200 The classic findings of cough,
fever, and dyspnea may be absent in over half of older adults.201 Chills
and rigors may be less frequently seen as well.44,180 Tachypnea (respira-
tory rate of greater than 24 to 30 breaths per minute) is a more fre-
quent finding in older adults and has been observed in up to 69% of
patients. Rales are common and are noted in 78% to 84% of patients,
although signs of true consolidation are found in only 29%. Nonres-
piratory symptoms may be the major presenting feature. The initial
presentation of older adults with pneumonia may include decline in
functional status, weakness, subtle changes in mental status, and
anorexia or abdominal pain. It has been suggested that the nonspecific
presentation of pneumonia in older adults may result in great part
from the prevalence of dementia in this population.201 Bacteremia,
metastatic foci of infection, and death are more frequent in older
populations.48,67,183
Specific etiologic diagnoses are made less frequently in older adults,
with approximately 20% to 50% of patients having an etiologic agent
64  Acute Pneumonia 905
defined.200 The absence of productive cough and common prior use of
antibiotics may explain this observation. Etiologies have varied in dif-
ferent series depending on the means of diagnosis, the patient popula-
tion studied (outpatient versus institutionalized older adults), and the
geographic location. In general, the cause of community-acquired
pneumonia in the older population follows the general trend of infec-
tion in younger populations. S. pneumoniae remains the predominant
organism, accounting for 20% to 60% of cases. H. influenzae, usually
a nontypeable strain, is frequently the second most common agent,
accounting for 7% to 11% of episodes.202 The importance of other
aerobic gram-negative bacilli in causing pneumonia in older adults
remains a question in part because the criteria for diagnosis of true
pneumonia versus colonization vary. In recent studies, 1% to 3% of
pneumonia may be caused by non-Haemophilus gram-negative
bacilli.200 Although increased oropharyngeal colonization with aerobic
gram-negative bacilli has been documented in the older population
and is thought to be a predisposition to development of pneumonia
caused by these organisms, colonization appears to be related to debil-
ity of the patient rather than age.203 Other factors associated with
increasing colonization with gram-negative organisms include prior
use of antibiotics, decreased activity, diabetes, alcoholism, and incon-
tinence. Older adults are at greater risk for infection with group B
streptococci, M. catarrhalis, and Legionella species, although the overall
incidence of these agents in the older population is relatively low.197
Legionella has been described as a cause of severe pneumonia (see later
definition) in the elderly. Polymicrobial infections and pneumonia due
to aspiration have both been noted to occur more frequently in older
adults.67,204
It is unclear which agents cause atypical pneumonia in the older
population. Most series suggest that M. pneumoniae pneumonia is
unusual, although it has been documented by other investigators to be
a significant cause of pneumonia leading to hospitalization in older
adults.47,205,206 In one series, over 15% of the documented cases of
mycoplasmal pneumonia were in patients 60 years or older.205 Chla-
mydophila infections appear commonly in the older population and
may cause up to 32% of pneumonias.207
Viral agents play an important role as etiologies of pneumonia in
the elderly although historically their role has been underestimated
given the difficulty in culturing them and the relative insensitivity of
serologic tests.208,209 With the development of sensitive nucleic acid
amplification tests like the reverse transcriptase polymerase chain reac-
tion, their role as a cause of pneumonia has begun to be more clearly
defined.208-210 Recent studies have suggested a viral etiology in 15% to
29% of all patients hospitalized with pneumonia with significantly
more viral infections noted in the older age groups (median age of
76).210, 211 Influenza is consistently the most commonly isolated virus
usually followed by respiratory syncytial virus (RSV), human meta-
pneumovirus, parainfluenza virus, enterovirus, and coronavirus.
Approximately 16% to 27% of viral pneumonias are mixed infections
with bacteria.210,211 Increased adherence of S. pneumoniae to human
tracheal epithelial cells in the presence of rhinovirus has been reported
with a similar relationship observed with enteroviruses.212 This rela-
tionship raises the question as to whether some viruses play a role as
facilitators for bacterial infection rather than roles as true pulmonary
pathogens.
Clinically, viral pneumonia in the elderly cannot be differentiated
from bacterial pneumonia by clinical, routine laboratory, or radiologic
parameters. As with bacterial disease, the signs of viral pneumonia may
be more subtle and may only involve fever and altered mental status.209
Dyspnea, wheezing, and productive cough are commonly observed.
Myalgia, though commonly found with most viral etiologies, is most
often seen with influenza. Bronchospasm and wheezing are seen more
commonly with RSV.208
NURSING HOME PNEUMONIA
Residents of nursing homes represent an important subpopulation of
older adults at risk for pneumonia.213 Pneumonia is the second most
906 Part II  Major Clinical Syndromes
frequent infection in this setting and carries the highest mortality of
any infection.214 In addition, it is a common reason for the elderly to
be hospitalized.215 Silent aspiration is a major risk factor, as are poor
functional status, poor oral hygiene, nasogastric feeding, swallowing
difficulties, confusion, the presence of obstructive lung disease, the
presence of a tracheostomy, and advancing age.214,216 The subtle pre-
sentation noted in other older adult populations occurs in those in a
nursing home setting. S. pneumoniae remains the predominant etiol-
ogy, followed by nontypeable strains of H. influenzae and M. catarrha-
lis. Other organisms such as Chlamydophila, M. pneumoniae, Legionella,
and aerobic gram-negative bacilli including P. aeruginosa, are infre-
quent causes. Outbreaks of pneumonia have occurred in nursing
homes and have involved Legionella, Chlamydophila, influenza, para-
influenza, respiratory syncytial virus, and rhinovirus.217
COMMUNITY-ACQUIRED PNEUMONIA IN
PATIENTS WITH AIDS
The cause of community-acquired pneumonia in patients with AIDS
has changed significantly since the beginning of the epidemic. With
the development of highly active antiretroviral therapy (HAART) and
effective prophylactic strategies, the incidence of P. jirovecii (carinii)
pneumonia has been halved with associated mortality rates reduced by
60%. Even with prophylaxis, however, Pneumocystis infection may
develop in the setting of severe immune deficiency.218 Pneumocystis
remains the most frequent AIDS-defining opportunistic pneumonia
in the United States. Bacterial pneumonia has recently been shown to
have a ten times higher incidence in HIV-positive versus HIV-negative
cohorts.218 The rate of invasive pneumococcal disease may be as high
as 100 to 300 times greater in HIV-infected patients than in non–HIV-
infected controls.219 H. influenzae and S. aureus are also important
pathogens.60,219-222 A variety of other bacteria have been implicated,
including R. equi, Escherichia coli, Serratia species, and P. aeruginosa.
Infections with Pseudomonas are associated with late stages of disease,
the presence of central venous catheters, the presence of urinary cath-
eters, and the use of steroids. Mycobacterium tuberculosis, nontubercu-
lous mycobacteria, C. neoformans, and cytomegalovirus also play
important roles as etiologic agents.60 The incidence of pneumonia
reported to be caused by atypical agents is low. Although influenza and
rhinovirus have been shown to be common causes of febrile respira-
tory illnesses in HIV-infected patients, pneumonia is unusual.223 Even
with careful study, up to 75% of HIV-infected patients with pneumo-
nia may have an infection without a proven etiology.
SEVERE COMMUNITY-ACQUIRED PNEUMONIA
Approximately 10% of patients with community-acquired pneumonia
will develop severe disease, as defined by admission to an intensive care
unit due to the presence of shock requiring vasopressors or respiratory
failure requiring mechanical ventilation.224 Early identification of
patients who are at higher risk for developing severe pneumonia is
important because these patients have a higher mortality rate and
require more supportive care. Further, patients with severe pneumonia
are infected with a different spectrum of etiologic agents and would
therefore benefit from different empirical antibiotic strategies than
patients with less severe disease. Advanced age, presence of significant
comorbidities, inadequate or delayed antibiotic therapy, and genetic
predisposition have all been thought to be associated with the develop-
ment of severe community-acquired pneumonia.225 Approximately
one third of patients with severe pneumonia would have been previ-
ously healthy.
Although shock or respiratory failure are usually evident and serve
as major criteria for defining severe pneumonia, patients without these
findings may also benefit from intensive care unit monitoring. A
variety of prediction scores have been developed to assess severity in
patients with pneumonia, including the modified British Thoracic
Society severity score, the pneumonia Patient Outcome Research
Team (PORT) score (also known as the pneumonia severity index
[PSI]),226 Confusion, Urea, Respiratory rate, low Blood pressure
(CURB) score,227 CURB plus age older than 65 (CURB-65) score,228
and CURB-65 without the urea level (CRB-65) score.229 (Further use
of these scoring systems will be discussed later in “Management and
Therapy of Pneumonia.”) When compared as a means of predicting
mortality and need for intensive care unit admission, sensitivities and
specificities have been variable, with the best predictors being the
PORT score, modified British Thoracic Society severity score, and the
CURB systems.226
Recently, the American Thoracic Society and Infectious Diseases
Society of America combined elements of these previously devised
systems to define severe pneumonia.78 Shock requiring vasopressors
and need for mechanical ventilation were major criteria, either one of
which defined severe disease. In addition, a series of minor criteria were
listed, any three of which defined severe disease. These minor criteria
included respiratory rate higher than 30 breaths/minute, Pao2/Fio2 less
than 250, multilobar infiltrates, new-onset disorientation, BUN greater
than 20 mg/dL, leukopenia (WBC less than 4000 cells/mm3), throm-
bocytopenia (platelet count less than 100,000 cells/mm3), core tem-
perature lower than 36° C, and hypotension requiring fluid resuscitation.
These remain suggested but not validated criteria. The most recent
prediction tool is the SMART-COP developed by the Australian com-
munity-acquired pneumonia study.230 Using a scoring system based on
vital sign parameters, including oxygen saturation, mental status,
albumin level, extent of radiographic abnormalities, and arterial pH,
the schema identified 92% of patients needing ventilator or vasopressor
support, including those not initially admitted to an ICU.
S. pneumoniae and L. pneumophila are the organisms most com-
monly involved in cases of severe pneumonia. Gram-negative bacilli,
especially Klebsiella species, must be considered in patients who have
significant underlying disease, such as COPD, diabetes, and alcohol
abuse.224 In some series, M. pneumoniae is involved in up to 11% of
patients with community-acquired pneumonia requiring intensive
care.
Mortality rates in patients with severe pneumonia have recently
been reported as high as 28% versus the 4% to 8% noted in patients
admitted to non-ICU services.47,224 Tachypnea (more than 30 breaths/
minute), diastolic blood pressure less than 60 mm Hg, and blood urea
nitrogen levels above 7 mmol/L have been shown to be independently
associated with death from pneumonia.231,232 Other parameters identi-
fied with increased mortality include severe underlying disease, under-
lying neoplastic disease, age older than 60 years, absence of pleuritic
chest pain, a change in mental status, acute respiratory failure requir-
ing ventilator support, bilateral pulmonary involvement, bacteremia,
a neutrophil count under 3500  mm3, a total serum protein level less
than 45 g/L, a serum creatinine level greater than 15 mg/L, the presence
of shock, inadequate initial antibiotic therapy, radiographic progres-
sion in the first 48 hours, and pneumonia caused by S. aureus or
gram-negative bacilli.232-234
HEALTH CARE–ASSOCIATED PNEUMONIA
In the past, a basic distinction in the epidemiology of pneumonia has
been whether the infection developed in the community or in the
hospital (see Chapter 303). The distinction was clinically relevant
because the importance of various etiologic agents differed as did
antibiotic susceptibilities. Consequently, the guidelines for empirical
antibiotic therapy differed depending on where the infection devel-
oped. Since an increased amount of health care delivery has been
shifted to the outpatient setting, even complex medical conditions may
be handled without hospitalization. Subsequently, a growing number
of patients develop pneumonia after extensive outpatient contact with
various aspects of the health care system. This has led to a blurring of
the distinction between community-acquired and nosocomial pneu-
monia. Recently it has been recognized that health care–associated
pneumonia represents a new syndrome, which is a hybrid of commu-
nity-acquired pneumonia and hospital-associated pneumonia.68-70
Patients who have been hospitalized within 90 days of developing

pneumonia; patients attending hemodialysis clinics; patients receiving
intravenous therapy, wound care, or chemotherapy at home; and resi-
dents of long-term care facilities or nursing homes are the most likely
involved. S. aureus including MRSA, aerobic gram-negative bacilli
including P. aeruginosa, and mixed aerobic-anaerobic pathogens asso-
ciated with aspiration have been most commonly reported. The role
of S. pneumoniae has been variable, but in general it appears to play a
lesser role than in patients with classic community-acquired pneumo-
nia. Overall mortality appears to be higher in patients with health
care–associated pneumonia (10.3%) than in community-acquired
pneumonia (4.3%).70 It is not clear whether this is due to increased
comorbidities in patients, more virulent organisms causing infection,
or an increased incidence of inappropriate antibiotic usage in the first
48 hours of care.
ATYPICAL PNEUMONIA SYNDROME
By the late 1930s, most of the main bacterial causes of pneumonia had
been defined. In 1938, Hobart Reimann235 described a small number
of patients with a clinical picture that was atypical in that episodes
began as a mild respiratory tract illness that was followed by pneumo-
nia with dyspnea and cough without sputum. M. pneumoniae, C. pneu-
moniae (formerly known as Chlamydia pneumoniae), L. pneumophila,
and respiratory viruses are the most significant causes of atypical pneu-
monia. Other agents such as Chlamydophila psittaci (formerly Chla-
mydia psittaci), Francisella tularensis, M. tuberculosis, and C. burnetii
may also cause atypical pneumonia. In patients with AIDS, Pneumo-
cystis and nontuberculous mycobacteria should also be included.
Although some series report that almost 50% of patients with com-
munity-acquired pneumonia demonstrate serologic evidence of myco-
plasmal or chlamydial pneumonia, or both, other series suggest an
incidence of 7% to 28%.47,179,236
Historically, the epidemiology and clinical features of the atypical
pneumonias were thought to be distinct enough to differentiate them
clearly from other causes of community-acquired pneumonia. It is
now clear that differentiation between atypical agents and typical bac-
terial causes of community-acquired pneumonia is imprecise.180
The difficulty in identifying the various etiologic agents associated
with atypical pneumonia has made consistent estimates of incidence
difficult. Although a variety of nucleic acid amplification tests have
been used to diagnose the major etiologic agents involved in atypical
pneumonia, lack of standardized assays makes comparison of infection
rates in different studies difficult.237,238
M. pneumoniae may account for 10% to 30% of cases of commu-
nity-acquired pneumonia, with the highest percentage noted in
patients well enough to be treated as outpatients.205 It is most likely to
occur in the older child (older than 5 years), the adolescent, and the
young adult. The majority of cases occur in those younger than 40
years, although 15% of patients hospitalized with mycoplasmal pneu-
monia were older than 60.47,179,205 An increased incidence of disease and
true epidemics has been documented in relatively enclosed popula-
tions of young adults at military bases, colleges, and boarding schools.
Mycoplasmal infection occurs throughout the year, although a relative
increase in incidence is noted in the late summer and fall.
The course of M. pneumoniae is characterized by up to 10 days of
symptoms before presentation, as is true with many of the other agents
involved in atypical pneumonia. In its classic form, mycoplasmal infec-
tion presents with constitutional symptoms and a progression from the
upper to the lower respiratory tract. Sore throat is often the initial
finding. Bullous myringitis is seen in only about 5% of cases but when
present is suggestive of mycoplasmal infection. Fever, malaise, coryza,
headache, and cough represent the major clinical findings. Pleuritic
chest pain, splinting, and respiratory distress are not usually seen.
Moist or crepitant rales may be heard. Sputum production is variable,
and the sputum is purulent in one third to one half of the cases. Gram
stain and culture of sputum usually reveal mouth flora. White blood
cell counts greater than 10,000/mm3 are uncommon, occurring in
approximately 20% of the patients.83 An elevated sedimentation rate is
64  Acute Pneumonia 907
noted in about 25% of the cases. Pulmonary involvement seen on
radiographs is commonly more extensive than the physical examina-
tion would indicate. Unilateral or bilateral patchy infiltrates in one or
more segments, usually in the lower lobes, are noted in a bronchial or
peribronchial distribution. Upper lobe involvement and pleural effu-
sions are rare. Progression of the radiographic picture, despite a stable
clinical picture, may be seen. The overall clinical course in most cases
is benign. Disappearance of constitutional symptoms is usually noted
in the first and second weeks, although cough and radiographic changes
may persist for several weeks. Occasionally, M. pneumoniae infection
presents as severe community-acquired pneumonia requiring intensive
care. A number of extrapulmonary manifestations may occur with M.
pneumoniae, including involvement of skin, central nervous system,
blood, and kidneys (see Chapter 184).
C. pneumoniae has emerged as an important cause of atypical pneu-
monia and may account for approximately 6% to 20% of community-
acquired pneumonia cases.47,179,239-242 It has also been postulated to be
an important co-pathogen, most often associated with S. pneumoniae.
Although disease is uncommon in those younger than 5 years, sero-
logic evidence of infection has been noted in over 50% of adults, and
more recent studies suggest an important role for Chlamydophila in
community-acquired pneumonia in those older than 65 years.242
Disease usually occurs sporadically, although epidemics have been well
documented. The majority of infections are either asymptomatic or
produce mild symptoms. As with mycoplasmal infection, sore throat
and hoarseness herald the onset of pneumonia, although the progres-
sion of symptoms appears slower than that noted with mycoplasma or
viral pneumonia. Cough may begin after several days to weeks, sug-
gesting a biphasic illness. Hoarseness and sinus tenderness appear
more commonly than in patients infected with Mycoplasma or viruses.
The white blood cell count is rarely elevated. Pneumonia with C.
pneumoniae is usually mild, although complete recovery may be slow.
Cough and malaise may persist for weeks to months. Reinfection
occurs and appears to be milder than primary infection and is usually
not associated with pneumonia. Chronic and latent infections have
also been described. Infection with C. pneumoniae has been associated
with exacerbations of COPD and asthma. In general, few features
distinguish chlamydial pneumonia from infection caused by other
atypical agents or other bacteria. C. pneumoniae infections have been
associated with extrapulmonary manifestations, including otitis,
sinusitis, pericarditis, myocarditis, and endocarditis. It has also been
associated with coronary artery disease, although the definite relation-
ship remains unclear (see Chapter 182).
C. trachomatis may be a pulmonary pathogen in immunocompro-
mised and in healthy hosts, including newborns.243 Productive cough,
myalgias, and fever associated with diffuse nonsegmental infiltrates
appear most commonly. The agent has also been associated with
chronic pneumonia in neonates and infants. Onset occurs at 2 to 3
weeks of age and is associated with tachypnea, a staccato cough with
periods of cyanosis and emesis, a lack of fever, and diffuse interstitial
and patchy alveolar infiltrates on chest radiographs. Elevated IgG and
IgM levels and absolute eosinophilia have also been noted (see
Chapter 180).
Of the viral agents associated with atypical pneumonia in adults,
influenza A and B, adenovirus types 3, 4, and 7 (especially in military
recruits), human metapneumovirus,244,245 respiratory syncytial virus
(especially in older adult and immune-suppressed patients), and para-
influenza virus are the most common.210,246-248 Data suggest that respi-
ratory syncytial virus may cause pneumonia in 1% to 5% of
immunocompetent adults. Reports of other viral agents causing pneu-
monia are scant but have included enterovirus, coronavirus, the her-
pesviruses, and hantavirus. A coronavirus has been shown to be the
agent involved in SARS (see Chapter 155). Rhinovirus has been iso-
lated in nasopharyngeal secretions and BAL fluid from immunocom-
petent hosts with pneumonia but may play a more important role as
a cause of pneumonia in the immune-compromised patient.209,210,249
Elderly patients, especially those with comorbidities, are frequently the
population at greatest risk for viral pneumonias.
908 Part II  Major Clinical Syndromes
Legionella is now recognized as an important cause of the atypical
pneumonia syndrome, although patients infected with Legionella may
also present with the syndrome of acute bacterial community-acquired
pneumonia. It accounts for 2% to 8% of cases involving hospitaliza-
tion.47 Legionella species are among the top three to four organisms
causing pneumonia that requires intensive care unit monitoring.250,251
L. pneumophila causes over 80% of cases of Legionella pneumonia, with
approximately 50% of cases caused by serogroup 1.236 Inhalation of
aerosolized organisms after exposure to environmental reservoirs,
such as fresh water and moist soil, has been the usual means of acquir-
ing the organism, although aspiration is now thought to be an alternate
route of infection.252 An increased incidence during summer months
has been observed.
Cigarette smoking, chronic lung disease, and immunosuppression
are consistently noted risk factors for the development of disease.
Although early symptoms of malaise, muscle aches, headaches, and
nonproductive cough resemble the onset of a viral syndrome, the rapid
progression of pulmonary symptoms and relatively high fever, often
exceeding 40° C, is noteworthy.252
L. pneumophila pneumonia is associated with a variety of extrapul-
monary findings and laboratory abnormalities, including mental status
changes, abdominal complaints (loose stools or diarrhea), headache,
bradycardia, elevation of hepatic enzyme levels, hypophosphatemia,
hyponatremia, elevated serum lactate dehydrogenase levels, and ele-
vated serum creatinine levels. No single finding or laboratory test can
distinguish L. pneumophila pneumonia from pneumonias of other
causes. Scoring systems have been developed that may help identify
Legionella, but the systems have not been validated in large prospective
series.196 Extrapulmonary infection is unusual, but when it does occur,
it usually involves the heart with myocarditis, pericarditis, and post-
cardiotomy-like syndrome.252 Unfortunately, none of these findings
distinguishes between L. pneumophila pneumonia, pneumonia caused
by other atypical agents, and pneumonia caused by more typical bacte-
rial pathogens. Similarly, radiographic manifestations do not distin-
guish Legionella infections from those of other causes. Patchy interstitial
infiltrates, or nodular infiltrates that may progress rapidly even with
adequate therapy, are characteristic. Pleural effusions may be noted in
up to one third of patients.
PNEUMONIA IN THE SETTING OF ASPIRATION
The clinical setting in which aspiration occurs includes any disease
state in which consciousness is altered and the normal gag and swal-
lowing reflexes are abnormal. Older adult patients; patients in chronic
care facilities, especially those who are neurologically impaired;
patients during the acute phase of stroke; bedridden patients receiving
tube feedings; and patients with dementia fit into the category of indi-
viduals susceptible to aspiration.253,254
The pathogenesis of lung injury due to acid aspiration has been
delineated.255 The presence of acidic contents in the lung induces the
release of proinflammatory cytokines including TNF-α and IL-8.
These and other cytokines recruit neutrophils into the lung. Activated
neutrophils appear to be the key mediators of acute lung injury after
acid aspiration, although a role for complement has also been
demonstrated.256
Although aspiration may be a witnessed event, the majority of epi-
sodes are silent and are brought to medical attention by their sequelae.
Three major syndromes are recognized as a consequence of aspiration:
chemical pneumonitis, bronchial obstruction secondary to aspiration
of particulate matter, and bacterial aspiration pneumonia.257 Aspira-
tion may be associated with the acute respiratory distress syndrome,
atelectasis, bronchial hyperreactivity, and fibrosis. Bacterial aspiration
pneumonia occurs in more than 60% of cases of chemical aspiration.204
Although chemical pneumonitis and mechanical obstruction usually
cause acute symptoms, aspiration pneumonia is more insidious, with
symptoms usually occurring gradually several days after the initial
episode of aspiration. Pneumonitis, necrotizing pneumonia, abscess,
and empyema are common. Symptoms often include fever, weight
loss, and productive cough. Putrid sputum is produced in 50% of the
cases.72 Anemia and an elevated white blood cell count are frequently
associated findings. The bacteriologic findings in aspiration pneumo-
nia reflect the flora of the oropharynx, and the importance of peri-
odontal disease in this regard has been noted. Studies have documented
anaerobic involvement alone in 45% to 58% of cases258 or in combina-
tion with aerobes in 22% to 46% of cases.72,259 Bacteroides species,
Porphyromonas species, Prevotella melaninogenica, Fusobacterium
species, and anaerobic gram-positive cocci are the predominant
anaerobes isolated. In community-acquired aspiration pneumonia,
Streptococcus species and H. influenzae are the most common aerobic
isolates.258,260 M. catarrhalis and Eikenella corrodens may also be
involved. In contrast, gram-negative bacilli (including P. aeruginosa)
and S. aureus are the most commonly isolated aerobes from
nosocomial aspiration pneumonia including ventilator-associated
pneumonia.258,260
PULMONARY INFILTRATES WITH EOSINOPHILIA
Pulmonary infiltrates with eosinophilia (PIE) is a syndrome associated
with a variety of clinical entities, only some of which have an infectious
cause.261 Pulmonary eosinophilia with transient, peripheral pulmonary
infiltrates and minimal symptoms has been associated with Ascaris and
Strongyloides infections. Ascaris is probably the leading parasitic cause
of the syndrome worldwide. Prolonged pulmonary eosinophilia asso-
ciated with weight loss, fever, cough, and dyspnea may be due to
tuberculosis, brucellosis, psittacosis, coccidioidomycosis, histoplas-
mosis, and parasitic infections including ascariasis, strongyloidiasis,
paragonimiasis, echinococcosis, visceral larva migrans, cutaneous
larva migrans, and infections with Schistosoma, Dirofilaria immitis, and
Ancylostoma species. Noninfectious causes include drug allergy, sar-
coidosis, eosinophilic leukemia, Hodgkin’s disease, and hypersensitiv-
ity pneumonitis (e.g., pigeon breeders’ disease).262 A PIE syndrome has
been associated with Pneumocystis pneumonia in AIDS patients.
Acute eosinophilic pneumonia is a distinct clinical entity occurring
in younger (20 to 30 years) otherwise healthy individuals. It is marked
by the acute onset of dyspnea, nonproductive cough, fever, hypoxia,
and chest pain. Although leukocytosis is common, peripheral eosino-
philia is usually absent. Bilateral, diffuse pulmonary infiltrates are
commonly seen. Radiographic abnormalities usually begin as intersti-
tial infiltrates that progress to alveolar infiltrates. Chest CT reveals a
ground-glass opacification with interlobular septal thickening. BAL
yields marked (25% to 62%) eosinophilia, which is the diagnostic
feature of the disease. Although most patients have received antibiot-
ics, rapid stabilization occurs with steroid use.
It has been suggested that chronic eosinophilic pneumonia may
represent a unique clinical entity that is a form of collagen-vascular
disease or an infection in a hyperimmune patient. A subacute onset of
cough, dyspnea, fever, and weight loss associated with peripheral
eosinophilia are the common features. Unlike the situation in acute
eosinophilic pneumonia, respiratory failure is rare. Peripheral infil-
trates are usually seen on radiographs. Focal interstitial fibrosis, bron-
chiolitis obliterans, microabscesses, and sarcoid-like granulomas are
characteristic pathologic features. A rapid response to steroids has
been reported.
Tropical eosinophilia consists of myalgia, fatigue, weight loss, and
anorexia associated with cough, frequently with nocturnal exacerba-
tions, wheezing, dyspnea, and marked peripheral eosinophilia in
patients who have lived in or visited the tropics. Radiographic changes
are distinctive and include increased interstitial markings with 2- to
4-mm nodules throughout the lungs with preferential involvement of
the bases. Most cases are thought to represent immunologic hyperre-
sponsiveness to microfilarial infection and can be treated with
diethylcarbamazine.
Other causes of PIE syndrome include bronchopulmonary Aspergil-
lus, which should be suspected when a patient with PIE presents with
asthma and pulmonary vasculitis. Patients with Churg-Strauss syn-
drome frequently have eosinophilia along with allergic angiitis and

granulomatosis and present with asthma, diffuse pulmonary infil-
trates, and multiorgan involvement. Hypereosinophilic syndrome,
eosinophilic granuloma (also known as primary pulmonary Langer-
hans cell histiocytosis), bronchiolitis obliterans organizing pneumonia
(BOOP), Sjögren’s syndrome, and postradiation pneumonitis are
unusual cases of pulmonary infiltrates with eosinophilia.
NOSOCOMIAL PNEUMONIA AND PNEUMONIA IN
THE IMMUNOSUPPRESSED HOST
Nosocomial pneumonia is the second leading type of nosocomial
infection and accounts for 13% to 18% of all such infections. It is the
leading cause of infection-related deaths in hospitalized patients with
an attributable mortality of 33% to 50%.263 Higher mortality rates have
been observed when patients are bacteremic or have pneumonia
caused by P. aeruginosa or Acinetobacter species. The morbidity associ-
ated with nosocomial pneumonia includes longer hospital stays (an
average of 7 to 9 days) and higher costs for health care (an estimated
$2 billion annually).264
Risk factors for the development of nosocomial pneumonia have
been categorized as patient related, infection-control related, or inter-
vention related. Patient-related risk factors include age greater than 70
years, severe underlying disease, malnutrition, coma, metabolic acido-
sis, and the presence of any of a number of comorbid illnesses (COPD,
alcoholism, azotemia, central nervous system dysfunction). Risk
factors related to infection control include a lack of hand hygiene and
glove-use practices and the use of contaminated respiratory equip-
ment. Intervention-related risk factors involve those procedures and
therapies that undermine normal host defenses or allow the host to be
exposed to large inocula of bacteria. Sedatives and narcotics may lead
to aspiration; corticosteroids and cytotoxic agents blunt the normal
host response to infection; and the prolonged use of antibiotics engen-
ders resistance. Surgical procedures, especially involving the chest and
abdomen, are associated with changes in host defenses that predispose
to pneumonia. The use of ventilator support is perhaps the greatest
risk factor for the development of nosocomial pneumonia, presenting
a risk over 20 times that of unventilated patients.265 Data suggest that
there is a 1% to 3% per day risk for developing pneumonia while on
a ventilator with a higher risk during the first 5 days of intubation.265
Because of this preeminence as a risk factor, the term ventilator-
associated pneumonia (VAP) has been accepted as an important
subcategory of nosocomial pneumonia.
The use of antacids and histamine type 2 blockers that raise the
gastric pH has been shown to increase stomach colonization with
aerobic gram-negative rods. Whether this leads to an increase in
nosocomial pneumonia remains controversial.266,267 As noted, acid-
suppressive medications have recently been shown to increase the
incidence of pneumonia in hospitalized patients, although the exact
mechanism involved remains unclear.32a The percentage of patients
with VAP caused by organisms initially found in the stomach ranges
from 0% to 55%.268
Approximately 60% of cases of nosocomial pneumonia are caused
by aerobic gram-negative bacilli, with members of the family Entero-
bacteriaceae (K. pneumoniae, E. coli, Serratia marcescens, Acinetobacter
species, Enterobacter species) and Pseudomonas species accounting for
the majority of these. S. aureus causes 13% to 40% of nosocomial
pneumonia and appears to be more common in burn units, in patients
with wound infections, and in patients recently ventilated after neu-
rosurgery or head trauma.69,269 MRSA and multidrug-resistant (MDR)
organisms now play major etiologic roles. In contrast to its prominent
role in community-acquired pneumonia, S. pneumoniae causes only
3% to 20% of nosocomial pneumonias in most studies and is associ-
ated with infection developing early in the hospital course.66,270 Anaer-
obic bacteria have been isolated in up to 35% of cases of nosocomial
pneumonia, although usually less than 5% of infections are thought to
be caused by these organisms. They play a role when aspiration is likely
to have occurred. Pneumonia caused by Legionella species may occur
sporadically or as part of outbreaks.
64  Acute Pneumonia 909
Recent consensus guidelines have been established concerning the
risks, etiologies, diagnostic work-up, and therapies for nosocomial
pneumonia and VAP.69 A more in-depth review can be found in
Chapter 303.
Pneumonia in the immunocompromised host is perhaps the most
complex of all the pneumonia syndromes, because it represents the
interaction of host defense defects engendered by the underlying
disease as well as the chemotherapy of that disease, exposure to poten-
tial pathogens in the community and within the hospital setting, and
reactivation of infectious processes that had previously been dormant.
Community-acquired pneumonia, atypical pneumonia, aspiration
pneumonia, and nosocomial pneumonia all take place in the compro-
mised host. A large number of bacterial, fungal, viral, and noninfec-
tious etiologies must be considered.271 Reviews of the topic are found
in Chapter 303 and Chapters 308 to 312.
Management and Therapy
of Pneumonia
The first decision confronting the clinician is whether the patient pre-
senting with respiratory symptoms in fact has pneumonia. The difficul-
ties in establishing a diagnosis on clinical grounds and the potential
problem of overprescribing empirical antibiotics for all patients with
respiratory findings have been reviewed. A chest radiograph is usually
necessary to establish a definitive diagnosis of pneumonia.
The next decision is whether the patient is to be hospitalized, as will
be the case 18% to 30% of the time.272-274 Numerous studies have
examined prognostic features and predictors of the clinical outcome
for patients with community-acquired pneumonia that have been
adapted to help make this decision. Although early assessment tools
used a combination of clinical, epidemiologic, laboratory, and radio-
graphic parameters, more recently developed tools have relied on clini-
cal parameters alone that can be evaluated at the bedside. 225-228,230
One of the earliest developed and most widely used assessment tool
is the PORT score, also known as the pneumonia severity index
(PSI).225 This system uses 20 clinical parameters in categories of age,
presence of comorbidities, vital sign abnormalities, and laboratory and
radiologic findings. Based on a point system, five prognostic groups
(I-V) were defined. The lowest scores (Group I) are associated with
low mortality (0.1%), and the highest scores (Group V) are associated
with the highest mortality (27%). As a guideline for hospitalization,
patients in Groups I and II are usually treated as outpatients, patients
in Group III are in a “borderline” group, and patients in Groups IV
and V are admitted to either a routine ward or ICU. The PORT score
or PSI has been validated and widely endorsed.275,276 A problem with
this assessment tool, however, has been the need to obtain a variety of
laboratory and radiologic results before being able to numerically
assess the patient. Alternative systems, such as the CURB and CURB-65
scores, use parameters that are more readily obtained.227,228 The CURB
index was formulated from the British Thoracic Society study and uses
four clinical parameters, which include new onset of confusion, urea
level greater than 7 mmol/L, respiratory rate greater than 30 breaths/
minute, and systolic blood pressure less than 90 mm Hg or diastolic
blood pressure less than 60  mm  Hg. The presence of two or more
criteria suggested an increased mortality and defined severe pneumo-
nia.227 The CURB-65 system, which was developed later, added age
older than 65 to the system, with the presence of greater than three
parameters leading to prediction of increased mortality.228 In both
the CURB and CURB-65 systems, patients with fewer abnormal
parameters had lower mortality predicted and could be treated as
outpatients. The CRB-65 score removed the requirement for a urea
level, making the system laboratory-free with patient assessment done
completely at the bedside.229
There have been few comparative trials of the various assessment
systems. The CURB-65 and CRB-65 tools appear comparable in pre-
dicting high and low mortality groupings.277 A recent comparison of
the PORT or PSI system with the CURB-65 system suggested that the
PSI system predicted mortality more accurately.278
910 Part II  Major Clinical Syndromes
It is important to recognize that any severity assessment tool serves
only as a guideline, not as an absolute. Clinical judgment regarding
presence of hypoxia, stability of the home situation, ability to take oral
medications, reliability in taking medication, likelihood of returning
for follow-up, and likelihood of calling for help when needed all play
a role in deciding whether a patient can be treated at home or in a
hospital.279 Further, it has been shown that patients with low PSI or
CURB-65 scores may need hospitalization and ICU monitoring and
that severity assessment scoring systems may underestimate mortality
depending on the type of clinical setting in which they are used.280
It has been suggested that a three-step appraisal be used to decide
where a patient should be treated. The first step identifies any contra-
indications to care outside the hospital (e.g., hypoxia, social instability,
emotional or psychological instability). The second step involves cal-
culating the pneumonia severity index (although other scoring systems
could be used) and assigning the patient to a risk group. The final step
is using clinical judgment to be sure the decision to treat a patient at
home is consistent with the information gleaned from the history and
physical examination.281 Strict reliance on severity indices has failed to
predict complex outcomes in up to 39% of patients thought to be well
enough to be treated as outpatients.282
EMPIRICAL THERAPY OF COMMUNITY-
ACQUIRED PNEUMONIA
The next problem is determining the most likely cause of pneumonia.
If diagnostic studies, as described previously, yield a likely cause, then
specific therapy can be initiated. For most patients, a specific diagnosis
cannot be established with certainty before the onset of therapy. Select-
ing an empirical antibiotic regimen is a continuing clinical challenge.
Recent controversies and questions have included when antibiotics
should be started, how to determine the most appropriate antibiotics
to use, and how long therapy should continue.
Timing of Antibiotics
In 1997, a retrospective review of over 14,000 Medicare patient hospi-
talizations suggested that antibiotic therapy given within 8 hours of
presentation was associated with a decreased mortality.283 A second
retrospective study of similar design in 2004 showed that antibiotics
given within 4 hours of presentation would result in lower mortality.284
Neither study corrected for pneumonia etiology or antibiotics used.
Despite the lack of a prospective randomized study, advising and regu-
latory agencies including the Joint Commission and the Centers for
Medicare and Medicaid Services used the 4-hour rule as a core quality
measure. Subsequent meta-analysis failed to substantiate these find-
ings, although other series suggested that in critically ill patients, earlier
appropriate antibiotic therapy had a mortality advantage compared to
delayed or inappropriate antibiotic use.285,286 Misdiagnosis, delays in
making the correct diagnosis, overuse of antibiotics, and an increase
in Clostridium difficile colitis in patients, many of whom should not
have received antibiotics at all, occurred as a result of this rule.287-289 In
2007, the Joint Commission suggested that antibiotics be started
within 6 hours, even though no other data had been presented. The
joint IDSA/ATS guidelines have suggested a more commonsense
approach that antibiotic treatment for pneumonia be started “as soon
as possible after the diagnosis is considered likely.”78
Empirical Antibiotic Therapy
It has recently become evident that an understanding of pharmacoki-
netics and pharmacodynamics is important in selecting appropriate
empirical antibiotic therapy for patients with pneumonia. This is espe-
cially true when resistant S. pneumoniae is a consideration.290-293
In the past, in vitro susceptibilities were reported independent of
body sites. Therefore, pneumococcal resistance was designed to be true
for meningitis as well as pneumonia. Because all β-lactam compounds,
including penicillin, are time-dependent killers, active drug levels need
to be above the minimal inhibitory concentration (MIC) of the organ-
ism being treated for 30% to 35% of the dosing interval for a successful
outcome when penicillin is used, 40% to 50% of the dosing interval
when a cephalosporin is used, and 20% to 25% of the dosing interval
when a carbapenem is being used. This principle explained why
patients could be cured with penicillin even when the pneumococcus
being treated was shown to be nonsusceptible to penicillin. Based upon
this understanding, and with the acknowledgment that in vitro sus-
ceptibility thresholds should be appropriate for the site of infection,
the Clinical and Laboratory Standards Institute changed the suscepti-
bility breakpoints for penicillin against S. pneumoniae to now be
defined as susceptible at less than or equal to 2 µg/mL, intermediate
at 4  µg/mL, and resistant at equal to or greater than 8  µg/mL.294,295
Using these new standards, approximately 92% of S. pneumoniae
strains are susceptible to penicillin.295 Risk factors for the presence of
penicillin resistance appear to be age, residence in a long-term care
facility, and perhaps most important, exposure to β-lactam antibiotics
within the previous 3 months.296 Similar relationships between prior
use of other antibiotic classes and subsequent resistance developing to
members of that class of antibiotics have also been established.296
Increased MICs to penicillin have been associated with parallel resis-
tance to other agents frequently used in the therapy of pneumonia.
Using the old susceptibility standards, 25.5% of pneumococci resistant
to penicillin were shown to be resistant to other antibiotics. Data
concerning multidrug-resistant strains of pneumococci using the new
susceptibility thresholds are lacking. Although overall rates may cer-
tainly decrease, it is still important to recognize general patterns of
resistance as shown in Table 64-4. It remains unclear as to what level
of resistance will yield clinical failures.
It is important to note that as with penicillins, in vitro susceptibility
to other agents does not always predict clinical efficacy. Resistance of
S. pneumoniae to macrolides and azalides (azithromycin, clarithromy-
cin) occurs either because of a blockage of the ribosomal binding area
encoded by the erm (B) gene or because of an efflux pump mechanism
encoded by the nef (A) gene that removes drug from the cell’s interior.
The latter usually leads to low-level resistance that may be overcome
by higher dosages. The former mechanism is usually associated with
high-level resistance that cannot be overcome by higher dosages. Clini-
cal failure has been described even with low-level resistance, making
the empirical use of azalides and macrolides problematic.297,298
A number of “respiratory tract quinolones” (levofloxacin, moxi-
floxacin, gemifloxacin) are licensed for use in the United States as
therapy for respiratory infections. These agents possess activity against
the majority of bacterial and atypical agents involved in lower respira-
tory infections, and their potency is not significantly affected by the
presence of penicillin resistance. Interestingly, when these agents are
compared clinically with β-lactam antibiotics with various activities
against nonsusceptible strains of pneumococci and no real activity
TABLE S. pneumoniae Resistance to Commonly Used
64-4 Antibiotics
Antibiotic % Resistance
Penicillin, amoxicillin-clavulanic acid 10
Cefuroxime axetil 20
Ceftriaxone 5
Trimethoprim-sulfamethoxazole 35
Azithromycin 15-25
Clarithromycin 18-25
Doxycycline 29
Imipenem 5
Meropenem 5
Respiratory tract quinolones (levofloxacin, moxifloxacin, etc.) 1-5
Quinupristin/dalfopristin 1
Linezolid 1
Adapted from Musher DM. Streptococcus pneumonia. In Mandell GM, Bennett JB,
Dolin RD, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious
Diseases. 7th ed. Elsevier; 2010; Jacobs MR. Clinical significance of antimicrobial
resistance in Streptococcus pneumoniae. S Afr Med J. 2007;97:1133-1140.
 64  Acute Pneumonia 911

against atypical agents, the overall outcomes have, in general, been
equivalent. No clear clinical superiority for any respiratory tract qui-
nolone has been consistently demonstrated. Resistance to the respira-
tory tract quinolones by pneumococcal strains has already been
reported. Overall resistance rates are less than 1%, but rates may be
significantly higher in certain geographic areas, and patient popula-
tions with resistance rates as high as 5% noted in patients in long-term
care facilities.299 Failure of quinolone therapy for S. pneumoniae infec-
tion due to resistance is very uncommon.300
The need for antibiotic combinations in the empirical therapy of
pneumonia remains an ongoing question. Combination therapy with
β-lactam antibiotics and macrolides, especially azithromycin, has been
associated in some studies with decreased mortality and decreased
length of hospital stay. Older patients with community-acquired pneu-
monia and patients with proven pneumococcal pneumonia, including
those with bacteremia, were the patients involved in these studies.301-303
Many of the studies were retrospective, could not identify the etiology
of pneumonia in up to 60% to 90% of cases, and did not always control
for confounding variables. Smaller subsequent studies, one of which
was prospective, could not substantiate these findings.304,305 Although
combination therapy may lower mortality in patients with severe
pneumonia, it remains unclear if this occurs in hospitalized patients
who are not severely ill. It would appear that effects, when observed,
are related to the use of macrolides rather than other classes of agents
like quinolones.306 The anti-inflammatory effect of macrolide com-
pounds may be a critical aspect of their interaction with other antimi-
crobial agents.307
Guidelines have been recently developed by the American Thoracic
Society (ATS) and the Infectious Diseases Society of America (IDSA).78
In general, patients are stratified into outpatient versus inpatient treat-
ment based on PSI or CURB-65 scoring systems. Recognition of the
most likely etiologic agent in any given clinical situation and recogni-
tion of the organisms most likely to cause morbidity and mortality are
emphasized. Finally, prevalence of common antibiotic resistance pat-
terns and risks of acquisition are recognized. Empirical antibiotic
therapy is reviewed in Table 64-5.

TABLE
64-5 Guide to Empirical Choice of Antimicrobial Agent for Treating Patients with Community-Acquired Pneumonia (CAP)

Patient Characteristics Preferred Treatment Options

Outpatient
Previously Healthy
No recent antibiotic therapy Oral-based β-lactam, macrolide,* or doxycycline
Recent antibiotic therapy† A respiratory fluoroquinolone‡ alone, an advanced macrolide§ plus high-dose amoxicillin,¶ or
an advanced macrolide plus high-dose amoxicillin-clavulanate¶
Comorbidities (COPD, Diabetes, Renal Failure or Congestive Heart Failure, or Malignancy)
No recent antibiotic therapy An advanced macrolide§ plus β-lactam or a respiratory fluoroquinolone
Recent antibiotic therapy A respiratory fluoroquinolone‡ alone or an advanced macrolide plus a β-lactam**
Suspected aspiration with infection Amoxicillin-clavulanate or clindamycin
Influenza with bacterial superinfection Vancomycin, linezolid, or other coverage for MRSA or CA-MRSA
Inpatient
Medical Ward
No recent antibiotic therapy A respiratory fluoroquinolone alone or an advanced macrolide plus a β-lactam††
Recent antibiotic therapy An advanced macrolide plus a β-lactam, or a respiratory fluoroquinolone alone (regimen
selected will depend on nature of recent antibiotic therapy)
Intensive Care Unit (ICU)
Pseudomonas infection is not an issue A β-lactam†† plus either an advanced macrolide or a respiratory fluoroquinolone
Pseudomonas infection is not an issue but patient has a β-lactam allergy A respiratory fluoroquinolone, with or without clindamycin
Pseudomonas infection is an issue‡‡ (cystic fibrosis, impaired host Either (1) an antipseudomonal β-lactam§§ plus ciprofloxacin, or (2) an antipseudomonal
defenses) agent plus an aminoglycoside¶¶ plus a respiratory fluoroquinolone or a macrolide
Pseudomonas infection is an issue but the patient has a β-lactam allergy Aztreonam plus aminoglycoside plus levofloxacin¶¶ or other respiratory quinolone
Health care–associated exposure Anti-Pseudomonas cephalosporin, carbapenem (not ertapenem) or β-lactam/β-lactamase
inhibitor with anti-Pseudomonas activity plus vancomycin (for MRSA coverage)
± quinolone or aminoglycoside
Nursing Home
Receiving treatment in nursing home A respiratory fluoroquinolone alone or vancomycin (for S. aureus including MRSA) plus a
β-lactam (cefepime or piperacillin/tazobactam if Pseudomonas is suspected; ceftriaxone if
Pseudomonas is not suspected)
Hospitalized Same as for medical ward and ICU
*Azithromycin, or clarithromycin.
†
That is, the patient was given a course of antibiotic(s) for treatment of any infection within the past 3 months, excluding the current episode of infection. Such treatment is a risk
factor for drug-resistant Streptococcus pneumoniae and possibly for infection with gram-negative bacilli. Depending on the class of antibiotics recently given, one or another of the
suggested options may be selected. Recent use of a fluoroquinolone should dictate selection of a nonfluoroquinolone regimen, and vice versa.
‡
Moxifloxacin, levofloxacin, or gemifloxacin.
§
Azithromycin or clarithromycin.
¶
Dosage, 1 g PO three times/day.
¶
Dosage, 2 g PO two times/day.
**High-dose amoxicillin (1 g, 3 times/day), high-dose amoxicillin-clavulanate (2 g, 2 times/day), cefpodoxime, cefprozil, or cefuroxime.
††
Cefotaxime, ceftriaxone, ampicillin-sulbactam, or ertapenem.
‡‡
The antipseudomonal agents chosen reflect this concern. Risk factors for Pseudomonas infection include severe structural lung disease (e.g., bronchiectasis) and recent antibiotic
therapy, health care–associated exposures or stay in hospital (especially in the ICU). For patients with CAP in the ICU, coverage for S. pneumoniae and Legionella species must always
be considered. Piperacillin-tazobactam, imipenem, meropenem, and cefepime are excellent β-lactams and are adequate for most S. pneumoniae and H. influenzae infections. They may
be preferred when there is concern for relatively unusual CAP pathogens, such as P. aeruginosa, Klebsiella species, and other gram-negative bacteria.
§§
Piperacillin, piperacillin-tazobactam, imipenem, meropenem, or cefepime.
¶¶
Data suggest that older adults receiving aminoglycosides have worse outcomes.
¶¶
Dosage for hospitalized patients, 750 mg/daily.
COPD, chronic obstructive pulmonary disease.
Data from Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines of community-acquired
pneumonia in adults. Clin Infect Dis. 2007;44:S27-S72.
912 Part II  Major Clinical Syndromes
For a patient who does not require hospitalization and for whom
no clear distinction between typical (e.g., pneumococcal) and atypical
(mycoplasmal, chlamydial) pneumonia can be made, both types of
organisms should be covered. Risks for the presence of drug-resistant
S. pneumoniae should be assessed. Previous use of antibiotics, espe-
cially a β-lactam or macrolide, is most predictive of the presence of
resistance. Age alone, in general, should not influence drug choice.
Where risk of drug-resistant S. pneumoniae is low, oral β-lactam agents
(amoxicillin-clavulanic acid, cefuroxime axetil), azalides/macrolides
(azithromycin, clarithromycin, or erythromycin), or respiratory tract
quinolones (levofloxacin, gemifloxacin, moxifloxacin) are all adequate
choices. Increased resistance in strains of pneumococci to the azalide/
macrolide agents is a problem because therapeutic failures have been
noted. Although it has been suggested that these agents may be used
as long as the resistance rate is less than 25%, recent analysis suggests
that resistance level is too high and will be associated with increased
morbidity and mortality.308 Doxycycline (a preferred treatment option
in the IDSA guideline) and trimethoprim-sulfamethoxazole may be
used but are less favored because of decreasing activity against strains
of pneumococci.
For patients with an increased risk for poor outcome because of age
or underlying disease, or where the risk for infection with resistant
pneumococci exists because of prior antibiotic use, the respiratory
tract quinolones are the agents most likely to be effective. They have
activity against all strains of S. pneumoniae, including penicillin-resis-
tant strains, and they have the added benefit of activity against atypical
agents. Although resistance is a potential problem of increased use of
quinolones, it has not yet emerged as a significant problem. A β-lactam
plus a macrolide is a comparable regimen.
Regardless of the initial choice of antibiotic, once an organism is
isolated, coverage should be narrowed down, if possible, on the basis
of susceptibility.
Patients who are ill enough to require hospitalization should be
treated with parenteral agents that cover the likely pathogens. Our
choice would be a β-lactam (ceftriaxone or cefotaxime) plus azithro-
mycin. A carbapenem may be used as the β-lactam component of this
regimen, although overall experience with it in this setting is limited.
A respiratory tract quinolone would be a comparable regimen. If there
are factors that suggest a specific etiology, or a Gram stain is revealing,
specific antibiotic coverage should be used.
Although these regimens represent the basic course of therapy, spe-
cific clinical circumstances may warrant variation. For example, S.
aureus pneumonia, including CA-MRSA, should be considered during
an influenza outbreak even though S. pneumoniae is still the major
etiologic agent. Agents with activity against methicillin-resistant S.
aureus (MRSA) should be used if there is reason to suspect its presence
as the etiology of pneumonia. Vancomycin, linezolid, and quinupris-
tin-dalfopristin are considerations. Where aspiration pneumonia is a
possibility, agents with activity against oral anaerobes are needed,
including ampicillin-sulbactam or clindamycin. Seven percent to 18%
of community-acquired pneumonia cases are caused by aerobic gram-
negative bacilli, including P. aeruginosa. Risk factors previously noted
for gram-negative pneumonia should therefore be sought. Where
gram-negative bacilli are suspected, infection with P. aeruginosa should
be a concern, and therapy with an antipseudomonal β-lactam com-
pound (e.g., cefepime, piperacillin-tazobactam, imipenem, or merope-
nem) is a reasonable choice. Where Pseudomonas involvement can be
excluded, agents such as cefotaxime, ceftriaxone, or a carbapenem
could be considered. Debate exists as to whether agents such as ami-
noglycosides or quinolones need to be added to a β-lactam therapy for
gram-negative pneumonia. Data exist to support both sides of the
controversy.309-311 We favor combination therapy for patients who are
severely ill, at least until culture results from sputum and blood are
available. In patients who are allergic to penicillin, aztreonam with a
respiratory tract quinolone, with or without an aminoglycoside, could
be used.
In the patient admitted to an intensive care unit, therapy should be
directed against S. pneumoniae, penicillin-resistant strains, Legionella
species, gram-negative rods, and M. pneumoniae. If infection with P.
aeruginosa is unlikely (no recent hospitalization, no recent antibiotic
use, no pulmonary comorbidities, no gram-negative rods), a β-lactam
plus either an azalide/macrolide or a respiratory tract quinolone would
be therapies of first choice. Ceftriaxone or cefotaxime would be rea-
sonable choices for the β-lactam. Where Pseudomonas infection cannot
be excluded, an antipseudomonal β-lactam (cefepime, imipenem,
meropenem, doripenem, or piperacillin-tazobactam) plus a respira-
tory tract quinolone or azalide/macrolide could be used. We favor
cefepime or piperacillin-tazobactam plus a respiratory tract quinolone.
An aminoglycoside could be added as a third agent for synergy against
Pseudomonas. Evidence in the literature favoring one regimen over any
other is lacking.
The effect of initial antibiotic selection on outcomes in patients with
pneumonia remains an area of ongoing controversy and study.312,313
Most of the evidence involves the use of nonexperimental cohort
studies where the role of unmeasured variables is hard to determine.
Therefore, until prospective, well-controlled studies are carried out,
the real effect of initial antibiotic choice on pneumonia outcomes can
only be estimated.
DURATION OF THERAPY
Until recently, the duration of antibiotic therapy for pneumonia has
been based on anecdotal patterns of behavior. The classic 10 to 14 days
of care is unsupported by evidence.314 Recent data suggest that clinical
stability occurs more quickly, and therefore antibiotic therapy may be
safely discontinued earlier.315-317 Clinical stability is defined as normal-
ization of previously abnormal physiologic parameters, including
heart rate, respiratory rate, oxygenation, blood pressure, mental state,
and ability to care for oneself.315 Most physiologic abnormalities will
correct in 2 to 3 days. Normalization of all physiologic abnormalities
may take 5 to 7 days. Patients who score higher on the severity scale
take longer to stabilize than patients who score lower. By day 3, relapses
of previously corrected physiologic abnormalities occur only 4% to 6%
of the time.
Although meta-analysis has shown that there are few studies that
are prospective, well controlled, use the same antibiotic and dosing
schedule, and only vary the duration of therapy, those few studies
have suggested that less than 7 days and as short as 3 days are just as
effective as any longer durations of therapy316,317 for mild to moderate
pneumonia. With age, presence of underlying comorbidities including
immune compromise, and more virulent pathogens, clinical stability
may be delayed, and therefore duration of antibiotic therapy may be
lengthened.
Oral antibiotic therapy is safe after clinical stability has been
reached.318-320 There is no clear usefulness of observing a patient within
the hospital after a switch to oral therapy.321 However, it is important
to recognize that discharging patients before stability has been reached
may lead to increased rehospitalization and mortality.322 Using the
same definitions of clinical stability, it has been shown that the greater
the number of factors remaining abnormal at discharge, the greater
the chance of readmission or death.
Once discharged, outpatient follow-up may be required, because
greater than 64% of patients with community-acquired pneumonia
will have some related residual symptoms, including fever, cough,
shortness of breath, chest pain, sputum production, fatigue, or gastro-
intestinal symptoms. In younger patients without underlying pulmo-
nary disease, these findings are more likely to resolve earlier.
Aspiration pneumonia and lung abscess are discussed in Chapter
66. Nosocomial pneumonia is discussed in Chapter 303.
ADJUNCTIVE THERAPY
With the recognition that the inflammatory response is a balance
between proinflammatory and anti-inflammatory mediators, the
effects of agents with anti-inflammatory properties on the treatment
of pneumonia is being studied. The effects of the macrolides in this
 64  Acute Pneumonia 913

regard has been discussed earlier. Critical illness-related corticosteroid
insufficiency (CIRCI) has been associated with community-acquired
pneumonia. Theoretically, steroid use would help correct the deficient
performance of the hypothalamic-pituitary-adrenal axis. Though
several studies have examined the role of steroids in this setting, results
have been contradictory and no clear role has been defined.323-325
Statins also possess anti-inflammatory properties. Recent observa-
tional studies have reported decreased mortality in patients who had
been using statins before admission for pneumonia. The studies were
not randomized or controlled for other potentially important variables
such as underlying health, or socioeconomic status.326,327 Although
other adjunctive therapies have been described, they have not yet been
shown to have a significant role in therapy.328
Pneumonia Prevention
Vaccination against influenza and perhaps S. pneumoniae are impor-
tant interventions in preventing pneumonia. In older adults, influenza
vaccine may decrease the incidence of pneumonia by 53%.329,330 Influ-
enza vaccine is suggested for any person 6 months of age or older, who,
because of age or underlying disease, is at risk for influenza-related
complications. This includes persons older than 50 years; nursing
home residents; people with chronic pulmonary or cardiac disease, or
with chronic diseases such as diabetes, renal failure, or hematologic
disorders; patients who are immunosuppressed; those taking chronic
salicylate therapy; and women in their second or third trimester of
pregnancy. Health care workers, workers in nursing homes, and those
who provide care to older adults or debilitated persons should also be
targeted for influenza vaccination.331
The role of pneumococcal polysaccharide vaccine continues to be
somewhat controversial. The incidence of bacteremia may be reduced,
but the incidence of pneumonia appears unchanged.332 The currently
available protein polysaccharide vaccine is for pediatric use only.
Although initial data showed that disease in adults was reduced by the
introduction of the conjugate vaccine in children, it is clear that non-
vaccine strains, including those resistant to penicillin, are emerging as
important causes of pneumonia. Pneumococcal vaccine is recom-
mended for patients older than 65 and those who have recovered from
community-acquired pneumonia (see Chapter 200).

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