Pathophysiology

Six mechanisms have been identified in the pathogenesis of pneumonia in

immunocompetent adults. Inhalation of infectious particles is probably the most
important pathogenetic mechanism in the development of community-acquired
pneumonia, with particular importance of pneumonia caused by Legionella species
and M. tuberculosis.
Table 2: Pathogenetic Mechanisms in Pneumonia

Mechanism Frequency
Inhalation of infectious particles Common
Aspiration of oropharyngeal or gastric
Common
contents
Hematogenous deposition Uncommon
Invasion from infection in contiguous
Rare
structures
Direct inoculation Less common
More common in immunocompromised
Reactivation
hosts
2002 The Cleveland Clinic Foundation.

The aspiration of oropharyngeal or gastric contents is the most prevalent pathogenetic

mechanism in nosocomial pneumonia, with several contributing factors. Swallowing and
epiglottic closure may be impaired by neuromuscular disease, stroke, states of altered
consciousness, or seizures. Endotracheal and nasogastric tubes interfere with these
anatomic defenses and provide a direct route of entry for pathogens. Impaired lower
esophageal sphincter function and nasogastric and gastrostomy tubes increase the risk of
aspiration of gastric contents. Fortunately, aspiration rarely leads to overt bacterial
pneumonia.
Direct inoculation rarely occurs as a result of surgery or bronchoscopy but may play a
role in the development of pneumonia in patients supported with mechanical ventilation.
Hematogenous deposition of bacteria in the lungs is also uncommon but is responsible
for some cases of pneumonia caused by S. aureus, Pseudomonas aeruginosa,
and Escherichia coli. The direct extension of infection to the lung from contiguous areas,
such as the pleural or subdiaphragmatic spaces, is rare.
Reactivation of pathogens can take place in the setting of deficits of cell-mediated
immunity. Pathogens such as Pneumocystis jiroveci, Mycobacterium tuberculosis, and
cytomegalovirus can remain latent for many years after exposure, with flares of active
disease occurring in the presence of immune compromise. Reactivation tuberculosis
occasionally occurs in immunocompetent hosts.
Once bacteria reach the tracheobronchial tree, defects in local pulmonary defenses can
make infection more likely. The cough reflex can be impaired by stroke, neuromuscular
disease, sedatives, or poor nutrition. Mucociliary transport is depressed with the aging
process, tobacco smoking, dehydration, morphine, atropine, prior infection with influenza
virus, and chronic bronchitis. Anatomic changes such as emphysema, bronchiectasis, and
obstructive mass lesions prevent the clearance of microbes. Inflammatory cells drawn to
infected areas of the pulmonary tree release proteolytic enzymes, altering the bronchial
epithelium and ciliary clearance mechanisms and stimulating the production of excess
mucus. Community-acquired MRSA strains contain Panton-Valentine leukocidin, a toxin
that creates holes in neutrophil cell membranes, releasing chemotactic and inflammatory
factors.7
A blunted cellular and humoral immune response can also increase the risk of
pneumonia. For example, granulocyte chemotaxis is reduced with aging, diabetes
mellitus, malnutrition, hypothermia, hypophosphatemia, and corticosteroids.
Granulocytopenia may be caused by cytotoxic chemotherapy. Alveolar macrophages are
rendered dysfunctional by corticosteroids, cytokines, viral illnesses, and malnutrition.
Diminished antibody production or function can accompany hematologic malignancies
such as multiple myeloma or chronic lymphocytic leukemia.

PATHOPHYSIOLOGY
Six mechanisms have been identified in the pathogenesis of pneumonia in immunocompetent
adults.
Inhalation of infectious particles is probably the most important pathogenetic mechanism in the
development of community-acquired pneumonia, with particular importance in pneumonia due
to Legionella species and Mycobacterium tuberculosis.
Aspiration of oropharyngeal or gastric contents is by far the most prevalent pathogenetic
mechanism in nosocomial pneumonia, with several factors contributing. Swallowing and epiglottic
closure may be impaired by neuromuscular disease, stroke, states of altered consciousness, or
seizures. Endotracheal and nasogastric tubes interfere with these anatomic defenses and provide
a direct route of entry for pathogens. Finally, impaired lower esophageal sphincter function and
nasogastric and gastrostomy tubes increase the risk of aspiration of gastric contents. Fortunately,
aspiration rarely leads to overt bacterial pneumonia.
Direct inoculation rarely occurs as a result of surgery or bronchoscopy but may play a role in the
development of pneumonia in patients supported with mechanical ventilation. Hematogenous
deposition of bacteria in the lung is also uncommon but is responsible for some cases of
pneumonia due to Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. The
direct extension of infection to the lung from contiguous areas such as the pleural or
subdiaphragmatic spaces is rare.
Reactivation of pathogens can take place in the setting of deficits of cell-mediated immunity.
Pathogens such as Pneumocystis carinii, Mycobacterium tuberculosis, and cytomegalovirus may
remain latent for many years after exposure, with flares of active disease in the face of immune
compromise. Reactivation tuberculosis occasionally occurs in immunocompetent hosts.
Once bacteria reach the tracheobronchial tree, defects in local pulmonary defenses may make
infection more likely. The cough reflex can be impaired by stroke, neuromuscular disease,
sedatives, or poor nutrition. Mucociliary transport is depressed with the aging process, tobacco
smoking, dehydration, morphine, atropine, prior infection with influenza virus, and chronic
bronchitis. Anatomic changes such as emphysema, bronchiectasis, and obstructive mass lesions
prevent clearance of microbes. Inflammatory cells drawn to infected areas of the pulmonary tree
release proteolytic enzymes, altering the bronchial epithelium and ciliary clearance mechanisms,
and stimulating the production of excess mucus.
A blunted cellular and humoral immune response may also increase the risk of pneumonia. For
example, granulocyte chemotaxis is reduced with aging, diabetes mellitus, malnutrition,
hypothermia, hypophosphatemia, and corticosteroids. Granulocytopenia may be caused by
cytotoxic chemotherapy. Alveolar macrophages are rendered dysfunctional by corticosteroids,
cytokines, viral illnesses, and malnutrition. Diminished antibody production or function can
accompany hematologic malignancies such as multiple myeloma or chronic lymphocytic
leukemia.
HISTORY AND PHYSICAL EXAMINATION
Because the clinical syndromes characterizing pneumonic infections caused by various agents
frequently overlap with each other and interobserver variability regarding physical findings of
pneumonia is high, the diagnosis of pneumonia can be challenging. A diligent history and
physical examination can help narrow the differential diagnosis.

In general, typical bacterial pathogens such as S pneumoniae, H influenzae, and the enteric
gram-negative organisms usually present acutely with high fever, chills, tachypnea, tachycardia,
and productive cough. Examination findings are localized to a specific lung zone and may include
rales, rhonchi, bronchial breath sounds, dullness, increased fremitus, and egophony. In contrast,
atypical pathogens such as Mycoplasma, Chlamydophilia, and viruses can present in a subacute
fashion with fever, nonproductive cough, constitutional symptoms, and absent or diffuse findings
on lung examination. Rapid progression of disease to respiratory failure can be seen in severe
pneumococcal or Legionella pneumonia. Influenza may be complicated by bacterial pneumonia
with S. aureus or S. pneumoniae.
SARS presents with high fever and myalgia for 3-7 days followed by non-productive cough and
progressive hypoxemia with progression to mechanical ventilation in 20%. This can be
distinguished from other viral infections by the higher fever and lack of conjunctivitis, sneezing,
rhinorrhea, and pharyngitis. Inhalation anthrax can present with "flu-like" symptoms of myalgia,
fatigue, and fever before rapidly progressing to respiratory distress, mediastinitis, meningitis,
sepsis, and death.
The age of the patient can play an important role in disease presentation. Older patients often
have humoral and cellular immunodeficiency as a result of underlying diseases,
immunosuppressive medications, and aging. They are more frequently institutionalized with
anatomic problems that inhibit pulmonary clearance of pathogens. The presentation is often more
subtle than in younger adults, with more advanced disease and sepsis despite minimal fever and
sputum production.
Extrapulmonary physical findings can provide clues to the diagnosis. Poor dentition and foul-
smelling sputum may indicate the presence of a lung abscess with an anaerobic component.
Bullous myringitis can accompany infection with M pneumoniae. An absent gag reflex or altered
sensorium raises the question of aspiration. Encephalitis can complicate pneumonia with M
pneumoniaeor Legionella pneumophila. Cutaneous manifestations of
infection can include erythema multiforme (M pneumoniae), erythema
nodosum (C pneumoniae and M tuberculosis), or ecthyma gangrenosum
(P aeruginosa).
DIAGNOSIS AND TREATMENT SETTING
The composition of the diagnostic workup for pneumonia is the subject of
some disagreement between experts (see "National Guidelines"), but a
well-chosen evaluation can both support a diagnosis of pneumonia and
identify a pathogen.

Radiography
A cornerstone of diagnosis is the chest x-ray, which usually reveals an
Pulmonary infiltrate in
infiltrate (Figure 1) at presentation. However, this finding may be absent Legionella pneumonia.
in the dehydrated patient. Also, the radiographic manifestations of Source:
chronic diseases such as congestive heart failure, chronic obstructive CDC/Dr. William B. Baine
pulmonary disease (COPD), and malignancy may obscure the infiltrate of Figure 1
pneumonia.
Although radiographic patterns are usually nonspecific, they can suggest a microbiologic
differential diagnosis(Table 4).
Initial Management
Risk Stratification and Treatment Setting
When community-acquired pneumonia is strongly suspected on the basis of history, physical
examination, and chest radiography, the next critical management decision is whether the patient
will require hospital admission. Health care budgetary constraints have given rise to a number of
studies addressing the need for hospitalization in community-acquired pneumonia. A recent study
by the Patient Outcome Research Team (PORT) investigators validated a risk scale for mortality
in community-acquired pneumonia, assigning point values based on patient characteristics,
comorbid illness, physical examination, and basic laboratory findings (Table 5).7

Patients less than 50 years of age without comorbid illness or significant vital sign abnormalities
(risk class I) were found to have a low risk for mortality. The authors suggested that such patients
might be eligible for outpatient antibiotic therapy without extensive laboratory evaluation. All
others were evaluated with the laboratory testing listed in Table 5 and assigned to risk classes by
point totals (Table 6).
Classes I and II are considered excellent candidates for outpatient oral therapy, assuming no
hemodynamic instability, no chronic oxygen dependence, immunocompetence, and ability to
ingest, absorb, and adhere to an oral regimen. Patients in risk class III may be considered for
either outpatient or brief inpatient therapy, depending on clinical judgment. Patients in risk
categories IV and V are recommended for hospital admission. Ultimately, each decision to admit
must be individualized.
Diagnostic Testing
When the patient with few risk factors falls into PORT class I, the guidelines of the Infectious
Disease Society of America suggest empiric therapy without extensive lab evaluation (Table 7).
For the patient falling outside of this group, basic labs and a chest radiograph should be used to
stratify the patient into classes II through V.
If the patient is hospitalized, further workup may help to identify a pathogen (Table 7).
The value of such studies is not uniformly agreed upon (see "National Guidelines"). However,
pathogen identification has important implications for breadth of therapeutic antibiotic spectrum,
development of resistance, and epidemiology. A gram-stained sputum specimen can help focus
empiric therapy. Unfortunately, sputum is frequently difficult to obtain from elderly patients
because of a weak cough, obtundation, and dehydration. Nebulized saline treatments may help
mobilize secretions. Nasotracheal suctioning can sample the lower respiratory tract directly but
risks oropharyngeal contamination. A sputum specimen reflects lower respiratory secretions
when more than 25 white blood cells (WBCs) and less than 10 epithelial cells are seen in a low-
powered microscopic field.8 Empiric therapy based on a predominant organism in such a
specimen is likely to contain appropriate coverage.9 Other stains, such as the acid-fast stain for
mycobacteria, modified acid-fast stain for Nocardia, or the toluidine blue and Gomori
methenamine silver stains should be employed when directed by the history or clinical
presentation. Direct fluorescent antibody (DFA) staining of sputum, bronchoalveolar lavage fluid,
or pleural fluid may help identify Legionella species. In a like fashion, DFA testing of
nasopharyngeal specimens provides rapid diagnosis of influenza A and B, as well as other
common respiratory viruses such as respiratory syncytial virus, adenovirus, and parainfluenza
virus. In an outbreak setting, DFA and other rapid techniques can assist in therapeutic and
infection control decision-making.
The sputum culture remains a controversial tool but is still recommended to help tailor therapy.
Culture is particularly helpful in identifying organisms of epidemiologic significance, either for
patterns of transmission or resistance. Expectorated morning sputum specimens should be sent
for mycobacterial culture when the history is suggestive.
Blood cultures may also shed light on a pathogen, and should be drawn in hospitalized
patients (see "Outcomes"). Pleural or cerebrospinal fluid should be sampled when infections in
these spaces are suspected.
When these procedures fail to yield a microbiologic diagnosis and when the patient fails to
respond to empiric antibiotic therapy, more invasive diagnostic techniques may be indicated.
Fiberoptic bronchoscopy allows the use of several techniques in the diagnosis of pneumonia.
Bronchoalveolar lavage with saline can obtain deep respiratory specimens for the gamut of stains
and cultures mentioned above. Transbronchial biopsy of lung parenchyma can reveal alveolar or
interstitial pneumonitis, viral inclusion bodies, and fungal or mycobacterial elements. The
protected brush catheter is used to quantitatively distinguish between tracheobronchial colonizers
and pneumonic pathogens.
A more substantial amount of lung tissue may be obtained for culture and histologic examination
by thoracoscopic or open-lung biopsy. Because these procedures can carry considerable
morbidity, they are usually reserved for the deteriorating patient with a pneumonia that defies
diagnosis by less invasive techniques.

Serologic Testing
Often relegated to retrospective or epidemiologic interest because of delays in testing or
reporting, serologic testing for such pathogens as Legionella species, Mycoplasma species,
and C pneumoniae should include sera drawn in both the acute and convalescent phases for
comparison. A fourfold increase in the immunoglobulin G (IgG) titer is suggestive of recent
infection with these organisms. An IgM microimmunofluorescence titer of > 1:16 is considered
diagnostic of C pneumoniae infection. Infection with SARS associated coronavirus is most often
diagnosed by antibody testing and polymerase chain reaction testing.
A sensitive enzyme immunoassay has been developed for the detection of L pneumophila type 1
antigen in urine. Because the antigen persists for up to a year after infection, it is difficult to
differentiate between past and current infections when using this assay.
A newer urinary assay for detection of S pneumoniae cell wall polysaccharide has recently been
approved by the FDA. This assay may offer some advantage in the rapid diagnosis of
pneumococcal pneumonia in culture proven or unknown cases, but assay specificity is an
ongoing question.
Molecular Techniques
Powerful molecular techniques are now being applied to the early diagnosis of pneumonia. DNA
probes have been used for the detection of Legionella species, M pneumoniae, and M
tuberculosis in sputum. These probes have excellent sensitivity and specificity but can produce
some false-positive results. The polymerase chain reaction has been shown to be a sensitive tool
for the early detection of M tuberculosis in sputum specimens. Given the large percentage of
pneumonia cases for which no microbial etiology is identified, it is likely that molecular tools will
eventually be applied to identification and antimicrobial susceptibility testing of nearly all agents of
pneumonia.