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Clinical presentation and diagnosis of ventilator-associated pneumonia

Official reprint from UpToDate


www.uptodate.com 2014 UpToDate
Clinical presentation and diagnosis of ventilator-associated pneumonia
Author
Marin H Kollef, MD

Section Editors
Polly E Parsons, MD
John G Bartlett, MD

Deputy Editor
Geraldine Finlay, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2014. | This topic last updated: Mar 19, 2014.
INTRODUCTION Ventilator-associated pneumonia (VAP) is a type of hospital-acquired (ie, nosocomial)
pneumonia that develops after more than 48 hours of mechanical ventilation. It is a common and serious
problem, with an estimated incidence of 10 to 25 percent and an all-cause mortality of 25 to 50 percent [1,2].
Early diagnosis is important because prompt, appropriate treatment can be lifesaving.
The clinical presentation and diagnosis of VAP are reviewed here. The risk factors for VAP and its prevention
and treatment are discussed separately. (See "Treatment of hospital-acquired, ventilator-associated, and
healthcare-associated pneumonia in adults" and "Risk factors and prevention of hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia in adults" and "The ventilator circuit and ventilator-associated
pneumonia".).
CLINICAL FEATURES
Presentation VAP typically presents with a new or progressive pulmonary infiltrate and one or more of the
following findings: fever, purulent tracheobronchial secretions, leukocytosis, increased respiratory rate,
decreased tidal volume, increased minute ventilation, and decreased oxygenation [3]. These symptoms and
signs may develop gradually or suddenly.
Medical history Patients with VAP are typically unable to provide any history because they are either
sedated or their ability to communicate is impaired by the endotracheal or tracheostomy tube. Those few
patients who are able to convey symptoms are likely to report dyspnea or chest congestion.
Physical examination Fever and an increased volume of purulent tracheobronchial secretions are common
among patients with VAP. On auscultation, patients typically have diffuse, asymmetric rhonchi due to the
tracheobronchial secretions that the patient is unable to mobilize. The rhonchi are often accompanied by focal
findings, such as crackles and decreased breath sounds. In addition, many patients are tachypneic with
increased respiratory effort. Bronchospasm (wheezing and increased expiratory time) and hemoptysis are also
common. These pulmonary signs may be accompanied by systemic abnormalities, such as encephalopathy or
sepsis. (See "Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and
prognosis", section on 'Sepsis'.)
Ventilator performance Deterioration in the patients respiratory performance, as identified during routine
assessment of the mechanical ventilator, may be the initial sign of VAP. This includes an increased respiratory
rate, decreased tidal volume, increased minute ventilation, or decreased oxygenation. Many patients will require
more ventilatory support or inspired oxygen than they did previously.
DIAGNOSTIC EVALUATION Diagnostic evaluation is required any time that VAP is suspected because
clinical features alone are nonspecific [4-6]. The goal is to confirm VAP and to identify the likely pathogen, so
that the appropriate treatment can be initiated. The evaluation begins with a chest radiograph. Patients who have
an abnormal chest radiograph should have their respiratory tract sampled and specimens sent for microscopic
analysis and culture.
These steps are ideally performed prior to the initiation of antibiotic therapy because antibiotic therapy reduces
the sensitivity of both the microscopic analysis and culture [7,8] (similarly, these steps are ideally performed
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prior to changing the antibiotic regimen of patients suspected of developing VAP while receiving antibiotics
[9,10]). Once the respiratory specimens have been obtained, empiric antibiotic therapy is indicated for all cases
of suspected VAP, unless the clinical suspicion is low and the microscopic analysis of lower respiratory tract
samples is negative (ie, few neutrophils). Occasionally, the severity of illness or delays in sampling requires that
empiric antibiotic therapy be initiated prior to diagnostic sampling. (See "Treatment of hospital-acquired,
ventilator-associated, and healthcare-associated pneumonia in adults", section on 'Empiric treatment'.)
Chest imaging A chest radiograph should be performed on all patients with suspected VAP [1]. A normal
chest radiograph excludes VAP, while an abnormal radiograph should prompt the collection of respiratory tract
secretions. Common radiographic abnormalities in VAP include alveolar infiltrates, air bronchograms, and
silhouetting of adjacent solid organs.
While an abnormal chest radiograph is required to diagnose VAP, it is not sufficient. The reason that
radiographic abnormalities alone are insufficient to diagnose VAP is that they are nonspecific (ie, they frequently
exist in the absence of VAP) [1,4,11,12]. This was illustrated by an observational study in which only 43 percent
of patients who had clinical and radiographic evidence of VAP at the time of their death were subsequently
confirmed to have VAP by postmortem examination [12].
Additional benefits of the chest radiograph are that it can help determine the severity of the disease (multilobar
versus unilobar) and identify complications, such as pleural effusions or cavitation.
Respiratory sampling Lower respiratory tract sampling is indicated for all patients who are suspected of
having VAP and have an abnormal chest radiograph [1]. There are a variety of methods available to sample
material from the airways and alveoli, including nonbronchoscopic (ie, blind) and bronchoscopic techniques.
Nonbronchoscopic lower respiratory tract sampling includes tracheobronchial aspiration or mini-BAL [13-21]:
Tracheobronchial aspiration is performed by advancing a catheter through the endotracheal tube until
resistance is met and then applying suction.
Mini-BAL is performed by advancing a catheter through the endotracheal tube until resistance is met,
infusing sterile saline through the catheter, and then aspirating.
A clinician is not necessary to perform or supervise nonbronchoscopic sampling. This reduces the cost, allows
specimens to be obtained quickly, and facilitates serial sampling when necessary.
Bronchoscopic sampling is performed using either bronchoalveolar lavage (BAL) or a protected specimen brush
(PSB) (see "Flexible bronchoscopy: Indications and contraindications" and "Flexible bronchoscopy: Equipment,
procedure, and complications"):
BAL involves the infusion and aspiration of sterile saline through a flexible bronchoscope that is wedged in
a bronchial segmental orifice. The technique of BAL is discussed in detail separately. (See "Basic
principles and technique of bronchoalveolar lavage".)
A PSB is a brush that is contained within a protective sheath. It is designed to minimize the likelihood that
the brush will be contaminated during bronchoscopy. The procedure involves placing the bronchoscope tip
next to a bronchial segmental orifice, pushing the sheath through the bronchoscope, and then advancing
the brush out of the sheath and into the airway. Specimens are collected by brushing the airway wall,
withdrawing the brush into the sheath, and then removing the sheath from the bronchoscope.
Bronchoscopic sampling and nonbronchoscopic sampling have been compared in the setting of suspected VAP
[22-26]. The evidence indicates that bronchoscopic sampling does not improve mortality, length of hospital stay,
duration of mechanical ventilation, or length of intensive care unit stay [22,24,26,27]. However, it minimizes
airway contamination of the alveolar samples and provides an accurate assessment of the alveolar cell
population. Bronchoscopic sampling may lead to a narrower antimicrobial regimen and more rapid de-escalation
of antimicrobial therapy [22,23,25,28], which presumably reduces antibiotic resistance.
The decision about whether to perform nonbronchoscopic or bronchoscopic sampling ultimately depends upon a
case-by-case determination of the benefits of a narrow antibiotic regimen versus the risks of bronchoscopy. In
patients for whom the risk of bronchoscopy is low, we frequently perform bronchoscopic BAL [29].
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Microscopic analysis The lower respiratory specimens should be sent for microscopic analysis. The most
common microscopic analysis is the Gram stain. It can be used to semi-quantitate polymorphonuclear
leukocytes and other cell types, as well as to characterize the morphology of bacteria. The presence of
abundant neutrophils is consistent with VAP and the bacterial morphology may suggest a likely pathogen.
Gram stain analysis may decrease the incidence of inappropriate antimicrobial therapy and improve diagnostic
accuracy when correlated with culture results [1].
A differential cell count can also be performed by microscopic analysis following a BAL. It determines the
proportion of total nucleated cells in the spun sediment of BAL fluid that are neutrophils, lymphocytes,
macrophages, eosinophils, basophils, or other nucleated cells. In a prospective cohort study of 39 patients,
VAP was correctly excluded in all patients in whom neutrophils were fewer than 50 percent of the total
nucleated cells [30].
Respiratory culture The lower respiratory specimens should also be sent for culture. Quantitative or
semiquantitative cultures are both acceptable, with the choice depending largely upon availability.
Quantitative culture Quantitative cultures can be performed on bronchoscopic or nonbronchoscopic
specimens. VAP is supported when an established threshold of bacterial growth is exceeded. Only bacteria that
are pulmonary pathogens should be counted. As examples, Staphylococcus epidermidis, enterococci, and
most gram positive bacilli (except actinomycosis and nocardia) should not be counted.
Thresholds of 1,000,000 colony forming units (cfu)/mL for samples obtained by tracheobronchial aspiration,
10,000 cfu/mL for samples obtained by BAL, or 1000 cfu/mL for samples obtained by PSB are most accurate
because they are sufficiently high that patients with tracheobronchial colonization are unlikely to be mistaken for
patients with VAP [1,9,31]. Lower thresholds are reasonable if the risk of a missing a VAP (ie, a false-negative
result) exceeds the risk of unnecessary treatment (ie, a false-positive result) [32]. According to a prospective
cohort study of 122 patients, thresholds between 1000 and 10,000 cfu/mL for BAL specimens and between 100
and 1000 cfu/mL for PSB specimens decrease the likelihood of a false-negative result to a greater degree than
they increase the likelihood of a false-positive result [33].
Generally speaking, quantitative cultures derived from nonbronchoscopic specimens tend to have a lower
specificity than quantitative cultures derived from bronchoscopic specimens [15,17]. However, this is balanced
by a higher sensitivity, resulting in comparable diagnostic accuracy. In a prospective cohort study of 38
patients, the accuracy of quantitative cultures was greatest when the sample was obtained by tracheobronchial
aspiration, followed (in order of decreasing accuracy) by BAL, mini-BAL, and PSB [15].
Quantitative cultures do not appear to improve clinical outcomes, compared with semiquantitative cultures. This
was illustrated by a meta-analysis of three randomized trials (1240 patients), which found that quantitative
cultures did not alter mortality, days of mechanical ventilation, or length of ICU stay, compared with
semiquantitative cultures [27]. Despite the lack of improvement in clinical outcomes, many clinicians believe
that quantitative cultures are advantageous because they may lead to more judicious use of antibiotics [29].
Semiquantitative culture Semiquantitative cultures can also be performed on bronchoscopic or
nonbronchoscopic samples. They are typically reported as showing heavy, moderate, light, or no growth [1]. The
amount of growth that suggests VAP has not been firmly established, but it is reasonable to consider a
semiquantitative culture with moderate or heavy growth to be positive. Compared with quantitative cultures,
semiquantitative cultures are less likely to distinguish patients whose airways are colonized from those who
have VAP [1]. As a result, false-positive results are more likely, which can lead to inappropriate therapy.
Other diagnostic tests Procalcitonin, the clinical pulmonary infection score, and lung biopsy are additional
diagnostic tests that are often discussed; however, they have little role in the evaluation of suspected VAP.
Biological markers Biologic markers are sometimes used to try to distinguish between bacterial and
non-bacterial causes of pneumonia.
Procalcitonin is a promising biologic marker. The use of serum procalcitonin to facilitate the decision about
whether or not to initiate antibiotics in patients admitted with suspected community-acquired pneumonia
was evaluated in several randomized trials that found that serum procalcitonin decreased antibiotic
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exposure without affecting clinical outcomes [34-36]. In suspected VAP, however, it is unknown if serum
procalcitonin levels are a useful guide for the decision about whether to initiate antibiotics because the
evidence is conflicting [37,38]. Until higher quality studies resolve the uncertainty, we believe that serum
procalcitonin levels should not be used for this purpose. However, there are two situations in which
procalcitonin may be useful in patients with confirmed VAP. First, procalcitonin may be helpful in the
decision of whether to discontinue antibiotic therapy [39]. Second, procalcitonin may be a useful
prognostic marker, since progressive increases in serum procalcitonin have been associated with septic
shock and mortality [40-42].
Other biomarkers, such as C-reactive protein (CRP) and soluble triggering receptor expressed on myeloid
cells-1 (sTREM-1), were initially considered promising markers for improving diagnostic strategies for VAP.
However, more recent studies suggest that the measurement of such biomarkers in BAL fluid has minimal
diagnostic value for VAP [43-45].
Clinical Pulmonary Infection Score (CPIS) The CPIS combines clinical, radiographic, physiologic, and
microbiologic data into a numerical result (table 1). Initial validation of the CPIS found that a score greater
than six correlated with VAP [46]. However, subsequent studies failed to confirm this. In one prospective
cohort study, the CPIS identified VAP with a sensitivity and specificity of only 60 and 59 percent,
respectively [47].
Lung biopsy Histologic examination of lung tissue obtained by biopsy is an imperfect and seldom used
method of diagnosing VAP. In addition to requiring an invasive procedure, its reliability and reproducibility
are uncertain. This is probably due to a lack of standardized histologic criteria to define VAP. In a
prospective cohort study, 39 patients who died while receiving mechanical ventilation underwent post
mortem open lung biopsy [48]. The histology was reviewed separately by four pathologists who reported a
prevalence of VAP ranging from 18 to 38 percent. One pathologist reinterpreted the histology six months
later and reclassified the VAP status of two patients.
Laboratory tests Patients with VAP usually develop leukocytosis with a neutrophil predominance.
However, there are no laboratory findings that are specific for VAP.
DIAGNOSTIC CRITERIA The diagnosis of VAP is made when a patient who has been mechanically
ventilated for 48 hours develops a new or progressive infiltrate and the respiratory specimens are positive (ie,
increased neutrophils are seen in the microscopic analysis and growth of a pathogen in culture exceeds a
predefined threshold).
VAP cannot be confirmed or excluded until the culture results are complete, which generally takes two to three
days. At that time, the patient should be reevaluated to determine if additional diagnostic evaluation or changes
in management are warranted. These decisions are based upon the culture results and response to empiric
therapy (algorithm 1):
Patients with negative cultures who have not improved may not have VAP; therefore, other diagnoses or
sites of infection should be sought.
Patients with negative cultures who have improved may not have VAP; antimicrobial therapy should be
discontinued.
Patients with positive cultures who have not improved probably have VAP, but they may be receiving
inappropriate antimicrobial therapy, have a complication of the VAP (eg, abscess, empyema), have a
second source of infection, or have a second diagnosis. The antimicrobial regimen should be adjusted and
then potential causes for failing to improve clinically should be sought.
Patients with positive cultures who have improved probably have VAP, which has responded to
antimicrobial therapy; the antimicrobial therapy should be narrowed according to the culture results.
Antimicrobial therapy for VAP is discussed separately. (See "Treatment of hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia in adults".)
DIFFERENTIAL DIAGNOSIS There are many causes of pulmonary infiltrates, fever, respiratory
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abnormalities, and leukocytosis other than VAP. The following conditions can present with this constellation of
findings:
Aspiration pneumonitis Aspiration pneumonitis refers to chemical aspiration without infection; it is
distinguished from VAP by history (ie, witnessed aspiration), microscopic analysis and culture of
respiratory secretions (ie, negative), and clinical course (ie, self-limited). (See "Aspiration pneumonia in
adults".)
Pulmonary embolism with infarction Pulmonary embolism can mimic VAP if it causes pulmonary
infarction; it is distinguished from VAP when computed tomography pulmonary angiography (CT-PA),
ventilation-perfusion (V/Q) scanning, or conventional pulmonary angiography reveals pulmonary embolism.
(See "Diagnosis of acute pulmonary embolism".)
Acute respiratory distress syndrome Acute respiratory distress syndrome (ARDS) is characterized by
an acute onset of bilateral pulmonary infiltrates and severe hypoxemia in the absence of an elevated left
atrial pressure; it is distinguished from VAP by history (ie, risk factors for ARDS may be present) and the
microscopic analysis and culture of respiratory secretions (ie, negative). (See "Acute respiratory distress
syndrome: Clinical features and diagnosis in adults".)
Pulmonary hemorrhage Both pulmonary hemorrhage and VAP may cause hemoptysis in addition to the
constellation of findings described above. Pulmonary hemorrhage tends to present with frank bleeding
while VAP often appears as blood mixed with purulent secretions, but this distinction is imperfect.
Definitively distinguishing pulmonary hemorrhage from VAP requires that the cause of the hemoptysis be
identified. (See "Etiology and evaluation of hemoptysis in adults".)
Lung contusion Pulmonary contusion is due to trauma, but it may be difficult to distinguish from VAP
because the clinical and radiographic manifestations are similar and often delayed following the trauma.
Pulmonary contusion is distinguished from VAP by history (ie, recent trauma) and the microscopic
analysis and culture of respiratory secretions (ie, negative). (See "Overview of inpatient management in the
adult trauma patient", section on 'Pulmonary contusion'.)
Infiltrative tumor The lung is a common site of primary or metastatic cancer and the manifestations of a
diffuse infiltrative cancer are similar to VAP. Diffuse infiltrative cancer is distinguished from VAP by history
(ie, history of malignancy), as well as both culture (ie, negative) and microscopic analysis (ie, negative for
neutrophils and bacteria, but positive for malignant cells) of respiratory secretions.
Radiation pneumonitis Radiation-induced lung injury may cause acute pneumonitis or chronic fibrosis.
The former develops approximately four to twelve weeks after irradiation, with symptoms and signs that
mimic VAP; it is distinguished from VAP by history (ie, prior irradiation) and the microscopic analysis and
culture of respiratory secretions (ie, negative). (See "Radiation-induced lung injury".)
Drug reaction Pulmonary drug toxicity can result from many different drugs, most notably antineoplastic
agents (eg, cyclophosphamide, methotrexate). The clinical manifestations of pulmonary drug toxicity can
be identical to VAP and the timing of the onset of symptoms and signs is highly variable (ie, days to
months after receiving the medication). Pulmonary drug toxicity is distinguished from VAP by history (ie,
received a potentially toxic agent within the past months) and the microscopic analysis and culture of
respiratory secretions (ie, negative). (See "Pulmonary toxicity associated with systemic antineoplastic
therapy: Clinical presentation, diagnosis, and treatment".)
Cryptogenic organizing pneumonia Cryptogenic organizing pneumonia (COP) is an idiopathic form of
organizing pneumonia. Its clinical features may be identical to VAP; it is distinguished from VAP by
history (ie, risk factors for COP may be present, such as a recent viral infection) and the microscopic
analysis and culture of respiratory secretions (ie, negative). Definitive diagnosis of COP requires lung
biopsy. (See "Cryptogenic organizing pneumonia".)
VENTILATOR ASSOCIATED EVENTS The CDC National Healthcare Safety Network implemented ventilatorassociated events (VAE) surveillance in January 2013 [49]. This is a three-tier surveillance definition algorithm.
This algorithm uses objective, readily available data elements to identify a broad range of conditions and
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complications occurring in mechanically ventilated adult patients. These include, but are not limited to VAP. The
first tier definition, ventilator-associated condition (VAC), identifies patients with a period of sustained respiratory
deterioration following a sustained period of stability or improvement on the ventilator (changes in PEEP or
FiO2). The second tier definition, infection-related ventilator-associated complication (IVAC), requires that
patients with VAC also have an abnormal temperature or white blood cell count, and be started on a new
antimicrobial agent. The third tier definitions, possible and probable VAP, require that patients with IVAC also
have laboratory and/or microbiological evidence of respiratory infection [50]. The effect of implementing this
surveillance system and of VAP bundles on the prevention of VACs is unknown.
SUMMARY AND RECOMMENDATIONS
Ventilator-associated pneumonia (VAP) is a type of hospital-acquired (ie, nosocomial) pneumonia that
develops after more than 48 hours of mechanical ventilation. (See 'Introduction' above.)
VAP typically presents with the gradual or sudden onset of a new or progressive pulmonary infiltrate and
one or more of the following findings: fever, purulent tracheobronchial secretions, leukocytosis, increased
respiratory rate, decreased tidal volume, increased minute ventilation, and decreased oxygenation. (See
'Clinical features' above.)
A diagnostic evaluation is required whenever VAP is suspected because clinical features alone are
nonspecific. The goal of the diagnostic evaluation is to confirm VAP and identify the likely pathogen. A
typical evaluation begins with a chest radiograph. For patients with an abnormal chest radiograph, the
respiratory tract is sampled and the specimens are sent for microscopic analysis and culture. (See
'Diagnostic evaluation' above.)
These steps are ideally performed prior to the initiation of antibiotic therapy because antibiotic therapy
reduces the sensitivity of both the microscopic analysis and culture (similarly, these steps are ideally
performed prior to changing the antibiotic regimen of patients suspected of developing VAP while receiving
antibiotics). Once the respiratory specimens have been obtained, empiric antibiotic therapy is indicated for
all cases of suspected VAP, unless the clinical suspicion is low and the microscopic analysis of lower
respiratory tract samples is negative (ie, few neutrophils). Occasionally, the severity of illness or delays in
sampling requires that empiric antibiotic therapy be initiated prior to diagnostic sampling. (See 'Diagnostic
evaluation' above.)
The diagnosis of VAP is made when a patient who has been mechanically ventilated for at least 48 hours
develops a new or progressive pulmonary infiltrate and cultures of the respiratory specimens are positive
(ie, increased neutrophils are seen in the microscopic analysis and growth of a pathogen in culture
exceeds a predefined threshold). (See 'Diagnostic criteria' above.)
There are many causes of pulmonary infiltrates, fever, respiratory abnormalities, and leukocytosis other
than VAP. These include aspiration pneumonitis, pulmonary embolism with infarction, acute respiratory
distress syndrome, pulmonary hemorrhage, pulmonary contusion, infiltrative tumor, radiation pneumonitis,
pulmonary drug toxicity, and cryptogenic organizing pneumonia. (See 'Differential diagnosis' above.)
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2013; 368:1472.
50. Magill SS, Klompas M, Balk R, et al. Developing a new, national approach to surveillance for ventilatorassociated events*. Crit Care Med 2013; 41:2467.
Topic 1635 Version 9.0
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GRAPHICS
Clinical Pulmonary Infection Score (CPIS)
Temperature
36.5 or 38.4 = 0 point
38.5 or 38.9 = 1 point
39 or <36.5 = 2 points

Blood leukocytes, microL


4000 or 11,000 = 0 points
<4000 or >11,000 = 1 point
Band forms 50 percent = add 1 point

Tracheal secretions
Absence of tracheal secretions = 0 point
Presence of nonpurulent tracheal secretions = 1 point
Presence of purulent tracheal secretions = 2 points

Oxygenation
PaO 2 /FIO 2 , mmHg >240 or ARDS (defined as PaO 2 /FIO 2 200, PAWP 18 mmHg and
acute bilateral infiltrates) = 0 points
PaO 2 /FIO 2 240 and no ARDS = 2 points

Pulmonary radiography
No infiltrate = 0 point
Diffuse (patchy) infiltrate = 1 point
Localized infiltrate = 2 points

Progression of pulmonary infiltrate


No radiographic progression = 0 point
Radiographic progression (after HF and ARDS excluded) = 2 points

Culture of tracheal aspirate


Pathogenic bacteria cultured in rare or few quantities or no growth = 0 point
Pathogenic bacteria cultured in moderate or heavy quantity = 1 point
Same pathogenic bacteria seen on Gram stain, add 1 point
Total (a score of >6 was considered suggestive of pneumonia)

An initial score is based upon the first five variables. The last two variables are assessed
on day 2 or 3.
ARDS: acute respiratory distress syndrome; HF: heart failure; PAWP: pulmonary arterial wedge
pressure.
Adapted with permission from: Singh N, Rogers P, Atwood CW, et al. Short-course empiric antibiotic
therapy for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for
indiscriminate antibiotic prescription. Am J Respir Crit Care Med 2000; 162:505. Copyright 2002
American Thoracic Society.
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Graphic 77054 Version 4.0

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Diagnostic algorithm for hospital-acquired, ventilator


associated pneumonia

WBC: white blood cell.


Reproduced with permission from: American Thoracic Society and the Infectious
Diseases Society of America. Guidelines for the management of adults with hospitalacquired, ventilator associated, and healthcare-associated pneumonia. Am J Respir Crit
Care Med 2005; 171:388. Copyright 2002 American Thoracic Society.
Graphic 76508 Version 2.0

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Disclosures
Disclosures: Marin H Kollef, MD Nothing to disclose. Polly E Parsons, MD Nothing to disclose. John G Bartlett, MD Nothing to
disclose. Geraldine Finlay, MD Employee of UpToDate, Inc.
Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are addressed by vetting
through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately
referenced content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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