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Diagnosis of ventilator-associated pneumonia
Microbes and Infection 7 (2005) 262–267 www.elsevier.com/locate/micinf
Current focus
Diagnosis of ventilator-associated pneumonia Robert P. Baughman * Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0565, USA Available online 04 January 2005
Abstract The diagnosis of ventilator pneumonia remains a controversial area. Use of standard clinical criteria has been found to be inadequate. Use of a clinical pulmonary infection score (CPIS) has improved the diagnostic utility of clinical criteria. For the intubated patient, there is ready access to the lower respiratory tract. Samples include endotracheal aspirates, bronchoalveolar lavage and protected brush specimen. The latter two can be obtained blindly or via a bronchoscope. The culture results are more meaningful if reported in a semi-quantitative model. There is increasing evidence that culture results predict mortality and can be used to direct duration and type of therapy. © 2005 Elsevier SAS. All rights reserved. Keywords: Bronchoalveolar lavage; Protected brush specimen; Clinical pulmonary infection score
1. Introduction The diagnosis of pneumonia is made on the basis of clinical and radiological criteria. Microbiological confirmation of pneumonia is useful, but approximately half of pneumonias never have an identifiable agent. For ventilator-associated pneumonia (VAP), these same criteria have been used [1,2]. However, there are two major differences for VAP: the ready access to the lower respiratory tract and the high mortality seen in these patients. Elsewhere in this issue are discussions of the higher mortality encountered in patients not treated with adequate initial therapy [3,4]. An important feature of this observation on adequate antibiotics is the importance of early therapy. If the bacteria causing the pneumonia are not adequately treated, there is a significantly higher mortality. 2. Clinical diagnosis The clinical suspicion of pneumonia is the first step in any evaluation of patients with possible VAP. The ventilated patient who develops a fever, leukocytosis, increased secretions, worsening hypoxia, and has a localized infiltrate probably has pneumonia. However, no single clinical criterion has been specifically diagnostic for VAP [5]. * Tel.: +1 513 584 5225; fax: +1 513 584 5110. E-mail address: [email protected] (R.P. Baughman). 1286-4579/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.micinf.2004.11.001
Fever and hypothermia are commonly recognized features of infection. However, immunosuppressed patients may fail to mount a fever. In the elderly, absence of fever in response to pneumonia is more common than in the younger population [6,7]. The presence of leukocytosis requires that the patient have a bone marrow capable of responding to infection. Patients with community-acquired pneumonia can develop significant leukopenia due to the infection. In one study, if the resulting white blood count was less than 2000 cells per mm3, the observed mortality was 50% [8]. The presence of an infiltrate in the lungs is required for the diagnosis of pneumonia. Mechanically ventilated patients are usually evaluated by portable chest X-rays. A new or worsening infiltrate is fairly sensitive but not very specific for VAP. The presence of a localized infiltrate is more specific. Fig. 1 summarizes the sensitivity and specificity of a new or worsening infiltrate. Andrews studied patients with underlying acute respiratory distress syndrome. In this situation, the change in infiltrate was only 57% sensitive for pneumonia [9]. Wunderink compared roentgenographic patterns and subsequent autopsy findings. He found a localized infiltrate was 87% sensitive for VAP, but only 25% specific [10]. Others have found similar sensitivities and specificity [11–13]. The findings of airbronchograms have been proposed as more specific for the diagnosis of VAP [10]; as shown in Fig. 1, this does not really increase the specificity. In all the studies shown in Fig. 1, more than 10% of the cases of pneumonia failed to have a new or worsening infil-
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Table 1 CPIS Criteria
Fig. 1. The sensitivity and specificity of a new or worsening filtrate in the diagnosis of VAP. The first author of each paper is indicated. The confirmation of pneumonia was made either by autopsy (Andrews [9], Wunderink [10] and Torres [13]) or bronchoscopic-derived cultures (Meduri [11] and Winer-Muram [12]).
trate. These missed cases were diagnosed at autopsy [10,13]. CT scans increase the sensitivity; however, the scan is no more specific than routine chest roentgenogram. The finding of a routine CT scan of the chest essentially rules out pneumonia [14]. Worsening hypoxia is a standard feature of pneumonia. As opposed to community-acquired pneumonia, a ventilated patient’s level of oxygenation is usually well documented by both continuous oximetry and intermittent arterial blood gases. A worsening of oxygenation is obviously multifactorial. However, pneumonia is one of the more frequent and important causes of worsening oxygenation for the ventilated patient [15]. The clinical criteria used to establish the diagnosis of VAP have been summarized in the clinical pulmonary infection score (CPIS). Originally described by Pugin et al. [16], this score summarizes the major features used to diagnose pneumonia and gives them a relative weight. This CPIS has been modified by others: these modifications either minimize the importance of bacterial cultures [17] or do not use the bacterial culture data at all [15]. Table 1 summarizes the score and the modifications by Luna et al. [15]. The CPIS has its limitations. In one study comparing CPIS to autopsy findings, Fabregas et al. [18] found no advantage over routine clinical evaluation for pneumonia. Others have found that CPIS was significantly improved by the addition of culture results [19,20]. However, culture results are not available for 2–4 days after the procedure. The delay in diagnosis has been used as a reason to go with CPIS alone. Luna et al. performed a prospective study of patients with bronchoalveolar lavage (BAL)-confirmed VAP. There was a significant rise in the CPIS score from 3 days before the pneumonia until the day of pneumonia [15]. However, this was on average only 1.5 points (on a 10-point scale); thus, one can appreciate that the change can be somewhat subtle.
Original Simplified CPIS [16] CPIS [15]
Temperature (°C) ≥36.5 ≤38.4 ≥38.5 ≤38.9 <36 or ≥39 White blood count (cells per mm3) ≥4000 ≤11,000 <4000 or >11,000 Secretions (per day) Small Moderate Large Purulent Chest roentgenogram No infiltrate Diffuse/patchy infiltrate Localized infiltrate PF ratio * >240 without ARDS * ≤240 without ARDS or ARDS Culture <10,000 cfu bacteria per ml BAL or no growth ≥10,000 bacteria cfu/ml BAL Positive Gram stain
0 1 2
0 1 3
0 1
0 1
0 1 1 +1a
0 1 2 +1
0 1 2
0 1 2
0 2
0 2
0
NA
1 +1
NA NA
PF ratio = arterial oxygenation (PO2)/fraction inspired oxygen (FiO2) ratio; ARDS = acute respiratory distress syndrome; BAL= bronchoalveolar lavage; NA = not applicable. a If present, add an additional point.
The serial study did demonstrate that clinical evaluation remains important in defining response to therapy. Three days after the onset of pneumonia, patients who ultimately survived the pneumonia would have a drop in their CPIS. Again, this was only one to two points; however, those who eventually died from this episode of VAP had no fall in their CPIS.
3. Samples for culture The intubated patient allows ready access to the lower respiratory tract for sampling. Several different samples can be obtained, but three major samples have been studied (Table 2). These lung samples have all been shown to be of value in detecting the cause of VAP. On the other hand, blood cultures are of limited value, since most bacterial pneumonias in the ICU are not associated with bacteremia. In fact, the presence of a positive culture suggests an alternative cause, such as line sepsis [21]. Table 2 Lower respiratory tract samples obtained to diagnose VAP Sample EA (cfu/ml) BAL (cfu/ml) PBS (cfu/ml)
Proposed cut-off using semi-quantitative cultures ≥100,000 ≥10,000 ≥1000
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The endotracheal aspirate (EA) remains the most common method to obtain a lower respiratory sample. Since the patient is intubated, expectorated sputum is not available. The aspirated sample is usually captured in a trap, set up in line with a suction catheter. The sample can be analyzed by qualitative or quantitative means. As will be discussed later, the quantitative technique enhances the specificity of the sample. Beyond the EA, one can obtain deeper specimens. These include either the protected brush specimen (PBS) or the BAL sample. Both techniques have been extensively studied and validated as methods to obtain lower respiratory tract specimens [22,23]. Both of these samples can be obtained either by a bronchoscope or by directly placing a catheter through the endotracheal tube (non-bronchoscopic sample) [24]. The use of a protected brush to obtain a lower respiratory tract sample was the first technique used to obtain lower respiratory samples for routine bacterial culture [25]. Although originally described for the non-intubated patient, it was quickly used for the ventilated patient. A major advantage of the PBS is the fact that a specific area is sampled by the brush. Using this technique in patients with localized VAP, it has been shown that there is a greater than 100-fold difference between the affected and unaffected lobes [26]. In a study comparing PBS with BAL, Chastre et al. [27] found the PBS to provide a more specific diagnosis of the cause of VAP. In that study, the authors used the immediate post mortem findings to verify whether the patient had pneumonia and to determine the causative agent. The use of BAL to obtain bacterial cultures came a few years after the PBS technique was introduced. The initial BAL samples in pneumonia concentrated on diagnosis of opportunistic infections such as Pneumocystis carinii (jiroveci) and Mycobacterium tuberculosis [28]. It was subsequently demonstrated that the use of semi-quantitative cultures could distinguish between patients with and without bacterial pneumonia [29]. This was confirmed in another study of nonventilated patients [30]. The technique was adopted in the diagnosis of VAP. It has been verified as a reliable method to diagnose VAP [22] and has been found to be more sensitive than the PBS [27]. Both the PBS and BAL have been obtained without a bronchoscope [24]. The non-bronchoscopic BAL has been the most commonly used method. It has been verified as a reliable technique using bronchoscopic BAL [31] and autopsy studies [32]. In a study using non-physician medical personnel to obtain the samples, we found that pre-established criteria were useful to assure adequate sample. These criteria required that at least 10% of the introduced fluid be aspirated and that less than 5% of the nucleated cells be epithelial cells [33]. Using these criteria, the diagnostic yield of nonbronchoscopic BAL was higher than we had previously achieved with bronchoscopic BAL [33,34]. This higher yield probably reflects the ability to do the procedure prior to changing antibiotics, rather than then next day, when adequate support personnel are available to perform a bronchoscopy. Although non-bronchoscopic BAL may be less specific than
bronchoscopic samples [31], the lower cost and ease of performance make it an acceptable alternative to bronchoscopic techniques.
4. Value of quantitation The respiratory tract secretions can be cultured either qualitatively or quantitatively. Traditionally, sputum has been reported qualitatively, with the growth scored light to heavy. Use of such a qualitative score is limited. The growth will be affected by the size of the inoculum of the bacteria. Also, some bacteria grow more rapidly than others. For example, Staphylcoccus aureus is much easier to recover than Streptococcus pneumonia. Since both of these are serious pulmonary pathogens, the rate of growth of one versus the other means little. Attempts to perform quantitative cultures of the sputum require special techniques. These include liquefying the sputum. The use of quantitative sputum cultures for bacterial samples has been limited [35]. On the other hand, the other lower respiratory samples can easily be quantitated. This is especially true for both the PBS and BAL samples. Both of these techniques were described using semi-quantitative cultures from the earliest reports [25,29]. Subsequent studies have verified that the proposed criteria for separating infection from colonization are reproducible [36]. In an analysis of over 20 studies using bronchoscopic BAL to diagnose VAP, the criterion of >10,000 colony-forming units (cfu) bacteria per ml of BAL fluid was associated with the best sensitivity and specificity [22]. For some groups, there has been resistance to the use of semi-quantitative cultures to diagnose VAP [37]. Part of this resistance has been due to issues of having to change the method of handling the sample. Another issue is the whether there is additional value associated with the procedures. The diagnosis of urinary tract infections relies heavily on the use of quantitative cultures of the urine [38,39]. The concept is that the presence of greater than 100,000 cfu bacteria per ml of urine corresponds to infection, while less than 1000 cfu bacteria per ml of urine corresponds to colonization. This interpretation has been supported by many years of clinical practice. The resistance of the microbiology laboratory in obtaining semi-quantitative cultures remains unexplained. The rationale behind performing bacterial cultures is summarized in Table 3. Each of these indications has been shown to be of value in the management of VAP. The use of quantitation to enhance specificity has been appreciated by most studies which compare the qualitative versus quantitative technique. After an evidence-based review of the literature, a panel recommended that quantitative methods be used for EAs, PBS, and BAL cultures [40]. Fig. 2 demonstrates the specific culture results of PBS and tracheal samples from five patients with VAP and five ventilated patients without VAP [26]. In four of five patients with pneumonia, the same bacteria were recovered in the tracheal
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Table 3 Reasons for performing bacterial cultures Indication Increased specificity Improved clinical outcome Identifying which bacteria needed to be covered by empiric therapy Identifying which patients may be treated with shorter course of therapy Serial studies to demonstrate resolution
Supportive literature (first author) Baughman [26], el Ebiary [48] Fagon [41] Kollef [4], Luna [3] Chastre [44] Dennesen [46], Baughman [47]
Fig. 2. The results of PBS and tracheal cultures from five patients with VAP and five ventilated patients without VAP. In seven cases, tracheal cultures identified bacteria not found in the PBS. Adapted from Baughman et al. [26].
sample as that found in the PBS. However, seven patients, including four without VAP, had bacteria detected in the tracheal samples which were not detected in the PBS. There was one patient with two such bacteria. The use of semiquantitative cultures and previously established cut-off (Table 2) distinguished between colonization and infection. The value of invasive diagnostic techniques was studied in a large randomized trial by Fagon et al. [41]. In that study, 204 patients underwent invasive management compared to 209 who had only clinical management. There was nearly a 10% reduction in mortality 14 days after the onset of VAP (P < 0.05). In addition, the invasively managed group was treated with significantly fewer antibiotics per day. A study comparing BAL to EA has not shown an advantage of either technique [42]; however, there were far fewer patients studied than in the Fagon trial. The major role of microbiology has been to identify which bacteria need to be treated. Several studies have demonstrated that failure to treat adequately for bacteria found in significant numbers in BAL samples is associated with increased mortality [3,4]. The use of microbiologic cultures to improve subsequent empiric antibiotic choices has been demonstrated by Ibrahim et al. [43]. Using culture results, a strategy for empiric therapy was developed that increased the rate of adequate antibiotics from 50% to 94%. The duration of treatment with antibiotics for presumed VAP has been the subject of much discussion. A study by
Singh et al. [17] compared the results of administering only 3 days of antibiotics versus “conventional” therapy in a group of patients with possible VAP. In the study, 20% of patients with an initial simplified CPIS < 6 had a rise in their CPIS at day 3. These patients were treated with a more prolonged course of antibiotics. Over 80% of these patients had significant bacteria recovered from the original microbiologic cultures. In a randomized trial of 8 versus 15 days of antibiotic therapy for VAP, Chastre et al. [44] demonstrated no decrease in mortality for the overall group treated with short duration of antibiotics. They did demonstrate that shorter initial therapy was associated with less overall antibiotic use and lower rate of superinfection with multidrug-resistant bacteria. The Gramnegative enteric bacteria had a trend towards treatment failure if treated only 8 days. This would support the position that microbiologic cultures are useful in determining duration of therapy. Total resolution of some bacteria, such as Pseudomonas aeruginosa and S. aureus, from the lung is rare in ventilated patients. Once these bacteria occur, they may persist for some time, due to mechanical and nutritional issues [45]. However, during treatment for pneumonia, there is a reduction in the bacterial burden [46]. This resolution is seen within 3 days of successful treatment of VAP. In a study from our institution, we found that patients unable to successfully reduce the bacterial burden had an increased mortality. Fig. 3 shows the
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Fig. 3. Twenty-eight-day mortality of patients with initially ≥10,000 cfu bacteria per ml BAL fluid. The group with ≥1000 cfu bacteria per ml BAL had a significantly higher mortality than those with <1000 cfu bacteria per ml BAL (P <0.05) [47].
28-day mortality of 24 patients with VAP who had greater than 10,000 cfu bacteria per ml BAL in their initial culture. Follow-up cultures were done 2–5 days later. The mortality was significantly higher for those patients who still had at least 1000 cfu bacteria per ml of BAL fluid [47].
5. Conclusion The use of microbiologic cultures to confirm VAP can assist in the initial evaluation of patients and subsequent therapy. Several methods are available to obtain lower respiratory secretions. The relative value of one versus another sample is still unclear.
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Current focus
Diagnosis of ventilator-associated pneumonia Robert P. Baughman * Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0565, USA Available online 04 January 2005
Abstract The diagnosis of ventilator pneumonia remains a controversial area. Use of standard clinical criteria has been found to be inadequate. Use of a clinical pulmonary infection score (CPIS) has improved the diagnostic utility of clinical criteria. For the intubated patient, there is ready access to the lower respiratory tract. Samples include endotracheal aspirates, bronchoalveolar lavage and protected brush specimen. The latter two can be obtained blindly or via a bronchoscope. The culture results are more meaningful if reported in a semi-quantitative model. There is increasing evidence that culture results predict mortality and can be used to direct duration and type of therapy. © 2005 Elsevier SAS. All rights reserved. Keywords: Bronchoalveolar lavage; Protected brush specimen; Clinical pulmonary infection score
1. Introduction The diagnosis of pneumonia is made on the basis of clinical and radiological criteria. Microbiological confirmation of pneumonia is useful, but approximately half of pneumonias never have an identifiable agent. For ventilator-associated pneumonia (VAP), these same criteria have been used [1,2]. However, there are two major differences for VAP: the ready access to the lower respiratory tract and the high mortality seen in these patients. Elsewhere in this issue are discussions of the higher mortality encountered in patients not treated with adequate initial therapy [3,4]. An important feature of this observation on adequate antibiotics is the importance of early therapy. If the bacteria causing the pneumonia are not adequately treated, there is a significantly higher mortality. 2. Clinical diagnosis The clinical suspicion of pneumonia is the first step in any evaluation of patients with possible VAP. The ventilated patient who develops a fever, leukocytosis, increased secretions, worsening hypoxia, and has a localized infiltrate probably has pneumonia. However, no single clinical criterion has been specifically diagnostic for VAP [5]. * Tel.: +1 513 584 5225; fax: +1 513 584 5110. E-mail address: [email protected] (R.P. Baughman). 1286-4579/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.micinf.2004.11.001
Fever and hypothermia are commonly recognized features of infection. However, immunosuppressed patients may fail to mount a fever. In the elderly, absence of fever in response to pneumonia is more common than in the younger population [6,7]. The presence of leukocytosis requires that the patient have a bone marrow capable of responding to infection. Patients with community-acquired pneumonia can develop significant leukopenia due to the infection. In one study, if the resulting white blood count was less than 2000 cells per mm3, the observed mortality was 50% [8]. The presence of an infiltrate in the lungs is required for the diagnosis of pneumonia. Mechanically ventilated patients are usually evaluated by portable chest X-rays. A new or worsening infiltrate is fairly sensitive but not very specific for VAP. The presence of a localized infiltrate is more specific. Fig. 1 summarizes the sensitivity and specificity of a new or worsening infiltrate. Andrews studied patients with underlying acute respiratory distress syndrome. In this situation, the change in infiltrate was only 57% sensitive for pneumonia [9]. Wunderink compared roentgenographic patterns and subsequent autopsy findings. He found a localized infiltrate was 87% sensitive for VAP, but only 25% specific [10]. Others have found similar sensitivities and specificity [11–13]. The findings of airbronchograms have been proposed as more specific for the diagnosis of VAP [10]; as shown in Fig. 1, this does not really increase the specificity. In all the studies shown in Fig. 1, more than 10% of the cases of pneumonia failed to have a new or worsening infil-
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Table 1 CPIS Criteria
Fig. 1. The sensitivity and specificity of a new or worsening filtrate in the diagnosis of VAP. The first author of each paper is indicated. The confirmation of pneumonia was made either by autopsy (Andrews [9], Wunderink [10] and Torres [13]) or bronchoscopic-derived cultures (Meduri [11] and Winer-Muram [12]).
trate. These missed cases were diagnosed at autopsy [10,13]. CT scans increase the sensitivity; however, the scan is no more specific than routine chest roentgenogram. The finding of a routine CT scan of the chest essentially rules out pneumonia [14]. Worsening hypoxia is a standard feature of pneumonia. As opposed to community-acquired pneumonia, a ventilated patient’s level of oxygenation is usually well documented by both continuous oximetry and intermittent arterial blood gases. A worsening of oxygenation is obviously multifactorial. However, pneumonia is one of the more frequent and important causes of worsening oxygenation for the ventilated patient [15]. The clinical criteria used to establish the diagnosis of VAP have been summarized in the clinical pulmonary infection score (CPIS). Originally described by Pugin et al. [16], this score summarizes the major features used to diagnose pneumonia and gives them a relative weight. This CPIS has been modified by others: these modifications either minimize the importance of bacterial cultures [17] or do not use the bacterial culture data at all [15]. Table 1 summarizes the score and the modifications by Luna et al. [15]. The CPIS has its limitations. In one study comparing CPIS to autopsy findings, Fabregas et al. [18] found no advantage over routine clinical evaluation for pneumonia. Others have found that CPIS was significantly improved by the addition of culture results [19,20]. However, culture results are not available for 2–4 days after the procedure. The delay in diagnosis has been used as a reason to go with CPIS alone. Luna et al. performed a prospective study of patients with bronchoalveolar lavage (BAL)-confirmed VAP. There was a significant rise in the CPIS score from 3 days before the pneumonia until the day of pneumonia [15]. However, this was on average only 1.5 points (on a 10-point scale); thus, one can appreciate that the change can be somewhat subtle.
Original Simplified CPIS [16] CPIS [15]
Temperature (°C) ≥36.5 ≤38.4 ≥38.5 ≤38.9 <36 or ≥39 White blood count (cells per mm3) ≥4000 ≤11,000 <4000 or >11,000 Secretions (per day) Small Moderate Large Purulent Chest roentgenogram No infiltrate Diffuse/patchy infiltrate Localized infiltrate PF ratio * >240 without ARDS * ≤240 without ARDS or ARDS Culture <10,000 cfu bacteria per ml BAL or no growth ≥10,000 bacteria cfu/ml BAL Positive Gram stain
0 1 2
0 1 3
0 1
0 1
0 1 1 +1a
0 1 2 +1
0 1 2
0 1 2
0 2
0 2
0
NA
1 +1
NA NA
PF ratio = arterial oxygenation (PO2)/fraction inspired oxygen (FiO2) ratio; ARDS = acute respiratory distress syndrome; BAL= bronchoalveolar lavage; NA = not applicable. a If present, add an additional point.
The serial study did demonstrate that clinical evaluation remains important in defining response to therapy. Three days after the onset of pneumonia, patients who ultimately survived the pneumonia would have a drop in their CPIS. Again, this was only one to two points; however, those who eventually died from this episode of VAP had no fall in their CPIS.
3. Samples for culture The intubated patient allows ready access to the lower respiratory tract for sampling. Several different samples can be obtained, but three major samples have been studied (Table 2). These lung samples have all been shown to be of value in detecting the cause of VAP. On the other hand, blood cultures are of limited value, since most bacterial pneumonias in the ICU are not associated with bacteremia. In fact, the presence of a positive culture suggests an alternative cause, such as line sepsis [21]. Table 2 Lower respiratory tract samples obtained to diagnose VAP Sample EA (cfu/ml) BAL (cfu/ml) PBS (cfu/ml)
Proposed cut-off using semi-quantitative cultures ≥100,000 ≥10,000 ≥1000
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The endotracheal aspirate (EA) remains the most common method to obtain a lower respiratory sample. Since the patient is intubated, expectorated sputum is not available. The aspirated sample is usually captured in a trap, set up in line with a suction catheter. The sample can be analyzed by qualitative or quantitative means. As will be discussed later, the quantitative technique enhances the specificity of the sample. Beyond the EA, one can obtain deeper specimens. These include either the protected brush specimen (PBS) or the BAL sample. Both techniques have been extensively studied and validated as methods to obtain lower respiratory tract specimens [22,23]. Both of these samples can be obtained either by a bronchoscope or by directly placing a catheter through the endotracheal tube (non-bronchoscopic sample) [24]. The use of a protected brush to obtain a lower respiratory tract sample was the first technique used to obtain lower respiratory samples for routine bacterial culture [25]. Although originally described for the non-intubated patient, it was quickly used for the ventilated patient. A major advantage of the PBS is the fact that a specific area is sampled by the brush. Using this technique in patients with localized VAP, it has been shown that there is a greater than 100-fold difference between the affected and unaffected lobes [26]. In a study comparing PBS with BAL, Chastre et al. [27] found the PBS to provide a more specific diagnosis of the cause of VAP. In that study, the authors used the immediate post mortem findings to verify whether the patient had pneumonia and to determine the causative agent. The use of BAL to obtain bacterial cultures came a few years after the PBS technique was introduced. The initial BAL samples in pneumonia concentrated on diagnosis of opportunistic infections such as Pneumocystis carinii (jiroveci) and Mycobacterium tuberculosis [28]. It was subsequently demonstrated that the use of semi-quantitative cultures could distinguish between patients with and without bacterial pneumonia [29]. This was confirmed in another study of nonventilated patients [30]. The technique was adopted in the diagnosis of VAP. It has been verified as a reliable method to diagnose VAP [22] and has been found to be more sensitive than the PBS [27]. Both the PBS and BAL have been obtained without a bronchoscope [24]. The non-bronchoscopic BAL has been the most commonly used method. It has been verified as a reliable technique using bronchoscopic BAL [31] and autopsy studies [32]. In a study using non-physician medical personnel to obtain the samples, we found that pre-established criteria were useful to assure adequate sample. These criteria required that at least 10% of the introduced fluid be aspirated and that less than 5% of the nucleated cells be epithelial cells [33]. Using these criteria, the diagnostic yield of nonbronchoscopic BAL was higher than we had previously achieved with bronchoscopic BAL [33,34]. This higher yield probably reflects the ability to do the procedure prior to changing antibiotics, rather than then next day, when adequate support personnel are available to perform a bronchoscopy. Although non-bronchoscopic BAL may be less specific than
bronchoscopic samples [31], the lower cost and ease of performance make it an acceptable alternative to bronchoscopic techniques.
4. Value of quantitation The respiratory tract secretions can be cultured either qualitatively or quantitatively. Traditionally, sputum has been reported qualitatively, with the growth scored light to heavy. Use of such a qualitative score is limited. The growth will be affected by the size of the inoculum of the bacteria. Also, some bacteria grow more rapidly than others. For example, Staphylcoccus aureus is much easier to recover than Streptococcus pneumonia. Since both of these are serious pulmonary pathogens, the rate of growth of one versus the other means little. Attempts to perform quantitative cultures of the sputum require special techniques. These include liquefying the sputum. The use of quantitative sputum cultures for bacterial samples has been limited [35]. On the other hand, the other lower respiratory samples can easily be quantitated. This is especially true for both the PBS and BAL samples. Both of these techniques were described using semi-quantitative cultures from the earliest reports [25,29]. Subsequent studies have verified that the proposed criteria for separating infection from colonization are reproducible [36]. In an analysis of over 20 studies using bronchoscopic BAL to diagnose VAP, the criterion of >10,000 colony-forming units (cfu) bacteria per ml of BAL fluid was associated with the best sensitivity and specificity [22]. For some groups, there has been resistance to the use of semi-quantitative cultures to diagnose VAP [37]. Part of this resistance has been due to issues of having to change the method of handling the sample. Another issue is the whether there is additional value associated with the procedures. The diagnosis of urinary tract infections relies heavily on the use of quantitative cultures of the urine [38,39]. The concept is that the presence of greater than 100,000 cfu bacteria per ml of urine corresponds to infection, while less than 1000 cfu bacteria per ml of urine corresponds to colonization. This interpretation has been supported by many years of clinical practice. The resistance of the microbiology laboratory in obtaining semi-quantitative cultures remains unexplained. The rationale behind performing bacterial cultures is summarized in Table 3. Each of these indications has been shown to be of value in the management of VAP. The use of quantitation to enhance specificity has been appreciated by most studies which compare the qualitative versus quantitative technique. After an evidence-based review of the literature, a panel recommended that quantitative methods be used for EAs, PBS, and BAL cultures [40]. Fig. 2 demonstrates the specific culture results of PBS and tracheal samples from five patients with VAP and five ventilated patients without VAP [26]. In four of five patients with pneumonia, the same bacteria were recovered in the tracheal
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Table 3 Reasons for performing bacterial cultures Indication Increased specificity Improved clinical outcome Identifying which bacteria needed to be covered by empiric therapy Identifying which patients may be treated with shorter course of therapy Serial studies to demonstrate resolution
Supportive literature (first author) Baughman [26], el Ebiary [48] Fagon [41] Kollef [4], Luna [3] Chastre [44] Dennesen [46], Baughman [47]
Fig. 2. The results of PBS and tracheal cultures from five patients with VAP and five ventilated patients without VAP. In seven cases, tracheal cultures identified bacteria not found in the PBS. Adapted from Baughman et al. [26].
sample as that found in the PBS. However, seven patients, including four without VAP, had bacteria detected in the tracheal samples which were not detected in the PBS. There was one patient with two such bacteria. The use of semiquantitative cultures and previously established cut-off (Table 2) distinguished between colonization and infection. The value of invasive diagnostic techniques was studied in a large randomized trial by Fagon et al. [41]. In that study, 204 patients underwent invasive management compared to 209 who had only clinical management. There was nearly a 10% reduction in mortality 14 days after the onset of VAP (P < 0.05). In addition, the invasively managed group was treated with significantly fewer antibiotics per day. A study comparing BAL to EA has not shown an advantage of either technique [42]; however, there were far fewer patients studied than in the Fagon trial. The major role of microbiology has been to identify which bacteria need to be treated. Several studies have demonstrated that failure to treat adequately for bacteria found in significant numbers in BAL samples is associated with increased mortality [3,4]. The use of microbiologic cultures to improve subsequent empiric antibiotic choices has been demonstrated by Ibrahim et al. [43]. Using culture results, a strategy for empiric therapy was developed that increased the rate of adequate antibiotics from 50% to 94%. The duration of treatment with antibiotics for presumed VAP has been the subject of much discussion. A study by
Singh et al. [17] compared the results of administering only 3 days of antibiotics versus “conventional” therapy in a group of patients with possible VAP. In the study, 20% of patients with an initial simplified CPIS < 6 had a rise in their CPIS at day 3. These patients were treated with a more prolonged course of antibiotics. Over 80% of these patients had significant bacteria recovered from the original microbiologic cultures. In a randomized trial of 8 versus 15 days of antibiotic therapy for VAP, Chastre et al. [44] demonstrated no decrease in mortality for the overall group treated with short duration of antibiotics. They did demonstrate that shorter initial therapy was associated with less overall antibiotic use and lower rate of superinfection with multidrug-resistant bacteria. The Gramnegative enteric bacteria had a trend towards treatment failure if treated only 8 days. This would support the position that microbiologic cultures are useful in determining duration of therapy. Total resolution of some bacteria, such as Pseudomonas aeruginosa and S. aureus, from the lung is rare in ventilated patients. Once these bacteria occur, they may persist for some time, due to mechanical and nutritional issues [45]. However, during treatment for pneumonia, there is a reduction in the bacterial burden [46]. This resolution is seen within 3 days of successful treatment of VAP. In a study from our institution, we found that patients unable to successfully reduce the bacterial burden had an increased mortality. Fig. 3 shows the
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Fig. 3. Twenty-eight-day mortality of patients with initially ≥10,000 cfu bacteria per ml BAL fluid. The group with ≥1000 cfu bacteria per ml BAL had a significantly higher mortality than those with <1000 cfu bacteria per ml BAL (P <0.05) [47].
28-day mortality of 24 patients with VAP who had greater than 10,000 cfu bacteria per ml BAL in their initial culture. Follow-up cultures were done 2–5 days later. The mortality was significantly higher for those patients who still had at least 1000 cfu bacteria per ml of BAL fluid [47].
5. Conclusion The use of microbiologic cultures to confirm VAP can assist in the initial evaluation of patients and subsequent therapy. Several methods are available to obtain lower respiratory secretions. The relative value of one versus another sample is still unclear.
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