Parapneumonic Effusions and Empyema
Despite the advent of potent antibiotics, bacterial pneumonia still results in significant morbidity and mortality in the American population. The annual incidence of bacterial pneumonia is estimated to be 4 million, with approximately 25% of patients requiring hospitalization (1). Because as many as 40% of hospitalized patients with bacterial pneumonia have an accompanying pleural effusion (2), effusions associated with pneumonia, parapneumonic effusions (PPE), account for a large percentage of pleural effusions. The morbidity and mortality rates in patients with pneumonia and pleural effusions are higher than those in patients with pneumonia alone. In one study of 1,424 patients hospitalized with community-acquired pneumonia, patients with pleural effusions were 2.7 times more likely to be treatment failures than were those without pleural effusions (3). In another study, the relative risk of mortality in patients with community-acquired pneumonia was 7.0 times higher for patients with bilateral pleural effusions and 3.4 times higher for patients with unilateral pleural effusion of moderate or greater size as compared with other patients with community-acquired pneumonia alone (4). In assessing risks of patients with community-acquired pneumonia, the presence of a pleural effusion is given the same weight as a Po2 less than 60 mm Hg (5). Espana et al. (6) recommend that any patient with pneumonia and a loculated effusion or an effusion greater than 2 cm in thickness on the decubitus be hospitalized. Some of the increased morbidity and mortality in patients with parapneumonic effusions are due to mismanagement of the pleural effusion (7).
Pleural infection (complicated parapneumonic effusion and empyema) is rising in incidence across all age groups worldwide, confirmed by reports from the United States, Canada, Europe, and Asia (8). The mortality rate of empyema has risen alarmingly. In Utah, death rates from empyema were sixfold higher in 2000-2004 compared to 1950-1975 (9). Overall in the United States, the incidence of empyema per 100,000 persons had roughly doubled between 1996 and 2008 with roughly equal increases occurring in all age groups (10). In this study, the increase was largely due to increases in nonpneumococcal empyema and staph empyema (10). The explanation for the increase in empyema incidence is not clear but has been attributed at least in part to the induction of the heptavalent pneumococcal conjugate vaccine (PCV7) in 2000. After the introduction of this vaccine, there was a reduction in invasive pneumococcal disease, but the incidences of pneumococcal empyema in children and adults have both increased (8). The decrease in incidence of empyema from serotypes covered by the vaccine was overcompensated by an emergence of disease caused by nonvaccine serotypes (particularly serotype 1) (8).
Most pleural effusions associated with pneumonia resolve without any specific therapy directed toward the pleural fluid (2), but approximately 10% of patients require operative intervention. Delay in instituting proper therapy for these effusions is responsible for some of the morbidity associated with parapneumonic effusions. In one series of 39 patients from San Francisco General Hospital selected on the basis of pus in the pleural space, a positive Gram’s stain or culture, a pH of less than 7.0, or a glucose level of less than 40 mg/dL, the mean duration of pleural drainage was 21 ± 18 days, with a mortality rate of 10% (11).
HISTORY
Empyema has been recognized to be a serious problem for centuries. Around 500 B.C., Hippocrates recommended treating empyema with open drainage (12). He made the following interesting observation (12): “Those cases of empyema which are treated by incision or the cautery, if the water flows rapidly all at once certainly prove fatal. When empyema is treated, either by the incision or the cautery, if pure and white pus flows slowly from the wound, the patients recover.” His observation is contrary to that which most of us would have anticipated. However, when one reflects on the observation, its validity becomes obvious. If the fluid was thin, the patient probably did not have an empyema and the lung would collapse. However, if the fluid was pus, the patient had an empyema and drainage was likely to be beneficial.
From the time of Hippocrates, the treatment of empyema remained essentially unchanged until the middle of the 19th century. At this time, Bowditch (13) in the United States and Trousseau (14) in France popularized the use of thoracentesis and demonstrated that open drainage was not necessary in many patients. The next advance in the management of empyema came in 1876 when Hewitt (15) described a method of closed drainage of the chest in which a rubber tube was placed into the empyema cavity through a cannula. He was the first to use the water seal for chest tubes.
In the 1890s, two articles appeared that described thoracoplasty as a means of obliterating the empyema cavity (16,17). Thoracoplasty involves resecting the ribs, intercostal muscles, and parietal pleural peel over the cavity, and covering the remaining defect by the few remaining muscles, the scapula, and the subcutaneous tissue and skin. At approximately the same time, the initial reports (18,19) describing decortication appeared. By 1923, Eggers (20) had reported on a series of 99 patients treated by decortication at the Walter Reed Hospital, of whom two-thirds subsequently healed.
Although Hippocrates had recognized before the birth of Christ that open drainage procedures were dangerous if the empyema fluid was not thick (12) and Paget (21) had emphasized in 1896 that open drainage should not be instituted for empyema before at least the 15th day of the illness, by World War I, open drainage was the accepted treatment for all cases of empyema. During World War I, there was a high incidence of parapneumonic empyema in American soldiers and the treatment of all such patients with open drainage had disastrous results. In a survey in 1919, the U.S. Surgeon General found an average mortality rate of 30.2% in the armed forces for individuals with pleural infections, with a range of up to 70% in some hospitals (22). The primary reason for this very high mortality rate was that many cases of parapneumonic effusions in military recruits were due to Streptococcus hemolyticus, which is associated with large amounts of pleural fluid but without loculation of the pleural space (23). When an open procedure is performed on such patients, there is a high likelihood that the lung will collapse. In a study from Fort Riley, Kansas, 285 patients with empyema were subjected to surgery (24). The first 85 had early surgery and the mortality was 61%, 96 had early aspiration and later surgery and the mortality fell to 15.6%, whereas the last 94 patients had early aspiration and late surgery and the mortality was only 9.5% (24).
In 1918, Graham (25) reported that when chest tubes were inserted early in dogs with experimental empyemas, the mortality rate was higher and the dogs died sooner. The Empyema Commission headed by Dr. Evarts Graham soon made the following recommendations, which really form the basis for the treatment of empyema today: (a) The pleural fluid should be drained, but one must avoid an open pneumothorax in the acute exudative phase; (b) care should be taken to avoid a chronic empyema by rapid sterilization and obliteration of the infected cavity; and (c) careful attention should be paid to the nutrition of the patient. When these guidelines were observed, the mortality rate from streptococcal empyema secondary to influenza fell to 4.3% (26,27).
The next advance in the treatment of parapneumonic effusion came about in 1950, when Tillett and Sherry proposed enzymatic debridement with a combination of streptokinase and streptodornase for parapneumonic empyema (28). Then in the 1950s and 1960s, a low pleural fluid glucose was proposed as an indicator for tube thoracostomy (29). Then in 1972, Light et al. (30) suggested that a low pleural fluid pH was an indicator for tube thoracostomy, and in 1980, the same group suggested that a high pleural fluid lactic dehydrogenase (LDH) level was an indicator for a poor prognosis (2). In the last decade, the use of video-assisted thoracoscopy (VATS) has become widespread in the treatment of loculated parapneumonic effusions (31).
DEFINITIONS
Any pleural effusion associated with bacterial pneumonia, lung abscess, or bronchiectasis is a parapneumonic effusion (30). An empyema, by definition, is
pus in the pleural space, but how many white blood cells (WBCs) need be present in pleural fluid to make it pus? Weese et al. (32) defined an empyema as pleural fluid with a specific gravity greater than 1.018, a WBC count greater than 500 cells/mm3, or a protein level greater than 2.5 g/dL. Vianna (33) defined an empyema as pleural fluid on which the bacterial cultures are positive or the WBC is greater than 15,000/mm3 and the protein level is above 3.0 g/dL. Because many parapneumonic pleural effusions meeting these criteria resolve without operative intervention (2), I prefer to reserve the term empyema for those pleural effusions with thick, purulent appearing pleural fluid. Of course, some patients with empyema have no associated pneumonic process, as shown in Table 12.1.
pus in the pleural space, but how many white blood cells (WBCs) need be present in pleural fluid to make it pus? Weese et al. (32) defined an empyema as pleural fluid with a specific gravity greater than 1.018, a WBC count greater than 500 cells/mm3, or a protein level greater than 2.5 g/dL. Vianna (33) defined an empyema as pleural fluid on which the bacterial cultures are positive or the WBC is greater than 15,000/mm3 and the protein level is above 3.0 g/dL. Because many parapneumonic pleural effusions meeting these criteria resolve without operative intervention (2), I prefer to reserve the term empyema for those pleural effusions with thick, purulent appearing pleural fluid. Of course, some patients with empyema have no associated pneumonic process, as shown in Table 12.1.
The main decision in managing a patient with a parapneumonic effusion is whether to insert chest tubes. Therefore, I use the term complicated parapneumonic effusion to refer to those effusions that do not resolve without therapeutic thoracentesis or tube thoracostomy. Many complicated parapneumonic effusions are empyemas, but some parapneumonic effusions with nonpurulent appearing pleural fluid are also complicated parapneumonic effusions.
TABLE 12.1 ▪ Event or State Precipitating Empyema in 319 Patients | ||||||||||||||||||||||||||||||||||||
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PATHOPHYSIOLOGIC FEATURES
The evolution of a parapneumonic pleural effusion can be divided into three stages, which are not sharply defined but gradually merge together (34). First is the exudative stage, characterized by the rapid outpouring of sterile pleural fluid into the pleural space. The origin of this fluid is not definitely known, but it is probably the interstitial spaces of the lung. The origin of the pleural fluid in sheep with Pseudomonas aeruginosa pneumonia is the interstitial spaces of the lung (35). It is possible that some of the pleural fluid originates in the capillaries in the visceral pleura owing to their increased permeability secondary to the contiguous pneumonitis. The pleural fluid in this stage is characterized by a low WBC count, a low LDH level, and a normal glucose level and pH (36). If appropriate antibiotic therapy is instituted at this stage, the pleural effusion progresses no further, and the insertion of chest tubes is not necessary.
If appropriate antibiotic therapy is not instituted, in some instances, bacteria invade the pleural fluid from the contiguous pneumonic process, and the second, fibropurulent stage evolves. This stage is characterized by the accumulation of large amounts of pleural fluid with many polymorphonuclear leukocytes, bacteria, and cellular debris. Fibrin is deposited in a continuous sheet covering both the visceral and parietal pleura in the involved area. As this stage progresses, there is a tendency toward loculation and the formation of limiting membranes. These loculi prevent extension of the empyema but make drainage of the pleural space with chest tubes increasingly difficult. As this stage progresses, the pleural fluid pH and glucose levels become progressively lower and the LDH level becomes progressively higher.
The last stage is the organization stage, in which fibroblasts grow into the exudate from both the visceral and parietal pleural surfaces and produce an inelastic membrane called the pleural peel. This inelastic pleural peel over the visceral pleura encases the lung and renders it virtually functionless. At this stage, the exudate is thick, and if the patient remains untreated, the fluid may drain spontaneously through the chest wall (empyema necessitatis) or into the lung, producing a bronchopleural fistula.
Empyemas may arise without an associated pneumonic process. When three series (37,38,39) totaling 319 cases of empyema are combined (Table 12.1), most patients had pulmonary infections, but post-surgical empyemas were also important. A small percentage of empyemas complicate thoracentesis or tube thoracostomy for pneumothorax, hence the
necessity for maintaining sterile techniques during these procedures. The pleural effusions associated with esophageal perforation are almost always infected (see Chapter 18). Patients with rheumatoid pleural effusions frequently develop empyema (see Chapter 21); the genesis of the empyema in this situation is thought to be the formation of a bronchopleural fistula through necrotic subpleural nodules (40).
necessity for maintaining sterile techniques during these procedures. The pleural effusions associated with esophageal perforation are almost always infected (see Chapter 18). Patients with rheumatoid pleural effusions frequently develop empyema (see Chapter 21); the genesis of the empyema in this situation is thought to be the formation of a bronchopleural fistula through necrotic subpleural nodules (40).
EXPERIMENTAL EMPYEMA
There has been surprisingly little work done with experimental empyema. This work is summarized in Chapter 4.
BACTERIOLOGIC FEATURES
The bacteriologic features of culture-positive parapneumonic effusions have changed since the introduction of antibiotics. Before the antibiotic era, most empyema fluids grew Streptococcus pneumoniae or Streptococcus hemolyticus (41). Then between 1955 and 1965, Staphylococcus aureus was the bacteria most commonly isolated from pleural fluid (41). In the early 1970s, anaerobic organisms were most commonly isolated (42). However, in the 1980s and 1990s, it appeared that the aerobic organisms were again responsible for most empyema. Brook and Frazier (43) in 1993 reviewed the microbiology of 197 patients whose pleural fluid was culture positive for bacteria in two military hospitals. In 64% of patients, only aerobic bacteria were isolated, whereas in 13% of patients, only anaerobic organisms were isolated and, in 23% of patients, both aerobic and anaerobic organisms were isolated. Alfrageme et al. (44) again in 1993 reviewed the microbiology of 82 patients treated for empyema at a respiratory unit in Spain and reported results similar to those of Brook and Frazier (43). Of their 76 patients with positive cultures, 62% had exclusively aerobic bacteria, whereas 16% had exclusively anaerobic bacteria, 17% had both aerobic and anaerobic organisms, and 5% Mycobacterium tuberculosis or fungi.
The organisms isolated from positive pleural fluid cultures in three separate series (42,43,45) are tabulated in Table 12.2. These series represent 342 patients, from whom 580 organisms were isolated. Aerobic organisms alone were isolated from 181 patients (53%), anaerobic organisms only were isolated from 76 patients (22%), and both aerobic and anaerobic organisms were isolated from 85 patients (25%).
Several conclusions can be made from Table 12.2. First, aerobic organisms are isolated slightly more frequently than anaerobic organisms. Second, S. aureus and S. pneumoniae account for approximately 70% of all aerobic gram-positive isolates. Third, when there is a single aerobic gram-positive organism in the pleural fluid, it almost always is S. aureus, S. pneumoniae, or Streptococcus pyogenes. Fourth, gram-positive aerobic organisms are isolated approximately twice as frequently as are gram-negative aerobic organisms. Fifth, although Escherichia coli is the most commonly isolated gram-negative aerobic organism, it is rarely the lone pathogen isolated from pleural fluid. Sixth, Klebsiella sp, Pseudomonas sp, and Hemophilus influenzae are the next three most commonly isolated aerobic gram-negative organisms, and these three organisms account for approximately 75% of all aerobic gram-negative empyemas with a single organism. Seventh, Bacteroides sp and Peptostreptococcus are the two most commonly isolated anaerobic organisms from infected pleural fluid. Eighth, it is uncommon for a single anaerobic organism to be isolated from pleural fluid.
The most recent comprehensive report on the bacteriology of complicated parapneumonic effusions comes from the large trial of intrapleural streptokinase in the United Kingdom (46). In this study of 434 patients, the Gram’s stain was positive in 250 (58%) patients, the cultures grew a single aerobic growth in 151 (35%) patients, a single anaerobic growth in 29 (7%) patients, and a polymicrobial growth in 52 (12%) patients (46). Pleural fluid was available for molecular microbiologic analysis in 404 of the subjects. For 70 of the culture-negative cases, bacteria were identified by subsequent nucleic acid amplification. Overall, a microbiologic diagnosis was obtained in 320 patients (74%). In patients with community-acquired pneumonia, the organisms most commonly responsible were Streptococcus intermedius-anginosus-constellatus (milleri) group in 80, S. pneumoniae 71, and other streptococcus species 25, S. aureus 34 (7 methicillin resistant Staphylococcus aureus [MRSA]), gram negatives 29, and anaerobes 67. In patients with hospital-acquired parapneumonic effusions, the most common organism was S. aureus 21, of which 15 were MRSA (46). In a second study (47), Streptococcus intermediusanginosus-constellatus (milleri) was also the most common organism isolated in culture positive complicated parapneumonic effusions.
The bacteriology of complicated parapneumonic effusions seems to be different in Taiwan. One series in the late 1990s from Taiwan reported that Klebsiella pneumonia was isolated from 34 of 139 patients
(24.4%) with positive pleural fluid cultures (48). If the patient is in the intensive care unit, gram-negative aerobic organisms are most likely to be responsible, with K. pneumonia being the most common organism (49). The microbiology of empyema in elderly patients and young adults is similar (50).
(24.4%) with positive pleural fluid cultures (48). If the patient is in the intensive care unit, gram-negative aerobic organisms are most likely to be responsible, with K. pneumonia being the most common organism (49). The microbiology of empyema in elderly patients and young adults is similar (50).
TABLE 12.2 ▪ Organisms Isolated from Infected Pleural Fluid in Three Separate Series | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Several other points should be made concerning the bacteriology of infected pleural fluid. First, to a large part, the incidence of anaerobic isolates is dependent on the care with which the pleural fluid is cultured for anaerobes. The relatively high incidence of anaerobes in the series of Bartlett et al. (42) is partially explained by the intense interest these investigators had in culturing anaerobes. Second, the organisms cultured depend somewhat on the population studied. If aspiration is responsible for the underlying pneumonia, anaerobic organisms are more likely to be responsible (43). This also explains somewhat the high incidence of anaerobes in Bartlett’s series because their patient population was made up of elderly veterans. In contrast, S. pneumoniae is more likely to be the causative factor in young ambulatory patients whereas in postthoracotomy patients, S. aureus is most likely to be responsible.
The bacteriology of infected pleural fluid in children varies somewhat from that in adults in that H. influenzae is more common and anaerobic organisms are less common. In one study of 72 culture-positive pleural fluids, aerobic organisms were found in 48 (67%), anaerobic organisms were found
in 17 (24%), and mixed aerobes and anaerobes were found in 7 (10%) (51). The most commonly isolated organisms in this series were H. influenzae (15 isolates), Bacteroides sp (15), S. pneumoniae (13), S. aureus (10), and anaerobic cocci (9). In another series of 173 culture-positive pleural fluids in children younger than 15 years, 38% were due to S. aureus, 28% were due to S. pneumoniae, 23% were due to H. influenzae, and 11% were due to other organisms. In this series, anaerobic isolates were rare (52).
in 17 (24%), and mixed aerobes and anaerobes were found in 7 (10%) (51). The most commonly isolated organisms in this series were H. influenzae (15 isolates), Bacteroides sp (15), S. pneumoniae (13), S. aureus (10), and anaerobic cocci (9). In another series of 173 culture-positive pleural fluids in children younger than 15 years, 38% were due to S. aureus, 28% were due to S. pneumoniae, 23% were due to H. influenzae, and 11% were due to other organisms. In this series, anaerobic isolates were rare (52).
INCIDENCE OF PLEURAL EFFUSIONS WITH VARIOUS BACTERIAL PNEUMONIAS
Once a patient has a bacterial pneumonia, the incidence of associated pleural effusion and the frequency with which the pleural fluid becomes infected largely depend on the infecting organism (Table 12.3). Infected pleural fluid is most common in anaerobic pneumonia. In one series of 143 patients with anaerobic infections of the lung (53), 50 (35%) had pleural effusions, and in 47 (94%) of these, the pleural fluid cultures were positive for anaerobic organisms. Aerobic organisms were also cultured from the pleural fluid in 18 (40%) of the patients with positive anaerobic pleural fluid cultures. Some patients with anaerobic pleural infection have no concomitant parenchymal disease.
TABLE 12.3 ▪ Percentage of Pleural Effusions and of Positive Pleural Fluid Cultures with Various Bacterial Pneumonias | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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GRAM-POSITIVE BACTERIA
S. pneumoniae is still responsible for many bacterial pneumonias, and many patients have an associated pleural effusion. Taryle et al. (54) studied 53 patients with pneumococcal pneumonia and found that 57% had an associated parapneumonic effusion, whereas my colleagues and I found that 40% of 153 patients with pneumococcal pneumonia had an associated pleural effusion (2). In a more recent paper, 40% of 52 patients with bacteremic pneumococcal pneumonia had pleural effusions as compared with 21% of patients with pneumococcal pneumonia without bacteremia (55). Pleural fluid cultures are usually negative in patients with pneumococcal parapneumonic effusions. Of the 81 patients with pleural effusions in the foregoing two
series, only 3 (4%) had pleural fluid cultures that were positive for S. pneumoniae. Nevertheless, as shown in Table 12.2. S. pneumoniae is responsible for many positive pleural fluid cultures. The explanation for this apparent paradox is the fact that such a large percentage of pneumonias is due to S. pneumoniae. The incidence of parapneumonic effusions is higher when patients wait 48 hours or more after the development of symptoms before seeking medical attention (54).
series, only 3 (4%) had pleural fluid cultures that were positive for S. pneumoniae. Nevertheless, as shown in Table 12.2. S. pneumoniae is responsible for many positive pleural fluid cultures. The explanation for this apparent paradox is the fact that such a large percentage of pneumonias is due to S. pneumoniae. The incidence of parapneumonic effusions is higher when patients wait 48 hours or more after the development of symptoms before seeking medical attention (54).
Pneumonia secondary to S. aureus is likely to have an accompanying culture-positive pleural effusion. Indeed, in one study of the causes of pleural effusion in children, staphylococcal empyema was the most frequent cause (56). Wolfe et al. (56) reviewed 98 children with pleural effusions seen at Duke University between 1952 and 1967 and reported that S. aureus was responsible for 35 (36%) of the effusions. In a series of 75 cases of staphylococcal pneumonia in infants and young children (57), more than 70% had pleural effusions, and the pleural fluid cultures were positive in approximately 80%. In adults, more than 50% of patients with staphylococcal pneumonia will have an accompanying pleural effusion (58), and effusions are more common with MRSA than with MSSA. Pleural fluid cultures are positive in at least 20% of adults with pleural effusions (59). In one series (60) of 14 patients with community acquired MRSA pneumonia, pleural effusions were present in nine patients (64%) and pleural fluid cultures were positive in 5 of the 9 patients (55%) with pleural effusion. Patients who have right-sided endocarditis from S. aureus frequently have pleural effusions, but the cultures are positive in only a small percentage (61). In this situation, the effusions are exudates with a very high pleural fluid LDH.
Pneumonias due to S. pyogenes are uncommon, but they are associated with parapneumonic effusion in most cases. Welch et al. (62) reported that 95% of 20 patients had an associated pleural effusion, whereas Basiliere et al. (63) reported that 57% of 95 patients with streptococcal pneumonia had a pleural effusion. The pleural fluid cultures are positive in 30% to 40% of those with pleural effusion (62,63). The pleural effusions secondary to streptococcal pneumonia are located more commonly on the left side. Of the 73 pleural effusions in the foregoing series, nearly two-thirds were on the left side. Streptococcal pneumonia occurs in epidemics, particularly among military recruits (63). In some patients, the development of the pleuritis is explosive with this organism. Patients may develop large pleural effusions with low glucose levels and pH in less than 12 hours (64).
GRAM-NEGATIVE BACTERIA
Of pneumonias due to gram-negative aerobic organisms, those caused by E. coli are most likely to have complicated parapneumonic effusions. In one series of 20 patients (65), 40% had pleural effusion, and in 6 of these 8 patients, pleural fluid cultures were positive. All eight patients with pleural effusion in this series had to be treated by tube thoracostomy or open thoracotomy. Rarely, however, is E. coli the sole isolate from pleural fluid (Table 12.2). Patients with Pseudomonas pneumonia are also likely to have pleural effusions. In one series of 56 patients with ventilatorassociated P. aeruginosa pneumonia, 13 (23%) had a pleural effusion and 7 (12.5%) developed empyema (66). In another series of 28 patients with nosocomial pneumonia due to P. aeruginosa, 13 (46%) had bilateral effusions and an additional 5 (18%) had a unilateral effusion (67). As evident in Table 12.2, Pseudomonas sp and E. coli account for more than 50% of all aerobic gram-negative isolations from pleural fluid. In Taiwan, K. pneumonia is the most frequent cause of community-acquired thoracic empyema or complicated parapneumonic effusion accounting for 40 of 169 positive cultures in one study (68). Pleural effusion occurs in about 50% of patients with Klebsiella pneumoniae (69). The mortality rate is significantly higher in patients with pleural fluid cultures positive for K. pneumoniae than it is for patients with cultures positive for other organisms (68).
In recent years, H. influenzae has been responsible for an increasing number of pneumonias in both children (52,70,71) and adults (72). With H. influenzae pneumonia, the pleura is frequently involved, particularly in children (71). In a series of 65 cases of pneumonia in children, 49 (75%) had pleural effusions, and the cultures were positive in 36 of 46 patients (78%) (71). In one large series (73) of 211 patients with H. influenzae pneumonia, only 22 patients (10.4%) had a pleural effusion. Proteus sp causes a substantial proportion of gram-negative pneumonias, but associated pleural effusions are uncommon, and when they are present, they are usually small and uncomplicated (74).
ANTHRAX
Bacillus anthracis is a large gram-positive, spore-forming, rod-shaped organism that may contaminate goat hair, wool, or animal hides (75). Although only one case of anthrax was reported in the United States between 1980 and 2000, interest has been
rekindled in this organism with its use as a bioterrorism agent in Washington, D.C. in 2001 (76). This virulent organism causes pulmonary disease when the spores are inhaled into the alveoli, are engulfed by alveolar macrophages, and are carried to the hilar lymph nodes, where they multiply in their vegetative state. After causing flu-like symptoms for several days, the bacteria are disseminated hematogenously. This dissemination is marked by the acute onset of dyspnea, cyanosis, tachycardia, fever, and shock. In the cases in Washington, the medium time from exposure to symptoms was 4 days and then patients did not seek medical attention for another 3.5 days (76). The characteristic radiologic findings are mediastinal widening, patchy nonsegmental pulmonary infiltrates, and unilateral or bilateral pleural effusions.
rekindled in this organism with its use as a bioterrorism agent in Washington, D.C. in 2001 (76). This virulent organism causes pulmonary disease when the spores are inhaled into the alveoli, are engulfed by alveolar macrophages, and are carried to the hilar lymph nodes, where they multiply in their vegetative state. After causing flu-like symptoms for several days, the bacteria are disseminated hematogenously. This dissemination is marked by the acute onset of dyspnea, cyanosis, tachycardia, fever, and shock. In the cases in Washington, the medium time from exposure to symptoms was 4 days and then patients did not seek medical attention for another 3.5 days (76). The characteristic radiologic findings are mediastinal widening, patchy nonsegmental pulmonary infiltrates, and unilateral or bilateral pleural effusions.
Pleural effusions were present in all 10 of these patients treated in Washington, D.C. with the bioterrorism attack (76) and 7 patients required drainage. Indeed, when Kyriacou et al. (77) compared the clinical characteristics of 47 cases of anthrax with those of 376 patients with community-acquired pneumonia or influenza, they found that the most accurate prediction was the presence of a pleural effusion or mediastinal widening on the chest radiograph. All 47 patients with anthrax had a pleural effusion and/or mediastinal widening (77). In the recent outbreak, the pleural fluid was a bloody exudate (the pleural fluid red blood cell [RBC] count was above 70,000 cells/mm3 in all), with a relatively low WBC count (200-3,000 cells/mm3) and an LDH that varied from 282 to 1,762 IU/L (no upper limit of normal for serum provided) (76). Immunohistochemical stains for B. anthracis were positive on all pleural fluid cytologic and pleural tissue specimens (76).
It is important to make the diagnosis of anthrax early. In the outbreak in Washington, 6 of the 10 patients received antibiotics before they entered the fulminant stage and all survived. In contrast, none of the four patients who received antibiotics after they entered the fulminant stage survived (76). In a review of the world literature, Holty et al. (78) reported that the mortality rate was 97% in patients who reached the fulminant stage. The only patient who survived was a veterinarian who might have had partial immunity (78). This diagnosis should be considered in all patients with an acute illness and with mediastinal widening or pleural effusions (77). After blood cultures are obtained, appropriate antibiotics, for example, ciprofloxacin, should be started. The pleural fluid cytologic specimen should be stained immunohistochemically for anthrax.
MISCELLANEOUS PATHOGENIC ORGANISMS
Pleural effusions may also occur in 30% to 65% of patients with pneumonias due to Legionella sp (75,76,79). In one series (80) of 43 patients with Legionnaire’s disease, pleural effusions were present in 10 patients (23%) on admission, whereas another 14 developed effusions during the first week after admission, and 3 new effusions were discovered after the first week. In some cases, the organisms can be demonstrated by direct immunofluorescence or culture of the pleural fluid (81). Usually, the pleural effusions are small and clinically unimportant, but one patient had a multiloculated pleural effusion due to Legionella sp and required a decortication (82).
Several unusual organisms should be considered in patients with pneumonia and pleural effusions. Tularemia may be manifested as a pneumonia, and, if so, there is frequently an accompanying pleural effusion (83). Interestingly, the pleural fluid in association with tularemia is a lymphocyte predominant exudate with a high adenosine deaminase (ADA) level (83). Pleural effusions occurred in 5 to 33% of the cases of acute melioidosis (84). As with tularemia, the pleural fluid with melioidosis can be lymphocyte predominant (84). Clostridial pleuropulmonary infections are uncommon; by 1970, only 17 cases had been reported (85). Almost all patients with clostridial pulmonary infections have a pleural effusion that is culture positive (85). Complicated parapneumonic pleural effusions have also been reported with pneumonias due to brucellosis (86), Hemophilus parainfluenzae (87), Bacillus cereus (88), Citrobacter diversus (89), and Listeria monocytogenes (90) and can probably occur with any bacterium that is a pathogen in humans.
CLINICAL MANIFESTATIONS
The clinical manifestations of parapneumonic effusions and empyema depend to a large part on whether the patient has an aerobic or anaerobic infection.
Aerobic Bacterial Infections
The clinical presentation of patients with aerobic bacterial pneumonia and a pleural effusion is no different from that of patients with bacterial pneumonia
without effusion (2,54,91). The patients first manifest an acute febrile illness with chest pain, sputum production, and leukocytosis. In one series, the incidence of pleuritic chest pain was 59% in 113 patients without effusion and 64% in 90 patients with effusion (2). The mean peripheral WBC was 17,100 in patients without effusion and 17,800 in patients with effusion. The longer the patient has symptoms before seeking medical attention, the more likely he or she is to have a pleural effusion (54). A complicated parapneumonic effusion is suggested by the presence of fever for more than 48 hours after antibiotic therapy is instituted, but, of course, the diagnosis of parapneumonic effusion should be established when the patient with pneumonia is first evaluated.
without effusion (2,54,91). The patients first manifest an acute febrile illness with chest pain, sputum production, and leukocytosis. In one series, the incidence of pleuritic chest pain was 59% in 113 patients without effusion and 64% in 90 patients with effusion (2). The mean peripheral WBC was 17,100 in patients without effusion and 17,800 in patients with effusion. The longer the patient has symptoms before seeking medical attention, the more likely he or she is to have a pleural effusion (54). A complicated parapneumonic effusion is suggested by the presence of fever for more than 48 hours after antibiotic therapy is instituted, but, of course, the diagnosis of parapneumonic effusion should be established when the patient with pneumonia is first evaluated.
Not all patients with aerobic pneumonias and pleural effusions have acute illnesses. Sahn et al. (92) reported three cases of aerobic empyema in patients who were receiving corticosteroid therapy, and all were afebrile with minimal symptoms referable to the chest. The absence of fever or chest symptoms should not deter one from considering the diagnosis of complicated parapneumonic effusions because, in recent years, a higher percentage of such effusions has occurred in hospitalized patients, many of whom are debilitated or are receiving corticosteroids (41).
A complicated parapneumonic effusion should be suspected in febrile patients in the intensive care unit who have temperature elevations. Tu et al. (49) performed a diagnostic thoracentesis in 175 patients with a temperature elevation above 38°C for more than 8 hours and a pleural effusion. They found that 78 of the 175 patients had complicated parapneumonic effusions (49). The mortality was 41% in these 78 patients.
Anaerobic Bacterial Infections
In contrast to patients with aerobic bacterial pneumonias, patients with anaerobic bacterial infections involving the pleural space are usually first seen with subacute illnesses. In a series of 47 patients, 70% had symptoms for more than 7 days before presentation, with a median symptom duration of 10 days (53). In this same series of patients (53), 60% had substantial weight loss (mean 29 lb). Many patients have a history of alcoholism, an episode of unconsciousness, or another factor that predisposes them to aspiration. Most patients also have poor oral hygiene. Laboratory evaluation reveals leukocytosis (median WBC 23,500/mm3) and mild anemia (median hematocrit 36%) in most patients (53).
DIAGNOSIS
The possibility of a parapneumonic effusion should be considered during the initial evaluation of every patient with a bacterial pneumonia. At this evaluation, it is important to determine whether a complicated parapneumonic effusion is present because a delay in instituting proper pleural drainage in such patients substantially increases morbidity. The possibility of a parapneumonic effusion should also be suspected in patients who do not respond to antimicrobial therapy. In one study of 49 such patients, the prevalence of pleural effusions increased from 18% on admission to 43% at the time of repeat investigation 72 hours after admission (93). Six of these patients were found to have an empyema (93).
The presence of a significant amount of pleural fluid is usually suggested by the appearance of the lateral chest radiograph. If both diaphragms are visible throughout their length and the posterior costophrenic angle is not blunted, one can assume that a significant amount of free pleural fluid is not present. If either of the posterior costophrenic angles is blunted or if a diaphragm is obscured by the infiltrate, however, the possibility of a pleural effusion should be evaluated with a computed tomography (CT) scan of the chest, ultrasound of the pleural space, or bilateral decubitus chest radiographs. The purpose of these additional studies is to document whether fluid is present and to semiquantitate the amount of fluid if it is present. Brixey et al. (94) reviewed the chest radiographs of 61 patients with pneumonia who had a pleural effusion on CT scan. They reported that the sensitivities of the lateral, PA, and AP chest radiographs were 85.7%, 82.1%, and 78.4%, respectively (94). The majority of effusions missed in each view were on films with lower lobe consolidation (94).
On the decubitus view with the suspect side down, free pleural fluid is indicated by the presence of fluid between the chest wall and the inferior part of the lung (Fig. 6.3). The view with the suspect side up is also valuable because, in this position, the free fluid gravitates toward the mediastinum and allows one to assess how much of the increased radiodensity is due to the fluid and how much is due to the parenchymal infiltrate. Of course, the chest CT scan provides more definitive information than do decubitus films and it has replaced the decubitus films for the evaluation of the possibility of pleural effusions in many institutions. It should be noted that many patients with parapneumonic effusions have mediastinal lymphadenopathy. Kearney et al. (95) reviewed the CT
scans of 50 patients with parapneumonic effusions and reported that 18 (36%) had lymph nodes in their mediastinum that were greater than 1 cm in diameter.
scans of 50 patients with parapneumonic effusions and reported that 18 (36%) had lymph nodes in their mediastinum that were greater than 1 cm in diameter.
The possibility of a pleural effusion can also be evaluated by ultrasound. Ultrasound has two advantages: first, it is portable and can be performed easily in the intensive care unit and second, it also will delineate whether the pleural fluid is septated. However, in one study of 50 patients with parapneumonic effusions, there was no relationship between the appearance on ultrasound and whether the patient would need surgical treatment (96). In contrast, a second study (97) of 141 patients with complicated parapneumonic effusions found that patients with a complex nonseptated sonographic pattern were more frequently successfully treated with a small-bore catheter 48/60 (80%) than were patients with a complex septated sonographic pattern 41/81 (51%).
The amount of free pleural fluid can be semiquantitated by measuring the distance between the inside of the chest wall and the bottom of the lung on either the decubitus radiograph or the CT scan of the chest. This distance can also be measured with ultrasound. If this distance measures less than 10 mm, one can assume that the effusion is not clinically significant and, therefore, a thoracentesis is not indicated. My colleagues and I reported that 53 patients with acute bacterial pneumonia had such small effusions, and in each of the patients, the pneumonia and the pleural effusion cleared with only antibiotics and left no residual pleural disease (2). Moffet et al. (98) have demonstrated that a pleural fluid thickness of 2.5 cm on a CT scan correlates to a thickness of 1.0 cm on the decubitus radiograph. Moreover, a recent article (99) suggested that a thoracentesis is indicated only if the thickness of the pleural fluid is greater than 20 mm on the CT scan because effusions smaller than this are rarely complicated.
If the thickness of the fluid is greater than 10-20 mm, a therapeutic thoracentesis should be performed immediately because it is impossible to separate complicated from uncomplicated effusions without a thoracentesis. The pleural fluid is examined grossly for color, turbidity, and odor. Aliquots are sent for determination of the pleural fluid glucose, LDH, and protein levels, pH (must be analyzed with a blood gas machine), and differential and total WBC counts. Samples of pleural fluid are also sent for bacterial cultures, both aerobic and anaerobic, and for Gram’s stain, as well as for cytologic studies and mycobacterial and fungal smears and cultures, if clinically indicated. When pleural fluid is sent for bacterial cultures, higher yields will be obtained if the pleural fluid is directly inoculated into blood culture bottles at the time of thoracentesis (100,101).
The pleural fluid cultures in patients with parapneumonic effusions are frequently negative, even when the fluid is pus. To identify the organism responsible for the pneumonia, nuclei acid amplification has been used to identify the bacteria responsible for a complicated parapneumonic effusion. Maskell et al. (102) performed this procedure on 404 pleural fluid specimens obtained during the First Multicenter Intrapleural Sepsis Trial (103). They reported that the nucleic acid amplification technique identified bacteria in 70 samples which were negative on culture (102).
Not all patients with an acute illness, parenchymal infiltrates, and pleural effusion have an acute bacterial pneumonia; pulmonary embolization, acute pancreatitis, tuberculosis, Dressler’s syndrome, and other diseases can produce identical pictures. The possibility of pulmonary embolization should always be considered if the patient does not have purulent sputum or a peripheral leukocytosis above 15,000/mm3. Most patients with acute tuberculous pleuritis have no infiltrate on the decubitus film with the involved side superior or on the chest CT scan.
The pleural fluid with parapneumonic effusions varies from a clear, yellow exudate to thick, foul-smelling pus. If the odor of the pleural fluid is feculent, the patient is likely to have an anaerobic pleural infection (53,104). Although Sullivan et al. (104) reported that 11% of aerobic empyemas were described as foul smelling, it is probable that these represented mixed aerobic and anaerobic pleural infections in that sophisticated anaerobic culture techniques were not used in this study. Only approximately 60% of anaerobic empyemas have a foul odor (53,104). If frank pus is obtained with diagnostic thoracentesis, a pleural fluid pH determination should not be done. When thick, purulent material is processed through blood gas machines, it is likely to plug up the machine or damage the membranes. Once laboratory personnel have this experience with one such pleural fluid, they are hesitant to process additional pleural fluids. The differential WBC on the pleural fluid usually reveals predominantly polymorphonuclear leukocytes. If many small lymphocytes, mesothelial cells, or macrophages are seen, alternate diagnoses should be considered. If food particles are seen in the pleural fluid, the patient has an esophageal-pleural fistula (105).
Not all patients with parapneumonic effusions have an acute illness, so the possibility of a
parapneumonic effusion should be considered in all patients with pleural effusion. Anaerobic pleural infections are particularly likely to produce subacute or chronic illness (53,106), and many patients with anaerobic pleural infections do not have associated parenchymal infiltrates (106). Accordingly, aerobic and anaerobic bacterial cultures should be obtained on all exudative pleural effusions of undetermined etiology.
parapneumonic effusion should be considered in all patients with pleural effusion. Anaerobic pleural infections are particularly likely to produce subacute or chronic illness (53,106), and many patients with anaerobic pleural infections do not have associated parenchymal infiltrates (106). Accordingly, aerobic and anaerobic bacterial cultures should be obtained on all exudative pleural effusions of undetermined etiology.
INDICATORS OF POOR PROGNOSIS FROM PLEURAL FLUID ANALYSIS
Pleural fluid characteristics associated with a need for pleural fluid drainage are tabulated in Table 12.4. If the pleural fluid is thick pus, the patient has an empyema and drainage of the pleural space is indicated. No other tests are needed for confirmation of the need for drainage. The odor of the fluid should be noted because a feculent odor is an indication that the pleural fluid is infected with anaerobic bacteria and is hence an indication for anaerobic antibiotic coverage and pleural drainage.
If the fluid is not thick pus, then much information on the prognosis of the patient can be obtained from the Gram’s stain and culture of the pleural fluid, as well as the levels of glucose, pH, and LDH in the pleural fluid. If the Gram’s stain is positive, there is a large bacterial burden in the pleural space and the fluid needs to be drained. If the Gram’s stain is negative but the culture is positive, it is likely that the patient will have difficulty with the pleural infection, and the pleural space should be drained.
The pleural fluid chemistries are also useful in identifying which patients have complicated parapneumonic effusions. Patients with complicated parapneumonic effusions have a lower pleural fluid glucose and pH, and a higher pleural fluid LDH than those with uncomplicated parapneumonic effusions (Fig. 12.1). If the pleural fluid pH is higher than 7.20, the pleural fluid glucose is higher than 60 mg/dL, and the pleural fluid LDH is below three times the upper normal limit for serum, the parapneumonic effusion is a Class 3 parapneumonic effusion by Light’s classification (Table 12.5) and a Category 2 by the American College of Chest Physicians (ACCP) classification (Table 12.6) (107), and no further diagnostic or therapeutic maneuvers need be directed toward the pleural effusion.
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