Thoracic

"Shake him by the shoulders and listen to where the noise is heard and right at this place make an incision; then it produces death more rarely. If pure and white flows from the wound, the patients recover; but if mixed with blood, slimy and fetid, they die." Hippocrates, 460 BC

Anthony R. Dal Nogare, M.D. University of Texas Southwestern Medical School Internal Medicine Grand Rounds November 5, 1998

This is to acknowledge that Anthony R. Dal Nogare. M.D. has disclosed no financial interests or other relationships with commercial concerns related directly or indirectly to this program. BIOGRAPHICAL INFORMATION:

Name: Anthony R. Dal Nogare, M.D.

Rank: Associate Professor

Division: Pulmonary and Critical Care Medicine

Interests: pathogenesis, septic shock INTRODUCTION

Over 2,400 years ago the Greek physician Hippocrates described and emphasized the importance of surgical drainage for a successful outcome. Since then our understanding of the microbiology, pathophysiology, and molecular biology of empyema has advanced considerably, but the principal of adequate empyema drainage remains as important now as it was in Hippocrates time. An empyema represents one end of the spectrum of a parapneumonic effusion. An exact empyema definition, applicable to all cases, does not exist but most authorities consider either gross pleural pus, a positive bacterial culture or of pleural fluid, or a parapneumonic effusion requiring drainage as evidence of an empyema. This review will concentrate on recent developments in empyema pathophysiology and treatment, concluding with discussion of a new surgical technique, video assisted thoracoscopic surgery or VATS.

MICROBIOLOGY

Most empyemas occur after an underlying pneumonia or infects the ipsilateral pleural space. Unusual routes of infection include esophageal rupture, spread of an intra-abdominal abscess across the diaphragm, and iatrogenic infection following chest surgery or instrumentation of the pleural space. Although empyemas are generally considered to represent infected pleural fluid, both gram stains and culture are often negative, even in patients with clinically evident pleural pus. Some sterile empyemas are due to prior administration, failure to properly collect anaerobic specimens for culture, or failure to request anaerobic cultures (1 ). Table 1 lists the frequency with which bacterial are complicated by empyema.

TABLE 1

Empyema as a Pneumonia Complication

Microbe Empyema(%) Reference Group A Streptococci"' 59 2 Anaerobic 33 3 Aerobic gram-negative 32 4, 5 10 6 pneumonia 3 7 Of all bacterial pneumonias Group A streptococcal () pneumonias are most often complicated by empyema but are rare, occurring in closed populations such as military recruits. Multiple species of commensal oral anaerobic bacteria cause anaerobic pneumonia and lung abscess, and these often progress to empyema formation. Aerobic gram-negative pneumonias usually occur in critically ill medical and surgical patients and thus are usually nosocomial infections; similarly Staphylococcus aureus is usually a nosocomial pathogen but can cause community acquired infections in diabetics and intravenous drug addicts. S. pneumonia is the commonest cause of community acquired pneumonia and was a common cause of empyema prior to the introduction of , but in the modem antibiotic era pneumococcal empyemas have become rare. In one recent series of 35 hospitalized pneumococcal pneumonia patients 20, or 57%, had parapneumonic effusions but most of these were small, developed after hospital admission while the patients were receiving , and resolved without drainage procedures. Three of the 2

parapneumonic effusions were empyemas and in these three cases the effusion was present on the initial f:lnd the patients had been symptomatic for >48 hours (8). Thus, although parapneumonic effusions commonly complicate pneumococcal pneumonias, empyemas are rare, unless the effusion was present on initial evaluation. Atypical pneumonias are caused by viruses, and Chylamidia pneumonia and are rarely complicated by empyema. Most recent investigators, using careful anaerobic culture techniques, have found that anaerobic bacteria, either in pure culture or mixed with aerobic bacteria, cause about 75% of empyemas (Table 2).

TABLE2

Microbiology of 83 Empyemas - Anaerobes only 29 ( 35%) - Anaerobes plus aerobes 34 (41%) -Aerobes only 20 (24%) - Average 3 anaerobic species/case Prevotella melaninogenicus Fusobacteria Bacteroides fragilis Peptostreptococci The data in Table 2 came from a series of adult patients on medical wards in a Veterans Administration Hospital and Cook County Hospital in Chicago (9). As shown in the table most anaerobic empyemas are polymicrobial, with an average of 3.0 anaerobic and 0.6 aerobic species isolated per case. The common anaerobic species isolated, which are listed on Table 2, are all present in healthy people as normal oral flora. The aerobic bacteria present in mixed anaerobic infections are usually aerobic gram-negative bacteria or S. aureus. Anaerobic bacteria cause most of the empyemas admitted to Parkland Hospital. ... CLINICAL FEATURES OF ANAEROBIC PLEUROPULMONARY INFECTIONS

Anaerobic pleuropulmonary disease usually occurs in a selected group of patients, easily identifiable by the presence of one (or more) of the following risk factors.

TABLE 3

Risk Factors for Anaerobic Pleuropulmonary Disease

- Periodontal disease - Decreased level of consciousness - Bronchial obstruction

Most patients have both poor oral hygiene and an impaired sensorium, which predisposes them to aspirate saliva into their lungs. The commensal normal oral anaerobic bacteria which cause most empyemas colonize the gingival crevice, the area where the gums reflect off teeth. Normal saliva contains about 108 anaerobic bacteria/mi. whereas concentrations of 1010-10 11 /ml are not uncommon in saliva obtained from subjects with significant gingivitis; therefore gingivitis is associated with a 3 larger anaerobic inoculum when saliva is aspirated (1 0). , a seizure disorder, ·or illicit use of sedative drugs are the usual conditions causing loss of consciousness and aspiration. Occasionally anaerobic infections develop in patients without these risk factors and in such cases one should suspect the presence of an endobronchial obstruction impairing normal bronchial clearance. This is especially germane for edentulous patients, since they have relatively few oral anaerobic bacteria; in recent large series of anaerobic lung disease, about 50% of the edentulous patients were diagnosed with bronchogenic cancer (3).

The combination of known risk factors and certain distinctive clinical features usually enables rapid diagnosis of anaerobic pleuropulmonary disease on clinical grounds alone.

TABLE 4 Clinical Features of Anaerobic Empyema

Feature Percent Periodontal disease 64 Aspiration 55 Symptoms >7 days 70 Right sided disease 72 Putrid sputum/pleural fluid 64 Hematocrit <38% 81 Amer. Rev. Resp. Dis. 110:56-77,1974 The data in Table 4 came from a series of 47 anaerobic empyemas, 46 of which had an identifiable lung abscess or anaerobic pneumonia. A striking feature of anaerobic empyemas is their chronicity. In the above referenced series the mean duration of symptoms 'prior to hospital admission was 23 days, with a median of 10 days; such prolonged symptoms reflect both the low grade nature of anaerobic symptoms as well as socioecormmic factors hindering health care access in empyema prone populations. The right-sided predominance is due to bronchial anatomy because most aspirated material drops down the straighter right main stem . Foul, fetid smelling sputum originates from the underlying anaerobic lung infection and is diagnostic when present. An anemia of chronic disease is common and secondary to chronic inflammation.

VIRULENCE FACTORS OF ANAEROBIC BACTERIA

Most empyemas are caused by commensal oral anaerobes which are relatively avirulent until they enter the lower . What factors account for the propensity of anaerobes to produce necrotizing infections such as lung abscesses and empyemas, and why are anaerobes so often found as part of a mixed infection with aerobic pathogens? Investigation of anaerobic virulence factors has focused on Bacteroides species and Fusobacteria, since these two are isolated from clinical sites far out of proportion to their presence in the normal anaerobic flora (10). The three best established anaerobic virulence factors are synergy between anaerobic and aerobic pathogens, succinic acid, and polysaccharide capsule formation. 4

BACTERIAL SYNERGY - Both empyemas and abdominal abscesses usually contain multiple anaerobic and aerobic species. Synergy, where two bacterial species facilitate each others growth, probably explains the polymicrobial nature of anaerobic infections (Table 5).

TABLE 5

Bacterial Synergy in an Animal Abscess Model

Increase Increase Aerobic Species Aerobe Anaerobe (log 10 CFU) E. coli 3.3 1.0 K. pneumonia 2.4 0.8 P. aeruginosa 2.2 1.2 S. aureus 2.8 2.1 H. 2.1 1.8 The data shown in Table 5 came from a study of subcutaneous abscess formation in mice (11 ). . Animals were infected with either only anaerobic bacteria, aerobic bacteria, or a mix of one aerobe and one anaerobe and the number of bacteria in the abscess measured five days later; the anaerobes used were Bacteroides species commonly found in normal oral flora. The data in the columns is the increase in bacterial growth which occurred during a mixed infection, compared to bacterial growth in a single-species abscess. In general, anaerobes increase aerobic bacterial growth more than aerobes increase anaerobes, but both types of bacteria benefited. Aerobes facilitate anaerobic growth because they use up the available oxygen, thereby reducing oxidation-reduction potential in the infected site (12). Aerobes benefit from the propensity of anaerobes to form abscesses; an abscess is a protected area where host defenses and antibiotic penetration is impaired. The clinical relevance of synergy is supported by the observation that antibiotic therapy of mixed infections will usually succeed if an anti-anaerobe drug is administered; adding antibiotics active against the aerobic pathogen is usually not required (3).

Succinic acid is a low molec1Jiar weight, short chain fatty acid produced by many anaerobic bacteria which also contributes to synergy. It is present in millimolar concentrations in anaerobic abscesses and accounts for the characteristic odor of anaerobic pus. Concentrations of succinic acid identical to those measurable in abscess fluid decrease human neutrophil chemotaxis by 90% and significantly reduce both phagocytosis and killing of aerobic gram-negative bacteria (13-15) (Figure 1 ). Succinic acid also markedly decreases neutrophil superoxide generation and, since oxygen radicals are important for bacterial killing, reduced superoxide generation probably accounts for decreased bactericidal activity (16). 5

100- :tI ------1 70

60 50 40

30

20 10 i OL------L------~------~~------~---- 0 5 10 15 20 Duration of Incubation (min)

FIGURE 1. Phagocytic Killing of E. coli by Human Neutrophils Incubated with Succinic Acid. Infect. lmmun. 57:747, 1989

POLYSACCHARIDE CAPSULE - A number of in vivo and in vitro observations have implicated capsule formation as a major virulence factor. Most commensal anaerobes are unencapsulated when obtained from their normal mouth environment but are covered with a thick acidic polysaccharide capsule when isolated from abscesses (17). In animal models unencapsulated oral anaerobes are avirulent whereas encapsulated strains of the same species proquce abscesses. Serial passage of unencapsulated strains through an animal host eventually produces an encapsulated and virulent anaerobe and, if an unencapsulated strain is injected subcutaneously with aerobic bacteria such as E. coli, the anaerobe quickly becomes encapsulated and abscess formation occurs (17). This is another example of bacterial synergy in which aerobic bacteria facilitate abscess formation. Bacteroides species, Prevotella, Fusobacteria, and peptostreptococci all produce capsules. How does the polysaccharide capsule promote abscess formation? For many years its major effect was thought to be protective; encapsulated bacteria resist opsonophagocytic killing by neutrophils (18). Encapsulated bacteria also adhere better to mesothelial cells in vitro ( 18 ). Recently the Bacteroides capsular polysaccharide (CPS) has been purified and experiments have shown that the CPS itself stimulates abscess formation through an interaction with the hosts immune system. Bacteroides CPS is a heteropolymer composed of a tetrasaccharide (polysaccharide A) and a hexasaccharide (polysaccharide B) (19). Both polysaccharides contain positively charged amino groups and negatively charged carboxyl groups; the structure of polysaccharide A, which is the more bioactive of the two, is shown on Figure 2. 6

FIGURE 2. Structure of Bacteroides CPS A

Science 262:417, 1993

Nanogram concentrations of purified CPS cause macrophages to release TNF, IL-1, and IL-8, and these CPS -elicited cytokines stimulate mesothelial cell expression of leukocyte adhesion molecules such as ICAM-1 (20, 21 ). All of these effects could potentiate abscess formation and indeed CPS by itself. without any added bacteria, is sufficient for abscess formation (Table 6). ~oreover, the presence of one positive and one negatively charged group on CPS A is required; as shown on Table 6, removing either of the charged moieties, by chemical reduction or N-acetylation, markedly reduces abscess formation in vivo (22).

Table 6

Bacteroides CPS and Abscess Formation Abscess dose 50 ug CPSA 0.67 CPSB 25 CPS A. reduced >200 CPS A, N-acetylated >200 Exactly how the zwitterionic characteristics of CPS A promote abscess formation remains to be determined, but interactions with host T cells are involved. T cell depleted animals inoculated with live Bacteroides do not develop abscesses (23). CPS immunized animals also do not develop abscesses when challenged with live Bacteroides, and the CPS immunized · animals also do not form abscesses when inoculated with other, non-Bacteroides anaerobes or with mixed cecal bacteria (24) (Table 7). The latter observation suggests that most pathogenic anaerobes have 7

capsules similar to Bacteroides fragilis. As observed with abscess formation, the charged nature of CPS A is essential for immunity, as removal of a charged group destroys CPS immunogenicity. The alternating positive and negative charges on CPS must promote either recognition or signaling by T cells. Other bacterial polysaccharides with similarly arranged charged groups also cause abscess formation in animal models (25).

TABLE 7

CPS A Immunization and Abscess Formation

Immunization Challenge Abscess Formation N (%)

Saline B. fragilis 15/18 ( 83) CPSA B. fragilis 1/19( 5) Saline Fusobacteria + Enterococcus 13/15 ( 87) CPSA Fusobacteria + Enterococcus 5/17 ( 29) Saline Cecal contents 18/18 (100) CPSA Cecal contents 12/25 ( 48)

PATHOGENESIS OF EMPYEMA FORMATION

Empyemas evolve over time from an initial collection of thin, free flowing fluid to the thick, loculated pus of a full blown empyema. Dividing empyema formation into three stages is artificial, since the three stages all evolve concurrently, but the concept is helpful for understanding clinical features and choosing appropriate treatment. The initial stage, or Stage 1, is marked by acute pleural space inflammation and is followed by Stages 2 and 3. Animal models and clinical experience suggest that empyemas proceed rapidly through these stages; marked fibrin formation is present within 48-72 hours and collagen formation can be observ~d within 96 hours of intrapleural bacterial inoculation (26-28). Thus empyemas, especially when seen early in their course, are not static conditions. The cellular and molecular characteristics of the three stages are detailed in the following sections.

Stage 1 - An exudative forms in response to the presence of bacteria and/or bacterial products. Initially pleural fluid is free flowing, contains many serum proteins, has normal pH and glucose concentrations, and contains measurable and physiologically relevant amounts of the inflammatory cytokines TNF, IL-1, IL-8, and TGF-B (29,30). TNF is released by many lung cells early during bacterial infections and rapidly induces IL-8 production by pleural mesothelial cells (31 ). IL-8 is a chemokine which both attracts neutrophils into the pleural space and activates them to release toxic oxygen radicals and proteolytic enzymes; these substances are bactericidal but also damage pleural mesothelial cells. The importance of IL-8 for neutrophil recruitment is shown by the direct correlation between pleural fluid IL-8 concentration and neutrophil counts (Figure 3) (32).

-- 8

1000000 • • • •• • Empyemic 100000 • • • Parapneumonie • a Tuberculous Pleural .. o Malignant 10000 ~ • Neutrophil ~- • • Mise. exudative • A Transudative Count 1000 ,~ ..• (cells I ~I) 0 • 100 ICI ~r·~ .... a a. 10 lie . • ~I : 1~~~~-~.~~~.~~~~--~~-, .1 1 10 100 1000 lnterleukin·S (ng/ml)

FIGURE 3. IL-8 Concentration and Pleural Neutrophil Counts

ARRD 146:825, 1992

Stage 2 - This stage is marked by increasing neutrophil counts, pleural fluid acidosis and hypoglycemia, massive pleural fibrin deposition, and fibrinous adhesion formation between the visceral and parietal pleura. Both neutrophils and bacteria consume the available glucose and produce lactic acid and carbon dioxide; efflux of these metabolic end products is blocked and their accumulatioh results in pleural fluid acidosis (33). Several factors combine to promote fibrin formation. Human pleural mesothelial cells spontaneously express tissue factor activity; tissue factor activates Factor VII thereby causing fibrin formation via the extrinsic clotting pathway (34 ). In vitro unstimulated pleural mesothelial cells form fibrin when the necessary clotting factors are present (35). Large amounts of Factor VII, other clotting factors, and fibrinogen are present in exudative pleural effusions, and large amounts of tissue factor and activated Factor VII are present in empyema fluid (36,37). The net result is fibrin formation through extrinsic clotting pathway activation. Normal homeostatic mechanisms, which involve activation of plasminogen by tissue and urokinase type plasminogen activators, usually are activated when fibrin forms and cause fibrinolysis, which limits fibrin formation (38). These mechanisms fail in empyemas. Investigators at the University of Texas Health Science Center in Tyler have extensively studied pleural fluid fibrin formation and have measured large amounts of plasminogen, increased levels of urokinase type plasminogen activator, and normal levels of tissue type plasminogen activator in empyemas. Despite the presence of all the necessary substrates for plasmin generation fibrinolytic activity of empyema fluid is zero (Figure 4). Fibrinolysis does not occur because excess plasminogen activator inhibitor 1 (PAI-1 ) is present (Figure 5); PAI-1 inhibits both UPA and TPA catalyzed plasmin formation. Alpha-1 anti-plasmin, a circulating inhibitor of plasmin, is also present in empyema fluid (37). Since little plasmin can be generated in the inhibitor-rich empyema mileu fibrin deposits remain on the pleural surface and fibrinous

- 9

adhesions bridge the pleural space between the visceral and parietal pleura. These fibrin deposits act as scaffolds for subs~quent pleural space loculation.

0 .2 ~ 0 0 ~ -' 0 0 ~ ~ ~ 2 ~ ~

CA EMP CHF PNEU LOC

FIGURE 4. Fibrinolytic Activity in Pleural Fluid (IU/ml) EMP = empyema LOC = loculated parapneumonic effusion ARRD 144:190, 1991

iii 0 0 5 i .zooo ! - :.. - i!5. - ~

r I

I __ ! I 0 I-=:-=- -. I

CA EMP CHF PNEU LOC

FIGURE 5. Plasminogen Activator Inhibitor 1 (PAI-1) Levels in Pleural Fluid

ARRD 144:187, 1991

--- 10

Stage 3- In this final stage collagenous.loculations form, walling off empyema fluid and forming a thick abscess capsule. Histologically fibroblasts enter the pleural space from both pleural surfaces and deposit collagen as they migrate along the fibrin matrix, converting fibrin locules to collagen.

Transforming growth factor - beta (TGF-B) and empyema formation - TGF-B is produced and released during tissue inflammation and is measurable in infected pleural fluid (29, 39). It plays an important role in wound repair, promoting healing and scar formation by its unique ability to stimulate connective tissue formation. Figure 6 illustrates the effects of TGF-8.

Nonnal Tissue Injury Healed Tissue I

t Matrix proteins

~ Proteases

t Protease inhibHors

t lntegrins

Protease -<::' t TGF-Jl ' FIGURE 6. Effects of Transforming Growth Factor Beta (TGF-B) NEJM 331:1287, 1994

Excess or unregulated TGF-B may be harmful and it has been implicated in the pathogenesis of many fibrotic diseases, including , glomerulosclerosis, and hepatic fibrosis (40). TGF-B acts rapidly; histologically evident collagen deposition is present within 48 hours of subcutaneous administration in animals (41). TGF-B causes collagen deposition by simultaneously increasing fibroblast collagen production and decreasing collagen removal; the latter effect is due to increased release of protease inhibitors which inhibit metalloenzymes such as collagenase (42). Of particular relevance to empyema formation are TGF-B effects on protease inhibitors and fibroblasts. In addition to collagenase inhibitors, another protease inhibitor upregulated by TGF-B is PAI-1, which is released by TGF-B stimulated cells within 24 hours (43). Human pleural mesothelial cells release PAI-1 when stimulated with either TNF or TGF-B (35). As previously reviewed, high PAI-1 concentrations are present in empyemas and prevent pleural fibrinolysis, and fibrin acts as a matrix for activated fibroblasts. Transgenic animals which overexpress PAI-1

-- 11

develop pu lmonary fibrosis after bleomycin-induced inflammation (44). TGF-B is chemotactic for fibroblasts, bringing them into sites where TGF-B is present, and it simultaneously activates them. Activated fibroblasts are characterized by co llagen production and expression of a cell-surface adhesion molecule called CD 44. Activated human lung fibroblasts, obtained from ARDS patients, express CD 44 and use it to ad here to and move along fibrin matrices (Figure 7) (45).

40

.!! 30 Gi 0 a =oc 20 (IS :> .5.... 10 G) ..D E z::::1 0

0 2 3 4 5 6 Days

FIGURE 7. Movement of Human Lung Fibroblasts on a Fibrin Matrix The open squares and open circles repj\esent fibroblast movement in the presence of an anti-CD 44 antibody; the closed circles and open triangles show fibroblast movement without antibody present. J. Clin. Invest. 98:1713, 1996

In addition to fibrin , CD 44 mediates fibroblast adherence to fibronectin and proteoglycans. Transgenic animals with organ-specific TGF-B expression develop fibrosis and increased PAI-1 levels in affected organs (46). TGF-B plays a central role in the rapid development of fibrosis occurring during bleomycin-induced injury, Idiopathic Pulmonary Fibrosis, and ARDS (47-49). Microgram amounts of TGF-B promote peritoneal loculation in an animal model of postoperative adhesion formation (50) . . Thus, it is likely that TGF-B is a central mediator driving both fibrin deposition and loculation in the infected pleural space.

-- 12

MANAGEMENT OF PARAPNEUMONIC EFFUSIONS

PARAPNEUMONIC EFFUSIONS

Stage I Stage II Stage Ill UNCOMPLICATED COMPLICATED EMPYEMA

FIGURE 8. The Spectrum of Parapneumonic Effusions

As shown on Figure 8, early Stage 1 empyemas are referred to as uncomplicated parapneumonic effusions because they usually resolve with antibiotic therapy alone. Stage 2 and especially 3 empyemas are referred to as complicated parapneumonic effusions because external drainage with a or surgery is often required (51, 52). Unfortunately there is no single clinical feature or laboratory test result able to prospectively distinguish uncomplicated from complicated parapneumonic effusions, so that the distinction is usually a retrospective one. However, the findings shown on Table 8 are usually present. TABLE 8 Features of Uncomplicated Parapneumonic Effusions

- Small effusion - Free flowing,effusion - Negative gram stain -pH >7.20, glucose >60 mg% Parapneumonic effusions which deveihp after a patient has been started on appropriate antibiotic therapy will usually resolve, as will small, free-flowing fluid collections (53). If the effusion is large enough to be tapped then a negative gram stain and normal pH and glucose levels predict an uncomplicated course, but only if the fluid is free flowing; pH and glucose measurements are not reliable in loculated effusions, probably because the sampled fluid often comes from relatively uninvolved areas around the loculated main empyema collection (54). TABLE9 Complicated Parapneumonic Effusions

- Symptoms > one week - Anaerobic infection - Effusion present on initial chest radiograph - Loculated effusion -pH <7.00, glucose <40 mg%

A relatively long period of symptoms, which usually indicates the presence of an anaerobic infection, and the presence of a significantly sized effusion on the initial chest

- 13

radiograph suggest a complicated effusion. Loculations can usually be detected by performing decubitus chest radiographs; if inconclusive, a chest ultrasound examination or CT scan can be performed (55). As previously reviewed acidosis and hypoglycemia are due to pleural bacteria and neutrophils and thus reflect the degree of acute inflammation. An initial measurement of pH and glucose has been proposed as a useful way to differentiate uncomplicated from complicated effusions; in one study of 37 patients, all of whom had free-flowing effusions, all effusions with pH values <7.00 or glucose <40mg% required drainage, whereas none with pH >7.20 or glucose >60 mg% did (56, 57). Other studies have not confirmed these results and some investigators have reported that as many as 75% of low pH, low glucose effusions resolve without drainage (54, 58). Since normal pH and glucose values may be obtained when frank empyemas are tapped, neither normal nor abnormal values are diagnostic and should not be exclusively relied on to classify parapneumonic effusions or guide therapy. Pleural fluid white blood cell count and protein content are also rarely helpful in distinguishing complicated from uncomplicated effusions (56). In addition to routine EPA and decubitus chest radiographs chest CT scans are helpful. It can be difficult to differentiate densely consolidated lung or a lung abscess from a pleural effusion on a chest radiograph, but a chest CT will usually easily discriminate between parenchymal and (59-61 ). An inflamed visceral or parietal pleura can often be visualized on a CT scan, especially after administration of IV contrast; the split pleura sign, which represents separation of the contrast enhanced pleuras around a parapneumonic effusion, and diffuse, >2 mm parietal pleural thickening, suggest the presence of a complicated effusion (62). Therefore, unless contraindicated, contrast enhanced scans should always be ordered when imaging empyemas. Pleural thickening is not a specific sign of empyema and also occurs in mesothelioma, mycobacterial infections, and rheumatoid pleural disease (59).

Most patients with complicated parapneumonic effusions will need some sort of pleural fluid drainage. This is especially true if their clinical condition and chest radiograph deteriorates or fails to improve on antibiotic therapy alone; in such patients it is inadvisable to delay drainage for more than 72 hours. Review of large, recent empyema series shows that hospital stays of 20 to 35 days are common, most patients get at least two separate drainage proced\Jres, and the average delay between procedures is six days (63-65). Appropriate initial selection of an effective drainage method should result in shorter hospitalizations and less morbidity and mortality. Available drainage methods are listed on Table 10 in order of their invasiveness.

TABLE 10

Drainage Procedures for Empyemas

- - Image guided catheter -Thoracostomy tube -Video-assisted thoracoscopic surgery (VATS) - Open thoracotomy -

Thoracentesis - A simple thoracentesis, with removal of as much fluid as possible at the time of the initial diagnostic tap, may suffice for uncomplicated parapneumonic effusions, especially if the pH and glucose 14 are normal and the patient has a community acquired pneumococcal pneumonia.

Image guided catheter- Relatively small, 8 to 12 french catheters can be inserted with ultrasound or CT guidance directly into loculated fluid collections and the fluid drained. Reported success rates for loculated, complicated effusions range from 70 to 94% (66-69). Successful treatment of even thickly encapsulated empyemas has been reported (70). For this technique to succeed proper catheter placement, frequent follow-up CT scans to ensure adequate drainage, careful catheter irrigation (necessary to maintain patency of these small bore catheters), and sometimes multiple catheters are required. Therefore availability of experienced interventional radiologists and easy access to a chest CT scanner are important. Thoracostomy tube drainage - Most empyemas are treated initially with blind bedside placement of a large bore, 28 to 34 french catheter into the pleural space. Reported success rates vary widely but are often <50% and may be as low as 11% (63, 71 ). Complications include perforation of the diaphragm, insertion of the chest tube into necrotic lung, soft tissue chest wall infection, and bleeding (72). The commonest problem is poor tube placement resulting in incomplete drainage, which usually occurs with loculated effusions. To improve drainage from either a standard chest tube or from one of the smaller image-guided catheters many investigators advocate administration of a thrombolytic drug, usually urokinase or streptokinase, through the tube. Theoretically, large doses of thrombolytics should dissolve fibrin in loculations thereby establishing drainage even if the chest tube is not inserted directly into the loculated fluid. In animal models thrombolytic therapy, if started at the same time as intrapleural bacterial inoculation and continued for several days, significantly decreases loculation (73). Numerous retrospective series have reported success rates of 70 to 90% for loculated effusions treated with streptokinase or urokinase for two to six consecutive days; these success rates are higher than results obtained with chest tubes alone (74- 77). The choice of agent does not seem to be important; both success rates and side effects are similar whefil urokinase has been compared to streptokinase, although febrile reactions are more frequent with streptokinase (78). However, the only prospective trial in which patients were randomly assigned to tube thoracostomy alone or a chest tube plus thrombolytic instillation found no difference in outcome, with both treatments having a 70% success rate (79). Thrombolytic administration is probably most successful when done early, either before loculations have formed or when loculations are recent and consist mainly of fibrin; disruption of old, collagenized loculations with a thrombolytic drug is unlikely. Video assisted thoracoscopic surgery - VATS is a minimally invasive surgical method for treating empyemas. After general anesthesia the underlying lung is collapsed and three small incisions are made; a fiberoptic video scope is inserted through one and the other two incisions are used to insert instruments. Under direct visualization pleural loculations can be mechanically disrupted, all exudate and fibrin deposits removed, extensive irrigation performed, and a chest tube inserted at the end of the procedure. Surgical morbidity and mortality is minimal and 15

po~toperative recovery rapid . Three series have reported success rates of 60-83%, with post-VATS hospital stays of 7 to 12 days, in patients who had failed previous chest tube drainage (80-82). VATS failures occur when a thick visceral pleural peel traps the underlying lung, a condition which is easily recognizable at the time of the VATS; in such cases a regular thoracotomy can be performed at the same time, sparing the patient a second procedure.

Thoracotomy/decortication - These are the most invasive procedures. They are virtually 100% successful and are sometimes required for patients with old, heavily loculated empyemas or trapped lung. Morbidity and mortality are a concern, especially in a debilitated or elderly patient, and prolonged post-operative stays may result.

It is difficult to compare the outcomes reported for these drainage procedures. Most of the data comes from retrospective series in which one particular treatment was given to selected patients. Variation in both patient population and empyema stage exist, and no studies have prospectively compared different procedures. What is clear from a review of the literature is that better selection of the initial drainage procedure should reduce the need for multiple procedures and get patients out of hospital quicker. Recently a prospective, randomized comparison of two empyema therapies has been published. The patients had parapneumonic effusions which were either loculated or had pH <7.20 and were randomly assigned, within 24 hours of hospital admission, to treatment with a chest tube plus streptokinase (CT/SK) or to VATS. The two groups were well matched with respect to effusion size, microbiology, loculations, and pleural fluid pH (83). Most of the patients had large, loculated empyemas due to an anaerobic infection. Outcomes for the two groups are compared on Table 11.

TABLE 11

Patient Outcomes

~ .QILS.K Number patients 11 9 Hospital days 8.7 ;- 0.9 12.8 + 1 ICU days 1.8 + 1.1 4.2 + 1.8 Complications 1 1 Success 11 4 Failure 0 5 Cost($1 ,000) 17 + 3 24 + 3

These results suggest that VATS works well and should be initial therapy for many empyemas. Chest tubes, even when coupled with streptokinase administration, often fail and additional procedures are then required. Based on the available imperfect literature reviewed in the preceding section a reasonable, clinically useful approach for treating patients with parapneumonic effusions is outlined on Figure 9. It requires a decubitus chest radiograph, diagnostic thoracentesis, and in some cases a chest CT scan. The underlying goal of the algorithm is to ensure effective, timely treatment for empyema patients. 16 PARAPNEUMONIC.. EFFUSION .------..Decubitus CXR-----. Free Flowing Loculated

Thoracentesis+ Chest+ CT Scan /~ /"1.. pH>7.10 pH<7.10 Small Large GLU>40 GLU<40 Mu~ilora••d - gm. stain ffi gm. stain unilora••d

Observe+ Chest+ tube Image Guided VATS Thrombolytic Catheter Agent Thrombolytic Agent

FIGURE 9. Guideline for Managing Parapneumonic Effusions

' 17

REFERENCES

1. Gorbach, S.L., and J.G. Bartlett: Anaerobic infections. New Engl. J. Med . 290:1177-1184, 1974.

2. Basiliere, J.L., H.W. Bistrong, and W.F. Spence: Streptococcal pneumonia. Am. J. Med. 44:4580, 1968.

3. Bartlett, J.G., and S.M. Finegold: Anaerobic infections of the lung and pleural space. Am. Rev. Respir. Dis. 110:56-77, 1974

4. Tillotson, J.R., and A.M . Lerner: Characteristics of pneumonias caused by Escherichia Coli. New Engl. J. Med. 277:115, 1967.

5. Tillotson, J.R., and A. Martin Lerner: Characteristics of non-bacteremic pseudomonas pneumonia. Ann . Intern. Med. 68:295, 1968.

6. Musher, D.M., and S.O. McKenzie: Infections due to Staphylococcus aureus. Medicine 56:383, 1977.

7. Austrian, R., and J. Gold: Pneumococcal bacteremia with especial reference to bacteremic pneumococcal pneumonia. Ann. Intern. Med. 60:759, 1964.

8. Taryle, D.A., D.E. Potts, and S.A. Sahn: The incidence and clinical correlates of parapneumonic effusions in pneumococcal pneumonia. Chest 74:170-173, 1978.

9. Bartlett, J.G., Gorbach, S.L., H. Thadepalli, et al: Bacteriology of empyema. Lancet 1:338-340, 1974.

10. Styrt, B., and S.L. Gorbach: Recent developments in the understanding of the pathogenesis and treatment\ of anaerobic infections (Two Parts). New Engl. J. Med. 321:240-246, 298-302, 1989.

11. Brook, 1.: Enhancement of growth of aerobic and facultative bacteria in mixed infections with Bacteroides Species. Infect. lmmun. 50:929-931, 1985.

12. Rotstein, O.D., T.L. Pruett, and R.L. Simmons: Mechanisms of microbial synergy in polymicrobial surgical infections. Rev. Infect. Dis. 7:151 -170, 1985.

13. Rotstein, O.D., T. Vittorini, J. Kao, et al: A soluble Bacteroides by-product impairs phagocytic killing of Escherichia coli by neutrophils. Infect. lmmun. 57:745-753, 1989. 18

14. Namavar, F., A.Marian, J.J. Verweij, et al: Effect of anaerobic bacteria on killing of Proteus mirabilis by human polymorphonuclear leukoycytes. Infect. lmmun. 40:930-935, 1983.

15. Rotstein, 0.0., T.L. Pruett, J.J. Sorenson, et al: A Bacteroides by-product inhibits human polymorphonuclear leukocyte function. Arch. Surg. 121:82-88, 1986.

16. Rotstein, O.D., P.E. Nasmith, and S. Grinstein: The Bacteroides by-product succinic acid inhibits neutrophil respiratory burst by reducing intracellular pH. Infect. lmmun. 1987:864-870, 1987.

17. Brook, 1.: Role of encapsulated anaerobic bacteria in synergistic infections. Crit. Rev. Microbial. 14:171-193, 1987.

18. Simon, G.L., M.S. Klempner, D.L. Kasper, et al: Alterations in opsonophagocytic killing by neutrophils of Bacteroides fragilis associated with animal and laboratory passage: effect of capsular polysaccharide. J. Infect. Dis. 145:72-77, 1982.

19. Tzianabos, A.O., A. Pantosti, H. Baumann, et al: The capsular polysaccharide of Bacteroides tragi/is comprises two ionically linked polysaccharides. J. Bio. Chern. 267:18230-18235, 1992.

20. Gibson, Ill, F.C., A.O. Tzianabos, and A.B. Onderdonk: The capsular polysaccharide complex of Bacteroides tragi/is induces cytokine production from human and murine phagocytic cells. Infect. lmmun. 64:1065-1069, 1996.

21. Gibson, Ill, F.C., A.B. Onderdonk, D.L. Kasper, et al: Cellular mechanism of intraabdominal abscess formation by Bacteroides tragi/is. J. lmmunol. 160:5000- 5006, 1998.

22. Tzianabos, A.O., A.B. Onderdonk, B. Rosner, et al: Structural features of polysaccharides that induce intra-abdominal abscesses. Science 262:416-419, 1993.

23. Shapiro, M.E., D.L. Kasper, D.F. Zaleznik, et al: Cellular control of abscess formation: role of T cells in the regulation of abscesses formed in response to Bacterioides fragilis. J. lmmunol. 137:341-346, 1986.

24. Tzianabos, A.O., D.L. Kasper, R. I. cisneros, et al: Polysaccharide-mediated protection against abscess formation in experimental intra-abdominal . J. Clin. lnvest. 96:2727-2731, 1995.

25. Tzianabos, A.O., D.L. Kasper, and A.B. Onderdonk: Structure and function of Bacteroides fragilis capsular polysaccharides: relationship to induction and prevention of abscesses. Clin. Infect. Dis. 20(Suppi2):S132-S140, 1995. 19

26. Sasse, S.A., L.A. Causing, M.E. ·Mulligan, et al: Serial pleural fluid analysis in a new experimental model of empyema. Chest 109:1043-1048, 1996.

27. Strange, C., J.R. Tomlinson, C. Wilson, et al: The histology of experimental pleural injury with Tetracycline, empyema, and Carrageenan. Exper. Mol. Pathol. 51:205-219, 1989.

28. Landay, M.J., E.E. Christensen, L.J. Bynum, et al: Anaerobic pleural and pulmonary infections. Am. J. Roentgen. 134:233-240, 1980.

29. Marie, C., M.R. Lasser, C. Fitting, et al: Cytokines and soluble cytokine receptors in pleural effusions from septic and nonseptic patients. Am. J. Respir. Crit. Care Med. 156:1515-1522, 1997.

30. Segura, R.M., J. Alegre, E. Varela, et al: lnterleukin-8 and markers of neutrophil degranulation in pleural effusions. Am. J. Respir. Crit. Care Med . 157:1565- 1572, 1998.

31. Goodman, R.B:, R.G. Wood, T.R. Martin, et al: Cytokine-stimulated human mesothelial cells produce chemotactic activity for neutrophils including NAP-1/IL- 8. J. lmmunol. 148:457-465, 1992.

32. Broaddus, V.C., C.A. Hebert, R.V. Vitangcol, et al: lnterleukin-8 is a major neutrophil chemotactic factor in pleural liquid of patients with empyema. Am. Rev. Respir. Dis. 146:825-830, 1992.

33. Sahn, S.A., LB. Reller, D.A. Taryle, et al: The contribution of leukocytes and bacteria to the low pH of empyema fluid. Am. Rev. Respir. Dis. 128:811-815, 1983.

34. Kumar, a., K.B. Koenig, A-IR. Johnson, et al: Expression and assembly of procoagulant complexes by human pleural mesothelial cells. Thrombo. Haemost. 71:587-592, 1994.

35. ldell, S., C. Zwieb, A. Kumar, et al: Pathways of fibrin turnover of human pleural mesothelial cells In Vitro. Am. J. Respir. Cell Mol. Bioi. 7:414-426, 1992.

36. Glauser, F.L., P.T. Otis, R.I. Levine, et al: Coagulation factors and fibrinogen in pleural effusions. Respiration 33:396-402, 1976.

37. ldell, S., W. Girard, K.B. Koenig, et al: Abnormalities of pathways of fibrin turnover in the human pleural space. Am. Rev. Respir. Dis 144:187-194, 1991.

38. Collen, D., and H.R. Lijnen: Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 78:3114-3124, 1991. 20

39. Maeda, N. Ueki, T. Ohkawa, et al: Local production and localization of transofrming growth factor-beta in tuberculous . Clin. Exp. lmmunol 92:32-38, 1993.

40. Border, W.A., and N.A. Noble: Transforming growth factor p in tissue fibrosis. New Engl. J. Med. 331, 1286-1292, 1994.

41 . Roberts, A.B., M.B. Sporn, R.K. Assoian, et al : Transforming growth factory type p: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl. Acad. Sci. 83:4167-4171, 1986.

42. Roberts, A.B. : Molecular and cell biology of TGF-p. Miner. Electrolyte Metab. 24:111 -119,1998.

43. Laiho, M., 0. Saksela, and J. Keski-Oja: Transforming growth factor-p induction of Type-1 plasminogen activator inhibitor. J. Bioi. Chern. 262:17467-17474, 1987.

44. Eitzman, D.T., R.D. McCoy, Xianxian Zheng, et al: Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J. Clin. Invest. 97:232-237, 1996.

45. Svee, K., J. White, P. Vaillant, et al: Acute lung injury fibroblast migration and invasion of a fibrin matrix is mediated by CD44. J. Clin. Invest. 98:1713-1727, 1996.

46. Clouthier, D.E. , S.A. Comerford, and R.E . Hammer: Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-P1 transgenic mice. J. Clin. Invest. 100:2697-2713, 1997.

47. Kapanci, Y., A. Desmouliere, J.C. Pache, et al: Cytoskeletal protein modulation in pulmonary alveolar myofibroblasts during idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 152:2163-2169, 1995.

48. Broekelmann, T.J., A.H. Limper, T.V. Colby, et al: Transforming growth factor P1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc. Natl. Acad. Sci. 88:6642-6646, 1991.

49. Shenkar, R, W.F. Coulson, and E. Abraham: Anti-transforming growth factor p monoclonal antibodies prevent lung injury in hemorrhaaged mice. Am. J. Respir. Cell Mel. Bioi. 11 :351 -357, 1994.

50. Williams, R.S., A.M. Rossi, N. Chegini, et al: Effect of transforming growth factor p on postoperative adhesion fo!TTlation and intact peritoneum. J. Surg. Res. 52:65-70, 1992. 21

51 . Sahn, S.A.: Management of complicated parapneumonic effusions. Am. Rev. Respir. Dis. 148:813-817, 1993 ..

52. Light, R.W.: A new classification of parapneumonic effusions and empyema. Chest 108:299-301, 1995.

53. Bartlett, J.G., and L.M. Mundy: Community-acquired pneumonia. New Engl. J. Med. 333:1618-1624, 1995.

54. Berger, H.A., and M.L. Morganroth: Immediate drainage is not required for all patients with complicated parapneumonic effusions. Chest 97:731-735, 1990.

55. Himelman, R.B., and P.W. Callen: the prognostic value of loculations in parapneumonic pleural effusions. Chest 90:852-856, 1986.

56. Light, R.W., W.M. Girard, S.G. Jenkinson, et al; Parapneumonic effusions. Am. J. Med. 69:507-512, 1980.

57. Potts, D.E., D.C. Levin, and S.A. Sahn: Pleural fluid pH in parapneumonic effusions. Chest 70:328-331, 1976.

58. Poe, R.H ., M.G. Marin, R.H. Israel, et al: Utility of pleural fluid analysis in predicting tube thoracostomy/decortication in paraapneumonia effusions. Chest 100:963-967' 1991.

59. Muller, N.L.: Imaging of the pleura. Radiology 186:297-309, 1993.

60. Bressler, E.L., I.R. Francis, G.M. Glazer, et al: Bolus contrast medium enhancement for distinguishing pleural from parenchymal lung disease: CT features. J. Comput. Assist. Tomogr. 11:436-440, 1987.

61 . Stark, D.O., M.P. Federle, P.C. Goodman, et al: Differentiating lung abscess and empyema: radiographytand computer tomography. Am. J. Roentgen. 141:163- 167, 1983.

62. Waite, R.J., R.J. Carbonneau, J.P. Balikian, et al: Parietal pleural changes in 1 empyema: appearances at CT • Radiology 175:145-150, 1990.

63. LeMense, G.P., C. Strange, and S.A. Sahn: Empyema thoracis. Therapeutic management and outcome. Chest 107:1532-1537, 1995.

64. Mandai, A.K., and H. Thadepalli: Treatment of spontaneous bacterial empyema thoracis. J. Thorac. Cardiovasc. Surg. 94:414-418, 1987.

65. Lemmer, J.H., M.J. Botham, and M.B. Orringer: Modem management of adult thoracic empyema. J. thorac. Cardiovasc. Surg. 90:849-855, 1985. 22

66. Lee, K.S., J.G. lm, Y.H . Kim, . et al: Treatment of thoracic multiloculated empyemas with intracavitary urokinase: A prospective study. Radiology 179:771-775, 1991.

67. Silverman, S.G., P.R. Mueller, S. Saini, et al: Thoracic empyema: Management with image-guided catheter drainage. Radiology 169:5-9, 1988.

68. Moulton, J.S., R.E. Benkert, K.H. Weisiger, et al: Treatment of complicated pleural fluid collections with image-guided drainage and intracavitary urokinase. Chest 108:1252-1259, 1995.

69. Moulton, J.S., P.T. Moore, and R.A. Mencini: Treatment of loculated pleural effusions with transcatheter intracavitary urokinase. Am. J. Roentgen. 153:941- 945, 1989.

70. Neff, C.C., E. vanSonnenberg, D.W. Lawson, et al: CT follow-up of empyemas: Pleural peels resolve after percutaneous catheter drainage. Radiology 176:195- 197, 1990.

71. Way, Ill, C.V., J. Narrod, and A. Hopeman: The role of early limited thoracotomy in the treatment of empyema. J. Thorac. Cardiovasc. Surg. 96:436-439, 1988.

72. Urschel, J.D., H. Takita, and J.G. Antkowiak: Necrotizing soft tissue infections of the chest wall. Ann. Thorac. Surg. 64:276-279, 1997.

73. Strange, C., M.L. Allen, R. Harley, et al: Intrapleural streptokinase in experimental empyema. Am. Rev. Respir. Dis. 147:962-966, 1993.

74. Aye, R.W., D.P. Froese, and L.D. Hill: Use of purified streptokinase in empyema and . Am. J. Surg. 161:560-562, 1991.

75. Robinson, L.A., A.L. ~ oulton, W.H. Fleming, et al: Intrapleural fibrinolytic treatment of multiloculated thoracic empyemas. Ann. Thorac. Surg. 57:803-814, 1994.

76. Ternes, R.T., F. Follis, R.M . Kessler, et al: Intrapleural fibrinolytics in management of empyema thoracis. Chest 110;102-106, 1996.

77. Henke, C.A., and J.W. Leatherman: lntrapleurally administered streptokinase in the treatment of acute loculated nonpurulent parapneumonic effusions. Am. Rev. Respir. Dis. 145:680-684, 1992.

78. Bouros, D., S. Schiza, G. Patsourakis, et al: Intrapleural streptokinase versus urokinase in the treatment of complicated parapneumonic effusions. Am. J. Respir. Crit. Care Med. 155:291 -295, 1997. 23

79. Chin, N.K., and T.K. Lim: Controlled trial of intrapleural streptokinase in the treatment of pleural empyema and complicated parapneumonic effusions. Chest 111:275-279, 1997.

80. Ridley, P.O., and M.V. Braimbridge: Thoracoscopic debridement and pleural irrigation in the management of empyema thoracis. Ann. Thorac Surg. 51 :461- 4"64, 1991.

81 . Striffeler, H. , M. Gugger, V.I. Hot, et al: Video-assisted thoracoscopic surgery for fibrinopurulent pleural empyema in 67 patients. Ann. Thorac. Surg. 65:319-323, 1998.

82. Landreneau, R.J ., R.J . Keenan, S.R. Hazelrigg, et al: Thoracoscopy for empyema and hemothorax. Chest 190:18-24, 1995.

83. Wait, M.A., S. Sharma, J. Hohn, et al: A randomized trial of empyema therapy. Chest 111 :1548-1551, 1997.