Pleural Infection
What We Need to Know but Don't
Curr Opin Pulm Med. 2012;18(4):321-325. © 2012 Lippincott Williams & Wilkins
Abstract and Introduction
Abstract
Purpose of review Pleural infection remains a common and difficult problem to manage in the 21st century. Despite advances in modern healthcare, the rising incidence and mortality of empyema highlights a need for better understanding of the disease and more effective strategies in its diagnosis and treatment.
Recent findings Recent studies have progressed our knowledge and understanding of the bacteriology and pathophysiology of pleural infection. However, rather than providing firm conclusions, examination of current literature provokes several unanswered questions on most aspects of the disease.
Summary This review aims to challenge traditional current concepts and approaches to clinical practice in pleural infection, to stimulate debate and research into potential novel future therapies.
Introduction
Empyema has remained one of the oldest and most severe respiratory diseases since its first description over 2000 years ago. Potent antimicrobials, better access to primary and tertiary healthcare, improved living conditions and nutritional status of the population, and new vaccines were all previously expected to eliminate pleural infection in the developed world. Not only have these factors failed to eradicate the disease, pleural infection is now reemerging as a growing health threat worldwide.
Pleural infection (complicated parapneumonic effusion and empyema) is rising in incidence across all age groups worldwide, confirmed by studies from the USA, Canada, Europe, and Asia. [1–5] The mortality rate of empyema has risen alarmingly. In Utah, death rates from empyema were six-fold higher in 2000–2004 compared with 1950–1975. [6] The view among the public and many clinicians that pleural infection is no longer a serious illness is misguided, and must be corrected to heighten awareness of the disease.
Many of the traditional concepts on the pathophysiology and management of pleural infection are not evidence based, and have been accepted for generations without careful scrutiny. Dissection of existing evidence and willingness to challenge 'conventional wisdom' in clinical practice of pleural infection are key requirements to advance the field. This review aims to highlight major shortcomings of current beliefs and approaches to pleural infection to stimulate thoughts, debates, ideas, and hopefully future research.
Etiology
Bacterial infection of the pleura is the hallmark of empyema. How bacteria reach the pleural cavity remains poorly understood. Conventional teaching suggests that pleural infection is a direct consequence of pneumonia. Increasing evidence reveals this is an oversimplistic concept. A wide range of microbial, host, and environmental factors (and their complex interactions) are likely to play a role.
The Microbial Factors
A new murine model of Streptococcus pneumoniae empyema lends support that pleural infection can result from direct spread of lung infection. S. pneumoniae, delivered intranasally, crossed the visceral pleura and invaded the pleural space rapidly, resulting in high bacteria load in the pleural space by 24 h, and early adhesion formation by 48 h in immune-competent mice. [7] However, several lines of evidence suggest that other mechanisms may be at play, at least for a significant subset of patients. Many patients with empyema have no evidence of an underlying pneumonia, even on computed tomography. The disparity between the common organisms of pneumonia and of empyema also challenges the concept of direct pleural spread from pneumonia. The most common causative organisms in adult empyema are the Streptococcus intermedius, Streptococcus anginosus, Streptococcus constellatus (milleri) group of bacteria, [8] which are rarely implicated in pneumonia. Conversely, some common causative organisms of pneumonia (e.g., Haemophilus influenzae) are disproportionately underrepresented in empyema. The mortality also differs among the organisms underlying the empyema. For example, empyema complicates methicillin-resistant Staphylococcus aureus pneumonia in up to 75% of patients, and is associated with high mortality rates. [9,10] Understanding the differential predilection of different bacteria in invading and infecting the lung and pleural cavity and how they breach the pleura are important.
The use of pneumococcal vaccine raises even more intriguing questions. S. pneumoniae is the commonest organism for paediatric empyema and second commonest in adult cases. [11] Despite the reduction in invasive pneumococcal disease since the introduction of the heptavalent pneumococcal conjugate vaccine in 2000, the incidences of pneumococcal empyema in children and adults have both increased. [12,13] 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). [13] It is likely that vaccines of wider coverage will not reduce the development of empyema but merely produce a shift in favour of nonvaccine serotypes, [11] or even other related species. This raises the importance of factors other than bacterial virulence in determining development of pleural infection.
The Host Factors
Why does a small subset of patients with pneumonia develop empyema when most do not? Do clinical presentation and/or other host factors govern development of postpneumonic empyema? A large prospective observational study ( n = 1269) [14] showed that pneumonia and generic sepsis severity scores failed to predict development of pleural infection in patients with community-acquired pneumonia (CAP). However, low serum albumin (<30 g/l) and sodium (<130 mmol/l) levels, raised C-reactive protein (CRP; >100mg/l) and platelet count (>400 × 10 9 platelets/l), intravenous drug use and chronic alcohol abuse were independent predictors of the development of pleural infection following CAP. The results have yet to be confirmed on other cohorts, and other potentially important features (e.g., radiographic appearances including location of the pneumonic process) have not been assessed in this study.
A practical and reliable predictive algorithm will help identify at-risk patients for closer followup and early drainage of parapneumonic effusions to prevent empyema. However, only a relatively small percentage of patients with CAP develop empyema. Studies to identify predictors, therefore, require a massive number of CAP patients in order to incorporate likely confounders (e.g., common comorbidity, different microorganisms, radiographic appearances and so on). Empyema development is also likely to be governed in part by a complex genetic trait with strong modification from gene–environment interactions. Such components can only be decoded by very large multicentre studies. The extents to which wider use of immunosuppression therapy, increased life expectancy and hence comorbid diseases, and increasing amount of drug-resistant organisms contribute to the rising incidence of pleural infection have yet to be defined.
The very different disease presentation and course between paediatric and adult patients with empyema provokes other intriguing questions on host factors. The mortality (~15%) seen in adult patients [8] is significantly higher than in children, who usually recover from the illness. Adult patients typically have more comorbidity and poorer nutritional status (and a lower protein) at presentation, which may contribute to the poorer outcome. [15] The bacteriology of the adult population is much more diverse, whereas paediatric empyema is mostly due to Gram-positive organisms, especially S. pneumoniae. Understanding the pathobiology underlying themany differences in the disease course and outcome of paediatric and adult empyema may provide insight in disease pathogenesis.
Diagnosing Pleural Infection
The presence of pus and/or bacteria in pleural fluid defines empyema. Identification of the causative organism can guide antibiotics use and allow better understanding of disease cause. However, in up to 40% of patients with pleural infection, no microbes can be grown from the pleural fluid. [8] More reliable culture methods are required to enhance microbiological diagnosis. A higher yield can be achieved with inoculation of pleural fluid into blood-culture bottles at the bedside (from 38 to 59%), instead of transporting the samples in a sterile container. [16]
Many hypotheses have been proposed to explain the low-culture yield, but few have been formally tested in research studies. Pus is formed from degranulated leukocytes and it is possible that pleural pus results from an intense inflammatory response triggered by bacteria, which continues after the bacteria have been eradicated. Likewise, whether bacteria in the pleural cavity form biofilms is unknown. If pleural biofilm exists, it may contribute to the difficulty of isolating organisms.
The preceding use of empirical antibiotics prior to sample collection may contribute to the low yield. PCR can be more sensitive in detecting the presence of bacteria, including those that may have been killed by prior antibiotic use. Paediatric empyema studies have shown that PCR targeting 16S ribosomal DNA may increase the detection of pathogens, especially Gram-positive organisms. One study reports nearly a 10-fold increase in sensitivity using a PCR-based approach compared with pleural fluid culture for identification of S. pneumoniae in children with empyema. [17] The use of PCR in adult empyema samples, however, has shown significant false-positive and false-negative results, limiting its clinical usefulness. [18]
Where in the pleural cavity are the bacteria most abundant in empyema? Conventional strategies have all targeted capturing bacteria from the pleural fluid (and/or blood). Few data exist on wherein bacteria inhabit within the pleural cavity. However, in tuberculous pleuritis, culture of pleural tissue has a significantly higher yield than from pleural fluid, often by several folds. [19] In the animal model of S. pneumoniae described above, [7] bacteria are found in abundance in the parietal and diaphragmatic pleura. This prompts the question whether culture of pleural biopsy tissue in empyema may have additional value over standard fluid culture.
Can biomarkers help improve management? Pleural fluid pH, glucose, and lactate dehydrogenase (LDH) have remained important biochemical markers for pleural infection since 1980. A huge number of potential molecules have been evaluated in recent years (reviewed elsewhere), [20] ranging from cytokines [21] to inflammatory markers (e.g., procalcitonin, CRP), and bacterial-related proteins (e.g., lipopolysaccharide-binding protein). [22] None has been shown to be superior to the currently used markers of pH, glucose, and LDH for diagnosing pleural infection. It is unlikely that any single biomarker, especially in isolation without clinical/radiological/bacteriological data, will be able to determine pleural infection with sufficient accuracy to replace current practice.
Efforts to date have concentrated on capturing the causative bacteria in empyema. It is likely that the quantity of bacteria present may also be informative on disease progress and prognosis, as shown in recent studies of quantifying pneumococci in pneumonia patients. [23]
Treatment
Despite generations of research, the best management of pleural infection remains controversial with wide variations in clinical practice seen. The principle of management is straightforward: control the sepsis with antibiotics and remove the infected pleural collection.
Antibiotics
Antibiotic therapy is well accepted as the mainstay of treatment for pleural infection. Clinicians often based the choice of antibiotics on ex-vivo sensitivity of the cultured pleural fluid. However, we have alarmingly little understanding of the pharmacokinetics of antibiotics. Marked variations exist in the penetration of antibiotics into empyemic fluid. A lot of data came from animal studies that did not resemble human illness, or from clinical series of small numbers of patients. In a rabbit model of empyema, penicillin and metronidazole were shown to equilibrate most rapidly within the infected fluid, and penicillin levels remained elevated in the fluid even after serum levels had decreased. [24] By contrast, the concentration of parenterally administered aminoglycosides in empyemic fluid in humans has been shown to be very low, particularly for gentamicin, which was not detected at all. [25]
Penetration of common antibiotics into thickened pleura or loculated effusions has not been defined. The bioactivity of different antibiotics specifically in the empyema environment, among purulent material and acidic pH, needs to be studied. Even when an organism is identified from the fluid, given the poor capture rate of bacteria (see above), concurrent infection by other bacteria is likely underestimated. These factors need to be addressed to improve the rate of antibiotic failure.
As most patients with empyema undergo tube thoracostomy, pleural instillation of antibiotics is a tempting strategy that will guarantee adequate pleural space penetration. The role of intrapleural antibiotic therapy in empyema has often been raised, although never properly tested.
Pleural Drainage
Surgery still remains the first line of treatment for empyema in many centres. Surgical techniques employed are varied, such as debridement via video-assisted thoracoscopic surgery (VATS) or open thoracotomy, decortication, thoracoplasty, and open window thoracostomy. A review of the current surgical literature highlights that neither a universally acceptable primary modality nor the gold standard of their sequence is available. [26] The lack of a single ideal treatment modality or policy reflects the complexity of this heterogeneous disease and is likely to have an effect on morbidity and mortality. Four randomized clinical trials have compared firstline VATS with conservative treatment (antibiotics and chest tube drainage with/without fibrinolytics), in both the paediatric populations [27,28] and in adults. [29,30] No advantage in mortality or major morbidity has been shown with early surgical approach in all the trials. [31] Surgery is not without complications. In particular, there is increasing recognition of postpleural surgery complications especially intercostal neuralgia, which must be taken into consideration. [32]
A significant breakthrough in the search for nonsurgical means to clear the infected pleural fluid has recently been published. Combined intrapleural therapy of tissue plasminogen activator (tPA) to breakdown locules and DNase to thin the pus was shown in a factorial multicentered double-blinded randomized trial to cure 96% of patients with pleural infection, avoiding surgery. [33] The length of stay was 6.7 days shorter in the combination treatment group compared with placebo controls. In the study, the combination therapy was given to patients at the time of pleural infection diagnosis. As approximately 80% of pleural infection patients can be successfully treated with antibiotics and tube drainage alone, future studies should define if tPA/DNase should be used immediately at time of diagnosis or as rescue therapy when simple drainage fails. Only 46 patients were treated with tPA/DNase in the randomized trial, hence, larger open-label studies are needed to confirm the efficacy and safety.
Along the line of adjunct intrapleural therapy, many strategies have been piloted over the years to reduce the bacterial burden within an infected pleural space. Regular pleural lavage with physiological saline via chest tube has been a standard practice in some European centres, although formal comparison with standard therapy is lacking. Irrigation with antiseptic or antimicrobial washouts to sterilize the pleural cavity has been reported in observation series/cases, predominantly after surgical intervention. [34–36] Although there are no randomized trial data on such potential techniques, the ideas seem logical and are worthwhile investigating in clinical studies. In the setting of postpneumonectomy empyema, the use of thoracic debridement followed by continuous antibiotics irrigation (via two chest drains) has been shown to successfully sterilize the pneumonectomy space. [34] The sample size was small in this study and mean irrigation duration was 40 days, but there was no associated morbidity or mortality and no subsequent requirement for further surgery. A similar method using continuous pleural lavage has shown this to be a feasible way to clear pleural pus discharge without prolongation of hospitalization in patients postthoracotomy for stage II empyema. [35] Intrapleural treatment with povidone iodine is another interesting concept. As it is now widely accepted as a pleurodesing agent in many regions, extending the use of intrapleural iodine instillation to empyema has the advantage of sterilizing and potentially obliterating the cavity. This approach has been described in case reports. [36] These potential adjunct therapies to clear the pleural cavity of infected material are worth investigating, and if successful, may help negate more invasive approaches such as surgery.
Conclusion
The rising incidence and mortality rate of empyema in the modern era confirms that gaps in our understanding of its cause and pathophysiology remain. Although research over the last few decades has provided significant insight into the disease, current data on pleural infection generate as many questions as answers. Novel approaches to diagnostic and therapeutic strategies are needed to stimulate future trials in an attempt to provide more effective, standardized, evidence-based management strategies for this complex disease.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
••of outstanding interest
Acknowledgements
Dr Lee receives research grants from Cancer Council Western Australia, Sir Charles Gairdner Research Advisory grants and Westcare Australia.
Curr Opin Pulm Med. 2012;18(4):321-325. © 2012 Lippincott Williams & Wilkins
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