Current Management of Pediatric Parapneumonic Pleural Effusions and Pleural Empyema

Pediatric parapneumonic pleural effusions (PPEs) and pleural empyema (PE) are the main complications of pediatric community-acquired pneumonia (pCAP) in childhood. While PPE is defined as an exudative pleural effusion, in case of bacterial detection or surrogate markers such as low pH or leukocytosis, the term PE is established. In the past, different systems to classify stages of PPE/PE have been proposed and categorization remains an area of debate.1–3 In clinical practice, PPE/PE are commonly classified by a grading system referring to findings of pleural ultrasonography introduced by Jaffe et al.2 (Table 1). Other systems to categorize PPE/PE additionally include findings of pleural fluid chemistry and microbiology to predict outcomes and facilitate decision-making on drain insertion.9 TABLE 1. - Recommendation for Empiric Antibiotic Treatment of Pediatric Pleural Empyema According to the National Guidelines Organization (Country) Recommended Empiric Antibiotic Therapy Further Comments Regarding the Proposed Antibiotic Therapy Infectious Disease Society of America4 (United States) No specific recommendation The antibiotic treatment of parapneumonic effusion or empyema is similar to that for CAP without effusion. Bacterial pathogens responsible for CAP and for parapneumonic effusion or empyema are also similar, with S. pneumoniae the most commonly isolated pathogen though S. aureus remains an important cause of empyema. American Association of Thoracic Surgeons5 (United States) Community-acquired empyema:aminopenicillin/beta-lactamase inhibitorORSecond- or third-generation cephalosporin AND metronidazoleHospital-acquired or postprocedural empyema:include antibiotics active against methicillin-resistant S. aureus and P. aeruginosa (vancomycin AND piperacillin-tazobactam OR vancomycin, cefepime AND metronidazole) Avoid aminoglycosides in the management of empyema.There is no role for intrapleural administration of antibiotics British Thoracic Society6 (United Kingdom) Penicillin AND flucloxacillin ORAmoxicillin AND flucloxacillin ORCo-amoxiclavORCefuroximeORClindamycin Antibiotic choice must include cover for S. pneumoniae.Broader spectrum cover is required for hospital-acquired infections, secondary to surgery, trauma and aspiration.Penicillin allergic patients can be treated with clindamycin alone Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften7 (Germany) Aminopenicillin/beta-lactamase inhibitorORSecond-generation cephalosporin Thoracic Society of Australia and New Zealand8 (Australia and New Zealand) Benzylpenicillin AND flucloxacillinORCo-amoxiclavORCefotaxime/ceftriaxone AND flucloxacillin Empirical antibiotic treatment must ensure S. pneumoniae and S. aureus cover. Methicillin-resistant S. aureus must be covered in communities at risk ETIOLOGY Bacterial Etiology Evaluation of the bacterial etiology of PPE/PE from Asia, Europe and the United States show that Streptococcus pneumoniae (21%–56%), S. pyogenes (19%–27%) and Staphylococcus aureus (7%–31%) are the most prevalent pathogens. Relevant rates of methicillin-resistant S. aureus have been reported in Australia (4%)10 and the United States (10%)11 but not in Europe.12,13 Viridans streptococci and anaerobes are less frequently isolated and Enterobacteriaceae and nonfermenting gram-negative rods should especially be considered in children with underlying conditions or bronchiectasis. Pathogens causing atypical pneumonia such as Mycoplasma pneumoniae or Chlamydia pneumoniae are rarely detected in PPE/PE.11,12,14 Inflammation Pleural inflammation is of high importance for the formation and preservation of PPE/PE, and presumably a therapeutic target. Proinflammatory cytokines and bacterial metabolites act via direct tissue damage and the formation of septations in late stages. Cytokines are elevated in PPE/PE, correlate with the activation of fibrinolytic system enzymes, and rise in progressive stages.15,16 Therefore, additional anti-inflammatory treatment of children and adults with PPE/PE has been evaluated in clinical studies.17,18 DIAGNOSIS Clinical Diagnosis and Baseline Laboratory PPE/PE is the most frequent complication of pCAP and should therefore be considered in all children not responding to conventional therapy within 48–72 hours. Children with PPE/PE may present with persisting symptoms such as fever, respiratory distress or chest pain. In the clinical examination, tachycardia, tachypnea, attenuated breath sounds or dull percussion sound and especially in patients with prolonged course of disease, scoliosis may be observed. In addition to laboratory findings such as leukocytosis with left shift, elevated C-reactive protein and procalcitonin, elevated D-dimers or hyponatremia may be also observed in severe cases. Imaging Performing PPE/PE chest radiography serves 2 purposes: confirming the presence of pleural fluid and ruling out other complications such as pneumothorax or necrotizing pneumonia. Thorax ultrasonography is the method of choice to diagnose PPE/PE and will support decision-making between conservative and invasive treatment options. The most frequently used staging system for PPE/PE by Jaffe et al.,2 includes 4 grades acknowledging the distinct characteristics and a substantial proportion of solid components present (grade 1, anechoic fluid; grade 2, echoic fluid without septations; grade 3, effusions showing multiple thick septations; grade 4, effusions showing multiple septations with solid appearing components comprising more than one-third of the collection). Advantages of chest sonography compared with computed tomography (CT) include its rapid deployment on ward, and its safety due to the lack of ionizing radiation and the need for sedation.19 CT imaging is usually not recommended and should only be considered in refractory cases, for example, to rule out or quantify lung abscess formation or reaccumulation of pleural fluid.6,20 Magnetic resonance imaging is a radiation-free alternative to CT imaging with the shortcoming of its availability and the frequent necessity of sedation in children. Pleural Fluid Analysis/Cytology While in pleural fluid of lobulated PPE/PE, cell counts of >50,000/µL can be found in the early stages, in chronic or tuberculoid PPE/PE, cell count may be low. In biochemical analyses of pleural fluid, pH 1000 IU/mL are associated with empyema, and in some experts’ view, may guide the decision for drainage. Analysis of pleural biomarkers such as calprotectin, TNF-alpha or IL-1 are not routinely recommended, but show promising results.21–23 Microbiology In children hospitalized with suspected bacterial pneumonia, blood culture should be obtained with adequate sample volumes to increase pathogen detection rate.12 If PPE/PE is diagnosed and thoracentesis is performed, pleural fluid microscopy (gram staining), bacterial culture and polymerase chain reaction (PCR) should be performed. Culture remains an important pillar of pathogen detection, as it is the only method providing phenotypical antibiotic susceptibility testing. Nevertheless, additional pleural fluid PCR significantly increases the pathogen detection rate in PPE/PE.24,25 The sensitivity of PCR differs between commercial and in-house approaches specific for S. pneumoniae (45%–84%) and the amplification and sequencing of bacterial 16S rDNA (50%–69%).24–27 TREATMENT Antibiotic Treatment Reasonable options for empiric antibiotic treatment of PPE/PE as a complication of pCAP are first, aminopenicillin/beta-lactamase inhibitor combinations and second, second-generation cephalosporins (Table 1).4–6,8,28 However, regional epidemiology and patient factors should be considered. In regions with a high incidence of high-level resistance to penicillin of S. pneumoniae, a third-generation cephalosporin is appropriate. Coverage of methicillin-resistant S. aureus in empiric antibiotic therapy, for example by vancomycin, is indicated in areas or communities with high rates of colonization or in case of colonization of the affected child.8 Clindamycin is recommended for children allergic to penicillin.6 For its anaerobe coverage and high tissue penetration, clindamycin may be used as a combination partner to cephalosporins. However, obligate anaerobes resistant to beta-lactam antibiotics are infrequently detected in pleural fluid of PPE/PE and pathogens derived from the orofacial flora such as viridans streptococci or anaerobic Peptostreptococcus spp. are in general susceptible to aminopenicillin/beta-lactamase inhibitor or cephalosporins. Aminoglycosides are not recommended in empiric antibiotic therapy of PPE/PE, since they are inactivated in acidic empyema fluid.5 In children with underlying diseases or bronchiectasis, empiric treatment should be guided by prior results of respiratory samples and should include coverage of Pseudomonas aeruginosa, for example, using piperacillin-tazobactam or ceftazidime plus clindamycin. Anti-inflammatory Treatment The application of systemic steroids in PPE/PE is not recommended in the current guidelines. However, the attenuation of the cytokine-triggered inflammatory process seems a reasonable approach as an adjunctive treatment. Thimmesch et al.29 analyzed 97 children with PPE/PE in a retrospective single-center observational study of whom 55 received methylprednisolone as a rescue therapy. Children receiving steroids had fewer chest tube insertions (62% vs. 81%, P = 0.041) but no differences were observed in total length of fever or hospital length of stay. In a multicenter, double-blind, clinical trial, 60 children with CAP complicated by PPE/PE were randomized to receive dexamethasone (0.25 mg/kg/dose every 6 hours for 48 hours) or placebo along with antibiotics. The primary end point was time to recovery defined by continuous ambient oxygen saturation, resolution of fever, absence of respiratory distress, end of invasive procedures, pneumonia in resolution and oral feeding. The median time to recovery for patients receiving dexamethasone was 68 hours (2.8 days) shorter than for patients receiving placebo (109 vs. 177 hours, P = 0.037). There were no significant differences in complications or adverse events except for hyperglycemia.17 Further studies are required to point out optimal timing, dosage and duration as well as the general safety. Steroids may be used based on an individual patient decision. Thoracentesis As a principle of infectious disease management, source control of infected tissue is of major importance in PPE/PE to establish bacterial clearance and prevent the progression of the disease. Further, drainage of large empyema is crucial to establish re-expansion of the affected lung. Small effusions (≤¼ hemithorax) usually can be managed by antibiotic therapy alone, whereas thoracentesis should be considered in respiratory-compromised children with effusions of >¼ hemithorax, large effusions (>½ hemithorax) or any mediastinal shift.4,30 Drainage Chest drains should be inserted in large effusions and in loculated effusions to avoid serial thoracentesis and to prepare potential administration of fibrinolytics.6,31 The use of catheters of a small-bore size (8–10 Fr) and pigtail catheters are recommended as placement is less traumatic and children’s discomfort is minimized.6,32 The thoracic drainage is usually left in place with a continuous suction rate 10–15 cm H2O until the drainage rate has decreased significantly (<0.5 mL/kg body weight in 24 hours), there is no sign of intrathoracic leakage and the lungs have fully expanded.30,33,34 Fibrinolytics When pleural drainage is in place, intrapleural fibrinolytic therapy with either urokinase, streptokinase or alteplase may be considered.35–38 Especially in the fibrinopurulent stages of PPE/PE, additional debridement of the pleural space may result in a shorter course of disease and avoid further surgical, invasive procedures. Instillation of fibrinolytics in the pleural space supports drainage by unblocking the frequently obstructed pleural tube and dissolving the intrapleural adhesions and fibrin cavities. The choice of fibrinolysin, dosage and therapeutic regimens are controversial. While urokinase or streptokinase are most applied, there is an emerging use of tissue plasminogen activator alteplase.35–40 Urokinase in a dose of 40,000 units in 40 mL 0.9% saline for children 1 year and older and 10,000 units in 10 mL 0.9% saline for children younger than 1 year can be administered twice daily (with a 4-hour dwell time) for 3 days.6 Surgical Treatment Pleural drainage and instillation of fibrinolytics are effective treatment options in more than 80% of children with PPE/PE.41,42 Video-assisted thoracoscopy should therefore be reserved for PPE/PE refractory to 2–3 days of drainage and fibrinolytics.6,34 Formation of a solid pleural rind is another indication to perform video-assisted thoracoscopy. Open chest debridement with decortication remains an option in very severe cases with excessive findings.4,43 Postdischarge Controls and Therapy The prognosis of PPE/PE in most children is generally good, fatal cases are rare and most children will completely recover without any impairment. In mildly affected children, treated with antibiotics alone, clinical examination after completion of the treatment course seems reasonable. In more severe cases, a thorax ultrasound and lung function tests should be performed to detect residual effusion, sufficient diaphragm movement and impairment of lung function. In children with very severe cases and complications such as lung abscess or necrotizing pneumonia, an underlying condition as immunodeficiency should be ruled out. Prevention PPE/PE and pCAP results from bacterial infections and viral-bacterial coinfections. The most important preventive measure against pCAP and its complications is early childhood vaccination against potential bacterial pathogens such as S. pneumoniae, Haemophilus influenzae type B and Bordetella pertussis. In addition, given the close interaction between viral and bacterial pathogens in pCAP, established and future vaccines against viral respiratory pathogens (eg, influenza virus, measles virus, respiratory syncytial virus and human metapneumovirus) will contribute to reduce the risk of complicated pCAP. Following the introduction of conjugated pneumococcal vaccines (PCV 7), there was an observation of a reduction of childhood pneumonia hospitalizations by 20%–30%. This reduction was initially less pronounced in PPE/PE; however, the introduction of a higher-valent PCV 13 vaccine including important PPE/PE serotypes as ST 1 led to a reduction of this complication in numerous countries. Nevertheless, a reincrease of pediatric PPE/PE was observed after several years of ongoing PCV 13 use, with an increasing number of documented PPE/PE breakthrough cases due to serotype 3, a serotype that is today considered to be only incompletely prevented by PCV 13 vaccination. Future pneumococcal vaccines should therefore not only have increased coverage against different S. pneumoniae serotypes, but should also provide effective protection against S. pneumoniae serotype 3.