Pediatric Pleural Effusion

The inner surface of the chest wall and the surface of the lungs are covered by the parietal and visceral pleura, respectively. The small amount of fluid (< 1 mL) between the parietal and visceral pleura in humans forms a thin layer about 10 μL thick.[1] The protein concentration in the pleura is similar to that of the interstitial fluid. Compared with the interstitial fluid in humans, the pleural fluid has a higher level of bicarbonate, a lower level of sodium and large ̶ molecular-weight proteins (eg, lactate dehydrogenase [LDH]), and a similar level of glucose.[2]

The cells in pleural fluid in healthy humans are small in number and are mostly macrophages with few lymphocytes and RBCs.[1] In disease state, these parameters change and large amounts of fluid can accumulate in the pleural space.

The amount of fluid in the pleural space is regulated through a delicate balance between the oncotic and hydrostatic pressures of the pleural space and the capillary intravascular compartments and pleurolymphatic drainage.[1] Chest wall and diaphragmatic movements enhance absorption of excess pleural fluid, large particles, and cells through preformed stomas.[1]

The etiologic mechanisms involved in the formation of most pleural effusions include pleural space infection (empyema), abnormal capillary permeability (exudates), increased hydrostatic or decreased oncotic pressure in the setting of normal capillaries (transudates), abnormal lymphatic clearance (exudates), and blood in the pleural space (hemothorax).

In children, infection is the most common cause of pleural effusion. Congestive heart failure constitutes the second most common etiology, followed by malignancy.[3, 4] In a Canadian study of 127 children with pleural effusion, about 50% of effusions were parapneumonic, 17% were caused by congestive heart failure, 10% were caused by malignancy, 9% were caused by renal disease, 7% were caused by trauma, and 6% were associated with other causes.[3]

In another North American report of 210 children admitted with pleural effusion, Hardie et al showed that 68% of the effusions were parapneumonic (50 of 143 associated with empyema), 11% were caused by congenital heart disease, 5% were caused by malignancy, and 3% were associated with other causes.[4]

Infection

Pleural effusions caused by nonbacterial infectious agents are more common than those caused by bacterial organisms.[5] Viral effusions are usually asymptomatic and resolve without therapy.

Parapneumonic effusion and empyema are serious complications of bacterial pneumonia. Over the years, the etiologic agents have become more diverse, and their sensitivities to different antibiotics have changed.[6] In industrialized countries, Streptococcus pneumoniae remains the most common pathogen that causes parapneumonic effusions and empyema in children.[7, 8, 9] .

S pneumoniae reemerged as a more virulent, penicillin-resistant and cephalosporin-resistant organism in the 1980s and 1990s. Penicillin resistance was reported in 26-76% of S pneumoniae isolates from pleural fluid.[10, 11]

Out of the 46 recognized pneumococcal serogroups, 10 are responsible for the most invasive diseases in children.[12] Serotype 1 is the dominant serotype in children with empyema.[13, 12, 14, 15]

Although a marked decrease has been noted in the incidence of invasive pneumococcal disease across all age groups since the introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) in 2000,[16, 17, 18] the empyema hospitalization rate has increased.[19] Of note, unlike the heptavalent pneumococcal conjugate vaccine, which does not include serotype 1, the current 13-valent pneumococcal conjugate vaccine that replaced the heptavalent pneumococcal conjugate vaccine in 2010 for routine vaccination of children, does include serotype 1.

In developing countries, Staphylococcus aureus is probably the most common infectious agent that causes empyema in children.[20] However, community-acquired methicillin-resistant S aureus that produces toxins (eg, Panton-Valentine leukocidin) is becoming an increasingly common pathogen in some centers in the United States.[20, 21, 22]

Haemophilus influenzae type B was the predominant etiologic organism for empyema in children in the 1980s.[23] Current published data show the near disappearance of H influenzae as a major pathogen in children.[4, 24] The decrease in complicated parapneumonic effusion caused by H influenzae is attributed to widespread immunization of infants.[5]

A wide range of less-common organisms are now recognized as causes of empyema in children. These include coagulase-negative staphylococcus, other streptococcal species (viridans streptococcus, Group A streptococcus, alpha-hemolytic streptococcus), Actinomyces species, and fungi.

Group A beta-hemolytic S pneumoniae with pleural effusion and streptococcal toxic shock syndrome has been described in association with varicella infections in children.[25]

Anaerobes, including Bacteroides and Fusobacterium species, have been found, particularly in empyema associated with aspiration pneumonia in neurologically impaired children.[26] Anaerobes have also been found in empyema associated with intraoral and subdiaphragmatic abscesses.[26]

Pneumocystis jiroveci (previously, P carinii) infection in children with acquired immunodeficiency syndrome (AIDS) can be associated with pleural effusion, with an incidence of about 5%.[5]

Pleural effusion occurs in 2-38% of all cases of pulmonary tuberculosis in children.[27] Tuberculous pleural effusions can be either primary or the result of reactivation disease. Primary tuberculous pleural effusion results from direct hematogenous invasion of the pleural space by Mycobacterium tuberculosis; it is usually unilateral and is often found in the absence of pulmonary parenchymal disease. Tuberculous pleural effusion due to reactivation disease is typically associated with focal parenchymal disease.[28] Tuberculous pleural effusion commonly occurs in adolescents and is uncommon in the preschool-aged child.[29]

Congestive heart disease

Congestive heart disease is a less-common cause of pleural effusion in children than it is in adults. It occurs primarily as a result of elevated left atrial or pulmonary capillary wedge pressure.[30] Effusions are usually bilateral and transudative.

Malignancy-related effusion

Lymphoma is the most common of all childhood malignancies that is associated with pleural effusion.[30] Other childhood malignancies, such as leukemia, neuroblastoma, chest wall sarcoma, Wilms tumor, and hepatoma, rarely cause pleural effusions.[30]

In malignancies, effusion can result from direct pleural invasion by the tumor, obstruction of the lymphatic pathway, or pneumonia or atelectasis that results from bronchial obstruction either by the tumor or by accompanying lymphadenopathy. The pleural effusion is usually unilateral and bloody or chylous in nature.

Chylothorax

Chylous effusion is a rare cause of pleural effusion in children, although it is the most common cause of pleural effusion in the first week of life.[31] Chylothorax may be congenital or acquired. It arises from the leakage of chyle into the pleural space as a result of damage to the thoracic duct by rupture, laceration, tear, or compression.[32] (See the images below.)

A higher incidence of chylothorax is seen in children with Down syndrome, Noonan syndrome, extralobar sequestration, diaphragmatic hernia, hydrops fetalis, and/or pulmonary hypoplasia.

Hemothorax

Hemothorax should be suspected if pleural fluid hematocrit is more than 50% of peripheral blood. It mostly occurs as a result of trauma. Other causes of hemothorax include malignancy, pulmonary infarction, rupture of pulmonary sequestration or arteriovenous malformation, spontaneous intrathoracic vessel rupture, and postpericardiotomy syndrome.

Other causes

Other causes of transudative effusions include hypoalbuminemia, nephrosis, hepatic cirrhosis, and iatrogenic causes (eg, a misplaced central line or a complication of ventriculopleural shunt).

Other, rare causes of pleural effusion include pancreatitis (effusions are usually hemorrhagic, unilateral and left sided), rupture of a pulmonary hydatid cyst into the pleural space, and Lemierre syndrome (postpharyngitis anaerobic sepsis with thrombophlebitis of the internal jugular vein).

Parapneumonic effusions and empyema are more common in boys than girls.[23] In addition, parapneumonic effusions and empyema are more commonly encountered in infants and young children than in older children. In a Spanish study, children younger than 5 years had a higher incidence of empyema than did children aged 5-17 years.[33]

Occurrence in the United States

Pleural effusion in children is usually a manifestation of an underlying disorder, and its prevalence mirrors that of the underlying disease. Empyema was reported in about 0.6-2% of children with bacterial pneumonia.[34, 35] The prevalence of pleural infections appears to be increasing in some industrialized countries. In the United States, the empyema-associated hospitalization rate increased 70% between 1997 (2.2 per 100,000) and 2006 (3.7 per 100,000 children).[36]

Byington et al reported that a significant increase in the incidence of empyema in children, from 1 case per 100,000 children to 14 cases per 100,000 children, occurred in Utah between 1993 and 2003.[37, 13]

International occurrence

Information on the incidence of pleural effusion in children is limited. As in the United States, infectious agents are the most common cause of pediatric pleural effusion internationally. The distribution of pleural effusion depends on the population studied.

In Spain, the incidence of parapneumonic effusion in children younger than age 5 years increased from 1.7 per 100,000 (in 1999) to 8.5 per 100,000 (in 2004).[38] In France, the incidence of empyema increased from 0.5 per 100,000 (in 1995) to 13 per 100,000 (in 2003).[39]

Transudative, chylous, and hemorrhagic pleural effusions respond to treatment of the underlying condition, and their prognosis is identical to that of the underlying cause. Viral and mycoplasmal effusions usually resolve spontaneously, while most patients recover well from parapneumonic effusion or empyema if appropriately treated.

Empyema has a complicated course if not treated and drained early, especially in children younger than 2 years. In a systemic review, Avansino et al reported a higher mortality rate for children treated with antibiotics and chest tubes (3.3%) compared with those treated with fibrinolytic therapy, video-assisted thoracoscopic surgery (VATS), or thoracotomy (0%).[40] The mortality rate is higher in children younger than age 2 years.[41]

Most tuberculosis effusions completely resolve with the use of proper antituberculous agents. Residual pleural thickening can occur in 50% of patients.[42]

A malignant cause worsens the prognosis for patients with pleural effusion, depending on the underlying tumor.

Empyema causes significant acute morbidity. However, death from empyema in previously healthy children in the industrialized world is uncommon. The mortality rate is higher for children younger than age 2 years.[41] In a series of 74 children with pneumococcal empyema, 5% died, 5.5% had hemolytic uremic syndrome, 38% had bacteremia, and 51% were admitted to intensive care.[43]

The clinical picture and presenting symptoms of pleural effusion depend on the underlying disease and the size and location of the effusion.

Symptoms linked to the underlying disease

Children with effusion as a complication of pneumonia (parapneumonic effusion or empyema) often have a history of recent upper respiratory tract infection, bronchitis, or pneumonia. These children usually present with the following symptoms:

• Persistent fever

• Cough

• Anorexia

• Malaise

• Tachypnea

• Dyspnea

• Chest pain

Children with tuberculous pleural effusions may present with the following symptoms[44] :

• Cough

• Pleuritic chest pain

• Dyspnea

• Night sweats

• Fever

• Hemoptysis

• Weight loss

Malignant effusions may be more indolent and cause either no symptoms or only cough and low-grade fever.[5] Pleural effusion due to a malignant lymphoma may present with respiratory distress, because of the size of the effusion, the mediastinal mass, or both.[45]

In transudative effusions (congestive heart failure, nephrotic syndrome), the underlying disease usually determines the presenting symptoms. Occasionally the child may be asymptomatic until the accumulation becomes large enough to cause symptoms.[35]

Although effusion occurs in association with systemic lupus erythematosus and other autoimmune diseases, it is rarely the initial manifestation.

Symptoms related to the size and location of the pleural effusion

An accumulation of a small amount of fluid may be asymptomatic. A large collection of fluid leads to dyspnea, respiratory distress, dull pain, and coughing. These symptoms may vary with an alteration in body position.

Subpulmonic fluid collection can be associated with vomiting, abdominal pain, and abdominal distention caused by partial paralytic ileus.

Chest pain

Chest pain is pleuritic in origin. Patients with an exudative effusion are more likely to have pain than are patients with a transudative effusion. The pain can be localized or referred to the shoulder and abdomen. It is typically described as sharp or stabbing and worsens with inspiration. The pain intensity lessens as the effusion increases in size; as the effusion increases, it separates the pleural membranes, and the pain becomes dull or disappears.

The patient may look dyspneic and anxious because of pain, discomfort, or hypoxemia. A pleural rub may be the only initial manifestation during the early stage of pleurisy. The rub disappears as fluid accumulates between the pleural surfaces.

A large fluid collection causes fullness of the intercostal spaces and diminished chest excursion on the affected side. Excessive unilateral fluid accumulation shifts the mediastinum and displaces the trachea and cardiac apex to the contralateral side.

Dullness to percussion, decreased air entry, decreased tactile and vocal fremitus, and voice egophony over the effusion may be present but difficult to detect in younger children.

Tests may need to be ordered to rule out immune dysfunction or other underlying systemic or local pulmonary disorders that cause empyema.

Analysis of the pleural fluid is the single best method to determine the cause of a pleural effusion. Thoracentesis should be performed when sufficient fluid is present to allow a safe procedure, except when the suspected effusion is clearly secondary to a specific underlying disease (for example, congestive heart failure, nephrotic syndrome, ascites, or recent initiation of peritoneal dialysis).[30]

Simple observation of the gross appearance of the fluid may provide a clue as to the cause of the pleural effusion, as follows:

• Grossly purulent fluid indicates an empyema

• A putrid odor suggests an anaerobic empyema

• Clear, pale yellow fluid suggests a transudate

• Milky fluid is consistent with a chylothorax

• Bloody pleural fluid is seen with trauma, malignancy, tuberculosis, uremia, and empyema due to group A Streptococcus

• Aspergillus nigrans infection produces a black pleural fluid

In the appropriate clinical setting, measurement of pleural fluid triglyceride levels (chylous effusion), amylase (pancreatitis, esophageal rupture), and pleural fluid hematocrit (hemothorax) may be useful.

A complete blood count (CBC) with differential, blood cultures, and C-reactive protein (CRP) may help to establish the presence of infection. The white blood cell (WBC) count and CRP may be useful in monitoring treatment progress in infectious effusions. A positive blood culture finding may facilitate the selection of antibiotics in sterile empyema. (Approximately 10-22% of children with complicated parapneumonic effusions have a positive blood culture result.)[37, 46]

Measurement of titers may be helpful if specific organisms, such as Mycoplasma species, Legionella species, or adenovirus, are suspected. However, the use of these tests in early management of parapneumonic effusions is limited due to the need for convalescent titer.

If risk factors for tuberculosis are present, sputum (or gastric aspirates) for acid fast bacilli and a purified protein derivative (PPD) test should be performed.

Serum protein, LDH, amylase, glucose, and hydrogen ion concentration (pH) may be helpful in interpreting results of pleural fluid analysis. If chylous effusion is suspected, serum cholesterol and triglyceride levels should be obtained.

Conventionally, the initial evaluation of pleural fluid is directed at determining whether the effusion is an exudate or a transudate. The classification is based on simple biochemical criteria first proposed by Light et al.[47] However, the Light criteria was developed and tested in adults, and its accuracy in children has been questioned.[6]

According to the Light criteria, the pleural fluid is defined as an exudate if it fulfils at least one of 3 criteria. If none of the criteria are met, then the fluid is considered a transudate. The criteria are as follows:

• Pleural fluid–to–serum lactate dehydrogenase (LDH) ratio of more than 0.6

• Pleural fluid–to–serum protein ratio of more than 0.5

• Pleural fluid LDH level of two thirds the upper limit of the reference range

In general, exudates have protein concentration higher than 2.9 g/dL, with the pleural fluid cholesterol level more than 45 mg/dL.[48]

Biochemical analysis of the pleural fluid provides further information that may be useful in narrowing the differential diagnosis of exudative effusion, as follows:

• Low pleural glucose level (< 60 mg/dL) or pleural fluid–to–serum glucose ratio of less than 0.5 - Seen in several conditions, such as parapneumonic effusion, tuberculosis, malignancy, esophageal rupture, and rheumatoid effusions[49]

• LDH levels of more than 1000 IU/L - Found in empyema[50] and rheumatoid effusions[51]

• Pleural fluid–to–serum LDH ratio of 1 and pleural fluid–to–serum protein ratio less than 0.5 -Suggest effusion due to P jiroveci pneumonia[52]

• Pleural fluid pH below 7.3 (with normal arterial pH) - Seen in parapneumonic effusion, tuberculosis, malignancy, esophageal rupture, systemic acidosis, urinothorax, and rheumatoid effusions;[49] most exudative effusions have a pH of 7.3-7.45, whereas transudates have a pleural fluid pH ranging from 7.4-7.55[49] (the pH of normal pleural fluid is about 7.6)[53]

Pleural fluid cell count, although routinely performed, is not particularly helpful in establishing any of the diagnoses likely to occur in children. However, in certain settings, the predominant cell type may be helpful in determining etiology. Polymorphonuclear cells tend to predominate in recent effusions, and lymphocytes in long-standing ones.

• Neutrophilic predominance - Bacterial etiology, pancreatitis (fluid, often hemorrhagic), esophageal rupture (very low pH), and the early stages of pleural tuberculosis[54]

• Lymphocytic predominance (85-95% of total nucleated cells) - Tuberculosis, malignancy, uremia, connective tissue disease, and mycotic infections[55]

• Monocytic effusion - Viral and mycoplasma pneumonia[30]

• Eosinophilic effusion (>10% eosinophils) - Reactive eosinophilic pleuritis (recent pneumothorax or blood in pleural space), drugs (eg, dantrolene and nitrofurantoin), uremia, fungal and parasitic infections[56, 57]

Microbiologic analysis of the pleural fluid should be obtained from patients with undiagnosed exudative pleural effusion. Such analysis includes the following:

• Gram, acid-fast bacilli, and fungal (KOH) staining

• Culture for bacteria (both aerobic and anaerobic), mycobacteria, and fungi

• Direct and enrichment culture for aerobic and anaerobic organisms - In addition send some pleural fluid in anaerobic blood culture bottle[58]

The yield of microbiologic diagnosis in children may be increased by the use of adjunct techniques to detect bacterial antigens. These include counterimmunoelectrophoresis, latex agglutination, specific (eg, pneumolysin) polymerase chain reaction (PCR) assay, and broad range (eg, 16S rDNA) PCR assay.[7, 8, 59] These tests may be particularly useful in patients who have received antibiotics prior to thoracentesis.

Tuberculous pleuritis

The pleural fluid adenosine deaminase and interferon-γ levels are elevated in almost all patients with tuberculous pleuritis. Measurement of adenosine deaminase or interferon-γ may be used to establish the diagnosis.[60] However, no universally accepted cutoff point is noted for either of these parameters.

In a meta-analysis, a maximum joint sensitivity and specificity of 93% for adenosine deaminase and 96% for interferon-γ was noted.[61] The specificity of this parameter may be higher when used in conjunction with a lymphocyte-to-neutrophil ratio in pleural fluid of 0.75 or greater.[62]

Molecular techniques, such as PCR assay to detect specific mycobacterial deoxyribonucleic acid (DNA) in pleural fluid, are now available for diagnosis of tuberculous pleuritis.[63] Although PCR assay tests have a great potential for providing a rapid and specific diagnosis of mycobacterial infection, they are limited by low sensitivity.[46]

Malignant pleuritis

Cytology can be performed if a malignancy is suspected. However, negative cytology does not rule out malignancy.[64] In a retrospective study, Chaignaud et al found that cytologic examination and immunotyping of cells in pleural fluid were diagnostic in 71% of children with lymphoblastic lymphoma, obviating general anesthesia and open biopsy of the mediastinal masses.[64]

A chest radiograph, while nonspecific, is the simplest and least expensive method of identifying a pleural effusion.[30] A chest radiograph may also reveal underlying pneumonia before pleural fluid starts accumulating. (See the image below.)

Frontal, lateral, and decubitus radiographs may be used to detect a pleural effusion. In general, free-flowing pleural fluid collects in the most dependent part of the pleural space on an upright chest radiograph, usually the posterior costophrenic recess and, less often, the lateral recess.[65] Blunting of the costophrenic recess is the earliest sign of pleural fluid accumulation. (See the images below.)

As effusions increase in size, they produce a characteristic meniscus sign as the fluid tracks superiorly along the pleural surface.[66] Large effusions result in opacification of the hemithorax, with mediastinal shift (see the image below). Absence of shift is suggestive of underlying lobar collapse.

In adults, approximately 50 mL of fluid causes blunting of the posterior costophrenic recess on a lateral chest radiograph. By contrast, at least 200 mL is necessary to blunt the lateral recess on an upright chest radiograph.[67] A lateral decubitus film is the most sensitive view and can detect as little as 5-10 mL of free fluid.[68] A lateral decubitus film obtained with the affected side down provides valuable information about the quantity and quality of effusion.

A fluid layer of more than 1 cm on decubitus film is amenable to thoracentesis. Nonshifting fluid suggests either thick fluid or loculation. A lateral decubitus image obtained with the affected side up may facilitate the evaluation of the underlying lung for atelectasis or infiltrates.

Pleural ultrasonography permits easy characterization of pleural effusion. In experienced hands, it is superior to standard upright chest radiography and supine chest radiography for detecting pleural effusion.[69]

Ultrasonography can easily distinguish between free and loculated pleural effusion (see the images below) and allow pleural fluid to be differentiated from pleural thickening and solid masses. Ultrasonography may also facilitate the identification of the best site for thoracentesis or insertion of a thoracotomy tube.[70, 71] The main limitation of ultrasonography is that its usefulness depends on the examiner’s skill.

Pleural fluid can easily be identified on computed tomography (CT) scans. However, CT scan findings lack the accuracy required for the differentiation of exudates from transudates and chylothorax[72, 73, 74] and for accurately predicting the presence of empyema in patients with parapneumonic effusion.[75] Although CT scanning detects more parenchymal abnormalities than chest radiography does, studies found that the additional information obtained does not seem to alter management decisions or help to predict clinical outcomes. (See the image below.)[76, 77]

CT scanning is increasingly used as the study of choice in empyema; it may provide additional information in complicated cases.[78] In addition, CT scan guidance may also be useful in interventions in which effusions are difficult to access.[35] However, the modality is comparatively expensive, invasive, and time consuming. The omission of routine CT scanning in empyema reduces the exposure of children to unneeded radiation and cuts costs.[76]

Pleural evaluation is greatly aided by the use of intravenous contrast, as the unenhanced pleura cannot normally be visualized.[79]

Thoracentesis

Thoracentesis is recommended for most pleural effusions of sufficient size whenever the cause of the effusion is uncertain.

Thoracentesis should not be performed if the diagnosis is thought to be certain and the likelihood of empyema or malignancy is low. Such circumstances include small, bilateral infiltrates in congestive heart failure or nephrosis or a small parapneumonic effusion in an afebrile child recovering from pneumonia.

Thoracentesis should be performed in patients whose respiratory status is compromised by pleural effusion, in patients with empyema or malignancy, or in newborns.

Pleural biopsy

This may be needed in cases of unexplained inflammatory effusion, suspected tuberculosis, or malignancy. The two major complications of pleural biopsy are bleeding and pneumothorax.

Bronchoscopy

Routine flexible bronchoscopy is not indicated in children with pleural effusion. Aspiration of a foreign body in younger children is a possibility and is an indication for bronchoscopy.

Noninflammatory pleural effusions (such as transudates) are managed by treating the underlying cause and by supportive care of any functional disturbances. Treatment of tuberculous pleural effusion (TPE) is similar to that of pulmonary tuberculosis.

Treatment goals in empyema include sterilization of pleural fluid, reexpansion of the lung, and restoration of normal lung function. Prospective studies in pediatric empyema are lacking. Hence, the management of empyema in children remains controversial; given the limited evidence, no consensus has been reached on the role of medical versus surgical management.[20]

Parapneumonic effusion usually progresses through different stages over time, including exudative, fibrinopurulent, and organizational stages.[20] Therefore, different management strategies may be appropriate at different stages.

Currently available treatment options for pediatric parapneumonic effusion and empyema include antibiotics alone or in combination with thoracocentesis, chest tube drainage with or without instillation of fibrinolytic agents, and surgery (video-assisted thoracoscopic surgery or open thoracotomy with decortication). In practice, the care that a child with empyema receives depends on local practice, which is largely determined by the availability of medical personnel and their preferences.[80]

Consultations

Consultations may include the following:

• Pediatric pulmonologist

• Pediatric surgeon

• Interventional radiologist

• Pediatric infectious disease specialist

• Intensivist

In the earlier stages of parapneumonic effusion formation (mild symptoms, short duration), institution of appropriate empiric antibiotics, based on the patient's age and the organisms and sensitivities commonly present in the community, may discourage a small effusion from developing into a complicated parapneumonic effusion. Whenever possible, a pleural fluid sampling should be performed prior to the initiation of antibiotics.

If a causative organism is identified, antibiotic choice should be guided by the sensitivity pattern of the organism.

Some groups of antibiotics (eg, penicillins, cephalosporins, aztreonam, clindamycin, and ciprofloxacin)[81, 82] exhibit more satisfactory pleural fluid penetration than others (eg, aminoglycosides).[82, 83]

In a hospitalized patient with complicated parapneumonic effusion, antibiotics are commonly administered intravenously while a thoracostomy tube is present and the patient is febrile. No data from randomized trials on an appropriate length of treatment are available, and no data on whether different organisms require different durations are noted.[20] Many centers continue with intravenous antibiotics at least 48 hours after the patient is afebrile and the chest drain is removed. Thereafter, oral antibiotics are commonly continued for 2-4 weeks.

A study by Tagarro et al that included 60 randomized children with community-acquired pneumonia and pleural effusion reported that patients receiving dexamethasone along with antibiotics had a shorter time to recovery than the placebo group.[84]

Effusions that are enlarging or compromising respiratory function in a febrile, unwell child require drainage.[20] Other risk predictors indicating the need for chest tube placement include frank pus on thoracentesis, a positive pleural fluid Gram stain and culture finding, a pleural fluid pH level of less than 7, a glucose concentration of less than 40 mg/dL, or an LDH level of more than 1000 IU.

Controversy still remains about the optimum chest tube size. Although small-bore tubes (eg, pigtail catheters) are commonly used for free-flowing fluid and large-bore tubes are commonly employed for thick pus, good-quality data that can be used to recommend one size of chest tube over another are lacking. In the absence of evidence that large-bore chest drains confer any advantage, the British Thoracic Society (BTS) guidelines recommend using small-bore chest tubes (including pigtail catheters) whenever possible to minimize patient discomfort.[20] When combined with fibrinolytic therapy, the use of small chest tubes was found to have some advantages over large tubes.[85]

The timing of elective removal of the drain depends on numerous factors, including the amount of fluid draining, the child’s overall clinical condition, the presence of fever, and the radiographic and ultrasonographic appearance of the chest, as well as a fall in acute phase reactants.[20] In most cases, the chest tube may be removed when the pleural drainage becomes minimal (< 10-15 ml/24 h) and the fluid is clear or yellow.[35]

A study by Gilbert et al aimed to review outcomes in patients with hematologic malignancy undergoing indwelling tunneled pleural catheter (IPC) placement. The study reported that IPC placement appears to remain a reasonable clinical option for patients with recurrent pleural effusions related to hematologic malignancy.[86]

As the effusion becomes fibrinopurulent and subsequently organizes, chest tubes often become ineffective because fibrinous strands and loculations divide the pleural space into compartments. Fibrinolytics instilled into the pleural cavity may facilitate drainage by lysing fibrinous strands and clearing lymphatic pores.

Three fibrinolytic agents have been used: streptokinase, urokinase, and alteplase (or tissue plasminogen activator). Urokinase is no longer available in North America.

In a large double-blind study in adults, Maskell et al reported that use of intrapleural streptokinase did not improve mortality, the rate of surgery, or the length of the hospital stay.[87]

However, numerous published case series have detailed the use of fibrinolytics in children.[88, 89, 90, 91] All indicate improved pleural drainage with these agents and an overall success rate of 80-90% without the need for surgical intervention. Three randomized placebo control trials have been performed in children.

In a multicenter, double-blind, randomized study in children on the use of fibrinolytics for empyema, Thompson and colleagues reported that urokinase resulted in a modest decrease in length of stay (7.39 d vs 9.49 d) and lower treatment failure. The study involved 60 children who were administered either intrapleural urokinase or saline.[85]

In a second study, in which 60 children were randomized to receive either percutaneous chest drain with intrapleural urokinase or video-assisted thoracoscopic surgery (VATS), the authors concluded that urokinase treatment is the better economic option and should be the primary treatment of choice. Treatment costs were significantly lower ($9127 vs $11,379) in the urokinase group than in the VATS patients, while no difference in clinical outcome between the 2 groups was noted.[92] The median duration of hospital stay was 6 days for both groups, with a range of 4-25 days for the urokinase group and 3-16 days for the patients treated with VATS.

In a prospective, randomized trial, St. Peter and colleagues concluded that fibrinolysis should be the first modality selected in children with empyema and that rescue can be done with VATS if necessary. In the study, VATS with decortication was compared with chest tube insertion and administration of tissue plasminogen activator. Eighteen children with empyema were in each group.[93]

The investigators found no difference between the groups with regard to days of hospitalization after intervention, days of oxygen required, days until the children were afebrile, or analgesic requirements. VATS was associated with significantly higher charges. The failure rate for fibrinolysis was 16.6%.

Adverse effects of fibrinolytic agents are usually minor and include discomfort during intrapleural injection, transient blood staining of the drainage fluid, fever, and, rarely, massive bleeding.[20] Rare immediate hypersensitivity reactions have been reported in adults after intrapleural urokinase. Streptokinase that is administered intrapleurally generates a systemic antibody response similar to that found when the drug is given systemically.[94]

Fibrinolytics should not be used in patients with bronchopleural fistula or bubbling chest tube (suggestive of an air leak).

Whether surgery should be the initial treatment of choice or should be reserved for failed medical management is not definitively known. Historically, children with empyema and parapneumonic effusion who failed to improve with antibiotic therapy (with or without drainage) subsequently underwent operative management. Other indications for surgery include persistent sepsis in association with a persistent pleural collection (despite antibiotics, chest tube drainage, and fibrinolytics), complex empyema with significant lung pathology (eg, delayed presentation with a significant peel and trapped lung), and bronchopleural fistula with pyopneumothorax.[20]

Three surgical options are noted for management of children with parapneumonic effusion and empyema:

• VATS

• Minithoracotomy

• Open thoracotomy with decortication.

VATS

VATS has emerged as the preferred procedure to treat empyema in children and is being increasingly used as primary therapy. VATS is much less invasive than open thoracotomy and is associated with a more favorable outcome.

In a nonrandomized study, VATS use (compared with open thoracotomy with decortication) was associated with shorter duration of analgesia use, postoperative length of hospital stay, time to normothermia, and number of chest tube days.[95]

In a small, prospective, randomized trial, early VATS use (compared with conventional thoracostomy drainage) was associated with few complications and short hospital stays (approximately 7 d).[96]

In a retrospective, 10-year study, Padman et al reported their experience and clinical course of 109 children; 50 patients had VATS, and 59 did not.[97] The use of VATS within 48 hours of admission lead to significant reduction of hospital stay (by 4 days), compared with delayed use of VATS after 48 hours of admission.

A review of 49 pediatric patients with pneumonia complicated by parapneumonic effusion or empyema suggested that patients treated by primary VATS had shorter stay and hospital charges than patient treated by chest tube and antibiotics alone.[98]

Several authors have reported that early VATS is safe and effective and that it shortens hospital stay in the management of empyema in children and adults.[99, 100, 101] However, two prospective studies (mentioned above) comparing early VATS with chest tube and instillation of fibrinolytics[92, 93] suggested that therapy with a chest tube and instillation of fibrinolytics may be more cost effective, may pose less risk of acute clinical deterioration, and should be the first-line therapy for children with empyema.

Mini-thoracotomy

Mini-thoracotomy achieves debridement and evacuation in a similar manner to VATS but is an open procedure.[20]

Decortication

Decortication is a major thoracic operation requiring full thoracotomy. It involves an open, posterolateral thoracotomy and removal of all the fibrous tissue from the visceral pleural peel, with all pus being evacuated from the pleural space. It is rarely needed in children with empyema. The BTS guidelines suggest that decortication should be reserved for children with organized empyema, in which a thick, fibrous peel is restricting lung expansion and causing chronic sepsis with fever.[20] [stopped]

Diet

A dietitian should be consulted early in patients with chylothorax and in those with complicated pleural effusion and empyema, for whom the course may be prolonged.

Chylothorax may respond to a diet with fat supplied as medium-chain triglycerides (MCTs), with a resolution of the chylous effusion at the end of 2 weeks. MCT oil is absorbed directly into the portal circulation and does not contribute to chylomicron formation. Its use may decrease lymph flow by as much as 10-fold. If chylothorax persists, a trial of intravenous (IV) alimentation for 4-5 weeks may be considered.

Children with complicated pleural effusion and empyema may have clinically significant anorexia and increased needs. High-calorie, high-protein foods that appeal to the child should be provided early, and nasogastric feeds should be considered early, particularly in young children.

Activity

Pain and chest-tube placement may limit the patient's motility. Analgesia can facilitate cough and clearance of the airway, especially in the presence of an underlying pneumonic process.

For transudative effusions, further outpatient therapy is directed at the underlying etiology of the pleural effusion.

Children with parapneumonic effusion or empyema should be seen for follow up within 4–6 weeks of discharge; the timing depends on the child’s clinical status at discharge.[20] Chest radiography findings are inevitably abnormal at discharge, and a radiograph should be obtained at 4-6 weeks.[20] Complete radiological resolution is usually expected by 3-6 months.[102, 103]

The treatment of a transudative, chylous, or hemorrhagic pleural effusion involves treatment of the underlying process. Antibiotics are administered for parapneumonic effusions caused by aerobic and anaerobic organisms. Specific agents should be based on the patient's age and the types of organisms and sensitivities common in the community. Therefore, the list of antibiotics below is only a guide. More than 1 agent may be used for synergy and for polymicrobial infections. Antibiotics may be changed if the organisms and their sensitivities are identified.

Initially, administer antibiotics intravenously while a thoracostomy tube is present until some time after the child is afebrile and improving clinically; then, the IV drugs can be switched to oral medications for 2-4 weeks. Empyema usually requires prolonged antimicrobial therapy.

Antituberculous drugs for tuberculosis-associated effusion should be administered for 6-9 months. Chemotherapeutic agents are used for malignancy. Steroids are indicated for connective-tissue disorders and may be useful for tuberculosis effusion. Fibrinolytic drugs are used to lyse fibrinous strands in loculated empyemas.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Nafcillin

Nafcillin is a broad-spectrum penicillin. It is used for methicillin-sensitive S aureus and is the initial therapy for suspected penicillin G–resistant streptococcal or staphylococcal infections. In severe infections, start with parenteral therapy, and change to oral therapy as the condition warrants. Because of thrombophlebitis, particularly in elderly persons, administer parenterally for only 1-2 days; change to oral therapy as indicated clinically.

Oxacillin

Oxacillin is a bactericidal antibiotic that inhibits cell-wall synthesis. It is used to treat infections caused by penicillinase-producing staphylococci. Oxacillin may be used to start therapy when a staphylococcal infection is suspected.

Vancomycin (Vancocin)

Vancomycin can be used for methicillin-resistant S aureus and for S pneumoniae. It is a potent antibiotic against gram-positive organisms and is active against Enterococcus species. Vancomycin is indicated for patients who cannot receive or whose conditions fail to respond to penicillins and cephalosporins or those with infections with resistant staphylococci. To avoid toxicity, the current recommendation is to assay vancomycin trough levels 30 minutes before the fourth dose. Use creatinine clearance (CrCl) to adjust the dose in renal impairment.

Penicillin G aqueous (Pfizerpen)

Penicillin G is used to treat S pneumoniae infection and anaerobic bacteria. It interferes with synthesis of cell-wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.

Cefotaxime (Claforan)

Cefotaxime is a third-generation cephalosporin. It can be used for S pneumoniae or H influenzae infection. Cefotaxime arrests bacterial cell-wall synthesis, inhibiting bacterial growth.

Ceftriaxone (Rocephin)

Ceftriaxone is a third-generation cephalosporin; it can be used for S pneumoniae or H influenzae infection. Ceftriaxone arrests bacterial growth by binding to 1 or more penicillin-binding proteins.

Clindamycin (Cleocin, Cleocin Pediatric, ClindaMax Vaginal)

Clindamycin can be used for S pneumoniae infection and anaerobes and as alternative drug for methicillin-resistant S aureus. It is also effective against aerobic and anaerobic streptococci (except enterococci). Clindamycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl transfer ribonucleic acid (tRNA) from ribosomes, causing RNA-dependent protein synthesis to arrest.

Linezolid (Zyvox)

Linezolid prevents the formation of a functional 70S initiation complex, which is essential for the bacterial translation process. It is bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci. Linezolid is used as an alternative in patients who are allergic to vancomycin and for the treatment of vancomycin-resistant enterococci.

Class Summary

These agents are used for the treatment of drug-susceptible tuberculosis infection. Recommendations include 6-9 months of therapy. The 6-month regimen includes either 2 months of isoniazid (INH), rifampin, and pyrazinamide once per day, followed by 4 months of INH and rifampin daily, or 2 months of INH, rifampin, and pyrazinamide daily, followed by 4 months of INH and rifampin twice weekly under directly observed therapy (DOT).

For drug-resistant tuberculosis, initial treatment should include 4 drugs until susceptibility is determined. Therapy should last 12-18 months.

Isoniazid

Isoniazid offers the best combination of effectiveness, low cost, and minor adverse effects. It is a first-line drug unless resistance or another contraindication is known. Therapeutic regimens of less than 6 months have an unacceptably high relapse rate. Coadministration of pyridoxine is recommended if peripheral neuropathies secondary to INH therapy develop. Prophylactic doses of 6-50 mg/d are recommended.

Rifampin (Rifadin)

Rifampin is for use in combination with at least 1 other anti-tuberculosis drug. It inhibits RNA synthesis in bacteria by binding to the beta subunit of DNA-dependent RNA polymerase, which in turn blocks RNA transcription. Cross-resistance may occur. Treat the patient for 6-9 months or until 6 months have elapsed from conversion to negative sputum cultures.

Pyrazinamide

This is a pyrazine analog of nicotinamide that may be bacteriostatic or bactericidal against M tuberculosis, depending on the concentration of drug attained at the site of infection. The mechanism of action is unknown. In drug-susceptible patients, administer pyrazinamide for the initial 2 months of a regimen lasting 6 months or longer. Treat drug-resistant cases with individualized regimens.

Streptomycin

Streptomycin is administered for the treatment of susceptible mycobacterial infections. It is used in combination with other anti-tuberculosis drugs (eg, INH, ethambutol, rifampin).

Class Summary

Fibrinolytic drugs may lyse the fibrinous strands in loculated empyemas and thereby clear the lymphatic pores and restore pleural fluid circulation.[104, 105]

Alteplase (Activase, Cathflo Activase, TPA)

Tissue plasminogen activator binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin, thereby initiating local fibrinolysis. Alteplase's serum half-life is 4-6 minutes, but the half-life is lengthened when alteplase is bound to fibrin in a clot. Circulating plasma levels are not expected to reach pharmacologic concentrations after intrapleural administration.