Parapneumonic empyema in children: a scoping review of the literature

Abstract

Community-acquired pneumonia can lead to a serious complication called empyema, which refers to pus within the pleural space. While it poses a significant threat to morbidity, particularly in children, it is fortunately not associated with high mortality rates. However, determining the best course of management for children, including decisions regarding antibiotic selection, administration methods, and treatment duration, remains a topic of ongoing debate. This scoping review aims to map the existing literature on empyema in children, including types of studies, microbiology, therapies (both antimicrobial and surgical) and patient outcomes. We systematically searched PubMed and SCOPUS using the terms “pediatric” (encompassing children aged 0 to 18 years) and “pleural empyema” to identify all relevant studies published since 2000. This search adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA ScR) checklist.

A total of 127 studies was included. Overall, 15 attempted to compare medical treatments (alone or in combination with pleural drainage or fibrinolysis) with more invasive surgical approaches, and six studies compared diverse surgical interventions. However, the diversity of study designs makes it difficult to derive firm conclusions on the optimal approach to pediatric empyema. The heterogeneity in inclusion criteria, pharmacological/surgical approaches and settings limit the ability to draw definitive conclusions. Overall, 78 out of 10,896 children (0.7%) included in the review died, with mortality being higher in Asia and Africa. Our scoping review highlights important gaps regarding several aspects of empyema in children, including specific serotypes of the most common bacteria involved in the etiology, the optimal pharmacological and surgical approach, and the potential benefits of newer antibiotics with optimal lung penetration. New trials, designed on a multi-country level a higher number of patients and more rigorous inclusion criteria and designs, should be urgently funded.

Introduction

Parapneumonic empyema, characterized by pus accumulation on the pleura, is a common local complication of childhood community-acquired pneumonia (CAP) [1,2,3,4,5]. While estimates suggest parapneumonic effusions develop in approximately 1 in every 100 to 150 children with CAP [6, 7], hospitalized children with CAP may have a prevalence as high as 40% [8].

The primary causative agent of CAP is predominantly Streptococcus pneumoniae, and its incidence has demonstrated fluctuations over time [9]. Notably, there has been a significant global decrease in pneumococcal disease and mortality rates following the introduction of the heptavalent pneumococcal conjugate vaccine (PCV7), which targets serotypes 4, 6B, 9 V, 14, 18 C, 19 F, and 23 F, into routine childhood immunization schedules [10]. However, in subsequent years, the USA observed an uptick in pneumococcal empyema cases associated with serotypes not covered by PCV7 [11]. Following the transition from PCV7 to PCV13, which additionally includes pneumococcal serotypes 1, 3, 5, 6 A, 7 F, and 19 A, there has been a noteworthy reduction in the incidence and hospitalization rates related to empyema [12]. This shift to PCV13 is particularly significant given the strong correlation between parapneumonic empyema and pneumococcal serotype 1 [13]. Although other bacteria, such as group A Streptococcus and Staphylococcus aureus, are less commonly linked with CAP, they are potential bacterial pathogens associated with parapneumonic empyema [13].

The clinical manifestation of parapneumonic empyema closely resembles that of uncomplicated CAP [9, 13]. Suspecting empyema is prudent in children experiencing prolonged fever (lasting 7 days or more) or those showing no improvement after 48–72 h of appropriate antibiotic therapy. Physical examination typically reveals reduced air entry and dullness to percussion [9]. Chest X-ray and/or pulmonary ultrasound are used to confirm suspected parapneumonic empyema. Ultrasound is particularly valuable due to its higher sensitivity compared to X-ray in assessing fluid collection extension and nature; additionally, it avoids radiation exposure for children. While thoracic computed tomography (CT) isn’t a first-line diagnostic tool for empyema, it may be warranted when diagnosis is unclear or malignancies are suspected, such as Burkitt’s lymphoma.

Treatment for parapneumonic empyema always includes empiric intravenous broad-spectrum antibiotic therapy targeting common bacteria like Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus [5, 14]. In cases of significant effusion (> 2 cm) or respiratory compromise, chest drainage is recommended [14]. Ultrasound-guided chest drainage is standard, often performed with children under sedation or general anesthesia. Intrapleural fibrinolytics, like urokinase, can expedite hospital discharge for cases with slow drainage or thick, loculated fluid [5, 14]. Thoracic surgery should be considered in cases of antibiotic therapy failure, ineffective chest drainage, or inadequate response to fibrinolytics. However, current guidelines lack clear recommendations on the ideal surgical procedure, timing of intervention, duration of drainage and antibiotic therapy, transition to oral antibiotics, and how these factors influence outcomes. This scoping review aims to comprehensively outline the literature on study types, microbiology, therapeutic interventions (both antimicrobial and surgical), and outcomes of empyema in children since 2000.

Methods

Review questions

To address the lack of consensus on optimal treatment for pediatric parapneumonic empyema literature [15], this review primary focus will be to examine the existing literature on antibiotic and surgical interventions about pediatric empyema. This will include investigating the selection of first-line agents, appropriate dosages, routes of administration, and treatment durations. Furthermore, this review will address the following sub-questions:

• 1. What are the most commonly identified pathogens reported in literature?

• 2. What are the predominant outcomes and complication rates associated with empyema, as reported in the literature?

• 3. Which conservative or invasive treatments are most frequently reported, and which demonstrate improvements in outcomes and reduced length of stay?

The protocol for this review has been published prospectively and can be accessed at https://osf.io/9wkma/.

Inclusion criteria

This review encompasses studies involving children and adolescents (under 18 years old) who have received a confirmed diagnosis of empyema, defined by the presence of pus within the pleural cavity. Diagnosis of empyema is established through the identification of pus, positive Gram’s stain, culture, or nucleic-acid amplification tests in the pleural fluid. Only studies explicitly mentioning the performance of microbiological investigations, administration of antimicrobial and surgical treatments, as well as outcomes (at least until discharge), have been included.

The primary focus of this review is to comprehensively examine all aspects of empyema, with particular attention given to treatment options. Due to the severity of the condition, articles involving non-hospitalized patients were not anticipated, thus only inpatient studies have been considered.

To capture a broad range of evidence, this review includes randomized controlled trials, non-randomized controlled trials and all observational studies, (prospective and retrospective, including case-control, cohort, and cross-sectional studies, as well as small case series or single case reports).

Search strategy

The search was conducted by one reviewer. It began in April 2023, using the bibliographic databases PubMed and SCOPUS. We limited our search to English-language articles published between January 1, 2000, to March 31, 2023. The search strategy incorporated a combination of keywords and their synonyms, including “pediatric,” “empyema,” and “treatment.” The PubMed search strategy is accessible in the supplementary data section of this protocol; the terms used in this search were adjusted for use with other bibliographic databases.

Following the search, studies were exported to Rayyan. Initially, one author screened for duplicates. Subsequently, titles and/or abstracts of retrieved studies were independently screened by two reviewers to identify potentially relevant studies for inclusion in the review. Full texts of potentially eligible studies were then retrieved and independently assessed for eligibility by two reviewers. Each researcher was blinded to the decision of the other. Any discrepancies regarding study eligibility were resolved through discussion and, if necessary, consultation with a third reviewer.

Studies failing to meet the inclusion criteria were excluded, and a table detailing the reasons for exclusion was included in the final manuscript. The results of the search were reported using the PRISMA flow diagram.

Data extraction was performed independently by two review authors, each using a separate Excel spreadsheet. Each researcher remained blinded to the other’s decisions. In cases of discordance, disagreements were identified and resolved through discussion (with involvement of a third author if needed).

An Excel file was utilized to store extracted data, which included the following when available:

• 1. Study details: title, author, year of publication, study type, number of patients, geographic location.

• 2. Participant characteristics: sample size, nationality, age, socio-economic status, comorbidities.

• 3. Clinical manifestations: fever duration, cough with mucus, dyspnea, chest pain, and others.

• 4. Imaging findings: lung involvement type on chest X-rays, lung ultrasound (US), CT scans, or MRI.

• 5. Details of antimicrobial treatments administered during empyema (e.g., duration, antibiotics used).

• 6. Adjunctive treatments and their durations during empyema (e.g., steroids, other immunomodulatory medications).

• 7. Surgical interventions and their durations during empyema (e.g., drainage, thoracoscopy, surgical resection).

• 8. Outcomes (e.g., death, survival, survival with sequelae, type of sequelae).

Data analysis and presentation

To present our findings, we adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist, as detailed in the supplementary material. A narrative synthesis was conducted to summarize the results obtained from the studies included in the review, providing our interpretation of the findings. Special attention was given to antimicrobial and surgical therapies, with a focus on the frequency of antibiotic selection, efficacy, and treatment duration. more than 100 records were included after the initial selection process, preference was given to original articles and those published within the last 5 years.

Tables and charts were employed to concisely summarize both the characteristics of included studies and essential clinical, diagnostic, treatment, and outcome data. Various tables and figures were compiled to outline the types of studies and their primary findings, covering microbiology, therapies, and outcomes. Additionally, we emphasized areas for future research to address existing gaps in knowledge.

Patient and public involvement

Patient and public involvement was not directly incorporated into this review. However, the primary inquiries that motivated our research project were influenced by public dialogues initiated by family associations in the media. These conversations underscored the significance of gaining a deeper understanding of how empyema can be identified earlier in the disease progression, prior to clinical deterioration becoming uncontrollable. Additionally, they raised questions about the potential for preventing empyema if it arises as a complication of a previously undetected and untreated lung infection.

Results

Characteristics of available literature

We reviewed literature published between January 2000 to January 2023 and identified 127 articles in our systematic review. Figure 1 shows the included studies according to PRISMA flowchart. The majority of studies were observational studies (93), 77 retrospective and 16 prospective, 20 case series, 9 randomized clinical trials and 5 case series. Geographically, most studies originated from Asia, Europe and North America, with a minority from low-income countries. Interestingly, Fig. 2 reveals a slight increase in publications on pediatric empyema over the last decade.

Fig. 1

PRISMA flowchart of included studies

Fig. 2

Temporal distribution of studies on pediatric empyema

Microbiology of empyema

All 127 studies in our scoping review assessed microbiological etiology of empyema. Microbiological examinations were performed on either pleural fluid or biological samples obtained from bronchoalveolar lavage, blood culture, or a combination of two or more of these samples. Overall, 2% (n = 2) of the studies, despite investigating the microbiological etiology, did not provide quantitative results or the percentage of patients for each pathogen. Another 2% (n = 2) of the studies did not report microbiological results in the specific text. Moreover, 6% (n = 9) of the studies reported that the examined microbiological samples yielded negative results. Finally, 90% (n = 114) of the studies specified the pathogen by reporting the number of patients with positive results.

In the 114 studies where the microbiological diagnosis of empyema was specified, various etiological agents were implicated. Streptococcus pneumoniae was highlighted in patients from 92 studies, group A Streptococcus in 42, and Staphylococcus aureus in 91 (Fig. 3). In 80 studies, other microorganisms implicated were reported, different from those previously mentioned, including: Haemophilus influenzae, Streptococcus anginosus, Streptococcus viridans, Escherichia coli, Neisseria spp, Klebsiella pneumoniae, Pseudomonas aeruginosa, Fusobacterium necrophorum, coagulase-negative Staphylococcus, Enterococcus spp., Enterobacter aerogenes, Enterobacter cloacae, and influenza A, as well as fungi. Notably, 107 studies documented negative microbiological results.

Fig. 3

Description of bacteria involved in the pathogenesis of empyema

Antibiotic treatment

Details on medical therapy were available only in 71 out of the 127 included studies. In 30 cases out of 71, the molecule used was not specified. Of the studies reporting specific antibiotics, the rest of them was mentioned as follows, often administered in combination: in 73.1% (n = 30 studies) Ceftriaxone was the most frequent, followed by Vancomycin 46.3% (n = 19), Amoxicillin-Clavulanic acid, 41.4% (n = 17), Clindamycin 41.4% (n = 17), Linezolid 17% (n = 7) and Teicoplanin 4.8% (n = 2). Furthermore, no studies compared the effectiveness of different antibiotic classes, single vs. combination therapies, or explored variations in treatment durations and administration routes (fully intravenous vs. partial intravenous vs. fully oral).

Surgical management

The studies employed various surgical approaches, as detailed in Fig. 4. Pleural drainage was the most frequent procedure, reported in 123 studies (97%), intrapleural fibrinolysis in 73 (58%), video-assisted thoracoscopy surgery (VATS) in 79 (62%), surgical treatments as lung decortication or lobectomy in 51 (40%). In 26 studies (20%), all types of surgical techniques were performed, mostly in Europe and Asia, while in 18 (14%) only pleural drainage and in 3 (2%) only VATS was conducted. The remaining studies involved combinations of various surgical techniques. Most studies originated from Asia, Europe and North America, and the application of surgical techniques displayed significant geographical variability.

Fig. 4

Surgical treatments performedin studies on pediatric empyema

It’s noteworthy that VATS procedures became more prelevant from 2019 onwards, whereas their use was less consistent in earlier years. Similarly, the use of fibrinolysis primarily began after 2012.

Treatment comparisons

Fifteen studies tried to compare medical treatments (alone or in combination with pleural drainage or fibrinolosis) with more invasive surgical approaches, and 6 studies that compared diverse surgical intervetions. Nearly half of these studies originated from Asia.

To assess the safest and most effective tratmente, these studies employed various criteria, which exhibited significant heterogeneity between studies.

Interestingly, most studies considered the total duration of hospitalization as a marker of treatment severity and, indirectly, treatment success.

However, the different inclusion criteria, diverse pharmacological/surgical approaches and study settings, do not allow to reach firm conclusions. Table 1 summarizes the main findings from those studies that attempted to perform specific therapeutic comparisons [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37].

Table 1 Characteristics of studies that compared different interventions

Mortality

Mortality data was reported in 100 out of 127 studies. Two studies did not mention mortality in outcome (2/127). Among the studies reporting mortality (25/127), the mortality rate was below the 5% of the sample size (21/25) and under 15% in the rest of cases (4/25). Overall, 78 deaths occurred among the 10,896 children (0.7%) included in the review.

Focusing on the region, mortality was predominantly in developing countries (19/25); the majority were conducted in Asia, while the highest percentages of mortality related to sample size (up to 10% of the sample size) were recorded in studies conducted in Africa.

Discussion

This scoping review mapped the existing literature on pediatric empyema published over the past 23 years. To the best of our knowledge, this represents the most extensive description of current knowledge in the topic. Overall, we have found that evidence on the topic is still inconclusive and difficult to translate into rigorous guidelines. Aetiologies are frequently reported, with a probable role of molecular assays in improving microbe detection. As expected, S. pneumoniae, Group A Streptococcus and S. aureus are the most frequent pathogens. However, gaps remain: the serotypes of S. pneumoniae are rarely reported, as well as children’ vaccination status. Therefore, the real burden of S. pneumoniae serotype 3 in empyema in vaccinated children remains unclear, as current vaccines may offer/provide lower protection against it [38]. Studies have in fact described vaccine breakthrough cases of serotype 3 complicated pneumonia in vaccinated children [38]. Additionally, the distinction between methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) is seldom reported, even though their pathogenicity might differ. Finally, M. pneumoniae was rarely identified as a leading pathogen.

Currently, there are no rigorous guidelines concerning antibiotic treatment for pediatric empyema, and the literature still appears lacking solid scientific evidence, which is why pediatricians relies mainly on expert opinions. It is common to start with empirical broad-spectrum antibiotics which can be switched to narrow-spectrum following examination culture and susceptibility testing also considering local antibiotic resistance. However, while this is what is usually suggested, in routine practice there is confusion in terms of number of drugs, routes and length of antibiotic therapies, as well as optimal surgical approaches.

In general, we observed that the most common performed surgical treatment was pleural drainage, while the less performed one was open surgery, reserved for the most severe cases. Video-assisted thoracoscopic surgery (VATS) and fibrinolysis were performed almost equally. However, the studies included patients with diverse characteristics and employed different criteria for inclusion. Additionally, the causative organisms were often unknown, making it difficult to translate these findings directly into routine clinical practice-. Specifically, a recent ongoing systematic review and meta-analysis, which continuously updates its findings, compared various treatment approaches for pediatric empyema management. This review revealed that therapies such as fibrinolytic therapy, (VATS), and thoracotomy were linked to shorter hospital stays compared to chest tube drainage alone [39]. However, is it important to acknowledge that assessing hospital length of stay can be subjective, potentially limiting the generalizability of these findings. Notably, short- and long-term morbidity rates were similar across different treatment options, and mortality rates were low across all interventions, consistent with the outcomes observed in our study. In addition, inclusion criteria for the diagnosis of empyema varied. Some studies included biochemical findings in the pleural fluid, while others considered loculations on imaging. However, interpreting pleural fluid loculations can be subjective, and lung ultrasound might be a more reliable imaging tool for this purpose [40], which however has only recently been significantly implemented in pediatric practice [41]. Small studies conducted by expert pediatricians in the field found that lung ultrasound seems to be very sensitive in predicting empyema, and may guide therapeutic choices. However, there are currently no trials to evaluate whether children diagnosed with lung ultrasound and given to different pharmacological arms may benefit from one intervention over another.

Importantly, another limitation in the interpretation of available literature is the absence of clinical trials comparing antibiotic therapies while having a fixed surgical intervention, nor trials comparing surgical approaches while having fixed antibiotic therapies. As such, it is challenging to understand the impact of each drug, or surgical intervention, on the patient’s improvement. Our review identified that children often undergo multiple antibiotic treatments due to an apparent lack of clinical response to pharmacological treatment. However, in many cases, it is possible that persistence of fever may not to be attributed to the lack of pharmacological efficacy but could simply be due to the persistence of inflammation. As such, multiple antibiotics are frequently administered, whereas a single effective antibiotic paired with a single effective surgical approach may suffice. The absence of bacteria-specific trials makes it difficult to provide clear treatment recommendations. Also, a recent brief review from the European Society of Pediatric Infectious Disease provides reasonable options rather than defined indications [42], and also five of the major international societies have similar but still different recommendations [43,44,45,46,47]. Of note, only a few studies have described the role of newer drugs with optimal lung penetration such as linezolid, yet with no trials available.

Importantly, despite the mentioned limitations of the available literature and uncertainties about optimal management, mortality in children with empyema is overall low. However, significant differences have been highlighted between high and low-to-middle income countries. Such differences may be multifactorial, both associated with availability of healthcare resources like intensive care units and surgery, but also pathogen- (e.g., multidrug resistance in specific countries) and host- (e.g., malnutrition, genetics, delay in diagnosis due to socioeconomic issues) related factors. Such differences would need more studies to better understand this point and reduce inequalities in children’s outcomes.

Conclusions

Despite an increase in pediatric empyema research over the past two decades, a significant gap exists in high quality clinical trials. This hinders to fully understand the disease and the optimal surgical approach. While some existing surgical trials suggest potential benefits for fibrinolysis in terms of safety, costs and success rates, the best antibiotic regimen remain unclear. Future well-designed trials should aim to investigate different antibiotics (including newer ones with optimal lung penetration) accompanied by fixed surgical approaches, as well as different surgical interventions accompanied by optimal antibiotic therapies.