Systematic review of case series and case reports on pediatric pulmonary embolism

Abstract

Background

Pediatric pulmonary embolism is a rare yet potentially life-threatening condition, presenting significant diagnostic and therapeutic challenges owing to its nonspecific symptoms and diverse underlying risk factors. This systematic review aims to consolidate data from case series and case reports to provide a comprehensive overview of pediatric pulmonary embolism, focusing on clinical characteristics, diagnostic approaches, treatment strategies, and outcomes.

Methods

This systematic review was conducted in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines and the Cochrane Handbook for Systematic Reviews of Interventions, version 6.3. The study protocol was registered with PROSPERO (ID: CRD42024532471). We utilized the Covidence systematic review software for deduplication and screening of search results. The literature search was developed with a subject specialist and included Medical Subject Headings terms and free-text keywords such as “pulmonary embolism,” “pediatric,” and “case reports.” Databases searched included PubMed, Scopus, Web of Science, and the Cochrane Library up to April 2024, limited to English-language publications. Reference lists of relevant articles were also reviewed.

Results

Pulmonary embolism affected males and females with age ranging from 1 to 18 years. Common underlying conditions included malignancies (for example, Wilms tumor), chronic diseases (for example, nephrotic syndrome), and recent surgical interventions. Diagnostic practices primarily relied on computed tomography pulmonary angiography, supplemented by chest X-ray and ultrasound. Treatment typically involved anticoagulation therapy with unfractionated heparin and low-molecular-weight heparin, transitioning to oral anticoagulants for long-term management. Thrombolytic therapy was used in severe cases. Outcomes varied, with many patients recovering well, though complications such as recurrent embolism and pleural effusion were observed. Fatal cases underscored the critical need for early detection and prompt treatment.

Conclusion

This systemic review underscores the rarity and complexity of pediatric pulmonary embolism, highlighting the necessity for increased clinical vigilance given its nonspecific presentation and diverse underlying risk factors. Accurate diagnosis, primarily via computed tomography pulmonary angiography, with the prompt initiation of anticoagulation therapy are essential for optimal outcomes. Despite favorable recovery rates for most patients, the potential for severe complications and fatalities reinforces the value of timely diagnosis and personalized management approaches. Further research is essential to refine diagnostic protocols, optimize treatment approaches, establish evidence-based guidelines, and improve long-term outcomes for children with pulmonary embolism.

Introduction

Pediatric pulmonary embolism (PE) is a relatively rare but potentially life-threatening condition that has become a subject of heightened interest recently. The incidence of pediatric PE is markedly lower compared with adults, with studies estimating a rate of 0.14–0.9 cases per 100,000 children annually [1]. Although rare, pediatric PE is associated with significant morbidity and mortality risks [2]. Early recognition and management are crucial to prevent adverse outcomes. Known risk factors for pediatric PE include underlying chronic conditions such as congenital heart disease, malignancies, nephrotic syndrome, and the use of central venous catheters [3, 4]. In addition, genetic predispositions such as thrombophilia can significantly increase the risk of PE in children [5]. Inherited thrombophilia predisposes children to first-onset venous thromboembolism (VTE); it is more prevalent in adolescents with unprovoked thrombosis and in those with a family history of VTE. However, it is less common in children who develop catheter-related thrombosis due to underlying cardiac disease or malignancy necessitating central venous access [6].

The clinical presentation of PE in children is often highly variable and nonspecific, complicating early diagnosis. Common symptoms include sudden onset of dyspnea, chest pain, tachypnea, and hypoxia. In some cases, children may present with cough, hemoptysis, or symptoms indicative of deep vein thrombosis (DVT), such as limb swelling and pain [7, 8]. The nonspecific nature of these symptoms often results in delays in diagnosis and treatment, potentially worsening outcomes.

The diagnosis of PE in children relies heavily on clinical suspicion supported by diagnostic imaging. Although various criteria such as the Wells criteria, the pulmonary embolism rule-out criteria (PERC), and the Geneva score are widely used in adults, they lack specificity when applied to pediatric populations. For instance, Biss et al. assessed the modified Wells simplified probability score in children with PE and found it to be of limited effectiveness, even when combined with D-dimer testing [9]. Similarly, Hennelly et al. reported that the Wells criteria and PERC low-risk rule show a significantly low diagnostic specificity of 86% and 60%, respectively, underscoring the importance of diagnostic modalities such as computed tomography (CT) [10]. Computed tomography pulmonary angiography (CTPA) is considered the gold standard for diagnosis; however, its use in pediatric patients is limited by the associated risks of radiation exposure [11]. Alternative imaging modalities, such as magnetic resonance angiography (MRA) and echocardiography, are also employed but have their limitations [12, 13]. Although useful for diagnosing PE in adults, D-dimer testing has limited diagnostic value in children owing to its lower specificity in this age group [14].

The management of pediatric PE is adapted from adult treatment protocols, focusing primarily on anticoagulation lotherapy. Low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) are commonly used initial treatments, followed by long-term management with oral anticoagulants such as warfarin or direct oral anticoagulants (DOACs) [15, 16]. Thrombolytic therapy and surgical interventions, such as thrombectomy, are considered in severe cases, particularly in instances of massive PE causing hemodynamic instability or when anticoagulation is contraindicated or ineffective [17]. Pediatric PE is a challenging condition requiring heightened clinical awareness and a multidisciplinary approach for optimal management. This systematic review aims to consolidate findings from case series and case reports to provide a comprehensive understanding of the clinical characteristics, diagnostic strategies, treatment modalities, and outcomes associated with pediatric PE.

Methods

The current systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guidelines and the Cochrane Handbook for Systematic Reviews of Interventions, version 6.3 [18]. The study protocol was registered in PROSPERO (ID: CRD42024532471).

Eligibility criteria

Study selection

The search results were imported into the Covidence systematic review software for deduplication and screening. Two independent reviewers screened titles and abstracts against predefined inclusion and exclusion criteria. Studies were included if they met the following criteria:

• Population: pediatric patients (aged 0–21 years) diagnosed with PE

• Study design: case series and case reports

For studies involving both adult and pediatric populations, only pediatric-specific data were extracted, while adult subpopulation data were excluded from the review. Discrepancies in screening decisions were resolved by discussion or by a third reviewer if necessary.

Literature search

We developed our search strategy in consultation with a subject specialist to ensure completeness and relevance. The strategy used a combination of Medical Subject Headings (MeSH) terms and free-text keywords, incorporating terms such as “pulmonary embolism,” “pediatric,” “children,” “case series,” and “case reports.” Databases searched included PubMed, Scopus, Web of Science, and the Cochrane Library, covering publications up to April 2024. The search was limited to articles published in English. Reference lists of relevant articles and reviews were also screened to identify additional studies.

Study selection

We removed all duplicates using EndNote software (Clarivate Analytics, PA, USA). To assess their eligibility criteria, all retrieved records were screened by two independent authors. The process included title and abstract screening, followed by full-text screening. In addition, references of the included studies were reviewed and considered if they met our criteria.

Data extraction

Data extracted from each study included:

• Study characteristics: author(s), publication year, and country of study

• Patient demographics: age, sex, and relevant medical history

• Clinical presentation: symptoms and signs at presentation

• Diagnostic methods: imaging techniques (for example, CT, magnetic resonance imaging [MRI], and ultrasound) and laboratory tests (for example, D-dimer levels)

• Treatment modalities: type of anticoagulation therapy, use of thrombolysis, surgical interventions, and supportive therapies

• Outcomes: clinical outcomes (for example, recovery and recurrence), complications, mortality rates, and follow-up duration

Two independent reviewers extracted data using a standardized form. Discrepancies were resolved through discussion or consultation with a third reviewer.

Quality assessment

The methodological quality of included studies was evaluated using the Joanna Briggs Institute (JBI) Critical Appraisal Tools for case reports and case series. The assessment focused on eight criteria for case reports and ten criteria for case series, including clarity of patient demographics, comprehensiveness of case descriptions, diagnostic assessments, interventions, and outcome reporting. Each criterion was scored as “yes,” “no,” “unclear,” or “not applicable.” Studies were rated as “good” if they met ≥ 75% of the criteria, “fair” if they met 50–74%, and “poor” if they met < 50%. Detailed quality assessments for each study are presented in Supplementary Tables 1 and 2.

Statistical analysis

Microsoft Excel (Microsoft Corp, Seattle, WA, USA) was used for data collection and organization. Descriptive statistics were used to summarize the raw data, presenting means and standard deviations for continuous variables, while frequencies and percentages were reported for categorical variables.

Results

Literature search

Among the 2958 records retrieved from the literature search, 2237 records were screened. After the exclusion of irrelevant articles, 77 articles were assessed for eligibility, of which 64 articles were included for quantitative synthesis. This included 50 case reports and 14 case series, comprising 111 patients. The details of the selection process are shown in the PRISMA flow diagram in Fig. 1.

Fig. 1

The Preferred Reporting Items for Systematic Reviews and Meta-analysis flow diagram of the included studies

Demographic characteristics

The detailed baseline characteristics of the included studies are reported in Table 1. In the reviewed cases, the age of pediatric patients with PE ranged from 1 to 18 years. Most cases were reported among the 12–16 age group, with a median age of 7.5–8 years reported across studies [19, 20]. Cases involving congenital heart conditions, such as patent foramen ovale (PFO), were noted among newborns [21], while conditions such as Klippel–Trenaunay syndrome and Arnold–Chiari malformation with sacral myelomeningocele were more common among children aged 11–14 years [22, 23]. There was a marked prevalence of coexisting cases of DVT among the 5–9-years age group [24]. Gender distribution varied, with studies frequently reporting a higher occurrence among males [19, 25]. Additionally, males more commonly presented with coexisting conditions, including respiratory tract diseases such as pneumonia (left lower lobe) and parapneumonic effusion, bronchitis, coronavirus disease 2019 (COVID-19) pneumonia, and bronchopneumonia [20, 26, 27], though females were also significantly represented in these cases [28].

Table 1 Baseline characteristics of the included cases

Contributing factors and risk factors

The contributing factors to PE, as outlined in Table 1, include male gender (52.68%), thrombophilia (32.14%), DVT (19.64%), previous surgeries (17.86%), systemic infections (16.07%), immobility/travel (15.18%), obesity (13.39%), central venous catheter (9.82%), previous trauma (7.14%), oral contraceptive pills (OCP) (7.14%), congenital heart diseases (6.25%), malignancy (4.46%), dehydration (4.46%), and prematurity (3.57%).

The most common presenting symptoms/signs were dyspnea (47.32%), hypoxia (37.50%), elevated D-dimer (37.50%), chest pain (33.04%), and fever (32.14%), among others.

Diagnostic modalities

The diagnostic modalities used were CTA (25.89%), computed tomography (CT) (21.43%), autopsy (8.93%), ventilation–perfusion scans (8.04%), chest X-ray (8.04%), echocardiography (6.25%), D-dimer (0.89%), and Doppler ultrasound (0.89%), as presented in Table 1.

CTPA is the primary diagnostic tool, widely utilized to identify filling defects within the pulmonary arteries. Its effectiveness was demonstrated in cases reported by Song et al. [19] and Wang et al. [29], where emboli were clearly visualized. Chest X-ray and ultrasound are primarily used for initial assessment and to detect associated complications such as pleural effusion. These imaging modalities were used in studies by Kosch et al. [27] and Profitlich et al. [30], where they provided extensive clinical insights, aiding in accurate diagnosis.

Treatment approaches

Treatment approaches for pediatric PE vary depending on the severity of the condition and the underlying causes. Anticoagulation therapy is the cornerstone of treatment, with several options tailored to different clinical situations.

UFH is commonly used initially or in acute cases, as demonstrated by Tetsuhara et al. [28] and Xu et al. [31]. UFH provides rapid anticoagulation with a short half-life and the advantage of being reversible, making it suitable for unstable patients.

LMWH is also frequently administered to achieve therapeutic anti-factor Xa levels, with dosages adjusted in specific populations such as neonates, patients with renal impairment, or patients with obesity [32]. For example, Wang et al. [29] reported dose adjustments in a patient with renal dysfunction to avoid accumulation and minimize bleeding risks.

For long-term management, oral anticoagulants such as warfarin or rivaroxaban are employed, offering a sustained treatment option, as evidenced by Shrader et al. [25] and Yoo et al. [32]. Warfarin requires regular monitoring of the international normalized ratio (INR), while DOACs, such as rivaroxaban, offer fixed dosing without the need for routine monitoring; however, their use in children is still under study.

Thrombolytic therapy, which involves agents such as urokinase or tissue plasminogen activator (tPA) to rapidly dissolve clots [33], is reserved for severe cases, such as massive PE causing hemodynamic instability or when anticoagulation is contraindicated or ineffective [34]. This approach was highlighted in the studies by Song et al. [19] and Xu et al. [31]. However, the decision to use thrombolytics requires careful consideration owing to the risk of major bleeding.

In addition to anticoagulation and thrombolytic therapies, supportive measures were integral to patient care. Antibiotics are administered to treat underlying infections that may have triggered PE, such as pneumonia [29]. Analgesics help manage pleuritic chest pain associated with PE [35]. Invasive procedures, such as thoracentesis for significant pleural effusion are performed to relieve respiratory distress and improve oxygenation [19]. The placement of inferior vena cava (IVC) filters may also be employed in specific cases to prevent recurrent emboli when anticoagulation is contraindicated or ineffective, as demonstrated in the studies by Song et al. [19] and Xu et al. [31].

Outcomes and follow-up

The outcomes and follow-up for pediatric PE varied according to the severity of the condition and the treatment administered. As seen in Table 2, most patients recovered with appropriate anticoagulation and supportive care (66.96%). A smaller proportion required admission to the pediatric intensive care unit (PICU) (24.11%), and all-cause mortality occurred in 17.86% of cases, with PE-related mortality at 12.50%. Mechanical ventilation was needed in 12.50% of cases, while 13.39% required supplemental oxygen. Vasopressor support was necessary in 6.25% of cases, with 6.25% needing hemodynamic or mechanical support. Extracorporeal membrane oxygenation (ECMO) was used in 3.57% of cases.

Table 2 Outcomes of PE in the included cases

Right ventricular (RV) dilation was observed in 13.39% of cases, with cardiac arrest (12.50%), cardiac arrhythmia (8.04%), RV dysfunction (8.04%), and pulmonary hypertension (chronic thromboembolic pulmonary hypertension [CTEPH]) (8.04%) also noted as outcomes. Shock occurred in 7.14% of cases, and tricuspid regurgitation and organ failure were observed in 6.25%. Recurrent thrombosis was noted in 4.46%, major bleeding in 3.57%, and acute respiratory distress syndrome (ARDS) in 3.57%.

In the short term, most patients recover with appropriate anticoagulation and supportive care. Studies such as those by Song et al. [19] and Wang et al. [29] reported favorable recoveries following effective treatment strategies.

However, some patients experience complications during their recovery. Issues such as recurrent PE or pleural effusion were observed, as shown in the case reported by Staser et al. [36]. Long-term follow-up is crucial for managing ongoing risks and complications. The duration of follow-up varies widely, ranging from a few months to more than a year. Extended monitoring is particularly important for patients with chronic conditions or those who have experienced severe episodes of PE. Yoo et al. [32] and Xu et al. [31] highlight the need for continued management in these cases to address any persistent health issues.

In some cases, outcomes are fatal, often owing to severe or unrecognized PE. Studies by Zaidi et al. and Biss et al. [35, 37] underscore the importance of timely diagnosis and intervention, as delayed or inadequate treatment can lead to dire consequences (Table 2).

Quality assessment

Quality assessment of the included studies demonstrated that all the included case reports and case series are of good quality. Of the 50 case reports, 48 were of good quality, and 2 were of fair quality. The 14 case series were of good quality. The details of the quality assessment are presented in Supplementary Tables 1 and 2.

Discussion

The reviewed studies provide a comprehensive overview of pediatric PE. Gender distribution shows a consistent male predominance, though female patients are also significantly represented. This trend aligns with general epidemiological data suggesting a male predominance in pediatric PE cases. The wide age range observed highlights that PE can affect children across different developmental stages.

There are several key contributing factors and risk factors associated with PE. Trauma and surgical interventions are well-established risk factors for PE in children. Our findings support this, with cases of PE occurring following ankle fractures and surgeries. This observation is consistent with broader studies indicating that orthopedic trauma—particularly when combined with immobilization or surgical procedures—can substantially increase the risk of thromboembolic events in children. Shrader et al. [25] reported a case where an ankle fracture and subsequent surgery triggered PE. Similarly, Song et al. [19] noted that trauma and immobilization following infections increased the risk of developing pulmonary emboli. These factors alter blood flow and heighten the likelihood of thrombus formation, thereby raising the risk of PE.

Infections, particularly Mycoplasma pneumoniae pneumonia and bronchopneumonia, were frequently reported in our review. This correlates with existing literature that emphasizes the role of infections as risk factors for PE. Severe pneumonia can lead to systemic inflammation and hypercoagulability, both of which are well-known contributors to thromboembolism.

Malignancies contribute to hypercoagulability through the release of procoagulant substances such as tissue factor and cancer procoagulant, which activate the coagulation cascade [38]. Chemotherapy agents can further promote thrombosis by damaging the endothelium. Zhang et al. [39] identified Wilms tumor as a notable malignancy associated with PE. Tetsuhara et al. [28] pointed out nephrotic syndrome as a significant risk factor.

Chronic conditions, including nephrotic syndrome, increase the risk of thrombosis owing to the loss of natural anticoagulants—antithrombin III, protein C, and protein S—in the urine [38].

Diagnosing pediatric PE is particularly challenging owing to nonspecific symptoms such as tachypnea, dyspnea, and chest pain, which often overlap with other common pediatric conditions [40]. While the D-dimer test is a valuable diagnostic tool in adults, its specificity in children is limited. Elevated D-dimer levels can result from a variety of conditions such as infections, inflammation, or trauma, which are prevalent in pediatric patients [41]. Emerging biomarkers such as fibrin monomers and microparticles are being studied for their potential to enhance diagnostic accuracy in pediatric PE [42].

The imaging techniques utilized for diagnosing PE in pediatric patients vary, with CTPA being the most frequently used modality. Compared with adults, children are more sensitive to ionizing radiation, and CTPA entails considerable radiation exposure, potentially increasing long-term cancer risks [43]. Ethical considerations necessitate the use of the lowest effective radiation doses and encourage exploring alternative imaging modalities when feasible.

MRA and ventilation–perfusion scans are potential alternatives to reduce radiation exposure [44]. The use of chest MRI in children is limited by factors such as difficulty remaining still and the low signal-to-noise ratio of lung parenchyma. However, recent technological advancements are facilitating the utilization of this imaging modality, particularly pulmonary MRA, in diagnosing pediatric PE.

Autopsy provided a definitive diagnosis of PE in fatal cases. This was illustrated in the studies by Zaidi et al. and Biss et al. [35, 37], who relied on autopsy findings to confirm the presence and extent of massive pulmonary emboli.

Management strategies for pediatric PE reflect a multifaceted approach consistent with current clinical practices and highlight areas of variability and evolution in treatment strategies. Anticoagulation remains the cornerstone of treatment for PE in children [34]. The use of UFH is well-documented for initial, acute management owing to its rapid onset and ease of reversal. This aligns with existing guidelines that recommend UFH for initial therapy in severe or unstable cases [45].

Transitioning to LMWH is often preferred for its convenience, ease of administration, and more stable pharmacokinetics. This practice is supported by the reviewed studies, which frequently highlight LMWH as the preferred option. Oral anticoagulants such as warfarin and rivaroxaban are employed for long-term management, consistent with their established roles in preventing recurrent thromboembolic events. The growing use of rivaroxaban signifies a shift toward newer oral anticoagulants, which offer fixed dosing and eliminate the need for regular monitoring [46].

Thrombolytic therapy, particularly urokinase or tPA, was used in severe cases and when cardiac embolism was present. This approach is consistent with literature, which supports the use of thrombolytics in life-threatening or massive PE when rapid dissolution of clots is necessary. Despite its efficacy, thrombolytic therapy is typically reserved for critical situations owing to the risk of significant bleeding. The decision to use thrombolytics or surgical interventions requires a multidisciplinary approach, weighing the risks of bleeding against the benefits of rapid clot resolution. Recent advancements, such as catheter-directed thrombolysis, offer targeted treatment with potentially reduced systemic side effects [33].

The outcomes of pediatric PE vary considerably. While many patients recover well with appropriate anticoagulation and supportive care, complications such as recurrent embolism or pleural effusion are not uncommon. Follow-up durations ranged from a few months to more than a year, reflecting the need for ongoing management, particularly for chronic conditions or after severe embolic events.

Several factors influence outcomes, including the type and extent of treatment, overall health status, and underlying conditions. The studies highlight that, while many patients recover with appropriate treatment, others experience complications such as recurrent embolism or pleural effusion, emphasizing the need for personalized treatment plans and comprehensive follow-up care.

On the basis of the findings of this review, several key recommendations emerge for clinicians managing pediatric patients with PE. Diagnostic practices should prioritize the use of CTPA as the primary imaging modality owing to its high sensitivity and specificity in detecting PE. However, clinicians should remain aware of the potential need for alternative or supplementary diagnostic tools, such as chest X-ray or ultrasound, particularly in settings where CTPA may not be immediately available. Early and accurate diagnosis is crucial for initiating timely intervention and preventing complications.

Management of pediatric PE should be tailored to the severity of the condition and patient-specific needs. For acute cases, UFH is recommended owing to its rapid action and reversibility. Following stabilization, transitioning to LMWH or oral anticoagulants, such as warfarin or rivaroxaban, is generally advised for long-term management. In cases of severe embolism or when cardiac involvement is significant, thrombolytic therapy with urokinase or tPA may be necessary. Clinicians should also be prepared to employ supportive measures, including oxygen therapy, antibiotics for underlying infections, and analgesics for pain management.

Long-term outcomes in pediatric patients with PE can include the development of chronic thromboembolic pulmonary hypertension (CTEPH), a condition characterized by persistent pulmonary hypertension due to unresolved emboli [47]. Early recognition and management are critical to hinder progression. Long-term follow-up involving regular imaging assessments is essential for evaluating recovery and managing any potential complications, including CTEPH [48, 49]. Regular follow-up visits should include assessments to evaluate the effectiveness of anticoagulation therapy and to monitor for signs of recurrent embolism or other complications. Additionally, clinicians should be vigilant in addressing any long-term effects or sequelae resulting from PE and its treatment.

Early detection of PE in children is vital given the potential for rapid clinical deterioration and the diverse underlying conditions that predispose them to this serious condition. The diverse range of risk factors underscores the need for heightened vigilance in at-risk populations. Timely identification of symptoms and prompt management can significantly improve outcomes and reduce the risk of severe complications.

Limitations

This systemic review highlights several limitations related to the quality of the included studies. One primary concern is the variability in study design, which includes differences in methodologies, sample sizes, and reporting practices. The studies included range from single case reports to retrospective analyses and case series, leading to heterogeneity in the quality of evidence presented.

There are notable gaps in the available data, particularly concerning long-term outcomes and treatment variability. Many studies focus on short-term recovery and immediate treatment responses, with limited information on the long-term prognosis of pediatric patients with PE. Moreover, there is considerable variability in treatment approaches reported across studies, reflecting a lack of standardized protocols.

Conclusion

This systematic review of case series and case reports emphasizes the complexity and variability of pediatric PE, which is a rare but serious condition. Pediatric PE presents unique diagnostic and therapeutic challenges owing to its nonspecific symptoms and diverse underlying risk factors, such as malignancies, chronic diseases, genetic disorders, and recent surgeries.

The findings confirm that CTPA is the most effective diagnostic tool for identifying pulmonary emboli in pediatric patients, although alternative imaging modalities such as MRA and clinical judgment remain critical in specific scenarios. Anticoagulation therapy, particularly with UFH and LMWH, is the cornerstone of treatment, with oral anticoagulants such as rivaroxaban serving as viable options for long-term management. Thrombolytic therapies, including urokinase and tPA, are reserved for severe cases, highlighting their role in life-threatening situations.

Outcomes vary significantly. Many patients achieve favorable outcomes following appropriate treatment, while others develop complications such as recurrent embolism or pleural effusion. To address these complications and improve long-term outcomes, personalized treatment plans and rigorous follow-up care are required.

Future research should focus on conducting large-scale, multicenter clinical trials to establish pediatric-specific diagnostic criteria and evidence-based treatment guidelines, enhancing the early recognition, management, and long-term care of patients.