DISCUSSION
To our knowledge, this is the first Portuguese, and one of the few
European studies on PE in children, and one of the largest series on
number of patients, time period and data analyzed. Furthermore, we
describe three incidentally detected PE, a subgroup of patients whose
management is particularly unclear, and about whom diagnostic methods,
treatment and outcomes details have not been previously
reported8. We also found a higher sensitivity for
diagnosis of PE applying adults’ scores, compared to pediatric ones.
The number of PE admissions of 9.19/10.000 is similar to the one
reported by Rajpurkar and colleagues (5.12-9.22/10.000 admissions).
Although we didn´t observe an increase in the diagnosis rate along the
13 years studied, the incidence during 2020 was one of the highest. All
four cases tested negative for SARS-COV-2 PCR at admission and none
presented suggestive clinical symptoms, but serological tests were not
performed.
We found an overall predominance of female patients, especially in the
adolescent group, presumably due to the influence of CHC. The mean age
at presentation was similar to that described in other
reviews8, however, as others7,16, we
didn´t find the classical bimodal age distribution described in
pediatric PE4,10. PE is probably underdiagnosed,
especially in infants, whose diagnosis is even more challenging due to
the unspecific clinical presentation. The unexpected predominance of
central emboli and massive or submassive PE further corroborates the
underdiagnosis of less clinically obvious events, missing the
opportunity to identify and treat patients with high thromboembolic
risk.
The failure to consider PE as part of the differential diagnosis in
pediatrics, even in the presence of typical complains, is a major
concern20. An important clue is the presence of
thromboembolic risk factors since it is unlikely for PE to occur in
pediatric patients in their absence16. We found a
higher prevalence of CHC utilization, immunomediated diseases and
inherited thrombophilia in PE than previously
reported8. Risk factors were different in outpatients
versus inpatients. In outpatients PE occurred exclusively in
adolescents, mainly female, and CHC intake, obesity, immunomediated
diseases or a positive family history were the most important risk
factors. Remarkably, all the female patients were on CHC, the majority
for less than one year, a period in which the risk of VTE is
higher21. Most, however, had other associated risk
factors, and these should be considered when first prescribing CHC in
teenagers. Besides the classic prothrombotic conditions, as lupus or
antiphospholipid syndrome, recently VTE has been increasingly recognized
in patients with several systemic immunomediated diseases, as found in
our series22-24. In outpatients there was an important
delay in diagnosis, although we found a shorter than the mean lag time
described8. As reported, other diagnosis had been
considered during the previous medical observation, namely infections or
psychological distress, emphasizing that the presence of fever or
anxiety should not exclude PE.
Inpatients with PE were younger than outpatients, more frequently male,
and presented different risk factors, such as CVC, infections and
complex chronic diseases. Infections are important triggers and may
delay PE diagnosis due to symptoms overlap25. As
reported, in long-term hospitalizations, especially in critically ill
patients, immobilization could have contributed for PE, emphasizing the
importance of mechanical methods for DVT prophylaxis in these
patients23. A worsening of their clinical condition,
particularly unexplained cardiorespiratory deterioration, must prompt a
PE workout. We found three asymptomatic PE (Table 2) in inpatients that
were being studied for other reasons. These patients had multiple risk
factors and negative D-dimer testing, possibly corresponding to chronic
or subacute PE.
Recently, two distinct patterns of pediatric PE have been
acknowledged8: classic thromboembolic PE and in situ
pulmonary artery thrombosis (ISPAT), which results from local causes,
such as congenital heart disease or anomalies of the pulmonary
artery26. Two patients from our study may fit into
this category: an asymptomatic (table 2) and a 13-years old girl, with a
Truncus arteriosus type 1, with a right ventricle-pulmonary artery
conduct, hospitalized with endocarditis suspicion. Clinically, decrease
in pulmonary sounds and worsening of tricuspid regurgitation prompted
CTPA with right central PE diagnosis. She was successfully treated with
thrombectomy and conduct substitution surgery and maintained
anticoagulation for one year. During follow-up a May-Thurner Syndrome
was also detected. Several relevant studies7,10 have
included patients with possible septic or tumor thrombus in pediatric PE
series, advocating that, in clinical practice, it is often not possible
to differentiate septic emboli or tumor thrombus from true
thromboembolic PE, as these are independent risk factors for
VTE10. Furthermore, in the reported case, culture of
the conduct and emboli were negative. Hence, we decided to include this
patient in the study, even if this cannot be considered a classic
thromboembolic PE, but rather an ISPAT.
ECG and CXR are often performed to investigate thoracic pain or dyspnea.
However, the normality of these exams may be misleadingly reassuring, as
happened in several of our outpatients. In highly suspicious cases,
CTPA, the gold standard method to diagnose PE, should be directly
performed. In our series, this happened only in one case, revealing the
hesitancy to consider this diagnosis in pediatric patients. In
lower-risk patients, other first-line exams can be considered. Although
not sensitive, ECG may show unspecific alterations suggestive of
PE27, as sinus tachycardia, an alarm sign present in
most of our cases. D-dimer testing was reported to lack utility in the
diagnosis of childhood PE14, but in a recent
multicentric study28 revealed a 100% sensitivity. In
our data, D-dimer were positive in all acute PE, and negative only in a
subacute PE in an anticoagulated patient and an asymptomatic PE, also
antiaggregated. As others, we didn´t find an association between the
degree of D-dimer increase and PE severity29.
PE clinical diagnostic prediction models, validated for adult
population, have been described as performing poorly in pediatric
populations16. In a 36 pediatric PE population,
Hennelly et al.15 found Wells criteria to have a
sensitivity and specificity of 86% and 58%, and PERC criteria of 100%
and a 24%, respectively. Agha et al found the PERC criteria unable to
rule out PE in 84% of pediatric emergency room
patients30. In contrast, in our study these criteria
had a high sensitivity and false negatives were only found in
asymptomatic PE. Two pediatric models have been proposed, both derived
from single-center studies and including a small number of
PE15,16. Hennelly et al. model15performed similarly to Wells criteria in a setting with 36 PE, missing
to diagnose four cases of children with clinical findings suggestive of
a DVT or a history of malignancy or immobilization. Its application in
our PE patients misclassified four patients as non-risk, two of them
asymptomatic. A further model developed by Lee et
al.16 missed two of our PE patients, one asymptomatic.
Both models misclassified a patient with a protein C deficiency, who had
a positive family history. We propose that this should be considered in
future pediatric models.
In our series, investigation after PE diagnosis was not uniform.
May–Thurner Syndrome was diagnosed in a significant proportion of
patients, years after PE, due to PTS. Although rare, this syndrome is
likely underestimated and should be investigated in patients with
unexplained left lower extremity thrombosis31.
A minority of our patients received thrombolysis and two of the massive
PE were not eligible due to critical bleeding. Contrastingly, a
systematic review8 reported that a third of pediatric
PE patients receive pharmacologic thrombolysis as initial treatment,
although recent guidelines reserve it for massive
PE32. LMWH was used more often to initiate
anticoagulation treatment, given its pharmacokinetics profile, while UFH
was the first option in high bleeding risk
patients33-34. Anticoagulant therapy duration in our
study was in average longer than described8,13.
Management of asymptomatic PE lacks evidence, but most physicians claim
to treat them similarly to symptomatic PE26. In a
literature review8, up to 17% of patients had PE
detected incidentally but details on diagnostic methods, treatment and
outcomes of this type of PE in pediatric patients had not been reported.
Rajpurkar et al.8 referred a significant mortality
rate in pediatric PE (26%), acknowledging, however, a possible
reporting bias and that, in many studies, the cause of death might have
been attributable to underlying diseases. Indeed, in our series,
PE–related mortality 6.9%, while all causes mortality during follow-up
reached 17.3%. Most deaths occurred in inpatients with cardiovascular,
oncologic or other complex chronic conditions, as well as younger
patients, as described in previous studies7,8,10.
Follow up practices after a pediatric PE event are highly variable and
data on long-term outcomes, including CTPH, pulmonary function or
quality of life, and predictors of outcome are
sparse26. Recurrence of VTE was within the expected
reported values (0–18.8%). PTS was an important cause of morbidity for
several years after PE. Evaluation of residual thrombosis at the end of
anticoagulation therapy is not consensual among experts, 60% admitting
they routinely re-image although 35% would not change the duration of
anticoagulation therapy based in the results.13 More
than half our patients had a control CTPA, in a variable period after
PE, and CTPH was indirectly accessed by ECHO.
Our study has important limitations: it is a single center retrospective
study, and it does not necessarily generalize to other settings or
communities. Importantly, autopsy-diagnosed PE were not trackable in a
database and thus, reported mortality could be underestimated. Data on
the autopsy-diagnosed PE case was not possible to analyze. The
application of clinical scores retrospectively can be misleading. Also,
due to the lack of a control group, we could not compare risk factors to
those of the general population. Due to the 13-years span, and the lack
of an institutional protocol, clinical management could have changed
along the time, although this wasn´t noticed.
Our data emphasizes the need for a high suspicion index for pediatric PE
in outpatients with risk factors, as half the cases were initially
misdiagnosed. Towards compatible complains, risk factors, including CHC
use, obesity, immunomediated diseases and family history should be
explored. In inpatients, risk factors are often inherent to underlying
diseases, immobilization, co-infections and CVC presence and thus
unexplained cardiorespiratory deterioration should prompt PE
investigation. May–Thurner Syndrome is likely underestimated and should
be considered. The use of validated adult scores merits to be explored
and improved in prospective pediatric multicentric studies.