DISCUSSION
Our prospective observational study is the first study that evaluates
the LUS findings of cardiopulmonary interactions in acutely ill children
with elevated pro-BNP levels, with the aim of establishing the specific
LUS pattern in this category of patients without primary lung diseases.
We found that LUS findings in these acutely ill children are
different from the ultrasound pattern of other categories of children
and in particular 1) children with acute lower respiratory tract
infections and 2) healthy infants (Figures 1,2 and 3). In
particular, we found that no children belonging to the category ofacutely ill children had short vertical artifacts but all had
multiple long artifacts that were well delineated and non-blurred,
non-confluent, with localization mainly at the bases and bilateral
distribution. At the origin of these artifacts, the pleural line always
appeared regular and none had subpleural consolidations. Many had
anechoic pleural effusions, most of them unilateral.
We also found that the distribution pattern of vertical artifacts (with
or without spared areas) is influenced not only by the cause, severity
and timing of onset of pulmonary congestion - as already described in
the literature7,8,10 - but also by the level of
pro-BNP and the type of pathology (cardiac disease; systemic
inflammatory disease/sepsis; heart disease and systemic inflammatory
disease/sepsis) that causes the increase in pro-BNP (Tables 5 and 6).
However, due to the scarcity of the comparison population, we can
consider this last detection as a preliminary result pending the
execution of a study with a larger sample of patients, in order to
understand if there is a correlation between the ultrasound results and
their distribution with pro-BNP levels and / or specific diagnosis.
From a theoretical point of view, our results reinforce the need for a
better understanding of the physical mechanisms that generate
artifacts27 even in children.
In the presence of cardiogenic edema, ARDS, interstitial lung diseases,
bronchiolitis and non-consolidating pneumonia and contusions, part of
the lung volume originally occupied by air, can be replaced with water,
connective, cells, hyaline membrane or edematous tissue, eventually
creating acoustic traps for the US beam containing a medium that is
physically (in terms of acoustic impedance) very different from the
surrounding environment (air).7,8,10,25
Therefore, the B lines, in their variable appearances, indicated a loss
of peripheral lung aeration (without tissue consolidation) due to
interstitial disease or simply to lung deflation without histologic
changes.7,8,10,25However, the B lines, in the absence
of an analysis of their appearance, cannot easily differentiate the
cause.7,8,10,12,25 Studies performed on physical
models and in adult patients7-12,21,25,have shown that
the vertical artifacts generated by an inflammatory lung have a
different appearance from those generated by cardiogenic edema and / or
pulmonary congestion not primarily due to lung
diseases.7-12,21,25
In the first case, as for example in the context of lung inflammation or
in ARDS, the random peri and intralobular distortion can explain the
appearance of acoustically permissive irregular channels and
consequently the appearance of different arrangements of the B lines,
pleural irregularities, consolidations, inhomogeneous isolated air
spaces and inhomogeneous edema.7,8,10,25 Inhomogeneous
edema, alveolar collapses, fibrosis and lung inflammation contribute to
the development of pleural irregularities and the reduction of lung
compliance and pleural flow in ARDS and other lung inflammatory
diseases.
In the second case, the presence of homogeneously distributed edema due
to the absence of inflammation and / or fibrosis causes the secondary
interlobular septa to be thickened but anatomically intact and therefore
can act as acoustic traps in which specific frequencies give rise to
separate B lines , uniform, bright and long, associated with regular
pleural line, with no spared areas especially in early cardiogenic
edema.7,8,10,25
When cardiogenic pulmonary edema is severe or in an advanced stage, some
LUS findings can be superimposed on the LUS findings of ARDS such as: -
irregularities of the pleural line with small supleural consolidations
or - the presence of ”spared areas”.8,9
None of the acutely ill patients that we enrolled for the study had a
clinical and functional picture of ARDS: in fact, these are patients
with isolated heart disease with early cardiogenic pulmonary edema and
patients with systemic inflammatory syndrome and / or sepsis who did not
have such a severe picture as to develop ARDS. In agreement with the
data in the literature8,9, in none of the acutely ill
patients we found short vertical artifacts, pleuric line irregularities
and sub pleural consolidations.
Furthermore, a recently published2 study showed that
healthy young children can also generate vertical artifacts and this
discovery has provided us with new information and a new group of
patients to study the B lines. We have in fact applied these new results
in the design. and in the execution of our study.
From a practical point of view, our study confirms what we have learned
so far from these preclinical and clinical
studies.7-12,21,25 It underlines the idea that
vertical artifacts must be interpreted according to the clinical
scenario case by case and how through this interpretation it is possible
to find specific patterns for some categories of patients different from
each other in order to use LUS as an aid to orient ourselves more easily
in the differential diagnosis of the pathologies that are accumulated by
the presence of SIS.
In particular, in consideration of the finding of statistically
significant differences (Table 4) for all the ultrasound findings
studied between the group of acutely ill children compared to
that of bronchiolitis but also compared to that of healthy
patients , it was possible to find a specific ultrasound pattern of
cardio-pulmonary interactions.
This means that the finding in a child of a SIS with multiple, bright,
long, separate and non-confluent B-lines/long vertical artifacts
deriving from a normal and regular pleural line, in the absence of
subpleural consolidations, is strongly predictive of cardiogenic
pulmonary edema or pulmonary congestion in the course of systemic
inflammatory disease/sepsis (Figure 1).
Regarding the latter subcategory of acutely ill of patients, in our
clinical practice we have observed elevated levels of pro-BNP and lung
ultrasound findings suggesting a pulmonary imbibition picture even in
patients with systemic inflammatory pathology / sepsis in the absence of
cardiac dysfunction. Therefore we have decided to include in the
category of acutely ill children not only patients with heart
disease but also those with systemic inflammatory pathology with and
without cardiac dysfunction (such as rheumatic carditis, Kawasaki
disease, PIMS-ST, sepsis) with high levels of pro-BNP.
BNP and NT-proBNP are released into the bloodstream by cardiomyocytes in
response to stress and pressure placed on the atria and ventricles.
pro-BNP is a biomarker of cardiac overload associated with the severity
of cardiovascular disease14and the severity of
sepsis.15,16,17 It has long been proven that patients
show signs of heart failure during sepsis.14-17Indeed,
the destructive systemic inflammatory response and intensive
resuscitation occurring during sepsis result in widespread organ
overload and damage, including myocardial damage.15-17
However, today we know that in the course of sepsis and / or systemic
inflammatory disease, the increase in plasma levels of pro-BNP can be
present even in the absence of damage or dysfunction on the
cardiomyocytes.16,17 In particular, Meader and
colleagues and by Renana and colleagues16,28, have
shown that in patients with sepsis, the level of BNP in the blood
increases even without heart failure and that it is positively
correlated with the level of CRP, suggesting the role of inflammation in
the increase of BNP.16,28 Furthermore, experimental
studies17,29 have shown that endotoxins and
pro-inflammatory cytokines released in conspicuous quantities during
sepsis or systemic inflammation, as well as playing a direct role on
cardiac toxicity, directly increase the gene expression of the BNP in
cardiomyocytes. This would explain the higher levels of this biomarker
(positively correlated with the level of CRP and IL-6), in systemic
inflammatory processes even in the absence of significant organic or
functional cardiac alterations. 16,17,28,29
In this sub-category of acutely ill of patients with systemic
inflammatory disease / sepsis, we found a lung ultrasound picture of
pulmonary congestion. But, although none of our enrolled acutely ill
children developed ARDS during sepsis and / or systemic inflammatory
disease, we know that these patients can also develop an inflammatory of
ARDS pulmonary picture9,10,30 especially in the most
severe cases. In these cases, according to what emerged from our study,
LUS would support the clinic and laboratory data in distinguishing the
two conditions with different ultrasound patterns - congestion and
inflammation - with clinical implications, important diagnostics and
therapeutics.
We have also found that the distribution pattern of long vertical
artifacts (“with or without spared areas”) is influenced not only by
the severity and time of onset of pulmonary
congestion8, but also by the level of pro-BNP
and the type of pathology (cardiac disease, systemic inflammatory
disease / sepsis, cardiac disease and systemic inflammatory disease /
sepsis) which causes the increase in pro-BNP (Tables 5 and 6).
In fact, in the literature there is discussion on homogeneous septal
distribution “without spared areas” in the case of early cardiogenic
edema. In the later stages of pulmonary edema, the thickening of the
interlobular septa becomes excessive and goes beyond their capacity,
therefore alveolar flooding occurs when the secondary interlobular
septae are maximally distended by the transudative fluid. Flooding and
alveolar instability, together with the collapse of peripheral airspace,
generate many different types of acustic channels and consequently
different artifacts with many arrangements. Therefore, pulmonary
cardiogenic edema, in the later stages of the pathology, can lose the
ultrasound characteristic of the septal and homogeneous B lines and
increasingly tend to resemble the edema of early ARDS without
consolidation “with spared areas”.8,9,10
We found that in 85.71% of cases of children belonging to the group
with proBNP> 1000 pg / ml (most of these belong to the
group of heart disease with or without systemic inflammation / sepsis as
shown in Table 1 and Table 2 ) vertical artifacts are homogeneously
distributed “without spared areas” (as from early cardiogenic edema).
On the other hand, 100% of acutely ill patients with pro-BNP
<1000 pg / ml have destruction of long vertical artifacts
”with spared areas” (Table 5). However, the majority of children with
pro-BNP <1000 belong to the group of acutely ill children with
systemic inflammatory disease / sepsis in the absence of organic and /
or functional damage in the myocardium (Table 1, Table 3). Table 6 also
shows that 87.5% of patients with inflammatory pathology and / or
sepsis in the absence of cardiac dysfunction have a distribution of
artifacts ”with spared areas”. We therefore hypothesized that in this
subcategory of patients the distribution of artifacts can also be
influenced by the underlying inflammatory process. Due to the scarcity
of the comparison population, we can consider these results as
preliminary pending the execution of a study on a larger sample of
patients, in order to understand if there is a correlation between the
ultrasound results, their distribution and BNP levels and the type of
cardiac and / or inflammatory disease (Tables 5 and 6).
Recent studies and systematic reviews performed in adult patients have
shown that LUS can identify acute heart failure and pulmonary edema with
high sensitivity and specificity, demonstrating greater sensitivity and
specificity than chest x-ray.11,12,13
With our study we could not compare the ultrasound results with the
X-ray results because not all acutely ill children performed chest
X-rays. It has not been performed for example in children with a
diagnosis of heart disease already known or for those children for whom
it was not necessary to perform it by virtue of the diagnostic suspicion
already clear from the initial symptoms as in some cases of systemic
inflammatory disease/sepsis. Others, however, in particular children
with a diagnosis of not known heart disease in the acute phase (such as
acute heart failure in the course of unknown heart disease or acute
rheumatic carditis not known with atrioventricular overload) who
presented in the emergency room with cough and dyspnea or those
presenting with persistent fever (with subsequent diagnosis of systemic
inflammatory disease/sepsis) underwent chest x-rays to rule out
infectious respiratory disease.
As has happened in our clinical practice, -in some cases (as in the case
of mild and early pulmonary edema), the x-ray can be completely
negative; - in other cases (such as in the presence of pleural effusion
with consensual atelectasis), chest x-ray may be a confounding factor in
suspecting an quadro of pleuropneumonia; - and in still other cases (in
children who present a febrile clinical picture in the context of a
systemic inflammatory disease / sepsis) chest X-ray can once again
erroneously suspect a suspected viral infection and / or bacterial of
the lower airways as responsible for fever
peaks.3,4,12
All this obviously has implications in clinical practice: using only the
chest X-ray in the initial phase of the diagnostic process, there is a
risk of making an incorrect diagnosis with the risk of delaying the
correct diagnosis on one side and on the other side of administering
unnecessary therapies by making inappropriate use especially of
antibiotic therapy.
Therefore, in addition to the now well-known advantages of LUS in the
pediatric population (non-invasive, non-ionizing radiation tool
characterized by a rapid, affordable, point-of-care imaging modality
that allow both real-time diagnosis and follow-up of respiratory
diseases31-34), integrating LUS in the
earliest phase of the diagnostic process of acutely ill patients also in
the pediatric population allows for a greater possibility of earlier
diagnosis and appropriate diagnosis in light of the result of the
specific lung ultrasound pattern such as our results prove.
Our study has some limitations. First of all, due to the COVID-19
pandemic we have been able to enroll and evaluate a small number of
acutely ill patients.
Secondly, having a small patient population, despite being a
heterogeneous patient population by age, we were unable to stratify
patients according to age and evaluate differences with respect to LUS
findings and their distribution.
Finally, due to the scarcity of the comparison population, we could not
adequately analyze the presence or absence of correlations between the
ultrasound parameters analyzed, their distribution and the type of
pathology (cardiac disease, systemic inflammatory disease, cardiac
diasease and systemic inflammatory disease) and the values of pro-BNP,
thus obtaining preliminary results regarding this aspect.
In conclusions, the LUS pattern we described in our “acutely ill
children” population is in line with recent advances in SIS analysis
in preclinical models and adult patients with respiratory disease and/or
with cardiopulmonary interactions and reinforces the need to focus more
efforts on studies of LUS artifacts also on the pediatric population.
Dedicated software, algorithms and transducers, and artificial
intelligence are all needed to explore the information contained in US
signals.35 However, pending the development and
testing of new software that can obtain objective information
(quantitative and qualitative), our results confirm that the knowledge
of the different origin and the histological characteristics of the B
lines allows us to perform a qualitative and semi-quantitative analysis
of the SIS. In fact now, point-of-care physicians and sonographers can
also apply our results in the first-line work-up in the diagnostic
approach to this category of patients.
To date, it remains fundamental to have the clinical and laboratory
background of each patient as a guideline in the interpretation of SIS
even in acutely ill children . Indeed, new studies, including
preclinical ones along with the use of artificial intelligence, are
needed to validate our results.