1. Introduction
Respiratory Syncytial Virus Bronchiolitis (RSVB) is the leading cause of lower respiratory infection and hospital admission among children up to 2 years of age worldwide [
1]. Approximately 2–6% cases of RSVB will develop a severe form of the disease, requiring admission to the paediatric intensive care unit (PICU) and mechanical ventilation (MV) [
1,
2]. RSVB constitutes approximately 13% of all PICU admissions [
2]. Current guidelines recognize the identification of specific risk factors (congenital heart disease (CHD), chronic lung disease (CLD), prematurity, etc.) and clinical evaluation as the best tools to assess severity, predict evolution and tailor management [
3].
Cardiovascular involvement seems to be a relevant prognostic factor in RSVB. Cardiovascular complications are present in up to 9% of cases of RSVB and constitute the second most common extrapulmonary manifestation after infectious complications [
4]. These events usually present in an abrupt and unexpected manner in children with severe RSVB, and infants with CHD are particularly susceptible to these complications and adverse outcomes [
5]. Interestingly, nearly half of the children admitted to PICU with RSVB are healthy prior to the clinical event [
2]. In these patients, the presence of acute lung injury secondary to RSVB can also lead to important cardiovascular effects, especially elevated pulmonary vascular resistance and overload on the right ventricle (RV) [
6,
7,
8]. Moreover, previous studies assessing the plasma levels of cardiac troponin in RSVB suggest an underrecognized yet clinically significant incidence of myocardial damage in this population [
9,
10,
11]. Furthermore, RV global dysfunction in ventilated healthy infants has been reported [
12]. Recently, we found that mild to moderate forms of pulmonary hypertension (PH) could impact the outcome of healthy infants with RSVB [
13].
Adverse RV–LV interactions and left ventricle (LV) myocardial dysfunction (LVMD) are emerging as important determinants of PH outcomes. PH can induce complex changes in LV geometry and causes an abnormal relaxation and non-uniform contraction pattern in the LV wall, leading to LVMD [
14,
15,
16]. However, most studies in healthy infants with RSVB found no abnormalities when assessing LVMD through conventional echocardiographic parameters [
12,
13,
17,
18,
19]. Remarkably, there are no studies to date assessing LVMD in RSVB by more sensitive methods such as tissue Doppler imaging (TDI) echocardiography.
N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a hormone synthesized and released into the circulation by ventricular myocytes in response to pressure/volume overload and an increase in myocardial wall stress [
20]. Elevated serum NT-proBNP levels have been defined as a powerful biomarker in the diagnosis of PH, and both LVMD and RV myocardial dysfunction (RVMD) secondary to pulmonary diseases [
21,
22,
23,
24,
25]. Of note, we recently showed how NT-proBNP could be considered an adequate biomarker for PH in previously healthy infants with RSVB [
13].
In this study, we aimed to investigate the presence of adverse RV–LV interactions and LVMD (assessed by TDI-echocardiography) in previously healthy infants with RSVB. We hypothesized that acute PH with RV pressure overload may indeed have a direct impact on LV performance. We also hypothesized that those infants with LVMD are prone to developing a more severe form of disease. Finally, we sought to test NT-proBNP as a biomarker for LVMD and explore whether NT-proBNP increases the accuracy of traditional clinical markers in predicting the severity of the disease.
4. Discussion
The main finding of our study is that LVMD was observed at the early stages of the disease in up to 18% of previously healthy infants with RSVB when assessed by DTI-derived LVTX. The LVMD was associated with a more severe respiratory state, PICU admission, and echocardiographic signs of RV pressure overload and RVMD, indicating the presence of adverse RV–LV interactions in cases of severe RSVB. Also, we observed that NT-proBNP accurately identified LVMD. Moreover, we found an added benefit to the addition of NT-proBNP to the clinical evaluation in predicting the development of severe disease in this population.
CHD is an important cause of morbidity and mortality in RSVB [
5]. This may be related to multiple physiological factors including baseline compromised cardiorespiratory function and the potential development of PH. However, little is known about LVMD and its association with RV function, pulmonary hemodynamics, and outcomes in previously healthy infants with RSVB. In accordance with the literature, the present study reveals that conventional parameters of myocardial function are not altered in RSVB [
17,
18,
19]. Only one previous study has assessed myocardial performance using the TEI index in RSVB [
12]. Our results are consistent with those reported by Thorburn et al. who found RVMD in ventilated patients with severe RSVB. However, they did not demonstrate any association between PH and RVMD. This may be due to the use of TRJG alone as an echocardiographic marker of RV pressure, and the presence of PH may had been underestimated. In a recent work from our group, we used a combination of different echocardiographic parameters to assess RV pressures and PH was reported in up to 22% of RSVB cases at early stages of the disease. In agreement with Thorburn et al., we did not find an association between PH and RV or LVMD [
13]. We assessed ventricular function only by conventional parameters (TAPSE and LVSF).
To the best of our knowledge, this is the first study to evaluate LVMD using TDI-derived LVTX, and to assess RV–LV interactions in infants with RSVB. LVTX, which includes both systolic and diastolic time intervals to assess the global cardiac dysfunction, is an easily performable, recordable and reproducible parameter with normal reference values that can be applied to the entire spectrum of the paediatric population, regardless of age, heart rate, and BSA [
36]. Using LVTX, we found LVMD in nearly 20% of cases. The RV shares muscle fibres, the inter-ventricular septum (IVS), and the pericardial sac with the LV. Consequently, changes in RV affect the LV, a concept termed ventricular interdependence [
16,
37,
38]. In this study, we observed a moderate to strong correlation between LVTX and leftward displacement of the IVS (LVEI), raised RV pressures (TRGJ, ATET) and reduced RV global function (RVTX), confirming the presence of adverse RV–LV interactions in cases with severe RSVB. These results do not imply casualty, but in the absence of primary (myocarditis, cardiomyopathies, CHD) or secondary (sepsis, severe acidosis...) causes of LVMD, we suggest RV pressure overload and RV dysfunction due to pulmonary disease as the underlying condition for LVMD in our RSVB cohort. Recent paediatric studies have reported that PH can induce complex changes in LV geometry and causes an abnormal relaxation and non-uniform contraction pattern in the LV wall, leading to LVMD [
14,
15,
16], supporting our hypothesis. These observations could add new insights into the pathophysiology of RSVB, highlighting a key role of the cardiovascular system, especially LV myocardial performance in this setting. Validating our findings in similar populations in different settings may also provide a basis to implement new therapeutic approaches for this disease, which currently has no effective treatment. Possible new therapeutic approaches may include the initiation of early respiratory support in cases with increased NT-proBNP, pulmonary vasodilators to reduce RV pressure overload and avoiding epinephrine in cases with LVMD.
In RSVB, the major goals are the prevention and early identification of infants at risk for severe disease in order to provide the best management options and decrease morbidity. Current guidelines recommend only clinical observation for this purpose in infants without known comorbidities [
3]. However, most clinical scores for RSVB are not well validated and fail to predict outcomes [
39,
40]. Recently, the BROSJOD score, a validated clinical score for RSVB, has shown a strong capacity to predict the evolution in the course of RSVB, but it is not yet generalizable due to the single-centre character of the study [
26]. In this context, the identification of novel biomarkers with adequate predictive value for disease severity in RSVB is an area of increasing research interest. Neutrophins, cytokines and leukotrienes are promising but not widely available for clinical practice [
41]. Previous studies have also tested cardiac troponin as a prognostic marker with inconsistent results [
9,
10,
12,
13]. The LVMD found in our population was only identifiable by TDI-echocardiography, suggesting that it was mild in most of our patients. Nevertheless, this does not mean that LVMD is inconsequential in RSVB. Remarkably, most patients with LVMD presented with severe disease at admission and most of them required PICU admission. Of note, we included non-ventilated infants at early stages of the disease (mean time of 2.76 (1.23) days after the initial symptoms), when the patients had not yet been admitted to the PICU, increasing the prognostic value of our results. Therefore, assessing and understanding myocardial function in RSVB seems to be relevant.
Another interesting finding of our study was that NT-proBNP could be a useful biomarker for LVMD and subsequent outcomes in RSVB. Previous studies have also documented the correlation between LVTX and NT-proBNP plasma levels [
42,
43,
44]. We explored the diagnostic accuracy of NT-proBNP to detect LVTX > 0.50, which was high (AUC 0.91), with an optimal cut-off value of 1500 pg/mL (Se 0.80, Sp 0.95, PPV 0.80, NPV 0.95). We also tested the benefit in adding NT-proBNP to the currently used clinical data to assess outcomes in RSVB. Although the predictive models including age and BROSJOD score presented a high predictive accuracy for PICU admission in our population, we observed that the addition of NT-proBNP to this model increased the predictive value significantly, and that NT-proBNP was the only independent factor within the analysed values that predicted a severe course of the disease. Most cases of RSVB are mild forms manageable on an outpatient basis without the need for laboratory exams. Nevertheless, many children sufficiently ill to require hospitalization will routinely have laboratory studies drawn. Adding NT-proBNP measurement to these studies could be useful in order to identify high-risk patients who benefit from echocardiographic screening to PH, RVMD or LVMD. Based on our results, it might be reasonable to perform an echocardiogram in those patients with NT-proBNP levels > 1500 pg/mL.
This work included some limitations. Our study was performed at a single centre and with a relatively small size. We excluded irritable or unstable patients, where the technical difficulties due to respiratory comorbidity and the patient’s inability to tolerate the evaluation could impact the results. The PICU admission criteria and, subsequently, the definition of severe diseases in the study are based on the protocol of our hospital, which can vary between institutions. Therefore, a larger multicentre cohort study including irritable or unstable cases and with uniform PICU admission criteria may be needed for the verification and generalization of our results. Finally, the assessment of myocardial function and PH on echocardiography was not confirmed by an independent gold-standard method, such as cardiac magnetic resonance imaging or right heart catheterization, and therefore some patients could have been misclassified.