Article
Title: Left ventricular myocardial dysfunction secondary to adverse
ventricular-ventricular interactions in previously healthy infants with
Respiratory Syncytial Virus Bronchiolitis…
Moises Rodriguez-Gonzalez 1,4*, Alvaro Antonio
Perez-Reviriego1,4, Ana
Castellano-Martinez2,4, Simon
Lubian-Lopez3,4 and Isabel
Benavente-Fernandez3,4
1 Pediatric Cardiology Division, Puerta del Mar
University Hospital, Cadiz, Spain;doctormoisesrodriguez@gmail.com;alvaro.apr@hotmail.com
2 Pediatric Nephrology Division, Puerta del Mar
University Hospital, Cadiz, Spain;anacastellanomart@gmail.com
3 Neonatology Division, Puerta del Mar University
Hospital, Cadiz, Spain;isabenavente@gmail.com;slubian@yahoo.es
4 Biomedical Research and Innovation Institute of
Cadiz (INiBICA), Research Unit, Puerta del Mar University Hospital
* Correspondence: doctromoisesrodriguez@gmail.com.
Received: date; Accepted: date; Published: date
Abstract: Aim: To investigate if the presence of left
ventricular myocardial dysfunction (LVMD) assessed by Tei index (LVTX)
may have a direct impact on the outcomes in Respiratory Syncytial Virus
bronchiolitis (RSVB), and if NT-proBNP will increase the accuracy of
traditional clinical and laboratory markers in predicting the severity
of the disease. Methods: A single-centre, prospective, cohort study
including healthy infants aged 1-12 month-old admitted due to RSVB
between October 1, 2016 and April 1, 2017. All patients underwent
clinical, laboratory and echocardiographic evaluation within 24 hours of
admission. PICU admission was defined as severe disease. Results: We
enrolled 50 cases of RSVB (median age of 2 (1-6.5) months; 40% female)
and 50 age-matched controls. We observed higher values of LVTX in
infants with RSVB than in controls (0.42 vs 0.36; p=0.008). A total of 9
(18%) cases presented LVMD (LVTX>0.5), with higher
incidence of PICU admission (89% vs 5%; p<0.001). The
diagnostic performance of NTproBNP to predict LVMD in infants with RSVB
resulted high (AUC 0.91 (CI95% 0.79-0.98). The diagnostic yield of the
predictive model for PICU admission that included NTproBNP was excellent
(AUC 0.945, CI95% 0.880-1), and significantly higher than the yields
for models without NTproBNP. Conclusions: LVMD could be present in
healthy infants with RSVB, negatively impacting the outcome. NTproBNP
seems to be an adequate biomarker for LVMD and subsequently outcome.
Keywords: Respiratory Syncytial Virus; NT-proBNP;
Echocardiography; Pulmonary hypertension; Myocardial dysfunction; Tissue
Doppler Imaging; Tei Index; Biomarkers; Infants.
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 disease, requiring ad mission at the pediatric
intensive care unit (PICU) and mechanical ventilation (MV) [1,2].
RSVB constitutes approximately 13% of all PICU admissions [2].
Current guidelines recognise identification of specific risk factors
(congenital heart disease (CHD), chronic lung disease (CLD),
prematurity, etc.) and clinical evaluation as the best tools to asses
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 extra pulmonary
manifestations after infectious complications [4]. These events
present usually in an abrupt and unexpected manner in those children
with severe RSVB, and infants with CHD are particularly susceptible to
have these complications and adverse outcomes [5]. Interestingly,
nearly half of 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 raising pulmonary vascular resistance and
overloading the right ventricle (RV) [6-8]. Moreover, previous
studies assessing plasmatic levels of cardiac troponin in RSVB suggest
an underrecognized but yet clinically significant incidence of
myocardial damage in this population [9-11]. Furthermore, RV global
dysfunction in ventilated healthy infants has been reported [12].
Recently, we found that mild to moderate forms of 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 a non-uniform contraction pattern in the LV
wall, leading to LVMD [14-16]. However, most studies in healthy
infants with RSVB found no abnormalities when assessing LVMD through
conventional echocardiographic parameters [12,13,17-19]. 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
[21-25]. Of note, we recently showed how NTproBNP could be
considered an adequate biomarker for PH in previously healthy infants
with RSVB [13].
In this study we aimed to investigate the adverse RV-LV interactions and
LVMD through 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 develop a more severe form of disease.
Finally, we sought to test NT-proBNP as a biomarker for LVMD, and to
explore if NT-proBNP will increase the accuracy of traditional clinical
and laboratory markers in predicting the severity of the disease.
2. Materials and Methods
2.1. Design, settings and study population:
This was a single-centre, prospective, cohort study including infants
aged 1-12 month-old admitted to the Pediatric Department of our
institution (a tertiary university-affiliated hospital in Spain) due to
RSVB (determined by a confirmed RSV antigen testing) between October 1,
2016 and April 1, 2017. All patients underwent clinical, laboratory and
echocardiographic evaluation within 24 hours of admission. We excluded
patients with co-existing CHD or CLD, prematurity, those that received
MV or intravenous fluid before assessment, and those with poor quality
echocardiographic images or incomplete medical records. Severe cases
were screened for coinfection and if existed they were also excluded.
The control group consisted of age-matched healthy infants who underwent
evaluation for heart murmur at our Pediatric cardiology outpatient
clinic during the study period. These controls followed the same
echocardiographic protocol as study patients. Our Institutional Review
Board approved the study. Informed consent was obtained for all
patients.
2.2. Clinical and laboratory assessment and outcomes:
The bronchiolitis score of Sant Joan de Déu (BROSJOD) [26]was used to assess severity at admission clinically. A BROSJOD score
greater than 10 points is indicative of severe clinical state. Venous pH
and pCO2 were determined, and respiratory acidosis (RA) was considered
when pH<7.35 and pCO2>45 mmHg coexisted in the
same patient. Plasma NT-proBNP levels at admission were determined using
a commercially available electrochemiluminescent immunoassay kit
(ElecSys 2010, Roche Diagnostics). The primary outcome was PICU
admission during the hospitalization. PICU admission criteria for RSVB
at our institution rely on the presence of: apnea, extreme bradycardia,
need of respiratory support greater than high-flow nasal cannula oxygen
therapy, or inotropic support.