European Journal of Cardiovascular Medicine

Acute bronchiolitis (AB) is one of the most common lower respiratory tract illnesses in children under two years of age and contributes substantially to global morbidity and healthcare burden. In 2019, nearly 33 million respiratory syncytial virus (RSV)–associated lower respiratory tract infections were reported worldwide, with 3.6 million hospitalizations and approximately 26,300 deaths.[1] AB is defined as an acute inflammatory injury of the bronchioles, which is most commonly of viral origin.[2] Although the disease is usually mild and self-limiting, a proportion of infants develop severe respiratory distress requiring hospitalization, and nearly 5% progress to critical illness necessitating pediatric intensive care and advanced respiratory support, including mechanical ventilation, with risk of mortality if not managed appropriately.[3] Early identification of infants at risk for severe disease is therefore essential. While prematurity, bronchopulmonary dysplasia, congenital heart disease (CHD), immunodeficiency, and Down syndrome are recognized risk factors, several studies indicate that the majority of hospitalized infants lack these conditions, and nearly half of those admitted to intensive care were previously healthy.[4]

RSV is the most common etiological agent of bronchiolitis, followed by parainfluenza virus, influenza virus, human metapneumovirus, coronavirus, adenovirus, and rhinovirus.[5] In India, RSV accounts for approximately 30%–70% of bronchiolitis cases, with seasonal peaks during the rainy and winter months from September to March.[6] Clinically, AB typically presents with a prodrome of upper respiratory symptoms followed by cough, tachypnoea, wheeze, and crackles, predominantly affecting infants younger than one year, with peak severity around the fourth day of illness.[2] Severe disease is characterized by poor feeding, hypoxemia, chest retractions, accessory muscle use, and apnoea, the latter being an important marker of impending respiratory failure. Management remains primarily supportive, with respiratory support ranging from supplemental oxygen to high-flow nasal cannula therapy and mechanical ventilation, along with maintenance of adequate hydration.[7]

Cardiovascular involvement in acute bronchiolitis is increasingly recognized and clinically significant. In infants with CHD, severe disease is attributed to compromised cardiopulmonary reserve, altered pulmonary vascular regulation, ventilation–perfusion mismatch, pulmonary hypertension, and myocardial dysfunction.[8] Importantly, cardiovascular complications have also been reported in previously healthy infants, including arrhythmias, bradycardia, myocardial dysfunction, shock, and need for inotropic support, occurring in up to 9% of cases, particularly among those requiring intensive care.[9] Emerging evidence suggests that serum vitamin D plays an immunomodulatory role in bronchiolitis, especially in RSV infection.[10] Vitamin D deficiency at birth, defined as umbilical cord blood levels below 20 ng/mL, has been identified as a risk factor for RSV-associated lower respiratory tract infection in infancy.[11] Although vitamin D status may influence susceptibility, its impact on disease severity remains unclear, which is clinically relevant given the association of severe bronchiolitis with long-term respiratory morbidity such as asthma.[12] Low serum vitamin D levels have also been linked to ventricular dysfunction, heart failure, and pulmonary hypertension in pediatric conditions,[13] and myocardial dysfunction and pulmonary hypertension have been shown to predict adverse outcomes in severe bronchiolitis.[14]

The present study aimed to evaluate the relationship between serum vitamin D levels and cardiopulmonary status in children aged 2 months to 2 years diagnosed with acute bronchiolitis. This prospective observational study was conducted over 18-month period from 1st January 2023 to 30th June 2024 in the Pediatric Intensive Care Unit (PICU), Department of Paediatrics, Dr. B. C. Roy Post Graduate Institute of Paediatric Sciences, Kolkata, West Bengal. All consecutive children fulfilling the predefined case definition of acute bronchiolitis were enrolled,[2] resulting in a total sample size of 96. Acute bronchiolitis was defined as persistent cough following a prodrome of coryza, accompanied by tachypnoea and clinical signs of respiratory distress such as chest retractions or grunting, with or without fever (temperature <39°C), occurring in children within the specified age group. Children admitted to pediatric general wards, high-dependency units, or PICU with a diagnosis of acute bronchiolitis were included. To reduce potential confounding, children with known or incidentally detected congenital structural heart disease, congenital lung disease, chest wall or diaphragmatic deformities, previously diagnosed malnutrition, or chronic cardiac, renal, endocrine, or metabolic disorders were excluded. A detailed clinical assessment was performed for all enrolled patients, including documentation of demographic characteristics, presenting symptoms, severity of illness, need for respiratory support, duration of hospitalization, requirement for intensive care, and clinical outcomes. Cardiopulmonary evaluation included electrocardiography and comprehensive transthoracic echocardiography. Pulmonary hypertension was assessed by echocardiography and graded based on right ventricular systolic pressure (RVSP). Mild pulmonary hypertension was defined as RVSP one-third to one-half of systemic pressure, with mild right ventricular dilation or hypertrophy, systolic septal flattening, and preserved right ventricular function. Moderate pulmonary hypertension was defined as RVSP between one-half and two-thirds of systemic pressure, with moderate right ventricular dilation or hypertrophy and possible right ventricular dysfunction. Severe pulmonary hypertension was defined as RVSP greater than two-thirds of systemic pressure, presence of predominant right-to-left shunting when applicable, septal flattening throughout the cardiac cycle, left ventricular compression, marked right ventricular dilation, and right ventricular dysfunction. Left ventricular systolic function was assessed using ejection fraction (EF), calculated from end-diastolic and end-systolic volumes [15]. An EF ≥55% was considered normal, 41–55% mild systolic dysfunction, 31–40% moderate systolic dysfunction, and ≤30% severe systolic dysfunction. Laboratory investigations of serum vitamin D levels were sent on day 1 of enrolment in the study, and according to the level patients were categorized as deficient (<20 ng/mL) or sufficient (≥20 ng/mL). Cardiac biomarkers, including Troponin-T, NT-proBNP, and ferritin, were measured to assess myocardial involvement. Chest radiography was done to evaluate pulmonary pathology, and respiratory viral panel testing was conducted to identify viral etiology. Echocardiographic evaluation was done, measurements were taken over three consecutive cardiac cycles, and the mean was taken to improve accuracy. Data were entered into Microsoft Excel and analysed using SPSS version 24. Continuous variables were expressed as mean ± standard deviation, while categorical variables were presented as frequencies and percentages. Appropriate statistical tests, including the Mann–Whitney U test and Chi-square test, were applied, and a p-value <0.05 was considered statistically significant. This study was approved by the institutional ethical committee and ethical standards on human experimentations were complied with and informed consent was taken.

Among the study subjects of 96 children age group 2 months to 2 years, 58(60.4%) of the subjects were male, and 38(39.6%) were female. No significant gender differences were found in vitamin D levels, with males and females almost equally distributed in both deficient and sufficient groups. The mean vitamin D level was 23.52±9.40 ng/ml. Among total subjects(n=96), 44(45.8%) subjects had deficient vitamin D (<20ng/ml) among which male were 59.1% (n=26) and female were 40.9% (n=18). Mean age of subjects in deficient group is 10.27+/-3.61 month and sufficient group was 11.71±4.97 months. Vitamin D deficiency was among more than one third of patients (45.8%). Vitamin D deficiency was higher among female patients (48.7%) compared to males (43.9%) with insignificant association (p>0.05).

Age-wise distribution indicated that 72.7% of children under 1 year had vitamin D deficiency, while 61.5% of children over 1 year had sufficient levels. However, this difference was not statistically significant (p=0.24). The mean age of children with vitamin D deficiency was 10.27±3.61 months, compared to 11.71±4.97 months in those with sufficient levels, also showing no significant difference (p=0.24).

Table 1 showed statistically significant increase in duration of fever, cough, respiratory distress, invasive ventilation days in vitamin D deficient children (p<0.001). There was significant negative correlation was found between vitamin D levels and PICU stay duration (r=-0.673, p<0.001). Children with lower vitamin D levels had longer PICU stays.

Table 2 and 3 showed that children with vitamin D deficiency had significantly higher NT-proBNP (5306.73±3727.02 pg/ml) and ferritin levels (507.52±441.43 ng/ml) compared to those with sufficient vitamin D levels (NT-proBNP: 1687.27±1743.51 pg/ml, Ferritin: 222.96±146.13 ng/ml, both p<0.001). These findings indicated more severe cardiac stress and inflammation in vitamin D-deficient children.

Table 4 showed that pulmonary arterial hypertension (PAH) severity also varied significantly with vitamin D levels. A greater proportion of children with sufficient vitamin D levels had no PAH (51.9%) or mild PAH (32.7%) compared to those with deficient levels (22.7% and 15.9%, respectively). Conversely, moderate and severe PAH were more common in vitamin D-deficient children (43.2% and 18.2%, respectively) than in those with sufficient levels (13.5% and 1.9%, respectively, p<0.01).

Cardiac dysfunction was more prevalent in vitamin D-deficient children. Normal cardiac function was observed in 69.2% of children with sufficient vitamin D, compared to only 27.3% of those with deficient levels. Severe left ventricular dysfunction was observed exclusively in the vitamin D-deficient group (18.2%, p<0.001).

ECG findings showed no significant difference between the groups, with normal ECGs in 54.5% of deficient and 69.2% of sufficient children (p=0.13). Sinus tachycardia was slightly more common in the deficient group (45.5%) compared to the sufficient group (30.8%).

Chest x-ray findings revealed bilateral hyperinflation in the majority of subjects, with no significant difference between the groups (81.8% in deficient vs. 76.9% in sufficient, p=0.55). Patchy bilateral opacity was noted in 18.2% of deficient and 23.1% of sufficient children.

Final outcomes showed a higher discharge rate in children with sufficient vitamin D levels (100%) compared to those with deficiency (90.9%). There were 4 deaths in the vitamin D -deficient group and none in the sufficient group, indicating a significant difference in mortality (p=0.04).

Respiratory viral infections varied, with RSVB being the most common (53.1%), followed by Rhino (26.0%), Adeno (15.6%), and HMPV (5.2%). Cardiac dysfunction was significantly associated with the type of viral infection (p=0.04), with RSVB linked to the highest incidence of moderate left ventricular dysfunction. Figure 1 and 2 showed distribution of PAH and left ventricular dysfunction according to the respiratory viral infection pattern.

Table-1: Comparison of Vitamin D level with duration of symptoms and INV(invasive mechanical ventilation days (n=96)

¹Unpaired t-test, *Significant

Table:2 Mean NT pro-BNP level and Ferritin level according to vitamin D level (n=96)

¹Mann-Whitney U test, *Significant                                                                                            

Table :3 Correlation of Vitamin D level with NTpro-BNP level and ferritin level in study subjects

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applying Pearson coefficient to test correlation in sample size n=96

Table:4 correlation of pulmonary arterial hypertension(PAH), and left ventruclar function in study subjects according to vitamin D level (n=96)

Figure 1: Left ventricular cardiac dysfunction according to types of respiratory viral infection

Figure 2: Grades of PAH (pulmonary arterial hypertension) according to types of respiratory viral infection

Acute bronchiolitis is generally a self-limiting illness in infancy and early childhood; however, a subset of affected children may develop severe disease with life-threatening complications. Vitamin D plays an important role in innate immune defence during lower respiratory tract infections by enhancing mucociliary clearance, maintaining epithelial integrity, and modulating inflammatory pathways. Although, the relationship between vitamin D status, disease severity, and associated cardiopulmonary involvement in bronchiolitis remains incompletely understood [16]. Chinellato et al,2021 have described that the level of baby cord vitamin D levels is inversely associated with the occurrence of acute respiratory tract infections. [17]

Rodriguez-Gonzalez et al,2022 have found that severe lung involvement can be accompanied by a significant impairment of the cardiovascular status in acute bronchiolitis.[18] Increased troponin I level, and echocardiographic measures indicative of pulmonary hypertension and right ventricular diastolic dysfunction have been observed earlier in patients with hypoxia and acidosis.

Cardiac biomarker NT-proBNP is secreted by myocytes in response to increased stress, and it is an accurate diagnostic and prognostic biomarker of heart failure and pulmonary hypertension. [19] Notably, we observed that infants with vitamin D deficiency(<20ng/ml) had increased rates of abnormal echocardiographic parameters indicative of pulmonary hypertension and myocardial dysfunction, with increased values of NT-proBNP. Vitamin D exerts its action through the vitamin D receptor, which has also been localized in the cardiovascular system on vascular smooth muscle cells, endothelial cells, and cardiomyocytes. Vitamin D exerts cardioprotective actions and regulates cardiac function by modulating serum and calcium parathyroid hormone levels. Vitamin D also exerts an inhibitory action on the renin-angiotensin-aldosterone axis in vitro, such that hypovitaminosis D can increase the renin levels, promoting arterial hypertension, myocardial hypertrophy, and raised plasma levels of natriuretic peptides. Vitamin D deficiency is associated with the development of dilated cardiomyopathy with severe hypocalcemia in infants with nutritional rickets and the development of pulmonary hypertension. [20]

In this study, vitamin D deficiency (<20 ng/ml) was found in more than one-third of patients (45.8%). Yalaki et al (2019) observed that Vitamin D deficiency was found in 36.9% and vitamin D insufficiency was found in 33.8% of the acute bronchiolitis patients.[21]

Golan-Tripto et al (2021) described that serum 25(OH) vitamin D levels were notably lower in the bronchiolitis group; median [28 vs. 50 nmol/L, respectively, (p = 0.005) than in controls. Deficient vitamin D levels (< 50 nmol/L) were found more frequently in the bronchiolitis patients than in controls; 73% vs. 51% (p = 0.028).[22]

In this study, it was found that more than half of patients were <12 months of age (66.7%) followed by ≥12 months (33.3%). The mean age of patients was 11.10±4.47 months. Yalaki et al (2019) reported that the median age of 130 acute bronchiolitis patients was 8 months.[21]

In the current study, vitamin D deficiency was higher among patients of age <12 months (50%) compared to ≥12 months (37.5%), with an insignificant association (p>0.05). In contrast to this study, Rahmati et al (2020) showed that there was a statistically significant difference between the mean age in the two study groups (between with and without vitamin D deficiency) (P=0.007). [23]

More than half of patients were males (60.4%) in this study. Similarly, a study conducted by Rahmati et al (2020) found that of the 85 patients, 62.4% and 37.6% were males and females respectively.[23] In the study by Mahyar et al (2017), of the 57 children with acute bronchiolitis, 38 children (66.6%) were males and 19 (33.4%) females. [24]

In our study showed that vitamin D deficiency was higher among female patients (48.7%) compared to males (43.9%) with an insignificant association (p>0.05). In the study by Yalaki et al (2019), male patients who were given prophylactic vitamin D had significantly higher 25 (OH) vitamin D levels than other groups (p< 0.05). [21]

In the present study, the duration of fever, cough and respiratory distress was significantly (p=0.001) higher among patients with vitamin D deficiency than without deficiency.

In this study, RSVB was the most common respiratory panel (53.1%) followed by RHINO (26%), ADENO (15.6%), and HMPV (5.2%). Yalaki et al (2019) reported that 25 (OH) D vitamin D level of the patients with RSV infection was 21.9 ng/mL (3.09-58.7), and it was 24.2 ng/mL (3-57.9) in other viral swab specimens, and a statistical difference was not present (p= 0.058). [21] Vitamin D deficiency (<20ng/ml) was detected in 40.3% of the patients with RSV infection and vitamin D sufficiency (>=20ng/ml) in 36.1% of the patients (p= 0.289). In the study by Estalella-Mendoza et al (2022), the most prevalent (70%) causative agent was RSV.[25]

Viruses are the most common cause of respiratory tract infections in children. These viruses can lead to a clinical picture without symptoms or severe infections necessitating intensive care. RSV, which leads to both upper and lower respiratory tract infections, is the most common cause of respiratory tract infections in children worldwide.

The study conducted by Beigelman et al, 2015 found that vitamin D deficiency, which also plays a part in the development of immunity, has been reported to be of utmost importance in bronchiolitis that develops with RSV.[11]

In this study, it was observed that serum vitamin D level <20ng/ml was found to be maximum among patients with RHINO virus respiratory panel (52%) and was lowest among ADENO & HMPV (40%). Although there was no significant (p>0.05) association of Vitamin D deficiency with the respiratory viral panel. Adenovirus was associated with a larger number of patients with severe left ventricular dysfunction and PAH, only second to RSVB, though it was not statistically significant.

In this study, the mean total duration of PICU/HDU stay was significantly (p=0.001) higher among patients with vitamin D deficiency (6.02±1.06 days) than sufficiency (2.96±0.96 days). In the present study, the mean NIV days was significantly (p=0.001) higher among patients with vitamin D deficiency (4.41±0.84 days) than sufficiency (2.52±0.67 days). This study showed that the mean INV days was significantly (p=0.001) higher among patients with vitamin D deficiency (1.09±1.19 days) than sufficiency (0.17±0.43 days). Estalella-Mendoza et al (2022) showed that low 25-OHD levels were associated with increased risk for PICU admission (OR 3.9 (95% CI 1.5-10.1); P=0.004), higher rates of non-invasive ventilation, (P= 0.048), mechanical ventilation (P=0.005), and longer duration of hospitalization (P=0.015).[25]

In this study, CRP <0.6 mg/dl was among majority of patients (83.3%) in the current study. This study found that vitamin D deficiency was higher among patients with CRP >0.6 mg/dl (50%) than <0.6 mg/dl (45%) with an insignificant (p>0.05) association.

In this study, the mean NT proBNP was significantly (p=0.001) higher among patients with vitamin D deficiency (5306.73±3727.02 pg/ml) than sufficiency (1687.27±1743.51 pg/ml). Similar to the current study, in the study by Estalella-Mendoza et al (2022) found that the median serum NT - ProBNP levels were higher in those with low 25 - OHD levels than normal 25 - OHD levels [2232.2 and 830.4] (pg/ml), respectively; P=0.003.[25]

Mild and moderate PAH were each in 26% patients. Severe PAH was in 9.4% patients in this study. This study found that vitamin D deficiency was higher among patients with severe PAH (88.9%) than moderate (72%) and mild (2%), with a significant (p=0.001) association.

In this study, the mean ferritin was significantly (p=0.001) higher among patients with vitamin D deficiency (507.52±441.43) (ng/ml) than the sufficiency group (222.96±146.13) (ng/ml).

This study showed that mild and moderate ventricular dysfunction each occurred in 20.8% patients. Severe ventricular dysfunction was present in 8.3% patients. It was found  that vitamin D deficiency was among all patients with severe ventricular dysfunction (100%), with a significant (p=0.001) association. In the study by Estalella-Mendoza et al (2022), 43 (47%) patients had serum below 20 ng/ml with left ventricle dysfunction (P=0.008), right ventricle dysfunction (P=0.008), and pulmonary hypertension (P=0.007) on echocardiography than those with serum 25 - OHD > 20 ng/ml. [25]

Sinus tachycardia on ECG was found in 37.5% patients in this study. In this study, vitamin D deficiency was higher among patients with sinus tachycardia on ECG (55.6%) than in normal ECG (40%) with an insignificant (p>0.05) association.

In this study, Bilateral hyperinflation on CXR was among the majority of patients (79.2%) followed by Bilateral Patchy opacity (20.8%).  Vitamin D deficiency was higher among patients with bilateral hyperinflation on CXR (47.4%) than bilateral Patchy opacity (40%), with an insignificant (p>0.05) association.

Mortality was 4.2% in this study. This study showed that mortality was among all patients in whom Vitamin D deficiency (< 20ng/ml) was present (100%), with a significant (p<0.001) association.

It is possible that hypovitaminosis favours a baseline subclinical myocardial dysfunction in infants that could worsen in the acute respiratory setting, leading to the development of a severe course of the disease. Nevertheless, the pathophysiology of hypovitaminosis D causing altered cardiovascular status might be different in acute respiratory disease and in a chronic cardiovascular setting. The lack of immunomodulatory effect of vitamin D in deficiency states would lead to more severe airway inflammation and subsequent hypoxemia, acidosis, leading to raised pulmonary pressures and myocardial dysfunction (Skaaby et al, 2017).[26]

Therefore, early screening of vitamin D in severe bronchiolitis children requiring ICU admission might help to predict the stormy course and cardiorespiratory status in those children in ICU, and might help in decision making and better management of these patients.

This study demonstrated that vitamin D deficiency in children with acute bronchiolitis was associated with longer PICU stays, higher levels of cardiac biomarkers, LV dysfunction, PAH, and increased mortality. These findings underscore the importance of maintaining adequate vitamin D levels to potentially improve clinical outcomes in pediatric acute bronchiolitis.

LIMITATIONS

Due to limit time period, smaller sample space, single centre study, inadequate history taking of feeding history, sunlight exposure and dose of vitamin D supplementation decreases the validity of the study to generalised population. Serial measurements of hemodynamic variables instead of single point observation could have provided more real time information as the hemodynamic status is subjected to change. Right Ventricular function could have been assessed in details. only acute bronchiolitis cases were included in the study. No controls were included in respect to bronchiolitis; hence, the risk factors could not be assessed.

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