Clinical features of respiratory syncytial virus bronchiolitis in an infant: rapid and fatal brain involvement

Respiratory Syncytial Virus (RSV) infection is a significant cause of hospitalization and infant death worldwide [1]. It affects 60–70% of children by the age of 1 year and almost all children by 2 years of age and it is mostly responsible for 45–90% of episodes of bronchiolitis and 15–35% of pneumonia [2, 3]. However, in recent years the importance of extrapulmonary RSV manifestations, such as neurological, myocardial or endocrine, have become evident [4, 5].

Focusing on neuropathy, the most reported clinical signs and symptoms are seizures (reported in 7% of children and 12.9% of newborn), apnoeas, lethargy, ataxia, status epilepticus, encephalopathies and encephalitis [5‐9].

The pathophysiological mechanism of encephalopathy associated with acute bronchiolitis remains undefined, but a direct invasion of the central nervous system by RSV seems to be the major mechanism responsible for cerebral involvement in RSV disease [4, 10]. As reported by Li et al. (2006), RSV can infect pulmonary neurons and interact with the chemokine receptor for CX3CL1 (CX3CR1) expressed in these cells, overrunning the Central Nervous System with resulting neurological abnormalities in patients [11].

Here, we report a case of an infant admitted with RSV-related severe bronchiolitis and a consequential rapid neurological involvement, resulting in a fatal outcome.

A 40-day old male infant was admitted to the Emergency Department (ED) with bronchiolitis and dyspnea. He showed no comorbidities during pregnancy, he was born at full-term and normal.

At the time of admission, the patient was reported to be coughing for a week, worsening with a vomiting episode in the previous two days and reduction of feeding. Diuresis was regular. At the same time, he was treated with nasal and aerobic salbutamol administration. Patient’s parents also reported an older sister with phlogosis of upper respiratory tract.

The physical examination highlighted persistent dry cough, globus abdomen, marbled skin with thoracic rush, respiratory rate of 52 breaths/minute, heart rate of 160 beats/minute and arterial oxygen saturation (SaO₂) of 93%. No sign of neuropathological damage was evident. A nasopharyngeal swab performed with molecular assay Xpert® Xpress Flu/RSV (Cepheid, USA) tested positive for RSV. No Flu A and B were detected. During observation, SaO₂ remained 93% until one hour and half from admission in ED when, due to hypoxaemia (SaO₂ 89%) and respiratory acidosis (pH 7.347; pCO₂ 56.6 mmHg) (Table 1, BG1), the patient was given low-flow oxygen therapy (1 l/minute). After an initial improvement in clinical parameters (respiratory rate: 40 breaths/minute; SaO₂ 96%), flow oxygen therapy was reduced and stabilized to 0.5 l/minute until 12 h from admission in ED. Within this time frame, SaO₂ was observed to be settled on 96–97%. Subsequently, a sudden worsening of respiratory dynamics happened (respiratory rate: 60 breaths/minute; SaO₂ 92%) and the therapy was changed to high-flow oxygen administration (8 l/minute). The subsequently BG2 performed after oxygen administration showed a correction in the parameters (pH 7.447; pCO₂ 45.5 mmHg) (Table 1, BG2). Nevertheless, three hours after BG2, despite an improvement in the respiratory dynamics (respiratory rate: 48 breaths/minute; SaO₂ 96%), a re-evaluation of the patient’s parameters was performed showing again hypercapnia and respiratory acidosis (pH 7.336; pCO₂ 59.2 mmHg) (Table 1, BG3).

Moreover, the chest Xrays performed at time of BG3 and two hours apart highlighted how fast was the clinical worsening: the first one (Fig. 1a) showed normo expanded lungs with no opacification, while the second Xray (Fig. 1b) showed diffuse bilateral pulmonary opacification with marked ectasia of the stomach.

Because of the persistent respiratory failure, the patient was treated with nebulized epinephrine and prepared for endotracheal intubation, however he died before this could be done.

Postmortem examination was carried out on the infant’s body.

Lung’s microscopic examination revealed severe vascular congestion with massive bleeding, peribronchiolitis due to lymphocytic infiltrates and sporadic foci of pneumonia with reactive interstitial infiltrates and alveolar atelectasis (Fig. 2).

Also, extensive injury was present in the brain, characterized by white matter degradation in the left hemisphere, basal ganglia, hippocampus, bulbar region and pons with edema (Fig. 3a).

A detailed microscopic analysis showed hypertrophic astrocytes, acutely damaged glia and focal necrosis at the bulbar level (Fig. 3b), features reported to be associated with viral infection [12]. Basal ganglia were affected by neuronal necrosis with perineuronal halo and white matter strongly damaged (Fig. 3c, d). The brain’s histological examination didn’t exclude injuries in the cardiovascular center, probably due to viral infection.

No narcotic or psychotropic drugs were detected in the blood.

Microbiological analysis performed on autoptic samples confirmed the viral etiology of brain damage and death. In fact, using molecular assay BioFire® FilmArray® RP2 Panel Plus (BioMérieux, France), RSV was detected in tracheobronchial aspirate, meningeal swabs, pericardic and abdominal fluids, lung and brain biopsies. On the contrary, the samples tested negative for Adenovirus, Coronavirus, Human Metapneumovirus, Human Rhinovirus/Enterovirus, Influenza A and B, Human parainfluenza virus, Bordetella pertussis, Bordetella parapertussis, Chlamydophila pneumoniae and Mycoplasma pneumoniae. Moreover, the microbiological cultures found neither fungal nor specific pathogenic bacteria.

Therefore, post-mortem examination revealed a severe bronchiolitis resulting in a fatal cerebral involvement due to RSV and its neurotropic behaviour.

Respiratory Syncytial Virus is usually associated with respiratory diseases whose most common symptoms are fever, cough, wheezing and it typically affects children during the first two years of life. However systemic dissemination of RSV during severe disease can lead to cerebral involvement with sudden infant death [13]. The pathogenesis of RSV-related neurological damage is not yet fully understood but it has been hypothesized that RSV may enter the Central Nervous System through the hematogenous/blood-brain barrier route causing the release of several humoral neurotoxic cytokine mediators. Anyways, the direct role of RSV in inducing encephalopathy was supported by the detection of RSV antibodies or viral genome in cerebrospinal fluids (CSF) [5, 14].

Morichi et al. (2011) classified RSV-related encephalopathies into four groups (metabolic error, cytokine storm, excitotoxicity and hypoxic type) and reported that the brain imaging during RSV infection showed massive cerebral edema with subsequent diffuse brain atrophy [15]. Several other studies reported neurological complications of RSV infection, which mainly include central apnea, seizures and encephalopathy [14‐17].

According to the clinical pictures described above, the index patient had an RSV infection that dramatically worsened within hours leading to cerebral edema and death. Detection of RSV genome in CSF confirmed neurological involvement.

Also noteworthy, is the finding of the virus in the pericardic fluid that could suggest a myocardial damage as probably contributing cause of death.

Unlike the previously described clinical cases, in which patients reported a confirmed RSV infection together with at least one cerebral evidence (Table 2), in our report the infant showed no neurological signs and symptoms at the time of admission. For this reason and due to the rapid worsening of the patient’s conditions, CSF sample for cytokines and nitrogen oxide determination was not collected.

Respiratory Syncytial Virus usually affect respiratory tract but, although rare, it can also determine a widespread organ involvement, including the brain and heart. Cerebral damage caused by RSV and perhaps concomitant cardiac involvement may led to sudden cardiac arrest in infants with bronchiolitis. Our findings, in conjunction with the before above reported cases underline the need for clinicians to pay more attention and awareness to neurological sequelae of RSV infection, even in the absence of evidence of cerebral damage.