Respiratory syncytial virus (RSV) infection is the most common cause of admission to the pediatric intensive care unit (PICU) due to respiratory failure in childhood[1]. Along with influenza virus, RSV is also the most common cause of admissions in adults with chronic heart and lung disorders and acute respiratory failure[2].
Extrapulmonary presentations of severe RSV infection were first highlighted in a report of an epidemic affecting infants admitted to a children’s hospital in Cleveland (OH, USA).
The authors described the characteristics of a ’sepsis syndrome’ and apneas observed in a significant proportion of infants[3]. Caregivers should be aware of manifestations of RSV infection outside the respiratory tract because it can cause unexpected deteriorations in their patients.
Awareness of the effects of RSV infections outside the respiratory tract is important in the management of patients with known underlying comorbidities[2].
It is important to know how much of an organ dysfunction is a temporary effect of RSV or a sign of a deterioration of a pre-existing organic disease, for example, in infants with congenital heart disease[4]. This systematic review aims to summarize the evidence on the extrapulmonary effects of RSV infection.
| Methods |
This systematic review summarizes findings from articles reporting manifestations of RSV infection outside the respiratory tract.
Studies in patients of all age groups with RSV infection were included in the analysis.
Studies on manifestations that were not specific for RSV but were nonspecific immunological effects of an acute viral infection were excluded.
| Results |
> RSV and the cardiovascular system
The first report of clinically symptomatic myocardial involvement during RSV bronchiolitis was a case of fatal interstitial myocarditis in a child in 1972 [6].
Other reports also include the development of second-degree heart block during the illness. Subsequently, a report of RSV-associated multifocal atrial tachycardia appeared, a phenomenon that was reported again in a subsequent series of patients with RSV-associated atrial tachycardias [7,8].
Other forms of supraventricular tachycardias have also been reported during RSV infection; they appeared to occur in patients with structurally normal hearts and were not associated with hypoxia or beta-agonist therapy[8,9]. Life-threatening arrhythmias have also been reported. Atrial flutter was associated with cardiogenic shock in one patient[10].
Another case of ventricular tachycardia requiring cardioversion was subsequently reported[11]. Another life-threatening complication can be cardiac tamponade that evolves from pericardial effusion[10,12].
Cardiovascular compromise in the form of hypotension without cardiac arrhythmias has also been described and has been associated with evidence of myocardial damage as indicated by elevated levels of cardiac troponin I and T. Elevated levels of cardiac troponin were found in 35 to 54% of infants. with RSV infection ventilated in PICUs[13,14].
Elevated levels of cardiac troponin I have also been found in children with RSV infection who did not require mechanical ventilation[15]. The degree of cardiovascular support described varied from the administration of fluid boluses[14] to inotropic support[13,16].
> Manifestations of RSV in the central nervous system
Acute neurological signs and symptoms such as central apneas, seizures, lethargy, difficulties in eating or swallowing, tone abnormalities or strabismus, cerebrospinal fluid (CSF) or electroencephalogram abnormalities were found in 39% (n = 121) of patients with RSV. positive in a PICU[19].
In a population of RSV-positive patients admitted to the general pediatric ward, neurological complications were found in 1.2% of patients (n = 964)[20]. Looking at the occurrence of seizures as a manifestation of encephalopathy, another group found an incidence of seizures of 1.8% (n = 487) in patients with RSV bronchiolitis admitted to a tertiary pediatric referral center [21].
CSF abnormalities were found in one study in 12 of 30 RSV patients who had a lumbar puncture[19]. Other studies have found RSV-specific antibodies in the CSF of patients with RSV bronchiolitis[23,24].
• Central apneas
Apneas defined as respiratory arrest for more than 20 seconds and/or bradycardia with cyanosis or oxygen desaturation below 90% have been found in 16 to 21% of children admitted to hospital with RSV infection[25]. The most important risk factor associated with apneas was age under two months.
Apneas on admission increased the risk of recurrent apneas, and these children were significantly more likely to require mechanical ventilation[25]. A prospective experimental study in infants investigated apnea responses in infants with RSV infection.
Both the duration of the first apnea and the total duration of apnea (all apneas) were significantly longer in patients with RSV than in controls. There was a significant negative correlation between nasopharyngeal IL-1β levels and apnea duration[26]. Apneas were not associated with a higher level of proinflammatory cytokines.
• Seizures
The types of seizures that are associated with RSV infection include generalized and partial tonic-clonic seizures with altered consciousness and focal motor features or ocular deviation[19,20]. Some patients presented status epilepticus[20]. Electroencephalogram abnormalities have been observed in some patients[19]. A previously identified cause of seizures in infants with RSV infection is hyponatremia 27].
• Other neurological manifestations
Strabismus has been reported to be a neurological complication in two large studies[19,20]. It was found in the form of isotropy in four of 12 patients with neurological complications[20]. A case of acute axonal polyneuropathy[19] and a case with features of encephalitis on magnetic resonance imaging and positron emission tomography[28] were also described.
Diaphragmatic flutter was described, characterized by high-frequency involuntary contractions of the diaphragm, occurring at a rate of 150 to 480 contractions per minute asynchronous with the heartbeat[29]. Diaphragmatic flutter has been associated with the inability to wean patients from mechanical ventilation[30].
> Endocrine effects of RSV bronchiolitis
• Antidiuretic hormone
Hyponatremia (a serum sodium level of less than 136 mmol/l) was found in 33% of infants requiring intensive care with RSV infection; 11% had a serum sodium level less than 130 mmol/l[27].
In a less selected population of children, including patients with milder disease, only 0.6% of patients had a serum sodium level of less than 130 mmol/l[31].
Investigations revealed that antidiuretic hormone (ADH) levels were significantly higher in patients with bronchiolitis than in patients with apneas or upper respiratory tract infections with RSV. The highest levels were found in patients who received mechanical ventilation[33].
Increased HAD levels were associated with high arterial partial pressure of CO2 and hyperinflation on chest x-ray. However, there was no association between HAD levels and serum sodium levels in this study. Hyponatremia and hyponatremic seizures in this setting have been associated with the application of hypotonic fluids at 100 to 150 ml/kg per day [27].
• Hormonal responses to stress
A prospective study comparing ventilated infants with RSV infection and patients admitted to the ward showed that ventilated patients had higher levels of prolactin and growth hormone and significantly lower levels of leptin and insulin-like growth factor. 1.
Cortisol levels were no different. Leptin and prolactin levels accounted for 57% of the variation in lymphocyte count, which was significantly lower in ventilated patients with RSV infection[34].
| Hepatitis associated with respiratory syncytial virus |
Elevated transaminase levels have been found in 46 to 49% of ventilated children with RSV bronchiolitis[35,36]. Severe hepatitis was found with alanine aminotransferase levels of almost 3,000 IU/L and this was associated with coagulopathy[35]. The peak of transaminase levels was found to be between two and four days after admission.
Respiratory disease, as judged by duration of ventilation, was more severe in infants with elevated transaminase levels[35,36]. The prevalence of hepatitis was 80% in children with congenital heart disease. This was a significantly higher prevalence than that found in children without congenital heart disease[36].
Direct invasion of the liver in an immunocompetent infant with RSV infection has been documented by the successful culture of RSV from liver biopsy material[37]. Liver involvement in the form of fatty changes was described in a fatal case of Reye’s syndrome associated with RSV infection[38].
> Other extrapulmonary manifestations of RSV bronchiolitis
Several other extrapulmonary manifestations of RSV infection have been described but most of them are only single case reports and none of them appear to be fatal. They include hypothermia[3], rashes involving the trunk and face in the form of a finely granular scarlatiniform rash[3,39], thrombocytopenia and conjunctivitis[40].
> Supportive management of extrapulmonary manifestations of RSV infection
Previous case series showed that RSV-associated ventricular arrhythmias may respond to antiarrhythmic drugs such as lidocaine and beta-blockers, and cardioversion[10]. Hypotension may respond to simple fluid resuscitation[14] and, if this is not sufficient, successful inotropic support for a few days[16].
Strategies used to treat RSV-associated apneas in previous studies, none of which were randomized controlled trials, included caffeine loading, continuous positive nasal airway pressure, negative pressure ventilation, and intubation and mechanical ventilation[41,42] .
Caffeine loading significantly reduced the frequency of apneas in seven infants with RSV infection. Hyponatremic seizures have been successfully and safely managed by increasing sodium levels to less than 25 mmol/L for 48 hours (approximately 0.5 mmol/L per hour). Liver involvement should prompt the physician to investigate structural heart disease causing ischemic hepatitis.
| Discussion |
Extrapulmonary manifestations suggest that RSV can infect organs other than the lung. Systemic coinfection with bacterial pathogens is unlikely to be responsible for most extrapulmonary manifestations.
Previous studies have shown that severe bacterial infection is present in 0.6 to 1.2% of children admitted with RSV infection[43]. A previous study found that in 63% of newborns and 20% of infants with RSV detected in nasopharyngeal aspirate in the PICU, RSV RNA was detectable in peripheral blood by nested RT-PCR[44]. These findings demonstrate how RSV is delivered to extrapulmonary sites.
It can be postulated that apneas and arrhythmias have caused unexpected deaths in infants with RSV in the community, although the detection of RSV nucleic acid in the postmortem tissue of infants who died from sudden infant death syndrome did not was more common than in infants who died of unrelated causes during the same time period[46].
> RSV and the cardiovascular system
Some of the authors of reports on arrhythmias or myocardial failure in RSV infection doubted a direct role for the virus. As highlighted in a previous report[47], right ventricular decompensation due to pulmonary hypertension is a possible cause of myocardial damage, cardiac troponin elevation, and systolic hypotension. Lung disease is associated with pulmonary hypertension in bronchiolitis[48].
Elevation of cardiac troponin T has been previously reported in patients with bacterial pneumonia[49]. Right ventricular distention can also precipitate arrhythmias[50]. However, a direct involvement of RSV is suggested by its isolation from myocardial tissue and the reported occurrence of significant pericardial effusion.
> RSV and the central nervous system
Apneas were the most common neurological manifestation of RSV infection. A prospective experimental study[26] has clearly demonstrated that there is an abnormal response at the level of the central nervous system rather than apneas being secondary to respiratory compromise or seizures alone. The detection of RSV in CSF has also supported a direct invasion of the central nervous system in RSV disease.
> RSV and the endocrine system
The lack of association of HAD levels with reduced sodium levels may be due to the associated hyperreninemia and characteristics of secondary hyperaldosteronism leading to sodium retention found in another study [51].
It can be speculated that hypovolemia perceived by intrathoracic receptors may be involved. It appears that the development of hyponatremia requires the presence of elevated levels of HAD and a source of electrolyte-free water[27].
The study evaluating the response to neuroendocrine stress found that, consistent with previous studies, lymphopenia is not related to increased cortisol levels and provided new data on a possible relationship of low lymphocyte count with increased prolactin and low leptin levels. There is good evidence for the role of leptin in preventing stress-induced apoptosis of T cells[52].
> RSV and the liver
The higher prevalence of hepatitis in children with congenital heart disease may indicate that hepatic venous congestion as a result of right ventricular failure causing ischemic hepatitis may be involved in the elevation of transaminases in some of these children.
> Agenda for future research
Future research should include randomized controlled trials on the treatment of RSV-related central apneas using medications such as caffeine, which may prevent the need for mechanical ventilation.
Data are lacking on extrapulmonary manifestations of RSV infection in the elderly where comorbidities such as ischemic heart disease and cerebrovascular insufficiency may increase the risk of complications.
Future studies need to clarify how common extrapulmonary manifestations, such as arrhythmia and hepatitis, occur in patients with mild RSV infection. Long-term follow-up with case-control studies, including detailed neuroimaging, of infants with acute neurological manifestations of RSV infection is necessary to clarify whether there are potential long-term sequelae.
| Conclusion |
Extrapulmonary manifestations are common in ventilated infants with severe RSV infection. This systematic review highlights that heart rate and blood pressure should be carefully monitored in these patients to detect life-threatening complications.
Plasma sodium levels should be monitored daily in patients requiring intravenous fluids, and fluid intake should be adjusted to avoid the development of hyponatremia and associated seizures.
These requirements must be balanced against the potential complications of invasive monitoring and overtreatment of infants with RSV infection in the PICU, which has been associated with increases in costs and morbidity without improvement in outcome[54].
