The first report of clinically symptomatic myocardial involvement during RSV bronchiolitis was that of a case of fatal interstitial myocarditis in a child in 1972 6. Other early reports include also the development of a second-degree heart block during the disease. Subsequently a report of an RSV-associated multifocal atrial tachycardia appeared, a phenomenon that was again reported in a later series of patients with RSV-associated atrial tachycardias 78. Other forms of supraventricular tachycardias have also been reported during RSV infection; they seemed to occur in patients with structurally normal hearts and were not associated with hypoxia or beta-agonist therapy 89. Life-threatening arrhythmias have also been reported. Atrial flutter was associated with cardiogenic shock in one patient. This previously healthy patient had also had long runs of ventricular tachycardia including torsades de pointes. Ventricular fibrillation developed after an attempt at overdrive pacing 10. Another case of ventricular tachycardia requiring cardioversion was reported subsequently 11. Another life-threatening complication can be cardiac tamponade evolving from pericardial effusion 1012.

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 cardiac troponin I and T levels. Features of shock have first been described in seven infants in an observational study on 218 infants admitted to a children's hospital 3. Elevated cardiac troponin levels were found in 35 to 54% of infants with RSV infection ventilated in PICUs 1314. Elevated cardiac troponin I levels have also been found in children with RSV infection not requiring mechanical ventilation 15. The degree of cardiovascular support described ranged from the administration of fluid boluses 14 to inotropic support 1316.

The first report on detection of RSV in the myocardium in patients with bronchiolitis was in an infant with combined immunodeficiency; the virus was cultured from myocardium 17. More recently RSV was again detected in the myocardium by PCR in a patient with myocarditis 18.

Acute neurological signs and symptoms such as central apnoeas, seizures, lethargy, feeding or swallowing difficulties, abnormalities of tone or strabism, abnormalities of the cerebrospinal fluid (CSF) or the electroencephalogram were found in 39% (n = 121) of RSV-positive patients on a PICU 19. In a population of RSV-positive patients admitted to the general paediatric ward – that is, with milder disease and excluding patients with simple febrile convulsions – neurological complications were found in 1.2% of patients (n = 964) 20. Looking at the occurrence of seizures as a manifestation of an encephalopathy, another group found an incidence of seizures of 1.8% (n = 487) in patients with RSV bronchiolitis admitted to a paediatric tertiary referral centre 21. RSV was detected by RT-PCR in the CSF of a four-month-old infant with apathy and what seemed to be a febrile convulsion 22. CSF abnormalities were found in one study in 12 of 30 RSV patients who had a lumbar puncture 19. Other studies have found antibodies specific for RSV in the CSF of patients with RSV bronchiolitis 2324.

Elevated transaminase levels have been found in 46 to 49% of ventilated children with RSV bronchiolitis 3536. Severe hepatitis with alanine aminotransferase levels of nearly 3,000 IU/l has been noted and this was associated with coagulopathy 35. The peak of transaminase levels was found to be between two and four days after admission (see Figure 1). Respiratory disease, as judged by duration of ventilation, was more severe in infants with elevated transaminase levels 3536. The prevalence of hepatitis was 80% in children with congenital heart disease. This was a significantly higher prevalence than the one 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 material of a liver biopsy 37. Hepatic involvement in the form of fatty changes was described in a fatal case of Reye's syndrome associated with RSV infection 38.

Several other extrapulmonary manifestations of RSV infection have been described but most of them only in single case reports and none of them seem to be life threatening. They include hypothermia 3, exanthems involving the trunk and face in the form of a finely granular, scarlatiniform rash 339, thrombocytopenia and conjunctivitis 40.

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 successful, inotropic support for a few days 16.

Strategies used to treat RSV-associated apnoeas in previous studies, none of which were randomized controlled trials, included loading with caffeine, nasal continuous positive airway pressure, negative-pressure ventilation, and intubation and mechanical ventilation 4142. Loading with caffeine significantly reduced the frequency of apnoeas in seven infants with RSV infection. Hyponatraemic seizures have been managed successfully and safely by increasing the sodium levels of less than 25 mmol/l over 48 hours (about 0.5 mmol/l per hour). Hyponatraemic seizures may be resistant to anticonvulsive therapy and may require a more rapid correction by a 3% saline bolus of 3 to 5 ml/kg followed by fluid restriction 27. Hepatic involvement should prompt the clinician to investigate for structural heart disease causing ischaemic hepatitis.

Some of the authors of reports on arrhythmias or myocardial failure in RSV infection doubted a direct role of the virus. As highlighted in a previous report 47, right ventricular decompensation due to pulmonary hypertension is a possible cause for myocardial damage, cardiac troponin elevation and systolic hypotension. Pulmonary disease is associated with pulmonary hypertension in bronchiolitis 48. Cardiac troponin T elevation has previously been reported in patients with bacterial pneumonia 49. Right ventricular strain may 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.

Apnoeas were the most common neurological manifestation of RSV infection. A prospective experimental study looking at the laryngeal chemoreflex 26 has clearly demonstrated that there is an abnormal response at the level of the central nervous system involved rather than that the apnoeas are secondary to respiratory compromise or seizures alone. Detection of RSV in the CSF has also supported a direct invasion of the central nervous system in RSV disease.

The lack of association of ADH levels with the reduced serum sodium levels may be due to the associated hyperreninaemia and features of secondary hyperaldoseronism leading to sodium retention found in another study 51. One can speculate that perceived hypovolaemia by intrathoracic receptors may be involved. It seems that the development of hyponatraemia requires the presence of both raised ADH levels and a source of electrolyte-free water 27. The study looking at the neuroendocrine stress response found that, in keeping with previous studies, lymphopenia is not related to increased cortisol levels and provided new data on a possible relationship of the low lymphocyte counts with increased prolactin and low leptin levels. There is good evidence for a role of leptin in the prevention of stress-induced apoptosis of T lymphocytes 52.

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 ischaemic hepatitis may be involved in transaminase elevation in some of these children. Apart from the documented direct invasion of the liver, a possible effect of cytotoxic CD8-positive T lymphocytes not requiring the presence of RSV itself has recently been implicated in collateral damage to the liver in mild influenza virus infection 53.

Future research needs to include randomized controlled trials on the treatment of RSV-related central apnoeas by medication such as caffeine, which may be able to prevent the need for mechanical ventilation. There is a lack of data on extrapulmonary manifestations of RSV infection in the elderly where co-morbidities such as ischaemic heart disease and cerebrovascular insufficiency may put them at higher risk of their complications. Future studies need to clarify how common extrapulmonary manifestations such as arrhythmia and hepatitis are in patients with mild RSV infection. Long-term follow-up case control studies, including detailed neuroimaging, of infants with acute neurological manifestations of RSV infection need to clarify whether there are potential long-term sequelae.