Respiratory syncytial virus and bronchiolitis in infants

Respiratory Syncytial Virus (RSV) is an RNA negative-sense stranded enveloped virus. Infection with the virus is implicated in the condition bronchiolitis, which is a condition which affects predominantly infants. The condition is characterized by flu-like symptoms, including runny nose, fever, coughing and wheezing. Often there is little need for laboratory diagnosis as the clinical symptoms and history allow for accurate diagnosis of the condition. The treatment of RSV currently focuses on treatment of the condition's symptoms. This involves the use of anti-inflammatories to control the fever, and bronchodilators or corticosteroids to control the effects present in the pulmonary system. The use of ribavirin, which is an antiviral medication, is indicated in those that are immunocompromised or those with severe symptoms. There may also be a need to implement oxygen supplementation therapy in those with severe respiratory problems resulting from the condition. While around 70% of those contracting the condition recover fully, there is a risk of developing a recurring wheeze or asthma later in life. There is currently no preventative vaccine for RSV although there have been developments relating to prophylactic medication which can be administered to at risk children.

Respiratory Syncytial Virus

Introduction

Respiratory Syncytial Virus (RSV) is a causative micro-organism of the condition bronchiolitis. This is a fairly significant health problem in the U.S., where around 3% of children hospitalized each year suffer from the condition. The virus may also be a contributory factor to the development of acute asthma in children. It is estimated that around 200,000 children in the U.S. are hospitalized for bronchiolitis or acute asthma each year. Thomas and colleagues (2004) used data from the 1990s to analyze the number of deaths in the U.S. which may be attributed to RSV each year. Their findings suggested that an average of 2707 deaths occurred each year during the 1990s as a result of RSV. The number of sufferers in the U.S. alone confirms that RSV is a significant public health concern. The virus has a substantial effect on not only the child who contracts the virus, but also families and communities due to the contagious nature of the disease (Jartti et al., 2004).

Micro-organism

RSV is caused by an RNA virus which is negative-sense stranded, non-segmented and enveloped. The virus belongs to the Paramyxoviridae family of viruses. It is the most important viral cause of respiratory tract infections in infants in the U.S. (Openshaw, 2005). The virion ranges from 120nm to 300nm and is highly variable in nature. The virus is unstable in the environment which is external to the human body and is able to survive for only a few hours outside of the body. The virus is fairly easy to inactivate through soap and water or disinfectants (CDC, 2005).

Around 70% of bronchiolitis cases are caused by RSV in the developed world. Although the vast majority of those who are affected are children under 2 years old there are a number of adults who are at particular risk from the virus. This includes those with underlying cardiopulmonary illness, the elderly and those who are immunosuppressed. Patients who have received a bone marrow transplant are believed to be particularly at risk of contracting RSV (Openshaw, 2005).

Transmission

RSV is transmitted in respiratory secretions. This means that it may be contracted through close contact with anyone who has the infection, or contact with contaminated surfaces or objects. The fact that the virus is able to survive for only short periods outside the body reduces the probability of contracting the virus through contact with surfaces. Infection occurs when the infected respiratory secretions come into contact with the mucous membranes of the eyes, mouth or nose. It is possible that the disease may also be transmitted through inhaling droplets from the coughs or sneezes of infectious persons.

In areas which have the correct type of temperate climate to encourage proliferation, community outbreaks of RSV occur. These usually begin in the fall and may last from four to six months. It is possible that the outbreaks will begin at any time during the year except for the summer, depending on the seasonal variation in the country (CDC. 2005). For example in Finland it is typical for a minor RSV epidemic to occur in the spring and be followed by a major epidemic in the winter (Jartti et al., 2004). While the length and severity of the community outbreak may vary from year to year it is likely that children in these communities will almost certainly contract the virus by the time they are two years old (CDC, 2005). These epidemics often overlap with influenza epidemics, which can make it difficult to determine the cause of the symptoms without thorough laboratory exploration (Thompson et al., 2003).

Symptoms

RSV is the most common cause of bronchiolitis and pneumonia in children under one-year-old. The illness is characterized by fever, runny nose, coughing and wheezing. In a small number of cases the symptoms may be so severe that the child requires hospitalization. In subsequent outbreaks of the virus the symptoms will often be similar, although severe lower respiratory tract disease often occurs later in life as a result of RSV. This may occur at any age although it is most common in the elderly or people who are vulnerable through other health problems. Health problems which may make an individual particularly vulnerable to RSV are those with compromised cardiac, pulmonary or immune systems (CDC, 2005). The inflammation which is suffered in the initial infection is highly variable from person to person (Openshaw, 2005).

RSV infections have been associated with significant levels of morbidity and mortality. The infection originally caused problems predominantly in children who contracted the virus, although the effect on morbidity and mortality in older adults has increased over recent years (Thompson et al., 2003).

The most dangerous complications which arise from RSV are the problems which it may cause in the cardiac and respiratory systems (Thompson et al., 2003). The severity of pulmonary system symptoms which are often associated with RSV in small infants is partially caused by the vulnerability of the organs as they are still in the stage of adapting to extrauterine functioning. The most extreme symptoms of RSV are observed in the extremes of age. This means that neonates are particularly at risk, also as a result of their underdevelopment of their lungs. In the elderly, deficits in the immune system are likely to contribute to the severity of symptoms observed. Other underlying conditions are also likely to impact on disease symptom severity (Openshaw and Tregoning, 2005).

Pathology of the Disease

The effects of RSV are seen predominantly in the cells in the lung epithelium. This leads to loss of the specialized function in these cells including loss of cilial motility. The onset of RSV in these cells may also lead to destruction of the epithelial lining. As with the symptoms of RSV, the effects which may be observed as a result of the virus are highly variable between different individuals. There will also be a presence of mononuclear cell infiltrate which may be accompanied by submucosal edema and mucus secretion. This may lead to obstruction in the bronchioles, resulting in compensatory emphysema. Only a small minority of children develop severe levels of inflammation, which is the reason why there is such variation in the symptoms which are displayed by different individuals. There is very little known about the pathology of the disease in those who develop only mild symptoms. This is because the mild symptoms which are developed are often not serious enough to warrant the children being seen by a physician. As a result this means that relatively little investigation is conducted in those with mild symptoms in comparison to those with severe pathology and symptoms (Openshaw, 2005).

There are several explanations for the variations in pathogenesis which are observed between individuals. Genetic variation is one possible cause of the variation. Bronchiolitis risk has been linked to variations in the chemokine receptor CCR5 and IL-8. Studies have suggested that RSV-induced bronchiolitis is related specifically to an increase in IL-8 transcription. There has also been shown to be increased incidence of RSV-induced bronchiolitis associated with mutations in the IL-4 gene, and in variants of the IL-9, IL-10, Tumor Necrosis Factor (TNF) alpha and protein surfactant D (Openshaw and Tregoning, 2005).

Onset and Incubation Period

Symptoms in the child typically persist for between 8 and 15 days. Once children have contracted RSV they are likely to suffer repeated outbreaks of symptoms throughout their life. Only between 25% and 40% of children display symptoms on their first instance however (CDC, 2005).

The peak of viral infection usually precedes the period in which the height of symptoms are experienced. The peak in symptoms is experienced as a result of cellular infiltration and the subsequent release of inflammatory mediators. In RSV many of the symptoms are a direct result of the effects caused by the immune response to the virus (Openshaw, 2005). The development of specific T-cell and B-cell responses are the major cause in the various stages of pathophysiology in the disease (Openshaw and Tregoning, 2005).

It has also been suggested that low-level viral replication associated with RSV may be a driver in chronic inflammation in some sufferers of chronic lung disease, although this is so far uncertain (Openshaw, 2005). It is estimated that infants who develop a wheeze as a result of RSV contraction develop a recurring wheeze in around two thirds of all cases. It is also estimated that around half of these children will develop some form of asthma (Lehtinen et al., 2007). It is unclear why there are some who experience delayed onset of RSV, although both immune 'imprinting' and viral persistence have been implicated (Openshaw and Tregoning, 2005).

Diagnosis

The condition is diagnosed through rapid antigen-detection tests. It is difficult to diagnose RSV in adults as the tests are insensitive in persons other than children, and practitioners rarely request tests for RSV in adults. This means that it is difficult to differentiate between influenza and RSV in adults. It has been suggested that a certain amount of deaths which have been attributed to influenza in adults may actually be a result of RSV (Thompson et al., 2003).

Although this is the most popular method for diagnosis there is also the possibility of using virus isolation, detection of viral RNA, serum antibody detection, or a combination of approaches in order to diagnose RSV. The techniques require either the collection of a sample from nasal drainage or a blood sample. The use of blood samples is more reliable in adults than in children, as there is the possibility that infants' blood may remain contaminated by their mother's blood. There may be a need to perform other tests on a child's blood however as blood gas analysis may be necessary to ensure that the child is receiving enough oxygen. There is often no need to perform diagnostic tests to confirm the diagnosis of RSV as the symptoms and clinical history often allow a diagnosis to be made with enough certainty to begin treatment (Health-Cares.net, 2005).

Prevention

There is currently no vaccine available to guard against RSV infection. The predominant method of RSV prevention is currently thorough infection control procedures. The vulnerability of the virus to soap and water or disinfectant means that thorough cleaning of anything which may become infected, along with good hand washing practices, should prevent cross-contamination (CDC, 2005).

There have recently been some advances toward drug-based prophylaxis for prevention of RSV. The lack of an effective vaccine has meant that developments have focused on passive immunotherapy strategies in those children considered to be at risk of RSV contraction.

There are two medications which are currently FDA approved for prevention of RSV in children who are considered to be at high risk. Both of the medications provide RSV-neutralizing antibody to those taking the medication. The first goes by the commercial name RespiGam, which was licensed in 1996. This is a form of immunoglobulin G, which contains high titers of antibody against RSV. The second is palivizumab, which is possibly the most common treatment. This is a humanized murine monoclonal antibody which targets the F. glycoprotein in the RSV envelope. In phase III clinical trials palivizumab was shown to significantly reduce hospitalization associated with RSV-induced conditions (Feltes and Sondheimer, 2006). Both of these medications have been approved for some time in prophylaxis, although neither is approved for treatment of the virus. Neither drug is approved for use in those with congenital heart disease, which means that any child which is considered at risk of RSV with that condition has no option for prophylaxis at the current time.