Respiratory Syncytial Virus Research Paper
CHAPTER ONE
INTRODUCTION
Human respiratory syncytial virus (RSV) is a virus that causes respiratory tract infections. The Respiratory Syncytial Virus (RSV), discovered in 1956, is capable of causing a broad spectrum of illnesses. In 1956, Morris and colleagues initially isolated RSV from chimpanzees with upper respiratory tract (URT) infections as the causative agent of most epidemic bronchiolitis cases. Subsequently, Channock et al (1956) associated this agent with bronchiolitis and lower respiratory tract (LRT) infection in infants. Since then, multiple epidemiologic studies have confirmed the role of this virus as the leading cause of lower respiratory tract infection in infants and young children. (Lancet, 1999)
Respiratory syncytial …show more content…
virus is one of the viruses that cause the common cold and infections in the upper parts of the respiratory tract. Respiratory syncytial virus is the major cause of lower respiratory tract infections (LRT) in infants and young children, and hospital visits during infancy and childhood. Older children and adults commonly experience a "bad cold" lasting one to two weeks accompanied with fever, nasal congestion, and cough. However, in infants and toddlers, RSV can produce severe pulmonary diseases, including bronchiolitis inside the smallest airways (bronchioles) of the lungs (inflammation of the terminal airways which produces wheezing) and pneumonia (infection of these terminal airways) (Krilov, 2011).
Greatest risk individuals of serious illness from Respiratory syncytial virus are:
Preterm birth Infants and infants with congenital heart defects (CHD) or bronchopulmonary dysplasia (BPD).
The elderly.
People of any age with certain types of heart disease, chronic lung disease or weakened (compromised) immune systems. (Centers for Disease Control and Prevention, 2008)
The clinical entity of bronchiolitis was described at about 100 years ago.
EPIDEMIOLOGY
It is globally distributed, causing outbreak each year. In the U.S, peak period of Respiratory Syncytial Virus infectivity generally occurs between January and March. Respiratory Syncytial Virus is highly contagious and it`s the major nosocomial pathogen in paediatric wards. RSV spreads easily by direct contact, and can remain viable for a half an hour or more on hands or for up to 5 hours on countertops (Dupont, 2008).
RSV is the most common cause of pneumonia and bronchiolitis in the U.S. in children under 1 year of age (Centers for Disease Control and Prevention, 2008). Almost all children have been infected with the virus by the time they are 2 years old, but less than 2% of these infections are severe enough to require hospitalization. This small percentage still translates to about 75,000 to 125,000 hospitalized children each year, most of them under 6 months old. The World Health Organization (WHO) estimates that globally there may be as many as 64 million cases of RSV infection each year and as many as 160,000 RSV-related deaths. (Zachariah, 2009)
Peak incidence of occurrence of severe RSV disease is observed at age 2-8 months. Overall, 4-5 million children younger than 4 years acquire an RSV infection, and more than 125,000 children are hospitalized annually in the United States because of this infection. This translates to 3 - 9 per 1000 children younger than 1 year who are hospitalized annually for this condition. Virtually all children have had at least one RSV infection by their third birthday. The World Health Organization has targeted RSV for vaccine development, which is not surprising, given the prevalence and potential severity of this condition.
RSV is a common viral respiratory infection that tends to be seasonal, causing community epidemics in young children, older adults, and in the immunocompromised. Outbreaks typically begin in November or December and disappear in early spring. In these high-risk groups, RSV can cause pneumonia and bronchiolitis (American Lung Association, 2010).
RACIAL/ETHICAL DIFFERENCES
African Americans
Children of all races can contract RSV. However, one study found that African American children tended to have less serious RSV infections than Caucasian children. The results were surprising because African Americans are more likely to suffer from asthma than Caucasians and RSV infection is linked to childhood asthma. The researchers believed they would find that African American children would be at increased risk for serious RSV infection, although they found just the opposite. This may be due to a quicker use of healthcare when the disease first appears, or a genetic advantage.
Hispanics
Little data are available concerning RSV infection among Hispanic populations. However, one study in Colorado found that areas with longer RSV seasons tended to be more crowded, urban, have larger families, a greater percent of children under 5 years of age, and a proportionately larger Hispanic population. (Yorita, 2007)
Asian Americans and Native Hawaiians/Pacific Islanders
Little data are available concerning RSV infection among Asian American and Native Hawaiian/Pacific Islander populations. One study of Native Hawaiian and other Pacific Islander children in Hawaii found much higher hospitalization rates among these populations for bronchiolitis and RSV, compared to national averages or other racial/ethnic groups living in Hawaii. (Yorita, 2007)
American Indians/Alaska Natives
American Indians and Alaska Natives have been documented to have high rates of RSV hospitalization. According to a recent study, American Indian and Alaska Native infants were 26 percent more likely to be hospitalized for RSV than the general U.S. population. Hospitalization rates for American Indians/Alaska Natives infants living in the Southwest and Alaska were much higher than the overall rate for infants in the U.S. (70.9 and 48.2 per 1,000, respectively). RSV accounted for 14.4 percent of all American Indians/Alaska Native infant hospitalizations (Holman, 2004)
Study found that hospitalization for severe RSV infection in Alaska Native children was associated with a significant increase in wheezing and lower respiratory infections during the first 4 years of life. The association decreased with age and was no longer significant by 5 years of age. However, hospitalization for RSV infection was associated with increased chronic bronchitis and respiratory symptoms including cough at 5-8 years of age. (American lung association, 2010)
CHAPTER TWO
VIROLOGY OF RESPIRATORY SYNCYTIAL VIRUS
RSV is a medium-sized enveloped RNA Paramyxovirus of the genus Pneumovirus. The viral genome is composed of 15,000 nucleotides which encodes 10 viral proteins.
Fig.1 Morphology of Respiratory Syncytial Virus (McNamara and Smyth, 2002)
The genome is tightly encapsidated by the nucleocapsid N protein, which, together with the phosphoprotein P and large polymerase subunit L, forms the minimum unit for RNA replication. Replication of the genome involves the synthesis of a positive-sense, exact-copy, encapsidated, replicative intermediate called the Antigenome, which serves as the template for progeny genome i. e Transcription. As well as the nucleocapsid-associated proteins, transcription requires the M2 (second Matrix protein) open reading frame 1 (ORF1) protein. The second matrix protein ensures efficient production of full-length mRNA. It also encodes the open reading frame 2 (ORF-2) proteins that has a negative regulatory effect and may render nucleocapsid quiescent prior to incorporation into virions. In addition, RSV encodes a matrix protein M, which is thought to mediate interaction between the nucleocapsid and envelope during virion morphogenesis.
There are two non-structural proteins, NS1 and NS2. Their function is not yet known although NS1 appears to be a negative regulatory factor for RNA synthesis.
RSV encodes three surface envelope proteins that are components of the virion: the attachment protein G, the fusion protein F, and the small hydrophobic protein SH. The heavily glycosylated RSV G protein comprises 289–299 amino acids and is responsible for viral attachment to cells. RSV strains have been classified into antigenic groups A and B (RSV-A and RSV-B, respectively) on the basis of the reactivity of the viruses with monoclonal antibodies directed against the attachment glycoprotein (G protein) and also by genetic analyses (Anderson, 1990).
G protein is the most variable RSV protein, and its C-terminal region (the second hyper-variable region) accounts for strain-specific epitopes. Antigenic variability in this protein i. e the G protein accounts for the majority of the differences between the two major RSV strains. The G protein of the A and B strains can differ by up to 47%, whilst G proteins from the same strain can differ by as much as 20%. Despite this variability, all human RSV strains contain an immutable 13 amino-acid region in the G protein that is loop-like in structure; possibly candidate for the host receptor binding site. Two forms of the G protein are synthesized from alternative initiation codons on the same gene. One form is membrane bound whilst the other, representing 15% of the total, is secreted. The secreted form is associated with antibody since much of the RSV antibody response is to the G protein. Both the membrane and secreted forms have been recently suggested to provoke differing immune responses (Mufson, 1985)
The G protein may not be the only attachment protein, because recombinant RSV lacking G protein can still infect cells. Thus, there is possibility that the F protein may have additional functions of attachment to a host co-receptor, though no host cell receptor(s) for RSV have been identified. The RSV F protein in its inactivated form (F0) comprises 574 amino acids and has a trimeric coiled-coil structure, similar to other viral fusion proteins10. Activation occurs through cleavage of F0 into two disulphide linked subunits, F1 and F2. The F protein promotes both fusion of viral and cell membranes resulting in the transfer of viral genetic material, and fusion of infected and adjacent cell membranes causing the formation of SYNCYTIA. These syncytia are the hallmark of the RSV cytopathic effect and are necessary for cell-to-cell viral transmission. The interaction between the F protein and a small GTPase, RhoA, facilitates RSV-induced syncytium formation14. Syncytia formation is also associated with the expression of cytokeratin-17 by RSV-infected respiratory epithelial cells. Cytokeratins are among the major components of the filament networks that make up the cytoskeleton. Cytokeratin-17 expression in RSV infection is neutralized by anti-RSV F protein antibody (McNamara, 2002).
The precise role of the third transmembrane protein, SH (comprising 64 amino acids), is unknown at the moment. The SH protein is not required for viral replication or syncytium formation although it does facilitate fusion. Recombinant RSV without the SH gene, when inoculated intranasally into mice, is indistinguishable from wild-type with regard to replication in the lower respiratory tract, but replication is restricted 10-fold in the upper respiratory tract.
A possible future therapeutic intervention may involve blocking this interaction. This site-specific attenuation of viral replication may have implications for future vaccine development.
PATHOGENESIS AND HOST RESPONSE TO RSV INFECTION Mainly spread by aerosols, but also by fomites and contact. The virus enters mainly through the eyes and nose. Incubation period is usually 2 – 8 days. The G glycoprotein is responsible for viral attachment to the host cells while the F glycoprotein promotes syncytia formation. The infection progresses into blockage of the airways, the hallmark of bronchiolitis. In children, the disease is most prevalent when the infant is least immunologically mature (McNamara, 2002). Pathogenesis of infections assumes that disease manifestations are a direct result of microbial replication and cytotoxicity. Several observations suggest that immunological mechanisms may be the key to the severity of RSV bronchiolitis in infancy. First, the disease is most prevalent when the infant is least immunologically mature, despite the possession of maternally derived specific RSV antibody; second, the experience with vaccine-enhanced disease. The immunological response to RSV infection in humans can be divided into innate and adaptive arms. The innate immune response recruits effector molecules and phagocytic cells to the site of the infection through the release of cytokines. The first line of innate lung defence is the pulmonary surfactant composed of phospholipids mainly lecithin and sphingomyelin, together with several surfactant proteins. In RSV infection, the most important cellular components of the innate response are phagocytic cells (Neutrophils and Macrophages), Eosinophil and Natural killer cells. Neutrophils are the predominant airway leukocytes in RSV bronchiolitis. RSV infection provokes the production of serum antibodies. The F and G proteins stimulate the production of potent neutralizing antibodies which are important in protective immunity. Both CD8+ cytotoxic lymphocytes (CTL) and CD4+ T helper have antiviral as well as immunopathogenic capabilities in the host (McNamara, 2002)
CLINICAL MANIFESTATIONS RSV infection is associated with a variety of clinical manifestations ranging from mild cold-like symptoms to severe lower respiratory tract illness with significant wheezing, breathing difficulty, cyanosis and possibly apnoeic episodes.
The symptoms caused by RSV tend to be more severe than the average common cold. Symptoms generally begin within a week after an exposure to someone with a Respiratory Syncytial Virus infection. Most children who develop RSV infection have mild symptoms of fever, nasal congestion, and nasal discharge (CDC, 2008).
High-risk groups (Infants with congenital heart disease (CHD), Infants with underlying pulmonary disease and cystic fibrosis, immunocompromised infants) are more likely to have a more severe disease process, including wheezing (bronchiolitis in infants) and/or pneumonia. In infants and children younger than age 3, or older children with underlying lung, heart or immune problems, RSV may start out looking like a mild cold with sneezing and runny nose. After two or three days, RSV may spread to the chest, causing a cough, breathing that is faster than normal and wheezing. Infants with breathing difficulties may grunt, flare the nostrils or have retractions, i. e the chest muscles are drawn in so that the ribs can be seen as the baby struggles to breathe.
Summarily, RSV infection symptoms are;
Sore throat
Runny nose
Stuffy nose
Difficult and rapid breathing/tachyponea (primarily in infants)
Cough
Mild wheezing
Slight headache
Mild fever
Bronchiolitis in infants
Pneumonia.
Upper respiratory tract symptoms usually precede lower respiratory tract involvement by a few days. Dyspnoea is associated with lower tract infection caused by RSV. In bronchiolitis, wheeze may be present with a prolonged expiratory phase and crackles. Air trapping results in a rapid respiratory rate, palpable spleen and liver, and a typical radiographic pattern of hyperinflation with diffuse interstitial markings and peribronchial thickening. Segmental atelectasis is often seen. Bronchiolitis may lead to acute respiratory failure with severe bronchospasm, moderate to severe hypoxia and carbon dioxide retention. Apnoea tends to occur in infants under 2 months of age and often in those born prematurely (CDC, 2008).
CHAPTER THREE
DIAGNOSIS: RSV TESTING
The specific diagnosis of RSV infection is made by the detection of the virus or viral antigens or virus specific nucleic acid sequences in respiratory secretions. RSV infection based may be on the symptoms and physical examination during certain times of the year when RSV is most common. In most adults and older children, further testing is unnecessary because RSV symptoms generally are mild, and the illness can be treated at home.
RSV testing detects the presence of respiratory syncytial virus (RSV) in nasal secretions. Testing is done during RSV season to determine whether runny nose, congestion, coughing and/or difficulty breathing are due to RSV or to other causes. The best and most frequently used sample is usually a nasal aspirate or nasal wash; occasionally a nasopharyngeal (NP) swab. (Pagana, 2001)
COLLECTION OF SAMPLES FOR TESTING
A syringe is used to push a small amount of sterile saline into the nose, then gentle suction is applied (for the aspirate) or the resulting fluid is collected into a cup (for a wash).
Sometimes, a nasopharyngeal (NP) swab is used, although it is not preferred because of decreased virus quantity in the sample. The NP swab is collected by having a person tip their head back, then a Dacron swab (like a long Q-tip) is gently inserted into one of the nostrils until resistance is met (about 1 to 2 inches in), then rotated several times and withdrawn. This is not painful, but it may tickle a bit and cause the person 's eyes to tear (Park, 2002).
What is being tested?
RSV testing detects virus that is being shed in the respiratory/nasal secretions of an infected person. Since detectable amounts of virus are usually only shed for the first few days of an infection, most testing must be done during this time period. There are several methods to test for the virus, but rapid RSV antigen testing is by far the most popular. Rapid RSV antigen tests are frequently performed on-site, in the doctor 's office or the emergency room, with most results available within an hour. In some cases, the sample may be collected and sent to a laboratory for a more sensitive testing method. Results of these RSV tests are usually available the same day.
Occasionally, a doctor will order a viral culture (to grow the RSV virus) or a test to detect the virus 's genetic material. These tests have the advantage of identifying not only the RSV virus but also other respiratory viruses that may be present. The main disadvantages of these tests are that they are not available in every laboratory and that the results take longer than the rapid RSV test. This makes them less clinically useful for evaluating an individual, but they can be useful for documenting that RSV or another virus, such as influenza, has reached a community and for identifying outbreaks in particular populations, such as a nursing home, school, or neighborhood.
There are blood tests for RSV antibodies – the immune system’s response to the virus. These tests can detect previous exposure to RSV, but they are not usually considered clinically useful for diagnosing an active case of RSV. (Falsey, 2003)
Most RSV infections will go away within 1 or 2 weeks. People can be re-infected with different strains of RSV from year to year, although subsequent infections tend to be less severe than the first/primary infection. Since most RSV infections are mild, symptoms from these re-infections are usually attributed to "a cold." These cases of RSV are usually not formally diagnosed and are often self-treated by the person with over-the-counter cold remedies for symptom relief. (Park, 2002)
LABORATORY DIAGNOSIS Laboratory methods currently available for the detection of RSV include virus isolation in tissue culture, detection of viral antigens by direct or indirect immunofluorescent (IF) staining (DFA/IFA) or by enzyme-linked immunosorbent assays (ELISA) and the detection of viral nucleic acids by amplification assays, predominantly reverse transcription polymerase chain reaction (RT-PCR) (Johnston,1990)
Virus Isolation in Tissue Culture
Isolation of RSV in tissue culture was considered as the gold standard for confirmation of presumed RSV infection for quite a long period of time. This technique requires an average of 3 to 6 days until syncytial cytopathic effect appears. Shell vial centrifugation cultures followed by DFA or immunoperoxidase staining using virus specific monoclonal antibodies significantly increases the sensitivity of the tissue culture technique and shortens the turnaround time for virus identification to 1 to 2 days. It is more sensitive than rapid antigen detection kits and also provides the ability of further antigenic and genetic characterization of the amplified virus which can be used for the screening of epidemiological relevant mutations or for the confirmation of nosocomial transmission by sequence analysis (Park, 2002).
Antigen Detection Antigen detection assays include direct immunofluorescence assays (DFA), enzyme immunosorbent assays (ELISA), chromatographic and optical immunoassays. The direct immunofluorescence assay (DFA) uses fluorescein-labelled antibodies that detect RSV antigen in epithelial cells in respiratory secretions In the ELISA, RSV antigen, if present, is captured by RSV-specific antibodies and will be detected by a second enzyme-linked antibody. Antigen detection kits are easy to perform and the results are available in a short time which makes it widely used in clinical practice. Currently available antigen detection kits in paediatric specimens have sensitivities of 72 to 94% and specificities of 95 to 100% as compared to cell culture. However, in older children and adults, detection rates for ELISA are extremely low with sensitivities of 0 to 20 % (Johnston, 1990)
Nucleic Acid tests (NATs) Nucleic acid assays have revolutionized the diagnostic procedures in virology and are the most sensitive and specific methods for the detection of RSV, regardless of the patient population tested.
Of the different nucleic acid amplification techniques, reverse transcription polymerase chain reaction (RT-PCR) was the first and most frequently used nucleic acid-based assay
TREATMENT
This is mainly limited to supportive care, including oxygen therapy. For mild RSV infections, treatment is aimed at making the person comfortable and this includes:
For fever and pain --Acetaminophen (Tylenol) or ibuprofen (Advil)
Drinking lots of fluids to prevent dehydration.
Bed rest.
A humidifier to soothe the throat and nose and possibly relieve cough.
Saline (salt water) nose drops.
A bulb syringe to gently loosen mucus blocking a child 's or infant 's nose.
Infants and younger children with severe RSV infection may need to be hospitalized. In the hospital, the infant or child may receive oxygen, fluids (by vein) and medications to help him or her breathe easier (CDC, 2008).
Ribavirin can also be administered in aerosol form. Ribavirin is an anti-viral medication that on rare occasions is used to treat the most severe RSV infections. However, it has not been shown to help that much due to difficulty in administering and it`s very …show more content…
expensive.
Supportive care is the mainstay of therapy (primary treatment of RSV lower respiratory tract infections). For high-risk patients, palivizumab (Synagis) preventative therapy is available (Lancet, 1999).
Other treatment regimens include the use of bronchodilators and anti-inflammatory agents (controversial).
Salbutamol may be used in an attempt to relieve any bronchospasm if present. Increased airflow, humidified and delivered via nasal cannula, may be supplied in order to reduce the effort required for respiration (Ventre, 2007).
PREVENTION
RSV prevention is difficult because the virus is highly contagious and is spread easily from person to person. RSV vaccines currently are being developed, but progress has been slow and one dose of a vaccine is unlikely to protect well against being infected again. The easiest way to prevent RSV infection is to wash hands regularly, especially when someone in the family has cold symptoms. Adults and older children should always wash their hands frequently, avoid touching their face and eyes unnecessarily, and stay away from direct contact with people who have obvious cold symptoms. Young infants should be kept away from anyone who has symptoms of a respiratory infection, even if it 's just a slight cold (CDC, 2008).
Babies who were born prematurely or those with lung problems, congenital heart disease or problems with their immune systems have a higher chance of getting a serious RSV infection. For these babies, two medications are available to help prevent an RSV infection, or at least make it less severe. Respiratory syncytial virus immune globulin (RSV-IG) is made from the blood of healthy people who have had RSV infection, and it contains antibodies (substances in the blood that fight infection) against RSV.
In 1998, a new product called palivizumab (Synagis) was licensed to help prevent severe RSV disease in certain high-risk infants with predisposing factors such as moderate/severe prematurity, chronic lung disease, congenital heart disease, etc. Palivizumab is not a treatment for RSV but rather a tool to help prevent RSV infection. Palivizumab (Synagis) also contains antibodies against RSV, but this type of antibody is made in the laboratory. Both medicines must be given once a month from just before RSV season (November) to the end of it (April). Palivizumab is given as a shot in a muscle (like standard childhood vaccines) and RSV-IG is given through a vein (intravenously). (Handforth, 2004)
PROGNOSIS
Most RSV infections go away completely with no lasting effects. With prompt diagnosis and appropriate treatment, most infants and children recover from serious respiratory illnesses caused by RSV infections. Deaths from RSV infections are relatively rare, but RSV infection can cause death in high-risk infants aged 2 months to 6 months and in older people who have immune system problems. Children who have RSV bronchiolitis in infancy have a slightly higher risk of having recurrent wheezing as they get older. It 's not known if RSV causes this or whether children who are at higher risk of asthma is more likely to become ill with RSV exposure during infancy (Centers for Disease Control and Prevention, 2008).
CONCLUSION
Currently, no vaccines for RSV are available for general use, but research in the area continues. Until a safe, effective and relatively inexpensive method for prophylaxis is available, RSV infections will continue to cause significant morbidity and mortality in children.
REFERENCES
Bradley, J.P., et al, (2005) Severity of Respiratory Syncytial Virus Bronchiolitis is Affected by Cigarette Smoke Exposure and Atopy. Paediatrics ; 117:7-14.
Casiano-Colon, A.E., Hulbert, B.B., Mayer, T.K., Walsh, E.E., Falsey, A.R. (2003). Lack of sensitivity of rapid antigen tests for the diagnosis of respiratory syncytial virus infection in adults. Journal of Clinical Virology; 28: 169-74.
Everard, M.L., Milner, A.D. (1992) The respiratory syncytial virus and its role in acute bronchiolitis. European Journal of Pediatrics ; 151: 638–51
Freymuth, F., Eugene, G., Vabret, A. (1995). Detection of respiratory syncytial virus by reverse transcription-PCR and hybridization with a DNA enzyme immunoassay. Journal of Clinical Microbiology ; 33: 3352-5.
Glezen, P., Denny, F.W. (1973) Epidemiology of acute lower respiratory disease in children. New England Journal of Medicine ; 288: 498-505
Hall, C.B. (2009). The Burden of Respiratory Syncytial Virus Infection in Young Children. New England Journal of Medicine ; 360(6) :588-98.
Hall, Caroline Breese; Weinberg, Geoffrey, A.; Iwane, Marika, K.; Blumkin, Aaron, K.; Edwards, Kathryn, M.; Staat, Mary, A.; Auinger, Peggy; Griffin, Marie, R.
(2009). "The Burden of Respiratory Syncytial Virus Infection in Young Children". New England Journal of Medicine 360 (6): 588–98.
Handforth, J.; Sharland, M; Friedland, J.S. (2004). "Prevention of respiratory syncytial virus infection in infants". BMJ 328 (7447): 1026–7.
Henderson, F.W., Collier, A.M., Clyde, W.A., Denny, F.W. (1979) Respiratory-syncytial-virus infections, reinfections and immunity. A prospective, longitudinal study in young children. New England Journal of Medicine; 300: 530-4.
Holman, R.C. (2004) Respiratory Syncytial Virus Hospitalizations among American Indian and Native Alaskan Infants and the General United States Infant Population. Paediatrics. 114(4): 437-44.
Hornsleth, A., Friis, B., Andersen, P., Brenoe, E. (1982) Detection of respiratory syncytial virus in nasopharyngeal secretions by ELISA: comparison with fluorescent antibody technique. Journal of Medical Virology; 10: 273-81.
Johnston, S.L., Siegel, C.S. (1990) Evaluation of direct immunofluorescence, enzyme immunoassay, centrifugation culture, and conventional culture for the detection of respiratory syncytial virus. Journal of Clinical Microbiology; 28:
2394-7.
Kim, H.W., Arrobio, J.O., Brandt, C.D., (1973) Epidemiology of respiratory syncytial virus infection in Washington, D.C. I. Importance of the virus in different respiratory tract disease syndromes and temporal distribution of infection. America Journal of Epidemiology; 98: 216-25.
Simoes, E.A., Lancet, (1999) Respiratory syncytial virus infection; 354: 847–52
Ventre, Kathleen; Randolph, Adrienne (2007). Ventre, Kathleen. (ed). Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children.pub 3
Wu, P.; Dupont, W. D.; Griffin, M. R.; Carroll, K. N.; Mitchel, E. F.; Gebretsadik, T.; Hartert, T. V. (2008). "Evidence of a Causal Role of Winter Virus Infection during Infancy in Early Childhood Asthma". American Journal of Respiratory and Critical Care Medicine 178 (11): 1123–9.
Yorita, K.L. (2007). Severe Bronchiolitis and Respiratory Syncytial Virus among Young Children in Hawaii. Paediatric Infectious Disease Journal. ; 26(12):1081-8.
Zachariah, P., Shah, S., Gao, D., Somões, E.A. (2009). Predictors of the Duration of the Respiratory Syncytial Virus Season. Paediatric Infectious Disease Journal ; 28(9):772-6.
INTRODUCTION
Human respiratory syncytial virus (RSV) is a virus that causes respiratory tract infections. The Respiratory Syncytial Virus (RSV), discovered in 1956, is capable of causing a broad spectrum of illnesses. In 1956, Morris and colleagues initially isolated RSV from chimpanzees with upper respiratory tract (URT) infections as the causative agent of most epidemic bronchiolitis cases. Subsequently, Channock et al (1956) associated this agent with bronchiolitis and lower respiratory tract (LRT) infection in infants. Since then, multiple epidemiologic studies have confirmed the role of this virus as the leading cause of lower respiratory tract infection in infants and young children. (Lancet, 1999)
Respiratory syncytial …show more content…
virus is one of the viruses that cause the common cold and infections in the upper parts of the respiratory tract. Respiratory syncytial virus is the major cause of lower respiratory tract infections (LRT) in infants and young children, and hospital visits during infancy and childhood. Older children and adults commonly experience a "bad cold" lasting one to two weeks accompanied with fever, nasal congestion, and cough. However, in infants and toddlers, RSV can produce severe pulmonary diseases, including bronchiolitis inside the smallest airways (bronchioles) of the lungs (inflammation of the terminal airways which produces wheezing) and pneumonia (infection of these terminal airways) (Krilov, 2011).
Greatest risk individuals of serious illness from Respiratory syncytial virus are:
Preterm birth Infants and infants with congenital heart defects (CHD) or bronchopulmonary dysplasia (BPD).
The elderly.
People of any age with certain types of heart disease, chronic lung disease or weakened (compromised) immune systems. (Centers for Disease Control and Prevention, 2008)
The clinical entity of bronchiolitis was described at about 100 years ago.
EPIDEMIOLOGY
It is globally distributed, causing outbreak each year. In the U.S, peak period of Respiratory Syncytial Virus infectivity generally occurs between January and March. Respiratory Syncytial Virus is highly contagious and it`s the major nosocomial pathogen in paediatric wards. RSV spreads easily by direct contact, and can remain viable for a half an hour or more on hands or for up to 5 hours on countertops (Dupont, 2008).
RSV is the most common cause of pneumonia and bronchiolitis in the U.S. in children under 1 year of age (Centers for Disease Control and Prevention, 2008). Almost all children have been infected with the virus by the time they are 2 years old, but less than 2% of these infections are severe enough to require hospitalization. This small percentage still translates to about 75,000 to 125,000 hospitalized children each year, most of them under 6 months old. The World Health Organization (WHO) estimates that globally there may be as many as 64 million cases of RSV infection each year and as many as 160,000 RSV-related deaths. (Zachariah, 2009)
Peak incidence of occurrence of severe RSV disease is observed at age 2-8 months. Overall, 4-5 million children younger than 4 years acquire an RSV infection, and more than 125,000 children are hospitalized annually in the United States because of this infection. This translates to 3 - 9 per 1000 children younger than 1 year who are hospitalized annually for this condition. Virtually all children have had at least one RSV infection by their third birthday. The World Health Organization has targeted RSV for vaccine development, which is not surprising, given the prevalence and potential severity of this condition.
RSV is a common viral respiratory infection that tends to be seasonal, causing community epidemics in young children, older adults, and in the immunocompromised. Outbreaks typically begin in November or December and disappear in early spring. In these high-risk groups, RSV can cause pneumonia and bronchiolitis (American Lung Association, 2010).
RACIAL/ETHICAL DIFFERENCES
African Americans
Children of all races can contract RSV. However, one study found that African American children tended to have less serious RSV infections than Caucasian children. The results were surprising because African Americans are more likely to suffer from asthma than Caucasians and RSV infection is linked to childhood asthma. The researchers believed they would find that African American children would be at increased risk for serious RSV infection, although they found just the opposite. This may be due to a quicker use of healthcare when the disease first appears, or a genetic advantage.
Hispanics
Little data are available concerning RSV infection among Hispanic populations. However, one study in Colorado found that areas with longer RSV seasons tended to be more crowded, urban, have larger families, a greater percent of children under 5 years of age, and a proportionately larger Hispanic population. (Yorita, 2007)
Asian Americans and Native Hawaiians/Pacific Islanders
Little data are available concerning RSV infection among Asian American and Native Hawaiian/Pacific Islander populations. One study of Native Hawaiian and other Pacific Islander children in Hawaii found much higher hospitalization rates among these populations for bronchiolitis and RSV, compared to national averages or other racial/ethnic groups living in Hawaii. (Yorita, 2007)
American Indians/Alaska Natives
American Indians and Alaska Natives have been documented to have high rates of RSV hospitalization. According to a recent study, American Indian and Alaska Native infants were 26 percent more likely to be hospitalized for RSV than the general U.S. population. Hospitalization rates for American Indians/Alaska Natives infants living in the Southwest and Alaska were much higher than the overall rate for infants in the U.S. (70.9 and 48.2 per 1,000, respectively). RSV accounted for 14.4 percent of all American Indians/Alaska Native infant hospitalizations (Holman, 2004)
Study found that hospitalization for severe RSV infection in Alaska Native children was associated with a significant increase in wheezing and lower respiratory infections during the first 4 years of life. The association decreased with age and was no longer significant by 5 years of age. However, hospitalization for RSV infection was associated with increased chronic bronchitis and respiratory symptoms including cough at 5-8 years of age. (American lung association, 2010)
CHAPTER TWO
VIROLOGY OF RESPIRATORY SYNCYTIAL VIRUS
RSV is a medium-sized enveloped RNA Paramyxovirus of the genus Pneumovirus. The viral genome is composed of 15,000 nucleotides which encodes 10 viral proteins.
Fig.1 Morphology of Respiratory Syncytial Virus (McNamara and Smyth, 2002)
The genome is tightly encapsidated by the nucleocapsid N protein, which, together with the phosphoprotein P and large polymerase subunit L, forms the minimum unit for RNA replication. Replication of the genome involves the synthesis of a positive-sense, exact-copy, encapsidated, replicative intermediate called the Antigenome, which serves as the template for progeny genome i. e Transcription. As well as the nucleocapsid-associated proteins, transcription requires the M2 (second Matrix protein) open reading frame 1 (ORF1) protein. The second matrix protein ensures efficient production of full-length mRNA. It also encodes the open reading frame 2 (ORF-2) proteins that has a negative regulatory effect and may render nucleocapsid quiescent prior to incorporation into virions. In addition, RSV encodes a matrix protein M, which is thought to mediate interaction between the nucleocapsid and envelope during virion morphogenesis.
There are two non-structural proteins, NS1 and NS2. Their function is not yet known although NS1 appears to be a negative regulatory factor for RNA synthesis.
RSV encodes three surface envelope proteins that are components of the virion: the attachment protein G, the fusion protein F, and the small hydrophobic protein SH. The heavily glycosylated RSV G protein comprises 289–299 amino acids and is responsible for viral attachment to cells. RSV strains have been classified into antigenic groups A and B (RSV-A and RSV-B, respectively) on the basis of the reactivity of the viruses with monoclonal antibodies directed against the attachment glycoprotein (G protein) and also by genetic analyses (Anderson, 1990).
G protein is the most variable RSV protein, and its C-terminal region (the second hyper-variable region) accounts for strain-specific epitopes. Antigenic variability in this protein i. e the G protein accounts for the majority of the differences between the two major RSV strains. The G protein of the A and B strains can differ by up to 47%, whilst G proteins from the same strain can differ by as much as 20%. Despite this variability, all human RSV strains contain an immutable 13 amino-acid region in the G protein that is loop-like in structure; possibly candidate for the host receptor binding site. Two forms of the G protein are synthesized from alternative initiation codons on the same gene. One form is membrane bound whilst the other, representing 15% of the total, is secreted. The secreted form is associated with antibody since much of the RSV antibody response is to the G protein. Both the membrane and secreted forms have been recently suggested to provoke differing immune responses (Mufson, 1985)
The G protein may not be the only attachment protein, because recombinant RSV lacking G protein can still infect cells. Thus, there is possibility that the F protein may have additional functions of attachment to a host co-receptor, though no host cell receptor(s) for RSV have been identified. The RSV F protein in its inactivated form (F0) comprises 574 amino acids and has a trimeric coiled-coil structure, similar to other viral fusion proteins10. Activation occurs through cleavage of F0 into two disulphide linked subunits, F1 and F2. The F protein promotes both fusion of viral and cell membranes resulting in the transfer of viral genetic material, and fusion of infected and adjacent cell membranes causing the formation of SYNCYTIA. These syncytia are the hallmark of the RSV cytopathic effect and are necessary for cell-to-cell viral transmission. The interaction between the F protein and a small GTPase, RhoA, facilitates RSV-induced syncytium formation14. Syncytia formation is also associated with the expression of cytokeratin-17 by RSV-infected respiratory epithelial cells. Cytokeratins are among the major components of the filament networks that make up the cytoskeleton. Cytokeratin-17 expression in RSV infection is neutralized by anti-RSV F protein antibody (McNamara, 2002).
The precise role of the third transmembrane protein, SH (comprising 64 amino acids), is unknown at the moment. The SH protein is not required for viral replication or syncytium formation although it does facilitate fusion. Recombinant RSV without the SH gene, when inoculated intranasally into mice, is indistinguishable from wild-type with regard to replication in the lower respiratory tract, but replication is restricted 10-fold in the upper respiratory tract.
A possible future therapeutic intervention may involve blocking this interaction. This site-specific attenuation of viral replication may have implications for future vaccine development.
PATHOGENESIS AND HOST RESPONSE TO RSV INFECTION Mainly spread by aerosols, but also by fomites and contact. The virus enters mainly through the eyes and nose. Incubation period is usually 2 – 8 days. The G glycoprotein is responsible for viral attachment to the host cells while the F glycoprotein promotes syncytia formation. The infection progresses into blockage of the airways, the hallmark of bronchiolitis. In children, the disease is most prevalent when the infant is least immunologically mature (McNamara, 2002). Pathogenesis of infections assumes that disease manifestations are a direct result of microbial replication and cytotoxicity. Several observations suggest that immunological mechanisms may be the key to the severity of RSV bronchiolitis in infancy. First, the disease is most prevalent when the infant is least immunologically mature, despite the possession of maternally derived specific RSV antibody; second, the experience with vaccine-enhanced disease. The immunological response to RSV infection in humans can be divided into innate and adaptive arms. The innate immune response recruits effector molecules and phagocytic cells to the site of the infection through the release of cytokines. The first line of innate lung defence is the pulmonary surfactant composed of phospholipids mainly lecithin and sphingomyelin, together with several surfactant proteins. In RSV infection, the most important cellular components of the innate response are phagocytic cells (Neutrophils and Macrophages), Eosinophil and Natural killer cells. Neutrophils are the predominant airway leukocytes in RSV bronchiolitis. RSV infection provokes the production of serum antibodies. The F and G proteins stimulate the production of potent neutralizing antibodies which are important in protective immunity. Both CD8+ cytotoxic lymphocytes (CTL) and CD4+ T helper have antiviral as well as immunopathogenic capabilities in the host (McNamara, 2002)
CLINICAL MANIFESTATIONS RSV infection is associated with a variety of clinical manifestations ranging from mild cold-like symptoms to severe lower respiratory tract illness with significant wheezing, breathing difficulty, cyanosis and possibly apnoeic episodes.
The symptoms caused by RSV tend to be more severe than the average common cold. Symptoms generally begin within a week after an exposure to someone with a Respiratory Syncytial Virus infection. Most children who develop RSV infection have mild symptoms of fever, nasal congestion, and nasal discharge (CDC, 2008).
High-risk groups (Infants with congenital heart disease (CHD), Infants with underlying pulmonary disease and cystic fibrosis, immunocompromised infants) are more likely to have a more severe disease process, including wheezing (bronchiolitis in infants) and/or pneumonia. In infants and children younger than age 3, or older children with underlying lung, heart or immune problems, RSV may start out looking like a mild cold with sneezing and runny nose. After two or three days, RSV may spread to the chest, causing a cough, breathing that is faster than normal and wheezing. Infants with breathing difficulties may grunt, flare the nostrils or have retractions, i. e the chest muscles are drawn in so that the ribs can be seen as the baby struggles to breathe.
Summarily, RSV infection symptoms are;
Sore throat
Runny nose
Stuffy nose
Difficult and rapid breathing/tachyponea (primarily in infants)
Cough
Mild wheezing
Slight headache
Mild fever
Bronchiolitis in infants
Pneumonia.
Upper respiratory tract symptoms usually precede lower respiratory tract involvement by a few days. Dyspnoea is associated with lower tract infection caused by RSV. In bronchiolitis, wheeze may be present with a prolonged expiratory phase and crackles. Air trapping results in a rapid respiratory rate, palpable spleen and liver, and a typical radiographic pattern of hyperinflation with diffuse interstitial markings and peribronchial thickening. Segmental atelectasis is often seen. Bronchiolitis may lead to acute respiratory failure with severe bronchospasm, moderate to severe hypoxia and carbon dioxide retention. Apnoea tends to occur in infants under 2 months of age and often in those born prematurely (CDC, 2008).
CHAPTER THREE
DIAGNOSIS: RSV TESTING
The specific diagnosis of RSV infection is made by the detection of the virus or viral antigens or virus specific nucleic acid sequences in respiratory secretions. RSV infection based may be on the symptoms and physical examination during certain times of the year when RSV is most common. In most adults and older children, further testing is unnecessary because RSV symptoms generally are mild, and the illness can be treated at home.
RSV testing detects the presence of respiratory syncytial virus (RSV) in nasal secretions. Testing is done during RSV season to determine whether runny nose, congestion, coughing and/or difficulty breathing are due to RSV or to other causes. The best and most frequently used sample is usually a nasal aspirate or nasal wash; occasionally a nasopharyngeal (NP) swab. (Pagana, 2001)
COLLECTION OF SAMPLES FOR TESTING
A syringe is used to push a small amount of sterile saline into the nose, then gentle suction is applied (for the aspirate) or the resulting fluid is collected into a cup (for a wash).
Sometimes, a nasopharyngeal (NP) swab is used, although it is not preferred because of decreased virus quantity in the sample. The NP swab is collected by having a person tip their head back, then a Dacron swab (like a long Q-tip) is gently inserted into one of the nostrils until resistance is met (about 1 to 2 inches in), then rotated several times and withdrawn. This is not painful, but it may tickle a bit and cause the person 's eyes to tear (Park, 2002).
What is being tested?
RSV testing detects virus that is being shed in the respiratory/nasal secretions of an infected person. Since detectable amounts of virus are usually only shed for the first few days of an infection, most testing must be done during this time period. There are several methods to test for the virus, but rapid RSV antigen testing is by far the most popular. Rapid RSV antigen tests are frequently performed on-site, in the doctor 's office or the emergency room, with most results available within an hour. In some cases, the sample may be collected and sent to a laboratory for a more sensitive testing method. Results of these RSV tests are usually available the same day.
Occasionally, a doctor will order a viral culture (to grow the RSV virus) or a test to detect the virus 's genetic material. These tests have the advantage of identifying not only the RSV virus but also other respiratory viruses that may be present. The main disadvantages of these tests are that they are not available in every laboratory and that the results take longer than the rapid RSV test. This makes them less clinically useful for evaluating an individual, but they can be useful for documenting that RSV or another virus, such as influenza, has reached a community and for identifying outbreaks in particular populations, such as a nursing home, school, or neighborhood.
There are blood tests for RSV antibodies – the immune system’s response to the virus. These tests can detect previous exposure to RSV, but they are not usually considered clinically useful for diagnosing an active case of RSV. (Falsey, 2003)
Most RSV infections will go away within 1 or 2 weeks. People can be re-infected with different strains of RSV from year to year, although subsequent infections tend to be less severe than the first/primary infection. Since most RSV infections are mild, symptoms from these re-infections are usually attributed to "a cold." These cases of RSV are usually not formally diagnosed and are often self-treated by the person with over-the-counter cold remedies for symptom relief. (Park, 2002)
LABORATORY DIAGNOSIS Laboratory methods currently available for the detection of RSV include virus isolation in tissue culture, detection of viral antigens by direct or indirect immunofluorescent (IF) staining (DFA/IFA) or by enzyme-linked immunosorbent assays (ELISA) and the detection of viral nucleic acids by amplification assays, predominantly reverse transcription polymerase chain reaction (RT-PCR) (Johnston,1990)
Virus Isolation in Tissue Culture
Isolation of RSV in tissue culture was considered as the gold standard for confirmation of presumed RSV infection for quite a long period of time. This technique requires an average of 3 to 6 days until syncytial cytopathic effect appears. Shell vial centrifugation cultures followed by DFA or immunoperoxidase staining using virus specific monoclonal antibodies significantly increases the sensitivity of the tissue culture technique and shortens the turnaround time for virus identification to 1 to 2 days. It is more sensitive than rapid antigen detection kits and also provides the ability of further antigenic and genetic characterization of the amplified virus which can be used for the screening of epidemiological relevant mutations or for the confirmation of nosocomial transmission by sequence analysis (Park, 2002).
Antigen Detection Antigen detection assays include direct immunofluorescence assays (DFA), enzyme immunosorbent assays (ELISA), chromatographic and optical immunoassays. The direct immunofluorescence assay (DFA) uses fluorescein-labelled antibodies that detect RSV antigen in epithelial cells in respiratory secretions In the ELISA, RSV antigen, if present, is captured by RSV-specific antibodies and will be detected by a second enzyme-linked antibody. Antigen detection kits are easy to perform and the results are available in a short time which makes it widely used in clinical practice. Currently available antigen detection kits in paediatric specimens have sensitivities of 72 to 94% and specificities of 95 to 100% as compared to cell culture. However, in older children and adults, detection rates for ELISA are extremely low with sensitivities of 0 to 20 % (Johnston, 1990)
Nucleic Acid tests (NATs) Nucleic acid assays have revolutionized the diagnostic procedures in virology and are the most sensitive and specific methods for the detection of RSV, regardless of the patient population tested.
Of the different nucleic acid amplification techniques, reverse transcription polymerase chain reaction (RT-PCR) was the first and most frequently used nucleic acid-based assay
TREATMENT
This is mainly limited to supportive care, including oxygen therapy. For mild RSV infections, treatment is aimed at making the person comfortable and this includes:
For fever and pain --Acetaminophen (Tylenol) or ibuprofen (Advil)
Drinking lots of fluids to prevent dehydration.
Bed rest.
A humidifier to soothe the throat and nose and possibly relieve cough.
Saline (salt water) nose drops.
A bulb syringe to gently loosen mucus blocking a child 's or infant 's nose.
Infants and younger children with severe RSV infection may need to be hospitalized. In the hospital, the infant or child may receive oxygen, fluids (by vein) and medications to help him or her breathe easier (CDC, 2008).
Ribavirin can also be administered in aerosol form. Ribavirin is an anti-viral medication that on rare occasions is used to treat the most severe RSV infections. However, it has not been shown to help that much due to difficulty in administering and it`s very …show more content…
expensive.
Supportive care is the mainstay of therapy (primary treatment of RSV lower respiratory tract infections). For high-risk patients, palivizumab (Synagis) preventative therapy is available (Lancet, 1999).
Other treatment regimens include the use of bronchodilators and anti-inflammatory agents (controversial).
Salbutamol may be used in an attempt to relieve any bronchospasm if present. Increased airflow, humidified and delivered via nasal cannula, may be supplied in order to reduce the effort required for respiration (Ventre, 2007).
PREVENTION
RSV prevention is difficult because the virus is highly contagious and is spread easily from person to person. RSV vaccines currently are being developed, but progress has been slow and one dose of a vaccine is unlikely to protect well against being infected again. The easiest way to prevent RSV infection is to wash hands regularly, especially when someone in the family has cold symptoms. Adults and older children should always wash their hands frequently, avoid touching their face and eyes unnecessarily, and stay away from direct contact with people who have obvious cold symptoms. Young infants should be kept away from anyone who has symptoms of a respiratory infection, even if it 's just a slight cold (CDC, 2008).
Babies who were born prematurely or those with lung problems, congenital heart disease or problems with their immune systems have a higher chance of getting a serious RSV infection. For these babies, two medications are available to help prevent an RSV infection, or at least make it less severe. Respiratory syncytial virus immune globulin (RSV-IG) is made from the blood of healthy people who have had RSV infection, and it contains antibodies (substances in the blood that fight infection) against RSV.
In 1998, a new product called palivizumab (Synagis) was licensed to help prevent severe RSV disease in certain high-risk infants with predisposing factors such as moderate/severe prematurity, chronic lung disease, congenital heart disease, etc. Palivizumab is not a treatment for RSV but rather a tool to help prevent RSV infection. Palivizumab (Synagis) also contains antibodies against RSV, but this type of antibody is made in the laboratory. Both medicines must be given once a month from just before RSV season (November) to the end of it (April). Palivizumab is given as a shot in a muscle (like standard childhood vaccines) and RSV-IG is given through a vein (intravenously). (Handforth, 2004)
PROGNOSIS
Most RSV infections go away completely with no lasting effects. With prompt diagnosis and appropriate treatment, most infants and children recover from serious respiratory illnesses caused by RSV infections. Deaths from RSV infections are relatively rare, but RSV infection can cause death in high-risk infants aged 2 months to 6 months and in older people who have immune system problems. Children who have RSV bronchiolitis in infancy have a slightly higher risk of having recurrent wheezing as they get older. It 's not known if RSV causes this or whether children who are at higher risk of asthma is more likely to become ill with RSV exposure during infancy (Centers for Disease Control and Prevention, 2008).
CONCLUSION
Currently, no vaccines for RSV are available for general use, but research in the area continues. Until a safe, effective and relatively inexpensive method for prophylaxis is available, RSV infections will continue to cause significant morbidity and mortality in children.
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