Pathogenesis of Respiratory Syncytial Virus Infections
C. Pathogenesis
The incubation period for RSV is usually 3 - 6 days but may
vary from 2 - 8 days. The virus enters the body usually through
the eye or nose, rarely through the mouth. The virus then spreads
along the epithelium of the respiratory tract, mostly by cell to
cell transfer. As the virus spreads to the lower respiratory
tract, it may produce bronchiolitis and /or pneumonia. Early in
bronchiolitis, a peribronchiolar inflammation with lymphocytes
occur, which progresses to the characteristic necrosis and
sloughing of the bronchiolar epithelium. This sloughed necrotic
material may plug the bronchioles resulting in an obstruction to
the flow of air, the hallmark of bronchiolitis. Air may be
trapped distal to the sites of occlusion, causing the
characteristic hyperinflation of bronchiolitis, which, when
absorbed, results in multiple areas of focal atelectasis.
Resolution of these pathological changes may take weeks. The
pathological findings of bronchiolitis may progress or coexist
with those of pneumonia during RSV infection. In pneumonia,
infiltration of the interstitial tissue with mononuclear cells is
seen.
D. Immunity
No one appears to escape infection with RSV, almost all infections are acquired during the first 3 years of life and thus virtually all adults possess specific antibody. Passive antibody is present in all newborns and young infants, the age at which the most severe RSV disease occurs. Lower respiratory tract disease from RSV appears to be generally limited to the first 3 years of life. Repeated infections may occur throughout life, but after 3 years of age, they are generally milder, consisting of URTI or bronchitis. Repeated infections may occur during the first 3 years of life and the second infection in that period of time may be as severe as the first infection. Immunity against RSV is thus not durable. Second infections with the homologous subgroup were detected as often as the alternate subgroup. Protection against lower respiratory disease after 3 years of age is not understood.
It had been postulated that immune mechanisms may be responsible for the pathogenesis of the disease, as severe RSV disease develops in infants who have high levels of passive maternal antibodies. It was postulated that maternal antibody-RSV immune complexes formed in the infant's lung may be responsible for the pathogenesis of severe disease. An inactivated vaccine which was tried in the late 60s induced high levels of RSV specific circulating antibodies in the vaccinees, but when the vaccinees were subsequently challenged by the wild virus, they develop more severe disease. However, recent studies have suggested that maternal antibodies may actually be protective. Higher levels of maternal antibodies seem to correlate inversely with the severity of RSV disease and are associated with an older age at which the infant acquires its first RSV infection. A cell mediated immune mechanism, as well as an IgE mediated mechanism had also been postulated but further evidence is needed. Other researchers have suggested that it is not necessary to postulate an abnormal immune response to explain the severity of lower respiratory tract disease in the first few months of life. Anatomical considerations and the relative immunological immaturity of the young baby may explain much of the severity of RSV infection during the first few months of life.
Precisely which components of the immune response against RSV are responsible for protection remains unknown. Primary infection in infants is associated with a specific IgM response which is transitory. IgG appears after the second week of infection. An IgA response may not be detectable in infants. The importance of the specificity and type of antibody in protection and recovery from infection remains unclear. Little is known about the cell- mediated response in infants with RSV infection. Of interest is the observation that RSV infection in both infants and adults is associated with little or no detectable interferon in the nasopharyngeal secretions.
E. Clinical Features
RSV is the most common cause of severe lower respiratory disease in young infants. It is responsible for 50 - 90% of cases of bronchiolitis, 5 - 40% of pneumonias and bronchitis and less than 10% of croups in young children. Despite an equal attack rate, boys require hospitalization more often than girls. Socioeconomic factors also plays a role. In a non-urban middle class area, 1 in 1000 infants infected in the first year of life require hospitalization, whereas in industrialized poorer areas, the rate may be as high as 1 in 50.
Primary infections are almost always symptomatic but may vary from a mild common cold to a life threatening lower respiratory tract infection. Typically, the infants presents initially with a febrile URTI, with lower respiratory tract involvement becoming manifest over the next several days. The infant develops a worsening cough, and, as the disease progresses, tachypnoea and dyspnoea. In bronchiolitis, the respiratory rate may be elevated, with wheezing and hyperinflation. Cyanosis may be present in severe cases and most hospitalized infants are hypoxaemic. In pneumonia, crackles may be present which may be localized or diffuse. However, crackles may sometimes be present in bronchiolitis, indeed, bronchiolitis and pneumonia often appear to represent a continuum and may be difficult to differentiate clinically. The course of the illness is variable, lasting from one to several weeks. Most infants show signs of improvement within 3 or 4 days after the onset of lower respiratory tract disease.
The radiological picture in infants with lower respiratory tract disease due to RSV may vary from a virtually normal appearance to one which mimics bacteria pneumonia. However, the severity of the infant's illness is not generally mirrored by the radiological changes. The most characteristic radiological changes are hyperinflation, inflation, and atelectasis. Hyperlucency, which occur as the sole abnormality in 15% of cases, is associated with RSV infection. Consolidation, which may be similar to that found in bacterial infection, is found in 25% of cases. RSV infection in the newborn may present atypically and may be missed. Neonates may present with lethargy and poor feeding. Signs of URTI may only be present in half the infants and signs of lower respiratory infection are usually absent. Primary infections may be milder, especially in older infants, manifest only tracheobronchitis or URTI. Such URTI tend to be more prolonged and severe than the usual cold. Otitis media is a frequent accompaniment of RSV infection in the first few years of life, particularly in the first year. RSV has been recovered from middle aspirates as the sole pathogen or in conjunction with a bacterial agent. Certain groups of children appear to be at risk of developing complicated, severe or fatal RSV infection. These groups include the following :-
1. Infants with congenital heart disease - infants who were hospitalized within the first few days of life with congenital disease are particularly at risk. One long term study found a mortality of 37% in such infants. In infants with secondary pulmonary hypertension, the mortality was 70%.
2. Infants with underlying pulmonary disease - infants with underlying pulmonary disease, especially bronchopulmonary dysplasia, are at risk of developing prolonged infection with RSV, even in their second year of life.
3. Immunocompromized infants - children who are immunosuppressed or have a congenital immunodeficiency disease may develop lower respiratory tract disease at any age.
RSV infection has also been shown to be associated with
exacerbations and complications in children and nephrotic
syndrome and cystic fibrosis.
Complications
Apnoea is a frequent complication of RSV infection, occurring in approximately 20% of cases. Apnoea may be the initial sign of RSV infection and is more likely to occur in premature infants with a gestation of 32 weeks or less. The apnoea associated with RSV infection is non-obstructive and tends to develop at the onset or within the first few days of illness. Secondary bacterial infection is an unusual complication. Antibiotic therapy does not improve the rate of recovery of infants with RSV lower respiratory tract disease. The most common complication from RSV lower respiratory tract disease in early infancy is prolonged alterations in pulmonary function which may lead to chronic lung disease in later life. These children may present with recurrent bouts of lower respiratory tract disease and wheezing.
Infection in older children and adults
Repeated RSV infections occur throughout life and the interval
between infections may only be months. In older children and
adults, these repeated infections usually manifest as URTI or
sometimes as tracheobronchitis. In a minority of adults, less
than 15%, the infection may be asymptomatic. Even in young
adults, RSV infection may be associated with pulmonary function
abnormalities, mostly a hyperreactivity of the airway to
cholinergic stimulus, which may last for a couple of months. RSV
infection in the elderly may be more severe and have some
similarities to infection at the other end of the age spectrum.
In the elderly, RSV have been associated with exacerbations of
COAD, an influenza like syndrome and pneumonia. Outbreaks of RSV
infection occur from time to time in institutions for the elderly
and can result in a high frequency of pneumonia.
F. Diagnosis
RSV infection may be diagnosed by cell culture techniques or by the identification of viral antigen through rapid diagnosis techniques. Rapid diagnosis is important for the initiation of proper infection control procedures and for possible antiviral chemotherapy. The diagnosis may be backed up by serological tests but these require a long time for the result to become available.
1. Rapid Diagnosis :-
(a) Immunofluorescence - both direct and indirect IF utilizing either polyclonal or monoclonal antibodies are available which possess a high degree of sensitivity and specificity. The general sensitivity of IF is 80 - 90% and for monoclonal antibody 95 - 100%. IF techniques are fast and easy to perform but the interpretation of results is subjective and the specimen must contain adequate nasopharyngeal cells.
(b) ELISA - several ELISA kits are available for the detection of RSV antigens on a solid phase. ELISA techniques offer the advantages of objective interpretation, speed, and the possibility of screening a large number of specimens. Disadvantages include a generally poorer sensitivity and a "grey zone" of equivocal results, which requires confirmation by a time-consuming blocking ELISA procedure.
2. Cell culture :- RSV has a high liability and any specimens should be transported to the laboratory promptly and inoculated into cell cultures. Nasopharyngeal aspirates, nasal washes or tracheal secretions are generally the best specimens for isolation. Specimens should not be subjected to major temperature changes such as freezing and thawing. Human heteroploid cells, such as HEP-2 and HeLa generally provide the best tissue culture for the isolation of RSV. RSV produces a characteristic CPE consisting of syncytia formation and appears in 4 to 5 days.
3. Serology :- serological diagnosis can be made by detecting antibody rises in acute and convalescent sera. It is unlikely to be of help in the management of the patient because of the length of time required. Furthermore, the serological response in young infants may be poor and not detectable by some antibody assays. Seroconversion does not occur for at least 2 weeks and may require 4 - 6 weeks. CFTs are less sensitive than neutralization and ELISA assays.
Syncytial formation caused by RSV in cell culture. (Courtesy of Linda Stannard, University of Cape Town, SA)
G. Management
Most infants with RSV infection recover with no difficulty. In infants with lower respiratory disease, the quality of the supportive care is most important. Virtually all infants with RSV lower respiratory tract disease are hypoxaemic and oxygen should be given to hospitalized infants. An antiviral agent, ribavirin, has been approved for specific treatment of RSV infection. Ribavirin is a synthetic nucleoside that appears to interfere with the expression of mRNA. It appears to have broad-spectrum antiviral activity against both DNA and RNA viruses in vitro and in vivo. For hospitalized infants with RSV lower respiratory disease, ribavirin can be administered by small-particle aerosol into an oxygen tent, oxygen hood or via a ventilator. The drug may be administered this way for 12 or more hours per day for 3 to 5 days. Controlled studies carried out in the UK and US showed that ribavirin aerosol have a beneficial effect on the clinical course of RSV infection in terms of the rate of clinical improvement and on the measured levels of oxygen saturation. Furthermore, ribavirin aerosol is not associated with any significant toxicity. Viral resistance to ribavirin has not occurred.
Administration of the drug requires hospitalization and is
expensive and therefore should be aimed at infants at most risk
for severe lower respiratory tract RSV disease. The American
Academy of Pediatrics has recommended that the children who
should be considered for ribavirin therapy are those with
underlying diseases, such as cardiac, pulmonary,
immunocompromising and neurological diseases. Premature and
infants with multiple congenital abnormalities should also be
considered. Infants who develop severe RSV infection, and those
who contract RSV in the neonatal period, should be considered for
ribavirin therapy.
H. Prevention
The obvious choice for the prevention of serious RSV infection would be the development of a vaccine. However, a vaccine against RSV poses particular problems, (1) it would have to induce an immunity which is more durable than that seen after natural infection, and (2) it would have to be given at a very young age, when maternal antibodies may be present. The first vaccine produced was an inactivated vaccine which produced high levels of serum antibody but resulted in a more severe course of disease following infection by the wild virus. Several live attenuated vaccines have been tried but these were found to be too reactive, unstable or overly attenuated. A double temperature-sensitive mutant strain of RSV is being evaluated at the moment. Research is also being carried out on the F and G envelope glycoproteins as possible candidates for subunit vaccines.
Other means of protection for limited periods may be possible e.g. immunization of the mother before the birth of the infant or chemoprophylaxis of high-risk infants may be feasible. Prevention of the nosocomial spread of RSV infection is of prime importance, as many hospitalized infants have underlying conditions which make them susceptible to severe RSV infection. Of the infection control measures employed, hand washing is the most important. The routine use of gowns and masks has not been shown to be of additional benefit. The use of gowns may be advisable during periods of close contact in which the infant's secretions are apt to contaminate the clothing. Since RSV primarily infects via the eyes and nose, masks are of limited value. Eye-nose goggles have been reported to be of benefit.
Other possible infection control procedures include the isolation or cohorting of infected infants and assigning nursing personnel to care for either infected infants or uninfected infants, but not both simultaneously. During epidemic periods, the numbers of patient contacts and visitors should be limited. Elective admission of infants with high-risk conditions should be avoided during epidemic periods. Recognition and cleaning of objects contaminated with infant secretions should be carried out as soon as possible.
RSV Hyperimmunoglobulin
RespiGam has been approved by the FDA for the prevention of respiratory syncytial virus (RSV) disease in children under 24 months with a chronic lung disease called bronchopulmonary dysplasia or a history of premature birth. RespiGam is made from plasma taken from large numbers of normal, healthy individuals and contains a high concentration of protective antibodies against RSV. These antibodies do not prevent RSV infections but help protect children against the most serious consequences of RSV. RespiGam is given intravenously in five monthly doses, with the first dose given in November before the start of the RSV season. RSV outbreaks occur in the U.S. during the late fall, winter, and early spring. Data supporting the licensing of RespiGam was obtained in several clinical trials including one known as the Prevent trial. This randomized, placebo-controlled double-blind study included 510 patients with BPD less than two years old or children under six months old with a history of premature birth (less than 35 weeks gestation). RespiGam reduced the number of hospitalizations by 41% and time in the hospital by 53% in the Prevent trial. In addition, children required fewer days of supplemental oxygen during their hospital stays.
