Respiratory Syncytial Virus

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Respiratory syncytial virus (RSV) is the most important respiratory pathogen of childhood, being responsible for about half of all cases of bronchiolitis and a quarter of all cases of pneumonia during I he first few months of life.

Pathogenesis and Immunity

The virus multiplies in the mucous membranes of the nose and throat; in the very young and very old it may involve the trachea, bronchi, bronchioles, and alveoli. The incubation period is 4-5 days. Fatal cases usually show extensive bronchiolitis and pneumonitis with scattered areas of atelectasis and emphysema resulting from bronchiolar obstruction (Figs. 28-6, 36-1, and 36-2).

A challenging unanswered question is why severe lower respiratory disease develops only in certain very young infants. Undoubtedly the airways of such young babies, being narrower than those of older children, are much more readily obstructed by inflammation, edema, and shedding of necrotic cells into copious mucus. However, this does not explain why only a minority of these small infants develop bronchiolitis. There is evidence that the condition may have an immunologic basis.

Many years ago, an experimental formalin-inactivated RSV vaccine was tested in children. When the immunized children encountered RSV during a subsequent epidemic, they actually suffered significantly more serious lower respiratory disease than did unimmunized controls. It was subsequently demonstrated that, although the formalin-inactivated virus induced a good antibody response, the antibodies did not have good neutralizing activity. This alarming occurrence led not only to the abandonment of the killed vaccine but also to speculation about the immunologic basis of the episode and its possible relationship to natural RSV bronchiolitis. The first hypothesis was that maternal IgG, present only in young infants, might react with virus multiplying in the lung to produce a hypersensitivity reaction of the Arthus type. However plausible, this idea had to be abandoned when a negative correlation was demonstrated between the titer of maternal antibody and the severity of the RSV-induced illness. Anti-RSV IgE as well as histamine and leukotrienes have been reported in respiratory secretions of infants with RSV bronchiolitis. There is also evidence in rodent models that cytotoxic T cells, while expediting recovery by eliminating infected epithelial cells, may nevertheless exacerbate the symptomatology by augmenting the inflammatory response. The last word has yet to be spoken on this important but complex question.

Immunity acquired as a result of RSV infection is notoriously poor. For example, during the annual winter epidemics that plague babies' homes, the majority of children become reinfected; the severity of the illness is generally,

Diaphragm Weak Chest Wall
Fig. 28-6 Radiographs of lungs of a baby with respiratory syncytial viral bronchiolitis and pneumonitis. Note grossly overinflated lung fields with depression of the diaphragm and bulging of the anterior chest wall in the lateral view. (Courtesy Dr. H Williams and Dr. P. Phelan )

but not always, diminished the second time. This poor immunity is partially explicable by the fact that the immune response of infants to the protective F and G glycoproteins is very weak. However, studies in adult volunteers showed that they, too, became reinfectable experimentally within a year or so following natural infection with a similar strain of virus. Cotton rats can be protected against RSV pneumonia by immunization with F or G protein, or with high-titer neutralizing monoclonal antibodies raised against either. The F protein generally induces the higher antibody titers and confers a degree of heterotypic as well as homotypic immunity; the less immunogenic G protein confers protection only against strains within the same group or subgroup.

None of this answers the question of whether naturally acquired immunity, such as it is, is principally attributable to antibody and, if so, whether serum IgG or secretory IgA is paramount. It is possible that IgA protects (poorly) against infection of the upper respiratory tract but that IgG protects the lungs rather more effectively. Clearly, maternal antibody fails to protect infants beyond the first 6 weeks or so of life, even though it is generally transferred at quite high levels. A role for cell-mediated immunity, presumably Tc cells, is indicated by the finding that immunization with a vaccinia recombinant bearing the RSV internal N nucleoprotein is also protective, not by preventing infection, but by expediting recovery. Children with congenital T-cell immunodeficiencies have been shown to excrete RSV from their lungs for months following infection. Furthermore, RSV is a much less effective inducer of interferon synthesis in normal infants than are influenza and parainfluenza viruses.

Clinical Features

The commonest manifestation of RSV infection in all age groups is a febrile rhinitis and/or pharyngitis with limited involvement of bronchi However, the consequences may be much more serious in certain babies between the second and sixth months of life. Almost 1% of all babies develop an RSV infection severe enough to require admission to hospital, and of these about 1% die, particularly those with congenital heart defects, bronchopulmonary dysplasia, very low birth weight, or immunodeficiency. Characteristically, an infant with rhinorrhea develops a pronounced cough and wheezing, progressing to dyspnea with a markedly elevated respiratory rate and hypoxemia (Fig. 28-7). Death may occur very rapidly and may account for a proportion of cases of the so-called sudden infant death syndrome (SIDS). RSV infections in children also frequently involve the middle ear, making this virus the most important causal agent of otitis media. Of the children who recover from a severe pulmonary infection with RSV, some retain evidence of impaired lung function for years and in particular are predisposed to recurrent bouts of wheezing (asthma).

In older children and adults, RSV infections are reinfections against a background of partial immunity. The disease resembles a cold, with or without cough and fever. However, in the elderly, during winter epidemics of RSV, and in immunosuppressed transplant patients, severe pneumonia can occur.

Although all strains of RSV are considered to belong to a single species, they may be divided into two major groups by genomic and antigenic analysis. The F protein is serologically cross-reactive, but the G protein is group-specific; strains within each group can be differentiated using selected anti-G monoclonal antibodies. Group A strains are somewhat commoner than B and may be more often associated with severe disease.

Oxygen Tent For Infant 1960s
Fig. 28-7 Respiratory syncytial viral bronchiolitis. The baby is maintained in an oxygen tent (Courtesy Dr H. Williams and Dr P. Phelan )

Laboratory Diagnosis

Three diagnostic methods of approximately equal sensitivity are currently favored by different laboratories: (1) isolation of the virus in cell culture, (2) immunofluorescence on exfoliated cells, and (3) enzyme immunoassay on antigen from nasopharyngeal mucus.

Virus may be recovered from a nasopharyngeal aspirate (see Fig. 12-1E) or nasal wash by inoculation of cultured cells. The extreme lability of RSV makes it mandatory that the specimen be taken early in the illness and that it be added to cultured cells without delay and without preliminary freezing. Human heteroploid cell lines such as HeLa or HEp-2 are the most sensitive, though human embryonic lung fibroblasts may also be used. Up to 10 days may elapse before the characteristic syncytia become obvious (see Fig. 5-2C), although a trained eye can usually detect early CPE by about the third to fifth day. Fixation and staining generally reveal extensive syncytia containing acidophilic cytoplasmic inclusions, but some strains produce only rounded cells. Absence of hemadsorption distinguishes RSV from all the other paramyxoviruses. Definitive identification can be established by IF as soon as early CPE first becomes apparent.

Although only one species of human RSV is currently recognized, strains can be allocated into groups A and B, then into various subgroups by EIA using monoclonal antibodies to the G protein. Monoclonal antibody can also be used for IF on exfoliated cells aspirated from the nose and/or oropharynx. This method has the advantage of speed and, in addition, can produce a positive result even if the specimen is taken too late to expect viable virus still to be available for culture, or if the virus is neutralized by bound IgA. However, the preferred option today is detection of detergent-solubilized antigen by EIA,! which is as sensitive and as specific as either of the foregoing methods. Usiing appropriate monoclonal antibodies as capture and detector reagents, EIA can detect as little as 10-50 ng of antigen and lends itself to automation in large diagnostic or reference laboratories.

For epidemiologic surveys, serum antibodies can be assayed most readily by EIA using recombinant DNA-cloned antigens, but serology is not customarily used for diagnosis because (1) satisfactory antibody responses do not regularly occur and (2) venipuncture of a tiny infant is not to be undertaken lightly.

Epidemiology

Respiratory syncytial virus is highly contagious, being shed in respiratory secretions for several days, sometimes weeks, and conveyed by contact to a generally susceptible population, including those with prior experience of the virus but with a negligible degree ol acquired immunity Not surprisingly, therefore, RSV causes a sharply defined epidemic every winter (see Fig. 14-1). Most children become infected in their first year or two, then reinfections occur repeatedly throughout life.

During a given epidemic, one or more strains from both group A and group B may cocirculate, even in the same city. This resembles the pattern observed with influenza type B but differs from that of influenza A, in which one variant (or a small number of variants) with the particular constellation of mutations best equipping it to escape herd immunity dominates the scene to the exclusion of all others. The epidemiologic, immunologic, and clinical significance of these RSV variants remains to be established.

Nosocomial infections are frequent. Outbreaks occur in neonatal wards of maternity hospitals, sometimes inflicting high mortality. Moreover, hospital staff and parents of babies with RSV bronchiolitis often develop febrile colds and/or pharyngitis, and staff are largely responsible for spreading the virus within the ward via aerosol, fomites, and direct contact.

Control

Improvements in intensive care facilities have led to a marked reduction in the mortality from RSV pneumonia. Ribavirin (see Chapter 16) reduces the severity and duration of the illness as well as the titer of virus in the lungs. A nebulizer is used to generate a small-particle aerosol into the oxygen tent, hood, ventilator, or mask for 12-18 hours per day for 3-6 days. Since the magnitude of the benefit is still in dispute and the cost of the treatment is very high, it is currently advocated only for infants who are severely ill, very young, or otherwise considered to be at high risk.

The success of neutralizing anti-G or anti-F antibodies in preventing or even treating experimental RSV infections in cotton rats encouraged clinical trials of purified, high-titer human IgG administered intravenously for the treatment of RSV bronchiolitis/pneumonia in infants. Some benefit was demonstrated and the trials have been extended to prophylaxis of RSV in high-risk infants during winter epidemics. Recently, human monoclonal Fab fragments against the F protein, isolated from a combinatorial antibody library expressed on the surface of bacteriophage, have been shown to neutralize RSV. Whereas Fab fragments may suffice for delivery by aerosol, intact human monoclonal antibodies will be required for parenteral administration to humans.

Nosocomial transmission via medical and nursing staff must be minimized by giving proper attention to such matters as hand washing, wearing gowns, gloves, and perhaps masks when undertaking high-risk duties, as well as segregation of RSV-infected patients, and temporary redeployment of staff with respiratory infections to avoid transmission of RSV to high-risk infants.

Following the disappointment with the inactivated vaccine in the late 1960s, workers at the U.S. National Institutes of Health have been struggling valiantly for over 20 years to develop a genetically stable, cold-adapted, and temperature-sensitive RSV strain for use as a live vaccine for intranasal administration. Others are working on vaccines comprising just the F protein, either purified from lysed virions by affinity chromatography or genetically engineered using a baculovirus expression system. In light of the paradoxical experience with formalin-inactivated vaccine, however, the testing of any RSV vaccine will have to be approached with special caution. Moreover, the principal target group for a safe RSV vaccine would be very young, especially sickly inlants in babies' homes and hospitals. A satisfactory immune response to a vaccine at this very be exceedingly difficult to achieve.

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Responses

  • ulrich
    Is rsv killed by freezing?
    8 years ago

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