Respiratory Syncytial Virus Infections Melvin I. Marks, M.D.
Introduction
high is
espiratory syncytial
virus
is the most
com-
mon
(RSV)
of serious respiinfection in infants and ratory children in North America.’ Two major groups and nine subgroups of the virus have been identified thus far.2It is estimated that in the United States 100,000 hospitalizations yearly, costing over $300 million, 3 are due to RSV:3 In elderly patients, RSV may cause severe lower respiratory infections, but in most adults, this infection often results only in mild pharyngitis or common cold symptoms.’ In newborns, infants, and cause
preschool-aged children, however, the manifestations
are
often
more
severe; they include pneumonia, bronchopneumonia, and bron-
chiolitis.5 When the host has some other condition, such as chronic lung and/or congenital heart disease, the risk of serious respiratory insufficiency and life-threatening pneumonia is increased.’ Mortality associated with RSV occurs in 1 % to 3% of hospitalized patients (0.5% of normals) and in 20% to 40% of patients with severe heart disease. Hospitalization rates are
From the University of California-Irvine and Memorial Miller Children’s Hospital, Long Beach Memorial Medical Center,
Long Beach, California. Address
correspondence to: Melvin I.
Marks, M.D., Long Beach Memorial Medical Center, 2801 Atlantic Avenue, Long Beach, CA 90801
688
and
respiratory insufficiency
among RSV-infected with bronchopulmonary
common
patients dysplasia,
or immunodefiin those who are ciencies, than 6 to 8 weeks. younger
cancer, or
and will subsequently have asthmatic attacks brought on by a variety of precipitating viral infections or allergen exposures.&dquo; A recent survey of 102 hospitalized infants with RSV infections, and no underlying or co-existing dis-
orders, noted that
two
thirds
re-
Pathogenesis/ Immunity/Clinical Features
mained in the
understanding of the pathogenesis of RSV infection indi-
respiratory epithelial cytotoxicity
Recent
that the host responds with humoral and local immune reactions, including the production of RSV-specific circulating immunoglobulin (IG) mostly IgG - and local IgA and IgE in the bronchial secretions of the respiratory tract. Humoral neutralizing antibodies to RSV F and G glycoproteins correlate with resistance to reinfection; however, this protection is effective in only about 75% of patients?7 An increase in respiratory secretions, as well as other components of the inflammatory reaction, together with the small size of the bronchial tree, contribute to the clinical picture of acute bronchiolitis in young infants. This is characterized by wheezing, cough, fever, and increased respiratory rate. Chest radiographs indicate air trapping, with flattened diaphragms and darkened lung fields, suggestive of radiographs of patients with asthma. In fact, the clinical syndrome may be indistinguishable from an asthmatic attack. Most infections are mild and self-limited. When broncates
-
chiolitis is severe and recurrent, it is likely that the patient is atopic
hospital
for at least
three days.9 Endobronchial infection with characterizes infection in nonallergic hosts of all ages, resulting in
bronchitis,
bronchopneumonia, pneumonia.&dquo; Allergic hosts have may significant bronIn RSV seems addition, chospasm. virulent in particularly young inand
fants with cystic fibrosis.l~ Immunodeficient hosts may also have
systemic invasion, persistent respiratory infection, and extensive bron-
chial/pulmonary tissue injury;l2 this pathologic process has recently been described in adult bone-marrow
transplant recipients.&dquo;
Diagnosis Because RSV infection may be manifested as an upper respiratory infection in adult contacts or
nonspecific pneumonia or bronchopneumonia in newborns and young infants, respectively, the difficulty of identifying this specific etiologic agent by clinical criteria is compounded. Identification has been simplified in paas
tients with bronchiolitis, in whom the majority of cases are due to RSV, by the development of rapid
fluorescent
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antibody
and enzyme-
linked
immunosorbent
assay
(ELISA) techniques for RSV antigen detection directly in respirasecretions, preferably tory obtained by nasopharyngeal aspiration. 14 Both rapid tests have sensitivities and specificities ap-
proaching 90%.15 It is especially important to identify RSV in hospitalized newborns and infants with marked degrees of acute pulmonary compromise, other high-risk hosts.
as
well
as
in
Treatment
duced RSV
developments in our understanding of RSV virus and its rapid diagnosis have allowed isolation techniques to be individualized, as mentioned above, and offer prospects for improved control of this infection both in the hospital and in the community. Included in these control measures are specific antiviral therapy and vaccination. Bacterial co-infection or superinfection is rare with New
RSV.21
Transmission/Isolation The transmission of RSV has extensively, since it is a common cause of nosocomial infection in hospitalized children and infants and is frequently spread in day-care centers, family units, and other community situations as well. 16 The virus is transmitted predominantly through direct contact, similar to the transmission of rhinovirus infections. Both patients and personnel are at risk.&dquo; Thus, aerosolization of small particles containing RSV is not the major mechanism for spread. Direct inoculation of nasal and conjunctival mucosa by contaminated fingers is an important route. Because of this, isolation procedures include hand-washbeen studied
ing, masks, gloves, and goggles or other ways of interrupting transmission of the virus. 18 Forming patient cohorts can also be effective in reducing nosocomial infection.’9 Often, however, the patient has a lower respiratory infection that is not characteristically identified as bronchiolitis; hence, respi-
ratory precautions
are
necessary until a specific etiology is defined. This is important because influenza, adenovirus, and other respiratory pathogens may be spread by the aerosol route. in such
patients
by 98%
in
respiratory
secretions.33 The aerosol
Supportive care, especially nursing management, oxygen, and hydration, are useful for hospitalized RSV patients,21 especially those with a predisposition to asthma. Currently, the only specific of this infection is antiviral substance that has in vitro activity against RSV, as well as parainfluenza, and influenza viruses.22 The ribavirin is aerosolized directly into the trachea or into the inspired air via mask, hood, or tent. Oral and parenteral forms of this drug are available, but therapeutic concentrations are seldom achieved by these routes. Ribavirin therapy appears to be effective for RSV infections in controlled comparative studies, 23-26 and recent results indicate that early initiation of therapy can reduce morbidity in patients at high risk for RSV complicationS.27 Ribavirin also has therapeutic activity against influenza and parainfluenza. 28-31 The drug is suspended in water at a concentration of 20 mg/mL, and a small-particle aerosol is produced by a specially detreatment
ribavirin,
signed
an
generator
(SPAG
or
Collison generator) and administered via tent, hood, mask, or tube over 16 to 18 hours, usually for three to seven days.2 Recently, 60mg/mL of aerosolized ribavirin, given for two hours three times daily, was well-tolerated and re-
misty fog
that
creates a
precipitates
out on
skin and respiratory surfaces. The initial result may be an increase in respiratory distress (increased respiratory rate, mild bronchospasm, or increased inspiratory pressure requirements in ventilated patients) after the first dosage period of 8 to 12 hours. Thereafter, clinical, physiologic, and virologic benefits become prominent. Mechanically ventilated patients should be treated only in tertiarycare units by personnel experienced in the techniques needed for this specialized use of the drug and capable of constant patient observation.34 In a recent placebo-controlled study, ribavirin decreased the duration of mechanical ventilation, supplemental oxygen, and the need for intensive care in such patients.35 There is experimental evidence that RSV antibody (humoral IgG) may act as an adjunct to ribavirin in treating RSV infection.36,37 This should be considered in the treatment of immunodeficient children. Ribavirin treatment may also reduce the host’s specific IgG, IgA, and IgE anti-RSV responses. 38 Whether this reduces the frequency of recurrent wheezing remains to be studied. Specific indications for treating high-risk hosts include presumptive or proven RSV infection in new-
borns, immunocompromised patients, and children with serious
underlying pulmonary or cardiovascular conditions.’9-4’ Treatment of patients with no underlying conditions hospitalized for RSV infection is controversial because of the unpredictability of the natural course of illness in RSV-infected patients and the characteristics of ribavirin therapy: its aerosol route, cost, need for intensive monitoring, and potential for patient and caretaker toxicity.
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689
Although systemic administration of ribavirin has caused developmental toxicity in rodents, it has not in primates, nor have significant serum concentrations of the drug been detected in erythrocytes (except in one published case), plasma, or urine of patient caretakers. 42 Pregnant caretakers and visitors need to be aware of the animal toxicity data and, therefore, should avoid exposure to ribavirin in the patient’s room .43 Despite this potential risk, however, approximately 60,000 infants with RSV infection have been treated with ribavirin in the United States since January 1986 with no evidence of major toxicity in patients or personnel.44 Reasonable precautions include good room ventilation (at least six air changes per hour), shutting off the aerosol when personnel enter the tent, and exclusion of pregnant caretakers.39 Other antiviral compounds are active in vitro but have not yet reached clinical testing in human RSV infection
several
but studies stages .4’ A
in killed
are
1991;163:687-692. 3.
4.
field-tested it stimulated an years ago; however, intense hypersensitivity response in the host, which resulted in increased morbidity and some mortality when the vaccine was exposed to the natural RSV in patients. With this experience in mind, and improved understanding of host immunity to RSV,
syncytial
690
vaccine
for respiratory syncytial virus diagnosis by cell culture, indirect immunofluorescence assay, and enzymelinked immunosorbent assay. J Clin Microb. 1987;25:763-767. 15.
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