Respiratory Syncytial Virus Infections Melvin I. Marks, M.D.


high is

espiratory syncytial


is the most




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




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



respiratory insufficiency

among RSV-infected with bronchopulmonary


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




Pathogenesis/ Immunity/Clinical Features

mained in the

understanding of the pathogenesis of RSV infection indi-

respiratory epithelial cytotoxicity


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


for at least

three days.9 Endobronchial infection with characterizes infection in nonallergic hosts of all ages, resulting in


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


Downloaded from at UNIVERSITY OF TOLEDO LIBRARIES on March 15, 2015


and enzyme-




(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.






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


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


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


by 98%



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







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


creates a


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.

Downloaded from at UNIVERSITY OF TOLEDO LIBRARIES on March 15, 2015


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


but studies stages .4’ A

in killed


1991;163:687-692. 3.


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,




for respiratory syncytial virus diagnosis by cell culture, indirect immunofluorescence assay, and enzymelinked immunosorbent assay. J Clin Microb. 1987;25:763-767. 15.

1990;161:402-406. Agius G, Dindinaud R, Biggar J,

et al. of respiratory syncytial vi-

epidemic in elderly people: clinical and serological findings. J Med Virol.


1990;30:117-127. 5. 6.

Ribavirin and

virus. Lancet. 1986;1:362-363. Editorial. Anderson LJ, Parker RA, Strikas RL. Association between respiratory

respiratory syncytial

syncytial virus outbreaks and lower respiratory tract deaths of infants and children. young J Infect Dis.



1990;161:640-646. 7.

Hall CB, Walsh EE, Long CE, Schnabel KC. Immunity to and frequency of reinfection with respiratory syncytial virus. J 1991:163:693-698.





JR, Salbenblatt CK, Lauer respiratory syncytial virus in older children. Am J Dis




Solon J, Sweet JI, ConRespiratory syncytial virus: a nursing perspective. Pediatr Nursing.




1989;15:342-345. 22.

Hall CB, McBride JT. Vapors, viruses and views: ribavirin and respiratory syncytial virus. Am J Dis Child.

al. Role of respiratory syncytial virus in early hospitalizations for respiratory distress of young infants with cystic fi-


brosis. J Pediatr. 1988;113:826-830. Chandwani S, Borkowsky W, Krasinski K, et al. Respiratory syncytial virus infection in human immunodeficiency virus-infected children. J Pediatr.

NJ. Economic and long-term benefits of ribavirin therapy on respiratory syncytial virus infection. Lung.


et al. Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection. N Engl J Med. 1983;308:1443-


Taber LH,

Abman SH, Ogle JW, Butler-Simon N,


1990;117:251-254. 13.

Nederhand KC, ner



Krasinski K, LaCouture R, Holzman RS,

Timmons OD, Yamauchi T, Collins SR, et al. Association of respiratory syncytial virus and Streptococcus pneumoniae infection in young infants. Pediatr Infect Dis J.

BA. Severe

infection Child. 1990;144:346-348.

ing for children with RSV infections. Am J Dis Child. 1987;141:695-697. Leclair JM, Freeman J, Sullivan BF, et al. Prevention of nosocomial respiratory syncytial virus infections through compliance with glove and gown isolation precautions. N Engl J Med. 1987 ;317 :329-

J Pediatr. 1990;116:894-898. sion.

al. Prediction of the duration of

parameters. 1988;81:22-26.

ruses. Semin Respir Infect. 1987;2:48-56. Agah R, Cherry JD, Garakian AJ, Chapin M. Respiratory syncytial virus (RSV) infection rate in personnel car-


hospitalization in patients with respiratory syncytial virus infection: use of clinical

ral isolation and direct immunofluoresfor the identification of cence J Clin Microrespiratory syncytial virus. biol. 1990;28:480-483. Hall CB. Hospital-acquired pneumonia in children: the role of respiratory vi-

et al. Screening for respiratory syncytial virus and assignment to a cohort at admission to reduce nosocomial transmis-

Welliver RC, Sun M, Rinaldo D, Ogra PL. Predictive value of respiratory syncytial virus-specific IgE responses for recurrent wheezing following bron-


Waner JL, Whitehurst NJ, Todd SJ, et al. Comparison of directigen RSV with vi-



chiolitis. J Pediatr. 1986;109:776-780. McMillan JA, Tristram DA, Weiner LB,


Ahluwalia G, Embree J, McNicol P, et al. Comparison of nasopharyngeal aspirate and nasopharyngeal swab specimens

Respiratory syncytial and parainfluenza viruses. J Infect Dis.




Heilman CA.



early respiratory


REFERENCES 1. Denny F. Acute respiratory infections in children: etiology and epidemiology. Pediatr Rev. 1987;9:135-146. 2. Anderson LJ, Hendry RM, Pierik L, et al. Multicenter study of strains of respiratory syncytial virus . J Infect Dis.


yet been determined.4’ The prospects for a vaccine are promising,




Preliminary studies have examined the feasibility, safety, and pharmacokinetics of intravenous gamma globulin to prevent RSV infection in high-risk hosts, but the efficacy of this approach has not

lung injury in adult patients with transplants: a clinical approach and review of the literature.

lines of investigation followed in an attempt to being an effective vaccine. develop new


Hertz MI,

Englund JA, Respiratory syncytial

Snover D, et al. virus-induced


1990;168:S422-S429. CB, McBride JT, Walsh EE,



Downloaded from at UNIVERSITY OF TOLEDO LIBRARIES on March 15, 2015

Knight V,





Ribavirin aerosol treatment of bronchiolitis associated with respiratory syncytial virus infection in infants. Pediatrics.







Conrad DA, Christenson JC, Waner JL, Marks MI. Aerosolized ribavirin treatment of respiratory syncytial virus infection in infants hospitalized during an

epidemic. Pediatr Infect Dis J. 1987;6: 152-158. Groothuis JR, Woodin KA, Katz R, et al. Early ribavirin treatment of respiratory syncytial viral infection in high-risk chilJPediatr. 1990;117:792-798. dren. Browne MJ. Comparative inhibition of influenza and parainfluenza virus replication by ribavirin in MDCK cells. Antimicrob Agents Chemother. 1981;19:712-715. McClung HW, Knight V, Gilbert BE, et al. Ribavirin aerosol treatment of influB virus enza infection. JAMA.



Wilson SZ, Gilbert BE, Quarles JM, et al. Treatment of influenza A (H1N1) virus infection with ribavirin aerosol. Antimi-



Ferrara EA, Oishi

RW Jr, Stephen ance, urine




bution of ribavirin in






J. 1987;6:159-163. Janai HK, Marks MI,

Zaleska M, StutHR. Ribavirin: adverse drug reactions, 1986 to 1988. Pediatr Infect Dis J. man

1990;9:209-211. 45.


Kawana F, et al. Inhibitory effects of antiviral compounds on respiratory

syncytial virus replication in vitro. Antimicrob Agents Chemother. 1987 ;31 :1225-

Gruber WC, Wilson SZ, Throop BJ, Wyde


Immunoglobulin administration and ribavirin therapy: efficacy in respiratory syncytial virus infection of the cotton rat. PediatrRes. 1987;21:270-274. Rosner IK, Welliver RC, Edelson PH, et al. Effect of ribavirin therapy on respiratory syncytial virus-specific IgE and after infection.

J Infect


culture and in


1983;2:732-733. McIntosh K, Kuracheck SC, Cairns LM, et al. Treatment of respiratory viral infection in an immunodeficient infant

Am J Dis

cotton rats.

Antiviral Res.

1990;14:215-226. Groothuis JR, Levin MJ, Rodriguez W, al. Use of intravenous gamma to passively immunize highrisk children against respiratory syncytial virus: safety and pharmacokinetics. Antimicrob Agents Chemother. et

Gelfand EW. Ribavirin treatment of viral pneumonitis in severe combined imdisease. Lancet. munodeficiency



osine against respiratory syncytial and parainfluenza type 3 viruses in tissue

Report of the

with ribavirin aerosol.

Wyde PR, Ambrose MW, Meyer HL,

al. Evaluation of the toxicity and antiviral activity of carbocyclic 3-deazaaden-




Rodriguez WJ,


Committee on Infectious Diseases. 22nd ed. Elk Grove Village, IL: American Academy of Pediatrics; 1991.


Englund JA, Piedra PA, Jefferson LS, et al. High-dose, short-duration ribavirin aerosol therapy in children with suspected respiratory syncytial virus infecJ Pediatr. 1990;117:313-320. tion.


1991;325:24-29. Hemming VG, Rodriguez W, Kim HW,


1981;19:1042-1049. 33.


IgA responses

and rhesus


Kim HW, Brandt CD, et al. Aerosolized ribavirin in the treatment of patients with respiratory syncytial virus disease. Pediatr Infect Dis



excretion, and tissue distri-

Smith DL, Frankel LR, Mathers LH, et al. A controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection. N Engl J Med.



EL. Plasma




1987 ;31 :1285-1287.


al. Intravenous immunoglobulin of respiratory syncytial virus infections in infants and young chil-

Stein DS, Creticos CM, Jackson GG, et al. Oral ribavirin treatment of influenza A and B. Antimicrob

Kochhar DM, Penner JD, Knudsen TB. Embryotoxic, teratogenic, and metabolic effects of ribavirin in mice. Toxicol Appl Pharmacol.


crob Agents Chenwther. 1984;26:200-203. 31.



1983;249:2671-2674. 30.

Frankel LR, Wilson CW, Demers RR, et al. A technique for the administration of ribavirin to mechanically ventilated infants with severe respiratory syncytial virus infection. Crit Care Med.



1991;35:1469-1473. 48.

Murphy BR, Sotnikov A, Paradiso PR, et al. Immunization of cotton rats with the fusion (F) and large (G) glycoproteins of respiratory syncytial virus (RSV)

protects against RSV challenge without

potentiating RSV disease.



Downloaded from at UNIVERSITY OF TOLEDO LIBRARIES on March 15, 2015


Respiratory syncytial virus infections.

Respiratory Syncytial Virus Infections Melvin I. Marks, M.D. Introduction high is espiratory syncytial virus is the most com- mon (RSV) of se...
402KB Sizes 0 Downloads 0 Views