Clinical Studies

1. Bar-on ME, Zanga JR. Bronchiolitis. Prim Care. 1996;23:805-819.
A detailed summary of the current knowledge about bronchiolitis. Bronchiolitis is frequently associated with RSV infection, but may also be caused by other viruses. Outlined are the cause of the disease, epidemiology, pathophysiology, clinical presentation, diagnosis, long-term outcome, and treatment.

2. Brunell PA. The respiratory season is upon us. Infectious Diseases in Children. Thorofare, NJ: Slack Inc; 1997;10(1):5.
This article shares facts and statistics regarding RSV and alerts physicians to the "respiratory season" that is approaching. A brief review of current therapies for treating RSV is addressed.

3. Fete TJ, Noyes B. Common (but not always considered) viral infections of the lower respiratory tract. Pediatr Ann. 1996;25(10):577-584.
In the US, the most common cause for visits to pediatricians is acute respiratory tract infections. Viral infections of the lower respiratory tract (LRT) are commonly the cause, but are not always considered. Drs. Fete and Noyes describe the clinical syndromes associated with viral LRT disease in children, review the common viral etiologic agents, and outline current management options.

4. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B, Bjorksten B. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics. 1995;95(issue 4):500-505.
Children who had experienced RSV bronchiolitis as infants (approximately 3 months old) and a control group were tested for asthma and sensitization to common allergens, such as egg white, cat, and birch allergens, one to three years following infection. Serum IgG antibodies against RSV were also measured, and hereditary and environmental factors were recorded. IgG antibodies against RSV were found in 89% of children who had RSV, and 23% of them had asthma.

5. Update: respiratory syncytial virus activity--United States, 1994-95 season. MMWR. 1994;43:920-923.
Monitored by the National Respiratory and Enteric Virus Surveillance System, RSV activity in the US has commenced for the 1994-95 season, and healthcare providers are urged to consider RSV as a cause of acute respiratory disease in patients.

6. Englund JA, Sullivan CJ, Jordan C, et al. Respiratory syncytial virus infection in immunocompromised adults. Ann Intern Med. 1988;109:203-208.
RSV disease was documented in 11 immunocompromised adults aged 21 to 50 with underlying conditions including bone marrow transplant, renal and pancreas transplants, and T-cell lymphoma. Aerosolized ribavirin therapy was used in the recipients of bone marrow transplants. Four of 11 patients died as a result of their viral infection. The virus was an unexpected finding in these patients, but it is concluded that RSV disease must be considered in the diagnosis of immunocompromised adults.

7. Harrington RD, Hooton TM, Hackman RC, et al. An outbreak of respiratory syncytial virus in a bone marrow transplant center. J Infect Dis. 1992;165:987-993.
RSV infection is serious and life-threatening in bone marrow transplant patients. Once pneumonia develops, there is a high mortality rate for these immunocompromised patients. In 1990, during a 13-week outbreak of RSV infection among 31 patients in a bone marrow transplant center, 14 of 18 patients with pneumonia died, whereas the 13 with upper respiratory tract infection survived. These patients with pneumonia might have benefited from early treatment with ribavirin.

8. Hall CB. Respiratory syncytial virus. In: Feigin RD, Cherry JD, eds. Textbook of Pediatric Infectious Diseases. Philadelphia, Pa: W.B. Saunders Co; 1981:1247-1267.
With reference to over 200 sources, this paper gives a comprehensive history of RSV, its properties, epidemiology, pathology, and clinical characteristics. It goes on to provide clinical and epidemiologic diagnosis, therapy and prognosis including complications, and an outline of prevention.

9. Jeng M-J, Lemen RJ. Respiratory syncytial virus bronchiolitis. Am Fam Physician. 1997;55:1139-1146.
Preventive steps in the management of RSV bronchiolitis includes strict hand washing, avoidance of exposure during peak seasons, and prophylactic anti-RSV immune globulin. Fluid hydration, bronchodilators, and steroids are supportive measures used in the management of symptoms. Ribavirin, the only antiviral available for treating RSV infection, may be useful in severely ill children or those with underlying cardiopulmonary disease.

10. Long CE, McBride JT, Hall CB. Sequelae of respiratory syncytial virus infections: a role for intervention studies. Am J Respir Crit Care Med. 1995;151:1678-1681.
There are two hypotheses regarding the association between RSV infections in infancy and respiratory abnormalities later in life. One states that recurrent wheezing and subsequent airway dysfunction are caused by damage to the lung during an infant's viral infection. The other holds that genetics plays a major role in predisposing infants to long-term respiratory abnormalities. This paper summarizes the research on viral infection and long-term sequelae.

11. Pullan CR, Hey EN. Wheezing, asthma, and pulmonary dysfunction 10 years after infection with respiratory syncytial virus in infancy. BMJ. 1982;284:1665-1669.
A study of children 10 years after being admitted to hospitals in Tyneside, England in the first year of life with proven RSV lower respiratory tract infection identifies the incidence of further episodes of wheeze, asthma, and pulmonary dysfunction. Skin tests, lung function tests, and histamine-challenge and exercise tests for bronchial lability were undertaken in index children and control children.

12. Henry RL, Hodges IGC, Milner AD, Stokes GM. Respiratory problems 2 years after acute bronchiolitis in infancy. Arch Dis Child. 1983;58:713-716.
The clinical progress of 55 children two years after admission to the hospital with acute bronchiolitis was assessed. Episodes of wheezing (75%), two or more lower respiratory symptoms lasting more than two weeks (36%), more than 100 days of lower respiratory symptoms (33%), and readmission to the hospital with acute respiratory disease (13%) were reported. There was also evidence of hyperinflation on lung function tests, suggesting airway obstruction.

13. Welliver RC, Doffy L. The relationship of RSV-specific immunoglobulin E antibody responses in infancy, recurrent wheezing, and pulmonary function at age 7-8 years. Pediatr Pulmonol. 1993;15:19-27.
A prospective study of 43 infants with an initial RSV bronchiolitis episode was undertaken to determine if RSV-specific IgE responses at the time of diagnosis were related to recurrent wheezing and pulmonary function at 7 to 8 years of age. Skin testing to environmental allergens and pulmonary function testing were done at 7 to 8 years of age. It was found that passive cigarette smoke exposure and atopy in this group were determinants in decreased pulmonary function following bronchiolitis, and RSV-IgE specific responses were unrelated to pulmonary function.

14. Mok JYQ, Simpson H. Symptoms, atopy, and bronchial reactivity after lower respiratory infection in infancy. Arch Dis Child. 1984;59:299-305.
Early findings speculate that family history of atopy may play a role in the pathogenesis of bronchiolitis and other acute or recurrent respiratory infections caused by viruses. A study of 200 index children and their controls seven years after acute respiratory tract infection in infancy was undertaken to examine the possible relation between symptoms, atopic status, and bronchial reactivity. It was concluded that atopic background and bronchial reactivity may contribute independently to the persistence of symptoms following respiratory infections in infancy.

15. Korppi M, Reijonen T, Poysa L, Juntunen-Backman K. A 2- to 3-year outcome after bronchiolitis. Am J Dis Child. 1993;147:628-631.
A three year prospective study of 127 children under two years of age hospitalized for wheezing or pneumonia was undertaken in 1981. It was concluded that although bronchiolitis and pneumonia may be caused by the same virus or bacteria, subsequent wheezing is common only following bronchiolitis. No other specific risk factors for subsequent wheezing were identified.

16. Gurwitz D, Mindorff C, Levinson H. Increased evidence of bronchial reactivity in children with a history of bronchiolitis. J Pediatr. 1981;98:551-555.
Methacholine challenges were given to 48 children, 9 to 10 years following hospitalization for bronchiolitis in infancy. This study was done to assess subsequent bronchial reactivity. Children with positive methacholine challenges tended to be more susceptible to bronchial reactivity. Also, pulmonary function was evaluated and PFTs demonstrated lower flow rates in children with positive response. The authors conclude that children with hyperreactive airways and a previous history of bronchiolitis may be at an increased risk for chronic obstructive pulmonary disease.

17. Webb MSC, Henry RL, Milner AD, Stokes GM, Swarbuck AS. Continuing respiratory problems three and a half years after acute viral bronchiolitis. Arch Dis Child. 1985;60:1064-1067.
In a prospective study of 81 children, more than 50% were still affected by lower respiratory symptoms three and a half years after acute bronchiolitis as infants. Maternal passive smoking seems to play a role in subsequent illness whereas atopy did not.

18. Sly PD, Hibbert ME. Childhood asthma following hospitalization with acute viral bronchiolitis in infancy. Pediatr Pulmonol. 1989;7:153-158.
To learn whether family history of atopy and passive smoke exposure increases the frequency of wheezing in children in the years following RSV bronchiolitis as infants, a six-year prospective study was undertaken. Ninety-two percent (44 of 48) had symptoms suggestive of asthma in the five years following their initial illness. Thirty-five (of 44) were clinically examined and given pulmonary function testing and histamine challenges. Results were inconclusive regarding the relationship between asthma, family atopy, and results of the bronchial provocation tests.

19. Hall CB, Hall WJ, Gala CL, MaGill FB, Leddy JP. Long-term prospective study in children after respiratory syncytial virus infection. J Pediatr. 1984;105:358-364.
Twenty-one percent of children involved in an eight-year prospective study continue to have recurrent lower respiratory tract disease following an RSV illness as an infant. A history of family smoking was significantly associated with hospitalized infants versus the control group, whereas history of atopy and breastfeeding were not. The study suggests that the relationship between pulmonary function abnormalities and RSV infections may be detected sequentially through the first eight years of life.

20. Shaw KN, Bell LM, Sherman NH. Outpatient assessment of infants with bronchiolitis. Am J Dis Child. 1991;145:151-155.
The emergency room evaluation of 213 infants younger than 13 months with bronchiolitis were reviewed. The historical, physical, and laboratory clues were compared between the patients with mild disease (139) and those with severe disease (74). General characteristics of severe illness included "ill" or "toxic" general appearance, oxygen saturation less than 95%, gestational age younger than 34 weeks, respiratory rate of 70/min or greater, atelectasis on a chest x-ray, and age younger than 3 months.

21. Rooney JC, Williams HE. The relationship between proved viral bronchiolitis and subsequent wheezing. J Pediatr. 1971;79:744-747.
Subsequent wheezing episodes were evaluated in 62 children who had experienced RSV bronchiolitis in infancy. Review took place at ages ranging from two to seven years. There was a significantly higher incidence of asthma in first degree relatives of those infants who developed recurrent wheezing in comparison with those of infants who did not. A history of allergy was also prevalent in these children.

22. Krilov LR, Mandel FS, Barone SR, Fagin JC, and The Bronchoniolis Study Group. Follow-up of children with respiratory syncytial virus bronchiolitis in 1986 and 1987: potential effect of ribavirin on long term pulmonary function. Pediatr Infect Dis J.
One hundred patients were evaluated in a study to determine whether ribavirin therapy of initial RSV infection affects the long term outcome of pulmonary function. There was less bronchitis reported in ribavirin-treated patients but no difference in the subsequent diagnosis of reative airway disease compared to those not treated with ribavirin.

23. Jamie E. Fergie, Richard K. Purcell, Diane M. Wanat , Steve D. Seidel. Two Year Outcome of Children Hospitalized with RSV Lower Respiratory Tract Infection (LTRI) and its Relation to Ribavirin (R) Treatment. Pediatric Academic Societies Annual Meeting; May 1-5, 1998;Abstract#834.
Fergie, et al at the Driscoll Children's Hospital in Corpus Christi, Texas conducted a two-year pulmonary health status study of VIRAZOLE-treated and untreated infants with RSV bronchiolitis. The patients treated with VIRAZOLE had fewer hospitalizations two years following the initial admissions and fewer patients required asthma medications.

24. Rodriguez WJ, Arrobio J, Fink R, Kim HW, Milburn C. Prospective (7 yrs) follow up (FU) and pulmonary functions (PFT) from a placebo (P) controlled randomized trial of ribavirin (R) in RSV bronchiolitis (B). Pediatr Res. May 1996. Abstract.
Previously healthy, preterm infants and infants with chronic pulmonary disease were assessed for the prevalence of subsequent RAD for up to 7 years at the Children's National Medical Center and George Washington University in Washington DC. Weighted severity scores suggested a long-term beneficial effect of VIRAZOLE.

25. Hiatt P, Treece D, Morris L, Taber L. Longitudinal pulmonary function (PF) following treatment with ribavirin in infants hospitalized with RSV bronchiolitis. Am J Resp Crit Care Med. 1994;149:A354. Abstract.
Ninety-four RSV-positive, previously healthy, full-term or premature infants with no previous history of lower respiratory tract infections were enrolled in the study at Baylor College of Medicine, Houston, Texas. Forty-two of the 94 infants returned at 6 and 12 months after hospitalization for PFTs. VmaxFRC was significantly higher in VIRAZOLE recipients at the end of hospitalization and 12 months after discharge.

26. Long CE, Voter KZ, Barker WH, Hall CB. Long term follow-up of children hospitalized with respiratory syncytial virus lower respiratory tract infection and randomly treated with ribavirin or placebo. Pediatr Infect Dis J. 1997;16:1025-8
A prospective study of 54 children enrolled in a poor randomized study of ribavirin were assessed to determine the long term effects of the antiviral therapy. Ribavirin-treated children did not have exacerbated respiratory symtoms compared to the control group, and the pulmonary function measurements were equal in the two groups, suggestion no long term adverse effects of ribavirin therapy.

27. Whimbey E. Community respiratory viral infections in the immunocompromised host (Introduction). Am J Med. 1997;102(suppl 3a):1.
Dr. Estella Whimbey of The University of Texas reports on an investigator's meeting convened to increase awareness among the medical community of the importance of community respiratory virus infections in immunocompromised adults. The medical community shared knowledge about diagnosis, prophylaxis, and therapy for these illnesses and raised awareness of the need for establishing clear treatment guidelines.

28. Couch RB, Englund JA, Whimbey E. Respiratory viral infections in immunocompetent and immunocompromised persons. Am J Med. 1997;102(suppl 3a):2-9.
At the M.D. Anderson Cancer Center, RSV was the most frequently reported infection in a study of mostly hospitalized adults with leukemia or a recent bone marrow transplant. Respiratory virus was present in 27.1% of respiratory illness episodes. High frequency of nosocomial acquisition occurred. The immune deficiencies in this patient population and options for control of these infections have been described. Approaches to prevention and treatment have been summarized.

29. Leshin L. Respiratory syncytial virus (RSV). www.KidsHealth.org. 1996.

30. Groothuis JR, Woodin KA, Katz R, et al. Early ribavirin treatment of respiratory syncytial viral infection in high-risk children. J Pediatr. 1990;117:792-798.
To assess the efficacy of early ribavirin intervention in mild RSV illness in children (178 children younger than 36 months) with bronchopulmonary dysplasia or with congenital heart disease, a three-year prospective, blinded, multicenter study was done. Groups were similar in age, gender, family size, passive smoking, baseline oxygen saturations in room air, and duration of symptoms before treatment. It was concluded that early and aggressive medical intervention, including ribavirin therapy, may help to reduce morbidity from RSV infection in high-risk young children.

31. Hall CB, McBride JT, Gala CL, Hildreth SW, Schnabel KC. Ribavirin treatment of respiratory syncytial viral infection in infants with underlying cardiopulmonary disease. JAMA. 1985;254:3047-3051.
Fifty-three infants, 36 with underlying diseases, were used in a study to evaluate aerosolized ribavirin in the treatment of RSV lower respiratory tract disease. Infants with bronchopulmonary dysplasia and congenital heart disease who were treated with ribavirin showed a significantly faster rate of improvement than those infants receiving placebo. No toxic or adverse effects of the aerosol therapy were observed.

32. McIntosh K, Chanock RM. Respiratory syncytial virus. In: Fields BN, Knipe DM, Chanock RM, et al, eds. Virology. 2nd ed. New York, NY: Raven Press Ltd.; 1990:1045-1072.
This study in patients with lower respiratory tract infection demonstrated the activity of VIRAZOLE as most effective before the viral load had peaked (usually within 3 days of symptom onset). Symptoms typically emerged approximately 8 days after infection, then resolution of symptoms usually began 4 days later.

33. ICN Physician's Guide. www.icnpharm.com. Costa Mesa, Cal: ICN Pharmaceuticals, Inc. 1996.