Spectrum of Clinical Illness in Hospitalized Patients with “Common Cold” Virus Infections (original) (raw)
Clin Infect Dis. 2000 Jul; 31(1): 96–100.
Hana M. El-Sahly
1Department of Medicine, Baylor College of Medicine, Houston, Texas
Robert L. Atmar
1Department of Medicine, Baylor College of Medicine, Houston, Texas
2Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
William P. Glezen
2Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
3Department of Pediatrics, Baylor College of Medicine, Houston, Texas
Stephen B. Greenberg
1Department of Medicine, Baylor College of Medicine, Houston, Texas
2Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
1Department of Medicine, Baylor College of Medicine, Houston, Texas
2Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
3Department of Pediatrics, Baylor College of Medicine, Houston, Texas
Reprints or correspondence: Dr. Stephen B. Greenberg, Dept. of Medicine, One Baylor Plaza, 559E, Baylor College of Medicine, Houston, TX 77030 (ude.cmt.mcb@gnehpets).
Copyright © 2000 by the Infectious Diseases Society of America
This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.
Abstract
The viruses associated most frequently with the “common cold” are rhinoviruses and coronaviruses. The first prospective cohort study to determine the prevalence of rhinovirus and coronavirus infections in patients of all ages hospitalized for acute respiratory illnesses is described. Hospital admissions for acute respiratory illnesses were identified, and cell culture for rhinovirus and serologic assays on paired sera for coronaviruses 229E and OC43 were performed. A total of 61 infections with rhinoviruses and coronaviruses were identified from 1198 respiratory illnesses (5.1%); in addition, 9 additional infections associated with ≥1 other respiratory viruses were identified. Of those infected with only rhinovirus or coronavirus, underlying cardiopulmonary diseases were present in 35% of the patients aged <5 years, in 93% aged between 5 and 35 years, and in 73% aged >35 years. The predominant clinical syndromes varied by age: pneumonia and bronchiolitis in children aged <5 years; exacerbations of asthma in older children and young adults; and pneumonia and exacerbations of chronic obstructive pulmonary disease and congestive heart failure in older adults. Therefore, rhinovirus and coronavirus infections in hospitalized patients were associated with lower respiratory tract illnesses in all age groups.
Rhinoviruses and coronaviruses are the most frequently identified causes of the “common cold” syndrome [1–3]. Rhinoviruses are members of the Picornaviridae family and were first identified in 1956 [4]. Since then, >100 different serotypes have been identified [5]. Human coronaviruses, members of the Coronaviridae family, were first identified in 1962 and have been particularly difficult to isolate by use of standard cell culture techniques [6, 7]. A self-limited upper respiratory tract illness, or “common cold” syndrome, is the usual clinical manifestation of infection with these viruses. However, over the past 3 decades, several studies have found these viruses to be associated with clinical syndromes that require hospital care [8–19]. We recently performed a prospective, cohort study to evaluate the association of respiratory virus infection with respiratory conditions identified in hospitalized patients [20]. In this article, we describe the demographics and clinical characteristics of hospitalized patients identified with recent rhinovirus or coronavirus infection.
Methods
Study design. This prospective study was conducted in an urban public teaching hospital (Ben Taub General Hospital), a children's hospital (Texas Children's Hospital), and a community hospital (St. Luke's Episcopal Hospital) in Houston, Texas, from 1991 through 1995 [20]. Patients with an admitting diagnosis suggestive of an acute respiratory condition or congestive heart failure (CHF) were visited in the hospital to confirm eligibility and to seek consent for participation. Acute respiratory disease diagnoses included the following: pneumonia, tracheobronchitis, bronchitis, croup, and exacerbations of asthma or chronic obstructive pulmonary disease (COPD). Patients with active tuberculosis or known HIV disease were excluded. On admission to the hospital, a nasal and/or throat swab and an acute serum specimen were obtained. A convalescent serum was collected ≥10 days after obtaining the acute serum. Patients' inpatient medical records were reviewed. Information collected included sociodemographic data, symptoms, signs, acute respiratory diagnosis and other diagnoses, the location of admission (i.e., general ward or intensive care unit), the duration of hospitalization, the need for ventilatory support, and the chest radiograph interpretation.
Laboratory methods. Respiratory secretion specimens were inoculated on 4 cell culture lines, including human embryonic lung fibroblast cells (WI-38), continuous human epithelioid carcinoma cells (Hep-2), rhesus monkey kidney cells (LLC-MK2), and primary rhesus monkey kidney or Madin-Darby canine kidney (MDCK) cells. Rhinoviruses were identified initially by the characteristic cytopathic changes induced in cell culture. Rhinoviruses were differentiated from enteroviruses by use of acid lability or reverse transcriptase (RT)—PCR assays [21]. Coronavirus infections were identified serologically by use of paired serum samples, with the convalescent serum being collected at least 10 days after the acute serum collection. Antibody tests for coronavirus 229E were performed by use of a microneutralization assay, and infection was defined by the presence of a ≥4-fold increase in antibody levels [22]. An ELISA was used to measure antibodies to coronavirus OC43, and infection was defined as a ≥4-fold increase in ELISA IgG antibodies or by a ≥2.5 increase that was confirmed on a repeated test [23]. Coinfections with other respiratory viruses were identified by cell culture and serology, as described elsewhere [24].
Results
A total of 1068 patients were enrolled in the study, and these patients had 1198 illnesses evaluated. Of these illnesses, 408 (34.1%) had paired sera available for testing for coronavirus infection. Sixty-one illnesses were identified that were associated with a rhinovirus or coronavirus infection, but infection with no other respiratory viruses (table 1); 9 additional illnesses were associated with both a “common cold” virus (6 rhinoviruses and 3 coronavirus OC43) and an additional respiratory virus (influenza virus, respiratory syncytial virus [RSV], or parainfluenza virus). These patients with dual virus infections tended to be younger (5 of 9, aged <5 years) and more likely to have had paired sera collected (6 of 9 versus 18 of 61, respectively) than the group identified to have only “common cold” virus infections. These illnesses were not considered further because of the potential confounding effect of the additional respiratory virus infection.
Sociodemographics and laboratory abnormalities in hospit-alized patients with infections caused by rhinoviruses and corona-viruses.
The racial/ethnic distribution of the patients with a “common cold” virus infection was similar to that of the overall study population: 41% (n = 25) versus 51% black; 38% (n = 23) versus 31% Hispanic; 17% (n = 12) versus 16% white; and 1% (n = 1) versus 1% Asian. In addition, the age distribution of patients with a rhinovirus or coronavirus infection was similar to that of the overall study population: 33% versus 37% aged <5 years, 25% versus 19% aged 5–35 years, and 43% versus 44% aged >35 years. Eighteen (90%) of the 20 patients aged <5 years, 14 (93%) of 15 patients between the ages of 5 and 35 years, and 13 (50%) of 26 patients aged >35 years had rhinovirus infections. The remaining 16 patients had coronavirus infections.
Illnesses associated with “common cold” viruses occurred throughout the year but were less frequent during summer months. The distribution of illnesses was as follows: 28% of cases occurred between January and March, 25% between April and June, 13% between July and September, and 34% between October and December. Fifty-eight percent of rhinovirus infections and 81% of coronavirus infections occurred between October and March; 8 of the 9 infections associated with other respiratory viruses also occurred during this period.
The patients' admitting diagnoses were tabulated (table 2). In the group aged <5 years, the most common clinical diagnoses on admission were asthma (_n_ = 7), bronchiolitis (5), possible sepsis (5), and pneumonia (4). For patients between the ages of 5 and 35 years, the primary reason for admission was for the treatment of asthma (14); 1 patient had pneumonia. For patients aged >35 years, most clinical diagnoses on admission were for the treatment of pneumonia (n = 8) CHF (7), COPD (7), and asthma (5). Overall, a chronic cardiopulmonary disease diagnosis was present in 39 (64%) of 61 patients, with asthma being the most common illness, followed by CHF and COPD.
Spectrum of clinical illness in hospitalized patients with “common cold” virus infections.
Hospital care took place on the wards in 66% of the cases; however, 34% of the cases were treated in the intensive care unit or the intermediate care unit. One patient aged <35 years required mechanical ventilation compared with 2 patients aged >35 years (table 3). Fever and an elevated WBC count were more common in patients aged <5 years, and wheezing was seen in all age groups. Two of 9 cultures of blood obtained from patients aged <5 years were positive for _Staphylococcus_ species (probable contaminants). Two cultures of blood obtained from patients who were aged >35 years and had pneumonia were positive for Streptococcus pneumoniae. Antibiotics were prescribed for the majority of patients. All patients survived, and the mean (median) length of stay was 3.4 (3) days for patients aged 0–5 years; 3.5 (2) days for patients aged 5–35 years; and 6.0 (6) days for patients aged >35 years.
Clinical features and medical care requirements for patients with infections caused by “common cold” viruses.
Changes seen on chest radiographs largely reflected the clinical diagnoses. For patients aged <5 years, abnormalities were reported in 9 (56%) of 16 patients (infiltrates or pneumonia, 6; hyperinflation, 2; and atelectasis, 1). Abnormalities were seen in 6 (55%) of 11 patients aged between 5 and 35 years (hyperinflation, 4; and infiltrates, 2), and abnormalities were detected in 18 (72%) of 25 patients aged >35 years (pneumonia, 7; CHF/cardiomegaly, 5; emphysematous changes, 4; and pulmonary nodule, 2).
Discussion
Rhinoviruses and coronaviruses are usually recognized as causes of upper respiratory illnesses that are mostly benign and self-limited. However, these “common cold” viruses have also been associated with illnesses that require hospitalization. In previous reports, the role of one or both of these viruses has been evaluated in a select population, on the basis of age or underlying disease [8–19]. Our study is the first to analyze the clinical characteristics of patients from all age groups who were admitted with acute respiratory disease and were infected with a rhinovirus or coronavirus. We found that the distribution of presentations varied with the age and underlying disease of the patient. Only 35% of patients aged <5 years had underlying chronic pulmonary disease (asthma). In contrast, 93% of patients aged between 5 and 35 years had asthma, and 73% of patients aged >35 years had asthma, COPD, or CHF.
Bronchiolitis and pneumonia are the most common clinical syndromes associated with rhinovirus infection in hospitalized children aged <5 years [8–16], a finding confirmed by our study. RSV is the most frequently identified respiratory virus for which young children are hospitalized for an acute respiratory condition, and in some studies rhinovirus has been the second most common [10–13]. The clinical presentation of rhinovirus infection may be similar to that of RSV [15]. In addition, coronavirus infections have been associated with lower respiratory tract illness, including pneumonia and bronchiolitis, in children aged <5 years [19]. There is less information available regarding the relative importance of coronavirus infections in this age group. We identified only 2 coronavirus infections in patients aged <5 years, although paired sera were available for only ∼20% of the patients in this age group.
The association of respiratory virus infections with exacerbations of asthma has been recognized for several decades [25–27]. In the last several years, respiratory virus infections have been identified in up to 80% of wheezing episodes in school-aged children and in >50% of wheezing episodes in adults [17, 28, 29]. Virus-associated exacerbations can be severe enough to require hospitalization [17, 18], and a correlation between hospitalizations for asthma and the seasonal prevalence of upper respiratory virus infections has been noted, especially in children. In several studies, rhinovirus is the most common respiratory virus associated with asthma exacerbations, and coronavirus is the second most frequent [17, 28, 29]. In the current study, the principal reason for hospitalization of older children and young adults with a rhinovirus or coronavirus infection was an asthma exacerbation.
Respiratory virus infections have also been associated with worsening of other chronic diseases, including cardiopulmonary disorders such as COPD and CHF [31–34]. Although the proportion of exacerbations of these diseases associated with respiratory virus exacerbations has been lower than that seen for asthma, the burden of these infections is substantially greater in chronically ill patients than in healthy subjects of a similar age [33, 34]. In the current study, many of the patients aged >35 years had underlying lung disease or CHF. In addition, several patients were admitted with pneumonia. It is unclear whether rhinovirus can cause pneumonia itself [35, 36]. It has been recovered from the lower respiratory tract of infected individuals [37, 38], and an increase in the number of inflammatory cells in the bronchial mucosa has been noted after experimental infection of the upper respiratory tract [39]. The possibility that these viruses might be associated with an increased risk of bacterial pneumonia, similar to that described for influenza [40, 41], is suggested by the identification of at least 2 pneumonia illnesses in the oldest age group associated with a concomitant S. pneumoniae infection. However, this study was not designed to delineate such a virus-bacteria interaction.
There are several potential shortcomings of the current study. Paired sera were available for only a subset of the population; thus, there is substantial potential for the introduction of a bias in identifying the relative importance of coronavirus infections in this population. On the other hand, infections with additional respiratory viruses, such as influenza virus or RSV, may have been missed in those persons who did not have serologic studies performed. Another potential shortcoming is that control populations were not included in the study; therefore, the frequency of rhinovirus or coronavirus infections in ambulatory populations, in populations hospitalized with nonrespiratory conditions, or in asymptomatic populations cannot be determined. However, in a study for which virologic studies were performed in the same laboratory during the same period, <2% of cultures were positive for any respiratory virus from an asymptomatic adult and <1% of serologic studies identified a respiratory virus infection during an asymptomatic period [33]. The use of RT-PCR assays for rhinovirus and coronavirus has increased the frequency with which these virus infections were identified, compared with cell culture or serologic methods in previous studies of asthmatic patients [17, 28, 29]. Such assays were not performed in the current study; therefore, the burden of these infections detected in this study is likely to be a minimal estimate of their infection frequency.
The morbidity associated with rhinovirus and coronavirus infections, especially in high-risk populations such as patients with chronic lung disease, suggests that these infections should be a target for prevention or treatment strategies. The development of a conventional vaccine for rhinovirus has been hampered by the existence of >100 different serotypes and by the lack of protection associated with experimental parenteral vaccines [42]. Less is known about the number of coronavirus serotypes, and no experimental human vaccines have been evaluated. IFN-α is an antiviral agent that has been effective in both experimental rhinovirus and coronavirus infection [43–45], and also has been used effectively as postexposure prophylaxis for natural colds [46, 47]. The utility of IFN-α in normal healthy populations has been limited by its local (nasal) toxicity. Only a single study has evaluated its efficacy for the prevention of respiratory virus infections and the resulting complications in patients with chronic lung disease [48]. No beneficial effects of IFN-α were seen in this population of patients with asthma and COPD; however, the study had insufficient power to demonstrate an effect caused by the prevention of rhinovirus and coronavirus infections. Newer antirhinovirus drugs, such as tremacamra and pleconaril, have recently been shown to have beneficial effects in the treatment of experimental rhinovirus infection [49, 50], which suggests that there may be a role for these drugs in high-risk populations. Because of the morbidity associated with rhinovirus and coronavirus infections in high-risk patients, these groups should be targeted in future evaluations of antiviral chemotherapy strategies.
Acknowledgments
We thank Eula Landry for typing the manuscript and Barbara Baxter for technical support for virus isolation and serology assays.
Footnotes
Grant support: Division of Microbiology and Infectious Diseases, National Institute for Allergy and Infectious Diseases, National Institutes of Health. Contract: NO1-AI-15103.
References
1. Tyrrell DA. Hot news on the common cold. Annu Rev Microbiol. 1988;42:35–47. [PubMed] [Google Scholar]
2. Arruda E, Pitkaranta A, Witek TJJ, Doyle CA, Hayden FG. Frequency and natural history of rhinovirus infections in adults during autumn. J Clin Microbiol. 1997;35:2864–8. [PMC free article] [PubMed] [Google Scholar]
3. Makela MJ, Puhakka T, Ruuskanen O, et al. Viruses and bacteria in the etiology of the common cold. J Clin Microbiol. 1998;36:539–42. [PMC free article] [PubMed] [Google Scholar]
4. Pelon W, Mogabgab WJ, Phillips IA, Pierce WE. A cytopathogenic agent isolated from naval recruits with mild respiratory illnesses. Proc Soc Exp Biol Med. 1957;94:262–7. [PubMed] [Google Scholar]
5. Couch RB. Rhinoviruses. In: Fields BN, Knipe DM, Howley PM, editors. Virology. 3d ed. Philadelphia: Lippincott-Raven; 1996. pp. 713–34. [Google Scholar]
6. Hamre D, Procknow JJ. A new virus isolated from the human respiratory tract. Proc Soc Exp Biol Med. 1966;121:190–3. [PubMed] [Google Scholar]
7. Dick EC, Inhorn SL, Atmar RL. Coronaviruses. In: Feigin RD, Cherry JD, editors. Textbook of pediatric infectious diseases. 4th ed. Philadelphia: WB Saunders; 1998. pp. 2132–41. [Google Scholar]
8. Cherry JD, Diddams JA, Dick EC. Rhinovirus infections in hospitalized children: provocative bacterial interrelationships. Arch Environ Health. 1967;14:390–6. [PubMed] [Google Scholar]
9. Stott EJ, Eadie MB, Grist NR. Rhinovirus infections of children in hospital: isolation of 3 possibly new rhinovirus serotypes. Am J Epidemiol. 1969;90:45–52. [PubMed] [Google Scholar]
10. Jacobs JW, Peacock DB, Corner BD, Caul EO, Clarke SK. Respiratory syncytial and other viruses associated with respiratory disease in infants. Lancet. 1971;1:871–6. [PMC free article] [PubMed] [Google Scholar]
11. Paisley JW, Lauer BA, McIntosh K, Glode MP, Schachter J, Rumack C. Pathogens associated with acute lower respiratory tract infection in young children. Pediatr Infect Dis. 1984;3:14–9. [PubMed] [Google Scholar]
12. Krilov L, Pierik L, Keller E, et al. The association of rhinoviruses with lower respiratory tract disease in hospitalized patients. J Med Virol. 1986;19:345–52. [PubMed] [Google Scholar]
13. Kellner G, Popow-Kraupp T, Kundi M, Binder C, Kunz C. Clinical manifestations of respiratory tract infections due to respiratory syncytial virus and rhinoviruses in hospitalized children. Acta Paediatr Scand. 1989;78:390–4. [PubMed] [Google Scholar]
14. Abzug MJ, Beam AC, Gyorkos EA, Levin MJ. Viral pneumonia in the first month of life. Pediatr Infect Dis J. 1990;9:881–5. [PubMed] [Google Scholar]
15. McMillan JA, Weiner LB, Higgins AM, Macknight K. Rhinovirus infection associated with serious illness among pediatric patients. Pediatr Infect Dis J. 1993;12:321–5. [PubMed] [Google Scholar]
16. Kim JO, Hodinka RL. Serious respiratory illness associated with rhinovirus infection in a pediatric population. Clin Diagn Virol. 1998;10:57–65. [PubMed] [Google Scholar]
17. Atmar RL, Guy E, Guntupalli KK, et al. Respiratory tract viral infections in inner-city asthmatic adults. Arch Intern Med. 1998;158:2453–9. [PubMed] [Google Scholar]
18. Rakes GP, Arruda E, Ingram JM, et al. Rhinovirus and respiratory syncytial virus in wheezing children requiring emergency care: IgE and eosinophil analyses. Am J Respir Crit Care Med. 1999;159:785–90. [PubMed] [Google Scholar]
19. McIntosh K, Chao RK, Krause HE, Wasil R, Mocega HE, Mufson MA. Coronavirus infection in acute lower respiratory tract disease of infants. J Infect Dis. 1974;130:502–7. [PMC free article] [PubMed] [Google Scholar]
20. Glezen WP, Greenberg SB, Atmar RL, Piedra PA, Couch RB. Impact of respiratory virus infections on persons with chronic underlying conditions. JAMA. 2000;283:499–505. [PubMed] [Google Scholar]
21. Atmar RL, Georghiou PR. Classification of respiratory tract picornavirus isolates as enteroviruses or rhinoviruses by using reverse transcription-polymerase chain reaction. J Clin Microbiol. 1993;31:2544–6. [PMC free article] [PubMed] [Google Scholar]
22. Kraaijeveld CA, Reed SE, Macnaughton MR. Enzyme-linked immunosorbent assay for detection of antibody in volunteers experimentally infected with human coronavirus strain 229 E. J Clin Microbiol. 1980;12:493–7. [PMC free article] [PubMed] [Google Scholar]
23. Gill EP, Dominguez EA, Greenberg SB, et al. Development and application of an enzyme immunoassay for coronavirus OC43 antibody in acute respiratory illness. J Clin Microbiol. 1994;32:2372–6. [PMC free article] [PubMed] [Google Scholar]
24. Drews AL, Atmar RL, Glezen WP, Baxter BD, Piedra PA, Greenberg SB. Dual respiratory virus infections. Clin Infect Dis. 1997;25:1421–9. [PMC free article] [PubMed] [Google Scholar]
25. Pattemore PK, Johnston SL, Bardin PG. Viruses as precipitants of asthma symptoms. I. Epidemiology. Clin Exp Allergy. 1992;22:325–36. [PMC free article] [PubMed] [Google Scholar]
26. Berkovich S, Millian SJ, Snyder RD. The association of viral and mycoplasma infections with recurrence of wheezing in the asthmatic child. Ann Allergy. 1970;28:43–9. [PubMed] [Google Scholar]
27. Gern JE, Busse WW. Association of rhinovirus infections with asthma. Clin Microbiol Rev. 1999;12:9–18. [PMC free article] [PubMed] [Google Scholar]
28. Johnston SL, Pattemore PK, Sanderson G, et al. Community study of role of viral infections in exacerbations of asthma in 9- to 11-year-old children. BMJ. 1995;310:1225–9. [PMC free article] [PubMed] [Google Scholar]
29. Nicholson KG, Kent J, Ireland DC. Respiratory viruses and exacerbations of asthma in adults. BMJ. 1993;307:982–6. [PMC free article] [PubMed] [Google Scholar]
30. Johnston SL, Pattemore PK, Sanderson G, et al. The relationship between upper respiratory infections and hospital admissions for asthma: a time-trend analysis. Am J Respir Crit Care Med. 1996;154:654–60. [PubMed] [Google Scholar]
31. Smith CB, Golden CA, Kanner RE, Renzetti ADJ. Association of viral and Mycoplasma pneumoniae infections with acute respiratory illness in patients with chronic obstructive pulmonary diseases. Am Rev Respir Dis. 1980;121:225–32. [PubMed] [Google Scholar]
32. Walsh EE, Falsey AR, Hennessey PA. Respiratory syncytial and other virus infections in persons with chronic cardiopulmonary disease. Am J Respir Crit Care Med. 1999;160:791–5. [PubMed] [Google Scholar]
33. Greenberg SB, Allen M, Wilson J, Atmar RL. Respiratory tract viral infections in older adults with and without chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;162:167–73. [PubMed] [Google Scholar]
34. Wald TG, Shult P, Krause P, Miller BA, Drinka P, Gravenstein S. A rhinovirus outbreak among residents of a long-term care facility. Ann Intern Med. 1995;123:588–93. [PubMed] [Google Scholar]
35. Ghosh S, Champlin R, Couch R, et al. Rhinovirus infections in myelosuppressed adult blood and marrow transplant recipients. Clin Infect Dis. 1999;29:528–32. [PubMed] [Google Scholar]
36. Kaiser L, Hayden FG. Editorial response: rhinovirus pneumonia: a clinical entity? Clin Infect Dis. 1999;29:533–5. [PubMed] [Google Scholar]
37. Gern JE, Galagan DM, Jarjour NN, Dick EC, Busse WW. Detection of rhinovirus RNA in lower airway cells during experimentally induced infection. Am J Respir Crit Care Med. 1997;155:1159–61. [PubMed] [Google Scholar]
38. Las HJ, Swanson VL. Sudden death of an infant with rhinovirus infection complicating bronchial asthma: case report. Pediatr Pathol. 1983;1:319–23. [PubMed] [Google Scholar]
39. Fraenkel DJ, Bardin PG, Sanderson G, Lampe F, Johnston SL, Holgate ST. Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects. Am J Respir Crit Care Med. 1995;151:879–86. [PubMed] [Google Scholar]
40. Bisno AL, Griffin JP, Van Epps KA, Niell HB, Rytel MW. Pneumonia and Hong Kong influenza: a prospective study of the 1968–1969 epidemic. Am J Med Sci. 1971;261:251–63. [PubMed] [Google Scholar]
41. Schwarzmann SW, Adler JL, Sullivan RJJ, Marine WM. Bacterial pneumonia during the Hong Kong influenza epidemic of 1968–1969. Arch Intern Med. 1971;127:1037–41. [PubMed] [Google Scholar]
42. Couch RB. The common cold: control? J Infect Dis. 1984;150:167–73. [PubMed] [Google Scholar]
43. Samo TC, Greenberg SB, Couch RB, et al. Efficacy and tolerance of intranasally applied recombinant leukocyte A interferon in normal volunteers. J Infect Dis. 1983;148:535–42. [PubMed] [Google Scholar]
44. Hayden FG, Gwaltney JMJ. Intranasal interferon α 2 for prevention of rhinovirus infection and illness. J Infect Dis. 1983;148:543–50. [PubMed] [Google Scholar]
45. Higgins PG, Phillpotts RJ, Scott GM, Wallace J, Bernhardt LL, Tyrrell DA. Intranasal interferon as protection against experimental respiratory coronavirus infection in volunteers. Antimicrob Agents Chemother. 1983;24:713–5. [PMC free article] [PubMed] [Google Scholar]
46. Hayden FG, Albrecht JK, Kaiser DL, Gwaltney JMJ. Prevention of natural colds by contact prophylaxis with intranasal α 2-interferon. N Engl J Med. 1986;314:71–5. [PubMed] [Google Scholar]
47. Douglas RM, Moore BW, Miles HB, et al. Prophylactic efficacy of intranasal α 2-interferon against rhinovirus infections in the family setting. N Engl J Med. 1986;314:65–70. [PubMed] [Google Scholar]
48. Wiselka MJ, Nicholson KG, Kent J, Cookson JB, Tyrrell DA. Prophylactic intranasal α 2-interferon and viral exacerbations of chronic respiratory disease. Thorax. 1991;46:706–11. [PMC free article] [PubMed] [Google Scholar]
49. Turner RB, Wecker MT, Pohl G, et al. Efficacy of tremacamra, a soluble intercellular adhesion molecule 1, for experimental rhinovirus infection: a randomized clinical trial. JAMA. 1999;281:1797–804. [PubMed] [Google Scholar]
50. Hayden FG, Hassman HA, Coats T, Menendez R, Bock T. Program and abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy Addendum (San Francisco) Washington, DC: American Society for Microbiology; 1999. Pleconaril treatment shortens duration of picornavirus respiratory illness in adults [abstract LB-3] p. 13. [Google Scholar]
Articles from Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America are provided here courtesy of Oxford University Press