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Serious respiratory illness associated with rhinovirus infection in a pediatric population
Clinical and Diagnostic Virology 10 (1998) 57 – 65
Serious respiratory illness associated with rhinovirus infection in a pediatric population Jean O. Kim a, Richard L. Hodinka a,b,* a
Department of Pediatrics, Children’s Hospital of Philadelphia and School of Medicine, Uni6ersity of Pennsyl6ania, 34th and Ci6ic Center Boule6ard, Philadelphia, PA 19104, USA b Department of Pathology and Clinical Virology Laboratory, Children’s Hospital of Philadelphia and School of Medicine, Uni6ersity of Pennsyl6ania, 34th and Ci6ic Center Boule6ard, Philadelphia, PA 19104, USA Received 4 November 1997; received in revised form 24 December 1997; accepted 2 January 1998
Abstract Background: Rhinoviruses have long been associated with mild upper respiratory illness in both adults and children. However, the role of rhinoviruses as lower respiratory tract pathogens has not been fully characterized. Previous data suggests that rhinoviruses may cause severe lower respiratory illness in young children or infants. Objectives: The present study describes the clinical presentations, severity of illness and outcomes for a large cohort of pediatric patients with documented rhinovirus infections. Subjects and methods: A retrospective chart review was done on 93 pediatric patients from whom 101 nasopharyngeal or endotracheal specimens were positive by viral culture for a rhinovirus. All patients were hospitalized or seen in the pediatric emergency department at The Children’s Hospital of Philadelphia between 1 January, 1990 and 31 May, 1996.Results: Of the 93 patients, 52 were male and 41 female. The age range was 0 days to 18 years with 25 (27%) less than 3 months, 42 (45%) between 3 and 12 months and 26 (28%) over the age of 12 months. Clinical presentations on evaluation in the emergency department or admission included 78 (84%) patients with acute respiratory illness, 13 (17%) with fever and suspected sepsis and 11 (12%) with other complaints. Reported physical findings on examination included one or more lower respiratory symptoms or signs of acute distress and fever greater than or equal to 38.1°C. A total of 64 (69%) children were noted to have significant past medical histories, including 28 (44%) with prematurity or complicated neonatal courses, 11 (17%) with prior reactive airways, 8 (12%) with congenital cardiac disease and 7 (11%) with neurologic disorders. Of the patients, 29 (31%) were considered to be otherwise healthy children with no underlying dysfunctions. The mean duration of hospitalization for 69 patients admitted with respiratory illness who did not develop subsequent unrelated complications was 3.7 days. No significant bacterial or fungal pathogens were identified in 91% of the cases.
* Corresponding author. Tel.: +1 215 5902028; fax: +1 215 5902556; e-mail: [email protected] 0928-0197/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved. PII S0928-0197(98)00004-X
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Conclusions: This study shows that rhinoviruses were associated with severe lower respiratory illness and hospitalization in a large pediatric population and that rhinovirus infection was a complicating factor in those patients with underlying or predisposing conditions. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Rhinovirus; Pediatrics; Lower respiratory disease
1. Introduction The rhinoviruses, which comprise over 100 serotypes of the family Picorna6iridae, have long been recognized as the single most important cause of uncomplicated upper respiratory tract illness in both adults and children (Reilly et al., 1962; Bloom et al., 1963; Fox et al., 1985). In the majority of cases, persons experience mild, self-limited colds, with symptoms of sneezing, nasal obstruction, nasal discharge, sore throat, headache, cough and malaise. Comparatively little is known about the causal role and significance of rhinoviruses in lower respiratory disease. Earlier reports have provided conflicting evidence and other causes for lower respiratory tract symptoms were suggested in patients who had rhinovirus isolated from respiratory specimens (Portnoy et al., 1965; Cherry et al., 1967). Atypical pneumonia associated with rhinovirus infection has been described in military trainees (Mogabgab, 1968; George and Mogabgab, 1969) and rhinovirus has been recovered from post-mortem lung specimens of an immunocompromised adult who died of pneumonia (Craighead et al., 1969). Rhinoviruses have also been associated with exacerbations of acute bronchitis (Horn et al., 1979; Boldy et al., 1990), chronic bronchitis (Eadie et al., 1966; Stenhouse, 1967; McNamara et al., 1969), acute otitis media (Arola et al., 1990), community-acquired sinusitis (Pitkaranta et al., 1997), and have precipitated asthmatic attacks in older children and adults (Minor et al., 1974a,b, 1976; Halperin et al., 1985; Frick and Busse, 1988; Calhoun et al., 1991; Mertsola et al., 1991; Pattemore et al., 1992). Evidence is also accumulating that rhinoviruses can cause serious lower respiratory illness in otherwise healthy infants and young children (Reilly et al., 1962; Hamparian et al., 1964; Jacobs et al., 1971; Paisley et al., 1984; Abzug et al., 1990; Schmidt and Fink, 1991; McMillan et al., 1993). Rhinovirus infections have been linked to
bronchiolitis and pneumonia, which is described as being clinically indistinguishable from infection with respiratory syncytial virus (RSV) (Kellner et al., 1989). It has also been reported that rhinoviruses are a frequent cause of lower respiratory tract infection in hospitalized infants and children (Krilov et al., 1986; Kellner et al., 1988, 1989). More recently, serious lower respiratory infections with rhinoviruses have been documented in children with bronchopulmonary dysplasia (Chidekel et al., 1994, 1997) and among elderly people (Nicholson et al., 1996). The present retrospective study describes the development of significant lower respiratory illness with rhinovirus infection in a large cohort of infants and children evaluated and managed at a pediatric institution during a 6-year period. The clinical presentations, severity of illness, underlying or predisposing conditions and the outcome of rhinovirus infection in this patient population are discussed.
2. Materials and methods
2.1. Patients The medical records of 93 pediatric patients from whom 101 respiratory specimens were positive for rhinoviruses by viral culture from 1 January, 1990 to 31 May, 1996 were reviewed. All patients were either hospitalized or evaluated in the emergency department at The Children’s Hospital of Philadelphia for signs and symptoms of acute respiratory illness. Diagnostic evaluations included a physical exam and clinical history on all patients and complete blood counts and chest radiographs on 58 and 64 children, respectively. Although clinical presentations varied among patients, their illness prompted physicians to also collect and submit a respiratory specimen to the laboratory for viral
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isolation. Information extracted from medical records included age, gender, clinical presentation, underlying diseases or predisposing factors, date and duration of hospitalization, presence or absence of documented concomitant bacterial or fungal infection, antimicrobial therapy administered, complete blood counts, chest radiographs and complications.
2.2. Specimens Nasopharyngeal or endotracheal aspirates were collected and submitted to the Clinical Virology Laboratory at The Children’s Hospital of Philadelphia. All specimens were promptly stored at 4oC following collection and were immediately transported on wet ice to the laboratory for processing.
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guinea pig red blood cells (Cleveland Scientific, Cleveland, OH) were performed on the PRMK cells of all specimens between days 3 and 7 and again on day 14 of culture. A presumptive diagnosis of rhinovirus was made by observing various sizes of rounded, refractile cells with lytic CPE similar to enteroviruses but progressing at a slower rate on MRC-5 cells. Suspicious rhinovirus isolates were confirmed by testing viral lability to acid at pH 3. Other respiratory viruses for which CPE was recognized or that were hemadsorption positive were confirmed by immunofluorescence staining of acetone-fixed infected cells using mouse monoclonal antibodies directed against respiratory syncytial virus, influenza A and B, parainfluenza 1, 2 and 3, and adenovirus and a goat anti-mouse fluorescein isothiocyanate (FITC) conjugate (Bartels, Issaquah, WA).
2.3. Viral culture 2.4. Rapid respiratory 6iral antigen detection Monolayers of human embryonic lung fibroblasts (MRC-5) and human carcinoma cells of the lung (A549) and the larynx (HEp-2) were propagated in 16×125 mm sterile plastic tissue culture tubes (Corning Glass Works, Corning, NY) using modified Eagle’s minimum essential medium (MEM; BioWhittaker, Walkersville, MD) supplemented with Earle’s balance salts solution, 1% L-glutamine, 7.5% fetal bovine serum (FBS), HEPES buffer and antimicrobial agents (5 mg/ml gentamicin, 10 mg/ml vancomycin and 10 mg/ml amphotericin B). The tubes were incubated in an atmosphere of 5% CO2 at 37oC until confluent and were used within 7 days of confluency. Tubes of primary rhesus monkey kidney (PRMK) cells were purchased from either BioWhittaker or Viromed Laboratories (Minneapolis, MN) and used within 1 week of receipt. Confluent monolayers of PRMK, MRC-5, A549 and HEp-2 cells were inoculated with 0.2 ml of each clinical specimen. The culture tubes were maintained in slanted stationary racks at 33oC for 14 days and examined daily for viral-induced cytopathic effects (CPE). All tubes were periodically refed with fresh MEM containing Earle’s balance salts solution, 1% L-glutamine, 2% FBS, HEPES buffer and antimicrobials as above. To assist in the detection of influenza and parainfluenza viruses, hemadsorption assays using washed
All specimen material used to inoculate conventional tube viral cultures was also used to perform rapid direct RSV antigen detection using the Abbott RSV TestPack (Abbott Diagnostics, Abbott Park, IL) and for the detection of influenza A and B, parainfluenza 1, 2 and 3 and adenovirus by an indirect immunofluresence assay (Bartels).
3. Results
3.1. Patient population Of the 93 patients studied, 52 were male and 41 female. Ages ranged from 0 days to 18 years with a distribution of 25 (27%) less than 3 months of age, 42 (45%) between 3 and 12 months and 26 (28%) over the age of 12 months.
3.2. Clinical presentation Of the 93 patients with documented rhinovirus infections, five were evaluated for acute respiratory illness in the emergency department and sent home after nasopharyngeal specimens were obtained. A total of 88 (95%) children were hospitalized during the 6-year period. Clinical
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Table 1 Signs and symptoms of respiratory illness in the 93 patients with rhinovirus infection Signs and symptoms
Fever (\38.1oC) Rhinorrhea/rhinitis Pharyngitis Stridor Cough Tachypnea Nasal flaring/grunting Retractions Rhonchi Wheezing Crackles Cyanosis Apnea Hypoxia (O2 saturation 593%) Conjunctivitis Otitis media Vomiting Sinus tenderness
No. (%) of patients at age: B3 months (n = 25)
3 – 12 months (n =42)
\12 months (n =26)
11 17 2 1 13 18 0 6 1 0 2 1 2 3 0 1 0 0
13 26 4 2 25 30 7 22 3 22 8 2 4 13 1 10 2 0
6 17 1 0 19 17 4 10 1 11 5 0 0 14 1 6 0 1
(44) (68) (8) (4) (52) (72) (0) (24) (4) (0) (8) (4) (8) (12) (0) (4) (0) (0)
presentations on evaluation in the emergency department or admission included 78 (84%) patients with signs or symptoms of acute respiratory illness, 13 (14%) with fever (seven in the neonatal period) and a diagnosis of suspected sepsis, and 11 (12%) with other complaints. On examination, the patients with respiratory illness had one or more signs or symptoms of respiratory infection and distress, including cough, congestion, nasal discharge, tachypnea, wheezing, crackles, grunting, nasal flaring, retractions or hypoxia (Table 1). Six patients (6%) presented with only rhinorrhea or nasal crusting and 17 (18%) were diagnosed with acute otitis media. Six patients (6%) had episodes of apnea, 30 (32%) had temperatures greater than or equal to 38.1oC and four (4%) were reported to have normal, nonfocal exams. During the course of hospitalization, 64 (69%) patients had chest radiographs performed with 44 readings of abnormal findings, including peribronchial thickening, atelectosis and hyperinflation. A total of 15 patients had a diagnosis of pneumonia with interstitial infiltrates or lobar consolidations on radiographs of their chest.
(31) (62) (10) (5) (60) (71) (17) (52) (19) (52) (19) (5) (10) (31) (2) (24) (5) (0)
(23) (65) (4) (0) (73) (65) (15) (38) (4) (42) (19) (0) (0) (54) (4) (23) (0) (4)
3.3. Underlying disorders Of the patients in this study, 29 (31%) were considered to be otherwise healthy children with no underlying dysfunctions, while 64 (69%) children were noted to have significant past medical histories at the time of admission (Table 2). Of these, 28 (44%) were either premature or had a complicated neonatal course with seven (11%) patients having bronchopulmonary dysplasia secondary to their prematurity. Review of medical records also revealed that 11 (17%) patients had a prior history of reactive airway disease, eight (13%) had congenital cardiac disease and seven (11%) had significant neurologic disorders. Four patients (6%) were noted to have either an immunologic or oncologic disease and two (3%) were HIV-positive. Other significant underlying illnesses included failure to thrive, congenital anatomic anomalies and trauma.
3.4. Duration of hospitalization The duration of hospitalization for 69 of the 93 patients with and without underlying diseases can
J.O. Kim, R.L. Hodinka / Clinical and Diagnostic Virology 10 (1998) 57–65 Table 2 Underlying conditions for the 93 patients with rhinovirus infection Underlying condition
No. (%) of patients
None (otherwise healthy children) Prematurity/complicated neonatal course Reactive airway disease Cardiac history Neurologic disorder Human immunodeficiency virus infection Immunologic/oncologic disease Failure to thrive Acute respiratory distress syndrome Metabolic disorder Sickle cell disease Hydronephrosis Genitourinary anomalies Head trauma Cleft palate Recurrent respiratory infection Dysmorphia
29 (31) 28 (30) 11 8 7 2
(12) (9) (8) (2)
4 2 1 1 1 1 1 2 1 1 1
(4) (2) (1) (1) (1) (1) (1) (2) (1) (1) (1)
be found in Fig. 1. The mean duration of hospitalization for those patients admitted with a respiratory illness who did not develop subsequent, unrelated complications was 3.7 days. The dura-
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tion of hospitalization for the different age groups was 3.8 days (range 1–17 days) for patients less than 3 months old, 6.0 days (range 1–22 days) for children 3–12 months of age and 8.4 days (range 1–49 days) for patients greater than 12 months old. Seven patients were admitted for overnight observation following evaluation in the emergency department.
3.5. Antimicrobial use Of the 93 patients evaluated, 38 (40.9%) received courses of antimicrobial therapy, including 13 courses of coverage for neonatal fever/sepsis, 19 orders for antibiotics for otitis media, conjunctivitis, or urinary tract infection and six courses of cefuroxime with or without erythromycin for pneumonia.
3.6. Complications The majority of hospitalizations were uncomplicated. However, five patients required endotracheal intubation and ventilatory support secondary to respiratory failure, including one cardiorespiratory arrest following loss of airway control. Two patients expired secondary to underlying disorders, including complicated cardiac dis-
Fig. 1. Duration of hospitalization for 69 of the 93 pediatric patients with rhinovirus infections. The black portion of the bars represent those patients with underlying disorders, while the white portion of the bars represent otherwise healthy children with respiratory illness.
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ease and perforation of bowel in a HIV-positive patient. No significant bacterial or fungal pathogens were identified in 91% of the individuals studied. Only eight patients were diagnosed with concomitant infections including: one with adenovirus; two with RSV; and one with adenovirus, influenza B virus and RSV identified from respiratory specimens; one with bacteremia and meningitis due to viridans streptococci; one with Streptococcus pneumoniae meningitis; and two with Escherichia coli urinary tract infections. One patient suffered exacerbation of congestive heart failure and one was rehospitalized for persistent respiratory difficulties. It was not possible to attribute respiratory illness to rhinovirus in the presence of the other recognized pathogens in these eight patients. In the four patients that had more than one virus identified from respiratory specimens, the severity of their respiratory illness was no different than that observed for those patients with only rhinovirus.
4. Discussion Recent reports suggest that rhinoviruses as possible pathogens in lower respiratory tract disease of infants and children may be more common than realized (Krilov et al., 1986; Kellner et al., 1988, 1989; Schmidt and Fink, 1991; McMillan et al., 1993; Chidekel et al., 1994, 1997). Reported here is the largest series to date of pediatric patients with documented rhinovirus infection and their clinical presentations and outcomes over a 6-year period at The Children’s Hospital of Philadelphia. Of the 93 patients evaluated, 95% were hospitalized for lower respiratory tract disease associated with rhinovirus infection. All but five patients were either acutely admitted or already hospitalized during the time of specimen collection for viral culture. Most patients presented with signs of acute respiratory illness in the absence of other identifiable infectious etiologies. Their mean duration of hospitalization was 3.7 days; those patients with unrelated medical complications had substantially longer hospital stays. Of significance is that a large number of patients (69%) carried previous diagnoses of underlying
diseases or predisposing conditions, with prematurity or complicated neonatal history being most often noted. Interestingly, the other most common underlying disorders included reactive airway disease followed by congenital cardiac disease and neurological disorders. This suggests that certain underlying diseases or predisposing factors lead to either more severe respiratory disease with rhinovirus infection or hospitalization for observation and further evaluation of the acute illness. To date, only a few reports have emphasized the risk of serious rhinovirus infections in pediatric patients with underlying disease. This observation has been made by Krilov et al. (1986) in 32 hospitalized infants and children, McMillan et al. (1993) in a series of 48 patients and Chidekel et al. (1997) in a report of eight patients with bronchopulmonary dysplasia who were infected with a rhinovirus. Severity of disease in the current study was quite variable, ranging from mild URI symptoms to intubation and ventilatory support. The majority of patients showed objective signs of lower respiratory disease on physical examination, though only approximately one-third had lowgrade fevers at time of presentation. This suggests that patients with underlying lung disease may be prone to develop lower airway disease, as suggested by recent experimental studies of rhinovirus infection and hosts with reactive airway disease or allergic disease (Johnston et al., 1993; Gern and Busse, 1995; Gwaltney, 1995; Johnston, 1995; Smyth et al., 1995). In those studies, obstructive airway processes were measured objectively using pulmonary function tests as well as quantitation of IgE. It would follow that patients with a predisposition to wheezing would be at considerable risk for development of more severe exacerbation of symptoms when infected with a viral pathogen such as rhinovirus, that is normally thought to cause only mild respiratory infections. Of note in this age of cost containment, was the fact that the primary physicians caring for the patients reported in this study felt that the symptoms of respiratory disease, signs of distress or fever warranted further evaluation in their patients, including complete blood counts in 62%, chest radiographs in 69%, antibiotic therapy in 41% and nasopharyngeal aspirates for the detec-
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tion of RSV and other respiratory viral infections in 100%. In total, over the observed 6-year period, the costs incurred for hospital stays, laboratory tests and the use of antibiotics in patients who had a documented rhinovirus infection but a clinical diagnoses of suspected bacterial sepsis and neonatal fever was significant. Due to the potential severity of lower respiratory tract disease associated with rhinovirus infections, the practice of laboratory identification of these viruses should be considered along with other respiratory pathogens in both healthy patients and those with underlying disease or a predisposing condition who have signs and symptoms of lower respiratory illness. However, despite continued reports of significant respiratory illness, it is still widely believed that rhinoviruses cause infections of little clinical significance and many diagnostic virology laboratories no longer make an attempt to routinely identify these viruses from respiratory specimens. Also, detection of rhinoviruses is problematic and generally limited to conventional viral isolation. Viral culture for rhinoviruses, however, is slow, labor-intensive and time-consuming; these viruses can also be difficult to grow and are sensitive to the conditions under which the cultures are maintained. Methods for the direct detection of rhinovirus antigens from clinical specimens have been developed and include enzyme-linked immunosorbent assays and immunofluorescence and immunoperoxidase staining of exfoliated epithelial cells using antiserum to type-specific antigen (Dreizin et al., 1975; Turner et al., 1982; Dearden and Al-Nakib, 1987; Al-Nakib et al., 1989). An enzyme-linked immunosorbent assay has also been evaluated for the measurement of rhinovirus-specific antibodies in human sera (Barclay et al., 1988). The lack of suitable rhinovirus group-specific antigens, however, has hampered the utility of immunologic identification or serologic diagnosis. Nucleic acid hybridization with synthetic oligonucleotide probes have been applied to rhinovirus detection, although such assays are most sensitive for homologous virus and during the later phase of infection (Bruce et al., 1989; Forsyth et al., 1989). More recently, the polymerase chain reaction has been described for the amplification of rhinovirus-
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specific RNA and would appear to be the most promising alternative for rapid and accurate identification of rhinoviruses (Gama et al., 1989; Hyypia et al., 1989; Arruda and Hayden, 1993). With the advent of effective antiviral agents for treatment of rhinovirus infections (Johnston et al., 1993; Arruda and Hayden, 1996) and continued development of the polymerase chain reaction for routine clinical use, the detection of rhinoviruses will have increased importance in the effective management of patients with severe respiratory disease.
Acknowledgements We gratefully thank the personnel of the Clinical Virology Laboratory at The Children’s Hospital of Philadelphia for their technical and scientific contributions.
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Serious respiratory illness associated with rhinovirus infection in a pediatric population Jean O. Kim a, Richard L. Hodinka a,b,* a
Department of Pediatrics, Children’s Hospital of Philadelphia and School of Medicine, Uni6ersity of Pennsyl6ania, 34th and Ci6ic Center Boule6ard, Philadelphia, PA 19104, USA b Department of Pathology and Clinical Virology Laboratory, Children’s Hospital of Philadelphia and School of Medicine, Uni6ersity of Pennsyl6ania, 34th and Ci6ic Center Boule6ard, Philadelphia, PA 19104, USA Received 4 November 1997; received in revised form 24 December 1997; accepted 2 January 1998
Abstract Background: Rhinoviruses have long been associated with mild upper respiratory illness in both adults and children. However, the role of rhinoviruses as lower respiratory tract pathogens has not been fully characterized. Previous data suggests that rhinoviruses may cause severe lower respiratory illness in young children or infants. Objectives: The present study describes the clinical presentations, severity of illness and outcomes for a large cohort of pediatric patients with documented rhinovirus infections. Subjects and methods: A retrospective chart review was done on 93 pediatric patients from whom 101 nasopharyngeal or endotracheal specimens were positive by viral culture for a rhinovirus. All patients were hospitalized or seen in the pediatric emergency department at The Children’s Hospital of Philadelphia between 1 January, 1990 and 31 May, 1996.Results: Of the 93 patients, 52 were male and 41 female. The age range was 0 days to 18 years with 25 (27%) less than 3 months, 42 (45%) between 3 and 12 months and 26 (28%) over the age of 12 months. Clinical presentations on evaluation in the emergency department or admission included 78 (84%) patients with acute respiratory illness, 13 (17%) with fever and suspected sepsis and 11 (12%) with other complaints. Reported physical findings on examination included one or more lower respiratory symptoms or signs of acute distress and fever greater than or equal to 38.1°C. A total of 64 (69%) children were noted to have significant past medical histories, including 28 (44%) with prematurity or complicated neonatal courses, 11 (17%) with prior reactive airways, 8 (12%) with congenital cardiac disease and 7 (11%) with neurologic disorders. Of the patients, 29 (31%) were considered to be otherwise healthy children with no underlying dysfunctions. The mean duration of hospitalization for 69 patients admitted with respiratory illness who did not develop subsequent unrelated complications was 3.7 days. No significant bacterial or fungal pathogens were identified in 91% of the cases.
* Corresponding author. Tel.: +1 215 5902028; fax: +1 215 5902556; e-mail: [email protected] 0928-0197/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved. PII S0928-0197(98)00004-X
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Conclusions: This study shows that rhinoviruses were associated with severe lower respiratory illness and hospitalization in a large pediatric population and that rhinovirus infection was a complicating factor in those patients with underlying or predisposing conditions. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Rhinovirus; Pediatrics; Lower respiratory disease
1. Introduction The rhinoviruses, which comprise over 100 serotypes of the family Picorna6iridae, have long been recognized as the single most important cause of uncomplicated upper respiratory tract illness in both adults and children (Reilly et al., 1962; Bloom et al., 1963; Fox et al., 1985). In the majority of cases, persons experience mild, self-limited colds, with symptoms of sneezing, nasal obstruction, nasal discharge, sore throat, headache, cough and malaise. Comparatively little is known about the causal role and significance of rhinoviruses in lower respiratory disease. Earlier reports have provided conflicting evidence and other causes for lower respiratory tract symptoms were suggested in patients who had rhinovirus isolated from respiratory specimens (Portnoy et al., 1965; Cherry et al., 1967). Atypical pneumonia associated with rhinovirus infection has been described in military trainees (Mogabgab, 1968; George and Mogabgab, 1969) and rhinovirus has been recovered from post-mortem lung specimens of an immunocompromised adult who died of pneumonia (Craighead et al., 1969). Rhinoviruses have also been associated with exacerbations of acute bronchitis (Horn et al., 1979; Boldy et al., 1990), chronic bronchitis (Eadie et al., 1966; Stenhouse, 1967; McNamara et al., 1969), acute otitis media (Arola et al., 1990), community-acquired sinusitis (Pitkaranta et al., 1997), and have precipitated asthmatic attacks in older children and adults (Minor et al., 1974a,b, 1976; Halperin et al., 1985; Frick and Busse, 1988; Calhoun et al., 1991; Mertsola et al., 1991; Pattemore et al., 1992). Evidence is also accumulating that rhinoviruses can cause serious lower respiratory illness in otherwise healthy infants and young children (Reilly et al., 1962; Hamparian et al., 1964; Jacobs et al., 1971; Paisley et al., 1984; Abzug et al., 1990; Schmidt and Fink, 1991; McMillan et al., 1993). Rhinovirus infections have been linked to
bronchiolitis and pneumonia, which is described as being clinically indistinguishable from infection with respiratory syncytial virus (RSV) (Kellner et al., 1989). It has also been reported that rhinoviruses are a frequent cause of lower respiratory tract infection in hospitalized infants and children (Krilov et al., 1986; Kellner et al., 1988, 1989). More recently, serious lower respiratory infections with rhinoviruses have been documented in children with bronchopulmonary dysplasia (Chidekel et al., 1994, 1997) and among elderly people (Nicholson et al., 1996). The present retrospective study describes the development of significant lower respiratory illness with rhinovirus infection in a large cohort of infants and children evaluated and managed at a pediatric institution during a 6-year period. The clinical presentations, severity of illness, underlying or predisposing conditions and the outcome of rhinovirus infection in this patient population are discussed.
2. Materials and methods
2.1. Patients The medical records of 93 pediatric patients from whom 101 respiratory specimens were positive for rhinoviruses by viral culture from 1 January, 1990 to 31 May, 1996 were reviewed. All patients were either hospitalized or evaluated in the emergency department at The Children’s Hospital of Philadelphia for signs and symptoms of acute respiratory illness. Diagnostic evaluations included a physical exam and clinical history on all patients and complete blood counts and chest radiographs on 58 and 64 children, respectively. Although clinical presentations varied among patients, their illness prompted physicians to also collect and submit a respiratory specimen to the laboratory for viral
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isolation. Information extracted from medical records included age, gender, clinical presentation, underlying diseases or predisposing factors, date and duration of hospitalization, presence or absence of documented concomitant bacterial or fungal infection, antimicrobial therapy administered, complete blood counts, chest radiographs and complications.
2.2. Specimens Nasopharyngeal or endotracheal aspirates were collected and submitted to the Clinical Virology Laboratory at The Children’s Hospital of Philadelphia. All specimens were promptly stored at 4oC following collection and were immediately transported on wet ice to the laboratory for processing.
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guinea pig red blood cells (Cleveland Scientific, Cleveland, OH) were performed on the PRMK cells of all specimens between days 3 and 7 and again on day 14 of culture. A presumptive diagnosis of rhinovirus was made by observing various sizes of rounded, refractile cells with lytic CPE similar to enteroviruses but progressing at a slower rate on MRC-5 cells. Suspicious rhinovirus isolates were confirmed by testing viral lability to acid at pH 3. Other respiratory viruses for which CPE was recognized or that were hemadsorption positive were confirmed by immunofluorescence staining of acetone-fixed infected cells using mouse monoclonal antibodies directed against respiratory syncytial virus, influenza A and B, parainfluenza 1, 2 and 3, and adenovirus and a goat anti-mouse fluorescein isothiocyanate (FITC) conjugate (Bartels, Issaquah, WA).
2.3. Viral culture 2.4. Rapid respiratory 6iral antigen detection Monolayers of human embryonic lung fibroblasts (MRC-5) and human carcinoma cells of the lung (A549) and the larynx (HEp-2) were propagated in 16×125 mm sterile plastic tissue culture tubes (Corning Glass Works, Corning, NY) using modified Eagle’s minimum essential medium (MEM; BioWhittaker, Walkersville, MD) supplemented with Earle’s balance salts solution, 1% L-glutamine, 7.5% fetal bovine serum (FBS), HEPES buffer and antimicrobial agents (5 mg/ml gentamicin, 10 mg/ml vancomycin and 10 mg/ml amphotericin B). The tubes were incubated in an atmosphere of 5% CO2 at 37oC until confluent and were used within 7 days of confluency. Tubes of primary rhesus monkey kidney (PRMK) cells were purchased from either BioWhittaker or Viromed Laboratories (Minneapolis, MN) and used within 1 week of receipt. Confluent monolayers of PRMK, MRC-5, A549 and HEp-2 cells were inoculated with 0.2 ml of each clinical specimen. The culture tubes were maintained in slanted stationary racks at 33oC for 14 days and examined daily for viral-induced cytopathic effects (CPE). All tubes were periodically refed with fresh MEM containing Earle’s balance salts solution, 1% L-glutamine, 2% FBS, HEPES buffer and antimicrobials as above. To assist in the detection of influenza and parainfluenza viruses, hemadsorption assays using washed
All specimen material used to inoculate conventional tube viral cultures was also used to perform rapid direct RSV antigen detection using the Abbott RSV TestPack (Abbott Diagnostics, Abbott Park, IL) and for the detection of influenza A and B, parainfluenza 1, 2 and 3 and adenovirus by an indirect immunofluresence assay (Bartels).
3. Results
3.1. Patient population Of the 93 patients studied, 52 were male and 41 female. Ages ranged from 0 days to 18 years with a distribution of 25 (27%) less than 3 months of age, 42 (45%) between 3 and 12 months and 26 (28%) over the age of 12 months.
3.2. Clinical presentation Of the 93 patients with documented rhinovirus infections, five were evaluated for acute respiratory illness in the emergency department and sent home after nasopharyngeal specimens were obtained. A total of 88 (95%) children were hospitalized during the 6-year period. Clinical
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Table 1 Signs and symptoms of respiratory illness in the 93 patients with rhinovirus infection Signs and symptoms
Fever (\38.1oC) Rhinorrhea/rhinitis Pharyngitis Stridor Cough Tachypnea Nasal flaring/grunting Retractions Rhonchi Wheezing Crackles Cyanosis Apnea Hypoxia (O2 saturation 593%) Conjunctivitis Otitis media Vomiting Sinus tenderness
No. (%) of patients at age: B3 months (n = 25)
3 – 12 months (n =42)
\12 months (n =26)
11 17 2 1 13 18 0 6 1 0 2 1 2 3 0 1 0 0
13 26 4 2 25 30 7 22 3 22 8 2 4 13 1 10 2 0
6 17 1 0 19 17 4 10 1 11 5 0 0 14 1 6 0 1
(44) (68) (8) (4) (52) (72) (0) (24) (4) (0) (8) (4) (8) (12) (0) (4) (0) (0)
presentations on evaluation in the emergency department or admission included 78 (84%) patients with signs or symptoms of acute respiratory illness, 13 (14%) with fever (seven in the neonatal period) and a diagnosis of suspected sepsis, and 11 (12%) with other complaints. On examination, the patients with respiratory illness had one or more signs or symptoms of respiratory infection and distress, including cough, congestion, nasal discharge, tachypnea, wheezing, crackles, grunting, nasal flaring, retractions or hypoxia (Table 1). Six patients (6%) presented with only rhinorrhea or nasal crusting and 17 (18%) were diagnosed with acute otitis media. Six patients (6%) had episodes of apnea, 30 (32%) had temperatures greater than or equal to 38.1oC and four (4%) were reported to have normal, nonfocal exams. During the course of hospitalization, 64 (69%) patients had chest radiographs performed with 44 readings of abnormal findings, including peribronchial thickening, atelectosis and hyperinflation. A total of 15 patients had a diagnosis of pneumonia with interstitial infiltrates or lobar consolidations on radiographs of their chest.
(31) (62) (10) (5) (60) (71) (17) (52) (19) (52) (19) (5) (10) (31) (2) (24) (5) (0)
(23) (65) (4) (0) (73) (65) (15) (38) (4) (42) (19) (0) (0) (54) (4) (23) (0) (4)
3.3. Underlying disorders Of the patients in this study, 29 (31%) were considered to be otherwise healthy children with no underlying dysfunctions, while 64 (69%) children were noted to have significant past medical histories at the time of admission (Table 2). Of these, 28 (44%) were either premature or had a complicated neonatal course with seven (11%) patients having bronchopulmonary dysplasia secondary to their prematurity. Review of medical records also revealed that 11 (17%) patients had a prior history of reactive airway disease, eight (13%) had congenital cardiac disease and seven (11%) had significant neurologic disorders. Four patients (6%) were noted to have either an immunologic or oncologic disease and two (3%) were HIV-positive. Other significant underlying illnesses included failure to thrive, congenital anatomic anomalies and trauma.
3.4. Duration of hospitalization The duration of hospitalization for 69 of the 93 patients with and without underlying diseases can
J.O. Kim, R.L. Hodinka / Clinical and Diagnostic Virology 10 (1998) 57–65 Table 2 Underlying conditions for the 93 patients with rhinovirus infection Underlying condition
No. (%) of patients
None (otherwise healthy children) Prematurity/complicated neonatal course Reactive airway disease Cardiac history Neurologic disorder Human immunodeficiency virus infection Immunologic/oncologic disease Failure to thrive Acute respiratory distress syndrome Metabolic disorder Sickle cell disease Hydronephrosis Genitourinary anomalies Head trauma Cleft palate Recurrent respiratory infection Dysmorphia
29 (31) 28 (30) 11 8 7 2
(12) (9) (8) (2)
4 2 1 1 1 1 1 2 1 1 1
(4) (2) (1) (1) (1) (1) (1) (2) (1) (1) (1)
be found in Fig. 1. The mean duration of hospitalization for those patients admitted with a respiratory illness who did not develop subsequent, unrelated complications was 3.7 days. The dura-
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tion of hospitalization for the different age groups was 3.8 days (range 1–17 days) for patients less than 3 months old, 6.0 days (range 1–22 days) for children 3–12 months of age and 8.4 days (range 1–49 days) for patients greater than 12 months old. Seven patients were admitted for overnight observation following evaluation in the emergency department.
3.5. Antimicrobial use Of the 93 patients evaluated, 38 (40.9%) received courses of antimicrobial therapy, including 13 courses of coverage for neonatal fever/sepsis, 19 orders for antibiotics for otitis media, conjunctivitis, or urinary tract infection and six courses of cefuroxime with or without erythromycin for pneumonia.
3.6. Complications The majority of hospitalizations were uncomplicated. However, five patients required endotracheal intubation and ventilatory support secondary to respiratory failure, including one cardiorespiratory arrest following loss of airway control. Two patients expired secondary to underlying disorders, including complicated cardiac dis-
Fig. 1. Duration of hospitalization for 69 of the 93 pediatric patients with rhinovirus infections. The black portion of the bars represent those patients with underlying disorders, while the white portion of the bars represent otherwise healthy children with respiratory illness.
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ease and perforation of bowel in a HIV-positive patient. No significant bacterial or fungal pathogens were identified in 91% of the individuals studied. Only eight patients were diagnosed with concomitant infections including: one with adenovirus; two with RSV; and one with adenovirus, influenza B virus and RSV identified from respiratory specimens; one with bacteremia and meningitis due to viridans streptococci; one with Streptococcus pneumoniae meningitis; and two with Escherichia coli urinary tract infections. One patient suffered exacerbation of congestive heart failure and one was rehospitalized for persistent respiratory difficulties. It was not possible to attribute respiratory illness to rhinovirus in the presence of the other recognized pathogens in these eight patients. In the four patients that had more than one virus identified from respiratory specimens, the severity of their respiratory illness was no different than that observed for those patients with only rhinovirus.
4. Discussion Recent reports suggest that rhinoviruses as possible pathogens in lower respiratory tract disease of infants and children may be more common than realized (Krilov et al., 1986; Kellner et al., 1988, 1989; Schmidt and Fink, 1991; McMillan et al., 1993; Chidekel et al., 1994, 1997). Reported here is the largest series to date of pediatric patients with documented rhinovirus infection and their clinical presentations and outcomes over a 6-year period at The Children’s Hospital of Philadelphia. Of the 93 patients evaluated, 95% were hospitalized for lower respiratory tract disease associated with rhinovirus infection. All but five patients were either acutely admitted or already hospitalized during the time of specimen collection for viral culture. Most patients presented with signs of acute respiratory illness in the absence of other identifiable infectious etiologies. Their mean duration of hospitalization was 3.7 days; those patients with unrelated medical complications had substantially longer hospital stays. Of significance is that a large number of patients (69%) carried previous diagnoses of underlying
diseases or predisposing conditions, with prematurity or complicated neonatal history being most often noted. Interestingly, the other most common underlying disorders included reactive airway disease followed by congenital cardiac disease and neurological disorders. This suggests that certain underlying diseases or predisposing factors lead to either more severe respiratory disease with rhinovirus infection or hospitalization for observation and further evaluation of the acute illness. To date, only a few reports have emphasized the risk of serious rhinovirus infections in pediatric patients with underlying disease. This observation has been made by Krilov et al. (1986) in 32 hospitalized infants and children, McMillan et al. (1993) in a series of 48 patients and Chidekel et al. (1997) in a report of eight patients with bronchopulmonary dysplasia who were infected with a rhinovirus. Severity of disease in the current study was quite variable, ranging from mild URI symptoms to intubation and ventilatory support. The majority of patients showed objective signs of lower respiratory disease on physical examination, though only approximately one-third had lowgrade fevers at time of presentation. This suggests that patients with underlying lung disease may be prone to develop lower airway disease, as suggested by recent experimental studies of rhinovirus infection and hosts with reactive airway disease or allergic disease (Johnston et al., 1993; Gern and Busse, 1995; Gwaltney, 1995; Johnston, 1995; Smyth et al., 1995). In those studies, obstructive airway processes were measured objectively using pulmonary function tests as well as quantitation of IgE. It would follow that patients with a predisposition to wheezing would be at considerable risk for development of more severe exacerbation of symptoms when infected with a viral pathogen such as rhinovirus, that is normally thought to cause only mild respiratory infections. Of note in this age of cost containment, was the fact that the primary physicians caring for the patients reported in this study felt that the symptoms of respiratory disease, signs of distress or fever warranted further evaluation in their patients, including complete blood counts in 62%, chest radiographs in 69%, antibiotic therapy in 41% and nasopharyngeal aspirates for the detec-
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tion of RSV and other respiratory viral infections in 100%. In total, over the observed 6-year period, the costs incurred for hospital stays, laboratory tests and the use of antibiotics in patients who had a documented rhinovirus infection but a clinical diagnoses of suspected bacterial sepsis and neonatal fever was significant. Due to the potential severity of lower respiratory tract disease associated with rhinovirus infections, the practice of laboratory identification of these viruses should be considered along with other respiratory pathogens in both healthy patients and those with underlying disease or a predisposing condition who have signs and symptoms of lower respiratory illness. However, despite continued reports of significant respiratory illness, it is still widely believed that rhinoviruses cause infections of little clinical significance and many diagnostic virology laboratories no longer make an attempt to routinely identify these viruses from respiratory specimens. Also, detection of rhinoviruses is problematic and generally limited to conventional viral isolation. Viral culture for rhinoviruses, however, is slow, labor-intensive and time-consuming; these viruses can also be difficult to grow and are sensitive to the conditions under which the cultures are maintained. Methods for the direct detection of rhinovirus antigens from clinical specimens have been developed and include enzyme-linked immunosorbent assays and immunofluorescence and immunoperoxidase staining of exfoliated epithelial cells using antiserum to type-specific antigen (Dreizin et al., 1975; Turner et al., 1982; Dearden and Al-Nakib, 1987; Al-Nakib et al., 1989). An enzyme-linked immunosorbent assay has also been evaluated for the measurement of rhinovirus-specific antibodies in human sera (Barclay et al., 1988). The lack of suitable rhinovirus group-specific antigens, however, has hampered the utility of immunologic identification or serologic diagnosis. Nucleic acid hybridization with synthetic oligonucleotide probes have been applied to rhinovirus detection, although such assays are most sensitive for homologous virus and during the later phase of infection (Bruce et al., 1989; Forsyth et al., 1989). More recently, the polymerase chain reaction has been described for the amplification of rhinovirus-
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specific RNA and would appear to be the most promising alternative for rapid and accurate identification of rhinoviruses (Gama et al., 1989; Hyypia et al., 1989; Arruda and Hayden, 1993). With the advent of effective antiviral agents for treatment of rhinovirus infections (Johnston et al., 1993; Arruda and Hayden, 1996) and continued development of the polymerase chain reaction for routine clinical use, the detection of rhinoviruses will have increased importance in the effective management of patients with severe respiratory disease.
Acknowledgements We gratefully thank the personnel of the Clinical Virology Laboratory at The Children’s Hospital of Philadelphia for their technical and scientific contributions.
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