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Underestimation of Influenza Viral Infection in Childhood Asthma Exacerbations
Underestimation of Influenza Viral Infection in Childhood Asthma Exacerbations Alexis Mandelcwajg, MD, Florence Moulin, MD, Cedric Menager, MD, Flore Rozenberg, PhD, Pierre Lebon, PhD, and Dominique Gendrel, MD Bocavirus was found in 11.6% of hospitalized children and 13% of ambulatory patients with exacerbations of asthma, and respiratory syncytial virus was found in 13.5% and 17.7%, respectively. In addition, influenza A virus was detected in 2.6% of hospitalized children and 14.1% (P < .001) of ambulatory-treated patients. Thus, the influenza burden in asthma may be underestimated. (J Pediatr 2010;157:505-6)
I
t has long been recognized that viral infections are associated with asthma exacerbations in childhood. A respiratory virus is usually identified in children with asthma exacerbations and rhinovirus, respiratory syncytial virus (RSV), and bocavirus are the most commonly detected. The relative importance of influenza viruses in children with asthma is widely debated. Some studies have concluded that influenza vaccination did not result in a significant reduction of asthma exacerbations,1,2 but other studies have shown that influenza-attributable health care use is frequent in children with asthma.3-5 In earlier studies, we have found influenza viruses in only 3% to 4% of children hospitalized for acute asthma.6-7 For this reason, we have compared inpatients and outpatients with asthma exacerbations to determine the burden of influenza virus.
Methods This prospective study included children of 1.5 to 15.0 years of age examined for acute asthma in the emergency department of a Paris hospital from November through March during 4 successive winters (2005 to 2009) with the same design as previously reported studies.6-7 All children with symptoms considered to be severe (marked expiratory wheezing despite 3 inhalations of b2-adrenergic aerosols in 1 hour or transcutaneous oxygen saturation <95% for >3 hours) were hospitalized. Other children were discharged after a length of stay of 1 to 3 hours in the emergency department. Only children in whom asthma was diagnosed by their physician were included, and all the children had previously had $1 acute asthma episodes.7 No children who received an influenza vaccination during the winter season studied were included. Nasopharyngeal aspirates were tested for common viral respiratory pathogens with direct immunofluorescence assays using monoclonal antibodies to RSV, influenza A and B viruses, adenovirus, parainfluenza type 1, 2, and 3 viruses, human metapneumovirus, and with viral culture.6,7 Polymerase chain reaction for human bocavirus was performed on the
same specimen7: the 2 primers and the Taqman probe were designed in the NS1 gene (Taqman, Argene, France). Rhinovirus was not evaluated in the study because of the lack of an available technique in our hospital. The c2 test and the Fischer exact test were used to compare proportions of the same virus between the hospitalized and ambulatory groups.
Results During the winter months (Nov 1-Mar 31) from 2005 to 2009, 369 children >18 months of age previously diagnosed as having asthma were referred to the emergency department of our hospital for acute wheezing. Nasopharyngeal aspirates or a precise clinical history were absent in 30 patients, so only 339 patients were included in the study (55% males), 232 hospitalized (mean age, 44.7 months; range, 21-107 months) and 107 discharged home (mean age, 38 months; range, 18-84 months). None of these patients was given an influenza vaccine during the winter season studied. Results of viral detection are shown (Table). We found no significant difference between children hospitalized for RSV and human bocavirus and children who were discharged. Parainfluenza virus 3 was found in 2 hospitalized patients and 1 ambulatory patient, and adenovirus was found in 1 patient in each group. For technical reasons, immunofluorescence for detection of human metapneumovirus was performed only during the two last winter seasons in 90 patients, and results were positive in 5 of 61 hospitalized patients (8.2%) and in 1 of 29 ambulatory patients (3.5%; no significant difference). Influenza A virus was detected in 6 of 232 patients hospitalized for acute asthma exacerbation (2.6%) and in 15 of 107 ambulatory patients (14.1%, P < .001). No influenza B virus was found in these groups, and only 1 patient had a RSV and bocavirus coinfection.
From the Pediatric (A.M., F.M., C.M., D.G.) and Virology (F.R., P.L.) Units, Paris Descartes University, and AP-HP Saint Vincent de Paul-Cochin Hospital, Paris, France The authors declare no conflicts of interest.
RSV
Respiratory syncytial virus
0022-3476/$ - see front matter. Copyright ª 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2010.04.067
505
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Table. Results of viral investigations in children (age >18 months) with acute exacerbation of asthma examined in the emergency department n Human bocavirus Respiratory syncytial virus Influenza A virus Parainfuenza virus 3 Human metapneumovirus Adenovirus
Hospitalized patients
Ambulatory patients
232 27 (11.6%) 31 (13.8%) 6 (2.6%)) 2 (0.8%) 5/61 (8.2%) 1 (0.3%)
107 14 (13.1%) 19 (17.7%) 15 (14.1%)) 1 (0.6%) 1/29 (3.5%) 1 (0.6%)
*P < .001.
Discussion One-third of children with asthma require immediate therapy for acute complications per year, and >50% of the annual costs for childhood asthma relate to hospitalizations or emergency care. Viral infections are more often associated with asthma exacerbations in young children than in adults, but the respective roles of the different respiratory viruses in acute exacerbations remain disputed. The relative importance of influenza vaccination in children with asthma has been debated. Most guidelines support the opinion that influenza vaccination should be given to children with asthma.8 However, for some doctors, the evidence for influenza vaccination is insufficient because of the lack of randomized trials.9 A Dutch randomized placebocontrolled trial concluded that influenza vaccination did not result in a significant reduction of asthma exacerbations. However, this trial was performed in 6- to 18-year-old children with a mean age of 10.5 years, and it has been shown that influenzaassociated excess hospitalization rates are greater in children <4 years old.1,2 A retrospective study from four large health maintenance organizations in the United States including >100 000 patients found that influenza vaccination protects against asthma exacerbations, especially in children from 1 to 6 years of age.3 In a recent laboratory-confirmed and population-based surveillance study, influenza-attributable health care use, hospitalizations, and visits were higher in children with asthma than in healthy children.5 In earlier studies, we found that 13% to 25% of children hospitalized for severe asthma exacerbation were infected with Mycoplasma pneumonia, and 17% to 30% were infected with viruses. In these two studies, the rate of detection of influenza viruses remained low (2.5%-3.0% of patients).6,7 The predominant viruses were human bocavirus and RSV. This study was based on the same design, but we added ambulatory-treated non-hospitalized children after a length of stay <6 hours in the emergency department. All the children included were known to have asthma after diagnosis by their physician, and all the children had an earlier acute asthma crisis, but this clinical definition gives only a probable diagnosis of asthma, especially in younger patients. Rhinoviruses, which are extensively involved in asthma attacks, were not evaluated in this study because of a lack of polymerase chain reaction or culture available in our hospital during that period. With this limitation to our study, we observed that human bocavirus, RSV, and human 506
Vol. 157, No. 3 metapneumovirus were found with the same frequency in children with exacerbations requiring hospitalization and in ambulatory-treated children. However, we found that influenza A virus was 3-times more frequent in ambulatory patients than in hospitalized patients. As discussed by Neuzil et al,4 nonhospitalized patients with destabilization of asthma are not always included in studies on influenza-attributable crises. It is well known that influenza-carrying children frequently have no symptoms. A French study performed during the peak of an influenza epidemic showed that only every fifth child with influenza required hospitalization.10 Although rhinoviruses commonly identified in children hospitalized for asthma were not evaluated in this study, we have found that, with the exception of influenza virus, the common respiratory viruses were identified at the same rate in hospitalized and ambulatory patients. The enrollment criteria for these patients were an acute exacerbation of asthma, leading to attendance at the emergency department of a hospital and not merely a common destabilization of asthma. The only difference between patients was in severity, which determined the decision whether to hospitalize or to give treatment at home. Our data show that viral detection performed only in children hospitalized for acute asthma exacerbations may result in an underestimation of the role of influenza virus in the disease. n Submitted for publication Nov 16, 2009; last revision received Mar 31, 2010; accepted Apr 28, 2010. Reprint requests: Professeur Dominique Gendrel, Hopital Saint Vincent de Paul, 82 Avenue Denfert-Rochereau, 75014 Paris, France. E-mail: dominique. [email protected].
References 1. Bueving HJ, Roos M, Bernsen D, de Jongste JC, van SuijlekomsSmit LWA, Rimmelzwann GF, et al. Influenza vaccination in children with asthma. Randomized double blind placebo controlled trial. Am J Respir Crit Care Med 2004;169:488-93. 2. Bueving HJ, van der Wouden J, Raat H, Bernsen D, de Jongste JC, van Suijlekoms-Smit LWA, Osterhaus ADME, et al. Influenza vaccination in asthmatic children: effects on quality of life and symptoms. Eur Respir J 2004;24:925-91. 3. Kramarz P, Destephano F, Garguillo PM, Chen RT, Lieu TA, Davis RL, et al. Does influenza vaccination prevent asthma exacerbations in children? J Pediatr 2001;138:306-10. 4. Neuzil KM. Influenza vaccine in children with asthma: why no progress? J Pediatr 2001;138:301-3. 5. Miller EK, Griffin MR, Edwards KM, Weinberg GA, Szilagyi PG, Staat MA, et al. Influenza burden for children with asthma. Pediatrics 2008;121:1-8. 6. Biscardi S, Lorrot M, Marc E, Moulin F, Bouttonat-Faucher B, Heilbronner C, et al. Mycoplasma pneumoniae and asthma in children. Clin Infect Dis 2004;38:1341-6. 7. Vallet C, Pons-Catalano C, Mandelcwajg A, Wang A, Raymond J, Lebon P, et al. Human bocavirus: a cause of severe asthma exacerbation in children. J Pediatr 2009;155:286-8. 8. American Academy of Paediatrics Committee on Infection Diseases. Recommendations for influenza immunization of children. Pediatrics 2004;113:1441-7. 9. Cates CJ, Jefferson TO, Bara AI, Rowe BH. Vaccines for preventing influenza in people with asthma. Cochrane Database Syst Rev 2004;(2):CD 000364. 10. Ploin D, Liberas S, Thouvenot D, Fouilhoux A, Gillet Y, Denis A, et al. Influenza burden in children newborn to eleven months of age in a pediatric department during the peak of an influenza epidemic. Pediatr Infect Dis J 2003;22:S218-22.
Mandelcwajg et al
I
t has long been recognized that viral infections are associated with asthma exacerbations in childhood. A respiratory virus is usually identified in children with asthma exacerbations and rhinovirus, respiratory syncytial virus (RSV), and bocavirus are the most commonly detected. The relative importance of influenza viruses in children with asthma is widely debated. Some studies have concluded that influenza vaccination did not result in a significant reduction of asthma exacerbations,1,2 but other studies have shown that influenza-attributable health care use is frequent in children with asthma.3-5 In earlier studies, we have found influenza viruses in only 3% to 4% of children hospitalized for acute asthma.6-7 For this reason, we have compared inpatients and outpatients with asthma exacerbations to determine the burden of influenza virus.
Methods This prospective study included children of 1.5 to 15.0 years of age examined for acute asthma in the emergency department of a Paris hospital from November through March during 4 successive winters (2005 to 2009) with the same design as previously reported studies.6-7 All children with symptoms considered to be severe (marked expiratory wheezing despite 3 inhalations of b2-adrenergic aerosols in 1 hour or transcutaneous oxygen saturation <95% for >3 hours) were hospitalized. Other children were discharged after a length of stay of 1 to 3 hours in the emergency department. Only children in whom asthma was diagnosed by their physician were included, and all the children had previously had $1 acute asthma episodes.7 No children who received an influenza vaccination during the winter season studied were included. Nasopharyngeal aspirates were tested for common viral respiratory pathogens with direct immunofluorescence assays using monoclonal antibodies to RSV, influenza A and B viruses, adenovirus, parainfluenza type 1, 2, and 3 viruses, human metapneumovirus, and with viral culture.6,7 Polymerase chain reaction for human bocavirus was performed on the
same specimen7: the 2 primers and the Taqman probe were designed in the NS1 gene (Taqman, Argene, France). Rhinovirus was not evaluated in the study because of the lack of an available technique in our hospital. The c2 test and the Fischer exact test were used to compare proportions of the same virus between the hospitalized and ambulatory groups.
Results During the winter months (Nov 1-Mar 31) from 2005 to 2009, 369 children >18 months of age previously diagnosed as having asthma were referred to the emergency department of our hospital for acute wheezing. Nasopharyngeal aspirates or a precise clinical history were absent in 30 patients, so only 339 patients were included in the study (55% males), 232 hospitalized (mean age, 44.7 months; range, 21-107 months) and 107 discharged home (mean age, 38 months; range, 18-84 months). None of these patients was given an influenza vaccine during the winter season studied. Results of viral detection are shown (Table). We found no significant difference between children hospitalized for RSV and human bocavirus and children who were discharged. Parainfluenza virus 3 was found in 2 hospitalized patients and 1 ambulatory patient, and adenovirus was found in 1 patient in each group. For technical reasons, immunofluorescence for detection of human metapneumovirus was performed only during the two last winter seasons in 90 patients, and results were positive in 5 of 61 hospitalized patients (8.2%) and in 1 of 29 ambulatory patients (3.5%; no significant difference). Influenza A virus was detected in 6 of 232 patients hospitalized for acute asthma exacerbation (2.6%) and in 15 of 107 ambulatory patients (14.1%, P < .001). No influenza B virus was found in these groups, and only 1 patient had a RSV and bocavirus coinfection.
From the Pediatric (A.M., F.M., C.M., D.G.) and Virology (F.R., P.L.) Units, Paris Descartes University, and AP-HP Saint Vincent de Paul-Cochin Hospital, Paris, France The authors declare no conflicts of interest.
RSV
Respiratory syncytial virus
0022-3476/$ - see front matter. Copyright ª 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2010.04.067
505
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Table. Results of viral investigations in children (age >18 months) with acute exacerbation of asthma examined in the emergency department n Human bocavirus Respiratory syncytial virus Influenza A virus Parainfuenza virus 3 Human metapneumovirus Adenovirus
Hospitalized patients
Ambulatory patients
232 27 (11.6%) 31 (13.8%) 6 (2.6%)) 2 (0.8%) 5/61 (8.2%) 1 (0.3%)
107 14 (13.1%) 19 (17.7%) 15 (14.1%)) 1 (0.6%) 1/29 (3.5%) 1 (0.6%)
*P < .001.
Discussion One-third of children with asthma require immediate therapy for acute complications per year, and >50% of the annual costs for childhood asthma relate to hospitalizations or emergency care. Viral infections are more often associated with asthma exacerbations in young children than in adults, but the respective roles of the different respiratory viruses in acute exacerbations remain disputed. The relative importance of influenza vaccination in children with asthma has been debated. Most guidelines support the opinion that influenza vaccination should be given to children with asthma.8 However, for some doctors, the evidence for influenza vaccination is insufficient because of the lack of randomized trials.9 A Dutch randomized placebocontrolled trial concluded that influenza vaccination did not result in a significant reduction of asthma exacerbations. However, this trial was performed in 6- to 18-year-old children with a mean age of 10.5 years, and it has been shown that influenzaassociated excess hospitalization rates are greater in children <4 years old.1,2 A retrospective study from four large health maintenance organizations in the United States including >100 000 patients found that influenza vaccination protects against asthma exacerbations, especially in children from 1 to 6 years of age.3 In a recent laboratory-confirmed and population-based surveillance study, influenza-attributable health care use, hospitalizations, and visits were higher in children with asthma than in healthy children.5 In earlier studies, we found that 13% to 25% of children hospitalized for severe asthma exacerbation were infected with Mycoplasma pneumonia, and 17% to 30% were infected with viruses. In these two studies, the rate of detection of influenza viruses remained low (2.5%-3.0% of patients).6,7 The predominant viruses were human bocavirus and RSV. This study was based on the same design, but we added ambulatory-treated non-hospitalized children after a length of stay <6 hours in the emergency department. All the children included were known to have asthma after diagnosis by their physician, and all the children had an earlier acute asthma crisis, but this clinical definition gives only a probable diagnosis of asthma, especially in younger patients. Rhinoviruses, which are extensively involved in asthma attacks, were not evaluated in this study because of a lack of polymerase chain reaction or culture available in our hospital during that period. With this limitation to our study, we observed that human bocavirus, RSV, and human 506
Vol. 157, No. 3 metapneumovirus were found with the same frequency in children with exacerbations requiring hospitalization and in ambulatory-treated children. However, we found that influenza A virus was 3-times more frequent in ambulatory patients than in hospitalized patients. As discussed by Neuzil et al,4 nonhospitalized patients with destabilization of asthma are not always included in studies on influenza-attributable crises. It is well known that influenza-carrying children frequently have no symptoms. A French study performed during the peak of an influenza epidemic showed that only every fifth child with influenza required hospitalization.10 Although rhinoviruses commonly identified in children hospitalized for asthma were not evaluated in this study, we have found that, with the exception of influenza virus, the common respiratory viruses were identified at the same rate in hospitalized and ambulatory patients. The enrollment criteria for these patients were an acute exacerbation of asthma, leading to attendance at the emergency department of a hospital and not merely a common destabilization of asthma. The only difference between patients was in severity, which determined the decision whether to hospitalize or to give treatment at home. Our data show that viral detection performed only in children hospitalized for acute asthma exacerbations may result in an underestimation of the role of influenza virus in the disease. n Submitted for publication Nov 16, 2009; last revision received Mar 31, 2010; accepted Apr 28, 2010. Reprint requests: Professeur Dominique Gendrel, Hopital Saint Vincent de Paul, 82 Avenue Denfert-Rochereau, 75014 Paris, France. E-mail: dominique. [email protected].
References 1. Bueving HJ, Roos M, Bernsen D, de Jongste JC, van SuijlekomsSmit LWA, Rimmelzwann GF, et al. Influenza vaccination in children with asthma. Randomized double blind placebo controlled trial. Am J Respir Crit Care Med 2004;169:488-93. 2. Bueving HJ, van der Wouden J, Raat H, Bernsen D, de Jongste JC, van Suijlekoms-Smit LWA, Osterhaus ADME, et al. Influenza vaccination in asthmatic children: effects on quality of life and symptoms. Eur Respir J 2004;24:925-91. 3. Kramarz P, Destephano F, Garguillo PM, Chen RT, Lieu TA, Davis RL, et al. Does influenza vaccination prevent asthma exacerbations in children? J Pediatr 2001;138:306-10. 4. Neuzil KM. Influenza vaccine in children with asthma: why no progress? J Pediatr 2001;138:301-3. 5. Miller EK, Griffin MR, Edwards KM, Weinberg GA, Szilagyi PG, Staat MA, et al. Influenza burden for children with asthma. Pediatrics 2008;121:1-8. 6. Biscardi S, Lorrot M, Marc E, Moulin F, Bouttonat-Faucher B, Heilbronner C, et al. Mycoplasma pneumoniae and asthma in children. Clin Infect Dis 2004;38:1341-6. 7. Vallet C, Pons-Catalano C, Mandelcwajg A, Wang A, Raymond J, Lebon P, et al. Human bocavirus: a cause of severe asthma exacerbation in children. J Pediatr 2009;155:286-8. 8. American Academy of Paediatrics Committee on Infection Diseases. Recommendations for influenza immunization of children. Pediatrics 2004;113:1441-7. 9. Cates CJ, Jefferson TO, Bara AI, Rowe BH. Vaccines for preventing influenza in people with asthma. Cochrane Database Syst Rev 2004;(2):CD 000364. 10. Ploin D, Liberas S, Thouvenot D, Fouilhoux A, Gillet Y, Denis A, et al. Influenza burden in children newborn to eleven months of age in a pediatric department during the peak of an influenza epidemic. Pediatr Infect Dis J 2003;22:S218-22.
Mandelcwajg et al