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Kenmoe S, Atenguena Okobalemba E, Takuissu GR, Ebogo-Belobo JT, Oyono MG, Magoudjou-Pekam JN, Kame-Ngasse GI, Taya-Fokou JB, Mbongue Mikangue CA, Kenfack-Momo R, Mbaga DS, Bowo-Ngandji A, Kengne-Ndé C, Esemu SN, Njouom R, Ndip L. Association between early viral lower respiratory tract infections and subsequent asthma development. World J Crit Care Med 2022; 11:298-310. [PMID: 36051944 PMCID: PMC9305678 DOI: 10.5492/wjccm.v11.i4.298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 04/25/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The association between hospitalization for human respiratory syncytial virus (HRSV) bronchiolitis in early childhood and subsequent asthma is well established. The long-term prognosis for non-bronchiolitis lower respiratory tract infections (LRTI) caused by viruses different from HRSV and rhinovirus, on the other hand, has received less interest. AIM To investigate the relationship between infant LRTI and later asthma and examine the influence of confounding factors. METHODS The PubMed and Global Index Medicus bibliographic databases were used to search for articles published up to October 2021 for this systematic review. We included cohort studies comparing the incidence of asthma between patients with and without LRTI at ≤ 2 years regardless of the virus responsible. The meta-analysis was performed using the random effects model. Sources of heterogeneity were assessed by stratified analyses. RESULTS This review included 15 articles (18 unique studies) that met the inclusion criteria. LRTIs at ≤ 2 years were associated with an increased risk of subsequent asthma up to 20 years [odds ratio (OR) = 5.0, 95%CI: 3.3-7.5], with doctor-diagnosed asthma (OR = 5.3, 95%CI: 3.3-8.6), current asthma (OR = 5.4, 95%CI: 2.7-10.6), and current medication for asthma (OR = 1.2, 95%CI: 0.7-3.9). Our overall estimates were not affected by publication bias (P = 0.671), but there was significant heterogeneity [I 2 = 58.8% (30.6-75.5)]. Compared to studies with hospitalized controls without LRTI, those with ambulatory controls had a significantly higher strength of association between LRTIs and subsequent asthma. The strength of the association between LRTIs and later asthma varied significantly by country and age at the time of the interview. The sensitivity analyses including only studies with similar proportions of confounding factors (gender, age at LRTI development, age at interview, gestational age, birth weight, weight, height, smoking exposure, crowding, family history of atopy, and family history of asthma) between cases and controls did not alter the overall estimates. CONCLUSION Regardless of the causative virus and confounding factors, viral LRTIs in children < 2 years are associated with an increased risk of developing a subsequent asthma. Parents and pediatricians should be informed of this risk.
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Affiliation(s)
- Sebastien Kenmoe
- Department of Microbiology and Parasitology, University of Buea, Buea 00237, Cameroon
- Department of Virology, Centre Pasteur of Cameroon, Yaounde 00237, Cameroon
| | | | - Guy Roussel Takuissu
- Centre of Research in Food, Food Security and Nutrition, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | - Jean Thierry Ebogo-Belobo
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | - Martin Gael Oyono
- Laboratory of Parasitology and Ecology, The University of Yaounde I, Yaounde 00237, Cameroon
| | | | - Ginette Irma Kame-Ngasse
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | | | | | - Raoul Kenfack-Momo
- Department of Biochemistry, The University of Yaounde I, Yaounde 00237, Cameroon
| | - Donatien Serge Mbaga
- Department of Microbiology, The University of Yaounde I, Yaounde 00237, Cameroon
| | - Arnol Bowo-Ngandji
- Department of Microbiology, The University of Yaounde I, Yaounde 00237, Cameroon
| | - Cyprien Kengne-Ndé
- Epidemiological Surveillance, Evaluation and Research Unit, National Aids Control Committee, Douala 00237, Cameroon
| | - Seraphine Nkie Esemu
- Department of Microbiology and Parasitology, University of Buea, Buea 00237, Cameroon
| | - Richard Njouom
- Department of Virology, Centre Pasteur of Cameroon, Yaounde 00237, Cameroon
| | - Lucy Ndip
- Department of Microbiology and Parasitology, University of Buea, Buea 00237, Cameroon
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Fujiogi M, Dumas O, Hasegawa K, Jartti T, Camargo CA. Identifying and predicting severe bronchiolitis profiles at high risk for developing asthma: Analysis of three prospective cohorts. EClinicalMedicine 2022; 43:101257. [PMID: 35028545 PMCID: PMC8741473 DOI: 10.1016/j.eclinm.2021.101257] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/04/2021] [Accepted: 12/14/2021] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Bronchiolitis is the leading cause of infants hospitalization in the U.S. and Europe. Additionally, bronchiolitis is a major risk factor for the development of childhood asthma. Growing evidence suggests heterogeneity within bronchiolitis. We sought to identify distinct, reproducible bronchiolitis subgroups (profiles) and to develop a decision rule accurately predicting the profile at the highest risk for developing asthma. METHODS In three multicenter prospective cohorts of infants (age < 12 months) hospitalized for bronchiolitis in the U.S. and Finland (combined n = 3081) in 2007-2014, we identified clinically distinct bronchiolitis profiles by using latent class analysis. We examined the association of the profiles with the risk for developing asthma by age 6-7 years. By performing recursive partitioning analyses, we developed a decision rule predicting the profile at highest risk for asthma, and measured its predictive performance in two separate cohorts. FINDINGS We identified four bronchiolitis profiles (profiles A-D). Profile A (n = 388; 13%) was characterized by a history of breathing problems/eczema and non-respiratory syncytial virus (non-RSV) infection. In contrast, profile B (n = 1064; 34%) resembled classic RSV-induced bronchiolitis. Profile C (n = 993; 32%) was comprised of the most severely ill group. Profile D (n = 636; 21%) was the least-ill group. Profile A infants had a significantly higher risk for asthma, compared to profile B infants (38% vs. 23%, adjusted odds ratio [adjOR] 2⋅57, 95%confidence interval [CI] 1⋅63-4⋅06). The derived 4-predictor (RSV infection, history of breathing problems, history of eczema, and parental history of asthma) decision rule strongly predicted profile A-e.g., area under the curve [AUC] of 0⋅98 (95%CI 0⋅97-0⋅99), sensitivity of 1⋅00 (95%CI 0⋅96-1⋅00), and specificity of 0⋅90 (95%CI 0⋅89-0⋅93) in a validation cohort. INTERPRETATION In three prospective cohorts of infants with bronchiolitis, we identified clinically distinct profiles and their longitudinal relationship with asthma risk. We also derived and validated an accurate prediction rule to determine the profile at highest risk. The current results should advance research into the development of profile-specific preventive strategies for asthma.
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Affiliation(s)
- Michimasa Fujiogi
- Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, 125 Nashua Street, Suite 920, Boston, MA 02114-1101, USA
| | - Orianne Dumas
- Équipe d'Épidémiologie Respiratoire Intégrative, Université Paris-Saclay, UVSQ, Université Paris-Sud, Inserm, CESP, Villejuif 94807, France
| | - Kohei Hasegawa
- Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, 125 Nashua Street, Suite 920, Boston, MA 02114-1101, USA
| | - Tuomas Jartti
- PEDEGO Research Unit, Medical Research Center, University of Oulu, Oulu, Finland
- Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, Oulu, Finland
- Department of Pediatrics and Adolescent Medicine, University of Turku and Turku University Hospital, Turku, Finland
| | - Carlos A. Camargo
- Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, 125 Nashua Street, Suite 920, Boston, MA 02114-1101, USA
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Gastaldi A, Donà D, Barbieri E, Giaquinto C, Bont LJ, Baraldi E. COVID-19 Lesson for Respiratory Syncytial Virus (RSV): Hygiene Works. CHILDREN (BASEL, SWITZERLAND) 2021; 8:children8121144. [PMID: 34943339 PMCID: PMC8700687 DOI: 10.3390/children8121144] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/25/2021] [Accepted: 12/02/2021] [Indexed: 02/05/2023]
Abstract
Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections (LRTIs) in infants worldwide. The global direct medical cost associated with RSV LRTIs reaches billions of dollars, with the highest burden in low–middle-income countries. Many efforts have been devoted to improving its prevention and management, including both non-pharmaceutical and pharmaceutical strategies, often with limited routine use in high-income countries due to high costs. During the ongoing COVID-19 pandemic, a dramatic decrease in RSV infections (up to 70–90%) has been reported around the globe, directly related to the implementation of containment measures (face masks, hand hygiene, and social distancing). Primary prevention has demonstrated the highest cost effectiveness ratio in reducing the burden of a respiratory infection such as RSV, never reached before. Thus, we emphasize the importance of non-pharmaceutical preventive hygiene measures that should be implemented and maintained even after the COVID-19 outbreak.
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Affiliation(s)
- Andrea Gastaldi
- Division of Pediatric Infectious Diseases, Department of Women’s and Children’s Health, University of Padua, 35128 Padua, Italy; (A.G.); (E.B.); (C.G.)
- Department of Pediatrics, Woman and Child Hospital, University of Verona, 37126 Verona, Italy
| | - Daniele Donà
- Division of Pediatric Infectious Diseases, Department of Women’s and Children’s Health, University of Padua, 35128 Padua, Italy; (A.G.); (E.B.); (C.G.)
- Correspondence:
| | - Elisa Barbieri
- Division of Pediatric Infectious Diseases, Department of Women’s and Children’s Health, University of Padua, 35128 Padua, Italy; (A.G.); (E.B.); (C.G.)
| | - Carlo Giaquinto
- Division of Pediatric Infectious Diseases, Department of Women’s and Children’s Health, University of Padua, 35128 Padua, Italy; (A.G.); (E.B.); (C.G.)
| | - Louis J. Bont
- Department of Pediatrics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;
- Respiratory Syncytial Virus Network (ReSViNET) Foundation, 3703 CD Zeist, The Netherlands
| | - Eugenio Baraldi
- Neonatal Intensive Care Unit, Department of Women’s and Children’s Health, University of Padua, 35128 Padua, Italy;
- Fondazione Istituto di Ricerca Pediatrica, 35127 Padua, Italy
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de Koff EM, Man WH, van Houten MA, Vlieger AM, Chu MLJN, Sanders EAM, Bogaert D. Microbial and clinical factors are related to recurrence of symptoms after childhood lower respiratory tract infection. ERJ Open Res 2021; 7:00939-2020. [PMID: 34195257 PMCID: PMC8236756 DOI: 10.1183/23120541.00939-2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 02/17/2021] [Indexed: 12/16/2022] Open
Abstract
Childhood lower respiratory tract infections (LRTI) are associated with dysbiosis of the nasopharyngeal microbiota, and persistent dysbiosis following the LRTI may in turn be related to recurrent or chronic respiratory problems. Therefore, we aimed to investigate microbial and clinical predictors of early recurrence of respiratory symptoms as well as recovery of the microbial community following hospital admission for LRTI in children. To this end, we collected clinical data and characterised the nasopharyngeal microbiota of 154 children (4 weeks–5 years old) hospitalised for a LRTI (bronchiolitis, pneumonia, wheezing illness or mixed infection) at admission and 4–8 weeks later. Data were compared to 307 age-, sex- and time-matched healthy controls. During follow-up, 66% of cases experienced recurrence of (mild) respiratory symptoms. In cases with recurrence of symptoms during follow-up, we found distinct nasopharyngeal microbiota at hospital admission, with higher levels of Haemophilus influenzae/haemolyticus, Prevotella oris and other gram-negatives and lower levels of Corynebacterium pseudodiphtheriticum/propinquum and Dolosigranulum pigrum compared with healthy controls. Furthermore, in cases with recurrence of respiratory symptoms, recovery of the microbiota was also diminished. Especially in cases with wheezing illness, we observed a high rate of recurrence of respiratory symptoms, as well as diminished microbiota recovery at follow-up. Together, our results suggest a link between the nasopharyngeal microbiota composition during LRTI and early recurrence of respiratory symptoms, as well as diminished microbiota recovery after 4–8 weeks. Future studies should investigate whether (speed of) ecological recovery following childhood LRTI is associated with long-term respiratory problems. Composition of nasopharyngeal microbiota during LRTI in children is related to recurring respiratory symptoms in the following months, and to incomplete microbiota recovery. Future research may pinpoint host and microbial predictors of clinical outcomes.https://bit.ly/3aInAwN
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Affiliation(s)
- Emma M de Koff
- Spaarne Academy, Spaarne Gasthuis, Hoofddorp and Haarlem, The Netherlands.,Dept of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital and University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Wing Ho Man
- Spaarne Academy, Spaarne Gasthuis, Hoofddorp and Haarlem, The Netherlands.,Dept of Paediatrics, Willem-Alexander Children's Hospital and Leiden University Medical Centre, Leiden, The Netherlands
| | - Marlies A van Houten
- Spaarne Academy, Spaarne Gasthuis, Hoofddorp and Haarlem, The Netherlands.,Dept of Paediatrics, Spaarne Gasthuis, Hoofddorp and Haarlem, The Netherlands
| | - Arine M Vlieger
- Dept of Paediatrics, St Antonius Ziekenhuis, Nieuwegein, The Netherlands
| | - Mei Ling J N Chu
- Dept of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital and University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Elisabeth A M Sanders
- Dept of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital and University Medical Centre Utrecht, Utrecht, The Netherlands.,Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands
| | - Debby Bogaert
- Dept of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital and University Medical Centre Utrecht, Utrecht, The Netherlands.,Medical Research Council and University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
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Bush A, Nagakumar P. Preschool Wheezing Phenotypes. EUROPEAN MEDICAL JOURNAL 2016. [DOI: 10.33590/emj/10310308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2023] Open
Abstract
Wheezing in preschool children is very common, with a wide differential diagnosis. It is essential to be sure of the exact sound that parents are describing; the term ‘wheeze‘ is often applied to non-specific sounds. Structural airway disease such as vascular ring should be considered. Thereafter we propose that umbrella terms for preschool wheeze should be abandoned in favour of ‘Hargreave phenotyping’, in which the presence and extent of the components of infection, inflammation, variable airflow obstruction, and fixed airflow obstruction are determined as far as is possible, rather than using a general umbrella term such as ‘asthma’. The justification for this approach is that it leads to a logical approach to treatment in the disparate airway diseases presenting in the preschool years, and should hopefully prevent over-treatment with inhaled corticosteroids. If, despite this approach, doubt remains as to the nature of the airway disease, then a therapeutic trial of treatment is permissible, but it should be for a short defined period only. In any event, such children should be reviewed regularly to see if treatments need to be changed.
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Affiliation(s)
- Andrew Bush
- Department of Paediatrics, Imperial College London, London, UK; Department of Paediatric Respirology, National Heart and Lung Institute, Imperial College London, London, UK; Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK
| | - Prasad Nagakumar
- Department of Paediatric Respirology, National Heart and Lung Institute, Imperial College London, London, UK; Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK
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Gidaris D, Urquhart D, Anthracopoulos MB. 'They said it was bronchiolitis; is it going to turn into asthma doctor?'. Respirology 2014; 19:1158-64. [PMID: 25138566 DOI: 10.1111/resp.12371] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 05/26/2014] [Accepted: 07/15/2014] [Indexed: 12/14/2022]
Abstract
Acute bronchiolitis is a common paediatric disease of infancy. Its association with subsequent asthma development has puzzled clinicians and epidemiologists for decades. This article reviews the current state of knowledge regarding the role of acute bronchiolitis in the inception of asthma. There is little doubt that acute bronchiolitis is associated with an increased risk of recurrent wheezing throughout the primary school years although the direction of causality--i.e. whether bronchiolitis in infancy leads to asthma or it merely represents the first clinical presentation of predisposition to asthma--is uncertain. Existing evidence suggests that both host factors (e.g. prematurity, atopic predisposition) and acute viral infection characteristics (e.g. type of virus, severity) are operating in this relationship, perhaps with variable involvement in different individuals. Further clarification of these issues will help paediatricians provide evidence-based information regarding the long-term prognosis of this common disease to the families, and at the same time, it will facilitate prophylactic approaches and therapeutic strategies.
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Affiliation(s)
- Dimos Gidaris
- 1st Paediatric Department, Aristotle University of Thessaloniki, Hippokrateion General Hospital, Thessaloniki, Greece
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Clinical and epidemiologic factors related to subsequent wheezing after virus-induced lower respiratory tract infections in hospitalized pediatric patients younger than 3 years. Eur J Pediatr 2014; 173:959-66. [PMID: 24535712 DOI: 10.1007/s00431-014-2277-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Revised: 10/23/2013] [Accepted: 01/27/2014] [Indexed: 10/25/2022]
Abstract
UNLABELLED Most wheezing episodes in infants are caused and exacerbated by virus-induced lower respiratory tract infections. However, there are few reports of epidemiologic and clinical virus-specific research with a focus on virus-induced wheezing. The purpose of the current study was to characterize the clinical presentation of virus-induced wheezing in pediatric patients <3 years of age who were hospitalized with lower respiratory tract infections. Of the 412 patients in the study, 216 were followed for 3 years. Nasopharyngeal aspirates collected from the patients at the time of admission were examined for the presence of respiratory syncytial virus (RSV), rhinovirus (RV), parainfluenza-3 virus (PIV-3), human metapneumovirus (hMPV), and influenza virus (Flu) using reverse-transcription polymerase chain reaction and rapid diagnostic tests. Clinical signs were assessed using a severity scoring system. In patients with wheezing at the time of admission, RSV, RV, RSV+RV, Flu, PIV-3, and hMPV were detected in 33, 14, 8, 8, 5, and 3 % of samples, respectively. There were no differences in age and severity scores between patients harboring more prevalent viruses (RSV and RV) and those with less common infections. Patients with wheezing and RV-positive aspirates at the time of admission were more likely to develop subsequent wheezing during the following 3 years. CONCLUSION RSV and RV infections are factors in the development and exacerbation of wheezing after virus-induced lower respiratory tract infections. Moreover, RV-induced wheezing may be associated with subsequent recurrent wheezing and the development of asthma.
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Sadreameli SC, Reller ME, Bundy DG, Casella JF, Strouse JJ. Respiratory syncytial virus and seasonal influenza cause similar illnesses in children with sickle cell disease. Pediatr Blood Cancer 2014; 61:875-8. [PMID: 24481883 PMCID: PMC4415511 DOI: 10.1002/pbc.24887] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Accepted: 11/07/2013] [Indexed: 02/02/2023]
Abstract
BACKGROUND Respiratory syncytial virus (RSV) is a cause of acute chest syndrome (ACS) in sickle cell disease (SCD), but its clinical course and acute complications have not been well characterized. We compared RSV to seasonal influenza infections in children with SCD. PROCEDURE We defined cases as laboratory-confirmed RSV or seasonal influenza infection in inpatients and outpatients <18 years of age with SCD from 1 September 1993 to 30 June 2011. We used Fisher's exact test to compare proportions, Student's t-test or Wilcoxon rank-sum test to compare continuous variables, and logistic regression to evaluate associations. RESULTS We identified 64 children with RSV and 91 with seasonal influenza. Clinical symptoms, including fever, cough, and rhinorrhea were similar for RSV and influenza, as were complications, including ACS and treatments for SCD. In a multivariable logistic regression model, older age (OR 1.2 per year, 95% CI [1.02-1.5], P = 0.04), increased white blood cell count at presentation (OR 1.1 per 1,000/μl increase, 95% CI [1.03-1.3], P = 0.008), and a history of asthma (OR 7, 95% [CI 1.3-37], P = 0.03) were independently associated with increased risk of ACS in children with RSV. The hospitalization rate for children with SCD and RSV (40 per 1,000 <5 years and 63 per 1,000 <2 years) greatly exceeds the general population (3 in 1,000 <5 years). CONCLUSIONS We conclude that RSV infection is often associated with ACS and similar in severity to influenza infection in febrile children with SCD.
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Affiliation(s)
- Sara Christina Sadreameli
- Division of Pediatric Pulmonology, Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland
| | - Megan E. Reller
- Division of Medical Microbiology, Department of Pathology, Johns Hopkins University, Baltimore, Maryland
| | - David G. Bundy
- Divisions of General Pediatrics and Epidemiology, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina
| | - James F. Casella
- Division of Pediatric Hematology, Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland
| | - John J. Strouse
- Division of Pediatric Hematology, Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland
- Division of Hematology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
- Correspondence to: John J. Strouse, 720 Rutland Ave., Ross 1125, Baltimore, MD 21205.
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Munywoki PK, Ohuma EO, Ngama M, Bauni E, Scott JAG, Nokes DJ. Severe lower respiratory tract infection in early infancy and pneumonia hospitalizations among children, Kenya. Emerg Infect Dis 2013; 19:223-9. [PMID: 23347702 PMCID: PMC3559052 DOI: 10.3201/eid1902.120940] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Close postdischarge follow-up could help prevent future severe respiratory
disease. Severe lower respiratory tract infection (LRTI) in infants caused by respiratory
syncytial virus (RSV) has been associated with later pneumonia hospitalization
among children. To determine risk for pneumonia after RSV hospitalization in
infancy, we conducted a retrospective cohort analysis of 2,813 infants admitted
to a hospital in Kenya and identified readmissions for pneumonia among this
group during early childhood (<60 months of age).
Incidence of readmission for pneumonia was higher for children whose first
admission as infants was for LRTI and who were <3
months of age than for children who were first admitted as infants for non-LRTI,
irrespective of RSV status. Incidence of readmission for pneumonia with wheeze
was higher for children whose first admission involved RSV compared with those
who had non-RSV LRTI. Excess pneumonia risk persisted for 2 years after the
initial hospitalization. Close postdischarge follow-up of infants with LRTI,
with or without RSV, could help prevent severe pneumonia later in childhood.
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Affiliation(s)
- Patrick Kiio Munywoki
- KEMRI-Wellcome Trust Research Programme Centre for Geographic Medicine Research–Coast, Kilifi, Kenya.
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Persistent recurring wheezing in the fifth year of life after laboratory-confirmed, medically attended respiratory syncytial virus infection in infancy. BMC Pediatr 2013; 13:97. [PMID: 23782528 PMCID: PMC3703269 DOI: 10.1186/1471-2431-13-97] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 06/13/2013] [Indexed: 11/26/2022] Open
Abstract
Background Respiratory syncytial virus (RSV) infection in infancy is associated with subsequent recurrent wheezing. Methods A retrospective cohort study examined children born at ≥32 weeks gestation between 1996–2004. All children were enrolled in an integrated health care delivery system in Northern California and were followed through the fifth year of life. The primary endpoint was recurrent wheezing in the fifth year of life and its association with laboratory-confirmed, medically-attended RSV infection during the first year, prematurity, and supplemental oxygen during birth hospitalization. Other outcomes measured were recurrent wheezing quantified through outpatient visits, inpatient hospital stays, and asthma prescriptions. Results The study sample included 72,602 children. The rate of recurrent wheezing in the second year was 5.6% and fell to 4.7% by the fifth year. Recurrent wheezing rates varied by risk status: the rate was 12.5% among infants with RSV hospitalization, 8% among infants 32–33 weeks gestation, and 18% in infants with bronchopulmonary dysplasia. In multivariate analyses, increasing severity of respiratory syncytial virus infection was significantly associated with recurrent wheezing in year 5; compared with children without RSV infection in infancy, children who only had an outpatient RSV encounter had an adjusted odds ratio of 1.38 (95% CI,1.03–1.85), while children with a prolonged RSV hospitalization had an adjusted odds ratio of 2.59 (95% CI, 1.49–4.50). Conclusions Laboratory-confirmed, medically attended RSV infection, prematurity, and neonatal exposure to supplemental oxygen have independent associations with development of recurrent wheezing in the fifth year of life.
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Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A, Kimpen JLL, Bont L. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med 2013; 368:1791-9. [PMID: 23656644 DOI: 10.1056/nejmoa1211917] [Citation(s) in RCA: 494] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Respiratory syncytial virus (RSV) infection is associated with subsequent recurrent wheeze. Observational studies cannot determine whether RSV infection is the cause of recurrent wheeze or the first indication of preexistent pulmonary vulnerability in preterm infants. The monoclonal antibody palivizumab has shown efficacy in preventing severe RSV infection in high-risk infants. METHODS In the double-blind, placebo-controlled MAKI trial, we randomly assigned 429 otherwise healthy preterm infants born at a gestational age of 33 to 35 weeks to receive either monthly palivizumab injections (214 infants) or placebo (215 infants) during the RSV season. The prespecified primary outcome was the total number of parent-reported wheezing days in the first year of life. Nasopharyngeal swabs were taken during respiratory episodes for viral analysis. RESULTS Palivizumab treatment resulted in a relative reduction of 61% (95% confidence interval, 56 to 65) in the total number of wheezing days during the first year of life (930 of 53,075 days in the RSV-prevention group [1.8%] vs. 2309 of 51,726 days [4.5%] in the placebo group). During this time, the proportion of infants with recurrent wheeze was 10 percentage points lower in patients treated with palivizumab (11% vs. 21%, P=0.01). CONCLUSIONS In otherwise healthy preterm infants, palivizumab treatment resulted in a significant reduction in wheezing days during the first year of life, even after the end of treatment. These findings implicate RSV infection as an important mechanism of recurrent wheeze during the first year of life in such infants. (Funded by Abbott Laboratories and by the Netherlands Organization for Health Research and Development; MAKI Controlled Clinical Trials number, ISRCTN73641710.).
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Affiliation(s)
- Maarten O Blanken
- Division of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands
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Blanken M, Rovers M, Sanders E, Bont L. Ethical considerations and rationale of the MAKI trial: a multicenter double-blind randomized placebo-controlled trial into the preventive effect of palivizumab on recurrent wheezing associated with respiratory syncytial virus infection in children with a gestational age of 33-35 weeks. Contemp Clin Trials 2012; 33:1287-92. [PMID: 22820319 DOI: 10.1016/j.cct.2012.07.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2011] [Revised: 06/21/2012] [Accepted: 07/16/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) is the most frequent cause of bronchiolitis during infancy. Long-term airway morbidity with recurrent post bronchiolitis wheezing (PBW) episodes, which are probably associated with respiratory infections, occurs in 30 to 70% of infants that were hospitalised with RSV LRTI. METHODS We set up a multicenter, placebo-controlled double-blind randomized clinical trial in healthy preterm infants born between 33 and 35 weeks gestational age (WGA). The children received either one-monthly intramuscular palivizumab or placebo injection during the RSV season with a minimum of 2 injections. RESULTS The primary objective was to determine the preventive effect of RSV immunoprophylaxis (palivizumab) on the development of recurrent wheezing during the first year of life. The primary outcome measure was the number of wheezing days during the first year of life as obtained by daily logs. As a secondary outcome nasal swabs were taken for viral analysis in case of respiratory symptoms. We will also examine wheezing at age 1, 3 and 6 years both reported by the parents and the general practitioner and quality of life as secondary outcomes. This trial is possible because RSV immunoprophylaxis, although effective in this population, is not completely used in the Netherlands due to its high costs. CONCLUSION The Institutional review board (IRB) concluded the study has high clinical relevance because the benefit of 50% chance of protection by palivizumab outweighs the risk of side adverse events due to intramuscular administration of placebo.
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Affiliation(s)
- Maarten Blanken
- University Medical Center Utrecht, Pediatric Immunology and Infectious Diseases, Room KE.04.133.1, P.O. Box 85090, 3584 EA Utrecht, The Netherlands.
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Meijboom MJ, Rozenbaum MH, Benedictus A, Luytjes W, Kneyber MCJ, Wilschut JC, Hak E, Postma MJ. Cost-effectiveness of potential infant vaccination against respiratory syncytial virus infection in The Netherlands. Vaccine 2012; 30:4691-700. [PMID: 22561315 DOI: 10.1016/j.vaccine.2012.04.072] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 04/11/2012] [Accepted: 04/21/2012] [Indexed: 10/28/2022]
Abstract
INTRODUCTION Respiratory syncytial virus (RSV) infection is one of the major causes of respiratory illness in infants, infecting virtually every child before the age of 2 years. Currently, several Phase 1 trials with RSV vaccines in infants are ongoing or have been completed. As yet, no efficacy estimates are available for these vaccine candidates. Nevertheless, cost-effectiveness estimates might be informative to enable preliminary positioning of an RSV vaccine. METHODS A decision analysis model was developed in which a Dutch birth cohort was followed for 12 months. A number of potential vaccination strategies were reviewed such as vaccination at specific ages, a two- or three-dosing scheme and seasonal vaccination versus year-round vaccination. The impact of the assumptions made was explored in various sensitivity analyses, including probabilistic analysis. Outcome measures included the number of GP visits, hospitalizations and deaths, costs, quality-adjusted life years and incremental cost-effectiveness ratios (ICERs). RESULTS Currently, without vaccination, an annual number of 28,738 of RSV-related GP visits, 1623 hospitalizations, and 4.5 deaths are estimated in children in the age of 0-1 year. The total annual cost to society of RSV in the non-vaccination scenario is €7.7 million (95%CI: 1.7-16.7) and the annual disease burden is estimated at 597 QALYs (95%CI: 133-1319). In case all infants would be offered a potentially safe and effective 3-dose RSV vaccination scheme at the age of 0, 1 and 3 months, the total annual net costs were estimated to increase to €21.2 million, but 544 hospitalizations and 1.5 deaths would be averted. The ICER was estimated at €34,142 (95%CI: € 21,652-€ 87,766) per QALY gained. A reduced dose schedule, seasonal vaccination, and consideration of out-of-pocket expenses all resulted in more favorable ICER values, whereas a reduced vaccine efficacy or a delay in the timing of vaccination resulted in less favorable ICERs. DISCUSSION Our model used recently updated estimates on the burden of RSV disease in children and it included plausible utilities. However, due to the absence of clinical trial data, a number of crucial assumptions had to be made related to the characteristics of potential RSV vaccine. The outcomes of our modeling exercise show that vaccination of infants against RSV might be cost-effective. However, clinical trial data are warranted.
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Affiliation(s)
- M J Meijboom
- Unit of PharmacoEpidemiology & PharmacoEconomics (PE(2)), Department of Pharmacy, University of Groningen, Groningen, The Netherlands
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Schuurhof A, Janssen R, de Groot H, Hodemaekers HM, de Klerk A, Kimpen JL, Bont L. Local interleukin-10 production during respiratory syncytial virus bronchiolitis is associated with post-bronchiolitis wheeze. Respir Res 2011; 12:121. [PMID: 21910858 PMCID: PMC3179726 DOI: 10.1186/1465-9921-12-121] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Accepted: 09/12/2011] [Indexed: 01/11/2023] Open
Abstract
Background Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Following RSV bronchiolitis, 50% of children develop post-bronchiolitis wheeze (PBW). Animal studies have suggested that interleukin (IL)-10 plays a critical role in the pathogenesis of RSV bronchiolitis and subsequent airway hyperresponsiveness. Previously, we showed that ex vivo monocyte IL-10 production is a predictor of PBW. Additionally, heterozygosity of the single-nucleotide polymorphism (SNP) rs1800872 in the IL10 promoter region was associated with protection against RSV bronchiolitis. Methods This study aimed to determine the in vivo role of IL-10 in RSV pathogenesis and recurrent wheeze in a new cohort of 235 infants hospitalized for RSV bronchiolitis. IL-10 levels in nasopharyngeal aspirates (NPAs) were measured at the time of hospitalization and the IL10 SNP rs1800872 genotype was determined. Follow-up data were available for 185 children (79%). Results Local IL-10 levels during RSV infection turned out to be higher in infants that later developed physician diagnosed PBW as compared to infants without PBW in the first year after RSV infection (958 vs 692 pg/ml, p = 0.02). The IL10 promoter SNP rs1800872 was not associated with IL-10 concentration in NPAs. Conclusion The relationship between high local IL-10 levels during the initial RSV infection and physician diagnosed PBW provides further evidence of the importance of the IL-10 response during RSV bronchiolitis.
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Affiliation(s)
- Annemieke Schuurhof
- Laboratory for Health Protection Research, National Institute for Public Health and the Environment, Postbak 12 GBO, P.O.BOX 1, 3720 BA Bilthoven, The Netherlands
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Abstract
Wheeze, a common symptom in pre-school children, is a continuous high-pitched sound, with a musical quality, emitting from the chest during expiration. A pragmatic clinical classification is episodic (viral) wheeze and multiple-trigger wheeze. Diagnostic difficulties include other conditions that give rise to noisy breathing which could be misinterpreted as wheeze. Most preschool children with wheeze do not need rigorous investigations. Primary prevention is not possible but avoidance of environmental tobacco smoke exposure should be strongly encouraged. Bronchodilators provide symptomatic relief in acute wheezy episodes but the evidence for using oral steroids is conflicting for children presenting to the Emergency Department [ED]. Parent initiated oral steroid courses cannot be recommended. High dose inhaled corticosteroids [ICS] used intermittently are effective in children with frequent episodes of moderately severe episodic (viral) wheeze or multiple-trigger wheeze, but this associated with short term effects on growth and cannot be recommended as a routine. Maintenance treatment with low to moderate continuous ICS in pure episodic (viral) wheeze is ineffective. Whilst low to moderate dose regular ICS work in multi-trigger wheeze, the medication does not modify the natural history of the condition. Even if there is a successful trial of treatment with ICS, a break in treatment should be given to see if the symptoms have resolved or continuous therapy is still required. Maintenance as well as intermittent Montelukast has a role in both episodic and multi trigger wheeze. Good multidisciplinary support and education is essential in managing this common condition.
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Affiliation(s)
- Jayesh M Bhatt
- Consultant in Respiratory Paediatrics, Nottingham University Hospitals NHS Trust (QMC campus), Nottingham, NG7 2UH.
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16
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Nuijten MJ, Wittenberg W. Cost effectiveness of palivizumab in Spain: an analysis using observational data. THE EUROPEAN JOURNAL OF HEALTH ECONOMICS : HEPAC : HEALTH ECONOMICS IN PREVENTION AND CARE 2010; 11:105-15. [PMID: 19967425 PMCID: PMC2816247 DOI: 10.1007/s10198-009-0206-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2008] [Accepted: 11/03/2009] [Indexed: 05/28/2023]
Abstract
OBJECTIVES To assess the cost effectiveness of palivizumab for prevention of severe respiratory syncytial virus (RSV) disease in high-risk infants in Spain, incorporating country-specific observational hospitalisation data. METHODS An existing decision tree model, designed using data from a large international clinical trial of palivizumab versus no prophylaxis, was updated to include Spanish observational hospitalisation data. The analysis was performed for preterm children born at or before 32 weeks gestational age, who are at high risk of developing severe RSV disease requiring hospitalisation. Data sources included published literature, official price/tariff lists and national population statistics. The primary perspective of the study was that of the Spanish National Health Service in 2006. RESULTS The base-case analysis included the direct medical costs associated with palivizumab prophylaxis and hospital care for RSV infections. Use of palivizumab produces an undiscounted incremental cost-effectiveness ratio (ICER) of euro6,142 per quality-adjusted life-year (QALY), and a discounted ICER of euro12,814/QALY. CONCLUSION Palivizumab provides a cost-effective method of prophylaxis against severe RSV disease requiring hospitalisation among preterm infants in Spain.
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Affiliation(s)
- Mark J. Nuijten
- IMTA, Erasmus University, Rotterdam, The Netherlands
- Ars Accessus Medica, Amsterdam, The Netherlands
| | - Wolfgang Wittenberg
- Global Health Economics and Outcomes Research, Abbott GmbH & Co, KG , Knollstrasse, P.O. Box 21 08 06, 6700 Ludwigshafen, Germany
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Bont L. Current concepts of the pathogenesis of RSV bronchiolitis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2009; 634:31-40. [PMID: 19280846 DOI: 10.1007/978-0-387-79838-7_3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Louis Bont
- Department Pediatric Infectious Diseases, University Medical Center Utrecht, Rm KE4.133.1, POB 85090, 3508 AB Utrecht.
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Abstract
Bronchiolitis and preschool recurrent wheeze (PSRW) are common paediatric problems causing significant morbidity and mortality in the first years of life. Respiratory syncytial virus (RSV) and rhinoviruses are the commonest pathogens associated with these illnesses. Why some infants are severely affected, requiring admission to hospital, whilst others experience a simple cold is not fully understood: research has suggested that the innate immune response to these viruses is important. The innate immune system has many components and activation or deficiency in one or many areas may explain the different clinical presentations and disease severities that can occur in these infants. This review will summarize the recent evidence highlighting how RSV and rhinoviruses may modulate the innate immune response in both bronchiolitis and PSRW, and discuss how these illnesses affect the long-term development of the infant lung and the possible susceptibility to persistent airway disease.
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Resch B, Gusenleitner W, Nuijten MJC, Lebmeier M, Wittenberg W. Cost-effectiveness of palivizumab against respiratory syncytial viral infection in high-risk children in Austria. Clin Ther 2008; 30:749-60. [PMID: 18498923 DOI: 10.1016/j.clinthera.2008.03.014] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2008] [Indexed: 01/11/2023]
Abstract
OBJECTIVE The aim of this study was to estimate the cost-effectiveness of palivizumab, a monoclonal antibody against severe respiratory syncytial virus infection, in high-risk infants in Austria. METHODS A decision tree model was developed to determine cost-effectiveness in infants born prematurely (<or=35 weeks' gestational age), those with bronchopulmonary dysplasia (BPD), and children with congenital heart disease (CHD). The primary perspective of the analysis was that of the compulsory health insurance fund. The societal perspective was also considered. RESULTS From the health insurance fund perspective, including the costs associated with asthma, the incremental cost-effectiveness ratio (cost per quality-adjusted life year [QALY] gained) without discounting was estimated to be euro 4484 (2006 euros) in preterm infants, euro 6719 in children with BPD, and euro 2668 in the CHD population. When discounted, these figures increased to euro 14,439, euro 21,672, and euro 9754, respectively. The results from the societal perspective were substantially more cost-effective in all populations. The undiscounted cost per QALY was euro 1435 in preterm infants, euro 4881 in children with BPD, and euro 251 in the CHD group. Discounted figures were euro 4623, euro 15,741, and euro 917, respectively. Sensitivity analyses confirmed the robustness of the model, and scenario analyses found that the inclusion of indirect costs led to further improvement in the cost-effectiveness outcomes for palivizumab. CONCLUSION Use of palivizumab was cost-effective compared with no prophylaxis in high-risk infants and children in Austria.
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Affiliation(s)
- Bernhard Resch
- Department of Pediatrics, University Hospital Graz, Graz, Austria
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20
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Semple MG, Dankert HM, Ebrahimi B, Correia JB, Booth JA, Stewart JP, Smyth RL, Hart CA. Severe respiratory syncytial virus bronchiolitis in infants is associated with reduced airway interferon gamma and substance P. PLoS One 2007; 2:e1038. [PMID: 17940602 PMCID: PMC2001182 DOI: 10.1371/journal.pone.0001038] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2007] [Accepted: 09/24/2007] [Indexed: 11/18/2022] Open
Abstract
Background Severe human respiratory syncytial virus (hRSV) bronchiolitis in previously well infants may be due to differences in the innate immune response to hRSV infection. Aim: to determine if factors mediating proposed mechanisms for severe bronchiolitis differ with severity of disease. Methodology/Principle Findings 197 infants admitted to hospital with hRSV bronchiolitis were recruited and grouped according to no oxygen requirement (n = 27), oxygen dependence (n = 114) or mechanical ventilation (n = 56). We collected clinical data, nasopharyngeal aspirate (NPA) and if ventilated bronchoalveolar lavage (BAL). Interferon-gamma (IFN-γ), substance P (SP), interleukin 9 (IL-9), urea and hRSV load, were measured in cell free supernatant from NPA and BAL. Multivariate analysis compared independent effects of clinical, virological and immunological variables upon disease severity. IFN-γ and SP concentrations were lower in NPA from infants who required oxygen or mechanical ventilation. Viral load and IL-9 concentrations were high but did not vary with severity of disease. Independent predictors of severe disease (in diminishing size of effect) were low weight on admission, low gestation at birth, low NPA IFN-γ and NPA SP. Nasal airway sampling appears to be a useful surrogate for distal airway sampling since concentrations of IFN-γ, SP, IL-9 and viral load in NPA correlate with the same in BAL. Conclusions Our data support two proposed mechanisms for severe hRSV disease; reduced local IFN-γ response and SP mediated inflammation. We found large amounts of hRSV and IL-9 in airways secretions from the upper and lower respiratory tract but could not associate these with disease severity.
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Affiliation(s)
- Malcolm G Semple
- Division of Child Health, School of Reproductive & Developmental Medicine, University of Liverpool, Liverpool, United Kingdom.
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21
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Ermers MJJ, Hoebee B, Hodemaekers HM, Kimman TG, Kimpen JLL, Bont L. IL-13 genetic polymorphism identifies children with late wheezing after respiratory syncytial virus infection. J Allergy Clin Immunol 2007; 119:1086-91. [PMID: 17313976 DOI: 10.1016/j.jaci.2006.12.655] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2006] [Revised: 11/09/2006] [Accepted: 12/06/2006] [Indexed: 11/28/2022]
Abstract
BACKGROUND The nature of wheezing after respiratory syncytial virus lower respiratory tract infection (RSV LRTI) is usually transient. However, some children will develop persistent or late wheezing. OBJECTIVE We hypothesized that early and late postbronchiolitis wheezing are determined by distinct clinical, immunologic, and genetic variables. METHODS A cohort of 101 children hospitalized for RSV LRTI was prospectively followed for 6 years. During RSV LRTI, cytokine studies were performed and genetic polymorphisms were determined. Parents performed daily log registration of respiratory symptoms during the first 3 years of follow-up and again at age 6 years during the winter season. RESULTS Distinctive associations for early and late postbronchiolitis wheezing were found. We previously showed that airflow limitation during RSV LRTI as well as convalescent monocyte IL-10 production are associated with early wheezing. These variables were not associated with late wheezing. On the other hand, atopic family history was not associated with early wheezing, but it was associated with late wheezing. Most importantly, the IL-13 Gln allele was associated with late wheezing (odds ratio 3.27, 95% confidence interval 1.32-8.06), but it was not associated with early wheezing. CONCLUSION This study revealed distinct clinical, immunologic, and genetic determinants of early and late wheezing after RSV LRTI, indicating distinct pathophysiological mechanisms. We conclude that late wheezing at age 6 years, but not early postbronchiolitis wheezing, is an asthmatic phenomenon and genetically related to a functional IL-13 polymorphism. CLINICAL IMPLICATIONS After RSV LRTI, wheezing at age 6 years is not related to early postbronchiolitis wheezing and represents a distinct disease entity.
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Affiliation(s)
- Marieke J J Ermers
- Department of Paediatric Infection Diseases, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands
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23
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Abstract
Bronchiolitis is a distressing, potentially life-threatening respiratory condition that affects young babies. Around 2-3% of all infants younger than 1 year are admitted to hospital with bronchiolitis, usually during the seasonal epidemic. The majority of these infants are infected with respiratory syncytial virus and all have an intense inflammatory response in their airways. Although most infants recover, they have an increased risk of recurrent wheezing. Although bronchiolitis is common, little is known about what causes infants to be susceptible. Diagnostic interventions have little effect on clinical outcome, and apart from supportive measures, there is no specific treatment. Bronchiolitis therefore presents an intriguing clinical conundrum and a major challenge to researchers. High quality clinical studies are needed to clarify assessment of disease severity and criteria for hospital admission, particularly the use of pulse oximetry and chest radiography. Careful mapping of the inflammatory pathways in the pathogenesis of bronchiolitis should lead to development of new therapies to alleviate symptoms.
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Affiliation(s)
- Rosalind L Smyth
- Division of Child Health, School of Reproductive and Developmental Medicine, University of Liverpool, Alder Hey Children's Hospital, Liverpool L12 2AP, UK.
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Lindemans CA, Kimpen JLL, Luijk B, Heidema J, Kanters D, van der Ent CK, Koenderman L. Systemic eosinophil response induced by respiratory syncytial virus. Clin Exp Immunol 2006; 144:409-17. [PMID: 16734609 PMCID: PMC1941978 DOI: 10.1111/j.1365-2249.2006.03084.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract disease (LRTD) in infants. Eosinophils have been suggested to play a role in the disease pathogenesis of LRTD. Inflammation can induce functional and morphological alterations of peripheral blood granulocytes. In patients with RSV LRTD, we aimed to investigate the eosinophil activation status by analysing surface markers. In vitro stimulation of eosinophils with cytokines leads to up-regulation of CD11b and priming markers recognized by the recently developed priming markers A17 and A27, whereas interleukin (IL)-5Ralpha is being down-regulated. In 51 patients and 10 controls we examined the expression of these surface markers on eosinophils in moderate to severe RSV-induced LRTD patients at the time of admission and 6 weeks later during the convalescence phase. RSV-patients were characterized by a higher eosinophil CD11b expression compared to controls. Although basal A17 and A27 expression was not increased, we observed a significantly higher expression of these priming epitopes on N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated cells of RSV patients compared with cells of controls, indicative of prior in vivo priming. Furthermore, IL-5Ralpha expression was down-regulated on peripheral blood eosinophils of these patients. Follow-up blood samples showed normalization of all markers but CD11b, which was persistently increased. Utilizing cellular markers, we observed that peripheral blood eosinophils from infants with RSV LRTD are in a more activated state compared to eosinophils of controls, which normalizes only partially during convalescence.
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Affiliation(s)
- C A Lindemans
- Department of Pulmonary Diseases, University Medical Centre, Utrecht, the Netherlands
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Singam R, Jena PK, Behera S, Hellermann GR, Lockey RF, Ledford D, Mohapatra SS. Combined fluticasone propionate and salmeterol reduces RSV infection more effectively than either of them alone in allergen-sensitized mice. Virol J 2006; 3:32. [PMID: 16719922 PMCID: PMC1488829 DOI: 10.1186/1743-422x-3-32] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2006] [Accepted: 05/23/2006] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Respiratory syncytial virus (RSV) infection is the major cause of bronchiolitis in infants and is a risk factor for the development of asthma. Allergic asthmatics are more susceptible to RSV infection and viral exacerbation. METHODS Since the effectiveness of corticosteroids in treating RSV infection has been controversial, we tested fluticasone propionate (FP) and salmeterol (Sal) alone versus FP plus Sal (FPS) on RSV-induced airway inflammation. Mice were sensitized and challenged with ovalbumin (OVA) and infected with RSV. Following infection they were treated with FP, Sal, or FPS intranasally and airway hyperreactivity (AHR), inflammation and RSV titers were examined. RESULTS The group treated with FPS showed significantly lower AHR compared to the group treated with FP or Sal alone. The group treated with FP alone showed slightly decreased (non-significant) AHR compared to controls. Treatment with FPS resulted in significant decreases in the percentage of eosinophils and neutrophils in bronchoalveolar lavage fluid and in lung pathology compared to FP or Sal. FP alone decreased eosinophils but not neutrophils or lymphocytes, while Sal alone decreased eosinophils and neutrophils but not lymphocytes. FPS treatment of mice infected with RSV in the absence of allergen sensitization resulted in a 50% decrease of RSV titer in the lung and a reduction in neutrophils compared to FP or Sal. CONCLUSION Together, these results indicate that fluticasone in combination with salmeterol is a more effective treatment for decreasing airway hyperreactivity and inflammation than either of them alone in allergen-sensitized, RSV-infected mice.
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Affiliation(s)
- Rajeswari Singam
- Division of Allergy and Immunology, Joy McCann Culverhouse Airway Disease Research Center, University of South Florida College of Medicine and James A. Haley VA Hospital, Tampa, FL, USA
| | - Prasanna K Jena
- Division of Allergy and Immunology, Joy McCann Culverhouse Airway Disease Research Center, University of South Florida College of Medicine and James A. Haley VA Hospital, Tampa, FL, USA
| | - Sumita Behera
- Division of Allergy and Immunology, Joy McCann Culverhouse Airway Disease Research Center, University of South Florida College of Medicine and James A. Haley VA Hospital, Tampa, FL, USA
| | - Gary R Hellermann
- Division of Allergy and Immunology, Joy McCann Culverhouse Airway Disease Research Center, University of South Florida College of Medicine and James A. Haley VA Hospital, Tampa, FL, USA
| | - Richard F Lockey
- Division of Allergy and Immunology, Joy McCann Culverhouse Airway Disease Research Center, University of South Florida College of Medicine and James A. Haley VA Hospital, Tampa, FL, USA
| | - Dennis Ledford
- Division of Allergy and Immunology, Joy McCann Culverhouse Airway Disease Research Center, University of South Florida College of Medicine and James A. Haley VA Hospital, Tampa, FL, USA
| | - Shyam S Mohapatra
- Division of Allergy and Immunology, Joy McCann Culverhouse Airway Disease Research Center, University of South Florida College of Medicine and James A. Haley VA Hospital, Tampa, FL, USA
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Kondo Y, Matsuse H, Machida I, Kawano T, Saeki S, Tomari S, Obase Y, Fukushima C, Kohno S. Effects of primary and secondary low-grade respiratory syncytial virus infections in a murine model of asthma. Clin Exp Allergy 2004; 34:1307-13. [PMID: 15298574 DOI: 10.1111/j.1365-2222.2004.02033.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Respiratory syncytial virus (RSV) infection is known to develop and exacerbate asthma in young children. In adult, RSV causes recurrent but asymptomatic infections. However, the impact of asymptomatic RSV infection on adult asthma is yet to be determined. The present study is designed to determine the effects of primary and secondary low-grade RSV infections on allergic airway inflammation in a murine model of allergic asthma. METHODS A low-grade RSV (2 x 10(3) plaque-forming units/mouse) was inoculated, and this caused neither pulmonary inflammation nor symptoms but induced significant IFN-gamma production in thoracic lymph nodes. To investigate interaction between low-grade virus and Dermatophagoides farinae (Df), airway hyper-responsiveness, lung inflammation and cytokine production from thoracic lymph nodes were compared after primary and secondary low-grade RSV infections in four groups of mice; control, Df allergen-sensitized, RSV-infected and Df-sensitized RSV-infected mice. A direct comparison between low- and high-grade RSV infections was also performed in primary infection. To investigate the role of IL-5 during secondary RSV infection, anti-IL-5 monoclonal antibody (anti-IL-5 mAb) was injected in mice and similar parameters were compared in four groups of mice. RESULTS Primary high-grade RSV infection increased allergen-induced airway inflammation, while primary low-grade RSV infection attenuated allergen-induced airway inflammation concomitant with significant IFN-gamma production in lung-draining lymph nodes. In marked contrast, secondary low-grade RSV infection increased both IFN-gamma and IL-5 production, resulting in exacerbation of allergen-induced airway inflammation. Anti-IL-5 mAb treatment in secondary low-grade RSV infection and Df allergen-sensitized mice attenuated virus and allergen-induced airway inflammation. CONCLUSIONS Low-grade RSV infection per se does not cause pulmonary inflammation, whereas it induces a significant immunological response in the allergen-sensitized host. These results indicate that subclinical and recurrent RSV infection may play an important role in exacerbation and maintenance of asthma in adults, wherein IL-5 is critically involved.
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Affiliation(s)
- Y Kondo
- Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan
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Brown KL, Walker G, Grant DJ, Tanner K, Ridout DA, Shekerdemian LS, Smith JH, Davis C, Firmin RK, Goldman AP. Predicting outcome in ex-premature infants supported with extracorporeal membrane oxygenation for acute hypoxic respiratory failure. Arch Dis Child Fetal Neonatal Ed 2004; 89:F423-7. [PMID: 15321962 PMCID: PMC1721757 DOI: 10.1136/adc.2003.033308] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
OBJECTIVE To identify predictors of outcome in ex-premature infants supported with extracorporeal membrane oxygenation (ECMO) for acute hypoxic respiratory failure. METHODS Retrospective review of ex-premature infants with acquired acute hypoxic respiratory failure requiring ECMO support in the United Kingdom from 1992 to 2001. Review of follow up questionnaires completed by general practitioners and local paediatricians. RESULTS Sixty four ex-premature infants (5-10 each year) received ECMO support, despite increased use of advanced conventional treatments over the decade. The most common infective agent was respiratory syncytial virus (85% of cases). Median birth gestation was 29 weeks and median corrected age at the time of ECMO support was 42 weeks. Median ECMO support duration was relatively long, at 229 hours. Survival to hospital discharge and to 6 months was 80%, remaining similar throughout the period of review. At follow up, 60% had long term neurodisability and 79% had chronic pulmonary problems. Of pre-ECMO factors, baseline oxygen dependence, younger age, and inpatient status were associated with non-survival (p < or = 0.05). Of ECMO related factors, patient complications were independently associated with adverse neurodevelopmental outcome and death (p < 0.01). CONCLUSIONS Survival rates for ex-premature infants after ECMO support are favourable, but patients suffer a high burden of morbidity during intensive care and over the long term. At the time of ECMO referral, baseline oxygen dependence is the most important predictor of death, but no combination of the factors considered was associated with a mortality that would preclude ECMO support.
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Affiliation(s)
- K L Brown
- Cardiac Intensive Care Unit, Great Ormond Street Hospital for Children NHS Trust, London, UK
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Bont L, Steijn M, Van Aalderen WMC, Brus F, Th Draaisma JM, Van Diemen-Steenvoorde RAAM, Pekelharing-Berghuis M, Kimpen JLL. Seasonality of long term wheezing following respiratory syncytial virus lower respiratory tract infection. Thorax 2004; 59:512-6. [PMID: 15170037 PMCID: PMC1747053 DOI: 10.1136/thx.2003.013391] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND It is well known that respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) is associated with subsequent wheezing episodes, but the precise natural course of wheezing following RSV LRTI is not known. This study aimed to determine the continuous development of wheezing following RSV LRTI in children up to the age of 3 years. METHODS A prospective cohort study was performed in 140 hospitalised infants with RSV LRTI. Continuous follow up data were obtained with a unique log in which parents noted daily respiratory symptoms. RESULTS A marked decrease in wheezing was seen during the first year of follow up. The burden of wheezing following RSV LRTI was observed during the winter season. Signs of airflow limitation during RSV LRTI were strongly associated with wheezing during the follow up period. Total and specific serum immunoglobulin E levels, patient eczema, and parental history of atopy were not associated with wheezing. CONCLUSIONS Airway morbidity following RSV LRTI has a seasonal pattern, which suggests that viral upper respiratory tract infections are the predominant trigger for wheezing following RSV LRTI. There is a significant decrease in airway symptoms during the first 12 months after admission to hospital. Simple clinical variables, but not allergic risk factors, can predict the development of wheezing following RSV LRTI.
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Affiliation(s)
- L Bont
- Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands
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Wang SZ, Rosenberger CL, Bao YX, Stark JM, Harrod KS. Clara cell secretory protein modulates lung inflammatory and immune responses to respiratory syncytial virus infection. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2003; 171:1051-60. [PMID: 12847279 DOI: 10.4049/jimmunol.171.2.1051] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Clara cell secretory protein (CCSP) has been shown to have anti-inflammatory and immunomodulatory functions in the lung. Respiratory syncytial virus (RSV) is the most common cause of respiratory infection in infants and young children. RSV usually infects small airways and likely interacts with the Clara cells of bronchioles. To determine a possible role for CCSP during acute RSV infection, CCSP-deficient (CCSP(-/-)) and wild-type (WT) mice were intratracheally infected with RSV and the lung inflammatory and immune responses to RSV infection were assessed. RSV-F gene expression was increased in the lungs of CCSP(-/-) mice as compared with WT mice following RSV infection, consistent with increased viral persistence. Lung inflammation was significantly increased in CCSP(-/-) mice as compared with WT mice after infection. Moreover, although the levels of Th1 cytokines were similar, the levels of Th2 cytokines and neutrophil chemokines were increased in the lungs of CCSP(-/-) mice following infection. Physiologic endpoints of exacerbated lung disease, specifically airway reactivity and mucus production, were increased in CCSP(-/-) mice after RSV infection. Importantly, restoration of CCSP in the airways of CCSP(-/-) mice abrogated the increased viral persistence, lung inflammation, and airway reactivity. These findings suggest a role for CCSP and Clara cells in regulating lung inflammatory and immune responses to RSV infection.
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Affiliation(s)
- Shan-Ze Wang
- Asthma and Pulmonary Immunology Program, Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA
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