Introduction
Methods
Definition of Asthma and Recurrent Wheezing
Outcomes of Interest
Evaluation of Data
Compliance with Ethics Guidelines
Results
Articles Selected
RSV LRTI in Early Life and the Risk of Developing Recurrent Wheezing/Asthma
Study | Country | Study design | RSVH status | Study definition of wheezing, asthma or chronic respiratory morbidity | Years of follow-up | Asthma/wheezing RSV vs. control |
---|---|---|---|---|---|---|
Schauer 2002 [34] | Germany | Prospective study of 42 infants with RSV without concomitant chronic respiratory, cardiac, or other disease and 84 controls | <12 months old | Asthma and wheezing not defined | 1 | Recurrent wheezing: 15.5% vs. 3.6% |
Sigurs 1995 [28] | Sweden | Prospective cohort study of 47 infants with RSV and 93 age- and gender-matched controls | <12 months old | Asthma: ≥3 episodes of bronchial obstruction verified by a physician. Recurrent wheezing: ≥3 episodes of bronchial obstruction not verified by a physician | 1 and 3 | At 1 year: Asthma (mean: 11% vs. 0% (P = 0.004) Recurrent wheezing (mean: 4% vs. 8% (NS)) At 3 years: Asthma (mean: 23% vs. 1% (P < 0.001) Recurrent wheezing (mean: 21% vs. 12% (NS)) |
Karaman 2011 [44] | Turkey | Prospective study of 70 children, 40 with RSV and 30 with non-RSV bronchiolitis | 0–36 months old | Wheezing not defined | 1–3 | Recurrent wheezing: 35% vs. 53.3% (P = 0.064; NS) |
Escobar 2010 [39] | US | Retrospective cohort study of 71,102 children born ≥32 wGA | 1.7% with medically attended RSV <12 months old | Recurrent wheezing: combination of encounter events, patient diagnoses using ICD codes, and prescription patterns | 3 | Recurrent wheezing: 16.2% vs. 6.2%a
|
Bont 2004 [35] | Netherlands | Prospective cohort study of 140 infants with RSV (29% born 25–36 wGA; 3% cardiac disease, 2% CLD) | ≤12 months old | Respiratory symptoms and wheezing episodes: parent-reported (daily log). Disease episode: presence of respiratory symptoms for ≥2 consecutive days | 3 | Wheezing: >50% decrease in first year of follow-up (P < 0.001) |
Escobar 2013 [38] | US | Retrospective cohort study of 72,602 children born ≥32 wGA | 1.74% with medically attended RSV < 12 months old [0.69% hospitalized and 1.05% treated as outpatient) | Recurrent wheezing: as in Escobar 2010 [39], using a combination of encounter events, patient diagnoses, and prescription patterns | 5 | Recurrent wheezing year 5: 12.5% vs. 4.6%a
Recurrent wheezing year 3-5: 40.0% vs. 12.3%a
|
Carbonell-Estrany 2015 [14] | Spain | Multicenter, observational, nested, case-control study of preterm (32-35 wGA) infants with RSV (n = 125) and controls (n = 362) | <12 months old | Recurrent wheezing: ≥3 wheezing episodes within 12 months. Severe recurrent wheezing: recurrent wheezing associated with at least one episode of hospitalization, or ≥3 medical attendances or ≥1 courses of systemic steroids, or asthma medication for ≥3 consecutive months or 5 cumulative months in a year | 6 | At 6 years of age: Recurrent wheezing: 46.7% vs. 27.4% (P = 0.001) Severe wheezing: 37.7% vs. 23.7% (P = 0.010) Total wheezing: 71.4% vs. 54.4% (P = 0.006) |
Zomer-Kooijer 2014 [23] | Netherlands | Prospective, population-based study of 155 previously healthy term infants with RSV and 553 unselected term infants | <12 months old (0.7% hospitalized with RSV) | Asthma: recorded asthma diagnosis (ICPC coded); for ‘current asthma’ included diagnosis plus asthma symptoms or medication use during preceding 12 months. Wheezing episodes: parent-reported | 6 | Current wheeze: 21.3% vs. 8.1% Current asthma: 21.4% vs. 5.3% |
James 2013 [37] | US | Retrospective study of 264 010 infant births from 2 cohorts (1996–2003 and 1995–2003) (15% with bronchiolitis during RSV season) | History of bronchiolitis <12 months of age during the RSV season | Asthma identified using ICD-9 codes | 6 | Asthma: 16–23% vs. 8–12%b
|
Bacharier 2012 [40] | US | Prospective cohort study of 206 infants with RSV | ≤12 months old hospitalized or seen in emergency department | Asthma and wheezing: physician-diagnosed. Active asthma: physician-diagnosed asthma at any time along with parent-reported wheezing during the last year of follow-up between the child’s 3rd and 7th birthdays | 6 | Recurrent wheezing: 92% ≥1 additional wheezing episode before 3 years Asthma by 7 years: 48% Active asthma by 7 years: 35% |
Jackson 2008 [42] | US | Prospective study of 259 children with wheezing viral infections in first 3 years of life (21% RSV LRTI) | ≤36 months old medically attended (majority seen in outpatients) | Asthma: combination of physician diagnosis and prescription patterns | 6 | Asthma (RSV before age 1): 38% Asthma (RSV before age 2): 43% Asthma (RSV before age 3): 76% |
Koponen 2012 [33] | Finland | Prospective study of 166 healthy, full-term infants with bronchiolitis (70.5% RSV) | <6 months old | Asthma: physician-diagnosed or parent-reported wheezing episodes and episodes of other asthma-like symptoms | 6.5 (mean) | Current asthma: 8.2% if RSV vs. 24% if non-RSV (P = 0.01)c
|
Henderson 2005 [31] | UK | Prospective population-based study of 14,062 live births [284 infants with bronchiolitis enrolled (1.1% total study cohort had RSV)] | <12 months old | Asthma: physician-diagnosed and wheezing as parent-reported | 7 | Asthma (at 91 months): 38.4% vs. 20.1% (P = 0.002) Wheezing (30-42 months): 28.1% vs. 13.1% (P = 0.002) Wheezing (69-81 months): 22.6% vs. 9.6% (P = 0.0001) |
Fjaerli 2005 [36] | Norway | Follow-up study of 57 infants with RSV and 64 age-matched controls | <12 months old | Asthma: physician-diagnosed Wheezing: episodes of difficult breathing accompanied by a whistling noise in the chest during expiration (by authors) | 7 | Asthma: 54% vs. 8% (P < 0.001) Wheezing ≥3 episodes during follow-up period: 51% vs. 14% (P < 0.001) |
Sigurs 2000 [10] | Sweden | Prospective cohort study of 47 infants with RSV and 93 age- and gender-matched controls (follow-up of Sigurs 1995 [28]) | <12 months old | Asthma: ≥3 episodes of physician-verified wheeze Recurrent wheezing: ≥3 episodes of parent-reported wheeze | 7.5 | Asthma: 23% vs. 2% (P < 0.001) Recurrent wheezing: 13% vs. 0% (P <0.001) |
Szabo 2014 [27] | Canada | Retrospective, population-based study of 145,430 children born 1996–1997 (birth cohort): LRTI cohort: 7,104 (4.9%) RSV cohort: 230 (0.2% of birth cohort and 3.2% of the LRTI cohort) Comparison cohort: 138,326 infants | <2 years old | Chronic respiratory morbidityd: identified by physician using ICD-9 codes – included asthma, chronic wheezing, chronic bronchitis, CLD | 10 | Chronic respiratory morbidityd: 2 to <10 years: 50.4% vs. 27.9%e
2 to <5 years: 41.7% vs.19.4%e
5 to <10 years: 31.7% vs. 18.1%e
|
Sigurs 2005 [11] | Sweden | <12 months old | Asthma: ≥3 episodes of physician-verified wheezing Recurrent wheezing: ≥3 episodes of wheezing not verified by a physician | 13 | Asthma/recurrent wheezing during year prior to follow-up: 43% vs. 8% (P < 0.001) Asthma (current): 28% vs. 3.3% (P < 0.001) Asthma (cumulative): 37% vs. 5.4% (P < .0001) Recurrent wheezing (current): 15% vs. 4.3% (P = 0.065; NS) Recurrent wheezing (cumulative): 30% vs. 16.3% (P = 0.093) | |
Stein 1999 [30] | US | Prospective study of 888 children with LRTI in first 3 years of life | 472 (90.2%) had recorded virus test; of these, 207 (43.9%) had RSV but were not hospitalized | Current wheeze: infrequent wheeze (up to 3 episodes in preceding 12 months) or frequent wheeze (>3 episodes in preceding 12 months) | 13 | Frequent wheezing: 4.3 times more likely at year 6 compared to children with no LRTI |
Ruotsalainen 2013 [32] | Finland | Prospective study of 67 children with RV or RSV bronchiolitis and 155 matched controls | <2 years old | Asthma: physician-diagnosed or self-reported | 15.6 (median) | Wheezing symptoms: 32.8% vs. 12.9% |
Sigurs 2010 [29] | Sweden | <12 months old | Asthma: ≥3 episodes of physician-verified wheeze Recurrent wheezing: ≥3 episodes of parent-reported wheeze | 18 | Asthma/recurrent wheezing: 39% vs. 9% (P = 0.001) Asthma alone: 33% vs. 7% (P < 0.001) | |
Korppi 2014 [12] | Finland | Prospective study of 36 children with RSV and 45 age-matched controls | <2 years old | Asthma: physician-diagnosed or self-reported wheezing or prolonged cough during the preceding 12 months | 18–20 | Asthma: 17–22%ef vs. 11% |
Ruotsalainen 2010 [13] | Finland | Prospective study of 40 children with RSV and 80 matched controls | <2 years old | Asthma: physician-diagnosed or self-reported | >25 | Asthma: 13–30% vs. 1.3–3.8%e
Wheezing: 35% vs. 16.3% |
Backman 2014 [41] | Finland | Prospective follow-up study of 43 adults with RSV (24 confirmed and 19 probable RSV) and 86 population-based controls | <2 years old | Asthma: physician-diagnosed or self-reported | 30 | Asthma: 23–28% vs. 13–17%e
|
Summary | ||||
---|---|---|---|---|
Number of studies | Number of countries | Years of follow-up | Recurrent wheezing (%) | Asthma (%) |
2 | 2 | 1 | 4–15.5 | 11 |
4 | 4 | 1–3 | 16.2–35 | 23 |
1 | 1 | 3–5 | 12.5–40.0 | – |
9 | 7 | 6–8 | 13–46.7 | 8.2–76 |
4 | 2 | 13–30 | 15–35 | 13–37 |
Long-term Respiratory Morbidity in Specific High-risk Groups
Premature Infants
Wheezing | Year 2 | Year 3 | Year 4 | Year 5 | Year 6 | |||||
---|---|---|---|---|---|---|---|---|---|---|
RSVb
| Control | RSVb
| Control | RSVb
| Control | RSVb
| Control | RSVb
| Control | |
Number of children (%) | 41.4 | 12.1 | 29.3 | 15.4 | 18.5 | 12.6 | 15.0 | 9.3 | 12.4 | 9.7 |
P
| <0.001 | 0.001 | NS | NS | NS | |||||
OR (95% CI) | 5.14 (2.68–9.87) | 2.28 (1.41–3.70) | 1.58 (0.91–2.75) | 1.72 (0.92–3.20) | 1.32 (0.68–2.59) |
Congenital Heart Disease
Down Syndrome
Reduced Lung Function
Factors Associated with the Development of Recurrent Wheezing/Asthma after RSV LRTI in Early Life
Risk Factors
Atopy and Allergy
Genetic Factors
Altered Immunology
Eosinophilia
Maternal Antibody
Long-term Respiratory Morbidity and Impact on Quality of Life and Cost of Care
Limitations
Key statements/findings | Level of evidencea
|
---|---|
There is increasing evidence that RSV LRTI in early life is a significant risk factor for subsequent recurrent wheezing/asthma, persisting at least through early childhood Recurrent wheezing rates of 4–47% and asthma rates of 8–76% have been reported in studies with up to 25 years follow-up (average follow-up 6–8 years) | Level 1 (Level 1 studies: n = 21; Risk of biasb: very low) |
RSV LRTI in early life is associated with reduced lung function and increased airway reactivity Abnormalities reported for spirometric airway function include reduced FEV1, FEV1/FVC, and FEF25–75
| Level 1 (Level 1 studies: n = 8; Risk of biasb: very low) |
RSV-related respiratory morbidity may be related to a combination of the viral insult, preexisting abnormal lung function and/or other factors predisposing for wheezing/asthma Other factors include: genetics (e.g. increased production of IL10), altered immunology (e.g., altered plasmacytoid dendritic cell levels), eosinophilia, transfer of maternally derived RSV antibody, and other risk factors (e.g., tobacco smoke exposure) | Level 1 (Level 1 studies: n = 17; Risk of biasb: very low) |
There is conflicting evidence on the association between RSV LRTI in early life and the subsequent development of clinical allergy and/or allergic sensitization | Level 1 (Level 1 studies: n = 7; Risk of biasb: very low) |
RSV LRTI is associated with decreased quality of life and increased healthcare costs, although data are limited | Level 1 (Level 1 studies: n = 6; Risk of biasb: very low) |
Key areas for research:
Further prospective, follow-up studies are needed to clarify the risk factors and long-term respiratory outcome of children hospitalized for severe RSV LRTI (including in specific populations, such as those with CHD, and the potential link with COPD/emphysema) | |
Future research should aim to elucidate the pathophysiological mechanisms through which RSV LRTI causes recurrent wheezing/asthma |