Table 1.

Summary of the Available Evidence in Support of, against, or Lacking a Link between Respiratory Syncytial Virus and Rhinovirus Lower Respiratory Tract Infection with Asthma Inception

	RSV LRTI		RV LRTI
	Evidence*	Data Summary	Evidence*	Data Summary
Association with asthma	+	Among infants with RSV LRTI, the estimated risk of later developing asthma ranges from OR 2.07 to 12.7 (95% CI, 1.2–47.1) (13, 30–32, 48, 76, 79–82).	+	Among infants with RV LRTI, the estimated risk of later developing asthma ranges from OR 1.99 to 10 (95% CI, 1.04–23) (13, 30–32, 48, 76, 81).
				RV is a frequent cause of asthma exacerbations (119)
Precedes asthma onset	+	Longitudinal studies demonstrate that RSV LRTI precedes atopic sensitization and asthma onset (76, 77).	+/−	Longitudinal studies demonstrate that RV LRTI precedes asthma onset (76, 77).
				Allergic sensitization precedes RV wheezing in some infants (12, 78).
Dose–response relationship demonstrated	+	RSV LRTI severity is associated in a dose-dependent fashion with both increasing asthma risk and increasing asthma severity (34, 76).	0/+	A dose–response relationship has not yet been demonstrated with RV LRTI.
		A dose–response relationship with no infection, mild infection, and infection with wheezing has been demonstrated for RSV (73).		A dose–response relationship with no infection, mild infection, and infection with wheezing has been demonstrated for RV (73).
Contributes to a substantial proportion of asthma	+	A majority of infant LRTIs are attributable to RSV infection (111, 112).	+	Although the risk of asthma associated with RV LRTI is higher in most studies compared with RSV LRTI, RV LRTI may contribute to a smaller proportion of asthma because infant RV LRTI is less common (32).
		Infant RSV LRTIs therefore contribute to a higher proportion of asthma in the population.
Defined risk groups	+	Family history of asthma (12, 77)	+	Family history of asthma/atopy (77)
		Premature birth (77, 116, 118)		Precedent allergen sensitization (77)
		Male sex (77)		Genetic polymorphisms (17)
		White race (77)
		Seasonality of birth (118, 120)
		Genetic polymorphisms commonly in immune response genes (1, 9)
Host genetic and viral genetic determinants of disease risk and severity	+	Host: Several genes are associated with both RSV infection and asthma, suggesting a genetic susceptibility to both (1, 9, 10).	+	Host: 17q21 variants are associated with asthma in children with RV wheezing illnesses in early life (17).
		Virus: RSV strain differences have been shown in mouse and human studies to affect the pathogenicity, which await demonstration as to whether they are associated with asthma risk after infant infection (41, 43).		Virus: RV strain differences may have an impact on pathogenicity (47, 48).
Biologic mechanisms through which these viruses may cause asthma	+	Pathology: RSV in animal models causes acute and chronic lung changes similar to asthma (80, 90, 98).	+	Pathology: RV in animal models causes acute and chronic lung changes similar to asthma (92, 100).
		Physiology: RSV infection is associated with prolonged airway hyperresponsiveness (90, 99, 101).		Physiology: RV infection is associated with prolonged airway hyperresponsiveness (92, 100).
		Immune development: In animal models RSV infection results in long-term immunomodulatory changes and impairs regulatory T cells (88, 103, 107–110).		Immune development: In animal models RV infection results in long-term immunomodulatory changes (92, 93).
		Epithelial barrier function: In a cell culture model, RSV degrades epithelial barrier function, which could increase allergen sensitization through the airways (96).		Epithelial barrier function: RV degrades epithelial barrier function in cell culture and infected mice, which could lead to increase allergen sensitization through the airways (97).
Currently available interventions	+	Avoidance	0	Avoidance
		Birth timing (118, 120)		Different classes of RV inhibitors have been evaluated in clinical trials but are no longer being developed (117, 121).
		RSV immunoprophylaxis (110–113)		Pre- and probiotics may prevent rhinovirus infection in premature infants (69).
		Ribavirin (114)
Acceptable interventions in pregnant women and children	+	Most would consider both birth timing and the currently available RSV immunoprophylaxis as acceptable interventions (110–113).	0	There is currently no available vaccine or preventive treatment other than avoidance.
Proof of concept studies available by challenging, preventing or removing	+	Randomized controlled trial of RSV immunoprophylaxis among premature infants demonstrated reduced risk of wheezing at 1 yr (110).	0	No evidence, and there is currently no available vaccine or preventive treatment to test.
		Observational studies of infants treated with ribavirin or RSV immunoprophylaxis demonstrated significantly lower incidence of asthma or recurrent wheezing (111–114).

Definition of abbreviations: CI = confidence interval; LRTI = lower respiratory tract infection; OR = odds ratio; RSV = respiratory syncytial virus; RV = rhinovirus.

^*+ = evidence in support of a causal relationship; − = evidence against a causal relationship; 0 = no available evidence or none available.