upper airway and is mainly problematic in children aged 6–48 months of age. Biennial epidemics starting in Autumn are associated with both HPIV-1 and 2; however, HPIV-2 can also have yearly outbreaks. Additionally, HPIV-1 tends to cause biennial outbreaks of croup in the Fall. In the United States, large peaks have presently been occurring during odd-numbered years. HPIV-3 has been closely associated with bronchiolitis and pneumonia and principally targets those aged <1 year. HPIV-4 remains infrequently detected. However, it is now believed to be more common than previously thought, but is less likely to cause severe disease. By the age of 10, the majority of children are sero-positive for HPIV-4 infection which may be indicative of a large proportion of asymptomatic or mild infections. Important epidemiological factors that are associated with a higher risk of infection and mortality are those who are immuno-compromised and may be taken ill with more extreme forms of LRI. Associations between HPIVs and neurologic disease are known; for example, hospitalisation with certain HPIVs has a strong association with febrile seizures. HPIV-4B has the strongest association (up to 62%) followed by HPIV-3 and -1. HPIVs have also been linked with rare cases of virally caused meningitis and Guillain–Barré syndrome. HPIVs are spread from person to person ('horizontal transmission') by contact with infected secretions through respiratory droplets or contaminated surfaces or objects. Infection can occur when infectious material contacts mucous membranes of the eyes, mouth, or nose, and possibly through the inhalation of droplets generated by a sneeze or cough. HPIVs can remain infectious in airborne droplets for over an hour. Overall, HPIVs remain best known for its effects on the respiratory system and this appears to be where the majority of the focus has been upon. Airway inflammation The inflammation of the airway is a common attribute of HPIV infection. It is believed to occur due to the large scale up-regulation of inflammatory cytokines. Common cytokines, expected to be up-regulated, include IFN–α, various other interleukins (IL–2, IL-6) and TNF–α. Various chemokines and inflammatory proteins are also believed to be associated with the common symptoms of HPIV infection. Recent evidence seems to suggest that virus-specific antibodies (IgE) may be responsible for mediating large-scale releases of histamine in the trachea, which are believed to cause croup. More detail on the pathways and interactions can be found here. Immunology The body's primary defense against HPIV infection remains humoral immunity.