Human metapneumovirus: Clinical and virological aspects in Norwegian children

Abstract

Background Human metapneumovirus (HMPV) was discovered in 2001. Later studies have shown that HMPV is quite similar to respiratory syncytial virus (RSV), and a common cause of respiratory tract infections (RTI) in children. Aims The aims of my thesis were to study the occurrence and clinical manifestations of severe HMPV infections in Norwegian children and the impact of viral co-detections and HMPV genotypes. I also wanted to compare severe HMPV and RSV infections. I wanted to study the HMPV shedding time during acute RTI and HMPV in asymptomatic hospital controls, to get an impression of HMPV in non-infected children. Finally, I wanted to study HMPV and other respiratory viruses among children in day-care centers. Materials and Methods The thesis is based on data from 3 clinical studies, a cohort study of 3,650 hospitalized children with RTI and 339 asymptomatic hospital controls, the shedding study including 32 hospitalized HMPV-infected children and a cross-sectional study in two day-care centers, including 161 apparently healthy children. The day-care children were examined median 2 times during four visits in 2012-2014. Informed, written consents to participate were collected from caregivers and the majority of children underwent clinical examination. Nasopharyngeal samples were analyzed by polymerase chain reaction (PCR) tests for HMPV, RSV and 17 other pathogens, and cultured for virus. HMPV-positive samples were genotyped and phylogenetic analyses were performed. Results HMPV was detected in 7.3% and RSV in 28.7% among children in the hospital cohort during the period 2006-2015. Among the controls, 2.1% had HMPV with low viral load by PCR, but all were culture negative. HMPV occurred in regular winter and spring-summer epidemics, and with a median duration of 3.5 months. The average annual hospitalization rates in children <5 years old with lower RTI were 1.8/1,000 (HMPV) and 9.9/1,000 (RSV). All HMPV subtypes (A2a, A2b, B1 and B2), except subtype A1, were detected. In each season, at least two subtypes circulated. The F gene sequencing revealed no clusters or new strains, whereas several known HMPV strains circulated during the entire period. The clinical manifestations were relatively similar in HMPV- and RSV-infected children with lower RTI, and the clinical manifestations in HMPV lower RTI were not related to viral co-detection and HMPV genotypes. Age was an important risk factor for disease severity, in addition to a history of prematurity and chronic disease, for HMPV- and RSV-associated lower RTI. Children <6 months of age with HMPV had a milder disease than those with RSV, while in children 12-23 months old, the pattern was the opposite. Among children in day-care centers, HMPV was detected 4 times only, but rhinovirus, enterovirus and parechovirus were frequently appearing. The virus rates in day-care children varied in relation to age, clinical signs of RTI, day-care section (sections for younger and older children) and season. The median HMPV shedding time was estimated to be 13 days (range 6-28 days). Conclusions HMPV occurred in regular epidemics, and is a common cause of severe RTI in Norwegian children, but the hospitalization rate is five times lower than RSV. Clinically, severe HMPV and RSV infections manifest relatively similar, and independent of viral co-detections and HMPV genotypes in children with severe HMPV infections. Children shed HMPV shortly and HMPV appears seldom in asymptomatic children and healthy day-care children, in contrast to picornaviruses that may be detected frequently in Norwegian children attending day care.