DISCUSSION
In this prospective cohort, we demonstrate substantial burden of symptomatic-hMPV infection in children (5.7 cases per 100 person-years) and is an important cause of ALRI particularly for children in their first year of life. While the seroprevalence of hMPV in children varies globally, ranging from <5% to >30%3, the overall incidence among all children in the Nicaraguan cohort is one of the highest recorded in Central and South America 28,28–33. Few prospective cohort studies assess for hMPV in children, and studies that screen for hMPV primarily occur at surveillance hospitals making precise comparisons of incidence across communities and countries challenging. To our knowledge, this study is the longest running clinical-based community cohort in Central or South America assessing hMPV in children.
In the Nicaraguan study cohort, the majority of symptomatic-hMPV and critically hMPV-associated ALRI occurred in first year of life (Fig 3). Those under one year old were 3.2 times more likely to have a symptomatic hMPV episode compared to those aged 1-14. Worldwide hMPV infection is greatest in those <5 years old2,3, however there is considerable variation in age and infection in children under five 11,34–36. However, in long-running prospective cohort studies in children the burden appears to primarily affect those under a year of age34,37. Indeed, recent global modeling studies indicate that infants under one year have disproportionally high risks for hMPV-associated ALRI similar to Respiratory Syncytial Virus (RSV) and influenza 2. Indeed, the highest incidence for influenza-associated ALRI for children aged 9-11, in the same study cohort was 4.8 influenza-associated ALRI cases (95%CI: 2.8-8.3) per 100 person-year compared to 13.7 hMPV-associated ALRI per 100 person-year for children of the same age (95%CI: 8.7-20.6)20. This study also indicates that children under a year six months old in LMICs are at an increased risk of death compared to upper-middle-income countries. In the United States, a long-running cohort found that the hMPV infection was greatest in those under one year of age37. Similarly, in Guatemala, a hospital-based cohort similar in size and scope to our study, also found increasing hMPV incidence throughout the first year of life 34. Our study demonstrates that not only are children at a high risk of acquiring hMPV, but also infection with hMPV is likely to result in an ALRI event, particularly for infants under a year old.
We additionally found that symptomatic reinfection of hMPV was common. In total 87 (15%) of all observed episodes were symptomatic reinfections. While this study did not capture asymptomatic reinfections, the total number of symptomatic reinfections is substantial. Globally reinfection is common, likely due to poor development of T and B cell immunological memory or a lack of sterilizing immunity 12,17–19. Reinfection was positively associated with age, with most reinfections occurring after age three. However, there was variation in symptomatic reinfections in the study cohort and reinfection occurred across childhood.
Similar to other studies, hMPV-associated ALRI events accounted for a substantial proportion of symptomatic hMPV episodes3,11,37. Throughout the study period, hMPV-associated ALRI constituted 27% - 43% of all symptomatic hMPV infections. The likelihood of hMPV-associated ALRI was five-times higher in children under the age of one compared to those older than one. This severity is consistent with other hospital cohort studies 15. In the United States, the annual rate of hospitalization was highest for infants in the 0–5-month range 15.
Seasonality of symptomatic hMPV varied considerably year to year. While hMPV infection occurred throughout the study period, four epidemic peaks were identified. Effective reproductive numbers varied based on year and depending on the estimate of serial interval used. We were unable to find other published estimates of the reproductive number for hMPV and while better estimates of generation interval are needed for more precise estimates, this study is an important step forward in estimating the potential spread of pediatric hMPV. During the epidemic periods observed, cases peaked in July or August corresponding to the rainy season which lasts from June to November. This seasonality is similar to other studies conducted in tropical and subtropical areas where epidemic peaks tended to occur during periods of high rainfall and high relative humidity35,38,39, in contrast to temperate areas where hMPV infection predominately peaks in the winter and spring months3. Globally, seasonality of hMPV is broadly influenced by climatic features, but local metrological conditions likely influence variation regionally and locally3,16.
While longer time scales are needed to assess fixed patterns in seasonality, during the timeframe observed biennial seasonality across the first four years. While most studies observe annual hMPV epidemic cycles 16,29,34–36,39–43, biennial seasonality in hMPV infection is uncommon 44, and has not been observed in the tropics. For some infectious diseases, like measles, periodicity resulting in biennial transmission is due to the variation of the proportion of susceptible individuals in a population45,46. While age structure and distribution of those entering the cohort was stable throughout the study period, we are unable to broadly assess if the total number of susceptible individuals are changing and if this change influences the seasonality of hMPV.
This study was not without limitations. While this study is longer compared to many cohort studies on hMPV, it is not long enough to make to describe temporal patterns accurate of seasonal dynamics. Additionally, we did not assess genetic variation in hMPV, which might offer insight into seasonal dynamics and disease severity. Based on current literature, there are no strong associations between these lineages and disease severity, or when detected, were found in smaller studies lacking substantial power 16,40,43,47. It is likely that multiple lineages and changes in lineage are occurring during the study period. Studies assessing the seasonality of subgroup types have found alternating subgroup seasonality, with subgroup dominance shifting every 1-3 years while the clinical presentation of hMPV remained unchanged . This is consistent with our study where hMPV-associated ALRI events were consistently proportional to the number of symptomatic events. It is therefore unlikely that changes in lineage effect the number of severe ALRI outcomes. While specific genetic groupings are globally more common in specific regions, for example in Asian countries after 2005 A2c and A2b genetic groupings were more common 6, than samples derived from Europe, multiple lineages circulating in a specific season are common and found globally3,6,10,15,16,28,29,36,40,42,48–52 without substantial changes to their yearly seasonal dynamics.
Human metapneumovirus is a ubiquitous childhood respiratory illness. While seroprevalence for hMPV is high globally little is known about hMPV in Latin America or how its dynamics might influence prevention, prediction, and surveillance of hMPV. Here, we demonstrate that hMPV infection is an important cause of ALRI in children and is particularly important for children under one year of age. While hMPV infections occur throughout the year, distinct biennial seasonality for hMPV infection was evident in our cohort and may be important in defining timing of future interventions.