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.