Emerging Human Metapneumovirus Gene Duplication Variants in Patients with Severe Acute Respiratory Infection, China, 2017–2019

We detected human metapneumovirus (HMPV) in 72 (7.1%) of 1,021 patients hospitalized with severe acute respiratory infection in Luohe, China, during 2017–2019. We detected HMPV most frequently in young children and less often in adults. HMPV genotype A2c variants 111 nt and 180 nt duplications predominated, demonstrating their continuing geographic spread.

We detected human metapneumovirus (HMPV) in 72 (7.1%) of 1,021 patients hospitalized with severe acute respiratory infection in Luohe, China, during 2017-2019. We detected HMPV most frequently in young children and less often in adults. HMPV genotype A2c variants 111 nt and 180 nt duplications predominated, demonstrating their continuing geographic spread. patients in this study exhibited cough or dyspnea and were diagnosed with bronchopneumonia (74.6%). No clear differences in clinical signs and symptoms were apparent among the patients infected with duplication variants compared with other HMPV viruses.
Forty-three entire coding-region sequences of the G gene were obtained from 72 HMPV-positive samples, as described elsewhere (3,5,6) ( Table 2). The nucleotide sequences generated in this study were submitted to GenBank (accession nos. MN944056-97). We selected 86 subgroup A sequences (54 from GenBank and 32 from this study) and 23 subgroup B sequences (12 from GenBank and 11 from this study) to construct the phylogenetic tree by maximum-likelihood method ( Figure 2, https://wwwnc.cdc.gov/ EID/article/27/1/20-1043-F2.htm). The HMPV sequences obtained in this study were clustered into 4 genotypes, including A2c, A2b, B1, and B2 (Table 2; Figure 2). Twenty-eight out of 31 A2c sequences were grouped together in 1 distinct cluster with the duplication variants, mainly detected in Spain, Japan, Croatia, and Guangzhou, China. In the sequence alignment comparison analysis, we identified 22 viruses containing 111 nt-dup variants and 6 viruses contained 180 nt-dup variants in the G gene. The 111 nt-dup variants were detected in Luohe in 2018 and continued to spread in 2019, while 180 nt-dup variants were detected during 2017 and 2018 ( Table 2). The 111 nt-dup variants were separated from the 180 nt-dup variants in the phylogenetic tree, which indicates that the 2 duplication variants evolved by independent patterns in different evolutionary lineages (Figure 2, panel A).
The twenty-two 111 nt-dup variants circulating in Luohe during 2018-2019 were closely related to the duplication-variant viruses identified in Japan, Croatia, and Guangdong, China, in 2017, with nucleotide identity of 95.7% to 100%. Six 180 nt-dup variants circulating in Luohe during 2017-2018 were clustered in 1 small cluster with high nucleotide identity at 99.1% and 100% and closely related to the duplication viruses identified in Japan, Croatia, Spain, and Beijing, China, during 2014-2017 ( Figure 2A). This finding indicates that the 111 nt-dup and 180 nt-dup variants have already spread and might spread extensively throughout the world.

Discussion
Our findings show that 7.1% of SARI patients in the Luohe study tested positive for HMPV during 2017-2019. The rate of HMPV-positivity decreased gradually with patient age. Among the HMPV patients, 63.9% were co-infected with other respiratory viruses. Four different genotypes were cocirculating, including A2b, A2c, B1, and B2. We identified most of 276 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 27, No. 1, January 2021   the A2c viruses as duplication variants, including the 111 nt-dup and 180 nt-dup variants, and found that these 2 variants were the predominant viruses circulating in Luohe during 2017-2019. The 111 nt-dup and 180 nt-dup variants have also been detected in different regions of the world, including in Spain, Japan, Croatia, and Guangzhou, China, in recent years (5,(8)(9)(10)(11). Similar duplications in the G gene have been reported in HRSV, another member of the family Pneumoviridae. The HRSV duplication variants of both BA9 and ON1 have rapidly spread globally, becoming the predominant viruses in many countries for many years (14,15). These findings suggest that the emerging HMPV 111 nt-dup and 180 nt-dup variants might also become predominant viruses throughout the world.
There were some limitations in this study. The epidemic seasons were not covered for the entire 3 years, and only 1 hospital was involved in this study. Continuous surveillance will be required to determine whether these novel HMPV 111 nt-dup and 180 nt-dup variants will persist as predominant viruses and have a wider geographic distribution in the future.
Although no difference in clinical symptoms was observed between the patients infected with HMPV duplication variants and those with non-duplicationvariant viruses in this study, the increased transmission frequency of the duplication variants suggests a role for duplication in the G gene in potentially expanding its transmission. Therefore, further study is needed to clarify if and how the duplications result in an evolutionary advantage for HMPV.