High Prevalence of SARS-CoV-2 Genetic Variation, D614G Mutation in Children With COVID-19
By Denise Baez
NEW YORK -- November 20, 2020 -- A whole genome study in children with coronavirus disease 2019 (COVID-19), published in Open Forum Infectious Diseases, has found a greater than expected genetic diversity across the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome, increased mutation, and a high prevalence of the D614G mutation, which is associated with increased disease transmission.
In analysing serum from 141 paediatric patients who tested positive for SARS-CoV-2 between March 19, 2020, and June 16, 2020, Utsav Pandey, PhD, Children’s Hospital Los Angeles (CHLA), Los Angeles, California, and colleagues found all but 1 of the 141 isolates (99.3%) had the D614G mutation in the spike protein. The prevalence of the D614G mutation in February was about 10%, and about 65% in March, when the first peak was occurring in California.
Although the role of D614G mutation in SARS-CoV-2 pathogenicity continues to be investigated, it has been associated with lower cycle threshold values and increased transmissibility, but not with disease severity. In the current study, the mutation was present in almost all patients, regardless if they were asymptomatic or had severe infection.
Alongside D614G, the researchers found 2 other common mutations -- F924F and P4715L, the latter of which is important for viral replication and has been associated with higher fatality rates.
“Nevertheless the functional significance of these mutations still needs to be fully investigated,” the authors noted. “Confirmation of these observed mutations and better understanding of its potential significance will require sequencing and correlative studies of larger numbers of paediatric COVID-19 cases.”
The researchers also observed an unexpectedly increased mutation rate (22.5 substitutions per year) in this paediatric cohort when compared with other SARS-CoV-2 cases from California without the D614G mutation during the same period (13.5 substitutions per year). Again, the clinical and biological implications remain to be carefully ascertained, the authors noted.
All patients in the study had been tested at CHLA for a variety of reasons, including COVID-19-related symptoms, hospital admission unrelated to COVID-19, and asymptomatic pre-procedural screening. Most (67.4%) of the children were of Hispanic ethnicity, 53.2% were male, the median age was 8.3 years, and 13.4% had underlying conditions. Of the 141 patients, 14 (87.5%) required hospital admission due to COVID-19 related symptoms.
Consensus genomes obtained for the 141 CHLA isolates were compared with the Wuhan isolate (NC_045512.2) using SARS-CoV-2 Genome App v1.1 and the CHLA COVID-19 Analysis Research Database (CARD). The CHLA isolates were also compared against the global collection of 77,966 available SARS-CoV-2 sequences in CARD to identify Southern California specific haplotypes.
“From a genomic epidemiology perspective, the isolates in our study almost exclusively belonged to the 3 most recent SARS-CoV-2 phylogenetic clades (20A, 20B, 20C) as defined in Nextstrain,” the authors wrote. “This is consistent with previously described patterns of multiple introduction and community transmission of SARS-CoV-2 lineages in California.”
An extensive chart review of 88 of the 141 patients with available inpatient and outpatient data (to capture disease severity, comorbidities, and clinical course) found that phylogenetic clade 20C was associated with severe cases of COVID-19 (odds ratio = 6.95; P = .0467). Of the 10 patients with either moderate or severe forms of COVID-19, 9 were infected by virus from phylogenetic clade 20C, compared with only 44 of the 78 children with mild or asymptomatic disease.
The researchers also found that all patients aged younger than 5 years were symptomatic and had higher viral loads than older children, with detection of viral RNA as early as 1 one day post symptom onset and highest viral loads in the first 2 days of symptoms onset. No difference in viral load was observed in association with chronic underlying conditions, gender, or disease severity.
“Our study warrants larger and multi-institutional genomic evaluation and has implications for infection control practices,” the authors concluded.
SOURCE: Open Forum Infectious Diseases