Modeling the onset of symptoms of COVID-19: Effects of SARS-CoV-2 variant

Identifying order of symptom onset of infectious diseases might aid in differentiating symptomatic infections earlier in a population thereby enabling non-pharmaceutical interventions and reducing disease spread. Previously, we developed a mathematical model predicting the order of symptoms based on data from the initial outbreak of SARS-CoV-2 in China using symptom occurrence at diagnosis and found that the order of COVID-19 symptoms differed from that of other infectious diseases including influenza. Whether this order of COVID-19 symptoms holds in the USA under changing conditions is unclear. Here, we use modeling to predict the order of symptoms using data from both the initial outbreaks in China and in the USA. Whereas patients in China were more likely to have fever before cough and then nausea/vomiting before diarrhea, patients in the USA were more likely to have cough before fever and then diarrhea before nausea/vomiting. Given that the D614G SARS-CoV-2 variant that rapidly spread from Europe to predominate in the USA during the first wave of the outbreak was not present in the initial China outbreak, we hypothesized that this mutation might affect symptom order. Supporting this notion, we found that as SARS-CoV-2 in Japan shifted from the original Wuhan reference strain to the D614G variant, symptom order shifted to the USA pattern. Google Trends analyses supported these findings, while weather, age, and comorbidities did not affect our model’s predictions of symptom order. These findings indicate that symptom order can change with mutation in viral disease and raise the possibility that D614G variant is more transmissible because infected people are more likely to cough in public before being incapacitated with fever.Author summary: We developed a mathematical model to predict symptom order of symptomatic COVID-19 cases from patient characteristics data in the USA and China. Surprisingly, our model predicted that cough occurs first in the USA, while fever occurs first in China. We hypothesized the difference is due to the SARS-CoV-2 D614G variant, which was predominate in the USA during data collection, whereas the original Wuhan reference strain was predominate in China. To test this, we used patient data from the outbreak in Japan, which was initially dominated by the Wuhan reference strain but eventually dominated by the D614G variant. The predicted symptom order changed with the viral variant, but not region, weather, patient age, or comorbidity. These results support the notion that cough occurs earlier in the D614G variant than the Wuhan reference strain. The D614G variant’s greater transmissibility might be explained by infected individuals coughing and spreading the virus before they are incapacitated by fever. Additionally, we hope other researchers will further investigate symptom order of infectious diseases to understand how viral variants and comorbidities affect disease progression. Such work is especially important now as contagious and deadly variants of SARS-CoV-2 are under investigation and rapidly spreading worldwide.