The most likely order of symptoms that COVID-19 patients experience is different for different variants of the virus, according to a new study in PLOS Computational Biologby Peter Kuhn of the University of Southern California and colleagues.

The researchers previously developed a mathematical model predicting the order of COVID-19 symptoms based on data from the initial outbreak in China in early 2020. In the new work, they wanted to know whether the order of symptoms varied in patients from different geographical regions or with various patient characteristics. They used their modeling approach to predict symptom order in a set of 373,883 cases in the USA between January and May 2020.

Surprisingly, the most likely symptom order differed between the initial outbreak in China—where fever most often preceded cough, and nausea/vomiting was a common third symptom—and the subsequent spread to the USA, where cough was most likely to be the first symptom, and diarrhea was a more common third symptom.

By analyzing additional data from Brazil, Hong Kong and Japan, the team showed that the different orders of symptoms were associated not with geographic region, weather, or patient characteristics, but with SARS-CoV-2 variants. The presence of the D614G variant in an area—which was predominant in the USA in early 2020—was associated with a higher likelihood of cough being the first COVID-19 symptom experienced by patients. As Japan shifted from the original Wuhan reference strain to the D614G variant, symptom order shifted as well. The increased transmission of D614G could be linked to the symptom order, the authors hypothesize.

“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,” they say.