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Just days after the start of their academic year, over 20,000 pupils from 800 Mississippi schools have been told to quarantine due to Covid exposure.
Some 4,500 children became sick with Covid during this first week of school.
Across the US, states like Mississippi with low vaccination rates and relaxed mask rules have asked thousands of students and staff to quarantine.
The Delta variant, the dominant strain in the US, has been affecting younger people at a higher rate.
Children under 12 are not yet approved to be vaccinated in the US, putting them at a higher risk of catching the highly contagious variant.
Infections and hospital admissions are on the rise among the young in a way not seen earlier in the pandemic, when the virus was mostly affecting the elderly and people with pre-existing health conditions.
In Mississippi, since classes came back from summer break on 9 August, around 5% of all students have been asked to quarantine, according to data from the state's health department. Less than 36% of Mississippi residents are fully vaccinated.
State epidemiologist Dr Paul Byers described the number of children now in quarantine as "dramatic".
"That exceeds what we've experienced... when we were at our previous peak for the impact on the schools," he told reporters on Wednesday.
A 13-year-old girl died over the weekend, Dr Byers said, adding that she was the fifth child to die because of the virus in the state.
Mississippi's only paediatric hospital has had to turn parts of a garage into a field hospital due to the rise in admissions.
Mississippi is just the latest state to face such outbreaks among children.
In one school district in Florida, over 10,000 children and staff are being told to stay home. The outbreak made the Hillsborough County School Board vote on Wednesday to require masks in schools.
Hillsborough County joins others in the Sunshine State, like Miami-Dade, in approving such a policy despite threats from Florida's Republican governor to punish leaders who enact mask mandates in schools.
- Georgia's Ware County has closed all government-run schools after a "sharp increase" in cases saw over 800 students and faculty quarantining
- Nearly 1,000 students in Nashville, Tennessee, are in quarantine or isolation
- The New Orleans School District says over 3,000 student and staff are quarantining amid about 300 active Covid cases
- Alabama, another southern state with low vaccination rates, reported every hospital bed in the state was occupied as of Wednesday
- Several school districts in Texas have had to temporarily close due to outbreaks among staff or students