Many of the birds have been found off the coast of Orkney and Shetland.
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More than 100 dead puffins have been found washed up on the shores of the north east of Scotland in the last three weeks.
Many of the birds have been found off the coast of Orkney and Shetland.
Seabird ecologist, Dr Francis Daunt, from the UK Centre for Ecology & Hydrology (UKCEH), said the deaths represent “one of the most significant puffin wrecks (mass seabird deaths) for this time of year” since the centre started studying the species about 50 years ago.
UKCEH carries out long-term monitoring studies to detect the effects of environmental change on UK seabird populations.
Many of the puffins found have been described as “emaciated” which suggests the birds are struggling to find food, Dr Daunt added.
Some of the seabird bodies washed up in Orkney are adults, and there is a concern that this will have a negative impact on next year’s breeding numbers.
Earlier this year, in the autumn, several thousand razorbills and guillemots were found dead on the east coast of the UK.
More than 100 of these two species were tested for avian flu, but the results have since come back negative.
An ongoing investigation into the deaths is looking at a potential “significant failure of the marine food supply” or toxic poisoning from algal blooms, or a combination of both.
UKCEH said it is still yet to test the dead puffins found over the last three weeks for avian flu, and it remains unclear if their deaths are linked to the other dead seabirds found in the autumn.
Dr Francis Daunt said: “It is worrying to now see puffins also washing up dead and sick.
“We hope to be able to carry out post-mortems on them as well.”
UKCEH is working with the Marine Scotland directorate of Scottish Government, Plymouth Marine Laboratory, Edinburgh University, Centre for Environment, Fisheries and Aquaculture, Natural England and DEFRA to probe the earlier seabird deaths.
A spokesperson for the centre said due to the complex and varied nature of the investigation, results are not likely to be available until early next year.
Vets at Flett and Carmichael, a local practice on Orkney, said a “large number” of puffins handed into them by members of the public have been “very weak”, with some requiring rehydration fluids to help keep them alive.
Vet Leah Hunter previously told the PA News Agency: “At this time of year, the puffins should be far out at sea in groups so the fact that they are being washed up on land means that things have sadly gone wrong for them.”
Ms Hunter said the recent bout of extreme weather, including Storm Arwen which battered parts of the north-east of Scotland, could have had an impact on some of the birds.
The Scottish Government said it’s Marine Scotland Directorate is currently analysing water, plankton and fish samples for the presence of algal species that could potentially harm seabirds.
The RSPB has previously said while the exact cause of death for the dead seabirds found in their numbers this year is unknown, climate change has an impact on driving prey fish numbers down and creating more extreme weather events.