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Lisa Strug, associate director of the Centre for Applied Genomics at the Hospital for Sick Children, in Toronto. This photo shows her surrounded by the genome sequencing machines located within TCAG, which will be used for the genomic research study.Handout

For infectious disease experts, one of the most intriguing mysteries about COVID-19 is why there is so much variation in the virulence of the disease, particularly among people in different age groups – including children, who rarely experience severe illness.

While it’s been clear since the beginning of the pandemic that the elderly or those who have chronic medical conditions such as hypertension or diabetes are at higher risk of getting a severe case of COVID-19, it is also true, based on worldwide data, that there are some cases of healthy young adults as well as children, who are becoming critically ill.

“The question is why,” said Lisa Strug, associate director of the Centre for Applied Genomics at the Hospital for Sick Children in Toronto. “That’s where we believe we’re going to get some insight from genetics.”

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Now Dr. Strug and her colleagues have launched a cross-Canada initiative to sequence the DNA from a large number of individuals who have been infected with COVID-19. The project, which is partly funded through private donation, will make its data widely available with the goal of identifying genetic variations that are relevant to the severity of the disease and that could help inform treatment.

Key to the project is the question of age and its relationship to the progress of a COVID-19 infection.

“We are looking at the entire spectrum – from birth to over 70 – otherwise you might not get the full picture,” said Upton Allen, the hospital’s head of infectious disease, who is co-leading the effort with Dr. Strug.

Disease modellers have been starved for information about the character and prevalence of COVID-19 in the young. Evidence suggests that most children who are exposed to the virus will have only had mild symptoms or none at all. However, they may still be transmitting the virus to others. This means children could be an important factor in the community spread of the disease – a detail that is difficult to capture in forecasts that could help determine when physical distancing measures can be lifted.

While there have been theories about why the disease has the age profile that it does – a profile not seen in influenza, for example – researchers are looking to ground those ideas with hard data.

“It’s humbling,” said Jesse Papenburg, a pediatric infectious disease specialist at the Montreal Children’s Hospital. “It seems that many of the things we thought we knew about respiratory infectious disease in children don’t seem to be playing out that way with COVID-19.”

Dr. Papenburg is among the collaborators that the Toronto group has already reached out to in order to gather a diverse set of genetic samples for the study.

Because a patient’s genes do not change after the disease has come and gone, Dr. Allen said the project will be able to obtain genetic data from individuals who were ill and in hospital but are now recovered. The study will include a control group of individuals who were infected but who did not experience serious symptoms.

Some of those controls will be drawn from family members who live in the same household as those who became ill but who, for whatever reason, were spared despite a similar level of exposure. In that situation, Dr. Allen said, the strategy will be to find the family member who is most distantly related (such as a spouse) to see what genetic differences turn up.

Dr. Strug said the study will involve reading and comparing the entire DNA sequences of large numbers of individuals, and using statistical tools to see which variations may correlate to different responses to the COVID-19 virus. Researchers will also focus on genes that are linked to specific pathways in the immune system or that relate the way the virus attacks cells.

The project’s original aim was to sample the genomes of at least 1,000 people who have been infected with COVID-19, but that was before it was clear how extensive the outbreak would become across Canada.

“Unfortunately, access to individuals that are symptomatic is not going to be a challenge," said Dr. Strug, “so I think that we are going to far exceed a study of 1,000."

She added that initial results could emerge within the next six to 12 months. Parallel projects supported by the British-based Wellcome Sanger Institute and the Howard Hughes Medical Institute in the United States are also under way.

Stephen Freedman, a clinical scientist with the Alberta Children’s Hospital Research Institute in Calgary who is not involved in the genomic studies, said they would yield important information and potentially answer some of the biggest questions surrounding COVID-19. However, he added, COVID-19 is outpacing research to an extent that some of those answers are more likely to inform the next pandemic.

Dr. Freedman is leading a separate study that will combine Canadian and international data to help health workers spot COVID-19 in children and better predict which cases will likely require hospital care, as well as determine what interventions are most effective.

“Trying to glean out that data is really crucial to coming up with management strategies in real time,” he said. “Even though children do better than adults, there are still a host of children who do poorly and there are children who die," he said.

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