Study uncovers why COVID-19 is more deadly for some people with diabetes than others


New research being presented at the annual meeting of the European Association for the Study of Diabetes (EASD), held online this year, explored whether COVID-19 is more deadly for some people with diabetes than for others.

It found that type 2 diabetes is associated with a higher risk of mortality in hospitalised  COVID patients than type 1 diabetes.

The combination of an older age and high C-reactive protein (CRP) was also linked to a higher risk of death.

Younger people (under 70 years old) with chronic kidney disease, a common long-term complication of diabetes, also had a higher likelihood of dying.

BMI, however, was not linked to survival.

The information has been used to create a simple model which can be used to predict which patients are at higher risk of death.

While people with diabetes are no more likely to contract COVID-19 than others, they are more likely to become severely ill if they do catch it.   It has been unclear, however, if certain characteristics put some people with diabetes at higher risk of serious illness and death than others.

The ACCREDIT study, from Dr Daniel Kevin Llanera and Dr Rebekah Wilmington, at the Countess of Chester NHS Foundation Trust, England, UK, and colleagues, looked for links between a range of clinical and biochemical characteristics and the risk of mortality within seven days of admission to hospital in COVID-19 patients with diabetes.

The 1,004 patients from seven hospitals in northwest England had an average age of 74.1. Most (60.7%) were male and 45% lived in areas classed as the most deprived in the UK (based on the government’s Index of Multiple Deprivation).

Median BMI was 27.6 and 56.2% had macrovascular complications of diabetes (e.g. heart attack or stroke) and 49.6% had microvascular complications (e.g. neuropathy or retinopathy).

7.5% were admitted to intensive care and 24% died within seven days of admission to hospital.  The greater socio-economic deprivation and older age of the patients studied may help explain why the seven-day mortality was higher than in other studies, says Dr Llanera. However, further research is needed to confirm this.

Approximately one in ten patients (9.8%) required insulin infusions, meaning they were switched from other treatments to IV insulin to better control their blood sugar.

Analysis showed that those with type 2 diabetes were 2.5 times as likely to die within seven days of admission as those with other types of diabetes.  The study’s authors say this may be because type 2 diabetes usually occurs in older people and can be accompanied by other long-standing health conditions, putting them at higher risk of poorer outcomes.

Those who had insulin infusions were, however, half as likely to die as those who didn’t need IV insulin. The study’s authors say this may be a clue that better blood sugar control can improve outcomes in patients with severe COVID and diabetes.

Risk of death was also higher among under-70s with chronic kidney disease. They were 2.74 times more likely to die than under-70s without chronic kidney disease.

Dr Llanera, who has recently moved from the Countess of Chester NHS Foundation Trust to Imperial College London, says: “According to several studies, patients with diabetic kidney disease have a chronic pro-inflammatory state and immune dysregulation, making it difficult to ‘fight off’ the virus compared to someone who has a properly working immune system.

“In addition, ACE2 receptors are upregulated in the kidneys of patients with diabetic kidney disease. These are molecules that facilitate entry of SARS-COV-2 into the cells. This may lead to direct attack of the kidneys by the virus, possibly leading to worse overall outcomes.”

The combination of older age and high CRP (a marker of inflammation) was linked to a more than three-fold (3.44) higher risk of death by day 7. The study’s authors say that higher CRP correlates with a high degree of inflammation, which can eventually lead to organ failure.

The data has used to create a model, which, if applied to a patient with similar demographic characteristics, can predict a higher risk of death in 7 days using only age and CRP as variables.

Dr Llanera says: “Both of these variables are easily available during upon admission to hospital. This means we can easily identify patients early on their hospital stay who will likely require more aggressive interventions to try and improve survival.”

Unlike some previous studies, BMI and HbA1c (average blood sugar level) were not associated with death.

Nor was any significant association seen with diabetes complications, other than chronic kidney disease, or use of ACE inhibitors and angiotensin receptor blockers (ARBs) – types of blood pressure drugs.

The proportion of patients (9.8%) switched to insulin infusions is higher than the typical figure of 8%, suggesting Covid patients require higher levels of input from inpatient diabetes teams.

Dr Llanera concludes: “In order to help our patients with diabetes survive this pandemic, we needed to explore further what makes them at risk for worse outcomes.

“These results will allow other researchers and clinicians to find out how we can best intervene, allowing us to provide our patients with the most appropriate treatment.”

Why do people with diabetes develop severe COVID-19?

Throughout the COVID-19 pandemic, clinicians have noted that certain patients are at especially high risk of developing severe illness or dying from coronavirus infection. Type 2 diabetes—a condition affecting more than 10 percent of the U.S. population– is one of the main risk factors for severe COVID-19 illness. New research from U-M uncovers why this might be and offers hope for a potential therapy.

The culprit appears to be an enzyme called SETDB2. This same enzyme has been implicated in the non-healing, inflammatory wounds found in people with diabetes. Working in the lab of Katherine Gallagher, M.D. of the Michigan Medicine Departments of Surgery and Microbiology and Immunology, researcher W. James Melvin, M.D., and his colleagues decided to probe a possible link between the enzyme and the runaway inflammation they witnessed first-hand in COVID patients in the ICU.

Starting with a mouse model of coronavirus infection, they found that SETDB2 was decreased in immune cells involved in the inflammatory response, called macrophages, of infected mice with diabetes. They later saw the same thing in monocyte-macrophages in the blood from people with diabetes and severe COVID-19.

 “We think we have a reason for why these patients are developing a cytokine storm,” said Melvin.

In the mouse and human models, noted Melvin and Gallagher, as SETDB2 went down, inflammation went up. In addition, they revealed that a pathway known as JAK1/STAT3 regulates SETDB2 in macrophages during coronavirus infection.

Taken together, the results point to a potential therapeutic pathway. Previous findings from the lab demonstrated that interferon, a cytokine important for viral immunity, increased SETDB2 in response to wound healing. In their new study, they found blood serum from patients in the ICU with diabetes and severe COVID-19 had reduced levels of interferon-beta compared to patients without diabetes.

“Interferon has been studied throughout the pandemic as a potential therapy, with efforts going back and forth between trying to increase or decrease interferon levels,” said Gallagher. “My sense is that its efficacy as a therapy will be both patient and timing specific.”

To test this, the study team administered interferon beta to coronavirus-infected diabetic mice and saw that they were able to increase SETDB2 and decrease inflammatory cytokines.

“We’re trying to home in on what controls SETDB2, which is sort of the master regulator of a lot of these inflammatory cytokines that you hear about as being increased in COVID-19, such as IL-1B, TNFalpha, and IL-6,” explained Gallagher.

“Looking upstream at what’s controlling SETDB2, interferon is at the top end, with JaK1 and STAT3 in the middle. Interferon increases both, which increases SETDB2 in a sort of cascade.”

This is important, she added, because identifying the pathway presents other potential ways of targeting the enzyme.

Melvin and Gallagher hope the findings of this study will inform ongoing clinical trials of interferon or other downstream components of the pathway, including epigenetic targets, for COVID-19. Their work also highlights the need to understand the timing and cell-specificity of therapy and to tailor its application to patients’ underlying conditions, especially patients with diabetes.

“Our research is showing that maybe if we are able to target patients with diabetes with interferon, especially early in their infection, that may actually make a big difference,” Melvin said.

Other U-M researchers involved in this study include Christopher O. Audu, Frank M. Davis, Sriganesh B. Sharma, Amrita Joshi, Aaron DenDekker, Sonya Wolf, Emily Barrett, Kevin Mangum, Xiaofeng Zhou, Monica Bame, Alex Ruan, Andrea Obi, Steven L. Kunkel, and Bethany B. Moore.

Paper cited: “Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2”, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2101071118

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Autistic individuals have increased risk of COVID-19

Autistic adults, adults with intellectual disability, and adults with mental health diagnoses have multiple risk factors for infection with COVID-19 and for experiencing more severe disease if they contract COVID-19, according to research from the A.J. Drexel Autism Institute at Drexel University.

Identifying risk factors for COVID-19 among autistic adults, adults with intellectual disability and adults with psychiatric diagnoses is important for prioritizing public health initiatives and clinical practice – including vaccination, testing, masking and distancing. Additionally, awareness of risks can help with decision-making in caring for these populations.

Researchers used data from Medicaid to look at whether these groups were more likely to experience risk factors for COVID-19 and noted that though the Medicaid data examined is from 2008-2012, risk factors, such as living in a residential facility, are not likely to have lessened over time.

“These high-risk populations should be recognized by clinicians and these groups should be prioritized for vaccine outreach and education,” said Whitney Schott, PhD, a research scientist at the Autism Institute and lead author on the study.

The data showed that autistic adults had higher odds of living in a residential facility, receiving in-home services from outside caregivers, having had an avoidable hospitalization and having a high-risk health condition, compared to neurotypical adults without mental health conditions.

It also showed adults with intellectual disability had similar odds of having these conditions. Adults with other mental health conditions were also more likely to live in a residential facility, receive services from outside caregivers and have had avoidable hospitalizations compared to the neurotypical population without mental health conditions. They had three times higher odds of having a high-risk health condition.

Researchers examined risk factors for COVID-19 among adults enrolled in Medicaid from 2008-12 who were ages ages 20-64 with autism, intellectual disability, mental health conditions and with no mental health conditions. They estimated prevalence, as well as logistic regressions for these groups to find the odds of these risk factors. From a random sample, 372,807 had any mental health condition; 683,778 did not. Of the full population of autistic adults and adults with intellectual disability, 31,101 were autistic, 52,049 were autistic with intellectual disability, and 563,558 were diagnosed with intellectual disability but not autism.

“Care providers, policymakers and advocates should be aware of the higher rates — among autistic adults, adults with intellectual disability and adults with mental health diagnoses — of risk factors for contracting COVID-19 and more severe illness if infected,” said Lindsay Shea, DrPH, director of the Policy and Analytics Center and leader of the Life Course Outcomes Research Program at the Autism Institute, an associate professor and co-author of the report.

It is important to intensify outreach efforts to vaccinate these vulnerable groups, added Shea. Trusted providers with preexisting relationships may be in the best position to help those in this population become vaccinated. Efforts should also be made to provide up-to-date information about safe practices, such as wearing face-coverings, maintaining physical distance, handwashing, avoiding crowds and increasing ventilation.

The report, “Covid-19 Risk: Adult Medicaid Beneficiaries with Autism, Intellectual Disability, and Mental Health Conditions” was published in Autism in August 2021.

Does COVID-19 vaccination affect rheumatic and musculoskeletal disease flares?

Does COVID-19 vaccination affect rheumatic and musculoskeletal disease flares?
Does COVID-19 vaccination affect rheumatic and musculoskeletal disease flares?


In a study of 1,377 patients with rheumatic and musculoskeletal diseases—such as inflammatory arthritis and lupus—flares of their conditions were uncommon following two-dose COVID-19 mRNA vaccination. In a study of 1,377 patients with rheumatic and musculoskeletal diseases—such as inflammatory arthritis and lupus—flares of their conditions were uncommon following two-dose COVID-19 mRNA vaccination.

In the Arthritis & Rheumatology study, 11% of patients reported flares after vaccination that required treatment, and there were no reports of severe flares. Flares were associated with prior SARS-CoV-2 infection, flares in the six months preceding vaccination, and use of combination immunomodulatory therapy.

“’Our findings demonstrate that the vaccines are safe and should alleviate the safety concerns of any hesitant patients,” said first author Caoilfhionn Connolly, MD, MSc, of Johns Hopkins University School of Medicine. “This study highlights that most of our rheumatic patients tolerated the vaccine well with mostly having local reactions such as injection site pain, which was quite reassuring, but most importantly, we did not observe any severe flares of their underlying autoimmune disease,” added co–senior author Julie J. Paik, MD, MHS, also of Johns Hopkins University School of Medicine.