some people — even those who had mild versions of the disease — have symptoms that last weeks or months after an initial COVID infection. These ongoing health problems, called post-COVID conditions (PCC), post-COVID-19 syndrome, long COVID-19, and post-acute sequelae of SARS COV-2 infection (PASC), can decrease quality of life for patients and increase the burden of disease on health systems. As more patients suffer from long COVID, it’s increasingly important to define the symptoms associated with long COVID for effective diagnosis and treatment of the disease.

New research from physicians and researchers at Kaiser Permanente, the Mid-Atlantic Permanente Research Institute (MAPRI) and Johns Hopkins University identified 17 conditions associated with long COVID in order to better diagnose and treat the condition. The study, “Post-Acute Sequelae of SARS-CoV-2 with Clinical Condition Definitions and Comparison in a Matched Cohort,” was published October 12, 2022, in Nature Communications [1].

“Although there has been significant research done to determine a clinical definition of long COVID, the reality is that the disease may look very different from patient to patient,” said lead author of the study Michael Horberg, MD, an infectious diseases physician and associate medical director at Kaiser Permanente, Mid-Atlantic Permanente Medical Group. “Our study set out to determine conditions that were most likely to be associated with long COVID.” The research, funded by the National Institutes of Health, looked at medical records of over 100,000 Kaiser Permanente Mid-Atlantic States’ adult patients – over 30,000 who tested positive for COVID-19 and over 70,000 who tested negative for COVID-19 – in 2020.

The 17 conditions identified were:
• Other lower respiratory disease
• Fatigue and malaise
• Diabetes
• Cardiac dysrhythmias
• Gastrointestinal disease
• Nervous system disorders
• Dizziness or vertigo
• Respiratory failure
• Abdominal pain
• Anosmia (loss of smell)
• Nonspecific chest pain
• Nausea and vomiting
• Mental health disorders
• Fluid and electrolyte disorders
• Anxiety disorders
• Nutritional, endocrine and
• Genitourinary symptoms metabolic disorders
Researchers were most interested in conditions that developed in their patients within 30 days of a positive COVID-19 test and persisted for nearly four months post-test date, and conditions that developed in the 30-to-120-day period after a positive test. Key conditions included loss of smell, cardiac dysrhythmia, diabetes, genitourinary disorders, fatigue and chest pain.

Researchers used Kaiser Permanente’s robust electronic medical records to categorize conditions into three distinct time intervals based on when a patient tested positive for COVID-19. By organizing the conditions by date of when a patient tests positive, researchers were able to effectively evaluate if the resulting symptoms were related to long COVID as opposed to being caused by a pre-existing health condition. Additionally, by comparing COVID-19 positive patients to COVID-negative patients (the control group), researchers were able to tease out which symptoms appeared more often in the COVID-positive group, which symptoms occurred more often in the COVID-negative group and which symptoms appeared at the same rate in both groups.

“One reason long COVID is difficult to identify is that many of its symptoms are similar to those of other diseases and conditions,” Dr Horberg said. “Some pre-existing conditions may have been present or worsened at the time of COVID-19 infection, but that doesn’t mean it should be defined as long COVID.” “When we compared the COVID-positive population to the COVID-negative population, especially within and post the first 30 days of the positive test date, some of the predicted symptoms and conditions appeared less significant than we anticipated,” said Eric Watson, MAPRI’s director of research analytics and co-author of the study.

Overall, 16.5 % of COVID-positive patients within the study developed at least one long COVID-related condition within 120 days of a positive test. This finding is lower than national averages, which shows that nearly 20% of American adults who’ve had COVID-19 report having long COVID symptoms after the acute infection period.

Diabetes and long COVID
Researchers found that some patients may have developed diabetes after a COVID-19 infection. Over 780 patients received a new diagnosis of diabetes between 30 and 120 days after a positive COVID-19 test. Dr Horberg said it is too early to determine if diabetes should be considered a condition associated with long COVID.

“It’s possible that some patients were simply undiagnosed until they sought care for their COVID-19 infection, and that’s why we saw such a jump in new diabetes diagnoses,” Dr Horberg said. “There needs to be more research on the relationship between diabetes and COVID-19 before we can definitively say this is a long COVID condition.”

Future research
Dr Horberg and researchers are expanding their examination of conditions associated with long COVID in another study funded by the National Institutes of Health. The next phase of research will look at data from 2021 through 2022 and take a deeper dive into the relationship between diabetes and COVID-19, the effects of Delta and Omicron variants, the impact of vaccines and boosters, and the influence of widespread at-home testing.

“In contrast to 2020, in 2021, the U.S. underwent mass public vaccination, so we’re very interested to see if vaccines reduced the incidence of long COVID. We’re also interested to see if the newer

variants had any effect on long-COVID symptomology,” said Watson.
“This list will likely evolve as we conduct more research,” Dr Horberg said. “We are eager to continue to study long COVID in order to better diagnose and treat those who may be suffering months after a COVID-19 infection.”

According to the Centers for Disease Control and Prevention (CDC), long COVID is more likely to impact people who have not been vaccinated against COVID-19. Boosters are recommended for everyone 12 years and older and children 5 years and older who received the Pfizer vaccine.

References
1. Horberg, M.A., Watson, E., Bhatia, M. et al. Post-acute sequelae of SARS-CoV-2 with clinical condition definitions and comparison in a matched cohort. Nat Commun 13, 5822 (2022). https://doi.org/10.1038/s41467-022-33573-6

New Omicron subvariant largely evades neutralizing antibodies

A study at Karolinska Institutet in Sweden shows that the coronavirus variant BA.2.75.2, an Omicron sublineage, largely evades neutralizing antibodies in the blood and is resistant to several monoclonal antibody antiviral treatments. The findings, published in the journal The Lancet Infectious Diseases [1], suggest a risk of increased SARS-CoV-2 infections this winter, unless the new updated bivalent vaccines help to boost immunity in the population.
“While antibody immunity is not completely gone, BA.2.75.2 exhibited far more dramatic resistance than variants we’ve previously studied, largely driven by two mutations in the receptor binding domain of the spike protein,” says the study’s corresponding author Ben Murrell, assistant professor at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet.

The study shows that antibodies in random serum samples from 75 blood donors in Stockholm were approximately only one-sixth as effective at neutralizing BA.2.75.2 compared with the now-dominant variant BA.5. The serum samples were collected at three time points: In November last year before the emergence of Omicron, in April after a large wave of infections in the country, and at the end of August to early September after the BA.5 variant became dominant.
Only one of the clinically available monoclonal antibody treatments that were tested, bebtelovimab, was able to potently neutralize the new variant, according to the study. Monoclonal antibodies are used as antiviral treatments for people at high risk of developing severe COVID-19.

BA.2.75.2 is a mutated version of another Omicron variant, BA.2.75. Since it was first discovered earlier this fall, it has spread to several countries but so far represents only a minority of registered cases.
“We now know that this is just one of a constellation of emerging variants with similar mutations that will likely come to dominate in the near future,” Murrell says, adding “we should expect infections to increase this winter.”

Some questions remain. It is unclear whether these new variants will drive an increase in hospitalization rates. Also, while current vaccines have, in general, had a protective effect against severe disease for Omicron infections, there is not yet data showing the degree to which the updated COVID vaccines provide protection from these new variants. “We expect them to be beneficial, but we don’t yet know by how much,” Murrell says.
The study was conducted in collaboration with researchers at ETH Zürich in Switzerland and Imperial College London in the U.K.

References
1. Daniel J. Sheward, Changil Kim, Julian Fischbach, et. al. Omicron sublineage BA.2.75.2 exhibits extensive escape from neutralising antibodies.
The Lancet Infectious Diseases, online October 13, 2022, doi: https://doi.org/10.1016/S1473-3099(22)00663-6