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Center for Infectious Disease Research and Policy
Mary Van Beusekom, MS
A large study published yesterday in BMJ concludes that long-COVID symptoms in patients who had mild infections resolved within a year, but some physicians say the research design was flawed, and the findings don’t match their clinical experiences, could provide false assurance, and may have unintended consequences for those with persistent symptoms.
Shortness of breath, weakness
Researchers at the KI Research Institute and Maccabi Healthcare Services in Israel analyzed the electronic health records of 1,913,234 Maccabi members of all ages tested for COVID-19 from Mar 1, 2020, and Oct 1, 2021. The team used a test-negative design to compare the risk of 70 reported long-COVID outcomes in unvaccinated, infected patients with that of uninfected patients, as well as with the risk of breakthrough infection in unvaccinated, infected controls.
The team concluded that COVID-19 was significantly linked to an elevated risk of anosmia (loss of smell) and dysgeusia (loss of taste) in both the early period (first 30 to 180 days; hazard ratio [HR], 4.59; risk difference, 19.6) and late period (181 to 360 days; HR, 2.96; risk difference, 11.0).
The risks were also elevated for cognitive impairment in the early (HR, 1.85; risk difference, 12.8) and late periods (HR, 1.69; risk difference, 13.3) and for shortness of breath (HR, 1.79 and 1.30; risk difference, 85.7 and 35.4, respectively), weakness (HR, 1.78 and 1.30; risk difference, 108.5 and 50.2), and heart palpitations (HR, 1.49 and 1.16; risk difference, 22.1 and 8.3).
The risk of streptococcal tonsillitis and dizziness were lower but still significantly elevated in both periods, while hair loss, chest pain, cough, myalgia, and respiratory disorders were significantly higher only in the early period. Risks among males and females were slightly different, and children had fewer persistent symptoms than adults in the early period, which mostly resolved by 1 year.
The results were similar, regardless of whether the wild-type, Alpha, or Delta SARS-CoV-2 variant was dominant. Vaccinated participants who later were infected had a lower risk of shortness of breath than their unvaccinated, infected counterparts but had a comparable risk of other lingering symptoms.
“This nationwide study suggests that patients with mild COVID-19 are at risk for a small number of health outcomes, most of which are resolved within a year from diagnosis,” the authors concluded.
The problem with test-negative designs
Ziyad Al-Aly, MD, clinical epidemiologist at the Washington University School of Medicine in St. Louis and chief of research and development at the Veterans Affairs St. Louis Healthcare System, told CIDRAP News that the conclusions are puzzling. “They don’t jibe with our understanding of long COVID, and I think I know why” he said.
The study’s fundamental flaw, Al-Aly said, is its test-negative design. “People don’t usually test for SARS-CoV-2 or for any other reason without an indication,” he said. “People who seek care often do so for other reasons, and they are tested. This is not the normal population; these are people who had the need to test and tested positive.”
In other words, “When you test people, you’re testing against people who are sick,” Al-Aly said. “It makes it look like COVID-positive people have a resolution of symptoms when in reality it’s a suboptimal design that may give us a false assurance.”
When the pandemic began, he said, many researchers thought a test-negative design was useful, but Al-Aly’s group soon ran into confounding when conducting a COVID-19 study. “What we found is that people with a COVID-negative test had a higher risk of cancer, and it turns out that people who had come to the hospital for testing did so for chemotherapy or other reasons,” he said. “The patients were not the average person in Israel or the United States or Italy.”
It makes it look like COVID-positive people have a resolution of symptoms when in reality it’s a suboptimal design that may give us a false assurance. Ziyad Al-Aly, MD.
The problematic design also confounded the results of the study in question, he said. “For example, in Figure 7, the team found that vaccination actually gives you brain fog, which is unlikely to be true,” he said. “This doesn’t mean the vaccine is bad for you; it just means that this was a badly designed study.”
A better-designed study would have compared COVID-19 patients with uninfected patients rather than people who needed to be tested because they were ill, he said, acknowledging that this type of study has become increasingly difficult because a high proportion of the population has been infected.
Robert Wachter, MD, chair of the Department of Medicine at the University of California San Francisco, said the study was comprehensive but not systematic. “Are these [results] coming from whether patients complained of something when they came into a clinic visit?” he asked. “That’s important, because if I have COVID and believe that it can cause long COVID and now I’m fatigued 6 months later, and I normally wouldn’t tell anyone about it, but I’m wondering if this is long COVID.”
For example, he said, his wife likely has long COVID but hasn’t been tested because her symptoms are relatively mild, “The bias is there,” he said.
Eric Topol, MD, founder and director of the Scripps Research Translational Institute, said in an email that the study results may also have been influenced by the average participant age. “I believe the optimistic outlook was colored by the very young age of the cohort (mean of 25), and the results do not conform with my experience with patients in their 30s and 40s,” he said.
False assurances, gaslighting
Al-Aly and others worry that the study’s faulty conclusions could jeopardize the care and mental health of people with serious long-term symptoms as well as lull people into not taking precautions because they think long COVID can’t be a serious and disabling illness.
I believe the optimistic outlook was colored by the very young age of the cohort (mean of 25), and the results do not conform with my experience with patients in their 30s and 40s. Eric Topol, MD
Wachter said the study authors appear at times to minimize the effects of long COVID. “In some ways, they editorialize and say these are mild effects,” he said. “Well, they’re not massive, but when you talk about this many patients and if the chances of being short of breath or having abnormal taste or smell or having weakness or palpitations has a risk ratio of 1 to 2, that’s not nothing,” he said.
Wachter said that when people ask him why he still takes precautions after receiving five COVID-19 vaccine doses, he says it isn’t so much because of fear of the initial infection: “If you tell me I’ll have a 20% higher chance of being short of breath or not have a sense of smell or taste or of still being fatigued a year from now, I still don’t want to get it.”
When you talk about this many patients and if the chances of being short of breath or having abnormal taste or smell or having weakness or palpitations has a risk ratio of 1 to 2, that’s not nothing. Robert Wachter, MD.
Al-Aly worries that long-COVID patients, many of whom have reported struggling to get healthcare providers to take their symptoms seriously, may suffer from this study’s conclusions.
“My main worry is that this provides a false assurance, that long COVID is a nothing burger and will resolve after a year” he said. “It may further fuel the gaslighting that people with long COVID experience, the ‘it’s all in your head.’
“The broader effect may be false assurance to the broader country to policymakers, providers, and patients that this isn’t the big problem you think it is.