Different Variants May Cause Different Long COVID Symptoms: Study

Becky McCall

March 25, 2022

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Long COVID symptoms may differ depending on which SARS-CoV-2 variant is behind a person' s infection, a new study shows.

The data from Italy compared long COVID symptoms reported by patients infected with SARS-CoV-2 from March to December 2020 (when the original, or "Wuhan," variant was dominant) with those reported by patients infected from January to April 2021 (B.1.1.7-, or Alpha variant-dominant). It showed a substantial change in the pattern of neurological and cognitive/emotional problems — the latter mostly seen with the Alpha variant.

Infectious disease specialist Michele Spinicci, MD, from the University of Florence and Careggi University Hospital, Italy, led the work. "Many of the symptoms reported in this study have been measured [before], but this is the first time they have been linked to different COVID-19 variants," he told Medscape Medical News. "Findings in patients with long COVID were focused on neurological and psychological difficulties."

However, he pointed out that much remains to be understood about long COVID in terms of symptoms, diagnosis, and treatment. 

"Long COVID is a huge area that involves many different fields of medicine so there is not one single piece of advice to give on management. There's lots to consider when evaluating a long COVID patient," he said.

Results showed that when the Alpha variant was the dominant variant, the prevalence of myalgia (10%), dyspnea (42%), brain fog/mental confusion (17%), and anxiety/depression (13%) significantly increased relative to the wild-type (original, Wuhan) variant, while anosmia (2%), dysgeusia (4%), and impaired hearing (1%) were less common.

When the wild-type (original, Wuhan) variant was dominant, fatigue (37%), insomnia (16%), dysgeusia (11%), and impaired hearing (5%) were all more common than with the Alpha variant. Dyspnea (33%), brain fog (10%), myalgia (4%), and anxiety/depression (6%) were less common. 

Overall, 76% of the patients in the trial reported at least one persistent symptom, while the most common reported symptoms were dyspnea (37%) and chronic fatigue (36%), followed by insomnia (16%), visual disorders (13%), and brain fog (13%).

The findings come from an early-release abstract that will be presented at the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) 2022, in Lisbon, Portugal, in a few weeks' time.

"The Take Home Point"  

Michael A. Horberg, MD, associate medical director, Kaiser Permanente - Mid-Atlantic Permanente Medical Group, Rockville, Maryland, has recently presented data on symptoms seen with long COVID in over 28,000 people, as reported by Medscape Medical News, at the Conference on Retroviruses and Opportunistic Infections 2022. These people were infected with the wild-type virus.

Commenting on the study by Spinicci, he said: "The issue is that as we go along the COVID lifespan from acute to long COVID, what prompts patients to seek medical attention may change. If symptoms are not severe or were not well publicized previously, patients may not see the need to seek care or evaluation. As such, it doesn't surprise me to find these changes over time, independent of any potential biological activity of the virus or its consequences."

Horberg noted that their own study results are consistent with those of Spinicci et al from March to December 2020 (original, Wuhan variant). "To me, the take home point is long COVID is real, and physicians need to be on the lookout for it. However, not all symptoms are due to long COVID, and we need to keep the time course of symptoms during evaluation of such patients."

Also providing comment on the findings was Debby Bogaert, MD, chair of Pediatric Medicine, University of Edinburgh, United Kingdom. Reflecting on whether the symptoms were due to long COVID or another underlying disease, she said: "the number of patients with ongoing symptoms is very high, therefore unlikely that all of this is re-emergence of underlying or previous health problems. The type of symptoms reported are also as reported by other cohorts, so not unexpected. And irrespective of the root cause, they require care."

Bogaert also noted that the data reiterate that COVID-19 is a new disease, and that "new variants might show shifting clinical pictures, not only regarding severity and symptoms of acute disease, but possibly also regarding sequela," and that this, "underlines the importance of ongoing surveillance of variants, and ongoing evaluation of the acute and long-term clinical picture accompanying these, to ensure we adapt our public health approaches, clinical treatment plans, and long-term follow up when and where needed."

Bogaert stressed that only by keeping track of the changes in symptoms both acute and long-term — by patients and doctors — would the best patient care be provided.

"Patients need to know so they can report these back to their doctors, and doctors need to know over time that the picture of sequela might shift, so sequela are recognized early, and these patients receive the appropriate follow-up treatment," she said. These shifting patterns might also apply to community patients as well as those hospitalized with COVID-19.

Study Details

The retrospective, observational study included 428 patients, 59% men, with a mean age of 64 years, who had been treated at the Careggi University Hospital's post-COVID outpatient service between June 2020 and June 2021, when the original form of SARS-CoV-2, and later the Alpha variant, were circulating, with some overlap.

All patients had been hospitalized with COVID-19 and discharged 4-12 weeks prior to attending the outpatient post-COVID service. They were asked to complete a questionnaire on persistent symptoms at the median of 53 days after being discharged from the hospital. In addition, data on medical history, microbiological and clinical COVID-19 course, self-reported symptoms (at the point of the follow-up visit), and patient demographics were obtained from electronic medical records.

Newer Variants Being Studied

Upon analysis of long COVID symptoms according to treatment given during the acute phase using multivariate analysis, increasing oxygen support (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1 - 1.8), use of immunosuppressant drugs (OR, 6.4; 95% CI, 1.5 - 28), and female sex (OR, 1.8; 95% CI, 1.1 - 2.9) were associated with a higher risk for long COVID symptoms, while patients with type 2 diabetes (OR, 0.4; 95% CI, 0.2 - 0.7) had a lower risk of developing long COVID symptoms.

When asked whether the increased anxiety and depression seen with the Alpha variant might be also linked to the fact that people are living through hard times, with lockdowns, economic difficulties, possible illness, and even fatalities among family and friends due to COVID, Spinicci pointed out that "it's a preliminary study and there are lots of factors that we didn't explore. It's difficult to arrive at definite conclusions about long COVID because so much remains unknown. There are lots of external and environmental factors in the general population that might contribute to these findings."

Spinicci has continued to enroll patients from later periods of the pandemic, including patients who were infected with the Delta and Omicron variants of SARS-CoV-2.

"We' re interested in finding out if these other variants are also associated with different phenotypes of long COVID. This study is part of our follow-up program here in the hospital where lots of different specialties are following patients for 20 months," he said.

Horberg noted that one criticism of this study is that it was unclear whether the researchers accounted for preexisting conditions. "They note the co-morbidities in the table 1, but don't say how they accounted for that in their analyses. We found a lot of what patients were calling 'long COVID' were exacerbations of co-morbidities but not a new condition." 

Spinicci and his coauthors acknowledged that the study was observational. And, as such, it does not prove cause and effect, and they could not confirm which variant of the virus caused the infection in different patients, which may limit the conclusions that can be drawn.

"Future research should focus on the potential impacts of variants of concern and vaccination status on ongoing symptoms," Spinicci said.

Early release of an abstract will be presented at the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) 2022, in Lisbon, Portugal, April 23-26, 2022. Abstract 02768.

Spinicci and Horberg have disclosed no relevant financial relationships. Bogaert declared she is on the program committee of ECCMID; she has been a member of SIGN/NICE  COVID-19 rapid guideline: managing the long-term effects of COVID-19; she is involved in multiple ongoing COVID-related studies, both acute and long-term sequela (funding MRC, CSO, ZonMw).

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