Long COVID After Mild Infection: Most Symptoms Resolve After 1 Year, Finds Large Israeli Study

Although individuals who have had mild COVID-19 infection appear to be at significant risk for post-acute sequelae of SARS-CoV-2, or long COVID, the symptoms, including anosmia, cognitive impairment, dyspnea, weakness, and palpitations, tend to resolve within a year from diagnosis and risk for chronic outcomes is low, according to new data from a team of Israeli investigators.

A retrospective nationwide study of persons who tested positive for SARS-CoV-2 between March 1, 2020, and October 1, 2021, also found that persons who had a mild case experienced a narrower spectrum of long COVID symptoms, that sex had only a minor effect on risk of outcomes, and that findings were consistent across SARS-CoV-2 variants.

The presentation of acute SARS-CoV-2 infection is diverse, the authors write, ranging from asymptomatic to severe and life threatening. Average time to recovery is from 2 to 4 weeks after symptoms initially appear but the body of evidence supporting serious chronic sequelae continues to expand.

The study investigators, led by Shira Greenfeld, MD, of Maccabi Healthcare Serivces, Tel Aviv, Israel, also point out that the majority of the 500 million persons who have been infected with SARS-CoV-2 worldwide experience mild disease. To better understand long COVID risk, the team sought to characterize clinical sequelae of mild COVID-19 during 1 year following infection and to assess the association of symptoms with age, sex, SARS-CoV-2 variant infection, and vaccination status.

Greenfeld and colleagues tapped electronic health records from the nationwide database of Maccabi Healthcare Services, the second-largest health maintenance organization in Israel, comprising nearly 2 million citizens.

Complete data were available for 299 855 individuals (median age 25 years, half women), who tested positive for COVID-19 between March 1, 2020, and Oct 1, 2021, and had not been hospitalized within a month of their diagnosis.

The primary outcome measure of interest was the risk of 70 documented long COVID outcomes among unvaccinated patients infected with SARS-CoV-2 who were matched to uninfected controls, with risk adjusted for participant age and sex, and stratified by SARS-CoV-2 variant. Additional analyses were performed for the risk of long COVID outcomes among vaccinated patients who experienced a breakthrough infection compared to unvaccinated, infected controls.

FINDINGS

Overall investigators found that the following COVID-19 outcomes were significantly associated with both the early (30-180 days) and late (180-360 days) time periods after infection:

• Anosmia and dysgeusia (HR, 4.59; 95% CI, 3.63 – 5.8)
• Cognitive impairment (HR, 1.85; 95% CI, 1.58 – 2.17)
• Dyspnea (HR, 1.79; 95% CI, 1.68 – 1.90)
• Weakness (HR, 1.78; 95% CI, 1.69 – 1.88)
• Palpitations (HR, 1.49; 95% CI, 1.35 – 1.64)

Risk for hair loss, chest pain, cough, myalgia, and respiratory disorders were significantly increased during the early period of mild COVID-19 infection but not in the later period.

Investigators noted minor differences in long COVID outcomes among men and women and a decreased risk of negative outcomes among children which when present were likely to resolve during the late period after infection.

Overall dyspnea was the most common symptom of long COVID in the first year after infection – present in 5 of the 6 age groups analyzed, including adults aged 19-40, 41-60, and >60 years.

Investigators observed the highest number of long COVID health outcomes that were significantly elevated in both early and late time periods among those aged 41 to 60 years. The risk for 5 outcomes in the subgroup aged 41-60 years remained significantly higher throughout the year after infection, but only dyspnea remained significantly higher in the late period in the oldest subpopulation of >60 years.

Vaccinated patients with a breakthrough SARS-CoV-2 infection were at significantly lower risk of prolonged dyspnea, but at similar risk for the other long COVID outcomes as unvaccinated, infected patients. The team observed consistent outcomes based on SARS-CoV-2 variant infection.

“Although the long COVID phenomenon has been feared and discussed since the beginning of the pandemic, we observed that most health outcomes arising after a mild disease course remained for several months and returned to normal within the first year,” they wrote.

“Importantly, the risk for lingering dyspnea was reduced in vaccinated patients with breakthrough infection compared with unvaccinated people, while risks of all other outcomes were comparable,” they added.

The team concluded that their nationwide cohort analysis suggests mild COVID-19 infection “does not lead to serious or chronic long-term morbidity in that vast majority of patients.”

Reference: Mizrahi B, Sudry T, Flaks-Manov N, et al. Long covid outcomes at one year after mild SARS-CoV-2 infection: nationwide cohort study. BMJ. 2023;380:e072529.