Even mild COVID-19 cases can trigger lingering symptoms, especially in women and younger adults, while severe cases show a strong link to long-term fatigue, brain fog, and joint pain, setting COVID-19 apart from other respiratory infections. Study: Risk of post-acute symptoms among adults: A comparison study of severe COVID-19, pneumonia, and influenza. Image Credit: Lightspring / Shutterstock In a recent study published in the journal PLOS One, researchers at the University of Texas Southwestern Medical Center, USA, assessed the associations between the severity of coronavirus disease 2019 (COVID-19) and the risk of post-acute symptoms. Among symptomatic COVID-19 patients, nearly two-thirds regain their usual health status within one or two months, while others experience protracted recoveries. According to the United States Centers for Disease Control and Prevention, long COVID is defined as sequelae that persist for at least three months following the initial infection. However, other studies suggest post-acute COVID-19 as symptoms lasting up to 120 days after recovery. Further, while long COVID is more likely in subjects who had the most severe initial disease, individuals with mild initial disease also develop symptoms. Some studies have observed differences in long-term sequelae between COVID-19 and influenza. Moreover, while post-acute COVID-19 has been repeatedly studied, few studies have focused on the nuanced delineations of acute disease severity or compared it to other infectious respiratory diseases. About the study In the present study, researchers examined the risk of post-acute COVID-19 across severity levels of initial illness among US adults. They extracted data from the Clinformatics Data Mart database. Eligible subjects were aged ≥ 18 years and had clinically diagnosed or lab-confirmed COVID-19 in 2020, with continuous inclusion in the database from January to December 2020, and reported symptoms at diagnosis. Characteristics of disease cohorts. Similar criteria were used for individuals with influenza during the 2018–19 influenza season. Moreover, another cohort was created for subjects diagnosed with pneumonia in 2018. The primary outcome was the presence or absence of symptoms four weeks, three months, and six months after COVID-19 diagnosis. The following symptoms were considered: fatigue, cough, dyspnea, anosmia, ageusia, arrhythmias, brain fog, insomnia, joint pain, general pain, muscle weakness, and headache. Potential predictors of symptoms were gender, ethnicity/race, age, US region, and comorbidities (hypertension, diabetes, obesity, dementia, asthma, rheumatoid arthritis, chronic obstructive pulmonary disease [COPD], chronic renal disease, and ischemic heart disease). The disease severity index was adapted from the World Health Organization. The 10-point severity index was modified, and only six levels were considered. These were severity level 3 (symptomatic but ambulatory), 4 (symptomatic with emergency department visit), 5 (hospitalized), 6 (hospitalized and required supplemental oxygen), 7 (hospitalized and required mechanical ventilation), and 8 (hospitalized and required mechanical ventilation plus renal dialysis or extracorporeal membrane oxygenation). Logistic regression models examined the relationship between post-acute symptoms and the infectious agent. Presence of symptoms by cohort over time. Findings The COVID-19, flu, and pneumonia cohorts included 121,205, 20,844, and 29,052 subjects, respectively. Across cohorts, the most common gender was female, the race was non-Hispanic White, and the US region was the South. Consistent with other studies, females were found to be more likely to develop post-acute symptoms. The most common comorbidity across cohorts was hypertension. Notably, the flu cohort had the lowest frequencies of all comorbidities, except for asthma, and the pneumonia cohort exhibited higher frequencies, except for obesity. Interestingly, while racial and ethnic minorities often face higher risks for acute COVID-19, this study observed mild reductions in adjusted post-acute risks among non-Hispanic Black and Hispanic individuals within this insured population. An unexpected finding was a regional difference, with patients in the Northeast showing the greatest risk of post-acute symptoms. In the COVID-19 cohort, fatigue, dyspnea, and joint pain were the most common symptoms after four weeks. In the flu cohort, joint pain, fatigue, and cough were the most common after four weeks, while dyspnea, fatigue, and cough were the most common for pneumonia subjects. In the COVID-19 cohort, the odds of any symptom after four weeks were 1.12 for severity level 5, 1.16 for level 6, 1.46 for level 7, and 2.64 for level 8 compared to severity level 3. While symptoms tended to decrease over time, they persisted across all severity levels at three and six months, although the increased odds of having symptoms remained highest for the most severe initial cases (levels 7 and 8) compared to the least severe (level 3). The specific symptoms experienced also varied by age, with younger adults having increased risks for anxiety and headache, while older adults had increased risks for brain fog and fatigue. The presence of a comorbidity increased the odds of post-acute symptoms at all time points. The comorbidities with the highest increase in odds were rheumatoid arthritis, asthma, and ischemic heart disease. Further, the odds of any symptom in the flu cohort compared to COVID-19 were 0.77 at four weeks and three months and 0.68 at six months. Conversely, the corresponding odds ratios for pneumonia subjects were 2.24, 2.41, and 2.46, at four weeks, three months, and six months, respectively. The most common symptoms after four weeks were fatigue in the COVID-19 cohort, dyspnea in the pneumonia cohort, and joint pain in the flu cohort. After six months, the most common symptoms were the same for the pneumonia and flu cohorts, but joint pain was the most common symptom in the COVID-19 cohort. The odds of any symptom, except for cough, were lower for the flu cohort than for COVID-19 subjects at all time points. Likewise, the odds of any symptom, except for headache and brain fog, were higher for the pneumonia cohort than the COVID-19 cohort at all time points. The odds of headache were lower in the pneumonia cohort than in the COVID-19 cohort. There were no differences in the odds of brain fog between the COVID-19 and pneumonia cohorts. Conclusions The findings corroborate prior observations that fatigue, dyspnea, and joint pain are the most common persistent symptoms after acute COVID-19. The highest risk of post-acute symptoms was found in people with rheumatoid arthritis, asthma, or ischemic heart disease. Symptoms observed four weeks after initial COVID-19 were likely to improve later. However, appreciable levels of symptoms lingered that correlated with the severity of the initial COVID-19 episode. Although individuals with less severe initial illnesses had a lower risk of persistent symptoms, the paper notes that, because their numbers are significantly larger than those of hospitalized patients, they contribute substantially to the overall population burden of post-acute COVID-19. The post-acute symptoms differed among the three diseases, likely reflecting the differences in their pathophysiology, comorbidity levels, and age distributions. Overall, COVID-19 symptomatology cannot be perfectly described by pneumonia or influenza symptomatology, and there are differences in symptom prevalence and the time to resolution that better characterize long COVID, indicating that this persistence is unique to COVID-19. The study acknowledges limitations, including its reliance on administrative health claims data from an insured population during the early phase of the pandemic, which may affect generalizability and requires careful interpretation.