How common are post-acute sequelae of SARS-CoV-2 infection?

The coronavirus disease 2019 (COVID-19) pandemic has taken a heavy toll on human lives, with over two million casualties so far. Equally devastating has been its economic toll. Now, a new study, which was released on the medRxiv* preprint server, describes the features and frequency of long-haul symptoms in COVID-19.

Prolonged sequelae of COVID-19

The percentage of patients who suffer prolonged symptoms, also called post-acute sequelae of SARS-CoV-2 infection (PASC), is unclear. The most common symptoms include severe tiredness, shortness of breath (SOB), persistent anosmia and dysgeusia, and cognitive impairment. However, diagnostic criteria have not yet been developed, leading to prevalence estimates from 13% to 87%.

The first figure includes cases with symptoms persisting for four weeks or more from the time of diagnosis. The second comes from hospitalized patients who continue to have symptoms after 60 days from the onset of symptoms.

Other unknowns include the association between increasing age, female sex, severity of disease, the presence of specific comorbidities, and PASC.

The current study aims to address population-based estimates of PASC in Michigan, with its demographic and clinical risk factors.

Study details

The study subjects were in the Michigan COVID-19 Recovery Surveillance Study (MI CReSS). All had been diagnosed with COVID-19 following a positive polymerase chain reaction (PCR) test. The scientists sampled about 600 subjects with disease onset on or before April 15, 2020, as determined by the onset of symptoms, a positive PCR, or referral to the health department.

Over half the subjects were females, while almost 70% were aged 45 years or older. Almost half were non-Hispanic whites, and just over a third were Black.

Obesity was reported in over half, with 43% having high blood pressure, a quarter diabetes, 17% asthma, and just over a tenth cardiovascular disease.

About 40% had severe disease, while over a quarter had very severe illness. About a third had mild to moderate disease; a third required hospitalization, and a tenth intensive care.

What were the results?

Over half (53%) and one-third (35%) of patients had symptoms at 30 and 60 days post-onset, respectively. Older patients and those with more severe illness had a higher prevalence of PASC, but even those aged 18-34 years had significant prevalence, at 35% and 20%, after 30 and 60 days, respectively.

About a third and a quarter of patients with mild COVID-19 also had PASC at 30 and 60 days, respectively. Among non-hospitalized patients, the figures were 44% and 27%, respectively.

Among those with persistent symptoms by 60 days post-onset, over half had tiredness, and 44% reported SOB.

Risk factors for long-haul symptoms

In unadjusted models, advancing age, Hispanic ethnicity, and low annual household income (less than $75,000 a year) seemed to be associated with a higher prevalence of PASC at 30 and 60 days. For instance, subjects aged 55-64 years appeared to have twice the prevalence of PASC at 60 days compared to those aged 18-34 years.

When adjusted for demographic factors, other illnesses and the severity of illness, some of these apparent risk factors lost their significance. However, those with a psychological illness had a 42% higher prevalence at 60 days. In addition, those with a lower household income had a 40% higher risk at 30 days.

The most important risk factor was severity of illness. Those with very severe symptoms were 2.25 times more likely to have PASC at 30 days and 1.7 times more likely to have symptoms at 60 days, compared to those with mild symptoms.

Hospitalization conferred an increased risk of about 40% at 30 and 60 days. Among non-hospitalized patients, those with cardiovascular disease had a 54% higher prevalence of PASC at 30 days, though this was not obvious in the whole sample.

Among the non-hospitalized cohort, some substantial differences in 60-day PASC risk factors were observed. For one, psychological illness was not a risk factor at this point, but a history of chronic obstructive pulmonary disease (COPD) increased PASC prevalence. In addition, symptom severity was not a marker for the risk of PASC at this point.

What are the implications?

The study pioneers prevalence estimates among a geographically defined cohort, including all cases of COVID-19. Its finding of a 53% PASC prevalence at 30 days reflects the reported prevalence among Faroe Islanders at 125 days post-onset (in a non-hospitalized cohort).

However, the prevalence at 60 days in the current study is much lower, at 35%, perhaps because of the difference in the study cohorts.

Severity of illness was a major predictor of PASC risk. Surprisingly, a quarter of those with mild to moderate illness had a significant risk of such symptoms on day 60 post-onset.

Symptomatic but non-hospitalized cases also have a high risk of PASC at both 30 and 60 days. The higher risk among Black individuals would appear to be primarily because they are at higher risk of COVID-19 in the first place and not because they develop more severe disease. The higher rates of disease would drive a more adverse outcome overall.

Increased disease severity due to a higher viral load may drive the development of PASC. Individuals from low-income settings are more often exposed to a higher dose of the virus, as they are more likely to be essential workers who cannot work from home, live in crowded homes, use public transit, and often do not have access to suitable personal protective equipment. This could explain why these individuals are at a greater risk of PASC.

With increasing severity of illness, the patient is more likely to be experiencing dysregulated and severe inflammation. This prolongs the period of recovery and worsens the damage to various tissues and organs. The relationship between the viral load, the immune response, the severity of disease and the risk of PASC needs to be explored in greater detail.

COVID-19 continues to affect millions each day. “Although we are still attempting to control COVID-19 spread and treat acute illness, we cannot postpone developing robust efforts to characterize and treat PASC, which may potentially affect millions of COVID-19 survivors worldwide.”

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.