“Long COVID” is Yet Ill-Defined but Worthy of Attention

Health Letter, July 2022

By Michael T. Abrams, M.P.H., Ph.D.

long-covid
Image: sulit.photos/Shutterstock.com

Over the last two years, more than 1 million persons in the U.S. have died from COVID-19, and over 6 million died internationally according to official numbers, though World Health Organization estimates place that global burden at nearly 15 million. That devastating fact alone should be enough to activate the world towards solutions, but unfortunately COVID-19 also can lead to serious, lingering effects lasting months to years in those who recover from the acute infection. The prevalence, duration and overall nature of extended illness related to COVID-19 infection are yet unclear and thus are areas of active research.

Long COVID, according to the U.S. Centers for Disease Control and Prevention (CDC), is a condition also referred to by several other names, including post-COVID conditions, long-haul COVID, post-acute COVID-19, post-acute sequelae of SARS CoV-2 infection, long-term effects of COVID and chronic COVID. As these names imply, long COVID’s defining characteristic is that it emerges or persists well after that infection has seemingly resolved. Experts have thus suggested that the diagnosis of long COVID should not be assigned until at least four weeks after the primary COVID infection has ended.

Symptoms of long COVID, including fatigue, difficulty breathing, trouble concentrating, gastrointestinal problems, and joint or muscle pain, may be persistent or wax and wane. Estimates of the proportion of people who have had COVID-19 and then experience some form of long COVID vary depending upon the population and post-infection time-points studied (see Table). The numbers in the table suggest that serious COVID-19 is quite likely (in more than 30% of hospitalized patients) to lead to long COVID at six months after infection but that long COVID is otherwise much less likely to occur as the months pass. Early studies further indicate that being unvaccinated, having underlying health conditions prior to COVID-19, and racial or ethnic discrimination all add to a person’s risk of long COVID.

Various Estimates of the Rates of Long COVID

Population Studied Post-infection Time-Points Studied Proportion With Some Form of Long COVID
All COVID-19 cases At least 3 months after infection 3%
All COVID-19 cases At least 1 month after infection 13%
Hospitalized for COVID-19 6 months after infection >30%

Source: U. S. Centers for Disease Control and Prevention

New evidence of long COVID’s occurrence

On May 24, 2022, the Morbidity and Mortality Weekly Report (MMWR) published a study that offers some specifics about the risk of long COVID conditions in the U.S., based on observing new medical problems appearing 30–365 days post-infection in an adult population of over 353,000 COVID-19 survivors compared with over 1.6 million non-infected patients. Inpatient, emergency department and outpatient electronic health records were used retrospectively to identify new post-COVID-19 conditions (26 considered in all) including heart, lung, kidney and neurologic disorders, as well as diabetes, fatigue and disturbances of taste and smell.

Overall, the researchers found the rate of any such new medical problems was 38% in the COVID-19 survivors and 16% in the comparison patients (which translates to an absolute increased risk attributable to COVID-19 of 22%). The most common problems were respiratory problems and musculoskeletal pain. In persons older than 65 years, all 26 conditions considered were significantly more common in COVID-19 survivors than in the comparison patients. In persons 18–64 years old, 22 of those 26 conditions occurred more frequently in the COVID-19–surviving population. Notably, three of the five examined markers of psychiatric (mental) health were not elevated in the 18–64-year-old group, including mood (for example, depression) and substance-related (abuse or dependence) disorders. Although this study is limited because it did not consider important factors such as vaccination status, age, gender, race and duration of symptoms, it nonetheless indicates that COVID-19 can lead to a myriad of post-infection problems, especially in the elderly.

On May 25, 2022, Nature Medicine published a study that assessed vaccination status as a risk factor for long COVID. This study used the U.S. Department of Veterans Affairs national health care database to identify nearly 34,000 fully vaccinated persons who thereafter experienced breakthrough COVID-19 infections and compared their post-infection experiences (30–180 days after) with those of just over 113,400 persons who were unvaccinated and became infected.

Among all COVID-19 infection cases studied, vaccination correlated with a 34% reduction in risk of death. Vaccination also appeared to reduce the risk of long COVID sequelae (problems) by 15%. Still, the research revealed that breakthrough infections, compared with the absence of any infection, increased the risk of death, as well as the array of long COVID sequelae similar to those considered in the previously described MMWR study.

Accordingly, the researchers concluded that although vaccination alone offers partial protection, it does not fully eliminate the risks posed by breakthrough COVID-19 infections. Two other useful findings also come from this Nature Medicine study. First, it found that hospitalization for COVID-19 increased the future risk of long COVID. Second, it found that hospitalization for seasonal influenza did not lead to similar challenges with recovery as those seen with breakthrough COVID-19 hospitalizations.

Central nervous system (CNS) symptoms of long COVID

CNS problems, especially those suggesting brain injury, are particularly concerning because such illnesses are uniquely disruptive to quality of life, and they are difficult to diagnose and treat.

One study published online on May 11, 2022, in the Journal of the American Medical Association Psychiatry reviewed electronic health records from England corresponding to over 8 million adults. With that data, the researchers identified over 32,500 persons who survived hospitalization for COVID-19 and compared their proportion of new-onset neuropsychiatric conditions (anxiety, dementia, psychosis, depression and bipolar) to that of over 16,600 individuals who survived a hospitalization related to another severe acute respiratory infection (SARI).

Both the COVID-19 and SARI groups demonstrated significantly elevated risk of all such neuropsychiatric conditions, which overall were rare. For example, post-COVID-19 anxiety was observed in less than 1% of the cases studied over the 12 months following their infections.

A separate magnetic resonance imaging (MRI) study found evidence that COVID-19 infection correlates with certain lingering changes to brain structure that are discernible even in patients who experienced relatively mild infections. That study, published on March 7, 2022, in the journal Nature, used a database of brain scans maintained by researchers in the United Kingdom to construct a cohort of adults aged 51–81 years who received two MRI brain scans an average of 38 months apart. Retrospectively, the researchers identified 401 cases who tested positive for SARS-CoV-2 (the virus that causes COVID-19) between their two scans, with an average of 141 days separating their positive test and their second scan. They also identified 384 well-matched controls who received two similar scans but who did not become infected with SARS-CoV-2.

Computer-based measurements of global and regional brain structures, including some indicators of tissue damage, revealed statistically significant changes in the SARS-CoV-2–positive patients that distinguished them from their controls. For example, and most notably, the SARS-CoV-2 patients showed greater changes marking tissue damage in brain areas functionally connected to the primary olfactory cortex (the neurons responsible for the perception of smell). Additionally, brain-volume-to-skull-volume ratios decreased in the SARS-CoV-2 cases more than in the controls by an estimated average of 0.3%. Moreover, one simple cognitive test showed that SARS-CoV-2–positive subjects needed significantly more time to complete a paper-and-pencil challenge requiring them to connect a scattered trail of numbers and letters, known as the “trails B” test.

These findings remained even when 15 hospitalized COVID-19 cases (presumably the most severe cases) were removed from the MRI and trails B analyses. The researchers noted that additional studies are needed to determine whether such brain and cognitive performance changes are persistent or reversible.

Inchoate conclusions about long COVID

There is presently no single test for diagnosing long COVID. Still, recent analyses indicate that long COVID is a real and somewhat distinctive set of consequences of COVID-19 infection, which may impart a variety of health challenges. The most common problems observed in long COVID are those concerning smell and taste, lung ailments, musculoskeletal pain and fatigue.

Vaccination before COVID-19 infection offers substantial but incomplete protection. The precise clinical presentation and course — especially the duration of long COVID symptoms — remains uncertain. Accordingly, studies are currently underway to ascertain the long-term details of COVID-19 recovery.

In the meantime, persons concerned that they may have long COVID should consult with a doctor for proper diagnosis and treatment. Here’s a link to tips from the CDC to help prepare for that important medical interaction.