Definition

Even though the number of COVID-19 cases worldwide now approaches 30 million with almost 1 million dead (1), we are still amazed how little we know about this very complex disease. The clinical spectrum varies widely. Up to 40% of people infected with SARS-CoV-2 never develop symptoms. About 80% of those who do become symptomatic have a mild illness that does not require hospitalization; about 15% are sick enough to require hospitalization; but only 5% require care in an intensive care unit, usually for mechanical ventilation to treat respiratory insufficiency.

Early in the pandemic, many people believed that COVID-19 was a short-term illness. In February 2020, the World Health Organization, using preliminary data available at the time, reported the time from onset to clinical recovery for mild cases was approximately 2 weeks and that recovery took 3 to 6 weeks for patients with severe or critical disease (2). More recently, however, it has become clear that in some patients debilitating symptoms persist for weeks or even months. In some of these patients, symptoms have never gone away.

Many studies have documented lingering damage to many organs or systems, including lungs, heart, brain, kidneys, and vascular system, in patients infected with SARS-CoV-2. The damage seems to be caused by severe inflammatory responses, thrombotic microangiopathy, venous thromboembolism, and oxygen deprivation. Low blood oxygen saturation has been found even in asymptomatic and presymptomatic patients with COVID-19 pneumonia, where it has been called “silent hypoxia.” Organ damage has been documented to persist in the lungs, the heart, the brain, and the kidneys, even in some people who had only mild symptoms. The slow pace of recovery readily explains the duration of what has come to be called the “post-COVID syndrome.” Some people may also be suffering from post-intensive care syndrome, a group of symptoms that sometimes occur in people who were patients in an intensive care unit and that involves muscle weakness, balancing problems, cognitive decline, and mental health disturbances observed after discharge from critical care that usually involved a prolonged period of mechanical ventilation (3).

Persistence of symptoms also occurred after infection with another coronavirus, SARS-CoV-1, the virus that caused the severe acute respiratory syndrome (SARS) epidemic in 2002–2003. The persisting symptoms resemble chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Persistent fatigue, muscle pain, depression, and disrupted sleep prevented patients with SARS in Toronto, most of whom were healthcare workers, from returning to work for up to 20 months after infection (4). Forty percent of 233 survivors of SARS in Hong Kong were reported to have chronic fatigue after about 3 to 4 years, and 27% met the criteria outlined by the Centers for Disease Control and Prevention (CDC) for CFS/ME (5). Many remained unemployed and have experienced social stigmatization (5).

CFS/ME-like illness, in which some people get better quickly but others remain sick for prolonged periods, has followed many other infectious diseases. Examples include influenza, Epstein-Barr virus infection (infectious mononucleosis—6), brucellosis, Q fever (Coxiella burnetii infection—7), Ebola virus infection (8), and Ross River virus infection (9).

The persisting illness following COVID-19 also is said to resemble CFS/ME (10), and people with post-COVID-19 syndrome have given themselves the name “long-haulers.” However, there is no clear picture of what constitutes post-COVID-19 syndrome. Without a formally accepted definition of post COVID-19 syndrome, it is difficult to assess how common it is, how long it lasts, who’s at risk for it, what causes it, what its pathophysiology is, and how to treat and prevent it. But several studies are now beginning to define this group of patients.

The CDC conducted a multistate telephone survey in April and June 2020 of non-hospitalized adults who had a positive reverse transcription–polymerase chain (RT-PCR) test for SARS-CoV-2 infection (11). Respondents were asked about demographic characteristics, baseline chronic medical conditions, symptoms present at the time of testing, whether those symptoms had resolved by the interview date, and whether they had returned to their usual state of health at the time of interview. Of 274 respondents symptomatic at the time of PCR testing, about one third reported not having returned to their usual state of health when interviewed 2 to 3 weeks after testing. Of younger persons, aged 18 to 34 years, with no chronic medical conditions, 20% had not returned to their usual state of health. However, older age and presence of multiple chronic medical conditions were more commonly associated with prolonged illness, which was present in 26% of those aged 18 to 34 years, 32% of those aged 35 to 49 years, and 47% of those aged50 years or older. Fatigue (71%), cough (61%), and headache (61%) were the most frequently reported symptoms. These findings indicate that COVID-19 can result in prolonged illness even among people with milder outpatient illness, including young adults. This finding is particularly concerning as outbreaks are emerging on college campuses.

In another study in Rome, Italy of 143 patients (mean age 57 years) after about a 2-week-hospitalization for COVID-19, many patients still struggled with symptoms 60 days on average after onset of their illness; 87% still had at least one symptom, and 55% had 3 or more symptoms (12). Quality of life had worsened for 44%, with fatigue (53.1%), difficulty breathing (43%), joint pain, (27%) and chest pain (22%) persisting in many. None had fever or any signs or symptoms of acute illness.

Much information, however, that characterizes the post-COVID-19 syndrome’s demographics, time-course, and symptomatology has been generated and analyzed by long-haulers themselves who belong to the online Body Politic COVID-19 Support Group and who have expertise in research, survey design, and data analysis. The online survey they developed and targeted to those whose symptoms persisted for more than 2 weeks received 640 responses from April 21 to May 2, 2020 (13).

The respondents were predominately young (63% between the ages of 30 to 49 years), white (77%), and female (77%), and live in the United States (72%) or the U.K. (13%). Most were never hospitalized, or, if hospitalized, never admitted to an ICU or placed on a ventilator, so their cases technically counted as “mild.” Many were seen in an emergency department/urgent care facility but were not admitted. All respondents were included, regardless of SARS-CoV-2 RT-PCR testing status. In about 25%, the RT-PCR was positive; but almost 50% of participants never were tested because testing during those months (March and April 2020) was often limited to people hospitalized with severe respiratory problems, their symptoms were said to be “classic,” making testing unnecessary at a time when PCR testing kits were in short supply, or testing was denied because their symptoms did not match preset criteria.

Another 25% of respondents tested negative, but a negative result does not mean these people didn’t have COVID-19. Some negative tests were likely false-negative results, which occur up to 30 percent of the time (14). Others were tested relatively late in the course of their illness, at a time when virus may no longer be detectable (15). In the survey, respondents with negative RT-PCR test results were in fact tested a week later than those with positive test results.

The reported symptoms were diverse and spanned the respiratory tract, and the neurological, cardiovascular, gastrointestinal, and various other systems. The top 10 symptoms, reported by 70% or more respondents, included shortness of breath, tightness of the chest, fatigue, chills or sweats, body aches, dry cough, “elevated temperature” (98.8 to 100° F), headache, and brain fog/difficulty concentrating. Extreme fatigue to the point of preventing someone from getting out of bed, severe headache, fever (above 100.1° F), and loss of taste or smell were reported by 40 to 50% of respondents. Seventy percent (70%) experienced fluctuations in the type and 89% in the intensity of symptoms over the course of being symptomatic. Some patients noted that symptoms came back or intensified with physical activity or were strongest in the evening. About 70% had been physically fit before the onset of symptoms, but 70% reported being sedentary after the onset of symptoms.

About 10% of respondents had recovered in, on average, about 4 weeks. The 90% who had not recovered experienced symptoms for an average of 40 days. A large proportion of respondents experienced symptoms for 5 to 7 weeks. The chance of full recovery by day 50 was estimated to be smaller than 20%.

Results of surveys such as this, however, are subject to bias. Respondents to surveys might differ from non-respondents; for example, there might have been gender bias in that women might more likely join support groups and complete online surveys; patients with more severe illness might be unable to respond or be unable to recall events accurately. Online surveys may also be skewed toward more affluent, younger, and more computer savvy respondents and omit economically disadvantaged minorities, the homeless, those lacking broadband and computers, and those fearful of responding, such as undocumented migrants.

Since issuing their report, the Body Politic COVID-19 Support Group team has met with staff from the Centers for Disease Control and Prevention and the World Health Organization (16) and issued a second survey to fill in gaps in their first report; examine antibody testing results, neurological symptoms, and the role of mental health; and increase geographic and demographic diversity (17).

Many long-haulers report their persisting symptoms are being downplayed. They are told they are perhaps exaggerating, imagining, or even inventing their life-altering illness. Simple physical activities, like getting out of bed, grooming, preparing simple meals, and showering, can be exhausting for some. Being unable to care for themselves and their families, being unable to work, and losing income and possibly employer-based health insurance bring additional burdens. Healthcare planners and policy makers must prepare to meet the needs of the many people that have been affected by this illness and their families while ongoing studies investigate causes and ways to mitigate the post-COVID syndrome.