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Long-COVID Disease or Long-COVID Syndrome?

Defining Long COVID

What does long COVID mean? In an all-encompassing fashion, it refers to any symptoms following a SARS-CoV-2 infection that persist for an extended time. It is not uncommon for symptoms to persist after an infection. Long COVID is a new term, introduced by patients, to account for multiple symptoms that last months and interfere with daily life, yet have no clear medical explanation.

Initially, definitions of long COVID were based primarily on the duration of symptoms, with symptoms lasting for more than three months considered unusual. Since most individuals with SARS-CoV-2 infection recover completely within three months, we adopted the time frame for long COVID to include symptoms that last more than three months [1]. Subsequent case definitions included the most prominent lingering symptoms. Fatigue, shortness of breath (dyspnea), musculoskeletal pain, cognitive disturbances, sleep and mood disturbances, and headaches are the most common persistent symptoms; we included these symptoms in our long-COVID definition (Table 1.1).

What has made long COVID so important and controversial is how these characteristic symptoms persisted long after all signs of the initial infection disappeared. The National Institutes of Health (NIH) suggested the term, post-acute sequelae of SARS-Cov-2 (PASC) and defined post-acute symptoms as those that develop during or after COVID-19 infection that cannot be attributed to an alternative diagnosis. The National Institute for Health and Care Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN), and Royal College of General Physicians termed the symptoms post-COVID syndrome, defined as, "Signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis. It usually presents with clusters of symptoms, often overlapping, which can fluctuate and change over time and can affect any system in the body. Post-COVID-19 syndrome may be considered before 12 weeks while the possibility of an alternative underlying disease is also being assessed." [1, 2].

Table 1.1 Our definition of long COVID.

How do we define the absence of an underlying disease? For patients admitted to an intensive care unit (ICU) with severe COVID, these persistent symptoms align with a phenomenon often called post-ICU syndrome. Dr. Anthony David, Professor at the Institute of Mental Health, University College, London, stated in December 2021, "If a patient recovers from the acute respiratory illness, but remains short of breath and is found to have pulmonary fibrosis or pericarditis by accepted criteria, or, experiences brain fog and mental slowing, later linked to microvascular infarcts on magnetic resonance imaging (MRI)-can they be removed from the post-COVID-19 cohort? I would say yes. Their condition may be unusual, and it may be serious, but it is not mysterious. These conditions add to the tally of morbidity caused by COVID-19, but not to post-COVID-19 syndrome [3]." For those patients with organ damage during the initial infection, we will use the term long-COVID disease. When the persistent symptoms following a SARS-Cov-2 infection remain unexplained we use the term long-COVID syndrome.

Long-COVID Disease or Syndrome?

We believe that it is essential to recognize that long COVID is a disease in some situations whereas in others it is a syndrome. Disease is defined by organ damage, such as when a biopsy reveals cancer. A disease is characterized by its symptoms, such as pain or exhaustion, as well as physical signs, such as fever or swelling. In contrast, the term syndrome is applied to a medical disorder without obvious organ damage. Syndromes are diagnosed based solely by their symptoms. A syndrome is like a temporary placeholder for an illness, that may graduate to the more objective realm of a disease. Oftentimes, diseases originally considered syndromes were found to have a specific cause and/or organ damage/dysfunction, which lead to their recategorization as diseases.

Many patients have clinical evidence of organ damage during acute COVID infection. Their long-COVID symptoms follow the script of other severe, infectious diseases. The persistent symptoms correlate with the severity and duration of the acute infection. Almost all hospitalized patients have lung disease, and their persistent shortness of breath is the result of organ damage that may or may not be reversible. There is nothing mysterious about their long-lasting dyspnea and it can be measured by objective pulmonary abnormalities, such as pulmonary function tests and lung imaging. This is long-COVID disease.

However, other patients with persistent symptoms after a COVID-19 infection lack obvious organ damage and the underlying pathophysiologic mechanisms are unclear. Their physical examination, blood tests, X-rays, and imaging studies are normal. Syndromes are characterized by symptoms that involve many systems (multisystemic), occur together (cluster) and fluctuate in severity. These patients should be diagnosed with long-COVID syndrome, distinct from those patients suffering from well-described disease pathology.

To illustrate these differences, we will present two cases, one that we identify as long-COVID disease and the second, long-COVID syndrome.

Case 1. James, a 62-year-old man, was admitted to the hospital on June 1, 2020, because of increasing shortness of breath. His past medical history included adult-onset diabetes and obesity. He had experienced a cough and low-grade fever for three days, and a nasal swab tested positive for SARS-CoV-2 by polymerase chain reaction (PCR) the day before admission. Upon admission, he had a fever of 103° and was breathing rapidly. His initial chest X-ray demonstrated ground-glass opacities in both lungs and his oxygen saturation was 88%, normal oxygen saturation is greater than 94%. Over the first 48?hours, his breathing worsened despite nasal oxygen and prone positioning. He was transferred to the ICU where he was intubated and sedated as needed for mechanical ventilation. His treatment included corticosteroids and monoclonal antibodies in addition to the mechanical ventilation. After two weeks, the breathing tube was disconnected, and he was transferred from the ICU to a rehabilitation unit where he spent the next four weeks. In the rehabilitation unit, he needed a wheelchair at first, then graduated to a walker, but he was still profoundly weak. He described a constant worry about himself and his family, feeling "like being in a dark tunnel, trapped, and alone. I haven't seen my wife and children for more than a month, except on Zoom calls."

When James finally returned home, he was unable to stand without assistance and could only walk one block. He had lost 40 pounds. A repeat chest X-ray, taken one month after discharge, revealed scarring consistent with pulmonary fibrosis. Over the next six?months, he continued to have shortness of breath with minimal activity despite an intensive course of pulmonary and occupational rehabilitation. Gradually, his ability to take care of himself and his pulmonary function tests improved slightly. One year after his hospitalization he said, "I'm still quickly exhausted. Even having my grandchildren over for a few hours is so draining. I worry that I will never get back to the way I was."

Case 2. Sarah, a 48-year-old female, began having symptoms that she suspected were related to a COVID-19 infection in March of 2020. She had been in good health with no chronic medical problems other than a long history of migraine headaches. Her acute symptoms included a low-grade fever, cough, headaches, and generalized muscle aches. Coronavirus testing was not yet widely available, but her primary care physician told her that she likely had COVID-19 and told her to self-quarantine for two weeks. Gradually, she felt better and returned to work as a nurse's aide but almost immediately stopped working, because "I was completely exhausted, mentally and physically. I was unable to do the simplest tasks. My heart kept racing and each time I tried to take a short walk, I had to stop and catch my breath. I found myself falling asleep throughout the day but then unable to sleep at night. The worst is this brain fog. I can't focus or concentrate on anything." Her primary care doctor examined her, ordered a chest X-ray and blood tests, but found no abnormalities. During the next few months, she saw a cardiologist, neurologist, and pulmonologist. A...