Severe fatigue common in COVID-19, independent of disease severity

Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection often complain of fatigue, but now a new study shows that it also causes severe and frequent fatigue in those who recover after mild illness too. The study, published on the preprint server medRxiv* in July 2020, reports a startling prevalence of fatigue in people who recovered from acute COVID-19 illness, even when they had only a mild illness.

Colorized scanning electron micrograph of a cell (blue) heavily infected with SARS-CoV-2 virus particles (red), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

Colorized scanning electron micrograph of a cell (blue) heavily infected with SARS-CoV-2 virus particles (red), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

Fatigue is the presenting symptom in many patients with COVID-19, ranging from 44% to 70% of cases. The extent and duration of this symptom remain an unknown area, mainly whether it represents a post-viral fatigue syndrome triggered by the virus.

A prior report dealing with the long-term sequelae of the earlier severe acute respiratory syndrome (SARS) outbreak reports that patients had long-term fatigue, muscle aches, weakness, and depression even at one year from acute infection, severe enough to hinder their return to work. Another study reported fatigue in patients assessed at 40 months from infection in over 40%. Similar findings were reported after the Middle East Respiratory Syndrome (MERS) at six months or more.

The same results are seen with other viral infections too, including Epstein-Barr Virus (EBV), Q-Fever, and Ross River Virus (RRV) infections. Many earlier studies have described these post-viral fatigue syndromes, especially regarding the immune changes.

Immunological Changes in COVID-19

The immunological changes seen in COVID-19 are well recognized, including lymphopenia, leukocytosis, and a higher proportion of neutrophils to lymphocytes. Severe COVID-19 is marked by higher levels of C-reactive protein, ferritin, and D-dimers (markers of tissue damage and coagulation dysregulation), and IL-6, among other inflammatory cytokines. Intermediate monocytes, a class of monocytes that is found in infection and inflammation, are also increased.

The Study: COVID-19 Patients and Fatigue

The current study by a team of Irish researchers was aimed at a prospective evaluation of patients who had COVID-19 and then recovered, to detect chronic fatigue symptoms after recovery. The researchers wanted to avoid multiple etiologies for the fatigue by using a single infection as the population characteristics, to allow greater accuracy of the syndrome description. The link, if any, between the fatigue and any particular characteristic of the infection, was sought, as also the uncovering of any persistent disease markers after the resolution of infection.

The study included 128 patients with a mean age of 50 years, of whom about 56% were hospitalized with COVID-19, and the rest were outpatients. Over half were healthcare workers, as is characteristic of Irish COVID-19 outbreaks. The median duration from discharge from hospital or diagnosis of outpatients to testing during the study was 72 days, at which point only 2 of 5 patients said they felt fully recovered. Of the 82% who were employed before the illness, about a third were still not back at work at the time of the study.

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The researchers used the Chalder Fatigue Scale (CFQ-11), along with clinical characteristics and blood tests, to arrive at their conclusions. The mean fatigue score was ~16, with the score for physical fatigue and psychological fatigue being 11 and ~5, respectively. Over half the patients were diagnosed with fatigue based on this score, and in this group, the mean score was 20.

High Prevalence of Post-COVID Fatigue

Thus, the current study shows that at ten weeks from infection (median 72 days), over half of the patients who had COVID-19 continue to experience severe fatigue. In other words, these patients who have been medically certified as fully recovered fail to experience good health.

Secondly, as a result of such fatigue, daily functioning is impaired, and over a third do not return to work even by 10 weeks. This goes against the recommendation that following a viral infection, the patient should return to work four weeks later to prevent loss of conditioning. Again, given the high percentage of healthcare workers affected, this kind of employee attrition will significantly hit healthcare systems.

A third observation is that post-COVID-19 fatigue is much more frequent than that reported after the infections mentioned above but at a level comparable to that of post-SARS fatigue. However, the levels of fatigue in this cohort, though more significant than the fatigue levels in the general population, and meeting the CFQ-11 criteria for fatigue, were lower than required for a diagnosis of chronic fatigue syndrome. The CFQ-11 scores were comparable to those found in patients diagnosed with CFS.

Such levels are more typical of those seen in chronic disease states, and this is a concerning observation since most of these patients were not, in fact, actively infected at the time of testing, nor did they have severe disease. This is a surprising finding, and the researchers comment, “Our findings would suggest that all patients diagnosed with SARS-CoV-2 will require screening for fatigue.”

Also, females seem to be at higher risk for the development of fatigue following COVID-19, as is the case with previous CFS studies. Patients with pre-existing depression and on anti-depressants are also at higher risk of severe fatigue. However, further research is needed to find out if depression develops after fatigue sets in post-COVID and to trace the course of fatigue over time.

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Inflammation Not Related to Fatigue

There was no relationship between the values recorded in six inflammatory/cell death parameters and the occurrence of fatigue or the total CFQ-11 score. In the same way, IL-6 levels were independent of fatigue diagnosis or the total score. On the other hand, over 85% of the study subjects had normal CRP and IL-6 levels. Another inflammatory cytokine, soluble CD25, was normal in 94% of cases.

Thus, the development of fatigue is not apparently the result of any specifically inflammatory pattern, as none was found in the test results. In previous studies, CFS has been linked to a lot of different alterations in inflammatory markers and the populations of various immune cell types. Still, none have been found to remain constant across many studies.

Multidisciplinary Interventions

The researchers rule out obvious associations of specific disease conditions with either CFS or post-COVID fatigue, instead saying, “CFS may be the endpoint of a variety of distinct pathways, or maybe the consequence of pathological changes that are no longer systemically detectable.” This is an important suggestion since it means that immunomodulation is not a valid strategy in treating these conditions.

Instead, non-pharmacological interventions are favored to counter the multiple factors, including depression, that are involved in its etiology. Such interventions include graduated physical exercise and cognitive behavioral therapy, as well as implementing suggestions from occupational health experts.

The short period between the diagnosis/discharge and the study is a significant limitation since other studies on fatigue take place six months or more after the viral illness, which is supposed to have precipitated it. The researchers recommend that follow-up studies be done to examine the health of patients over time, in larger groups, and using multidisciplinary modes of treatment to identify the most effective therapies.  

*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.

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