Long COVID: German Study Finds That Almost 50 Percent Of Recovered ‘Mild’ COVID-19 Patients Exhibit Persistent Chronic Fatigue For Six Months Or More

Long COVID: German researchers from Charité - Universitätsmedizin Berlin in a new study have found that almost 50% of ‘recovered’ COVID-19 patients exhibit moderate to severe chronic fatigue syndrome six months or more.


 
The study done at the Charité Fatigue Center with clinical immunologists and rheumatologist, neurologists and cardiologists at the Charité University hospital involved 42 patients who presented with persistent moderate to severe fatigue six months following a mostly mild SARS-CoV-2 infection at the Charité Fatigue Center from July to November 2020.
 
The primary outcomes were clinical and paraclinical data and meeting diagnostic criteria for Chronic Fatigue Syndrome (ME/CFS). Relevant neurological and cardiopulmonary morbidity was excluded.
 
The median age was 36.5, range 22–62, 29 patients were female and 13 male. At six months post-acute COVID-19 all patients had fatigue (Chalder Fatigue Score median 25 of 33, range 14–32), the most frequent other symptoms were post exertional malaise (n=41), cognitive symptoms (n=40), headache (n=38), and muscle pain (n=35). Most patients were moderately to severely impaired in daily live with a median Bell disability score of 50 (range 15–90) of 100 (healthy) and Short Form 36 (SF-36) physical function score of 63 (range 15-80) of 100. 19 of 42 patients fulfilled the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These patients reported more fatigue in the Chalder Fatigue Score (p=0.006), more stress intolerance (p=0.042) and more frequent and longer post exertional malaise (PEM) (p=0.003), and hypersensitivity to noise (p=0.029), light (p=0.0143) and temperature (p=0.024) compared to patients not meeting ME/CFS criteria. Handgrip force was diminished in most patients compared to healthy control values, and lower in CCS/CFS compared to non-CFS CCS (Fmax1 p=0.085, Fmax2, p=0.050, Fmean1 p=0.043, Fmean2 p=0.034, mean of 10 repeat handgrips, 29 female patients). Mannose-binding lectin (MBL) deficiency was observed frequently (22% of all patients) and elevated IL-8 levels were found in 43% of patients.
 
The study findings showed that chronic COVID-19 syndrome at months 6 is a multisymptomatic frequently debilitating disease fulfilling diagnostic criteria of ME/CFS in about half of the patients in the study.
 
The study findings are published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2021.02.06.21249256v1
 
Typically infection with SARS-CoV-2 is associated with a wide variety of symptoms, ranging from mild fever and cough to severe pulmonary and cardiovascular complications. Although almost 80% of coronavirus disease 2019 (COVID-19) patients remain asymptomatic or mildly symptomatic, a growing pool of evidence indicates that a significant fraction of COVID-19 patients present with persistent symptoms referred to as ‘long COVID’. Most commonly reported symptoms of long COVID are fatigue, cognitive impairment, and post-exertional malaise (worsening of symptoms after minor physical or mental exertion).
 
The study team investigated mild to moderate COVID-19 patients who presented with persistent fatigue and other related symptoms. The team also investigated whether these patients meet the diagnostic criteria for chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), which is a neurological disease characterized by severe mental and physical fatigue, chronic pain, and sleep disorder.
 
Altogether a total of 42 COVID-19 patients presented with moderate to severe intensity chronic fatigue, exertion intolerance, cognitive dysfunction, and pain six months after SARS-CoV-2 infection were investigated in the study.
 
All participants were diagnosed with mild to moderate COVID-19. A team of experienced clinical immunologists, rheumatologists, neurologists, and cardiologists was involved for an accurate diagnosis of ME/CFS in these patients based on the Canadian Consensus Criteria. The intensity and duration of post-exertional malaise (symptoms lasting for more than 14 hours) was considered to be the main diagnostic criterion for ME/CCFS.
 
Importantly of all enrolled patients, 32 had mild COVID-19 and 10 had moderate COVID-19 because of pneumonia. The numbers of male and female patients were 29 and 13, respectively, and the average age of the patients was 36 years (age range: 22 – 62 years).
 
It was also found that of 42 enrolled patients, 19 met the diagnostic criteria for ME/CFS and were found to have severe fatigue and functional impairment, severe stress intolerance, and hypersensitivity to noise, light, and temperature.
 
The study team categorized these patients as Chronic COVID-19 Syndrome/Chronic Fatigue Syndrome (CCS/CFS). The rest of the patients who were not diagnosed with ME/CFS mainly because of the relatively shorter duration of post-exertional malaise (2 – 10 hours) were referred to as CCS. The patients with ME/CFS showed significantly reduced hand grip strength than those without ME/CFS.
 
Interestingly after 6 months of SARS-CoV-2 infection, all participants were found to have fatigue with different intensities. The most commonly observed symptoms were post-exertional malaise, cognitive impairment, and muscle pain. Although patients without ME/CFS exhibited less severe symptoms, most of them had severely impaired daily life activities. The majority of enrolled patients (n=28) were either unable to work or required a reduced work schedule because of post-COVID-19 symptoms.
 
It was also noted that in the study cohort, autonomic dysfunction was observed in most of the patients, with no significant difference in symptom intensity between patients with and without ME/CFS. The increase in systolic and diastolic blood pressure at standing position was significantly lower in patients with ME/CFS than those without it. Among patients with ME/CFS, four were diagnosed with postural tachycardia syndrome.   
      
In terms of biochemical parameters, only two patients in the entire study cohort showed mildly elevated C-reactive protein levels, indicating the absence of robust inflammatory response. Almost 50% of patients showed increased levels of interleukin 8 (IL-8), which is a clinical feature of severe COVID-19 patients.
 
Also a low level of mannose-binding lectin was observed in 22% of patients, indicating impaired immune functioning. An indication of autoimmune disorder was noticed in the study cohort as elevated levels of antinuclear antibody were found in 3 ME/CFS patients and 6 non-ME/CFS patients.
 
Significantly the study reveals that even mildly affected COVID-19 patients can develop a severe chronic syndrome characterized by moderate to severe fatigue and exertion intolerance. Because most of the post-COVID symptoms considered in this study did not differ significantly between patients with and without ME/CFS, the scientists suggest that chronic COVID-19 syndrome is a more appropriate terminology than ME/CFS in defining long-term symptoms related to SARS-CoV-2 infection.
 
There is still no specific treatment for ME/CFS and the knowledge of pathomechanisms is fragmented due to little interest and research support. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1263-z
 
There is evidence of immune, autonomic and metabolic dysregulation in post-infectious ME/CFS. https://pubmed.ncbi.nlm.nih.gov/29635081/
 
In line with these data, most patients in our study presented with symptoms of autonomic dysfunction. COVID-19 results in a strong inflammatory response and there is evidence for autoimmunity triggered by COVID-19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296326/
 
There is no evidence for ongoing overt inflammation as only two of the patients had mildly elevated CrP. Almost half of the patients had, however, elevated IL-8 levels in erythrocytes. IL-8 was significantly increased in critical compared to non-critical acute COVID-19. https://www.nature.com/articles/s41586-020-2355-0
 
Elevated ANA antibodies in nine patients and the preponderance of females may indicate an autoimmune mechanism similar to ME/CFS triggered by other infections. MBL deficiency which has been implicated in susceptibility and course of viral infections was found more frequently in CCS/CFS in accordance with findings from a past study in ME/CFS. https://pubmed.ncbi.nlm.nih.gov/26429318/
 
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