Long Covid/Long Haulers: Symptoms, Solutions and ME/CFS
As we go into the second year of the COVID pandemic, we are starting to get increasing data on patients who recover slowly from COVID; a syndrome known as “Long Covid” or “Long Haulers.” We estimate that 1 in 10 people with COVID will have prolonged symptoms that continue more than 6 months, often fighting symptoms well recognized by patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). Based on recent CDC estimates of 25% of the US population having had COVID, this could mean that more than 9 million Americans could face Long Covid type of symptoms.
What type of symptoms are being experienced?
The largest study published on Long Covid was published in the Lancet in January 2021. It was a follow-up study of 1773 patients who were hospitalized in Wuhan, China, the initial center of the outbreak looking at symptoms after 6 months. The study looked at hospitalized patients so the percentage of symptoms in these patients is likely higher than patients who are not hospitalized. The study found the following:
- 76% of patients had at least 1 symptom 6 months after symptom onset with a higher proportion in women
- 63% had fatigue or muscle weakness
- 26% had sleep difficulties
- 23% had anxiety or depression
- Patients with more severe disease had a high percentage of pulmonary diffusion abnormalities
A different type of study was pre-published in December 2020 in MedRxiv which utilized patient-driven research and online surveys of 257 questions. Because of the nature of the study, only 27% of the patients had a laboratory-confirmed diagnosis of COVID-19. It gives us a sense of what patients who are self-identifying with “Long-Covid” are experiencing.
- 57% of respondents did not seek hospital care
- 79% of respondents were women
- >30% of patients had symptoms after 6 months; the major symptoms included
- Fatigue (~80%)
- Post-exertional Malaise (~74%)
- Brain Fog (~58%)
- Headache (~54%)
- Memory issues (~52%)
- Insomnia (~44%)
- Myalgias (~42%)
- Palpitations (~42%)
- Shortness of breath (~40%)
- Dizziness (~36%)
- Speech issues (~34%)
- Joint Pain (~34%)
- Chest pain, tachycardia (~34%)
- Other sleeping issues (~32%)
Many of the underlying mechanisms are similar to other fatiguing illnesses
The global research community has been focusing on delineating the pathways that go awry in Long Covid. Many of these mechanisms are similar to what has been found in ME / CFS patients. The earlier research in ME/CFS demonstrated a high proportion (77%) of patients that reported acute infection at the onset of ME/CFS that supports the belief that an acute infection triggers ME/CFS in the majority of patients. In a recent review of pre- ME/CFS onset events, patients reported the most frequent infection-related episodes (64%) as opposed to stressful incidents (34%) or exposure to environmental toxins (20%) as a trigger to the onset of their symptoms.
These pathways include the following:
- Neurotropism and neuroinflammation – Covid-19 directly infects neurons using multiple pathways including the olfactory nerve / bulb as a pathway into the brain (a pathway also utilized by mold), and the angiotensin-converting enzyme receptor (ACE-2). While imaging studies have not yet been done, it is very likely that activation of the inflammatory pathways leads to neuroinflammation.
- Inflammation — A major feature of the reason Covid patients are usually hospitalized is a massive increase of pro-inflammatory factors often described as a cytokine storm. Cytokines that are disturbed in the early storm include high bradykinins, interleukin 6, cardiac reactive protein, and tumor necrosis factor alpha. Transcriptomics studies have shown that after 60 days, there are different metabolic and inflammation-related signatures, including those characteristic of oxidative phosphorylation, reactive oxygen species generation, and heme metabolism.
- Immune abnormalities – Patients who tend to be hospitalized have delayed response of the adaptive immune system. In most hospitalized patients CD4 T cell subsets were reduced, as were many CD8 T cell subsets. In a subset of these patients, the immune dysregulation does not fully recover and this may be connected to the metabolic abnormalities.
- Autoimmunity – A group at Rockefeller University in New York City reported that more than 10% of 987 individuals with severe Covid-19 had antibodies that blocked the action of interferon molecules. Surprisingly, these antibodies were present in people before the Covid infection. There have been a wide range of autoantibodies found in patients including antibodies to phospholipids (which can create clotting problems) and antibodies to annexin A2 (which can create pulmonary problems). Iwasaki used a new technique to broadly look for antibodies and found that patients with severe Covid-19 had elevated antibodies directed at many tissues including the immune system, the brain and blood vessel linings. The spotlight on antibodies is bringing up an association well known in the fatiguing illness community which is that infections are associated with autoimmunity.
Funding for additional research has been approved
In December signed legislation, $1.15 billion was approved for the Office of the Director at the National Institutes of Health to fund long-COVID and ME/CFS research and clinical trials over the next 3 years. For comparison, the estimated NIH spend on research for ME/CFS in 2017 was $15 million despite the estimated direct and indirect costs of ME/CFS to society of $17-24 billion. Patients with ME/CFS suffer from worse functional impairment compared to cancer, diabetes, heart disease, lung disease, multiple sclerosis, and rheumatoid arthritis.
What can be done now?
What should a patient do if they suspect they have Long Covid? The most important thing is to see a clinician who has experience and capabilities in fatiguing illnesses. While there is no FDA approved treatment it does not mean that healing cannot occur with the assistance of appropriate care. There is a great deal that can be learned from the experience of ME/CFS patients in the treatment of Long Covid. For example, many patients with post-exertional malaise, cannot recover properly likely due to problems with their mitochondrial metabolism. Over-exertion can lead to “crashing” and can cause real harm to patients. A precise assessment is important to understand and treat physiologic disturbances. While there is no one “signature” diagnostic test in ME/CFS there are multiple objective measures of dysfunction. For example, autonomic dysfunction and POTS can be readily measured with the NASA lean test and can be treated with improvement of symptoms.
- Huang et al. 6 month consequences of Covid-19 in patients discharged from hospital: a cohort study. Lancet January 2021. https://doi.org/10.1016/50140-6736(20)32656-8.
- David et al. Characterizing Long Covid in an International Cohort: 7 months of symptoms and their impact: MedRxiv https://doi.org/10.1101/2020.12.24.20248802
- Tremblay M, Madore C et al. Neuropathobiology of Covid 19: The role for Glia. Front. Cell. Neurosci., 11 November 2020. https://doi.org/10.3389/fncel.2020.592214
- Bergamaschi et al. Early immune pathology and persistent dysregulation characterize severe Covid-19. MedRxiv preprint. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3757074
- Wang et al. Diverse Functional Autoantibodies in Patients with Covid 19. https://doi.org/10.1101/2020.12.10.20247205
- Naess H, Sundal E, Myhr K-M, Nyland HI. Postinfectious and chronic fatigue syndromes: clinical experience from a tertiary referral center in Norway. In Vivo. 2010;24(2):185-188. http://iv.iiarjournals.org/content/24/2/185.long
- Lyons D, Frampton M, Naqvi S, Donohoe D, Adams G, Glynn K. Fallout from the COVID-19 pandemic – should we prepare for a tsunami of post-viral depression? [published online ahead of print, 2020 May 15]. Ir J Psychol Med. 2020;1-6. https://doi:10.1017/ipm.2020.40