Biomarkers of Long Covid
About 7.5% of US adults, and nearly 20% of Americans who’ve been infected with COVID-19, suffer from “long Covid,” a condition characterized by fatigue, difficulty breathing, heart rhythm abnormalities, dizziness, and difficulty thinking or concentrating (“brain fog”) experienced months or even years after infection with COVID-19.1 The condition is a public health crisis, in large part because it is poorly understood and has only recently gained official recognition; the World Health Organization only established a clinical definition in October 2021,2 nearly eighteen months after the first “long haulers” started showing signs of long Covid. A key research priority is to better understand the full scope of long Covid symptoms, as well as to better predict who will develop long Covid – questions that may be partially answered by studying biomarkers.
To study a previously unknown condition, scientists often look for biomarkers, a substance in an organism that indicates the presence of an infection or other biological phenomenon. Researchers have recently found several biomarkers for long Covid, which may assist with diagnosis and ultimately treatment of the condition.
In March 2022, a team of scientists from UC San Francisco reported in a study that people experiencing long Covid contained SARS-CoV-2 viral proteins in their blood long after infection.3 They analyzed exosomes, protein-filled sacs released by cells into blood, from neurons and other brain cells called astrocytes. They found much higher levels of the viral nucleocapsid and spike protein in the exosomes of patients infected with COVID-19 as compared to uninfected controls. Additionally, long Covid patients with neuropsychiatric symptoms had higher levels of the viral proteins in the blood than long Covid patients lacking these symptoms. The UC San Francisco team also found that long Covid patients with neuropsychiatric symptoms had lower levels of certain mitochondrial proteins – SARS-CoV-2 is known to target the mitochondria and interfere with its normal functioning. Though the viral proteins are not themselves infectious, they may account for the physiological dysfunction present in long Covid patients.
In a more recent study, a team of Canadian researchers analyzed a different set of biomarkers to better understand long Covid.4 Because SARS-CoV-2 affects the vascular system, and it is suspected that long Covi may arise, at least in part, from vasculature dysfunction,5 Patel et al. analyzed vascular transformation blood biomarkers in long Covid patients. They found that fourteen of these biomarkers were significantly elevated in long Covid patients. One of these biomarkers, ANG-1, is a protein that is involved in angiogenesis, the creation of new blood vessels. Though it is not understood exactly how an increased rate of angiogenesis could induce long Covid symptoms, the authors of this paper conclude that angiogenesis is a promising target for therapeutics research.
Searching for long Covid biomarkers is especially critical because it may serve to distinguish the condition from other similar post-viral syndromes, like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is usually classified as fatigue that lasts longer than six months accompanied by pain and other symptoms worsened by exertion.6 None of the 14 long Covid biomarkers identified by Patel et al. are elevated to the same degree in ME/CFS, suggesting that long Covid is a biochemically distinct condition. These studies are the important first step in understanding the molecular basis of long Covid and developing therapeutics to treat this still-mysterious condition.
References
1. Nearly One in Five American Adults Who Have Had COVID-19 Still Have ‘Long COVID’. https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2022/20220622.htm (2022).
2. A clinical case definition of post COVID-19 condition by a Delphi consensus, 6 October 2021. https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1.
3. Peluso, M. J. et al. SARS-CoV-2 and Mitochondrial Proteins in Neural-Derived Exosomes of COVID-19. Ann. Neurol. 91, 772–781 (2022), DOI: 10.1002/ana.26350
4. Patel, M. A. et al. Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism. Mol. Med. 28, 122 (2022), DOI: 10.1186/s10020-022-00548-8.
5. Østergaard, L. SARS CoV-2 related microvascular damage and symptoms during and after COVID-19: Consequences of capillary transit-time changes, tissue hypoxia and inflammation. Physiol. Rep. 9, e14726 (2021), DOI: 10.14814/phy2.14726
6. What is ME/CFS? | Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | CDC. https://www.cdc.gov/me-cfs/about/index.html.