Olivia Lee and Lawrence Robbins, MD
Over 325 million doses of COVID-19 vaccines have been distributed in the United States, and much of the country is looking forward to a return to normalcy. For many, the widespread access to vaccines signaled the pandemic’s defeat, but for millions of COVID-19 survivors, the sequelae following acute infection will trouble them long after the country has returned to its normal state of affairs.
Recent studies have reported that up to 30% of COVID-19 patients experience persistent symptoms in the months following acute illness.1 Lingering myalgias, joint pains, headaches, shortness of breath, fatigue, dizziness, cardiac issues, and brain fog are just some of the reported symptoms. These often continue long after the virus has been cleared from its host.2 Patients who experience lingering symptoms are collectively termed COVID-19 long-haulers, and diagnostic tests to quantify their disease status are being explored. Long haul COVID-19 has emerged as a growing challenge for physicians, who are working to identify effective treatment strategies for these chronic complications. This paper serves to briefly highlight diagnostic and therapeutic developments in the management of long haul COVID-19.
Demographics of Long Haul Covid Patients
Researchers have begun to establish a general profile of people with long hauling effects of COVID-19.. This may help identify those who are at the greatest risk for developing these chronic COVID-19 complications. Various studies have supported the notion that long haul COVID-19 disproportionately affects patients of older age, higher body mass index, female sex, or those with preexisting asthma.2,3 Female COVID-19 long-haulers are more likely than males to report anxiety, low mood, myalgia, fatigue, insomnia, and memory impairment.4
One study published in 2021 separated the most common symptoms into three “clusters” based on co-occurrence: Cluster A included myalgia and fatigue, Cluster B included low mood, anxiety, and sleep disturbance, and Cluster C included memory impairment, cognitive impairment, and attention deficit.4 Several reports indicate that the likelihood of experiencing these lingering symptoms may be independent from the severity of the acute COVID-19 infection. This suggests that the severity of the acute infection is not a reliable indicator of the risk for developing chronic complications.1,4
Currently there are no accepted diagnostic tests for long haul COVID-19. Diagnosing this condition is dependent upon the patient’s history.5 Many COVID-19 long-haul symptoms are nonspecific and could be attributed to other conditions. Long haul COVID-19 is a diagnosis of exclusion. Alternative explanations for a patient’s nonspecific symptoms must first be considered.
Some studies have identified pro-inflammatory markers as being associated with long term COVID-19 illness. Increased levels of pro-inflammatory markers found in long haul patients include CRP, TNF-alpha, IL-1α, IL-1β, IL-6, IL-17A, IL-18, MCP-1, natriuretic peptides, ferritin, troponin, and D-dimer. 2,5,6 These biomarkers are nonspecific and present in other inflammatory conditions. The inflammatory markers have to be interpreted with caution. There are several papers that describe a paucity of pro-inflammatory markers in suspected cases of long haul COVID-19.2 The reasons for these inconsistencies is unknown and warrants further analysis. Despite this conflicting information, it may still be worthwhile to examine pro-inflammatory markers in suspected long haul COVID-19 patients.5 While these markers do not definitively diagnose long haul Covid-19, they provide supporting evidence.
Additionally, the biopsychosocial impact of COVID-19 long haul symptoms is an important consideration. Experiencing brain fog, fatigue, anxiety, depression, and other symptoms will generate more anxiety and depression. The long haul syndrome sometimes resembles the post-traumatic syndromes observed following the Gulf War and 9/11.4 Thus, a psychological assessment may be indicated in evaluating cases of long haul COVID-19 to determine whether there are neuropsychiatric components that contribute.
Several medications are undergoing clinical trials for treating long haul COVID-19: C-C Chemokine Receptor Type 5, (CCR5) antagonists, antiparasitics, and monoclonal antibodies. Physicians at various treatment centers report repurposing medications (including maraviroc, ivermectin, and leronlimab) for treating COVID-19 long-haulers. They provide mixed accounts of the efficacy of these medications. Ivermectin, an antiparasitic medication, has demonstrated promising results in treating long haul COVID-19.7,8 Its clinical benefits in long-haulers may be attributed to its modulating effects on the immune system. Ivermectin’s suppression of IL-6 may be a key to its benefit.7
Psychotherapy may be helpful in dealing with the devastating consequences of COVID-19. Other avenues such as multi-disciplinary rehabilitation have demonstrated success in subsets of COVID-19 long-haulers. These interventions include stretching, light aerobic activity, breathing exercises, physical therapy, and behavior modification.2 These multi-disciplinary approaches are able to tailor the treatment plan to the individual. There are a growing number of clinics specializing in evaluating and treating long haul patients.
Vagus nerve stimulation, used for headaches, epilepsy, and depression, has recently been explored as a potential adjunctive therapy for long-haul COVID-19 9. There are reports of improvement in COVID-19 long-haulers undergoing non-invasive vagus nerve stimulation.10,11
Physicians are in the early stages of understanding how to effectively manage long haul COVID-19. Researchers have begun to characterize the profile of long-haulers. Clinical assessment currently depends primarily upon patient histories. Scientists and long haul COVID-19 treatment centers are conducting research into the immune status of long haulers. A vigorous autoimmune response seems to be the likely culprit for the majority of symptoms. Several pharmaceutical interventions are undergoing clinical trials, but there are no definitive results at this point. Many of the current recommendations are targeted towards symptom management. Over time recommendations for testing and therapy will emerge.
About the authors: Olivia Lee is a fourth year medical student at Des Moines University. Her clinical interests include the interface of psychiatry and neurology. Lawrence Robbins is an assistant professor of neurology, Chicago Medical School. He is in private (neurology and headache) practice in Riverwoods, Illinois. Lawrence has contributed to 380 articles/abstracts, and written 5 books (on headache). Address correspondence to Lawrence Robbins at email@example.com.
- Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in Adults at 6 Months after COVID-19 Infection. JAMA Netw Open. 2021;4(2). doi:10.1001/jamanetworkopen.2021.0830
- Yong SJ. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (London, England). 2021:1-18. doi:10.1080/23744235.2021.1924397
- Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long COVID. Nat Med. 2021;27(4):626-631. doi:10.1038/s41591-021-01292-y
- Sykes DL, Holdsworth L, Jawad N, Gunasekera P, Morice AH, Crooks MG. Post-COVID-19 Symptom Burden: What is Long-COVID and How Should We Manage It? Lung. 2021;199(2):113-119. doi:10.1007/s00408-021-00423-z
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- Xiao N, Nie M, Pang H, et al. Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications. doi:10.1038/s41467-021-21907-9
- Zaidi AK, Dehgani-Mobaraki P. The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article. J Antibiot (Tokyo). June 2021:1-13. doi:10.1038/s41429-021-00430-5
- Aguirre-Chang G, Castillo Saavedra E, Yui Cerna M, Trujillo Figueredo A, Cordova Masias J. Post-Acute or Prolonged Covid-19 : Treatment With Ivermectin for Patients With Persistent , or Post-Acute Symptoms. ResearchGate. https://www.researchgate.net/publication/344318845_post_acute_or_prolonged_COVID-19_ivermectin_treatment_for_patients_with_persistent_symptoms_or_post_acute. Published 2020. Accessed June 29, 2021.
- Azabou E, Bao G, Bounab R, Heming N, Annane D. Vagus Nerve Stimulation: A Potential Adjunct Therapy for COVID-19. Front Med. 2021;8:625836. doi:10.3389/fmed.2021.625836
- Silberstein S. Non-Invasive Vagus Nerve Stimulation May Treat Migraine in Patients with COVID-19, According to Neurologist Stephen D. Silberstein, M.D. | Business Wire. https://www.businesswire.com/news/home/20210216005737/en/. Published February 16, 2021. Accessed June 27, 2021.
- Lawson A. MUSC study to address post-COVID neurological and psychiatric symptoms using at-home format | MUSC | Charleston, SC. https://web.musc.edu/about/news-center/2020/11/16/musc-study-to-address-post-covid-neurological-and-psychiatric-symptoms-using-at-home-format. Published November 16, 2020. Accessed June 27, 2021.