Orthostatic Intolerance in Long-Haul COVID after SARS-CoV-2: A Case-Control Comparison with Post-EBV and Insidious-Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Background: As complaints of long-haul COVID patients are similar to those of ME/CFS patients and as orthostatic intolerance (OI) plays an important role in the COVID infection symptomatology, we compared 14 long-haul COVID patients with 14 ME/CFS patients with a post-viral Ebstein-Barr (EBV) onset and 14 ME/CFS patients with an insidious onset of the disease.
Methods: In all patients, OI analysis by history taking and OI assessed during a tilt test, as well as cerebral blood flow measurements by extracranial Doppler, and cardiac index measurements by suprasternal Doppler during the tilt test were obtained in all patients.
Results: Except for disease duration no differences were found in clinical characteristics. The prevalence of POTS was higher in the long-haul patients (100%) than in post-EBV (43%) and in insidious-onset (50%) patients (p = 0.0002). No differences between the three groups were present in the prevalence of OI, heart rate and blood pressure changes, changes in cerebral blood flow or in cardiac index during the tilt test.
Conclusion: OI symptomatology and objective abnormalities of OI (abnormal cerebral blood flow and cardiac index reduction during tilt testing) are comparable to those in ME/CFS patients. It indicates that long-haul COVID is essentially the same disease as ME/CFS.
Source: van Campen CMC, Visser FC. Orthostatic Intolerance in Long-Haul COVID after SARS-CoV-2: A Case-Control Comparison with Post-EBV and Insidious-Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Healthcare. 2022; 10(10):2058. https://doi.org/10.3390/healthcare10102058 (Full text)

How “long covid” is shedding light on postviral syndromes

Long covid really shouldn’t have been a surprise, says Vett Lloyd, a biologist at Mount Allison University in Sackville, Canada. “When the pandemic started, the general assumption was that there were two possible outcomes to an infection—you’d either get better or die,” she says.

But there’s a possible third outcome. It’s long been known that a number of disease causing pathogens—some viral and some bacterial—are associated with ongoing post-infection symptoms in a significant minority of patients.

“There was no real reason to think SARS-CoV-2 should be any different than the original SARS, which also caused post-infection syndromes,” says Lloyd. She is one of many researchers who hope that the attention and funding directed towards long covid will help to shed light on how and why other infections can lead to persistent and sometimes debilitating symptoms.

Read the rest of this article HERE.

Source: Owens B. How “long covid” is shedding light on postviral syndromes BMJ 2022; 378 :o2188 doi:10.1136/bmj.o2188  https://www.bmj.com/content/378/bmj.o2188 (Full text)

Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies

Abstract:

Forty-four patients, including 26 adults and 18 children under 15 years of age, were referred for evaluation of recurrent or persistent illnesses, with symptoms including pharyngitis, lymphadenopathy, fever, headaches, arthralgia, fatigue, depression, dyslogia, and myalgia. Thirty-nine patients were positive for Epstein-Barr virus antibody with antibody levels compatible with active infection for at least 1 year. Antiviral capsid antigen and anti-early antigen titers of patients were significantly greater (p less than 0.001) than age-group-matched controls. The frequency, number, duration, and patterns of symptoms, as well as patient sex, were compared by age in study patients seropositive and seronegative for Epstein-Barr virus. Illness patterns were not associated with changes in specific antibody titers or clinical findings. Lymphocyte phenotype and function analyses were done in 11 of the 39 patients positive for Epstein-Barr virus antibody; no consistent differences from normal were found. Only 1 of 32 patients had circulating interferon, in contrast to 7 of 7 patients with acute infectious mononucleosis. There were many adverse consequences of the illness. Epstein-Barr virus infection may not be self-limiting, and the virus may be associated with clinically recognizable illness other than infectious mononucleosis in children as well as in adults.

Source:Jones JF, Ray CG, Minnich LL, Hicks MJ, Kibler R, Lucas DO. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies. Ann Intern Med. 1985 Jan;102(1):1-7. doi: 10.7326/0003-4819-102-1-. PMID: 2578266. https://pubmed.ncbi.nlm.nih.gov/2578266/

Post-infectious disease syndrome

Abstract:

Many post-infectious syndromes have been recognized in the last 50 years, some following viral infections and others closely related to bacterial disease. The occurrence of prolonged fatigue following an apparent viral illness of varying severity is also well documented. The lack of a recognizable precipitating cause and the tendency for epidemic fatigue to occur among hospital staff led many to believe that the illness may be psychogenic in origin. However, there is serological evidence that some cases may follow enterovirus infections or occasionally delayed convalescence from infectious mononucleosis. Much interesting work is currently in progress relating fatigue to persisting immunological abnormalities, and the development of molecular immunology makes this a most exciting field of research. This paper reviews the evidence for and against a definitive post-viral fatigue syndrome and examines the results of research carried out in the last 50 years.

Source: Bannister BA. Post-infectious disease syndrome. Postgrad Med J. 1988 Jul;64(753):559-67. doi: 10.1136/pgmj.64.753.559. PMID: 3074289; PMCID: PMC2428896.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2428896/ (Full text)

Pale rider: the Spanish flu of 1918 and how it changed the world

Book Review:

Pale rider: The Spanish Flu of 1918 and How it Changed the World by Laura Spinney, Public Affairs; 1st edition (September 12, 2017)

Formerly Professor of Psychiatry, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

The COVID-19 pandemic has changed life for humanity, nothing is “normal” anymore! In the last 100 years, there has not been any similar event. The common feeling among professionals, planners, press, politicians, and people is that “life will not be the same as we knew it, after the pandemic.” Understanding the likely impact of the pandemic and its consequences would be valuable to humanity in general and mental health professionals in particular. Against this current world-shaking event, it is natural to look for similar events in human history. In this, the 1918 flu is the closest event to understand a variety of aspects of the current pandemic. The book, Pale Rider: The Spanish Flu of 1918 and how it changed the world, is one of the best books in this field.[1] That many people are looking at the 1918 flu can be seen by the number of articles in the lay press that have focused on the 1918 flu.[2],[3],[4],[5],[6],[7] Even now, a new book was published as latest as July 23, 2020.[8],[9]

Nevertheless, the book, under review, has 21 chapters with attractive chapter titles such as Like a Thief in the Night; The Doctor’s Dilemma; The Wrath of God; Chalking Doors with Crosses; Good Samaritans; The Human Factor; The Green Shoots of Recovery; Alternate Histories; and Health Care for all and Melancholy Muse.

Between the first case recorded on March 4, 1918, and the last case sometime in March 1920, it killed 50–100 million people, or between 2.5% and 5% of the global population. In terms of a single event causing major loss of life, it surpassed the First World War (17 million dead) and the Second World War (60 million dead). India was specially affected and lost around 6% of its population, the greatest loss in absolute numbers of any country in the world (an estimate of 13–18 million). The book has a special focus on India,[1] presented through the lives of Mahatma Gandhi, Tagore, Munshi Premchand, and Nirala and its impact on the Independence struggle.

Mahatma Gandhi was affected by the gastric variety of flu. At Gandhi’s ashram, several prominent members of the Independence Movement were laid low with flu. Gandhi was too feverish to speak or read; he couldn’t shake a sense of doom: “All interest in living had ceased.” Interestingly, Gandhi’s reaction was: This protracted and first long illness in my life thus afforded me a unique opportunity to examine my principles and to test them. Rabindranath Tagore returned his knighthood as a reaction to the Jallianwala Bagh massacre, and observed that British were guilty of “the same kind of ignorance of the eternal laws which primitive people show when they hunt for some so-called witch to whom they ascribe the cause of their illness, while carrying the disease germs in their own blood.” Spinney observes that disease was a major preoccupation in the writing that emerged in the 1920s, where it dovetailed with ideas about the need to reform the caste system and throw off the yoke of British rule. Munshi Premchand became the self-styled “chronicler of village life” around 1918 when he was living in the United Provinces (Uttar Pradesh), where the Spanish flu claimed an estimated 2–3 million lives alone. Also living there at that time was the poet Nirala, who lost his wife and many other members of his family to the flu. He later recalled seeing the River Ganges “swollen with dead bodies.” This was the strangest time in my life. My family disappeared in the blink of an eye.

There are sections in the book describing the feelings of anxiety accompanying the acute phase of the disease, and reports of people killing themselves while delirious. Following recovery, some patients found themselves plunged into a lingering state of lassitude and despair. Norwegian epidemiologist Svenn-Erik Mamelund studied asylum records in his country from 1872 to 1929 and found that, every year, in which there was no pandemic of influenza, only a few cases were admitted of mental illness associated with flu. However, in each of the 6 years following the 1918 pandemic, the average number of such admissions was seven times higher than in those nonpandemic years (emphasis added). Mamelund speculates that the patients admitted in those 6 years were survivors of Spanish flu who were suffering from what today we would call “postviral or chronic fatigue syndrome.”

The book provides similar creative responses in a number of countries following the pandemic. The paragraph about controversies about the quarantine makes for contemporary reading: “Quarantine and other disease containment strategies place the interests of the collective over those of the individual. When the collective is very large, those strategies have to be imposed in a top-down fashion. But mandating a central authority to act in the interests of the collective potentially creates two kinds of problems. First, the collective may have competing priorities-the need to make money, or the need to raise an army-and deny or water-down the authority’s powers of enforcement. Second, the rights of individuals risk getting trampled on, especially if the authority abuses the measures placed at its disposal.”

One of the quotes from the book can portend what we can expect in the coming years in the country. Spinney notes, “The 1918 pandemic accelerated the pace of change in the first half of the twentieth century, and helped shape our modern world. It influenced the course of the First World War and arguably, contributed to the Second. It pushed India closer to Independence, South Africa closer to Apartheid, and Switzerland to the brink of Civil War. It ushered in universal healthcare and alternative medicine, our love of fresh air and our passion for sport, and it was probably responsible, at least in part, for the obsession of twentieth-century artists with all the myriad ways in which the human body can fail.”

The book made me realize that the current pandemic will bring about extensive changes. Against this expected “mental health tsunami,” there are three tasks for each one of us: firstly, to document the experiences of individuals, families, communities, and the government; secondly, to identify the social factors contributing to vulnerabilities and resilience, to guide corrective actions; and lastly, to utilize the opportunity of heightened awareness of societal-level issues, to work toward addressing the predisposing causes for higher mortality and morbidity such as inequalities, intolerances, inadequate health infrastructure, the weak welfare network to support the vulnerable, and decentralization of powers and plans to enhance community participation.

I recommend it as an essential reading during the current pandemic period.

Source: Murthy R S. Pale rider: the spanish flu of 1918 and how it changed the world. Indian J Soc Psychiatry [serial online] 2020 [cited 2022 Jul 4];36, Suppl S1:189-90. Available from: https://www.indjsp.org/text.asp?2020/36/5/189/297158

Association Between SARS-CoV-2 RNAemia and Postacute Sequelae of COVID-19

Abstract:

Determinants of Post-Acute Sequelae of COVID-19 are not known. Here we show that 83.3% of patients with viral RNA in blood (RNAemia) at presentation were symptomatic in the post-acute phase. RNAemia at presentation successfully predicted PASC, independent of patient demographics, worst disease severity, and length of symptoms.

Source: Ram-Mohan N, Kim D, Rogers AJ, Blish CA, Nadeau KC, Blomkalns AL, Yang S. Association Between SARS-CoV-2 RNAemia and Postacute Sequelae of COVID-19. Open Forum Infect Dis. 2021 Dec 25;9(2):ofab646. doi: 10.1093/ofid/ofab646. PMID: 35111870; PMCID: PMC8802799. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8802799/ (Full text)

A Natural History of Disease Framework for Improving the Prevention, Management, and Research on Post-viral Fatigue Syndrome and Other Forms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

We propose a framework for the treatment, rehabilitation, and research into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using a natural history of disease approach to outline the distinct disease stages, with an emphasis on cases following infection to provide insights into prevention.

Moving away from the method of subtyping patients based on the various phenotypic presentations and instead reframing along the lines of disease progression could help with defining the distinct stages of disease, each of which would benefit from large prospective cohort studies to accurately describe the pathological mechanisms taking place therein. With a better understanding of these mechanisms, management and research can be tailored specifically for each disease stage.

Pre-disease and early disease stages call for management strategies that may decrease the risk of long-term morbidity, by focusing on avoidance of further insults, adequate rest to enable recovery, and pacing of activities.

Later disease stages require a more holistic and tailored management approach, with treatment—as this becomes available—targeting the alleviation of symptoms and multi-systemic dysfunction.

More stringent and standardised use of case definitions in research is critical to improve generalisability of results and to create the strong evidence-based policies for management that are currently lacking in ME/CFS.

Source: O’Boyle S, Nacul L, Nacul FE, Mudie K, Kingdon CC, Cliff JM, Clark TG, Dockrell HM and Lacerda EM. A Natural History of Disease Framework for Improving the Prevention, Management, and Research on Post-viral Fatigue Syndrome and Other Forms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Med. 8:688159. https://www.frontiersin.org/articles/10.3389/fmed.2021.688159/full (Full text)

An Open-Label, Pilot Trial of HRG80™ Red Ginseng in Chronic Fatigue Syndrome, Fibromyalgia, and Post-Viral Fatigue

Chronic fatigue syndrome and fibromyalgia (CFS/FMS) affect 2.1% of the world’s population and ~10–25% of people who have had COVID-19. Previous clinical data suggested that a unique Panax ginseng (C.A. Meyer, family Araliaceae) root extract (HRG80™ Red Ginseng) often resulted in marked improvement. We aimed to study this hydroponic form of red ginseng root, containing high levels of rare ginsenosides, for improving energy, cognition, and stamina. This open-label prospective study included participants with severe CFS/FMS who took a daily supplement of HRG80 capsules (200–400 mg) or tablets (100–200 mg) for one month.
A total of 188 subject patients completed the one-month treatment trial. Of these, 60.1% rated themselves as improved, with 13.3% rating themselves as being much better. In this group, the mean composite score improved from 11.9 to 18.8 (p < 0.001), with a 67% average increase in energy, 44% average increase in overall well-being, 48% average improvement in mental clarity, 58% average composite improvement in the previous three measurements (primary outcome measure), 46% average improvement in sleep, 33% average decrease in pain, and 72% average increase in stamina. Our study showed that HRG80 red ginseng root powder resulted in a marked improvement in people with CFS and fibromyalgia. This included the subgroup with post-viral CFS/FMS.
Source: Teitelbaum J, Goudie S. An Open-Label, Pilot Trial of HRG80™ Red Ginseng in Chronic Fatigue Syndrome, Fibromyalgia, and Post-Viral Fatigue. Pharmaceuticals. 2022; 15(1):43. https://doi.org/10.3390/ph15010043 (Full text)

Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome is a serious illness of unknown etiology, characterized by debilitating exhaustion, memory impairment, pain and sleep abnormalities. Viral infections are believed to initiate the pathogenesis of this syndrome although the definite proof remains elusive. With the unfolding of COVID-19 pandemic, the interest in this condition has resurfaced as excessive tiredness, a major complaint of patients infected with the SARS-CoV-2 virus, often lingers for a long time, resulting in disability, and poor life quality.

In a previous article, we hypothesized that COVID-19-upregulated angiotensin II triggered premature endothelial cell senescence, disrupting the intestinal and blood brain barriers. Here, we hypothesize further that post-viral sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome, are promoted by the gut microbes or toxin translocation from the gastrointestinal tract into other tissues, including the brain. This model is supported by the SARS-CoV-2 interaction with host proteins and bacterial lipopolysaccharide. Conversely, targeting microbial translocation and cellular senescence may ameliorate the symptoms of this disabling illness.

Source: Sfera A, Osorio C, Zapata Martín Del Campo CM, Pereida S, Maurer S, Maldonado JC, Kozlakidis Z. Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis. Front Cell Neurosci. 2021 Jun 25;15:673217. doi: 10.3389/fncel.2021.673217. PMID: 34248502; PMCID: PMC8267916. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267916/ (Full study)

COVID-19 and chronic fatigue syndrome: Is the worst yet to come?

Abstract:

There has been concern about possible long-term sequelae resembling myalgic encephalomyelitis/chronic fatigue syndrome in COVID-19 patients. Clarifying the mechanisms underlying such a “post-COVID-19 fatigue syndrome” is essential for the development of preventive and early treatment methods for this syndrome.

In the present paper, by integrating insights pertaining to the glymphatic system and the nasal cerebrospinal fluid outflow pathway with findings in patients with chronic fatigue syndrome, idiopathic intracranial hypertension, and COVID-19, I provide a coherent conceptual framework for understanding the pathophysiology of post-COVID-19 fatigue syndrome. According to this hypothesis, this syndrome may result from damage to olfactory sensory neurons, causing reduced outflow of cerebrospinal fluid through the cribriform plate, and further leading to congestion of the glymphatic system with subsequent toxic build-up within the central nervous system. I further postulate that patients with post-COVID-19 fatigue syndrome may benefit from cerebrospinal fluid drainage by restoring glymphatic transport and waste removal from the brain.

Obviously, further research is required to provide further evidence for the presence of this post-viral syndrome, and to provide additional insight regarding the relative contribution of the glymphatic-lymphatic system to it. Other mechanisms may also be involved. If confirmed, the glymphatic-lymphatic system could represent a target in combating post-COVID-19 fatigue syndrome. Moreover, further research in this area could also provide new insights into the understanding of chronic fatigue syndrome.

Source: Wostyn P. COVID-19 and chronic fatigue syndrome: Is the worst yet to come? Med Hypotheses. 2021 Jan 2;146:110469. doi: 10.1016/j.mehy.2020.110469. Epub ahead of print. PMID: 33401106. https://pubmed.ncbi.nlm.nih.gov/33401106/