Long-COVID, chronic fatigue and everything in between - what have we learned and where may it impact on fibromyalgia

As the COVID-19 pandemic made its gruesome initial appearance in the first months of 2020, it initially appeared as though nothing could be more distant from this acute, dramatic, life - threatening condition, treated in intensive care units and heroically combated behind personal protective equipment, than fibromyalgia, a chronic pain syndrome treated in clinics by primary care physicians and rheumatologists. Only gradually, as the medical community became more accustomed to the manifestations and complications of COVID-19, did the more chronic aspects of the pandemic come to light with the evolving entity of LONG-COVID syndrome (1). This syndrome was initially treated by a broad spectrum of specialties including infectious disease specialists, pulmonologists, neurologists, with rheumatologists not taking a central role. As more clinical experience was accumulated however, a surprising overlap begins to emerge between LONG-COVID and conditions such as fibromyalgia and chronic fatigue syndrome, an overlap most obvious on a clinical level to rheumatologists well acquainted with the spectrum of fibromyalgia (2). On a clinical level, LONG COVID patients most frequently suffer from fatigue, exercise intolerance, as well as cognitive impairment, all symptoms which overlap with the chronic fatigue syndrome. Sleep disturbances, abdominal complaints, anxiety /depression and myalgia are also not unusual (3). In addition, autonomic dysregulation appears to play a role in LONG COVID (4), as in fibromyalgia. Notably, symptoms typical of fibromyalgia among LONG-COVID patients appear to be particularly common among patients with a previous history of chronic pain, and patients who were actually diagnosed with fibromyalgia before contracting COVID-19 appear to be prone to get worse (5). Notably, an association between fibromyalgia / chronic fatigue and other chronic viral diseases such as EBV/CMV, HIV and viral hepatitis has been well known before the COVID-19 era, so that viral infection has traditionally been considered among the triggers responsible for instigation the syndrome (6). Another aspect of clinical importance regarding the relationship between fibromyalgia and COVID-19 relates to the effect of vaccinations. While vaccinations have previously been speculated to have a causative role in fibromyalgia, mainly based on data relating to the gulf war syndrome, the robustness of this association is not clear. In an era of significant vaccine - hesitancy which often hampers effective attempts at controlling the pandemic, clear data regarding the safety and effectivity of COVID-19 vaccinations regarding fibromyalgia is necessary. Fascinating data has emerged indicating that patients suffering from LONG - COVID may actually have low grade persistent infection, with identification of viral antigens and RNA in tissue as long as one year after initial infection (7). While the general applicability of these findings is not yet clear, they raise the provocative possibility that similar viral vectors might be identifiable in tissues of patients suffering from chronic fatigue or fibromyalgia. Last but not least, the COVID-19 pandemic, including the social distancing measures associated with it, have taken a toll on patients suffering from fibromyalgia even when not personally infected (8). Reduced access to healthcare, lockdown and lack of exercise, anxiety and isolation may all play a role and should be considered by physicians caring for fibromyalgia patients in this era.

Assessment of Diverse Biological Indicators in Gulf War Illness: Are They Replicable? Are They Related?

The complex of multiple symptoms known as Gulf War Illness (GWI) continues to affect a substantial number of the nearly 700,000 U.S. veterans who served in the 1990-1991 Gulf War. Despite considerable research, the biological processes underlying veterans symptoms have not yet been clearly elucidated. To develop useful diagnostic tests and effective GWI treatments, it is imperative to establish a more definitive and integrated understanding of GWI pathophysiology. This study was designed to evaluate diverse previously-identified and hypothesized biological alterations associated with GWI in a single, well-characterized sample of Gulf War veterans. Using a case-control design, the protocol included physical and neuropsychological evaluations, brain imaging (MRI, fMRI, DTI), adrenal function tests, and diverse immune, inflammatory, and coagulation measures. Despite ongoing good-faith attempts to operationalize and implement the project over an extended period, data collection was not initiated and there are no study results to report, owing to a variety of internal and external challenges that we were unable to successfully address. For the most recent period of performance, all study updates, preparations, and sample identification were in place for data collection, including protocol revisions to limit in-person contact and related COVID safety precautions. However, recruitment and data collection were not undertaken due to extended public health restrictions in place during the ongoing pandemic. It is therefore necessary, with great regret, that we close the project without performing the study. We acknowledge and extend our sincere appreciation to the USAMRAA CDMRP program for their support as we worked to address project challenges over the duration of the grant period.

Probiotic (VSL#3) for Gulf War Illness

The overall objective of the study is to determine whether probiotic VisbiomeTM will improve 1) Intestinal symptoms of Irritable Bowel Syndrome and 2) Non-intestinal symptoms (fatigue, joint pain, insomnia, general stiffness and headache) associated with IBS. All these symptoms are part of the Gulf War illness. We screened our first participant in September 2013. Overall, we have screened 101 and enrolled 62 Gulf War Veterans. We have stopped enrolling patients in this study. The stool samples analysis ongoing as well the statistical data analysis.

Treatment of Memory Disorders in Gulf War Illness with High-Definition Transcranial Direct Cortical Stimulation

The present study consists of the application of 1 ma anodal HD tDCS over the preSMA for 20 minutes a session for 10 sessions over a two week period. The treatment is hypothesized to lead to improvement in verbal retrieval, detectable in both performance measures of verbal retrieval tasks and in ERP markers of verbal retrieval processing. Our objective is to determine if 10 sessions of 1 ma anodal HD tDCS to the preSMA for 20 minutes a session are an effective treatment for verbal retrieval deficits in GWI. We have established the research team, laboratory setting, obtained approval of all regulatory documents for the study, and established recruiting procedures. In the first half of the year, we screened 8 veterans and enrolled 5 in the baseline testing and treatment phase of the study. We were required to halt in person human subject research for the second half of the year due to the Covid-19 pandemic.

Glutamate Receptor and Kynurenine Pathway Functioning in the Pathobiology of Gulf War Illness

This project has 2 aims: (i) examine the involvement in veterans with Gulf War Illness of a neural excitatory state as a consequence of impaired brain immune, neuron and glia functioning using biomarkers obtained from cerebrospinal fluid (CSF) in 1990-1991 Gulf War veterans with (n=46) and without (n=23) GWI, and (ii) examine involvement in veterans with GWI of a neural excitatory state defined as increased glutamatergic receptor functioning by testing the effect of a single infusion of 0.5 mg/kg of N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine on gamma band EEG (for NMDAR target engagement), other EEG markers, and on symptoms of Gulf War Illness in 19 cases. Outcomes will provide evidence of an expected neural excitatory and pro-inflammatory state in cases that could predispose to neuronal damage via NMDAR hyperactivation through kynurenine pathway activation, and will provide evidence in humans of possible effects of temporarily blocking NMDARs with a subanesthetic dose (0.5 mg/kg) of ketamine.