Case Study: COVID-19 Brain Fog or Auditory Processing Disorder?

A wide array of symptoms have been directly associated with COVID-19 following recovery, but they can also occur several weeks or months after the diagnosis. These include, but are not limited to, damage to the respiratory tract as well as decreased cognition and other brain functions. The nonmedical term used to describe these post-COVID-19 problems is “brain fog.”

The symptoms of brain fog are similar to mild cognitive impairment or, of interest to audiologists, an auditory processing disorder (APD). 2 COVID-19 has neurological consequences and affects specific areas of the brain, such as the cingulate cortex (i.e. emotions, memory, depression, and decision of action). 3 Brain fog is also associated with several symptoms related to hearing and communication, which can affect the accomplishment of routine daily tasks. Many of those can be mistaken for or coexist with APD symptoms. These include “difficulty attending or staying focused, difficulty concentrating, difficulty understanding or remembering instructions, language problems, short-term memory problems,” to mention a few. 2 However, what might appear as a brain fog case could be an undiagnosed or even a pre-existing APD issue. 2 Symptoms could include struggling to keep track of conversations, forgetfulness and memory issues, problems following directions, and several cognitive difficulties. 2

This report presents the case of a 31-year-old medical doctor who was diagnosed with COVID-19 in December 2020, and later identified with APD symptoms that are now commonly seen in post-COVID-19 brain fog patients. Auditory training following the Buffalo Model 4 resolved the patient’s chief complaints following 12 treatment sessions. This issue is one of many that could shed light on the great potential auditory training has in resolving brain fog complaints that overlap with what is commonly seen in APD patients, highlighting the concerns regarding COVID-19’s direct effects on auditory processing.

Source: Alexander, Angela Loucks AuD, MNZAS, CCC-A; DiSogra, Robert M. AuD; Abbas, Fatima BS; Braund, Stacey AuD, CCC-A; Spokes, Chelsea BSpHLSc, MClinAud. Case Study: COVID-19 Brain Fog or Auditory Processing Disorder?. The Hearing Journal 76(04):p 18,19,20,22,23,24, April 2023. | DOI: 10.1097/01.HJ.0000927332.17564.4e https://journals.lww.com/thehearingjournal/Fulltext/2023/04000/Case_Study__COVID_19_Brain_Fog_or_Auditory.2.aspx (Full text)

Incident autoimmune diseases in association with a SARS-CoV-2 infection: A matched cohort study

Abstract:

Objectives To investigate whether the risk of developing an incident autoimmune disease is increased in patients with previous COVID-19 disease compared to people without COVID-19.

Method A cohort was selected from German routine health care data covering 38.9 million individuals. Based on documented diagnoses, we identified individuals with polymerase chain reaction (PCR)-confirmed COVID-19 through December 31, 2020. Patients were matched 1:3 to control patients without COVID-19. Both groups were followed up until June 30, 2021. We used the four quarters preceding the index date until the end of follow-up to analyze the onset of autoimmune diseases during the post-acute period. Incidence rates (IR) per 1000 person-years were calculated for each outcome and patient group. Poisson models were deployed to estimate the incidence rate ratios (IRRs) of developing an autoimmune disease conditional on a preceding diagnosis of COVID-19.

Results In total, 641,704 patients with COVID-19 were included. Comparing the incidence rates in the COVID-19 (IR=15.05, 95% CI: 14.69-15.42) and matched control groups (IR=10.55, 95% CI: 10.25-10.86), we found a 42.63% higher likelihood of acquiring autoimmunity for patients who had suffered from COVID-19. This estimate was similar for common autoimmune diseases, such as Hashimoto thyroiditis, rheumatoid arthritis, or Sjögren syndrome. The highest IRR was observed for autoimmune disease of the vasculitis group. Patients with a more severe course of COVID-19 were at a greater risk for incident autoimmune diseases.

Conclusions SARS-CoV-2 infection is associated with an increased risk of developing new-onset autoimmune diseases after the acute phase of infection.

Source: Falko Tesch, Franz Ehm, Annika Vivirito, Danny Wende, Manuel Batram, Friedrich Loser, Simone Menzer, Josephine Jacob, Martin Roessler, Martin Seifert, Barbara Kind, Christina König, Claudia Schulte, Tilo Buschmann, Dagmar Hertle, Pedro Ballesteros, Stefan Baßler, Barbara Bertele, Thomas Bitterer, Cordula Riederer, Franziska Sobik, Lukas Reitzle, Christa Scheidt-Nave, Jochen Schmitt. Incident autoimmune diseases in association with a SARS-CoV-2 infection: A matched cohort study. medRxiv 2023.01.25.23285014; doi:https://doi.org/10.1101/2023.01.25.23285014 (Full text)

Chronic cough in post-COVID syndrome: Laryngeal electromyography findings in vagus nerve neuropathy

Abstract:

Background: Despite being a new entity, there is a large amount of information on the characteristics of SARS-CoV-2 infection and the symptoms of the acute phase; however, there are still many unknowns about the clinical features and pathophysiology of post-COVID syndrome. Refractory chronic cough is one of the most prevalent symptoms and carries both a medical problem and a social stigma. Many recent studies have highlighted the role of SARS-CoV-2 neurotropism, but no studies have demonstrated vagus nerve neuropathy as a cause of persistent chronic cough or other COVID-19 long-term effects.

Objective: The main objective was to assess the involvement of the vagus nerve neuropathy as a cause of chronic cough and other post-COVID syndrome symptoms.

Material and methods: This was a single-center observational study with prospective clinical data collected from 38 patients with chronic cough and post-COVID-19 syndrome. Clinical characteristics and laryngeal electromyographic findings were analyzed.

Results: Clinical data from 38 patients with chronic cough after 12 weeks of the acute phase of COVID-19 infection were analyzed. Of these patients, 81.6% suffered from other post-COVID conditions and, 73.6% reported fluctuating evolution of symptoms. Laryngeal electromyography (LEMG) of the thyroarytenoid (TA) muscles and cricothyroid (CT) muscles was pathological in 76.3% of the patients. Of the patients with abnormal LEMG, chronic denervation was the most frequent finding (82.8%), 10.3% presented acute denervation signs, and 6.9% presented myopathic pattern in LEMG.

Conclusions: LEMG studies suggest the existence of postviral vagus nerve neuropathy after SARS-CoV-2 infection that could explain chronic cough in post-COVID syndrome.

Source: García-Vicente P, Rodríguez-Valiente A, Górriz Gil C, Márquez Altemir R, Martínez-Pérez F, López-Pajaro LF, et al. (2023) Chronic cough in post-COVID syndrome: Laryngeal electromyography findings in vagus nerve neuropathy. PLoS ONE 18(3): e0283758. https://doi.org/10.1371/journal.pone.0283758 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0283758 (Full text)

Graded exercise therapy and cognitive behavior therapy do not improve employment outcomes in ME/CFS

1 Introduction:

In a 1989 article, Wessely et al. [1] proposed a model of the onset and perpetuation of chronic fatigue syndrome, the illness often called myalgic encephalomyelitis and now frequently referred to as ME/CFS. In this model, patients’ symptoms were attributed to the effects of deconditioning following an acute illness. The symptoms were said to be perpetuated by patients’ persistent but purportedly unwarranted conviction that they continued to suffer from a medical disease that was exacerbated by exertion. The proposed treatment strategy combined gradual increases in activity to reverse the presumed deconditioning with efforts to alter patients’ supposedly misguided perceptions about their ailment.

ME/CFS has long been associated with marked disability and long-term sickness absences [2], with estimated rates of unemployment among patients ranging from 35% to 69% [3]. From the start, the promotion of behavioral and psychological rehabilitation has been intertwined with questions about whether ME/CFS patients with limited capacity to work should be able to receive some form of income or disability support. In a section on “sickness benefits” in the 1989 paper [1], the authors argued that decisions about social welfare payments should be linked to patients’ willingness to undergo behavioral and psychological interventions. “It is reasonable to expect a patient to cooperate with treatment before being labelled as chronically disabled,” noted the authors, notwithstanding the theoretical and unproven status of their model.

This rehabilitative approach achieved dominance over the next couple of decades, not only in the UK but in the US and many other countries. Graded exercise therapy (GET) and an illness-specific form of cognitive behavior therapy (CBT) became the predominant and most heavily researched ME/CFS interventions and were enshrined in multiple clinical guidelines. A 2005 review of the natural history of the illness [4], which found that only 5% of patients fully recovered spontaneously, noted “increasing evidence” for GET and CBT and therefore advised that “medical retirement should be postponed until a trial of such treatment has been given.”

While many studies have included employment status as a demographic data point [2, 3], fewer have specifically examined the relationship between GET and CBT and employment-related outcomes. Nonetheless, the results from the latter group are consistent and clear: The interventions do not lead to improved outcomes in employment status [5–13].

This question has taken on renewed urgency given the overlaps between ME/CFS and the phenomenon known as long Covid, or more formally as post-acute sequelae of SARS CoV-2 (PASC). A significant proportion of patients with prolonged symptoms after a coronavirus infection appear to suffer from the same cluster of symptoms that characterize ME/CFS, including pronounced exhaustion, relapses after minimal exertion known as post-exertional malaise (PEM), cognitive impairments, and orthostatic intolerance, among others. Like ME/CFS patients, many of this new PASC cohort have found that they are unable to sustain their previous level of employment. While the similarities between the two conditions have been widely noted by clinicians and medical investigators, they have also led to efforts to promote the traditional ME/CFS rehabilitation paradigm for this large wave of post-viral patients.

2 Employment outcomes in the PACE trial

After gaining momentum during the 1990 s and 2000 s, the GET/CBT approach was significantly reinforced with the 2011 publication in the Lancet of the first results of the PACE trial, the largest study of the two interventions for ME/CFS [5]. Additional PACE results were published in 2012 and 2013 [6, 7]. The study was partially funded by the UK’s Department for Work and Pensions (DWP). Officials at the agency presumably believed or hoped that the trial would provide robust data to support the use of these two strategies.

The PACE investigators presumably hoped for that as well; key members of the team maintained strong links with disability insurance companies, advising them that GET and CBT were effective in helping this group of challenging patients recover. In a 2002 essay for a UNUMProvident report on trends in disability [14], Michael Sharpe, a lead PACE investigator, wrote that “symptoms and disability” in patients with unexplained conditions “are shaped by psychological factors,” and in particular by “patients’ beliefs and fears.” He suggested that the promotion of biological disease models by ME/CFS patient advocates could impact health outcomes among insurance claimants.

Commenting on how public messaging and related “social factors” influenced the course of illness for these patients, Sharpe wrote: “Relevant factors include the information patients receive about the symptoms and how to cope with them. This information may be helpful or may stress the chronicity of the illness and promote helplessness. Such unhelpful information is found in “self-help” (!) books and increasingly on the Internet (see for example www.meassociation.org.uk)…Other social factors that perpetuate illness are anger with the person or organisation the illness is attributed to, or toward the insurer for not believing them.” In the article, Sharpe further argued that receiving financial benefits ultimately discouraged such claimants from getting better.

However, the data from PACE did not provide evidence that GET and CBT were effective in helping ME/CFS patients in the employment domain [6]. With 641 participants, PACE was the largest treatment trial for ME/CFS [5]. The investigators themselves referred to it as the “definitive” test of the two interventions [15]. In touting it as a success, they reported that around 60% had improved and 22% had recovered after treatment with GET and CBT, much more than in the other groups [5, 7]. However, these positive findings were all from subjective, self-reported measures. When such measures are paired with unblinded treatments, as in the PACE trial, they are subject to an unknown amount of bias.

PACE also included an employment measure as one of four objective outcomes, along with whether or not the participant was receiving social welfare or disability benefits, a step-test to assess fitness, and a six-minute-walking test. The results were uniformly poor. The first three measures produced null findings across the board, with no advantages conferred by the interventions [6, 7]; in the six-minute walking test, the GET group showed a statistically significant but clinically insignificant improvement [5]. In terms of employment, the percentage of participants in the GET group reporting lost days of work increased from 83% at baseline to 86% at 12 months after randomization; in the CBT group, the percentage was 84% both before and after treatment. In all study arms, the percentage of participants receiving unemployment or disability benefits was higher after treatment [6].

In promoting GET and CBT as effective, the PACE authors downplayed the findings on employment, receipt of disability or unemployment support, and other objective results, suggesting these should be ignored when determining whether patients had improved and recovered. In correspondence, they challenged the reliability and even the objectivity of the measures they themselves had pre-designated as objective. As they wrote: “Recovery from illness is a health status, not an economic one, and plenty of working people are unwell, while well people do not necessarily work. Some of our participants were either past the age of retirement or were not in paid employment when they fell ill. In addition, follow-up at 6 months after the end of therapy may be too short a period to affect either benefits or employment.” [16].

It is indisputable that other factors besides health status play a role in employment outcomes. Nonetheless, if the PACE trial’s reported results of significant improvement and recovery were accurate, then a measurable benefit from GET and CBT in employment and in the receipt of financial support would have been expected. As has been well-documented, the investigators weakened key subjective outcome measures in ways that dramatically improved their reported results; published re-analyses of trial data have found that no one achieved “recovery” from either of the therapies, and rates of improvement were so marginal that they were likely due to bias and expectation effects [17, 18]. Given these findings, the similarly disappointing results for employment outcomes in PACE should not be surprising.

3 Other studies on CBT/GET and employment outcomes

In a review of treatment studies that included employment outcomes, Vink and Vink-Niese [8] found that the standard interventions did not have an overall positive effect on work status. Besides PACE, among the studies reviewed were two other randomized trials and five observational studies based on data from clinical services. The two other trials, one in the Netherlands with 278 participants and one in England with 153, both investigated CBT and reported no statistically significant differences in employment outcomes between the intervention and control groups [9, 10]. The largest observational study included 952 patients seeking care at specialty clinics in England, although a great many did not provide post-treatment outcomes; among a subgroup of 394, 18% reported having returned to work or increased work hours, while 30% reported having stopped work or reduced work hours [11]. According to a Belgian report, a review of 655 patients attending domestic clinics found that “employment status decreased” when assessed after treatment while the percentage of those “living from a sickness allowance” rose from 54% to 57% [12].

Other observational research had similarly unpromising findings. In the most recent study, Stevelink et al. [13], of 508 patients who attended clinical services between 2007 and 2014, only 316 provided information about post-treatment employment status, among other measures. Of those, 9% had returned to work after not having worked at baseline. On the other hand, 6% had stopped working after having been working at baseline, leaving a net return-to-work after treatment of just 3%–a handful of people. Moreover, that figure is likely to be overstated, given the high loss-to-follow-up from the initial sample of 508. The drop-outs were more seriously ill at baseline, so they might be expected to have worse employment outcomes than those who ended up providing data at the final time point.

According to the authors, “unhelpful beliefs such as fear of activity and exercise and concerns about causing damage, combined with all or nothing behaviour and behavioural avoidance, were associated with not working” [13]. This statement is problematic because “fear of activity,” “concerns about causing damage” and related indications of caution should be considered reasonable and prudent perspectives, not “unhelpful beliefs,” among patients with the core ME/CFS symptom of PEM. Beyond that, the study itself documented little or no change after treatment in the domains of “fear-avoidance,” “catastrophizing,” “embarrassment avoidance,” “symptom focusing,” “all-or-nothing behaviour,” and “avoidance/resting behaviour,” even though such factors were “specifically targeted in CBT and, to some extent, GET.”

Moreover, the authors reported no change in subjective fatigue scores, and only a marginal increase in subjective physical function scores, with participants remaining seriously disabled even after treatment. Thus, although the authors noted correctly that “meaningful occupation is important for well-being and psychosocial needs,” their study documented that their approach failed to impact factors presumed to be essential to helping participants achieve that important goal. (Since Stevelink et al’s senior author was one of the lead PACE investigators, it is unclear why the paper did not mention the null employment results from that “definitive” study.)

The theoretical illness model underlying all of these studies is essentially the one outlined by Wessely et al. more than three decades ago [1]. That illness model is at odds with the extensive physiological abnormalities that have been found in ME/CFS [17, 19]. Research findings have also undermined two core assumptions of the model–specifically, that ME/CFS patients are deconditioned and have an unwarranted fear of activity or exercise. [20–22]. In 2017, the US Centers for Disease Control and Prevention dropped its recommendations for GET and CBT as ME/CFS treatments. In 2021, the UK National Institute for Health and Care Excellence (NICE) reversed its earlier support for the interventions in new ME/CFS guidelines; in its analysis, NICE assessed the quality of the evidence supporting GET and CBT as either “very low” or merely “low” [23]. These developments are consistent with the failure of GET and CBT to lead to improved employment outcomes in PACE and other studies.

4 Conclusion

In a recent study of employment status among clinic attendees, Stevelink et al. [13] wrote that “work-related outcomes should be targeted” in treatment for ME/CFS. It is certain that people with ME/CFS experience disrupted occupational lives and that it would be desirable to identify treatments that could restore their full capacity for employment. However, the most common behavioral and psychological interventions— that is, GET and CBT–have already been tested sufficiently to reach a conclusive assessment that they do not lead overall to meaningful improvements in work status. These poor results are consistent across randomized trials, including the high-profile and “definitive” PACE study, as well as observational studies of patients seeking clinical services for their illness.

Some investigators and medical experts continue to promote GET and CBT as treatments for ME/CFS patients based on subjective findings from flawed studies. They also seek to extend these recommendations to patients with long Covid, or PASC, many of whom are receiving ME/CFS diagnoses and facing employment challenges. It is time to state the obvious: The objective data on work outcomes indicate that GET and CBT do not lead to readily apparent benefits in this domain. In consequence, they should no longer be recommended to ME/CFS patients as a strategy for achieving occupational rehabilitation and related benefits.

Source: Tuller D, Vink M. Graded exercise therapy and cognitive behavior therapy do not improve employment outcomes in ME/CFS. Work. 2023 Mar 10. doi: 10.3233/WOR-220569. Epub ahead of print. PMID: 36911962. https://content.iospress.com/articles/work/wor220569 (Full text)

Sex differences in post-exercise fatigue and function in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

To assess biobehavioral sex differences in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) utilizing a low burden exercise protocol, 22 females and 15 males with ME/CFS and 14 healthy controls underwent two six-min walk tests.

Fifteen daily assessments were scheduled for fatigue and function ratings and heart monitoring. Six-min walk tests were conducted on days 8 and 9. The ME/CFS group showed high self-report fatigue and impaired physical function, whereas healthy controls did not show fatigue or function abnormalities.

In patients, no significant post-exercise changes were found for heart rate variability (HRV); however, heart rate decreased in ME/CFS males from Day 14 to Day 15 (p = 0.046). Female patients showed increased fatigue (p = 0.006) after the initial walk test, but a downward slope (p = 0.008) in fatigue following the second walk test. Male patients showed a decrease in self-report work limitation in the days after exercise (p = 0.046). The healthy control group evidenced a decrease in HRV after the walk tests from Day 9-14 (p = 0.038).

This pilot study did not confirm hypotheses that females as compared to males would show slower exercise recovery on autonomic or self-report (e.g. fatigue) measures. A more exertion-sensitive test may be required to document prolonged post-exertional abnormalities in ME/CFS.

Trial registration: NCT NCT03331419.

Source: Friedberg F, Adamowicz JL, Bruckenthal P, Milazzo M, Ramjan S, Zhang X, Yang J. Sex differences in post-exercise fatigue and function in myalgic encephalomyelitis/chronic fatigue syndrome. Sci Rep. 2023 Apr 3;13(1):5442. doi: 10.1038/s41598-023-32581-w. PMID: 37012343. https://www.nature.com/articles/s41598-023-32581-w (Full text)

Natural killer cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a multi-site clinical assessment of ME/CFS (MCAM) sub-study

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem illness characterized by substantial reduction in function accompanied by profound unexplained fatigue not significantly relieved by rest, post-exertional malaise, and other symptoms. Reduced natural killer (NK) cell count and cytotoxicity has been investigated as a biomarker for ME/CFS, but few clinical laboratories offer the test and multi-site verification studies have not been conducted.

Methods: We determined NK cell counts and cytotoxicity in 174 (65%) ME/CFS, 86 (32%) healthy control (HC) and 10 (3.7%) participants with other fatigue associated conditions (ill control [IC]) from the Multi-Site Clinical Assessment of ME/CFS (MCAM) study using an assay validated for samples shipped overnight instead of testing on day of venipuncture.

Results: We found a large variation in percent cytotoxicity [mean and (IQR) for ME/CFS and HC respectively, 34.1% (IQR 22.4-44.3%) and 33.6% (IQR 22.9-43.7%)] and no statistically significant differences between patients with ME/CFS and HC (p-value = 0.79). Analysis stratified on illness domain measured with standardized questionnaires did not identify an association of NK cytotoxicity with domain scores. Among all participants, NK cytotoxicity was not associated with survey results of physical and mental well-being, or health factors such as history of infection, obesity, smoking, and co-morbid conditions.

Conclusion: These results indicate this assay is not ready for clinical implementation and studies are needed to further explore immune parameters that may be involved in the pathophysiology of ME/CFS.

Source: Querec TD, Lin JS, Chen Y, Helton B, Kogelnik AM, Klimas NG, Peterson DL, Bateman L, Lapp C, Podell RN, Natelson BH, Unger ER; MCAM Study Group. Natural killer cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a multi-site clinical assessment of ME/CFS (MCAM) sub-study. J Transl Med. 2023 Apr 3;21(1):242. doi: 10.1186/s12967-023-03958-2. PMID: 37013608. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03958-2 (Full text)

Neurocognitive and psychiatric symptoms following infection with COVID-19: Evidence from laboratory and population studies

Abstract:

Objective: The objective of the current investigation was to examine associations between symptomatic COVID-19 history, neurocognitive function, and psychiatric symptoms using cognitive task performance, functional brain imaging, and a prospective population survey.

Methods: Study 1 was a laboratory study conducted between 3 May 2022 and 16 Nov 2022 involving 120 fully vaccinated community dwelling adults between 18 and 84 years of age (Mage = 31.96 (SD = 20.71), 63.3% female). In this cross-sectional study we examined the association between symptomatic COVID-19 infection history and performance on three computer tasks assessing cognitive function (Flanker interference, delay discounting and simple reaction time) and measured oxygen saturation within the prefrontal cortex using functional near infrared spectroscopy (fNIRS). Study 2 was a 2-wave population survey undertaken between 28 September 2021 and 21 March 2022, examining the prospective relationship between symptomatic COVID-19 and self-reported symptoms of cognitive dysfunction, depressive symptoms, anxiety symptoms, and agitation at 6-month follow up. The sample (N = 2,002, M age = 37.0, SD = 10.4; 60.8% female) was collected using a quota process to ensure equal numbers of vaccinated and unvaccinated individuals. Structural equation modelling with latent variables was performed on the population-level data, evaluating the fit of the proposed mediational model of symptomatic COVID-19 to psychiatric symptoms through cognitive dysfunction.

Results: Findings from Study 1 revealed significant effects of symptomatic COVID-19 history on Flanker interference and delay discounting. Effects on flanker performance were significantly stronger among older adult women (effect: 9.603, SE = 4.452, t = 2.157, p = .033), and were accompanied by task-related changes cerebral oxygenation at the right superior frontal gyrus (F (1, 143.1) = 4.729, p = .031). Additionally, those with a symptomatic COVID-19 infection history showed evidence of amplified delay discounting (coefficient = 0.4554, SE = 0.2208, t = 2.0629, p = .041). In Study 2, baseline symptomatic COVID-19 history was associated with self-reported cognitive dysfunction and a latent variable reflecting psychiatric symptoms of anxiety, depression and agitation at follow-up. Mediational analyses revealed evidence of cognitive mediation of clinically significant psychiatric outcomes: depression (indirect effect = 0.077, SE = 0.026, p = .003) and generalized anxiety (indirect effect = 0.060, SE = 0.021, p = .004).

Conclusions: Converging findings from laboratory and population survey data support the conclusion that symptomatic COVID-19 infection is associated with task-related, functional imaging and self-reported indices of cognitive dysfunction as well as psychiatric symptoms. In some cases, these findings appear to be more amplified among women than men, and among older women than younger.

Source: Hall PA, Ayaz H, Meng G, Hudson A, Sakib MN, Quah ACK, Agar TK, Lee JA, Boudreau C, Fong GT. Neurocognitive and psychiatric symptoms following infection with COVID-19: Evidence from laboratory and population studies. Brain Behav Immun Health. 2023 Mar;28:100595. doi: 10.1016/j.bbih.2023.100595. Epub 2023 Jan 24. PMID: 36713476; PMCID: PMC9870612. https://www.sciencedirect.com/science/article/pii/S2666354623000091?via%3Dihub (Full study)

The original strain of SARS-CoV-2, the Delta variant, and the Omicron variant infect microglia efficiently, in contrast to their inability to infect neurons: Analysis using 2D and 3D cultures

Highlights:

  • None of the SARS-CoV-2 original, delta, or omicron strains can infect neurons.
  • The SARS-CoV-2 original, delta, and omicron strains can infect microglia.
  • The CNS cells differentiated from hiPSCs are useful to investigate the infectivity of the virus.

Abstract:

COVID-19 causes neurological damage, systemic inflammation, and immune cell abnormalities. COVID-19-induced neurological impairment may be caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which directly infects cells of the central nervous system (CNS) and exerts toxic effects. Furthermore, SARS-CoV-2 mutations occur constantly, and it is not well understood how the infectivity of the virus to cells of the CNS changes as the virus mutates.

Few studies have examined whether the infectivity of cells of CNS – neural stem/progenitor cells (NS/PCs), neurons, astrocytes, and microglia – varies among SARS-CoV-2 mutant strains. In this study, therefore, we investigated whether SARS-CoV-2 mutations increase infectivity to CNS cells, including microglia.

Since it was essential to demonstrate the infectivity of the virus to CNS cells in vitro using human cells, we generated cortical neurons, astrocytes, and microglia from human induced pluripotent stem cells (hiPSCs). We added pseudotyped lentiviruses of SARS-CoV-2 to each type of cells, and then we examined their infectivity. We prepared three pseudotyped lentiviruses expressing the S protein of the original strain (the first SARS-CoV-2 discovered in the world), the Delta variant, and the Omicron variant on their envelopes and analyzed differences of their ability to infect CNS cells. We also generated brain organoids and investigated the infectivity of each virus.

The viruses did not infect cortical neurons, astrocytes, or NS/PCs, but microglia were infected by the original, Delta, and Omicron pseudotyped viruses. In addition, DPP4 and CD147, potential core receptors of SARS-CoV-2, were highly expressed in the infected microglia, while DPP4 expression was deficient in cortical neurons, astrocytes, and NS/PCs.

Our results suggest that DPP4, which is also a receptor for Middle East respiratory syndrome-coronavirus (MERS-CoV), may play an essential role in the CNS. Our study is applicable to the validation of the infectivity of viruses that cause various infectious diseases in CNS cells, which are difficult to sample from humans.

Source: Kase Y, Sonn I, Goto M, Murakami R, Sato T, Okano H. The original strain of SARS-CoV-2, the Delta variant, and the Omicron variant infect microglia efficiently, in contrast to their inability to infect neurons: Analysis using 2D and 3D cultures. Exp Neurol. 2023 Mar 11;363:114379. doi: 10.1016/j.expneurol.2023.114379. Epub ahead of print. PMID: 36914084; PMCID: PMC10008041. https://www.sciencedirect.com/science/article/pii/S0014488623000638?via%3Dihub (Full text)

Potential Prion Involvement in Long COVID-19 Neuropathology, Including Behavior

Abstract:

Prion is a term used to describe a protein infectious particle responsible for several neurodegenerative diseases in mammals, e.g., Creutzfeldt-Jakob disease. The novelty is that it is protein based infectious agent not involving a nucleic acid genome as found in viruses and bacteria.

Prion disorders exhibit, in part, incubation periods, neuronal loss, and induce abnormal folding of specific normal cellular proteins due to enhancing reactive oxygen species associated with mitochondria energy metabolism. These agents may also induce memory, personality and movement abnormalities as well as depression, confusion and disorientation.

Interestingly, some of these behavioral changes also occur in COVID-19 and mechanistically include mitochondrial damage caused by SARS-CoV-2 and subsequent production of reactive oxygen species. Taken together, we surmise, in part, long COVID may involve the induction of spontaneous prion emergence, especially in individuals susceptible to its origin may thus explain some of its manisfestions post-acute viral infection.

Source: Stefano GB, Büttiker P, Weissenberger S, Anders M, Raboch J, Ptacek R, Kream RM. Potential Prion Involvement in Long COVID-19 Neuropathology, Including Behavior. Cell Mol Neurobiol. 2023 Mar 28:1–6. doi: 10.1007/s10571-023-01342-8. Epub ahead of print. PMID: 36977809; PMCID: PMC10047479. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10047479/ (Full text)

Association of Laparoscopically-confirmed Endometriosis with Long COVID: A Prospective Cohort Study

Abstract:

Background: Women are at greater risk than men of developing chronic inflammatory conditions and of developing ‘long COVID.’ However, few gynecologic health risk factors for long COVID have been identified. Endometriosis is a common gynecological disorder associated with chronic inflammation, immune dysregulation, and comorbid presentation with autoimmune and clotting disorders, all of which are pathophysiologic mechanisms proposed for long COVID. Therefore, we hypothesized that women with a history of endometriosis may be at greater risk of developing long COVID.

Objective: To investigate the association between history of endometriosis prior to SARS-CoV-2 infection and risk of long COVID.

Methods: We followed 46,579 women from two ongoing prospective cohort studies: the Nurses’ Health Study II and the Nurses’ Health Study 3, who participated in a series of COVID-19-related surveys administered from April 2020 to November 2022. Laparoscopic diagnosis of endometriosis was documented prospectively in main cohort questionnaires prior to the pandemic (1993-2020) with high validity. SARS-CoV-2 infection (confirmed by antigen, PCR, or antibody test) and CDC-defined long-term COVID-19 symptoms (≥4 weeks) were self-reported during follow-up. Among individuals with SARS-CoV-2 infection, we fit Poisson regression models to assess the associations between endometriosis and risk of long COVID-19 symptoms, with adjustment for potential confounding variables (demographics, body mass index, smoking status, history of infertility, and history of chronic diseases).

Results: Among 3650 women in our sample with self-reported SARS-CoV-2 infections during follow-up, 386 (10.6%) had a history of endometriosis with laparoscopic confirmation and 1598 (43.8%) reported experiencing long COVID symptoms. The majority of women were Non-Hispanic White (95.4%), with a median age of 59 years (interquartile range=44-65). Women with a history of laparoscopically-confirmed endometriosis had a 22% greater risk of developing long COVID (adjusted RR=1.22, 95% CI=1.05-1.42), compared to those who had never been diagnosed with endometriosis. The association was stronger when we defined long COVID as having symptoms ≥8 weeks (RR=1.28, 95% CI=1.09-1.50). We observed no statistically significant differences in the relationship between endometriosis and long COVID by age, infertility history, or comorbidity with uterine fibroids, although there was a suggestive trend that women <50 years may be at higher risk (<50 years, RR=1.37, 95% CI=1.00-1.88; ≥50 years, RR=1.19, 95% CI=1.01-1.41). Among persons who developed long COVID, women with endometriosis reported on average one additional long-term symptom compared to women without endometriosis.

Conclusions and relevance: Our findings suggest that those with a history of endometriosis may be at modestly increased risk for long COVID. Health care providers should be aware of endometriosis history when treating patients for signs of persisting symptoms post-SARS-CoV-2 infection. Future studies should investigate the potential biological pathways underlying these associations.

Source: Wang S, Farland LV, Gaskins AJ, Mortazavi J, Wang YX, Tamimi RM, Rich-Edwards JW, Zhang D, Terry KL, Chavarro JE, Missmer SA. Association of Laparoscopically-confirmed Endometriosis with Long COVID: A Prospective Cohort Study. Am J Obstet Gynecol. 2023 Mar 25:S0002-9378(23)00177-1. doi: 10.1016/j.ajog.2023.03.030. Epub ahead of print. PMID: 36972892. https://pubmed.ncbi.nlm.nih.gov/36972892/ https://www.ajog.org/article/S0002-9378(23)00177-1/pdf (Full text available as PDF file)