Self-reported Memory Problems 8 Months After COVID-19 Infection

 Arne Søraas, PhD¹; Ragnhild Bø, PhD²; Karl Trygve Kalleberg, PhD³; et al

doi:10.1001/jamanetworkopen.2021.18717

PDF: https://scholar.google.com/scholar_url?url=https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2782531/sraas_2021_ld_210153_1626974289.73379.pdf&hl=en&sa=T&oi=ucasa&ct=ufr&ei=pLUVYYe0KsjuygTi04DgAw&scisig=AAGBfm1GHgxG2TeLAp0Qed4DEMQGnGXkOg

Introduction

COVID-19 is an airway disease that also affects the nervous system.¹ Therefore, neurological and neurocognitive symptoms may be a part of the postacute sequelae of SARS-CoV-2 infection (PASC) syndrome. PASC may be found to affect a high proportion of people who had mild cases of COVID-19, and there is an urgent need for a detailed description of PASC in nonhospitalized patients.^2,3 This cohort study examines self-reported memory problems 8 months after COVID-19 infection.

Methods

This cohort study was approved by the Regional Research Ethics Committee according to the Declaration of Helsinki. Eligible participants provided informed consent by signing an online electronic consent form and completing an online baseline questionnaire and follow-up questionnaires. This study used the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

We followed a cohort of 13 001 adults who were invited after (1) having their clinical specimen analyzed for SARS-CoV-2 at 4 large accredited laboratories in Norway or (2) being randomly selected from the Norwegian population (untested). All adults who were tested for COVID between February 1 and April 15, 2020, were invited (eFigure in the Supplement). Nearly all testing in Norway during that time was on symptomatic patients and free of charge.⁴

We collected data on demographics, underlying medical conditions, symptoms, health-related quality of life from the RAND 36-Item Health Survey, memory problems, and known confounders for memory problems (eAppendix in the Supplement). Data from participants who were hospitalized are not reported in this study.

The main outcome was self-reported memory problems 8 months after infection, and the exposure was SARS-CoV-2 status (ie, positive, negative, or untested). To determine whether differences in the outcome between the exposure groups remained after adjusting for confounding, we applied a multiple logistic regression model that included age, gender, and known confounders for memory problems (RAND-36 items for physical health limitation, pain, feeling energetic, and mood). SPSS version 27 (IBM) and R version 4.0.3 (R Project for Statistical Computing) were used for the statistical computations. Statistical tests were 2-tailed, and the significance level was set to P < .05. Data analyses were performed on May 10 and May 13, 2021.

Results

We sent up to 3 electronic invitations to 53 168 invitees, and after exclusions, 13 001 (24%) participants completed the baseline questionnaire and were followed up for 8 months (Table). The mean (SD) age was 47 (14.3) years, and 8642 (66%) were women.

At follow-up, a mean (SD) of 257 (32) days after baseline, 9705 of 13 001 participants (75%) responded, and 72 of 651 of the participants (11%) in the SARS-CoV-2–positive group reported memory problems. In contrast, 254 of 5712 participants (4%) in the SARS-CoV-2–negative group or 80 of 3342 participants (2%) in the untested randomly selected reported memory problems (Figure).

In the multiple logistic regression model, SARS-CoV-2 positivity at baseline was strongly associated with reporting memory problems at 8 months follow-up (odds ratio [OR], 4.66; 95% CI, 3.25-6.66) compared to the untested randomly selected group. At follow-up, 267 of 649 participants (41%) in the SARS-CoV-2–positive group reported a significant worsening of health compared with 1 year prior, and 81 of 651 participants (12%) in the SARS-CoV-2–positive group also reported problems concentrating. Additionally, 59 of 267 participants (82%) in the SARS-CoV-2–positive group who reported memory problems also reported a worsening of health. Feeling depressed, having less energy, or pain were reported relatively equally by the different groups (Table).

Discussion

We examined the prevalence of self-reported memory problems in a large group of COVID-19 patients who were not hospitalized and had a relatively mild disease. Eight months after the positive SARS-CoV-2 test, the prevalence of memory problems in this group was higher than in the control group with a negative test or in the untested control population.

Most of the SARS-CoV-2–positive participants with memory problems also reported a worsening of their health compared with 1 year prior. Our findings suggest that SARS-CoV-2 may negatively impact memory even 8 months after having a mild case of the disease, and this can be associated with a worsening of health and PASC. The findings are a strong impetus to reconsider the notion that COVID-19 can be a mild disease. It also questions whether the current home-treatment strategies are optimal for the long-term outcome. Our results suggest that memory problems may be a part of PASC, but firmer conclusions should await a longer follow-up period.

This study had limitations. Although we ran multiple logistic regression that adjusted for several likely confounders, there may still have been unmeasured or residual confounding. An additional limitation of the study is that knowledge of COVID-19 status and symptoms at baseline could have led to participation bias or response bias during follow up. The low overall response rate of 24% may limit the generalizability of our findings. A strength of the study is the inclusion of 2 relevant comparison groups.

The lack of objective memory tests limits strong conclusions. However, subjective memory concerns have been shown to reflect objective problems and observable changes in everyday function even when controlling for associated factors, such as depression.⁵ Self-reported memory problems are also a risk factor for later mild cognitive impairment or dementia.⁶ Nevertheless, a more detailed examination of what type of memory problems are specific for PASC, like working memory vs long-term memory, is warranted in future studies.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2782531

Inhaled corticosteroids in early-stage COVID-19

 Dee Mangin, Michelle Howard

DOI: https://doi.org/10.1016/S0140-6736(21)01809-2

PDF: https://www.thelancet.com/action/showPdf?pii=S0140-6736%2821%2901809-2

The desperation of clinicians when faced with COVID-19 and the dearth of therapeutic options for its treatment have led clinical practice to reach for last-resort approaches, supported by tenuous data or hypotheses. The need for data-based clinical practice is clear from the initial wide use of hydroxychloroquine, shown subsequently to be harmful,

1

,  

2

 and the initial avoidance of oral corticosteroids, shown subsequently to be beneficial.

3

 Now practice is changing toward the usual measured approach of gathering data and using restraint, trying above all to do no harm in this viral illness.

Platforms for remarkable well designed pragmatic pandemic research, such as PRINCIPLE and the earlier RECOVERY study platform, have emerged to inform practice. The focus of the PRINCIPLE adaptive trial platform on management of COVID-19 in the primary care setting is vital—less than 10% of patients are managed in hospital.

Early in the pandemic, epidemiological data showing that patients with chronic obstructive pulmonary disease (COPD) and asthma had a lower incidence of COVID-19 infection led to speculation that inhaled corticosteroids could have some benefit. A small open-label trial suggested possible benefit in patients not admitted to hospital.

4

 Although there is a plausible mechanism for why inhaled corticosteroids could be beneficial, there are two reasons to be cautious: in the RECOVERY trial, although oral steroids offered benefit in seriously ill patients, they offered no benefit and possibly harm in those with less serious illness.

3

 And for those with COPD and asthma who do get infected, population studies suggest that use of inhaled corticosteroids is associated with worse outcomes.

5

,  

6

 These inconsistent results leave primary care practitioners, heavily involved in care of high-risk patients with early-stage COVID-19 in the community, with little certainty of the potential benefits and harms of inhaled corticosteroids.

A new analysis of the PRINCIPLE trial by Ly-Mee Yu and colleagues

7

 reported in The Lancet provides data from the largest trial of the use of inhaled corticosteroids in early-stage COVID-19. The primary outcome population included 833 participants who received inhaled budesonide plus usual care and 1126 who received usual care alone. The mean age was 64·2 years (SD 7·6), 1805 (92%) of 1959 participants were White, 1015 (52%) were women, and 1581 (81%) had comorbidities. The initial trial primary outcome was hospital admission or death, but this was changed before analysis because of lower than expected UK hospital admission rates (although the rate of hospital admissions or death in the trial was higher than the 5% estimated for the sample size calculation). Time to first self-reported recovery was added as a coprimary outcome. The results showed that using inhaled corticosteroids early in COVID-19 in patients aged 65 years and older and those aged 50 years and older with comorbidities shortened the time to first self-reported recovery by an estimated median of 2·94 days (95% Bayesian credible interval [BCI] 1·19–5·11), with an estimated time of 11·8 days (95% BCI 10·0–14·1) in the budesonide group versus 14·7 days (12·3–18·0) in the usual care group. The hospital admission or death outcome did not achieve the prespecified superiority threshold in the primary analysis population (72 [9%] of 787 in the budesonide group vs 116 (11%) of 1069 in the usual care group; model estimate 6·8% [95% BCI 4·1–10·2] vs 8·8% [5·5–12·7], odds ratio 0·75 [95% BCI 0·55–1·03]). The possibility of bias in the self-reported recovery outcome cannot be ruled out—placebos were not used and given that the primary and other secondary outcomes use self-report questions that are largely not based on instruments previously tested for reliability or validity, the well described placebo effect of inhalers could have inflated the effect size.

There remain puzzling questions about the dose–response and mechanisms of effect of inhaled corticosteroids in reducing time to self-reported recovery: in the patient group with less severe illness, the RECOVERY trial showed that use of systemic steroids appeared to result in worse outcomes than placebo, yet the dose of inhaled corticosteroids in the PRINCIPLE study is high enough to have systemic absorption. The data presented on differences in the effect of inhaled corticosteroids on individual symptoms are interesting: notably, the difference between groups was greater for gastrointestinal symptoms and myalgia than for respiratory symptoms as might have been anticipated. Also notable were the findings that the between-group difference in global self-rating of how well patients felt had largely disappeared by day 28 and the time to alleviation of all symptoms was not different between groups, yet the difference in the WHO-5 Well-Being Index, a subjective psychological wellbeing scale, was still present at 28 days. Longer-term follow-up clarifying the effects on the trajectory of illness, especially on persistent morbidity after COVID-19, would be useful.

On the basis of the PRINCIPLE trial data, it seems reasonable to consider inhaled corticosteroid use in early COVID-19 in patients similar to the trial population group (people with ongoing symptoms from COVID-19 aged ≥65 years or ≥50 years with specific comorbidities) who are interested in using them (80% of participants in the inhaled budesonide group in PRINCIPLE used the inhaled corticosteroids for at least a week). Various subgroup analyses in PRINCIPLE do not provide any pointers to which particular patient or illness characteristics in the included population might be more likely to predict benefit. These trial data do not support use in younger populations who are at lower risk of complications (<65 years with no comorbidities or anyone <50 years). Because vaccination was uncommon in trial participants, an important question is whether and what effect would be seen in the fully vaccinated population who have a different illness severity and trajectory.

We see through two recent pragmatic COVID-19 treatment trial platforms an important shift in approach: trials funded by governments and not industry, answering the crucial questions driven by immediate clinician need and not product marketing, and providing data in the spaces of clinical equipoise—this importance should not be underestimated or lost.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01809-2/fulltext#%20

In vitro determination of inhibitory effects by humic substances complexing Zinc and Selenium on SARS-CoV-2 virus replication

 Bernadett Palyi, Zoltan Kis, Polett Hajdrik, Noemi S Kovacs, Daniel S Veres, Krisztian Szigeti, Imre Hegedus, Tibor J Kovacs, Ralf K Bergmann, Domokos Mathe

doi: https://doi.org/10.1101/2021.08.11.456012

This article is a preprint and has not been certified by peer review [what does this mean?].

PDF: https://www.biorxiv.org/content/10.1101/2021.08.11.456012v1.full.pdf

Abstract

Humic substances are well known human nutritional supplement materials and play important performance-enhancing roles as animal feed additives, too. For decades, ingredients of humic substances have also been proven to carry potent antiviral effects against different viruses. Here, the antiviral activity of a humic substance containing ascorbic acid, Se- and Zn2+ ions intended as a nutritional supplement material was investigated against SARS-CoV-2 virus B1.1.7 Variant of Concern (Alpha Variant) in a VeroE6 cell line. Results show that this combination has a significant in vitro antiviral effect at a very low concentration range of its intended active ingredients. Even picomolar concentration ranges of humic substances, vitamin C and Zn/Se ions in the given composition were enough to achieve fifty percent viral replication inhibition in the applied SARS-CoV-2 virus inhibition test. Keywords: SARS-CoV-2, humic acid, fulvic acid, Zn-Se-ascorbic acid complex, antiviral activity, RT-PCR

Competing Interest Statement

The authors have declared no competing interest.

https://www.biorxiv.org/content/10.1101/2021.08.11.456012v1

What will it be like when COVID-19 becomes endemic?

 Immunity conferred from natural infection and vaccines, patterns of social contact, and virus transmissibility will all play a role in what COVID-19 will look like as it continues to circulate in the months and years ahead, says Yonatan Grad, Melvin J. and Geraldine L. Glimcher Associate Professor of Immunology and Infectious Diseases.

Q: Many experts have said they expect COVID-19 to become an endemic disease. How does a disease go from being acute to endemic? What factors shape the transition to endemicity? What’s a likely timeline for COVID-19 to become endemic?

A: The expectation that COVID-19 will become endemic essentially means that the pandemic will not end with the virus disappearing; instead, the optimistic view is that enough people will gain immune protection from vaccination and from natural infection such that there will be less transmission and much less COVID-19-related hospitalization and death, even as the virus continues to circulate.

The expected continued circulation of SARS-CoV-2 stands in contrast with the first round of SARS in 2003 and with the Ebola virus outbreak in West Africa in 2014, when public health measures ultimately stopped spread and brought both outbreaks to an end. While there are important differences among the viruses and the contexts, this comparison underscores the critical need to improve our global public health infrastructure and surveillance systems to monitor for and help respond to the inevitable next potential pandemic virus.

Since viruses spread where there are enough susceptible individuals and enough contact among them to sustain spread, it’s hard to anticipate what the timeline will be for the expected shift of COVID-19 to endemicity. It’s dependent on factors like the strength and duration of immune protection from vaccination and natural infection, our patterns of contact with one another that allow spread, and the transmissibility of the virus. So the patterns will likely differ considerably from what we saw with the other pandemics because of the heterogeneous responses to COVID-19 across the world—with some places engaging in “zero-COVID” policies, others with limited responses, and widely variable vaccine availability and uptake.

Q: What does history tell us about how deadly viruses such as COVID-19 can, over time, become manageable threats?

A: We know of a few respiratory viruses that were introduced into the human population, swept across the globe, and transitioned to endemic circulation, usually with annual wintertime peaks in incidence. The example most commonly invoked these days is the 1918 flu pandemic, caused by an A/H1N1 influenza virus. But there are other more recent examples from influenza: The 1957 flu pandemic caused by an A/H2N2 influenza virus, the 1968 flu pandemic from an A/H3N2 influenza virus, and the 2009 “swine flu” pandemic, from an A/H1N1 influenza virus.

The pandemics generally began with infection fatality rates higher than observed in the years following their introduction as the viruses continued to circulate. While declining fatality rates after pandemics may be due to a number of factors, one likely key contributor is that the first round of exposure to a pathogen confers some degree of protection against reinfection and severity of disease if reinfection does occur. Vaccines confer protection in much the same way, as the data from the COVID-19 vaccines has demonstrated.

Q: What is the likelihood that we will need booster shots every year? 

A: The need for annual boosters isn’t clear, and key biology and policy questions remain to be answered. On the biology side, how much antigenic evolution will we see in SARS-CoV-2—in other words, to what extent will it evolve to evade our immune system? We know of examples on both ends of the spectrum—some viruses, like influenza, require repeated vaccination because of its antigenic evolution, whereas others, like measles, are kept at bay for decades after childhood vaccination. How long does immune protection last, and what is the nature of that protection? How much does vaccine-conferred protection reduce the likelihood of infection, of severe disease if infected, or of the likelihood of transmission if infected? How quickly do each of these responses wane? On the policy side, what burden of disease are we willing to tolerate in a population?

These policy questions extend beyond COVID-19, of course, and should prompt us to reevaluate what we want to do about other preventable diseases. We’re in the midst of a wave of respiratory syncytial virus (RSV), another respiratory virus that for most of us causes cold and flu-like symptoms but that can be much more severe in infants, the elderly, and those with respiratory conditions. We don’t yet have an approved vaccine or highly effective treatment for RSV. And while we have modestly effective influenza vaccines and therapeutics, we usually see between 20,000 to 60,000 deaths a year in the U.S. from influenza. On a global scale, tuberculosis and malaria remain scourges that cause immense suffering. Investments in these areas and other measures that we’ve learned from COVID-19, such as the importance of ventilation and masking, can help reduce illness and death from a range of respiratory viruses and drive innovation in tools to tackle other infectious disease threats.

Past pandemics have led to massive changes in the way we live that we’ve come to accept as normal. Screens on our doors and windows helped keep out mosquitos that carried yellow fever and malaria. Sewer systems and access to clean water helped eliminate typhoid and cholera epidemics. Perhaps the lessons learned from COVID-19 in terms of disease prevention can yield similar long-term improvements in individual and global health.

https://www.hsph.harvard.edu/news/features/what-will-it-be-like-when-covid-19-becomes-endemic/

Neutralization of VOCs including Delta one year post COVID-19 or vaccine

 Sebastian Havervall, Ulrika Marking, Max Gordon, Henry Ng, Nina Greilert-Norin, Sarah Lindbo, Kim Blom, Peter Nilsson, Mia Phillipson, Jonas Klingstrom, Sara Mangsbo, Mikael Aberg, Sophia Hober, Charlotte Thalin

doi: https://doi.org/10.1101/2021.08.12.21261951

This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

PDF: https://www.medrxiv.org/content/10.1101/2021.08.12.21261951v1.full.pdf

Abstract

Background: SARS-CoV-2 variants, such as Alpha, Beta, Gamma and Delta, are raising concern about the efficiency of neutralizing antibodies (NAb) induced by wild-type infection or vaccines based on the wild-type spike. Methods: We determined IgG and NAb against SARS-CoV-2 variants one year following mild wild-type infection (n=104) and two-dose regimens with BNT162b2 (BNT/BNT) (n=67), ChAdOx1 (ChAd/ChAd) (n=82), or heterologous ChAdOx1 followed by BNT162b2 (ChAd/BNT) (n=116). Findings: Wild type spike IgG and NAb remained detectable in 80% (83/104) of unvaccinated participants one year post mild infection. The neutralizing capacity was similar against wild type (reference), Alpha (0.95 (0.92-0.98) and Delta 1.03 (0.95-1.11) but significantly reduced against Beta (0.54 (0.48-0.60)) and Gamma 0.51 (0.44-0.61). Similarly, BNT/BNT and ChAd/ChAd elicited sustained capacity against Alpha and Delta (1.01 (0.78-1.31) and 1.03 (0.95-1.11)) and (0.96 (0.84-1.09) and 0.82 (0.61-1.10) respectively), with reduced capacity against Beta (0.67 (0.50-0.88) and 0.53 (0.40-0.71)) and Gamma (0.12 (0.06-0.27) and 0.54 (0.37-0.80)). A similar trend was found following ChAd/BNT (0.74 (0.66-0.83) and 0.70 (0.50-0.97) against Alpha and Delta and 0.29 (0.20-0.42) and 0.13 (0.08-0.20) against Beta and Gamma). Interpretation: Persistent neutralization of the wide-spread Alpha and Delta variants one year after wild-type infection may aid vaccine policy makers in low-resource settings when prioritizing vaccine supply. The reduced capacity of neutralizing Beta and Gamma strains, but not the Alpha and Delta strains following both infection and three different vaccine regimens argues for caution against Beta and Gamma-exclusive mutations in the efforts to optimize next generation SARS-CoV-2 vaccines. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section

Competing Interest Statement

SoH has participated on Astra Zeneca COVID-19 SCG Virtual Advisory Board. Otherwise, the authors declare no competing interests.

Funding Statement

This work was funded by Jonas & Christina af Jochnick foundation; Lundblad family foundation; Region Stockholm; Knut and Alice Wallenberg foundation; Science for Life Laboratory (SciLifeLab); Erling-Persson family foundation; CIMED and the Swedish Research Council.

https://www.medrxiv.org/content/10.1101/2021.08.12.21261951v1