Ravindra Ganesh

Objectives: Long-term symptoms following infection with acute respiratory syndrome coronavirus-2 (SARS-CoV-2), termed post-acute sequelae of SARS-CoV-2 infection (PASC) or Long COVID (LC), persist beyond 90 days and may impact at least 10% of patients with acute infection. The exact cause of LC remains unknown, but several theories include persistent viral particles, immune dysfunction, and autonomic nervous system (ANS) imbalance, particularly involving the vagus nerve. Given the role of the vagus nerve in inflammation regulation, vagal nerve stimulation (VNS) is being explored as a treatment option. The present study aimed to evaluate the feasibility, safety, and exploratory effects of a handheld external transcutaneous cervical non-invasive VNS (tcVNS) on the primary endpoint of Post-COVID Functional Status (PCFS) grade, alongside secondary outcomes such as LC-related fatigue and other symptoms. Methods: Participants from our Post COVID Care Clinic were randomized into treatment (tcVNS treatments two minutes, three times a day) and control (no VNS) groups for a study period of 12 weeks. Participants completed validated questionnaires, PET-CT scans, and inflammatory cytokines at baseline and 12 weeks. Results: All randomized patients (8 tcVNS, 10 control) completed the 12-week study. Participants randomized to tcVNS were observed to have improvements in PHQ-9, PROMIS-F, and COMPASS-31 when compared to controls, but these differences were not statistically significant. Cortisol and DHEA were also observed to increase less in the tcVNS group when compared to the control group, but these changes were also not statistically significant. Conclusions: tcVNS was well tolerated and may be a promising therapeutic approach for LC, a chronic disease with no approved treatments and very low rates of complete recovery.

Objective: Long COVID (LC) refers to the long-term symptoms occurring after SARS-CoV-2 infection and resolution of the initial disease prodrome. While LC is increasingly recognized, knowledge about its biomarkers is still limited. This study examines imaging findings in ¹⁸ F-FDG PET-CT scans in 40 patients with LC from an academic LC Clinic, for potential imaging biomarkers. Methods: This study included patients aged 18 and older with confirmed positive SARS-CoV-2 PCR test and at least 28 days post-symptom onset. ¹⁸ F-FDG PET-CT scans were performed, and brain metabolic activity was compared to a control database to generate Z-scores. Participants were grouped based on their clinical phenotype and Z-scores of different brain regions were analyzed using t-tests. Results: The study group was mainly female (70%), with a median age of 53 years, and predominantly non-Hispanic White (90%). Most had pre-existing conditions such as gastrointestinal, cardiovascular, endocrine, and psychiatric disorders. The findings showed significant cerebral hypometabolism in 29 patients with fatigue and post-exertional malaise (PEM), particularly in the left sensorimotor cortex (p=0.0253) and bilateral primary visual cortex (right: p=0.0096, left: p=0.0016), which persisted up to two years after infection. Conclusions: In summary, this study identified persistent cerebral hypometabolism in LC patients, especially those with fatigue with PEM, up to two years post-infection. These results suggest that ¹⁸ F-FDG PET-CT could be a valuable tool for diagnosing and managing LC. Further research is essential to confirm these findings and improve treatment strategies for patients with LC.

Despite the increasing prevalence and median severity of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), medical education on the disease is scant, leading to a diagnostic crisis in which the majority of people with ME/CFS are undiagnosed. We created a care process algorithm in AskMayoExpert accessible to all Mayo Clinic medical providers as a source for information on diagnosis and management of ME/CFS. To evaluate whether the algorithm was associated with improved diagnostic accuracy, we compared concordance before versus after the algorithm was introduced, where concordance was defined as agreement between an appropriately coded referral to Mayo Clinic’s Chronic Fatigue Specialty Clinic and the specialty clinic with an expert diagnosis of ME/CFS. Referrals to the Chronic Fatigue Specialty Clinic increased overall and were more likely to show concordance between specialist diagnosis and referral after the introduction of the ME/CFS AskMayoExpert algorithm. Particularly in diseases that are prevalent and poorly understood, a point-of-care clinical tool may offer just-in-time opportunities to improve diagnosis and management.

Background: COVID-19 convalescent plasma (CCP) is obtained from people recently recovered from COVID-19 and contains viral-neutralizing antibodies. Because such treatment is safe and effective against SARS-CoV-2, the US Food and Drug Administration (FDA) has recently authorized the use of CCP for COVID-19 patients with immunodeficiencies. Currently available CCP is a “hybrid” product with antibodies from individuals who had both infection and vaccination (vaccine-boosted CCP). In this context, there is growing interest in CCP treatment outcomes in specific groups of immunocompromised patients. Specifically, B-cell depleted patients are at risk of not producing antibodies after either infection or vaccination. Hence, B-cell depleted patients are conceivably among those who would benefit the most from CCP. We thus conducted a systematic review and individual patient data meta-analysis to assess characteristics associated with 60-day survival in B-cell depleted patients transfused with CCP. Methods: The last search was April 2 ^nd , 2024, and included all studies using CCP in B-cell depleted patients. Whenever not available in the publication, we requested individual participant data from corresponding authors of eligible studies. Risk of bias was assessed using Joanna Briggs Institute Critical Appraisal Tools. Data were analyzed using conditional logistic regression. Results: We describe individual patient data extracted from 85 studies and synthesized into a cohort of 570 patients. The overall 60-day survival rate was 86.5%. Of patients with information available, 70.1% achieved SARS-CoV-2 clearance, and 64.3% had clinical improvement within 5 days of CCP transfusion. After controlling for age, sex, calendar year of infection and World Health Organization (WHO) disease severity, we found a significant association between 60-day survival and days since last anti-CD20 dose (OR=1.16 per 10-day increase; 95% CI 1.04 to 1.29; p=0.007) and transfusion of vaccine-boosted CCP (OR=9.49; 95% CI 2.01 to 44.82; p=0.005), but not with concomitant remdesivir treatment (OR=1.31; 95% CI 0.66 to 2.61; p=0.440). Discussion: Our study is limited to individual participant data analysis, with a majority of the studies included being case series and case reports. Overall survival in our cohort of B-cell depleted patients was consistent with prior meta-analysis of randomized controlled trials on survival of immunocompromised patient transfused with CCP (∼84%). A novel finding from this analysis is that vaccine-boosted CCP with a presumably higher content of neutralizing antibodies is associated with a high survival benefit. Registration: The protocol for this systematic review and individual participant data meta-analysis was registered with PROSPERO (CRD42024516513) on March 1st, 2024.

Objective: This study evaluated the feasibility and satisfaction of using a wearable brain activity sensing device for stress reduction among patients experiencing Long COVID (LC). Patients and Methods: Patients with LC (N = 45) were invited to participate in an open-label pilot study. Participants were asked to use a brain-sensing electroencephalogram (S-EEG) wearable device (Muse-S™) daily for 90 days and followed for an additional 90 days (180 days total participation). Study enrollment began June 28, 2022, and ended July 28, 2023. Results: Patients were predominantly female (82%), white (96%), and with an average age of 47.6 (±12.5) years. At the end of treatment (90 days), cognition, sleep, self-efficacy, and quality-of-life quality of life improved ( P < .001 to P = .04). In addition, stress and anxiety were significantly reduced ( P < .001). These significant changes persisted by end-of-study (180 days). For stress ( P = .023) and anxiety ( P = .033), a change from the baseline during follow-up was significantly associated with the amount of S-EEG usage. The end-of-study satisfaction survey indicated that patients were very satisfied with the S-EEG device, and 97% planned to continue using it. Conclusion: Results suggest that the S-EEG device improved cognition in LC, which is one of the main severe symptoms we see in our LC clinic. In addition, it helped reduce stress and anxiety. These findings have important clinical implications for LC patients using S-EEG as an adjunct to concurrent LC clinical care which includes pharmacotherapies.

Three-dimensional reconstruction of airways has shown increased luminal area in patients with COVID-19 and post-acute sequelae of COVID-19 when compared with healthy controls. These findings suggest the role of large conducting airways in the pathogenesis of post-acute sequelae of COVID 19.

Although severe coronavirus disease 2019 (COVID-19) and hospitalization associated with COVID-19 are generally preventable among healthy vaccine recipients, patients with immunosuppression have poor immunogenic responses to COVID-19 vaccines and remain at high risk of infection with SARS-CoV-2 and hospitalization. In addition, monoclonal antibody therapy is limited by the emergence of novel SARS-CoV-2 variants that have serially escaped neutralization. In this context, there is interest in understanding the clinical benefit associated with COVID-19 convalescent plasma collected from persons who have been both naturally infected with SARS-CoV-2 and vaccinated against SARS-CoV-2 (“vax-plasma”). Thus, we report the clinical outcome of 386 immunocompromised outpatients who were diagnosed with COVID-19 and who received contemporary COVID-19-specific therapeutics (standard-of-care group) and a subgroup who also received concomitant treatment with very high titer COVID-19 convalescent plasma (vax-plasma group) with a specific focus on hospitalization rates. The overall hospitalization rate was 2.2% (5 of 225 patients) in the vax-plasma group and 6.2% (10 of 161 patients) in the standard-of-care group, which corresponded to a relative risk reduction of 65% ( P = 0.046). Evidence of efficacy in nonvaccinated patients cannot be inferred from these data because 94% (361 of 386 patients) of patients were vaccinated. In vaccinated patients with immunosuppression and COVID-19, the addition of vax-plasma or very high titer COVID-19 convalescent plasma to COVID-19-specific therapies reduced the risk of disease progression leading to hospitalization. IMPORTANCE: As SARS-CoV-2 evolves, new variants of concern (VOCs) have emerged that evade available anti-spike monoclonal antibodies, particularly among immunosuppressed patients. However, high-titer COVID-19 convalescent plasma continues to be effective against VOCs because of its broad-spectrum immunomodulatory properties. Thus, we report clinical outcomes of 386 immunocompromised outpatients who were treated with COVID-19-specific therapeutics and a subgroup also treated with vaccine-boosted convalescent plasma. We found that the administration of vaccine-boosted convalescent plasma was associated with a significantly decreased incidence of hospitalization among immunocompromised COVID-19 outpatients. Our data add to the contemporary data providing evidence to support the clinical utility of high-titer convalescent plasma as antibody replacement therapy in immunocompromised patients.

Background Coronavirus disease 2019 (COVID-19) is associated with enlarged luminal areas of large conducting airways. In 10-30% of patients with acute COVID-19 infection, symptoms persist for more than 4 weeks (referred to as post-acute sequelae of COVID-19, or PASC), and it is unknown if airway changes are associated with this persistence. Thus, we aim to investigate if luminal area of large conducting airways is different between PASC and COVID-19 patients, and healthy controls. Methods In this retrospective case-control study seventy-five patients with PASC (48 females) were age-, height-, and sex-matched to 75 individuals with COVID-19 and 75 healthy controls. Using three-dimensional digital reconstruction from computed tomography imaging, we measured luminal areas of seven conducting airways, including trachea, right and left main bronchi, bronchus intermediate, right and left upper lobe, and left lower lobe bronchi. Findings Airway luminal areas between COVID-19 and PASC groups were not different (p>0.66). There were no group differences in airway luminal area (PASC vs control) for trachea and right main bronchus. However, in the remaining five airways, airway luminal areas were 12% to 39% larger among PASC patients compared to controls (pInterpretation Patients diagnosed with COVID-19 and PASC have greater airway luminal area in most large conducting airways compared to healthy controls. No differences in luminal area between patients with COVID-19 and PASC suggest persistence of changes or insufficient time for complete reversal of changes. Funding National Heart, Lung, and Blood Institute (F32HL154320 to JWS; 5R35HL139854 to MJJ); Postdoctoral Fellowship from the Natural Sciences and Engineering Research Council of Canada (AHR).

Objectives: To identify patient characteristics, health concerns, and barriers to care based on overweight or obesity. Methods: A 50-question anonymous survey was administered to patients. Data were compared by body mass index (BMI). Results: Among 3976 distributed surveys, 899 were returned and 682 were analyzed. Most respondents were women (60%), White (94%), and married/partnered (65%) and had some college education (80%). Younger and unmarried persons had higher BMI ( P < .001). Concern for quality of life ( P < .001) and importance of lifestyle changes ( P = .006) increased with BMI, but confidence in making changes decreased as BMI increased ( P < .001). Perceived good health decreased with increasing BMI ( P < .001), whereas depression and other comorbid conditions increased. Self-esteem decreased and stigma increased with higher BMI (both P < .001). Weight discussions with clinicians ( P < .001) and belief that clinicians should be involved in weight management ( P = .002) increased with BMI, yet self-perception of being judged by clinicians also increased ( P < .001). As BMI increased, delays in seeking health care increased ( P < .001). Conclusions: This survey study highlights perceived health concerns and barriers to care among persons with overweight and obesity. With higher BMI, self-esteem decreased, and stigma, self-perception of poor health, perception of being judged by clinicians, and delay in seeking medical care increased.