Brain fog in long COVID limits function and health status, independently of hospital severity and preexisting conditions.

Importance: The U.S. government has named post-acute sequelae of COVID-19 (longCOVID) as influential on disability rates. We previously showed that COVID-19 carries a medical/functional burden at 1 year, and that age and other risk factors of severe COVID-19 were not associated with increased longCOVID risk. Long-term longCOVID brain fog (BF) prevalence, risk factors and associated medical/functional factors are poorly understood, especially after mild SARS-CoV-2 infection. Methods: A retrospective observational cohort study was conducted at an urban tertiary-care hospital. Of 1,032 acute COVID-19 survivors from March 3-May 15, 2020, 633 were called, 530 responded (59.2 ± 16.3 years, 44.5% female, 51.5% non-White) about BF prevalence, other longCOVID, post-acute ED/hospital utilization, perceived health/social network, effort tolerance, disability. Results: At approximately 1-year, 31.9% (n = 169) experienced BF. Acute COVID-19 severity, age, and premorbid cardiopulmonary comorbidities did not differ between those with/without BF at 1 year. Patients with respiratory longCOVID had 54% higher risk of BF than those without respiratory longCOVID. BF associated with sleep disturbance (63% with BF vs.29% without BF, p < 0.0001), shortness of breath (46% vs.18%, p < 0.0001), weakness (49% vs.22%, p < 0.0001), dysosmia/dysgeusia (12% vs.5%, p < 0.004), activity limitations (p < 0.001), disability/leave (11% vs.3%, p < 0.0001), worsened perceived health since acute COVID-19 (66% vs.30%, p < 0.001) and social isolation (40% vs.29%, p < 0.02), despite no differences in premorbid comorbidities and age. Conclusions and relevance: A year after COVID-19 infection, BF persists in a third of patients. COVID-19 severity is not a predictive risk factor. BF associates with other longCOVID and independently associates with persistent debility.

Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID.

BACKGROUND: Mechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 "PASC" or "Long COVID") remain unclear. This study sought to elucidate mechanisms of cardiopulmonary symptoms and reduced exercise capacity. METHODS: We conducted cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults > 1 year after confirmed SARS-CoV-2 infection in a post-COVID cohort, compared those with or without symptoms, and correlated findings with previously measured biomarkers. RESULTS: Sixty participants (median age 53, 42% female, 87% non-hospitalized) were studied at median 17.6 months following SARS-CoV-2 infection. On CPET, 18/37 (49%) with symptoms had reduced exercise capacity (<85% predicted) compared to 3/19 (16%) without symptoms (p = 0.02). Adjusted peak VO2 was 5.2 ml/kg/min lower (95%CI 2.1-8.3; p = 0.001) or 16.9% lower percent predicted (95%CI 4.3-29.6; p = 0.02) among those with symptoms. Chronotropic incompetence was common. Inflammatory markers and antibody levels early in PASC were negatively correlated with peak VO2 more than 1 year later. Late-gadolinium enhancement on CMR and arrhythmias were absent. CONCLUSIONS: Cardiopulmonary symptoms >1 year following COVID-19 were associated with reduced exercise capacity, which was associated with elevated inflammatory markers early in PASC. Chronotropic incompetence may explain exercise intolerance among some with cardiopulmonary Long COVID.

Survival ≠ Recovery: A Narrative Review of Post-Intensive Care Syndrome

: Surviving critical illness does not always equate to recovery, with its aftermath frequently complicated by post-intensive care syndrome (PICS). This syndrome consists of a collection of new or worsening impairments in the physical, psychological, or cognitive domains that develop after critical illness. In this review, we describe the clinical manifestations, evaluation, and management of PICS. We also examine the interplay between PICS and social determinants of health. Finally, we discuss how multidisciplinary PICS clinics can be utilized to care for intensive care unit (ICU) survivors and potentially improve care within the ICU.

Prevalence and Characteristics of Long COVID 7-12 Months After Hospitalization Among Patients From an Urban Safety-Net Hospital: A Pilot Study.

Introduction: Little is known about the burden of long COVID among Black and Hispanic patients in the U.S. We surveyed adult patients hospitalized for COVID-19 at John H. Roger, Jr. Hospital of Cook County, a safety-net hospital predominantly serving Black and Hispanic patients in Chicago, for persistent symptoms after hospitalization to assess prevalence and identify risk factors. Methods: Cross-sectional data were obtained over 6 months after discharge from patients hospitalized at John H. Roger, Jr. Hospital of Cook County who tested positive for SARS-CoV-2 between October 1, 2020 and January 12, 2021. Multivariable logistic regression was used to analyze the associations between patient characteristics and symptom persistence. Results: Of 145 patients surveyed at a median follow-up period of 255 days (IQR=238-302), 80% were Black or Hispanic, and 50 (34%) reported at least 1 symptom. In multivariable logistic regression, the risk of long COVID was associated with the severity of acute COVID-19 illness, consistent with findings from population-based cohort studies. Conclusions: Long COVID prevalence remains high 7 months to a year after an initial illness in a majority Black and Hispanic hospitalized cohort. There is a long-term and ongoing need to assess and address the burden of long COVID, especially among minority communities disproportionately affected by acute COVID-19.

A review of cytokine-based pathophysiology of Long COVID symptoms.

The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production. In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with "brain fog," arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines. There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS.

Inflammation and Epstein-Barr Virus at the Crossroads of Multiple Sclerosis and Post-Acute Sequelae of COVID-19 Infection.

Recent studies have strengthened the evidence for Epstein-Barr Virus (EBV) as an important contributing factor in the development of multiple sclerosis (MS). Chronic inflammation is a key feature of MS. EBV+ B cells can express cytokines and exosomes that promote inflammation, and EBV is known to be reactivated through the upregulation of cellular inflammasomes. Inflammation is a possible cause of the breakdown of the blood-brain barrier (BBB), which allows the infiltration of lymphocytes into the central nervous system. Once resident, EBV+ or EBV-specific B cells could both plausibly exacerbate MS plaques through continued inflammatory processes, EBV reactivation, T cell exhaustion, and/or molecular mimicry. Another virus, SARS-CoV-2, the cause of COVID-19, is known to elicit a strong inflammatory response in infected and immune cells. COVID-19 is also associated with EBV reactivation, particularly in severely ill patients. Following viral clearance, continued inflammation may be a contributor to post-acute sequelae of COVID-19 infection (PASC). Evidence of aberrant cytokine activation in patients with PASC supports this hypothesis. If unaddressed, long-term inflammation could put patients at risk for reactivation of EBV. Determining mechanisms by which viruses can cause inflammation and finding treatments for reducing that inflammation may help reduce the disease burden for patients suffering from PASC, MS, and EBV diseases.

Inpatient post-COVID-19 rehabilitation program featuring virtual reality-Preliminary results of randomized controlled trial.

Background: Numerous recommendations from pulmonary scientific societies indicate the need to implement rehabilitation programs for patients after COVID-19. The aim of this study was to propose an innovative comprehensive intervention based on a hospital-based pulmonary rehabilitation program for individuals with post-acute sequelae of COVID-19. Methods: It was decided to evaluate two forms of hospital rehabilitation: traditional and one provided through virtual reality. Preliminary results are based on a group of 32 patients (20 female and 12 male), of average age 57.8 (4.92) years in the period of 3-6 months after the initial infection. Primary outcomes included analysis of lung function, exercise performance and stress level. A 3-week, high-intensity, five-times per week pulmonary rehabilitation program was designed to compare the effectiveness of a traditional form with a VR-led, novel form of therapy. Results: The analysis of the results showed a statistically significant improvement in both groups with regard to exercise performance expressed as 6MWT distance. Moreover, a statistically significant decrease in dyspnoea levels following the 6MWT was also noted in intergroup comparison, but the between-group comparison revealed non-statistically significant changes with low effect size. Regarding lung function, the analysis showed essentially normal lung function at baseline and a non-statistically significant improvement after the completion of the rehabilitation program. The analysis of the stress level showed a statistically significant improvement in both groups within the inter-group comparison, yet the between-group comparison of deltas values showed a non-significant difference with low effect size. Conclusion: A 3-weeks inpatients pulmonary rehabilitation program led to improvement of the exercise performance of people with post-acute sequelae of COVID-19, but not lung function. Furthermore, the program was shown to reduce patients' stress levels. A comparison of the traditional form of rehabilitation to the novel form using VR, shows similar effectiveness in terms of exercise performance and stress levels.

Leveraging Serologic Testing to Identify Children at Risk For Post-Acute Sequelae of SARS-CoV-2 Infection: An Electronic Health Record-Based Cohort Study from the RECOVER Program.

Using an electronic health record-based algorithm, we identified children with Coronavirus disease 2019 (COVID-19) based exclusively on serologic testing between March 2020 and April 2022. Compared with the 131 537 polymerase chain reaction-positive children, the 2714 serology-positive children were more likely to be inpatients (24% vs 2%), to have a chronic condition (37% vs 24%), and to have a diagnosis of multisystem inflammatory syndrome in children (23% vs <1%). Identification of children who could have been asymptomatic or paucisymptomatic and not tested is critical to define the burden of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 infection in children.

What is the impact of post-COVID-19 syndrome on health-related quality of life and associated factors: a cross-sectional analysis.

BACKGROUND: After the acute phase, symptoms or sequelae related to post-COVID-19 syndrome may persist for months. In a population of patients, previously hospitalized and not, followed up to 12 months after the acute infection, we aim to assess whether and to what extent post-COVID-19 syndrome may have an impact on health-related quality of life (HRQoL) and to investigate influencing factors. METHODS: We present the cross-sectional analysis of a prospective study, including patients referred to the post-COVID-19 service. Questionnaires and scales administered at 3, 6, 12 months were: Short-Form 36-item questionnaire (SF-36); Visual Analogue Scale of the EQ5D (EQ-VAS); in a subgroup, Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI-II) and Pittsburgh Sleep Quality Index (PSQI). Linear regression models were fitted to identify factors associated with HRQoL. RESULTS: We considered the first assessment of each participant (n = 572). The mean scores in SF-36 and in EQ-VAS were significantly lower than the Italian normative values and remained stable over time, except the mental components score (MCS) of the SF-36 and EQ-VAS which resulted in lower ratings at the last observations. Female gender, presence of comorbidities, and corticosteroids treatment during acute COVID-19, were associated with lower scores in SF-36 and EQ-VAS; patients previously hospitalized (54%) reported higher MCS. Alterations in BAI, BDI-II, and PSQI (n = 265)were associated with lower ratings in SF-36 and EQ-VAS. CONCLUSIONS: This study provides evidence of a significantly bad perception of health status among persons with post-COVID-19 syndrome, associated with female gender and, indirectly, with disease severity. In case of anxious-depressive symptoms and sleep disorders, a worse HRQoL was also reported. A systematic monitoring of these aspects is recommended to properly manage the post-COVID-19 period.

Encephalic nocardiosis after mild COVID-19: A case report.

The COVID-19 pandemic and the associated post-acute sequelae of COVID-19 (PASC) have led to the identification of a complex disease phenotype that is associated with important changes in the immune system. Herein, we describe a unique case of Nocardia farcinica cerebral abscess in an individual with sudden immunodeficiency several months after mild COVID-19. Intravenous Bactrim and Imipenem were prescribed for 6 weeks. After this, a 12-month course of Bactrim and Clavulin was prescribed to be taken orally, given the N. farcinica infection at the level of the central nervous system. This case report highlights the need for future research into the pathophysiology of COVID-19 and PASC immune dysregulation in convalescent individuals. It also draws attention to the need for timely consideration of opportunistic infections in patients with a history of COVID-19.

SARS-CoV-2 Infection and Lung Regeneration.

The lung is the primary site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced immunopathology whereby the virus enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2). Sophisticated regeneration and repair programs exist in the lungs to replenish injured cell populations. However, known resident stem/progenitor cells have been demonstrated to express ACE2, raising a substantial concern regarding the long-term consequences of impaired lung regeneration after SARS-CoV-2 infection. Moreover, clinical treatments may also affect lung repair from antiviral drug candidates to mechanical ventilation. In this review, we highlight how SARS-CoV-2 disrupts a program that governs lung homeostasis. We also summarize the current efforts of targeted therapy and supportive treatments for COVID-19 patients. In addition, we discuss the pros and cons of cell therapy with mesenchymal stem cells or resident lung epithelial stem/progenitor cells in preventing post-acute sequelae of COVID-19. We propose that, in addition to symptomatic treatments being developed and applied in the clinic, targeting lung regeneration is also essential to restore lung homeostasis in COVID-19 patients.

COVID-19 vaccination for the prevention and treatment of long COVID: A systematic review and meta-analysis.

Empirical evidence addressing the association between SARS-CoV-2 vaccination and long COVID would guide public health priorities and inform personal health decisions. Herein, the co-primary objectives are to determine the differential risk of long COVID in vaccinated versus unvaccinated patients, and the trajectory of long COVID following vaccination. Of 2775 articles identified via systematic search, 17 were included, and 6 were meta-analyzed. Meta-analytic results determined that at least one vaccine dose was associated with a protective effect against long COVID (OR 0.539, 95% CI 0.295-0.987, p = 0.045, N = 257 817). Qualitative analysis revealed that trajectories of pre-existing long COVID following vaccination were mixed, with most patients reporting no changes. The evidence herein supports SARS-CoV-2 vaccination for the prevention of long COVID, and recommends long COVID patients adhere to standard SARS-CoV-2 vaccination schedules.

[Long COVID-A New Challenge in Medicine: Focus on Pregnancy and Breastfeeding]. / Long COVID ­ eine neue Herausforderung in der Medizin: Fokus auf Schwangerschaft und Stillzeit.

Long COVID (coronavirus disease) has been described as a new multi-organ disease, which appears to be more prevalent in women than in men. Pregnant and breastfeeding women are a special subgroup of patients to consider with long COVID, as only scarce data have been collected to date. Menstrual changes are commonly observed during or after COVID-19; some studies also attribute slight changes of cycle length to previous inoculation against the virus. Pregnant women who have a symptomatic infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are at a higher risk for adverse outcomes and pregnancy-associated complications. Moreover, more and robust data are required to evaluate vertical transmission. COVID vaccines are the most effective tool against the pandemic, as they prevent infection, but also appear to be able to ease long COVID symptoms. Vaccines have been proven safe and effective in both pregnant and breastfeeding women. This article aims to present current data on long COVID in pregnant and breastfeeding women and elucidate risk factors and possible treatment options.

Protective effect of COVID-19 vaccination against long COVID syndrome: A systematic review and meta-analysis.

BACKGROUND: The relationship between coronavirus disease 2019 (COVID-19) vaccination and long COVID has not been firmly established. We conducted a systematic review and meta-analysis to evaluate the association between COVID-19 vaccination and long COVID. METHODS: PubMed and EMBASE databases were searched on September 2022 without language restrictions (CRD42022360399) to identify prospective trials and observational studies comparing patients with and without vaccination before severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We also included studies reporting symptomatic changes of ongoing long COVID following vaccination among those with a history of SARS-CoV-2 infection. Odds ratios (ORs) for each outcome were synthesized using a random-effects model. Symptomatic changes after vaccination were synthesized by a one-group meta-analysis. RESULTS: Six observational studies involving 536,291 unvaccinated and 84,603 vaccinated (before SARS-CoV-2 infection) patients (mean age, 41.2-66.6; female, 9.0-67.3%) and six observational studies involving 8,199 long COVID patients (mean age, 40.0 to 53.5; female, 22.2-85.9%) who received vaccination after SARS-CoV-2 infection were included. Two-dose vaccination was associated with a lower risk of long COVID compared to no vaccination (OR, 0.64; 95% confidence interval [CI], 0.45-0.92) and one-dose vaccination (OR, 0.60; 95% CI, 0.43-0.83). Two-dose vaccination compared to no vaccination was associated with a lower risk of persistent fatigue (OR, 0.62; 95% CI, 0.41-0.93) and pulmonary disorder (OR, 0.50; 95% CI, 0.47-0.52). Among those with ongoing long COVID symptoms, 54.4% (95% CI, 34.3-73.1%) did not report symptomatic changes following vaccination, while 20.3% (95% CI, 8.1-42.4%) experienced symptomatic improvement after two weeks to six months of COVID-19 vaccination. CONCLUSIONS: COVID-19 vaccination before SARS-CoV-2 infection was associated with a lower risk of long COVID, while most of those with ongoing long COVID did not experience symptomatic changes following vaccination.

Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae.

The diagnosis of post-acute sequelae of COVID-19 (PASC) poses an ongoing medical challenge. To identify biomarkers associated with PASC we analyzed plasma samples collected from PASC and COVID-19 patients to quantify viral antigens and inflammatory markers. We detect SARS-CoV-2 spike predominantly in PASC patients up to 12 months post-diagnosis.

Sleep symptoms are essential features of long-COVID - Comparing healthy controls with COVID-19 cases of different severity in the international COVID sleep study (ICOSS-II).

Many people report suffering from post-acute sequelae of COVID-19 or "long-COVID", but there are still open questions on what actually constitutes long-COVID and how prevalent it is. The current definition of post-acute sequelae of COVID-19 is based on voting using the Delphi-method by the WHO post-COVID-19 working group. It emphasizes long-lasting fatigue, shortness of breath and cognitive dysfunction as the core symptoms of post-acute sequelae of COVID-19. In this international survey study consisting of 13,628 subjects aged 18-99 years from 16 countries of Asia, Europe, North America and South America (May-Dec 2021), we show that post-acute sequelae of COVID-19 symptoms were more prevalent amongst the more severe COVID-19 cases, i.e. those requiring hospitalisation for COVID-19. We also found that long-lasting sleep symptoms are at the core of post-acute sequelae of COVID-19 and associate with the COVID-19 severity when COVID-19 cases are compared with COVID-negative cases. Specifically, fatigue (61.3%), insomnia symptoms (49.6%) and excessive daytime sleepiness (35.8%) were highly prevalent amongst respondents reporting long-lasting symptoms after hospitalisation for COVID-19. Understanding the importance of sleep-related symptoms in post-acute sequelae of COVID-19 has a clinical relevance when diagnosing and treating long-COVID.

Personalized Computerized Training for Cognitive Dysfunction after COVID-19: A Before-and-After Feasibility Pilot Study.

The current pilot study was set to evaluate the feasibility and potential benefit of a personalized computerized cognitive training (CCT) intervention to improve cognitive function among people living with post-acute sequelae of COVID-19 (PASC). Seventy three adults who self-reported cognitive dysfunction more than 3 months after a diagnosis of COVID-19 took part in an 8-week training study. Participants' general cognitive function was assessed before they completed as many cognitive daily training sessions as they wished during an 8-week period, using a personalized CCT application at home. At the end of this period, participants repeated the general cognitive function assessment. The differences between the scores at 8 weeks and baseline in five cognitive domains (attention, memory, coordination, perception, reasoning), complemented with analyses of the changes based on the participants' age, training time, self-reported health level at baseline and time since the initial COVID-19 infection. Participants had significant cognitive dysfunction and self-reported negative health levels at baseline. Most of the participants obtained higher scores after CCT in each of the domains as compared with baseline. The magnitude of this score increase was high across domains. It is concluded that a self-administered CCT based on gamified cognitive tasks could be an effective way to ameliorate cognitive dysfunction in persons with PASC. The ClinicalTrials.gov identifier is NCT05571852.