Challenges and opportunities in long COVID research.

Long COVID (LC) is a condition in which patients do not fully recover from the initial SARS-CoV-2 infection but rather have persistent or new symptoms for months to years following the infection. Ongoing research efforts are investigating the pathophysiologic mechanisms of LC and exploring preventative and therapeutic treatment approaches for patients. As a burgeoning area of investigation, LC research can be structured to be more inclusive, innovative, and effective. In this perspective, we highlight opportunities for patient engagement and diverse research expertise, as well as the challenges of developing definitions and reproducible studies. Our intention is to provide a foundation for collaboration and progress in understanding the biomarkers and mechanisms driving LC.

Post-COVID-19 Condition.

An estimated 10-15% of those infected with SARS-CoV-2 may have post-COVID-19 condition. Common lingering signs and symptoms include shortness of breath, fatigue, high heart rate, and memory and cognitive dysfunction even several months after infection, often impacting survivors' quality of life. The prevalence and duration of individual symptoms remain difficult to ascertain due to the lack of standardized research methods across various studies and limited patient follow-up in clinical studies. Nonetheless, data indicate post-COVID-19 condition may occur independent of acuity of initial infection, hospitalization status, age, or pre-existing comorbidities. Risk factors may include female sex and underlying respiratory or psychiatric disease. Supportive therapies to mitigate symptoms remain the mainstay of treatment. Reassuringly, most patients experience a reduction in symptoms by 1 year. The use of a universal case definition and shared research methods will allow for further clarity regarding the pervasiveness of this entity and its long-term health consequences.

Nervous system-related tropism of SARS-CoV-2 and autoimmunity in COVID-19 infection.

The effects of SARS-CoV-2 in COVID-19 on the nervous system are incompletely understood. SARS-CoV-2 can infect endothelial cells, neurons, astrocytes, and oligodendrocytes with consequences for the host. There are indications that infection of these CNS-resident cells may result in long-term effects, including emergence of neurodegenerative diseases. Indirect effects of infection with SARS-CoV-2 relate to the induction of autoimmune disease involving molecular mimicry or/and bystander activation of T- and B cells and emergence of autoantibodies against various self-antigens. Data obtained in preclinical models of coronavirus-induced disease gives important clues for the understanding of nervous system-related assault of SARS-CoV-2. The pathophysiology of long-COVID syndrome and post-COVID syndrome in which autoimmunity and immune dysregulation might be the driving forces are still incompletely understood. A better understanding of nervous-system-related immunity in COVID-19 might support the development of therapeutic approaches. In this review, the current understanding of SARS-CoV-2 tropism for the nervous system, the associated immune responses, and diseases are summarized. The data indicates that there is viral tropism of SARS-CoV-2 in the nervous system resulting in various disease conditions. Prevention of SARS-CoV-2 infection by means of vaccination is currently the best strategy for the prevention of subsequent tissue damage involving the nervous system.

COVID-19 Recovery: Consistent Absence of Cerebrospinal Fluid Biomarker Abnormalities in Patients With Neurocognitive Post-COVID Complications.

BACKGROUND: To investigate evidence of residual viral infection, intrathecal immune activation, central nervous system (CNS) injury, and humoral responses in cerebrospinal fluid (CSF) and plasma in patients recovering from coronavirus disease 2019 (COVID-19), with or without neurocognitive post-COVID condition (PCC). METHODS: Thirty-one participants (25 with neurocognitive PCC) underwent clinical examination, lumbar puncture, and venipuncture ≥3 months after COVID-19 symptom onset. Healthy volunteers were included. CSF and plasma severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid and spike antigen (N-Ag, S-Ag), and CSF biomarkers of immune activation and neuronal injury were analyzed. RESULTS: SARS-CoV-2 N-Ag or S-Ag were undetectable in all samples and no participant had pleocytosis. We detected no significant differences in CSF and plasma cytokine concentrations, albumin ratio, IgG index, neopterin, ß2M, or in CSF biomarkers of neuronal injury and astrocytic damage. Furthermore, principal component analysis (PCA1) analysis did not indicate any significant differences between the study groups in the marker sets cytokines, neuronal markers, or anti-cytokine autoantibodies. CONCLUSIONS: We found no evidence of ongoing viral replication, immune activation, or CNS injury in plasma or CSF in patients with neurocognitive PCC compared with COVID-19 controls or healthy volunteers, suggesting that neurocognitive PCC is a consequence of events suffered during acute COVID-19 rather than persistent viral CNS infection or residual CNS inflammation.

The Association of Post-COVID-19-Related Symptoms and Preceding Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Fully Vaccinated Paramedics in Canada.

This study investigated the association between previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and risk of symptoms associated with post-COVID conditions among fully vaccinated paramedics in Canada. We included vaccinated paramedics who provided blood sample and questionnaire data on the same date during the study period. We examined the presence of symptoms associated with post-COVID conditions and depression severity against prior SARS-CoV-2 infection categories. Compared to the "no previous SARS-CoV-2 infection" group, there was no detected association between known prior SARS-CoV-2 infection (odds ratio [OR], 1.42 [95% confidence interval {CI}, 0.96-2.09]), nor unknown prior SARS-CoV-2 infection (OR, 0.54 [95% CI, 0.29-1.00]), and the presence of symptoms associated with post-COVID conditions.

Post-COVID-19 Condition After SARS-CoV-2 Infections During the Omicron Surge vs the Delta, Alpha, and Wild Type Periods in Stockholm, Sweden.

Little is known about the post-COVID-19 condition (PCC) after infections with different SARS-CoV-2 variants. We investigated the risk of PCC diagnosis after primary omicron infections as compared with preceding variants in population-based cohorts in Stockholm, Sweden. When compared with omicron (n = 215 279, 0.2% receiving a PCC diagnosis), the adjusted hazard ratio (95% CI) was 3.26 (2.80-3.80) for delta (n = 52 182, 0.5% PCC diagnosis), 5.33 (4.73-5.99) for alpha (n = 97 978, 1.0% PCC diagnosis), and 6.31 (5.64-7.06) for the wild type (n = 107 920, 1.3% PCC diagnosis). These findings were consistent across all subgroup analyses except among those treated in the intensive care unit.

Precision symptom phenotyping identifies early clinical and proteomic predictors of distinct COVID-19 sequelae.

BACKGROUND: Post-COVID conditions (PCC) are difficult to characterize, diagnose, predict, and treat due to overlapping symptoms and poorly understood pathology. Identifying inflammatory profiles may improve clinical prognostication and trial endpoints. METHODS: 1,988 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative post-COVID symptom scores were included in this analysis. Among participants who reported moderate-to-severe symptoms on surveys collected 6-months post-SARS-CoV-2 infection, principal component analysis (PCA) followed by K-means clustering identified distinct clusters of symptoms. RESULTS: Three symptom-based clusters were identified: a sensory cluster (loss of smell and/or taste), a fatigue/difficulty thinking cluster, and a difficulty breathing/exercise intolerance cluster. Individuals within the sensory cluster were all outpatients during their initial COVID-19 presentation. The difficulty breathing cluster had a higher likelihood of obesity and COVID-19 hospitalization compared to those with no/mild symptoms at 6-months post-infection. Multinomial regression linked early post-infection D-dimer and IL-1RA elevation to fatigue/difficulty thinking, and elevated ICAM-1 concentrations to sensory symptoms. CONCLUSIONS: We identified three distinct symptom-based PCC phenotypes with specific clinical risk factors and early post-infection inflammatory predictors. With further validation and characterization, this framework may allow more precise classification of PCC cases and potentially improve the diagnosis, prognostication, and treatment of PCC.

Proteomic Evolution from Acute to Post-COVID-19 Conditions.

Many COVID-19 survivors have post-COVID-19 conditions, and females are at a higher risk. We sought to determine (1) how protein levels change from acute to post-COVID-19 conditions, (2) whether females have a plasma protein signature different from that of males, and (3) which biological pathways are associated with COVID-19 when compared to restrictive lung disease. We measured protein levels in 74 patients on the day of admission and at 3 and 6 months after diagnosis. We determined protein concentrations by multiple reaction monitoring (MRM) using a panel of 269 heavy-labeled peptides. The predicted forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) were measured by routine pulmonary function testing. Proteins associated with six key lipid-related pathways increased from admission to 3 and 6 months; conversely, proteins related to innate immune responses and vasoconstriction-related proteins decreased. Multiple biological functions were regulated differentially between females and males. Concentrations of eight proteins were associated with FVC, %, and they together had c-statistics of 0.751 (CI:0.732-0.779); similarly, concentrations of five proteins had c-statistics of 0.707 (CI:0.676-0.737) for DLCO, %. Lipid biology may drive evolution from acute to post-COVID-19 conditions, while activation of innate immunity and vascular regulation pathways decreased over that period. (ProteomeXchange identifiers: PXD041762, PXD029437).

Reinforcing the Evidence of Mitochondrial Dysfunction in Long COVID Patients Using a Multiplatform Mass Spectrometry-Based Metabolomics Approach.

Despite the recent and increasing knowledge surrounding COVID-19 infection, the underlying mechanisms of the persistence of symptoms for a long time after the acute infection are still not completely understood. Here, a multiplatform mass spectrometry-based approach was used for metabolomic and lipidomic profiling of human plasma samples from Long COVID patients (n = 40) to reveal mitochondrial dysfunction when compared with individuals fully recovered from acute mild COVID-19 (n = 40). Untargeted metabolomic analysis using CE-ESI(+/-)-TOF-MS and GC-Q-MS was performed. Additionally, a lipidomic analysis using LC-ESI(+/-)-QTOF-MS based on an in-house library revealed 447 lipid species identified with a high confidence annotation level. The integration of complementary analytical platforms has allowed a comprehensive metabolic and lipidomic characterization of plasma alterations in Long COVID disease that found 46 relevant metabolites which allowed to discriminate between Long COVID and fully recovered patients. We report specific metabolites altered in Long COVID, mainly related to a decrease in the amino acid metabolism and ceramide plasma levels and an increase in the tricarboxylic acid (TCA) cycle, reinforcing the evidence of an impaired mitochondrial function. The most relevant alterations shown in this study will help to better understand the insights of Long COVID syndrome by providing a deeper knowledge of the metabolomic basis of the pathology.

SARS-CoV-2 Infection and Postacute Risk of Non-Coronavirus Disease 2019 Infectious Disease Hospitalizations: A Nationwide Cohort Study of Danish Adults Aged ≥50 Years.

BACKGROUND: Reports suggest that the potential long-lasting health consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may involve persistent dysregulation of some immune populations, but the potential clinical implications are unknown. We investigated the associated risk of hospitalization due to non-coronavirus disease 2019 (COVID-19) infectious diseases following the postacute phase of SARS-CoV-2 infection. METHODS: By cross-linking data from the comprehensive Danish test and surveillance system for COVID-19 together with nationwide healthcare and demographic registers, we established a study cohort of 2 430 694 individuals aged ≥50 years, from 1 January 2021 to 10 December 2022, with no evidence of SARS-CoV-2 infection prior to study entry. Using Poisson regression, we compared the outcome rates of non-COVID-19 infectious disease hospitalizations following the acute phase of (a first) SARS-CoV-2 infection (defined as ≥29 days since the day of infection) in recovered individuals with rates among SARS-CoV-2-uninfected individuals. RESULTS: Among 2 430 694 included individuals (mean age, 66.8 [standard deviation, 11.3] years), 930 071 acquired SARS-CoV-2 infection during follow-up totaling 4 519 913 person-years. The postacute phase of SARS-CoV-2 infection was associated with an incidence rate ratio (IRR) of 0.90 (95% confidence interval [CI]: .88-.92) for any infectious disease hospitalization. Findings (IRR [95% CI]) were similar for upper respiratory tract (1.08 [.97-1.20]), lower respiratory tract (0.90 [.87-.93]), influenza (1.04 [.94-1.15]), gastrointestinal (1.28 [.78-2.09]), skin (0.98 [.93-1.03]), urinary tract (1.01 [.96-1.08]), certain invasive bacterial (0.96 [.91-1.01]), and other (0.96 [.92-1.00]) infectious disease hospitalizations and in subgroups. CONCLUSIONS: Our study does not support an increased susceptibility to non-COVID-19 infectious disease hospitalization following SARS-CoV-2 infection.

Viral Suppression Trajectories Destabilized After Coronavirus Disease 2019 Among US People With Human Immunodeficiency Virus: An Interrupted Time Series Analysis.

We examined changes in the proportion of people with human immunodeficiency virus (PWH) with virologic suppression (VS) in a multisite US cohort before and since the coronavirus disease 2019 (COVID-19) pandemic. Overall, prior gains in VS slowed during COVID-19, with disproportionate impacts on Black PWH and PWH who inject drugs.

Household Transmission Dynamics of Asymptomatic SARS-CoV-2-Infected Children: A Multinational, Controlled Case-Ascertained Prospective Study.

BACKGROUND: Asymptomatic SARS-CoV-2 infection in children is highly prevalent but its acute and chronic implications have been minimally described. METHODS: In this controlled case-ascertained household transmission study, we recruited asymptomatic children <18 years with SARS-CoV-2 nucleic acid testing performed at 12 tertiary care pediatric institutions in Canada and the United States. We attempted to recruit all test-positive children and 1 to 3 test-negative, site-matched controls. After 14 days' follow-up we assessed the clinical (ie, symptomatic) and combined (ie, test-positive, or symptomatic) secondary attack rates (SARs) among household contacts. Additionally, post-COVID-19 condition (PCC) was assessed in SARS-CoV-2-positive participating children after 90 days' follow-up. RESULTS: A total of 111 test-positive and 256 SARS-CoV-2 test-negative asymptomatic children were enrolled between January 2021 and April 2022. After 14 days, excluding households with co-primary cases, the clinical SAR among household contacts of SARS-CoV-2-positive and -negative index children was 10.6% (19/179; 95% CI: 6.5%-16.1%) and 2.0% (13/663; 95% CI: 1.0%-3.3%), respectively (relative risk = 5.4; 95% CI: 2.7-10.7). In households with a SARS-CoV-2-positive index child, age <5 years, being pre-symptomatic (ie, developed symptoms after test), and testing positive during Omicron and Delta circulation periods (vs earlier) were associated with increased clinical and combined SARs among household contacts. Among 77 asymptomatic SARS-CoV-2-infected children with 90-day follow-up, 6 (7.8%; 95% CI: 2.9%-16.2%) reported PCC. CONCLUSIONS: Asymptomatic SARS-CoV-2-infected children, especially those <5 years, are important contributors to household transmission, with 1 in 10 exposed household contacts developing symptomatic illness within 14 days. Asymptomatic SARS-CoV-2-infected children may develop PCC.

Prevalence of and Risk Factors for Post-COVID-19 Condition during Omicron BA.5-Dominant Wave, Japan.

The increased risk for post-COVID-19 condition after the Omicron-dominant wave remains unclear. This population-based study included 25,911 persons in Japan 20-69 years of age with confirmed SARS-CoV-2 infection enrolled in the established registry system during July-August 2022 and 25,911 age- and sex-matched noninfected controls who used a self-reported questionnaire in January-February 2023. We compared prevalence and age- and sex-adjusted odds ratios of persistent COVID-19 symptoms (lasting ≥2 months). We evaluated factors associated with post-COVID-19 condition by comparing cases with and without post-COVID-19 condition. We analyzed 14,710 (8,392 cases and 6,318 controls) of 18,183 respondents. Post-COVID-19 condition proportion among cases was 11.8%, higher by 6.3% than 5.5% persistent symptoms among controls. Female sex, underlying medical conditions, mild to moderate acute COVID-19, and vaccination were associated with post-COVID-19 condition. Approximately 12% had post-COVID-19 condition during the Omicron-dominant wave, indicating the need for longer follow-up.

Estimates of Incidence and Predictors of Fatiguing Illness after SARS-CoV-2 Infection.

This study aimed to estimate the incidence rates of post-COVID-19 fatigue and chronic fatigue and to quantify the additional incident fatigue caused by COVID-19. We analyzed electronic health records data of 4,589 patients with confirmed COVID-19 during February 2020-February 2021 who were followed for a median of 11.4 (interquartile range 7.8-15.5) months and compared them to data from 9,022 propensity score-matched non-COVID-19 controls. Among COVID-19 patients (15% hospitalized for acute COVID-19), the incidence rate of fatigue was 10.2/100 person-years and the rate of chronic fatigue was 1.8/100 person-years. Compared with non-COVID-19 controls, the hazard ratios were 1.68 (95% CI 1.48-1.92) for fatigue and 4.32 (95% CI 2.90-6.43) for chronic fatigue. The observed association between COVID-19 and the significant increase in the incidence of fatigue and chronic fatigue reinforces the need for public health actions to prevent SARS-CoV-2 infections.

Temporal changes in the risk of six-month post-covid symptoms: a national population-based cohort study.

It is unclear how the risk of post-covid symptoms evolved during the pandemic, especially before the spread of Severe Acute Respiratory Syndrome Coronavirus 2 variants and the availability of vaccines. We used modified Poisson regressions to compare the risk of six-month post-covid symptoms and their associated risk factors according to the period of first acute covid: during the French first (March-May 2020) or second (September-November 2020) wave. Non-response weights and multiple imputation were used to handle missing data. Among participants aged 15 or more in a national population-based cohort, the risk of post-covid symptoms was 14.6% (95% CI: 13.9%, 15.3%) in March-May 2020, versus 7.0% (95% CI: 6.3%, 7.7%) in September-November 2020 (adjusted RR: 1.36, 95% CI: 1.20, 1.55). For both periods, the risk was higher in the presence of baseline physical condition(s), and it increased with the number of acute symptoms. During the first wave, the risk was also higher for women, in the presence of baseline mental condition(s), and it varied with educational level. In France in 2020, the risk of six-month post-covid symptoms was higher during the first than the second wave. This difference was observed before the spread of variants and the availability of vaccines.

People with a connective tissue disorder may be especially vulnerable to the endothelial damage that characterizes long COVID due to the fragility of their vasculature and slow wound healing.

A growing body of evidence documents the central role that endothelial damage plays in the pathophysiology of long COVID. But it remains unclear why only certain people get Long COVID and why recovery times are so long for many affected individuals. One potential explanation is that some forms of long COVID are experienced disproportionately by people with a connective tissue disorder who are more vulnerable than others to incurring serious damage to the endothelium and the vascular extracellular matrix from the inflammatory processes triggered by COVID-19 and much slower to heal. Further research is needed to explore this hypothesis.

Post-COVID-19 thrombotic sequelae: The potential role of persistent platelet hyperactivity.

Postacute COVID-19 sequelae affect millions of individuals, and active research into the pathophysiological mechanisms and potential treatments is underway. The report by Nara and colleagues shows persistent platelet hyperactivity in the chronic phase of the infection, suggesting a possible role of platelets in post-COVID-19 complications and, consequently, a possible therapeutic target. Commentary on: Nara et al. Prolonged platelet hyperactivity after COVID-19 infection. Br J Haematol 2024;204:492-496.

The significance of caloric restriction mimetics as anti-aging drugs.

Aging is an intricate process characterized by the gradual deterioration of the physiological integrity of a living organism. This unfortunate phenomenon inevitably leads to a decline in functionality and a heightened susceptibility to the ultimate fate of mortality. Therefore, it is of utmost importance to implement interventions that possess the capability to reverse or preempt age-related pathology. Caloric restriction mimetics (CRMs) refer to a class of molecules that have been observed to elicit advantageous outcomes on both health and longevity in various model organisms and human subjects. Notably, these compounds offer a promising alternative to the arduous task of adhering to a caloric restriction diet and mitigate the progression of the aging process and extend the duration of life in laboratory animals and human population. A plethora of molecular signals have been linked to the practice of caloric restriction, encompassing Insulin-like Growth Factor 1 (IGF1), Mammalian Target of Rapamycin (mTOR), the Adenosine Monophosphate-Activated Protein Kinase (AMPK) pathway, and Sirtuins, with particular emphasis on SIRT1. Therefore, this review will center its focus on several compounds that act as CRMs, highlighting their molecular targets, chemical structures, and mechanisms of action. Moreover, this review serves to underscore the significant relationship between post COVID-19 syndrome, antiaging, and importance of utilizing CRMs. This particular endeavor will serve as a comprehensive guide for medicinal chemists and other esteemed researchers, enabling them to meticulously conceive and cultivate novel molecular entities with the potential to function as efficacious antiaging pharmaceutical agents.

First trans-diagnostic experiences with a novel micro-choice based concentrated group rehabilitation for patients with low back pain, long COVID, and type 2 diabetes: a pilot study.

BACKGROUND: The health care is likely to break down unless we are able to increase the level of functioning for the growing number of patients with complex, chronic illnesses. Hence, novel high-capacity and cost-effective treatments with trans-diagnostic effects are warranted. In accordance with the protocol paper, we aimed to examine the acceptability, satisfaction, and effectiveness of an interdisciplinary micro-choice based concentrated group rehabilitation for patients with chronic low back pain, long COVID, and type 2 diabetes. METHODS: Patients with low back pain > 4 months sick-leave, long COVID, or type 2 diabetes were included in this clinical trial with pre-post design and 3-month follow-up. The treatment consisted of three phases: (1) preparing for change, (2) the concentrated intervention for 3-4 days, and (3) integrating change into everyday life. Patients were taught and practiced how to monitor and target seemingly insignificant everyday micro-choices, in order to break the patterns where symptoms or habits contributed to decreased levels of functioning or increased health problems. The treatment was delivered to groups (max 10 people) with similar illnesses. Client Satisfaction Questionnaire (CSQ-8)) (1 week), Work and Social Adjustment Scale (WSAS), Brief Illness Perception Questionnaire (BIPQ), and self-rated health status (EQ-5D-5L) were registered at baseline and 3-month follow-up. RESULTS: Of the 241 included participants (57% women, mean age 48 years, range 19-84), 99% completed the concentrated treatment. Treatment satisfaction was high with a 28.9 (3.2) mean CSQ-8-score. WSAS improved significantly from baseline to follow-up across diagnoses 20.59 (0.56) to 15.76 (0.56). BIPQ improved from: 22.30 (0.43) to 14.88 (0.47) and EQ-5D-5L: 0.715 (0.01) to 0.779 (0.01)), all P<0.001. CONCLUSIONS: Across disorders, the novel approach was associated with high acceptability and clinically important improvements in functional levels, illness perception, and health status. As the concentrated micro-choice based treatment format might have the potential to change the way we deliver rehabilitation across diagnoses, we suggest to proceed with a controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT05234281.

"The dream is that there's one place you go": a qualitative study of women's experiences seeking care from Long COVID clinics in the USA.

BACKGROUND: Seeking and obtaining effective health care for Long COVID remains a challenge in the USA. Women have particularly been impacted, as they are both at higher risk of developing Long COVID and of facing gendered barriers to having symptoms acknowledged. Long COVID clinics, which provide multidisciplinary and coordinated care, have emerged as a potential solution. To date, however, there has been little examination of U.S. patient experiences with Long COVID clinics and how patients may or may not have come to access care at a Long COVID clinic. METHODS: We conducted semi-structured interviews with 30 U.S. women aged 18 or older who had experienced Long COVID symptoms for at least 3 months, who had not been hospitalized for acute COVID-19, and who had seen at least one medical provider about their symptoms. Participants were asked about experiences seeking medical care for Long COVID. Long COVID clinic-related responses were analyzed using qualitative framework analysis to identify key themes in experiences with Long COVID clinics. RESULTS: Of the 30 women, 43.3% (n = 13) had been seen at a Long COVID clinic or by a provider affiliated with a Long COVID clinic and 30.0% (n = 9) had explored or attempted to see a Long COVID clinic but had not been seen at time of interview. Participants expressed five key themes concerning their experiences with seeking care from Long COVID clinics: (1) Access to clinics remains an issue, (2) Clinics are not a one stop shop, (3) Not all clinic providers have sufficient Long COVID knowledge, (4) Clinics can offer validation and care, and (5) Treatment options are critical and urgent. CONCLUSIONS: While the potential for Long COVID clinics is significant, findings indicate that ongoing barriers to care and challenges related to quality and coordination of care hamper that potential and contribute to distress among women seeking Long COVID care. Since Long COVID clinics are uniquely positioned and framed as being the place to go to manage complex symptoms, it is critical to patient wellbeing that they be properly resourced to provide a level of care that complies with emerging best practices.