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.

The impact of long COVID on health-related quality of life in patients 6 months after discharge with severe COVID-19.

This study investigates the relationship between long COVID and health-related quality of life (HRQOL) in patients discharged for 6 months. It included 192 patients with a history of severe COVID-19 and 192 patients with a history of non-severe COVID-19 patients that were selected through quota sampling methods from the Medical Care Monitoring Center (MCMC) of hospitals in Shiraz, Iran, in 2020. Phone-based interviews were conducted to collect data using the short form of the 12-item health-related quality of life (SF-12) questionnaire. Descriptive statistics, including mean (standard deviation) and frequency (percentage), were utilized. Statistical tests, such as the chi-squared test, independent samples t-test, Fisher's exact test, and multiple linear regression models were performed. Statistical analysis was performed using SPSS software version 24, with a significance level of 0.05. Among 384 patients, 79.95% were married, with a mean age of 53.95 years. The majority of patients in both groups were male (57.81% in the severe group and 51.04% in the non-severe group). Patients with severe COVID-19 had significantly lower quality of life scores compared to those with non-severe COVID-19 (p < 0.001, 34.45 [SD = 6.59] versus 39.64 [SD = 5.07]). Furthermore, multiple linear regression analysis indicated that severe COVID-19 inducts a significant negative effect on HRQOL in patients after adjustment of confounders (p < 0.001, B = - 4.84). Patients with severe COVID-19 had lower HRQOL compared to those with a non-severe level. It is necessary to consider implementing policies aimed at providing social, psychological, or medical support to improve the HRQOL of patients with a history of severe COVID-19.

Efficacy of dual-task augmented reality rehabilitation in non-hospitalized adults with self-reported long COVID fatigue and cognitive impairment: a pilot study.

BACKGROUND: Cognitive impairment and chronic fatigue represent common characteristics of the long COVID syndrome. Different non-pharmacological treatments have been proposed, and physiotherapy has been proposed to improve the symptoms. This study aimed to evaluate the effects of a dual-task augmented reality rehabilitation protocol in people with long COVID fatigue and cognitive impairment. METHODS AND MATERIALS: Ten non-hospitalized adults with reported fatigue and "brain fog" symptoms after COVID (7/10 females, 50 years, range 41-58) who participated in 20 sessions of a 1-h "dual-task" training, were compared to 10 long COVID individuals with similar demographics and symptoms (9/10 females, 56 years, range 43-65), who did not participate to any rehabilitation protocol. Cognitive performance was assessed with the Trail Making Test (TMT-A and -B) and Frontal Assessment Battery (FAB), and cardiovascular and muscular fatigue were assessed with the fatigue severity scale (FSS), six-minute walking test and handgrip endurance. Finally, transcranial magnetic stimulation (TMS) investigated cortical excitability. RESULTS: The mixed-factors analysis of variance found a significant interaction effect only in cognitive performance evaluation, suggesting TMT-B execution time decreased (- 15.9 s, 95% CI 7.6-24.1, P = 0.001) and FAB score improved (1.88, 95% CI 2.93-0.82, P = 0.002) only in the physiotherapy group. For the remaining outcomes, no interaction effect was found, and most parameters similarly improved in the two groups. CONCLUSION: The preliminary results from this study suggest that dual-task rehabilitation could be a feasible protocol to support cognitive symptoms recovery after COVID-19 and could be helpful in those individuals suffering from persisting and invalidating symptoms.

The Epidemiology of Long Coronavirus Disease in US Adults.

BACKGROUND: We estimated the prevalence of long COVID and impact on daily living among a representative sample of adults in the United States. METHODS: We conducted a population-representative survey, 30 June-2 July 2022, of a random sample of 3042 US adults aged 18 years or older and weighted to the 2020 US population. Using questions developed by the UK's Office of National Statistics, we estimated the prevalence of long COVID, by sociodemographics, adjusting for gender and age. RESULTS: An estimated 7.3% (95% confidence interval: 6.1-8.5%) of all respondents reported long COVID, corresponding to approximately 18 828 696 adults. One-quarter (25.3% [18.2-32.4%]) of respondents with long COVID reported their day-to-day activities were impacted "a lot" and 28.9% had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection more than 12 months ago. The prevalence of long COVID was higher among respondents who were female (adjusted prevalence ratio [aPR]: 1.84 [1.40-2.42]), had comorbidities (aPR: 1.55 [1.19-2.00]), or were not (vs were) boosted (aPR: 1.67 [1.19-2.34]) or not vaccinated (vs boosted) (aPR: 1.41 [1.05-1.91]). CONCLUSIONS: We observed a high burden of long COVID, substantial variability in prevalence of SARS-CoV-2, and risk factors unique from SARS-CoV-2 risk, suggesting areas for future research. Population-based surveys are an important surveillance tool and supplement to ongoing efforts to monitor long COVID.

Cognitive dysfunction in post-COVID-19 condition: Mechanisms, management, and rehabilitation.

The long-term effects of COVID-19 on cognitive function have become an area of increasing concern. This paper provides an overview of characteristics, risk factors, possible mechanisms, and management strategies for cognitive dysfunction in post-COVID-19 condition (PCC). Prolonged cognitive dysfunction is one of the most common impairments in PCC, affecting between 17% and 28% of the individuals more than 12 weeks after the infection and persisting in some cases for several years. Cognitive dysfunctions can be manifested as a wide range of symptoms including memory impairment, attention deficit, executive dysfunction, and reduced processing speed. Risk factors for developing PCC, with or without cognitive impairments, include advanced age, preexisting medical conditions, and the severity of acute illness. The underlying mechanisms remain unclear, but proposed contributors include neuroinflammation, hypoxia, vascular damage, and latent virus reactivation not excluding the possibility of direct viral invasion of the central nervous system, illustrating complex viral pathology. As the individual variation of the cognitive impairments is large, a neuropsychological examination and a person-centered multidimensional approach are required. According to the World Health Organization, limited evidence on COVID-19-related cognitive impairments necessitates implementing rehabilitation interventions from established practices of similar conditions. Psychoeducation and compensatory skills training are recommended. Assistive products and environmental modifications adapted to individual needs might be helpful. In specific attention- and working memory dysfunctions, cognitive training-carefully monitored for intensity-might be effective for people who do not suffer from post-exertional malaise. Further research is crucial for evidence-based interventions specific to COVID-19-related cognitive impairments.

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.

Treatable traits for long COVID.

Long COVID, or post-acute COVID-19 sequelae, is experienced by an estimated one in eight adults following acute COVID-19. Long COVID is a new and complex chronic health condition that typically includes multiple symptoms that cross organ systems and fluctuate over time; a one-size-fits-all approach is, therefore, not likely to be appropriate nor relevant for long COVID treatment. 'Treatable Traits' is a personalized medicine approach, purpose-built to address the complexity and heterogeneity of complex chronic conditions. This comprehensive review aimed to understand how a treatable traits approach could be applied to long COVID, by first identifying the most prevalent long COVID treatable traits and then the available evidence for strategies to target these traits. An umbrella review of 22 systematic reviews identified 34 symptoms and complications common with long COVID, grouped into eight long COVID treatable trait clusters: neurological, chest, psychological, pain, fatigue, sleep impairment, functional impairment and other. A systematic review of randomized control trials identified 18 studies that explored different intervention approaches for long COVID prevention (k = 4) or management (k = 14). While a single study reported metformin as effective for long COVID prevention, the findings need to be replicated and consensus is required around how to define long COVID as a clinical trial endpoint. For long COVID management, current evidence supports exercise training or respiratory muscle training for long COVID treatable traits in the chest and functional limitation clusters. While there are studies exploring interventions targeting other long COVID treatable traits, further high-quality RCTs are needed, particularly targeting treatable traits in the clusters of fatigue, psychological, pain and sleep impairment.

SARS-CoV-2 Reinfections and Long COVID in the Post-Omicron Phase of the Pandemic.

We are reviewing the current state of knowledge on the virological and immunological correlates of long COVID, focusing on recent evidence for the possible association between the increasing number of SARS-CoV-2 reinfections and the parallel pandemic of long COVID. The severity of reinfections largely depends on the severity of the initial episode; in turn, this is determined both by a combination of genetic factors, particularly related to the innate immune response, and by the pathogenicity of the specific variant, especially its ability to infect and induce syncytia formation at the lower respiratory tract. The cumulative risk of long COVID as well as of various cardiac, pulmonary, or neurological complications increases proportionally to the number of SARS-CoV-2 infections, primarily in the elderly. Therefore, the number of long COVID cases is expected to remain high in the future. Reinfections apparently increase the likelihood of long COVID, but less so if they are mild or asymptomatic as in children and adolescents. Strategies to prevent SARS-CoV-2 reinfections are urgently needed, primarily among older adults who have a higher burden of comorbidities. Follow-up studies using an established case definition and precise diagnostic criteria of long COVID in people with or without reinfection may further elucidate the contribution of SARS-CoV-2 reinfections to the long COVID burden. Although accumulating evidence supports vaccination, both before and after the SARS-CoV-2 infection, as a preventive strategy to reduce the risk of long COVID, more robust comparative observational studies, including randomized trials, are needed to provide conclusive evidence of the effectiveness of vaccination in preventing or mitigating long COVID in all age groups. Thankfully, answers not only on the prevention, but also on treatment options and rates of recovery from long COVID are gradually starting to emerge.

Small fiber neuropathy associated with SARS-CoV-2 infection.

INTRODUCTION/AIMS: The development and persistence of neurological symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is referred to as "long-haul" syndrome. We aimed to determine whether small fiber neuropathy (SFN) was associated with SARS-CoV-2 infection. METHODS: We retrospectively studied the clinical features and outcomes of patients who were referred to us between May 2020 and May 2021 for painful paresthesia and numbness that developed during or after SARS-CoV-2 infection and who had nerve conduction studies showing no evidence of a large fiber polyneuropathy. RESULTS: We identified 13 patients, Eight women and five men with age ranging from 38-67 y. Follow-up duration ranged from 8 to 12 mo. All patients developed new-onset paresthesias within 2 mo following SARS-CoV-2 infection, with an acute onset in seven and co-existing autonomic symptoms in seven. Three patients had pre-existing but controlled neuropathy risk factors. Skin biopsy confirmed SFN in six, all of whom showed both neuropathy symptoms and signs, and two also showed autonomic dysfunction by autonomic function testing (AFT). Of the remaining seven patients who had normal skin biopsies, six showed no clinical neuropathy signs and one exhibited signs and had abnormal AFT. Two patients with markedly reduced intraepidermal nerve fiber densities and one with normal skin biopsy had severe and moderate coronavirus disease 2019 (COVID-19); the remainder experienced mild COVID-19 symptoms. Nine patients received symptomatic neuropathy treatment with paresthesias controlled in seven (77.8%). DISCUSSION: Our findings suggest that symptoms of SFN may develop during or shortly after COVID-19. SFN may underlie the paresthesias associated with long-haul post-COVID-19 symptoms.