Tag: covid-19

Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights Into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges

Abstract:

Long COVID (LC) encompasses a constellation of long-term symptoms experienced by at least 10% of people after the initial SARS-CoV-2 infection, and so far has affected about 65 million people. The etiology of LC remains unclear; however, many pathophysiological pathways may be involved, including viral persistence; chronic, low grade inflammatory response; immune dysregulation and defective immune response; reactivation of latent viruses; autoimmunity; persistent endothelial dysfunction and coagulopathy; gut dysbiosis; hormonal dysregulation, mitochondrial dysfunction; and autonomic nervous system dysfunction.

There are no specific tests for the diagnosis of LC, and clinical features including laboratory findings and biomarkers may not specifically relate to LC. Therefore, it is of paramount importance to develop and validate biomarkers that can be employed for the prediction, diagnosis and prognosis of LC and its therapeutic response. Promising candidate biomarkers that are found in some patients are markers of systemic inflammation including acute phase proteins, cytokines and chemokines; biomarkers reflecting SARS-CoV-2 persistence, reactivation of herpesviruses and immune dysregulation; biomarkers of endotheliopathy, coagulation and fibrinolysis; microbiota alterations; diverse proteins and metabolites; hormonal and metabolic biomarkers; as well as cerebrospinal fluid biomarkers. At present, there are only two reviews summarizing relevant biomarkers; however, they do not cover the entire umbrella of current biomarkers or their link to etiopathogenetic mechanisms, and the diagnostic work-up in a comprehensive manner.

Herein, we aim to appraise and synopsize the available evidence on the typical laboratory manifestations and candidate biomarkers of LC, their classification based on main LC symptomatology in the frame of the epidemiological and pathogenetic aspects of the syndrome, and furthermore assess limitations and challenges as well as potential implications in candidate therapeutic interventions.

Source: Tsilingiris, D.; Vallianou, N.G.; Karampela, I.; Christodoulatos, G.S.; Papavasileiou, G.; Petropoulou, D.; Magkos, F.; Dalamaga, M. Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights Into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges. Preprints.org 2023, 2023051487. https://doi.org/10.20944/preprints202305.1487.v1 (Full text available as PDF file)

Musculoskeletal involvement: COVID-19 and post COVID 19

Abstract:

The worldwide pandemic of coronavirus disease 2019 (COVID-19) was known to predominantly affect the lungs, but it was realized that COVID-19 had a large variety of clinical involvement. Cardiovascular, gastrointestinal, neurological, and musculoskeletal systems are involved by direct or indirect mechanisms with various manifestations.

The musculoskeletal involvement can manifest during COVID-19 infection, due to medications used for the treatment of COVID-19, and in the post/long COVID-19 syndrome. The major symptoms are fatigue, myalgia/arthralgia, back pain, low back pain, and chest pain. During the last two years, musculoskeletal involvement increased, but no clear consensus was obtained about the pathogenesis. However, there is valuable data that supports the hypothesis of angiotensinconverting enzyme 2, inflammation, hypoxia, and muscle catabolism. Additionally, medications that were used for treatment also have musculoskeletal adverse effects, such as corticosteroid-induced myopathy and osteoporosis. Therefore, while deciding the drugs, priorities and benefits should be taken into consideration.

Symptoms that begin three months from the onset of the COVID-19 infection, continue for at least two months, and cannot be explained by another diagnosis is accepted as post/long COVID-19 syndrome. Prior symptoms may persist and fluctuate, or new symptoms may manifest. In addition, there must be at least one symptom of infection. Most common musculoskeletal symptoms are myalgia, arthralgia, fatigue, back pain, muscle weakness, sarcopenia, impaired exercise capacity, and physical performance. In addition, the female sex, obesity, elderly patients, hospitalization, prolonged immobility, having mechanical ventilation, not having vaccination, and comorbid disorders can be accepted as clinical predictors for post/long COVID-19 syndrome.

Musculoskeletal pain is also a major problem and tends to be in chronic form. There is no consensus on the mechanism, but inflammation and angiotensin-converting enzyme 2 seem to play an important role. Localized and generalized pain may occur after COVID-19, and general pain is at least as common as localized pain. An accurate diagnosis allows physicians to initiate pain management and proper rehabilitation programs.

Source: Evcik D. Musculoskeletal involvement: COVID-19 and post COVID 19. Turk J Phys Med Rehabil. 2023 Feb 28;69(1):1-7. doi: 10.5606/tftrd.2023.12521. PMID: 37201006; PMCID: PMC10186015.

Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection

Key Points:

Question  What symptoms are differentially present in SARS-CoV-2–infected individuals 6 months or more after infection compared with uninfected individuals, and what symptom-based criteria can be used to identify postacute sequelae of SARS-CoV-2 infection (PASC) cases?

Findings  In this analysis of data from 9764 participants in the RECOVER adult cohort, a prospective longitudinal cohort study, 37 symptoms across multiple pathophysiological domains were identified as present more often in SARS-CoV-2–infected participants at 6 months or more after infection compared with uninfected participants. A preliminary rule for identifying PASC was derived based on a composite symptom score.

Meaning  A framework for identifying PASC cases based on symptoms is a first step to defining PASC as a new condition. These findings require iterative refinement that further incorporates clinical features to arrive at actionable definitions of PASC.

Abstract:

Importance  SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.

Objective  To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.

Design, Setting, and Participants  Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.

Exposure  SARS-CoV-2 infection.

Main Outcomes and Measures  PASC and 44 participant-reported symptoms (with severity thresholds).

Results  A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.

Conclusions and Relevance  A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Source: Thaweethai T, Jolley SE, Karlson EW, et al. Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection. JAMA. Published online May 25, 2023. doi:10.1001/jama.2023.8823 https://jamanetwork.com/journals/jama/fullarticle/2805540 (Full text)

Viable SARS-CoV-2 Omicron sub-variants isolated from autopsy tissues

Introduction: Pulmonary and extrapulmonary manifestations have been described after infection with SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). The virus is known to persist in multiple organs due to its tropism for several tissues. However, previous reports were unable to provide definitive information about whether the virus is viable and transmissible. It has been hypothesized that the persisting reservoirs of SARS-CoV-2 in tissues could be one of the multiple potentially overlapping causes of long COVID.

Methods: In the present study, we investigated autopsy materials obtained from 21 cadaveric donors with documented first infection or reinfection at the time of death. The cases studied included recipients of different formulations of COVID-19 vaccines. The aim was to find the presence of SARS-CoV-2 in the lungs, heart, liver, kidneys, and intestines. We used two technical approaches: the detection and quantification of viral genomic RNA using RT-qPCR, and virus infectivity using permissive in vitro Vero E6 culture.

Results: All tissues analyzed showed the presence of SARS-CoV-2 genomic RNA but at dissimilar levels ranging from 1.01 × 102 copies/mL to 1.14 × 108 copies/mL, even among those cases who had been COVID-19 vaccinated. Importantly, different amounts of replication-competent virus were detected in the culture media from the studied tissues. The highest viral load were measured in the lung (≈1.4 × 106 copies/mL) and heart (≈1.9 × 106 copies/mL) samples. Additionally, based on partial Spike gene sequences, SARS-CoV-2 characterization revealed the presence of multiple Omicron sub-variants exhibiting a high level of nucleotide and amino acid identity among them.

Discussion: These findings highlight that SARS-CoV-2 can spread to multiple tissue locations such as the lungs, heart, liver, kidneys, and intestines, both after primary infection and after reinfections with the Omicron variant, contributing to extending knowledge about the pathogenesis of acute infection and understanding the sequelae of clinical manifestations that are observed during post-acute COVID-19.

Source: Santiago Maffia-Bizzozero, Cintia Cevallos, Federico Remes Lenicov, Rosa Nicole Freiberger, Cinthya Alicia Marcela Lopez, Alex Guano Toaquiza, Franco Sviercz, Patricio Jarmoluk, Cristina Bustos, Adriana Claudia D’Addario, Jorge Quarleri, and M. Victoria Delpino. Viable SARS-CoV-2 Omicron sub-variants isolated from autopsy tissues. Front. Microbiol., 22 May 2023. https://www.frontiersin.org/articles/10.3389/fmicb.2023.1192832/full (Full text)

How Does Long-COVID Impact Prognosis and the Long-Term Sequelae?

Abstract:

Context: We reviewed what has been studied and published during the last 3 years about the consequences, mainly respiratory, cardiac, digestive, and neurological/psychiatric (organic and functional), in patients with COVID-19 of prolonged course.
Objective: To conduct a narrative review synthesizing current clinical evidence of abnormalities of signs, symptoms, and complementary studies in COVID-19 patients who presented a prolonged and complicated course.
Methods: A review of the literature focused on the involvement of the main organic functions mentioned, based almost exclusively on the systematic search of publications written in English available on PubMed/MEDLINE.
Results: Long-term respiratory, cardiac, digestive, and neurological/psychiatric dysfunction are present in a significant number of patients. Lung involvement is the most common; cardiovascular involvement may happen with or without symptoms or clinical abnormalities; gastrointestinal compromise includes the loss of appetite, nausea, gastroesophageal reflux, diarrhea, etc.; and neurological/psychiatric compromise can produce a wide variety of signs and symptoms, either organic or functional. Vaccination is not associated with the emergence of long-COVID, but it may happen in vaccinated people.
Conclusions: The severity of illness increases the risk of long-COVID. Pulmonary sequelae, cardiomyopathy, the detection of ribonucleic acid in the gastrointestinal tract, and headaches and cognitive impairment may become refractory in severely ill COVID-19 patients.
Source: Baroni C, Potito J, Perticone ME, Orausclio P, Luna CM. How Does Long-COVID Impact Prognosis and the Long-Term Sequelae? Viruses. 2023; 15(5):1173. https://doi.org/10.3390/v15051173 https://www.mdpi.com/1999-4915/15/5/1173 (Full text)

Long COVID: Plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms

Abstract:

It is well known the potential of severe acute respiratory coronavirus type 2 (SARS-CoV-2) infection to induce post-acute sequelae, a condition called Long COVID. This syndrome includes several symptoms, but the central nervous system (CNS) main one is neurocognitive dysfunction. Recently it has been demonstrated the relevance of plasma levels of neurofilament light chain (pNfL), as a biomarker of early involvement of the CNS in COVID-19.

The aim of this study was to investigate the relationship between pNfL in patients with post-acute neurocognitive symptoms and the potential of NfL as a prognostic biomarker in these cases. A group of 63 long COVID patients ranging from 18 to 59 years-old were evaluated, submitted to a neurocognitive battery assessment, and subdivided in different groups, according to results. Plasma samples were collected during the long COVID assessment and used for measurement of pNfL with the Single molecule array (SIMOA) assays. Levels of pNfL were significantly higher in long COVID patients with neurocognitive symptoms when compared to HC (p = 0.0031).

Long COVID patients with cognitive impairment and fatigue symptoms presented higher pNfL levels when compared to long COVID patients without these symptoms, individually and combined (p = 0.0263, p = 0.0480, and 0.0142, respectively). Correlation analysis showed that levels of cognitive lost and exacerbation of fatigue in the neurocognitive evaluation had a significative correlation with higher pNfL levels (p = 0.0219 and 0.0255, respectively). Previous reports suggested that pNfL levels are related with higher risk of severity and predict lethality of COVID-19.

Our findings demonstrate that SARS-CoV-2 infection seems to have a long-term impact on the brain, even in patients who presented mild acute disease. NfL measurements might be useful to identify CNS involvement in long COVID associated with neurocognitive symptoms and to identify who will need continuous monitoring and treatment support.

Source: Gutman E, Salvio A, Fernandes R, et al. Long COVID: Plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms. Research Square; 2023. DOI: 10.21203/rs.3.rs-2921879/v1. https://www.researchsquare.com/article/rs-2921879/v1 (Full text)

COVID-19 and Cognitive Function: Evidence for Increased Processing Speed Variability in COVID-19 Survivors and Multifaceted Impairment with LongCOVID Symptoms

Abstract:

Background: There is increasing evidence for cognitive function to be negatively impacted by COVID-19. There is, however, limited research evaluating cognitive function pre- and postCOVID-19 using objective measures.

Methods: We examined processing speed, attention, working memory, executive function and memory in adults (≤69 years) with a history of COVID-19 (n=129; assessed ≥20 days after diagnosis, none acutely unwell), compared to those with no known history of COVID-19 (n=93). We also examined cognitive changes in a sub-group of COVID (n=30) and non-COVID (n=33) participants, compared to their pre-COVID-19 pandemic level (data available through the MyCognition database).

Results: Cross-sectionally, the COVID group showed significantly larger intra-individual variability in processing speed, compared to the non-COVID group. The COVID sub-group also showed significantly larger intra-individual variability in processing speed, compared to their
pre-COVID level; no significant change occurred in non-COVID participants over the same time scale. Other cognitive indices were not significantly impacted in the cross-sectional or withinsubjects investigations, but participants (n=20) who had needed hospitalisation due to COVID19 showed poor attention and executive function relative to those who had not required hospitalisation (n=109). Poor health and long-COVID symptoms  correlated with poor cognitive function across domains in the COVID group.

Conclusions: The findings indicate a limited cognitive impact of COVID-19 with only intraindividual variability in processing speed being significantly impacted in an adult UK sample. However, those who required hospitalisation due to COVID-19 severity and/or experience long-COVID symptoms display multifaceted cognitive impairment and may benefit from repeated cognitive assessments and remediation efforts.

Source: Vakani K, Ratto M, Sandford-James A, Antonova E, Kumari V. COVID-19 and Cognitive Function: Evidence for Increased Processing Speed Variability in COVID-19 Survivors and Multifaceted Impairment with Long-COVID Symptoms. Eur Psychiatry. 2023 May 12:1-34. doi: 10.1192/j.eurpsy.2023.25. Epub ahead of print. PMID: 37170616. https://www.cambridge.org/core/services/aop-cambridge-core/content/view/AE8EFA3BF7DC84334EEBC3039427801C/S0924933823000251a.pdf/covid-19-and-cognitive-function-evidence-for-increased-processing-speed-variability-in-covid-19-survivors-and-multifaceted-impairment-with-long-covid-symptoms.pdf (Full text available as PDF file)

Sonographic Diaphragm Abnormalities are an Unexpectedly Frequent Feature of Long COVID Outpatients with Unexplained Dyspnea and Fatigue

Abstract:

Purpose: The primary aim of this study is to define the sonographic diaphragm phenotype of Long COVID rehabilitation outpatients with non-specific dyspnea and fatigue. We analyzed patients referred from a pulmonary post-COVID clinic that were lacking a specific cardiopulmonary diagnosis for their symptoms. Additionally, we report the functional outcomes of subset of patients who completed an outpatient cardiopulmonary physical therapy program.

Methods: This was a retrospective cohort study (n = 58) of consecutive patients referred for neuromuscular ultrasound assessment of diaphragm muscle using B-mode technique. Patients were recruited from a single academic hospital between February 25, 2021 and November 22, 2022.

Results: Sonographic abnormalities were identified in 57% (33/58) of patients, and in the vast majority of cases (33/33) was defined by a low diaphragm muscle thickness. Thinner diaphragm muscles are correlated with lower serum creatinine and creatine kinase values, but there was no association with markers of systemic inflammation. Thirty three patients participated in outpatient cardiopulmonary physical therapy that included respiratory muscle training, and 75.8% (25/33) had documented improvement.

Conclusion: In the outpatient rehabilitation setting, patients with Long COVID display low diaphragm muscle thickness, but intact muscle contractility, with surprising frequency on neuromuscular ultrasound. We speculate this represents a form of disuse atrophy. Also, these patients appear to have a favorable response to cardiopulmonary physical therapy that includes respiratory muscle training.

Source: Prabhav P. Deo, Joseph I. Bailey, Alexandra S. Jensen, Ellen Farr, Meghan Fahey, Matthew Isherwood, Keerthana Chakka, Lisa F. Wolfe, Ishan Roy, Marc A. Sala, Colin K. Franz. Sonographic Diaphragm Abnormalities are an Unexpectedly Frequent Feature of Long COVID Outpatients with Unexplained Dyspnea and Fatigue. medRxiv 2022.06.29.22277054; doi: https://doi.org/10.1101/2022.06.29.22277054 (Full text)

Integrated Care Models for Long Coronavirus Disease

Key points:

  • The wide range of persistent symptoms in long COVID requires a coordinated response from multiple medical specialties.
  • Formalized models of care systems and multidisciplinary collaborations began in early 2021 as health care providers recognized the needs of the affected population.
  • Multidisciplinary models largely exist in academic centers and larger cities; however, most care for PASC patients is provided by the primary care providers.

Introduction:

As of July 2022, there have been more than 540 million confirmed cases of coronavirus disease (severe acute respiratory syndrome coronavirus 2 [SARS CoV-2], coronavirus disease 2019 [COVID-19]) during the global pandemic.
Severe acute cases of SARS-CoV-2 respiratory illness continue to strain communities, health care systems, and nations. Evidence-based medical treatments have greatly improved patient outcomes; however, a growing population of survivors with persisting long-term complications has been recognized. This syndrome has been labeled as long COVID or the Post-Acute Sequelae of SARS CoV-2 (PASC).
There is no single accepted definition of PASC. However, PASC is characterized by persistent and/or delayed symptoms or complications beyond 4 weeks of symptom onset or 3 months after a confirmed SARS CoV-2 infection.
The population that experiences PASC is extremely heterogeneous, from those initially asymptomatic with no prior comorbidities to those with preexisting respiratory conditions and prolonged intensive care unit (ICU) stays. The exact prevalence of PASC in the population is unknown with reports of patients with PASC ranging from 10% to 81% of confirmed cases.
Given this large population, treatment resource, health care needs, and social costs will continue to be a growing burden on already exhausted health care systems.
Source: Surendra Barshikar, MD, MBA, Martin Laguerre, MD, Patricia Gordon, MSN, MPH, APRN, FNP-BC, Marielisa Lopez, MD. Integrated Care Models for Long Coronavirus Disease.

 

Deficient GABABergic and glutamatergic excitability in the motor cortex of patients with long-COVID and cognitive impairment

Abstract:

Objective: Attention, working memory and executive processing have been reported to be consistently impaired in Neuro-Long coronavirus disease (COVID). On the hypothesis of abnormal cortical excitability, we investigated the functional state of inhibitory and excitatory cortical regulatory circuits by single “paired-pulse” transcranial magnetic stimulation (ppTMS) and Short-latency Afferent Inhibition (SAI).

Methods: We compared clinical and neurophysiological data of 18 Long COVID patients complaining of persistent cognitive impairment with 16 Healthy control (HC) subjects. Cognitive status was evaluated by means of the Montreal Cognitive Assessment (MoCA) and a neuropsychological evaluation of the executive function domain; fatigue was scored by the Fatigue Severity Scale (FSS). Resting motor threshold (RMT), the amplitude of the motor evoked potential (MEP), Short Intra-cortical Inhibition (SICI), Intra-cortical Facilitation (ICF), Long-interval Intracortical Inhibition (LICI) and Short-afferent inhibition (SAI) were investigated over the motor (M1) cortex.

Results: MoCA corrected scores were significantly different between the two groups (p = 0.023). The majority of the patients’ performed sub-optimally in the neuropsychological assessment of the executive functions. The majority (77.80%) of the patients reported high levels of perceived fatigue in the FSS. RMT, MEPs, SICI and SAI were not significantly different between the two groups. On the other hand, Long COVID patients showed a reduced amount of inhibition in LICI (p = 0.003) and a significant reduction in ICF (p < 0.001).

Conclusions: Neuro-Long COVID patients performing sub-optimally in the executive functions showed a reduction of LICI related to GABAb inhibition and a reduction of ICF related to glutamatergic regulation. No alteration in cholinergic circuits was found.

Significance: These findings can help to better understand the neurophysiological characteristics of Neuro-Long COVID, and in particular, motor cortex regulation in people with “brain fog”.

Source: Manganotti P, Michelutti M, Furlanis G, Deodato M, Buoite Stella A. Deficient GABABergic and glutamatergic excitability in the motor cortex of patients with long-COVID and cognitive impairment. Clin Neurophysiol. 2023 May 10;151:83-91. doi: 10.1016/j.clinph.2023.04.010. Epub ahead of print. PMID: 37210757; PMCID: PMC10170904. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10170904/ (Full text)