Tag: 2022

Deep Dive into the Long Haul: Analysis of Symptom Clusters and Risk Factors for Post-Acute Sequelae of COVID-19 to Inform Clinical Care

Abstract:

Long COVID is a chronic condition characterized by symptoms such as fatigue, dyspnea, and cognitive impairment that persist or relapse months after an acute infection with the SARS-CoV-2 virus. Many distinct symptoms have been attributed to Long COVID; however, little is known about the potential clustering of these symptoms and risk factors that may predispose patients to certain clusters. In this study, an electronic survey was sent to patients in the UC San Diego Health (UCSDH) system who tested positive for COVID-19, querying if patients were experiencing symptoms consistent with Long COVID.

Based on survey results, along with patient demographics reported in the electronic health record (EHR), linear and logistic regression models were used to examine putative risk factors, and exploratory factor analysis was performed to determine symptom clusters. Among 999 survey respondents, increased odds of Long COVID (n = 421; 42%) and greater Long COVID symptom burden were associated with female sex (OR = 1.73, 99% CI: 1.16-2.58; β = 0.48, 0.22-0.75), COVID-19 hospitalization (OR = 4.51, 2.50-8.43; β = 0.48, 0.17-0.78), and poorer pre-COVID self-rated health (OR = 0.75, 0.57-0.97; β = -0.19, -0.32–0.07).

Over one-fifth of Long COVID patients screened positive for depression and/or anxiety, the latter of which was associated with younger age (OR = 0.96, 0.94-0.99). Factor analysis of 16 self-reported symptoms suggested five symptom clusters-gastrointestinal (GI), musculoskeletal (MSK), neurocognitive (NC), airway (AW), and cardiopulmonary (CP), with older age (β = 0.21, 0.11-0.30) and mixed race (β = 0.27, 0.04-0.51) being associated with greater MSK symptom burden. Greater NC symptom burden was associated with increased odds of depression (OR = 5.86, 2.71-13.8) and anxiety (OR = 2.83, 1.36-6.14).

These results can inform clinicians in identifying patients at increased risk for Long COVID-related medical issues, particularly neurocognitive symptoms and symptom clusters, as well as informing health systems to manage operational expectations on a population-health level.

Source: Goldhaber NH, Kohn JN, Ogan WS, Sitapati A, Longhurst CA, Wang A, Lee S, Hong S, Horton LE. Deep Dive into the Long Haul: Analysis of Symptom Clusters and Risk Factors for Post-Acute Sequelae of COVID-19 to Inform Clinical Care. Int J Environ Res Public Health. 2022 Dec 15;19(24):16841. doi: 10.3390/ijerph192416841. PMID: 36554723; PMCID: PMC9778884. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9778884/ (Full text)

Low molecular weight cytotoxic components (DAMPs) form the post-COVID-19 syndrome

Abstract:

We studied the role of cytotoxic components (DAMPs) formed in the body of patients with COVID-19 in ensuring the long-term preservation of post-COVID-19 manifestations and the possibility of creating an experimental model by transferring DAMPs to rats. In patients with post-COVID-19 syndrome (PCS) 2 months after SARS-CoV-2 infection we determined the presence of cytotoxic components in the blood serum (Terasaki test, Dunaliella viridis test and content of DAMPs).

In post-COVID-19 syndrome patients with a high content of serum cytotoxic oligopeptide fraction (selective group, n = 16) we determined the number of leukocytes, lymphocytes, neutrophil granulocytes and monocytes in the blood, the content of C-reactive protein (CRP), the concentration of C3 and C4 complement components and circulating immune complexes, the serum content of IL-6, IL -10, IL-18, TNF-α, phagocytic activity of neutrophils, presence of neutrophil traps and autoantibodies ANA.

It has been shown that in patients with PCS, there are components with cytotoxicity in the blood serum, form specific immunopathological patterns, which are characterized by: an increased content of CRP, complement system components C3 and C4 and cytokines (TNF-α, IL-6, IL-10, IL-18) activation, the formation of a wide range of autoantibodies ANA, the low efficiency of endocytosis in oxygen-independent phagocytosis; their phagocytic activity reaches its functional limit, and against this background, activation of neutrophil traps occurs, which can contribute to further induction of DAMPs. This self-sustaining cell-killing activation provided long-term preservation of PCS symptoms.

The transfer of blood serum components from selective group patients with PCS to rats was accompanied by the appearance of cytotoxic components in them which induced sensitization and immunopathological reactions. Preventive administration of a biologically active substance with polyfunctional properties MF to experimental animals “corrected” the initial functional state of the body’s immune-metabolic system and eliminated or facilitated immuno-inflammatory reactions.

Source: Klimova EM, Bozhkov AI, Lavinska OV, Drozdova LA, Kurhuzova NI. Low molecular weight cytotoxic components (DAMPs) form the post-COVID-19 syndrome. Immunobiology. 2023 Jan;228(1):152316. doi: 10.1016/j.imbio.2022.152316. Epub 2022 Dec 20. PMID: 36565610; PMCID: PMC9764760. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9764760/ (Full text)

Generalisable long COVID subtypes: Findings from the NIH N3C and RECOVER programmes

Abstract:

Background: Stratification of patients with post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) would allow precision clinical management strategies. However, long COVID is incompletely understood and characterised by a wide range of manifestations that are difficult to analyse computationally. Additionally, the generalisability of machine learning classification of COVID-19 clinical outcomes has rarely been tested.

Methods: We present a method for computationally modelling PASC phenotype data based on electronic healthcare records (EHRs) and for assessing pairwise phenotypic similarity between patients using semantic similarity. Our approach defines a nonlinear similarity function that maps from a feature space of phenotypic abnormalities to a matrix of pairwise patient similarity that can be clustered using unsupervised machine learning.

Findings: We found six clusters of PASC patients, each with distinct profiles of phenotypic abnormalities, including clusters with distinct pulmonary, neuropsychiatric, and cardiovascular abnormalities, and a cluster associated with broad, severe manifestations and increased mortality. There was significant association of cluster membership with a range of pre-existing conditions and measures of severity during acute COVID-19. We assigned new patients from other healthcare centres to clusters by maximum semantic similarity to the original patients, and showed that the clusters were generalisable across different hospital systems. The increased mortality rate originally identified in one cluster was consistently observed in patients assigned to that cluster in other hospital systems.

Interpretation: Semantic phenotypic clustering provides a foundation for assigning patients to stratified subgroups for natural history or therapy studies on PASC.

Source: Reese JT, Blau H, Casiraghi E, Bergquist T, Loomba JJ, Callahan TJ, Laraway B, Antonescu C, Coleman B, Gargano M, Wilkins KJ, Cappelletti L, Fontana T, Ammar N, Antony B, Murali TM, Caufield JH, Karlebach G, McMurry JA, Williams A, Moffitt R, Banerjee J, Solomonides AE, Davis H, Kostka K, Valentini G, Sahner D, Chute CG, Madlock-Brown C, Haendel MA, Robinson PN; N3C Consortium; RECOVER Consortium. Generalisable long COVID subtypes: Findings from the NIH N3C and RECOVER programmes. EBioMedicine. 2022 Dec 21;87:104413. doi: 10.1016/j.ebiom.2022.104413. Epub ahead of print. PMID: 36563487; PMCID: PMC9769411. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9769411/ (Full text)

Characteristics and predictors of Long COVID among diagnosed cases of COVID-19

Abstract:

Background: Long COVID or long-term symptoms after COVID-19 has the ability to affect health and quality of life. Knowledge about the burden and predictors could aid in their prevention and management. Most of the studies are from high-income countries and focus on severe acute COVID-19 cases. We did this study to estimate the incidence and identify the characteristics and predictors of Long COVID among our patients.

Methodology: We recruited adult (≥18 years) patients who were diagnosed as Reverse Transcription Polymerase Chain Reaction (RTPCR) confirmed SARS-COV-2 infection and were either hospitalized or tested on outpatient basis. Eligible participants were followed up telephonically after four weeks and six months of diagnosis of SARS-COV-2 infection to collect data on sociodemographic, clinical history, vaccination history, Cycle threshold (Ct) values during diagnosis and other variables. Characteristics of Long COVID were elicited, and multivariable logistic regression was done to find the predictors of Long COVID.

Results: We have analyzed 487 and 371 individual data with a median follow-up of 44 days (Inter quartile range (IQR): 39,47) and 223 days (IQR:195,251), respectively. Overall, Long COVID was reported by 29.2% (95% Confidence interval (CI): 25.3%,33.4%) and 9.4% (95% CI: 6.7%,12.9%) of participants at four weeks and six months of follow-up, respectively. Incidence of Long COVID among patients with mild/moderate disease (n = 415) was 23.4% (95% CI: 19.5%,27.7%) as compared to 62.5% (95% CI: 50.7%,73%) in severe/critical cases(n = 72) at four weeks of follow-up. At six months, the incidence among mild/moderate (n = 319) was 7.2% (95% CI:4.6%,10.6%) as compared to 23.1% (95% CI:12.5%,36.8%) in severe/critical (n = 52). The most common Long COVID symptom was fatigue. Statistically significant predictors of Long COVID at four weeks of follow-up were-Pre-existing medical conditions (Adjusted Odds ratio (aOR) = 2.00, 95% CI: 1.16,3.44), having a higher number of symptoms during acute phase of COVID-19 disease (aOR = 11.24, 95% CI: 4.00,31.51), two doses of COVID-19 vaccination (aOR = 2.32, 95% CI: 1.17,4.58), the severity of illness (aOR = 5.71, 95% CI: 3.00,10.89) and being admitted to hospital (Odds ratio (OR) = 3.89, 95% CI: 2.49,6.08).

Conclusion: A considerable proportion of COVID-19 cases reported Long COVID symptoms. More research is needed in Long COVID to objectively assess the symptoms and find the biological and radiological markers.

Source: Arjun MC, Singh AK, Pal D, Das K, G A, Venkateshan M, Mishra B, Patro BK, Mohapatra PR, Subba SH. Characteristics and predictors of Long COVID among diagnosed cases of COVID-19. PLoS One. 2022 Dec 20;17(12):e0278825. doi: 10.1371/journal.pone.0278825. PMID: 36538532; PMCID: PMC9767341. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9767341/ (Full text)

Anti-Correlated Myelin-Sensitive MRI Levels in Humans Consistent with a Subcortical to Sensorimotor Regulatory Process-Multi-Cohort Multi-Modal Evidence

Abstract:

Differential axonal myelination synchronises signalling over different axon lengths. The consequences of myelination processes described at the cellular level for the regulation of myelination at the macroscopic level are unknown. We analysed multiple cohorts of myelin-sensitive brain MRI. Our aim was to (i) confirm a previous report of anti-correlation between myelination in subcortical and sensorimotor areas in healthy subjects, (ii) and thereby test our hypothesis for a regulatory interaction between them.

We analysed nine image-sets across three different human cohorts using six MRI modalities. Each image-set contained healthy controls (HC) and ME/CFS subjects. Subcortical and Sensorimotor regions of interest (ROI) were optimised for the detection of anti-correlations and the same ROIs were used to test the HC in all image-sets. For each cohort, median MRI values were computed in both regions for each subject and their correlation across the cohort was computed.

We confirmed negative correlations in healthy controls between subcortical and sensorimotor regions in six image-sets: three T1wSE (p = 5 × 10-8, 5 × 10-7, 0.002), T2wSE (p =2 × 10-6), MTC (p = 0.01), and WM volume (p = 0.02). T1/T2 was the exception with a positive correlation (p = 0.01). This myelin regulation study is novel in several aspects: human subjects, cross-sectional design, ROI optimization, spin-echo MRI and reproducible across multiple independent image-sets.

In multiple independent image-sets we confirmed an anti-correlation between subcortical and sensorimotor myelination which supports a previously unreported regulatory interaction. The subcortical region contained the brain’s primary regulatory nuclei. We suggest a mechanism has evolved whereby relatively low subcortical myelination in an individual is compensated by upregulated sensorimotor myelination to maintain adequate sensorimotor performance.

Source: Barnden L, Crouch B, Kwiatek R, Shan Z, Thapaliya K, Staines D, Bhuta S, Del Fante P, Burnet R. Anti-Correlated Myelin-Sensitive MRI Levels in Humans Consistent with a Subcortical to Sensorimotor Regulatory Process-Multi-Cohort Multi-Modal Evidence. Brain Sci. 2022 Dec 9;12(12):1693. doi: 10.3390/brainsci12121693. PMID: 36552153; PMCID: PMC9776387. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776387/ (Full text)

Nursing Diagnoses of Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Research Protocol for a Qualitative Synthesis

Abstract:

Although previously developed qualitative studies have explored the experience of illness of individuals with myalgic encephalomyelitis/chronic fatigue syndrome, these findings have not been undertaken for the purpose of enabling the identification of nursing care needs in such patients. This study aims to identify NANDA-I nursing diagnoses of adults with myalgic encephalomyelitis/chronic fatigue syndrome based on a qualitative literature review of their experience of illness.

The protocol includes: searches in the electronic databases Medline, Embase, CINAHL, PsycINFO, SCI-EXPANDED, SSCI, SciELO, LILACS, and Cuiden; and manual searches in specialised journals and the references of the included studies. The authors will systematically search qualitative research studies published in databases from 1994 to 2021. Searches are limited to studies in Spanish and English. All stages of the review process will be carried out independently by two reviewers. Any disagreements shall be resolved through joint discussions, involving a third reviewer if necessary.

The findings will be synthesised into a thematic analysis informed by the Domains and Classes of the NANDA-I Classification of Nursing Diagnoses, which will then serve to identify nursing diagnoses. This review will enable nursing professionals to identify the care needs of individuals with myalgic encephalomyelitis/chronic fatigue syndrome by taking into consideration their experience of illness in its entirety.

Source: Oter-Quintana C, Esteban-Hernández J, Cuéllar-Pompa L, Gil-Carballo MC, Brito-Brito PR, Martín-García A, Alcolea-Cosín MT, Martínez-Marcos M, Alameda-Cuesta A. Nursing Diagnoses of Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Research Protocol for a Qualitative Synthesis. Healthcare (Basel). 2022 Dec 10;10(12):2506. doi: 10.3390/healthcare10122506. PMID: 36554030; PMCID: PMC9777975. https://www.mdpi.com/2227-9032/10/12/2506 (Full text)

Computable Clinical Phenotyping of Postacute Sequelae of COVID-19 in Pediatrics Using Real-World Data

INTRODUCTION:

Since the SARS-CoV-2 pandemic began in late 2019, over 13 million children in the United States have been infected with the virus [1]. Although many of these acute infections have not resulted in severe morbidity or mortality, a subset of children and adolescents have experienced recurrent or persistent symptoms beyond the typical recovery period [2]. The constellation of findings that occur postinfection is known as postacute sequelae of SARS-CoV-2 (PASC), or colloquially as “long-Covid.” The U.S. Centers for Disease Control and Prevention (CDC) defines PASC as a wide range of health problems that linger for more than 4 weeks following an acute COVID-19 infection [3]. Although this is an area of active research, relatively little is currently known about its clinical epidemiology in the pediatric population.

Considering the large number of children who have been affected by COVID-19, it is critical that we monitor the rates, trends, and outcomes of PASC in this population. An important first step toward these efforts is the development of a tool that can quickly and easily identify cases in large clinical populations. With the widespread adoption of electronic health records (EHR), it is now possible to develop computable phenotypes using data that are collected for clinical care, which can be used for population-level analysis to inform the public health response [4, 5]. In this report, we describe a novel phenotyping algorithm to define the burden, clinical spectrum, and outcomes of pediatric PASC using real-world data.

Source: Tomini A Fashina, Christine M Miller, Elijah Paintsil, Linda M Niccolai, Cynthia Brandt, Carlos R Oliveira, Computable Clinical Phenotyping of Postacute Sequelae of COVID-19 in Pediatrics Using Real-World Data, Journal of the Pediatric Infectious Diseases Society, 2022;, piac132, https://doi.org/10.1093/jpids/piac132 https://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piac132/6957369 (Full text)

Pediatric Post-Acute Sequelae of SARS-CoV-2 infection

Abstract:

Aim: Youth who have not recovered from COVID-19 have been referred to as having Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). The goal of this study was to better understand which symptoms persisted since onset of infection and how these symptoms compare to symptoms experienced by those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Method: A sample of 19 parents who had a child with PASC were recruited using social media to fill out a questionnaire detailing symptoms at two time points. The first time point included their child’s current symptoms and the second captured symptoms at initial infection. These participants were compared to a sample of 19 youth with ME/CFS.

Results: Findings indicated significant decreases among several immune, neuroendocrine, pain, post-exertional malaise (PEM), and COVID-19 Centers for Disease Control and Prevention (CDC) domain symptoms from time of acute infection to time of current reporting. Fatigue remained at a high level as did several symptoms within the sleep and PEM domains. Participants with ME/CFS had overall worse symptomatology when compared to participants with PASC, especially in the neurocognitive domain.

Conclusion: Most symptoms of those with PASC decline over time, but several remain at high levels, including fatigue. These findings are helpful in better understanding common symptom presentation profiles for youth with PASC and can be used to more adequately tailor diagnostic criteria and treatment strategies for youth.

Source: Leonard A. Jason, Madeline Johnson & Chelsea Torres (2023) Pediatric Post-Acute Sequelae of SARS-CoV-2 infection, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2022.2162764 https://www.tandfonline.com/doi/abs/10.1080/21641846.2022.2162764

Orthostatic Intolerance after COVID-19 Infection: Is Disturbed Microcirculation of the Vasa Vasorum of Capacitance Vessels the Primary Defect?

Abstract:

Following COVID-19 infection, a substantial proportion of patients suffer from persistent symptoms known as Long COVID. Among the main symptoms are fatigue, cognitive dysfunction, muscle weakness and orthostatic intolerance (OI). These symptoms also occur in myalgic encephalomyelitis/chronic fatigue (ME/CFS).
OI is highly prevalent in ME/CFS and develops early during or after acute COVID-19 infection. The causes for OI are unknown and autonomic dysfunction is hypothetically assumed to be the primary cause, presumably as a consequence of neuroinflammation. Here, we propose an alternative, primary vascular mechanism as the underlying cause of OI in Long COVID.
We assume that the capacitance vessel system, which plays a key role in physiologic orthostatic regulation, becomes dysfunctional due to a disturbance of the microvessels and the vasa vasorum, which supply large parts of the wall of those large vessels. We assume that the known microcirculatory disturbance found after COVID-19 infection, resulting from endothelial dysfunction, microthrombus formation and rheological disturbances of blood cells (altered deformability ), also affects the vasa vasorum to impair the function of the capacitance vessels.
In an attempt to compensate for the vascular deficit, sympathetic activity overshoots to further worsen OI, resulting in a vicious circle that maintains OI. The resulting orthostatic stress, in turn, plays a key role in autonomic dysfunction and the pathophysiology of ME/CFS.
Source: Wirth KJ, Löhn M. Orthostatic Intolerance after COVID-19 Infection: Is Disturbed Microcirculation of the Vasa Vasorum of Capacitance Vessels the Primary Defect? Medicina. 2022; 58(12):1807. https://doi.org/10.3390/medicina58121807 https://www.mdpi.com/1648-9144/58/12/1807 (Full text)

Mid- and Long-Term Atrio-Ventricular Functional Changes in Children after Recovery from COVID-19

Abstract:

Background: Although most children may experience mild to moderate symptoms and do not require hospitalization, there are little data on cardiac involvement in COVID-19. However, cardiac involvement is accurately demonstrated in children with MISC. The objective of this study was to evaluate cardiac mechanics in previously healthy children who recovered from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in a long-term follow-up by means of two-dimensional speckle-tracking echocardiography (STE).
Methods: We analyzed a cohort of 157 paediatric patients, mean age 7.7 ± 4.5 years (age range 0.3–18 years), who had a laboratory-confirmed diagnosis of SARS-CoV-2 infection and were asymptomatic or mildly symptomatic for COVID-19. Patients underwent a standard transthoracic echocardiogram and STE at an average time of 148 ± 68 days after diagnosis and were divided in three follow-up groups (<180 days, 180–240 days, >240 days). Patients were compared with 107 (41 females—38%) age- and BSA-comparable healthy controls (CTRL).
Results: Left ventricular (LV) global longitudinal strain (post-COVID-19: −20.5 ± 2.9%; CTRL: −21.8 ± 1.7%; p < 0.001) was significantly reduced in cases compared with CTRLs. No significant differences were seen among the three follow-up groups (p = NS). Moreover, regional longitudinal strain was significantly reduced in LV apical-wall segments of children with disease onset during the second wave of the COVID-19 pandemic compared to the first wave (second wave: −20.2 ± 2.6%; first wave: −21.2 ± 3.4%; p = 0.048). Finally, peak left atrial systolic strain was within the normal range in the post-COVID-19 group with no significant differences compared to CTRLs.
Conclusions: Our study demonstrated for the first time the persistence of LV myocardial deformation abnormalities in previously healthy children with an asymptomatic or mildly symptomatic (WHO stages 0 or 1) COVID-19 course after an average follow-up of 148 ± 68 days. A more significant involvement was found in children affected during the second wave. These findings imply that subclinical LV dysfunction may also be a typical characteristic of COVID-19 infection in children and are concerning given the predictive value of LV longitudinal strain in the general population.
Source: Sabatino J, Di Chiara C, Di Candia A, Sirico D, Donà D, Fumanelli J, Basso A, Pogacnik P, Cuppini E, Romano LR, Castaldi B, Reffo E, Cerutti A, Biffanti R, Cozzani S, Giaquinto C, Di Salvo G. Mid- and Long-Term Atrio-Ventricular Functional Changes in Children after Recovery from COVID-19. Journal of Clinical Medicine. 2023; 12(1):186. https://doi.org/10.3390/jcm12010186 https://www.mdpi.com/2077-0383/12/1/186 (Full text)