Tag: covid-19

De-black-boxing health AI: demonstrating reproducible machine learning computable phenotypes using the N3C-RECOVER Long COVID model in the All of Us data repository

Abstract:

Machine learning (ML)-driven computable phenotypes are among the most challenging to share and reproduce. Despite this difficulty, the urgent public health considerations around Long COVID make it especially important to ensure the rigor and reproducibility of Long COVID phenotyping algorithms such that they can be made available to a broad audience of researchers. As part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative, researchers with the National COVID Cohort Collaborative (N3C) devised and trained an ML-based phenotype to identify patients highly probable to have Long COVID. Supported by RECOVER, N3C and NIH’s All of Us study partnered to reproduce the output of N3C’s trained model in the All of Us data enclave, demonstrating model extensibility in multiple environments. This case study in ML-based phenotype reuse illustrates how open-source software best practices and cross-site collaboration can de-black-box phenotyping algorithms, prevent unnecessary rework, and promote open science in informatics.

Source: Pfaff ER, Girvin AT, Crosskey M, Gangireddy S, Master H, Wei WQ, Kerchberger VE, Weiner M, Harris PA, Basford M, Lunt C, Chute CG, Moffitt RA, Haendel M; N3C and RECOVER Consortia. De-black-boxing health AI: demonstrating reproducible machine learning computable phenotypes using the N3C-RECOVER Long COVID model in the All of Us data repository. J Am Med Inform Assoc. 2023 May 22:ocad077. doi: 10.1093/jamia/ocad077. Epub ahead of print. PMID: 37218289. https://pubmed.ncbi.nlm.nih.gov/37218289/

The Renin-Angiotensin-System in COVID-19: Can Long COVID Be Predicted?

Abstract:

(1) Background: Co-morbidities such as hypertension and cardiovascular disease are major risk factors for severe COVID-19. The renin-angiotensin-system (RAS) is critically involved in their pathophysiology and is counterbalanced by both angiotensin-converting enzyme 2 (ACE2), the functional receptor of SARS-CoV-2, and the kallikrein-kinin-system (KKS). Considerable research interest with respect to COVID-19 treatment is, thus, currently directed towards the components of these systems. In an earlier study, we noticed significantly reduced carboxypeptidase N (CPN, KKS member) activity and partially excessive angiotensin-converting enzyme (ACE, RAS member) activity in the sera of both hospitalized (HoP) COVID-19 patients and a sub-group of covalescent patients, while in the majority of the probands recovering from the disease these values had returned to normal. The data had been obtained using bradykinin (BK) as a reporter peptide, which is a target of both CPN and ACE, and they were supplemented by serum proteomics of the same patient cohort. We hypothesized that the data could be indicative of Long COVID, which had not been fully appreciated at the time of our study.;

(2) Methods: The data were re-evaluated in the light of Long COVID. The recent literature on the RAS in COVID-19, antihypertensiva, and Long COVID was briefly reviewed.;

(3) Results: While the levels of the BK serum degradation products should return to normal concentrations during convalescence, this was not true for some patients. This could be due to persisting liver problems, because CPN is synthesized there, but also to a dysregulated RAS. This was not reflected in the levels of selected RAS/KKS serum proteins like angiotensinogen (AGT), although AGT correlated with disease severity in HoP. However, standard tests in routine patient care in Long COVID often come back normal, and it may be that BK degradation is specific in some pathophysiologies. Moreover, the HoP group was sub-divided based on the serum protein profiles and COVID-19 severity.;

(4) Conclusions: We point out two insights: 1) Sensitive technology such as omics methods might provide unexpected significant differences within the pre-defined patient groups of a clinical study. Those can only be explored, if the cohorts are large enough and properly matched with respect to the parameters known beforehand (e.g., age, gender, co-morbidities). 2) Results of the BK-reporter serum protease activity assay could be indicative of persisting liver problems and/or potentially of Long COVID. Clinical studies are required to test this hypothesis.

Source: König, S.; Vollenberg, R.; Tepasse, P. The Renin-Angiotensin-System in COVID-19: Can Long COVID Be Predicted?. Preprints.org 2023, 2023051298. https://doi.org/10.20944/preprints202305.1298.v1 (Full text available as PDF file)

Long COVID: An Epidemic within the Pandemic

Introduction:

Coronavirus disease 2019 (COVID-19), a life-threatening infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in the Chinese city of Wuhan in late 2019 and has subsequently spread worldwide, reaching pandemic proportions [1]. At the time of writing (i.e., May 2023), COVID-19 has already caused nearly 7 million official deaths, according to World Health Organization (WHO) statistics [2]. Although the WHO COVID-19 emergency committee recently decided to no longer classify COVID-19 as an international public health emergency, SARS-CoV-2 infections and/or reinfections still cause a large number of deaths worldwide, with an excess mortality still estimated at approximately 10,000 deaths per day [3]. In addition to the still significant organic injuries that can develop during an acute SARS-CoV-2 infection, particularly in frail, old and unvaccinated individuals, there is now established evidence that the so-called post-viral syndrome (i.e., a common consequence of many viral infections encompassing a kaleidoscope of organic and psychiatric disorders) [4] is a fairly common sequela of COVID-19 in officially recovered patients, variously termed “post-COVID”, “long-haul COVID”, “long COVID” and so forth.

Source: Mattiuzzi C, Lippi G. Long COVID: An Epidemic within the Pandemic. COVID. 2023; 3(5):773-776. https://doi.org/10.3390/covid3050057  (Full text)

First study results of the P4O2 long COVID cohort

Abstract:

Introduction: Several studies indicate that the acute phase of COVID-19 may be followed by persistent symptoms. However, the impact of COVID-19 on long-term health outcomes remains to be elucidated.

Aims: The Precision Medicine for more Oxygen (P4O2) COVID-19 study aims to identify long COVID patients that are that are at risk for developing chronic lung disease and to identify treatable traits and innovative personalized therapeutic strategies for prevention and treatment. This study describes the baseline characteristics of the P4O2 COVID-19 cohort.

Methods: Long COVID patients were recruited from 5 different hospitals in The Netherlands at 3-6 months post-COVID. Data from medical records and biological samples were collected, pulmonary function tests and chest computed tomography scans were performed and questionnaires were administered during 2 study visits.

Results: 95 long COVID patients were enrolled between May 2021 and September 2022. Study participants were aged 54.2 years on average and of female sex in 49.5% of all cases. Most patients were hospitalized(89.5%) for COVID-19 with a mean hospital stay duration of 8 days. The current study showed persistence of clinical symptoms and signs of pulmonary function test/radiological abnormalities in long COVID patients(81%). The most frequently reported symptom categories were respiratory(80%) and fatigue(69.5%). Both female sex and infection with the Delta, compared with the Beta, SARS-CoV-2 variant were significantly associated with more persisting symptoms.

Conclusions: The first descriptive results of the P4O2 COVID-19 cohort show that long COVID patients show signs of radiological/functional abnormalities and can suffer from a wide range of persisting symptoms.

Source: N Baalbaki, J Blankestijn, M Abdel-Aziz, J De Backer, S Bazdar, I Beekers, R Beijers, J Van Den Bergh, L Bloemsma, H J Bogaard, J Van Bragt, V Van Den Brink, J P Charbonnier, M Cornelissen, Y Dagelet, E H Davies, A Van Der Does, G Downward, C Van Drunen, D Gach, M Geelhoed, J Glastra, K Golebski, I Heijink, J Holtjer, S Holverda, L Houweling, J Jacobs, R Jonker, R Kos, R Langen, I Van Der Lee, A Leliveld, F Mohamed Hoesein, A Neerincx, L Noij, J Olsson, M Van De Pol, S Pouwels, E Rolink, M Rutgers, H Șahin, D Schaminee, A Schols, L Schuurman, P Skipp, G Slingers, O Smeenk, B Sondermeijer, M Tamarit, I Verkouter, R Vermeulen, R De Vries, E Weersink, M Van De Werken, Y De Wit-Van De Wijck, S Young, E Nossent, A Maitland-Van Der Zee. ERJ Open Research 2023 9: 68; DOI: 10.1183/23120541.LSC-2023.68 https://openres.ersjournals.com/content/9/suppl_10/68

 

Imbalance of Peripheral Temperature, Sympathovagal, and Cytokine Profile in Long COVID

Simple Summary:

In this study, we looked at how persistent inflammation affects peripheral body temperature and sympathovagal balance in individuals with long COVID. Increased temperature and reduced heart rate variability were directly related to the increase in inflammatory cytokines and reduction in anti-inflammatory cytokines. We identified a possible “molecular signature” for long COVID, characterised by a Th17 inflammatory profile with a reduced anti-inflammatory response, resulting in alterations in homeostatic functions and sympathovagal balance.

Abstract:

A persistent state of inflammation has been reported during the COVID-19 pandemic. This study aimed to assess short-term heart rate variability (HRV), peripheral body temperature, and serum cytokine levels in patients with long COVID. We evaluated 202 patients with long COVID symptoms categorized them according to the duration of their COVID symptoms (≤120 days, n = 81; >120 days, n = 121), in addition to 95 healthy individuals selected as controls.
All HRV variables differed significantly between the control group and patients with long COVID in the ≤120 days group (p < 0.05), and participants in the long COVID ≤120 days group had higher temperatures than those in the long COVID >120 days group in all regions analysed (p < 0.05).
Cytokine analysis showed higher levels of interleukin 17 (IL-17) and interleukin 2 (IL-2), and lower levels of interleukin 4 (IL-4) (p < 0.05). Our results suggest a reduction in parasympathetic activation during long COVID and an increase in body temperature due to possible endothelial damage caused by the maintenance of elevated levels of inflammatory mediators.
Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 appear to constitute a long-term profile of COVID-19 cytokines, and these markers are potential targets for long COVID-treatment and prevention strategies.
Source: Neves PFMd, Quaresma JAS, Queiroz MAF, Silva CC, Maia EV, Oliveira JSdS, Neves CMAd, Mendonça SdS, Falcão ASC, Melo GS, Santos IBF, Sousa JRd, Santos EJMd, Vasconcelos PFdC, Vallinoto ACR, Falcão LFM. Imbalance of Peripheral Temperature, Sympathovagal, and Cytokine Profile in Long COVID. Biology. 2023; 12(5):749. https://doi.org/10.3390/biology12050749 https://www.mdpi.com/2079-7737/12/5/749 (Full text)

Long- COVID and general health status in hospitalized COVID-19 survivors

Abstract:

Despite advances in clinical research, the long-term effects of COVID-19 on patients are not clear. Many studies revealed persistent long-term signs and symptoms. In a survey study, 259 hospitalized confirmed COVID-19 patients between 18 and 59 years were interviewed. Demographic characteristics and complaints were studied through telephone interviews. Any patient-reported symptoms that continued or developed from 4 weeks up to 12 weeks after the onset of the disease were recorded only if they did not exist prior to infection.

The 12-Item General Health Questionnaire was used for screening and assessing mental symptoms and psychosocial well-being. The mean age of participants was 43.8 ± 9.9 years. About 37% had at least one underlying disease. 92.5% showed ongoing symptoms that the most prevalent complications were hair loss (61.4%), fatigue (54.1%), shortness of breath (40.2%), altered smell (34.4%), and aggression (34.4%), respectively. In terms of factors affecting patients’ complaints, there were significant differences between age, sex, and underlying disease with long-remaining complications. This study shows a high rate of long COVID-19 conditions that should be considered by physicians, policymakers, and managers.

Source: Mohtasham-Amiri, Z., Keihanian, F., Rad, E.H. et al. Long- COVID and general health status in hospitalized COVID-19 survivors. Sci Rep 13, 8116 (2023). https://doi.org/10.1038/s41598-023-35413-z (Full study)

Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis

Abstract:

Long COVID describes an array of often debilitating symptoms in the aftermath of SARS-CoV-2 infection, with similar symptomatology affecting some people post-vaccination. With an estimated > 200 million Long COVID patients worldwide and cases still rising, the effects on quality of life and the economy are significant, thus warranting urgent attention to understand the pathophysiology. Herein we describe our perspective that Long COVID is a continuation of acute COVID-19 pathology, whereby coagulopathy is the main driver of disease and can cause or exacerbate other pathologies common in Long COVID, such as mast cell activation syndrome and dysautonomia.
Considering the SARS-CoV-2 spike protein can independently induce fibrinaloid microclots, platelet activation, and endotheliitis, we predict that persistent spike protein will be a key mechanism driving the continued coagulopathy in Long COVID. We discuss several treatment targets to address the coagulopathy, and predict that (particularly early) treatment with combination anticoagulant and antiplatelet drugs will bring significant relief to many patients, supported by a case study. To help focus attention on such treatment targets, we propose Long COVID should be referred to as Spike protein Induced Thrombotic Vasculitis (SITV). These ideas require urgent testing, especially as the world tries to co-exist with COVID-19.

Source: Kerr R, Carroll HA. Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis. Research Square; 2023. DOI: 10.21203/rs.3.rs-2939263/v1. https://assets.researchsquare.com/files/rs-2939263/v1_covered_7190a867-1475-4b57-b220-716a953649f1.pdf?c=1684433225 (Full text)

Biological mechanisms underpinning the development of Long COVID

Abstract:

As COVID-19 evolves from a pandemic to an endemic disease, the already staggering number of people that have been or will be infected with SARS-COV-2 is only destined to increase, and the majority of humanity will be infected. It is well understood that COVID-19, like many other viral infections, leaves a significant fraction of the infected with prolonged consequences.

Continued high number of SARS-CoV-2 infections, viral evolution with escape from post-infection and vaccinal immunity, and reinfections heighten the potential impact of Long COVID. Hence, the impact of COVID-19 on human health will be seen for years to come until more effective vaccines and pharmaceutical treatments become available.

To that effect, it is imperative that the mechanisms underlying the clinical manifestations of Long COVID be elucidated. In this article, we provide an in-depth analysis of the evidence on several potential mechanisms of Long COVID and discuss their relevance to its pathogenesis.

Source: Perumal R, Shunmugam L, Naidoo K, Wilkins D, Garzino-Demo A, Brechot C, Vahlne A, Nikolich J. Biological mechanisms underpinning the development of Long COVID. iScience. 2023 May 18:106935. doi: 10.1016/j.isci.2023.106935. Epub ahead of print. PMCID: PMC10193768. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193768/ https://www.cell.com/iscience/pdf/S2589-0042(23)01012-X.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS258900422301012X%3Fshowall%3Dtrue (Full text)

Cardiopulmonary testing in long COVID-19 versus non-COVID-19 patients with undifferentiated Dyspnea on exertion

Abstract:

Background: Dyspnea and fatigue are characteristics of long SARS-CoV-2 (COVID)-19. Cardiopulmonary exercise testing (CPET) can be used to better evaluate such patients.

Research question: How significantly and by what mechanisms is exercise capacity impaired in patients with long COVID who are coming to a specialized clinic for evaluation?

Study design and methods: We performed a cohort study using the Mayo Clinic exercise testing database. Subjects included consecutive long COVID patients without prior history of heart or lung disease sent from the Post-COVID Care Clinic for CPET. They were compared to a historical group of non-COVID patients with undifferentiated dyspnea also without known cardiac or pulmonary disease. Statistical comparisons were performed by t-test or Pearson’s chi2 test controlling for age, sex, and beta blocker use where appropriate.

Results: We found 77 patients with long COVID and 766 control patients. Long COVID patients were younger (47 ± 15 vs 50 ± 10 years, P < .01) and more likely female (70% vs 58%, P < .01). The most prominent difference on CPETs was lower percent predicted peak V̇O2 (73 ± 18 vs 85 ± 23%, p < .0001). Autonomic abnormalities (resting tachycardia, CNS changes, low systolic blood pressure) were seen during CPET more commonly in long COVID patients (34 vs 23%, P < .04), while mild pulmonary abnormalities (mild desaturation, limited breathing reserve, elevated V̇E/V̇CO2) during CPET were similar (19% in both groups) with only 1 long COVID patient showing severe impairment.

Interpretation: We identified severe exercise limitation among long COVID patients. Young women may be at higher risk for these complications. Though mild pulmonary and autonomic impairment were common in long COVID patients, marked limitations were uncommon. We hope our observations help to untangle the physiologic abnormalities responsible for the symptomatology of long COVID.

Source: Contreras AM, Newman DB, Cappelloni L, Niven AS, Mueller MR, Ganesh R, Squires RW, Bonikowske AR, Allison TG. Cardiopulmonary testing in long COVID-19 versus non-COVID-19 patients with undifferentiated Dyspnea on exertion. Prog Cardiovasc Dis. 2023 May 19:S0033-0620(23)00053-1. doi: 10.1016/j.pcad.2023.05.005. Epub ahead of print. PMID: 37211198; PMCID: PMC10198738. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10198738/ (Full text)

Prevalence of mental health problems among children with long COVID: A systematic review and meta-analysis

Abstract:

Introduction: The number of children with mental health problems has more than doubled since the COVID-19 pandemic. However, the effect of long Covid on children’s mental health is still debatable. Recognising long Covid as a risk factor for mental health problems in children will increase awareness and screening for mental health problems following COVID-19 infection, resulting in earlier intervention and lower morbidity. Therefore, this study aimed to determine the proportion of mental health problems post-COVID-19 infection in children and adolescents, and to compare them with the population with no previous COVID-19 infection.

Methodology: A systematic search was done in seven databases using pre-defined search terms. Cross-sectional, cohort and interventional studies reporting the proportion of mental health problems among children with long COVID in the English language from 2019 to May 2022 were included. Selection of papers, extraction of data and quality assessment were done independently by two reviewers. Studies with satisfactory quality were included in meta-analysis using R and Revman software programmes.

Results: The initial search retrieved 1848 studies. After screening, 13 studies were included in the quality assessments. Meta-analysis showed children who had previous COVID-19 infection had more than two times higher odds of having anxiety or depression, and 14% higher odds of having appetite problems, compared to children with no previous infection. The pooled prevalence of mental health problems among the population were as follows; anxiety: 9%(95% CI:1, 23), depression: 15%(95% CI:0.4, 47), concentration problems: 6%(95% CI: 3, 11), sleep problems: 9%(95% CI:5, 13), mood swings: 13% (95%CI:5, 23) and appetite loss: 5%(95% CI:1, 13). However, studies were heterogenous and lack data from low- and middle-income countries.

Conclusion: Anxiety, depression and appetite problems were significantly increased among post-COVID-19 infected children, compared to those without a previous infection, which may be attributed to long COVID. The findings underscore the importance of screening and early intervention of children post-COVID-19 infection at one month and between three to four months.

Source: Mat Hassan N, Salim HS, Amaran S, Yunus NI, Yusof NA, Daud N, et al. (2023) Prevalence of mental health problems among children with long COVID: A systematic review and meta-analysis. PLoS ONE 18(5): e0282538. https://doi.org/10.1371/journal.pone.0282538 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282538 (Full text)