Five cluster classifications of long COVID and their background factors: A cross-sectional study in Japan

Abstract:

Purpose: The long-term symptoms of coronavirus disease 2019 (COVID-19), i.e., long COVID, have drawn research attention. Evaluating its subjective symptoms is difficult, and no established pathophysiology or treatment exists. Although there are several reports of long COVID classifications, there are no reports comparing classifications that include patient characteristics, such as autonomic dysfunction and work status. We aimed to classify patients into clusters based on their subjective symptoms during their first outpatient visit and evaluate their background for these clusters.

Methods: Included patients visited our outpatient clinic between January 18, 2021, and May 30, 2022. They were aged ≥ 15 years and confirmed to have SARS-CoV-2 infection and residual symptoms lasting at least 2 months post-infection. Patients were evaluated using a 3-point scale for 23 symptoms and classified into five clusters (1. fatigue only; 2. fatigue, dyspnea, chest pain, palpitations, and forgetfulness; 3. fatigue, headache, insomnia, anxiety, motivation loss, low mood, and forgetfulness; 4. hair loss; and 5. taste and smell disorders) using CLUSTER. For continuous variables, each cluster was compared using the Kruskal–Wallis test. Multiple comparison tests were performed using the Dunn’s test for significant results. For nominal variables, a Chi-square test was performed; for significant results, a residual analysis was conducted with the adjusted residuals.

Results: Compared to patients in other cluster categories, those in cluster categories 2 and 3 had higher proportions of autonomic nervous system disorders and leaves of absence, respectively.

Conclusions: Long COVID cluster classification provided an overall assessment of COVID-19. Different treatment strategies must be used based on physical and psychiatric symptoms and employment factors.

Source: Tsuchida, T., Yoshimura, N., Ishizuka, K. et al. Five cluster classifications of long COVID and their background factors: A cross-sectional study in Japan. Clin Exp Med (2023). https://doi.org/10.1007/s10238-023-01057-6 (Full text)

Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of SARS-CoV-2: More in Common Than Not?

Abstract:

Topic importance: Post-Acute Sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from coronavirus disease 2019 (COVID-19). Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood.

Review findings: Early studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing (CPET) reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms.

Summary: This review aims to illustrate exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.

Source: Joseph P, Singh I, Oliveira R, Capone CA, Mullen MP, Cook DB, Stovall MC, Squires J, Madsen K, Waxman AB, Systrom DM. Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of SARS-CoV-2: More in Common Than Not? Chest. 2023 Apr 11:S0012-3692(23)00502-0. doi: 10.1016/j.chest.2023.03.049. Epub ahead of print. PMID: 37054777; PMCID: PMC10088277. https://pubmed.ncbi.nlm.nih.gov/37054777/

Data-driven analysis to understand long COVID using electronic health records from the RECOVER initiative

Abstract:

Recent studies have investigated post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) using real-world patient data such as electronic health records (EHR). Prior studies have typically been conducted on patient cohorts with specific patient populations which makes their generalizability unclear. This study aims to characterize PASC using the EHR data warehouses from two large Patient-Centered Clinical Research Networks (PCORnet), INSIGHT and OneFlorida+, which include 11 million patients in New York City (NYC) area and 16.8 million patients in Florida respectively.

With a high-throughput screening pipeline based on propensity score and inverse probability of treatment weighting, we identified a broad list of diagnoses and medications which exhibited significantly higher incidence risk for patients 30-180 days after the laboratory-confirmed SARS-CoV-2 infection compared to non-infected patients.

We identified more PASC diagnoses in NYC than in Florida regarding our screening criteria, and conditions including dementia, hair loss, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, malaise, and fatigue, were replicated across both cohorts. Our analyses highlight potentially heterogeneous risks of PASC in different populations.

Source: Zang C, Zhang Y, Xu J, Bian J, Morozyuk D, Schenck EJ, Khullar D, Nordvig AS, Shenkman EA, Rothman RL, Block JP, Lyman K, Weiner MG, Carton TW, Wang F, Kaushal R. Data-driven analysis to understand long COVID using electronic health records from the RECOVER initiative. Nat Commun. 2023 Apr 7;14(1):1948. doi: 10.1038/s41467-023-37653-z. PMID: 37029117; PMCID: PMC10080528. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10080528/ (Full text)

Prevalence and Characterization of Long Covid-19 Symptoms in Health Care Professionals- A Need of the Hour

Abstract:

Background: With the global advent of Covid-19, Healthcare workers (HCW) were under a lot of physical and psychological pressure. Information on persistent symptoms post Covid-19 Infection in HCWs is lacking.

Objectives: This Study is aimed at assessing the impact of the post Covid-19 syndrome in HCWs.

Materials and Methods: A Questionnaire was prepared as google form and shared with the HCWs through WhatsApp enquiring regarding the health conditions that are still persistent post recovery from Covid-19 infection.

Results: A total of 328 Health Care Professionals participated in the present survey (18-65 yrs). The gender distribution revealed 67.7% were females and 32.3% were males. 60.3% of the participants were infected with COVID-19 before taking the first dose of vaccination which is reduced to 17.5% after vaccination. The post COVID complications observed from the study were hair loss (35.4%), easy fatigability (25%), mood swings (22.9%), anxiety (18.8%), insomnia/sleeplessness (13.9%), depression (12.5%) and joint pains/arthritis (11.8%). The other complications observed were loss of taste (9%), lightheadedness/postural hypotension (8.3%), amnesia/loss of memory and anosmia/loss of smell (7.6%), gastritis (6.3%), palpitations, hypersomnia and pulmonary complications (5.6%) and chest pain (4.9%). Unpaired t-test and One-Way ANNOVA resulted in a significant value (p values of >0.05).

Discussion: Despite the fact that females experienced more post-Covid-19 symptoms (15 out of 17), males experienced more chest pain and anxiety symptoms. According to our findings, 57 of 100 Covid-19 health care workers have post-Covid complications. The participants presented with non-specific symptoms such as easy fatigability, mood swings, light headedness, anxiety but most of the participants quoted more specific symptoms such as depression, pulmonary complications, hair loss, joint pains, gastritis, chest pain, palpitations, loss of taste, amnesia, hyperglycemia, insomnia, hypersomnia and anosmia. However, non-specific symptoms such as fatigue, mood swings, lightheadedness, and anxiety were also mentioned. The symptoms of post-acute COVID-19 syndrome vary greatly. Early detection requires a unified definition of long COVID and characterization of its manifestation. Furthermore, more research should be conducted to identify risk factors and the precise mechanisms that lead to the development of long COVID syndrome. Such knowledge may aid future research aimed at preventing such a complication.

Source: Mote Srinath, Syeda Fakiha Mehreen, Surya Prem Kumar et al. Prevalence and Characterization of Long Covid-19 Symptoms in Health Care Professionals- A Need of the Hour, 05 April 2023, PREPRINT (Version 1) available at Research Square. https://doi.org/10.21203/rs.3.rs-2764197/v1 (Full text)

High levels of pro-inflammatory SARS-CoV-2-specific biomarkers revealed by in vitro whole blood cytokine release assay (CRA) in recovered and long-COVID-19 patients

Abstract:

Background: Cytokines induced by SARS-CoV-2 infection play a crucial role in the pathophysiology of COVID-19 and hyperinflammatory responses have been associated with poor clinical outcomes, with progression to severe conditions or long-term subacute complications named as long-COVID-19.

Methods: In this cross-sectional study, we aimed to evaluate a set of antigen-specific inflammatory cytokines in blood from recovered COVID-19 individuals or who suffered a post-acute phase of SARS-CoV-2 infection compared to healthy individuals with no history of COVID-19 exposition or infection. Interferon-gamma (IFN-γ), IFN-γ-induced protein 10 (IP-10), tumor necrosis factor (TNF), IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, and IL-17A were quantified by multiplex cytometric bead assay and enzyme-linked immunosorbent assay after stimulation of whole blood with recombinant Spike protein from SARS-CoV-2. Additionally, all participants have evaluated for anti-(S) protein-specific IgG antibodies. Clinical specimens were collected within two months of COVID-19 diagnosis.

Results: A total of 47 individuals were enrolled in the study, a median age of 43 years (IQR = 14.5), grouped into healthy individuals with no history of infection or exposure to SARS-CoV-2 (unexposed group; N = 21); and patients from the Health Complex of the Rio de Janeiro State University (UERJ), Brazil, who were SARS-CoV-2 positive by RT-PCR (COVID-19 group)–categorized as recovered COVID-19 (N = 11) or long-COVID-19 (N = 15). All COVID-19 patients presented at least one signal or symptom during the first two weeks of infection. Six patients were hospitalized and required invasive mechanical ventilation.

Our results showed that COVID-19 patients had significantly higher levels of IFN-γ, TNF, IL-1β, IL-2, IL-6, IL-8, and IP-10 than the unexposed group. The long-COVID-19 group has presented significantly high levels of IL-1β and IL-6 compared to unexposed individuals, but not from recovered COVID-19. A principal-component analysis demonstrated 84.3% of the total variance of inflammatory-SARS-CoV-2 response in the first two components, and it was possible to stratify IL-6, TNF, IL-1β, IL-10, and IL-2 as the top-five cytokines which are candidates to discriminate COVID-19 group (including long-COVID-19 subgroup) and healthy unexposed individuals.

Conclusion: We revealed important S protein-specific differential biomarkers in individuals affected by COVID-19, bringing new insights into the inflammatory status or SARS-CoV-2 exposition determination.

Source: Gomes SMR, Brito ACdS, Manfro WFP, Ribeiro-Alves M, Ribeiro RSdA, da Cal MS, et al. (2023) High levels of pro-inflammatory SARS-CoV-2-specific biomarkers revealed by in vitro whole blood cytokine release assay (CRA) in recovered and long-COVID-19 patients. PLoS ONE 18(4): e0283983. https://doi.org/10.1371/journal.pone.0283983 (Full text)

Gut Microbiota Dysbiosis Correlates With Long COVID-19 at One-Year After Discharge

Abstract:

Background: Long coronavirus disease 2019 (COVID-19) in recovered patients (RPs) is gradually recognized by more people. However, how long it will last and the underlining mechanism remains unclear.
Methods: We conducted a prospective follow-up study to evaluate the long-term symptoms and clinical indices of RPs at one-year after discharge from Union Hospital, Wuhan, China between December 2020 to May 2021. We also performed the 16S rRNA sequencing of stool samples from RPs and healthy controls (HCs) and analyzed the correlation between the gut microbiota and long COVID-19.
Results: In total, 187 RPs were enrolled, among them, 84 (44.9%) RPs reported long COVID-19 symptoms at one-year after discharge. The most common long-term symptoms were cardiopulmonary symptoms, including chest tightness after activity (39/187, 20.9%), palpitations on exercise (27/187, 14.4%), sputum (21/187, 11.2%), cough (15/187, 8.0%) and chest pain (13/187, 7.0%), followed by systemic symptoms including fatigue (34/187, 18.2%) and myalgia (20/187, 10.7%), and digestive symptoms including constipation (14/187, 7.5%), anorexia (13/187, 7.0%), and diarrhea (8/187, 4.3%). Sixty-six (35.9%) RPs presented either anxiety or depression (42/187 [22.8%] and 53/187 [28.8%] respectively), and the proportion of anxiety or depression in the long symptomatic group was significantly higher than that in the asymptomatic group (41/187 [50.6%] vs. 25/187 [24.3%]). Compared with the asymptomatic group, scores of all nine 36-Item Short Form General Health Survey domains were lower in the symptomatic group (all P < 0.05).
One hundred thirty RPs and 32 HCs (non-severe acute respiratory syndrome coronavirus 2 infected subjects) performed fecal sample sequencing. Compared with HCs, symptomatic RPs had obvious gut microbiota dysbiosis including significantly reduced bacterial diversities and lower relative abundance of short-chain fatty acids (SCFAs)-producing salutary symbionts such as Eubacterium_hallii_group,  SubdoligranulumRuminococcusDorea, Coprococcus, and Eubacterium_ventriosum_group. Meanwhile, the relative abundance of Eubacterium_hallii_group,  Subdoligranulum, and Ruminococcus showed decreasing tendencies between HCs, the asymptomatic group, and the symptomatic group.
Conclusion: This study demonstrated the presence of long COVID-19 which correlates with gut microbiota dysbiosis in RPs at one-year after discharge, indicating gut microbiota may play an important role in long COVID-19.
Source: Zhang D, Zhou Y, Ma Y, Chen P, Tang J, Yang B, Li H, Liang M, Xue Y, Liu Y, Zhang J, Wang X. Gut Microbiota Dysbiosis Correlates With Long COVID-19 at One-Year After Discharge. J Korean Med Sci. 2023;38(15):e120. https://doi.org/10.3346/jkms.2023.38.e120 (Full text)

Post-COVID-19 condition and persisting symptoms in English schoolchildren: repeated surveys to March 2022

Abstract:

Background: Both post-COVID-19 condition (long COVID) and the presence of persisting symptoms that do not meet formal definitions of post-COVID-19-condition may adversely affect quality of life and function. However, their prevalence among children and young people in England is unclear.

Methods: We used data from repeated surveys in a large cohort of English schoolchildren from the COVID-19 Schools Infection Survey (SIS) for the school year 2021/22 to describe the weighted prevalence of post-COVID-19-condition and compare persisting symptoms between individuals with a positive SARS-CoV-2 test and those with neither a positive test history nor suspected infection.

Results: Among 7797 children from 173 schools, 1.8% of primary school pupils (aged 4 to 11 years), 4.5% of secondary school pupils in years 7-11 (aged 11 to 16 years) and 6.9% of those in years 12-13 (aged 16 to 18 years) met a definition of post-COVID-19 condition in March 2022. Specific persisting symptoms such as anxiety or difficulty concentrating were frequently reported regardless of prior infection status and increased with age: 48.0% of primary school pupils, 52.9% of secondary school pupils in years 7-11 and 79.5% in years 12-13 reporting at least one symptom lasting more than 12 weeks. Persisting loss of smell and taste, cardiovascular and some systemic symptoms were more frequently reported by those with a previous positive test.

Conclusions: We showed that ongoing symptoms were frequently reported by English schoolchildren regardless of SARS-CoV-2 test results and some specific symptoms such as loss of smell and taste were more prevalent in those with a positive test history. Our study emphasises the wide-ranging impacts of the COVID-19 pandemic on the health and wellbeing of children and young people.

Source: Warren-Gash C, Lacey A, Cook S, Stocker D, Toon S, Lelii F, Ford B, Ireland G, Ladhani SN, Stephenson T, Nguipdop-Djomo P, Mangtani P; COVID-19 Schools Infection Survey 2 Study Group. Post-COVID-19 condition and persisting symptoms in English schoolchildren: repeated surveys to March 2022. BMC Infect Dis. 2023 Apr 5;23(1):201. doi: 10.1186/s12879-023-08203-1. PMID: 37020190; PMCID: PMC10075149. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10075149/ (Full text)

Long COVID: Cognitive and FDG PET evolutions in six patients

Abstract:

Long COVID is often characterized by cognitive complaints and deficits occurring immediately or several weeks after the infectious disease. Neuropsychological tests can revealed attention and executive function anomalies and FDG PET can display hypometabolic areas affecting various regions including frontal and cingulate cortices as well as precuneus and brainstem. We report here the cognitive and FDG PET evolutions over one year in 6 patients suffering from long COVID. Our study shows cognitive and FDG PET improvements in most of the cases and highlight the importance of a careful neurological follow-up in these patients.

Source: Jacques Hugon, Karim Farid, Mathieu Queneau et al. Long COVID: Cognitive and FDG PET evolutions in six patients, 03 April 2023, PREPRINT (Version 1) available at Research Square. https://doi.org/10.21203/rs.3.rs-2703691/v1 https://www.researchsquare.com/article/rs-2703691/v1 (Full text)

Long COVID symptoms, pathophysiology and possible mechanisms: Still, we are learning!

Abstract:
Long COVID is an unpredicted sequel of COVID-19 disease documented nearly in half cases globally. Long COVID is multisystem syndrome with nonspecific symptoms and organic signs of unidentified pathology occurs after COVID-19 disease. Long COVID symptoms has been documented in some cases irrespective of disease severity or hospitalization. Long COVID symptoms has significant impact on quality of life in those cases suffered from disease in recent past and lingering to almost two years since infection.
Importantly, not all cases of COVID-19 were shown long COVID symptoms. Most common long COVID symptoms (ten in number) as joint pain, fatigability, chest discomfort, shortness of breath, hair loss, chest pain, weight gain, anxiety/depression & memory impairment. Pathophysiology resulting into long COVID manifestations is still not completely validated.
Researchers have reported ‘immune dysregulation’ and ‘coagulation abnormalities’ are probable pathophysiological mechanism for long COVID. Some of the long COVID effects shown complete reversibility including post COVID lung fibrosis. Reboot system to restore immune dysregulation and recovery in long COVID is real concern. Long COVID symptoms cases are more health conscious and usually follows pattern of doctor shopping due to underestimation by family physicians either due to lack of suspicion or lack of knowledge regarding treatment protocol.
Source: Shital Patil, Sanika Narkar, Jayashree Dahiphale, Vipul Raka, Shubham Choudhari. and Gajanan Gondhali. Long COVID symptoms, pathophysiology and possible mechanisms: Still, we are learning! World Journal of Advanced Pharmaceutical and Medical Research, 2023, 04(01), 053–065. https://zealjournals.com/wjapmr/content/long-covid-symptoms-pathophysiology-and-possible-mechanisms-still-we-are-learning (Full text available as PDF file)

Immunological dysfunction and mast cell activation syndrome in long COVID

Abstract:

At least 65 million people around the world suffer from long COVID, with the majority of cases occurring in the productive age (36–50 years old). Individuals with long COVID are confounded with multiple organ system dysfunctions, long-term organ injury sequelae, and a decreased quality of life. There is an overlapping of risk factors between long COVID and other postviral infection syndromes, so advances in research could also benefit other groups of patients.

Long COVID is the consequence of multiple immune system dysregulation, such as T-cell depletion, innate immune cell hyperactivity, lack of naive T and B cells, and elevated signature of pro-inflammatory cytokines, together with persistent SARS-CoV2 reservoir and other consequences of acute infection.

There is an activated condition of mast cells in long COVID, with abnormal granulation and excessive inflammatory cytokine release. A study by Weinstock et al. indicates that patients with long COVID suffer the same clinical syndrome as patients with mast cell activation syndrome (MCAS).

Diagnosis and treatment of MCAS in patients with long COVID will provide further symptomatic relief, and manage mast cell-mediated hyperinflammation states, which could be useful in the long-term control and recovery of such patients.

Source: Sumantri, Stevent; Rengganis, Iris. Immunological dysfunction and mast cell activation syndrome in long COVID. Asia Pacific Allergy ():10.5415/apallergy.0000000000000022, March 30, 2023. | DOI: 10.5415/apallergy.0000000000000022 https://journals.lww.com/apallergy/Fulltext/9900/Immunological_dysfunction_and_mast_cell_activation.2.aspx (Full text)