Category: Overlapping Illnesses

The long-term health outcomes, pathophysiological mechanisms and multidisciplinary management of long COVID

Abstract:

There have been hundreds of millions of cases of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With the growing population of recovered patients, it is crucial to understand the long-term consequences of the disease and management strategies.

Although COVID-19 was initially considered an acute respiratory illness, recent evidence suggests that manifestations including but not limited to those of the cardiovascular, respiratory, neuropsychiatric, gastrointestinal, reproductive, and musculoskeletal systems may persist long after the acute phase. These persistent manifestations, also referred to as long COVID, could impact all patients with COVID-19 across the full spectrum of illness severity.

Herein, we comprehensively review the current literature on long COVID, highlighting its epidemiological understanding, the impact of vaccinations, organ-specific sequelae, pathophysiological mechanisms, and multidisciplinary management strategies. In addition, the impact of psychological and psychosomatic factors is also underscored.

Despite these crucial findings on long COVID, the current diagnostic and therapeutic strategies based on previous experience and pilot studies remain inadequate, and well-designed clinical trials should be prioritized to validate existing hypotheses. Thus, we propose the primary challenges concerning biological knowledge gaps and efficient remedies as well as discuss the corresponding recommendations.

Source: Li, J., Zhou, Y., Ma, J. et al. The long-term health outcomes, pathophysiological mechanisms and multidisciplinary management of long COVID. Sig Transduct Target Ther 8, 416 (2023). https://doi.org/10.1038/s41392-023-01640-z https://www.nature.com/articles/s41392-023-01640-z (Full text)

Long-term Prognosis at 1.5 years after Infection with Wild-type strain of SARS-CoV-2 and Alpha, Delta, as well as Omicron Variants

Highlights:

  • Trajectory of long COVID in SARS-CoV-2 wild-type, Alpha, Delta, and Omicron
  • Similar patterns of symptoms and severity of long COVID across all four variants
  • No clinically significant decline in median severity up to 1.5 years after infection
  • More than 50% of long COVID patients failed to improve using any outcome measure
  • Patients infected with Omicron may experience severe non-improving long COVID

Abstract:

Objectives: Knowledge is limited on how changing SARS-CoV-2 variants may translate into different characteristics and affect prognosis of patients with long COVID, especially following Omicron variants. We compared long-term prognosis of patients in a Danish Post COVID Clinic infected with wild-type strain, Alpha, Delta, or Omicron variants as well as the pre-Omicron compared to the Omicron period.

Methods: At enrollment a Post COVID symptom Questionnaire (PCQ), and standard health scores, were registered, and repeated four times until 1.5 years after infection. PCQ was the primary outcome to assess severity of long COVID, and delta PCQ to assess failure to improve.

Results: A total of 806 patients were enrolled. Patients infected with Omicron and Delta variants presented with more severe long COVID (median PCQ 43 in Delta vs 38 in wild-type, P=0.003) and health scores (EQ5D-index was 0.70 in Omicron vs 0.76 in wild-type, P=0.009 and 0.78 pre-Omicron, P=0.006). At 1.5 year after infection patients had no clinically meaningful decline in severity of long COVID, and 57% (245/429) of patients failed to improve 1.5 years after infection, with no differences between variants.

Conclusions: More than half of patients referred to a Post COVID Clinic failed to improve in long COVID severity 1.5 years after infection regardless of variants of SARS-CoV-2.

Source: Jane Agergaard , Jesper Damsgaard Gunst , Berit Schiøttz-Christensen , Lars Østergaard , Christian Wejse , Long-term Prognosis at 1.5 years after Infection with Wild-type strain of SARS-CoV-2 and Alpha, Delta, as well as Omicron Variants, International Journal of Infectious Diseases (2023), doi: https://doi.org/10.1016/j.ijid.2023.10.022 https://www.ijidonline.com/article/S1201-9712(23)00760-9/fulltext (Full text)

Long-COVID is Associated with Impaired Red Blood Cell Function

Abstract:

COVID-19 disease, caused by the severe acute respiratory syndrome virus 2 (SARS-CoV-2), induces a broad spectrum of clinical symptoms ranging from asymptomatic cases to fatal outcomes. About 10-35% of all COVID-19 patients, even those with mild COVID-19 symptoms, continue to show symptoms, i. e., fatigue, shortness of breath, cough, and cognitive dysfunction, after initial recovery.

Previously, we and others identified red blood cell precursors as a direct target of SARS-CoV-2 and suggested that SARS-CoV-2 induces dysregulation in hemoglobin- and iron-metabolism contributing to the severe systemic course of COVID-19. Here, we put particular emphasis on differences in parameters of clinical blood gas analysis and hematological parameters of more than 20 healthy and Long-COVID patients, respectively.

Long-COVID patients showed impaired oxygen binding to hemoglobin with concomitant increase in carbon monoxide binding. Hand in hand with decreased plasma iron concentration and transferrin saturation, mean corpuscular hemoglobin was elevated in Long-COVID patients compared to healthy donors suggesting a potential compensatory mechanism. Although blood pH was within the physiological range in both groups, base excess- and bicarbonate values were significantly lower in Long-COVID patients.

Furthermore, Long-COVID patients displayed reduced lymphocyte levels. The clinical relevance of these findings, e. g., as a cause of chronic immunodeficiency, remains to be investigated in future studies.

In conclusion, our data suggest impaired erythrocyte functionality in Long-COVID patients, leading to diminished oxygen supply. This in turn could be an explanation for the CFS, dyspnea and anemia. Further investigations are necessary to identify the underlying pathomechanisms.

Source: Kronstein-Wiedemann R, Tausche K, Kolditz M, Teichert M, Thiel J, Koschel D, Tonn T, Künzel SR. Long-COVID is Associated with Impaired Red Blood Cell Function. Horm Metab Res. 2023 Oct 27. doi: 10.1055/a-2186-8108. Epub ahead of print. PMID: 37890507. https://pubmed.ncbi.nlm.nih.gov/37890507/

Relevance of complement immunity with brain fog in patients with long COVID

Abstract:

Introduction: This study aimed to elucidate the prevalence and clinical characteristics of patients with long COVID (coronavirus disease 2019), especially focusing on 50% hemolytic complement activity (CH50).

Methods: This retrospective observational study focused on patients who visited Okayama University Hospital (Japan) for the treatment of long COVID between February 2021 and March 2023. CH50 levels were measured using liposome immunometric assay (Autokit CH50 Assay, FUJIFILM Wako Pure Chemical Corporation, Japan); high CH50 was defined as ≥59 U/mL. Univariate analyses assessed differences in the clinical background, long COVID symptoms, inflammatory markers, and clinical scores of patients with normal and high CH50. Logistic regression model investigated the association between high CH50 levels and these factors.

Results: Of 659 patients who visited our hospital, 478 patients were included. Of these, 284 (59.4%) patients had high CH50 levels. Poor concentration was significantly more frequent in the high CH50 group (7.2% vs. 13.7%), whereas no differences were observed in other subjective symptoms (fatigue, headache, insomnia, dyspnea, tiredness, and brain fog). Multivariate analysis was performed on factors that could be associated with poor concentration, suggesting a significant relationship to high CH50 levels (adjusted odds ratio [aOR], 2.70; 95% confidence interval [CI], 1.33–5.49). Also, high CH50 was significantly associated with brain fog (aOR, 1.66; 95% CI, 1.04–2.66).

Conclusions: High CH50 levels were frequently reported in individuals with long COVID, indicating a relationship with brain fog. Future in-depth research should examine the pathological role and causal link between complement immunity and the development of long COVID.

Source: Hagiya H, Tokumasu K, Otsuka Y, Sunada N, Nakano Y, Honda H, Furukawa M, Otsuka F. Relevance of complement immunity with brain fog in patients with long COVID. J Infect Chemother. 2023 Oct 20:S1341-321X(23)00261-1. doi: 10.1016/j.jiac.2023.10.016. Epub ahead of print. PMID: 37866620. https://www.sciencedirect.com/science/article/abs/pii/S1341321X23002611

Altered functional brain connectivity, efficiency, and information flow associated with brain fog after mild to moderate COVID-19 infection

Abstract:

COVID-19 is associated with increased risk for cognitive decline but very little is known regarding the neural mechanisms of this risk. We enrolled 49 adults (55% female, mean age = 30.7 +/- 8.7), 25 with and 24 without a history of COVID-19 infection. We administered standardized tests of cognitive function and acquired brain connectivity data using MRI.

The COVID-19 group demonstrated significantly lower cognitive function (W = 475, p < 0.001, effect size r = 0.58) and lower functional connectivity in multiple brain regions (mean t = 3.47 +/- 0.36, p = 0.03, corrected, effect size d = 0.92 to 1.5). Hypo-connectivity of these regions was inversely correlated with subjective cognitive function and directly correlated with fatigue (p < 0.05, corrected). These regions demonstrated significantly reduced local efficiency (p < 0.026, corrected) and altered effective connectivity (p < 0.001, corrected).

COVID-19 may have a widespread effect on the functional connectome characterized by lower functional connectivity and altered patterns of information processing efficiency and effective information flow. This may serve as an adaptation to the pathology of SARS-CoV-2 wherein the brain can continue functioning at near expected objective levels, but patients experience lowered efficiency as brain fog.

Source: Shelli R. Kesler, Oscar Y. Franco Rocha, Alexa De La Torre Schutz et al. Altered functional brain connectivity, efficiency, and information flow associated with brain fog after mild to moderate COVID-19 infection, 20 October 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3466991/v1] https://www.researchsquare.com/article/rs-3466991/v1 (Full text)

Clinical and pulmonary function analysis in long-COVID revealed that long-term pulmonary dysfunction is associated with vascular inflammation pathways and metabolic syndrome

Abstract:

Introduction: Long-term pulmonary dysfunction (L-TPD) is one of the most critical manifestations of long-COVID. This lung affection has been associated with disease severity during the acute phase and the presence of previous comorbidities, however, the clinical manifestations, the concomitant consequences and the molecular pathways supporting this clinical condition remain unknown. The aim of this study was to identify and characterize L-TPD in patients with long-COVID and elucidate the main pathways and long-term consequences attributed to this condition by analyzing clinical parameters and functional tests supported by machine learning and serum proteome profiling.

Methods: Patients with L-TPD were classified according to the results of their computer-tomography (CT) scan and diffusing capacity of the lungs for carbon monoxide adjusted for hemoglobin (DLCOc) tests at 4 and 12-months post-infection.

Results: Regarding the acute phase, our data showed that L-TPD was favored in elderly patients with hypertension or insulin resistance, supported by pathways associated with vascular inflammation and chemotaxis of phagocytes, according to computer proteomics. Then, at 4-months post-infection, clinical and functional tests revealed that L-TPD patients exhibited a restrictive lung condition, impaired aerobic capacity and reduced muscular strength. At this time point, high circulating levels of platelets and CXCL9, and an inhibited FCgamma-receptor-mediated-phagocytosis due to reduced FcγRIII (CD16) expression in CD14+ monocytes was observed in patients with L-TPD. Finally, 1-year post infection, patients with L-TPD worsened metabolic syndrome and augmented body mass index in comparison with other patient groups.

Discussion: Overall, our data demonstrated that CT scan and DLCOc identified patients with L-TPD after COVID-19. This condition was associated with vascular inflammation and impair phagocytosis of virus-antibody immune complexes by reduced FcγRIII expression. In addition, we conclude that COVID-19 survivors required a personalized follow-up and adequate intervention to reduce long-term sequelae and the appearance of further metabolic diseases.

Source: Sanhueza S, Vidal MA, Hernandez MA, Henriquez-Beltran ME, Cabrera C, Quiroga R, Antilef BE, Aguilar KP, Castillo DA, Llerena FJ, Fraga Figueroa M, Nazal M, Castro E, Lagos P, Moreno A, Lastra JJ, Gajardo J, Garcés P, Riffo B, Buchert J, Sanhueza R, Ormazába V, Saldivia P, Vargas C, Nourdin G, Koch E, Zuñiga FA, Lamperti L, Bustos P, Guzmán-Gutiérrez E, Tapia CA, Ferrada L, Cerda G, Woehlbier U, Riquelme E, Yuseff MI, Muñoz Ramirez BA, Lombardi G, De Gonzalo-Calvo D, Salomon C, Verdugo RA, Quiñones LA, Colombo A, Barría MI, Labarca G, Nova-Lamperti E. Clinical and pulmonary function analysis in long-COVID revealed that long-term pulmonary dysfunction is associated with vascular inflammation pathways and metabolic syndrome. Front Med (Lausanne). 2023 Oct 6;10:1271863. doi: 10.3389/fmed.2023.1271863. PMID: 37869162; PMCID: PMC10590130. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10590130/ (Full text)

A qualitative study to explore children’s experience of having long-Covid

There is currently uncertainty and limited research surrounding long-COVID in the paediatric population. Reports are conflicting regarding the prevalence, duration, and impact of long COVID on children. Despite the limited evidence, it is becoming increasingly apparent that numerous children are experiencing long-term physical and psychological effects of COVID19 many months after the initial infection. This thesis aimed to investigate the lived experience of children with long-COVID.
Part one of this portfolio presents a systematic review of the experiences of parents who provide care for a child with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The findings of the review indicate a paucity of research on parents’ experiences. However, it is apparent that caring for a child with ME/CFS is an all-encompassing, relentless undertaking, which can detrimentally impact parents’ well-being, everyday life, and relationships.
Given both ME/CFS and long-COVID are both post-viral illnesses, sharing similar symptoms, with low-level immune system activation. It may be conjectured that the existing knowledge on children with ME/CFS could benefit both children suffering from long-COVID and help inform parents on how best to care for their children.
Part two of this portfolio presents an empirical paper exploring the lived-experience of young people with long-COVID. Reflexive thematic analysis found three key themes, specifically, the perceived barriers to coping with long-COVID, ongoing associated emotional distress, and a desire for an integrated approach to long-COVID care.
Source: Carolyn Noorderhaven. A qualitative study to explore children’s experience of having long-Covid. Doctoral thesis: University of Surrey, School of Psychology. https://openresearch.surrey.ac.uk/esploro/outputs/doctoral/A-qualitative-study-to-explore-childrens/99813065702346?institution=44SUR_INST (Full text available as PDF file)

A National Evaluation of Outcomes in Long COVID Services using Digital PROM Data from the ELAROS Platform

Summary:

Key findings of this service evaluation study:
• Patient characteristics: A sample of 5,318 patients from 14 participating NHS LC sites were analysed. The sample had a female:male ratio of 2.1:1. The average age was 48.4 yrs, with 87% (of those whose ethnicity was recorded) of white ethnicity and 9% of Black or Asian ethnicity.
• Comorbidities: This sample of patients had a low prevalence of co-morbidities (7%) with a clear onset of new LC symptoms after their COVID-19 infection supporting the onset of a new condition in this cohort of previously healthy individuals.
• Duration of LC: The average duration of LC in this sample was 384 days (>12 months) at first assessment in an LC site, with symptoms still ongoing at presentation, with more than 90% of the sample being non-hospitalised patients.
• Digital platform: A total of 17,471 PROMs (C19-YRS and EQ-5D-5L) were completed by this sample of patients with at least 1,532 participants completing multiple assessments on the same PROM on the digital PROM platform. The completion of PROMs around the 3-month mark was low for both measures (11.7% for C19-YRS and 14.6% for EQ-5D-5L). The ones who completed PROMs both around the 3-month mark and the 6-month mark were 4.3% for C19-YRS and 5% for EQ-5D-5L. This limits the generalisability of the findings in this evaluation to all the LC population, but the findings remain valid for this cohort of individuals.
• New-onset disability: 3,395 patients who completed at least one C19-YRS questionnaire at first assessment showed significant new-onset symptom burden, functional disability, and deterioration of overall health since the COVID-19 infection.
• Comparison between LC and other chronic conditions: The cross-sectional EQ-5D-5L Index value of 3,438 patients suggests the burden and disability in LC are worse than that reported in the literature for Diabetes Mellitus, COPD, Heart Failure, and Multiple Sclerosis.
• 3-month follow-up: Among those who completed an initial C19-YRS assessment and another at 3 months, there was a statistically significant improvement in symptom burden, functional disability and overall health. Patients at 3 months however still had significant LC symptom
burden and disability compared to their pre-COVID-19 health status, i.e., their condition had improved, but they were far off from a complete recovery. Among those who completed EQ-5D- National Evaluation of Long COVID Service Outcomes using ELAROS Data (09 Oct 23) Page 3 of 31
5L, at first assessment and at 3 months, their EQ-5D-5L Index score did not show any statistically significant improvement, but the EQ-5D-5L VAS showed a statistically significant improvement.
• 6-month follow-up: Among those who completed measures at the first assessment, 3 months, and 6 months, C19-YRS and EQ-5D-5L VAS showed statistically significant improvement whereas EQ-5D-5L Index Value showed statistically significant deterioration. Patients at 6 months still had
significant LC symptom burden and disability compared to their pre-COVID-19 health status, i.e., their condition had improved but had not fully recovered. The follow-up changes in scores support the efficacy of interventions provided by LC services and suggest that continued specialist input is needed to manage these patients with persistent symptoms.
• C19-YRS (condition-specific measure) vs EQ-5D-5L (generic measure): The 3-month month follow-up changes in scores and responsiveness of PROMs highlight that C19-YRS is a more sensitive measure than EQ-5D-5L in this cohort of individuals with LC. This is in keeping with the literature recommending the use of condition-specific measures in addition to EQ-5D-5L.
• Vocational problems: 62% of this sample had their work role affected with them having to either be on sick leave, reduce hours, change roles, or quit roles. Only 21% were able to maintain their previous roles held prior to their COVID-19 infection. This is suggestive of considerable productivity loss and financial implications to the country.
• Fluctuating condition: In patients who completed multiple assessments, it was evident that LC is a fluctuant condition with no necessary linear trend of improvement or deterioration between the domains of symptom burden, functional disability, and overall health. This highlights the need to understand the triggers for the condition and invest in self-management and ongoing support from community healthcare services.
• Long-Term Condition: In most patients in this sample, LC has evidently become a Long-Term Condition (LTC) with fluctuations in their condition causing disability and significant deterioration of their overall health status seen even after 18 months of LC with no complete resolution or full recovery. There needs to be a national investment in managing this new LTC along with other LTCs.

Source: Dr Manoj Sivan, et al.  A National Evaluation of Outcomes in Long COVID Services using Digital PROM Data from the ELAROS Platform. National Evaluation of Long COVID Service Outcomes using ELAROS Data (09 Oct 23) https://locomotion.leeds.ac.uk/wp-content/uploads/sites/74/2023/10/National-Evaluation-of-LC-Service-Outcomes-using-ELAROS-Data-09-10-23.pdf (Full text)

A prospective randomized, double-blind placebo-controlled study to evaluate the effectiveness of neuroprotective therapy using functional brain MRI in patients with post-covid chronic fatigue syndrome

Abstract:

Background and purpose: to assess executive network using resting-state fMRI and patterns of brain activation using task fMRI with a cognitive paradigm, against the background of taking the drug in comparison with placebo in patients with post-COVID asthenic syndrome.

Methods: The study employed a prospective, randomized, double-blind, placebo-controlled trial approach to assess the efficacy of utilizing functional MRI of the brain as a neuroprotective therapy for treating patients with chronic fatigue syndrome following COVID-19. The study included 30 patients matched by sex and age with post-COVID asthenic syndrome. All patients were examined with MFI-20, MoCA, FAS-10 scales, MRI using a Siemens MAGNETOM Prisma 3 T scanner before and after a course of therapy with coordination complex with succinate acid anion (CCSA) or placebo (15 patients each) using resting state fMRI and with cognitive paradigm.

Results: The changes obtained as a result of the treatment of post-Covid asthenic syndrome demonstrated clinical superiority in the reduction of asthenic symptoms for the group of patients treated with CCSA (MFI-20 scores: -20·0 points in the CCSA group compared to -12 points in the placebo group, p = 0·043). The data obtained also correlate with the analysis of task fMRI and resting state fMRI may indicate an increase in the functional cognitive status after a course of therapy with CCSA. Clinically, this correlates with a statistically significant improvement in the MoCA score (2 points in the CCSA group compared to 1 point in the placebo group, p < 0·05).

Conclusions: The study demonstrates the potential effectiveness of CCSA therapy in relation to a wide range of symptoms (chronic fatigue syndrome/ asthenic syndrome and cognitive impairment) in patients with post-COVID syndrome. The first time demonstrated the effectiveness of neuroprotective therapy after post-COVID asthenic syndrome with the use of high-tech neuroimaging techniques.

Source: Tanashyan M, Morozova S, Raskurazhev A, Kuznetsova P. A prospective randomized, double-blind placebo-controlled study to evaluate the effectiveness of neuroprotective therapy using functional brain MRI in patients with post-covid chronic fatigue syndrome. Biomed Pharmacother. 2023 Oct 18;168:115723. doi: 10.1016/j.biopha.2023.115723. Epub ahead of print. PMID: 37862966. https://www.sciencedirect.com/science/article/pii/S0753332223015214 (Full study)

Cytometry profiling of ex vivo recall responses to Coxiella burnetii in previously naturally exposed individuals reveals long-term changes in both adaptive and innate immune cellular compartments

Abstract:

Introduction: Q fever, caused by the intracellular bacterium Coxiella burnetii, is considered an occupational and biodefense hazard and can result in debilitating long-term complications. While natural infection and vaccination induce humoral and cellular immune responses, the exact nature of cellular immune responses to C. burnetii is incompletely understood. The current study seeks to investigate more deeply the nature of long-term cellular recall responses in naturally exposed individuals by both cytokine release assessment and cytometry profiling.

Methods: Individuals exposed during the 2007-2010 Dutch Q fever outbreak were grouped in 2015, based on a C. burnetii-specific IFNγ release assay (IGRA), serological status, and self-reported clinical symptoms during initial infection, into asymptomatic IGRA-negative/seronegative controls, and three IGRA-positive groups (seronegative/asymptomatic; seropositive/asymptomatic and seropositive/symptomatic). Recall responses following in vitro re-stimulation with heat-inactivated C. burnetii in whole blood, were assessed in 2016/2017 by cytokine release assays (n=55) and flow cytometry (n=36), and in blood mononuclear cells by mass cytometry (n=36).

Results: Cytokine release analysis showed significantly elevated IL-2 responses in all seropositive individuals and elevated IL-1β responses in those recovered from symptomatic infection. Comparative flow cytometry analysis revealed significantly increased IFNγ, TNFα and IL-2 recall responses by CD4 T cells and higher IL-6 production by monocytes from symptomatic, IGRA-positive/seropositive individuals compared to controls. Mass cytometry profiling and unsupervised clustering analysis confirmed recall responses in seropositive individuals by two activated CD4 T cell subsets, one characterized by a strong Th1 cytokine profile (IFNγ+IL-2+TNFα+), and identified C. burnetii-specific activation of CD8 T cells in all IGRA-positive groups. Remarkably, increased C. burnetii-specific responses in IGRA-positive individuals were also observed in three innate cell subpopulations: one characterized by an IFNγ+IL-2+TNFα+ Th1 cytokine profile and lack of canonical marker expression, and two IL-1β-, IL-6- and IL-8-producing CD14+ monocyte subsets that could be the drivers of elevated secretion of innate cytokines in pre-exposed individuals.

Discussion: These data highlight that there are long-term increased responses to C. burnetii in both adaptive and innate cellular compartments, the latter being indicative of trained immunity. These findings warrant future studies into the protective role of these innate responses and may inform future Q fever vaccine design.

Source: Raju Paul S, Scholzen A, Reeves PM, Shepard R, Hess JM, Dzeng RK, Korek S, Garritsen A, Poznansky MC, Sluder AE. Cytometry profiling of ex vivo recall responses to Coxiella burnetii in previously naturally exposed individuals reveals long-term changes in both adaptive and innate immune cellular compartments. Front Immunol. 2023 Oct 11;14:1249581. doi: 10.3389/fimmu.2023.1249581. PMID: 37885896; PMCID: PMC10598782. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598782/ (Full text)