Persistence of circulating CD169+monocytes and HLA-DR downregulation underline the immune response impairment in PASC individuals: the potential contribution of different COVID-19 pandemic waves

Abstract:

The use of CD169 as a marker of viral infection has been widely discussed in the context of COVID-19, and in particular, its crucial role in the early detection of SARS-CoV-2 infection and its association with the severity and clinical outcome of COVID-19 were demonstrated. COVID-19 patients show relevant systemic alteration and immunological dysfunction that persists in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC).

It is critical to implement the characterization of the disease, focusing also on the possible impact of the different COVID-19 waves and the consequent effects found after infection. On this basis, we evaluated by flow cytometry the expression of CD169 and HLA-DR on monocytes from COVID-19 patients and PASC individuals to better elucidate their involvement in immunological dysfunction, also evaluating the possible impact of different pandemic waves.

The results confirm CD169 RMFI is a good marker of viral infection. Moreover, COVID-19 patients and PASC individuals showed high percentage of CD169+ monocytes, but low percentage of HLA-DR+ monocytes and the alteration of systemic inflammatory indices. We have also observed alterations of CD169 and HLA-DR expression and indices of inflammation upon different COVID-19 waves.

The persistence of specific myeloid subpopulations suggests a role of CD169+ monocytes and HLA-DR in COVID-19 disease and chronic post-infection inflammation, opening new opportunities to evaluate the impact of specific pandemic waves on the immune response impairment and systemic alterations with the perspective to provide new tools to monitoring new variants and diseases associated to emerging respiratory viruses.

Source: Fanelli M, Petrone V, Maracchioni C, Chirico R, Cipriani C, Coppola L, Malagnino V, Teti E, Sorace C, Zordan M, Vitale P, Iannetta M, Balestrieri E, Rasi G, Grelli S, Malergue F, Sarmati L, Minutolo A, Matteucci C. Persistence of circulating CD169+monocytes and HLA-DR downregulation underline the immune response impairment in PASC individuals: the potential contribution of different COVID-19 pandemic waves. Curr Res Microb Sci. 2023 Dec 12;6:100215. doi: 10.1016/j.crmicr.2023.100215. PMID: 38187999; PMCID: PMC10767315. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10767315/ (Full text)

Characteristics of long COVID and the impact of COVID-19 vaccination on long COVID 2 years following COVID-19 infection: prospective cohort study

Abstract:

This prospective cohort study aimed to identify characteristics of long COVID and any potential mitigating effects of COVID-19 vaccinations in patients 24 months following COVID-19 infection. Adult patients diagnosed with COVID-19 between February 17, 2020, and March 24, 2020, were scheduled to visit the study hospital four times (6, 12, 18, and 24 months after infection) to assess their symptoms, quality of life, and mental health. Among the 235 patients, 121 (51.5%) completed the study visits. Of these, 59.5% were female, with a median age of 52 years. Mild to moderate disease severity were identified in 101 (83.4%) patients.

A total of 75 participants (62.0%) were still experiencing long COVID symptoms 24 months after acute infection. Fatigue, amnesia, difficulty concentrating, and insomnia were the most common symptoms. The frequency of neuropsychiatric symptoms did not differ based on vaccination status or the number of doses received. Quality of life improved over time for the participants, but 32.2% of respondents still reported anxiety/depression at the end of the study. Overall, our cohort demonstrates that long COVID can persist up to 24 months after COVID-19 infection, affecting mental health and quality of life.

Source: Kim, Y., Bae, S., Chang, HH. et al. Characteristics of long COVID and the impact of COVID-19 vaccination on long COVID 2 years following COVID-19 infection: prospective cohort study. Sci Rep 14, 854 (2024). https://doi.org/10.1038/s41598-023-50024-4 https://www.nature.com/articles/s41598-023-50024-4 (Full text)

Increased von Willebrand and Factor VIII plasma levels in gynecologic patients with Post-Acute-COVID-Sequela (PASC)/Long COVID

Highlights:

  • Growing evidence suggests that persistent microvascular inflammation, clumping/clotting of blood cells and thrombotic complications may be key causes of Long COVID.
  • Plasma levels of von Willebrand factor and Factor VIII were uniformly higher in all gynecologic patients with Long COVID vs controls without Long COVID.
  • Persistently elevated levels of Von Willebrand and Factor VIII may represent the results of lingering microvascular damage (i.e., spike-induced endotheliosis).

Abstract:

Up to 30 % of COVID-infected patients may develop post-acute sequelae of COVID-19 (PASC), also known as Long COVID (LC), a syndrome characterized by a variety of debilitating symptoms lasting for more than 3 months after the acute infection. While the pathophysiological mechanisms behind PASC/LC are not completely understood, growing evidence suggests that an important component of this syndrome may be related to persistent microvascular inflammation causing clumping/clotting of red blood cells and platelets and thrombotic complications.

We retrospectively evaluated the plasma levels of von Willebrand factor (VWF), Factor VIII and D-dimer in 10 gynecologic patients (60 % with an endometrial or ovarian cancer diagnosis) affected by PASC/LC vs 5 control patients (60 % harboring endometrial or ovarian tumors). We found elevated VWF and Factor VIII levels in all 10 PASC/LC patients (means of 254 % and 229 %, respectively) vs none of the 5 randomly selected cancer control patients (means of 108 % and 95 %, respectively), p = 0.0046 and p < 0.0001, respectively. In contrast, no significant difference was noted in the levels of D-dimer in PASC/LC.

Importantly, abnormally elevated VWF and Factor VIII levels were found to persist for at least 2 years in patients with Long COVID symptoms. VWF and Factor VIII but not D-dimer levels are significantly elevated in the plasma of PASC/LC cancer patients. Abnormally and persistently elevated VWF and Factor VIII levels may represent the results of persistent microvascular damage (i.e., spike-induced endotheliosis) and may be biomarkers of persistent inflammation in gynecologic patients with PASC/LC.

Source: Stefania Bellone, Eric R. Siegel, David E. Scheim, Alessandro D. Santin.Increased von Willebrand and Factor VIII plasma levels in gynecologic patients with Post-Acute-COVID-Sequela (PASC)/Long COVID. Gynecologic Oncology Reports, Volume 51, February 2024, 101324. https://www.sciencedirect.com/science/article/pii/S2352578924000031 (Full text)

Association of nirmatrelvir for acute SARS-CoV-2 infection with subsequent Long COVID symptoms in an observational cohort study

Abstract:

Oral nirmatrelvir/ritonavir is approved as treatment for acute COVID-19, but the effect of treatment during acute infection on risk of Long COVID is unknown. We hypothesized that nirmatrelvir treatment during acute SARS-CoV-2 infection reduces risk of developing Long COVID and rebound after treatment is associated with Long COVID. We conducted an observational cohort study within the Covid Citizen Science (CCS) study, an online cohort study with over 100 000 participants.

We included vaccinated, nonhospitalized, nonpregnant individuals who reported their first SARS-CoV-2 positive test March–August 2022. Oral nirmatrelvir/ritonavir treatment was ascertained during acute SARS-CoV-2 infection. Patient-reported Long COVID symptoms, symptom rebound and test-positivity rebound were asked on subsequent surveys at least 3 months after SARS-CoV-2 infection. A total of 4684 individuals met the eligibility criteria, of whom 988 (21.1%) were treated and 3696 (78.9%) were untreated; 353/988 (35.7%) treated and 1258/3696 (34.0%) untreated responded to the Long COVID survey (n = 1611). Among 1611 participants, median age was 55 years and 66% were female.

At 5.4 ± 1.3 months after infection, nirmatrelvir treatment was not associated with subsequent Long COVID symptoms (odds ratio [OR]: 1.15; 95% confidence interval [CI]: 0.80–1.64; p = 0.45). Among 666 treated who answered rebound questions, rebound symptoms or test positivity were not associated with Long COVID symptoms (OR: 1.34; 95% CI: 0.74–2.41; p = 0.33).

Within this cohort of vaccinated, nonhospitalized individuals, oral nirmatrelvir treatment during acute SARS-CoV-2 infection and rebound after nirmatrelvir treatment were not associated with Long COVID symptoms more than 90 days after infection.

Source: Durstenfeld MS, Peluso MJ, Lin F, et al. Association of nirmatrelvir for acute SARS-CoV-2 infection with subsequent Long COVID symptoms in an observational cohort study. J Med Virol. 2024; 96:e29333. doi:10.1002/jmv.29333 https://onlinelibrary.wiley.com/doi/10.1002/jmv.29333 (Full text)

Spinal cord infarction attributed to SARS-CoV-2, with post-acute sequelae of COVID-19: A case report

Abstract:

Background: While stroke and lower extremity venous thromboemboli have been commonly reported following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spinal cord infarction or ischemia has been extremely rare. Findings of long coronavirus disease (COVID) in this select population have not been studied.

Case summary: We present the case of a 70-year-old female with sudden onset of trunk and lower extremity sensorimotor loss due to spinal cord infarction, attributed to acute infection with SARS-CoV-2. Diagnostic work up confirmed a T3 complete (ASIA impairment Scale A) paraplegia resulting from a thrombotic infarct. Her reported myalgias, neuropathic pain, spasticity, bladder spasms, and urinary tract infections exceeded the frequency and severity of many spinal cord injury (SCI) individuals of similar age and degree of neurologic impairment.

In her first year after contracting COVID-19, she underwent 2 separate inpatient rehabilitation courses, but also required acute hospitalization 6 additional times for subsequent infections or uncontrolled pain. Yet other complications of complete non-traumatic SCI (NTSCI), including neurogenic bowel and temperature hypersensitivity, were mild, and pressure injuries were absent. She has now transitioned from the acute to chronic phase of spinal cord injury care, with subsequent development of post-acute sequelae of SARS-CoV-2 infection (PASC).

Conclusion: This individual experienced significant challenges with the combined effects of acute T3 NTSCI and acute COVID-19, with subsequent progression to PASC.

Source: Oleson CV, Olsen AC, Shermon S. Spinal cord infarction attributed to SARS-CoV-2, with post-acute sequelae of COVID-19: A case report. World J Clin Cases. 2023 Dec 26;11(36):8542-8550. doi: 10.12998/wjcc.v11.i36.8542. PMID: 38188200; PMCID: PMC10768511. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10768511/ (Full text)

Incidence of persistent SARS-CoV-2 gut infection in patients with a history of COVID-19: Insights from endoscopic examination

Abstract:

Background and study aims Gut infection is common during acute COVID-19, and persistent SARS-CoV-2 gut infection has been reported months after the initial infection, potentially linked to long-COVID syndrome. This study tested the incidence of persistent gut infection in patients with a history of COVID-19 undergoing endoscopic examination.

Patients and methods Endoscopic biopsies were prospectively collected from patients with previous COVID-19 infection undergoing upper or lower gastrointestinal endoscopy (UGE or LGE). Immunohistochemistry was used to detect the presence of persistent SARS-CoV-2 nucleocapsid proteins.

Results A total of 166 UGEs and 83 LGE were analyzed. No significant differences were observed between patients with positive and negative immunostaining regarding the number of previous COVID-19 infections, time since the last infection, symptoms, or vaccination status. The incidence of positive immunostaining was significantly higher in UGE biopsies than in LGE biopsies (37.34% vs. 16.87%, P =0.002). Smokers showed a significantly higher incidence of positive immunostaining in the overall cohort and UGE and LGE subgroups ( P <0.001). Diabetic patients exhibited a significantly higher incidence in the overall cohort ( P =0.002) and UGE subgroup ( P =0.022), with a similar trend observed in the LGE subgroup ( P =0.055).

Conclusions Gut mucosal tissues can act as a long-term reservoir for SARS-CoV-2, retaining viral particles for months following the primary COVID-19 infection. Smokers and individuals with diabetes may be at an increased risk of persistent viral gut infection. These findings provide insights into the dynamics of SARS-CoV-2 infection in the gut and have implications for further research.

Source: Hany M, Sheta E, Talha A, Anwar M, Selima M, Gaballah M, Zidan A, Ibrahim M, Agayby ASS, Abouelnasr AA, Samir M, Torensma B. Incidence of persistent SARS-CoV-2 gut infection in patients with a history of COVID-19: Insights from endoscopic examination. Endosc Int Open. 2024 Jan 5;12(1):E11-E22. doi: 10.1055/a-2180-9872. PMID: 38188925; PMCID: PMC10769582. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10769582/ (Full text)

 

Long post-COVID-19 postural tachycardia syndrome (PoTS): A novel case

Introduction

There are no established ESC/NICE guidelines for early risk preventive strategies for postural tachycardia syndrome following long COVID-19 infection.1 A lack of early multi-disciplinary input and risk preventive strategies for this population has led to significant cardiovascular implications such as postural tachycardia and syncope, contributing to long-term emotional distress in recent years.1,2

Case presentation

A previously fit 36-year-old woman was admitted to our tertiary centre with a 3-month history of palpitations, chest discomfort and dizziness that were prominent while standing and improved with recumbence. She also described her palpitations, which were sometimes associated with missed beats, and it took longer than expected (at least 10–15 minutes) to settle after postural changes. These symptoms had all significantly impacted on her daily physical activities and caused emotional distress. She gave a history of serious COVID-19 infection requiring hospital admission 4 months previously. She reported that she was treated as having COVID pneumonitis requiring antibiotics, oxygen and steroids but no intensive care admission. Since then, she had noticed frequent episodes of postural palpitations with chest tightness, which had led to her recent admission. On examination, she has normal cardiorespiratory findings and no features of systemic involvement. She has no other significant family and social history with regard to other cardiovascular risk factors.

Initially, she was enrolled into a postural assessment of resting heart rate and blood pressure when she had her symptoms of palpitations. Her resting heart rate was 100 bpm while standing. Interestingly, her resting heart rate returned to normal (54 bpm) after 10 minutes of supine position. Her blood pressure 100/60 while supine and 98/74 when standing, which had ruled out postural hypotension. Following this, an active stand test (tilt table test) was administered on subsequent day. Her electrocardiogram (Fig 1) revealed sinus tachycardia when she had episodes of palpitation but it returned to normal sinus rhythm with heart rate 60 bpm after 10 minutes of recumbent position from standing. All blood investigations, including full blood count, troponins, inflammatory markers and renal profile including electrolytes, revealed normal findings, which had ruled out other differentials.

Discussion

As a whole, these postural assessments (Tables 1 and 2) had met the criteria for definition of postural tachycardia syndrome2 (typical symptoms with significant heart rate increase of >30 beats per minute within 10 minutes of standing and without orthostatic hypotension). To support this, her echocardiogram showed no significant signs of structural heart disease and satisfactory blood investigations. Given her timing of her postural cardiovascular symptoms related to post-COVID-19 infection and criteria being met for postural assessment, she was finally diagnosed as having postural tachycardia syndrome as a cause for long-COVID-19 symptoms.3 Overall, she was advised to increase her fluid intake to 3 litres per day with increased salt intake, to use lower body compression garments and to take non-upright exercise.1 This was followed by early multidisciplinary team (MDT) input, including the recommendation of webinars on living with POTS and psychological counselling.2

Conclusion

It is well-recognised in recent literature that a diagnosis of PoTS post-COVID infection is easily overlooked as it does not associate with structural or arrhythmic heart disease and its specific aetiology is poorly defined apart from autonomic dysregulation.1,3 Therefore, more epidemiology study and detailed prospective research in long-COVID-19 patients are crucial for early recognition of this syndrome and long-term risk prevention.1,2

Source: Khin Kay Kay Kyaw. Long post-COVID-19 postural tachycardia syndrome (PoTS): A novel case. Clinical Medicine Nov 2023, 23 (Suppl 6) 48-49; DOI: 10.7861/clinmed.23-6-s48 https://www.rcpjournals.org/content/clinmedicine/23/Suppl_6/48 (Full text)

Long COVID is not a uniform syndrome: Evidence from person-level symptom clusters using latent class analysis

Abstract:

Background: The current study aims to enhance insight into the heterogeneity of long COVID by identifying symptom clusters and associated socio-demographic and health determinants.

Methods: A total of 458 participants (Mage 36.0 ± 11.9; 46.5% male) with persistent symptoms after COVID-19 completed an online self-report questionnaire including a 114-item symptom list. First, a k-means clustering analysis was performed to investigate overall clustering patterns and identify symptoms that provided meaningful distinctions between clusters. Next, a step-three latent class analysis (LCA) was performed based on these distinctive symptoms to analyze person-centered clusters. Finally, multinominal logistic models were used to identify determinants associated with the symptom clusters.

Results: From a 5-cluster solution obtained from k-means clustering, 30 distinctive symptoms were selected. Using LCA, six symptom classes were identified: moderate (20.7%) and high (20.7%) inflammatory symptoms, moderate malaise-neurocognitive symptoms (18.3%), high malaise-neurocognitive-psychosocial symptoms (17.0%), low-overall symptoms (13.3%) and high overall symptoms (9.8%). Sex, age, employment, COVID-19 suspicion, COVID-19 severity, number of acute COVID-19 symptoms, long COVID symptom duration, long COVID diagnosis, and impact of long COVID were associated with the different symptom clusters.

Conclusions: The current study’s findings characterize the heterogeneity in long COVID symptoms and underscore the importance of identifying determinants of different symptom clusters.

Source: van den Houdt SCM, Slurink IAL, Mertens G. Long COVID is not a uniform syndrome: Evidence from person-level symptom clusters using latent class analysis. J Infect Public Health. 2023 Dec 29;17(2):321-328. doi: 10.1016/j.jiph.2023.12.019. Epub ahead of print. PMID: 38183882. https://www.sciencedirect.com/science/article/pii/S1876034123004616 (Full text)

Preferential Impairment of Auditory Working Memory in Long COVID: An Observational Study of Undergraduate Medical Students

Abstract:

Background: Long COVID is a multisystem condition with prolonged symptoms that develop after recovery from the COVID-19 infection, often following a mild infection. Few studies have been conducted on cognitive function among medical students after recovery from mild COVID-19. This study aimed to assess the attention span and working memory (WM) capacity of medical students after six months of recovery.

Methods: A cross-sectional study was performed on 17 young adult medical students who had suffered a mild COVID-19 infection at least six months prior. Eighteen age-matched healthy medical students served as the controls. Audio-visual WM tasks and attention spans were assessed using computerized software for both the cases and controls.

Results: The mean ages of the case and control were 19.67±1.6 and 20.0±1.2 years, respectively. The most common symptoms among cases were fatigue (33%), weight loss (26%), and nasal stuffiness (13%). The overall proportion of correct responses across all visual and auditory WM tasks (p=0.085) and reaction times (p=0.609) did not differ between the cases and controls. However, the overall target hit rate of the auditory WM task was significantly lower in cases than in controls (p=0.002). This difference was not observed in the visual WM task (p=0.374).

Conclusion: In the current study, the overall WM functions (visual and auditory combined) and attention span did not differ between cases and controls. However, auditory WM performance was significantly impaired in patients compared with controls, indicating selective impairment of auditory WM in patients with long COVID.

Source: Manna S, Ghosh Dastidar S, S R, et al. (January 01, 2024) Preferential Impairment of Auditory Working Memory in Long COVID: An Observational Study of Undergraduate Medical Students. Cureus 16(1): e51457. doi:10.7759/cureus.51457 https://www.cureus.com/articles/217296-preferential-impairment-of-auditory-working-memory-in-long-covid-an-observational-study-of-undergraduate-medical-students#!/ (Full text)

Single-Cell RNA Sequencing Reveals Alterations in Patient Immune Cells with Pulmonary Long COVID-19 Complications

Abstract:

Since the emergence of the COVID-19 pandemic, the effects of SARS-CoV-2 have been extensively researched. While much is already known about the acute phase of the infection, increasing attention has turned to the prolonged symptoms experienced by a subset of individuals, commonly referred to as long COVID-19 patients. This study aims to delve deeper into the immune landscape of patients with prolonged symptoms by implementing single-cell mRNA analysis.
A 71-year-old COVID-19 patient presenting with persistent viral pneumonia was recruited, and peripheral blood samples were taken at 3 and 2 years post-acute infection onset. Patients and control peripheral blood mononuclear cells (PBMCs) were isolated and single-cell sequenced. Immune cell population identification was carried out using the ScType script.
Three months post-COVID-19 patients’ PBMCs contained a significantly larger immature neutrophil population compared to 2-year and control samples. However, the neutrophil balance shifted towards a more mature profile after 18 months. In addition, a notable increase in the CD8+ NKT-like cells could be observed in the 3-month patient sample as compared to the later one and control. The subsequent change in these cell populations over time may be an indicator of an ongoing failure to clear the SARS-CoV-2 infection and, thus, lead to chronic COVID-19 complications.
Source: Vaivode K, Saksis R, Litvina HD, Niedra H, Spriņģe ML, Krūmiņa U, Kloviņš J, Rovite V. Single-Cell RNA Sequencing Reveals Alterations in Patient Immune Cells with Pulmonary Long COVID-19 Complications. Current Issues in Molecular Biology. 2024; 46(1):461-468. https://doi.org/10.3390/cimb46010029 https://www.mdpi.com/1467-3045/46/1/29 (Full text)