Tag: long covid immunology

SARS-CoV-2-Specific Immune Responses in Patients With Postviral Syndrome After Suspected COVID-19

Abstract:

Background and objectives: Millions of Americans were exposed to SARS-CoV-2 early in the pandemic but could not get diagnosed with COVID-19 due to testing limitations. Many have developed a postviral syndrome (PVS) including neurologic manifestations similar to those with postacute sequelae of SARS-CoV-2 infection (Neuro-PASC). Owing to those circumstances, proof of SARS-CoV-2 infection was not required for evaluation at Northwestern Medicine’s Neuro COVID-19 clinic. We sought to investigate clinical and immunologic findings suggestive of SARS-CoV-2 exposure in patients with PVS.

Methods: We measured SARS-CoV-2-specific humoral and cell-mediated immune responses against Nucleocapsid and Spike proteins in 29 patients with PVS after suspected COVID-19, 32 confirmed age-matched/sex-matched Neuro-PASC (NP) patients, and 18 unexposed healthy controls. Neurologic symptoms and signs, comorbidities, quality of life, and cognitive testing data collected during clinic visits were studied retrospectively.

Results: Of 29 patients with PVS, 12 (41%) had detectable humoral or cellular immune responses consistent with prior exposure to SARS-CoV-2. Of 12 PVS responders (PVS+), 75% harbored anti-Nucleocapsid and 50% harbored anti-Spike responses. Patients with PVS+ had similar neurologic symptoms as patients with NP, but clinic evaluation occurred 5.3 months later from the time of symptom onset (10.7 vs 5.4 months; p = 0.0006). Patients with PVS+ and NP had similar subjective impairments in quality of life measures including cognitive function and fatigue. Patients with PVS+ had similar results in objective cognitive measures of processing speed, attention, and executive function and better results in working memory than patients with NP.

Discussion: Antibody and T-cell assays showed evidence of prior SARS-CoV-2 exposure in approximately 40% of the PVS group. Three-quarters of patients with PVS+ had detectable anti-Nucleocapsid and one-half anti-Spike responses, highlighting the importance of multitargeted COVID-19 immunologic evaluation and the limitations of commercially available diagnostic tests. Despite their persistent symptoms, lack of COVID-19 diagnosis likely delayed clinical care in patients with PVS. Our data suggest that millions of Americans presenting with PVS resembling Neuro-PASC were indeed exposed to SARS-CoV-2 at the beginning of the pandemic, and they deserve the same access to care and inclusion in research studies as patients with NP with confirmed COVID-19 diagnosis.

Source:Orban ZS, Visvabharathy L, Perez Giraldo GS, Jimenez M, Koralnik IJ. SARS-CoV-2-Specific Immune Responses in Patients With Postviral Syndrome After Suspected COVID-19. Neurol Neuroimmunol Neuroinflamm. 2023 Aug 23;10(6):e200159. doi: 10.1212/NXI.0000000000200159. PMID: 37612134; PMCID: PMC10448973. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10448973/ (Full text)

Persistent symptoms after COVID-19 are not associated with differential SARS-CoV-2 antibody or T cell immunity

Abstract:

Among the unknowns in decoding the pathogenesis of SARS-CoV-2 persistent symptoms in Long Covid is whether there is a contributory role of abnormal immunity during acute infection. It has been proposed that Long Covid is a consequence of either an excessive or inadequate initial immune response.

Here, we analyze SARS-CoV-2 humoral and cellular immunity in 86 healthcare workers with laboratory confirmed mild or asymptomatic SARS-CoV-2 infection during the first wave. Symptom questionnaires allow stratification into those with persistent symptoms and those without for comparison.

During the period up to 18-weeks post-infection, we observe no difference in antibody responses to spike RBD or nucleoprotein, virus neutralization, or T cell responses. Also, there is no difference in the profile of antibody waning. Analysis at 1-year, after two vaccine doses, comparing those with persistent symptoms to those without, again shows similar SARS-CoV-2 immunity. Thus, quantitative differences in these measured parameters of SARS-CoV-2 adaptive immunity following mild or asymptomatic acute infection are unlikely to have contributed to Long Covid causality. ClinicalTrials.gov (NCT04318314).

Source: Altmann DM, Reynolds CJ, Joy G, Otter AD, Gibbons JM, Pade C, Swadling L, Maini MK, Brooks T, Semper A, McKnight Á, Noursadeghi M, Manisty C, Treibel TA, Moon JC; COVIDsortium investigators; Boyton RJ. Persistent symptoms after COVID-19 are not associated with differential SARS-CoV-2 antibody or T cell immunity. Nat Commun. 2023 Aug 23;14(1):5139. doi: 10.1038/s41467-023-40460-1. PMID: 37612310; PMCID: PMC10447583. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10447583/ (Full text)

L-Arginine in Restoring ‘Immune Dysregulation’ in Long COVID: It’s the Therapeutic Role Beyond the Routine Dietary Supplement!

Abstract:

COVID-19 pandemic is over now and we are in great peace of relief after three years. This pandemic has observed significant impact on quality of life globally and the put unforgettable imprints on history of mankind. Reason for more havoc in this pandemic was less studied virus by medical scientists regarding its pathophysiology, available treatment options and lack of effective vaccine to tackle this dragon. COVID-19 is the first observed and reported pandemic of corona virus related global disease apart from its previous SARS and MERS. Fast track developments in medical treatment options due to this ultrafast digital and artificial intelligence techniques have curtailed mortality on large scale globally.
Although mortality is significantly reduced, morbidity is documented on a large scale worldwide in this pandemic. Morbidity due to COVID-19 now called as ‘Long COVID’, which is underreported & half-heartedly evaluated globally. Long COVID is related to persistent immune dysregulation occurs during evolution of COVID-19 as natural trend of disease.
Immune dysregulation has documented during course of active viremia, during recovery of viral illness and after post viral phase. Immune dysregulation occurs in ‘selected group’ of cases irrespective of disease severity and vaccination status and observed in cases with negligible illness to advanced one mandates further research. Thus, Immune dysregulation in COVID-19 is predominant cause for long covid and leading to brainstorming effect on medical scientists and researchers as of today.
Globally, one third of recovered or affected cases of COVID-19 are facing long covid and needs prompt treatment options to tackle this dragon related long term effect on body. ‘Immunomodulatory’ or immunity modifying agents are the primary targets to curtail immune dysregulation and long covid. Some experts recommend ‘disease modifying agents’ to treat long covid cases. Still, many miles to go to reach to effective treatment options for long covid and we don’t have effective options for this ‘health issue of global concern’.
L-Arginine is amino acid with multiple beneficial effects such as immunomodulatory effects which will regulates immunological response in inhibit dysregulated immune system additional to its universally known antioxidant, vasodilatory and regenerative and cellular proliferation effects on immune cells. These Immunomodulatory and or diseases modifying effects of L-Arginine makes it the future candidate with ‘game changer’ role for management of Long covid resulting from immune dysregulation as a core pathophysiologic pathway of this Dragon Pandemic.
Source: Patil, Dr Shital, Patil, Swati, Gondhali, Gajanan. L-Arginine in Restoring ‘Immune Dysregulation’ in Long COVID: It’s the Therapeutic Role Beyond the Routine Dietary Supplement!  South Asian Journal of Life Sciences, 5(4):60-74. https://www.researchgate.net/publication/373217918_L-Arginine_in_Restoring_%27Immune_Dysregulation%27_in_Long_COVID_It%27s_the_Therapeutic_Role_Beyond_the_Routine_Dietary_Supplement (Full text)

Are fibrinaloid microclots a cause of autoimmunity in Long Covid and other post-infection diseases?

Abstract:

It is now well established that the blood-clotting protein fibrinogen can polymerise into an anomalous form of fibrin that is amyloid in character; the resultant clots and microclots entrap many other molecules, stain with fluorogenic amyloid stains, are rather resistant to fibrinolysis, can block up microcapillaries, are implicated in a variety of diseases including Long COVID, and have been referred to as fibrinaloids. A necessary corollary of this anomalous polymerisation is the generation of novel epitopes in proteins that would normally be seen as ‘self’, and otherwise immunologically silent.

The precise conformation of the resulting fibrinaloid clots (that, as with prions and classical amyloid proteins, can adopt multiple, stable conformations) must depend on the existing small molecules and metal ions that the fibrinogen may (and is some cases is known to) have bound before polymerisation. Any such novel epitopes, however, are likely to lead to the generation of autoantibodies.

A convergent phenomenology, including distinct conformations and seeding of the anomalous form for initiation and propagation, is emerging to link knowledge in prions, prionoids, amyloids and now fibrinaloids. We here summarise the evidence for the above reasoning, which has substantial implications for our understanding of the genesis of autoimmunity (and the possible prevention thereof) based on the primary process of fibrinaloid formation.

Source: Kell DB, Pretorius E. Are fibrinaloid microclots a cause of autoimmunity in Long Covid and other post-infection diseases? Biochem J. 2023 Aug 16;480(15):1217-1240. doi: 10.1042/BCJ20230241. PMID: 37584410. https://portlandpress.com/biochemj/article/480/15/1217/233389/Are-fibrinaloid-microclots-a-cause-of-autoimmunity (Full text)

Increased SARS-CoV-2 reactive low avidity T cells producing inflammatory cytokines in pediatric post-acute COVID-19 sequelae (PASC)

Abstract:

Background: A proportion of the convalescent SARS-CoV-2 pediatric population presents nonspecific symptoms, mental health problems and a reduction in quality of life similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID-19 symptomatic. However, data regarding its clinical manifestation and immune mechanisms are currently scarce.

Methods: In this study, we perform a comprehensive clinical and immunological profiling of 17 convalescent COVID-19 children with post-acute COVID-19 sequelae (PASC) manifestation and 13 convalescent children without PASC manifestation. A detailed medical history, blood and instrumental tests and physical examination were obtained from all patients. SARSCoV-2 reactive T cell response was analyzed via multiparametric flowcytometry and the humoral immunity was addressed via pseudovirus neutralization and ELISA assay.

Results: The most common PASC symptoms were shortness of breath/exercise intolerance, paresthesia, smell/taste disturbance, chest pain, dyspnea, headache and lack of concentration. Blood count and clinical chemistry showed no statistical differences among the study groups. We detected higher frequencies of spike (S) reactive CD4+ and CD8+ T cells among the PASC study group, characterized by TNFα and IFNγ production and low functional avidity. CRP levels are positively correlated with IFNγ producing reactive CD8+ T cells.

Conclusions: Our data might indicate a possible involvement of a persistent cellular inflammatory response triggered by SARS-CoV-2 in the development of the observed sequelae in pediatric PASC. These results may have implications on future therapeutic and prevention strategies.

Source: Krystallenia Paniskaki, et al. Increased SARS-CoV-2 reactive low avidity T cells producing inflammatory cytokines in pediatric post-acute COVID-19 sequelae (PASC) https://d197for5662m48.cloudfront.net/documents/publicationstatus/144335/preprint_pdf/a855de5e766f9457795050e56413075a.pdf (Full text)

Persistent immune and clotting dysfunction detected in saliva and blood plasma after COVID-19

Abstract:

A growing number of studies indicate that coronavirus disease 2019 (COVID-19) is associated with inflammatory sequelae, but molecular signatures governing the normal versus pathologic convalescence process have not been well-delineated. Here, we characterized global immune and proteome responses in matched plasma and saliva samples obtained from COVID-19 patients collected between 20 and 90 days after initial clinical symptoms resolved.

Convalescent subjects showed robust total IgA and IgG responses and positive antibody correlations in saliva and plasma samples. Shotgun proteomics revealed persistent inflammatory patterns in convalescent samples including dysfunction of salivary innate immune cells, such as neutrophil markers (e.g., myeloperoxidase), and clotting factors in plasma (e.g., fibrinogen), with positive correlations to acute COVID-19 disease severity. Saliva samples were characterized by higher concentrations of IgA, and proteomics showed altered myeloid-derived pathways that correlated positively with SARS-CoV-2 IgA levels.

Beyond plasma, our study positions saliva as a viable fluid to monitor normal and aberrant immune responses including vascular, inflammatory, and coagulation-related sequelae.

Source: Jang H, Choudhury S, Yu Y, Sievers BL, Gelbart T, Singh H, Rawlings SA, Proal A, Tan GS, Qian Y, Smith D, Freire M. Persistent immune and clotting dysfunction detected in saliva and blood plasma after COVID-19. Heliyon. 2023 Jul 4;9(7):e17958. doi: 10.1016/j.heliyon.2023.e17958. PMID: 37483779; PMCID: PMC10362241. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10362241/ (Full text)

Long COVID-19 and Insulin Autoimmune Syndrome: A Case Report

Abstract:

Purpose: To describe a case report of a patient with symptoms associated with metabolic alterations 1 month after having COVID-19.

Methods: Laboratory tests, clinical evaluations, and body composition assessments were performed by specialists.

Findings: The patient presented excessive sweating, hot flashes, dizziness, blurred vision, and seizure. Laboratory tests indicated low glucose levels after convulsions (50, 42.7, and 55 mg/dL), high insulin levels (basal, 638 µIU/mL; 2-hour, >1000 µU/mL), and positivity for anti-insulin antibodies. The patient was diagnosed with insulin autoimmune syndrome. Treatment with azathioprine and nutritional recommendations improved remission.

Implications: SARS-CoV-2 infection or vaccination might induce insulin tolerance failure.

Source: Corona-Meraz FI, Quintero-Castillo BP, Hernández-Palma LA, Machado-Sulbaran AC. Long COVID-19 and Insulin Autoimmune Syndrome: A Case Report. Clin Ther. 2023 Jul 29:S0149-2918(23)00250-3. doi: 10.1016/j.clinthera.2023.06.026. Epub ahead of print. PMID: 37524570. https://pubmed.ncbi.nlm.nih.gov/37524570/

Vagus nerve inflammation contributes to dysautonomia in COVID-19

Abstract:

Dysautonomia has substantially impacted acute COVID-19 severity as well as symptom burden after recovery from COVID-19 (long COVID), yet the underlying causes remain unknown. Here, we hypothesized that vagus nerves are affected in COVID-19 which might contribute to autonomic dysfunction.

We performed a histopathological characterization of postmortem vagus nerves from COVID-19 patients and controls, and detected SARS-CoV-2 RNA together with inflammatory cell infiltration composed primarily of monocytes. Furthermore, we performed RNA sequencing which revealed a strong inflammatory response of neurons, endothelial cells, and Schwann cells which correlated with SARS-CoV-2 RNA load. Lastly, we screened a clinical cohort of 323 patients to detect a clinical phenotype of vagus nerve affection and found a decreased respiratory rate in non-survivors of critical COVID-19.

Our data suggest that SARS-CoV-2 induces vagus nerve inflammation followed by autonomic dysfunction which contributes to critical disease courses and might contribute to dysautonomia observed in long COVID.

Source:Woo MS, Shafiq M, Fitzek A, Dottermusch M, Altmeppen H, Mohammadi B, Mayer C, Bal LC, Raich L, Matschke J, Krasemann S, Pfefferle S, Brehm TT, Lütgehetmann M, Schädler J, Addo MM, Schulze Zur Wiesch J, Ondruschka B, Friese MA, Glatzel M. Vagus nerve inflammation contributes to dysautonomia in COVID-19. Acta Neuropathol. 2023 Jul 15. doi: 10.1007/s00401-023-02612-x. Epub ahead of print. PMID: 37452829. https://link.springer.com/article/10.1007/s00401-023-02612-x (Full text)

Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations

Abstract:

Individuals with SARS-CoV-2 infection can develop symptoms that persist well beyond the acute phase of COVID-19 or emerge after the acute phase, lasting for weeks or months after the initial acute illness. The post-acute sequelae of COVID-19, which include physical, cognitive, and mental health impairments, are known collectively as long COVID or post-COVID-19 condition.

The substantial burden of this multisystem condition is felt at individual, health-care system, and socioeconomic levels, on an unprecedented scale. Survivors of COVID-19-related critical illness are at risk of the well known sequelae of acute respiratory distress syndrome, sepsis, and chronic critical illness, and these multidimensional morbidities might be difficult to differentiate from the specific effects of SARS-CoV-2 and COVID-19.

We provide an overview of the manifestations of post-COVID-19 condition after critical illness in adults. We explore the effects on various organ systems, describe potential pathophysiological mechanisms, and consider the challenges of providing clinical care and support for survivors of critical illness with multisystem manifestations.

Research is needed to reduce the incidence of post-acute sequelae of COVID-19-related critical illness and to optimise therapeutic and rehabilitative care and support for patients.

Source: Parotto M, Gyöngyösi M, Howe K, Myatra SN, Ranzani O, Shankar-Hari M, Herridge MS. Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations. Lancet Respir Med. 2023 Jul 17:S2213-2600(23)00239-4. doi: 10.1016/S2213-2600(23)00239-4. Epub ahead of print. PMID: 37475125. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00239-4/fulltext (Full text)

Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID

Abstract:

While immunologic correlates of COVID-19 have been widely reported, their associations with post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, understanding if specific disease features associate with discrete immune processes and therapeutic opportunities is important.

Here we profile patients in the recovery phase of COVID-19 via proteomics screening and machine learning to find signatures of ongoing antiviral B cell development, immune-mediated fibrosis, and markers of cell death in PASC patients but not in controls with uncomplicated recovery. Plasma and immune cell profiling further allow the stratification of PASC into inflammatory and non-inflammatory types.

Inflammatory PASC, identifiable through a refined set of 12 blood markers, displays evidence of ongoing neutrophil activity, B cell memory alterations, and building autoreactivity more than a year post COVID-19. Our work thus helps refine PASC categorization to aid in both therapeutic targeting and epidemiological investigation of PASC.

Source: Woodruff MC, Bonham KS, Anam FA, Walker TA, Faliti CE, Ishii Y, Kaminski CY, Ruunstrom MC, Cooper KR, Truong AD, Dixit AN, Han JE, Ramonell RP, Haddad NS, Rudolph ME, Yalavarthi S, Betin V, Natoli T, Navaz S, Jenks SA, Zuo Y, Knight JS, Khosroshahi A, Lee FE, Sanz I. Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID. Nat Commun. 2023 Jul 14;14(1):4201. doi: 10.1038/s41467-023-40012-7. PMID: 37452024; PMCID: PMC10349085. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10349085/ (Full text)