Long COVID News: Australian Study Shows That Immune Dysfunction Persists For Up To 8 Months After Initial Mild Or Moderate SARS-CoV-2 Infection!
Long COVID News
: A new study by researchers from The Kirby Institute at the University of New South Wales-Australia, St Vincent’s Hospital, Darlinghurst, New South Wales-Australia, University of Melbourne-Australia and Monash University-Australia has found that immune dysfunction persists for up to 8 months after initial mild or moderate SARS-CoV-2 infection!
There has been growing evidence that SARS-CoV-2 infections can not only cause a variety of immune dysfunction issues but also lead to immunodeficiency in some. Thailand Medical News has been warning about this since November 2020 in our various Long COVID News
Many other researchers are also now detailing how the SARS-CoV-2 virus is causing immune dysfunction.
Unfortunately, there are some British 'experts' at the UKHSA spreading misinformation that SARS-CoV-2 induced immune dysfunctional issues or immunodeficiency does not exists!
(You can find lots of arrogant and rude British garbage on Twitter including doctors, virologists and researchers etc… it’s a little wonder that the United King
dom is among one of the worse affected countries in the world with regards to COVID-19 with lots of Brits dying like flies every day and you also have the garbage media like the BBC censoring news and other websites etc using their Trusted News Initiative!)
According to the Australian researchers, a proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID or LC)) lasting longer than 12 weeks.
The research team studied individuals with Long COVID compared to age- and gender-matched recovered individuals without Long COVID, unexposed donors and individuals infected with other coronaviruses.
Significantly, the study team found that patients with Long COVID had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection.
Utilizing a log-linear classification model, the study team defined an optimal set of analytes that had the strongest association with Long COVID among the 28 analytes measured. Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5–81.6% accuracy.
The study findings define immunological parameters associated with Long COVID and suggests future opportunities for prevention and treatment.
The study findings were published in the peer reviewed journal: Nature Immunology.
The study findings also showed that convalescent immune profiles after COVID-19 are different from those following infection with other coronaviruses. Several cytokines (mostly type I and III IFN, but also chemokines downstream of IFN-γ) were highly elevated in individuals following the resolution of active SARS-CoV-2 infection compared to HCoVs and UHCs (unexposed healthy controls) at month 4 after infection.
IFN-β and IFN-λ1 remained elevated in the LC group at month 8 after initial infection, while their levels began to resolve in MCs (asymptomatic matched controls). Elevated plasma ACE2 activity was noted in the LC and MC groups at month 4 but trended toward normal by month 8 after infection.
The study team also identified a set of analytes (IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6) that highly associated with LC at month 8, indicating that components of the acute inflammatory response and activation of fibroblast or epithelial cells, T cells and myeloid cells are associated with LC.
Detailed immune cell phenotyping indicated chronic activation of a subset of CD8+ T cells, with expansion of PD-1+ and TIM-3+ subsets and pDCs and monocytes persisting from month 3 to month 8 in the LC group. These changes were accompanied by an absence of naive T and B cell subsets expressing low levels of CD127 and TIM-3 in peripheral blood of patients with LC.
The study findings suggest that SARS-CoV-2 infection exerts unique prolonged residual effects on the innate and adaptive immune systems and that this may be driving the symptomology known as LC.
Furthermore, IFN-β and IFN-λ1 were highly elevated in convalescent COVID-19 samples compared to HCoV and UHC samples. Although these levels decreased over time in patients who recovered, they remained high in patients with LC. The morbidity of acute COVID-19 infection appears to correlate with high expression of type I and III IFN in the lungs of patients.
IFN-λ produced by murine lung dendritic cells in response to synthetic viral RNA is associated with damage to lung epithelium, and IFN-λ signaling hampers lung repair during influenza infection in mice. Severe acute COVID-19 has been associated with diminished type I IFN and enhanced IL-6 and tumor necrosis factor (TNF) responses.
Though the study’s cohort of individuals with LC consisted mostly of patients with mild or moderate initial illness, elevated type I and III IFN levels were maintained to month 8 after infection and are consistent with the observed prolonged activation of pDCs, indicating a chronic inflammatory response.
Interestingly, patients with COVID-19 who are admitted to the intensive care unit have high plasma levels of sTIM-3. The study team found elevated levels of sTIM-3 in the LC group, but not in the MC or HCoV groups, which is consistent with the expanded subsets of memory CD8+ T cells expressing TIM-3 and PD-1 and indicates chronic T cell activation and potentially exhaustion.
Similarly, shedding of membrane-bound protein ACE-2 during acute infection, resulting in increased activity in plasma continues into convalescence, regardless of symptom severity at month 4, and normalizes at month 8 in most patients.
The study team utilized a log-linear classification model to assess all combinations of analytes to determine the subset of analytes most strongly associated with LC.
It was found that IFN-β, together with PTX3, IFN-λ2/3, IFN-γ and IL-6, differentiated LC from MCs with high accuracy at month 8. IFN-λ2/3 are secreted by pDCs following viral RNA sensing by TLR7, TLR9 and RIG-123. PTX3 increased in lung epithelia and plasma of patients with severe COVID-19 and can serve as an independent strong prognostic indicator of short-term mortality.
IL-6 is a pleiotropic mediator that drives inflammation and immune activation. A high IL-6/IFN-γ ratio is associated with severe acute COVID-19 infection. The observation that the best correlate for LC is an eclectic combination of biomarkers reinforces the breadth of host response pathways that are activated during LC.
T cell activation (indicated by CD38 and HLA-DR), T cell exhaustion and increases in B cell plasmablasts occur during severe COVID-19. These markers identified highly activated monocytes and pDCs, the frequencies of which decreased over time in MCs, but not in patients with LC. Type I and type III IFN upregulate major histocompatibility complex expression, including HLA-DR33. An unbiased large-scale dimensional reduction approach identified the depletion of three clusters of naive B and T cell subsets present in the LC group at month 8 after infection!
Collectively, these observations suggest persistent conversion of naive T cells into activated states, potentially due to bystander activation secondary to underlying inflammation and/or antigen presentation by activated pDCs or monocytes. The ultimate result of this chronic stimulation may be expansion of PD-1+ or TIM-3+ CD8+ memory T cells. Bystander activation of unactivated naive subsets into more activated phenotypes is consistent with observations in acute severe COVID-19.
The study findings indicate an ongoing, sustained inflammatory response following even mild-to-moderate acute COVID-19, which is not found following prevalent coronavirus infection. The drivers of this activation require further investigation, but possibilities include persistence of antigen, autoimmunity driven by antigenic cross-reactivity or a reflection of damage repair. These observations describe an abnormal immune profile in patients with COVID-19 at extended time points after infection and provide clear support for the existence of a syndrome of Long COVID.
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