covid: more on long covid insights

Another recent study also looked at PASC, Post-acute sequelae of Covid-19, an acronymic variant of POSC of the last blog) to elicit early risk factors that seem to anticipate PASC development, through a multi-omic assessment (see covid long covid early factors cell2022 in dropbox, or doi.org/10.1016/j.cell.2022.01.014). In brief (lots more details in this 52-page document:   

 

Details: 

-- 209 covid patients in their primary cohort were followed from initial diagnosis to convalescence (2-3 months later), paired with 457 healthy controls 

-- mean age 56, 50% female, BMI 30, 51% white/13% Asian/10% Black, 71% admitted to the hospital/56% respiratory support/30% ICU admission 

-- comorbidities: hypertension 40%, diabetes 23%, asthma 16%, cancer 11%, 

-- timelines assessed: initial clinical diagnosis (T1), acute disease (T2), and 2 to 3 months post onset of initial symptoms (T3) 

-- blood draws were assessed for a remarkably complex and wide-ranging evaluation, including the following (justifying the "multi-omic" moniker): 

    -- single-cell multi-omics assay: used to analyze the transcriptome (ie, the full array of the messenger RNA molecules expressed by an organism) 

    -- SARS-CoV-2 viral load measurements, isolated from plasma or nasopharyngeal swabs [quantitative PCR, where a cycle threshold <36 was considered positive]

    -- CMV and EBV viremia measurements 

    -- plasma proteomics and metabolomics (plasma concentrations of proteins and metabolites) 

    -- single-cell multiplex secretome (proteins expressed by an organism and secreted into the extracellular space) assay, isolating CD4 and CD8 T cells, as well as NK cells and monocytes 

    -- SARS-CoV-2 ELISAs: to assess the various classes of immunoglobulins (IgG, IgA, IgM) 

    -- Autoantibody ELISAs: the panel included anti-IFN-α2, and five anti-nuclear autoAbs (ANAs) (Ro/SSA, La/SS-B, U1-snRNP, Jo-1, and P1) commonly associated with lupus

    -- Neutralization assay: to assess neutralizing antibody titers 

    -- MIRA assay: to stimulate T cells and sort antigen-specific T cells 

    -- Bulk TCR (T cell receptor) sequencing: to look at CDR3 (complementary determining region 3) sequences, to assess the expression and utilization patterns in CD4 and CD8 cells 

    -- so, lots of "omes" involved, but they did (mysteriously) leave off my favorite one: the microbiome....

 

-- eight symptoms were specifically interrogated: fatigue, cough, dyspnea, sputum production, diarrhea, nausea or vomiting, abdominal pain and dysgeusia; however, they did allow for open-ended responses about persistent symptoms 

-- a subsequent analysis of 100 postacute Covid patients were assessed to validate their findings from the primary cohort, though this cohort was not so sick: mean age 50, 66% female, 10% hospitalized, comorbidities hypertension 14% and diabetes 6%

 

Results: 

-- at T3 (convalescence): 

    -- patients had antibodies against the spike protein receptor binding domain of SARS-CoV-2, and antibody titers correlated with disease severity and also with neutralizing antibodies 

    -- most prominent symptoms were fatigue (52% of participants), cough (25%) and anosmia/dysgeusia (18%) 

    -- symptoms were reclassified as:

        -- respiratory: 42%, consisting of cough, fatigue, shortness of breath, fever or chills, muscle/body aches, nausea  [not sure why nausea is here. ?misprint]

        -- neurological: 25%, consisting of anxiety, blurred vision, depression, memory problems, difficulty concentrating, difficulty sleeping, dizziness, headache

        -- anosmia/dysgeusia: 18%

        -- gastrointestinal: 9%, consisting of diarrhea and abdominal pain

 

-- Patients with respiratory symptoms had significantly depressed levels of cortisol at T3 [perhaps explaining why dexamethasone is helpful in patients with respiratory distress] 

-- patients with neurologic symptoms had higher protein levels associated with the negative regulation of circadian sleep/wake cycles [perhaps explaining some of the anxiety/memory problems/difficulty concentrating/difficulty sleeping reported by these patients] 

 

-- identified four early risk factors for PASC:

     -- SARS-CoV-2 viremia: specifically associated with increased memory problems and difficulty concentrating (2-2.5 increased odds ratio)

             -- SARS-CoV-2 nasal swab viral load was significantly associated with anosmia/dysgeusia [perhaps related to the easy access from the nasal cavity to the olfactory bulb in the brain]  

     -- diabetes: specifically associated with cough, fatigue, and other respiratory PASC symptoms (2-5 increased odds ratio)

    -- latent EBV (Ebstein-Barr Virus) reactivation: 

         -- EBV viremia detected in 14% at T1, decreasing in subsequent assessments 

             -- SARS-CoV-2 viremia was detected in 25% of patients (though only a few having both this and EBV viremia), also decreasing in subsequent assessments 

             -- PASC symptoms of fatigue and sputum production were specific for EBV viremia [perhaps paralleling the EBV association with chronic fatigue syndrome]

      -- Autoantibodies: 

            -- 44% had autoantibodies at T3, though 56% of those had mature antibodies and likely predated Covid infection 

            -- there was a strong negative correlation between anti-SARS-CoV-2 IgG titers and autoantibodies (anti-IFN-α2 and ANAs) 

        -- there was a correlation between anti-SARS-CoV-2 nucleocapsid protein IgG and neurologic PASC; elevated levels of multiple autoAbs at T3 and GI-related PASC and sputum production; anti-IFN-α2 antibodies and respiratory PASC. Several of these were evident at T1, suggesting that these autoantibody levels may anticipate biomarkers of different PASC symptom categories

 

-- the 100 patients in the validation sample, though significantly less sick, had very similar outcomes

 

Commentary: 

--PASC, or POSC, or long covid (or other acronyms to follow??) is defined by the CDC as new, returning, or ongoing health problems that people can experience 4 or more weeks following a Covid infection 

-- reactivation of latent EBV has been found in prior studies and has correlated with PASC  

 

-- This study found that 4 factors measured as early as the initial Covid diagnosis might anticipate later PASC development: type II diabetes, SARS-CoV-2 viremia, EBV viremia, and autoantibodies 

-- several of these findings suggest potential therapies at Covid onset, for example: 

    -- detectable SARS-CoV-2 viremia at T1 might lead to earlier antiviral therapy 

    -- respiratory PASC might be decreased by assessing cortisol levels at T1 and treating with steroids 

    -- hyperinflammation associated with autoantibodies might benefit from anti-inflammatory medications 

    -- the negative correlation between SARS-CoV-2 IgGs and certain autoantibodies might suggest that those with certain elevated autoantibodies might be more susceptible to breakthrough infections (since they had less robust IgG response to the infection) and benefit more from booster vaccination 

-- the relationship with EBV is particularly interesting to me, since some patients do develop severe neurologic symptoms after Covid infection (eg see https://www.nature.com/articles/s41591-021-01647-5.pdf , and perhaps EBV reactivation might lead to multiple sclerosis or other severe neuromuscular disorders (a very recent article provided even more evidence of the EBV/multiples sclerosis association: https://www.science.org/doi/10.1126/science.abj8222 ). EBV infection is also associated with meningitis, encephalitis, optic neuritis, transverse myelitis, facial nerve palsies, guillan-barre, and acute cerebellar ataxias.

 

Limitations: 

-- this was a relatively small study, and cannot therefore give detailed identification of PASC risk factors for the general population

    -- especially since the pretty high frequency of PASC may involve many different untested risk factors as well as complex interrelations between combinations of risk factors 

-- this study only assessed PASC at 2 to 3 months after Covid onset, thereby limiting our understanding of longer-term outcomes (ie, which patients will develop disabling long-term dysfunction from PASC?) 

    -- the short-term window of the study would also limit assessment of several T cell functions, which may come into play later after the acute infection 

-- the study just assessed associations between the risk factors derived through multiple investigations and PASC, and cannot identify causality. For that, there would need to be specific studies using perhaps animal models to help assess causality 

-- there was some arbitrariness to the construction of the study, which might limit our complete understanding: they looked at certain specific autoantibodies, they did not assess the microbiome which might well have an important role (http://gmodestmedblogs.blogspot.com/2022/02/long-covid-some-new-insights.html ), they were limited by the specific genomic data that was available, and they could not assess the wider range of potentially associated comorbidities 

-- these results may be limited to the specific SARS-CoV-2 variants involved in these patients (unspecified in the study above), and may not be applicable to subsequent SARS-CoV-2 variants which may have different structural changes and physiological effects at T1 (the time of initial infection) 

-- there were no data on the in innate immune system response, since granulocyte evaluation was not part of their assessment 

-- this study involved sick Covid patients, and since the majority of those with PASC have only mild to moderate infections, this limits the generalizability to the vast majority with long-term post-Covid symptoms. However, the small 100-patient validation cohort had similar results and were much less sick 

-- we do not have a sense of the attributable risk of these 4 high-risk PASC antecedents: do they explain, either individually or as any combination, a small, medium, or large percent of the likelihood to get PASC?

-- we have no information about the actual quality of the PASC symptoms. were they mild? severe? did they limit functionality (such as ability to work, interpersonal relationships)?

 

So, we really are starting to get more insight into potential predictors of long Covid/PASC/POSC/whatever.... The intriguing thing about this article is the specificity of some of their associations, which could lead to different therapies early on and potentially improve outcomes with some pretty simple tests.

 

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Another article assessed 22 adults with long covid/PASC, having cognitive problems vs 10 without cognitive issues, all with mild Covid infection (see covid brain fog csf changes AnnClinTransNeuro2022 in dropbox, or doi: 10.1002/acn3.51498)  

  

In brief:   

-- all had structured interviews, neuropsychological testing and some had optional cerebrospinal fluid evaluation (done in 53%: 13 with cognitive PASC and 4 controls)  

-- 43% had delayed onset of cognitive impairment, 1-6 months after covid (6 of 21 had onset more than 2 months after the infection)  

-- delayed onset PASC occurred more in younger people, more in those with a higher number of pre-existing cognitive risk factors (2.5 vs 0, p=0.03) and more abnormal CSF findings (77% vs 0, p=0.01) vs controls. Cognitive risk factors including lots of conditions (hypertension, diabetes, sleep apnea, HIV, depression, anxiety, learning disability, mild TBI, b12 deficiency, hypothyroidism, alcohol use, etc)  

    -- CSF findings included elevated CSF protein without other explainable cause or abnormal oligoclonal banding

 

so, an interesting but small study documenting CSF abnormalities in those with cognitive impairment after Covid infection. However, it is unclear if the CSF abnormalities were from the covid infection or from the underlying cognitive risk factors (though striking that in many people the cognitive issues did not manifest themselves until several months later). we really would need longitudinal CSF evaluations of people over the course of their cognitive impairment to assess a correlation between the lab findings and cognitive outcomes. And with many more people involved (eg, only 4 control patients had CSF examination, a small group of people but probably not so easy to get many volunteers....)

 

geoff

 

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