24 June 2022 Episode 269: Reinfection and long-term consequences of COVID revisited

Dear colleagues,

I do not have to convince you: COVID is not over and if new serious infections would go down (which is not the case as we saw in Ep 268), society will still have to face long-term health consequences. 

At present, leading scientists in US seem to recognize this more than we do it Europe and in Belgium, where there is hardly any attention for long COVID. Every time I give a talk, some people in the audience either have long-COVID themselves or in their family and most of the time, they feel that there is little medical attention to it….

Ep 269-1 A: Eric Topol A reinfection red flag 21 June 2022

Ep 269-1 B: Ziyad Nature Medicine 25 May 2022

• With each reinfection, the chances of a range of complications AFTER recovery, including premature death, increase (based on large cohort of UW Veterans Administration).

(See Ep 269-1 B)

• Although omicron may have 50-70 % less chance on long COVID (see Ep 269-2), reinfection is much more common with omicron, thus long-COVID may increase in absolute terms
• There are signs that vaccine effectiveness of 3 doses against hospitalization in non-immunocompromised subjects declines from 95 % (delta) to only 77% (omicron). 

His conclusion:

Despite lack of warnings by CDC, there should be gearing up with N95/KN95 masks, distancing when possible, attention to ventilation, air filtration, and all of the non-pharmacologic measures that we have at our disposal to limit infections and reinfections.

The lack of priority and resource allocation stems from the illusion that the pandemic is behind us, which is off-base. If ever there was a callout for don’t just stand there, do something, this is it.

WHAT IS LONG COVID? = Slippery and diffuse syndrome

Ep 269-2 A: Definition according to WHO

Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.

Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others (see Table 3 and Annex 2) which generally have an impact on everyday functioning.

Symptoms may be new onset, following initial recovery from an acute COVID19 episode, or persist from the initial illness. Symptoms may also fluctuate or relapse over time. A separate definition may be applicable for children.

Ep 269-2 B: Definition according to CDC

People who experience post-COVID conditions most commonly report:

General symptoms

• Tiredness or fatigue that interferes with daily life
• Symptoms that get worse after physical or mental effort (also known as “post-exertional malaise”)
• Fever

Respiratory and heart symptoms

• • Difficulty breathing or shortness of breath
  • Cough
  • Chest pain
  • Fast-beating or pounding heart (also known as heart palpitations)

Neurological symptoms

• • Difficulty thinking or concentrating (referred to as “brain fog”)
  • Headache
  • Sleep problems
  • Dizziness when you stand up (lightheadedness)
  • Pins-and-needles feelings
  • Change in smell or taste
  • Depression or anxiety

Digestive symptoms

• Diarrhea
• Stomach pain

Other symptoms

• Joint or muscle pain
• Rash
• Changes in menstrual cycles

HOW COMMON IS LONG COVID?

Ep 269-3:  Lara Bull-Otterson MMWR 27 May 2022: post-COVID March 2020-Nov 2021

COVID-19 survivors have twice the risk for developing pulmonary embolism or respiratory conditions;

One in five COVID-19 survivors aged 18–64 years and one in four survivors aged ≥65 years experienced at least one incident condition that might be attributable to previous COVID-19.

• Compare the incidence of 26 condi­tions often attributable to post-COVID among
• Cases = patients who had received a previous COVID-19 diagnosis
• Controls = matched patients without evidence of COVID-19

Ep 269-2: Anil Dhawan Lancet 17 June Comparison of long COVID during delta (June-Nov 2021)  and omicron BA.1 wave (Dec 2021-Feb 2022) in almost 100,000 UK residents with SARS-CoV-2

• A reduction in odds of long COVID with the omicron variant versus the delta variant of 0·24–0·50 depending on age and time since vaccination.
• However, given the high numbers of people infected with omicron in the UK , the numbers of long COVID actually increased from 1·3 million in January, 2022, to 1·7 million in March,

Ep 269-5: Heidi Ledford in Nature Briefing 20 June finds very discrepant figures in the literature: argues that  enormous databases do not necessarily allow scientists to solve long COVID mysteries, such as how well vaccination protects against the condition.

Why?  Because the definition is not really solid and electronic databases not necessarily as representative as they should be.

TRIANGLE THEORY TO EXPLAIN LONG COVID:

Ep 269-6: Jennifer Couzin-Frankel: Science 17 June 2022: Three clues to long-COVID

1. Microclots
2. Persistent virus
3. Hyper-inflammation

Ep 269-7: Pretorius Cardiovasc Diabet Nov 2021: Persisting clotting protein pathology in long COVID

• Microclots in both acute COVID-19 and Long COVID plasma samples resistant to fibrinolysis
• Substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits

Fig. 7 Simplified coagulation diagram depicting healthy and pathological processes.

(1A) The intrinsic and (1B) extrinsic pathways converge into the (1C) common pathway. These pathways lead to the conversion of soluble fibrinogen to insoluble fibrin, catalysed by thrombin.

(2) Tissue plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA) converts plasminogen into plasmin. A healthy fibrinolytic system regulates the coagulation pathway and assists with successful lysis of the insoluble fibrin clot.

(3) Plasmin cleaves fibrin into fibrin degradation products (FDPs), including D-dimer.

(4) Protein C and thrombomodulin both regulate coagulation: thrombin binds to its receptor, thrombomodulin, resulting in activated protein C (APC). APC then inhibits both Va and VIIIa.

Effect of dysregulated inflammatory molecules

(5) may interfere with tissue factor (TF) expression.

(6) may also down-regulate thrombomodulin, resulting in hypercoagulation, as Va and VIIIa activities are then not sufficiently modulated.

(7) can inhibit of the fibrinolytic system via up-regulation of plasminogen activator inhibitor-1 (PAI-1). PAI-I upregulation interferes with tissue plasminogen activator (TPA) function, and ultimately results in a dysregulated coagulation system.

(8) α2-antiplasmin (α2AP) inhibits plasmin and ultimately will prevent sufficient fibrinolysis

Note: In 269-6 (Couzin in Science) Danilo Biounsenso, a pediatrician in Rome, sees encouraging results of anti-coagulant therapy in a few patients, but this is a very small and uncontrolled trial.  

Ep 269-8: Andreas Zollner Gastro-enterology May 2022: Postacute COVID-19 is Characterized by Gut Viral Antigen Persistence in Inflammatory Bowel Diseases

Evidence for SARS-CoV-2 antigen persistence in the gut as a basis for immune perturbation in post-acute COVID-19.

Whether the reported link between gut viral antigen persistence and post-acute COVID-19 is applicable to patients without IBD warrants controlled clinical trials.

Ep 269-9: SARS-CoV-2 RNA detection in plasma, stool, and urine in patients with persistent symptoms after COVID-1

Note: Another rather puzzling observation in this paper is that patients, who received “antiviral treatment” (being either lopinavir/Ritonavir, Hydrocholoroquine, Azithromycine and/or glucocorticoids) achieved better outcome with significant differences (P< 0.01).  This, of course, is surprising, since none of these treatments nowadays is still considered really active.

To his credit, Dr Tejerina puts the result into perspective and worries about people experimenting on their own with therapies, including antivirals, that may be useless, or worse, dangerous.

Ep 269-10: Phetsouphanh Nature Immunology Feb 2022 Immunological dysfunction persists in long COVID

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

Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with Long COVID with 78.5–81.6% accuracy.

HOW WELL IS VACCINATION PROTECTING AGAINST POST-COVID?

This also remains a controversial question

Ep 269-11: Sokratis N. Zisis Open Forum Infectious Diseases May 2022: Very high protective effect of two doses of vaccine.

Retrospective matched case control study between Sept 2020 an Dec 2021 in a large US database, comparing incidence of post-acute COVID symptoms at 28 and 90 days after COVID diagnosis.

Table 1 shows that, after matching,  the patients with breakthrough infection were very comparable with the COVID patients without prior vaccination with regard to age, sex, ethnicity and (importantly) co-morbidity.

Table 2 and 3 suggest clear-cut protective effect of vaccination on post-acute (long) COVID at day 28 and day 30

Ep 269-1 B: Ziyad Nature Med May 2022 finds a less pronounced effect:

People with breakthrough infection (BTI) exhibited lower risk of death (HR = 0.66 (0.58, 0.74); and lower risk of post-acute sequelae (HR = 0.85 (0.82, 0.89);  compared to those with SARS-CoV-2 infection and no prior history of vaccination.

Hence only 15% overall protection against long-COVID in this study while in the Zisis study it was > 50%

Nevertheless, there is marked heterogeneity in this Ziyad study according to the symptom studied: much better protection against coagulation and respiratory complications.

It is also less clear how well the matching was done in the Ziyad paper, while it was explicitly shown by Zisis.

Finally the timing is different: Zisis evaluates after 1 and 3 months, while Ziyad evaluates after 6 months.

SOME CONCLUSIONS

• Post-acute or long COVID remains a rather poorly defined condition with many potential symptoms, but it is undeniable that a proportion of COVID patients has debilitating long-term consequences of the disease.
• Omicron may result in relatively less long COVID, but the high frequency of omicron infection may still result in many more long-COVID cases in absolute terms.
• Microclots and hyper)inflammation, associated with persistence of some viral material in tissues could explain the systemic and diffuse nature of long COVID
• Vaccination can partly protect against long COVID.

Best wishes,

Guido