26 Nov 2021 Episode 192 New South African variant B.1.1.529 Post-COVID and COVOD-FLU interactions

Fri, 11/26/2021 - 10:31

Dear colleagues,

This morning, the news was on the new South-African variant, labeled B.1.1.529, apparently dominant in Gauteng province and characterized by very high viral load.   You can find 3 papers ( 2 from Guardian, 1 from an Indian site). It is spreading to Botswana, but has also been found in Hong Kong and Israel. Single

There is a suggestion that it originated in an untreated HIV patient. That needs to be confirmed, but it is known that new variants can indeed arise from immune compromised patients, who are chronically (or recurrently? ) being infected, which may facilitate both mutations and recombination.

B.1.1.529 is said  to carry a total 50 mutations, of which more than 30 in the Spike and 10 in the receptor binding domain.  In a tweet Tom Peacock (Imperial College), points to the most prominent ones;    

Just spotted: very small cluster of variant associated with Southern Africa with very long branch length and really awful Spike mutation profile including RBD - K417N, N440K, G446S, S477N, T478K, E484A, Q493K, G496S, Q498R, N501Y, Y505H P681H

A more complete description of all mutations at https://github.com/cov-lineages/pango-designation/issues/343

Among these, you may recognize

K417N and E484A (same or similar as in beta and gamma) associated with immune escape

N501Y (also in alpha, beta, gamma)  increased transmissibility

T478K and P681H, reminiscent of Delta

 

The rest of this Episode is in two parts

In part 1, three papers on the long-term consequences of COVID

In part 1, a dozen of papers on differences and interaction Flu-COVID

 

Long COVID

Ep 192-1: A very comprehensive review on “Post-Acute Sequelae of SARS-CoV-2” (PACS)

  • According to Table 1, most studies find that over 2/3 of  adult patients have > 1 symptom left after weeks or months (fatigue, weakness, dyspnea, cough, headache, loss of taste and smell, cognitive and mental problems)
  • Increased risk of death beyond 30 days with hazard ratio 1.5 for both hospitalized and non-hospitalized patients.
  • Decreased diffusion capacity and total lung capacity in about 1/3 of patients
  • “Brain fog”, depression and anxiety and “post traumatic stress syndrome” are also common.

A very comprehensive approach for a “PACS clinic” is proposed, with a multidisciplinary team for both physical and mental health, partly inspired on the PICS (post-intensive care syndrome) clinics. It is nicely illustrated in Fig. 2.

Clearly,  after each acute “wave”, there is still a lot of work to do !!!

Ep 192-2: Long COVID in adolescents

A test-negative study in England suggests that the situation for adolescents (11-17 yrs), who presented for PCR testing (hence on suspicion of COVID), is better than in adults:

  • Common symptoms in adolescents include sore throat, headache, tiredness, shortness of breath and loss of smell.
  • At presentation: over 30 % of PCR(+) and 6 % of PCR(-) had 3+ symptoms
  • At 3 months: still 30 % of previously PCR(+), but also 16 % of previously PCR (-) had 3+ symptoms and those with multiple symptoms were more likely older, female and had worse pre-test physical and mental health.

From this study, we can learn that, in order to make any claim on “long-COVID”,  it is important to be sure about SARS-CoV-2 positivity and to carefully compare with a matched SARS-CoV-2 negative control group.      

Ep 192-3: A recent systematic meta-analysis of 23 studies further emphasizes the critical importance of a control group for youngsters.  In fact, most of the reported persistent symptoms were similar in cases and controls.  Nevertheless, there are small but significant differences: loss of smell occurred in 8% more cases than controls, as did headaches (5%), cognitive difficulties (3%) and sore throat and eyes (2% each).  

 

FLU-COVID

  1. Pathogenesis and clinic

Ep 192-4: Cambier in JCI Oct 2021: Neutrophilic broncho-alveolar inflammation distinguish critical

COVID-19 from critical influenza (subtype not specified)

  • In critical COVID more pronounced hyper-inflammation characterized by significantly increased cytokine and chemokine levels, hyperactivated neutrophils and elevated levels of protease inhibitors TIMP-1, SLPI and elafin in the lungs
  • Antibiotic treatment for bacterial co-infection: cytokine storm in the lungs persisted or even increased in COVID-19 patients, while it decreased in influenza

Synergy between bacterial co-infections and SARS-CoV-2 triggers a stronger production of

inflammatory mediators, despite antibiotics and corticosteroids treatment, which may account for the prolonged stay at ICU of COVID-19, in comparison to influenza patients.

 

Ep 192-5: Lorente in Critical Care shows also 100 % discriminatory metabolomic differences in serum of ARDS (Acute Respiratory Distress Syndrome) with either SARS-CoV-2 or H1N1 2009:

  • COVID-19: showed significant energy supply deficit more up-regulation of energy-generating pathways, i.e. glycolysis, fatty acid degradation, CoA biosynthesis, glycerolipids, and glycerophospholipids metabolism.
  • Influenza pneumonia is characterized by more marked inflammatory and oxidative stress responses  with increase in 2-hydroxybutyric acid, a readout of hepatic glutathione synthesis and marker of oxidative stress, and essential amino acids such as proline.

The conclusions of this metabolomic study seem different from the immunological study, with regard to dominance of inflammatory markers, but  the metabolic markers are different from immune markers and this study was done on serum. …. 

 

Ep 192-6: Rattanaburi in Exp Biol Med shows a clear-cut difference in upper respiratory microbiome in patients with “influenza like illness” (hence not ARDS as in the previous two papers):  see Fig 2 p 4

  • Influenza: clear predominance of Enterobacteriaceae
  • COVID enriched in Staphylococcus and Pseudomonas

These different “opportunistic”  pathogens may be derived from the environment, the GI tract or the skin (see Table 2 p 5).  They  can cause hospital-acquired infections involving multiple antibiotic resistances associated with pneumonia and high mortality rates.

 

Ep 192-7: Kong on laboratory and radiological differences

  • More chronic “co-morbidities” and higher neutrophil to lymphocyte ratio and more pleural effusion in severe Influenza
  • More ground-glass opacities in COVID patients.

However, the series is small and the Influenza patients were more critical: higher APACHE score and 40 % mortality vs no mortality in COVID.  Therefore not conclusive.

 

Ep 192-8 A: Yon Sung et al propose a simple lateral flow assay based on isothermal amplification of nasopharyngeal swab, using first reverse transcriptase (to transform viral RNA into complementary DNA), followed by amplification (using recombinase polymerase see Ep 192-B) and specific primers for COVID (ORF1 or polymerase and Nucleoprotein) and for Influenza A and B RNA’se P (RP) gene in a separate batch.   The reaction products are loaded on lateral flow strips which will reveal the amplicons from SARS-CoV-2 and Flu A/B respectively.  In a small validation study, the specificity is said to be 100 % and the sensitivity down to  10 copies.   The paper, however does not contain precise information on various reagents (e.g. which primers exactly were selected)

 

Ep 192-8 C: Bo Shu et al describe in Em. Infect Dis a multiplex RT-PCR.  In this case, we receive more information on the primer selection. The test has a similar sensitivity as single plex and a very high specificity, but can only be done in a specialized lab (not bedside).

 

  1. Vaccination

Ep 192-9: Lazarus in Lancet Nov 2021 show that concomitant administration of second doses of the ChAdOx1 (AZ) and BNT162b2 (Pfizer) COVID-19 vaccines with age-appropriate inactivated influenza vaccines raises no safety concerns and preserves antibody responses to both vaccines.                         In this study people over 65 were included, but I couldn’t find a sub-analysis on those. 

 

Ep 192-10: Toback in Lancet Resp Med Nov 2021 investigates co-administration of influenza with the first dose of Novavax S protein vaccine.  They see slightly more side effect, no effect on influenza titers, but a slight reduction of anti-Spike titers with minor non-significant decrease of efficacy.    Here, a limitation is that no 65+ were included.

 

Ep 192-11: Puri in Vaccines suggests that a previous vaccination with Influenza vaccine, especially when combined with polysaccharide pneumococcal vaccine increases the (in vitro) micro-neutralization against SARS-CoV-2 shortly after Pfizer vaccination, although the level of anti-RBD Spike antibodies and the T cell IFN-g Elispot to S peptides was not different.

The clinical significance of this finding is unclear, but, at least there is no evidence of negative interference by Flu or Pneumococcal vaccine on COVID vaccination.

 

Ep 192-12:  Colon in Am J of Infection Control retrospectively compared patients who received a positive versus a negative SARS-CoV-2 test in Michigan before 15 July 2021 (total over 27,000), with regard to previous influenza vaccination. 

As expected, the positive cases were older, more likely African-American, more obese, diabetic, had more pulmonary or cardiovascular conditions. 

Remarkably, the negative cases were also more likely to have received an influenza vaccine in the previous 1.5 year and this association remained highly significant in a multivariate analysis (Table 2). Moreover, flu-vaccinated SARS-CoV-2 patients tended to be clinically better off: lower hospitalization and mechanical ventilation rates as well as shorter duration of hospital stay (Fig 2 p 699).

Clearly, there is a possible association between previous flu vaccination with decreased risk of COVID-19 and improved clinical outcomes.

The mechanism of this association remains unclear, the authors refer to the vague concept of “trained immunity”, which has been invoked as well in the discussion on whether or not BCG and childhood vaccines could have a mitigating effect on SARS-CoV-2 infections. 

 

Ep 192-13: A large consortium compared side effects of COVID mRNA vaccines with inactivated and adjuvanted Influenza vaccines, based on a large WHO database.  They conclude:

  • Overall systemic reaction more frequent with COVID mRNA, but local reactogenicity more with flu vaccine.
  • COVID mRNA more cardiovascular (hypertensive crisis, supraventricular tachycardia); influenza vaccine more neurological side effects (Guillain-Barré, gait disturbance, neuralgia, visual impairment…)
  • COVID mRNA vaccine safe and have lower side effects than inactivated Influenza.

  

Ep 192-14: A very nice review on mRNA vaccines (already discussed as Ep 184-1).  Also showing in Table 2 p 32 that Modena is expanding this technology in clinical trials for several other viruses, including Influenza, Respiratory Syncytium Virus, Zika, Chikungunya …

 

Ep 192-15: An interesting concept: human para-influenza type 2, engineered to express SARS-CoV-2 Spike can be used as an effective intranasal vaccine against COVID in hamsters

 

GENERAL CONCLUSIONS

 

  1. The new B.1.529 variant harbors a new combination of known and new mutations that could make it more transmissible and escape immunity. To be followed up. 
  2. Post-COVID syndrome is becoming a serious problem in older adults, but seems less prevalent in youngsters.  Models for multidisciplinary care are available
  3. Pathogenic differences between critical COVID and Influenza are being studied:
  • COVID associated with more pronounced hyper-inflammation, more resistant to supportive treatment
  • There are clearly distinct metabolomic and microbiome profiles.
  1. Previous vaccination with Influenza vaccine may have beneficial effects: reduced susceptibility to SARS-CoV-2 infection and COVID disease
  2. Concomitant administration of COVID vaccines (mRNA, Adeno, S protein) and inactivated Influenza is safe and effective for both infections
  3. mRNA vaccines for Influenza may rather soon become available.   

 

Best wishes,

 

Guido

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