Cognitive decline from a computer science perspective

Bismillah, alhamdulillah: an interesting view on cognitive decline from a computer science perspective and the cost of recall when memory is effectively unlimited.

COVID Vaccines: Protective v Sterilizing immunity

Bismillah, alhamdulillah. Words are important, three closely related words which are used frequently inaccurately used interchangeably are: infection, disease and illness. For example: ‘I got infected‘ v ‘He has the disease‘ v ‘She is ill‘. The blurring of boundaries between these words in the normal world does not matter but in the COVID era and vaccination it is important to understand the difference.

In an ideal world a vaccine would prevent infection and prevent the chain of infection-disease-illness from developing.

The words lie on a spectrum: Infection occurs when a biological agent causing disease is inside you. Disease is when the infecting agent causes physical problems. Illness is how the disease affects you both physically and psychologically.

The importance of understanding the distinction between these terms is that a person may be infected but have not disease or illness. Others may be infected and have disease. Others may have disease and no longer have infection. And sometimes people are no longer infected, have no disease but still feel ill.

In an ideal world a vaccine would prevent infection and prevent the chain of infection-disease-illness from developing. The current COVID vaccine trials have a definition of “success”. In order to achieve FDA Emergency Use Approval (EUA) require the prevention of disease – not infection – in 50% of vaccinated people. In a recent meeting of the vaccine manufacturers they have decided to self-regulate and set a 80% reduction of disease in vaccinated people to say the vaccine is successful. But this definition of success has a potential problem:

People who have been “successfully” vaccinated will have protective immunity ie it will protect them from disease but it will not give sterilizing immunity. Sterilizing immunity is one that prevents infection. The effect of this is that people who get successfully vaccinated, with non-sterilizing vaccines, when infected will not get the disease but they will still be able to infect others. If health professionals are given such vaccines, though it may protect them it would make them a source of asymptomatic infections for their patients. They may be converted into millions of Typhoid Mary’s.

Other miscellaneous points from the TWiV team:

How are vaccines going to be given? Most are two dose regimens, some are designed to be one.

Demand for the COVID vaccine is expected to be huge. Flu vaccines are produced in the number of 100 million doses per year. But for COVID vaccine some of the major vaccine manufacturers are planning to scale up manufacture of the vaccine to 1 billion doses and are currently building new manufacturing facilities.

How many people do you need in a vaccine phase 3 trial for it to be statistically powerful enough to draw meaningful conclusions? 30,000 vaccine volunteers are required to give at least 200 infections and these people need to be present in an area where the disease is circulating.

What is antibody-dependent enhancement (ADE) and when does it become obvious? Wikipedia defines ADE as “a phenomenon in which binding of a virus to suboptimal antibodies enhances its entry into host cells, followed by its replication.” Dr Griffin from the TWiV pointed out that this can occur in vaccine induced immunity as the vaccine immune response wanes and you would only be able to pick up these problems at one year post vaccine. Which is why Phase 3 trials are run for and collect data over a period of 1 to 4 years.

References

Is a COVID vaccine safe or not?

Bismillah, alhamdulillah

Here is a podcast of some experts on the topic. Their conclusion was they would not be the first people to take the vaccine especially if it was fast tracked due to the changes in the regulatory process. They are referring to the changes in the FDA in the USA. These experts are professors of virology and immunology. They detail their concerns in the podcast.

They point out that most COVID vaccines candidates are using the spike protein of the virus to generate an immune response. The million dollar question that only time can answer is: will the vaccine trigger an immune reaction which will cause a vaccine induced version of COVID? Usually vaccine phase 3 safety and efficacy trials take at least 2 years before results are sufficiently detailed to make a good judgement about a vaccine being safe or not.

They also dicuss one side effect that has been noted called Transverse Myelitis in one current vaccine trial of the Oxford vaccine.

For a consultation to be a useful exercise it should be made with content matter experts. A public consultation is not going to give a valid answer. Most clinical doctors are NOT content matter experts when it comes to vaccines and immunology. The key people are the core scientific teams who are producing the vaccines, immunologists, virologists and public health experts.

Key points to reflect over:

  1. Have vaccines been withdrawn because they cause more harm than benefit? The answer is yes, examples include the initial Rotavirus vaccine and its causing of intussusception.
  2. Another key question that needs to be resolved is whether the presence of antibodies can actually enhance COVID disease. This is still unknown.
  3. Being sceptical or cautious about a single vaccine is not an anti vaxxer position.
  4. Prematurely introducing a vaccine that is shown to have more side effects later will support the anti vaxxer opinion and cause people to loose their confidence in vaccines in a greater way than delaying the introduction of a vaccine.
  5. Pandemics take their time. Getting fed up with lockdowns is not a sensible reason to rush a vaccine.

TWiV 661: SWAG with Ralph Baric

COVID19 What day is it?

Bismillah, alhamdulillah: COVID has disrupted awareness of which day it is. Especially as work is now a seemingly continously rolling shift system. To help us re-anchor ourselves in time, we have started something very basic. Taking a page out of our school days, we have started to write the day on our team whiteboard. Something small, but helpful.

COVID19 TWiV Update 651

Bismillah, alhamdulillah: interesting update from Dr Daniel Griffin, today, TWiV 651:

Conjunctivitis: occurs in 3% and is a post viral phenomena, usually happening at week 4.

Hair loss: also noted mainly in women and happening in week 4. Percentages are low but seema to be combination of hair growth arrest and hair loss.

Immune responses: seem to be divided into three categories: a. None b. T cell mediated c. B cell mediated. Those with the first response do best.

Quarantine post schools opening will remain a challenge as the 14 day recommended quarantine will renew itself every time a new member of the family is infected. Potentially daisy chaining a series of two week qùarantines multiplied by the number of family members.

Primary Care – Heroes Unsung

To every doctor and nurse in primary care

Who stands with unblinking stare

And a dedication beyond compare

By every patient, caught in despair

Like trees at the edge of fiery fire

They stand still, soaking every ire

Unlike smoke, that flies away

They, with every wind, only sway

Without them, there is no first line

To stop the covid tsunami of our time

Perhaps the world may not know

The endless effort, of those below

But should they ever tumble

Every one behind them would crumble

Whether stout or mighty and tall

For primary care is our defensive wall

Let these few words, witness, bear

Though unsung, you are beyond compare

If deeds were stars, in the sky yours would be

Let the thundering world, fall silent and see

Challenge – can you make this easy for patients to understand?

Bismillah, alhamdulillah: When is it important NOT to test patients without COVID19 symtoms for COVID19 PCR? The answer is when the pre-test probability is low which makes it more likely that a POSITIVE result is a FALSE POSITIVE.

Challenge: can you make an infographic or video explaining that in less that 3 minutes? Target audience: patients. Language: English and Arabic.

Here is an example but geared towards medical students/ doctors on YouTube

“Dominic’s coming” lockdown

Bismillah, alhamdulillah: perceptions are key in public policy. Undermining a lockdown message will have a profound impact on the way people behave and has the potential to unfortunately amplify a second wave of COVID19. Prophet Muhammad (S) described rulers as shepherds who deal with their flock. A straying sheep may not harm the flock immediately, but when it strays, others follow. Like a loose thread of a well knit dress, if not dealt with, do not be surprised if the entire dress dissolves away.

https://www.theguardian.com/politics/2020/may/24/boris-johnson-defence-dominic-cummings-anger-from-allies-and-opponents-alike

COVID19 & Vitamin D – harmful or helpful?

Bismillah, alhamdulillah: Dr Daniel Griffin was asked about Vitamin D and its role in boosting the immune system to fight COVID19. He said he was unable to say, but he highlighted experience with treating iron deficiency anaemia in children in Sub Saharan Africa to boost their immune system and the consequence was a tripling in childhood mortality (TWiV 617).

While iron ‘improves’ the immune system, it is not always beneficial for those with a deficiency. The same may apply to Vitamin D and a cautious approach is needed which proritises preventing harm over theoretical benefit.

Recent evidence from a large, randomized, controlled trial has suggested that the universal administration of iron to children in malaria-endemic areas is associated with an increase in adverse health outcomes. The purpose of this paper is to summarize the available ecologic and intervention trials related to iron and malaria in children, and to set these against current knowledge of the biology of host–pathogen interactions involving iron metabolism. We conclude that, although not fully consistent, the balance of evidence confirms that administration of iron (usually in combination with folic acid) increases the incidence of malaria when given without prophylaxis and in the absence of universal access to treatment.

Prentice, Andrew M., et al. “Iron Metabolism and Malaria.” Food and Nutrition Bulletin, vol. 28, no. 4_suppl4, Dec. 2007, pp. S524–S539, doi:10.1177/15648265070284S406.

COVID19 Remdesivir – Yes, No or Don’t know? and more gems from the TWiV team

person opening an ampoule

_Bismillah, alhamdulillah_ two studies on Remdesivir – the first negative the second positive. The first, fully released; the second, started with a press-release and no full results for analysis. Here is a quick summary from, TWiV 608, a look at false positive PCR’s from South Korea and a clinical reminder from Dr Daniel Griffin (MD, Internal Medicine and Infectious Diseases)

*STUDY 1 – Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial*

*Take home points*

*1/ Study design:* Multicentre (10 centres), RCT, DB, placebo controlled; in Wuhan; Between Feb 6, 2020, and March 12, 2020, 237 patients

*2/ Primary endpoint* was time to clinical improvement up to day 28

*3/ Clinical improvement definition* = Days from randomisation (in the trial)  to a two point decline in a six point scale:

(6) death;

(5) hospital admission for extracorporeal membrane oxygenation or mechanical ventilation;

(4) hospital admission for noninvasive ventilation or high-flow oxygen therapy;

(3) hospital admission for oxygen therapy (but not requiring high-flow or non-invasive ventilation);

(2) hospital admission but not requiring oxygen therapy;

(1) discharged or having reached discharge criteria (defined as clinical recovery—ie, normalisation of pyrexia, respiratory rate <24 breaths per minute, saturation of peripheral oxygen>94% on room air, and relief of cough, all maintained for at least 72 h

5/ *Time to clinical improvement*: Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87–1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95–2·43]).

6/ *Adverse events* were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse
events in 18 (12%) patients versus four (5%) patients who stopped placebo early.

*7/ Implications of all the available evidence.* _No statistically significant benefits were observed for remdesivir treatment beyond those of standard of care treatment. Our trial did not attain the predetermined sample size because the outbreak of COVID-19 was brought under control in China. Future studies of remdesivir, including earlier treatment in patients with COVID-19 and higher-dose regimens or in combination with other antivirals or SARS-CoV-2 neutralising antibodies in those with severe COVID-19 are needed to better understand its potential effectiveness._

*8/ TWiV Discussion:* This is a negative study; it has concerning adverse effects including ARDS; study started mainly in the second week – this may be too late as viral shedding has deceased significantly by then and an anti-viral is unlikely to work at this stage;

*STUDY 2 –  Adaptive COVID-19 Treatment Trial*

*Take home points*

*1/ Study details*: hospitalized patients with advanced COVID-19; Placebo controlled; 1063 patients; Trial name Adaptive COVID-19 Treatment Trial, or ACTT; sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health

*2/ Interim analysis* remdesivir “better” than placebo from the perspective of the primary endpoint, time to recovery. Recovery defined as “well enough for hospital discharge or returning to normal activity level.” 31% faster time to recovery than those who received placebo (p<0.001) (11 days v 15 days). Results also *suggested* a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059).

*3/ In short*: no results for full analysis; unclear how many patients withdrew; unclear what the ADRs are; survival benefits are non-signficant as per press-release; study also looked at a hospitalised cohort which is mainly a post-viral cytokine storm period; the drug is given IV so unlikely to make it to primary-care which is where patient’s with highest viral loads present.

*SOUTH KOREA – PCR can be falsely positive in recovered patients up to 2 months later as the half-life of respiratory epithelial cells is 1-3 months* Press conference with Korean infectious disease experts said that the PCR detected in previously recovered patients was due to dead virus fragments were the likely cause of over 260 people here testing positive again. One interesting fact quoted was  *“The respiratory epithelial cell has a half-life of up to three months, and RNA virus in the cell can be detected with PCR testing one to two months after the elimination of the cell,”* Dr Oh Myoung-don, Lead of  the Central Clinical Committee for Emerging Disease Control work at the Seoul National University as a hospital doctor.


 

*CLINICAL REMINDER FROM Dr Daniel Griffin* Supportive therapy works; keep an eye on your patients even after they recover for venous and arterial thrombi – *think PE if they are short of breath again*; there is no evidence of a viraemia  only evidence is of mucosal shedding; mucosal shedding peaks very early on from onset and becomes very low / undetectable by the end of the first week;


 

*References*

TWiV 608: Daniel Griffin’s COVID-19 clinical report

http://www.koreaherald.com/view.php?ud=20200429000724

https://www.nih.gov/news-events/news-releases/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19

Click to access PIIS0140-6736(20)31022-9.pdf