#MSCOVID19: digital health – what will survive?

Barts-MS rose-tinted-odometer: ★★★

I am doing a webinar with Professor Tjalf Ziemssen, a good friend and colleague from Dresden, Germany, this afternoon on the digital management of MS. Interestingly, many of the changes and innovations we have put in place to manage MS during the COVID-19 pandemic will survive and actually thrive in the new NHS, simply because we are a socialist healthcare system at the point of delivery. In comparison, in Germany, the reimbursement for digital consultations are an order of magnitude lower than old-fashioned face-2-face synchronous consultations. Therefore the adoption of digital tools to manage MS will be much slower due to the lack of financial incentives.

If you are interested in hearing about the differences between the UK and Germany please register and log-in today’s webinar.  

Please note this webinar will not be a didactic lectures, but more of a casual chat; banter between colleagues. I hope to see you later.

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

#MSCOVID19: good news

Barts-MS rose-tinted-odometer: ★★★★★

The late late-breaking session at the MSVirtual2020 meeting, which covered COVID-19 has already received a lot of air-time on social media. The big-data alliance confirmed the Italian data, i.e. that people with MS (pwMS) on anti-CD20 are at higher risk of getting COVID-19 and severe COVID-19 (hospitalisation, intensive care admission and/or ventilation) compared to pwMS on dimethyl fumarate. Importantly there was no mortality signal, i.e. pwMS on anti-CD20 don’t appear to be at higher risk of dying from COVID-19 and its complications. This is very good news! 

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However, the Big-Data alliance couldn’t confirm what the Italians have shown that treatment duration on an anti-CD20 is a risk factor. A clue to the latter is the observation that the COVID-19 risk was higher with rituximab compared to ocrelizumab in the Big-Data alliances graphs. As it is likely that rituximab-treated pwMS have been on treatment longer than ocrelizumab-treated patients would support this. Ocrelizumab has only recently been licensed and hence most people on ocrelizumab are likely to have been on it for a shorter period of time compared to rituximab-treated patients. 

Is all this good news? Yes, very good news. 

It clearly shows that people on anti-CD20 therapy have the ability to mount a robust immune response and recover from coronavirus infections, despite having a reduced B-cell and antibody response. This means that innate immunity and adaptive cellular immune responses are all that is required to recover from coronavirus and other viral infections. It will be important to study how robust the T-cell memory responses are post-COVID-19 in these patients as this will have implications for studying vaccine response when vaccines arise. What this means is that even if pwMS on an anti-CD20 don’t make an antibody response to a SARS-CoV-2 vaccine they may still have protective cellular immunity. This will also be good news. I sincerely hope Roche-Genentech and Novartis are planning to study vaccine responses in ocrelizumab- and ofatumumab-treated patients when the vaccines arrive. 

The observation that the longer you have been on an anti-CD20 the greater your chances of getting COVID-19 and severe COVID-19 implies the risk may be related to hypogammaglobulinaemia and blunting of past cross-reactive immunity from being exposed to other circulating community-acquired coronaviruses. I illustrate this in the following slide. In short pwMS on anti-CD20 therapy are shifted to the right and are less likely to have asymptomatic infections and more likely to have severe infections. 

This cross-reactive immunity to other coronaviruses may be the silver lining to the ominous grey clouds that have been hanging over us for months. It seems that between 40-60% of people in the general population have T-cell responses to SARS-CoV-2 without a history of having had COVID-19 and without an anti-SARS-CoV-2 antibody response. It now seems that these cellular memory responses protect these individuals from getting COVID-19. If this proves to be the case then herd immunity might be much higher than we realise and this could explain why the second surge in places like London and New York are much lower than other places that had smaller peaks during the initial wave of COVID0-19. 

If this background cross-reactive coronavirus immunity hypothesis, backed by the observations we see in pwMS on anti-CD20 therapy, turns out to be true we may have already reached herd immunity in London and are not far off it in other areas of the country. New models by Gomes and colleagues, at the University of Strathclyde, and Lourenco and colleagues, at the University of Oxford, suggest herd immunity may occur at levels of exposure of 20% or lower. If this is the case then we will see it first in London. So please watch the London COVID-19 numbers if they stay low this will be very good news. 

Gomes et al. Individual variation in susceptibility or exposure to SARS-CoV-2 lowers the herd immunity threshold. MedRxIV doi: https://doi.org/10.1101/2020.04.27.20081893

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads, the susceptible subpopulation is depleted causing the incidence of new cases to decline. Variation in individual susceptibility or exposure to infection exacerbates this effect. Individuals that are more susceptible or more exposed tend to be infected earlier, depleting the susceptible subpopulation of those who are at higher risk of infection. This selective depletion of susceptibles intensifies the deceleration in incidence. Eventually, susceptible numbers become low enough to prevent epidemic growth or, in other words, the herd immunity threshold (HIT) is reached. Although estimates vary, simple calculations suggest that herd immunity to SARS-CoV-2 requires 60-70% of the population to be immune. By fitting epidemiological models that allow for heterogeneity to SARS-CoV-2 outbreaks across the globe, we show that variation in susceptibility or exposure to infection reduces these estimates. Accurate measurements of heterogeneity are therefore of paramount importance in controlling the COVID-19 pandemic.

Lourenco et al. The impact of host resistance on cumulative mortality and the threshold of herd immunity for SARS-CoV-2. MedRxIV doi: https://doi.org/10.1101/2020.07.15.20154294

It is widely believed that the herd immunity threshold (HIT) required to prevent a resurgence of SARS-CoV-2 is in excess of 50% for any epidemiological setting. Here, we demonstrate that HIT may be greatly reduced if a fraction of the population is unable to transmit the virus due to innate resistance or cross-protection from exposure to seasonal coronaviruses. The drop in HIT is proportional to the fraction of the population resistant only when that fraction is effectively segregated from the general population; however, when mixing is random, the drop in HIT is more precipitous. Significant reductions in expected mortality can also be observed in settings where a fraction of the population is resistant to infection. These results help to explain the large degree of regional variation observed in seroprevalence and cumulative deaths and suggest that sufficient herd-immunity may already be in place to substantially mitigate a potential second wave.

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

#MSCOVID19: Interferon-beta and NABs

Barts-MS rose-tinted-odometer: ★

It is always nice to see evidence supporting a hypothesis you had more than a decade ago see daylight. 

If you are on interferon-beta or have been on interferon-beta in the past this post is important to you. It is clear type 1 interferons, such as interferon-beta and alpha, are important antiviral cytokines and are critical in the body’s fight against coronaviruses. There are two papers in Science that show that people with errors in the interferon pathway or neutralizing anti-interferon antibodies are at high and serious risk of severe COVID-19. The reason for this is that their immune system can’t mount an appropriate antiviral response.  

Why is this important to pwMS? The problem is that people on interferon-beta may generate anti-drug antibodies (ADAs)  to interferon-beta that can inhibit its antiviral activity. The rate of anti-interferon-beta neutralizing antibody (NABs) production depends on the preparation of interferon-beta you are on or have been on in the past. The NAB rates vary from about 2% to 35% and higher. The reason for this is based on whether or not the interferon-beta aggregates in the vial and whether or not there are other impurities in the particular formulation that may make the interferon-beta more immunogenic (more likely to stimulate the immune system to make NABs). 

Please note even if you have been treated with interferon-beta many years ago you may still have NABs. NABs may persist for many years and these will continue to inhibit your own interferon-beta’s activity. 

We reported a single case, our index case (see below), who developed recurrent severe genital herpes that coincided with her developing NABs. The herpes was such a problem that this patient is now on continuous antiviral prophylaxis and has been so for about 8 years. Any attempt to stop the antiviral is followed by rapid recurrent herpetic lesions. 

Based on this I suspect that pwMS who have NABs to interferon-beta may be at increased risk of getting severe COVID-19. I would urge anyone with a cohort of such patients to screen them for NABs and test this hypothesis. 

It is now clear that overall pwMS on interferon-beta are at lower risk of COVID-19 and severe COVID-19 presumably because the antiviral effects of interferon are protecting them against the virus. Therefore being on interferon-beta may be a double-edged sword depending on whether or not you have NABs.

If you don’t know your NAB status ask your HCP for a test. 

Would knowing that someone with MS was NAB-positive change practice? Yes, based on the science you would recommend increased vigilance and possibly self-isolation if the background risk of coronavirus infection is high. 

Fine et al. Do neutralising antibodies against exogenous interferon-beta inhibit endogenous signalling pathways? Mult Scler Relat Disord 2015 Jan;4(1):88-91.

Introduction: Interferon-beta (IFNβ) is currently the most used disease-modifying treatment for relapsing-remitting multiple sclerosis (RRMS), but it can lead to the production of neutralising antibodies (NABs) against IFNβ.

Clinical case: A lady with a past history of genital herpes was diagnosed with RRMS, started IFNβ treatment with a good initial response. Three years later her treatment was interrupted to become pregnant. After delivery she restarted IFNβ; she had more reactivations of genital herpes and experienced intermittent sensory symptoms often coinciding with herpes reactivation. High NABs titres against IFNβ were found. Since the introduction of famciclovir as prophylactic antiviral therapy and a switch from IFNβ to glatiramer acetate, herpes reactivations ceased and she had no further MS relapses.

Conclusion: Exacerbations of genital herpes coinciding with MS relapses suggest a potential link between the development of NABs and inhibition of anti-viral action of endogenous IFNβ. This case highlights that NABs not only decreases exogenous IFNβ treatment efficacy but may also interfere with anti-viral properties of endogenous IFNβ. Investigating patients who are treated with biological medication will allow us to better understand the biology and signalling pathways in humans.

Bastard et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science  24 Sep 2020: eabd4585 DOI: 10.1126/science.abd4585

Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Zhang et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science  24 Sep 2020: eabd4570 DOI: 10.1126/science.abd4570.

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

Beyond NEDA: protecting the end-organ or your brain

Barts-MS rose-tinted-odometer: zero-★’s 

It became clear to me at least 6 years ago that we need to go beyond NEDA (no evident disease activity) when treating MS and we have to focus on protecting the end-organ, i.e. normalising the brain volume loss that occurs in people with MS (pwMS). To do this you really need to diagnose and treat MS as effectively as possible early on. From a research perspective, this means a focus on smouldering MS and the mechanisms responsible for the smouldering disease or the ‘real MS’.

This study below is another study showing a link between brain atrophy and cognitive impairment and supports the therapeutic strategy above. The criticism that is alway levelled at the flipping-the-pyramid argument is that too many pwMS will end up on high-efficacy DMTs and then what? My response to this is that if the majority of pwMS end-up on high-efficacy DMTs eventually is a testament to fact that the majority of pwMS need high-efficacy DMTs and hence it is best to get them there as soon as possible (#TreatMSASAP). 

This #TreatMSASAP principle underpins our #AttackMS trial design of using natalizumab ASAP after presentation and is aping the management of stroke. 

Another argument about flipping the pyramid is safety, i.e. we are putting pwMS at risk of severe adverse events. Yes, we are, but we can derisk a lot of the anticipated adverse events, i.e. the known-knowns and the unknown-knowns (anticipated AEs based on the mode-of-action of DMTs). In any event it is not for the neurologist or HCP to make the call on risk; surely it is up to the person with the disease to make the call? 

The following is a recording of my presentation from ACTRIMS-ECTRIMS 2020 that discusses these issues. Please note the presentation is targeting HCPs, but most pwMS should understand it. 

Golan et al. The association between MRI brain volumes and computerized cognitive scores of people with multiple sclerosis. Brain Cogn 2020 Sep 11;145:105614. doi: 10.1016/j.bandc.2020.105614. Online ahead of print.

Background: Computerized cognitive assessment facilitates the incorporation of multi-domain cognitive monitoring into routine clinical care. The predictive validity of computerized cognitive assessment among people with multiple sclerosis (PwMS) has scarcely been investigated.

Objective: To explore the associations between brain volumes and cognitive scores from a computerized cognitive assessment battery (CAB, NeuroTrax) among PwMS.

Methods: PwMS were evaluated with the CAB and underwent brain MRI within 40 days. Cognitive assessment yielded age- and education-adjusted scores in 9 cognitive domains: memory, executive function, attention, information processing speed, visual-spatial, verbal function, motor skills, problem solving, and working memory. The global cognitive score (GCS) is the average of all domain scores. MRI brain and lesion volumes were assessed with icobrain ms, a fully automated tissue and lesion segmentation and quantification software.

Results: 91 PwMS were included [Age: 52.1 ± 11.7 years, 64 (70%) female, EDSS: 3.4 ± 2.0, 79 (87%) with a relapsing-remitting course]. Significant correlations were found between the GCS and whole brain, white matter, grey matter, thalamic, lateral ventricles, hippocampal and lesion volumes (Correlation coefficients: 0.46, 0.40, 0.25, 0.42, -0.36, 0.21, -0.3, respectively). Regression analysis revealed that lateral ventricles and thalamic volumes were the most consistent predictors of all cognitive domain scores.

Conclusion: Computerized cognitive scores were significantly associated with quantified MRI. These findings support the predictive validity of multi-domain computerized cognitive assessment for people with multiple sclerosis.

CoI: multiple Twitter: @gavinGiovannoni  Medium: @gavin_24211

#MSCOVID19 running the talk

Barts-MS rose-tinted-odometer: ★★★★★

In anticipation of a second-lockdown at a meeting with colleagues last night I was asked the question about what positive experiences I could reflect on from the first lockdown. Firstly, no international travel and a focus on family, home life and the realisation that we can live more sustainably. Secondly, walking or running the talk. I decided to take my own prehabilitation advice seriously and I have managed to rehabilitate my physical and mental self and get my right hip working again. This is quite remarkable. Three years ago I had written off any future prospect of running long distance never mind a marathon. Six months into the pandemic and I am getting ready to try and complete a marathon in a months time.  Why? Funding and important time-sensitive research for people with multiple sclerosis. 

We have a problem with the current antibody tests for detecting past infection with coronavirus. The current assays are not sensitive enough and are not detecting antibodies in a large number of people with asymptomatic or mild infection and possibly in pwMS who are on certain immunosuppressive disease-modifying therapies, in particular the anti-CD20 treatments rituximab, ocrelizumab and ofatumumab. Detecting antibodies in these people is really important in that it would indicate that they have been exposed to the virus and therefore likely to have cellular immunity. 

In response to this challenge and  thanks to a grant from the Barts Charity, our group (Dr Kang and his team) have developed an ultrasensitive assay (GloBody) that will work on blood spots. Preliminary results show  that the assay is detecting antibodies in samples that have been called negative with commercial antibody assays. This is not unexpected because the assay was designed to have amplification steps to detect very low levels of antibodies. We did this because we want to study low-level antibody responses in pwMS on and off different DMTs.

This assay will now allow us to test a large number of pwMS using self-collected blood spots to see if they have been infected with coronavirus and are now immune. The tragedy is we have been promised a grant to do the initial part of this study by a charity. However, as donations have dried up this charity can’t afford to give us the money to cover the initial costs of the study. This is when I took up your suggestion to crowdfund. To show how serious I am about the crowdfunding I have decided to run the virtual New York City Marathon. All I have to do is record a single 42.2km run using the GPS-tracking application STRAVA sometime between the 18th October and 1st November. 

one run at a time.

In reality, I started my training very late and don’t really have the time to get truly marathon ready. However, as it is so important for us to raise the money so we can get this critical time-sensitive research done I am going to give it a go anyway. 

I would like to thank those of you who have already sponsored me. I would also like to urge you to donate to our cause. Even a small donation or £2-£5 would help. Microdonations all add-up. 

Thank you. 

CoI: multiple

Twitter: @gavinGiovannoni 

Medium: @gavin_24211

#MSCOVID19: the new lepers?

Barts-MS rose-tinted-odometer: ★★★

Early this week my wife came down with a cold. Did she have coronavirus was the immediate question? She asked me for advice and I said she had better get herself swabbed and in the interim we should isolate ourselves. All she had was a mild headache (sinus-type), runny nose, sneezing and a sore throat. She did not have a temperature and only developed a mild cough after a few days. Her nasopharyngeal swab for coronavirus done via the post took almost 72 hours to come back and was fortunately negative. 

Interestingly despite a blocked and runny nose, she did not develop loss of smell or her taste; I tested it with coffee, chocolate and some fine white wine. Although loss-of-taste (ageusia) and smell (anosmia) occur in about 40-60% of subjects with COVID-19 it is really not specific enough to exclude coronavirus infection so don’t rely on it. In addition, it may not occur until several days into the infection, prior to which you could be highly infectious and spreading the virus.

Fortunately, my wife is now much better. I suspect she had rhinovirus infection, a common cause of rhinitis or the ‘common cold’, which is now circulating as it normally does this time of year.

In response to the emerging rhinovirus problem, the BBC and most of the newspapers have run articles or special features to highlight the differences between COVID-19, influenzae and the common cold. If you look at this list of symptoms below it is simply not possible to differentiate mild infections from each virus apart. Surely, it is not about diagnosing which infection you have but making sure you don’t act as a source of coronavirus and spread the infection. 

Therefore everyone with symptoms suggestive of an upper respiratory tract infection, including the common cold, should really consider themselves infected with coronavirus until proved otherwise. This means they need to get themselves swabbed and tested. Therein lies the problem. The UK at the moment does not have enough testing capacity outside of the NHS Trust’s to deal with this emerging problem. Hence anyone with a cold will probably have to self-isolate including their immediate contacts.  

The other thing is the new ‘COVID-19 leper syndrome’. Even if you go outdoors or travel, for example, to work, with a blocked nose and cold-like symptoms people will treat you like a leper and run a mile. This has been happening already before the rhinovirus problem; if anyone sneezes or coughs on the underground they immediately attract dirty looks and space clears around them as if they are radioactive. 

Things are only going to get worse the further we move into Autumn and Winter. In addition, young children are back in school and they are hothouses for acquiring and spreading viruses. The perfect storm is having two highly infectious viruses, which cause overlapping symptoms, circulating at the same time when we are trying to get society moving again. I can only imagine the chaos this going to cause in schools, universities and the workplace. The only solution is for the government to massively increase testing capacity ideally with the emerging point-of-care diagnostics, which can provide an answer within 60-90 minutes whether or not you have COVID-19. 

It is clear to me that an effective coronavirus vaccine can’t come soon enough. 

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19: European COVID-19 Cup Quarterfinals

There has been a lot of debate about which country has had the best strategy at dealing with their coronavirus epidemic. It is clear based on the epidemiology of pandemics that countries needed to play with the mid and end game in mind. We are now quite a way into the COVID-19 pandemic and have reached the quarterfinals stage. Which countries do you think are going to win the quarterfinals and get to the next round?

Quarter Final 1: Sweden vs. Denmark

Quarter Final 2: United Kingdom vs. Germany

Quarter Final 3: Italy vs. Spain

Quater Final 4: France vs. Switzerland

If you need some help in understanding the epidemiology of pandemic you can refer to my infographic below.

CoI: multiple

#MSCOVID19: round 2

Barts-MS rose-tinted-odometer: ★

Every now again it is worth covering a topic that is important for people living with MS (pwMS) a second time. Today’s topic is COVID-19 prehabilitation.

Today when I got on the  London Underground to come to work the carriages were ~75% full, i.e. very few empty seats and not much standing room. In other words, adequate social distancing was not possible. This was at 7.05 am, which means it will only be getting worse as we head to peak time. In an attempt to get the economy back on its feet and society working the government is encouraging people back to work, which is why we are seeing a second surge in COVID-19. The difference this time is the demographic is different. The average age of those with COVID-19 is younger and hence fewer people are needing hospitalisation and intensive care admission. However, this is likely to change as more and more people come down with COVID-19 in the next wave of infections. 

I sincerely hope that you are doing everything you can do to prepare for when you get COVID-19?

In the event of you getting severe COVID-19, there are a lot of things you can do to maximise your chances of surviving the infection and its immune complications. Prehabilitation is the term I have used to describe this programme. 

The following is a list of things I recommend you do:

  1. Smoker? If you are a smoker stop smoking. 
  2. If you have comorbidities make sure their management is optimised.
  3. Hypertension? Check your blood pressure yourself. If it is high see your GP. If you have established hypertension make sure your medications have been adjusted to render you normotensive.
  4. Diabetic? Make sure you adhere to your diabetic medication and be extra-vigilant with your glucose monitoring. You may need to check in with your diabetic nurse or diabetologist for advice if your blood glucose levels are all over the place. 
  5. Obese? Maybe it is time to get back on that diet and lose some weight? I would recommend looking into intermittent fasting and avoiding processed and ultra-processed foods. There are no magic diets. You need to find one that is suitable for your lifestyle, culture and metabolism. 
  6. Alcohol misuse? If you drink more than the national guidelines try and cut back on your excessive drinking? If you have a drinking problem and need help please speak to your GP. 
  7. Asthmatic? How is your asthma control? If you have bronchospasm you may need to get your meds/inhalers changed. You don’t want to have poorly controlled asthma when you get COVID-19. 
  8. Sleep-deprived or sleep disorders? It is important you optimise the amount of sleep you are getting. Sleep deprivation is associated with multiple poor health outcomes. PwMS are more likely than the general population to have a sleep disorder. If you use sedatives to sleep you may want to try and wean these as they can affect respiratory function if and when you get COVID-19.
  9. Exercise? There is no doubt that being deconditioned or unfit is a risk factor for a poor outcome from many serious diseases. If you are unfit this would be an opportune time to start exercising with the aim of increasing your fitness. For those of you who are mobile, I have suggested the couch-to-5 programme in the past. If you are not mobile there are upper body exercises that you can do. Ideally, an exercise programme should be personalised with a physiotherapist, but if this is not possible there are pragmatic ways of getting going on your own.
  10. Breathing exercises: A lot of clinicians are instructing the general population to start doing deep breathing exercises to increase the ventilation of the little-used parts of the lung. This can be done before or more importantly after you develop COVID-19. 
  11. Mental health: Anxiety and depression are stressors in themselves and will affect how your body responds to infection. It is important that if you are anxious and/or depressed you get this treated. Exercise, mindfulness (meditation) and cognitive behavioural therapy have all been shown to reduce anxiety and improve depression. These are things you can do yourself. I am aware that it may be hard to address depression and anxiety during the lockdown, but there are things you can do to help yourself; but, if you think you need help can please reach out to your general practitioner and/or MS team.
  12. Pulse oximeter: if you live alone and get COVID-19 I would recommend having access to a pulse oximeter to monitor the oxygen levels in your blood in the case you get COVID-19 pneumonia and are asked to stay at home. It is clear that many people with COVID-19 drop their blood oxygen levels without being aware of it.
  13. Advanced directives / Living wills: It is important to prepare for things in advance. If you did get severe COVID-19 and needed to go to ITU, possibly be ventilated and receive advanced life support. Is that what you would want? If it is not, make sure this is documented formally with your general practitioner and is included in your medical records. Also, let your family know what your wishes are. It may be a good time to update your will and instructions for your family in the event of you getting severe COVID-19 and passing away. You may want to prepare a folder summarising your medical condition, including your advanced directive, with all the necessary contact details of your next of kin. If you do get COVID-19 and are admitted to the hospital. Also, make a list of things you will need to take to hospital in the event of you getting COVID-19; please don’t forget your mobile charger. Please remember visitors are not allowed for COVID-19 patients so having a functioning mobile phone is an important way of keeping in contact with your family and friends.

CoI: multiple

Twitter: @gavinGiovannoni 

Medium: @gavin_24211

My position on anti-CD20 therapies has been criticised, why?

Barts-MS rose-tinted-odometer: ★★★★★

I have recently been criticised by a colleague for supporting the DODO (double-dose ocrelizumab study) and the ADIOS (adaptive dosing ocrelizumab study) studies. How you can I on the one hand support more ocrelizumab and on the other hand suggest reducing the dose in the longterm. I responded that it is all about timing and how you use anti–CD20 therapies.

You need higher doses of anti-CD20 therapy initially as an induction strategy to purge the various B-cell compartments of memory B-cells, which I hypothesise house latent EBV and the highly autoreactive population of B-cells that drive and maintain the MS-state. This population of cells may reside in the deep tissues and/or the central nervous system, which is why we are also testing CNS penetrant anti-B-cell strategies, simultaneously. 

However, once you have purged these compartments say after 2 years of treatment you don’t need to maintain such high-doses of anti-CD20 therapies that are then suppressing normal B-cell biology and immune responses, which result in longterm complications. This is why we want to test using ocrelizumab as an immune reconstitution therapy, i.e. high-dose upfront followed by no treatment and wait to see if MS remains in remission or disease-activity returns requiring additional courses. The latter is one of the arms of our proposed ADIOS study. 

In reality, if I could convince a national funding agency, a pharma company or wealthy philanthropist I would use anti-CD20 therapy as part of an induction-maintenance protocol. After two years of induction therapy with high-dose ocrelizumab, I would test different maintenance strategies in parallel. My agents of choice would be teriflunomide, leflunomide, IMU-838 or vidofludimus (selective second-generation DHODH inhibitor,) HAART (highly-active antiretrovirals), famciclovir or another anti-EBV viral agent. The hypothesis is to allow B-cell reconstitution after anti-CD20 therapy in the presence of ant-viral agent to prevent EBV reactivation and reinfection of new memory B cells. By doing this you will be derisking the long-term immunosuppression associated with anti-CD20 therapies and you should prevent the development of hypogammaglobulinaemia. 

The problem with this trial proposal is the outcome measure; the power calculations are not trivial and the study would have to be very long. I also have reservations about whether or not the regulators will accept the induction maintenance strategy. Maybe we can sell it to them on safety, i.e. to prevent the development of hypogammaglobulinaemia and infections rather than on efficacy? If we go this route then there is only one agent we can use and that is teriflunomide, which is licensed to treat MS. As teriflunomide is coming off patent there is a chance the  NHS may be interesting in funding such a trial; i.e. it would save them money. This is something I need to explore (another task for my expanding ToDo list). 

The good news is that Roche has bought into, and run, with the principle of the DODO study and announced at MSVirtual2020 two high-dose ocrelizumab trials (see below). These trials up the stakes in the anti-CD20 wars and I am confident that we need higher doses upfront to purge deep tissue and possibly CNS pools of B-cells. Please note that you don’t need higher doses of anti-CD20 therapy to suppress relapses and focal MRI activity you can do that with current or lower doses. I am confident both these studies will show that higher-dose ocrelizumab is superior to standard dose ocrelizumab on disability progression or smouldering MS, but not on focal inflammatory events. In relation to the latter, we have hit the ceiling already.

You need higher doses up-front to target the drivers of smouldering MS; i.e. disease progression independent of relapses, accelerated brain volume loss, slowly expanding lesions (SELs) and the subpial cortical lesions.  If these higher-dose studies are positive it will put clear daylight between ocrelizumab and the other anti-CD20 therapies and it would mean the ofatumumab and rituximab are currently being underdosed, at least initially in the first two years. 

CoI: multiple

Twitter: @gavinGiovannoni 

Medium: @gavin_24211

#MSCOVID19: has coronavirus cancelled the flu season?

Barts-MS rose-tinted-odometer: ★★★★★

I think COVID-19 has just cancelled the flu season. 

I and many public health officials were very concerned that we were heading for a double-whammy this winter with a second and third surge of COVID-19 and a bad influenzae pandemic superimposed on it. It is looking like this may not happen. In the Southern hemisphere,  including my country South Africa, it seems as if the flu season was cancelled. Incredibly the number of documented annual cases has dropped by over 99% (see table below). 

Country201820192020
Argentina1517462353
Chile2439500712
Australia925993333
South Africa71110946
Documented cases April through mid-August. Source Science 28-Aug-2020

It is clear that the behavioural changes we have put in place, such as social distancing and wearing of masks, has prevented the spread of influenzae virus. Will these behaviours become the new norm during future flu seasons? I am not sure if people realise that influenzae is one of the biggest infectious disease killers each year so preventing the spread of the virus via behavioural change makes sense. 

Saying this the UK Government has just ordered many more doses of influenzae vaccines than it normally does and is extending the so-called at-risk adult group who can get the vaccine free on the NHS this year. 

Does this change our recommendations regarding getting the annual flu-jab? No, it doesn’t. All pwMS should take up the offer by the NHS to get the annual flu vaccine.

Please note, if you are severely immunosuppressed and have small children, please make sure they don’t get the live intranasal flu vaccine at school. There is a risk that this attenuated vaccine strain, which they may bring home, will cause disease in severely immunocompromised subjects. If you want your children to be vaccinated against influenza they will need to be given the component vaccine by injection. The latter is done via GP practices and some pharmacists. Please note it is only patients recently treated with alemtuzumab and HSCT that fall into this category.

I suspect that after reading the post on complications in the Oxford-AstraZeneca coronavirus vaccine study many of you are nervous about vaccinations in general. Please don’t be. The regulatory authorities assess the efficacy and safety of all vaccines and make an informed decision that at a population level the risks justify the benefits. Influenzae vaccination is the most studied vaccine in pwMS and it has been shown to be safe, i.e. it does not appear to trigger relapses and/or MRI activity. 

CoI: multiple

Twitter: @gavinGiovannoni 

Medium: @gavin_24211