COVID19 – Page 5 – Prof G's MS Blog Archive

#MSCOVID19 ocrelizumab

Roche is the first company to publish their data on how patients with MS are doing with COVID-19 who are being treated with ocrelizumab. Please note the data is on the first 100 cases that have been reported to Roche via their adverse event (AE) reporting mechanisms. Twenty-six of the cases have been reported as being severe with 5 being critical (see table below). These figures are pretty much in line with what happens in the general population in relation to COVID-19 outcomes with a similar proportion of severe and critical cases. The one caveat is that ocrelizumab-treated patients may be younger and have fewer comorbidities than the general population.

Some of my colleagues have accused Roche of hiding data and selective reporting. Why would they do that? Pharma’s pharmacovigilance systems are transparent and open to audit by the regulators. It is not in Roche’s interests to not be open and frank about their data. At the end of the day, the data is what it is and we need to use it to help us make decisions about treatment.

I agree the data is full of warts and open to interpretation. It is likely to be biased in that clinicians are more likely to report hospitalised and severe cases as AEs and miss the milder cases. For example, I have collected 9 patients who have likely had COVID-19 over the last 8-10 weeks. Only one of these nine patients was admitted to a hospital with moderate COVID-19. In this case, the COVID-19 syndrome was confirmed on chest x-ray and other clinical features and her nasopharyngeal swab was positive for SARS-CoV-2. She was fortunately discharged after 4 days well and didn’t need any ventilatory support. The other 8 patients with MS all self-isolated and recovered at home and had no swabs taken. Only the admitted patient is part of the UK’s official figures the other 8 cases are not. Patients with COVID-19 who have mild disease, who don’t come to the hospital to get swabbed don’t get counted in the official figures. The same phenomenon is almost certainly happening with ocrelizumab and our other DMTs. Mild cases are not getting swabbed, diagnosed and reported. I, therefore, suspect that the Roche data represents the worse end of the spectrum.

Overall the Roche data is in keeping with the Italian, French and other registry data that people with MS on ocrelizumab don’t appear to be at higher risk of getting severe COVID-19. This also needs to be interpreted in the context of the immunology of COVID-19 and SARS-CoV-2. It looks as if innate immunity (monocytes and macrophages) and T-cells, in particular CD8+ T-cells, are the most important lines of defence against SARS-CoV-2. The fact that two patients with X-linked agammaglobulinaemia recovered from COVID-19 and that anti-CD20 treated patients with no B-cells in the peripheral blood are recovering from COVID-19 tells you that B-cells are not essential for the antiviral response. The latter is also in keeping with the trial data that patients on B-cell depleting therapies don’t seem to have a problem dealing with viral infections.

Could there be an upside to B-cell depletion? Yes, I suspect there may be. As the humoral or antibody response emerges antibody-mediated damage to lung with complement activation may be responsible for some of the delayed tissue damage that occurs in COVID-19. This is why it will be important to get more data and better-defined comparator groups to see if anti-CD20 therapy treated patients may be doing better than expected. The recently presented Swedish data suggests not. However, the Swedish data is on rituximab, and not ocrelizumab, and the rituximab doses used in Sweden may not be high enough to block antibody responses to SARS-CoV-2 and hence the data can’t simply be extrapolated to ocrelizumab or vice versa. For those of you who don’t know ocrelizumab is a much more potent B-cell depleter than rituximab.

Now, what about vaccine readiness? Are people on ocrelizumab less likely to develop an antibody response after COVID-19 and if they do is the antibody response good quality, i.e. capable of neutralizing the virus and preventing reinfection? We are in the process of validating an ultrasensitive assay and doing an antibody study to answer this question. So watch this space.

Even if antibody responses to SARS-CoV-2 are blunted in ocrelizumabers, who have had COVID-19, this doesn’t mean they are not immune to reinfection. Cellular responses are likely to be sufficient to prevent reinfection. The latter has been shown to occur with the measles virus.

Vaccine readiness may become a real issue if a vaccine for SARS-CoV-2 emerges. However, I suggest crossing that bridge when we get there. With anti-CD20 therapies, all you will have to do is miss a dose or two, wait for naive B-cell reconstitution and then have the vaccine. We have very good data that after 3 or 4 courses of ocrelizumab missing infusions for the next 12-18 months is unlikely to affect MS disease activity. The latter observation is why we are still planning to do an adaptive-dosing study in the UK (ADIOS Study).

I personally want to congratulate and thank Roche for putting their data into the public domain so rapidly. I have asked other Pharmaceutical companies to do the same. Having access to this data alongside other real-life data sets is what we and others are using to adjust treatment guidelines and is why we as an MS treatment centre are starting and redosing patients with MS with ocrelizumab. At last, we can say our practice is evidence-based rather than opinion-based.

Hughes et al. COVID-19 in persons with multiple sclerosis treated with ocrelizumab – a pharmacovigilance case series. MSARDs Available online 16 May 2020, 102192.

CoI: Multiple. Importantly I am a steering committee member on the ocrelizumab phase 3 development programme and I am PI on the ORATORIO-HAND study of ocrelizumab in PPMS.

#MSCOVID19 super-superspreader

A single man triggered a massive contact tracing exercise in Seoul, South Korea, after visiting 5 nightclubs in a Seoul neighbourhood on a weekend and later tested positive for COVID-19.

Not only does this case highlight the scope of the response which can be triggered by one infected individual but the willingness of Korean authorities to use mobile phone data, credit card data and CCTV footage to track down individuals who could have come into contact with the virus.

I wonder how citizens of other countries would feel about this? This is real big brother stuff.

Do you think the UK Government is up to the task of whack-a-mole to this degree?

The Korean Centers for Disease Control and Prevention said that as of 13th May, 119 new infections have been traced back to the 29-year-old and that 5,517 fellow clubgoers have been contacted in the process. This has led to 7,272 additional tests being administered on Tuesday (on top of the baseline of 4,000 to 5,000 tests carried out daily in the country) to patrons and their families/immediate contacts. Authorities said they had identified a total of more than 11,000 people who had been in the general area on the night in question.

Out of the 5,517 people who authorities are seeking contact with, 1,982 have so far not replied, showing that even a sophisticated method is not perfect. Since the bars and clubs in question catered to gay audiences, Korea’s traditional stance on sexual identity could be hampering peoples’ will to come forward.

This case also redefines how infectious a superspreader can be. May be he should referred to as a super-superspreader?

#MSCOVID19 De-deployed

This is a very good news post and worth a quiet celebration.

As you can see from the study and figure below that Barts Health NHS Trust, where we work, was at the epicentre, of the epicentre of the UK’s COVID-19 pandemic. London has had the most COVID-19 cases in the UK and it looks as if the majority of cases where managed in our four COVID active hospitals. This graph shows just is how effective the London lockdown has been in flattening the peak of the epidemic.

The bars show you the proportion of asymptomatic HCPs (healthcare professionals) who tested positive for SARS-CoV-2 on consecutive weeks from March 23, 2020:

28 of 396 HCPs (7.1%) in week 1
14 of 284 HCPs (4.9%) in week 2
4 of 263 HCPs (1.5%) in week 3
4 of 267 HCPs (1.5%) in week 4
3 of 269 HCPs (1.1%) in week 5

Importantly of the 44 HCPs who tested positive for SARS-CoV-2, 12 (27%) had no symptoms in the week before or after positivity. Although I was not one of the HCPs in this survey there is a chance that I have been exposed to SARS-CoV-2, which is why I am volunteering to get myself tested next week to see if I have antibodies to the virus. Knowing I have been infected or not will clearly affect my behaviour. This is why it is so important for widespread antibody testing to happen ASAP.

If you generalise these results to the wider HCP population, then so-called asymptomatic SARS-CoV-2 infection rates among HCWs tracked the general population infection curve in London. This suggests that the rate of asymptomatic infection among HCPs more likely reflects general community transmission rather than in-hospital exposure.

So if you are one of our, Barts-MS, patients these results should be very reassuring and as the overall epidemic wanes asymptomatic infection among us, your MS team is likely to be low and we are unlikely to be a major source of virus transmission. This means you need not fear us when we resume face-2-face consultations.

The other good news is that we now have so few new COVID-19 admissions at the Royal London Hospital that we have started closing down some of the extra medical wards that were created to deal with the surge. This means my services as a make-shift general physician are not required anymore and I have been de-deployed back to being a neurologist and MSologist. I hope this means that we will be able to resume our MS services, albeit with adaptations to make sure social distancing is maintained, very soon.

Treibel et al. COVID-19: PCR Screening of Asymptomatic Health-Care Workers at London Hospital. Lancet. 2020 May 8;S0140-6736(20)31100-4.

CoI: I work at the Royal London Hospital, which is one of five hospitals of Barts Health NHS Trust.

#MSCOVID19 Endemic musings

Fudging the issues or bumbling along is how the public, opposition politicians and the journalists are interpreting the Government’s handling of the exit strategy for the COVID-19 epidemic in the UK. I don’t agree. I think the Government has a clear plan, which is being driven primarily by economic considerations.

The primary objective of the lockdown was to protect the NHS and this has been successful. Well done! The primary objective of handling the epidemic’s tail is to get the country back to work and to try and turn COVID-19 into an endemic disease.

For those of you who are not epidemiologists, an epidemic is the rapid spread of disease to a large number of people in a given population within a short period of time compared to endemic infection when that infection is maintained at a constant baseline level in the population.

Making COVID-19 endemic is like walking on a tightrope. By allowing very young children back to school first who are unable to self-isolate effectively is asking them to spread the infection amongst themselves, their siblings and their parents who will all be relatively young and at low risk of severe COVID-19. This will allow the gradual spread of infection to continue in the community and the gradual build-up of herd immunity. Most people I speak to don’t seem to understand this.

At the same time, the more vulnerable groups in the population have been asked to continue shielding and to be extra cautious about avoiding getting infected with SARS-CoV to reduce the risk of a second surge in the epidemic, protect the NHS and to keep the death rate relatively low.

The Government is also putting in place the whack-a-mole strategy of active case finding and contact tracing to try and control local COVID flares. The whack-a-mole strategy is working well in China, South Korea and Singapore and it will almost certainly work well here if it is properly resourced.

The introduction of widespread antibody testing, with a reliable assay, to see who has been infected with SARS-CoV-2 will allow epidemiologists to track herd immunity and to finesse the Government’s strategy. The idea of getting a COVID-19 passport to show that you have been previously infected and are now immune to getting further infections, at least in the short-term, is unlikely to happen within the UK but may be required for safe international travel or to attend outpatient clinics or be admitted to cold (COVID-negative) hospitals for invasive procedures, etc. The latter is analogous to what happens with multi-drug resistant staphylococcus in clean surgical units in the NHS. Before you are allowed to be admitted for elective surgery you have a nasal swab taken to make sure you are not carrying the multi-drug resistant bacterium.

If the Government can allow herd immunity to gradually increase and to keep the R-value for the whole population at about 0.8 to 1.0 they will achieve their aims of making COVID-19 endemic, getting the economy going again and protecting the vulnerable. Clearly, this strategy will be a bit hit-and-miss and there will be collateral damage, i.e. people will continue to get severe COVID-19 and a proportion of them will die as a result. To expect anything else is unrealistic, which is why I find the posturing of the opposition politicians bewildering, to say the least. What is their solution; perpetual lockdown until we get a vaccine?

Most people think that a vaccine is the government’s end-game. I don’t want to disappoint you but there is no guarantee that a vaccine will work. I also worry that if the whole world exits lock-down with a trickle of cases we may not be able to test vaccines in an efficient manner.

To develop and test an effective vaccine we really need the COVID-19 epidemic to be in full swing, i.e. on the upside of the curve and not on the tail. A vaccine trial is like a drug trial; subjects are randomised to an active or SARS-CoV-2 vaccine arm or a comparator arm (placebo or another vaccine) and then you see whether or not there are fewer cases of COVID-19 on the active arm compared to the comparator arm. However, if there are too few cases developing COVID-19 because of social distancing, using face masks, hygiene measures, etc. it will take too long to get enough events or trial subjects getting COVID-19, to show the vaccine is working. There is a way around this and that is to shift to an active-challenge vaccine paradigm, i.e. to get groups of young volunteers who are anti-SARS-CoV-2 antibody negative and to randomise them to receive the vaccine or placebo and to then challenge them with the live virus. This is how they test the effectiveness of the seasonal flu vaccine each year. You may ask why would anybody take the risk of getting COVID-19 and severe COVID-19 voluntarily? The answer is money. These volunteers tend to be paid very handsomely for their time.

Another factor that may help the Government is that summer is on its way and as the temperature rises the less infectious coronaviruses become. SARS-CoV-2 viral particles are temperature sensitive and are viable for much shorter periods of time outside the body in hot climates. This may explain why we haven’t seen such rampant spread of the virus in warmer climates.

I think Boris Johnson’s recent bumbling performances when questioned about the Government’s exit strategy is deliberate so as to avoid questions about herd immunity, whack-a-mole and collateral damage. The sad truth is that at some point we as a society are going to have to realise that quite a large number of people are still going to have to die from COVID-19 as part of the exit strategy to get us to a point when we can chop off the tail of the UK’s COVID-19 epidemic. The consequences of not doing this are potentially far worse for the UK in the longterm. For example, some epidemiologists predict that the increase in poverty and inequality that the COVID-19 epidemic has caused will result in more excess deaths than the number of people dying from severe COVID-19. This may be hard to comprehend, but the social determinants of health have a powerful effect on health, health outcomes and survival. The challenge for the government is getting the balance right, which is what they are trying to do.

I would be interested to know if any of you have any thoughts on these issues.

CoI: none

#MSCOVID19 – a pyrrhic victory

Some of you may have read and being appalled by the following piece in this morning’s Guardian.

Robert Booth. Coronavirus: real care home death toll double official figure, study says. 13th May 2020

Excerpt: “More than 22,000 care home residents in England and Wales may have died as a direct or indirect result of Covid-19, academics have calculated – more than double the number stated as passing away from the disease in official figures.”

The hidden burden of COVID-19 goes way and beyond care homes. I was on a Zoom video conference with my UK colleagues last week and each person was asked about their centre’s COVID-19 experience. Almost everyone had had a COVID-19 related MS death. The tragedy was the deaths tended to be in older people with MS who were more disabled and with comorbidities. I am aware of two MS deaths in our patch, both bed-bound with end-stage MS. Whether or not these patients died from COVID-19 related problems is unknown. Both deaths have been ascribed to complications of MS.

Forget about the deaths what about MS disease activity? Before COVID-19 it was very unusual to have patients on established DMTs have severe relapses. Severe attacks were typically seen in patients presenting with their first attack or in patients who were non-adherent to their DMTs.

Since the lockdown, I have had three patients who have had severe relapses waiting to be initiated on treatment. One who has been furloughed and decided to be locked-down in her parents home far away from London. One waiting to start a DMT, but had delays in relation to baseline screening bloods and making a decision about treatment. As she has now had a severe and disabling brainstem or cerebellar relapse this shifts her into the high-disease activity group so she is now eligible for natalizumab. The latter could be viewed as some kind of “COVID-19 pyrrhic victory” as she now gets to be put on a high efficacy therapy. Fortunately, she is young so she should make a reasonable recovery from the relapse, but the damage has been done and some of her precious brain reserves has been shredded and lost forever.

The final patient is a bit of a procrastinator and he decided to delay starting his treatment until after the peak of the COVID-19 epidemic. If there was no COVID-19 he would have almost certainly be treated two months ago, which would have potentially prevented the relapse.

I would be interested to hear if any of you have had similar experiences, i.e. poor outcomes due to a delay in your treatment or untoward events due to your MS service being mothballed during the COVID-19 crisis.

I have little doubt that people with MS will be paying the price for COVID-19 for years to come. I suspect many will have been started on lower efficacy DMTs, some will have had their DMTs stopped or switched to lower efficacy or supposedly safer DMTs, others would have had their treatment initiation delayed and other would have had repeat dosing postponed to some yet to be determined date in the future. In addition, many people with very active MS who were lined-up to undergo HSCT have had their procedure delayed indefinitely.

I wonder what the true cost of the above will be for people with MS?

CoI: multiple

#MSCOVID19: ostrich

Do you want to know if you have been infected with SARS-CoV-2 the coronavirus strain that causes COVID-19? With 25-50% of infections being asymptomatic or very mild you will need an antibody test to find out.

If you are found to have antibodies to SARS-CoV-2 would you not want to know the titre or amount of antibody in your blood? And whether or not these antibodies are so-called neutralizing and capable of preventing reinfection with SARS-CoV-2?

Answering these questions is critical and underpins the strategy of allowing people to receive a so-called “COVID-19 passports”. The passport will state that you have immunity to the virus and hence you can rejoin the herd and get on with your life.

As an MS researcher, I am also interested to know what happens to the antibody response to SARS-CoV-2 in pwMS on different DMTs. For example, are people on rituximab and ocrelizumab less likely to develop an antibody response after COVID-19 and if they do is the antibody response good quality, i.e. capable of neutralizing the virus and preventing reinfection? What about the antibody responses in people on natalizumab? On fingolimod? Post-cladribine or post-alemtuzumab?

My predictions are that the IRTs (cladribine and alemtuzumab) and possibly natalizumab will come out on top both in term of qualitatively (neutralizing antibodies) and quantitatively (overall titre) in terms of anti-SARS-CoV-2 antibody responses. Anti-CD20s (rituximab, ocrelizumab and ofatumumab) and the S1P-modulators (fingolimod, siponimod and ozanimod) will come out on the bottom. Please note this is a hypothesis and as with all hypotheses they need to be tested in well-designed and appropriately powered studies.

Barts-MS has therefore proposed doing an antibody study of this kind, but it looks like pharma is chicken to collaborate with us. I suspect they don’t want to know the answer to the questions above. I call this the “ostrich syndrome”; you can put our head in the sand for as long as you like, but eventually, a rabid dog will come and “bite your arse”.

As the MS community gears up for ensuring their patients are “vaccine ready”, who if they are SARS-CoV-2 antibody-negative (no previous infection) will want to be on a DMT that blunts or prevents an adequate vaccine response. Why take a chance if you don’t have to particularly as there are several suitable alternative DMTs? However, if the above hypotheses are disproved then most of us will be happy with the status quo.

All these arguments above are predicated on the assumption that we will get an effective SARS-CoV-2 vaccine or vaccines. Please note there is no guarantee that this will happen. I would estimate the chances of getting an effective vaccine in the next 18-24 months as being close to 80%. Optimistic? Yes, but at the same time, I am trying to be realistic.

CoI: nil

#MSCOVID19: Lymphopaenia

I am giving an MS Academy masterclass webinar today on the topic of lymphopaenia and its relevance to managing MS during the COVID-19 pandemic. My talk goes back to basics and tries to explain how the normal range and WHO grading system came about and includes the important topic of immunosenescence.

You are welcome to sign-up for the webinar. If you can’t manage to log-on to the live webinar it will be recorded and put on-line after the event.

The following are my slides for today’s webinar:

CoI: multiple

#MSCOVID19: immunosuppression & vaccine-readiness

It is always a good idea to learn from others. We have stressed that the uneventful recovery from COVID-19 involves two processes. Firstly, an appropriate antiviral response, which is needed to clear the virus and secondly an anti-inflammatory response to prevent the delayed immunological damage to the lung that triggers ARDS (acute respiratory distress syndrome), which is the main cause of death with COVID-19. There clearly is a balancing act as if you suppress the delay immune response too much you may prevent clearing of the virus and ongoing damage from viral replication.

It is very heartening to see that patients with other immune-mediated inflammatory disorders that are on immunosuppressive therapies, predominantly biological therapies, are not at increased risk of severe COVID-19 (see Haberman et al below). This experience is mirroring our experience in MS.

However, in the transplant field where the levels of immunosuppression are an order of magnitude more intense, the message is mixed. Liver transplant recipients seem to do fine (see D’Antiga below) but in kidney transplant recipients those with the greatest T-cell depletion, particularly those who receive ATG (anti-thymocyte globulin), do the worst and have high mortality from COVID-19 (see Akalin below). The reason for the difference between liver transplant recipients and ATG-treated kidney transplant recipients are T-cells. ATG is one of the most potent T-cell depleting agents we have and rendering someone severely deficient in T-cells puts them at high risk of viral, in particular severe viral, infections. The latter does not only include exogenous (outside the body) viral infections such as SARS-CoV-2 but endogenous (inside the body) latent viruses such as CMV and EBV. The ATG treated transplant patients are likely to be succumbing to uncontrolled SARS-CoV-2 infection rather than the delayed immunological reactions or ARDS.

What this is telling us is that moderate immunosuppression, with reasonable T-cell counts and T-cell function, does not increase your risk of getting COVID-19 or severe COVID-19 and may reduce your risks of the latter. However, as soon as you drop your T-cell counts and profoundly suppress T-cell function you are increased risk of severe COVID-19, probably from uncontrolled viral replication.

So how is this relevant to MS? As always it is a balancing act between being sufficiently immunosuppressed to prevent the immunological complications of SARS-CoV-2, but not too immunosuppressed that you can’t control the viral infection. In my opinion, in the MS space, the only treatments that we need to be concerned about are the acute effects of alemtuzumab and HSCT on the immune system in the depletion phase of treatment, i.e. the initial 3-6 months until total lymphocyte counts recover to a level that gives you adequate anti-viral responses. I have set the latter at above 500/mm³ in younger pwMS and above 800/mm³ on older people (older than 60 years of age). The reason for the latter is that as you get older and develop immunosenescence the proportion of your T-cells that are naive and able to respond to new viruses and antigens shrinks. This may explain why older people are at more risk of getting severe COVID-19, i.e. their immune systems are just not as good at responding to new viral infections.

There is a third phase to SARS-CoV-2 and that is the delayed antibody response, which is B-cell dependent. The antibodies probably contribute to the tissue damage in the immune-mediated phase of COVID-19. However, you clearly don’t need B-cells and antibodies to recover from COVID-19. I base this on the case reports of two patients with agammaglobulinaemia from Italy who recovered from COVID-19. Please remember these patient don’t have B-cells. Another clue that B-cells are not needed is the fact that patients on anti-CD20 therapies tend to deal with viral infections, including novel or new viral infection, well and rarely get severe viral infections. The latter observation is borne out by how well anti-CD20 patients are weathering the COVID-19 storm.

The one downside of anti-B-cell therapies, however, is that you may need anti-SARS-CoV-2 antibodies to prevent yourself from getting reinfected with the virus. The latter has major implications for when a SARS-CoV-2 vaccine arrives. Will pwMS on anti-CD20 therapies be able to respond to a vaccine? Based on the fact that the SARS-CoV-2 spike protein, the main immunogen in future vaccines, is heavily glycosylated and that anti-CD20 therapies block antibody responses to glycoproteins (proteins covered in sugar molecules) patients on anti-CD20 therapies are unlikely to be vaccine ready unless their dosing is interrupted to allow peripheral B-cell recovery.

It is clear from social media activity and exchanges with my colleagues that many of us are now moving onto the next phase of preparedness for managing MS during COVID-19, i.e. how to ensure your patients are vaccine ready for a SARS-CoV-2 vaccine. The latter is something I have discussed before and is why I have added another column to my DMT table (version 4).

Haberman et al. Covid-19 in Immune-Mediated Inflammatory Diseases — Case Series from New York. N Engl J Med 2020 Apr 29. doi: 10.1056/NEJMc2009567.

A better understanding of the implications of Covid-19 in patients with immune-mediated inflammatory disease and the effects of anti-cytokine and other immunosuppressive therapies is urgently needed to guide clinicians in the care of patients with psoriasis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, and related conditions. Although our analysis was limited in sample size, our data reveal an incidence of hospitalization among patients with immune-mediated inflammatory disease that was consistent with that among patients with Covid-19 in the general population in New York City reported by the New York City Department of Health and Mental Hygiene (35,746 of 134,874 patients [26%]) (Table S5). These findings suggest that the baseline use of biologics is not associated with worse Covid-19 outcomes.

Lorenzo D’Antiga. Coronaviruses and Immunosuppressed Patients: The Facts During the Third Epidemic. Liver Transplantation 20 March 2020.

… the available data on past and present coronavirus outbreaks suggest that immunosuppressed patients are not at increased risk of severe pulmonary disease compared with the general population. Children under the age of 12 years do not develop severe coronavirus pneumonia, regardless of their immune status, although they get infected and can, therefore, spread the infection. The risk factors for severe disease remain old age, obesity and its complications, other comorbidities, and male sex. Although the surveillance of this particular group of patients should continue, there are no reasons to postpone lifesaving treatments, such as transplantation or chemotherapy for cancer, during coronavirus outbreaks both in children and in adults.

Akalin et al. Covid-19 and Kidney Transplantation. N Engl J Med. 2020 Apr 24.

In conclusion, at our institution, kidney-transplant recipients with Covid-19 had less fever as an initial symptom,3 lower CD3, CD4, and CD8 cell counts,4 and more rapid clinical progression than persons with Covid-19 in the general population. The number of our patients with very low CD3, CD4, and CD8 cell counts indirectly supports the need to decrease doses of immunosuppressive agents in patients with Covid-19, especially in those who have recently received antithymocyte globulin, which decreases all T-cell subsets for many weeks. Our results show a very high early mortality among kidney-transplant recipients with Covid-19 — 28% at 3 weeks as compared with the reported 1% to 5% mortality among patients with Covid-19 in the general population who have undergone testing in the United States and the reported 8 to 15% mortality among patients with Covid-19 who are older than 70 years of age.

CoI: multiple

#MSCOVID19: frontline

Working on the COVID-19 frontline comes with risks, not only personal risks but risks to your family, fellow NHS staff and for other patients who you have to see in face-to-face encounters on the wards or in urgent clinics. This explains why healthcare workers are so anxious.

It is now clear that COVID-19 is a bit of a lottery; most people survive, a few scrape through and tragically some don’t make it. The following is a personal account of a colleague of mine who made it through. He has kindly given me permission to share his story with you.

COVID 19: a personal experience not to be forgotten

I am a fit 61-year-old white male, with no comorbidities. I have been an NHS consultant for 24 years, with dual accreditation in acute medicine and my core speciality.

As the Coronavirus pandemic evolved, and although I had not practised acute general medicine for 10 years, I felt that my training and experience would be of clear value for frontline care delivery. I am not an NHS zealot, but I do strongly believe in its basic principles and have been grateful for the unusual privilege of having a secure, protected and well-paid career. I felt intrinsically that I had not only a clear duty of care but also had been given a clear opportunity to be of help in this crisis and to ‘payback’ in a small way.

The preparation period was intense, with rapid closure of our entire speciality services, vetting and triaging all referrals in the system for months ahead, calling many patients to explain the reasons for cancellation of two-week wait procedures, and doing telephone virtual outpatient clinics as far ahead as possible. In addition, there was a vast amount of new information to learn, with extensive on-line training about COVID 19, the clinical presentation of this weird novel virus, blood patterns, radiological changes, and progressive levels of respiratory support together with training sessions in CPAP. There was no doubt that both the nursing and the speciality medical staff were anxious and even scared, unsure about expectations, being deployed beyond their training and experience, and with the ever-present personal threat.

When I graduated the AIDS pandemic was evolving: however, it was much easier to deal with medically as the personal risk of infection from patients was so low. In contrast, this felt very much like preparing for battle with a real and tangible threat.

There were also evolving areas of concern. Communication with centralised NHS bodies, especially PHE, with CCG’s, and with the Trust management illustrated a massive disconnect between the drastic dissolution of our services, the measures and the rapid clinical decisions we were taking every day and the slow, stodgy, rules- bound response from the non-clinical bodies at all levels. The inability of the NHS management to think out of the box, to make quick decisions, to break rigid restrictive rules designed only for delay and procrastination was cruelly exposed. In contrast, our national speciality body, led by practising clinicians, was exemplary in providing rapid clear guidance.

Given our dual training, my team of specialists was deployed to cover the COVID 19 acute take, our speciality ward, and two pure COVID wards. I led six ward rounds -in full PPE- on the COVID wards. It was impossible not to admire the commitment of the junior doctors, the nurses and the allied medical professionals working in bizarre and extreme circumstances, and trying so hard to provide compassion and care to extremely sick, lonely patients. Ours is an old hospital, and the lack of ventilation on the wards together with the hot PPE did give a sensation of working in a murky COVID fog. I attempted to avoid a machine ward round of just looking at the NEWS chart and tried to talk to each patient, to explain, and to teach the junior doctors, starting in the donning area with discussions of COVID, explanation of bloods, interpretation of results and then teaching more during the rounds on COVID and non-COVID aspects.

Five days after my first ward round I developed classic symptoms of COVID, and so began the frustration of organisational inefficiency compounded by deteriorating health.

The Trust testing system was run by a non-clinical department and was designed with no regard for the anxiety or deteriorating health of the ill staff member, no ability to reliably speak directly to anybody organising the testing, no reassurance that anyone would ever get back to you, no recognition that many staff members did not drive, and the placement of the local testing centre a 40-minute drive from the Trust. Twenty-four hours after contacting the Trust team responsible for this shambolic mess, still completely in the dark as to whether I would ever be tested and with my health worsening, I considered the irony that just three weeks prior I had communicated to our Medical Director the importance of easily accessible, rapid testing for Staff members. He replied that he agreed but was constrained by PHE dictats. As the Easter weekend was approaching, I used my seniority to bypass the Trust testing department and asked my line manager to contact the local testing centre direct. They called me within 30 minutes to say they had received no request from my Trust but reassured me that they were exceptionally quiet and had in fact received (unusually they thought) very few requests for testing from our Trust. The lead for the testing centre contacted my Trust directly, called me back five minutes later to say that the testing request had miraculously appeared, and offered me a drive-through slot. Whilst driving, despite a high fever, to the testing centre I considered ruefully how many ill members of staff would be denied their rightful testing by organisational ineptitude, and how fortunate I was, but how unfair it also was, to be able to pull strings. There was no queue at the Testing centre. The nurse said they were hardly testing anyone.

Over the Easter weekend, my symptoms progressed. The COVID 19 symptoms are so unusual, so totally different from anything I have previously experienced, that there is a desperate need to have a clear result to at least explain what you are going through. And so began the wait. Four days later I was sicker, but still in the dark. My Trust testing department did not know where my test was sent to when it would ever be back, who would phone me with the result, or even whether it would be processed at all over Easter and was merely drying out somewhere in transit.

I was finally called, 92 hours after the test was taken to be told I was positive: my wife, desperately anxious, burst into tears that at least there was an explanation for my illness.

There was a further irony that within our Trust the Respiratory team had set up an alternative testing system to improve and enhance staff testing, but been thwarted by the Trust’s rigidity and adherence to PHE guidance. Despite being the experts, the Respiratory team were being dictated to and restrained from best practice by both non-respiratory clinicians in management leadership roles, and non-clinical management unable to relinquish their power. Again, only through the privilege of position, was I able to access the Respiratory team’s daily ‘check-up’ phone call: the reassurance in isolation of having someone who cares call you, discuss your symptoms, and give support is immense. The denial of this invaluable service by Trust inflexibility to many of my fellow staff was an unacceptable failure of care.

(Of note -since my documentation of my experience to our Trust’s Medical Director he led major changes to the entire testing process, the organisation for this process was taken away from the non-clinical department, on-site testing for staff was started and the Respiratory clinic has obtained control).

Since graduation, I have only taken off two days for illness, and so I make the traditional worst type of patient: one who is not used to being ill. The real kicker though with COVID is the ‘double hit’ impact: you feel unusually ill initially, get teased into feeling mildly better for a couple of days, and then get struck by the real illness, the cytokine storm. On day nine I became pyrexial again to 38, dropped my saturations to 88%, and was enveloped by a suffocating and blanketing exhaustion, apathy and myalgia. I felt frighteningly unwell, but worryingly I did not want to go back to the hospital -not through any lack of trust in the care but, it seemed like returning an injured combatant back to where the actual trauma occurred and I was desperate to avoid going back onto the COVID wards. I used instead proning (lying on my stomach) and deep breathing to get my saturations back above 92 %.

I had hoped that with the resolution of the cytokine storm recovery would beckon. However, this was not the case. By day 13 I spiked a temperature again, was short of breath talking on the phone, and noticed my pulse rate went up to 130 whilst making a slow 30-yard flat walk in my back garden. Through the intervention of the Respiratory team, I went into the hospital, and underwent a battery of tests. Although my CRP was (still) raised at 60, by this point there were just mild pneumonic changes on chest X-ray. The negative tests (for heart failure and pulmonary embolic disease) did provide reassurance, especially given my anxiety about post-viral myocarditis. I went back home on antibiotics, and by day 16 finally felt less virus and more human.

But what about the psychological impact of this exceptional virus? An illness which is severe, but requires isolation as a mainstay of care is counter-intuitive to all medical and human impulses. The inability to touch denies a basic comfort and is an especially cruel part of this disease. My wife and daughters provided vital ongoing and critical support. Whilst I slept in a separate room, and used separate facilities, we shared the same living space and could have some limited contact: just the squeeze of a hand provides solace. Their care highlighted the essence of the value of family.

The severity of the illness undermines your confidence and highlights vulnerability to factors completely out of one’s control. I have always loved my career and chosen speciality: I have been left though with a peculiar apathy and ennui about issues I was so passionate about before. I do not relish returning to work next week. I must confess to also being somewhat scared about the return to the Petri dish of the COVID wards. I am anxious about bringing back an infection to my wife and daughters. This illness is not suffered alone by the patient. Your family is as traumatised, and from what they experienced watching you suffer deserve to be given antibody testing as soon as available to minimise the impact of the unknown beast at the front door, brought into what is normally a place of sanctuary, by a partner just doing their job.

There are many lessons to be learned from this pandemic, globally, nationally and within organisations. As with other disasters, personal experience helps inform, educate and hopefully change for the better. I do hope that post-COVID there is an attempt to use individual stories such as mine to help us manage better should there be a repeat.

#MSCOVID19: inequality

We all focus on the obvious risk factors that predict who will and who won’t die of severe COVID-19, but the one that needs a deep think is deprivation the main social determinant of health. The latest data that has just been released from the ONS (Office for National Statistics) is a grim reminder that survival during COVID-19 is not only dependent on physical factors but social factors as well. In reality, the physical and the social are inseparable from each other because they depend on each other, for example, living in a poor area often means poor access to outdoor areas that promote physical activity. If you are interested in reading more on this I would suggest reading Micheal Marmot’s book ‘The Health Gap: The Challenge of an Unequal World‘.

I work at the Royal London Hospital, where our local patch consists of three boroughs Whitechapel, Hackney and Newham. It was quite alarming that Newham had the highest age-standardised COVID-19 rate with 144.3 deaths per 100,000 population followed by Brent with a rate of 141.5 deaths per 100,000 population and Hackney was third with a rate of 127.4 deaths per 100,000 population.

The following are the headline figures from the ONS:

Between 1 March and 17 April 2020, there were 90,232 deaths occurring in England and Wales that were registered by 18 April; 20,283 of these deaths involved the coronavirus (COVID-19).
When adjusting for size and age structure of the population, there were 36.2 deaths involving COVID-19 per 100,000 people in England and Wales.
London had the highest age-standardised mortality rate with 85.7 deaths per 100,000 persons involving COVID-19; this was statistically significantly higher than any other region and almost double the next highest rate.
The local authorities with the highest age-standardised mortality rates for deaths involving COVID-19 were all London Boroughs; Newham had the highest age-standardised rate with 144.3 deaths per 100,000 population followed by Brent with a rate of 141.5 deaths per 100,000 population and Hackney with a rate of 127.4 deaths per 100,000 population.
The age-standardised mortality rate of deaths involving COVID-19 in the most deprived areas of England was 55.1 deaths per 100,000 population compared with 25.3 deaths per 100,000 population in the least deprived areas
In Wales, the most deprived areas had a mortality rate for deaths involving COVID-19 of 44.6 deaths per 100,000 population, almost twice as high as the least deprived area of 23.2 deaths per 100,000 population.

On average the most deprived areas of the country had more than double the death rate than people in the least deprived areas. In the MS Academy webinar on Wednesday on ‘Preparing to get COVID-19’, I said there was nothing you could do about poverty or your level of deprivation in the short term, but maybe this is the wrong attitude to have. Although inequality is political and something the government needs to challenge with legislation there are lots of things we as individuals can do to tackle the problem.

To tackle inequality and its effect we need to start locally. Be mindful of its presence and how it impacts on health. Try to invest in local community projects and make everyone feel part of a community. It is remarkable to see how this is happening on such a large scale across the country in response to COVID-19. We need to make sure it continues post-COVID-19. We now realise the value of community that goes beyond the GDP of the country. Community and looking after each other and the health benefits of doing so are much more valuable than GDP.

As part of our ‘Raising the Bar‘ initiative, I am co-leading the workstream with Dr Helen Ford (Leeds) on the Social Determinants of Health and how they impact on the treatment and outcomes for pwMS. Our motto is that ‘no patient with MS should be left behind’. We have some interesting ideas that we are exploring with the wider MS community and would appreciate any input and help from you. The one that worries me the most at the moment is food security. We know that many pwMS in the UK are poor and many have problems paying for food and that the COVID-19 epidemic has exacerbated this. So if you know someone in your community with MS who is vulnerable please drop them a line and simply ask is there anything you can do to help. A friendly voice or helping with a food parcel delivery from the local food bank may be all that is required.

We have a grant application being processed at the moment to try and get an online platform set-up to help pwMS, who are part of Barts-MS, connect in a meaningful and helpful way. When I look at the statistics of COVID-19 from our local Burroughs we need this to happen sooner rather than later.

When the dust settles post-COVID-19 I suspect that high-income countries with the greatest inequality will have the highest per capita death rates. At the moment it looks like the US and the UK are heading for the top of the leaderboard and it comes as no surprise that the US and UK have relatively high Gini* indices compared to other high-income countries.

Some pundits argue that the relatively poor response of the UK and US to COVID-19 has more do with our slow response and preparation, despite knowing that a SARS pandemic was likely in the near future. Others argue is that it relates to our partisan political systems and that other democratic system, for example in most of Europe, make for less combative politics and a more common-sense consensus that is responsive to the needs of the people rather than vested interest groups. Whatever the reason or reasons for the lacklustre response of the UK compared to other European countries to COVID-19 we are going to have to make sure we become a more compassionate society post-COVID-19 and aspire to be a more inclusive society. Do you agree?

* The Gini index or coefficient is a measure of the income or wealth distribution of a nation’s people and is the most commonly used measurement of inequality. A Gini index of zero is perfect equality where everyone has the same income. A Gini index of one (or 100%) represents maximal inequality where only one person has all the income or consumption, and all others have none.

CoI: none