Prof G's MS Blog Archive

#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

Not COVID-19: obesity and MS

Are you sick and tired of hearing about COVID-19 and MS? How about something completely different; the destigmatization of obesity?

Finally, the medical community or at least a part of it are making amends for the half-century or more of treating obesity as a disorder of self-control. The joint internal consensus statement for ending the stigma of obesity is long overdue (see article and box below).

Even when I have done factual posts about childhood and adolescent obesity as a risk factor for developing MS I have been criticised by commentators for fat-shaming. I am not. All I am doing is quoting the evidence that childhood/adolescent obesity is associated with an increased risk of developing MS and may in fact be in the causal pathway that leads to developing MS.

What the consensus statement below is finally acknowledging is the irrefutable evidence that obesity is a disorder of metabolism; an endocrine disorder that leads to patients increasing the amount of energy they store as fat. Finally, the dogma that obesity is due to the excess consumption of calories and/or the reduced expenditure of calories is finally being put to rest as not being the root cause of obesity.

A simplified way of explaining the mechanisms that lead to obesity is that your metabolism gets hijacked by a hormonal imbalance that results in energy be hoarded away in your adipose tissue and it not being released for consumption by the remainder of the body. This triggers the brain to think that you are starving and sets off a behavioural response to seek more food or calories. In other words, the metabolic state associated with obesity causes hunger and the food-seeking behaviour associated with it and not the other way around.

The sad thing is that we the medical profession have known about this insight for centuries, but we decided to forget or ignore the metabolic research underpinning obesity being a metabolic disease in the 70’s and 80’s when we were hoodwinked by dodgy science and fake news. Yes, the high saturated-fat heart hypothesis of cardiovascular disease is to blame. The conspiracy underpinning the change in the dietary guidelines that have caused the global obesity pandemic has been well highlighted by investigative journalists in several extremely well-crafted exposes. The tragedy is as the population replaced saturated fat in our diets with polyunsaturated fats and carbohydrates, in particular, processed and ultra-processed carbohydrates, we created a metabolic storm that has resulted in an epidemic of obesity, diabetes, hypertension, fatty liver and the other ills associated the metabolic syndrome.

Shifting the focus sway from obesity as a result of an individual’s lack of self-discipline to it being a metabolic disease driven primarily by diet will allow us to tackle the epidemic, i.e. to flatten the curve and hopefully chop off its tail to steal a COVID-19 analogy.

The metabolic cause of obesity is rather quite simple; it is driven predominantly by raised insulin levels or hyperinsulinaemia. High blood sugar or glucose levels stimulate the pancreas to produce insulin. The insulin works to reduce blood glucose levels by signalling to the liver and muscles to make glycogen (short-term glucose storage) and to the liver and adipose tissues to make fat. Whilst insulin levels are high the adipose tissue is unable to release fat as an energy source and so the adipose tissue continues to take-up glucose to convert into fat. As glucose levels drop it triggers a counter-regulatory hormonal response that causes you to become hungry and you then seek out sugary foods. This then starts a vicious cycle that results in insulin levels being raised most of the day, instead of only being raised for a few hours after a meal. This hyperinsulinaemia eventually causes the liver and muscles to become resistant to insulin’s action, but less so in adipocytes particularly the adipocytes around the abdomen and internal organs. The latter causes the so-called centripetal and visceral obesity that is typical of insulin resistance.

The only way to break this vicious metabolic cycle is to try and lower your insulin levels as much as possible. This is why low carbohydrate or ketogenic diets work so well at correcting the metabolic syndrome (hyperinsulinaemia) and result in loss of weight. The good thing about keeping insulin levels low is that the body gets used to a new normal or steady-state glucose level that is driven by another metabolic process called gluconeogenesis (glucose from protein), which does not trigger the counter-regulatory hormonal response that makes you feel hungry. In addition, the ketones your body produce, particularly β-hydroxybutyrate, is known to suppress appetite and explains why people on ketogenic diets don’t feel the same levels of hunger as people on high carbohydrate diets.

If you have MS having high levels of circulating β-hydroxybutyrate maybe be good for your MS. β-hydroxybutyrate activates the hydroxycarboxylic acid receptor 2 (HCA2), which is also known as niacin receptor 1 (NIACR1) and GPR109A. This is the same receptor that fumaric acid works on. I suspect that ketosis works at a cellular level in the same way that dimethyl fumarate (DMF) and diroximel fumarate work, which are both licensed MS disease-modifying therapies (DMTs). By binding to the HCA2 receptor β-hydroxybutyrate stimulates a transcription factor called NRF2 and downregulates NFKappa-B the master regulator of inflammation. The NRF2 mechanism of ketosis almost certainly overlaps with what has been described in animals with intermittent fasting and the drug metformin to promote the rejuvenation of oligodendrocyte precursors, remyelination and recovery of function.

Despite criticism from dietary zealots the evidence that low-carbohydrate/ketogenic diets are bad for you is very weak. In fact, I would argue that from an evolutionary perspective man was first a low-carbohydrate species and only acquired the sophisticated carbohydrate metabolic response to fatten up for winter when fruits and grains are plentiful at the end of summer. We were never meant to metabolise carbohydrates 24/7 365 days a year. Feast and famine was the norm, which is how our primate cousins live in the wild.

Although we need controlled evidence before promoting low-carbohydrate/ketogenic diets as a treatment for MS and for MS prevention there is no reason why pwMS can’t try these dites improve their metabolic health. If I had MS I would not hesitate to hack my metabolism with either a low-carbohydrate/ketogenic diet or intermittent fasting, but not caloric restriction. The scientific case for using these former diets as an adjunct to other MS therapies is simply too compelling to ignore.

Rubino et al. Nat Med 2020 Apr;26(4):485-497.

Rubino et al. Joint International Consensus Statement for Ending Stigma of Obesity. Nat Med 2020 Apr;26(4):485-497.

People with obesity commonly face a pervasive, resilient form of social stigma. They are often subject to discrimination in the workplace as well as in educational and healthcare settings. Research indicates that weight stigma can cause physical and psychological harm, and that affected individuals are less likely to receive adequate care. For these reasons, weight stigma damages health, undermines human and social rights, and is unacceptable in modern societies. To inform healthcare professionals, policymakers, and the public about this issue, a multidisciplinary group of international experts, including representatives of scientific organizations, reviewed available evidence on the causes and harms of weight stigma and, using a modified Delphi process, developed a joint consensus statement with recommendations to eliminate weight bias. Academic institutions, professional organizations, media, public-health authorities, and governments should encourage education about weight stigma to facilitate a new public narrative about obesity, coherent with modern scientific knowledge.

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

#MSCOVID19 asymmetry

Many of my colleagues have criticised and reprimanded me for being over-enthusiastic in stating that immunosuppressive MS DMTs are relatively safe for pwMS if they happen to develop COVID-19 whilst on treatment. However, the issue has been asymmetry of knowledge. I have known that patients on DMTs who get COVID-19 are doing well. This is based on knowledge acquired from multiple sources albeit confidentially. I have been trying to encourage my colleagues to put this information into the public domain, but clearly it is not happening soon enough. The delays in getting this information out to you the MS community has been far too slow. Do you agree? The good news is there are now platforms to speed up the dissemination of data; let’s hope it changes behaviour.

At last, the Italian COVID-19 and MS pilot data has been published in a peer-reviewed journal. They report on the first 232 patients with MS who developed COVID-19. I actually commented on this data on the blog on the 10th April and it was only published yesterday. There is nothing new to report. This delay is simply unacceptable as HCPs and pwMS need this type of information to challenge current treatment guidelines with evidence and more importantly, pwMS need this information to make potentially life-threatening decisions about their MS care. The number of patients on each individual DMTs is probably too small to make a definitive judgement, but sufficient to be reassuring.

So if any of my colleagues are reading this post please put your data out in the public domain ASAP and in a form that is accessible to all. There are several platforms for doing this including the weekly iWiMS webinars (see below) and the MSIFs Global Data Sharing Initiative. The latest data presented in the most recent iWiMS webinar is in line with the Italian data and remains very reassuring. It clearly supports the need to update treatment guidelines and develop an exit plan. At the moment I am still on version 4 of my DMT table.

So what are the wider consequences of asymmetric knowledge? To understand this you need to become an economics scholar. Asymmetric knowledge is an economic construct to explain the consequences of what happens where one party has more or better information than the other in a transaction. It creates an imbalance and can sometimes cause market failure, in this case, a potential moral hazard for pwMS and the wider MS community. Other, examples of this problem are adverse selection and monopolies of knowledge. I abhor the latter and it is particularly important that we try and fight it.

In addition to me falling out with several of my colleagues over this issue, many wars have been caused by asymmetric information. If you are interested in reading more about this topic I would recommend Joseph Stiglitz’s work; he won and shared the Nobel prize for economics in 2002 for “analyses of markets with asymmetric information”.

Sormani et al. An Italian programme for COVID-19 infection in multiple sclerosis. Lancet 29th April 2020

Excerpt:

On March 14, 2020, we sent the case report form to more than 200 Italian neurologists from about 90 multiple sclerosis centres across Italy. As of April 7, 2020, we have collected data on 232 patients from 38 centres, 57 of whom tested positive for COVID-19 and 175 of whom had suspected COVID-19 symptoms but did not have a positive test (appendix p 1). Mean follow-up was 12·6 days (SD 7·4). The severity of COVID-19 infection in 232 patients was classified as mild (no pneumonia or mild pneumonia) in 223 (96%), severe (shortness of breath, respiratory rates ≥30 breaths per min, blood oxygen saturation ≤93%, PaO₂:FiO₂ <300 mmHg/%, and an increase in lung infiltrates of >50% within 24–48 h) in four (2%), and critical (respiratory failure, septic shock, and multiple organ dysfunction or failure) in six (3%). Of the six critical patients, one recovered and five died; all had a positive swab (appendix p 2). 21 patients had undergone a 5-day course of methylprednisolone within 3 months before the onset of COVID-19.

CoI: multiple

#MSCOVID19: pulse oximetry

If you are single I suggest going to extraordinary lengths to protect yourself if you have to self-isolate with COVID-19.

You may have heard about the tragic death of a young surgical trainee who died alone at home from COVID-19 in Belfast last week. He probably died from pulmonary complications of COVID-19 that had gradually crept up on him and by the time he needed hospitalisation and ventilatory support he was probably too unwell to do anything about it. A big issue is that as you become hypoxic (lack of oxygen) your thought processes become clouded and your ability to make a judgement about your own health become erratic.

I know of two close colleagues who self-isolated with COVID-19 and both of them developed severe exertional shortness of breath at the height of their infection. My one colleague said he could barely make it from his bed to the toilet due to shortness of breath. Fortunately, both have made a recovery now and are doing well.

A third colleague who has recently recovered from COVID-19 was bed-bound for two weeks and was on the verge of calling an ambulance, but decided against it. Fortunately, his wife is a GP and was monitoring him at home with a pulse oximeter, a device to measure how much oxygen is in your blood, that she uses for home visits. This colleague tells me that he did try and call 111 and after waiting 90 minutes hung-up. Waiting ninety minutes or longer for advice and to then be told to call an ambulance could be the difference between life and death.

When we do our ward rounds on patients with COVID-19 we don’t have to examine them, we mainly assess how well their lungs are functioning based on their oxygen saturation in their blood relative to how much oxygen they are getting, be it from room air (21% oxygen) or via a nasal cannula or face mask. When we use nasal cannula or a face mark we deliver oxygen at different flow rates and this is also taken into account.

In general, most people have an oxygen saturation rate above 94%. It does vary with age and altitude. It is relatively easy to measure yourself, but you need to have a pulse oximeter. In early COVID-19 pneumonia, exertional oxygen saturation levels fall first, i.e. if you attempt to walk or exercise and your blood saturation levels fall, for example, below 90% despite being normal at rest. This would indicate that your lungs are in trouble and that you probably need to go to hospital. People with COVID-19 can deteriorate very rapidly, i.e. within hours, so having an early warning system should help.

I wonder if the young surgeon above had been monitoring himself with a pulse oximeter and had notice that his exertional blood oxygen saturation levels dropped with exertion (walking in his home) he would have gotten himself to hospital and survived?

I personally think the Government’s and NICE’s guidance on when to be admitted to a hospital is potentially dangerous. The NICE guidance suggests using the following symptoms and signs to help identify who has more severe COVID-19 and may need admission to hospital:

severe shortness of breath at rest or difficulty breathing
coughing up blood
blue lips or face
feeling cold and clammy with pale or mottled skin
collapse or fainting (syncope)
new confusion
becoming difficult to rouse
little or no urine output

Can you imagine trying to pick these symptoms and signs up if you live alone and are self-isolated? I am sure self-monitoring of your peripheral blood oxygen saturation levels, in particular documenting their deterioration, will save lives during the COVID-19 pandemic.

So after reading about the tragic case of the young surgeon dying alone at home, I purchased my own pulse oximeter online. It is an insurance policy for my family and any of my neighbours or friends who may get COVID-19 and have to self-isolate and self-monitor. I think the NHS or local communities should arrange for pulse oximeters to be dropped off for single people with COVID-19 who are self-isolating and given guidance on how to use them and at what point to call 999. I am sure home pulse oximetry will take some pressure off the 111 services and save lives. The sceptics will say that as home self-monitoring of oxygen saturations is an untested technology we would need to study this intervention first before recommending it at a population level. I would say bollocks. My sister has a progressive interstitial lung disease and is on 24-hour home oxygen therapy. She and her cohort of fellow patients all manage their home oxygen therapy using pulse oximeters. If she can use a pulse oximeter so can most people in the general population. In fact, technology companies should think about building pulse oximetry into the next versions of their smartwatches and make the technology ubiquitous.

I am not saying that everyone should purchase a pulse oximeter, but if you are single and live alone without someone to monitor your status when you get COVID-19 it would be advisable to have one. I am convinced that my two colleagues who struggled through self-isolation at home would have been better off if they had known their own peripheral blood oxygen saturation levels, both on exertion and at rest. I suspect if they had they may. or at least one of them may, have been admitted to hospital for observation.

Do you agree with me that we should add access to home pulse oximetry, particularly if you are single, to my list of things to do to prepare for getting COVID-19?

CoI: none

#MSCOVID19: vitamin D & zinc

I have already made the case for pwMS to prehabilitate, i.e. to prepare themselves for getting COVID-19. You can read my proposed prehabilitation programme on MS-Selfie. One of the topics I cover is diet and I mention that you should ensure that you are vitamin D (vD) replete. There are three ways to do this. (1) The first is to get a healthy daily exposure to sunshine (~20mins of upper body exposure around midday in summer), which can be difficult if you are disabled and stuck indoors and it is winter where you live.

(2) Another source of vD is eating foods that are high in vD, for example, fatty fish. However, even the latter is often insufficient to raise your blood levels above 75 or 80 nmol/L, which are the two most common lower levels of normal used by UK laboratories. If you apply evolutionary medicine principles, i.e. what are the vD levels in hunter-gatherers or people who work outdoors, a level of above 100 nmol/L is probably normal. (3) The easiest way to get above 100nmol/L is with dietary supplements. I have always recommended the Vitamin D Council’s advice which is to take 5,000 U of vD3 per day. I note that the Vitamin D Council’s website has gone offline and I don’t know why. Does anybody know the reason?

The following small study below from Indonesia shows that low vD levels were associated with a higher chance of dying from COVID-19. As with all studies of this nature, it could be reverse causation, i.e. COVID-19 patients with the greatest level of inflammation in their lungs consumed more vD as part of the inflammatory process. In other words, inflammation caused the low vD levels not the other way round. I am prepared to go as far as saying that in inflammatory or infectious diseases the lower the vD levels the worse the prognosis; this is called the consumptive vD hypothesis of inflammation.

What is needed is a clinical trial to see if vD supplements prevent you from getting severe COVID-19. This type of trial is very difficult as a large number of the population are already taking vD3 supplements and a lot of vD experts will say we don’t have equipoise in that they think people should be vD replete for general health reasons regardless of COVID-19.

As low dose vD3 supplementation is safe and most of the UK population is vD deficient I would advise taking vD supplements rather than not taking them. Do you agree?

I am also asked what other supplements should you take? If you have a healthy balanced real food diet you don’t need to take any other supplements. However, if you eat an unbalanced diet for humans, for example, a purely plant-based diet, I would advise you to review your micronutrient intake. While not all vegans have low blood levels of zinc, a recent review showed that vegetarians — and especially vegans — have lower zinc intakes and slightly lower blood levels of zinc than omnivores. I focus on zinc because zinc deficiency is associated with an increased risk of infections and complications of infections. There is also a hypothesis that zinc may act against SARS-CoV-2 at several different points in its replicative cycle (see the article from below) and zinc is also important for anti-bacterial activity. A large number of COVID-19 deaths are due to secondary bacterial pneumonia.

A supplemental dose of 5mg or 10mg per day of zinc should be sufficient with other dietary sources to ensure you are zinc replete.

In the absence of a SARS-CoV-2 vaccine and an effective antiviral are you ready yet to get COVID-19? If not you need to start today. Prehabilitation is an attempt to lower your chances of getting severe COVID-19 and dying from the complications of COVID-19. If you haven’t please act now!

Vitamin D – the sunshine vitamin

Raharusun et al. Patterns of Covid-19 Mortality and Vitamin D: An Indonesian Study. SSRN April 26, 2020.

This is a retrospective cohort study which included two cohorts (active and expired) of 780 cases with laboratory-confirmed infection of SARS-CoV-2 in Indonesia. Age, sex, co-morbidity, Vitamin D status, and disease outcome (mortality) were extracted from electronic medical records. The aim was to determine patterns of mortality and associated factors, with a special focus on Vitamin D status. Results revealed that majority of the death cases were male and older and had pre-existing condition and below normal Vitamin D serum level. Univariate analysis revealed that older and male cases with pre-existing condition and below normal Vitamin D levels were associated with increasing odds of death. When controlling for age, sex, and comorbidity, Vitamin D status is strongly associated with COVID-19 mortality outcome of cases.

Zinc – an essential micronutrient

Skalny et al. Zinc and Respiratory Tract Infections: Perspectives for COVID‑19. Int J Mol Med. 2020 Apr 14. doi: 10.3892/ijmm.2020.4575.

In view of the emerging COVID‑19 pandemic caused by SARS‑CoV‑2 virus, the search for potential protective and therapeutic antiviral strategies is of particular and urgent interest. Zinc is known to modulate antiviral and antibacterial immunity and regulate inflammatory response. Despite the lack of clinical data, certain indications suggest that modulation of zinc status may be beneficial in COVID‑19. In vitro experiments demonstrate that Zn2+ possesses antiviral activity through inhibition of SARS‑CoV RNA polymerase. This effect may underlie therapeutic efficiency of chloroquine known to act as zinc ionophore. Indirect evidence also indicates that Zn2+ may decrease the activity of angiotensin‑converting enzyme 2 (ACE2), known to be the receptor for SARS‑CoV‑2. Improved antiviral immunity by zinc may also occur through up‑regulation of interferon α production and increasing its antiviral activity. Zinc possesses anti‑inflammatory activity by inhibiting NF‑κB signaling and modulation of regulatory T‑cell functions that may limit the cytokine storm in COVID‑19. Improved Zn status may also reduce the risk of bacterial co‑infection by improving mucociliary clearance and barrier function of the respiratory epithelium, as well as direct antibacterial effects against S. pneumoniae. Zinc status is also tightly associated with risk factors for severe COVID‑19 including ageing, immune deficiency, obesity, diabetes, and atherosclerosis, since these are known risk groups for zinc deficiency. Therefore, Zn may possess protective effect as preventive and adjuvant therapy of COVID‑19 through reducing inflammation, improvement of mucociliary clearance, prevention of ventilator‑induced lung injury, modulation of antiviral and antibacterial immunity. However, further clinical and experimental studies are required.

CoI: multiple