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”.
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.
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.
Prof G tests out his pulse oximeter!
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?
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!
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.
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.
This post explains why I have started to refer to cladribine as a small molecule anti-CD20/CD19 therapy and why oral cladribine should be part of the exit strategy to treat MS during the tail of the COVID-19 pandemic.
Although we use cladribine as an immune reconstitution therapy and often compare it to alemtuzumab it is, in fact, closer to anti-CD20 therapies in terms of its immunodepletion profile. This distinction is particularly important during the COVID-19 pandemic because it has allowed us to classify cladribine in an intermediate risk DMT, which allows us to treat MS with an IRT when we can’t use alemtuzumab.
Cladribine’s pros:
Cladribine is an oral therapy; hence no visits to COVID-HOT hospitals or institutions.
It kills cells gradually by a process called apoptosis. Cells dying from apoptosis are phagocytosed or swallowed by macrophages and as a result, there is no cell lysis or bursting open of the cells and the release of their contents that causes a cytokine release syndrome. This means there is no need to pre-treat patients with steroids, which we are trying to avoid at present.
Cladribine does not deplete monocytes and neutrophils and has a moderate impact on so-called NK cells. As the innate immune system is left intact there is a low risk of bacterial and other infections during the depletion phase and the innate cells can help fight viral infections, such as SARS-CoV-2.
T lymphocytes are in general depleted by about 40%-50% and most patients don’t drop their counts below 500/mm3. In the phase 3 programme about a quarter of patients had a grade 3 or 4 lymphopaenia, but this tended to occur after the second course in year 2 in subjects who were redosed when their lymphocyte counts had not recovered to above 800/mm3. We have used the trial data to model grade 3 and 4 lymphopaenia. I.e. less than 500/mm3, and estimate that less 5% of cladribine treated subjects will develop lymphocyte counts less than 500/mm3 if we stick to the redosing guidelines. This is very important as lymphopaenia is probably the most important risk factor for viral and severe viral infections.
In the T-cell compartment, the CD8+ T-cells were less effected than CD4+ T-cells. This is important because CD8+ T-cells are the cells responsible for fighting viral infections. This probably explains, apart from a small risk of herpes zoster reactivation, why we didn’t see an increase in viral infections compared to placebo in cladribine treated subjects in the phase 3 trial programme. The viral infections that did occur tended to be non-specific upper respiratory tract infections and were mild to moderate. In fact, the infection profile on cladribine, including the zoster signal, was much more similar to that which we see with ocrelizumab compared to alemtuzumab.
Cladribine is a remarkably good depleter of B-cells. B-cells number drop quicker than T-cells numbers; i.e. within days to weeks. In addition, B-cells are depleted by about 90% and importantly memory B-cells are severely depleted and to a similar level that we see with alemtuzumab. Importantly, when the B-cell numbers return these are so-called naive B-cells, which come from the bone marrow and are not memory B-cells. Interestingly, when you stop an anti-CD20 therapy such as ocrelizumab or rituximab and allow B-cell reconstitution they are also naive and are not memory B-cells that return in the short-term. In other words cladribine, alemtuzumab and ocrelizumab have similar effects on B-cells.
Please note that because ocrelizumab and rituximab are given as maintenance or continuous therapy there is a small increase in the incidence of serious infections over with time and the development of hypogammaglobulinaemia. This is not seen with cladribine. Once the immune system reconstitutes post-cladribine it can fight infections, immune survey the body for cancers and mount immune responses to new viral infections, such as SARS-CoV-2, and vaccines. In relation to vaccines both live and inactivated component vaccines can be given after cladribine.
The other important thing about cladribine is the monitoring requirements are low. Once you have had a course you only need a full blood count to be done 3 and 7 months after starting treatment. The rationale for this is that the 3-month time-point is where the nadir occurs and the 7-month time point is to check for recovery of lymphocyte counts. What this means during the COVID-19 pandemic is that if you are treated with oral cladribine and at 3 months your lymphocyte counts is above 500/mm3, which will be the vast majority of treated patients, you don’t need to self-isolate. In the 3-4% who have a lymphocyte count below 500/mm3 at month three, you will need to continue to self-isolate until your counts go above 500/mm3. To find out the latter you could wait another three months for the next blood test our you could ask your GP or MS team for an earlier test.
When you look at how cladribine works, i.e. it needs to be activated by an enzyme call DCK (deoxycytidine kinase) and broken down by an enzyme called ADA (adenosine deaminase), the profile of cells expressing the correct ratio of these enzymes matches the B-cell population that expresses CD19 and CD20 and explains why B-cells are more susceptible to the effects of cladribine than T-cells.
Another advantage of cladribine is that as a small molecule it penetrates the CNS. Cerebrospinal fluid (CSF) levels are about 25% of what is found the peripheral blood and at a level that would target B- and T-cells within the brain and spinal cord. I think this property of cladribine is very important and is one of the reasons why we are exploring cladribine as a treatment for progressive MS in the CHARIOT-MS trial.
In a similar way to ocrelizumab, I think cladribine has been hard done by COVID-19 guidelines that have stated not starting or not redosing cladribine during the COVID-19 pandemic. Why? Where is the science to support this position?
Now that we can see the pandemic is not going to end anytime soon and with a vaccine 18 or 24 months away I think we should reconsider using oral cladribine as it addresses many of the issues of treating highly active MS in these troubling times and it has the added advantage of leaving people with MS with a reconstituted vaccine-ready immune system if and when a SARS-CoV-2 vaccine arrives.
Please note that I am not saying cladribine and/or anti-CD20 therapies are safe. They have well-defined risk-benefit profiles that are less risky than what has been proposed by many people in terms of developing severe COVID-19. These risk-benefit profiles simply allow you to counsel patients with active MS about their treatment options during the COVID-19 pandemic.
I personally think both anti-CD20 therapies and cladribine are two highly effective therapies that allow a treatment exit strategy during the long tail of the SARS-CoV-2 pandemic.
I am on call at the Royal London Hospital and sitting in my office digesting some of my daily COVID-19 reading. However, something has just hit me between the eyes and I have to say wow aloud!
WOW!!
The paper and editorial below show you just how infective SARS-CoV-2 really is and why we are not going to win this battle for our vulnerable people without an effective anti-viral and/or vaccine. It also tells me that if we don’t get a vaccine things will not normalise for a very long time.
Who said the R0 (R-zero) for this virus was less than 3 and therefore we would get herd immunity at about a 60% seroprevalence rate? Not me!
R-zero or the basic reproduction number for SARS-CoV-2 is the expected number of cases infected by one case in a population where all individuals are susceptible to infection. The original calculations were based on symptomatic index cases and symptomatic contacts with positive swabs. The fact that a large number of people (possibly up to 50%) have now been shown to get asymptomatic infections and that the test for the virus is not 100% specific. This means that approximately 25% of cases with COVID-19 defined by clinical definition have negative nasopharyngeal (nose & throat) swabs; i.e. 25% of infected people who may be shedding are not detected with the swab test. Based on these assumptions I have estimated that in normal life (no social distancing) that the R-zero is likely to be somewhere between 6 and 7. This means that to get herd immunity, a point when natural transmission in the population stops, you need somewhere between 80% and 86% of the population to have immunity.
However, the study below just published in the New England Journal of Medicine makes me think this may even be an underestimate. In a well done ‘classic’ epidemiology study in a nursing home in Seatle, 23 days after the first positive test result in a resident, 64% tested positive for SARS-CoV-2; more than half (56%) of the residents were asymptomatic at the time of testing. Only half of these residents then went on to develop symptoms a few days later. A quarter of shedders never became symptomatic and most of these ‘asymptomatic shedders’ were shown to shedding viable virus. Tragically of the 57 residents who were shown to be infected with SARS-CoV-2 infection 15 died; a mortality rate of 26%.
Why is this so important? In short, a high or very high R-zero means that the government policy of relying on herd immunity to protect the vulnerable is not going to work.
Let me explain. Whilst we are socially distancing we reduce the R-zero of SARS-CoV-2 to less than 1 and hence the number of new cases falls and we flatten the curve. This is what is happening in the UK and many other countries at present. However, as soon as we stop the lockdown and allow social interaction the R-zero will rise above one and we will get more cases. But because this virus is so infectious we may need herd immunity to be well above 80% (possibly 90%) for the epidemic to peter out. At which time point the government is hoping to let vulnerable people remerge from self-isolation and feel confident that they will not be susceptible to being infected and dying from severe COVID-19.
The bad news is that 15.2% of the UK population is over 70 years of age (data from Age Concern) the government definition of the vulnerable population based on age. This is not taking into account all the other vulnerable groups who are less than 70 years of age, i.e. those who are obese and/or have diabetes, cardiovascular, respiratory diseases. This means that by the time we get herd immunity many more people will die from COVID-19. This is why the scientific community needs to push for anti-virals and an effective vaccine. But herein lies a problem.
To develop and test an effective vaccine we really need an 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. This is why we the rich-world may need to go to parts of the world where social distancing etc. is not feasible and the R-zero remains high, i.e. the squatter camps, shantytowns, favelas or slums of the low and middle-income countries of the world.
We, the rich world, may have no choice but to take this low/middle-income route for the sake of the world. But if ‘we’ do take this route to develop an effective vaccine we have to make it ethical. We will have to offer these countries priority access to the vaccine. If we don’t it will be a travesty. I can imagine the headlines in the press if we don’t. ‘Vaccine Imperialism: How the Rich World Exploited The Poor!’
What are the implications for you if you have multiple sclerosis. If you are vulnerable you need to be prepared to self-isolate/shield for a very long time. If you are not vulnerable then you really need to prepare yourself for becoming infected with SARS-CoV-2 and getting COVID-19. I have a section on MS-Selfie that addresses this issue. I will be updating this section over the weekend as there are additional things you can do as an individual and as a family to help derisk your chances further.
I am sorry for bringing you bad news at the beginning of the weekend, but as always I feel it is important, to be honest, and frank.
The information in this post is quite complex so if you have any questions please feel free to ask.
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can spread rapidly within skilled nursing facilities. After identification of a case of Covid-19 in a skilled nursing facility, we assessed transmission and evaluated the adequacy of symptom-based screening to identify infections in residents.
METHODS: We conducted two serial point-prevalence surveys, 1 week apart, in which assenting residents of the facility underwent nasopharyngeal and oropharyngeal testing for SARS-CoV-2, including real-time reverse-transcriptase polymerase chain reaction (rRT-PCR), viral culture, and sequencing. Symptoms that had been present during the preceding 14 days were recorded. Asymptomatic residents who tested positive were reassessed 7 days later. Residents with SARS-CoV-2 infection were categorized as symptomatic with typical symptoms (fever, cough, or shortness of breath), symptomatic with only atypical symptoms, presymptomatic, or asymptomatic.
RESULTS: Twenty-three days after the first positive test result in a resident at this skilled nursing facility, 57 of 89 residents (64%) tested positive for SARS-CoV-2. Among 76 residents who participated in point-prevalence surveys, 48 (63%) tested positive. Of these 48 residents, 27 (56%) were asymptomatic at the time of testing; 24 subsequently developed symptoms (median time to onset, 4 days). Samples from these 24 presymptomatic residents had a median rRT-PCR cycle threshold value of 23.1, and viable virus was recovered from 17 residents. As of April 3, of the 57 residents with SARS-CoV-2 infection, 11 had been hospitalized (3 in the intensive care unit) and 15 had died (mortality, 26%). Of the 34 residents whose specimens were sequenced, 27 (79%) had sequences that fit into two clusters with a difference of one nucleotide.
CONCLUSIONS: Rapid and widespread transmission of SARS-CoV-2 was demonstrated in this skilled nursing facility. More than half of residents with positive test results were asymptomatic at the time of testing and most likely contributed to transmission. Infection-control strategies focused solely on symptomatic residents were not sufficient to prevent transmission after SARS-CoV-2 introduction into this facility.
triMSx-online is hosting a webinar next Thursday, 30th April on the topic of managing MS during the COVID-19 pandemic. Things are moving so fast in terms of what is happening that we need some formal teaching course to keep everyone abreast with how to manage MS in these troubling times.
Our MS services have been transformed by the pandemic and the way we use DMTs has also changed. Advice on how to use DMTs seems to change on a weekly basis as new data emerges on the biology of SARS-CoV-2/COVID-19 and how patients with MS who get COVID-19 are doing. The programme (see below) has been designed to upskill you rapidly with developments across the globe and how these can potentially impact on your MS service. There will also be time to ask questions and discuss specific issues. Even if you can’t make the live event the presentations will be put online for later viewing and we will have a post-event Q&A session asynchronously.
I am being asked why I have moved ocrelizumab and other anti-CD20 therapies into the low-risk categories of DMTs in my latest version of my DMT table.
The reasons I use to justify the change are several-fold.
Anti-CD20 therapies deplete B-cells and only have a small impact on T-cell counts and innate immune cell function. This is important because anti-viral responses don’t seem to be affected to a great extent on ocrelizumab and other anti-CD20 therapies. In the phase three ocrelizumab trial programme apart from seeing a small herpes zoster signal there was no clear viral infection signal. When viral infections occurred they tended to be mild or moderate. The severe infections were bacterial (pneumonia, UTIs and cellulitis).
We are seeing an increasing number of patients who have been treated with anti-CD20 therapies who have had COVID-19 doing well. We have just published a case report in MSARDs of a man with PPMS treated with ocrelizumab who did well (see below). This has to be good news for patients on anti-CD20 therapies.
Ocrelizumab also blunts antibody responses, which may be important in severe COVID-19. This may delay or prevent damage to the COVID-19 lung as some of the damage seems to be mediated by complement activation and microthrombi. The latter is indicative of damage consistent with IgG3 anti-viral responses and IgG antibody-dependent cellular cytotoxicity by macrophages and in some instance neutrophils. Antibody production against the SARS-CoV-2 spike protein may promote cytokine production that activates macrophage to become more destructive. Blunting these antibody responses with an anti-CD20 therapy may actually be beneficial, which is why we are predicting that anti-CD20 treated patients will have a lower risk of getting severe COVID-19.
What about hypogammaglobulinaemia then?
Yes, this does occur with anti-CD20 therapies but occurs at a relatively low level. As SARS-CoV-2 is a new human pathogen and hence we don’t have immunological memory against the virus this makes little difference to the risk of becoming infected with SARS-CoV-2. Hypogammaglobulinaemia may, however, put you at risk of getting secondary bacterial infections. Fortunately, these can be treated with antibiotics.
What about vaccine responses?
Yes, anti-CD20 and other immunosuppressive therapies can blunt antibody responses to some vaccines. And yes, contrary to the dogma patients on anti-CD20 therapies do make antibodies to viruses and vaccines. I assume this happens because we still have B-cells in secondary lymphoid organs and/or there may be CD20 negative B-cells that can takeover antibody production. Please note that the latter is a hypothesis.
Antibody responses to glycoproteins (sugar antigens) are particularly affected by anti-CD20 therapies and this may be important in the context of coronavirus immunity as the spike protein is heavily modified with sugar molecules. However, all these arguments are theoretical; until a vaccine emerges I would focus on getting MS treated. We can cross the vaccine bridge if and when it gets built. I am still of the opinion that the government’s strategy is herd immunity and hence the majority of us will at some point become infected with SARS-CoV-2. Waiting for a vaccine that never arises is going to be difficult for individuals; how long can you realistically self-isolate and/or shield?
We are very keen to do an anti-SARS-CoV-2 seroprevalence study in pwMS to see how many have been exposed to the virus and have not developed COVID-19 and to also look at antibody responses to SARS-CoV-2 in patients on different DMTs. We hypothesise that patients on anti-CD20 therapies will have as good an antibody response to SARS-CoV-2 as patients not on anti-CD20 therapies. This hypothesis refers to qualitative antibody responses, i.e. neutralising or protective antibody responses.
For the reasons above I have not stopped offering patients with active MS anti-CD20 therapies during the pandemic. This refers to both starting and retreatment. Some patients have chosen to delay their treatments until the pandemic is over and others have taken my advice and gone ahead with their treatments; this is their choice. But as I have said before the pandemic won’t be over anytime soon; the tail is likely to extend for 18-24 months and possibly longer. Therefore all the guidelines that have recommended delaying or postponing treatment with depletion therapies, i.e. the anti-CD20s, cladribine, alemtuzumab, mitoxantrone, cyclophosphamide and HSCT will have to be reviewed. We can’t stop treating MS or offering patients less effective options for the next 18-24 months. If we do what will be the consequences?
How many swallows does it take to make a summer? I am aware that one case report is not much, but there are an increasing number of patients being reported on social media who have been treated with an anti-CD20 and have had gotten through COVID-19 without a problem.
I would urge all the national register studies to be please report your data on COVID-19 outcomes in pwMS as soon as possible. We need the data to formalise our treatment guidelines and to help allay the fears of our patients. Please use one of the archive repositories to get your data out to the MS community as soon as possible. Thank you.
Background: Coronavirus disease 19 (COVID-19) is a novel disease entity that is spreading throughout the world. It has been speculated that patients with comorbidities and elderly patients could be at high risk for respiratory insufficiency and death. Immunosuppression could expose infected patients to even higher risks of disease complications due to dampened immune response. However, it has been speculated that overactive immune response could drive clinical deterioration and, based on this hypothesis, several immunosuppressants are currently being tested as potential treatment for COVID-19.
Methods: In this paper we report on a patient that has been treated with ocrelizumab (a B-cell depleting monoclonal antibody) for primary progressive multiple sclerosis who developed COVID-19.
Results: Despite complete B cell depletion, patient symptoms abated few days after hospitalization, and he was discharged to home-quarantine. Phone interview follow-up confirmed that, after 14 days, no new symptoms occurred.
Discussion: This report supports the putative role of immunosuppressive therapy in COVID-19 affected patients.
I did a video consultation yesterday with a patient with MS who in the event of getting COVID-19 is at very high risk of severe COVID-19. This patient has type 2 diabetes with poor glucose control, is hypertensive and is also obese (BMI of 32). I asked what their GP had done to help them lose weight. The GP had recommended exercise and believe it or not hadn’t discussed diet with them.
The idea that exercise is a primary treatment for obesity is a myth. Obesity and metabolic syndrome is an endocrine disorder due to hyperinsulinaemia (high insulin levels). The idea that can you treat obesity with exercise, and not address the hyperinsulinaemia, is a dogma that has been disproven years ago. I actually take the contrary view that you first have to start losing weight to exercise properly. If you have a BMI of 32 and you start doing unsupervised exercise you are likely to get an injury and then become less active.
The other dogma is that obesity is too many calories in and too few out; i.e. obesity is a simple imbalance of what you eat with what you expend. This dogma has also been disproven. Not all calories are made equal. Carbohydrates, in particular, processed carbohydrates with a high glycemic index are much more obesogenic compared to fats, proteins and complex carbohydrates (low glycaemic index).
I briefly explained this to this patient and referred her to Dr David Unwin’s or ‘the diet doctor’s’ website. David Unwin is one of the NHS’ heroes and deserves to be knighted to his contribution to the health of the nation. David Unwin has been treating metabolic syndrome with a low carbohydrate diet and getting over 50% of his patients with type 2 diabetics off medication; he is putting their diabetes into remission. The science behind low carbohydrate diets as a treatment for obesity, hypertension and type 2 diabetes is well-grounded; in my opinion, it’s irrefutable.
The other positive spin-off of a low carbohydrate diet, beyond weight loss, is that it is also ketogenic. Ketosis may have other health benefits for pwMS. There is very compelling data from animal models that ketosis is neuroprotective and may promote remyelination (please see my blog post ‘COULD DIET BE THE NEW ADD-ON DMT?’ from 21-Feb-2020).
So if you consider yourself of being at-risk of severe COVID-19 and you are obese and/or diabetic and/or hypertensive maybe it is the right time to try a low carbohydrate diet.
I am not saying in this post that you shouldn’t exercise. However, exercise is a powerful appetite stimulant and what happens is that if you exercise without addressing your diet you will simply end up eating more calories than you expend. You need to get your diet right first. A correct diet allows you to maximise the benefits of exercise.
If you are an HCP battling to manage MS remotely under the COVID-19 lockdown, or you have any specific problems that you need help with, please don’t hesitate to register for tomorrow’s Q&A session. The feedback we have been getting about these webinars has been amazing.
My husband and I were hoping to start a family this year. What do you advise; should I attempt to fall pregnant or wait until after the COVID-19 pandemic?
How long is a piece of string? Mouse Doctor 2 would tell you to divide the string in half and the length of the original piece of string is twice that of one of the halves. With the flattening of the curve and the extension of the tail COVID-19 pandemic is likely to extend beyond 2020 and into 2021. Some epidemiologists are predicting the tail going out to 2022. Therefore, in my opinion, COVID-19 pandemic is not necessarily a reason to put your life on hold.
Image of flattening=the-curve is from the CDC
Clearly, for some people, there are economic reasons why they wouldn’t want to start a family in the current climate. For example, if you or your partner have lost your job, or you are uncertain about your long-term employment prospects, these economic factors will potentially impact on your decision to start a family.
What about SARS-CoV-2, a coronavirus, and pregnancy?
There is no published data that coronavirus infections are associated with foetal abnormalities or a higher miscarriage rate. It looks as if transplacental infection of the foetus with SARS-CoV-2 is unlikely. Saying this there is one case report of a neonate, born by caesarian section from a mother who had severe COVID-19, who tested positive for the virus. The problem with this case is that the neonate could have been infected at the time of birth. The good news is that children, including very young children, don’t seem to get COVID-19. Why children are resistant to COVID-19 is unknown at present, but it must have something to do with the biology of the virus. Therefore, it is unlikely that newborn babies are at significant risk of severe COVID-19 and there is no evidence to suggest worse foetal outcomes.
The other important thing to realise that if you do fall pregnant and get infected with SARS-CoV-2 and develop COVID-19 or not the antibodies you produce against the virus will cross the placenta and should give your newborn child some protection against will-type viral infection in early life (6-12 months). These transplacental antibodies may be sufficient to protect them and bridge the gap until we hopefully have an effective vaccine against SARS-CoV2.
What about being pregnant when you get COVID-19?
So far the data is very reassuring in that the case reports from China and elsewhere suggest being pregnant doesn’t increase the risk of getting severe COVID-19 and possibly to the contrary, i.e. less severe disease. However, there are relatively small numbers of pregnant women who do get severe COVID-19, whether this is a smaller proportion than the general aged-matched population is at present unknown.
As severe COVID-19 is a major stressor it may trigger premature labour. In an Italian case series of 42 pregnant women with COVID-19 and who were admitted to hospital only seven required respiratory support and eventually did well. Out of the 42 pregnancies, two premature labours occurred. This suggests COVID-19 in itself is not associated with adverse pregnancy outcomes. Saying this it is clear from the published data that if you are in the third trimester of pregnancy and you present with COVID-19 infection then a large number of women are having their babies born by caesarian section. I assume this is being driven by the medical condition of the mother; I doubt many women hospitalised with COVID-19 will be in a state to go through with normal vaginal delivery.
Overall, I think the data is reassuring in that it is unlikely being pregnant puts you at greater risk of COVID-19 or severe COVID-19. Based on the published data to date it is likely that pregnancy a state of mild immunosuppression may actually protect you from severe COVID-19.
What about the babies of woman who have had COVID-19 and subsequently delivered their babies?
The third-trimester data looks reassuring, but it is too early to make a call on the outcomes of babies born to mother who had COVID-19 during the first and second trimesters of pregnancy. Based on the biology of coronaviruses and pregnancy these babies are likely to be fine but will have to wait for the data to emerge. It will be important that not only the children of mothers with COVID-19 need to be studied but those born to mothers who had asymptomatic SARS-CoV-2 infection. For the latter, we need good population-based antibody studies to be done.
Please note some obstetricians have looked at what happened to pregnancy outcomes from the original SARS and MERS epidemics to make some predictions about SARS-CoV-2. I am not sure we can use this data as these two outbreaks were due to more virulent viruses with a much higher case-fatality rate.
Conclusion: So my advice, in general, would be not to put your lives on hold unless you have to for other reasons. It is unlikely that SARS-CoV-2 causes foetal abnormalities, transplacental transmission of the virus is likely to be rare and there is no suggestion of an increase miscarriage rate due to COVID-19. Pregnancy itself doesn’t put you at increased risk of COVID-19 or severe COVID-19 and may actually protect you from the latter. In the case of getting severe COVID-19 whilst pregnant, there is a small chance of premature labour and a high likelihood that if you are ready to deliver the delivery will be by caesarian section.
Introduction: The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has exposed vulnerable populations to an unprecedented global health crisis. The knowledge gained from previous human coronavirus outbreaks suggests that pregnant women and their fetuses are particularly susceptible to poor outcomes. The objective of this study was to summarize the clinical manifestations and maternal and perinatal outcomes of COVID-19 during pregnancy.
Material and methods: We searched databases for all case reports and series from February 12 to April 4, 2020. Multiple terms and combinations were used including COVID-19, pregnancy, maternal mortality, maternal morbidity, complications, clinical manifestations, neonatal morbidity, intrauterine fetal death, neonatal mortality and SARS-CoV-2. Eligibility criteria included peer-reviewed publications written in English or Chinese and quantitative real-time polymerase chain reaction (PCR) or dual fluorescence PCR confirmed SARS-CoV-2 infection. Unpublished reports, unspecified date and location of the study or suspicion of duplicate reporting, cases with suspected COVID-19 that were not confirmed by a laboratory test, and unreported maternal or perinatal outcomes were excluded. Data on clinical manifestations, maternal and perinatal outcomes including vertical transmission were extracted and analyzed.
Results: Eighteen articles reporting data from 108 pregnancies between December 8, 2019 and April 1, 2020 were included in the current study. Most reports described women presenting in the third trimester with fever (68%) and coughing (34%). Lymphocytopenia (59%) with elevated C-reactive protein (70%) was observed and 91% were delivered by cesarean section. Three maternal intensive care unit admissions were noted but no maternal deaths. One neonatal death and one intrauterine death were also reported.
Conclusions: Although the majority of mothers were discharged without any major complications, severe maternal morbidity as a result of COVID-19 and perinatal deaths were reported. Vertical transmission of the COVID-19 could not be ruled out. Careful monitoring of pregnancies with COVID-19 and measures to prevent neonatal infection are warranted.
From February 24, 2020, a COVID-19 obstetric task force was structured to deliver management recommendations for obstetric care. From March 1, 2020, six COVID-19 hubs and their spokes were designated. An interim analysis of cases occurring in or transferred to these hubs was performed on March 20, 2020 and recommendations were released on March 24, 2020. The vision of this strict organization was to centralize patients in high-risk maternity centers in order to concentrate human resources and personal protective equipment (PPE), dedicate protected areas of these major hospitals, and centralize clinical multidisciplinary experience with this disease. All maternity hospitals were informed to provide a protected labor and delivery room for nontransferable patients in advanced labor. A pre-triage based on temperature and 14 other items was developed in order to screen suspected patients in all hospitals to be tested with nasopharyngeal swabs. Obstetric outpatient facilities were instructed to maintain scheduled pregnancy screening as per Italian guidelines, and to provide pre-triage screening and surgical masks for personnel and patients for pre-triage-negative patients. Forty-two cases were recorded in the first 20 days of hub and spoke organization. The clinical presentation was interstitial pneumonia in 20 women. Of these, seven required respiratory support and eventually did well. Two premature labors occurred.
Background: 2019 novel coronavirus disease (COVID-19) has become a worldwide pandemic. Under such circumstance pregnant women are also affected significantly.
Objective: This study aims to observe the clinical features and outcomes of pregnant women who have been confirmed with COVID-19.
Methods: The research objects were 55 cases of suspected COVID-19 pregnant women who gave a birth from Jan 20th 2020 to Mar 5th 2020 in our hospital-a big birth center delivering about 30,000 babies in the last 3 years. These cases were subjected to pulmonary CT scan and routine blood test, manifested symptoms of fever, cough, chest tightness or gastrointestinal symptoms. They were admitted to an isolated suite, with clinical features and newborn babies being carefully observed. Among the 55 cases, 13 patients were assigned into the confirmed COVID-19 group for being tested positive severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) via maternal throat swab test, and the other 42 patients were assigned into the control group for being ruled out COVID-19 pneumonia based on new coronavirus pneumonia prevention and control program(the 7th edition).
Results: There were 2 fever patients during the prenatal period and 8 fever patients during the postpartum period in the confirmed COVID-19 group. In contrast, there were 11 prenatal fever patients and 20 postpartum fever patients in the control group (p>0.05). Among 55 cases, only 2 case had cough in the confirmed group. The imaging of pulmonary CT scan showed ground- glass opacity (46.2%, 6/13), patch-like shadows(38.5%, 5/13), fiber shadow(23.1%, 3/13), pleural effusion (38.5%, 5/13)and pleural thickening(7.7%, 1/13), and there was no statistical difference between the confirmed COVID-19 group and the control group (p>0.05). During the prenatal and postpartum period, there was no difference in the count of WBC, Neutrophils and Lymphocyte, the radio of Neutrophils and Lymphocyte and the level of CRP between the confirmed COVID-19 group and the control group(p<0.05). 20 babies (from confirmed mother and from normal mother) were subjected to SARS-CoV-2 examination by throat swab samples in 24 hours after birth and no case was tested positive.
Conclusion: The clinical symptoms and laboratory indicators are not obvious for asymptomatic and mild COVID-19 pregnant women. Pulmonary CT scan plus blood routine examination are more suitable for finding pregnancy women with asymptomatic or mild COVID-19 infection and can be used screening COVID-19, pregnant women, in the outbreak area of COVID-19 infection.
The current outbreak of the novel 2019 coronavirus disease (COVID-19) started in China in December 2019 and has since spread to several other countries. On March 25, 2020, a total of 375,498 cases had been confirmed globally with 2,201 cases in Brazil, showing the urgency of reacting to this international public health emergency. While in most cases, mild symptoms are observed, in some cases the infection leads to serious pulmonary disease. As a result, the possible consequences of the COVID-19 outbreak for pregnant women and its potential effects on the management of assisted reproductive treatments, demand attention. In this review, we summarize the latest research progress related to COVID-19 epidemiology and the reported data of pregnant women, and discuss the current evidence of COVID-19 infections during pregnancy and its potential consequences for assisted reproductive treatments. Reported data suggest that symptoms in pregnant women are similar to those in other people and that there is no evidence for higher maternal or fetal risks. However, considering the initial data and lack of comprehensive knowledge on the pathogenesis of SARS-CoV-2 during pregnancy, human reproduction societies have recommended postponing the embryo transfers and do not initiate new treatment cycles. New evidence must be considered carefully in order to adjust these recommendations accordingly at any time and to guide assisted reproductive treatments.
There are few cases of pregnant women with novel coronavirus 2019 (COVID-19) in the literature, most of them with a mild illness course. There is limited evidence about in utero infection and early positive neonatal testing. A 41-year-old G3P2 with a history of previous cesarean deliveries and diabetes mellitus presented with a 4-day history of malaise, low-grade fever, and progressive shortness of breath. A nasopharyngeal swab was positive for COVID-19, COVID-19 serology was negative. The patient developed respiratory failure requiring mechanical ventilation on day 5 of disease onset. The patient underwent a cesarean delivery, and neonatal isolation was implemented immediately after birth, without delayed cord clamping or skin-to-skin contact. The neonatal nasopharyngeal swab, 16 hours after delivery, was positive for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) real-time polymerase chain reaction (RT-PCR), and immunoglobulin (Ig)-M and IgG for SARS-CoV-2 were negative. Maternal IgM and IgG were positive on postpartum day 4 (day 9 after symptom onset). We report a severe presentation of COVID-19 during pregnancy. To our knowledge, this is the earliest reported positive PCR in the neonate, raising the concern for vertical transmission. We suggest pregnant women should be considered as a high-risk group and minimize exposures for these reasons.
…… In 2 reports describing 18 pregnancies with coronavirus disease 2019, all were infected in the third trimester, and clinical findings were similar to those in nonpregnant adults. Fetal distress and preterm delivery were seen in some cases. All but 2 pregnancies were cesarean deliveries and no evidence of in utero transmission was seen. Data on severe acute respiratory syndrome and Middle East respiratory syndrome in pregnancy are sparse. For severe acute respiratory syndrome, the largest series of 12 pregnancies had a case-fatality rate of 25%. Complications included acute respiratory distress syndrome in 4, disseminated intravascular coagulopathy in 3, renal failure in 3, secondary bacterial pneumonia in 2, and sepsis in 2 patients. Mechanical ventilation was 3 times more likely among pregnant compared with nonpregnant women. Among 7 first-trimester infections, 4 ended in spontaneous abortion. Four of 5 women with severe acute respiratory syndrome after 24 weeks’ gestation delivered preterm. For Middle East respiratory syndrome, there were 13 case reports in pregnant women, of which 2 were asymptomatic, identified as part of a contact investigation; 3 patients (23%) died. Two pregnancies ended in fetal demise and 2 were born preterm. No evidence of in utero transmission was seen in severe acute respiratory syndrome or Middle East respiratory syndrome. Currently, no coronavirus-specific treatments have been approved by the US Food and Drug Administration. Because coronavirus disease 2019 might increase the risk of pregnancy complications, management should optimally be in a health care facility with close maternal and fetal monitoring. Principles of management of coronavirus disease 2019 in pregnancy include early isolation, aggressive infection control procedures, oxygen therapy, avoidance of fluid overload, consideration of empiric antibiotics (secondary to bacterial infection risk), laboratory testing for the virus and coinfection, fetal and uterine contraction monitoring, early mechanical ventilation for progressive respiratory failure, individualized delivery planning, and a team-based approach with multispecialty consultations. Information on coronavirus disease 2019 is increasing rapidly. Clinicians should continue to follow the Centers for Disease Control and Prevention website to stay up to date with the latest information (https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html).
