#COVIDMS The Italians step-up to take action over COVID-19

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As you are aware Northern Italy is one of the European epicentres of the coronavirus / COVID-19 pandemic. To address the concerns of MS healthcare professionals the Milan group have produced guidelines for managing DMTs in their patients. Fortunately, we have a large number of Italians in our group (‘The Blizard Little Italy’) who, with Dr Saul Reyes (ECTRIMS Fellow), helped translated the guidelines for us.

Italian recommendations on the management of MS patients during the COVID-19 epidemics

These are recommendations made by Neurologists and Infectious diseases specialists whilst we have no evidence-based data at present. 

Treatment of MS patients

Given the lack of knowledge or data on the COVID-19 disease course in MS patients receiving DMTs, at present there is no recommendation to stop the different DMTs and therefore expose MS patients to the risk of MS exacerbations. We, therefore, recommend continuing the current DMT specifically with: 

1. First-line DMTs (Beta-interferons, Glatiramer acetate, Teriflunomide or Dimethyl fumarate). These DMTs can be prescribed as usual.

2. Fingolimod. 

3. Natalizumab.
 
For ‘lymphodepleting’ DMTs: Any decisions about these DMTS should be made based on individual circumstances. 

Temporarily delay the start of lymphodepleting DMTs such as Ocrelizumab, Alemtuzumab, Rituximab or Cladribine. 

Temporarily delay (between 6 and 12 months depending on the DMT) re-dosing of Alemtuzumab, Ocrelizumab and Cladribine. This decision should be made based on individual factors such as disease severity and disease activity.

For anti-CD2O DMTs it is recommended to delay next dose even beyond 6 months if CD19+ and CD20+ lymphocyte counts are severely decreased at the time the next dose is due. 

Some special considerations: for patients who have already received the first dose of the first cycle, it is recommended to give the second dose (i.e. complete the first cycle) and ‘extra precautions’ should be taken. 

Patients with confirmed COVID-19 infection: Withheld any first or second-line DMT until clinical resolution and/or approval to continue treatment by an infectious diseases specialist (given the potential antiviral activity of beta-interferons documented in the literature, for patients receiving treatment with beta-interferons the decision about continuing treatment resides on the treating neurologist). 

Symptoms of potential COVID-19 infection: fever, dry cough and asthenia. 

What to do in the event of COVID-19 symptoms?
Instruct your patients no to attend A&E services to avoid overcrowding them and further spreading of the virus. Instruct your patients to call the local emergency number, describe their symptoms and wait for instructions. 

Evaluate the temporary withdrawal of current DMT based on the guideline provided above.  

Recommendations for MS patients and healthcare professionals at MS centres:

If possible, avoid crowded places such as cinemas, theatres, schools, etc. 

In high risk, areas restrict access to MS centres to MS patients only. 

For patients on immunosuppressive infusion therapies, the use of protective surgical-grade masks is recommended. 

If travelling long distances or using public transport is absolutely necessary, it is recommended the use of protective masks and hand sanitizing (particularly for patients on Fingolimod, Alemtuzumab, Ocrelizumab, Cladribine or Rituximab).

If possible, work from home. 

Good personal hygiene is always important, specifically, it is recommended to wash your hands frequently. These recommendations are provided as a guideline only, please always refer to your local government advice.

These recommendations are likely to change depending on the evolution of the epidemics. 

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

59 comments

  • Have I read this right – that if infection is confirmed, the advice would be to come off the DMT (in my case, fingolimod).? I’d been thinking that if I did get coronavirus, it would ‘just’ be the virus that I’d be fighting. The prospect of the certain MS rebound if I came off gilenya is terrifying – I remember what happened when I transitioned from copaxone to gilenya. I feel this might push me in the direction of cancelling this year’s travel plans.

    • What Kay said 👆. Could we have more clarification on this? I too, will be worried about the rebound effect but I also want to be able to fight the virus. We’re kind of damned if we do and damned if we don’t.

    • If you stop taking a drug like fingolimod you are still getting protection from MS for some weeks. This is shown by the time taken for rebound to develop. A viral infection is typically dealt with within a couple of weeks.

  • I’m in the UK and on ocrelizumab – due 2nd full dose in May.
    Are these guidelines just relevant to Italy?
    I have the ability to work from home so should I be doing so?
    Also due to travel to the Maldives connecting in Dubai. Do I cancel this?

    • Debbie hi,

      I have family living in the UAE for the last 10 years or so. You ought to know a couple of things about Dubai.
      1) Public health is not a thing. They run a winner-take-all system where locals (i.e. natives) and wealthy expatriates have access to the Mayo and Clevland clinic in the Healthcare city. The rest receive sub-par care.
      2) A large part of the foreign population is from Iran and travels back and forth. Dubai and Beirut are trading hubs for Iranis to circumvent US sanctions. Qum in Iran is a much larger epicentre than Northern Italy and a number of Irani MPs are infected already. Khomeini’s senior advisor passed away last week.

      I would skip flying to the Middle East if I were you. Now I have family visiting from the middle east in the coming weeks….and am not sure how to deal with them yet.

      • Hi Tony,
        We are only flying to the Maldives via Dubai airport but not actually stopping there. It’s so difficult making this decision tbh as nobody is giving much advice.

        • People who work in the airport are Dubai residents…
          But on a positive note, I hear that the warmer the weather is the slower Covid goes around.

          • I just wish someone would give more guidance though. I don’t want to cancel unnecessarily but equally don’t want to take any risks with my health

        • Sorry Debbie, but your holidays to the Maldives are something of a first world problem – don’t you think?

          NHS overloaded with cases and planing for a contingency of 500,000 death in a worst case scenario. Why should they give a toss about your mojito on a sunny beach?

          • Gosh! Could we please try not to get mean or personal about this.
            Trying to find the correct line between not panicking/over-reacting and doing the correct things to keep ourselves and others safe isn’t easy in this fast moving situation.
            We’re all feeling it to some extent so let’s, please, not beat up on one another as it continues to unfold.
            Thanks.

    • The Italians around Milan are in a different environment as the have significantly higher number of infections than are current in the UK. This will probably change. However, Itay is now likely going to be the best source of information of what works and what doesn’t as the infection has started and people in those areas will start to inform the rest of the world what the risks are.

      The Neurologists at the ABN should surely be putting a statement in place concerning the UK situation, but I am sure ProfG will keep you infomred of what is happening in the UK. Remember at
      present there are relatively few cases and these can largely be traced to to their patient zero, putting a plan in place for when the infection spreads would be a sensible but we are not at that stage yet.

      • The panic is here, just went to the super market to buy a packet of paracetamol for headache (allergic to aspirin)….not a pill in sight…No soap and bog roll all but gone…Ah!

    • not replying as an expert, my 3rd dose is due in June- I may hold off until July or August, that is a personal choice- I have been managing lifestyle factors in my life so I am not worried about the MS flare just sharing

  • A couple of new things here:
    1) Beta-interferons have anti-viral capabilities! but then again, MD would make a case that platform therapies are pointless
    2) Completely silent on the neutropic thing with Tysabri – I was surprised to see it on the “OK” list in the absence of clarity on encephalitis.

    “For patients on immunosuppressive infusion therapies, the use of protective surgical-grade masks is recommended”
    This blog made a reference to FFP3 masks fitted by trained professionals. Is Barts considering fitting such masks on the faces of natalizumabers visiting for their 4-weekly infusion?

    Tony

    • Would be feasible for people on DMTs to be tested at regular intervals for this virus? Would that help in the management of their treatment in the current climate?

    • There are clear suggestions that the loose surgical masks are not much of a barrier viruses and are perhaps a crutch to give you pacificiation, however if you are infected they will reduce the aerosol and droplet risk for infecting others…as for masks they are few and far between and the price inflation is staggering a couple of kids made £10,000 a week selling 20p masks for £5.

      However you have raised a point, at the moment the infection numbers are too low. Importantly this is where we need mask etiquette, if you know someone is infected (by wearing a mask) you know. This is what many asians such as the Japanese do culturally. However, if every one whereas a mask you have no idea and there will always be people who don’t, on the train home the other night I was surrounded by coughs and sniffles. Seasonal cold or covid

  • Is this Italian advice being circulated around Europe and if so is it being heeded by the NHS, particularly by those centres that provide the ‘big guns’ such as HSCT and Alemtuzumab etc ????

  • I started Mavenclad on the 13th January this year, I finished the second dose of year 1 on 21st February, my body is struggling to fight off infections (chest, throat and UTIs) what are my chances of fighting off Corona Virus? At what stage should my lymphocytes start to pick up again allowing the immune system to regain its ability to fight off infection??
    Do we come under the category “Vulnerable” given the fact that our immune systems have been suppressed ???

    • Your T cells will stay flat (30-40%) for the rest of the year, your B cells with have dropped (80-90%) and start to pick up soon. These are the immature/mature cells which willl make an anti-covid.

  • Following my second year treatment cycle of Cladribine 10 months ago, my Lymphocyte count is taking a while to recover and has been hovering around 0.6 for several months. Is this what usually happens with Cladribine treatment and is there any way my Lymphocyte count can be boosted to normal levels more quickly, bearing in mind the risks of this new virus? Is it also usual to have long standing swollen glands in the neck area and generally feel unwell whilst on this treatment?

    • Yes they stay rather flat after depletion but if a new virus come along your existing memory cells are no use, it is the new ones that that you want, if there are T cells that can rsepond to the virus there is nothing to stop them doing so. If you look at the recent post I did on alemtuzumab it can be a long time before they go back to normal level.

      Swollen glands and feelng unwell,,,,I doubt it is normal…ProfK may know

      • Many thanks MD for taking the time to reply. This Barts blog is invaluable, long may it continue to inform everyone with MS and their carers/ health professionals.

  • So now the Italians have closed their schools!

    This worries me more than ease my fears. If kids show less to no symptoms, then if they are out playing with friends and passing it to other families then this might quicken the transmission rather than slow it.

    Guess it’s hard to know what more to do…

  • Would it be wise to request the Pneumoccocal vaccine at my local health centre ( lymphocyte count is very low)?

  • I find it interesting that fingolimod is on the short list of acceptable options given that it causes lymphopenia due to sequestration of lymphocytes in lymph nodes. I know there were safety signals around herpes zoster in Phase III trials, but perhaps the risk of an opportunistic respiratory viral infection is minimal.

    • The problem is what do you do if you stop fingolimod? Do you start an interferon-beta preparation or teriflunomide or GA? I would suggest we give patients the option of derisking themselves. The other issue is if you do get through the epidemic you may want to get vaccinated in the future that is if a vaccine becomes available; more reason to derisk onto an immunomodulatory therapy.

      • How interesting you mention that. I was just revisiting the MMR case on the blog:
        https://multiple-sclerosis-research.org/2020/02/measles-encephalitis-the-unknown-known/

        “Once you are on specific DMTs live vaccines such as the MMR are contraindicated.”
        Would patients have to stop Tysabri to receive the Covid-19 vaccine if/when it is marketed?
        That changes the decision making in that case: why take “neurotropicity”(!) risk today if we will have to let go Tysabri in 12 months time for vaccination….

        • The EMA’s natalizumab (Tysabri) SmPc is quite clear about the risks of neurotropic viruses (e.g. HSV and VZV). I have little doubt this will apply to live neurotropic vaccine strains and other neurotropic viruses:

          Infections including other opportunistic infections

          TYSABRI increases the risk of developing encephalitis and meningitis caused by herpes simplex and
          varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported in the
          postmarketing setting in multiple sclerosis patients receiving TYSABRI (see section 4.8). If herpes
          encephalitis or meningitis occurs, the medicinal product should be discontinued, and appropriate
          treatment for herpes encephalitis or meningitis should be administered.

          Acute retinal necrosis (ARN) is a rare fulminant viral infection of the retina caused by the family of
          herpes viruses (e.g. varicella zoster). ARN has been observed in patients being administered
          TYSABRI and can be potentially blinding. Patients presenting with eye symptoms such as decreased
          visual acuity, redness and painful eye should be referred for retinal screening for ARN. Following
          clinical diagnosis of ARN, discontinuation of TYSBABRI should be considered in these patients.
          Prescribers should be aware of the possibility that other opportunistic infections may occur during
          TYSABRI therapy and should include them in the differential diagnosis of infections that occur in
          TYSABRI-treated patients. If an opportunistic infection is suspected, dosing with TYSABRI is to be
          suspended until such infections can be excluded through further evaluations.

          With regard to vaccines it says the following; please note live vaccines have not been studied.

          Immunisations

          In a randomised, open label study of 60 patients with relapsing MS there was no significant difference
          in the humoral immune response to a recall antigen (tetanus toxoid) and only slightly slower and
          reduced humoral immune response to a neoantigen (keyhole limpet haemocyanin) was observed in
          patients who were treated with TYSABRI for 6 months compared to an untreated control group. Live
          vaccines have not been studied.

          • Your last post on mutations couldn’t be clearer. What a headache. There is no way I am de-escalating to platform therapy.
            And how to self isolate when my girls go to school, nursery and wife to the shops and see the midwife!

            The whole risk/benefit curve has shifted (or shattered into pieces now).

      • I have opted for aubigio as I have tolerance issues with Ocrevus. I had my last dose of ocrevus 7 months ago. How long will I need to wait before I can have live vaccinations please?

  • I’m not clear on the rationale for delaying dosing Ocrevus. Assuming that the CD-19 and CD-20 are at 0, would dosing not just keep them at that level? I don’t understand how the risk for infection increases in patients coming up to the scheduled dose. Surely the risk is the same as right now?
    Any insight would be appreciated, as I’m in Italy and facing an upcoming dose.

    • You are correct the aim of ocrelizumab is to keep the CD19 count at 0 and the next dose aims to keep that at 0 so as you say there is not really an increased risk over that current risk. However perhaps increased risk comes with a process of time becuase you have no B cells for another 6 months. Therefore the chance of an opportunistic infection increases. In trials ocrelizumab increased the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections but to put it in perspective the actual increase was not that much more than with interferon. However, in some people it eventually leads to a drop in the antibody producing cell capability and this increases infection risk. However, if we are worried about COVID one anticipates that this is going to a major problem for the next few months, so you would know if you are becoming hypogammaglobulinemic (not producing normal levels of antibodies). You drop producing IgM before IgA and IgG go. So the question is if you can’t make an anti-viral response is that critical?

      If you delay ocrelizumab does that matter to efficacy against MS and your capacity to make a new anti-viral response? This probably in part depends on how you deplete and repopulate after treatment. Based on the phase II ocrelizumab trial the median time to repopulation after 3-4 doses is 62-75 weeks and ranged from 27 weeks (7 months) to 175 (3.25 years). Cells in these populations will be new B cells that react to new pathogens. If the memory B cell related control of MS is true it is likely that memory B cells repopulation is very much slower than the CD19 population and so inhibition of MS could be longer than just 6 months.

      Sadly this has not been formally tested although there is supportive information that this may be the case. However, the question arises that if we stop dosing, does this allow anti-drug antibody responses to arise as B cells return when circulating ocrelizumab is present and dropping. If this occurred it could stop ocrelizumab from working. This is my concern but again unproven.

      • Thanks for the insightful response, MD, very much appreciated.
        As coming up to the 3rd full dose in mid march, based on the data above, it would imply repopulation by mid-late April at the earliest, or statistically by after the summer. Add that to the fact that, if I understand correctly, hypogammaglobulinemia has been detected over years of treatment and IgG/IgA/IgM levels are tested at each infusion, so it can be detected in time. Thus I can’t help but figure that for people who’ve been successfully on Ocrevus for a couple of years at most and have immunoglobulin levels above the warning threshold, postponing the infusion doesn’t really make a major difference, Vs the MS related risk. Have I interpreted the information correctly?
        The only other thing I’m wondering is if there may be a short term risk increase right after the infusion due to steroids and antihistamines… As I’ve personally observed increased colds in the couple of weeks after an Ocrevus dose. Is there any data on this as far as you know?
        Thanks again for all the dissemination work you do, this blog has been a tremendous source of insight for years.

      • Two follow-up questions to this comment:

        1) Based on the Phase II data, is the implication that someone would have to go off of Ocrevus for ~62-75 weeks (on average) in order to recoup enough B cells to have a “normal” anti-viral response (acknowledge that we don’t know anything for sure, just trying to follow the logic)

        2) Dos your comment about anti-drug antibody responses potentially arising mean that it’s possible that stopping Ocrevus could make it ineffective if/when you start taking it again?

        I’m 4 months out from my last Ocrevus dose and trying to figure out if I should just plan on hibernating for the next 2-3 months + delay my next dose…but your comments I think imply that even when I’m 6 months past my last dose, I’ll still potentially be B-cell deficient and less able to fight off viral infections.

        Thanks for the great posts and comments!

        • 1.(a) The phase II data has people who are treatment free for 18 months that are doing well and perhaps getting less infections, although the data past 12 months is weak because the numbers are low. However the implications are there that it may be possible to get protection for more that 6 months. The paper is online at MedRXiv
          1(b). Data from the phase II following treatment suggests activity for at least 12 months
          1(c). Dosing to repopulation of memory cells with rituximab has maintained efficacy but reduced dosing frequency.

          There is no hard evidence and needs a trial, we have proposed on called ADIOS, but we don’t have funding for this yet

          2. Yes this is the hypothetical that needs to be addressed. There is no evidence either way.

          3. Maybe Based on rituximab treatment memory B cells are depleted for at least 12 months, in some studies in non MS disease, efficacy was evident 5 years after dosing. However the anti viral cells will come from naive cells as they are depleted for at least 6 months and probably longer. You may be B cell deficient whilst antibody is still circulating, this can be tested, However, if an infection comes along it is not clear if the B cells will respond. Also the comments above are based on blood, however, rituximab does not clear the lymph glands as much as the blood and so the time spans and the responsiveness can be reduced.

          • Thank you so much, I really appreciate the detail. If I’m following the logic correctly, it sounds like either:
            (a) I’ll be in the “high risk of complications” from COVID/other infections well past the 6-month mark following my last dose
            -or-
            (b) I might still have B-cells in my lymph nodes that could fight, so I don’t need to keep locked away in my condo
            -or-
            (c) the B-cells that have been depleted in me might not have a big role in fighting COVID-19 in the first place, so I don’t need to keep locked away in my condo (I got this logic from a different post)

            I could handle the idea of locking myself away for a few months, but I don’t have enough discipline to go that much longer! If I decide to give up and venture out into public, I’ll give you my parents’ contact info so you can track what happens. 🙂

          • (a) Maybe it depends how long the B cells stay reduced for some people they have repopulated with 7 months for ome people it is longer, but anibodies are only part of the fight against viruses.
            (b) I don’t know the answer for this for ocrelizumab, but for rituximab, you are correct that in some people there are cells in the lymph nodes but in some they go too

            Cioc AM et al.Rituximab-induced changes in hematolymphoid tissues found at autopsy.Am J Clin Pathol. 2008 Oct;130(4):604-12

            Ramwadhdoebe TH et al.Effect of rituximab treatment on T and B cell subsets in lymph node biopsies of patients with rheumatoid arthritis.Rheumatology. 2019;58(6):1075-1085

            (c) You are probaly right. B cells have got a relatively short life span if they are not stimulated so what was made about two months ago will be long gone. But CD20 does not touch the precursor cells in the bone marrow so new ones will be made

      • Would you suggest that Ocrevus/Rituxan patients with igg below 700 mg/dl (bottom of normal range at the lab I go to) get IVIG?

  • Hi – would you know, please, what the advice is for PPMS sufferers, who are obviously not on DMTs? I haven’t come across any mention of advice applicable for PPMS people. My husband developed PPMS roughly 18 years ago – his current medication is Clonazepam, Duloxetine, Pregabalin, LDN (and Tamsulosin for controlling prostrate).

    • I don’t know, that is ProfGs Job, but the cocktail of drugs is probably not having a major immunosuppressive effect you should take the same pre cautions that we are all going to have to do.

    • People with PPMS are likely to be susceptible to complications of COVID-18 infection for several reasons linked to MS; more sedentary, deconditioning, high incidence of comorbid diseases (smoking, diabetes, etc.), greater risk of aspiration or secondary pneumonia, temperature-dependent conduction block from infection, premature ageing, etc.

      In general, people with MS will be at greater risk of complications of infections based on the impact MS has on general health. This is why pwMS are classed at being at high risk and are recommended to have the seasonal flu vaccine.

  • I delayed my Ocrevus infusion on 27th February- will be discussing with neuro today how to go forward.
    should I still consider wearing a mask in busy public spaces having had my first infusion in September? Living in London.

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