Yesterday I had the experience of a patient with highly active MS pull out of being treated with ocrelizumab (Ocrevus) because of concerns around being infected with the coronavirus COVID19. I suspect this will be the first of many patients with multiple sclerosis to do so.
It is clear that COVID19 epidemic is now a pandemic, i.e. it has involved enough continents and countries to be considered a major and very serious global health emergency. This was predicted to happen many weeks ago. Several basic epidemiological factors indicated that this would occur:
- A long asymptomatic period during which infected people shed the virus and are infectious
- Asymptomatic shedders who don’t get ill
- An estimated R0 (r-zero) of 3-5, which is an estimate of how many people or contacts that an infected person infects
- The identification of superspreaders; individuals who seem to be able to infect a large number of people
- Excessive national and international travel; the initial epidemic in Wuhan happened to coincide with the largest annual human migration of people (see graph below). Approximately 400 million people migrate in relation to the Chinese New Year and a lot of that migration was international, which explains why the virus has spread so rapidly to other countries
- Ubiquitous air travel, involving large airports and hubs, which has the ability to spread viruses very rapidly to people on the same aircraft and then to disperse them to all corners of the world before they get symptomatic disease
- COVID19 is also a new human pathogen having jumped to humans from animals and as a result of this, we have no pre-existing herd immunity that could buffer or reduce its rate of spread.
At the moment the mortality or death rate form the virus is approximately 2%, or 1 in 50, with the majority of deaths affecting the elderly or infirm. The mortality is likely to fall as case ascertainment and reporting gets better. This occurs because the less ill get counted into the so-called denominator. At a population level, this death rate has major implications for healthcare systems. The majority of the deaths are due to pneumonia and these sicker patients require intensive care support. All countries simply don’t have enough ITU beds to support large numbers of ventilated patients. In fact, Britain has too few ITU beds already, without having to deal with the coronavirus pandemic.
What to look out for?
Coronavirus infection presents very non-specifically with flu-like symptoms, i.e. fever, a cough, or difficulty breathing. Most cases are mild. Those who have died in often have pre-existing health conditions and this is where the problem lies for pwMS. If you have advanced MS, a history of recurrent chest infections and/or you are on immunosuppressive therapies you are considered at high risk of complications from coronavirus infection. The latter risk extends to other infections as well, which is why, for example, it is our policy to recommend the annual flu vaccine to all of our patients with MS.
What to do?
If you have symptoms following travel to a high-risk area or after coming into contact with someone who has had coronavirus infection you should contact the NHS hotline so that appropriate samples can be submitted to Public Health England for testing. In addition, you will need to self-isolate or be treated in isolation.
I would not recommend stopping your disease-modifying therapy. The immunosuppression associated with MS DMTs is relatively mild-moderate and hence most pwMS can handle infections relatively well. The exception being alemtuzumab (Lemtrada), and possibly cladribine (Mavenclad), during the lymphocyte depletion phase. Cladribine is less of a problem as T-cells are on average depleted by ~50%, whereas with alemtuzumab the T- and B-cell depletion is typically greater than 90%. The good thing about IRTs (immune reconstitution therapies) is that once your immune systems have reconstituted they are competent to deal with infections.
Although fingolimod (Gilenya) causes lymphopaenia it is not an absolute lymphopaenia as lymphocytes are sequestered or trapped in lymph nodes. Therefore, pwMS on fingolimod can in general deal with viral infections, although they have more frequent and possibly more severe infections. This also applies to other S1P modulators (siponimod, ponesimod, ozanimod, etc.), in other words it is a class effect.
Viral response on anti-CD20 therapies (rituximab, ocrelizumab and ofatumumab) should also be maintained, but maybe blunted as B-cell and antibody responses may be necessary to help clear the virus. The infections that people on anti-CD20 therapies have a problem with are encapsulated bacteria (pneumococcus, meningococcus, Haemophilus, etc.).
Coronaviruses can rarely cause and encephalitis, typically in severely immunocompromised patients. This would indicate that as a class coronaviruses are neurotropic. I am not aware of any data on whether or not COVID19 causes encephalitis. If COVID19 is neurotropic encephalitis would be a risk for people on natalizumab (Tysabri). As natalizumab blocks immune surveillance of the CNS, a person on natalizumab who develops a COVID19 encephalitis would be in danger of succumbing to the infection. The latter is analogous to PML, which is also viral encephalitis.
DMF (Tecfidera) is only mildly immunosuppressive and in my opinion, is unlikely to be a major worry in the event of you acquiring a COVID19 infection. The one caveat being patients on DMF with a significant lymphopaenia, i.e. with a total lymphocyte count of less than 0.8 x 109/L or 800/mm3.
Teriflunomide (Aubagio), glatiramer acetate (Copaxone) and interferon beta (Betaferon, Avonex, Rebif, Plegridy) are not immunosuppressive agents and hence should not increase your chances of having a severe COVID19 infection.
Whilst the risk of COVID19 infection to the general public, and hence pwMS, is very low I would not recommend changing your DMT or avoiding starting any planned infusions. I would, however, recommend that if you are immunosuppressive to be extra-vigilant about hygiene (handwashing, etc.) and to avoid travelling to high-risk areas. If you are travelling through high-risk areas, for example, China, Hong Kong or Singapore you need to be more vigilant.
I am also getting asked for advice about face masks. The evidence that cheap surgical masks work for coronaviruses is limited. Coronaviruses are spread in a different way to the flu virus. Coronaviruses are not aerosolized in the same way as the flu virus and hence are not breathed in, but are rather spread by droplets. These stick to surfaces and hence the need to wash your hands. So masks are likely to work both ways for coronavirus, where they are not very effective for flu. One thing masks do is they make you wearer change your behaviour in other ways.
If you are travelling to a high-risk area and are going to use a face mask can I suggest using a good quality one, i.e. an FFP3 mask that filters out small particulate matter? These work for larger organisms such as TB and may help reduce transmission of COVID19. It is important that you have the masks fitted and you know how to use them properly. Within the NHS the latter is typically done by a healthcare professional with the necessary training on how to assess adequate mask fitting and usage.
What did I recommend for my patient above?
As there was no way he was going to be treated with ocrelizumab I ended-up recommending teriflunomide. The advantage of teriflunomide is that it is not immunosuppressive and has pan anti-viral activity against many viruses.
Clearly the advice given above applies to pwMS living in the UK. In COVID19 hotspots, e.g. China, it may be safer to delay treatment with immunosuppressive therapies until the epidemic has passed and there is herd immunity to protect you. In addition, a COVID19 vaccine may become available within the next 6-12 months. Therefore, it may be worthwhile initially choosing an immunomodulatory DMT that won’t interfere with future vaccine responses.
P.S. (27-Feb-2020): Please be aware that the advice above may be time-limited. Once the coronavirus becomes established in the community and person-to-person spread becomes more common and the source of infection can’t be traced, which is happening in China and Italy at the moment, then the public health advice may change. In this situation reverse quarantine may be necessary, i.e. to ask high-risk individuals to self-isolate themselves so as not expose themselves to the virus. At the moment this is not necessary in the UK as all the cases have been linked to a clearly identifiable source.