Human coronaviruses are predominantly associated with respiratory tract infections. This group of viruses includes viruses that cause severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and now the COVID-19 pandemic.
One human coronavirus HCoV-OC43 is generally associated with mild upper respiratory tract infections, although it has been shown to have neuroinvasive properties. Studies in mice have shown that HCoV-OC43 can infect neurons and cause encephalitis and has also been shown to cause persistent infections in human neural-cell lines.
There are case reports that have identified HCoV-OC43 RNA in the cerebrospinal fluid or brain of children with acute disseminated encephalomyelitis and acute encephalomyelitis (see below).
Why are these observations important? They are important because it suggests that coronaviruses are potentially neurotropic and hence can infect the central nervous system. As coronaviruses are RNA viruses they have low fidelity, i.e. their reproduction results in many variants or mutations. The so-called wild-type strain tends to mutate very rapidly and hence may produce neurotropic strains quite quickly. The latter is particularly important in the context of natalizumab and potentially fingolimod and other S1P modulators.
As natalizumab blocks immune surveillance of the CNS, a person on natalizumab who develops a COVID-19 encephalitis would be in danger of major complications of the infection and possibly succumbing to the infection. The latter is analogous to PML, which is also viral encephalitis, and herpes-simplex and varicella -zoster encephalitis and CMV retinitis that have all been described in people with MS on natalizumab.
The reason why these complications happen on natalizumab is that natalizumab blocks trafficking of anti-viral lymphocytes into the central nervous system and so if a virus gets into the CNS it will cause damage unchecked by the immune system. The EMA’s summary of product characteristics (SmPC) for natalizumab is very clear on this issue:
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.
What to do about this knowledge in the current COVID-19 pandemic is very difficult. Professor Julian Gold, an HIV and infectious disease consultant in our group, is adamant that we need to relay this information to our patients and let them make the decision if they want to stop natalizumab or fingolimod. However, as stopping these agents can result in rebound MS disease activity it would be advisable for these patients to switch to an alternative or safer DMT, i.e. interferon-beta, glatiramer acetate or teriflunomide. Professor Gold favours interferon-beta or teriflunomide as they have been shown to have antiviral effects.
As there is no consensus on this I am doing a survey via the MS Academy to find out what the wider MS community of HCPs feels about this and other issues. Just maybe the wisdom of the crowd will be better than an individual or small group opinion.
In the event of widespread COVID-19 epidemic, the logistics of derisking natalizumab and fingolimod is this way may not be feasible. A better way of managing this problem is reverse quarantine, i.e. at-risk patients stay on natalizumab or fingolimod and self-isolate at home to prevent themselves from becoming infected with the virus.
The other issue I have already raised is when a vaccine emerges for COVID-19 pwMS may want to be on a DMTs that allows to receive the vaccine and mount a good response to the vaccine. Some DMTs blunt the vaccine responses.
I hope you appreciate that formulating advice when there is no evidence base is not easy. At the moment whilst the epidemic has yet to show its true extent in the UK I would advise MS patients on natalizumab or fingolimod to continue with treatment for now but to be extra-vigilant about hygiene measures. This advice may change or it may need to be personalised.
Finally, as soon as the ABN and MS Academy produce consensus guidelines I will post them on the blog. The problem about consensus is that it is often a compromise and in the absence of data may not be the best advice.
Yeh et al. Detection of Coronavirus in the Central Nervous System of a Child With Acute Disseminated Encephalomyelitis. Pediatrics January 2004, 113 (1) e73-e76.
We present a case in which human coronavirus was detected in the cerebrospinal fluid of a child presumed to have acute disseminated encephalomyelitis. In murine models, coronavirus has been found to cause a chronic demyelinating condition that resembles multiple sclerosis. Additionally, there is in vitro evidence of human coronavirus’s ability to infect neural cells. This case report provides additional support for the hypothesis that coronavirus may be an important etiologic factor in the pathogenesis of demyelinating disease in humans.
Morfopoulou et al. Human Coronavirus OC43 Associated with Fatal Encephalitis. N Engl J Med 2016; 375:497-498.
Excerpts:
….. Here we report the use of deep sequencing of a brain biopsy sample obtained from an 11-month-old boy with severe combined immunodeficiency who had symptoms of viral encephalitis with negative results on conventional diagnostic polymerase-chain-reaction (PCR) assay.
….. The boy underwent unconditioned cord-blood transplantation, which resulted in T-cell engraftment. Nonetheless, his condition continued to deteriorate, and he died 1.5 months after receiving the transplant. RNA sequencing of a brain biopsy sample obtained 2 months after the onset of symptoms showed the presence of human coronavirus OC43 (HCoV-OC43), which was subsequently confirmed on real-time PCR (threshold cycle, 24) and brain immunohistochemical analysis.
CoI: multiple
N.B. MOUSEDOC HERE So AS YOU KNOW THERE ARE ALREADY MUTATIONS IN THIS VIRUS THE ORIGINAL S VARIANTAND THE L VARIANT
Thank you so much for this informative post. I’ve been hugely concerned about this topic, as I’m on Tysabri.
I would greatly appreciate your answers to the following:
Do you believe that COVID-19 is not neurotropic at present, but it may become after mutation?
If it’s neurotropic and a Tysabri contracts COVID-19, what’s the probability of getting encephalitis?
I am not aware of any case reports of COVID-19 encephalitis or meningitis. The Chinese will have data on this and I suspect information will emerge on this topic.
Siponimod is an S1P agent yes?
S1P1 and S1P5
Although not directly affected by the body of this post, having received Alemtuzumab, I am sitting here thinking ‘Thank C****t for this site! Thank C****t for the reassurance of the best and most bang-up-to-date info on everything pertinent to MS, and to what impacts on it, on us!’
The commitment and diligence shown by the team who supply the Blog posts touches some of us in a very meaningful way
I hope the deliberations you reference are assisted soon by the advice coming from the likes of the ABN, taking account of position adopted by Italy, so as all HCPs can best facilitate the care of their patients.
Hopefully too what’s learned from this epidemic will be easily utilised to inform care and treatment in any similar events in the future.
I tried to work out what C****t was and I thought the c word was C**t but then I got a biblical clue.
😂
Will being on natalizumab select for neurotropic strains?
Theoretically yes. In the event of a person with MS on natalizumab becoming infected with COVID-19, there will be an evolutionary race between the immune system and viral escape mutants. This happens with many viruses; i.e. it is normal and to be expected. Normally the immune system wins, the virus is cleared and the patient recovers. However, if there is a sanctuary that the virus can escape to and hide from the immune system it will find it. In the case of natalizumab-treated patients, this could be the gut, CNS or other mucosal sites. So yes natalizumab may be the evolutionary selection pressure that drives the selection of neurotropic escape mutants. This is another reason for natalizumabers to try and avoid becoming infected with COVID-19.
Would you recommend plasma exchange to eliminate natalizumab?
Only if a patient on natalizumab develops and encephalitis. The same principle applies to PML. The problem is viral encephalitis on natalizumab is often very indolent and difficult to diagnose. The reason for this is that without a brisk immune response, patients often present with non-specific symptoms. Therefore vigilance is needed and if in doubt do a scan and lumbar puncture.
I too am very thankful for your blog posts. It’s now the only place I come to for up to date information. I look forward to hearing the general consensus of opinion regarding Tysabri and Fingolimod patients.
Just to be clear, are suggesting that one option might be that we self isolate until the pandemic subsides, which could be months? I know I’m asking you to speculate this option but I’m trying to get my head around the logistics of this possibility.
It took a long time for me to get back to work after a debilitating relapse that led to diagnosis. I had to keep quiet about MS to get work again as there was so much discrimination. If I self isolate then I will have no income as most of my work is through self employment. I’d probably have to give up other work as it is for a small company and involves lots of contact with others plus travelling around. What do I do? Give up just about everything or stay safe in splendid – or not so splendid – isolation?
Update please
Good news the case series from Wuhan, of over 1000 cases, published online in the NEJM shows no cases of encephalitis or meningitis.
Wei-jie Guan et al. Clinical Characteristics of Coronavirus Disease 2019 in China. NEJM February 28, 2020
DOI: 10.1056/NEJMoa2002032
BACKGROUND
Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients.
METHODS
We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death.
RESULTS
The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission.
CONCLUSIONS
During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)
Can you develop further?
How many of those are/were on Tysabri?
None with MS. Two with immunodeficiency who had mild disease.
Any MSers on Tysabri in this dataset?
Thoughts on de risking with extended dosing? It would seem the logic would be the same as for PML.
Thank you
Yep
Grateful just isn’t a good enough word to thank you for taking the time to publish these posts, and reply to comments.
Could you give us an idea of which DMTs are likely to ‘blunt the vaccine responses’? My 22 yrs daughter is on Fingolimod and we are trying to weigh up pros and cons of staying on it v’s taking the ‘rebound’ (and other) risks of changing?
Many thanks
Hi. I am MS patient using natalizumab.
Is the article below true and does this possibly cause major problems with coronavirus infection and the use of natalizumab?
http://www.xinhuanet.com/english/2020-03/05/c_138846529.htm
‘BEIJING, March 5 (Xinhua) — Chinese doctors have proved for the first time that the novel coronavirus can cause damage to patients’ central nervous system.’
‘The medical staff then conducted gene sequencing on samples of his cerebrospinal fluid and confirmed the presence of the novel coronavirus, diagnosing the COVID-19 patient with encephalitis, an inflammation of the brain’
The reason why these complications happen on natalizumab is that natalizumab blocks trafficking of anti-viral lymphocytes into the central nervous system and so if a virus gets into the CNS it will cause damage unchecked by the immune system.
Ebv is neurotropic?
Is tthere any report in the literature of complications of patients on natalizumab and Ebv in the cns ?
(simillar to coronavirus or jcv or cmv or herpes)
Obrigado
I am someone who rarely gets spooked by anything but I am hugely concerned as I am on Tysabri with a high JC +ve reading. Should I be avoiding public places?? Should I be self – isolating until this epidemic passes (which could be months!)
Ditto JR’s comments.
What should those of us on Tysabri do?
Regarding natalizumab fingolimod and siponimod what is more likely; to catch the Corona virus or have a serious rebound
As an ex tysabri patient who was given the early days recommended drug holiday and who then suffered a massive Relapse resulting in long-standing disability I worry that the information you posted here will not be considered by neurologist unless it is in the Rulebook
I remember reading on the ms UK website about the new tysabri drug holiday idea and that in America they were recommending copaxone to switch to to avoid any adverse reactions. This was not standard practice so so I sadly accepted my neurologist in London’s answer that this was not necessary as this was not something he knew about or something being circulated apparently
Not long after my big relapse they started prescribing a course of steroids during the drug holiday so perhaps I was one of the early cases leading to this change but I really wish I had pushed the point about the article
I would worry that people are waiting to see what their hcp suggests in case their hcp is neither up to speed nor that interested
What’s about dimethyl fumarate?
I am asking since fumaric acid esters were considered safer for patients with normal ish lymphocyte count. But then read about a case of encephalitis here:
https://www.neurologyadvisor.com/conference-highlights/cmsc-2019-coverage/dimethyl-fumarate-linked-with-vulnerability-to-herpes-simplex-encephalitis/
”I hope you appreciate that formulating advice when there is no evidence base is not easy.”
Appreciated. Still, expert opinion has a place in the EBM hierarchy even if it’s at the bottom of the pyramid (rightly or wrongly). In some knowledge disciplines expert opinion is primary-source material. We make decisions every day in our ADL based on good, middling or no evidence. In fact, when physicians offer us treatment choices and say “it’s your decision,” they’re acknowledging the limits of evidence in decision-making. They’re saying, in effect, “you’re the expert on you.” Difficult though it may be, you provide a tremendous service when you formulate advice or even structured observation about DMTs, COVID-19, immune response and CNS viral activity. Other comments here attest to that and as you can see, demand for timely expert opinion is elastic to say the least. Please don’t heed the inner voice saying “Don’t commit until you’re absolutely sure.” The rest of us have to kick that bastard out the kitchen door several times a day.
“The problem about consensus is that it is often a compromise and in the absence of data may not be the best advice.”
Seasoned jurors for book prizes and the like know that “consensus” sometimes means “everyone’s second choice.” This is not to impugn prize-giving but rather to underscore the importance of trustworthy individual voices. Thanks again for all you do at Barts MS.
Fantastic post, very helpful thank you. Does this development alter current thinking….?
http://www.xinhuanet.com/english/2020-03/05/c_138846529.htm