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.
….. 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.
N.B. MOUSEDOC HERE So AS YOU KNOW THERE ARE ALREADY MUTATIONS IN THIS VIRUS THE ORIGINAL S VARIANTAND THE L VARIANT