COVID19 – Page 3 – Prof G's MS Blog Archive

#MSCOVID19 transient antibody responses

The MS community is panicking because a handful of pwMS on anti-CD20 therapy don’t seem to make antibody responses to SARS-CoV-2. The implications are that these patients are susceptible to reinfection. We can’t be sure of this as lasting long-term antiviral immunity may rely more on T-cell responses, in particular CD8+-T-cell responses, than antibody responses. Let’s hope this is the case.

The study below done in London shows that even in people from the general population with confirmed virus-positive COVID-19 rapidly lose their neutralizing antibody response to the virus. Are we surprised? No this is well described with both SARS-CoV-1, SARS-CoV-2 and other coronaviruses.

What does this mean for the pandemic? It means that vaccine responses may need to be tracked with other immunological techniques outside of easy-to-develop and easy-to-do standard antibody assays. In short, we may not be able to rely on anti-SARS-CoV-2 antibodies to assess the effectiveness of a vaccine.

The monitoring of T-cell responses to viruses and other organisms is not trivial when you need to do it at scale. We will need to develop so-called T-cell proliferative-type response assay at speed. What this means is that we need to be able to measure if T-cells response to coronavirus antigens by dividing or activating themselves and producing cytokines. The latter is the easiest test to scale-up and is the method that is currently used in the Quantferon assay for latent or active TB.

The challenges posed by SARS-CoV-2 for the world community is quite extraordinary and one has to wonder why coronavirus research funding was not continued and ramped-up after the SARS-CoV-1 epidemic in 2002-2003. Black swan events can be predicted; it is all about odds. I was pleasantly surprised to read the World Bank in 2017 had set the risk of a coronavirus pandemic in the next decade at 5.9%. They thought that the odds of a coronavirus pandemic was more than a 1 in 20 and this is only one of the risks that underpinned their catastrophic pandemic bonds issue; i.e. an insurance policy for low-income countries to deal with a catastrophic event. If the World Bank had the foresight to do this why didn’t politicians in high-income countries respond in a similar fashion? There will be many questions to answer when the dust settles post-COVID-19. I sincerely hope a few political heads roll. We need to take a hard look at whether or not market solutions are really the answer to dealing with existential threats and we need to stop bashing scientists and academics? If we as a society spend billions on academic/intellectual infrastructure we need to maximise its use.

Seow et al. Longitudinal evaluation and decline of antibody responses in SARS-CoV-2 infection. MedRxIV doi: https://doi.org/10.1101/2020.07.09.20148429

Antibody (Ab) responses to SARS-CoV-2 can be detected in most infected individuals 10-15 days following the onset of COVID-19 symptoms. However, due to the recent emergence of this virus in the human population, it is not yet known how long these Ab responses will be maintained or whether they will provide protection from re-infection. Using sequential serum samples collected up to 94 days post-onset of symptoms (POS) from 65 RT-qPCR confirmed SARS-CoV-2-infected individuals, we show seroconversion in >95% of cases and neutralizing antibody (nAb) responses when sampled beyond 8 days POS. We demonstrate that the magnitude of the nAb response is dependent upon the disease severity, but this does not affect the kinetics of the nAb response. Declining nAb titres were observed during the follow-up period. Whilst some individuals with high peak ID50 (>10,000) maintained titres >1,000 at >60 days POS, some with lower peak ID50 had titres approaching baseline within the follow-up period. A similar decline in nAb titres was also observed in a cohort of seropositive healthcare workers from Guy′s and St Thomas′ Hospitals. We suggest that this transient nAb response is a feature shared by both a SARS-CoV-2 infection that causes low disease severity and the circulating seasonal coronaviruses that are associated with common colds. This study has important implications when considering widespread serological testing, Ab protection against re-infection with SARS-CoV-2 and the durability of vaccine protection.

CoI: nil in relation to this post

#MSCOVID19 Ding-dong round 2

A 15-round heavyweight boxing match is a good analogy when it comes to describing our fight against the coronavirus. We have spent the last 3 months sparring and looking for each other’s weaknesses as we land a few body blows but no knock-out punch. Although we have flattened the curve we have a long way to go. The ultimate aim will be to knock-out the virus with a strategically placed blow to the head in the form of a vaccine. However, before we get a vaccine there are many more rounds of boxing left in this pandemic and sadly many more deaths to come.

It looks as if Israel has lost round 2. There has been a worrying rise in daily coronavirus infections in Israel. The failure to contain the virus has led to the resignation of the head of public health services, who said in his resignation letter that “the entire country is burning”.

At one stage Israel was being held up as the poster child of how to control the pandemic at a countrywide level. Israel was one of the first countries to close down its borders and to lock down early. The strategy was so successful that by mid-May it only had a trickle of cases. Then Binyamin Netanyahu, the Israeli prime minister, relaxed the lockdown and urged Israelis to go out for a beer and “have fun”. Does this sound familiar? Boris Johnson and his cronies are even considering giving every adult in the UK a £500 voucher to spend on the service industries most hit by the economic fall-out of the COVID-19 to stimulate the economy. Don’t you think this is a good idea? I don’t.

Based on the Israeli experience the UK is likely to have a second wave of coronavirus infections and the anticipated second surge in NHS hospital admissions and deaths. The one glimmer of hope has to be our contact-tracing system, despite its imperfections, which may be able to quell the outbreaks locally and prevent spillover into the wider population.

The tragedy of a potential second, third and subsequent wave of infections is that it prevents the NHS from getting back to a relative state of normality and recommencing routine services again. The longer the tail wags the dog more of our patients with MS and other chronic diseases are suffering from a suboptimal service. Although we are providing a remote MS service, that I am actually quite proud of, it is not ideal. Many patients are trapped in limbo on a stalled diagnostic pathway or waiting for routine monitoring MRI scans and/or lumbar punctures and the list goes on.

The following is the summary of the recent survey we completed in relation to remote MS services in the UK. I think the results are self-explanatory and there is clearly room for improvement. I want to thank you for taking the time to fill out the survey; you will be surprised that we do take on board your feedback and just maybe we can improve things going forward.

Any additional thoughts or comments from yourself? They are much appreciated.

CoI: none in relation to this post

#MSCOVID19: summertime

To me three swallows make a summer; one from Sweden, a second from Iran and now a third from Italy. I have little doubt more will emerge soon.

A few weeks’ ago I explained that having asymmetrical information is never a good thing. Tragically I have known about the data published yesterday on the Lancet’s pre-publication archive for several weeks.

The new data shows that ocrelizumab-treated Italian pwMS were more likely to get COVID-19 and severe COVID-19 compared to other DMTs. This now supports the Swedish rituximab data presented by Jan Hillert on the iWiMS COVID-19 webinar in May and the Iranian survey data on rituximab (see Safavi et al. below). The message across these three data sets is now quite consistent; anti-CD20 therapies affect the biology of COVID-19 differently to other DMTs.

How anti-CD20 therapy increases your chances of getting COVID-19 suggests it either (1) increases your exposure to the SARS-CoV-2 virus, which to me is not plausible unless it is due to increased exposure to the virus as a result of attending hospitals for infusions, or (2) it reduces your chances of having an asymptomatic infection. To me, the latter seems most likely and is meanable to study.

The immune responses to other human coronaviruses, the ones that cause the common cold, may cross-react with SARS-CoV-2 and help keep the virus in check and explains why some people get asymptomatic or mild infections. Having had a common cold in the recent past has given you some built-in protection against getting COVID-19 and severe COVID-19.

I hypothesise that if you were B-cell depleted from being on an anti-CD20 when you had that common cold your immune system doesn’t make the necessary high-quality or high-affinity cross-reactive antibodies that you now need to protect yourself from getting symptomatic COVID-19 and potentially severe COVID-19.

Should this data on anti-CD20 therapy change clinical practice? If you are already on an anti-CD20 therapy there is little you can do about your preexisting immunity to community-acquired coronaviruses; you either have immunity or you don’t. Similarly, you can’t simply revere the action of anti-CD20 therapies as it takes months to years to reconstitute your peripheral B-cell pool. Therefore I would simply recommend that if you are on an anti-CD20 therapy being extra-vigilant when it comes to trying to avoid being exposed to SARS-CoV-2 (social isolation, personal hygiene and avoiding high-risk environments).

The issue of vaccine readiness may affect your decision to be treated with anti-CD20 therapy. People who are B-cell depleted, as a result of anti-CD20 therapies, make blunted vaccine responses. This is not surprising because anti-CD20 treated patients lack germinal centres in their lymph nodes and spleen. Germinal centres are the immunological equivalent of a university. It is in the germinal centres that T-cells help B-cell mature, class switch their antibodies, i.e. go from IgM to IgG for example, and to then undergo affinity maturation of the antibody genes to produce high-quality antibodies. Without germinal centres, your immune system can’t educate your B-cells to make high-quality antibodies and hence vaccine response are poor.

For people on anti-CD20 therapies, if they want to maximise your chances of responding to a vaccine you are going to have to pause your treatment to allow your immune systems to recover before receiving a coronavirus vaccine. When should you do this? Not now. I would not recommend this until an effective vaccine emerges. Only cross bridges when they are built and only if you need to cross them.

There is still a relatively high chance that all of the 150+ SARS-CoV-2 vaccine candidates will fail; vaccine development for respiratory viruses is notoriously difficult.

These data is likely to be relevant to ofatumumab and other anti-CD20 therapies.

Not surprisingly interferon-beta which is an antiviral protects you from COVID-19 and exposure to high-dose methylprednisolone in the last 4 weeks increased your chances of severe COVID-19. The latter supports our current policy of asking patients to shield for 2 weeks after steroids and to be extra-vigilant.

Interestingly, there is a strong trend in the Italian data suggesting that natalizumab-treated patients may be at increased risk of COVID-19. Whether this is a real signal or not waits further data, but again the Swedish data supports this. This observation would not be surprising as we know natalizumab reduces trafficking of lymphocytes to mucosal membranes, which may be relevant in early anti-coronavirus immunity.

I suspect these observations will have implications for other infectious diseases. I would not be surprised when we study the immune responses and outcomes to other viral infections, for example, seasonal influenza the same patterns will emerge. Now that we have set-up COVID-19 registries I would urge the MS community to keep them open so that we can study what happens with the next influenza epidemic emerges, which is only months away.

Sormani et al. Disease-Modifying Therapies and COVID-19 Severity in Multiple Sclerosis. The Lancet Preprint 8-Jul-2020.

Background: Immunosuppressive and immunomodulatory therapies are a major issue during the current coronavirus disease 2019 (Covid-19) pandemic, and in anticipation of possible next waves.

Methods: In a nationwide study we retrospectively collected data of persons with Multiple Sclerosis (PwMS) with suspected or confirmed Covid-19. We assessed the association of therapies for MS with Covid-19 by comparing their observed frequency with the one expected in non-pandemic conditions (expressing the association by Odds Ratios [OR]). We evaluated baseline characteristics and MS therapies associated to a severe Covid-19 course by multivariate logistic models.

Findings: Of 784 PwMS with suspected (n=593) or confirmed (n=191) Covid-19 and a median follow-up of 84 days (range=30-135), 13 (1·66%) died: 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-three (4·2%) were admitted to an Intensive Care Unit; 90 (11·5%) had a radiologically documented pneumonia; 88 (11·2%) were hospitalized. We found an excess of patients treated with Ocrelizumab (OR=1·84,95%CI=1·31-2·56, p<0·001) and a reduction of patients treated with Interferon (OR=0·47,95%CI=0·33-0·67, p<0·001) as compared to the frequency of use of these DMTs in the Italian MS population. After adjusting for region, age, sex, progressive MS course and recent methylprednisolone use, the therapy with an anti-CD20 agent (Ocrelizumab or Rituximab) was significantly associated (OR=2·59,95%CI=1·43-4·67, p=0·002) with an increased risk of severe Covid-19 course. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR=6·0,95%CI=2·2-16·5, p=0·007).

Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, the study detected elements of risk and protection with respect to Covid-19 in MS. These will need to be considered in countries where the pandemic is persisting and in preparation for post-pandemic scenarios.

Funding: Roche donated the web-Platform and funded a fellowship to the University of Genoa.

Safavi et al B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran. MSARDS Published:May 12, 2020.

Objective: To determine whether the course of COVID-19 is more severe in patients with MS and if MS disease-modifying treatments (DMTs) affect the risk of contracting the disease.

Methods: In a cross-sectional survey, data were collected by sending a questionnaire to 2000 patients with a demyelinating disease through an online portal system. Collected data included the current MS DMT and patient-reported disability level, history of recent sick contact, recent fever, respiratory symptoms, diagnosis with COVID-19, and the disposition after the diagnosis. We defined a COVID-19-suspect group as patients having fever and cough or fever and shortness of breath, or a presumptive diagnosis based on suggestive chest computed tomography. We calculated the proportion of COVID-19-suspect patients and compared their demographics, clinical characteristics, and DMT categories with the rest of survey-responders, using univariable and multivariable models.

Results: Out of 712 patients, 34 (4.8%) fulfilled our criteria for being in the COVID-19-suspect group. Only two patients required hospitalization. No patient required intensive care. In a multivariable model, disease duration (p-value=0.017), DMT category (p-value=0.030), and history of sick contact (p-values<0.001) were associated with the risk of being in the COVID-19-suspect group. Being on B-cell depleting antibodies (as compared to non-cell depleting, non-cell trafficking inhibitor DMTs) was associated with a 2.6-fold increase in the risk of being in the COVID-19-suspect group. (RR: 3.55, 95%CI: 1.45, 8.68, p-value=0.005).

Conclusions: The course of infection in patients with MS suspected of having COVID-19 was mild to moderate, and all patients had a full recovery. B-cell depleting antibodies may increase the susceptibility to contracting COVID-19.

Shen et al. Delayed Specific IgM Antibody Responses Observed Among COVID-19 Patients With Severe Progression. Emerg Microbes Infect. 2020 Dec;9(1):1096-1101.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide since it was confirmed as the causative agent of COVID-19. Molecular diagnosis of the disease is typically performed via nucleic acid-based detection of the virus from swabs, sputum or bronchoalveolar lavage fluid (BALF). However, the positive rate from the commonly used specimens (swabs or sputum) was less than 75%. Immunological assays for SARS-CoV-2 are needed to accurately diagnose COVID-19. Sera were collected from patients or healthy people in a local hospital in Xiangyang, Hubei Province, China. The SARS-CoV-2 specific IgM antibodies were then detected using a SARS-CoV-2 IgM colloidal gold immunochromatographic assay (GICA). Results were analysed in combination with sera collection date and clinical information. The GICA was found to be positive with the detected 82.2% (37/45) of RT-qPCR confirmed COVID-19 cases, as well as 32.0% (8/25) of clinically confirmed, RT-qPCR negative patients (4-14 days after symptom onset). Investigation of IgM-negative, RT-qPCR-positive COVID-19 patients showed that half of them developed severe disease. The GICA was found to be a useful test to complement existing PCR-based assays for confirmation of COVID-19, and a delayed specific IgM antibody response was observed among COVID-19 patients with severe progression.

CoI: multiple

#MSCOVID19: National Seroprevalence Study

We were hoping to do a UK-wide seroprevalence study in UK residents with MS to see how many had seroconverted to become anti-SARS-CoV-2 antibody positive and to see if there are differences in seroconversion rates between people on different DMTs. Unfortunately, our source of funding has fallen through.

Based on recent insights we would predict that people on ocrelizumab would have lower titres of anti-SARS-CoV-2 antibody titres, be more likely to be seronegative despite a history of COVID-19 and less likely to have neutralizing anti-spike protein RBD (receptor binding domain) antibodies than patients on other DMTs. Answers to these questions are really important for the MS community, have safety implications for pwMS and will address questions around vaccine readiness in the future.

In addition to the cross-sectional analysis, we want to follow the seronegative pwMS over time to study how the COVID-19 pandemic evolves and monitor the development of herd immunity in the MS population.

To do the first part of this study we need £25,000 to cover the costs of posting out blood spots and doing the initial assay. As this study is time sensitive we need to raise the money ASAP. Applying for grants will take too long. It has been recommended that we crowdfund this project. The question we want to ask you the MS community do you think this study is important enough and are you willing to help raise the money for us?

The results of this study will help the MS community prepare for a vaccine and whether or not the herd immunity strategy is working.

Please let us know your thoughts. Thank you.

CoI: multiple

#MSCOVID19 two swallows don’t make a summer

As you know I have had to backpedal with my SARS-CoV-2/COVID-19 advice in relation to anti-CD20 therapies. I have now had to reinterpret data on the role of immunoglobulins in protecting people from developing COVID-19 and severe COVID-19.

I have been using the two Italian cases of X-linked agammaglobulinaemia who got COVID-19 and make a recovery as an argument that you don’t need B-cells and immunoglobulins to recover from SARS-CoV-2 infection. I now think I am wrong. Both these patients were being managed with immunoglobulin replacement therapy or IVIG (intravenous immunoglobulin therapy). IVIG is essentially a mix of immunoglobulins from blood donors from the general population. The assumption I made was that as SARS-CoV-2 was a new virus there would be no antibodies in the general population that would neutralize the SARS-CoV-2. However, the study below shows that pooled immunoglobulin therapies are able to neutralise SARS-CoV-2 (see Díez et al. below). Therefore I can’t assume, based on these two cases, that you don’t need immunoglobulins to make a recovery from COVID-19. This observation of neutralizing anti-SARS-CoV-2 activity in IVIG is also compatible with the emerging data that rituximab and by implication other anti-CD20 therapies now appear to increase your chances of getting COVID-19 and severe COVID-19.

I suspect anti-CD20 therapies increase your chances of getting COVID-19 by reducing your chances of having an asymptomatic SARS-CoV2 infection. The immune responses to other human coronaviruses, the ones that cause the common cold, cross-react and help neutralise SARS-CoV-2, which explains why some people get asymptomatic or mild SARS-CoV-2 infections (see Shen et al. below). However, if you are B-cell depleted when getting the common cold, due to coronavirus, your immune system isn’t able to make the necessary high-quality or high-affinity cross-reactive antibodies that you now need to protect yourself from getting COVID-19.

In support of this the case study published last week of a person with MS on ocrelizumab who failed to seroconvert to having anti-SARS-CoV-2 antibodies despite having confirmed SARS-CoV-2 COVID-19 (see Conte. case report below). This particular patient had mild hypogammaglobulinaemia as a result of ocrelizumab treatment. The failure to seroconvert could be an assay problem, i.e. low sensitivity, or is more likely to be due to the blunted B-cell response from being treated with ocrelizumab. Clearly this case report is going to be very important in shaping our thinking in terms of doing further anti-SARS-CoV-2 seroprevalence studies in people with MS and preparing our patients for a potential SARS-CoV-2 vaccine. The latter gets more pressing as most countries have now abandoned herd immunity as a strategy to deal with COVID-19.

Díez et al. Cross-neutralization activity against SARS-CoV-2 is present in currently available intravenous immunoglobulins. BioRxiv doi: https://doi.org/10.1101/2020.06.19.160879

Background: There is a crucial need for effective therapies that are immediately available to counteract COVID-19 disease. Recently, ELISA binding cross-reactivity against components of human epidemic coronaviruses with currently available intravenous immunoglobulins (IVIG) Gamunex-C and Flebogamma DIF (5% and 10%) have been reported. In this study, the same products were tested for neutralization activity against SARS-CoV-2, SARS-CoV and MERS-CoV and their potential as an antiviral therapy.

Methods: The neutralization capacity of six selected lots of IVIG was assessed against SARS-CoV-2 (two different isolates), SARS-CoV and MERS-CoV in cell cultures. Infectivity neutralization was measured by determining the percent reduction in plaque-forming units (PFU) and by cytopathic effects for two IVIG lots in one of the SARS-CoV-2 isolates. Neutralization was quantified using the plaque reduction neutralization test 50 (PRNT50) in the PFU assay and the half maximal inhibitory concentration (IC50) in the cytopathic/cytotoxic method (calculated as the minus log10 dilution which reduced the viral titer by 50%).

Results: All IVIG preparations showed neutralization of both SARS-CoV-2 isolates, ranging from 79 to 89.5% with PRNT50 titers from 4.5 to >5 for the PFU method and ranging from 47.0%-64.7% with an IC50 ~1 for the cytopathic method. All IVIG lots produced neutralization of SARS-CoV ranging from 39.5 to 55.1 % and PRNT50 values ranging from 2.0 to 3.3. No IVIG preparation showed significant neutralizing activity against MERS-CoV.

Conclusion: In cell culture neutralization assays, the tested IVIG products contain antibodies with significant cross-neutralization capacity against SARS-CoV-2 and SARS-CoV. However, no neutralization capacity was demonstrated against MERS-CoV. These preparations are currently available and may be immediately useful for COVID-19 management.

Conte. Attenuation of antibody response to SARS-CoV-2 in a patient on ocrelizumab with hypogammaglobulinemia. MSARDS June 20, 2020.

Shen et al. Delayed Specific IgM Antibody Responses Observed Among COVID-19 Patients With Severe Progression. Emerg Microbes Infect. 2020 Dec;9(1):1096-1101.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide since it was confirmed as the causative agent of COVID-19. Molecular diagnosis of the disease is typically performed via nucleic acid-based detection of the virus from swabs, sputum or bronchoalveolar lavage fluid (BALF). However, the positive rate from the commonly used specimens (swabs or sputum) was less than 75%. Immunological assays for SARS-CoV-2 are needed to accurately diagnose COVID-19. Sera were collected from patients or healthy people in a local hospital in Xiangyang, Hubei Province, China. The SARS-CoV-2 specific IgM antibodies were then detected using a SARS-CoV-2 IgM colloidal gold immunochromatographic assay (GICA). Results were analysed in combination with sera collection date and clinical information. The GICA was found to be positive with the detected 82.2% (37/45) of RT-qPCR confirmed COVID-19 cases, as well as 32.0% (8/25) of clinically confirmed, RT-qPCR negative patients (4-14 days after symptom onset). Investigation of IgM-negative, RT-qPCR-positive COVID-19 patients showed that half of them developed severe disease. The GICA was found to be a useful test to complement existing PCR-based assays for confirmation of COVID-19, and a delayed specific IgM antibody response was observed among COVID-19 patients with severe progression.

CoI: multiple

#MSCOVID: updated international guidelines

The MSIF has just updated its COVID-19 International MS guidelines. What do they know that we don’t?

Advice regarding disease-modifying therapies for MS

Many disease modifying therapies (DMTs) for MS work by suppressing or modifying the immune system. Some MS medications might increase the likelihood of developing complications from a COVID-19 infection but this risk needs to be balanced with the risks of stopping or delaying treatment. We recommend that:

People with MS currently taking DMTs continue with their treatment.
People who develop symptoms of COVID-19 or test positive for the infection discuss their MS therapies with their MS care provider or another health care professional who is familiar with their care.
Before starting on any new DMT, people with MS discuss with their healthcare professional which therapy is the best choice for their individual disease course and disease activity in light of COVID-19 risk in the region. The following information should be considered during decision-making:
- Interferons and glatiramer acetate are unlikely to impact negatively on COVID-19 severity. There is some preliminary evidence that interferons may reduce the need for hospitalisation due to COVID-19.
- The limited evidence available suggests that people with MS taking dimethyl fumarate, teriflunomide, fingolimod and siponimod do not have an increased risk of more severe COVID-19 symptoms or death.
- Therapies that target CD20 – ocrelizumab and rituximab – may be linked to an increased chance of being admitted to hospital or requiring intensive care treatment due to COVID-19. This preliminary finding requires further investigation.
- More data on the use of natalizumab, alemtuzumab and cladribine during the COVID-19 pandemic are required to make any assessment of their safety.
People with MS who are currently taking anti-CD20 therapies (ocrelizumab, rituximab, ofatumumab or ublituximab) and are living in a community with a COVID-19 outbreak should be extra vigilant and may want to consider self-isolation to reduce their risk of infection.
People with MS who are currently taking alemtuzumab or cladribine and are living in a community with a COVID-19 outbreak should discuss their current lymphocyte counts with their healthcare professional. If their counts are considered to be low they should isolate as much as possible to reduce their risk.

Recommendations on delaying second or further doses of alemtuzumab, cladribine, ocrelizumab and rituximab due to the COVID-19 outbreak differ between countries. People who take these medications and are due for the next dose should consult their healthcare professional about the risks and benefits of postponing treatment.

CoI: multiple

#MSCOVID19: have a say about your COVID-19 MS service

As a result of COVID-19 the MS community has had to reconfigure their services. We want some feedback and advice about what we are doing right and what we are doing wrong.

Please watch this video for more information.

If you have time can you please complete this survey to help us evolve what we are doing. Not all the virtual services we are providing are going to stop post-COVID-19, which is why we need to improve our offering. We are also looking for volunteers to help with designing the service and helping with testing some of its features.

CoI: multiple

#MSCOVID19: bring it on

How is your COVID-19 prehabilitation going?

We are close to 4 months into the SARS-CoV-2 pandemic and two months since my blog post and my MS-Selfie microsite entry explaining how to prepare yourself for COVID-19. Are you ready?

Despite being redeployed to general medicine during which time I was exposed to COVID-19 patients I didn’t get infected with the virus. I am anti-SARS-CoV-2 antibody negative. However, I spent the last 3 months prehabilitating myself to get myself ready in case I get COVID-19. I am a strong believer in walking-the-talk and setting an example for my patients; you can’t tell your patients to do something for their general health if you are not prepared to do it yourself.

I have put in place an advanced directive with my wife and we are in the process of redoing our wills. I have also decided not to cancel my life insurance policy, which I was meant to do in April.
I have purchased a pulse oximeter for home monitoring of my oxygen saturation so that if I did get COVID-19 and had to self-manage and self-monitor at home I could do it with confidence.
I have purchased a battery pack for my mobile phone if I need to be admitted to hospital and have a spare mobile phone charger at hand in case my main charger malfunctions or goes missing. I also have a back-up old mobile phone for the same reason.
As for comorbidities; I have managed to get my BMI below 24, which is the first time in about 10 years that I have done this.
I have flattened the area under my insulin curve by being on a low carbohydrate diet. My last fasting blood glucose was 2.7mmol/L. I intermittent fast at least twice a week. I am keto-adapted and feel more alert as a result.
I am now normotensive with a resting blood pressure of around 116/ 78mmHg.
I exercise 4-5 times a week and even ran a half-marathon last weekend albeit a South London meander. The latter was in response to a challenge from a good friend of mine who did the same in Orlando, Florida. He now wants me to run a marathon with him on the original course from Marathon to Athens as a treat to ourselves once we survive and get out the other side of the pandemic.
I am not sleep-deprived; I am getting 6-7 hours a sleep a night which beats the 4-5 hours I used to sleep.
I am vitamin D, zinc and magnesium replete from taking supplements.
I have a natural suntan from spending between 6-8 hours a week outdoors; running, working in the garden, walking our dog who sadly passed away a few weeks ago, or sipping a G&T before sundown.
I do breathing exercises (stacking) once or twice a day in my office.
I am less anxious than before. Why?
- I have stopped watching the news in the evening
- I don’t read a daily newspaper
- I only read specific articles from newspapers I subscribe to (selective reading)
- I restrict my consumption of social media feeds to specific times of the day
- I am spending a lot of time in the garden
- I am listening to more music than I used to, which is very relaxing. I have recently discovered Melody Gardot and American jazz singer who is my current favourite and I have fallen back in love with Bob Marley.
I am practising social distancing and adopting the personal hygiene recommendations of the government.

I am as ready as I will ever be to get COVID-19. I think I have given myself the best chance of (1) having mild disease, (2) staying out of the hospital, (3) and in the event of getting severe COVID-19 of surviving. In the unlikely event of dying from COVID-19, I have made some preparations to provide for my family and to make it easier for them. I also have personal ambitions for what I plan to do when we get over the pandemic.

It is clear that there are some risk factors that you cannot modify in a three month period when it comes to getting severe COVID-19 and potentially dying from it. The study below from colleagues in my hospital show just how the BAME (Black, Asian and Minority Ethnic) community in East London are bearing the brunt of this pandemic. I suspect it is not because they are BAME but is due to social determinants of health, which will require a new political order and will to address over the next few decades. Sadly I am not convinced the current British government and leadership are up to the task.

Apea et al. Ethnicity and outcomes in patients hospitalised with COVID-19 infection in East London: an observational cohort study. MedRxIV doi: https://doi.org/10.1101/2020.06.10.20127621

Background: Preliminary studies suggest that people from Black, Asian and Minority Ethnic (BAME) backgrounds experience higher mortality from COVID-19 but the underlying reasons remain unclear.

Methods: Prospective analysis of registry data describing patients admitted to five acute NHS Hospitals in east London, UK for COVID-19. Emergency hospital admissions with confirmed SARS-CoV-2 aged 16 years or over were included. Data, including ethnicity, social deprivation, frailty, patient care and detailed risk factors for mortality, were extracted from hospital electronic records. Multivariable survival analysis was used to assess associations between ethnic group and mortality accounting for the effects of age, sex and various other risk factors. Results are presented as hazard ratios (HR) or odds ratios (OR) with 95% confidence intervals.

Findings: 1996 adult patients were admitted between 1st March and 13th May 2020. After excluding 259 patients with missing ethnicity data, 1737 were included in our analysis of whom 511 had died by day 30 (29%). 538 (31%) were from Asian, 340 (20%) Black and 707 (40%) white backgrounds. Compared to white patients, those from BAME backgrounds were younger, with differing co-morbidity profiles and less frailty. Asian and black patients were more likely to be admitted to intensive care and to receive invasive ventilation (OR 1.54, [1.06-2.23]; p=0.023 and 1.80 [1.20-2.71]; p=0.005, respectively). After adjustment for age and sex, patients from Asian (HR 1.49 [1.19-1.86]; p<0.001) and black (HR 1.30 [1.02-1.65]; p=0.036) backgrounds were more likely to die. These findings persisted across a range of risk-factor adjusted analyses.

Interpretation: Patients from Asian and Black backgrounds are more likely to die from COVID-19 infection despite controlling for all previously identified confounders. Higher rates of invasive ventilation in intensive care indicate greater acute disease severity. Our analyses suggest that patients of Asian and Black backgrounds suffered disproportionate rates of premature death from COVID-19.

CoI: none

#MSCOVID19: how safe is dimethyl fumarate?

During the COVID-19 pandemic, disease-modifying therapies (DMTs) have been scrutinised based on their mode of action and ability to cause immunosuppression. In general dimethyl fumarate has gotten off very lightly with most commentators referring it as an immunomodulator and being a relatively low-risk DMT should someone get COVID-19 on DMF. The latter is based on the assumption that DMF does not cause immunosuppression. I disagree with the latter assessment, but we need data. Where is the data?

How well are patients on DMF who get COVID-19 doing? I am aware that there are a lot of DMF-treated patients who have had COVID-19, but the investigators who have this information are being very slow at releasing their data. In fact, they have deliberately chosen to publish their data in high-impact journals rather than releasing it early into one of the prepublication archives. One could interpret this as them prioritising their academic ambitions above the concerns of the wider MS community during this crisis. The delay in getting this information to you is likely to be measured in months rather than weeks and is causing you anxiety. I personally think this is unacceptable.

In summary, DMF is an immunosuppressive therapy based on the five tests I apply when considering whether or not a drug is immunosuppressive.

1. Mode of action: DMF inhibits NF-κB (nuclear factor kappa B), which is one of the master transcription factors in controlling inflammation. You can’t be an NF-κB inhibitor and not be immunosuppressive.

2. Lymphopaenia: drugs that cause significant lymphopaenia tend to be immunosuppressive. Total lymphocyte counts drop on average by about 30% on DMF and about 15% of subjects lower their lymphocyte counts below 800/mm3 and 5% below 500/mm3. In addition, DMF has a greater impact on CD8+cells more than CD4+ cells, which may explain why there is a relatively large herpes zoster signal in DMF-treated patients. The following is the section on Zoster from the Tecfidera SmPC.

“Herpes zoster infections have been reported with Tecfidera use. In an ongoing long-term extension study, in which 1736 MS patients are treated with Tecfidera, approximately 5% experienced one or more events of herpes zoster, the majority of which were mild to moderate in severity. Most subjects, including those who experienced a serious herpes zoster infection, had lymphocyte counts above the lower limit of normal. Grade 2 and 3 lymphopenia prevailed in subjects with concurrent lymphocytopenia. In the post-marketing setting, most cases of herpes zoster infection were non-serious and resolved with treatment. Limited data is available on ALC in patients with herpes zoster infection in the post-marketing setting. However, when reported, most patients experienced grade 2 (< 0.8 × 109/L to 0.5 × 109/L) or grade 3 (<0.5 × 109/L to 0.2 × 109/L) lymphopenia (see section 4.4).”

3. Opportunistic infections: it is clear that there is a small opportunistic infection signal with DMF. It started with a few caes of PML and there has been a steady number of case reports of DMF-treated patients with different opportunistic infections. The case below of a patient presenting with cryptococcal meningitis an opportunistic fungal infection is an example. So if you are on DMF don’t think you are necessarily safe from infections you still need to be vigilant.

4. Vaccine responses: Vaccine responses to recall antigens (tetanus) and new antigens (meningococcus) were reasonable in DMF treated patients, but the response to the pneumococcal vaccine was variable. Differences in the response to both tetanus toxoid and pneumococcal serotype 3 polysaccharide antigen were less in MS patients on DMF compared to those on beta-interferon. Importantly there is no data on the effectiveness and safety of live vaccines in patients taking DMF. The SmPC in fact warns against live vaccines.

“Live vaccines might carry an increased risk of clinical infection and should not be given to patients treated with Tecfidera unless, in exceptional cases, this potential risk is considered to be outweighed by the risk to the individual of not vaccinating.”

Not being able to have live vaccines may be an issue for a SARS-CoV-2 as many of the candidate vaccines are using live viral vectors to deliver the immunogen.

5. Secondary malignancies: At present, there is no clear secondary malignancy signal on DMF. However, based on its mode of action and level of immunosuppression (relatively mild on average) a signal may take decades to emerge (known-unknown). An analogy is azathioprine monotherapy, a mild first-line immunosuppressive therapy, in which the secondary cancer risk (lymphoma) only emerges after 10 years of treatment. So again be vigilant particularly for skin cancers (squamous and basal cell carcinomas) and haematological malignancies which tend to be the sentinel cancers with longterm immunosuppression.

So in summary, the advice that DMF is safe if you get COVID-19 remains an opinion when the evidence is hidden behind several publication embargos. It is not an ideal DMT to be on if a live virus SARS-CoV-2 vaccine gets to market.

Workel et al. Cryptococcal Meningitis in a Patient With Multiple Sclerosis on Dimethyl Fumarate Treatment: A Case Report. Mult Scler Relat Disord 2020 Apr 29;42:102137.

Introduction: We present a case of meningitis caused by Cryptococcus neoformans var. grubii in a 46-year old non-HIV-infected patient with multiple sclerosis, treated with dimethyl fumarate monotherapy. We identified no other risk factors for developing cryptococcal meningitis. The patient presented with a slowly progressive headache during preceding weeks and acute onset of confusion, nausea and vomiting. Clinical examination revealed intermittent disorientation without focal neurological symptoms. A lumbar puncture showed an opening pressure of > 50cmH2O. Diagnosis of cryptococcal meningitis was made after culture of Cryptococcus neoformans var. grubii of cerebrospinal fluid.

Conclusion: This case emphasizes clinicians should bear in mind the possibility of cryptococcal meningitis in patients treated with dimethyl fumarate.

CoI: multiple

#MSCOVID19: an anti-CD20 backpedal

Science is not a religion and hence scientific advice, unlike beliefs, change as new evidence emerges. When the COVID-19 pandemic started we had to formulate advice on DMT use and their impact on SARS-CoV-2 infection and COVID-19 based on scientific principles and evidence of other viral infections. I created a table to summarise my opinions and as evidence has emerged I have updated the table accordingly. I have also added in new columns for example on advice about shielding/quarantine and on vaccine readiness. I have just updated the table for a sixth time changing the risk category of rituximab and other anti-CD20 therapies with a warning that it appears that this class of therapy increases your chance of getting COVID-19 and possibly severe COVID-19. This change is based on data from the Swedish MS registry and the survey below done in Iran. In short being on rituximab doubles your risk of getting COVID-19 and there is a suggestion that it increases your risk of getting severe COVID-19. At the moment there is not enough evidence to be firm about the latter or to comment on mortality risk.

How rituximab increases your chances of getting COVID-19 suggests it either (1) increases your exposure to the SARS-CoV-2 virus, which to me is not plausible unless it is due to increased exposure to the virus as a result of attending hospitals for infusions, or (2) it reduces your chances of having an asymptomatic infection. The latter seems most likely and is meanable to study.

It now seems that immune responses to other human coronaviruses, the ones that cause the common cold, may cross-react with SARS-CoV-2 and help keep the virus in check and explains why some people get asymptomatic or mild infections. So just maybe having had that common cold last winter or the year before has given you some built-in protection against getting COVID-19 and severe COVID-19. However, if you were B-cell depleted from being on an anti-CD20 when you had that common cold your immune system doesn’t make the necessary high-quality or high-affinity cross-reactive antibodies that you now need to protect yourself from getting symptomatic COVID-19 and potentially severe COVID-19. Please note this is a hypothesis, but it can be tested by studying people with MS and other condition on anti-CD20 therapies and screening them for antibodies against coronaviruses and comparing them to age-matched controls and patients on other DMTs. I am prepared to bet you the anti-CD20ers don’t have these cross-reactive antibodies or if they do they are at a lower level (titre) and are non-neutralizing.

Another possibility is that anti-SARS-CoV-2 antibody responses, in particular IgM antibodies, help clear the virus and aid in a more rapid recovery from COVID-19 and milder disease. Therefore, if your anti-SARS-CoV-2 antibody response is delayed or blunted by being on an anti-CD20 therapy this will increases your chances of getting more severe COVID-19. Whether this contributes to you being less likely to have asymptomatic SARS-CoV-2 infection is unknown, but again this can be studied in carefully designed studies.

Should this emerging data on rituximab change clinical practice? If you are already on an anti-CD20 therapy there is little you can do about your preexisting immunity to community-acquired coronaviruses; you either have immunity or you don’t. Similarly, you can’t simply revere the action of anti-CD20 therapies it takes months to years to reconstitute your peripheral B-cell pool. This is why I am now recommending that if you are on an anti-CD20 therapy you be extra-vigilant when it comes to trying to avoid being exposed to SARS-CoV-2 (social isolation, personal hygiene and avoiding high-risk environments). The good news is that the risk to individuals is low as a result of acquiring SARS-CoV-2 infection falls rapidly in most countries where anti-CD20 therapies are widely used to treat MS. I am still not recommending shielding because even though there is about a doubling of the risk of getting severe COVID-19 (hospitalization) the affected people with MS have been making a good recovery. The main determinants of death from COVID-19 in people with MS are older age, advanced disease and comorbidities and not the DMT they are on.

What about starting an anti-CD20 therapy? The decision to do this must be individualised and weighed against the risk of getting COVID-19. In countries where this risk is very low anti-CD20 therapies will be safe. The other issue that is emerging is vaccine readiness, i.e. having a peripheral immune system that is ready to respond to a SARS-CoV-2 vaccine if and when one emerges.

We know that people who are B-cell depleted, as a result of anti-CD20 therapies, make blunted vaccine responses. This is not surprising because anti-CD20 treated patients lack germinal centres in their lymph nodes and spleen. Germinal centres are the immunological equivalent of a university. It is in the germinal centres that T-cells help B-cell mature, class switch their antibodies, i.e. go from IgM to IgG for example, and to then undergo affinity maturation of the antibody genes to produce high-quality antibodies. Without germinal centres, your immune system can’t educate your B-cells to make high-quality antibodies and hence vaccine response will be poor. For people on anti-CD20 therapies, if they want to maximise your chances of responding to a vaccine you are going to have to pause your treatment to allow your immune systems to recover before receiving a coronavirus vaccine. When should you do this? I would not recommend this until a vaccine emerges; only cross bridges when they are built and if you need to cross them. There is still a relatively high chance that all of the 100+ SARS-CoV-2 vaccine candidates will fail; vaccine development for respiratory viruses is notoriously difficult.

At the moment the data we have from the Swedish registry and Iran is limited to rituximab but is likely to be relevant to ocrelizumab, ofatumumab and other anti-CD20 therapies. If you are conservative you may want to wait for the evidence base for these other anti-CD20 therapies to mature before incorporating the emerging evidence into your clinical decision-making. The good news is that there are several big data initiatives underway and we should report out within the next 1-2 months to confirm if this is a real signal, how robust the signal is and whether or not it applies to ocrelizumab and potentially other anti-CD20 therapies.

Does this have implications for other infectious diseases? I don’t know but I would not be surprised when we study the immune responses and outcomes to other viral infections, for example, seasonal influenza the same patterns may emerge. Now that we have set-up COVID-19 registries I would urge the MS community to keep them open so that we can study what happens with the next influenza epidemic that is only months away. The scary thought is what will happen if next season’s flu strain is a bad one? The impact of a more virulent flu strain on top of the tail of a SARS-CoV-2 pandemic is a scenario that makes me shudder. Do black swans ever emerge as twins?

Objective: To determine whether the course of COVID-19 is more severe in patients with MS and if MS disease-modifying treatments (DMTs) affect the risk of contracting the disease.

Methods: In a cross-sectional survey, data were collected by sending a questionnaire to 2000 patients with a demyelinating disease through an online portal system. Collected data included the current MS DMT and patient-reported disability level, history of recent sick contact, recent fever, respiratory symptoms, diagnosis with COVID-19, and the disposition after the diagnosis. We defined a COVID-19-suspect group as patients having fever and cough or fever and shortness of breath, or a presumptive diagnosis based on suggestive chest computed tomography. We calculated the proportion of COVID-19-suspect patients and compared their demographics, clinical characteristics, and DMT categories with the rest of survey-responders, using univariable and multivariable models.

Results: Out of 712 patients, 34 (4.8%) fulfilled our criteria for being in the COVID-19-suspect group. Only two patients required hospitalization. No patient required intensive care. In a multivariable model, disease duration (p-value=0.017), DMT category (p-value=0.030), and history of sick contact (p-values<0.001) were associated with the risk of being in the COVID-19-suspect group. Being on B-cell depleting antibodies (as compared to non-cell depleting, non-cell trafficking inhibitor DMTs) was associated with a 2.6-fold increase in the risk of being in the COVID-19-suspect group. (RR: 3.55, 95%CI: 1.45, 8.68, p-value=0.005).

Conclusions: The course of infection in patients with MS suspected of having COVID-19 was mild to moderate, and all patients had a full recovery. B-cell depleting antibodies may increase the susceptibility to contracting COVID-19.

Shen et al. Delayed Specific IgM Antibody Responses Observed Among COVID-19 Patients With Severe Progression. Emerg Microbes Infect. 2020 Dec;9(1):1096-1101.

Addendum

The following slides show some of the data I refer to above:

If you want to watch the iWiMS Webinar it is on YouTube; the relevant section starts at about 21 minutes.

CoI: multiple