Category: Lab Lessons

#MSCOVID19 – what about pregnancy?

My husband and I were hoping to start a family this year. What do you advise; should I attempt to fall pregnant or wait until after the COVID-19 pandemic? 

How long is a piece of string? Mouse Doctor 2 would tell you to divide the string in half and the length of the original piece of string is twice that of one of the halves. With the flattening of the curve and the extension of the tail COVID-19 pandemic is likely to extend beyond 2020 and into 2021. Some epidemiologists are predicting the tail going out to 2022. Therefore, in my opinion, COVID-19 pandemic is not necessarily a reason to put your life on hold. 

Image of flattening=the-curve is from the CDC

Clearly, for some people, there are economic reasons why they wouldn’t want to start a family in the current climate. For example, if you or your partner have lost your job, or you are uncertain about your long-term employment prospects, these economic factors will potentially impact on your decision to start a family.

What about SARS-CoV-2, a coronavirus, and pregnancy?

There is no published data that coronavirus infections are associated with foetal abnormalities or a higher miscarriage rate. It looks as if transplacental infection of the foetus with SARS-CoV-2 is unlikely. Saying this there is one case report of a neonate, born by caesarian section from a mother who had severe COVID-19, who tested positive for the virus. The problem with this case is that the neonate could have been infected at the time of birth. The good news is that children, including very young children, don’t seem to get COVID-19. Why children are resistant to COVID-19 is unknown at present, but it must have something to do with the biology of the virus. Therefore, it is unlikely that newborn babies are at significant risk of severe COVID-19 and there is no evidence to suggest worse foetal outcomes. 

The other important thing to realise that if you do fall pregnant and get infected with SARS-CoV-2 and develop COVID-19 or not the antibodies you produce against the virus will cross the placenta and should give your newborn child some protection against will-type viral infection in early life (6-12 months). These transplacental antibodies may be sufficient to protect them and bridge the gap until we hopefully have an effective vaccine against SARS-CoV2. 

What about being pregnant when you get COVID-19?

So far the data is very reassuring in that the case reports from China and elsewhere suggest being pregnant doesn’t increase the risk of getting severe COVID-19 and possibly to the contrary, i.e. less severe disease. However, there are relatively small numbers of pregnant women who do get severe COVID-19, whether this is a smaller proportion than the general aged-matched population is at present unknown.

As severe COVID-19 is a major stressor it may trigger premature labour. In an Italian case series of 42 pregnant women with COVID-19 and who were admitted to hospital only seven required respiratory support and eventually did well. Out of the 42 pregnancies, two premature labours occurred. This suggests COVID-19 in itself is not associated with adverse pregnancy outcomes. Saying this it is clear from the published data that if you are in the third trimester of pregnancy and you present with COVID-19 infection then a large number of women are having their babies born by caesarian section. I assume this is being driven by the medical condition of the mother; I doubt many women hospitalised with COVID-19 will be in a state to go through with normal vaginal delivery. 

Overall, I think the data is reassuring in that it is unlikely being pregnant puts you at greater risk of COVID-19 or severe COVID-19. Based on the published data to date it is likely that pregnancy a state of mild immunosuppression may actually protect you from severe COVID-19. 

What about the babies of woman who have had COVID-19 and subsequently delivered their babies?

The third-trimester data looks reassuring, but it is too early to make a call on the outcomes of babies born to mother who had COVID-19 during the first and second trimesters of pregnancy. Based on the biology of coronaviruses and pregnancy these babies are likely to be fine but will have to wait for the data to emerge. It will be important that not only the children of mothers with COVID-19 need to be studied but those born to mothers who had asymptomatic SARS-CoV-2 infection. For the latter, we need good population-based antibody studies to be done.

Please note some obstetricians have looked at what happened to pregnancy outcomes from the original SARS and MERS epidemics to make some predictions about SARS-CoV-2. I am not sure we can use this data as these two outbreaks were due to more virulent viruses with a much higher case-fatality rate. 

Conclusion: So my advice, in general, would be not to put your lives on hold unless you have to for other reasons. It is unlikely that SARS-CoV-2 causes foetal abnormalities, transplacental transmission of the virus is likely to be rare and there is no suggestion of an increase miscarriage rate due to COVID-19. Pregnancy itself doesn’t put you at increased risk of COVID-19 or severe COVID-19 and may actually protect you from the latter. In the case of getting severe COVID-19 whilst pregnant, there is a small chance of premature labour and a high likelihood that if you are ready to deliver the delivery will be by caesarian section. 

Zaigham & Andersson. Maternal and Perinatal Outcomes With COVID-19: A Systematic Review of 108 Pregnancies. Acta Obstet Gynecol Scand. 2020 Apr 7. doi: 10.1111/aogs.13867.

Introduction: The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has exposed vulnerable populations to an unprecedented global health crisis. The knowledge gained from previous human coronavirus outbreaks suggests that pregnant women and their fetuses are particularly susceptible to poor outcomes. The objective of this study was to summarize the clinical manifestations and maternal and perinatal outcomes of COVID-19 during pregnancy.

Material and methods: We searched databases for all case reports and series from February 12 to April 4, 2020. Multiple terms and combinations were used including COVID-19, pregnancy, maternal mortality, maternal morbidity, complications, clinical manifestations, neonatal morbidity, intrauterine fetal death, neonatal mortality and SARS-CoV-2. Eligibility criteria included peer-reviewed publications written in English or Chinese and quantitative real-time polymerase chain reaction (PCR) or dual fluorescence PCR confirmed SARS-CoV-2 infection. Unpublished reports, unspecified date and location of the study or suspicion of duplicate reporting, cases with suspected COVID-19 that were not confirmed by a laboratory test, and unreported maternal or perinatal outcomes were excluded. Data on clinical manifestations, maternal and perinatal outcomes including vertical transmission were extracted and analyzed.

Results: Eighteen articles reporting data from 108 pregnancies between December 8, 2019 and April 1, 2020 were included in the current study. Most reports described women presenting in the third trimester with fever (68%) and coughing (34%). Lymphocytopenia (59%) with elevated C-reactive protein (70%) was observed and 91% were delivered by cesarean section. Three maternal intensive care unit admissions were noted but no maternal deaths. One neonatal death and one intrauterine death were also reported.

Conclusions: Although the majority of mothers were discharged without any major complications, severe maternal morbidity as a result of COVID-19 and perinatal deaths were reported. Vertical transmission of the COVID-19 could not be ruled out. Careful monitoring of pregnancies with COVID-19 and measures to prevent neonatal infection are warranted.

Ferrazzi et al. COVID-19 Obstetrics Task Force, Lombardy, Italy: Executive Management Summary and Short Report of Outcome. Int J Gynaecol Obstet. 2020 Apr 8. doi: 10.1002/ijgo.13162.

From February 24, 2020, a COVID-19 obstetric task force was structured to deliver management recommendations for obstetric care. From March 1, 2020, six COVID-19 hubs and their spokes were designated. An interim analysis of cases occurring in or transferred to these hubs was performed on March 20, 2020 and recommendations were released on March 24, 2020. The vision of this strict organization was to centralize patients in high-risk maternity centers in order to concentrate human resources and personal protective equipment (PPE), dedicate protected areas of these major hospitals, and centralize clinical multidisciplinary experience with this disease. All maternity hospitals were informed to provide a protected labor and delivery room for nontransferable patients in advanced labor. A pre-triage based on temperature and 14 other items was developed in order to screen suspected patients in all hospitals to be tested with nasopharyngeal swabs. Obstetric outpatient facilities were instructed to maintain scheduled pregnancy screening as per Italian guidelines, and to provide pre-triage screening and surgical masks for personnel and patients for pre-triage-negative patients. Forty-two cases were recorded in the first 20 days of hub and spoke organization. The clinical presentation was interstitial pneumonia in 20 women. Of these, seven required respiratory support and eventually did well. Two premature labors occurred.

Yang et al. Clinical Features and Outcomes of Pregnant Women Suspected of Coronavirus Disease 2019. J Infect. 2020 Apr 12; S0163-4453(20)30212-7.

Background: 2019 novel coronavirus disease (COVID-19) has become a worldwide pandemic. Under such circumstance pregnant women are also affected significantly.

Objective: This study aims to observe the clinical features and outcomes of pregnant women who have been confirmed with COVID-19.

Methods: The research objects were 55 cases of suspected COVID-19 pregnant women who gave a birth from Jan 20th 2020 to Mar 5th 2020 in our hospital-a big birth center delivering about 30,000 babies in the last 3 years. These cases were subjected to pulmonary CT scan and routine blood test, manifested symptoms of fever, cough, chest tightness or gastrointestinal symptoms. They were admitted to an isolated suite, with clinical features and newborn babies being carefully observed. Among the 55 cases, 13 patients were assigned into the confirmed COVID-19 group for being tested positive severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) via maternal throat swab test, and the other 42 patients were assigned into the control group for being ruled out COVID-19 pneumonia based on new coronavirus pneumonia prevention and control program(the 7th edition).

Results: There were 2 fever patients during the prenatal period and 8 fever patients during the postpartum period in the confirmed COVID-19 group. In contrast, there were 11 prenatal fever patients and 20 postpartum fever patients in the control group (p>0.05). Among 55 cases, only 2 case had cough in the confirmed group. The imaging of pulmonary CT scan showed ground- glass opacity (46.2%, 6/13), patch-like shadows(38.5%, 5/13), fiber shadow(23.1%, 3/13), pleural effusion (38.5%, 5/13)and pleural thickening(7.7%, 1/13), and there was no statistical difference between the confirmed COVID-19 group and the control group (p>0.05). During the prenatal and postpartum period, there was no difference in the count of WBC, Neutrophils and Lymphocyte, the radio of Neutrophils and Lymphocyte and the level of CRP between the confirmed COVID-19 group and the control group(p<0.05). 20 babies (from confirmed mother and from normal mother) were subjected to SARS-CoV-2 examination by throat swab samples in 24 hours after birth and no case was tested positive.

Conclusion: The clinical symptoms and laboratory indicators are not obvious for asymptomatic and mild COVID-19 pregnant women. Pulmonary CT scan plus blood routine examination are more suitable for finding pregnancy women with asymptomatic or mild COVID-19 infection and can be used screening COVID-19, pregnant women, in the outbreak area of COVID-19 infection.

Monteleone et al. A Review of Initial Data on Pregnancy During the COVID-19 Outbreak: Implications for Assisted Reproductive Treatments. 2020 May 1;24(2):219-225. doi: 10.5935/1518-0557.20200030.

The current outbreak of the novel 2019 coronavirus disease (COVID-19) started in China in December 2019 and has since spread to several other countries. On March 25, 2020, a total of 375,498 cases had been confirmed globally with 2,201 cases in Brazil, showing the urgency of reacting to this international public health emergency. While in most cases, mild symptoms are observed, in some cases the infection leads to serious pulmonary disease. As a result, the possible consequences of the COVID-19 outbreak for pregnant women and its potential effects on the management of assisted reproductive treatments, demand attention. In this review, we summarize the latest research progress related to COVID-19 epidemiology and the reported data of pregnant women, and discuss the current evidence of COVID-19 infections during pregnancy and its potential consequences for assisted reproductive treatments. Reported data suggest that symptoms in pregnant women are similar to those in other people and that there is no evidence for higher maternal or fetal risks. However, considering the initial data and lack of comprehensive knowledge on the pathogenesis of SARS-CoV-2 during pregnancy, human reproduction societies have recommended postponing the embryo transfers and do not initiate new treatment cycles. New evidence must be considered carefully in order to adjust these recommendations accordingly at any time and to guide assisted reproductive treatments.

Alzamora et al. Severe COVID-19 During Pregnancy and Possible Vertical Transmission. Am J Perinatol. 2020 Apr 18. doi: 10.1055/s-0040-1710050. 

There are few cases of pregnant women with novel coronavirus 2019 (COVID-19) in the literature, most of them with a mild illness course. There is limited evidence about in utero infection and early positive neonatal testing. A 41-year-old G3P2 with a history of previous cesarean deliveries and diabetes mellitus presented with a 4-day history of malaise, low-grade fever, and progressive shortness of breath. A nasopharyngeal swab was positive for COVID-19, COVID-19 serology was negative. The patient developed respiratory failure requiring mechanical ventilation on day 5 of disease onset. The patient underwent a cesarean delivery, and neonatal isolation was implemented immediately after birth, without delayed cord clamping or skin-to-skin contact. The neonatal nasopharyngeal swab, 16 hours after delivery, was positive for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) real-time polymerase chain reaction (RT-PCR), and immunoglobulin (Ig)-M and IgG for SARS-CoV-2 were negative. Maternal IgM and IgG were positive on postpartum day 4 (day 9 after symptom onset). We report a severe presentation of COVID-19 during pregnancy. To our knowledge, this is the earliest reported positive PCR in the neonate, raising the concern for vertical transmission. We suggest pregnant women should be considered as a high-risk group and minimize exposures for these reasons. 

Rasmussen et al. Coronavirus Disease 2019 (COVID-19) and Pregnancy: What Obstetricians Need to Know. Am J Obstet Gynecol. 2020 Feb 24;S0002-9378(20)30197-6. 

…… In 2 reports describing 18 pregnancies with coronavirus disease 2019, all were infected in the third trimester, and clinical findings were similar to those in nonpregnant adults. Fetal distress and preterm delivery were seen in some cases. All but 2 pregnancies were cesarean deliveries and no evidence of in utero transmission was seen. Data on severe acute respiratory syndrome and Middle East respiratory syndrome in pregnancy are sparse. For severe acute respiratory syndrome, the largest series of 12 pregnancies had a case-fatality rate of 25%. Complications included acute respiratory distress syndrome in 4, disseminated intravascular coagulopathy in 3, renal failure in 3, secondary bacterial pneumonia in 2, and sepsis in 2 patients. Mechanical ventilation was 3 times more likely among pregnant compared with nonpregnant women. Among 7 first-trimester infections, 4 ended in spontaneous abortion. Four of 5 women with severe acute respiratory syndrome after 24 weeks’ gestation delivered preterm. For Middle East respiratory syndrome, there were 13 case reports in pregnant women, of which 2 were asymptomatic, identified as part of a contact investigation; 3 patients (23%) died. Two pregnancies ended in fetal demise and 2 were born preterm. No evidence of in utero transmission was seen in severe acute respiratory syndrome or Middle East respiratory syndrome. Currently, no coronavirus-specific treatments have been approved by the US Food and Drug Administration. Because coronavirus disease 2019 might increase the risk of pregnancy complications, management should optimally be in a health care facility with close maternal and fetal monitoring. Principles of management of coronavirus disease 2019 in pregnancy include early isolation, aggressive infection control procedures, oxygen therapy, avoidance of fluid overload, consideration of empiric antibiotics (secondary to bacterial infection risk), laboratory testing for the virus and coinfection, fetal and uterine contraction monitoring, early mechanical ventilation for progressive respiratory failure, individualized delivery planning, and a team-based approach with multispecialty consultations. Information on coronavirus disease 2019 is increasing rapidly. Clinicians should continue to follow the Centers for Disease Control and Prevention website to stay up to date with the latest information (https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html).

CoI: multiple

#MSCOVID19: vaccines and DMTs

So if you are someone with MS who is shielding or being very careful about social distancing and want to avoid getting COVID-19 you may be considering what your own exit strategy is. How do you de-risk yourself and prevent yourself from becoming infected with SARS-CoV-2? 

At present, it looks as if the UK government’s strategy is to ring-fence you with people who are immune to SARS-CoV-2, the so-called herd immunity paradigm, and hope an effective vaccine emerges in the next 12-18 months to secure the safety of the high-risk or vulnerable population. This strategy is high-risk because there is no guarantee that sufficient numbers of healthy people in the general population will get COVID-19 to ring-fence the vulnerable. To be honest there are too many vulnerable people. In addition, there will always be holes in the science behind the herd-immunity paradigm; who says immunity to SARS-CoV-2 will be long-term and why wouldn’t new strains of virus emerge to fool the immune system. This means that vulnerable people will have to live in fear that they may acquire COVID-19 unless they get an asymptomatic/mild infection and/or vaccinated and have proof they have neutralising anti-viral protective immunity against SARS-CoV-2. 

So the next questions are if and when an effective SARS-CoV-2 vaccine emerges (1) how good will the vaccine be and (2) if I am on a disease-modifying therapy will I respond to the vaccine? 

In general, vaccines can be hit and miss. Politicians, particularly Donald Trump, and the general public seem to think that an effective vaccine is imminent. Yes, it may be but it is more likely, based on industry timelines, that an effective vaccine for SARS-CoV-2 is years away. Developing a vaccine for respiratory viruses is not easy, particularly for viruses that mutate rapidly and have mechanisms built into their nucleic acid which results in antigenic drift, i.e. the proteins they express on their surface rapidly mutate to escape immune detection. The latter is a particular problem with for example the influenza virus; antigenic drift happens annually. We also know this is a problem with coronaviruses because immunity is not life long and wanes within years. This is why we get recurrent common colds.  

The other problem with viruses and vaccines is the so-called original antigenic sin. This is when you make an immune response to a virus or vaccine antigen. The virus then mutates and when you get infected with the new strain the antibodies you make to the original strain or vaccine don’t neutralise the new strain and may even enhance infection with the new strain. In addition, your immune system doesn’t treat the new strain as a new infection and thinks it is the original strain and hence doesn’t make new antibodies against the new strain. This why it is referred to as antigenic sin. Vaccine development has a long history of failing because of these sorts of issues and is why we haven’t got highly effective vaccines against major viruses such as dengue fever. 

Another issue with SARS-CoV-2 is that it looks like some of the important binding sites on the spike protein of the virus are heavily modified with sugar molecules. This means that neutralizing antibodies against SARS-CoV-2 may need to be against so-called glycoprotein segments of the spike protein. Glycoprotein vaccines are much more difficult to make and in themselves are less effective in inducing antibodies than pure protein vaccines. The reason for this is that the immune system processes sugar (glyco) antigens differently to protein antigens. 

I am telling you all this to make you aware that vaccine development is difficult, very difficult, and there are a lot of issues that will need to be considered to make sure a vaccine against SARS-CoV-2 is effective and safe. 

The other issue is having an immune system that is capable of mounting an immune response to a vaccine. I  think in general a live-attenuated SARS-CoV-2 vaccine is unlikely to be developed. Live vaccines tend to be legacy vaccines from an era before we had the tools to make recombinant proteins. Therefore it is highly likely that all the vaccines that will be developed will either be nucleic acid, protein or glycoprotein component vaccines. In general immune responses to vaccines are blunted by immunosuppressive therapies. This has relevance to pwMS because the DMT you are on may block the required immune response to the vaccine. So your careful and patient waiting for an effective vaccine may be futile.  

In general, interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate and natalizumab are unlikely to block or attenuate immune responses to a component SARS-CoV-2 vaccine. Similarly, once immune system reconstitution has occurred post alemtuzumab, cladribine, mitoxantrone or HSCT vaccine responses should be restored to normal or near normal. In the depletion phase of IRTs (immune reconstitution therapies) it is likely that vaccine responses will be blunted. In the case of S1P modulators, such as fingolimod and siponimod, and the anti-CD20 therapies (ocrelizumab and rituximab), which are continuous immunosuppressive therapies, vaccine responses are likely to be blunted. I use the term blunted rather than inhibited responses because pwMS on these therapies may still make antibodies to the vaccine components but not to the required level to create protective immunity. 

The story with anti-CD20 therapies is potentially more complex. Surprisingly, antibody response to common vaccines occur on anti-CD20 therapies, but antibody response to glycoprotein vaccines, for example, the pneumococcal vaccine are blunted or inhibited the most. This may be particularly relevant to a SARS-CoV-2 vaccine that is likely to require antibodies to glycoprotein antigens to generate neutralizing antibodies, i.e. antibodies that neutralise the virus and prevent infection. 

Is this information important for pwMS? Yes, I think it is and may affect whether or not pwMS start or continue treatment with S1P modulators or anti-CD20 therapies.  In other words, if you want to make yourself ‘vaccine ready’ you need to consider your DMT choice.

As a research group, we are very interested in the antibody responses to SARS-CoV-2 in pwMS who have had COVID-19. We are in the process of trying to rapidly develop an antibody assay for IgG and IgM antibodies that can differentiate between binding and neutralizing anti-SARS-CoV-2 antibodies. This will allow us to study whether or not the immune response to SARS-CoV-2 is different in patients on S1P-modulators and anti-CD20 therapies and to compare these responses to patients on other DMTs and to patients who are not on DMTs. This will potentially allow us to give patients detailed information in the future about their risk of getting delayed COVID-19 and whether or not they respond to emerging vaccines once they arrive.

In conclusion, as we start to think about exit strategies for pwMS post-COVID-19 being able to respond to a future SARS-CoV-2 vaccine is a major factor HCPs and pwMS need to consider when deciding on what DMT to start or continue with for the long-term. 

Now some questions for you. For those of you who consider yourself, ‘COVID-19 vulnerable’ is being able to respond to a future SARS-CoV-2 vaccine relevant to you? Does it affect your thinking about which DMT you want to be treated with? Please let’s start a discussion on this important topic. 

I think the vaccine issues is important enough for me to have added a new column to my DMT COVID-19 table (version 4.0) and to change the colouring scheme to a patchwork. 

CoI: multiple

#MSCOVID19 – DMT update (2)

This week saw several bits of information appear that has led me to change my position on several DMTs in terms of their risk for pwMS during the COVID-19 pandemic.

Firstly, the verbal update by Maria Pia-Sormani on the Italian cohort of patients with MS who had COVID-19. These figures were given during the iWiMS weekly COVID-19 &MS webinar. There are now 380 cases of pwMS and COVID-19 reported in the Italian register with only 5 deaths. The mortality rates are well below that of the general population and suggest that pwMS are not at increased risk of severe COVID-19. This is good news. This data also supports the hypothesis that mild-to-moderate immunosuppression may be good and in fact, reduce the chances of pwMS getting severe COVID-19. This is not surprising as severe COVID-19 is almost certainly immune-mediated disorder. The five patients that died (see table below) tended to be older, have more advanced disease and comorbidities.

It is now clear that SARS-CoV-2 is neurotropic with the second, but first published, case of meningoencephalitis with virus detectable in the spinal fluid. This now increases the risk of natalizumab for pwMS. You don’t want to be on natalizumab if SARS-CoV-2 disseminates to the CNS. It is very important that if you are on natalizumab and get COVID-19 that you look-out for CNS symptoms. The fact that most MS centres have shifted their patients onto EID (extended interval dosing) will reduce this risk but it remains concerning. For more information on how EID reduces this risk please see my explanation on MS-Selfie.

At a personal level I have now 6 patients with MS on various DMTs who have all come through having had COVID-19 without any problems. I have asked them to register themselves on the MS register study and I will be reporting them next week.

I would urge you to watch the weekly iWiMS webinar which will keep the MS community up-to-date with what is happening in relation to COVID-19 and MS.

I therefore updated my table and have added a ranking to reflect the changing advice. Please note I have downgraded the risk associated with anti-CD20 therapies based on the emerging evidence as well. More on this later.

For high-resolution view please see MS-Selfie.

Moriguchi et al.  A First Case of Meningitis/Encephalitis Associated With SARS-Coronavirus-2. Int J Infect Dis  2020 Apr 3 PMID: 32251791

Novel coronavirus (SARS-Coronavirus-2:SARS-CoV-2) which emerged in Wuhan, China, has spread to multiple countries rapidly. We report the first case of meningitis associated with SARS-CoV-2 who was brought in by ambulance due to a convulsion accompanied by unconsciousness. He had never been to any foreign countries. He felt generalized fatigue and fever (day 1). He saw doctors nearby twice (day2 and 5) and was prescribed Laninamivir and antipyretic agents, His family visited his home and found that he was unconsciousness and lying on the floor in his vomit. He was immediately transported to this hospital by ambulance (day 9). Under emergency transport, he had transient generalized seizures that lasted about a minute. He had obvious neck stiffness. The specific SARS-CoV-2 RNA was not detected in the nasopharyngeal swab but was detected in a CSF. Anti- HSV 1 and varicella-zoster IgM antibodies were not detected in serum samples. A brain MRI showed hyperintensity along the wall of right lateral ventricle and hyperintense signal changes in the right mesial temporal lobe and hippocampus, suggesting the possibility of SARS-CoV-2 meningitis. This case warns the physicians of patients who have CNS symptoms.

CoI: multiple

#MSCOVID19: assessing and managing relapses remotely

Can we assess MS relapses remotely? 

Yes, I think we can. Most neurological assessments are based on history and examination. You definitely can take a history of new-onset neurological symptoms by telephone, or preferably using video consultation. I am currently using accuRx the most widely adopted NHS platform for remote consultations. It is remarkably easy to use and satisfaction levels are very high for both clinicians and patients. In addition, you can also do a brief or truncated neurological examination using a video link. I am beginning to ask some of my patients to complete a battery of online assessments (webEDSS, 9PHPT, T25W) and PROMS (MSIS-29) to document the impact of the relapse on their physical functioning.

Once you have documented a relapse the question arises should you treat the relapse with steroids? 

At the moment I am trying to avoid steroids for relapses. Why? In general, the benefits of steroids in the treatment of relapses are quite small. They essentially speed-up the recovery by about 2 weeks. At 6-months the level of recovery from a relapse, as assessed by EDSS, is the same whether or not you have steroids. When you tell patients this they often agree not to be treated, particularly when you mention the potential side effects of high-dose steroids, i.e. avascular necrosis of the hip, steroid psychosis, diabetes, hypertension, insomnia and infections.

Despite this, some patients still prefer to be treated. This raises the question of IV (intravenous) versus oral. There have been several studies showing that there is no difference between high-dose IV or oral steroids in terms of relapse outcome. Therefore, in the current COVID-19 environment, when we are trying to avoid patients having to travel and come to the hospital, oral steroids are the prefered route. The steroids can be dispensed via your general practitioner or through our pharmacy with courier delivery if you live locally (within London or in the home counties).

Before starting steroids it is good to get some basic things done to try and de-risk the adverse events. This includes a recent blood pressure; we don’t want to prescribe high-dose steroids to someone with uncontrolled hypertension. Nowadays most people have access to some form of home BP measurement device. 

If you have a history of recurrent urinary tract infections it is always advisable to have a urine dipstick done to make sure you don’t have an asymptomatic infection. Five days of steroids are sufficient to blunt your innate immune response, which has the potential to allow a bacterial urinary tract infection to become a systemic infection and to cause septicaemia. I learned a hard lesson early my MS career when I agreed for a patient to have his relapse treated by his GP without considering a UTI. The patient was admitted to ITU on day 4 of his course of oral steroids in septic shock and nearly died.  A lesson to take UTIs seriously.

It is also important to make sure the relapse is not a pseudo-relapse, which are often triggered by a UTIs in patients with more advanced MS. 

Not all patients have urine dipsticks at home, which is why you may have to attend your local GP practice or come to the hospital to get this done. Another solution is to purchase urine dipsticks online and do the test yourself. The latter is an example of taking control and self-managing your MS or UTI. 

Please be aware in the context of a UTI the dipsticks assess two main things; (1) urine nitrite levels and (2) the presence of esterase and enzyme that is produced by white blood cells or leukocytes. Please be aware that about a third of UTIs are caused by bacteria that don’t produce nitrate reductase, the enzyme that converts nitrates to nitrite, so your urine, even if you have a UTI, maybe negative for nitrites, however, it should be positive for white cell esterase if you have a significant infection.

In summary, to diagnose a probable UTI you need white cells and possibly nitrites to be positive on the dipstick. Other abnormalities that can be found with UTIs are a raised protein and red blood cells, which are also detected on most commercial dipsticks. However, positive protein and red blood cells in the absence of the white cells and nitrites are not indicative of a UTI and can be caused by other pathologies.

If you have doubt about interpreting the dipstick you can always take a photograph of it and send it to your MS nurse, GP or neurologist for interpretation. If you have a UTI it is advisable to get your urine cultured in a laboratory and to start a course of antibiotics. The antibiotics can be changed if the culture grows a bacteria that is resistant to the antibiotic you are on. To get a culture done you need to drop-off fresh urine to your GP that needs to be sent to the laboratory within two hours. Please note you will have to collect a prescription for antibiotics from your GP. I personally like you to start your antibiotics for at least 24 hours before starting steroids.

If you are overweight or obese and have a family history of diabetes it is also worthwhile getting your blood glucose checked. We don’t want to give high-dose steroids to someone who has uncontrolled diabetes. Blood glucose is checked using a finger prick test that can be done by your GP or anyone who has a glucose home testing kit. 

Will high-dose oral steroid put you at risk of COVID-19 or severe COVID-19? 

I don’t know the answer to this question. However, significant immunosuppression is only considered to occur with a prolonged course of steroids, i.e. longer than 3 weeks at a dose of greater than 20mg of prednisone per day or equivalent.  Therefore the level of immunosuppression with a short 5-day course of high-dose 500mg/day of methylprednisolone is relatively low. Although this is medical dogma there is good scientific evidence that high-dose steroids blunt innate immune responses, i.e. neutrophil and monocyte/macrophage responses to infection, which is why short-term steroids can cause UTIs to become systemic. The blunting of the innate immune response may be important in the early stages of COVID-19. Because of this, I am telling my patients who opt for steroid treatment to self-isolate for a period of 14 days after completing the 5-day course. The logic of this is simple; with a lack of evidence, it is better to be safe than sorry. 

In addition to 500mg/day of methylprednisolone for 5-days, I also prescribe lansoprazole 30mg daily for 14 days to protect you from steroid-induced gastritis. I am aware that not all neurologists prescribe gastric protection with high-dose steroids. Steroid-induced gastritis is not an uncommon problem and the last thing you need is an upper GI bleed that needs hospitalisation.

If you have diabetes and/or hypertension it is important to monitor your blood sugars levels and blood pressure whilst you are on steroids in case your medications need to be adjusted. 

The one side effect that worries me the most is steroid-induced hypomania, psychosis and depression. I have a handful of patients in my career that have had to be sectioned because of psychosis. It is important to be mindful of the mood-altering effects of steroids and if necessary seek help. I always warn partners or family members of the possibility of hypomania, psychosis and depression and that it is better to address these as soon as possible if they occur. The good news is that steroid-induced psychosis tends to respond to treatment relatively quickly.

Another side effect that is common is steroid-induced insomnia. If you have a history of this please ask for a short course of sedatives to help you sleep. The sedatives are only needed for 4 to 5 days and shouldn’t be taken for longer than this.

As you can see assessing and treating relapses remotely is possible, but on balance we should try and avoid using steroids.

If you any queries I will happy to ask them. I will also post this information to MS-Selfie, my COVID-19 and MS microsite.

Does immunosuppression protect you from severe COVID-19?

The hypothesis that immunosuppression may protect you from severe COVID-19 is gaining traction. New data released on the 4th April 2020 from the UK’s Intensive Care National Audit & Research Centre suggests it may. When comparing 2249 patients admitted to ITU in the UK with severe COVID-19 the proportion of immunocompromised patients was 3.7x lower than the proportion of immunocompromised patients admitted to ITU with viral pneumonia (the comparator) between 2017 and 2019 (2.3% vs. 8.5%). This was a highly significant difference (p<0.00001).

This clearly justifies the current research strategy being tested across the planet to see if immunosuppressive therapies may improve disease outcome in patients with COVID-19.

Does this mean we can now assume that immunosuppression protects against severe COVID-19 and COVID-19-related ARDS (adult respiratory distress syndrome)? Not yet. The UK’s ITU cohort of severe COVID-19 is biased in that those patients who are deemed too frail and/or disabled may never get to ITU, which may include a disproportionate number of immunosuppressed patients. Whereas this specific bias is unlikely to apply to ITU admissions between 2017 and 2019 (viral pneumonia cohort) when there was no such pressure on resources.

Despite this caveat, this is an important tidbit of information that will allow pwMS on immunosuppression to sleep a bit easier. I sincerely hope the wider MS community will reconsider their advice about not giving MS DMTs that are if anything mildly immunosuppressive to patients with active MS. By not treating our patients we may unintentionally be increasing their chances of developing severe COVID-19. Could our guidelines be another example of the law of unintended consequences? Let’s hope the real-world data that is being collected at present will answer this question.

CoI: multiple

#MSCOVID19: update on the outcome of cases with MS & COVID-19

We keep getting asked about if there is any data on whether or not people with MS are more likely to get COVID-19 if they do get are they more likely to get the severe disease and die from the infection?

Last week I logged into a very useful webinar organised by the iWiMS. They have now put the webinar online for you to watch.

The Italian registry reported 143 patients with MS and COVID-19 with five deaths. As you can from the table below the five patients who died from COVID-19 had more advanced or progressive MS and were all over the age of 50. Only two were on DMTs; one on rituximab and the other on dimethyl fumarate. Importantly the observation that to date only a 143 patients with MS had developed COVID-19 suggests that pwMS are not at increased risk of COVID-19. Please be aware that these figures may be biased in terms of reporting. On the webinar the Spanish, French, Australians, Germans and Americans discussed their cases as well.

The messages I took away from the webinar were reassuring and in line with my expectations. People with MS don’t seem to more susceptible to COVID-19 than the general population, nor are they more likely to get severe COVID-19 and die from complications than the general population. Similar to the general population age is an important risk factor when it comes to COVID-19 mortality in pwMS.

CoI: multiple

#MSCOVID19 – natalizumab extended interval dosing

More questions around managing MS during the COVID-19 pandemic; this time in relation to natalizumab (Tysabri) dosing.

The COVID-19 NHS crisis is a double-whammy for pwMS. First, it is redeploying staff away from MS services to work on the frontline. Secondly, the message has gone out to stop pwMS coming to NHS hospitals, or even connecting with other healthcare facilities such as GP practices, in an attempt to prevent them from being exposed to SARS-CoV-2. Most MS centres, including ours, have converted all of our clinics to telemedicine. Saying that I saw a very anxious patient with recently diagnosed highly-active MS in our urgent face-2-face neurology clinic yesterday. She needed to be seen as she was in the middle of an attack and in my opinion, should start on a high-efficacy DMT as soon as possible (possibly natalizumab). I am not prepared to make her wait 3, 6, 9, 12 or 18 months to access a high-efficacy therapy and bridging her on a low efficacy DMT would not be in her best interests. If time is brain why should we be compromising on her treatment because of COVID-19? Do you agree?

Seeing this patient face-2-face yesterday helped. She was very anxious and being face-2-face allowed me to counsel her properly. The consultation felt right and is a possible example of why you can’t necessarily do everything using a telemedicine portal. 

One of the consequences of COVID-19 is that some pwMS are finding it difficult getting hold of NHS staff and getting their questions answered, which is one the reasons I started the MS-Selfie COVID-19 & MS microsite. Some centres such as ours have converted all our patients on natalizumab onto 6-weekly infusions, others have pushed this out to 8 weeks and some patients from other centres are reporting that their natalizumab infusions have been suspended indefinitely. The mixed messages around dosing and/or suspending dosing is causing a lot of anxiety (see my daily Q&A sessions on MS-Selfie). 

Is it safe to suspend natalizumab infusions?

No, it is not safe. I am particularly concerned that some patients are having their natalizumab infusions stopped without a definite date for recommencing their infusions or at least transitioning them onto another DMT to prevent rebound disease activity, which can on rare occasions be life-threatening. 

How does extended interval dosing work?

Yes, EID looks safe. Real-life data suggest from a clinical perspective it is not associated with an obvious increase in disease activity (relapses). However, the data on this is preliminary and Biogen is currently doing a study to address whether or not EID is associated with any loss of disease activity. This is called the NOVA trial and will include MRI monitoring as part of the outcome. One thing that is clear is that EID reduces the risk of PML in JCV positive patients substantially. 

The theory behind EID is that some cells are less sensitive to the effects of natalizumab and that if you delay the next natalizumab infusion by 1 or 2 weeks the saturation of their surface receptors drops below a threshold and allows these cells to traffic into the central nervous system. If these less natalizumab-sensitive cells are the antiviral CD8+ T-cells and/or the natural-killer cells that fight viruses then this could allow immune surveillance of the CNS to occur that will prevent PML from occurring. If you get the EID right the desaturation of the immune cells causing MS, possibly the memory B cells, is insufficient not to allow these cells to traffic and to reactivate MS. It is clear that not all cells are made equal when it comes to the effect of natalizumab. Importantly, there are several other adhesion molecules on cells that impact on their adhesion (stickiness) to the blood vessels in the CNS. It could also be a delicate balance between the availability of different accessory adhesion molecules that makes the difference.

How safe is extended interval dosing and does it matter if it is every 6 or 8 weeks?

Everyone gets a standard natalizumab dose of 300mg every 4 weeks. This means a 50kg person gets double the relative dose compared to a 100kg person. The half-life of antibody therapies, such as natalizumab, is linked to how much drug or antibody is given. Therefore for the 50kg smaller person, 8 weeks may be fine, but for the larger 100kg person 8 weeks is too long a gap. Based on the real-life data 6 weeks seems to be a good compromise. Therefore I personally would not be comfortable recommending an 8-week interval for all patients. Slide 38 in the deck below demonstrates that as the dosing interval increases so does the impact of  body weight on natalizumab’s efficacy. 

In reality every person with MS on natalizumab should probably have personalised dosing based on actual saturation of the VLA-4 molecule or equivalent biomarker (e.g. sVCAM-1). This would get us away from guessing and optimising the effectiveness of natalizumab at the same time as decreasing the risk of PML or other CNS complication linked to reduced immunosurveillance. 

Zhovtis Ryerson et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016 Aug;87(8):885-9.

BACKGROUND: Natalizumab (NTZ), a monoclonal antibody to human α4β1/β7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days.

METHODS: A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks.

RESULTS: 17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort.

CONCLUSIONS: Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.

CoI: multiple

#MSCOVID19: so what is a safe lymphocyte count?

What is a safe lymphocyte count; 500, 800 or 1000/mm3?

In your peripheral blood, you have circulating leukocytes or white blood cells which help fight infections. When you get your blood results back you often get told your total white cell count or WCC. However, the WCC is a composite and includes different populations of cells. The white cells can be divided into the lymphocyte and non-lymphocyte populations. The non-lymphocyte population or the innate (hard-wired) immune cells are often referred to as polymorphs (neutrophils, eosinophils and basophils) and monocytes (circulating macrophage precursors).

When it comes to lymphocytes we divide them into so-called B-cells and T-cells. B-cells come from the bone marrow; yes B is for Bone. In contrast, T-cells from the thymus; T is for Thymus, which is sweetbread if you like eating offal. 

B-cells are specialised cells that use antibodies to recognise infections or cancers. On the other hand, T-cells use T-cell receptors for identifying infections or cancers. There are two broad categories of T-cells. CD4+ T-cells that generally react to foreign protein (generally infections) and cancer proteins (onco-antigens) that circulate outside of cells (extracellular antigens). In contrast, the CD8 pathway is for recognising foreign proteins that are expressed inside cells such as viruses. The CD4 cells tend to orchestrate an immune response and help other cells clear the infection; for example, the stimulate B-cells to make antibodies and produce molecules that attract macrophages to the site of inflammation. A small population of CD4 cells cab cytotoxic and kill target cells directly by producing proteins that kill the target cell. 

In comparison, CD8 cells are much more sensitive to being activated and typically do their own killing; this is why a subset of them are called cytotoxic T-lymphocytes (CTLs). CTLs are like military commandos; they survey the body and if they identify a cell that is infected with a virus they kill it there and then. This is why CD8 CTLs are so important in fighting viral infections such as COVID-19. 

In a routine blood count, we don’t get back detailed numbers of the lymphocyte subpopulations we simply get the absolute lymphocyte count (ALC), which includes both the B-cells and T-cells.  

So what is a normal lymphocyte count?

There are different ways of defining a normal laboratory range in medicine. The most popular way is to take thousands of healthy volunteers of all ages and sexes and measure their ALC and then work out the normal range using the 2.5th and 97.5th percentile on the assumption that 2.5% of the population has abnormally low counts and 2.5% have abnormally high counts. If you do this then you get a different normal range for different populations; for example in the large Danish study below the normal range for Danish people, using this method is defined as 1.1–3.7×109/L or 1100 – 3700/mm3. 

To simplify and standardise things the WHO (World Health Organisation) has defined the lower limit of normal as 1.0×109/L or 1000/mm3. This is not necessarily correct because at a population level people with an ALC of 1000/mm3 are at a greater risk of having an infection and dying than someone with an ALC higher than this. What I am trying to say is that the so-called ‘normal’ cutoffs are not black and white boundaries and that the risk of infections is affected by many other factors, in particular age and comorbidities. 

For example, the older you get the greater the proportion of your lymphocytes in your peripheral blood become dedicated to fighting latent or dormant viruses such as cytomegalovirus (CMV) and Epstein-Bar virus (EBV). This means older people have less naive lymphocytes to fight new infections. So a younger person with an ALC of 1000/mm3 may have 10-20% of the peripheral T-cells dedicated to controlling CMV and EBV and someone over the age of 70 may be using 60-70% of their T-cells to keep CMV and EBV controlled. When the latter happens we refer to the T-cell repertoire (variability of all the T-cell clones) as being restricted and is indicative of immunosenescence, i.e. the majority of peripheral T-cell clones can’t be used for anything else other than controlling CMV and EBV. This may explain why an older age is such an important risk factor for developing severe COVID-19. 

The WHO has also created grades of lymphopaenia based on the ALC:

  1. Grade 0 >= 1000/mm3
  2. Grade 1 = 800-999/mm3
  3. Grade 2 = 500-799/mm3
  4. Grade 3 = 200-499/mm3
  5. Grade 4 < 200/mm3

I know that a lot of you are confused because some neurologists are saying that you are at high risk of severe COVID-19 if your ALC is less than 1000/mm3, others like me are saying that you are only at increased risk if your counts are less than 800/mm3 and still others who are saying that you should only worry if your ALC is less than 500/mm3.

Apologies, about the confusion, but as with most things in medicine nothing is certain or definitive; it is a soft call and advice also needs to be pragmatic and generalisable to the wider MS population. 

For example, if you are treated with alemtuzumab your counts may never get above 1000/mm3 before the next course. It is clear that the infection risk post-alemtuzumab drops quite precipitously after 3-6 months when most patients have ALC above 500/mm3. So should we use 500/mm3 then as the safe limit? I say no because most of the patients in the alemtuzumab trials were young and had no comorbidities. Therefore, this advice does not take into account immunosenescence and other factors.  So then why not recommend 1000/mm3? I personally think this is too conservative and means people will be hyper-cautious when they don’t necessarily have to be. 

To try and explain the subtleties to you I have hacked the data from the large Danish study below to show that infection risk increases linearly below an ALC of ~1700/mm3. Even at a WHO grade zero or ‘normal’, there is a 26% higher risk of infection, at Grade 2 (800/mm3 cut-off) there is a 44% increase in risk and with Grade 3 (500/mm3) it starts to increase rapidly (+76%). 

I hope you now understand the complexities about setting a normal lymphocyte range and advice about what is safe. Since I was taught how to use azathioprine, one of the original immunosuppressants, I have always used 800/mm3 as my target cut-off for pragmatic reasons. I think the evidence supports this position, but I am sure many of my critics will have other opinions. 

What COVID-19 is teaching me is that the MS community is not comfortable with uncertainty, but as we live in an uncertain world you are going to have to adapt to conflicting advice. Until data emerges we have only opinions, this is just one opinion, which may differ from the opinion you were given last week.

Warny et al. Lymphopenia and Risk of Infection and Infection-Related Death in 98,344 Individuals From a Prospective Danish Population-Based Study. PLoS Med, 15 (11), e1002685 2018 Nov 1 eCollection Nov 2018.

Background: Neutropenia increases the risk of infection, but it is unknown if this also applies to lymphopenia. We, therefore, tested the hypotheses that lymphopenia is associated with increased risk of infection and infection-related death in the general population.

Methods and findings: Of the invited 220,424 individuals, 99,191 attended examination. We analyzed 98,344 individuals from the Copenhagen General Population Study (Denmark), examined from November 25, 2003, to July 9, 2013, and with available blood lymphocyte count at date of examination. During a median of 6 years of follow-up, they developed 8,401 infections and experienced 1,045 infection-related deaths. Due to the completeness of the Danish civil and health registries, none of the 98,344 individuals were lost to follow-up, and those emigrating (n = 385) or dying (n = 5,636) had their follow-up truncated at the day of emigration or death. At date of examination, mean age was 58 years, and 44,181 (44.9%) were men. Individuals with lymphopenia (lymphocyte count < 1.1 × 109/l, n = 2,352) compared to those with lymphocytes in the reference range (1.1-3.7 × 109/l, n = 93,538) had multivariable-adjusted hazard ratios of 1.41 (95% CI 1.28-1.56) for any infection, 1.31 (1.14-1.52) for pneumonia, 1.44 (1.15-1.79) for skin infection, 1.26 (1.02-1.56) for urinary tract infection, 1.51 (1.21-1.89) for sepsis, 1.38 (1.01-1.88) for diarrheal disease, 2.15 (1.16-3.98) for endocarditis, and 2.26 (1.21-4.24) for other infections. The corresponding hazard ratio for infection-related death was 1.70 (95% CI 1.37-2.10). Analyses were adjusted for age, sex, smoking status, cumulative smoking, alcohol intake, body mass index, plasma C-reactive protein, blood neutrophil count, recent infection, Charlson comorbidity index, autoimmune diseases, medication use, and immunodeficiency/hematologic disease. The findings were robust in all stratified analyses and also when including only events later than 2 years after first examination. However, due to the observational design, the study cannot address questions of causality, and our analyses might theoretically have been affected by residual confounding and reverse causation. In principle, fluctuating lymphocyte counts over time might also have influenced analyses, but lymphocyte counts in 5,181 individuals measured 10 years after first examination showed a regression dilution ratio of 0.68.

Conclusions: Lymphopenia was associated with increased risk of hospitalization with infection and increased risk of infection-related death in the general population. Notably, causality cannot be deduced from our data.

CoI: multiple

#COVIDMS COVID-19 and Ondine’s curse

As a non-virologist, I have been relying on basic principles to make recommendations, and predictions, about what may happen to someone with MS who is infected with COVID-19. However, over time an observational evidence-base will emerge that will either confirm or refute some of these predictions. 

One thing I would not have predicted is Twitter being the platform for some of the early reports. Four patients with MS two on ocrelizumab, one on oral cladribine and other post alemtuzumab have acquired the infection and are apparently doing well. This is good news and congruent with expectations based on the mode of action of these DMTs. Both ocrelizumab and oral cladribine are predominantly anti-B cell therapies and only have a small impact on the T-cell compartment, which is the immunological compartment that is critical for fighting viruses. Anti-viral immunity post-alemtuzumab appears to be normal post immune reconstitution.

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It will be interesting to know what the antibody responses to COVID-19 will be in these patients. A serological or antibody test is urgently needed; this will allow us to test whether or not people have been exposed to the virus. I predict that despite these patients being in anti-B cell therapies they will have detectable anti-COVID-19 antibodies. The reason I say this is that both these agents are unlikely to block antibody responses completely; we already know this for ocrelizumab and as cladribine only depletes B-cells by about 90% it is likely to be similar. The immune system is remarkably resilient and there are deep tissue compartments that are relatively protected from ocrelizumab and cladribine. The latter is supported by data from phase 3 and extension trials and now real-life data, which show that severe viral infections are not a major problem in patients ocrelizumab or cladribine.  

An anti-COVID-19 serology test will allow seroepidemiology studies to be performed, which will allow us to determine how many people have had asymptomatic or undiagnosed mild COVID-19 disease. Variants of this assay will also be fundamental to testing a vaccine.  We will need to know which anti-COVID-19 antibodies are neutralizing, i.e. capable of preventing infection, and which are not. The effective vaccine will probably only have two or three COVID-19 components (antigens or antigen-epitopes) and hence the presence of these epitope-specific antibodies and the absence of antibodies against other COVID-19 antigens will be able to differentiate between vaccine immunity and wild-type infection. 

The following is a list of hypotheses or questions that will need to be answered once we have the tools at hand. 

  1. What is the asymptomatic infection rate in people with multiple sclerosis?
  2. Which DMTs prevent COVID-19 seroconversion after vaccination? I suspect none of the DMTs will suppress seroconversion completely, but based on other vaccine studies ocrelizumab and fingolimod and other S1P modulators will blunt the response. 
  3. Do people with MS on DMTs who are infected become superspreaders, i.e. continue to shed the virus in large amounts for longer periods of time? I predict that natalizumab will be the most likely DMT to do this. This is because it reduces lymphocyte trafficking into mucosal sites that may blunt antiviral responses, which will allow the virus to continue reproducing and being shed in oral and respiratory tract secretions and faeces. 
  4. When an effective antiviral emerges will it reduce or prevent prolonged viral shedding? The corollary to this is the question of whether pwMS on interferon-beta or teriflunomide shed less virus because these classes of DMT are antiviral?  
  5. Are people with MS on DMTs more likely to get severe COVID-19 infection? At the moment we are assuming that immunosuppressed patients will do worse. But this assumption may not necessarily be correct. It appears that severe infection may in fact be due to the immunological response to the virus and that by suppressing the immune response you dampen-down the damage in the lungs. This is why several anti-inflammatory therapies, for example, anti-IL6 and fingolimod, are currently being tested in acute COVID-19 infection. 
  6. How neurotropic is COVID-19 and will MS DMTs, in particular natalizumab, increase the neurotropism of the virus (ability to infect the CNS)? Natalizumab, by partially blocking immune surveillance of the CNS, may create a viral niche that will allow the virus to escape immune detection and cause encephalitis. This is analogous to what happens with PML. This remains my major concern for pwMS on natalizumab. 

In relation to neurotropism, the review paper below is quite sobering; it is extrapolating data on the SARS coronavirus epidemic to COVID-19 and suggests that a lot of the respiratory distress we see from COVID-19 is due to brainstem encephalitis. The hypothesis is that COVID-19 infects small nerves in the lung and other mucosal surfaces. The nerves then transport the virus up their fibres and across synapses into the neurons within the brains of people infected with COVID-19. This so-called retrograde and trans-synaptic transmission of viruses is well described, for example with rabies and other coronaviruses. Once the COVID-19 gets to the brain it destroys nerves cells. In relation to their hypothesis, they suggest the virus damages the respiratory centre in the brainstem that is responsible for the automatic reflex that drives involuntary breathing. If the respiratory centre is damaged you then develop central sleep apnoea; in other words, if you go to sleep you stop breathing and die. This is also referred to as Ondine’s curse or central hypoventilation syndrome. 

In their paper, Li and colleagues describe a survivor: “According to the complaints of a survivor, the medical graduate student (24 years old) from Wuhan University, she must stay awake and breathe consciously and actively during the intensive care. She said that if she fell asleep, she might die because she had lost her natural breath”. This description is typical of central sleep apnoea or Ondine’s curse. 

I think it is too early to accept the central apnoea hypothesis to explain at least part of the COVID-19 respiratory distress syndrome. This will require specific clinical studies on patients in intensive care units to see if they have central sleep apnoea and imaging and post-mortem studies to see if COVID-19 causes brainstem encephalitis. Based on the importance of this hypothesis I suspect intensive care clinicians, neurologists, neuroradiologists, virologists and pathologists are on the case and testing the hypothesis below using several different paradigms. 

If any pwMS have read this paper and are alarmed please don’t be. Like everything in medicine and science, their observations have to be confirmed. At the moment it doesn’t change much except the urgency of the need for an effective anti-COVID-19 antiviral. Ideally, any antiviral will also need to penetrate the CNS, in the event that COVID-19 causes encephalitis. I am also reassured that the one case report of COVID-19 encephalitis reported from China appears to have done well and recovered spontaneously. 

Importantly, this article does not change any of the general advice we are giving to pwMS. Please be vigilant about hand hygiene and avoid high-risk travel and contacts. This epidemic will eventually pass. It is important that we learn as much as possible from the pandemic for the future. 

Li et al. The neuroinvasive potential of SARS‐CoV2 may be at least partially responsible for the respiratory failure of COVID‐19 patients. Journal of Medical Virology Received: 14 February 2020, accepted: 24 February 2020 DOI: 10.1002/jmv.25728 

Following the severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV), another highly pathogenic coronavirus named SARS‐CoV‐2 (previously known as 2019‐nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS‐CoV and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID‐19) with clinical symptoms similar to those reported for SARS‐CoV and MERS‐CoV. The most characteristic symptom of patients with COVID‐19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some patients with COVID‐19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse‐connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. In light of the high similarity between SARS‐CoV and SARS‐CoV2, it is quite likely that the potential invasion of SARS‐CoV2 is partially responsible for the acute respiratory failure of patients with COVID‐19. Awareness of this will have important guiding significance for the prevention and treatment of the SARS‐CoV‐2‐induced respiratory failure.

Acknowledgements: I would like to thank one of our blog readers for bringing this paper to my attention.

Disclaimer: Please note this post, as with all of my blog posts, represents my personal opinions and not the views of my colleagues at Barts-MS.

CoI: multiple

#COVIDMS COVID-19 relevant case study

The following is a modified and anonymised email I received from a very concerned patient with MS. His treatment plan has been changed because of the COVID-19 epidemic. How would you advise him?

Dear Prof Giovannoni

I am a 51-year-old lady with active RRMS. I have only had MS for 3 years. 

I am due to have my first ocrelizumab infusion in 2 weeks time. 
My MS is active; I had a new lesion on my last MRI and my disability is progressing rapidly. My EDSS has moved from 2.5 to 3.5 in the last year. I was on glatiramer acetate, which I stopped a week ago. 

My MS team have advised me to delay ocrelizumab treatment indefinitely and to start dimethyl fumarate next week.
My job involves dealing with many members of the public in a very busy retail environment.

Could you advise me if it is okay to start ocrelizumab if my MS team are willing to provide treatment and whether I should self-isolate after treatment because of the amount of contact I have with the public? 

I realise that the Coronavirus situation is a very fast-moving situation, but as I am now only a few weeks away from my treatment date, I want to think through and carefully consider what to do. I don’t want to end up not having the most effective treatment for potentially another  6 to 12 months and missing the therapeutic window to slow down the progression of my MS. 
 
Any advice you can give me is greatly appreciated. 

Thank you 

With best wishes

******

This case illustrates the clinical issues the COVID-19 epidemic is raising and is only one example of what we are having to face in the clinic. There are no easy straightforward answers.

Post-script 14-March 2020

The core issue is that this patient appears to want to get on top of their MS disease activity as soon as possible and doesn’t want to take a chance on a lower efficacy option. If this is the case it excludes interferon-beta and teriflunomide as option, which would be the logical choices based on their putative anti-viral effects. 

I would not recommend DMF. Firstly, DMF is less effective as a second-line DMT and it is immunosuppressive with about 15% of treated patients developing a treatment-related lymphopaenia of <800/mm3. As this usually comes on within the first 6-12 months in may not be the best DMT to start with. 

In a normal treatment environment, fingolimod would be an option, but as it is immunosuppressive I would probably steer away from it as a treatment option. In addition, if a COVID-19 vaccine does emerge quite soon and high-risk patients get early access to the vaccine you don’t want to be on fingolimod. Fingolimod has been shown to blunt vaccine responses. 

Based on its impact on T-cells and innate immunity alemtuzumab is a no-no. You could make the same argument about cladribine, which is now enshrined in print in the Italian and ABN COVID-19 DMT guidelines. However, the data does not necessarily support these positions. The level of T -cell depletion post-cladribine is ~50% for CD4+ T-cells and ~40% for the CD8+ T-cells making a much safer IRT than alemtuzumab. The data on infections in patients who received cladribine in the phase 3 CLARITY  trial, including the subgroup who developed grade 3 & 4 lymphopaenia, is very reassuring with no severe viral infection signal. The advantage of cladribine is that with immune reconstitution occurs this patient will be able to receive a COVID-19 vaccine if and when it becomes available. 

For similar reasons to cladribine, ocrelizumab will be relatively safe.  However, once you start ocrelizumab you need to commit to at least 3 or 4 courses to prevent neutralizing anti-ocrelizumab antibodies. As ocrelizumab blunts vaccine responses it is not the ideal DMT thinking ahead to a vaccine. Ocrelizumab blunts vaccines responses.

This leaves natalizumab. Natalizumab is a high efficacy DMT, with a rapid onset of action and can be reversed by plasma exchange if necessary. It also will not exclude vaccination from a component (non-live) COVID-19 vaccine. From a theoretical perspective, natalizumab cannot be assumed to be safe if this patient became infected with COVID19. Natalizumab has been shown to slightly increase your chances of getting an upper respiratory tract infection and may hence increase the chances of a more severe COVID-19 infection. Then there is the theoretical risk that natalizumab may select for neurotropic strains of COVID-19, but I think this is only a theoretical risk at present. I would also predict that natalizumab has a chance of creating potential COVID-19 superspreaders as it blocks trafficking of T-cells into the gut. Even if this patient was JCV+ve I would still potentially go ahead with natalizumab treatment. To reduce the PML risk this patient could be converted to extended interval dosing of natalizumab after 6 months or switched to another DMT in sy 6-12 months. The elephant in the room is NHS England (NHSE); this patient doesn’t appear to fulfil the current criteria for treatment under the NHSE treatment algorithm. This case, however, highlights, why it is important that NHSE relaxes is criteria for using natalizumab to address the unmet need during the COVID-19 epidemic. 

The other aspect is this patient is in contact with the general public that may increase his chances of being exposed to COVID-19, which may be more important than the other factors predicted above. So if this patient can’t reduce their risk of potential exposure to the virus in the hope of hanging on until a vaccine or anti-COVID-19 anti-viral become available then one of the immunomodulatory DMTs will make the most sense. This is why I would favour teriflunomide as the DMT of choice. It is also worth mentioning that when teriflunomide is used 2nd- or 3rd-line it is more effective. Teriflunomide also does not exclude vaccines later on; vaccine responses to component vaccines is maintained on teriflunomide. 

If this patient is unhappy with the logic of going onto teriflunomide, my second choice would be natalizumab,  followed by cladribine or ocrelizumab. 

This case demonstrates the complexities of treating active MS during the COVID-19 epidemic. There are no right or wrong answers. Whatever decision you make there will be compromises. You may have to compromise on efficacy to increase the safety of the patient concerned and to potentially leverage the other attributes of DMTs to justify your treatment decision, for example in the case of teriflunomide that it is broadly antiviral and does not affect vaccine responses.

CoI: multiple