Q: severe COVID-19 infection

Is being immunosuppressed increase your risk of getting severe COVID-19 infection?

Possibly. Most commentators and experts would answer yes to this question, but there are some important caveats that need to be considered.

At the moment we suspect a significant number of people have asymptomatic infections, i.e. they get exposed to the virus, get colonised and then shed the virus, but don't develop any symptoms of disease. It is likely that people on immunosuppressive therapies are less likely to be asymptomatic. If this is the case then immunosuppressive DMTs are likely to increase your chances of getting COVID-19 or symptomatic infection.

This however does not necessarily mean you will have worse disease or be at increased risk of getting severe COVID-19. Why? It appears that severe COVID-19 infection is not necessarily due to the virus, but the immune response to virus. Therefore, paradoxically, it has been hypothesised that immunosuppressed people may be somewhat protected from severe disease.

An hypothesis being considered is that moderate immunosuppression may prevent severe complications associated with COVID-19 infection. The severe pulmonary complications of COVID-19 infection appear to be consistent with ARDS (acute respiratory distress syndrome) caused by an over-exuberant immune response to the virus. As a result of this, several exploratory trials are currently being undertaken in China using immunosuppressants to try and dampen the immune response to the virus. Interestingly, fingolimod the S1P modulator, which is licensed as DMT for MS, is being tested as a treatment for COVID-19 associated ARDS. Please note that this is a hypothesis and will need to be studied prospectively. It can only be answered by studying large numbers of pwMS, on and off DMTs, who get COVID-19.

It is also important not lump or categorise immunosuppressive therapies as one.

I had a discussion about the COVID-19 epidemic with our renal transplant team who informed me that they are not taking any specific action about the levels of immunosuppression they are providing their transplant patients during the pandemic. Apart from informing their transplant patients to improve their hand and home hygiene, to avoid high-risk travel and unnecessary contacts, to self-isolate if necessary and to reduce contact with the hospital and other medical institutions as much as possible, because they are more likely to be sources of COVID-19. It is business as usual. Nor are they halting their transplant programme. Their argument is that transplanted kidneys and other transplanted organs are too precious not to protect them with relevant immunosuppressive drugs. I personally have the same attitude about the brains and spinal cords of pwMS, particularly those with active multiple sclerosis.

I would argue that solid-organ transplant patients are significantly more immunocompromised than pwMS on a DMT. Most transplant patients are on triple immunotherapy, compared to pwMS who are on monotherapy and even then the level of immunosuppression is generally low on MS DMTs. Hence, the mortality risk to an individual on a DMT, who is unfortunate to be infected with COVID-19, maybe actually quite low.

Based on the immunological principles that antiviral responses are mainly driven by T-cells, in particular CD8+ cytotoxic T-lymphocytes, and natural-killer cells and less so, at least initially, by B-cells. Therefore there is a hierarchy of immunosuppression of the DMTs. The highest risk will be the immune reconstitution therapies during the depletion phase of the treatment, i.e. HSCT, alemtuzumab (Lemtrada), mitoxantrone (Novantrone) and possibly cladribine (Mavenclad). However, post-immune reconstitution once the total lymphocyte counts have returned to normal, or near normal, the risk of severe viral infections are probably no higher than what would occur in the background population and would be associated with age and other comorbidities. Please note immune reconstitution takes months to years, so if your last course of treatment was in the last 12-24 months you may still be immunocompromised. As a rough guide if the total lymphocyte count is above 0.8 x 10⁹/L or 800/mm³ you should be able to deal with viral infections reasonably well provided they have not other comorbidities and are relatively young (less than 45).

Of the IRTs, cladribine (Mavenclad) should be classed as being of intermediate risk, because it is a relatively poor T-cell depleting agent. T-cells are only depleted post-cladribine by an average of 50% with the CD4+ population being more sensitive than the CD8+ population. In the Phase 3 CLARITY study, viral infections were uncommon post-cladribine and apart from herpes zoster, infections were only slightly more common in cladribine-treated subjects compared to placebo-treated subjects. When viral infections occurred post-cladribine they tended to be mild or moderate in severity. Therefore I think cladribine should be classified as relatively low-risk DMT.

Similarly, anti-CD20 therapies such as ocrelizumab have a minor impact on T-cell counts and are not associated with severe viral infections. In the Phase 3 relapsing-remitting and primary progressive trials infections were more slightly more frequent on ocrelizumab compared to comparator arms (interferon-beta-1a or placebo). Most of these infections were mild and moderate with the severe infections being bacterial in nature (pneumonia, urinary tract infections and cellulitis). Similar to cladribine there was a small risk of herpetic infections, which were mild to moderate and manageable with antiviral agents. I, therefore, feel that anti-CD20 therapies are relatively safe based on their profiles defined in phase 3 trials and we should continue to use them in patients that need them.

Date & Disclaimer: 18-March-2020; please note this information will be time limited and will change as new data emerges.