Friday, 8 April 2016

ClinicSpeak: are you at risk of developing an opportunistic infection?

What has Donald Rumselfeld go to do with MS? #ClinicSpeak #MSResearch #MSBlog

"Last year I gave a rather serious lecture on adverse events of drugs at the NMSS comorbidties meeting in Toronto. My talk was on 'Distinguishing comorbidities from drug-related adverse events in MS clinical trials' (see SlideShare below). Although it was a serious talk I tried to lighten the mood by proposing we approach the issue using a Rumsfeldometer, after Donald Rumselfeld's infamous quote: 'There are known knowns; there are things we know that we know. There are known unknowns; that is to say, there are things that we now know we don't know. But there are also unknown unknowns – there are things we do not know we don't know'."

Donald Henry Rumsfeld (born July 9, 1932) is an American politician and businessman.
  1. Known-knowns - there are things we know that we know
  2. Unknown-knowns - these are the things we know will occur
  3. Known-unknowns - there are things that we now know we don't know
  4. Unknown-unknowns - there are things we do not know we don't know
"One of the things I predicted in my section of 'Known-Unknowns' is that because we haven't seen opportunistic infection X after immunosuppressive drug A doesn't mean that drug A is not associated with this particular infection. Based on scientific principles given the right time frame and the environment, or exposure risk, opportunistic infection X will occur in patients with MS treated with immunosupporessive drug A. Therefore it comes as no supprise no to me that a very unfortunate person with MS developed a relatively rare opportunistic infection of the brain, 4 months after having a course of alemtuzumab. The Known-Unknown infection was Nocardia which is a genus of gram-positive bacteria that forms beaded branching filaments or chains similiar to fungi. There are over 80 species of Nocardia that are found in soil rich in organic matter." 

"I have personally seen two cases of Nocardia in my career as a neurologist; my first case a neurology trainee in a patient with a renal transplant and my second case a young consultant in a patient with a recent bone marrow transplant. As people with MS on immunosuppressive treatments and as neurologists with a increasing number of patients who are immunocompromised we need to be more vigilant of this issue; the more patients we treat aggressively with immunosuppressive therapies the more opportunistic infections we will see. The one bit of good news with alemtuzumab the drug in question is that the risk of opportunistic infections is front-loaded. The risk of infection only occurs when the immune system is depleted; once the immune system has reconsituted itself the risk of opportunistic infections will fall. With drugs such as fingolimod the risk does not decrease; in fact in may increase and becomes cumulative over time. Using simple maths, or statistics, the risk of developing an opportunistic infection on maintenance immunosuppressive therapies will rise the longer you have been on the drug." 

"I now tell patients about front-loading of risk and cumulative risk. It may make things more complicated, but most of the pwMS I have discussed this with understand the concept. It is an important concept as it may be the difference between someone choosing a particular treatment stragtegy or not. Saying this most people don't like the concept of their immune systems being suppressed, be it short-term or long-term. Despite this risk the chance of acquring an opportunistic infection on alemtuzumab, fingolimod or the the other MS DMTs is low." 

Penkert et al. Fulminant Central Nervous System Nocardiosis in a Patient Treated With Alemtuzumab For Relapsing-Remitting Multiple Sclerosis. JAMA Neurol. 2016 Apr 4. doi: 10.1001/jamaneurol.2016.0146. [Epub ahead of print]

Excerpt: An MSer was abmitted with reduced ambulation and personality change. She had been treated with natalizumab (80 infusions), which was discontinued because of repeated relapses and seroconversion to become JC virus positive. She was treated alemtuzumab in February 2015 (EDSS 4.5), 18 weeks after the cessation of natalizumab treatment. On admission in June 2015, she was wheelchair-bound. She was found to have a brain lesion, which on biopsy was found to be an abscess. Culture of intracranial abscess material grew Nocardia farcinica

CoI: multiple


  1. But it's not just opportunistic infections - it's also the increased risk of cancer, which is so common anyway. I have known of several people who died before their time due to cancer that was not detected early enough and/or was not treatable.

  2. Prof G,

    Would acquiring an infection (eg: respiratory or GI) shortly after Lemtrada alter its effectiveness at all?

    Is the reconstitution of the immune system damaged by fluctuating cell counts and by pathogens as a result of the infection?

    1. ProfG knows more about this drug but probably not in terms of its effectiveness as many people can get infections during the early period during depletion

    2. Hopefully he can comment. If there's no data from the trials on how those who had an infection shortly after infusion went, perhaps just theoretically... It would be interesting to know how successful Lemtrada was in patients who has an early infection.


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