Help, my daughter has infectious mononucleosis
Help, my daughter has infectious mononucleosis
As I have MS my daughter has about a 1 in 40 risk of getting MS. I assume that as she now has IM her risk of getting MS is further increased. What can I do to reduce this risk?
Case study
I am a 44-year-old woman with multiple sclerosis. My 16-year-old daughter has just come down with infectious mononucleosis (IM). She has had a fever, sore throat, and fatigue for several days. She is very tired and listless. She cannot do school work or attend remote lessons online, an option available post-COVID. Her temperature reached 39.4°C yesterday. She saw our family doctor two days ago, who diagnosed her with tonsillitis and prescribed azithromycin. She had blood tests, and the practice nurse called today to say she could stop the antibiotics as her blood tests show she has IM. She has very large lymph nodes in her neck.
I am aware from your recent newsletter on pregnancy (2-Feb-2023) that because I have MS, my daughter has about a 1 in 40 risk of getting MS. I assume that as she now has IM, her risk of getting MS is further increased. Is there anything we can do to reduce this? Do you have any other recommendations for managing her IM; she is not well, and I don’t want her to develop post-viral fatigue syndrome. Thank you.
Prof G’s opinion
To be frank, your daughter’s case is really out of my comfort zone as a neurologist.
How your daughter’s IM has been diagnosed and managed is typical. IM is common in adolescents and young adults and typically presents with purulent pharyngitis, lymphadenopathy, fever and fatigue. About a third of cases will have an enlarged spleen on examination of the abdomen, but this figure is likely to be much higher (>80%) if an abdominal ultrasound is done.
We did an audit of our service at the Bart Health NHS Trust between 2011 and 2016 and found that half the cases with IM confirmed with serology were initially misdiagnosed and prescribed antibiotics for possible streptococcal pharyngitis. This is what happened with your daughter. I suspect the actual misdiagnosis rate is much higher than this in real life, as many general practitioners and emergency department doctors don’t even send serology off when they see patients with pharyngitis but simply prescribe antibiotics to cover streptococcal and other bacterial causes of pharyngitis. Post-COVID and with the rise of remote GPs (e.g. GP at hand) who see patients via a video portal, this will likely become the norm. In many countries, primary care doctors at least do a lateral flow test for streptococcal infection and prescribe antibiotics accordingly. This rapid streptococcal test, a lateral flow test, was not approved by NICE and is therefore not used in the NHS. Saying this, you can purchase them privately from a pharmacist.
The scenario above is one of the reasons why I am trying to get funding to sort out the IM diagnostic and management pathway. Something happens from an immunological perspective during symptomatic primary EBV infection, which sets the stage for the later development of autoimmunity and MS. People who have IM have an exuberant immune response to EBV, which is associated with a large increase in reactive lymphocytes in the peripheral blood and massive enlargement of lymphoid tissues, hence the enlarged tonsils, adenoids, lymph nodes and spleen. Immunological studies show dysregulated immune response induced to control EBV during IM. Several of us have hypothesised that if we can prevent IM with a non-sterilizing EBV vaccine or treat IM with antivirals, we may prevent this abnormal immune response and possibly prevent the triggering event that sets off the autoimmune cascade that subsequently leads to the development of MS.
The great tragedy is that despite having several antiviral agents that work against EBV in the laboratory, nobody has done a randomised controlled trial to test these agents in people to get an antiviral agent licensed to treat IM. Tragically there are no licensed treatments for IM. Why? There is a common misconception that IM is a benign self-limiting illness. This is what I was taught in medical school. This medical dogma is incorrect. IM may be relatively benign and self-limiting in most people, but there is a significant minority who have severe IM, with prolonged post-viral fatigue, which may develop into chronic fatigue syndrome. Some people develop severe and often other life-threatening complications, which include hepatitis, ruptured spleen, upper airway obstruction, haemolytic anaemia, thrombocytopaenia, aplastic anaemia, thrombotic thrombocytopaenic purpura or the haemolytic–uraemic syndrome, disseminated intravascular coagulation, haemophagocytic lymphohistiocytosis, Guillain–Barré syndrome, facial nerve palsy, meningoencephalitis, aseptic meningitis, transverse myelitis, peripheral neuritis, cerebellitis and post-infectious optic neuritis. Sadly there are a small number of people who die from IM.
I think there is a compelling reason to prevent IM with an EBV vaccine and to develop an effective antiviral therapy for IM. My problem is convincing funders, pharmaceutical companies and my general practice colleagues of the unmet need.
I suspect the reason for IM inertia is that the management of IM straddles several specialities, and hence there is no one group of doctors who primarily manage IM. In the UK, it is general practitioners and or accident and emergency doctors who see the majority of IM patients. If patients with IM need to be admitted to the hospital, they will be under paediatricians or general physicians, and infectious disease doctors and virologists may then get involved.
Virologists and infectious disease doctors do see EBV infections, but these tend to be EBV reactivation in severely immunocompromised patients. These patients are often critically ill and often have other herpes virus infections, in particular cytomegalovirus (CMV) reactivation. As a result, these patients get treated with antivirals that target CMV, such as intravenous ganciclovir or, in some cases, that are less severe with oral valganciclovir.
Because of these circumstances, it is difficult to get pharma companies interested in community-acquired EBV infections and IM. This has to change. If our MS salivary shedding famciclovir trial is positive, i.e. famciclovir stops EBV lytic infection and salivary shedding in people with MS, we are going to try and get funding to do a trial of famciclovir pwMS, and in parallel, we want to do a famciclovir trial in patients with acute IM. Saying this is not easy to set up and run an IM trial, given that the current IM management pathway is so dysfunctional. This is why we need a new service model to manage patients with purulent pharyngitis, and in doing this, we can diagnose, study and manage patients with IM.
Please note there is already good circumstantial evidence that famciclovir works well against EBV. Compared to aciclovir, famciclovir has a longer intracellular half-life, and in cell culture, it is very effective against EBV. Many case studies and small case series show that famciclovir works well in IM.
So in an ideal world, we would have an acute IM clinic running with the primary aim of studying and developing treatments for acute IM. We plan to perform a randomised placebo-controlled trial to see if famciclovir compared to placebo, reduces EBV viral shedding in the saliva, reduces peripheral blood EBV loads and results in rapid resolution of IM symptoms. In parallel, we will do detailed immunological studies on these patients to see if active treatment corrects or prevents the immunological dysregulation in IM. We will then enrol the study subjects into a long-term register and study them annually or biennially to see if they are less likely to develop MS and other autoimmune diseases. In parallel, we will collect data on EBV-associated cancers. Treating IM may also reduce the risk of cancer. Interestingly, the latent period from IM to the onset of an EBV-associated disease is the shortest for Hodgkin’s disease, a form of lymphoma or cancer of lymphocytes, being about four years. For MS, the average latency from IM to disease onset is likely to be in the order of 8-10 years.
Wouldn’t it be amazing if an effective treatment for IM could reduce delayed EBV-associated diseases? This is why I want to reinvent myself as an infectious disease doctor and start managing IM.
So if this were my daughter, I would take the following paper to her GP and ask the GP to prescribe a course of famciclovir. The rationale for famciclovir is to help her recover from IM quicker. Whether or not this will do anything for her MS risk is unknown.
It is also essential that this person’s daughter does not smoke or get obese and keeps herself vitamin D replete by taking vitamin D supplements. These are all potentially modifiable risk factors in reducing her chances of getting MS. I would also suggest she adopt a healthy lifestyle with plenty of outdoor activity with judicious sunlight exposure and only use sunblock if the exposure is prolonged and likely to cause sunburn.
Sadly we don’t yet know if the latitudinal gradient in terms of MS incidence is due to low vitamin D levels or lack of sunlight exposure. It may be the latter, as sunlight does have immunomodulatory effects on the immune system. T-cells, whilst traversing the capillaries in the skin, are exposed to sunlight, which alters their properties. This is how PUVA (psoralen and ultraviolet A light)) therapy works in psoriasis, an autoimmune skin condition. If this were my daughter, I would also suggest she avoids using sunblock-containing makeup. I am unsure if you have noticed, but the only make-up with no sunblock added tends to be formulations applied at night. The cosmetic industry includes sunblock in their products and badges them as antiaging. Ultraviolet-A light (UVA) exposure is very ageing to the skin, but the sunblock used is non-discriminatory and blocks UVB light required by the skin to make vitamin D.
Many dermatologists who read this will be rolling their eyes at this advice because it goes against their advice about preventing skin cancer. Chronic sun exposure is strongly associated with basal cell and squamous carcinoma of the skin and intermittent sunburn with melanoma risk. I am not denying this, but we need to try and create a healthy balance between too much sun exposure and too little. From a personal perspective, when I have some sun exposure in summer, it makes me feel healthy and lifts my spirits. I have always wondered if this is a placebo effect related to sunlight's effect on mood or a physiological effect from what is happening in my skin.
Please be aware that my advice in this newsletter is pragmatic and not supported by class 1 evidence (randomised controlled trials). Preventing IM, treating IM with an antiviral, not smoking, avoiding childhood and adolescent obesity, increasing outdoor activity, exposing oneself to sunlight and taking vitamin D supplements may reduce one’s risk of getting MS, but this has not been established with definitive studies.
If there is anyone out there with political clout, can you please help? These studies are so important to do. Thank you.
Luciano & Goldani. Treatment of severe infectious mononucleosis with famciclovir. J Infect. 2002 Feb;44(2):92-3. doi: 10.1053/jinf.2001.0954.
We report a patient with severe acute infectious mononucleosis who was successfully treated with famciclovir. A 15-year-old male was admitted with a 6-week history of fever, malaise, generalized lymphadenopathy, and hepatosplenomegaly, the patient was acutely ill with a temperature of 39.0 degrees C. Oropharingeal examination revealed enlarged tonsils partially obstructing the airways. EBV serology obtained during admission showed a positive Monospot test, virus capsid antigen IgM, 1:320, Epstein-Barr nuclear and early antigen, negative. After 72 hours of treatment with famciclovir (500 mg t.i.d.), the patient was afebrile with important regression of the lymphadenopathy, enlarged tonsils and hepatosplenomegaly. Because acute infectious mononucleosis may be associated with extensive and prolonged disease, the potential therapeutic role of famciclovir in the treatment of severe forms of the disease deserves further studies.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your own healthcare professional, who will be able to help you.
+1 here. IM aged 19 and PPMS from around 50 (retrospective estimate).
As you say, there's a big gap in the research between IM, MS and Infectious Diseases. Trouble is that IM and ID are of the episodic mindset, whereas the MS community are looking at a lifetime condition and still seeking the metaphorical source of the Nile.
MS needs its own Bill Gates. An evangelist with bottomless pockets determined to eradicate a particular disease.
I grew up in NZ where I was kept out of the sun after my godmother died from melanoma. I had glandular fever just before I turned 20 and I don't feel like I ever fully recovered. Life got harder from that point on. There were no more all nighters, that's for sure!
Now I live in the UK it's actually easier to get some sun. I don't have to spend ten minutes putting sunscreen on before going outside. I lead a very active life a lot of which involves being outside. I run, I cycle, I go camping, I walk everywhere as I don't have a car here (a necessity in NZ but not in London!). Last year I bought a ground floor flat with a garden and I feel so good when I've been working out there.
In terms of reducing MS risk there is some good advice in the book Overcoming MS - much of it the same as Prof G's. The book adds following the Overcoming MS diet. That works for me but from the evidence available it seems any of the MS diets will do. What they all have in common is a focus on whole foods and reduction or elimination of highly processed foods.