Came across a great article on the relationship between inflammation, allergies and a poor immunity in CLL. ncbi.nlm.nih.gov/pmc/articl...
Every now and then I hear about people with CLL on the forums saying that they never really get properly sick. So for example a cold comes along and it just doesn't really descend on them like it used to.
We might assume that was a good thing, until we realise that many of the symptoms of a cold are actually the effect of our immune system responding to the infection. So in fact sometimes we may be sicker than we think we are. So it is very possible for us to be harbouring a low grade infection without really realising we are. And of course low grade infections are well known to produce fatigue, so I do wonder sometimes how much of our fatigue might evaporate if we were able to get rid of any low grade infections floating around.
In my own case, this business of our immune system not responding properly caused some confusion to a local hospital when I first presented with pneumonia (and during that illness became diagnosed with CLL). Why weren't my neutrophils raised if I had a significant pneumonia? Why wasn't my temperature raised until several weeks in when I suddenly began to go into sepsis whereupon it hit almost 40C? Why weren't my inflammatory markers raised at the beginning of the illness till eventually they turned on like a switch? The answer once we were clear I had CLL seemed to be that my immune system really wasn't that bothered initially that bacteria were gnawing away at my lung tissue.
Practically this is why for some of us a raised temperature even before treatment might be a much more concerning symptom than it would be in someone with a normal immune system. If we are not successfully mounting an immune response to an infection (of which a temperature is) in the early stages, but then do mount one when it has become much more advanced, then the advice to go to an ER if we have a temperature over 38/100.4 seems very reasonable.
Since my diagnosis like many others I have also had a significant worsening in my allergy symptoms so that I am now constantly in need of high dose antihistamines to stop myself scratching my skin off and that coupled with steroid nose spray and a saline rinse just about keeps my sinuses at bay...although lately I am starting to realise that perhaps they haven't been kept quite as much at bay as I thought they were. A few weeks back I developed a severe sinus headache simultaneously to a chest infection, and am currently into my third week of treatment with an antibiotic on top of my regular prophylactics to try and sort all this out.
This over-activity of some of our immune systems against allergens and yet under activity against infectious agents is quite common in people with CLL. And of course our immune systems sometimes also turn against our own bodies leading to various autoimmune problems too.
The article I found had a lovely way of explaining the cause of all this:
"A paradoxical deregulation of the immune system that produces an exaggerated inflammatory response to minor insult or to self-antigens coupled with an inadequate response to infectious stimuli is typically found in patients with CLL"
To translate that into regular English
The immune system becomes confused and disorganised. It both over-reacts to non threatening things it comes into contact with (such as pollen, dust, and mosquito bites), can even attack the body itself, but also under reacts to infections.
The article then goes on to review what information was available in 2013 about all this, it would be interesting to find out how much more research has been done since then, though I rather get the idea there may not be that much more.
The paper describes a study that showed that certain inflammatory cytokines were higher in patients with CLL than healthy controls. It was a relatively small study.
In patients with ME/CFS and Fibromyalgia it has been shown that certain patterns of altered cytokine concentrations are associated with patients having worse symptoms. Despite careful searching of pubmed I have not been able to find any study to identify if certain patterns of dysregulation of cytokines are associated with more fatigue in patients with CLL. It would be fascinating to take a group of patients with severe, moderate, mild, or no fatigue and compare their cytokine profiles. Perhaps we could even have a blood test that proved there was a reason for how crap we were feeling...it would be great to be able to prove it is not just in our minds!
I wonder if any of you have had your cytokine profile measured? It doesn't seem to be done routinely.
Another test that could be of interest is looking at the number of T cells and natural killer (NK) cells. The paper explains these are often INCREASED at the time of diagnosis as the body tries to fight off the CLL, and one wonders why we don't measure them routinely as apparently if this increase is present it suggests there will be a longer time to first treatment, presumably because this increase is initially helpful.
Conversely it seems the real problem with CLL is when those cells give up and are no longer fighting CLL properly. CD8+ (cytotoxic) T cells will often increase more than the CD4+ Helper T cells, and apparently this ratio can also have important prognostic implications. But again I don't think we are often tested for the amounts of these subtypes, except perhaps the CD4 levels where I understand some doctors use that as a marker for whether or not you should be on some prophylactic medications.
Now of course the argument against testing for all these things would be, but is there anything we can actually DO about it? Perhaps there isn't just yet, but wouldn't it be interesting to begin to look at firstly how the derangement of the immune system is correlated with symptoms, but also to look in more detail at how predictive it is of our future health, and perhaps start to look at how it could be influenced.
The paper also explains that certain pro-inflammatory genetic mutations are also seen in patients with CLL.
How the inflammatory state could be influenced is where this paper gets really interesting. Advocates of certain diets sometime claim their diets are anti-inflammatory and that therefore they can reduce the rate of development of the disease. This paper might even support that hypothesis (if that is it could be proved that the diet itself genuinely was anti-inflammatory even if someone isn't actually allergic to the food they cut out). Since the idea seems to be that anything that switches off inflammation may help CLL. Of course most evidence for such diets is largely anecdotal and the paper doesn't mention diet as a possible intervention.
The paper does review evidence for the efficacy of a range of anti-inflammatory drugs including the ultimate anti-inflammatory steroids, non steroidal anti-inflammatory drugs including aspirin, statins, and even points out that Ibrutinib is actually working by counteracting certain inflammatory pathways.
So should we all be taking an aspirin a day and even if our cholesterol isn't up a statin? Sadly the studies haven't been conclusive (perhaps not large enough?), and I suspect the effect if real may be small, but if even 100 of us had to take an aspirin a day to delay a relapse in one patient by one year perhaps that would be worthwhile?
With all the excitement about new drugs I doubt that much interest will go into trying to further confirm the old data this paper reviews. Perhaps some younger haematologists may even forget that steroids can actually help our disease!
Speaking of steroids, on the occasions I have had to take a week of steroids (eg after my tonsil operations) I have felt an instant and dramatic improvement in my fatigue levels which is much more than just the fact they also stop you from sleeping. So much so I have often mused about begging a doctor to put me on a low dose steroid to as an old respiratory doctor actually suggested "just settle down any residual inflammation that may be there". There are serious side effects of steroids that mean that perhaps that is not as good an idea as it immediately sounds. But if I could just pop a single tablet on a day I wanted to achieve more.....
Anyway this has gone on long enough, and if you would like to learn more, the paper this article is based on can be found here:
Very interesting post, thank you for the information and for breaking down the article and issues. Now I understand why we are supposed to tell the doctor immediately about any high fever (I agree because of personal experience that by the time the body figures out to go into fever we are already well into the infection and need medical help). I also noticed the 'no cold' thing and wondered why I didn't catch stuff if others around me are sick, but now will try to watch if symptoms show up instead as increased fatigue.
I used to say I felt like I had a cold in my bones a lot. Sometimes I’m not ‘ill’ but it feels like my immune system is a bike in the wrong gear, pedals whizzing but going nowhere fast. It’s very confusing knowing what to do. The worst infection I had this year left me with a fever of 39.5 for a couple of days but that wasn’t until after a few days of being barely able to move. I couldn’t motivate myself to roll over and get water. A chest and bladder infection were to blame but when I’d been calling the GP before, there wasn’t much response because I didn’t have a fever so wasn’t seen. By the time I was, I was very unwell. Are there specific guidelines for us because it’s seems so random. On another occasion when I had another bout of cellulitis in my foot. I’d seen a GP (who reluctantly gave me anti biotics) but it was still spreading. I called and the GP told me to sleep on it and see how far it had spread up my leg overnight. It was the support of this group that made me insist on help. I emailed a photo of my foot to my GP surgery and was dealt with immediately. I’m coming down with something now, my colleagues could tell yesterday because my brain gets scrambled. Sorry about the typos.
So, after this waffling message, are there specific guidelines we can show our GPS as I’ve really had to battle to be seen or looked after in the past.
I am not aware of any guidelines. But I have found some of my GPs are much more on the ball than others. I recently attended one for the first time and they were the ones who said to me "in view of your history we should have a low threshold for antibiotics in your case"
It may be that one of the GPs in your practice is clearer about these things than the rest. It may be that you can influence one of them by speaking with them about it and by trying to see the same doctor each time.
Finally it is very important in my view to find out if your practice does electronic booking of appointments and get onto that system, also finding out when the same day appointments are released.
At my GP surgery at 7:15am you can log on and there is a mad dash for about the next 30-45 mins to nab the appointments they hold back for same day. We are encouraged not to abuse this, but actually not asked to justify the reasons for seeing a doctor at the point of booking at all. Presumably anyone who repeatedly abused it by booking in unnecessarily might have that privilege rescinded. But because they hold back at least a third of all their appointments to be booked this way it means that you can ALWAYS get a same day appointment.
This issue of access to GP appointments is so important that it is worth changing surgery over if there is another in town which has a better system. One could also request to speak to the practice manager about the situation you face. And finally one could get the consultant to write about the need for you to have antibiotics more early than others.
And as annoying as it is, sadly if one can't get a GP appointment it is down to A and E with any infection symptoms for us and especially temperature. Sounds like you should probably follow the rule of anything over 38 / 100.4 and its a quick trip to the A and E with "I have blood cancer and am immune compromised. I have a temperature and am concerned I may have sepsis." Those opening lines to the receptionist should get you seen promptly and actually represent the reality. We don't always have sepsis when we have a temperature but we only have to have it once. Nobody would think you were raising an alarm falsely by taking that action. And of course A and E can do a quick FBC to check if there has been any sudden developments in our CLL such as the development of neutropenia which can happen even prior to treatment and if you are having bloods every three months could easily creep up on you.
In fact once I got told off by my GP for coming to them and not going to A and E. And my last infection (a combined sinus infection and chest infection for a nice double whammy!) had me watching my temperature as it climbed during the early hours of the morning but just staying below the cut off of 38, booking the first GP slot of the morning, and actually reading 38.4 in the room with him! Since he could hear chest signs and I didn't appear otherwise unwell we agreed with him (and also my Clinical Nurse Specialist who I was on the phone to immediately before and after the GP slot) that I would try co-amoxiclav and if the temperature didn't immediately settle go up to A and E. Fortunately that time even the first dose of the antibiotic led to the temperature lowering and by the second it had gone...antibiotics are amazing when they work sometimes!
I totally agree...sadly at the moment not even FLAIR sites can all agree about which prophylactic anti-invectives they should give when people are on treatment arms...members of the forum have been given conflicting advice even about that.
So much of this is not really evidence based but experience driven.
So for example I had a run of throat infections that kept coming back really frequently, and usually didn't respond to a penicillin but did respond to clarithromycin.
Eventually my GP and I decided that perhaps it was the same bug growing back...so we gave a two week treatment instead of the standard one week and hey presto I didn't have a throat infection for months.
So now with my n of 1 I am an eager advocate of a longer course of antibiotics at least in me, and it turns out that several other CLLers have discovered the same thing and some doctors do recommend longer courses for us.
What would be nice is some more data on what to do to reduce the risk of infections. Even the data on IVIG is not that good presumably because the study wasn't long enough (and is very old now).
But the general principles do seem fairly self evident: if you don't have a good immunity treat early and maybe longer with antibiotics and hopefully you will not develop a worse infection. And if you have no antibodies and are getting infections its reasonable to assume you will probably get less if you replace the antibodies. That and the idea that there are some things you can do to reduce infection risk shouldnt be too controversial, but they are not hugely based on clinical trials or firm evidence. It is a bit trial and error really.
Wonderfully apt article as I've been feeling over tired recently and discovered that one antihistamine pill before bed makes me feel invincible the whole of the next day.
Thought it might have something to do with all the all the pollen floating around this month.
Hmm.. this had made me think! Might explain why I have only had one, short-lived, cold in the last 18 months, whilst many of my family and friends have had heavy, persistent coughs and colds, despite my slowly increasing ALC and WBC. But in the first few years following my CLL diagnosis (8 eight years ago), I used to get bad chest infections and was given antibiotics quite regularly, but haven't needed them for a long time now. However, for the last four years I have had to deal with fairly frequent flares of inflammatory arthritis, so have been taking anti- inflammatory meds more than I used to, and also trying out anti- inflammatory supplements. And, although feeling quite well, I have had to pace myself more during the day to combat general fatigue, so can't be as busy as I used to be!
An interesting read and SO very much we still do not know.
Add to causes of inflammation, the polluted air we breath.
This from The Guardian Newspaper in the UK today.
‘ The Guardian focuses on new research which says air pollution may be damaging every organ and virtually every cell in the human body.
The study by scientists from the Forum of International Respiratory Societies links toxic air to what the paper calls "head-to-toe harm", including diabetes, dementia, and brittle bones.
It blames particles so fine that they can pass through the lungs into the blood stream - triggering an immune response that causes inflammation to flood through the body.’
So if we live in many of the cities of the UK, and the world, our immune system is constantly working overtime with the resultant inflammation response.
In March my cll came back after about a 2 1/2 year reprieve after Ibrutinib and Gazyva. (had to d/c Ibrutinib due to cardiotoxicity). Suddenly lymph nodes were popping out and I went through a week of severe (body/ bone/ deep inside pain) that was not due to any kind of muscle injury. DR. vaguely mentioned cytokines being released as lymph nodes enlarged. I couldn't find too much on this online. Ibuprofen helped. Now it has only been happening a few days at a time, here and there. I also noticed my restless leg syndrome is much worse. I continue to have extremely low IGG levels that go from the 200's to high 300's after IVIG and then back down again. IGM and IGA also very ,very low.
I wish I could figure out the correlation between cytokines and lymph nodes and immunoglobulins.
Waiting now till symptoms get really bad again and then back on something else, maybe Venetoclax.
Fascinating information! My husband also battled constant infections before his CLL diagnosis and has hardly had a cold in the last few years. Also, dairy has been his favourite food and suddenly, just before his stem cell transplant, he developed a severe anaphylactic reaction to dairy. Definitely the body reacts in many different ways to what it is fighting.
Many oncology professionals acknowledge that CLL can be related to cytokine influenced inflammation and can cause many problems, but for some reason they weigh toward avoiding the discussion and impress that it is to complex to diagnose. Especially with regard to influence on joint pain, connective tissue and fatigue.
Excellent post, Adrian! Am going through this right now. On going, worsening fatigue since December when I got my first sinus infection in over two years. Did one round of antibiotics and went on my way. Symptoms gone, but have not felt great since December. Started in with severe sinus headaches this week, along with the normal this time of year allergy issues, sore throat, very runny nose. Because I am allergic to both penicillin and sulfa, I try not to take an antibiotic unless I know I have something bacterial, but because of my CLL my GP did not want to wait. Started it yesterday, already feel a tad bit better (probably in my head). Now wondering if I never really got over the infection in December. We will see if the fatigue lifts any as the week goes on. And I might do a second round of antibiotics just to be on the safe side.
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