Fatigue in CLL

Many patients with CLL complain about fatigue.

It is also true that many patients without CLL complain about fatigue.

The commonest reason for a general practitioner requesting a CBC is "tired all the time". I suspect that they suspect anemia, which is certainly a cause of fatigue. Hardly any of those patients have anemia.

There are many possible causes of fatigue. People feel fatigued when they have been working hard - either physically or mentally. If you play a hard game of rugby or soccer you certainly feel fatigued at the end of it. If you drive 200 miles, if you go for a job interview, if you watch you children perform in the school play, the emotional tension makes you feel tired afterwards.

Tiredness is the natural consequence of being awake for a while, an indication that we need to sleep. Clearly this is not what patients are complaining about.

There are medical conditions which manifest as tiredness. I'm not sure that tiredness is a good word to describe it, though it is certainly part of it. Fatigue is a word often used, though this is a technical word in medicine, which has a specific meaning. It refers to what happens when a muscles is stimulated repeatedly by electricity. After each stimulation there is a period when it cannot be stimulated again - the muscle is said to be fatigued and requires the regeneration of certain chemicals before it can be restimulated.

Asthenia was a word that was formerly used. It describes that feeling of exhaustion, lack of energy or indeed the will to do anything; being washed out and weak and watery. It was often associated with anemia or chronic infection, especially with TB.

Anemia induces this feeling because insufficient oxygen is reaching the muscles. In France and Germany doctors are prone to diagnose asthenic patients as having low blood pressure, and the German Health Service has quite a large budget to spend on drugs to raise the blood pressure, something that is unknown in the UK.

Some years ago I began to be referred patients who claimed that they had myalgic encephalitis or ME. There is an ME society. What these patients had in common was severe fatigue. Commonly they would sleep for 12-16 hours at night. Often they had muscle pains (hence the myalgia) and they would often complain of a muzzy head, being unable to concentrate or focus on anything (hence the encephalitis). They were unable to hold down a job. Many of them dated their symptoms from a viral infection, often glandular fever, that never seemed to have got better, although often the glandular fever had not been diagnosed virologically, but simply labelled as that from a GP without investigation. One woman dated her illness to when she was biten by a squirrel.

At the time I was interested in infectious mononucleosis. However, I could find no really convincing evidence of EBV having anything to do with it. A clinical trial of levamisole as an immune booster had no effect.

Nowadays this condition is called chronic fatigue syndrome and it is treated by cognitive behavioural therapy, though sometimes older doctors and rheumatologists label it as fibromyalgia (which being translated means, "I know you have aches and pains but I can't find anything wrong").

The problem about making the diagnosis of pathological fatigue is that it is a diagnosis of exclusion. That means that as it has no spcific symptoms and no clinical signs or characteristic blood tests, the doctor must first exclude all the conditions that can be tested for

Simply getting older is the commonest cause of fatigue. It affects some more than others.

Fatigue often has a psychological cause. It doesn't mean that you are psychologically ill, but things like children leaving home, retiring or nearing retirement, downsizing your house, divorce, bereavement, disappointments, fears, even the war in Iraq can leave us feeling fatigued.

Then there is actual depression. Subclinical depression is much commoner that is recognized. And so is anxiety neurosis.

Medications cause fatigue. Any sort of sleeping tablet, any type of blood pressure tablet, any type of anxiolytic, many antihistamines.

Sleep apnoea is a possibility, especially in anyone who is overweight, then there is any degree of heart failure, certain types of neurological disease, any type of cancer, diabetes, hypothyroidism, Addison's disease and I expect there are other conditions that I haven't thought of.

When a blood test for 'tired all the time' is done, some people will be found to have undiagnosed CLL. But perfectly well people having a blood test prior to, say, hernia repair, will also be found to have CLL. We can't just say, "Aha! We have found the cause of the fatigue." Lots of people, perhaps the majority, who have CLL do not have fatigue.

It must be galling for a patient to keep telling the doctor that the CLL is the cause of the fatigue and yet not have the doctor believe him or her. What more evidence do they want? I used to be well, then I got CLL, now I am fatigued. Why won't you believe me?

So what is the evidence that CLL is the cause of a particular patient's fatigue?

If you search for 'Fatigue' and 'CLL' on PubMed you find a couple of pages of papers most of which refer to fatigue as a complication of treatment or anemia. There is a paper which reviews studies of qualitiy of life in CLL.

This paper by Stephens et al Am J Ther 2005; 12:460-466. has the following quote: "We identified only 8 articles, and none of them analyzed the QOL in untreated CLL patients".

There has been no systematic study of the symptoms suffered by asymptomatic patients.

Some doctors are convinced that CLL causes fatigue. They believe this because a lot of CLL patients have told them that they suffer from fatigue. On the other hand doctors in some countries get paid a lot more if they give patients chemotherapy than if they simply offer watch and weight. Far be it for me to suggest that any doctor would be swayed by this, but some might opine that such a doctor might not be entirely objective.

There is a rationale for fatigue in CLL. We know that CLL cells in the test tube can be shown to secrete a number of cytokines including IL-1, IL-6, IL-8. IL-10, TNF-alpha, TGF-beta. It is also known that when certain cytokines are used therapeutically (IL-2 and interferon) the side effects include prostrating fatigue. In addition several conditions in which fatigue is prominent such as terminal cancer are associated with high levels of certain cytokine such as TNF alpha and IL-6.

If this is the mechanism then one would expect fatigue to be greatest in patients with the greatest bulk of disease. This is sometimes true, and it is behind the NCI guidelines that say that severe fatigue is an indication for treatment. On the other hand some patients who complain about fatigue have only small amounts of indolent disease. One then has to postulate that the tumor is an industrious cytokine secretor. Un fortunately there have been no studies done to measure cytokine levels in patients with fatigue, comparing them with levels in patients without fatigue.

Another possible cause for fatigue in patients with CLL is a chronic infection caused by the immunodefficiency. This might be a low grade bacterial infection; perhaps of the sinuses, or perhaps even TB. It could be the reactivation of a virus infection like EBV or CMV.

I am sure readers will see the theraputic conundrum here. If the fatigue is caused by cytokine secretion from the tumor, then chemotherapy will make it better. If, on the other hand, it is caused by chronic infection, chemotherapy will make the immunodeficiency worse and the infection will progress.

I am sbsolutely convinced that CLL patients get fatigue as a symptom. Trying to find out why is very difficult. Jumping into treatment may not be the correct path to follow. More research into this difficult problem is clearly needed.

If a trial of therapy is to be undertaken in a patient with low bulk disease, then I favor a trial of green tea extract. This will likely cause no harm, and it seems that some patients respond. Next in line would be rituximab alone.