Dr John Whiting is a prominent Brisbane GP who has a particular interest in chronic fatigue syndrome. He has treated Alastair Lynch, the Brisbane Lyons football player and keeps up to date with the very latest research findings. He has prepared a highly interesting and succinct discussion paper which summarises these findings.
So far, 1998 has been an extremely productive year in terms of new perspectives and new hopes for better treatment of chronic fatigue illnesses in general. Some of this work originates from overseas but has been elaborated upon in Australia by myself and by Newcastle University, as well as by others such as Dr Philip Stowell and Dr Gary Deed here in Brisbane:
1. Genetic Marker-HLA DR 1501
Of particular note is the high incidence of a genetic marker called HLA DR 1501 in my fatigue sufferer population. This genetic marker is four times more prevalent in my patient group than it is in a normal background population. This marker is also present in almost every patient with another fatigue condition known as narcolepsy, which is a brain disorder that results in excessive daytime sleepiness, as well as in other symptomatology. This finding of an increased prevalence of HLA DR 1501 in my CFS population suggests that some of these patients might also have narcolepsy, or a variant thereof. Alternatively, this marker may point not only to a genetic predisposition to narcolepsy, but perhaps to CFS as well.
The coagulase negative staphylococci that Newcastle University has been researching for the last number of years seem to find the human nasal passages to be an ideal location for persisting colonisation. This is in keeping with other staphylococcal species, including the notorious Golden Staph. Having said this, it is of interest how commonly it is for CFS patients to give a history of chronic sinus infection, nasal congestion, or hay fever, as well as (and perhaps most importantly) secondary post-nasal drip of varying degrees. Furthermore, much more than the average severity of such symptoms is reported by approximately 90% of the patients that I have thus far interviewed. Cultures of the nose for these specific staphylococcal strains is performed easily by swabbing the nasal passages. The majority of such strains that are isolated by QML and S & N have turned out to be toxin-producing strains. The latter status is ascertained by the transfer of the relevant specimens to Newcastle University where further specialised testing is performed. This particular additional testing is time consuming, and the cost for doing it is not yet covered by Medicare. Hence, a charge of $50 by the laboratory is required to have this test performed.
It seems the problem with this nasal carrier state is that if a virus or some other germ induces the nose to produce more mucus, or if there is a relapse of patients' pre-existing hayfever or sinus condition, that these staphylococci can then flourish all the more, and hence will produce much more toxin. Once this toxin is swallowed it may well have neurotoxic effects on the bowel's nervous system. Also, if it is absorbed into the body, it may also have toxic effects elsewhere. Thus, irritable bowel syndrome and even CFS itself may well be related to infection of the nose by these particular staphylococci as much of the research at Newcastle University strongly suggests. The purpose of the toxin produced by these organisms is as a defence mechanism against other bacteria, and thus is a means of ensuring that the staphylococci remain firmly entrenched in their particular niche in the nose. Evolution has it that these toxins help to eliminate other 'good bacteria' that compete with these pathogenic organisms for those sites in the nasal surface that both organisms have a preference and compete for. It just so happens (as an unfortunate byproduct really) that this toxin also adversely affects the human host.
As mentioned in another discussion paper, mycoplasma infection of the blood and elsewhere may well be a very important new discovery in the setting of Chronic Fatigue Syndrome. We at present do not have a grasp of the full extent of this particular organism in Australian Chronic Fatigue Syndrome sufferers, but a preliminary evaluation by Dr Philip Stowell indicates that we may well find a high incidence of mycoplasma in our CFS population. What is unusual and what probably is not even appreciated by many specialists im infectious diseases, is that these mycoplasma organisms have the ability to infect white blood cells on a long term basis, and may even remain in such cells indefinitely. The consequence of this is that the energy (in the form of Adenosine Tri-Phosphate, or ATP) produced by these cells and by other cells (including those of the brain, muscles and joints) that become infected, is 'siphoned off' by these pathogens. Thus, this very important energy currency (ATP) is scavenged by such mycoplasma orgamsms, which in turn probably contributes to the excessive fatiguability and dysfunction of these infections, and if it should occur on a chronic basis, would have many other secondary negative effects throughout the body due to the loss of the ATP energy necessary to drive the large number of biochemical ATP-dependent systems required for normal cellular function, including those of the brain itself.
How are we so far, to put all this information together? What we really may have here is a kind of symbiosis or synergistic effect occurring between different infectious invaders that together contribute to the disease framework currently known as Chronic Fatigue Syndrome. It is becoming increasingly likely that Chronic Fatigue Syndrome represents a multifactorially-based illness, and that for the full expression of chronic fatigue symptoms, many distinct events and conditions must co-exist in the same host. Thus, while the organisms in question that have been mentioned above each can effect the host independently, it now seems probable that any infection on its own is insufficient to bring about the chronic state of disease we call CFS. Furthermore, the presence of 'narcolepsy genes' in many CFS cases suggests that there probably also are other host-related predisposing factors that contribute in some unknown way to CFS-like events occurring in particular people.
The experience of fatigue by the brain may well have to do with yet another special biochemical substance normally made by the brain, commonly know as adenosine. Adenosine is a byproduct of ATP utilisation by brain tissues, and in fact of all living cells, and is the main energy currency of the body as already mentioned above. Not surprisingly, adenosine levels accumulate in the course of a normal day's activities. Adenosine has many effects, but in the brain it has several particularly important functions. Not only does it behave like an off-switch for actively firing nerves (or neurons) an action which protects these nerves from injury caused by their over-firing, but buildup of adenosine in the basal forebrain where many sleep-related functions are controlled results in a sense of sleepiness, which increases in strength according to how active we are during the day.
It is of interest that caffeine is a substance that blocks the effects of adenosine on the brain. Not only will it keep neurons firing for longer, but it also blocks its sleep-promoting effects. This may be useful perhaps for example if too much adenosine has built up for whatever reason. Slow wave sleep is associated with a major fall in glucose and energy utilisation in the brain, and hence allows the brain to rest. During this time, adenosine levels diminish through a variety of biochemical routes. CFS is associated with a reduction in this slow wave stage of sleep, and therefore may lead to elevated adenosine levels. Other factors that tend to increase adenosine levels in the brain include a reduced blood flow, and also a reduced glucose supply to the brain. Thus, a low blood flow to the brain shares many of the same symptoms as those of hypoglycaemia. This is because not only does a reduction in blood flow to the brain limit the brain of its supply of oxygen, but it reduces the amount of glucose delivered to the brain as well. Both of these in turn limit the reconversion of adenosine back to ATP.
Of particular note is that mycoplasma infections are also likely to elevate adenosine levels above normal. This is because it scavenges cellular ATP and turns it ultimately into adenosine. Those parts of the brain that work the hardest will feel the effects of such an infection the most. I suspect that the brain fog that many patients with CFS experience while concentrating hard is a consequence of the negative effects of too much adenosine in key brain locations. This might explain why many patients with CFS seem to benefit from drinking coffee, or from any other source of caffeine, including chocolate.
5. Blood Pressure
We now know that severe low blood pressure problems can occur with CFS. Alternatively, blood pressure may be maintained at the expense of a reduced blood supply to many organs, including perhaps even to the brain. In the latter instance, the problem is not always clinically very obvious, and one then has to resort to a Tilt Table Test in order to maximally challenge the blood pressure maintenance system. What this does is to make overt any hidden functional anomalies within the blood pressure control system. Tilt table test which prevents normal skeletal muscle contractions from compensating for falls in blood pressure that might occur as a consequence of defects in the autonomic nervous system usually provides a rapid and ready diagnosis of low blood pressure tendencies in CFS. By putting patients on a tilt table, this muscle contraction compensatory mechanism is prevented. We can thus assess the integrity and control of the cardiovascular system and its ability to maintain blood pressure in a more accurate and vigorous manner. A fall in blood pressure will result in diminished oxygen and glucose supply to the brain and thus will result in increased adenosine levels which may be a trigger for sugar cravings in some CFS patients, and encourage them to consider hypoglycaemia as the cause of their symptoms. It is interesting however, that a fall in blood pressure may result not only in symptoms of dizziness and faintness, but also headaches and nausea as well as sweating, and a rapid heart rate.
Another way that the body tries to maintain blood pressure is to constrict certain blood vessels, and thus limit the flow of blood to organs that are less essential, at least in immediate terms. These organs include the skin and the gut, for example. This might explain why absorption of many important nutrients is less effective than normal in many CFS sufferers, and why certain digestion-demanding meals tend to make some CFS sufferers so unwell. It also would explain why the hands and feet are so cold in many CFS sufferers. The shut down of one's peripheral blood supply means that in the upper levels of the body, namely from the face, the scalp and the neck, which in turn, may well be the mechanism and the cause for flushing in many CFS sufferers.
Red facial flushing is generally seen in those patients who exert themselves very acutely, and who have to lose body heat quickly. On the other hand, patients who prefer to pace themselves and therefore do not need to lose heat rapidly, instead become increasingly pale in the course of their activities. In other words, even blood flow to the face becomes compromised. Sometimes, when a patient is both pale and flushed simultaneously what often is seen are pink cheeks on a background of pallor, which gives a strawberries and cream sort of appearance to the face. The head and neck are the chief heat-losing skin regions of a normal person. As blood pressure maintenance is of more importance than facial and neck skin temperature, the body's homeostatic mechanisms opt to control blood pressure at the expense of temperature maintenance and facial comfort.
This problem with low blood pressure has probably little to do with the heart itself and has more to do with the nervous system control of heart rate and the calibre of blood vessels in the peripheries. This nervous control may have broken down as a consequence of mycoplasma infection or staphylococci infection, or even both. It may even have something to do with too much adenosine, which can also dilate blood vessels, and undermine blood pressure control. Disopyramadine seems to be extremely effective in preventing blood pressure falls, and may assist in maintaining blood pressure in the upright position in many CFS cases. Thus, one's stamina for upright activity may be increased by this measure, as well as by other measures such as low doses of betablockers, fludrocortisone, and even caffeine, that also can maintain blood pressure in such a clinical setting. This in turn will prevent the need for the body to compensate by every means possible to control blood pressure, which in turn may help conserve other body resources, such as tyrosine in particular. Tyrosine is the substance from which the body manufactures adrenaline and noradrenaline, as well as dopamine, all of which contribute in various ways to blood homeostasis. Low serum tyrosine levels may occur in CFS for this reason, although other plausible defects in metabolism may also contribute to this finding in CFS.
The increased turnover of adenosine in CFS patients is likely to result in increased adenosine breakdown into uric acid. It is for this reason that I am presently evaluating the 24 hour urinary output of uric acid in my patients.
When ATP is broken down to adenosine, there is also a release of three phosphate groups into the system. It is interesting during relapses that many patients show an elevation in their whole blood phosphate levels, compared to times when they are feeling much better. Thus, whole blood phosphate levels should turn out to be a good index for excessive adenosine output, and thus provide a clue to the basis for the fatigue subtype of individuals.
Of course, there still is a lot more to Chronic Fatigue Syndrome than the various factors mentioned above. Nevertheless, the importance of identifying staphylococci and mycoplasma in an individual is that there is the potential for a curative measure rather than a Band-Aid one, for CFS, just over the horizon. At this point in time, the best and most effective antibiotic or antibiotic combination is yet to be identified. Of course, one can already predict for some patients that we will encounter problems with hypersensitivity to certain antibiotics, particularly at the gastrointestinal level. Intravenous antibiotic therapy may therefore become necessary in some situations. It would be best if an antibiotic could be chosen that addresses both organisms (mycoplasma and staphylococci) simultaneously, if possible. This is why it is probably most prudent if both the nose and the blood are simultaneously screened so that one can select by sensitivity testing an effective antibiotic strategy that addresses both organisms with a greater degree of certainty. As of yet, we have no information as to the duration of therapy that will be required to control this problem. If Lyme's disease is anything to go by, it may eventuate that several months of antibiotic therapy may be necessary. Nevertheless, this mode of treatment may well turn out to be one of the most important break throughs in CFS management to date.
Reprinted from Emerge, Summer 1998