The Clinical Course of Chronic Fatigue Syndrome

Dr. Mazlen talks about why he feels Chronic Fatigue Syndrome is different from one person to another. There might be something as common as a starter point, but CFS is different from one person to another. The physician must try to understand what makes each individual patient unique and more specifically, what viruses they have had that makes them unique. CFS is a mosaic of what the patient has run into in his/her lifetime. Each patient has his own genetic background and his own unique experiential background and they have gone through a process over the years whereby they are accumulating viral load. He talks about some of the complex interactions between several viruses implicated in CFS and how the viral load may affect the clinical picture. He feels that many CFS patients are seriously immunosuppressed. He talks about the issue of contagiosity in patients that are immunosuppressed from the viral load they are carrying and feels that this is extremely important because it can be life-threatening in special clinical situations. Individual viruses may not be lethal, but when you take the totality of the viral load, CFS patients can die. And so he stresses the importance of serial testing of patients with Chronic Fatigue Syndrome and uses case studies of some patients to support his claim.

Epstein Barr Virus

By age 28 - 30 86% of the world populations has been exposed to Epstein Barr Virus.

There is a higher prevalence of autoimmune diseases in patients who have CFS, including lupus and connective tissue disease and there is a connection in many cases with these entities. Autoimmune hepatitis has been defined in patients with Epstein Barr Virus disease. Acute neprhritis and even acute encephalitis can also occur.

EBV has been demonstrated to invade Natural Killer cells and it can effect the placental barrier lining in the pregnant woman and may be transmissible to the fetus, though that has not been proven as yet.

Viremia can persist in EBV disease. A study from Japan with the identification of EBV by PCR of the DNA shows viremia lasting up to 90 days after infection and contamination of the urine with live virus for over 90 days.

Does EBV reactivate more frequently in patients with Chronic Fatigue Syndrome? No scientific study on that has been done as yet, but the answer in clinical practice is "yes."

Cytomegalovirus (CMV)

Cytomegalovirus is a disease spread in children very readily. It's very contagious. It's able to avoid immune surveillance. It can hide in a number of cells in the body. It can be found in almost all body fluids including vaginal secretions, so it is transmissible by sexual contact. It has the most complex genome of all of the herpes viruses. It is a double-stranded DNA in contrast to Epstein Barr Virus. It has a normal reactivation rate in normal adult of about 3 - 5%. In EBV and CFS patients, the reactivation rate can be much higher. One of Dr. Mazlen's patients reactivated CMV 4 times in one year and got pneumonia and developed IgG subclass deficiency each time. There was a paper recently about IgG subclass deficiencies in CFS patients alluding to the fact that they are not clinically significant but Dr. Mazlen has had patients in which they were life-threatening and they had to receive gamma-globulin injections to save their life. The CMV virus can spread within families within six months of initial contact. There is also a paper showing that in response to primary human CMV virus infection, HHV-6 can be reactivated.

Human Herpes Virus 6 (HHV-6)

HHV-6 is a human herpes virus. Some people say it may be a separate family of herpesvirus because of its failure to induce oncological changes in cancer as compared to the other herpes viruses. It can infect the EBV infected B-cells. The type A HHV-6 can infect the CD4 T Helper cells which Dr. Robert Gallo talked about as possibly being the trigger for all of Chronic Fatigue Syndrome but that hasn't been proven yet as only assays of IgG and IgM antibodies for HHV-6 Type B have been available. Dr. Mazlen has found quite a few of his CFS patients positive for HHV-6 especially for IgM. IgG antibody tests for HHV-6 are not totally accurate. The fact that everybody doesn't have a positive IgG doesn't mean that they do not have the presence of HHV-6 from a clinical standpoint. It has been shown in studies that have been done that the IgG antibodies can decline over time. In fact, it decreases almost universally over age 40. When a patient over 40 with CFS is positive acutely for IgG and IgM antibodies then you know you are dealing with acute reactivation. HHV-6 virus is present for life in the infected individual, which means the reactivation picture can go on and off sporadically.

Parvo B19

Parvo B19 is a single-stranded DNA virus which causes Fifth Disease in children. It causes a host of problems clinically. In adults, it is a very serious disease potentially more serious than we even realize because the papers that show the persistence of Parvo B19 in humans are coming out now. It started with a paper in the Lancet that showed that an individual had positive Parvo DNA in a bone marrow sample six years after the initial infection with Parvo B19 was documented. Since that time there has been a number of papers showing that Parvo B19 does not only persist and reactivate in bone marrow but, in fact, may be active on a low level of activity all along and it may have these ups and downs of activity which can last for an undefined period of time.

Coxsackie Virus

There are six serotypes of Coxsackie B virus and 23 serotypes of the Coxsackie A virus of which 8 to 16 of these are supposedly important. Of the B group, CVB-3 and CVB-5 have been shown to cause persistent infection of human vascular tissue replicating for greater than 260 days. In 8 CFS cases, 4 of the 8 were found to have closely related enteroviral sequences with a unique, shared pattern detectable for up to 24 months. This is what he sees clinically. One patient after another who has relapsing problems with muscle pain, decreased exercise intolerance, hypothalamic symptoms, brain fog, spaciness, etc. All the hypothalamic involvement you would expect. Coxsackie virus is myotropic and neurotropic and also an enterovirus which can cause enteritis. It can also cause pancreatitis and myocarditis, both of which are relapsing in nature.

Coxsackie virus is contagious which is demonstrated by the amount of people that have pleurisy caused by coxsackie virus. The leading researcher in coxsackie virus was called and asked how likely it was to hear pleurisy in patients that are exposed to coxsackie virus routinely. The researcher answered, "We use all the precautions in the world that you would consider, suits, gloves. Everybody in my laboratory has pleurisy." Coxsackie virus is extremely contagious and it is much more prevalent than people realize.

Case 1

Date	Clinical Conditions	CD4 (500 – 1750)	CD8 (150 – 1700)	CD4/CD8 (0.7 – 3.5)	NK Cell (20 – 250)
06/93	Pancreatitis Pleurisy	222	88	2.60	N/A
11/93	Lymphopenia	294	132	2.23	N/A
04/94	Enterocolitis Pleurisy	336	105	3.20	N/A
04/95	Hypoglobulinemia Pleurisy Lymphopenia	247	70	3,53	N/A
10/95	Pleurisy	261	72	3.63	6
05/96	Hypoglobulinemia IgG Subclass Deficiency Foot Abscess(non-resolving)	202	51	3.93	10
12/96	Pericarditis Neutropenia Lymphopenia	208	37	5.60	36
02/97	Leukopenia	314	60	5.20	31

Patient 1 has been seen since 1983 and graphed since 1993.
Her CD4/CD8 ratios are high in the borderline of autoimmune disease.
Her CD8 suppressor cells are never normal.
Her CD4 helper cells are never normal.
She was totally negative for all viruses that she was tested for.
She's not AIDS, she's not LNKS, she's Chronic Fatigue Syndrome.
Her Natural Killer cell function level is spiking up and down.
She has pleurisy when her NK cell function is very low at 6.
She has hypoglobulinemia in April of 1995 and May of 1996 with two major IgG subclass deficiencies and a non-resolving foot abscess in May as well.
In Feb, 1997 she develops leukopenia, neutropenia and reactivates EBV and over the years has reactivated EBV many times.

Dr. Mazlen is stressing the need for serial testing with patients such as the above one because they change with the viral load. He feels that when the doctor sees this type of thing developing, with these immune problems, you know the patient can be in some trouble and may be in life threatening risk. The treating doctor should think about these people in terms of being at risk and in terms of what the viral load may be inferring on them. Regardless of the etiology of the initial precipitating cause, the problem is clinically that these people are sometimes in a precarious position and they can even die.

Case 2

Date	Clinical Conditions	CD4 (500 – 1750)	CD8 (150 – 1700)	CD4/CD8 (0.7 – 3.5)	NK Cell (20 – 250)
07/93	Pneumonia Pleurisy	445	356	1.25	N/A
06/95	Leukopenia Lymphopenia Neutropenia	373	305	1.22	14
09/95	Pericarditis Pleurisy Leukopenia	316	279	1.13	32
02/96	Lymphopenia Neutropenia Pleurisy	339	272	1.25	N/A
06/96	Leukopenia Neutropenia UTI	164	140	1.20	34

The second patient has had the multiple immune serial work-up for approximately three years. This patient started out with an NK function of 14 and was OK as far as blood count, but when seen a month later had leukopenia, lymphopenia, neutropenia and seemingly innocuous pleurisy. This woman's white count went down as low as approximately 1200 and her neutrophils went down to 600 at one point. Pericarditis develops in Sept. 1995 and in Dec. 1996 her NK cell function goes down to 9 in spite of treatment. In June of 1995 her neutropenia resolved but her leukopenia came back in Sep. 1995. And during this entire course of time she had a urinary tract infection. At this point in time she had a bone marrow biopsy which showed a hypercellular marrow but no lymphoma, no leukemia, no abnormal cellular components, just a sparser bone marrow in terms of cellular components. She refused colony-stimulating factor and didn't want to be put on therapy and she is being treated naturally using some herbal types of immunostimulants.

If patients have granulocytopenia and they have CFS does that mean that they are the same or different from patients who have granulocytopenia for other reasons or post-transplants. The answer is that there is still a risk of serious infection regardless of the fact that these people are not post-transplant patients because they've been immunosuppressed. There is still an increase in risk, so when she was up to 1000 her risk would have been 30% greater than a non-CFS patient's. If her count went down under 1000 and it was sustained under 1000 it would have been prudent to start her on the colony stimulating factor but luckily she didn't stay under 1000 for a long enough period of time.

D.Conclusion

Chronic Fatigue Syndrome patients must be considered for their high risk immune status, they need to be treated seriously and they need to be studied serially. They need to be studied in depth to look at the viral load. What viruses are they accumulating? Do they have viremia? Do they have overlapping periods of immunosuppression? The key is to generate some respect for CFS as a serious clinical entity potentially. It can't kill people dramatically like some other viruses, but it can cause serious and persistent disability, it can cause loss of quality of life. CFS is a potentially life-threatening serious illness with many important medical complications, whether they be pancreatitis, myocarditis, encephalitis, persistent hepatitis or autoimmune diseases. Of course, the key is the treatment but right now no one has an answer. For all CFS cases, there fore, each one has to be treated individually until such time as the etiology is more specifically known.