In terms of ME/CFS, I viewed 1998-2001 as the years of huge promise for ME/CFS because of the research that was published that year. This post looks at what I deem to be breakthru research published at this time.

The following two articles are no longer on line, but were obtained from the Wayback Machine

Alison Hunter Memorial Foundation

1998 Clinical and Scientific Meeting

Butt HL [1,2], Dunstan RH [2], McGregor NR [2,3], Roberts TK [2], Harrison TL [2], and Grainger JR [2]

1 Collaborative Pain Research Unit (CPRU) Division of Microbiology & Infectious Disease Hunter Area Pathology Service John Hunter Hospital

2 Department of Biological Sciences University of Newcastle Newcastle Australia

3 Faculty of Dentistry University of Sydney Westmead Hospital Westmead Australia

Faecal Microbial Growth Inhibition in Chronic Fatigue/Pain Patients

Chronic fatigue/pain (CFS) patients reported frequent gastrointestinal symptoms (irritable bowel, constipation, abdominal pain, diarrhea, nausea) suggesting the possibility of an altered microbial flora in the gastrointestinal tract. The aim of this investigation is to determine if there is a change in the microbial intestinal flora of patients with CFS, and what causative factors may be implicated for these changes. Faecal samples from 27 polysymptomatic CFS patients and four age and sex matched control subjects were studied. Quantitative bacteriology of three aerobes (Escherichia coli, Klebsiella/Enterobacter group, and Enterococcus faecalis) and three anaerobes (Bacteroides spp., Bifidobacterium spp and Lactobacillus spp.) was performed on all samples. The mean distribution of E.coli as percentage of the total aerobic microbial flora for the control subjects and CFS patients was 92.3% and 49% respectively; Klebsiella/Enterobacter group, 0% and 3%; Enterococcus spp., < 1% and 24%. For the anaerobes, the mean percentage distribution of Bacteroides spp. for the control subjects and CFS patients was 92.8% and 91% respectively; Bifidobacterium spp, 7.1% and 2%; Lactobacillus spp., < 1% and 0%. The incidence of CFS patients with faecal E.coli greater than the percentage mean of control subjects was significantly different to that of the Bacteroides spp. (7 vs 21 respectively, p=0.0001) suggesting the possibility of an antimicrobial interaction among bacterial species.

Metabolites of Bacteroides spp. (lactic, propionic and butyric acids) were examined for growth inhibitory properties against three clinical faecal coliform ( E.coli, Klebsiella penumoniae and Proteus mirabilis). All three coliforms were susceptible to the three short chain fatty acids at pH3-4. At pH6-7 the three coliforms were not susceptible to lactic acid, partially to propionic acid, and fully to butyric acid. This study reported the marked alteration of the coliforms and lactic acid bacteria in the faecal microbial flora of CFS patients and that these changes may be related to inter-microbial activities among organisms.

2001 Clinical and Scientific Meeting

Richard Schloeffel

Two Case Studies of Successful Treatment of CFS/M.E.

Case 1
30 year old woman originally diagnosed with CFS after developing severe fatigue, weight loss and gastrointestinal dysfunction following excessive sports training in 1988. Initially seen in September 1999 with ongoing severe fatigue, constant headache, chronic sore throats, bowel dysfunction, amenorrhoea, sleep disturbance and post exertional fatigue. Found to have a positive PCR test for Chlamydia pneumoniae with positive IgG and IgA antibodies.

Commenced on Doxycycline 200 mg 2 mane, Nilstat tbd, probiotics, vitamins B/C, zinc, chromium, Acidophillus capsules, and a yeast-sugar free diet. After 11 months on Doxycycline 2 daily, changed to Doxycycline 2 daily for 10 days per month for another 12 months.

She has now fully recovered, with no symptoms of CFS, at full time work, playing tennis and planning her first pregnancy with her menstrual cycle now regular.

Case 2
61 year old man who first developed bowel problems in 1958 with constant abdominal discomfort, chronic diarrhoea and weight gain. Gradually experienced ongoing fatigue, cognitive dysfunction. In spite of a full working life as an executive, has always struggled to cope due to persistence of his symptoms. Developed Hypothyroidism after Thyroidectomy for a Retrosternal Goitre in 1992 and Sleep Apnoea in 1998. Diagnosed with Mycoplasma fermentens in 1998 on PCR testing.

Initially seen in June 1999 with moderate-severe CFS, relative Hypothermia (temp 34.8 to 37 degrees C) and constant headache, sinusitis, diarrhoea up to 40 times daily, brain fog and severe myalgia. Treated with Doxycycline 2 mane, Nilstat one bd, for 6 months, given Tertroxin (Liothyronine) 20 ug on mane in addition to Thyroxine 150 ug one daily. Also given Bactroban nasal ointment bd for 6 months following a positive Staphylococcal nasal swab with Deltatoxin. This resulted in improvement in brain fog, pain and fatigue.

The bowel problem persisted with very low E coli counts in Faecal Microbiological Assay. Received 13 donor faecal bacterial infusions per rectum, after a short course of antibiotics / bowel colonic irrigations. Followed by ongoing probiotic therapy.

Now no symptoms of CFS, normal cognitive function, and normal once daily bowel motions, and a sense of 40 plus years of diminished life.

Chronic fatigue syndrome and/or fibromyalgia as a variation of antiphospholipid antibody syndrome: an explanatory model and approach to laboratory diagnosis. 1999

Chronic Fatigue Syndrome (CFS) &/or Fibromyalgia (FM)
as a Variation of Antiphospholipid Antibody Syndrome (APS): An Explanatory Model and Approach to Laboratory Diagnosis.

D Berg, LH Berg , J Couvaras & H Harrison ^A
A  BLOOD COAGULATION & FIBRINOLYSIS 1999,10:p 1 – 4. (In press)

INTRODUCTION:

Chronic Fatigue Syndrome and Fibromyalgia have been considered diagnoses of exclusion where no other diagnosis fit well. In 1987, the AMA recognized FM as a major cause of disability¹. In 1994, CFS was defined by specific requirements of fatigue, duration, associated symptoms, initial clinical and laboratory evaluation, and medical or psychiatric exclusions².  At the most recent meeting of the American Association of Chronic Fatigue Syndrome, the prevalence, prognostic factors, pediatric and adult population studies, potential causal organisms, disruption of normal body functions, autoantibody identification and psychological implications were presented.

Antiphospholipid Antibody Syndrome³ (APS) is defined by both laboratory and clinical findings. Laboratory findings include, antiCardiolipin antibodies (aCL), Lupus Anticoagulants (LA), anti-PhosphatidylSerine antibodies (aPS), anti- anti-B₂GPI antibodies, and clinical findings of thrombocytopenia⁴, neurological complications⁵, venous thrombosis, arterial thrombosis, and/or recurrent fetal loss. Patients with primary APS (PAPS) have no clinical or laboratory evidence of another definable autoimmune disease⁶. Antiphospholipid (APL) antibodies have been long associated with a hypercoagulable state, involving both procoagulant activity as well as inhibition of anticoagulant and fibrinolytic activity⁷.
 

In CFS &/or FM patients, the principal antibodies found to date are the anti- anti-B₂GPI antibodies (unpublished data). This preceeds the generation of a hypercoagulable state based on our proposed model.  Endothelial cells are protected in the microvascular circulation by anti-B₂GPI and Annexin V proteins. This protective layer helps ECs maintain an anticoagulant environment. Exposure to pathogens, such as Herpesviruses [HV] (HHV6, EBV), CMV, mycoplasma, chlamydia pneumonia, result in both active persistent infection⁸ and latency in mononuclear and EC cells⁹.  Some pathogens like CMV and herpesviruses constitutively express phosphatidylserine- like procoagulant activity, capable of binding Xa and Va to form the prothrombinase complex¹⁰.  HHV6 is found in about 70% of all CFS patients¹¹.  In several studies, this same 70% infection rate is seen in Multiple Sclerosis (MS) patients with HHV6^12,13. HHV6 is also implicated in Chronic Myelopathy¹⁴. Endothelial cells serve as a reservoir for harboring HHV6¹⁵. Infected ECs lose their ability to synthesize prostacyclin with associated incapacity to deter platelet adhesion¹⁶.  In addition, CMV & HV express Tissue Factor (TF) antigen on each virus surface¹⁷. Herpesviruses can induce a prothrombotic phenotype in vascular ECs.  This phenotype markedly reduces heparan sulfate proteoglycan synthesis and surface expression by ECs¹⁸. Thrombomodulin (TM) expression is also reduced in infected endothelium. Activation of EC is seen by surface expression of P-Selectin and vonWillebrand Factor (vWF). Thrombin generated after the assembly of the prothrombinase complex on the virally infected endothelium mobilizes vWF from the Weibel-Palade body to the EC surface where it acts as a platelet receptor¹⁷. Cell-independent thrombin generation may be the earliest event in vascular pathology mediated by HV¹⁹.

Since exposure and expression of PhosphatidylSerine (PS) is part of the infectious process, these exposed phospholipids activate the immune system to form antiphospholipid antibodies. The primary targets of these IgG, IgM,& IgA antibodies are the protective proteins for ECs, specifically anti-B₂GPI and Annexin V. Both proteins bind to cells via Ca++ binding²⁰, just as the vitamin K dependent coagulation factors. In pregnancy loss, hypercoagulability may be due to the reduction of surface bound Annexin V by APL antibodies²¹.  As in other APS diseases, there is an increased incidence of thrombocytopenia in HHV6 patients²². With the loss of this protective layer due to APL antibodies, coagulation proteins can bind, react and form thrombin (IIa). If this process in not properly inhibited (Thrombin/AntiThrombin complexes), then excess thrombin can convert fibrinogen to soluble fibrin monomer (SFM).  SFM is a sticky protein that increases blood viscosity and can coat EC surfaces as fibrin or fibrinoid material.

The explanation of why one person may become chronically ill and another patient recover when both are exposed to the same pathogen comes in part from the dental community. Glueck,  McMahan, Triplett, et al., have identified that 73% of patients with Neuralgia-Inducing Cavitational Osteonecrosis have some form of genetic predisposition for thrombophilia or hypofibrinolysis²³, including: APC Resistance, anticardiolipin antibodies, protein C or protein S deficiencies, increased Lp(a) or PAI-1 or decreased  tPA activity. These patients responded well to oral anticoagulant therapy.
 

MODEL:

Our hypothesis is that a majority of individuals diagnosed as Chronic Fatigue Syndrome (CFS) &/or Fibromyalgia (FM) on clinical criteria may be defined as AntiPhospholipid Syndrome (APS) with the endothelial cell (EC) as the disease target with or without platelet activation (PA). These patients have a hypercoagulable state demonstrated by increased markers of coagulation activation and increased blood viscosity due to the generation of Soluble Fibrin Monomer (SFM). Because the CFS / FM process may be triggered by a variety of pathogens, we suggest that pathogen-mediated immune activation may induce antibodies, e.g., anti-B₂GPI, anti-AnnexinV antibodies, that dislodge protective proteins from EC surfaces, thereby exposing PhosphatidylSerine (PS) on the EC surfaces in capillary beds.  This PS exposure would allow binding of the coagulation tenase and prothombinase complexes to EC surfaces, with subsequent thrombin generation, SFM formation and low level fibrin deposition that could create local pathology by blocking nutrients and oxygen delivery in the microcirculation.  A hereditary defect in a coagulation regulatory protein, such as protein C, protein S, Factor V^L, prothrombin gene mutation, PAI-1, Lp(a), or elevated homocysteine is probably predispositional. Because this hypercoagulability does not result in a thrombosis, but rather in fibrin deposition, we suggest that an appropriate name for this antiphospholipid antibody process would be Immune System Activation of Coagulation (ISAC) syndrome. This model provides an explanation for the therapeutic benefits reported with low dose anticoagulant therapy (heparin followed by warfarin) in the majority of CFS/FM patients.
 

RESULTS:

At the American Association of Chronic Fatigue Syndrome meeting, we presented a retrospective study of 20 patients looking at a hypercoagulable state that could be reversed with anticoagulant therapies²⁴. Since then, we have conducted a blinded prospective study of 54 CFS &/or FM patients and 23 controls, using a panel of 5 tests to determine if patients could be differentiated from controls.  The tests included: fibrinogen (FIB), prothrombin fragment 1+2 (F1+2), thrombin/antithrombin complexes (T/AT), soluble fibrin monomer (SFM) and platelet activation by flow cytometry (PA) using CD62P and ADP with mean values for each group shown in the following table.
 

TESTS:		FIB mg/dl	F1+2 nM	T/AT ug/l	SFM nmol/l	PA Plt Act	CD62P %
Ref Rng	N	<310	<1.1	1.0 – 4.1	<20	Normal	<26
Controls	23	280	1.0	1.6	10	0% POS	17.5
# Abn / N		2/23	3/23	4/23	3/23	0/23	5/23
Patients	54	367	1.2	1.6	22	42% POS	22
# Abn / N		45/54	26/54	25/54	32/54	22/52	21/52
P Value		<0.001	<0.005	<0.025	<0.001	<0.001	<0.10

The criterion to separate patients from controls was positivity in 2 or more assays for classification as a patient. The P value for laboratory diagnosis based on this criterion was <0.001. Diagnostic data were obtained after all laboratory studies were completed.  22 of the 23 controls were correctly identified. One control was positive in two assays for a false positivity rate of 4%. Of the 54 patients, 4 had normal values, for a false negative rate of only 7.4%. This shows that 92+ % of CFS &/or FM patients had a demonstrable hypercoagulable state. What then is the underlying disease process?
 

CONCLUSIONS:

CFS &/or FM patients who have a hereditary deficiency for thrombophilia or hypofibrinolysis may be unable to control thrombin generation properly. We have found that 3 out of 4 CFS &/or FM patients have a genetic deficiency (unpublished data). Certain pathogens induce the immune system generation of APL antibodies and can be a triggering mechanism for APS. Once antibodies are formed, protective proteins are dislodged from endothelial cells, exposing PhosphatidylSerine. Coagulation proteins bind on exposed PS surfaces, generating thrombin on the EC surface. Excess thrombin converts fibrinogen to soluble fibrin monomer, which may be deposited on the EC surface and/or circulate in the plasma. Fibrin deposition leads to decreased oxygen, nutrient and cellular passage to tissues around the micro circulation. This hypercoagulable state may cause localized pathology in many tissues, yielding the systemic compromises and symptoms characteristic of the CFS/FM complex.

Since this hypercoagulable state does not necessarily result in a thrombosis, but rather in fibrin deposition, we suggest that an alternative name for this antiphospholipid antibody process would be Immune System Activation of Coagulation (ISAC) instead of antibody mediated thrombosis²⁵. Once this hypercoagulable state is detected, appropriate anticoagulant therapies may be given to relieve patient symptoms. These studies will be presented in a separate report.
 

REFERENCES:

1 . Starlanyl, D & Copeland, ME. Fibromyalgia & Chronic Myofascial Pain Syndrome. New Harbinger Pub, Inc. 1996, p8.

2. Ann Intern Med 1994:121:953-959.

3. Harris EN, et al. Clinical and serological features of the antiphospholipid syndrome (APS). Br J Rheumatol 1987; 26: p19.

4. Cervera R, et al. Isotype distribution of anticardiolipin antibodies in SLE. Prospective analysis of a series of 100 patients. Ann Rheum Dis 1990;49:109-113.

5. Hess, D. Models for central nervous system complications of APS. Lupus; 3,1994, p253-257.

6. Asherson RA & Cervera R. Primary, Secondary and other variants of the Antiphospholipid Syndrome. Lupus 1994; 3: 293-298.

7. Pierangeli SS & Harris EN. Antiphospholipid antibodies in an in vivo thrombosis model in mice. Lupus 1994; 3:247-251.

8. Knox KK, et al. Persistent active human herpesvirus (HHV6) infections in patients with CFS. AACFS Proceedings: Cambridge, MA, Oct 10-12, 1998, p38.

9. Zorzenon M, et al. Active HHV6 Infection in CFS Patients from Italy: New Data. Jrnl of Chron Fat Syn 1996;2(1):3-10.

10. Pryzdial ELG & Wright JF. Prothrombinase Assembly on an Enveloped Virus: Evidence That the CMV Surface Contains Procoagulant Phospholipid. Blood 1994;84(11): 3749-3757.

11. Buchwald D, Chaney PR, et al. A Chronic Illness Characterized by Fatigue, Neurologic and Immunologic Disorders and Active HHV6 Infection. Ann Int Med 1992;116:103-113.

12. Brewer JH, Knox KK & Carrigan D. Active HHV6 Infections are Present in the CNS, Lymphoid Tissues and Peripheral Blood of Patients with Multiple Sclerosis. Proceedings; Inf Dis Soc of Amer, Nov 14, 1998.

13. Clipper S, Emr M. Herpes Virus Strain Identified as a Trigger in Multiple Sclerosis. NIH National Institute of Neurological Disorders & Stroke. Nov 24, 1997.

14. Mackenzie I, et al. Chronic myelopathy associated with HHV6. Neurology 1995;45:2015-2017.

15. Wu CA & Shanley JD. Chronic infection of human umbilical vein endothelial cells by HHV6. J of General Virology 1998; 79: 1247-1256.

16. Jacob HS, et al. Herpes virus infection of endothelium: new insights in atherosclerosis. Trans Am Clin Climatol Assoc 1992; 103:95-104.

17. Van Dam-Mieras MC, et al. The procoagulant response of CMV infected endothelial cells. Thromb Haemost 1992;68(3):364-370.

18. Nicholson AC & Hajjar DP. Herpesviruses in Atherosclerosis and Thrombosis: Etiologic Agents or Ubiquitous Bystanders? Arterioscler Thromb Vasc Biol 1998; 18: 339-348.

19. Sutherland MR, et al. Coagulation initiated on herpesviruses. Proc Nat Acad Sci USA 1997; 94(25):13510-13514.

20. Kaburalic J, et al. Clinical Significance of Anti-Annexin V Antibodies in Patients with SLE. Am Jr Hematology 1997; 54:209-213.

21. Rand JH, et al. Pregnancy Loss in the APS Syndrome-A Possible Thrombogenic Mechanism. NEJM 1997; 337(3):154-160.

22. Yoshikawa t, et al. Thrombocytopenia induced by primary human herpesvirus 6 infection. Acta Paediatr Jpn 1998: June; 40(3):278-281.

23. Glueck CJ, et al. Heterozygosity for the Leiden mutation of the factor V gene, a common pathoetiology for osteonecrosis of the jaw, with thrombophilia augmented by exogenous estrogens. J Lab Clin Med 1997;130:540-43.

24. Berg D, Berg LH & Couvaras J. Is CFS/FM due to an undefined hypercoagulable state brought on by immune activation of coagulation? Does adding anticoagulant therapy improve CFS/FM patient symptoms?  AACFS Proceedings: Cambridge, MA, Oct 10-12, 1998, p62.

25.Vermyeln J, Hoylaerts MF, Arnout J. Antibody-Mediated Thrombosis. Thrombosis & Haemostasis 1997; 78(1): 420-426.

Manly Conference February 1999

The Rickettsial Approach
Dr. CL Jadin
2

Introduction The author, Cécile Jadin, is originally from Belgium, but has been practising in South Africa for the last 17 years. She is a surgeon by profession. In South Africa, in addition to practising as a surgeon, she also assisted her husband in his general practice. For the last 7 years, she has focused on the subject of Rickettsia and her approach has naturally been that of a clinician, and it is in this context that the paper is written.

To understand why she took the Rickettsial approach her background needs to be explained. Her father was Professor JB Jadin, who undertook groundbreaking research on tropical diseases, among them Rickettsial infection, with Professor Paul Giroud in Central Africa, South Africa, the Near East, and in Europe, developing the work started in the Pasteur Institute of Tunis, with Professor Charles Nicolle, who was a disciple of Louis Pasteur. Thus she was familiar with those germs from an early age and her work represents the results of teamwork through the last 100 years.

12 years ago, one of her friends became unable to walk and was diagnosed as having ME. For 4 years Dr. Jadin suggested the diagnosis of Rickettsial Infection, and therefore the Weil-Felix test was performed several times in South Africa, but the results were negative. The friend developed an acute appendicitis. After Dr. Jadin removed her appendix, her serum was sent to Prof. JB Jadin in Belgium to test for Rickettsiae, and the result was positive. Dr. Jadin treated her with Tetracyclines and 3 weeks later, she was riding her horse again. Dr. Jadin was sceptical. But this case brought her 200 patients and the publicity surrounding an investigation of her methodology by the South African Medical Council brought her several thousand more. Thus Dr. Jadin started to focus on the Rickettsial approach.

Original Research Research on Rickettsioses was originally developed by French, Polish and Russian scientists. They followed Charles Nicolle’s (Pasteur Institute, winner of the Nobel Prize for medicine in 1933) hypothesis, which is that occult diseases are a reality and their cohabitation in the same host will lead to the bankruptcy of the immune system (8). By occult disease Charles Nicolle implies the asymptomatic stage of the disease, where the agent is present in the host, but dormant (3). The emergence of a virus, bacteria, stress or pollution can activate this agent, which leads to the symptomatic stage.

An example of this cohabitation is the infant mortality rate described by J.B. Jadin in Central Africa. Neonates diagnosed with malaria and Coxiella Burnetti all died as opposed to those with malaria only (20).

The numerous publications of these authors are unfortunately all in French, so their circulation was limited. They also, as academics, excluded the media. Therefore the real importance of their discovery is still to be made widely known.

Rickettsia and CFS The fairly recently recognised entity of CFS gives us a perfect opportunity to try the etiological route to understand this disease. Along this route we will automatically enter other medical fields, inviting us to consider an infectious etiology in cardiology (4,5,9,11,12), in psychiatry (3,17), in neurology (3,29) and in rheumatology (28), rather than describing the symptoms and gathering them into syndromes (20, 40).

Obviously one germ can cause many diseases depending on a selective topicality for one or more particular tissues as well as one disease can be caused by different germs alone or simultaneously. Therefore we would like to concentrate on the causative agent, rather than on the name of, and the criteria to classify, the diseases.

There are many reasons suggesting the infectious etiology and, more specifically, Rickettsial-like organisms of CFS. Amongst those reasons:

1. Consider the following : – CFS was first reported in Incline, Nevada in 1984 (1) and developed into epidemic proportions. – Rocky Mountain Spotted Fever originated from the same place in 1916 (9,29). – The spirochete Borrelia Duttoni, first blamed for causing the recurrent Malgache fever described in the journals written by Drury in 1702 (24) in Madagascar, then by Scheltz in the Belgian Congo in 1933, by Palakov in Cape Town in 1944, by Heisch in Kenya in 1950. – Lyme Disease appeared (or reappeared?) more recently in Lyme, Connecticut in 1975 (Borrelia Burgdorferi) (25). Could these be new names for old diseases?

All of the above highlights the life of a germ as an individual emerging and disappearing in a wave pattern epidemically and historically. Like us, germs have to adapt, producing new variations of themselves, (not new species), that may or may not survive on their own, with or without the help of another germ. This is circumstance-dependent, and these particular circumstances will never reoccur. Some of those variations will acquire specific and consistent characteristics that will allow them to survive. This is their ‘civilisation’. We only see them when they succeed, and only then do new avenues of investigation open up, while others are abandoned. 1. A link has been established between Florence Nightingale disease and CFS (21). The fact that she was working surrounded by lice, fleas and ticks, treating soldiers with wounds and with epidemic typhus during the Crimean war, could be a logical explanation as to why she was terribly tired during the last 2 decades of her life; and possibly has relevance to Gulf War illnesses (13). Zinsser has developed the same concept in his classic book “Rats, Lice and History”. He contends: “Soldiers have rarely won wars. Typhus and other infectious diseases have decided the outcome of more military campaigns than Caesar, Hannibal, Napoleon and all generals in history. Depending on the outcome for each warring faction, either the epidemics were blamed

for defeat, or the generals were credited with victory.” (2). More examples of this phenomenon were reported by JB Jadin (29). 2. Lymphocyte studies conducted on sheep with tick-borne diseases (14), CFS patients (15,16), and patients with Q Fever endocarditis (11) are showing amazingly similar results. 3. Coincidentally, the new name suggested in the Lancet for CFS is PQFS (Post Q Fever Syndrome) in April 1996 edition (22). 4. During the First World War an estimated 25 million Russians contracted Louse-borne epidemic typhus, resulting in 3 million deaths. Why not before or after? It could suggest that the stress factor reactivates the virulence of Typhus Prowazeki (2, 3, 9). In the medical history of CFS patients, stress has often been described as the start of the illness. 5. The symptoms displayed by CFS, Fibromyalgia, RA, and even neurological patients as MS, show the same diversity of symptoms as Rickettsial patients. How many scientists blamed the diversity of symptoms for misleading unprepared practitioners in the diagnosis of chronic Rickettsial infection (30)? That same diversity could have contributed to the delay in recognising CFS. French authors (Giroud, Jadin, Legag) attribute those multiple aspects to a generalized micro-vascular invasion. They widely demonstrated the persistence of Rickettsiae in the vessels (4), (18). The suggestion here is that the well-known, well-documented entity of Rickettsial disease, showing the same symptoms as the newly arrived CFS, might simply, partially or totally be caused by the same agent. 6. The last, but not the least reason, is the success rate of the Rickettsia treatment, Tetracycline, applied on CFS, Fibromyalgia, Depression and MS etc. patients. Dr Phillipe Bottero on 100 patients since 1981, Dr Peter Tarbleton on 300 patients in 1993 in South Africa(17) and myself on a much larger number of patients, maintain an 84% – to 96% recovery rate.
Transmission of Rickettsiae

Rickettsiae are transmitted by arthropods (36), except for Q Fever, which does not really need vectors;

• they are resistant to humidity and to dryness – they will stay virulent for 60 days in milk – 4 months in sand – 6 months in meat – 7 – 9 months in cotton (4).

They are spread by rodents and birds. Through the centuries, bird migration has been responsible for changing the geographical distribution of disease (27) – but this is nothing compared to the effect of the explosion of these diseases due to the cocktail effect created by distribution through global air traffic (26).

Equally the transport of insects compared to the import and export of livestock – as in the case of the import of 10,000 parrots from Paraguay to Belgium when some 2,000 died, leaving the virus well and alive behind them (27), (identified by my father as Neo-Rickettsia Bedsonia).

This world distribution does not include Antarctica, where they do not survive.
Fish also share this disease, as Erlichioses is, according to breeders, a common problem (Psichi Rickettsia Salmoni, first described in Chile) (31).

Patients and Diagnosis

3,400 patients presented with CFS, Fibromyalgia, RA, depression and MS have been diagnosed as suffering from Chronic Rickettsial Infection (CRI) after eliminating other diseases as a cause (diabetes, cancer etc.).

The majority of my patients report a flu-like infection, with often an elevated temperature and severe headaches. This lasts for a few days, disappears or reoccurs, and then leaves them with a chronic condition of CFS, Fibromyalgia etc. as mentioned above.

Diagnosis of CRI is established by Giroud’s Micro-Agglutination test against five strains of Rickettsiae:

• R. Prowazeki: the epidemic type of Typhus – R. Mooseri, which is endemic – R. Conori, which belongs to the spotted fever group – Coxiella Burnetti, which is well known as Q Fever. It has 2 phases; Phase II is pathogenic – Neo Rickettsia Chlamydiae which falls into the Neo-Rickettsia group (18)

Important Points: a) A high reading means a high serological level of antibodies – a negative reading in endemic areas reflects the poverty of the immune system (24). b) Agglutination happens or does not – therefore there is no possibility of personal interpretation. Test quality depends on Antigen quality (3). c) Positive tests can be found in people who display no symptoms (Giroud, Jadin (18); 26% according to Drancourt (39)).

However, the Micro-Agglutination test of Giroud is not our only tool to establish the diagnosis of Rickettsial infections. We find the following blood tests most relevant:

• LFT: the hepatotoxicity of Rickettsiae has been reported as early as 1937 by Derrick in Q Fever (19, 29), followed by many others – Giroud, Lenette, Legag, Brezina, Perron, Kelly, Raoult, etc. In these cases, Tetracyclines are improving or normalizing liver function (6). – Iron study (50% of abnormalities corrected with Tetracyclines only and when necessary with a short course of iron supplement). – Thyroid AB rather than TFT, although the TFT show abnormalities in 3% of patients, the thyroid AB are elevated in 28% of cases and improve or normalise rapidly with treatment. – CRP, RF, ANF, WR was positive in 53% of patients, (39) and also improved with treatment and often normalised.
• Mycoplasma (only researched after the Manly conference, February 1998).
  The Rickettsial Approach
  Dr. CL Jadin
  6
• Symptoms Patients’ symptoms most commonly exhibited are:

• Tiredness (4,5) • Nausea (8,9,18) • Headaches, retroorbital and temporal, worst after prolonged horizontal position or mental effort (4).H • Recurrent sore throat (23) • Myalgia (3) • Memory and concentration deficit (4). • Arthralgia migrating (2,3,5) • Chest pain, palpitations (8,12, 18) • Loss of balance (29) • Sweats, low grade fever (4) • Vision abnormalities (3,29) • Bruising (4) • Raynaud syndrome (18) • Psychological and neurological disorders(4,5,18,29,30)

We find quite a valuable guideline in the physical examination, which often shows – An inflamed throat and multiple adenopathies, reflecting the selective topicality of Rickettsiae to endothelial tissue – Heart abnormalities (vascular (4,12,30) and valvular impact (2, 39)) – RIF tenderness (chlamydiae 18 in appendix (23))
Treatment After establishing these 3 cornerstones Symptoms Physical examination Blood tests treatment is administered: – Guided by our predecessors, (Giroud, Jadin, Legag etc.) – Refined by our contemporaries, (Bottero and Raoult) – And by my own daily, private lessons (each patient is one).

The treatment consists of 7 to 12 days per month of a specific Tetracycline. The monthly treatment aims to follow the Rickettsial development in the cell.

1. A high dosage is required (4,5) with the limitation of: – Safety (32) Goodman et al (33) highlights irreversible hepatotoxicity in intravenous administration only. Our experience was that when liver functions were normal to start with, they stay normal. If they were abnormal, they will improve during treatment and generally return to normal. Cases of fatty acid depots (as shown by liver scan, before and after 6 months to 1 year of treatment) have disappeared (1 MS, 4 ME). This confirms the fact that Rickettsiae are more hepatotoxic than Tetracyclines. – Tolerance. a) The gastric intolerance will be successfully prevented by using a gastric pump inhibitor during and if necessary before and after the administration of the Tetracyclines. b) The tolerance of the treatment is directly related to the Herxheimer reaction (4, 6, 26, 37), which is a reactivation of old symptoms and/or exacerbation of present symptoms that occurs on antibiotherapy. Its presence has a very important diagnosis and prognosis value (4). They might or might not be parallel to a serological reactivation. It will fade with the number of treatments received. When very severe, the HR is treated with Probenecid. 1. The Tetracyclines are alternated because:

a) A patient is frequently contaminated by many strains of Rickettsiae (5) and different Rickettsiae have different sensitivity to different Tetracyclines or combinations. (4). b) A patient might build resistance to each Tetracycline (4, 17). c) Patients show individual sensitivity to different Tetracyclines or combinations and there is very often a privileged reaction to a specific treatment (6). 3. The Tetracyclines are combined with Quinolones, Macrolides or Metronidazole (7), because Rickettsiae present a wide heterogenicity of susceptibility to different drugs (4). 4. The treatment is often long due to: a) The chronicity of the germ (4) b) The multiple foci of Rickettsiae (18) c) The fact that Rickettsiae have a slow evolution and some foci are dormant, encapsulated and therefore protected from antibiotherapy. Only when they become active can they be treated (5). d) Each treatment will allow the immune system to produce and maintain a proper and efficient level of antibodies. This happens each time the antigen Rickettsiae are released from the cell to the blood stream while on antibiotherapy (Legag) (4). e) The length of the disease should logically imply a lengthy treatment. In our experience, this point is not always true. Patients, ill for many years, may recover after a few months treatment. 3. Antimalaria has been found efficient to improve Rheumatoid symptoms and Rheumatoid biological findings (see patients’ files). Christopher Columbus knew it in the 15th century, as he gave tree bark containing quinine to his crew to prevent malaria and also mysterious body pains. The Imperial army of Queen Victoria did the same and so was born Indian Tonic water. 4. Adjuvants such as Vitamin B complex and acidobacillus are also used. 5. Cortisone is avoided as much as possible as it is known to weaken the Immune System in general (3) and also to reactivate the disease in experiments on guinea-pigs (39). Cortisone has been accused of interfering with the diagnosis of Rickettsia by masking the antibody level (4). 6. Exercise is recommended, for the following 3 reasons: • Rickettsiae is a vascular disease and exercise, properly done, will improve the smooth peri-vascular muscle function, as well as develop the most important muscle, the heart. • The fact that strains of Rickettsiae grow better in vitro when maintained in a CO2 enriched atmosphere (34). • The suggestion that Rickettsiae grow best when the metabolism of the host cell is low (38). 7. Hot baths are important to eliminate toxins via the skin, produced by Rickettsiae antigens when liberated in the bloodstream by antibiotherapy. 8. Reinfection may obviously occur. Reactivation (called so rather than relapse) may also happen due to the interaction of bacteria, virus, stress, pollution, etc. causing the Rickettsiae forms’ to change to active from dormant (35).
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Measurement of Progress Patients are seen monthly to judge progress on: 1. Symptoms 2. Activity increase (From bedridden to back to exercise or back to work) 3. From being treated by painkillers, antidepressants, sedatives, cortisone to none 4. Medical examination

1. Biological investigation: from having:

• LFT • RF raised • CRP raised • ANF raised • KFT raised • Thyroid antibodies raised • Iron

Back to normal, or nearly so

Based on this assessment, the treatment is prolonged or stopped (3 months to 2 years: 8 months on average). However, as previously mentioned, the length of treatment is not directly correlated to the length of illness:

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Therefore patients can be divided into 2 categories:

1. Fast progress – their illness was mainly Rickettsia
2. Slow progress – their illness was Rickettsia plus other factors (20). “La santé est comme une mongolfière: il faut parfois lâcher du lest”

Health is like a hot air balloon. You have to get rid of excess burdens to keep it in the air. Rickettsia is the easiest one to lose
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Dr. CL Jadin
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Appendix 1: CFS – Rickettsial Infection: Sources of References

References Authors 1 CFS in Incline Village 1991 Mauff & Gon RSA 2 Annals New York Academy of Sciences 1990 Preface 3 Acta Mediterranea di Patologia. Infectiva e Tropicale. 1984 Vol 3 1986 Vol 5
1987 Vol 6 no 3 JB Jadin, Ph. Bottero P213 4 Bulletin Societé de Pathologie Exotique 1963 J. Gear Monteiro S. Nicolau J.G.Bernard N.R.Grist
A. MasBernard Roche
P588 P680 P691-714 P758-793 P684-687 P714-724 P724-740 5 Clinique de la Résidence du Parc 1986 MS P. Le Gag Relationship between protozoa, virus & bacteria J.B. Jadin Psychopathies Ph. Bottero Buerger Disease C. Bourde / Delanoï Dermatology Aymard 6 Extrait Bull. Acad. Nat. Médecine Vol 158 No 1 P. Giroud & J. Jadin 7 European Journal of Epidemiology 1991 D. Raoult P276 8 Academie Royale des Sciences d’Outre Mer 1963 No 6 J.B. Jadin P1128-1129 9 Ann. Soc. Belge Med. Tropic. : Au Sujet des Maladies Rickettsiennes 1962 Vol 3 J. Jadin P321 10 Infectious Diseases and Medical Microbiology 2nd Ed. Braude P810-814 11 Arch. Int. Med.: Chronic Q Fever March 8 1993 Vol 153 T. Brouqui et al. P.643 12a Department of Pathology SA April 1992 Alan Shore? 12b Update: Does Infection Cause Coronary Disease? Nov. 1997 P. Welsby P15 13 International Journal of Medicine Garth Nicholson 14 Res. Vet. Scient.: Lympho. Subpopulations in Peripheral Blood of Sheep Experimentally infected with Tick-Borne Disease
July 1991 Woldehiwet 15 Journal of Clinical Immunology (US): Lymphocytes Phenotype and Function in the C.F.S. Jan. 1993 13 (1) Strauss et al. P30 16 S. Maryland Clin Immunol. Jan 93 13 (1) P30-40 17 Affidavit: “To Whom It May Concern” to the SA Medical Council January 1995 Dr P. Tarbleton, 18 Bulletin Acadèmie Nationale de Mèdècine 1979 No 6 Masson Ed. Paris Paul Giroud P163 19 Maladies Infectieuses 1976 Ch 41 J. Orfila 20 Arch. Inst. Pasteur Tunis: Les Infections Superposées Sont à la Base des Faillites de L’Humanité 1986 Vol 63 P. Giroud J.B. Jadin P 97-99 21 Study Annales Internat. Med.: CFS: May 12: F. Nightingale’s Birthday Comprehensive Approach 1994 – 121 T. Hennessy P953-959 22 Lancet Vol 347, April 1996 P977,978 23 Bulletin Acadamie Nationale Medicine Vol 163 No 6 1979 24 Bulletin Societé Pathologie Exotique January 1952 25 Lyme Disease CDC 26 Rickettsiae and Rickettsial Diseases 1973 Brezinia 27 Bulletin Societé Pathologie Exotique 1969 JB Jadin 28 Annales of Internal Medicine January 1995 29 ASBMT Vol 3 1952 JB Jadin 30 EEG report of 18 year old Epilectic February 1998 CL Jadin 31 An Emerging Group of Pathogens in Fish 1997 Oregon S U Synopsis JL Fryer M. Mauel 32 SAMJ Tetracycline in ME – fad or fact? Vol 82 1992 Bettina Schön 33 Pharmalogical Basis of Therapeutics 1991 Goodman et al
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34 In vitro susceptibilities of Rickettsiae 1997 University of NC 35 Relation entre Protozoaires, Virus et Bacteries 1984 JB Jadin 36 Arthropods 37 Martindale 6th Ed 1995 P314-318 38 Rickettsial Disease – Review of Medical Biology Ch 21 1980 Jawetz 39 8th Congress of American Rickettsioses Society 1990 M. Drancourt. P Levy 40 Académie Royale des Science d’Outre-Mer 1991 JB Jadin

Bottom Line

The above 4 research items all come together into a single model for me:

• The shift of microbiome
• The correction of the shift by selected antibiotics (Jadin)
• The bacteria shifts causing a change of metabolites (i.e. triggering thick blood/hypercoagulation)

To this, we could also add the bacteria shifts causing a change of metabolites resulting in:

• histamine/mast cell issues
• lactic acidosis