cfs2tarello

CHRONIC FATIGUE SYNDROME: FROM BABESIAE TO MICROCOCCI Chronic Infection Conference, Engers Castle, Germany, 9 February 2008.
Walter Tarello, DVM, MRCVS
Zikkos Veterinary Clinic 81, Griva DigeniAvenue6043Larnaka,CYPRUS

The clinical syndrome variously named Myalgic Encephalomyelitis (ME), Epidemic Neuromyasthenia, Chronic Fatigue Syndrome (CFS) or Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) is a poorly understood, highly debilitating disease affecting 0.2 to 0.7% of people in developed Countries (1). This means that in Germany alone, at least 200,000-600,000 adults are affected.

Public and scientific awareness into Chronic Fatigue Syndrome (CFS) started to grow after the 1985 epidemic that occurred in Incline Village, Nevada (1). Dan Peterson and Paul Cheney, two physicians working in a private practice on Tahoe Lake, noticed an unusual and devastating illness showing symptoms very similar to ‘flu’ which do not resolved in few days. Chronic Epstein-Barr Herpes-virus infection was the first diagnosis, although one third of cases resulted negative to EBV. The involvement of an animal herpesvirus was considered. A National Cancer Institute team searched for herpesvirus antibodies from cattle, pigs, horses, cats, dogs, mice, rabbits, chickens and deer: all came back negative (1). The hypothesis of an animal virus crossing the species was rejected, but the suspect of a CFS animal involvement continued to grow.

In 1992, a team of British researchers published a letter detailing “Equine Fatigue Syndrome” in 32 horses with ‘persistent and marked lethargy’ for as long as two years (2). Decreased immunological defenses were evident in most of these animals, and prolonged rest was the only treatment advised. This is the first known description of CFS in animals.

That same year I got involved with CFS. In my practice, I began seeing an increased number of cats and dogs showing an unusual syndrome characterized by chronic fatigue/weakness and initially diagnosed as Mycoplasmosis, an infection transmitted by fleas, caused by the bacterium Mycoplasma haemofelis which induces fatigue, depression, anemia and poor appetite. The condition is diagnosed by finding pleomorphic (cocci or rod) organisms on the external surface of the erythrocites.

However, there are 2 main discrepancies between the unusual cases observed and the true Mycoplasmosis. Bacteria in the blood of CFS cases appear always as cocci (micrococci) much smaller than the Mycoplasma organisms, sometimes coupled as in active replication, and unresponsive to doxycyclines, the antibiotic of choice for mycoplasmosis. Differently, the cure was rapid and complete when an arsenic-based drug (thiacetarsamide, melarsomine, potassium arsenite) was used.

Anecdotal and unscrupulous old reports indicate the efficacy of arsenic derivatives against babesiosis, a tick-borne malaria-like disease affecting cats, dogs and humans, as well. Unfortunately, shape and size of babesial organisms do not match with those of micrococci and it is today acknowledged that babesiosis is better treated with medicaments others than arsenic.

The main questions were: which kind of microrganism the arsenicals are targeting, and what actually are these micrococci? Most common clinical signs of the unusual condition, diagnosed as animal CFS because of the similarities with the syndrome in humans, were the followings: persistent fatigue with reluctance to perform normal activities, increased muscular enzyme Creatine Kinase (CK), pharingitis/sore throat, poor appetite, weight loss, muscle and multi-joint pain, tender and large lymph-nodes, abnormal mood and personality, unrefreshing sleep, post-exertional malaise and hairs shedding (3-7).
Many animals had secondary opportunistic infections, such as dermatophytosis, suggestive of an underlying immune-suppressive agent (8). These cases regularly showed micrococci in the blood and were responsive to low-dosage arsenic-based drugs.

During the XIX-XX centuries arsenicals were used to treat ‘chronic exhaustion’, ‘nervous diseases’ and ‘dermatological conditions’ in animals and humans as well, and this constitutes the rational basis for their use (9).

In September 1992, my wife and I suddenly became severely ill and were diagnosed with CFS. Examination of scientific literature revealed striking similarities between the animal syndrome and the human CFS picture. Symptoms, resistance to antibiotics and immunological anomalies overlap the features observed in animals diagnosed with CFS/ME (8). A relationship between CFS and the unusual animal illness became evident with the microscopic observation of micrococcus-like bodies in blood smears obtained from myself and my wife (10), later on confirmed by the examination of more slides from CFS patients.

Actually, micrococci are absent in blood smears from healthy humans (10) and healthy animals (7) and in medically treated (3-6) and differently diseased individuals (7). The bacterial activity seems to affect the erythrocytes themselves, as abnormal red blood cell morphology was reported in patients with myalgic encephalomyelitis (11) and non-discocytic erythrocytes are routinely seen in the smears of CFS patients.

As early as 1972, cell-wall deficient forms were detected by microscopy on the erythrocytes of arthritic patients (12). Accordingly, Tedeschi and colleagues from the University of Camerino, Italy, published in 1975 a paper titled ’L- and conventional forms of micrococci in the circulating blood of thrombocytopenic patients’ (13), and in 1976 they reported the unusual presence of staphylococci in the blood of autoimmune thrombocytopenic patients (14). Interestingly enough, arthritis and auto-immunity are common features of CFS (1). Moreover, thrombocytopenia and immune dysfunctions have been recorded in animals diagnosed with CFS and carrying micrococci in the blood (8).

In this view, the presence of micrococci in the blood of CFS/ME patients should not be regarded as controversial. In fact, blood cultures from 2 CFS patients - the author and his wife - handling with CFS animal cases, confirmed the isolation of slow-growing Staphylococcus spp. colonies unresponsive to prior antibiotic treatment, suggesting the presence of a small colony variant (SCV) phenotype (10). Blood samples were collected and rapidly inseminated in sterile conditions on 5% ram blood Columbia plates and incubated at 37°C in CO2-enriched atmosphere for 3 days. This procedure enhances the isolation of staphylococcal SCVs (10). Two control plates inoculated with sterile water resulted negative 5 days later, thus excluding the risk of contamination.

Eventually, blood culture studies revealed that micrococci in the blood of animals CFS patients were staphylococci belonging to several species such as Staphylococcus intermedius, S. xylosus, S. epidermidis, S. cohnii, S. chromogenes and S. lugdunensis, some strains of which are resistant to most known antibiotics (3-8). These isolates are assumed to be SCVs due to their slow growth, small colony size, partial pigmentation and antibiotic resistance. Size and shape compatible cocci, single or coupled as in active replication by binary fission, are commonly observable in blood smears from these cases.

A peculiar feature that differentiates SCVs from the wild phenotype is the increased intercellular substance or biofilm, which enable a better bacterial adhesion to the substrate, thus increasing its antibiotic-resistance. The biofilm can be detected and evaluated in Gram stainings by light or SEM microscopy.

Other important features are the smaller size of colonies, a Staphylococcus aureus wild-type colony is much larger than a small colony variant colony, the scarsity or lack of pigmentation, and the paler crystal violet dye intensity in Gram stains.

Researches from Australia, led by Professors Tim Roberts and Hugh Dunstan, demonstrated that patients suffering with chronic pain and CFS showed increased carriages of Staphylococcus sp. compared with control subjects (15-17) thus indicating that these bacteria, and particularly Staphylococcus lugdunensis and S. hominis, more so their small colony variant (SCV) phenotypes (10), are significantly correlated with the core clinical signs of CFS and could be implicated in the cause and/or the sustainability of these conditions (16).

The clinical presentation of SCVs staphylococci can be associated with chronic fatigue, due to a reduction of electron transport activity, enhanced persistence within host tissues and reduced quantities of adenosine triphosphate at disposal (18-19). These peculiarities might also explain their in vivo multiple antibiotic resistance (20).

Staphylococci cause diseases in both humans and animals and there are many similarities between symptoms and laboratory anomalies (increased CK, low Magnesium levels and immune dysfunctions) observed in animals and humans with CFS (3-8). In animal CFS, such anomalies returned within normal ranges following arsenic-based treatment and recovery, confirming their diagnostic and prognostic importance in the condition (3-8).

Why arsenic based medicaments are efficacious against CFS/ME? Arsenic is a natural substance that has been used medicinally for over 2,400 years (21). In the 19th century, it was the mainstay of the materia medica. A solution of potassium arsenite (Fowler's solution) was used for a variety of systemic illnesses from the 18th until the 20th century (21).

The first chemoterapic agent, the organic arsenical compound named Salvarsan, was introduced in 1910 by Paul Ehrlich to provide the first real cure for syphilis (22). The compound rapidly became the most widely prescribed drug in the world. By 1920 Salvarsan showed to be effective against other diseases and its demand remained very strong until 1943 when penicillin became available (22). From 1910 to 1943, many arsenic-based preparations were used to treat a variety of medical conditions, including chronic fatigue (9).

The past 50 years have seen a precipitous decline in arsenic use and, by the mid-1990s, the only recognized indication was the treatment of trypanosomiasis. Much of this decline in the medical use of arsenic was due to concerns about the toxicity and potential carcinogenicity, particularly for skin cancer (21).

Environ- mentalists refer to arsenic as the number one carcinogen. In 1979, the International Agency for Research on Cancer introduced an overall classification system for carcinogens and placed arsenic and certain arsenic compounds in group 1, agents that are carcinogenic to humans.

Interestingly, Arsenic has never been shown to be carcinogenic in animal models or responsible for an increase in solid tumors in humans. Furthermore, its long-term toxic effects remain unexplored (21).

In the 1960s, the efficacy of potassium arsenite was tested in a variety of animal malignancies and found to be effective in animals with Ehrlich ascites tumor, one of the eight tumor models studied. Arsenic showed a preferential selectivity for malignant cells both clinically and in radioactive tracer studies. However, despite this observation, arsenic and other sulfhydryl inhibitors were replaced by other anticancer agents in the early 1970s (21).

The rebirth of Arsenic therapy occurred in the 1970s when physicians in China began using arsenic trioxide in the treatment of acute promyelocytic leukemia (APL). Their accumulated experience showed that a stable solution of arsenic trioxide given by intravenous infusion was remarkably safe and effective both in patients with newly diagnosed APL leukemia and in those with refractory and relapsed APL (21).

Trisenox, an arsenic trioxide based drug, recently won approval from the Food and Drug Administration to treat leukemia, multiple myeloma and myelo-dysplastic syndrome and currently constitutes a promising therapy for CFS in both animals and humans (21).

Potassium arsenite proved recently efficacious against lymphoid leukaemia in animals (23), as well as viral infections such as pox (Capripoxvirus) in sheep (24).

It seems more than coincidental that outbreaks of CFS/ME started to be increasingly reported from 1948 onward, concurrently with the declining use of arsenicals and the increased use of antibiotics (25). CFS/ME occurs both in isolated cases and large-scale outbreaks. In a number of documented cases several people in a building or in a community came down with the disease simultaneously, indicating that CFS/ME is caused by an infectious agent (25). Moreover, the fact that hospital staffs have born the brunt of several outbreaks suggests an occupational hazard (25). Observations concerning the possible mode of transmission are available for nine outbreaks of CFS/ME (25). Instances of spread by personal contact have been recorded and most authors agree that this is the probable means of dissemination (25). Actually this is the way of transmission of Staphylococcus species (1).

Staphylococci are common to animals and humans and can be transmitted by close contact, causing disease in many species. As a matter of fact, animal caretakers appear to be more prone to suffer from CFS/ME compared with control subjects (26). Prevalence surveys indicate that 97% of CFS patients had animal contact, particularly with dogs, cats and birds (26) and that 75% of these animals appeared sick, with symptoms and signs which mimicked CFS/ME in humans, strongly suggesting a zoonotic transmission (27).

The discovery of antibiotic resistant staphylococci SCVs and their relation to persistent diseases is an intriguing finding because of its clinical implications in CFS (28). SCV exhibit many processes necessary in the pathogenesis and maintenance of staphylococcal related nosocomial infections. This phenotype affords the bacterium several advantages, such as intracellular living and a metabolic diet. The main consequence is long term survivability within the host cells and thus sustenance of relapsing infectious states even at low bacterial populations. The ability to live intracellularly is a mechanism of bacterial survival adopted not only by SCV but others such as Chlamydia, Mycoplasma and Rickettsia, altough with different clinical outcomes (28). Because bacterial survival within an environment is also dependent on the ability to co-exist with other microbes, staphylococci SCV may have evolved as a result of combined traits acquired from close association with several of these intracellular pathogens. Bacterial co-habitation may also explain why coagulase-negative staphylococci, previously deemed apathogenic, have become frequent isolates in aggressive nosocomial infections (28).

REFERENCES
(1) JOHNSON, H. Osler’s Web. Inside the labyrinth of the Chronic Fatigue Syndrome epidemic. Crown Publishers, New York, 1996, 1-720.
(2) RICKETTS, S.W., MOWBRAY, J.F., YOUSEF, G.E. & WOOD, J. (1992) Equine Fatigue Syndrome. Veterinary Record 18, 58-59.
(3) TARELLO, W. (2001) Chronic Fatigue Syndrome (CFS) associated with Staphylococcus spp. bacteraemia, responsive to thiacetarsamide sodium in 7 dogs. Revue de Médecine Vétérinaire 152, 785-792.
(4) TARELLO, W. (2001) Chronic Fatigue Syndrome (CFS) in cats: symptoms, diagnosis and treatment of 7 cases. Revue de Médecine Vétérinaire 152, 793-804.
(5) TARELLO, W. (2001) Chronic Fatigue and Immune Dysfunction Syndrome associated with Staphylococcus spp. bacteraemia, responsive to thiacetarsamide sodium, in eight birds of prey. Journal of Veterinary Medicine B 48, 267-281.
(6) TARELLO, W. (2001) Chronic Fatigue Syndrome in horses: diagnosis and treatment of 4 cases. Comparative Immunology Microbiology & Infectious Diseases 24, 57-70.
(7) TARELLO, W. (2001) Chronic Fatigue Syndrome (CFS) in 15 dogs and cats with specific biochemical and microbiological anomalies. Comparative Immunology Microbiology & Infectious Diseases 24, 165-185.
(8) TARELLO, W. (2003) Immunological anomalies and thrombocytopenia in 117 dogs and cats diagnosed with Chronic Fatigue Syndrome. Acta Veterinaria Hungarica 51, 61-72.
(9) THE MERCK INDEX (1983) An Encyclopedia of Chemicals and Drugs. Merck & Co. Inc. Rahway, N.J. USA.
(10) TARELLO, W. (2001) Chronic Fatigue Syndrome (CFS) associated with Staphylococcus spp. bacteraemia, responsive to potassium arsenite 0.5% in a veterinary surgeon and his co-working wife, handling with CFS animal cases. Comparative Immunology Microbiology & Infectious Diseases 24, 233-246.
(11) MUKHERJEE, T.M., SMITH, K. & MAROS, K. (1987) Abnormal red blood cell morphology in myalgic encephalomyelitis. Lancet 8, 328-329.
(12) POHLOD, D.I., MATTMAN, L.H. & TUNSTALL, L. (1972) Structures suggesting cell-wall-deficient forms detected in circulating erythrocytes by fluoro-chrome staining. Applied Microbiology 23, 262.
(13) TEDESCHI, G.G., AMICI, D. & SANTARELLI, I. (1975) L- and conventional forms of micrococci in the circulating blood of thrombocytopenic patients. Experientia 31, 1088-9.
(14) TEDESCHI, G.G., AMICI, D., SPROVERI, G. & VECCHI, A. (1976) Staphylococcus intermedius in the circulating blood of normal and thrombocytopenic human subjects: immunological data. Experientia 32, 1600-2.
(15) BUTT, H.L., DUNSTAN, R.H., McGREGOR, N.R., ROBERTS, T.K., ZERBES, M. & KLINEBERGER, I.J. (1998) An association of membrane damaging toxins from coagulase negative staphylococci and chronic orofacial muscle pain. Journal of Medical Microbiology 47, 577-584.
(16) DUNSTAN, R.H., McGREGOR, N.R., BUTT, H.L. & ROBERTS, T.K. (1999) Biochemical and microbiological anomalies in Chronic Fatigue Syndrome: the development of laboratory based tests and the possible role of toxic chemicals. Journal of Nutrition and Environmental Medicine 9, 97-108.
(17) DUNSTAN, R.H., McGREGOR, N.R., ROBERTS, T.K., BUTT, H.L., NIBLETT, S.H. & ROTHKIRSH, T. (2000) The development of laboratory-based tests in Chronic Pain and Fatigue: 1. Muscle catabolism and coagulase-negative staphylococci which produce membrane damaging toxins. Journal of Chronic Fatigue Syndrome 7, 23-27.
(18) McNAMARA, P.J. & PROCTOR, R.A. (2000) Staphylococcus aureus small colony variants, electron transport and persistent infections. International Journal of Antimicrobial Agents 14, 117-22.
(19) PROCTOR, R.A., von EIFF, C., KAHL, B.C., BECKER, K., MCNANAMA, P., HERRMANN, M. & PETERS, G. (2006) Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Natural Review of Microbiology 4, 295-305.
(20) VON EIFF, C., PETERS, G. & BECKER, K. (2006) The small colony variant (SCV) concept – the role of staphylococcal SCVs in persistent infections. Injury 37, Suppl 2, 26-33.
(21) WAXMAN, S. & ANDERSON, K.C. (2001) History of the development of arsenic derivatives in cancer therapy, Oncologist, 6 (Suppl 2), 3-10.
(22) LLOYD, N.C., MORGAN, H.W., NICHOLSON, B.K., RONIUS, R.S. & RIETHMILLER, S. (2005) Salvarsan – the first chemotherapeutic compound, Science and Engineering Papers, University of Waikato, posted at Research Commons@Waikato, http://researchcommons.waikato.ac.nz/sci_eng_papers/62
(23) TARELLO, W. (2006) Lymphoid leukaemia in a saker falcon. Veterinary Record, 158, 212.
(24) TARELLO, W. & KINNE, J. (2007) Complete remission after treatment of Capripoxvirus infection in sheep using potassium arsenite 0.5% (Fowler’s solution). Revue de Médecine Vétérinaire 158, 418-424.
(25) ACHESON, E.D. (1959) The clinical syndrome variously called Benign Myalgic Encephalomyelitis, Iceland Disease and Epidemic Neuromyasthenia, American Journal of Medicine 26, 569-595.
(26) GLASS, T. (2000) The human/animal interaction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a look at 127 patients. Journal of Chronic Fatigue Syndrome 6, 65-72.
(27) GLASS, T. (2000) Abnormal signs found in animals of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients: a look at 463 animals. Journal of Chronic Fatigue Syndrome 6, 73-81.
(28) ONYANGO, L. A., DUNSTAN, R. H. & ROBERTS, T. K. (2008) Small colony variants of staphylococci: Pathogenesis and evolutionary significance in causing and sustaining problematic human infections. JNEM (In Press).

reprinted with kind permission from Walter Tarello, DVM, MRCVS
Zikkos Veterinary Clinic Larnaca, CYPRUS
Email: wtarello@yahoo.it