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| CHRONIC FATIGUE SYNDROME IN HORSES |
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| Figure 1 |
This 2-year-old male horse was visited in Castiglione del Lago (Central Italy) in May 1994. The animal had already been treated for intestinal worms twice (one and two months before), with the purpose of eliminating the symptoms of asthenia it had developed since shortly after birth (owner’s statement). The appetite was normal, but the animal was grossly underweight. Head and neck were constantly kept low, with drooping lips and profuse sialorrhea. Tiredness and reluctance to perform normal activities, also present for the same length of time, were confirmed at the visit. The internal temperature was normal (37°5 C). The coat of hair was dull, shedding plenty of hair and with abundant scurf.
The fresh blood smears demonstrated, also in this horse, that 5-8 % of RBCs were carrying micrococci-like organisms 0.3-0.5 mm in diameter, hanging on their outer surface ( Figs 1,2,3). The horse had normocitic normochromic anaemia (PCV = 25%, haemoglobin = 9,8 gr/dl, RBCs = 6.160.000/mm3, MCV = 40,6 fl., MCH = 15,9 pg.) .
There was a slight serum magnesium deficiency (Mg = 1.4 mEq/L). At rest, serum activity of creatin-kinase (CK = 125,9 IU/L), lactate dehidrogenase (LDH = 365,9 IU/L) and AST (GOT = 273 IU/L) were between the ranges. Total proteins were 6.35 g/dl, with the g-globulin fraction at 1.11 g/dl.
After diagnosing CFS, treatment with intravenous thiacetarsamide sodium was started. In a few days, the condition of the horse improved considerably.
At the 2-month interval control (August 1994), the anaemia had disappeared (PCV = 31 %, haemoglobin = 11,8 gr/dl, RBCs = 7.520.000/mm3) and the serum level of magnesium was in the high range of normality (Mg = 2.4 mEq/L). At rest, the LDH activity in the serum was reduced to 254.7 IU/L; and that of CK was at 106.4 IU/L. Total proteins were slightly increased to 6.54 g/dl, especially in the g-globulin fraction (1.34 g/dl). Repeated fresh blood smears were negative for micrococci. The horse did not show tiredness anymore, was thriving with its muscle mass grown to normal, and its coat of hair had regained luster.
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| Figure 2 |
This 4-year-old male horse was visited in nearby Panicarola (also in Central Italy) in June 1994. The prominent aspect of the disease was a chronic infection of the upper airways, with cough and bilateral nasal mucous-purulent discharge, marked weakness and reluctance to being ridden. One month before, it had been treated for a week with kanamycin and desametazone. The owner had observed that symptoms might subside during treatment, but would flare up again after its completion.
Rectal temperature was normal (38°C). There was a normocytic normochromic anaemia (PCV = 27,8 %, haemoglobin = 10,3 mg/dl, RBCs = 6.840.000 mm3, MCV = 40,6 fl., MCH = 15 pg.), meanwhile WBC and platelet count was normal (respectively at 7.400/mm3 and 220.000/mm3).
In this horse, too, fresh blood smears showed 5-6% of RBCs with micrococci on their surface. All other laboratory examinations gave results within normal limits, with the exception of an increased LDH activity (1.394 IU/L) at rest.
Culture from a swab of the nasal discharge on a specific agar plate gave growth to a Staphylococcus species.
A diagnosis of CFS was made, based upon the fatigue-related symptoms, the ineffectiveness of the previous treatment, the presence of unusual bacteria in the blood and, by now, the previous personal experience. In this case, treatment with Caparsolate was given, by the same route and at the same dosage, for 3 days instead of two, with the aim of eliminating first the underlying chronic immune dysfunction before attacking the upper respiratory infection. No other drug was used. The mucous-purulent discharge decreased and stopped altogether in a matter of a few days, while the weakness made a progressive disappearance in 3-5 days.
At a control 2 months later (August 1994), the horse looked healthy and had no evidence of upper respiratory infection. Blood examinations showed remission of the anaemia (PCV = 34,5%, haemoglobin = 13,5 gr/dl, RBCs = 8.960.000/mm3) and total disappearance of the micrococci. At rest, LDH levels were restored to within normal limits (371 IU/L).
Throughout the recorded history of CFS, animals have frequently been implicated by their owners, with anecdotical reports of strange diseases or disfunctions.
A recent report from England [32] has suggested that CFS also affects equines and is becoming a problem in veterinary practice. Preliminary studies seem to confirm the zoonotic implications of CFS. A recent study [14] showed that there is in humans a definite association (97%) between CFS and ownership of animals (usually indoor pets), and/or frequent contact with them; and, that most (75%) of these animals suffer from unusual diseases that certainly have points of similarity with CFS. Publications on CFS-like illnesses in animals, apart from the afore mentioned study on Equine Fatigue Syndrome [32], can hardly be found. Muscular weakness [6,18], neurological disorders [12, 20, 24] and immune dysfunction [20] are frequently studied in veterinary medicine, but apparently never in relation with the human illness known as CFS or CFIDS.
The present study seems to confirm the existence of an equine form of CFS, which can then be well called "Equine Fatigue Syndrome"; and, also, it introduces the interesting feature of the striking effectiveness of an arsenical compound, thiacetarsamide sodium, in its therapy.
The unexpected finding of micrococci-like bacteria in the blood led to the suspicion of a chronic infection, resistant or scarcely responsive to previously given, standard therapeutic agents. This abnormal microbial presence, no longer found after treatment with the arsenical preparation, was the only remarkable difference in the fresh blood smears taken from, respectively, "chronically fatigued" and healthy horses. According to these observations and to advances in research reported in recent literature [4, 27, 49], which rule out the HHV’s as causative agents of CFS, a search for EHV’s was never attempted.
Symptoms and signs, in horse #1 and #2, were compatible with those of the initial stage of Borna’s equine encephalomyelitis, caused by an RNA virus [24]. However, the second stage of this sickness is characterized by a rapid, acute worsening of the neurological disorders, and death. In these horses, instead, the illness had had its onset three months before, followed by some worsening of the symptoms but in a chronic course.
The real nature of the bacteria found in our cases is difficult to assess, in the absence of culture studies that could not be performed because of the rural conditions of work .
However in 1993, 15 similar cases of CFS in cats and dogs came under this writer’s personal observations (unpublished material). These animals also were the carriers of a high number of micrococci-like germs adhering to the outer surface of their RBC’s. Bacteriological studies with blood cultures were then possible and allowed a better identification. The necessary sterile conditions were obtained with a laminar-flux hood (Mini Securitas, PBI); blood cultures were rapidly carried out (1-2 minutes for sampling, insemination on 5% ram blood in Columbia plates and placement under incubation at 37°C in a CO2-enriched atmosphere). Cultures from five cats and four dogs proved positive for the growth of Staphilococcus spp. (Gram + and catalase-positive cocci)[19], whereas no growth was obtained in the other plates. In 2 cats and 2 dogs of the nine animals thus affected ( Staph-positive cases), a biochemical method (Api-Staph, bioMerieux) of identification of the bacteria was carried out, leading to one good identification (98,6%) of Staphylococcus intermedius and 3 very good identifications (99,8%) of Staphylococcus xilosus , all mannitol-fermenting.
Material taken from an interdigital pustule of a dog suffering from CFS and pyoderma gave a 99.8% identification of a catalase-positive, vancomycin-resistant Staphylococcus xilosus strain.
All these house-pets obtained a total recovery after low-dosage arsenical treatment. The therapeutic efficacy of arsenic on pyoderma and various respiratory tract illnesses is acknowledged in both human [34, 45] and veterinary [15] medicine . Personal experience suggests a frequent relation of these ailments with chronic fatigue and micrococci in the blood. Such was the case, in this study, of horse #1, that presented pyoderma which, in veterinary practice [19], is notoriously caused by S. intermedius, and of horse #4, suffering from an upper respiratory infection sustained by Staph. species.
All four horses of the present study presented the clinical picture of CFS as seen in humans, had proven resistant to a variety of previous treatments, and had various hematological and biochemical abnormalities in common. They were submitted to a course of treatment with thiacetarsamide sodium at least one month after previous therapy: the beneficial effect of the arsenical compound by itself, even against pyoderma (horse #1) and upper respiratory disease (horse #4), was soon evident. Complete recovery was obtained in a matter of days (2-10) and maintained in the time.
It appears to be conjectural, if this effect could be due to some peculiar anti-microbial action of arsenic.
The treatment of infectious diseases with synthetic chemicals (chemotherapy) began in 1907 , with Ehrlich-Hata’s "magic bullet" (or "preparation 606": arsphenamine, Salvarsan) against protozoan (trypanosomyasis) and bacterial (syphilis) infections [17]. The discovery paved the way for the preparation of hundreds of drugs based on arsenic.
Arsenic (As) is commonly known for its toxicity, but has also been shown to have beneficial effects when fed in minimal amounts to laboratory animals [2]. Several studies on rats, hamsters, minipigs, goats and chicks have provided circumstantial evidence suggesting that As is essential as an oligodynamic element ; its physiological role, however, has not been clearly defined (there is some evidence [47] that it could have to do with the metabolism of methionine). The Merck Index [48] lists several arsenical preparations as ‘tonic for horses’ useful against ‘asthenia in horses’ and ‘general debility’. However, no relationship has ever been established with underlying chronic bacterial infections or with the presence of micrococci in the blood .
Recent research [35] seems to confirm such ‘obsolete’ indications, since myopathy with atrophy of both types of muscular fibers and mitochondrial abnormalities have been observed in goats artificially raised in conditions of dietetic arsenic deficiency. Similar damage was noticed in the muscles of dogs suffering from episodic weakness associated with exertional lactic acidosis and myopathy [6] and humans with Postviral Fatigue Syndrome [3]. Another recent study on humans [47] correlates low arsenic in the serum with disorders of the CNS and with certain forms of cancer . In the past, arsenic receives much "bad press" as a ‘carcinogen’, but it is all based on some statistical results in poor epidemiological studies.
Separate studies in China, U.S.A. and Europe are showing that inorganic arsenic trioxide (As(2)O(3)) exhibits an ample anti-leukemic activity in both newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) [31,42]. An As-containing organic compound, melarsoprol , has been found effective in APL, inducing programmed death of leukemic blood cells both in vitro and in vivo [43]. The anti-cancer action of arsenic trioxide and melarsoprol is due to the induction of apoptosis. The effectiveness of As(2)O(3) has recently been demonstrated in vitro against cancer cell lines of gastric [52], head and neck [37], oesophageal [39], epithelial [53] and neural [1] origin, and against the plasma cells of myeloma [33].
Apoptosis and cell-growth inhibition in malignant lymphocytes, after treatment with arsenic trioxide may prove it useful even against malignant lympho-proliferative disorders [54].
A working hypothesis for research is that a similar mechanism of action could be involved even in the therapeutic results apparently obtainable in CFS-like illnesses of animals associated with the presence of micrococci in the blood. As melarsoprol, thiacetarsamide sodium is a trivalent organic arsenical, and these compounds are known to be effective binders of –SH univalent radicals (sulphydrils). Apparently, such is the mechanism of arsenical deactivation of enzymes, especially those containing two contiguous –SH groups.
Evidences is available [5] that solutions in certain concentrations of iron and arsenic inhibit the growth of thermophylic bacteria in mixed cultures, with As(III) being more active than As(V) in reducing the rate of bacterial oxidation .
Until the ’70’s, CFS-resembling conditions in horses were frequently treated with arsenical drugs. These medicaments were later abandoned with the advent of more modern chemo-therapeuticals and antibiotics. A comparison of thiacetarsamide sodium with other therapies would not be allowable without randomized studies. However, it is intriguing how all CFS-diagnosed horses reported here could obtain such a rapid improvement and complete, lasting remission from a chronic state of exhaustion with a drug that is considered as obsolete and useless, apart from treatment of heartworm disease in dogs. These results seem notable, considering also that arsenicals have been widely used for thousands of years, in particular against syphilis, tuberculosis, malaria and, even nowadays, the African sleeping sickness due to Trypanosoma brucei, in both human and animals [42].
The preliminary consideration, borne out of the evidence gained from these four horses, and other animals with CFS where bacteriological studies (blood cultures) were possible, is that bacteria of the Micrococcaceae family and of the Staphylococcus genus are to be found in the blood of such cases ( Figs 1,2,3). There is no direct evidence that they cause the disease, but surely, they could no longer be found with the control fresh blood smears of the horses at the post-treatment controls.
It can therefore be suggested that their presence could be used as a coadjutor tool in the diagnosis of this particular kind of arsenic-responsive ‘general debility’ of horses.
For at least 15 years the CFS-related symptoms were thought to be caused by a virus , possibly a retrovirus [29, 38, 51]. Claims of improvements following anti-viral treatment have been advanced, but no consistently effective, single viral agent has yet been found [44, 46]. However, an increased prevalence of reactivation of multiple viruses has been reported [29, 51] in CFS patients: it may be the result of increased protein turnover [27] and therefore, of secondary nature.
Recent advances in human medicine strongly indicate a bacterial etiology . Australian researchers [8,10] claim evidence that the symptoms and signs of debilitation in CFS are the product of infection from otherwise harmless commensal bacteria and consequent changes of the intestinal bacterial flora. An increase of the prevalence of the toxic Staphylococcus species was found in patients complaining of chronic pain and/or fatigue [26] or diagnosed with CFS by compliance with a clinical definition [13]. The coagulase-negative staphylococci found in these patients produced a significant association of membrane-damaging toxins ( d- and/or ‘horse’ –haemolysins), whereas those isolates from an ideal musculo-skeletal symptom-free control group did not [9].
In chronic muscle pain patients, who usually complain of fatigue and muscular weakness, an increased toxicity of the two Staph hemolysins was associated with increased fibrillar and non-fibrillar proteolysis corresponding to increase of pain, cardiac palpitations, chest pain, irritable bowel, muscle fatigue and nocturnal sweat and/or fever [26]. The control subjects who did not complain of musculo-skeletal symptoms or fatigue, were free of these Staphilococcus spp. Thus, the carriage of toxin-producing commensal staphylococci does initiate an increase in proteolysis, and may act to trigger off reactivation of viruses of the herpes family. It has been suggested [27] that CFS outbreaks such as those that occurred in Incline Village, may result from the acquisition of low-grade toxic Staphilococcus which in turn may facilitate the reactivation of HHV-6 and other herpesviruses [27]
Furthermore, Dr. Luther Lindner, pathologist on the faculty of Texas A&M University, is reportedly studying a newly recognized bacterium, usually present in high numbers in the blood of patients with CFS or multiple sclerosis. He has no evidence that the bacterium can be completely eliminated using the standard FDA-approved antibiotics and he affirms that, under certain circumstances, antibiotics can actually stimulate bacterial growth and make the patient worse.
The resistance to antibiotics of bacteria that cause diseases in the community and in hospitals is leading to an increase in illness, deaths, and social costs. The extent of the problem has not yet been fully assessed, but such a resistance has become a major public health problem in Europe and in the U.S.A today [28].
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| Figure 3 |
The uncertainty about the diagnosis of CFS and the increasing public demand for an effective therapy and proper support, has produced a certain degree of confusion and emotion in human medicine. Many medicaments have been tried and some partial success has been obtained. Treatment has mostly been focused on vitamins, aminoacids and health foods, in the belief that the fatigue is due to some metabolic impairment. These lines of treatment cannot be successful, as the disease is caused by factors that cannot be influenced by vitamins [11]. Until now, few therapies designed for CFS have enough clinical trial data to support their validity, and a curative and resolving effect cannot be attributed to any of them [11, 46].
It was thus deemed worthy reporting these four horses with Chronic ("Equine") Fatigue Syndrome, on which intravenous thiacetarsamide sodium in low dosages was successful in obtaining complete and lasting remission, whereas recurrences had occurred after extensive prior therapy following current criteria. The use of this single drug was able to cause a fast recuperation from lethargy and, in some cases, a cure of some associated condition such as anaemia, pyoderma and upper respiratory infection, concomitant with the primary chronic illness. These observations are not in contrast with the indications of The Merck Index for the use of similar arsenical drugs against some chronic equine conditions.
An added element of interest of this report is the finding of micrococci-like bacteria in the blood of the described horses before treatment, with constant and stable disappearance after treatment and clinical recovery. This element seems to suggest a possible connection of CFS with an underlying chronic bacterial infection resistant to other treatments.
It has been personal experience that the same treatment also appears to be useful in cats and dogs similarly affected by a CFS-like illness, where identical findings were obtained in fresh blood smears and culture studies produced bacteria of the Staphilococcus species ( -intermedius and -xilosus ).
In human medicine also, recent advances seem to confirm an implication of Staph in syndromes characterized by chronic fatigue and muscular pain.
Further multidisciplinary studies are necessary for an adequate solution of the problem since, up to date, every accepted symptomatic and antibacterial treatment for CFS have obtained, at best, a slight improvement in function.
English translation by Giorgio Iraci, Casella Postale 289, I-06100 Perugia-Centro (Italy) (iragi@dada.it).
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For further information regarding Chronic Fatigue Syndrome in Horses, please contact
Walter Tarello, veterinary surgeon
C.P. 42, I - 06061 Castiglione del Lago
PERUGIA (Italy)
tarello@iol.it
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