Tuberculosis and Cysticercosis in Brazil : A Review

Tuberculosis and the taeniasis-cysticercosis complex, typical cases of zoonosis, have great importance for public health, since they cause economic liabilities to the Brazilian beef production chain. They are actually a synonym of technical inadequateness in Good Production Practices. Both diseases have existed since ancient times and their occurrence should be controlled by basic sanitary measures. However, there is a significant neglect attitude by authorities of countries with high occurrence rates, or rather, tropical underdeveloped nations, to focus on public policies for the control and decrease of the prevalence and the occurrence of these diseases. Current review elucidates the epidemiological profile of the diseases and contributes towards the elucidation and establishment of measures ensuring control.


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Introduction
The World Health Organization (WHO) defines zoonoses as "the interface of diseases and infections between animals and humans", which may be acquired through contact with animals or by consumption of contaminated food. According to WHO, the main diseases related to the consumption of meat in Brazil are salmonellosis, tuberculosis, cysticercosis and other diseases of the food toxic-infections group (PINTO, 2008). In the main, cysticercosis and tuberculosis are highly relevant in public health since they affect populations with high morbidity rates. In fact, the two diseases are associated to socially and economically low level populations and to eating customs, hygiene and inadequate handling and the clandestine commerce of products derived from animals. Clandestine commerce is a constant concern to veterinary inspection services worldwide. Difficulties to eradicate this trade are proportional to the state of development of the country, to economic issues and to cultural standards. The clandestine meat and milk commerce in Brazil (implying the purchase and selling of cattle contaminated by tuberculosis, contaminated dairies, falsification of Sanitary Inspection labels and cattle pens that seem to come directly from the Middle Ages, on the outskirts of big cities) and the lack of reliable statistical data on cattle tuberculosis and cysticercosis in the country are a great threat to public health.
Estimates reveal that the clandestine conditions of beef and milk in Brazil are shocking. Actually it is a source of deep concern to realize that 50% of beef consumed in Brazil come from illegal abattoirs and that 48% of the milk produced in Brazil have shady origins, without any sanitary inspection. What actually occurs in Brazil in the case of tuberculosis boils down to complex social phenomena. As a rule, dairymen ignore the product's sanitary risks. They are small, non-organized farmers, with low schooling, who circumvent the law to survive. If they sell milk to the official dairies, their product becomes commercially non-feasible since they would earn less than when they work within illegal purchase conditions. To make matter worse, most buyers do not have sufficient information on food safety and ignore the risks to which they are exposed. They drink raw milk, considering it healthier. They also have the "advantage" of buying the product by installments. Government authorities should guide the population, give technical assistance to milk and beef producers, and enforce the law on the matter, acknowledging the seriousness of the issue. They often fail in their duty, excusing themselves by saying that financial resources are lacking.
The taeniasis-cysticercosis complex in cattle focuses on the parasite cycle that starts by the ingestion of Taenia saginata eggs through the consumption of contaminated water or food. Cysts harbor in the muscles of the intermediate host (cattle) and form cysticerci. The ultimate host (humans) is infected by eating raw or undercook meat, or drink larva-contaminated water. Larvae develop in the small intestine. When they turn adults, they eliminate proglottids with the eggs at the moment of defecation and contaminate the environment. The taeniasis-cysticercosis cycle ends when a series of preventive measures are taken against human infection by the etiological agent, with the extermination of the parasite from the environment. In several regions, however, few prophylactic measures are taken. In fact, Brazil lacks basic sanitation, especially in the poor, government-abandoned areas where diseases prevail. The establishment of beef inspection in abattoirs is highly relevant to hinder or, at least, to reduce the number of cattle carcasses improper for human consumption.

History
Tuberculosis, caused by a single microbe agent in humans, is one of humanity's and Lessel recommended change in the classification for a new species [8].
Tuberculosis arrived in Brazil with the Portuguese colonial enterprise and the subsequent contact between the natives and the infected settlers and Jesuits during the Evangelization process. In fact, several natives died of tuberculosis [6] [9]. Letters written in 1555 by Ignatius of Loyola and in 1583 by José de Anchieta to the Portuguese Government report that "several catechized Indians fell ill, most of whom exhibiting phlegm, coughs and fever; many spit blood and died alone in the villages" [6]. In 19 th century Brazil, an epidemic of tuberculosis, called "paupers' plague", became widespread in the towns and cities, killing 700 in every 100,000 inhabitants [6]. High mortality rates occurred up to the 1940s.
During this period, approximately 10% of death causes in the city of São Paulo were due to tuberculosis [6] [12].
In the 1960s and 1970s, human tuberculosis was completely under control in most developed and underdeveloped countries. However, population growth in large cities, high poverty rates worldwide, the arrival of Acquired Immunodeficiency Syndrome (AIDS), forest reserves, the persistence of the microorganism in herds and the rise of resistant multidrug strains caused tuberculosis to become a re-emergent health issue [13].

Bovine Tuberculosis
Bovine tuberculosis is a chronic and zoonotic infectious-contagious disease with Mycobacterium bovis as its etiological agent [14] [15] [16]. Its cell wall has singular characteristics and is composed of lipids forming between 20% and 40% of the bacillus's dry weight, most of which are mycolic acids which impair the removal of fuchsine by the alcohol-acid bleacher used in Gram method. They act within the colonies' characteristics and, coupled to wall glycolipids, induce toxicity responses that stimulate the host for a granulomatose inflammatory response [11]. They also contribute towards cell permeability, resistance to several disinfectant agents and enzyme activity of macrophages by inhibiting the formation of phagolysosomes [14].
Although mycobacteria are not spore-forming, the features of the external section of the bacterium wall formed by the mycolicarabinogalactan complex act as a layer of wax that impermeabilizes cells and protects them from hydrophilic substances and from dissection, becoming viable even in extreme environmental conditions, from chlorhexidine and quaternary ammonia-based disinfectants [22] [27] [28]. In favorable temperature, humidity and shade conditions, the viability of M. bovis in the environment may last more than two years. However, a host is required so that the agent may multiply [21] [22] [23]. On the other hand, they are destroyed by pasteurization, heat, direct sunlight and by formaldehyde and sodium hypochlorite-based disinfectants [11] [23] [29].
Although M. bovis tends to develop in bovines, other species of wild and domestic mammals may be occasionally affected, which also includes humans [23] [30]. The disease generally affects bovines, with prevalence for older and milk-producing animals. The above is due to the production system with greater agglomeration and higher permanence rate on the farm when compared to beef cattle which are slaughtered young [23] [31] [32]. However, greater agglomeration in beef cattle confinement and the permanence of female matrixes for longer periods on farms constitute similar conditions as those infected by tuberculo- The proximity of infected animals is the main infection source in cattle.
Transmission is horizontal and interspecies. It may occur from bovines to bovines, from bovines to wild animals and humans, and from wild animals and humans to bovines, mainly involving the inhalation of particles released by coughs and respiration, or even by the consumption of bacillus-infected milk and meat [23] [34]. Immediately on being infected by the agent and even prior to the formation of lesions in the tissue, the animal may disseminate the disease to the rest of the herd [35]. In fact, the respiration system is the infection's main entrance (80% -90% of all cases) through the inhalation of aerosols with the bacillus [11] [14] [36]. Although M. bovis may also be eliminated in milk, faeces, semen, urine, utero-vaginal secretions, caused by abscedation of lymph nodes, the contagiousness of susceptible animals in contact with contaminated pasture, water and troughs is rare [22] [30] [31]. Consumption of bacillus-contaminated pasture, water and fomites rank second to respiration. However, the mouth is the main entrance of M. bovis in the case of young animals and humans [14] [27] [37]. Clinical symptoms depend on the infected organ or system. The main clinical signs comprise progressive slimming, apathy, high fever, dyspnea, dysphagy, noisy respiration and coughing [23] [30]. Live animals are diagnosed by tuberculinization, or rather, intradermal inoculation of tuberculin (simple and comparative intradermal proof), which causes a reaction of type 4 hypersensitiveness in M. bovis infections. Post-mortem exams and microbiological and histopathological cultures are also a help in the diagnoses of bovine tuberculosis [38].

R E T R A C T E D
Macroscopic findings are characterized by granulomatous nodular lesions, called tubercles, which develop in any type of organ or tissue. They may lie in any lymph node, although usually in bronchial, retropharynx and mediastinal ones [26] [29] [39], and in other organs, such as the liver, spleen and mesenteric lymph nodes [26] [38]. In the case of lesions in the lungs, miliary abscesses occur. They exhibit characteristic colored pus, ranging between cream and orange color, and consistency ranging between thick cream and crumbled cheese. Lesions may be disseminated by the organ causing suppurating bronco-pneumonia, with possible extensions to the pleura and the peritoneum [26] [27] [30]. Further, the formation of fibrous capsule may be triggered as the lesion progresses and the latter may develop in all the tuberculosis lesions [26] [30].
Generalization is featured by miliary tuberculosis defined by spot-shaped lesions in several organs or by caseified and badly encapsulated lesions in the lungs. Chronic lesions are generally calcified or surrounded by a thick fiber capsule and by nodules with yellowish-orange thick caseous material [26] [30] [40].
The treatment of tuberculosis in bovines is not recommended. The most adequate means for reducing the negative impact of the disease is the control and the eradication of the disease [38]. Since 2001, the control and eradication of bovine tuberculosis in Brazil have been undertaken by the Brazilian National Plan for the Control and Eradication of Animal Brucellosis and Tuberculosis (PNCEBT) of the Ministry of Agriculture, Broodstock and Supply (MAPA) [41] [42]. PNCEBT's main role comprises the elimination of tuberculosis and brucellosis through prophylactic activities involving diagnosis and sanitation of bovine breeding sites, active sanitary vigilance, reduction of the prevalence and occurrence of the disease and the decrease of impacts on human and animal life. The above also includes totally free and monitored homesteads and, consequently, the competitiveness of Brazilian beef cattle herds through the production of animal-derived products with low sanitary risks for the public health [41].
Joint work between PNCEBT and official government inspection service and agricultural-broodstock defense service by slaughtering positive bovines, coupled to notification of lesions suggesting tuberculosis in carcasses and viscera during post-mortem inspections, should improve sanitary vigilance activities and the monitoring of the efficaciousness of the program in Brazil [43].

Economic Impact of Tuberculosis on Cattle
Mean prevalence percentage of tuberculosis-infected cattle in Brazil between occur not only on the homestead due to the death of the animal, to the destruction of test-positive tuberculine reagents and to decrease in production rates, but also at the slaughtering point, precisely at the sanitary post-mortem inspection.
This is due to the reduction of the price paid to the producer according to carcass degradation by the disease-causing lesions [35].
According to Rulings for Industrial and Sanitary Inspection of Animal-Derived Products (RIISPOA), the carcasses with tuberculosis-suggestive lesions in the muscles, bones, intramuscle tissues, thorax and abdomen organs, multiple or generalized miliary lesions should be forwarded for the rendering process. In the case of localized and discrete lesions, restricted to lymph nodes and organs, the removal of the affected parts and sterilization by heat become mandatory [48]. There is a 50% decrease in total price rate when diseased carcasses are heat sterilized, whereas no payment is due in the case of rendering [35].  [59].
People in contact with infected cattle or with products derived from these animals, such as veterinaries, abattoir workers, animal handlers and butchers are prone to be affected by the disease, especially those recovering from other diseases or immunodeficient persons [42] [44] [60]. Moreover, physiological and immunological factors linked to children, elderly people and AIDS patients raise infection risks in these people. The most common is the extrapulmonary form of tuberculosis [56].
Pet animals, such as cats and dogs inhabiting a rural environment, may also be infected through an aerogenic mode and by the ingestion of milk, meat and raw offal. They become vectors of the disease and transmit it to humans and other animals [23]. Moreover, bovine abattoirs are the most critical environ-

Historical Review
Parasitism by the genus Taenia in humans predates history. Several investigations have revealed that such interrelationships occurred prior to the domestication of animals and the introduction of agriculture [63]. The conviction that eating the flesh of certain animals may cause illnesses is a concept hailing from 3000BC. For example, Jewish ancient laws prohibited the consumption of meat of certain animals (pork, for instance) due to their awareness of the transmission of cysticercosis [64]. Taxonomy of the larval form, called Cysticercus bovis, originates from the Greek terms "kystic" and "kercos", respectively meaning gallbladder and appendix [65]. However, the relationship between the adult and larval forms of Taenia saginata in bovines was only discovered by Levckart in 1861 after observing the development of cysticerci in calf tissues artificially infected by Taenia saginata proglottids [63]. A revision of Levckart's observations

Bovine Cysticercosis
Bovine cysticercosis is a powerful zoonotic parasite disease causing great economic and health liabilities. Its etiological agent is Cysticercus bovis, the infecting larval form of Taenia saginata [66] [67] [68]. Taenia saginata is the adult cestode which, coupled to the larval form Cysticercus bovis forms the tapeworm-cysticercosis complex with different diseases triggered by the same parasite at different stages of development [69]. Cestodes belong to the class Cestoidea, order Cyclophillidea, family Taeniidae and genus Taenia [70]. Human taeniasis manifests itself clinically and sub-clinically. Symptoms comprise belly aches, nausea, headache, fatigue, slimming, constipation, increase in appetite and diarrhea. In some cases symptoms may be almost imperceptible, except for slight discomfiture caused by the evacuation of the proglottids [63].
Further, cestodes in the small intestine damage the mucus and alter intestine motility. Appendicitis may occur due to the penetration of the proglottids in the appendix or even bronchial obstruction when the proglottids are regurgitated and inhaled [63]. Due to low toxicity, a 90% cure rate is usual. Niclosamida is the most efficient drug in the treatment of taeniasis. However, other drugs, such as Praziquantel, Paramomicina and Mebendazol, are also efficient [35]. In the case of cattle, Albendazole is the main anti-helminth for the treatment of cysticercosis with 86.7% efficiency for the degeneration of cysts [81].

Economic Impact and Control against Bovine Cysticercosis
In Brazil cysticercosis has a very high occurrence rate, with enzootic characteris-  [88].
Liabilities caused by bovine cysticercosis within the beef chain are a great concern to abattoirs, beef industries and stock breeders. Since diagnosis is impractical throughout the breeding process, the detection of the disease occurs during the post-mortem examination and the economic losses caused by total or  [90].
Several measures for the interruption of the parasite's evolution cycle and avoidance of the dissemination of infection by parasites may be found in the Good Practices for Agriculture and Stock Breeding and in the Codex Alimentarius of Brazilian beef production chain [91].
Training workers involved in the production in process makes them aware of the need to adopt basic hygiene habits, such as washing hands after going to the toilette, proper hygiene of fruits and vegetables prior to ingestion, the use of proper sites for human sanitary necessities, correct disposal of excreta, ingestion of cooked beef and supply of food and water to animals in places distant from human dejects-contaminated areas [92]. [90].

R E T R A C T E D
The war on clandestine animal-derived products makes mandatory a politically coercive attitude, even though such policy would be considered unpopular to people who prefer the product in natura and purchased by installments. If

R E T R A
C T E D development programs vis-à-vis small producers are not forthcoming to reallocate them within the market, if educational and consciousness-raising activities remain lacking among consumers, if sanitary supervision and inspection fail to warrant food safety to the population, the issue of clandestine commerce of animal-derived products will not be eliminated in Brazil. In the wake of current paradigms, it may be concluded that the magnitude of clandestine beef commerce in Brazil makes mandatory urgent sanitary measures to protect the population exposed not merely to infections with bovine tuberculosis but also with several other diseases vectored by contaminated milk and beef.

Future Research
Neglected diseases are a worldwide issue in public health. Since the pharmaceutical industries' Research and Development program is exclusively run for profit, the private industrial sector focuses on global diseases and the production and commercialization of products for the generation of profit. Due to their low buying power and lacking political influence, poor patients and ill-equipped health systems fail to generate financial returns required by most profit-minded firms.
Tuberculosis and the taeniasis-cysticercosis complex partake of the group of neglected diseases which affect in a disproportionate way developing countries and with less relative development. Future research on these diseases should give priority to global activities and strategies to enhance innovation in treatments.
Activities should aim at giving priority and enhancement of R&D, establishment and improvement of innovating capacities, promote transference of technology, enable countries to manage and enhance access to intellectual property, ensure mechanisms for sustainable financing, and establish monitoring systems. More attention should be given to funding institutions for medicines involving parasitology since neglected diseases, such as tuberculosis, receive less than 3% of laboratory funds.
One may expect that future research enhances the establishment of a national network which is capable of organizing international integrated R&D projects, including the production of medicines. Brazil has great importance in this field due to the fact that it features several neglected diseases and has a considerable infrastructure for research and production of medicines for these morbidities. Some studies have also been found in the literature that also retrospective evaluation of the evolution of the occurrence of tuberculosis and cysticercosis in certain states and establishments of slaughter, but these were composed of maximum of five years of evaluations. In this study, the long period of 21 years of monitoring of the data provided a greater insight into the behavior of occurrence of both diseases.

Final Considerations
New studies, like this one, will be extremely important in order to be evaluated the epidemiological behavior of both tuberculosis and cysticercosis, in the prophylactic and corrective measures, not ruling out the need for intensification of prophylactic and corrective measures implemented by public agencies, in order to reduce even more these problems. It is also expected that this work will contribute to studies aimed at reducing tuberculosis cases caused by M. bovis and the increased awareness of the influence of man's role in cysticercosis bovine.