**3. Control**

The control of Bovine respiratory disease (BRD) mainly based on therapeutic management because of its multifactorial etology past prophylactic measures, including different vaccination programmes with using both mono- and polyvalent inactivated or modified live vaccines are not sufficiently effective till now. Therefore, at present new advanced, mostly complex - adjunctive therapeutic strategies are widely recommended in order to minimise the economic impact of the respiratory syndrome. According to the generally accepted opinion preferred by Pierre Lekeux (2006), i.e. a very known international expert in this

(RAPD-PCR) found excellent correlation between lung and nasal isolates. The nasal passages of sick animals may provide clues as to what strain is present in the lung (Jared et

In the diagnosis of mycoplasmal infection there are used both microbiological, serological and molecular biology methods. It is worth mentioning that mycoplasmas need specific media (Eaton's or Hayflik's medium) and suitable conditions to grow, i.e. 37ºC and 5% of CO2. Mycoplasma culture methods were also described by Autio et al. (Autio et al., 2007). A characteristic feature of mycoplasmas is their growth on solid media in the form of "fried eggs" (Miles, 1998). Some species of mycoplasmas such as *M. bovis* have the ability to create spot and film reactions and the latest increase their resistance to adverse environmental conditions during culture. In order to diversify the presence of mycoplasmas and bacteria in the material from culture microscope method by Diens's was applied. In this method, mycoplasmal colonies are visible due to their ability to absorb dye (Malinowski & Kłossowska, 2002). Polymerase Chain Reaction (PCR) and its modification - real-time PCR (rt-PCR) are the techniques for identifying mycoplasmas from biological material (Sachse et al. 2010; McAuliffe et al., 2005; Miles et al., 2004; Vasconcellos et al., 2000) but they have some limitations. Technique which is devoid of these limitations is denaturing gradient gel electrophoresis (DGGE) that allows differentiation of sixty seven mycoplasma species from one sample, including thirteen bovine pathogens in this *M. bovis*, *M. dispar*, *M. bovirhinis* and *M. canis* (McAuliffe et al., 2005). However, to detect the presence of anti-mycoplasma antibodies in sera samples

The diagnosis of bacterial infections involved in BRD is based on many species-specific methods, such as conventional bacterial cultivation (Autio et al. 2007, Angen et al., 1998), phenotyping characterization (Angen et al., 2002), indole reaction (Autio et al., 2007) or molecular biology techniques. From the latest a PCR method was applied for main bacterial agents of the syndrome, such as *P. multocida* (Miflin & Blackall 2001), *M. haemolytica* (Angen

In order to identify viral infections in the respiratory syndrome there are used methods detecting the presence of both antigens and specific antibodies. An antigen of some virus species, such as BVDV, BHV1, PIV-3 or BRSV can also be identified using isolation test or Elisa methods (Uttenthal et al., 1996; Autio et al., 2007). From molecular biology techniques to identify the viruses species-specific PCR and rt-PCR methods were applied (Autio et al., 2007; Vilcek et al., 1994). However, the presence of specific anti-viral antibodies in sera samples is possible to detect using Elisa techniques (Anderson et al., 2011) and others.

The control of Bovine respiratory disease (BRD) mainly based on therapeutic management because of its multifactorial etology past prophylactic measures, including different vaccination programmes with using both mono- and polyvalent inactivated or modified live vaccines are not sufficiently effective till now. Therefore, at present new advanced, mostly complex - adjunctive therapeutic strategies are widely recommended in order to minimise the economic impact of the respiratory syndrome. According to the generally accepted opinion preferred by Pierre Lekeux (2006), i.e. a very known international expert in this

there were applied ELISA tests (Ghadersohi, 2005; Bansal et al., 1995).

et al., 2009) or *H. somni* (Angen et al., 1998).

**3. Control** 

al., 2010b).

discipline, the fully effective BRD system of treatment should be included three independent steps and the system could be called as "a three-pillar therapeutic strategy of BRD". The first is an elimination of infectious agents using an appropriate antibacterials, the second is modulation of the pulmonary inflammatory reaction and the third – correction of mechanical and secretolitic lung disorders.

However, directly before undertaking of the treatment due to the economic considerations and potencial reduction of therapeutic costs, the field cases of the syndrome should be classified into four grades: Grade 1, subclinical disease (therapy is usually not necessary); Grade 2, compensated clinical disease (at this stage, the inflammatory reaction generated tends to limit the impact of the disease on the animal, this clinical form of the disease needs mainly antibacterial therapy); Grade 3, noncompensated clinical disease (at this stage, the inflammatory reaction is excessive and must be controlled by additional use of antiinflammatory drugs); Grade 4, irreversible clinical disease (which threatens the animal's survival, this BRD form is not treated because conceivable profitable effects not compensate costs, and affected animals most often die).

The first element of complex therapeutic strategy of BRD aimed quick pathogenic bacteria elimination, particularly these originated from *Pasteurellacae* family (*M. haemolytica, P. multocida, H. somni*) which as important infectious factors participate in the development of pulmonary lesions and dysfunction associated with the syndrome. These bacteria play a crucial role in the pathologic cascade: therefore, the antibiotic must be administered as soon as possible after the induction of the infection, which is most often clinically characterized by hyperthermia, reduced appetite, and nasal discharge. Antibiotic treatment must be initiated before irreversible damage (characterized by oral breathing, orthopnea, lactatemia, and cyanosis) occurs. Among antibiotics presently used most often are administered long acting antibacterials such as some tetracyklines (oxyteracykline), macrolides (florfenicol, tulathromycin, gamythromycin) and fluoroquinolones (enrofloxacin, marbofloxacin, danofloxacin) with a wider antibacterial spectrum included also mycoplasmas (*M. bovis, M. bovirhinis, Ureaplasma diversum*). Significant role of mycoplasma in BRD etiology is not now questioned, and it is especially important because their effective control is very difficult. It is generally known that the mycoplasmas are resistant to beta-lactames and cephalosporins because of the lack of cell wall. The same resistance can be observed to nalidixic acid, polymyxin, rifamycin, tylosin, lincomycin, tylmicosin, trimethoprim and to sulfonamides (Poumarat *et al*., 1996; Ayling *et al*., 2007). Therefore, in this case there are intensively searching new more effective generations of antibiotics against mycoplasma infection. The most important mycoplasmal etiological agent in BRD i.e. *M. bovis* as other mycoplasmas is sensitive to antibiotics, which inhibit the protein or nucleic acid synthesis. Recently, in cattle respiratory treatment there are recommended antibiotics which were only applied in swine medicine i.e. pleuromutilins (tiamulin, valnemulin). At present it is known too, that tiamulin has also excellent activity against cattle mycoplasmas like *M. bovis*. In addition an analog compound of tiamulin is valnemulin, which has proven to be affective in the control *M. bovis* infection under field conditions (Stipkovits *et al*., 2001; Tenk, 2005).

Recently, new antibiotic-treatment conceptions of BRD have been presented during the first European Buiatrics Forum in Marseille (2009). There were described three independent conceptions which in shortening forms are called as SISAAB, SILAAB and MILAAB. The

Bovine Respiratory Syndrome (BRD) Etiopathogenesis, Diagnosis and Control 371

mg/k b.w. *i.v.*), carprofen (1.4 mg/kg b.w. *i.v., s.c.*), ketoprofen (3 mg/kg b.w. *i.v., i.m.*), meloxicam (0.5 mg/kg b.w. *s.c., i.v.*), tolfenamic acid (2 mg/kg b.w. *i.m.*), metamisole

In the most severe cases of BRD, a short-acting steroidal anti-inflammatory drug, bronchodilator, and diuretic could be added to the NSAID when pulmonary fulminating infalammation, bronchospasm, and edema are present, respectively. These additional supparative drugs i.e. bronchodilators and diuretics are included into the third component of the complex therapeutic strategy of BRD. Among bronchodilators mostly atropine sulfate (cholinolitics) and theophylline (methylxanthines) are administered. The first of them is classified as an anticholinergic drug (parasympatholytic). In general, atropine lowers the parasympathetic activity of all muscles and glands regulated by the parasympathetic nervous system. This occurs because atropine is a competitive antagonist of the muscarinic acetylcholine receptors (acetylcholine being the main neurotransmitter used by the parasympathetic nervous system). Therefore, it may cause bronchictasis and reduced secretions salivary, sweat, and mucus glands. As adjuncts in BRD therapy atropine sulfate 1% is recommended by Lekeux (2002) once a day for three consecutive days at a dose of 0.06 mg/kg b.w. s.c. Theophylline, also known as dimethylxanthine, as a methylxanthine drugs is rarely administered in cattle practice against bronchoconstriction in course of BRD mostly intramuscularly or slowly intravenously at a dose of 1-10 mg/kg b.w. However, it is recommended in veterinary medicine as bronchodilators in adjuntive therapy for respiratory diseases such as BRD, COPD in horses and feline asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it bears structural and pharmacological

On the other hand within the veterinary diuretics mostly in calves suffering from severe form of BRD caused with pulmonary edema is furosemide (1 mg/kg b.w. i.v.). Furosemide (INN) or frusemide (former BAN) is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix. It has also been used to prevent Thoroughbred and Standardbred race horses from

It should be remember that very important is also to use expectorants (mucolitic drugs) like bromhexine hydrochloride (bromhexine HCl) in order to inflammatory mucose evacuation from the obturated respiratory airways. Bromhexine is a mucolytic agent used in the treatment of respiratory disorders associated with viscid or excessive mucus. In addition, bromhexine has antioxidant properties (Morton, 1999). Bromhexine supports the body's own natural mechanisms for clearing mucus from the respiratory tract. It is secretolytic: that is, it increases the production of serous mucus in the respiratory tract and makes the phlegm thinner and less sticky. This contributes to a secretomotoric effect: it helps the cilia - tiny hairs that line the respiratory tract - to transport the phlegm out of the lungs. For this reason at present it is generally recommended as a adjunct in the complex therapy of BRD. In clinical studies, bromhexine showed secretolytic and secretomotoric effects in the bronchial tract area which facilitates expectoration and eases cough. It is indicated as "secretolytic therapy in bronchopneumonia of calves associated with abnormal mucus secretion, impaired mucus transport and bromhexine has also antiinflammatory properties"

sodium (10 – 50 mg/kg b.w. i.m., i.v.).

similarity to caffeine.

bleeding through the nose during races.

first of them means: Single Injection Shot Acting AntiBiotic among others things represented by new formulations of fluoroquinolones like Marbocyl S (marbofloxacin 100 mg/ml, administered at a single dose of 8 mg/kg b.w. *i.m.*), Baytril One or Enroxil Max (enrofloxacin 100 mg/ml, administered at a single dose of 7.5 mg/kg b.w. *s.c.*). Moreover, also long acting tetracyclines (Tetradur) could be administered here in a form of single intramuscular injections. The second conception is Single Injection Long Acting AntiBiotic represented by new generations of macrolides such as tultromycin (Draxxin) and gamytromycin (Zactran), and also the third one i.e. Multiple Injection Long Acting AntiBiotic which however is considered to be a little controversial conception due to take real risks of antibiotic-resistance increasing.

In the complex of advanced therapeutic strategy of BRD the second its component is the modulation of pulmonary inflammatory reaction. In this aspect, at present there are use anti-inflammatory medicines originated from both steroidal (SAIDs) and non-steroidal antiinflammatory drugs (NSAIDs) (Lekeux, 2006). Steroids are powerful anti-inflammatory agents, but their effects on the animal's defensive machanisms reduce the value of their use in syndromes of infectious origin unless they have a short duration of action or are administered locally. Generally the drugs stabilise cellular and lysosomal membranes and thereby inhibit release of the chemical pro-inflammatory mediators and proteolytic enzymes. Other steroidal effects include inhibition of antibody synthesis; suppression of activity of fibroblasts; elevation of circulating neutrophil count and reduction in eosinophil count. Steroids also increase microvascular tone and decrease permeability thus reducing exudation and oedema formation. In BRD adjunctive therapy there were used different kinds of corticosteroids include betamethasone (2-10 mg/animal), dexamethasone (2-5 mg/animal), prednisolone (up to 20 mg/animal), cortisone (up to 500 mg/animal), hydrocortisone (up to 300 mg/animal), flumethasone (0.5 mg/animal) and trimcinolone (up to 5 mg/animal). The drugs because of their strong immunosupresive character were usually use only in a single administration throughout of the therapy.

In contrast to steroids, which reduce the yield of all products of arachidonic acid cascade, nonsteroidal anti-inflammatory drugs (NSAIDs) have a narrower anti-inflammatory spectrum, acting as inhibitors of cyclooxygenase. However, NSAIDs have a wider safety margin, which largely compensates for their narrower spectrum. NSAIDs act principally to inhibit the biosynthesis of prostaglandins. They also inhibit kallikrein activity and kinin formation and at the same time pharamacologically antagonise the tissue effects of kinins, prostaglandins and slow-reacting substance of anaphylaxis (SRS-A). NSAIDs are, with some exceptions, analgesic and antipyretic: effects not shown by steroids. Apart from that NSAIDs have also the ability to improve gas exchange what it has been shown in pneumonic calves in experimental conditions (Van de Weerdt *et al*, 1999). The benefits of NSAIDs therapy in bovine respiratory disease have also been demonstrated multiple in a field study (Bednarek *et al*, 2003; Bednarek *et al*, 2004; Lockwood *et al* 2003; Weingarten, 2009).

NSAIDs should be administered to animals at grade 3 of severity, which is mainly characterized by hyperthermia, anorexia, and dyspnea. NSAIDs act rapidly in the pneumonic lung, so the modulation of inflammation and the resulting improvement in the clinical status should follow quickly in the absence of irreversible damages (Lekeux, 2006). The drugs most commonly used in BRD therapy in Europe are flunixin meglumine (2.2

first of them means: Single Injection Shot Acting AntiBiotic among others things represented by new formulations of fluoroquinolones like Marbocyl S (marbofloxacin 100 mg/ml, administered at a single dose of 8 mg/kg b.w. *i.m.*), Baytril One or Enroxil Max (enrofloxacin 100 mg/ml, administered at a single dose of 7.5 mg/kg b.w. *s.c.*). Moreover, also long acting tetracyclines (Tetradur) could be administered here in a form of single intramuscular injections. The second conception is Single Injection Long Acting AntiBiotic represented by new generations of macrolides such as tultromycin (Draxxin) and gamytromycin (Zactran), and also the third one i.e. Multiple Injection Long Acting AntiBiotic which however is considered to be a little controversial conception due to take

In the complex of advanced therapeutic strategy of BRD the second its component is the modulation of pulmonary inflammatory reaction. In this aspect, at present there are use anti-inflammatory medicines originated from both steroidal (SAIDs) and non-steroidal antiinflammatory drugs (NSAIDs) (Lekeux, 2006). Steroids are powerful anti-inflammatory agents, but their effects on the animal's defensive machanisms reduce the value of their use in syndromes of infectious origin unless they have a short duration of action or are administered locally. Generally the drugs stabilise cellular and lysosomal membranes and thereby inhibit release of the chemical pro-inflammatory mediators and proteolytic enzymes. Other steroidal effects include inhibition of antibody synthesis; suppression of activity of fibroblasts; elevation of circulating neutrophil count and reduction in eosinophil count. Steroids also increase microvascular tone and decrease permeability thus reducing exudation and oedema formation. In BRD adjunctive therapy there were used different kinds of corticosteroids include betamethasone (2-10 mg/animal), dexamethasone (2-5 mg/animal), prednisolone (up to 20 mg/animal), cortisone (up to 500 mg/animal), hydrocortisone (up to 300 mg/animal), flumethasone (0.5 mg/animal) and trimcinolone (up to 5 mg/animal). The drugs because of their strong immunosupresive character were

In contrast to steroids, which reduce the yield of all products of arachidonic acid cascade, nonsteroidal anti-inflammatory drugs (NSAIDs) have a narrower anti-inflammatory spectrum, acting as inhibitors of cyclooxygenase. However, NSAIDs have a wider safety margin, which largely compensates for their narrower spectrum. NSAIDs act principally to inhibit the biosynthesis of prostaglandins. They also inhibit kallikrein activity and kinin formation and at the same time pharamacologically antagonise the tissue effects of kinins, prostaglandins and slow-reacting substance of anaphylaxis (SRS-A). NSAIDs are, with some exceptions, analgesic and antipyretic: effects not shown by steroids. Apart from that NSAIDs have also the ability to improve gas exchange what it has been shown in pneumonic calves in experimental conditions (Van de Weerdt *et al*, 1999). The benefits of NSAIDs therapy in bovine respiratory disease have also been demonstrated multiple in a field study (Bednarek *et al*, 2003; Bednarek

NSAIDs should be administered to animals at grade 3 of severity, which is mainly characterized by hyperthermia, anorexia, and dyspnea. NSAIDs act rapidly in the pneumonic lung, so the modulation of inflammation and the resulting improvement in the clinical status should follow quickly in the absence of irreversible damages (Lekeux, 2006). The drugs most commonly used in BRD therapy in Europe are flunixin meglumine (2.2

usually use only in a single administration throughout of the therapy.

*et al*, 2004; Lockwood *et al* 2003; Weingarten, 2009).

real risks of antibiotic-resistance increasing.

mg/k b.w. *i.v.*), carprofen (1.4 mg/kg b.w. *i.v., s.c.*), ketoprofen (3 mg/kg b.w. *i.v., i.m.*), meloxicam (0.5 mg/kg b.w. *s.c., i.v.*), tolfenamic acid (2 mg/kg b.w. *i.m.*), metamisole sodium (10 – 50 mg/kg b.w. i.m., i.v.).

In the most severe cases of BRD, a short-acting steroidal anti-inflammatory drug, bronchodilator, and diuretic could be added to the NSAID when pulmonary fulminating infalammation, bronchospasm, and edema are present, respectively. These additional supparative drugs i.e. bronchodilators and diuretics are included into the third component of the complex therapeutic strategy of BRD. Among bronchodilators mostly atropine sulfate (cholinolitics) and theophylline (methylxanthines) are administered. The first of them is classified as an anticholinergic drug (parasympatholytic). In general, atropine lowers the parasympathetic activity of all muscles and glands regulated by the parasympathetic nervous system. This occurs because atropine is a competitive antagonist of the muscarinic acetylcholine receptors (acetylcholine being the main neurotransmitter used by the parasympathetic nervous system). Therefore, it may cause bronchictasis and reduced secretions salivary, sweat, and mucus glands. As adjuncts in BRD therapy atropine sulfate 1% is recommended by Lekeux (2002) once a day for three consecutive days at a dose of 0.06 mg/kg b.w. s.c. Theophylline, also known as dimethylxanthine, as a methylxanthine drugs is rarely administered in cattle practice against bronchoconstriction in course of BRD mostly intramuscularly or slowly intravenously at a dose of 1-10 mg/kg b.w. However, it is recommended in veterinary medicine as bronchodilators in adjuntive therapy for respiratory diseases such as BRD, COPD in horses and feline asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it bears structural and pharmacological similarity to caffeine.

On the other hand within the veterinary diuretics mostly in calves suffering from severe form of BRD caused with pulmonary edema is furosemide (1 mg/kg b.w. i.v.). Furosemide (INN) or frusemide (former BAN) is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix. It has also been used to prevent Thoroughbred and Standardbred race horses from bleeding through the nose during races.

It should be remember that very important is also to use expectorants (mucolitic drugs) like bromhexine hydrochloride (bromhexine HCl) in order to inflammatory mucose evacuation from the obturated respiratory airways. Bromhexine is a mucolytic agent used in the treatment of respiratory disorders associated with viscid or excessive mucus. In addition, bromhexine has antioxidant properties (Morton, 1999). Bromhexine supports the body's own natural mechanisms for clearing mucus from the respiratory tract. It is secretolytic: that is, it increases the production of serous mucus in the respiratory tract and makes the phlegm thinner and less sticky. This contributes to a secretomotoric effect: it helps the cilia - tiny hairs that line the respiratory tract - to transport the phlegm out of the lungs. For this reason at present it is generally recommended as a adjunct in the complex therapy of BRD. In clinical studies, bromhexine showed secretolytic and secretomotoric effects in the bronchial tract area which facilitates expectoration and eases cough. It is indicated as "secretolytic therapy in bronchopneumonia of calves associated with abnormal mucus secretion, impaired mucus transport and bromhexine has also antiinflammatory properties"

Bovine Respiratory Syndrome (BRD) Etiopathogenesis, Diagnosis and Control 373

must ensure absence of other potential contaminats, both viral and other pathogens. Subsequently, modified live intranasal vaccines have been available (eg. Rispoval RS+PI3 IntraNasal). Till now numerous studies have demonstrated that immunization calves via the intranasal route not only is most effective and it gives active immunity in very young animals despite maternal antibodies, it also generates a significant systemic response and interferon induction (Stokes, 2006). Given the relative ease of antigen delivery and the organization of the local lymphoid tissue (MALT), intranasal immunization offers attractive possibilities. However, to successfully achieve this there are a number of obstacles that have to be overcome. For example in the context of IBR vaccination, sometimes, although good immunity was conferred to animals by modified live vaccination, it was shown that some

In multifactorial etiology of BRD at present there is also valued the role of mycoplasmal infectious agents. Therefore, many scientific centers all over the world try to produce suitable vaccines mainly against the most important mycoplasma i.e. *M. bovis*. Till now in Europe the saponin inactivated vaccine has been produced in the UK (by The Mycoplsma Group, AHVLA in Webridge), but it has had only limited success experimentally. The inactivated vaccine containing saponin-killed cells was shown to be safe, highly immunogenic and protective against a strong experimental challenge with virulent *M. bovis* (Nicholas *et al*., 2002). Vaccinated calves showed few respiratory signs while all unvaccinated calves developed signs of pneumonia. Moreover, vaccination gave a statistically significant degree of protection against pyrexia, lung lesions and loss of body weight. The vaccine also reduced the spread of *M. bovis* to internal organs, including the joints. This vaccine is now under commercial development and AHVLA (Weybridge) has a licence to produce this as an autogenous vaccine in the UK. Therefore, practically no commercial vaccines currently exist for *M. bovis* in Europe. Various commercial vaccines, including autogenous preparations, are available in the USA; however there is no published

Recapitulating, the control of the Bovine respiratory syndrome is essential to maintain the profitability of most intensive bovine ventures, and veterinary practitioners have the opportunity to play an important role in this effort. Preventive and therapeutic measures must be adapted to the type of production operation, the specific features associated with the individual animal, the environment and the pathogens, the availability of drugs, and the

Adamu, J.Y. (2007): *Mannheimia haemolytica*: phylogeny and genetic analysis of its major

Anderson, S.; Wakeley, P.; Wibberley, G.; Webster, K. & Sawyer, J. (2011). Development and

Andrews A.H. (2004): Calf respiratory diseases. In: *Bovine medicine*, edited by Andrews A.

evaluation of a Luminex multiplex serology assay to detect antibodies to bovine herpes virus 1, parainfluenza 3 virus, bovine viral diarrhea virus, and bovine respiratory syncytial virus, with comparison to existing ELISA detection methods. *J* 

cattle became carriers after exposure to field strains of BHV.

virulence factors. *Isr J Vet Med*, 62, pp. 6-13

H., ISBN 0-632-05596-0, Oxford, UK, pp. 239-248

*Immunol Methods,* 366, pp. 79-88

evidence to support their effectiveness.

state of the art in science.

**4. References** 

(Bednarek & Kondracki, 2002). Bromhexine also enhances mucus transport by reducing mucus viscosity and by activating the ciliated epithelium. Bromhexine is contained in various formulations (high and low strength syrups, tablets intended mainly for companies animals), however in cattle practice the most useful form is injectable preparation (Eres, Bisolvon, Bisolvomicin, Flegamina) recommended in affected calves at a dose of 0.5 mg/kg b.w. *i.m.* for 5 to 7 consecutive days. Bromhexine is a well established and well tolerated product in its indication.

Other expectorants have been used too in chronic cases of coughing in course of BRD (Andrews, 2004). These include a mixture of strychnine hydroxide, arsenic trioxide and ferric ammonium citrate given at a dose of about 5 ml orally twice daily, or diphenhydramine hydrochloride, ammonium chloride, sodium citrate and menthol at 5-10 ml orally two or three times daily. There is limited benefit form the antihistaminic action of diphenhydramine hydrochloride in cases of calf pneumonia. This resent indication has been accepted too but many clinicians consider that using antihistamines is a little effective in calf bronchopneumonia. This is probably because the main proinflammatory mediator of cattle is not histamine like and human and other mammals but 5-HT (5-hydroxytryptamine). The histamine that is released occurs very quickly following the antibody-antigen reaction so that antihistamines can only be of use in the early stages of the inflammatory response. Among of the drugs in USA recently for the large animal medicine (horses, cattle) are used tripelennamine hydrochloride at a dose of 1 mg/kg b.w. *i.m.* once a day (Divers, 2011). The dose may be repeated in 6 to 12 hours if necessary.

Presented above the basic principles and drugs used for the optimal therapeutic strategy of BRD especially within Grade 3 of the disease are very important to maintain the profitability of cattle breading. This strategy is a combination of an antibiotic acting against the relevant pathogens (eg. florfenicol) and an NSAID acting against the deleterious effects of inflammation (eg, flunixin) additionally supported by the correctors of mechanical and secretolitic lung disorders (Expectorants, bronchodilators). This strategy were confirmed by several experimental and field tests showing an improvement of clinical signs and a reduction of pulmonary dysfunction and lung consolidation in animals receiving such a combined therapy.

In the complex control measures of BRD should be added too about prevention using vaccination programmes. There are various vaccines available both live or attenuated consist of only one or a few bacterial or/and viral antigens. Dead vaccines are used to provide immunity against *P. multocida* and septicemic and pneumonic strains of *M. haemolytica* and *H. somni* (eg, Hiprabovis pneumos, Pastobov, Bovilis Bovipast). Killed or modified live polyvalent vaccines are used in many countries and also in Poland, and contain antigens such as BRSV, PI3 (Rispoval, Bovilis Bovipast), BVDV (Mucosiffa, Bovilis BVD) and BHV1. Recently the last presented antigen is widely utilized in the construction of so-called marker vaccines both live (eg, Rispoval-IBR marker vivum, Hiprabovis-IBR marker live) and inactivated (eg, Ibraxion, Rispoval-IBR-marker inactivatum, Bovilis IBR – marker inactivatum) applied in IBR eradication based on DIVA system i.e. **D**ifferentiating **I**nfected from **V**accinated **A**nimals. The vaccines are usually administered parenterally and usually require two injections to produce immunity. Recent developments have included combined live and dead viral components of the four main antigens which are injected intramuscularly (eg, Rispoval 3). When live vaccines are used, the integrity of the vaccine must ensure absence of other potential contaminats, both viral and other pathogens. Subsequently, modified live intranasal vaccines have been available (eg. Rispoval RS+PI3 IntraNasal). Till now numerous studies have demonstrated that immunization calves via the intranasal route not only is most effective and it gives active immunity in very young animals despite maternal antibodies, it also generates a significant systemic response and interferon induction (Stokes, 2006). Given the relative ease of antigen delivery and the organization of the local lymphoid tissue (MALT), intranasal immunization offers attractive possibilities. However, to successfully achieve this there are a number of obstacles that have to be overcome. For example in the context of IBR vaccination, sometimes, although good immunity was conferred to animals by modified live vaccination, it was shown that some cattle became carriers after exposure to field strains of BHV.

In multifactorial etiology of BRD at present there is also valued the role of mycoplasmal infectious agents. Therefore, many scientific centers all over the world try to produce suitable vaccines mainly against the most important mycoplasma i.e. *M. bovis*. Till now in Europe the saponin inactivated vaccine has been produced in the UK (by The Mycoplsma Group, AHVLA in Webridge), but it has had only limited success experimentally. The inactivated vaccine containing saponin-killed cells was shown to be safe, highly immunogenic and protective against a strong experimental challenge with virulent *M. bovis* (Nicholas *et al*., 2002). Vaccinated calves showed few respiratory signs while all unvaccinated calves developed signs of pneumonia. Moreover, vaccination gave a statistically significant degree of protection against pyrexia, lung lesions and loss of body weight. The vaccine also reduced the spread of *M. bovis* to internal organs, including the joints. This vaccine is now under commercial development and AHVLA (Weybridge) has a licence to produce this as an autogenous vaccine in the UK. Therefore, practically no commercial vaccines currently exist for *M. bovis* in Europe. Various commercial vaccines, including autogenous preparations, are available in the USA; however there is no published evidence to support their effectiveness.

Recapitulating, the control of the Bovine respiratory syndrome is essential to maintain the profitability of most intensive bovine ventures, and veterinary practitioners have the opportunity to play an important role in this effort. Preventive and therapeutic measures must be adapted to the type of production operation, the specific features associated with the individual animal, the environment and the pathogens, the availability of drugs, and the state of the art in science.
