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Bordetella bronchiseptica infections

Bordetella bronchiseptica infections

M-L PENRITH AND M M HENTON

GENERAL INTRODUCTION: GRAM-NEGATIVE AEROBIC OR CAPNOPHILIC RODS AND COCCI

Introduction

Infection with Bordetella bronchiseptica has been associated with disease in a number of species, but the most important animal diseases caused by this bacterium are non-progressive atrophic rhinitis in pigs and kennel cough in dogs.47 Bordetella bronchiseptica has also been implicated in lower respiratory tract disease29 and haematogenous septic arthritis48 in foals, as well as in respiratory disease in horses, especially following surgery.72

The first isolates of B. bronchiseptica obtained from pigs emanated from cases of bronchopneumonia.25, 46, 68 The organism is relatively unimportant as an agent of pneumonia in pigs, although it has occasionally been recorded as the primary pathogen in bronchopneumonia in young piglets and more often as a secondary pathogen.25 Experimental infection resulted in pneumonia in five-day-old piglets in the absence of any other agents,41 as well as in nine-day-old caesarean-derived piglets.37 It was first isolated from the nasal cavity of pigs with atrophic turbinates in 1956,65 and its ability to produce turbinate atrophy was demonstrated. As a result, it was considered to be the primary agent of atrophic rhinitis in pigs by some authors.66 Severe atrophic rhinitis, however, was produced only by combined infection with toxigenic strains of Pasteurella multocida and B. bronchiseptica. 57, 58 It is currently accepted that progressive atrophic rhinitis (PAR) is caused by toxigenic strains of P. multocida, but that colonization of the nasal mucosa by B. bronchiseptica is the most important predisposing factor for the development of PAR.19, 25 A complex interaction between B. bronchiseptica and P. multocida may be necessary to cause PAR.23 However, a field outbreak of severe progressive atrophic rhinitis caused by toxigenic P. multocida in the absence of B. bronchiseptica has been reported.59 Infection with B. bronchiseptica alone can cause acute rhinitis in young piglets, accompanied by varying degrees of turbinate hypoplasia, which appears to resolve if not complicated by infection with toxigenic P. multocida.17

Bordetella bronchiseptica infection of pigs and other species occurs worldwide. During the past decade at the Onderstepoort Veterinary Institute in South Africa, 74 per cent of approximately 50 isolates emanated from pigs, 12 per cent from dogs, 6 per cent from rodents, 4 per cent from rabbits, and 2 per cent each from goats and ostriches. Atrophic rhinitis yielded 73 per cent of the pig samples, pneumonia 24 per cent, and nephritis 3 per cent.28

Aetiology

Bordetella bronchiseptica organisms are Gram-positive, motile rods or coccobacilli. Other characteristics are that they are aerobic, urease positive, do not ferment carbohydrates, and use citrate.25 Sixteen ribotypes have been identified in a study using the restriction enzyme PvuII.52 In that study, 88 per cent of the pig isolates analysed belonged to ribotype 3. Refinement of the technique resulted in the identification of three more ribotypes, designated 17, 18 and 19.54, 55 There are four phase variations, I to III and a rough phase. Phase I organisms are encapsulated, capable of attaching to pig nasal epithelial cells, and pathogenic.36 Flagella are characteristic of the avirulent phenotype.45 Culture conditions can modify colony morphology and antigenic expression.33 Capsule formation is inhibited by sulphonamides that contain methoxy groups but not by other sulphonamides.36 A single genetic locus is responsible for the expression of most of the factors considered to be responsible for virulence of Bordetella.49, 73 This locus also regulates flagellin gene transcription.2

Epidemiology

Bordetella bronchiseptica is widely prevalent in pigs and may be isolated from nasal swabs of healthy piglets as well as those with clinical rhinitis,25 and its prevalence may not differ between herds with and without clinical signs of atrophic rhinitis.38 According to estimates based on culture of nasal swabs, up to 50 per cent of herds in the USA may be infected, although the number of pigs infected per herd is closer to 10 per cent.25 Serological surveys usually indicate a higher prevalence rate,25 since these include pigs that are no longer positive on culture.

Transmission from pig to pig is usually by aerosol droplets. Sows that carry the organism in their nasal cavities are an important source of infection for their litters. Virulent strains have been isolated from the air of pig houses and have proven capable of colonizing the nasal mucosa and inducing rhinitis and pneumonia in piglets.62, 63 Pigs can be infected at any age, but clinical signs commonly develop only in young piglets under six weeks of age, either in suckling piglets infected by their dams or in recently weaned piglets that become infected when litters are mixed. The prevalence of infection generally reaches a peak when piglets are about 12 weeks old, but signs and lesions in the late weaning and fattening periods are few.25

Carrier pigs are presumed to be the source of infection for clean herds. The role played by other species such as cats and rodents, from which strains of B. bronchiseptica may be isolated, is dubious. Only porcine strains have been demonstrated to cause severe damage25 although strains isolated from other species have been used to induce a mild degree of turbinate hypoplasia in pigs experimentally.56

Multiple management factors may influence susceptibility or resistance to B. bronchiseptica and thus infection with the organism and P. multocida.20 These include immunization programmes that induce a high level of immunity in the sows and all-in-all-out management of weaner houses, as well as factors such as environment temperature and ventilation.

Pathogenesis

Bordetella bonchiseptica possesses a variety of virulence factors. 49 As most, if not all, of these are encoded by a single gene, bvg, it has proven difficult to separate the functions of the different toxins, adhesins and other virulence factors.49 Nevertheless, experimental studies have demonstrated the role that some of the factors play in the pathogenesis of bordetellosis in pigs. Certain survival factors, such as the transferrin- and lactoferrin-binding proteins of B. bronchiseptica, and an acid phosphatase that affects intracellular survival, may not be encoded by the bvg locus.10, 40

Colonization of the nasal mucosa of pigs is essential for the development of the lesions of turbinate hypoplasia. Preferential attachment to, and invasion of, ciliated cells of the respiratory epithelium, resulting in loss of cilia, has been demonstrated.1, 37 The ability of B. bronchiseptica to colonize epithelium is an important predisposing factor for infection with toxigenic strains of P. multocida, as it enhances adherence of P. multocida.15, 19 The key factor for adherence is probably stagnation of the nasal epithelium, which can also be induced by acetic acid, and possibly environmental factors such as hydrogen sulphide and ammonia.24, 26 Bordetella bronchiseptica produces a low molecular weight glycopeptide, tracheal cytotoxin, that is ciliostatic and causes extrusion of ciliated cells in vitro.15 Colonization by B. bronchiseptica is confined to the ciliated epithelium, and the bacteria do not penetrate more deeply into the underlying tissue.7 A haemagglutinin located on the surface of Phase I organisms that is able to bind sialic acid is considered to be responsible for adherence to nasal epithelium, which is a prerequisite for colonization.32 A study in HeLa cells suggested that filamentous haemagglutinin (FHA) is the major adhesin.61

However, another study demonstrated a high level of adhesion in the absence of FHA and pertactin, and suggested that another adhesin, expressed only by modulated bvg+ strains, might be a key factor for initial colonization.50 The role of both fimbriae and flagella in adherence to eukaryotic cells has not been fully elucidated.60 Fimbriae may not be necessary for adherence,61 although they may play a role in host specificity.9

The pathogenic effects of B. bronchiseptica are attributed to the activity of a dermonecrotic toxin (DNT).34, 49 Severe effects on bone formation, including periosteal necrosis and degeneration of osteoblasts, and thinning and fragmentation of the bone matrix, have been reported after injection of DNT.31 It is believed that DNT elicits inhibition of osteoblastic differentiation by activation of the small GTP-binding protein Rho, in contrast to the toxin of P. multocida, which apparently exerts its effect on Rho indirectly through activation of phospholipase C.44 Atrophy of the spleen with concomitant loss of immune competence has been attributed to the action of DNT30 which is also considered to contribute to the development of lung lesions.49 Early lesions of necrotic vasculitis suggest that vascular changes may be responsible for pneumonia.16

Infection with B. bronchiseptica elicits IgG and IgA antibodies that are present in both serum and nasal secretions. 20, 35 It has been suggested that a strong immune response results in mucosal immunity that eliminates and/or antigenically modulates highly virulent bacteria.20 Various strategies of B. bronchiseptica to evade immune clearance mechanisms and establish infection have been identified. The ability of B. bronchiseptica to adhere to porcine alveolar macrophages, to survive intracellularly when phagocytosed, and to kill the macrophages has been demonstrated. 8, 22 This ability is restricted to certain phenotypes and depends on various factors, including temperature during growth; cytotoxicity is apparently restricted to bvg+ bacteria.8, 22 Phagocytosis of B. bronchiseptica by porcine neutrophils, which may aid spread, is mediated by more than one adhesion mechanism, some of which depend upon CD18 and the availability of carbohydrates.51

Clinical signs

Clinical signs are usually seen in young piglets. Signs may develop in piglets as young as a week old, and often a whole litter is infected. However, clinical disease most frequently occurs about a week after weaning, and is therefore most prevalent at four to six weeks of age. The signs are typical of rhinitis and consist of sneezing, snuffling and snorting, with a serous to often mucopurulent nasal discharge. There is usually only slight to moderate loss of appetite, and affected piglets are lively and alert.

Rarely, infection may result in bronchopneumonia, usually in piglets less than a week old. Coughing, sometimes with whooping, and dyspnoea may be observed. Signs of fever are not a characteristic of the disease,66 but untreated piglets may die. Entire litters are often affected.

Pathology

Catarrhal rhinitis that may be accompanied by varying degrees of turbinate hypoplasia is the most important gross lesion. As in progressive atrophic rhinitis caused by toxigenic P. multocida, the ventral scroll of the ventral turbinate is the first to be affected, and it may be slightly reduced or distorted to completely absent. In more severe cases the dorsal scroll and the dorsal turbinates are also involved. Histologically, the epithelium is hyperplastic to metaplastic, with loss of cilia and flattening and stratification of the cells, accompanied by an infiltrate consisting of neutrophils and mononuclear cells. Fibroblasts may be evident in the lamina propria. The osseous trabeculae of the terminate may be reduced in size, with replacement fibrosis, an increased number of osteoblasts, and very few osteoclasts.17, 66 Regeneration of atrophic turbinates five months after experimental infection at the age of three days has been reported, as well as possibly more rapid regeneration in pigs infected at four weeks. Various distortions of the regenerated turbinates were, however, present.17

Infection of the lungs is characterized by a lobular pneumonia that affects mainly the cranial and middle lobes. Lesions are initially dark red, but become brown to yellowish brown and sunken over time.25 Microscopically, necrosis of the walls of some blood vessels is evident, haemorrhage, oedema and necrosis occur in alveolar walls, and bronchioles contain neutrophilic exudate. In the acute stages of the disease, there is marked infiltration of neutrophils. Later stages are characterized by epithelialization and fibrosis, and alveoli may contain large alveolar macrophages.16, 41

Diagnosis

Infection with B. bronchiseptica is confirmed by isolation of the organism from nasal swabs and other relevant tissue samples, e.g. lung in cases of pneumonia. Lung lavage also yields suitable samples.13, 21 Amplified ribosomal DNA restriction analysis (ARDRA) can distinguish between the different species of Bordetella,71 while randomly and repetitive element-primed polymerase chain reaction can not only distinguish between B. avium and B. bronchiseptica, but also detects several intraspecific types. The 16S ribosomal RNA gene may also be used to construct oligonucleotide probes to detect B. bronchiseptica.67 A colony lift-hybridization assay has proved to be more sensitive than conventional methods of detection, and is equally specific, and permits simultaneous detection of B. bronchiseptica and toxigenic P. multocida.53 Antibodies against B. bronchiseptica are usually detected by means of an enzyme-linked immunosorbent assay (ELISA). An ELISA that detects IgG and IgA antibodies in serum and nasal secretions has been described.35

Differential diagnosis

Rhinitis caused by porcine cytomegalovirus is the most important differential diagnosis in young piglets (see Suid herpesvirus 2 infection). Although older piglets tend to be affected by toxigenic P. multocida, the clinical signs of the two diseases are indistinguishable. Piglets may also sneeze and snuffle if the environment or the feed is dusty.

Pneumonia in pigs has many causes, most of which are more common than B. bronchiseptica. Isolation of B. bronchiseptica in the absence of other organisms that commonly cause pneumonia in pigs (P. multocida, Actinobacillus pleuropneumoniae, Mycoplasma hyopneumoniae being the most frequent causes) will serve to implicate it as a primary or secondary pathogen.

Control

Antimicrobial treatment may be used to control clinical rhinitis caused by B. bronchiseptica. Various studies have demonstrated that isolates from pigs are usually sensitive to colistin, neomycin, gentamicin, trimethoprim-sulfamerazine, chloramphenicol, oxytetracycline, nalidixic acid, enrofloxacin, and sulphonamides, but variably resistant to penicillins, clindamycin, lincomycin, lincospectin, ampicillin, streptomycin, and several sulphonamides.3, 36, 64, 70, 74 In one study tilmicosin administered in feed did not result in elimination of B. bronchiseptica infection, but did lower the rate of infection.6 Lipopolysaccharide plays an important role in resistance of B. bronchiseptica to antimicrobial substances, owing to the presence of highly charged O-specific side chains.4

Vaccination has proved more effective in controlling clinical disease caused by B. bronchiseptica than in preventing infection.18, 49 Efficacy may be impaired by heavy challenge and mixing of vaccinated and unvaccinated pigs.18 Immunogenicity has been attributed to toxoids prepared from inactivated DNT34 as well as to bacterins prepared from phase I strains regardless of their potential for cytotoxicity.39 Experimental vaccination with a vaccine comprising cell-free antigen obtained from culture supernatant of B. bronchiseptica and an oil adjuvant gave excellent protection against the development of turbinate atrophy.43 Adverse reactions to vaccination with commercially available vaccines, including vomiting, respiratory distress, and death, have been reported. 5, 69 Combination vaccines against B. bronchiseptica and P. multocida are usually used: vaccination with a commercial vaccine containing inactivated B. bronchiseptica and the DNT of P. multocida Type D achieved the best immunity when gilts were given two primary injections before parturition followed by a booster before subsequent parturitions.42

An all-in-all-out system, particularly in the weaner house, assists in controlling infection. When this is not practised, infection with B. bronchiseptica may become endemic owing to constant transmission from infected pigs to new batches of susceptible pigs.25 Medicated early weaning managemental systems have proved to be efficacious in preventing transmission of B. bronchiseptica, but they may not achieve eradication.11, 12

A holistic approach that includes vaccination, reducing stocking density, and good hygiene can result in a marked decrease in clinical disease and pathological lesions,7 although it may not necessarily result in eradication. Antimicrobial prophylaxis may be included in such programmes.27 Because B. bronchiseptica occurs widely, usually causes only mild disease if any, and is difficult to eliminate completely, eradication may not be justified, and a more logical approach to prevention of progressive atrophic rhinitis is to prevent infection with toxigenic P. multocida.14

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