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Progressive atrophic rhinitis

Progressive atrophic rhinitis

M-L PENRITH

GENERAL INTRODUCTION: FACULTATIVELY ANAEROBIC GRAM-NEGATIVE RODS Pasteurella and Mannheimia spp. infections

Introduction

Progressive atrophic rhinitis (PAR) is an important disease of pigs characterized by turbinate atrophy with varying degrees of facial deformation. It is caused by infection with toxigenic strains of Pasteurella multocida. Clinical disease can cause production losses due to growth retardation in fattening pigs.17 Subclinical disease also occurs.

The aetiology of PAR was long disputed, as various causes of turbinate atrophy have been identified. Infection with Bordetella bronchiseptica can cause severe rhinitis with turbinate atrophy in piglets less than six weeks old. However, it is accepted that the progressive form of the disease, which can affect older pigs, is caused only by toxigenic strains of P. multocida,17, 22, 24, 67 although various factors including infection with B. bronchiseptica can predispose to PAR. The progressive nature of the disease probably depends upon chronic infection with toxigenic P. multocida, as turbinate atrophy experimentally induced by a single intraperitoneal administration of toxin resolved within approximately three months.57

Progressive atrophic rhinitis has probably been known since 1830, when it was described as ‘Schnüffelkrankheit’.17 It was reported from the USA in 194428 and the UK in 1954.8 It is widespread, occurring in most countries that produce pigs, including South Africa. It has recently been reported in Kenya.82 Lesions suggestive of PAR have been described in extensively kept pigs of local breed in Zimbabwe,36 although this was not confirmed by bacterial isolation.

The importance of PAR lies not only in its ability to cause production losses, but in the fact that subclinical disease is common. Herds that have never shown clinical signs of atrophic rhinitis may nevertheless harbour carriers that, introduced into herds under different management, may spread the infection. Detection of carriers is therefore of critical importance to prevent introduction into clean herds. Because even modern techniques may fail to identify infected individuals, continuous monitoring of herds is necessary to ensure freedom from PAR.

Although PAR is of importance only in pigs, toxigenic strains of P. multocida have been isolated from rabbits, humans, and calves, in which they produce similar effects of turbinate atrophy, as well as from dogs, cats, goats and poultry.44

Aetiology

A toxin produced by particular strains of P. multocida is the cause of progressive turbinate atrophy in pigs, either alone or in combination with B. bronchiseptica.17, 24, 74, 75 Pasteurella multocida is best cultured in broth media.17 Strains of both types A and D cultured from pigs, rabbits and humans have been identified that produce a thermolabile dermonecrotic protein toxin. An untypable strain was isolated from cattle with turbinate atrophy and found also to produce a dermonecrotic toxin.44 The majority of toxigenic strains isolated from pigs belong to type D, but occasionally toxigenic type A strains are reported.33, 85 Identification of the gene that encodes for the toxin indicated that it may be located in a bacteriophage, transfer of which may be able to cause non-toxigenic strains to produce toxin.7 This hypothesis was supported by the finding in another study that the toxin-encoding gene may have had a different origin from the rest of the genome of the organism studied.47

Epidemiology

Clinical PAR usually occurs in young pigs. Experimental infection has succeeded in producing typical lesions of PAR in pigs up to 16 weeks old, although infection usually occurs in the farrowing unit before piglets are four weeks old.62 Lesions decrease in severity with age, and infection of adults may result in subclinical disease with subsequent infection of piglets by their dams, 10 to 15 per cent of which may be carriers.17 The highest prevalence of carriers was found in the 6- to 12-month age group.83

Introduction into clean herds is usually by means of carriers, which may shed organisms when stressed by transport and mixing with other pigs. Molecular fingerprinting of isolates in Australia suggested that importation of infected pigs from a single source was responsible for PAR in Australia.33

Transmission is usually by direct nose-to-nose contact or aerosol, but, since toxin administered by various routes can produce lesions of PAR, and it appears that toxin can be produced in sites other than the nasal mucosa, infection by other routes may be possible.1, 2, 85 Toxigenic P. multocida is usually carried in the pharyngeal tonsils1, 2 but may be isolated from the nasal mucosa and the lungs.60 It has also been isolated from the vaginas of sows.17 Transmission between species might occur, but it has been suggested that this may not always result in disease.45 However, piglets developed turbinate atrophy after inoculation with toxigenic P. multocida cultured from a human patient.59

Although toxin produced by P. multocida is capable of producing typical lesions of PAR, colonization of the nasal mucosa is enhanced by the presence of B. bronchiseptica.17, 29, 74, 75 However, vaccination with purified P. multocida toxin alone gave good protection against severe lesions of PAR.32 Damage induced by high levels of ammonia and dust also facilitates colonization.17, 38

The severity of PAR, and indeed whether it will manifest clinically at all, depends on environmental factors and above all management. In the USA, it was demonstrated that pigs slaughtered in spring or summer (but farrowed and raised in winter) were more frequently affected with PAR.16, 77 Enclosed housing with limited, controlled ventilation was also associated with a higher incidence of PAR.16

Toxigenic P. multocida has also been associated with pneumonia in pigs.60

Pathogenesis

Progressive atrophic rhinitis results from colonization by a toxigenic strain of P. multocida, followed by elaboration of the toxin which exerts a direct effect on turbinate growth. The pharyngeal tonsil is a predilection site for colonization by P. multocida. 1, 2, 38, 72 In the absence of damage to the nasal mucosa caused by chemical effects, such as those resulting from poor air quality or infection with B. bronchiseptica, colonization by P. multocida is poor.29, 38, 66 Very high doses of P. multocida toxin as well as infection with B. bronchiseptica and various chemical mediators61 cause ciliostasis, which facilitates colonization of the nasal mucosa. Colonization of the nasal mucosa by toxigenic P. multocida results in more severe lesions,32 but is not essential for the induction of PAR: toxin produced in the tonsils or the lungs can also cause turbinate lesions.1 It has been demonstrated that not only intranasal but also subcutaneous, intramuscular and intraperitoneal administration of toxin can produce turbinate atrophy.2, 85

Colonization of the nasal mucosa by toxigenic P. multocida results in epithelial hyperplasia and atrophy of mucosal glands, accompanied by an influx of neutrophils and mononuclear cells.17 The osteoporotic changes in the turbinate bones induced by the toxin are the result of increased bone resorption and impaired osteogenesis,25, 30, 50, 66 characterized by decreased mineralization, and replacement fibrosis. Increased osteoclasia induced by P. multocida toxin has been demonstrated to result from an increase in both numbers and activity of osteoclasts.50

The increase in number is ascribed to the ability of the toxin to induce the differentiation of osteoclast- like cells from precursors in the bone marrow,51 possibly indirectly via cytokine production by a subpopulation of stromal cells.37 The marked effect on turbinate bones is probably due to the fact that these consist of endochondral bone with few trabeculae and a large amount of bone marrow that is actively haemopoietic.51 Stimulation of osteoclasia appears to be transient,25 which may explain why an increased number of osteoclasts is not always observed.

The effects on osteoblasts appear to include cytolysis and impairment of differentiation and function. There is evidence that P. multocida toxin may prevent differentiation of precursor cells into osteoblasts.63, 64, 73 Ultrastructural studies revealed degenerative changes in differentiated osteoblasts.66 In vitro studies have shown that incubation of cells with osteoblastic activity with P. multocida toxin at doses comparable to those required to induce turbinate atrophy resulted in a marked reduction in alkaline phosphatase activity,37, 78 which would account for decreased mineralization. Cytolysis induced by P. multocida toxin appears to be dose-dependent.37

The way in which P. multocida toxin causes growth retardation has not been fully eludicated. It is generally accepted that PAR can result in growth retardation.17, 57, 60 Pigs inoculated with a single dose of purified P. multocida toxin developed growth retardation within a week, which was maximal at two weeks and still observed, although reduced, at slaughter.57 The degree to which PAR results in increased time to market is not strictly correlated with the severity of lesions observed at slaughter.2, 77 It could be surmised that any condition that affects the upper respiratory tract chronically would lead to reduced feed intake and therefore poorer growth. However, experimentally induced disease appeared to have little effect on the appetite of the pigs38 and did not affect the feed conversion ratio.4 Growth hormone plasma concentrations and pituitary response have been shown to be normal in pigs suffering from natural and experimentally induced PAR,34 and the authors speculated that the toxin may exert an effect through modulation of signal transduction pathways. Adverse effects on physeal growth have been reported.3, 4 Physeal area and chondrocyte proliferation were reduced in piglets infected parenterally with P. multocida toxin.3

Clinical signs and pathology

Clinical signs usually do not develop until piglets are 4 to 12 weeks of age. The first signs are sneezing and snuffling as a result of acute rhinitis. Piglets affected with PAR continue to sneeze and snuffle throughout the growing period,producing varying amounts of serous to mucopurulent nasal and ocular discharges. As a result of the ocular discharge, triangular dark stains, or tear-marks, develop below the medial canthi of the eyes. Animals that are severely affected may suffer bouts of epistaxis, which is usually unilateral, and this may be evident from the presence of blood stains on the walls of the pens. Pieces of turbinate bone may be expelled during particularly violent sneezing. As the disease progresses, deformities of the snout may become evident. Shortening of the upper jaw (brachygnathia superior) is the most commonly observed deformity, with folding of the skin over the dorsum of the snout (Figure 167.1). Turbinate lesions may be asymmetrical, with deviation of the nasal septum, which causes deviation of the snout towards the side that is more severely affected (Figure 167.2). Growth retardation and poor feed conversion may occur in severely diseased pigs.

Figure 167.1 Progressive atrophic rhinitis. Note deviation of the snout, skin folds over dorsum of the snout and tear-staining below the medial canthus of the eyes

Figure 167.2 Progressive atrophic rhinitis. Note atrophy and distortion of the turbinates

In order to evaluate the turbinate lesions, snouts of slaughtered pigs should be cut at the level of premolars 1 and 2 and examined in cross-section. Comparison with a normal snout cut at the same level facilitates evaluation of the severity of the lesions.

The ventral conchae are the first to be affected, and may be so reduced in size to be absent. In severe cases the dorsal and ventral conchae are markedly reduced, and in very severely affected pigs the conchae may be absent. The lesions exhibit varying degrees of asymmetry. The nasal septum may be normal or deflected to one side, depending on the degree of asymmetry of the lesions.

Other organs are usually normal, but signs of pneumonia may be present, as infection with Mycoplasma hyopneumoniae has been reported to predispose to PAR, and toxigenic P. multocida has also been isolated from pneumonic lesions. 60 The toxin of P. multocida has also been demonstrated to cause thickening of the epithelium of the urinary bladder.39 Experimental infection with high doses of purified toxin resulted in icterus due to severe hepatocellular degeneration and necrosis, and gastric ulceration and polioencephalomalacia were also observed.27

Diagnosis

Pigs suffering from clinical PAR may be smaller than their litter mates, have a dull hairy coat, and exhibit varying degrees of facial deformation as described above. Tear stains are often present and are suggestive of but not pathognomonic for PAR.

Because the disease may be subclinically present in herds that have never shown any clinical signs of PAR, abattoir monitoring is frequently used to detect lesions suggestive of PAR. To facilitate diagnosis, various methods of scoring snouts have been developed, ranging from subjective scoring severity lesions on a 0 to 5 scale to more sophisticated methods to try to achieve an objective evaluation. The latter include morphometric approaches10, 26, 52 and computerized tomography scans.41 However, the cut-off point at which the lesion is classified as PAR remains a problem.35 In order to make a definitive diagnosis, involvement of toxigenic P. multocida must be confirmed in the laboratory.

The highest number of organisms usually occurs in the tonsils,18, 38, 72 making this the specimen of choice for isolation and identification of the organism.

Traditionally, confirmation of the diagnosis depended upon isolation of the organism, and subsequent testing in guinea pigs or mice to establish the production of dermonecrotic toxin, but this method has been superseded by an in vitro test in which Vero cells are employed to avoid the use of guinea pigs.70 These methods are slow, laborious and expensive. Culture of P. multocida is hampered by difficulty of growing it on solid media.17 The use of liquid or selective media is recommended.17, 46 More modern techniques, in particular the polymerase chain reaction (PCR) technique are currently used.43, 55 An ELISA has been developed in which monoclonal antibodies are used to detect the toxin.14, 53, 54

Both the ELISA and the PCR are highly sensitive and specific,6 as well as being faster than conventional tests. The results of a study on the age distribution of pigs found to be positive with the antigen-detecting ELISA suggested that pigs 6 to 12 months of age should be used in herd screening tests, as many pigs younger than this were negative, and the number of positive pigs also declined with age.83

Since specific antibodies against P. multocida toxin are produced, tests to determine serum antibody levels can detect unvaccinated herds that have been exposed to infection. Serum neutralization tests and an ELISA have been developed.5, 11, 31 A skin test based on the presence of antitoxin antibodies has been developed.15 These tests are more useful for herd screening than for the detection of individual carrier pigs, since they depend on the response of the pig to antigenic stimulation, and furthermore do not necessarily imply active infection.

In the absence of any clinical signs of PAR, detection of toxigenic P. multocida does not constitute a definitive diagnosis of PAR. It has been suggested, on the basis of identification of toxigenic P. multocida in the prolonged absence of disease in a closed herd in Ireland, that the strain identified, which differed from the usual strain that causes PAR in the UK, may have been derived from a different host and therefore did not spread and cause disease in pigs.45

Differential diagnosis

Acute rhinitis in young piglets has various causes, including B. bronchiseptica, inclusion body rhinitis caused by porcine cytomegalovirus, dusty feed, or poor environmental conditions. The diagnosis of PAR depends on isolation or detection of toxigenic P. multocida, and progression to development of lesions typical of PAR. Later stages of the disease must be differentiated from other causes of facial deformation such as abscesses, trauma to the nasal bones, and congenital conditions. These conditions are likely to affect individual animals only.

Control

Treatment during an outbreak of atrophic rhinitis is aimed at controlling the infection in pigs with clinical signs and preventing its spread in the herd by reducing the overall bacterial load.17 This should be accompanied by preventive measures that usually include vaccination and medication of sows, and improving the environment for the pigs, with particular attention to management of ventilation and housing.17

Various vaccines provide protection. Combinations of killed B. bronchiseptica cells and inactivated P. multocida organisms and toxin have been used with good effect.23, 42, 48, 76, 81 The P. multocida type D toxoid cross-protects against type A.76 Good protection with this type of vaccine was reported after sows were vaccinated five to six and two to three weeks before farrowing,79 but a single vaccination in weaned piglets did not protect against challenge with cellfree toxin. The use of different adjuvants does not appear to affect vaccine efficacy.42, 65 Toxin purified with monoclonal antibodies alone is capable of protecting piglets against infection with B. bronchiseptica and toxigenic P. multocida.31, 80 Promising results have been obtained with a recombinant vaccine.13, 58, 71 Commercial vaccines are widely available. In South Africa they are often used in conjunction with medication of sows with oxytetracycline.

Medication may be used alone or in combination with vaccination to treat or prevent PAR. A wide variety of antimicrobials has proved effective against PAR. Potentiated sulphonamides, oxytetracycline, penicillin/streptomycin combinations, lincomycin/spectinamycin combinations, tilmicosin, and enrofloxacin have all been reported to be efficacious.9, 12, 17, 40, 69

Various régimes have been advocated, including in-feed or parenteral medication of sows during the last month of pregnancy, and parenteral, intranasal or in-feed medication of piglets and growers.9, 12, 40, 69 Combining vaccination of sows with antimicrobial treatment has been reported to give the best results.49, 68 When toxigenic P. multocida is isolated during an outbreak, the performance of an antibiogram is advisable in order to ensure that an antimicrobial of optimal sensitivity is selected. If an antibiogram is not carried out, a broad-spectrum antibiotic should be selected according to affordability and practicality, and administered according to the manufacturer’s instructions.

To eradicate PAR from infected sow herds, vaccination over a period of at least four years combined with testing nasal and tonsillar swabs, using polymerase chain reaction (PCR) or a combination of the PCR and antigen-detecting ELISA, has been advocated.19, 21 This should be combined with purchasing new stock only from herds known to be free of PAR. Screening to ensure freedom from carriers is performed by obtaining nasal and tonsillar swabs, as well as tonsillar biopsies, from the entire breeding herd20 to ensure freedom from infection.

Measures are necessary to prevent introduction of PAR into naive herds by carrier pigs. New stock should be acquired from herds known to be free of the disease, if an accreditation system exists.

New pigs should be quarantined separately from the herd for at least six weeks, and nasal and tonsillar swabs taken for bacteriological testing should prove negative before the pigs are introduced into the herd.

Management is very important in the prevention of clinical PAR. Poor air quality in the farrowing unit, mixing of animals of different ages, and high stocking densities, particularly in continuous flow systems, predispose to PAR.56, 84 Reducing the level of toxigenic P. multocida in the farrowing unit and optimizing piglet defence mechanisms are helpful in controlling PAR.62 Ensuring that the environmental temperature is correct and excluding factors such as draughts that may stress piglets and lower their resistance contribute to its control.17 It is possible that artificial insemination could contribute to the control of PAR by eliminating contact with carrier boars.17 Modified medicated early weaning, all-in-all-out systems, strict hygienic measures, and improvement of the environment to ensure that ammonia levels are acceptable and that excessive dust is not present in the atmosphere or generated by the feed, are helpful in the control of PAR.

References

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