MAMMALIAN ASPERGILLOSIS

Disease Name Aspergillosis. Syn. pneumonomycosis aspergillina, bronchomycosis.

Pathogen Aspergillus fumigatus Fresenius (Zurn, 1876). Aspergillus nidulans (Eidam) Wint. (Tscherniak, 1928). Aspergillus flavus Link (Tscherniak, 1928).

Hosts Cattle (Zurn, 1876), horse (Rivolta, 1856), sheep (Mazzanti, 1884), pig (Berg, 1898-99), cat (Sautter et al., 1955), dog (Gotti, 1871), guinea-pig (Ainsworth & Austwick, 1955a), rabbit (Smit, 1915), bison (Rewell & Ainsworth, 1947). hare (Thjostta, 1933), deer (Rousseau &. Serrurier, 1841), goat (Mori, 1916), monkey lScott, 1928).

Geographical Distribution Europe, North America, South-East Asia and New Zealand.

Except in man, aspergillosis is not a well-known disease of mammals, although it has been recognized with increasing frequency in the past few years and the literature now consists of approximately a hundred papers dating from the brief mention of the disease in a deer by Rousseau & Serrurier (1841). It is probable that the most important aspect of mammalian aspergillosis is in connexion with mycotic abortion (see Chapter 12), in which infection of the placenta of cows is thought to be a sequel to subclinical pulmonary aspergillosis. The aspergilli may also contribute to allergic types of respiratory troubles such as pneumonitis and asthma, especially in young animals. There is no recent review of mammalian aspergillosis, but Renon (1897) gave a comprehensive survey of the cases up to that time.

Symptomatology

Most of the reported cases have been of the pulmonary disease, but generalization has been described. The clinical condition greatly resembles tuberculosis and is characterized by general wasting, followed by death.

As in avian aspergillosis a large number of the accounts are unsatisfactory both from the clinical and the mycological points of view. A few are no more than passing references to cases in which the fungus concerned has not always even been classed as an Aspergillus sp., and because of this the published reports have been carefully examined before their inclusion as apparently authentic cases.

The different forms of the disease in animals have not been studied sufficiently for a workable classification to be given, but the categories made by Renon (1897) of chronic, acute and subacute may still be used. When a large enough number of cases is on record it should be possible to distinguish the different clinical manifestations of aspergillosis with reference to the type of lesion and its stage of development, individual susceptibility, and the allergic and environmental factors of each case.

Cattle

Although there are several earlier reports of aspergillosis in bovines, that of Bournay (1895) in an eight-year-old cow is one of the better documented accounts. The symptoms developed in fifteen days in this case from a slight cough to laboured respiration, bloody and foetid diarrhoea, slight fever and loss of appetite. The pulmonary lesions consisted of cavitated sub-pleural nodules and interlobular emphysema, whilst there was inflammation of the small intestine. Typical pulmonary infection with nodule formation was also reported by Pearson & Ravenel (1900) and further reports have been made at intervals (Bartolucci, 1903; Del Giudice, 1956). Bendixen (1926) described what appeared to have been a case of generalized aspergillosis in a cow with invasion of the lungs, liver, spleen and kidneys, and another form of the disease was reported by Lucet (1897) in which generalized interstitial haemorrhage was a pronounced feature and the lungs showed centres of hepatization without nodule formation.

Horse

Aspergillosis in horses was recorded earlier than in cattle (Rivolta, 1856) but was frequently restricted to infection of the nasal sinuses and the guttural pouches (Ries, 1903). Foulerton (1899) described the lung of a horse with typical aspergillotic nodules and Noller & Krause, (1924) and Tscherniak (1928) gave details of several more cases. Meningeal involvement was reported by Romanov (1928). In the case described by Thary & Lucet (1895) in a four-year-old mare the disease developed rapidly and showed generalized interstitial haemorrhage with caseous nodules in the kidneys.

 Sheep

There have been only five reports of aspergillosis in sheep. The lesions in lambs consist of small (2-3 mm. Diam.) bluish-grey nodules surrounded by a narrow haemorrhagic zone, and closely resemble those caused by the lungworm Muellerius capillaris (Andersen 1927). The most recent report of the disease is in the Annual Report of the New Zealand Department of Agriculture for 1955.

Van Hellens (1902-03) investigated in Finland one of the few epidemics of aspergillosis on record among sheep. The animals were adult and showed chronic bronchitis and catarrhal pneumonia closely resembling the symptoms of tuberculosis.

Death occurred up to one year after the appearance of symptoms. Conidiophores of A.fumigatus were found in the sputum of affected sheep and numerous discrete and sometimes well calcified nodules 1-7 mm. in diam. were present in the lungs. Nobel & Shamir (1956) described a rather different condition in which granulomatous lesions containing the hyphae of A.fumigatus were found in the lungs of a day-old lamb, and they considered the infection had taken place in utero.

Pig

Records of aspergillosis in pigs are also rare. Berg (1898-99) first described the disease as a persistent cough associated with a lobar pneumonia and nodule formation. The spleen and kidney were enlarged and congested, and nodular lesions were found in the mesenteric lymph nodes. Berg did not obtain any isolates from the lesions but assumed that an Aspergillus was the cause of the disease. Generalized infection in a pig was also reported by Nuvoletti & Casella (1903).

Other species of domestic animals. Spontaneous aspergillosis in domestic rabbits has been reported by Schöppler (1919) and Höppli (1923), whilst Ainsworth & Austwick (1955a) have recorded the disease in guinea-pigs. Apparently no authentic case of pulmonary aspergillosis has been found in the dog for the main records from this animal by Gotti (1871) and Stazzi (1905) are of nasal and auricular fungal infection due to a variety of fungi. A case in a cat has been described by Sautter et al. (1955) and Ainsworth & Austwick (1955a) briefly report the occurrence of a large aspergillotic nodule in the udder of a goat which was associated with chronic mastitis.

Wild animals

As in birds captive wild mammals have provided several examples of aspergillosis. Dobberstein (1936) reported a case of meningeal infection in an elk in the Berlin zoo, whilst Rewell & Ainsworth (1947) showed how the respiratory passages of an American bison at the London zoo were found on post-mortem examination to be lined with a greenish felt of A.fumigatus absence of severe lung lesions.

Scott (1930) gave details of nine cases of mycosis (aspergillosis?) and a further nine associated with tuberculosis in captive monkeys encountered at the London zoo. The lungs were the chief organs involved but miliary nodules were occasionally found throughout the viscera.

Free-living wild animals have also been found infected by A.fumigatus and outbreaks of pulmonary aspergillosis have been reported in hares in Sweden (Thjostta, 1933; Hölphers & Lilleengen, 1947) and also in roe-deer in that country and Switzerland, in which the conchal and ethmoid bones as well as the lungs and other organs became affected by tumour-like growths containing hyphae (Krembs, 1937; Burgisser, 1955). When specific determination had been carried out, A.fumigatus was the most frequent isolate but Burgeon (1929) reported A.niger from nodular lesions in the lungs of a bull, a heifer and a stag in Indo-China.

 Pathology

  The diagnosis of aspergillosis in mammals may be made, as in birds, by crushing the nodules for microscopic examination and by isolation. Even in the pneumonic form of the disease, hyphae can generally be seen in the lung tissue without difficulty and in the soft nodules from lamb lungs they have been found in great profusion (Watkins & Austwick, unpublished data). It may also be, possible to examine the sputum and nasal discharge of large animals, bearing in mind however that this material reflects the atmospheric spore content of the environment and the results require careful interpretation.

Many of the pathological features of avian aspergillosis have been found in mammals, but chronic lesions seem to be more frequent probably because of the relatively longer life of the latter. The lung nodules generally have a central necrotic zone containing hyphae, surrounded by atelectiased pulmonary tissue. At a later stage cavitation may occur with the development of an internal greenish, powdery surface consisting of the sporing heads of Aspergillus fumigatus (Bournay, 1895). Bendixen (1926) described the pathology of the nodular lesions in the liver, kidney and spleen of a cow as showing severe interstitial infiltration. Unfortunately no isolate was obtained from this case but the morphology of the hyphae in the lesions corresponded to infection by an Aspergillus sp. The development of the nodules in the lungs of sheep was traced by Van Hellens (1902-03) from small accumulations of leucocytes and red blood corpuscles in the blood vessels to calcified lesions in which a few giant cells were present together with extensive invasion by fibroblasts.

Occasionally in chronic infections closely radiating groups of hyphae are found in the kidneys or spleen and these have been termed the "actinomycotic forms" of A. fumigatus. Lichtheim (1882) first observed them and Nicaud (1928) produced them experimentally by repeated inoculation of spores into rabbits. Drake (1948) also saw these forms in longstanding experimental infections with A.nidulans. They were considered by Renon (1897) to indicate the extreme defence of the organs of the body and a lowered vitality of the fungus. Other structures sometimes encountered are the "asteroid" bodies surrounding hyphae which consist of radiating acidophilic processes, closely resembling the "clubs" seen in actinomycotic granules.

Epidemiology .Mammalian aspergillosis is most probably a primary pulmonary disease which is non-contagious and is contracted by exposure to large numbers of fungal spores from mouldy hay, etc.The presence of the viable spores of A.fumigatus and many other fungi in hay is easily demonstrated by culture, and mouldy samples appear to support a tremendous fungal growth. The events which follow the inhalation of spores are still largely unknown but Lucet (1897) claimed to have detected spores in the blood stream, which was a means of dissemination also considered by Folger (1906-07). The latter went further however in suggesting that the interstitial nature of the lung lesions in the cow he examined indicated that infection was of embolic origin and had spread from the inflamed uterus by thrombosis of the uterine veins.  

It seems that housed animals fed on hay during the winter are more likely to inhale large numbers of fungus spores and it will be surprising if many more cases of aspergillosis are not diagnosed following the development of methods for the detection of subclinical infection. Tschernick (1928) has claimed that the routine examination of horses for glanders revealed an incidence of aspergillosis of 16%, whilst earlier (1924) he had given details of seventy-eight cases of the disease in horses. The incidence of aspergillosis in cattle has yet to be estimated, even though it may be of considerable importance in relation to mycotic abortion. Figures are not available for other animals.

Prognosis and Treatment

As in birds, aspergillosis has rarely been diagnosed in a live animal and in consequence there are few accounts of successful treatment. Moreover the prognosis is grave since Van Hellens (1902-03) found that only a very few sheep out of a flock of eighty survived the slow infection.

Control would appear to be best carried out by the methods described under the avian disease, i. e., by the careful removal of the source of infection. Renon (1897) found that potassium iodide given intravenously increased the survival time of rabbits inoculated with spores of Aspergillus fumigatus and the method has frequently been used in the therapy of the human disease (Conant et al,1954, p.71).

Serology and Toxicology

The serological study of aspergillosis is unfortunately not nearly so advanced as in histoplasmosis and coccidioidomycosis. Reliable serological diagnostic methods would be particularly useful in large animals in which radiography is difficult, and in which subclinical infection appears to be more common than at present supposed.

Complement-fixation was found by Boe et al. (1939) to be the most sensitive method for the detection of antibodies. They obtained titres of 1:1000 to 1:1600 irrespective of whether spores or the powdered mycelium was used as the antigen. The agglutination and precipitin tests performed were as unsuccessful as those performed by Macaigne & Nicaud (1927a). Matsumoto (1929) obtained a titre of 1:10 for A.fumigatus and an inhibition of haemolysis by A.amstelodami of 1:320. Tests for skin sensitivity have been successfully used in man by Macaigne & Nicaud (1927b), Hyde et al, (1956) and others, but urgently require further study.

Research on production of toxins has mostly been carried out using A. fumigatus but often with conflicting results. Leber (1882), Ceni & Besta (1905) and Bodin & Lenormand (1912) all considered that they had evidence of toxin production, but this was contrary to the findings of Kotliar (1894) and Obici (1898). Henrici (1939) seems to have clearly demonstrated the presence of an endotoxin in A. fumigatus and Salvin (1952) later confirmed this observation. Henrici found that a thermolabile substance could be extracted by cutting up, squeezing and centrifuging the mycelium, and that this affected all experimental animals when injected by subcutaneous, intraperitoneal and intravenous routes, producing nervous symptoms and proving fatal in quite small doses. Many of the properties of the toxin indicated that it was a toxalbumin but it was apparently a non-protein substance.

 Immunity

  There is no record of immunity to aspergillosis in animals following recovery from the disease, chiefly because so few cases have been diagnosed before death. Of the experimental attempts to produce immunity, those recorded by Renon (1897) appear to have been the most extensive. Using over fifty animals he found that only three rabbits showed any signs of resistance to infection after progressively greater doses of spores.

Other attempts at immunization, using antisera, killed spores and attenuated strains of A. fumigatus, were unsuccessful. Henrici (1939) was able to produce immunity to aspergillosis in rabbits using the endotoxin he obtained from the mycelium and found that this immunity could be transferred passively to guinea-pigs and mice.

Experimental aspergillosis

The earliest experimental inoculations were made in Germany by Grohe (1870) and Bloch (1870) both of whom claimed to have produced nodular lesions in rabbits with A.glaucus and Penicillium glaucum. Grawitz repeated this work without success in 1877 but succeeded in 1881. Various attempts were made to explain this but Lichtheim (1882) effectively demonstrated that these workers had been using impure cultures which grew the pathogenic Aspergillus fumigatus at high temperature of incubation and the non-pathogenic A.glaucus which may superficially resemble it at a lower temperature. The two species are easily distinguished by the much smaller size of the spores of the former.

Most of the later experimental work has been concentrated on A.fumigatus and a great range of experimental animals has been found susceptible. In birds, the pigeon is the most easily infected, but intra-tracheal inoculation is generally successful in most domestic species. Rabbits and guinea-pigs are highly susceptible by the intravenous route but cats, dogs and sheep are said to be refractory (Renon, 1897; Lucet, 1897).

The route of inoculation influences the ultimate development of the disease, intravenous inoculation in rabbits characteristically giving rise to renal lesions and subcutaneous inoculation to small abscesses. intestinal infection has been produced in rabbits by feeding excessive quantities of spores (Renon;, 1897) and arthritis can be caused by injection of spores into the joints. Inoculation of the cornea causes a keratitis which may lead to the invasion of the eye and in calves, Bendixen (1928) observed infection of the eye in one animal and extensive pneumonia in another inoculated by this route. This author's experimental production of abortion in cattle with A.fumigatus is described in the section on mycotic abortion.

Apparently the size of the inoculum is critical, at least by the intravenous route. Renon (1897) found a direct relationship between the quantity of spores injected and the survival of the animal. The earliest time of death with large numbers of spores was 4-7 days. Henrici (1939) found that large intravenous doses in pigeons caused haemorrhagic necrosis with little reaction, whilst very small doses gave a typical picture of miliary nodules after a longer time. On the other hand whilst the blowing of large numbers of spores into the trachea caused rapidly fatal pneumonia, the feeding of heavily infected grain produced the chronic form of the disease. The quantitative relations of spores to infection appear to be the key to the epidemiology and pathology of aspergillosis.  

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