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Pseudotuber culosis in man: Possible epidemiological role of the cats
Comp. Immun. MicrobioL infect. Dis., Vol. 1, pp. 243-251. © Pergamon Press Ltd., 1979. Printed in Great Britain
0147-9571/79/03014)243505.00/0
PSEUDOTUBERCULOSIS IN MAN: POSSIBLE E P I D E M I O L O G I C A L R O L E O F THE CATS M. BOURDIN 5 Rue Eug6ne Varlin, 94450 Limeil Brevannes, France I N S E R M SCN3, Abstract--Human infection by Malassez and Vignal's bacillus (Yersinia pseudotuberculosis) can take many clinical aspects, the most frequent of which is mesenteric adenitis with pseudoappendicular syndrome, but occasionally also appearing as a tumor of the right lower abdominal quadrant. In a subsequent stage this mesenteric adenitis is often accompanied by erythema nodosum. There also exist some septicemia-like forms, which have become more and more frequent of late, always appearing on a particular terrain (predisposed persons). These various forms all correspond to contamination via the digestive route. Other, more exceptional modes of contamination may result in much rarer forms, such as ocular or pulmonary forms. Diagnosis is based on: (a) demonstrating the presence of Yersinia pseudotuberculosis, (b) serodiagnosis, (c) a positive intradermal reaction, (d) the characteristic aspect of lymph node lesions. Pseudotuberculosis is extremely frequent in animals. Many species, most of them rodents or birds, can serve as healthy carriers. This is how cats, through their access to this natural "reservoir", get contaminated and thus act as a "conveyor belt" in transmitting the disease to man.
Key words: Pseudotuberculosis, yersiniosis, Yersinia pseudotuberculosis, mesenteric, adenitis, erythema nodosum, septicemias, diagnosis, epidemiology LA PSEUDOTUBERCULOSE CHEZ L'HOMME: ROLE EPIDEMIOLOGIQUE POSSIBLE DU CHAT Resum6--L'infection humaine par le Bacille de Malassez et Vignal peut rev&ir cliniquement plusieurs aspects, le plus fr&luent, voire le plus banal est l'addnite mdsentdrique ~t symptomatologie pseudo-appendiculaire mais pouvant aussi se pr6senter comme une tumeur de lafosse iliaque droite. L "drythdme noueux est souvent associ6 dans un second temps ~ cette ad6nite m6sent6rique. I1 existe des formes septicdmiques de plus en plus fr~quentes survenant toujours sur un terrain particulier. Toutes ces formes correspondent fi une contamination par vole digestive. D'autres modes de contaminations plus exceptionnelles aboutissent h des formes beaucoup plus rarement rencontr6es: forme oculaire, forme pulmonaire. Le diagnostic est fonde, sur la mise en ~vidence de Yersinia pseudotuberculosis soit dans le ganglion soit dans le sang selon le cas, sur le sero-diagnostic, a l'aide de l'intradermoreaction, enlin par l'aspect particulier des 16sions ganglionnaires. Chez l'animal la pseudotuberculose est d'une extreme fr6quence. De nombreuses esp6ces essentiellement rongeurs et oiseaux peuvent ~tre porteurs sains. C'est en accb,dant fi ce reservoir naturel que le chat peut se contaminer et constituer ainsi le chainon assurant la transmission /~ rHomme.
Mots-clefs: Pseudotuberculose, yersiniose, Yersinia pseudotuberculosis, ad6nite m6sent6rique, erytheme noueux, septicemies, diagnostic, 6pidemiologie
INTRODUCTION P s e u d o t u b e r c u l o s i s , a y e r s i n i o s i s d u e to Yersinia pseudotuberculosis ( M a l a s s e z a n d V i g n a l ' s bacillus) w a s first d e s c r i b e d in a n i m a l s , e s p e c i a l l y g u i n e a pigs, b y M a l a s s e z a n d V i g n a l in 1883 [1]. F o r a l o n g t i m e it w a s t h o u g h t t o b e a strictly a n i m a l disease. E v e n t u a l l y Yersinia pseudotuberculosis w a s f o u n d in m a n y o t h e r species o f d o m e s t i c a n d wild a n i m a l s , as well as in b i r d s [2, 3]. 243
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The role of this bacillus in human pathology was brought to light only recently. Yersinia pseudotuberculosis official entry into human pathology took place 25 years ago, following the discoveries of the Tiibingen school [4, 51 on mesenteric adenitis. These discoveries were very quickly confirmed in many countries of Western Europe. In France, as early as 1954, Girard 161 drew the attention of the surgical community on the role played by this bacillus in mesenteric adenitis: observations by Ingelrans et al. [7], and Mollaret 181 revealed the frequency, not to say the common-place character of this syndrome. During the following years, a whole body of new knowledge accumulated rapidly and new clinical aspects were considered 191. CLINICAL STUDY The traditional classification differentiates between the general septisemic forms and the localised forms, the most frequent of which by far is mesenteric adenitis. But between these two extremes, a whole gamut of intermediate aspects exists. In this study we will consider first those forms secondary to enteral contamination, i.e. essentially mesenteric adenitis, erythemia nodosum, and the septicemic forms, as well as some other forms involving extra-mesenteric lymphatic adenitis. Then we will discuss the other forms, i.e. those secondary to non-enteral contamination: ocular forms, pulmonary forms and miscellaneous manifestations.
A. Forms secondary to enteral contamination Mesenteric adenitis This is by far the most frequent clinical form, even if it has been known for a relatively short time only: the first case was described by Albrecht [10]. It is only from 1954 onwards that mesenteric adenitis was systematically studied, thanks to the work of the Tiibingen school. In 1953, Masshoff and Dolle [11] described under the name of abscessing reticulocytic lymphadenitis a clinico-pathological picture consisting of inflammatory lymphatic lesions made up of reticulocytic proliferations preceding leucocytic infiltrations which, in turn, lead to necrosis and abscesses. In 1954, Knapp [12] succeeded in isolating Yersinia pseudotuberculosis from mesenteric lymph-nodes of children operated for mesenteric adenitis. From then on, many publications confirmed Knapp and Masshoff's discoveries and, in 1960, the first review article on French observations was written by Mollaret [8] who listed 30 cases. In its appendicular or "typical" form, mesenteric adenitis is a genuine surprise to the surgeon who operates after a diagnosis of acute appendicitis. The appendix proper is intact and a cluster of lymph nodes is discovered in the ileo-caecal area: exceptionally, only one lymph node is appended to the caecum; most of the time, the number of lymph nodes ranges from 2 or 3 to more than a dozen, their size sometimes exceeding that of an olive or even a walnut. The course is almost always benign, even without antibiotics: a mere appendectomy is sufficient to initiate a quick disappearance of the lymph-node cluster. From this rather schematic canvas, many variations have been noted, which range from: (1) severe toxic forms, to (2) nearly asymptomatic "formes frustes", detectable only inasmuch as they are systematically looked for in the brothers and sisters of an initial patient having had one of the typical forms of the disease.
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These "family"forms are practically the only ones to include a genuinely "silent" form, detectable only by means of serological diagnosis or systematic intradermal reaction. Other variants include forms with diarrhea, simulating paratyphoid fever and two other uncommon forms, namely (1) the form characterised by intussusception of the intestine, and (2) the pseudotumoral form. Intussusceptive forrns. Acute intestinal intussusception, as a revealing sign of mesenteric adenitis due to Yersinia pseudotuberculosis, is not exceptional. Several observations have been published [13, 14, 15, 16]. Pseudotumoralforms. These are frequent and their existence should be known, in view of the diagnosis problems they create. This form is not characterised by a mere increase in volume of the lymph-nodes but by a peculiar and alarming macroscopic aspect, raising a suspicion of malignancy. Numerous publications have reported this form. The "observatio princeps" was made by Albrecht, 1910 [10] cited above, and was followed by Graber and Knapp [ 171, Graber [ 18], and Mollaret et al. [19]. The circumstances causing a patient to consult are extremely varied, since the initial symptoms of the disease may resemble those of acute appendicitis or peritonitis or simply abdominal pains. But in all cases, on surgery, the findings are constant: there exists a bulky polylobated mass, frequently purplish in color, studded with numerous hemorrhagic spots, adhering to contiguous tissues and, to all appearances, giving the impression of a malignant tumor. All too often, unfortunately, on seeing this macroscopic aspect, a right hemicolectomy, based on this mere impression, is then performed whereas the fight attitude should be one of maximum conservatism. Complete recovery can be achieved without undue mutilation by a simple appendectomy, reinforced by antibiotherapy, and no need for surgically removing the lymph-node cluster other than that required for providing the material necessary for bacteriological and histological examinations.
Erythema nodosum The onset of erythema nodosum during the course of a Yersinia pseudotuberculosis infection is a very recent discovery. In 1962 Morger [20] published his observation of a young girl in whom erythema nodosum broke out in the few days following the operation she had had for mesenteric adenitis due to Yersinia pseudotuberculosis. ShOrtly afterwards, Mollaret 19] described 5 identical cases, while Boissiere et al. [21] brought forth new observations. Kerzoncuf [22] reports 52 cases of erythema nodosum, all of them observed in France, the aetiology of which was diagnosed by Mollaret at the Institut Pasteur in Paris. Finally Kleibl and Guiche [23] report the first case of autochtonous erythema nodosum observed in Algeria. This manifestation is freouent, especially among young boys, and makes its appearance during mesenteric adenitis, whether or not this latter disease has been clinically detected. The rash has a characteristic look and extends preferentially to the lower limbs, although it can occasionally spread to the forearms. Sometimes the erythema nodosum will seem to be isolated, but a well-conducted interview will retrieve the existence of a more or less discrete, painful syndrome having appeared in the preceding days or weeks. In all cases of erythema nodosum with unclear causes, it is recommended to look for a previous history of abdominal pains, and have a serologic diagnosis and an intradermal reaction performed.
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Septicemic forms These forms are more and more frequent and always appear on a specific "terrain": old age, diabetes, alcoholism, or else in young patients suffering from certain hematological diseases [24]. Such forms make up a septicopyohemic picture where, in an altogether sensitive abdomen, an enlarged and painful liver is the sign most frequently encountered. Solenomegaly, too, is frequent. A very valuable sign is afforded by manifestations of slight or marked jaundice. The course remains fatal, in spite of the treatment, in one case out of three, in view of the "terrain" over which septicemia develops.
Extra-mesenteric adenitis Superficial or deep adenopathies have been reported, usually during mesenteric adenitis and, exceptionally, in the course of generalised forms. Cervical localisations have been described by Lawrynomicz [25], Bouton and Hall [26], MoUaret and Berthon [27]. The joint occurrence of a cervical with an inguinal localisation has been reported by Ingelrans et aL [7].
B. Forms secondary to non-enteral contamination These are exceptional.
Ocular forrns This is the classical oculoglandular syndrome, known as Parinaud's syndrome, in which bacilli can be observed in cultures made from conjunctival secretions. The only two authentic cases of Parinaud's conjunctivitis are the ones described by Grancini [28] and by Knapp [291.
Pulmonary forms Although exceedingly rare, these forms should not be ignored, in view of their clinical identity with pulmonary plague. The only genuine case known to this day took place in Brussels in 1925 and was never published. The patient was a rag-peddler who died within a few days. The general clinical picture he presented led to a diagnosis of Yersinia pestis pneumonia. Only afterwards was a bacteriological study undertaken and the strain recognised as Yersiniapseudotuberculosis.
Miscellaneous manifestations Some cases of arthritis have been reported in 1975 by Freland et al. [30] and Zaremba et al. [31].
Recapitulation Apart from the appendicular form of mesenteric adenitis, all the clinical manifestations of Yersinia pseudotuberculosis infection are proteiform, rather unspecific and often deceiving. Laboratory tests are the only means of arriving at a reliable diagnosis.
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DIAGNOSIS A. Clinical diagnosis (a) Septicemic forms, even in their classical jaundice-like aspect, are not specific enough to permit a firm diagnosis. Only a blood culture will be able to identify the nature of the germ involved. (b) Mesenteric adenitis is usually discovered on surgery, the operation being performed under a diagnosis of acute appendicitis. Tumoral forms are liable to be confused with a malignant tumor, a sarcoma of the small intestine, etc. (c) Erythema nodosum will have to be distinguished from those due to tuberculosis or streptococcemia or simply to drugs. (d) Ocularforms are liable to be confused with tularemia or other forms of conjunctivitis of various origins.
Recapitulation Whatever clinical presumptions may be entertained by certain suggestive cases, resorting to laboratory tests is absolutely indispensable.
B. Laboratory investigations Four classes of methods may be used: Demonstration of the presence of the bacillus by blood or fecal cultures. Serology. Intradermal reaction. Histological examination of tissues obtained by an appendicular or lymph node biopsy.
Demonstration of the bacillus by means of a blood or fecal culture This is the choice procedure to demonstrate the role of Yersinia pseudotuberculosis. Not only is it the surest criterion but it also is the only one to provide an indication for the correct therapy to be adopted after studying the germ's sensitivity to antibiotics. Tissue sampling: most of the time this will concern a mesenteric lymph node or possibly, on autopsy of septicemic forms, the liver, the spleen or the red marrow of bones. Blood culture is imperative in the case of a septicemic form. Fecal culture is usually performed too late after surgery or after administration of antibiotics. The identification of Yersinia pseudotuberculosis is easy. This bacillus is gram-negative, motile below 30°C, non-motile above 30°C, with a rapidly-acting urease. The differential diagnosis of Yersinia pseudotuberculosis is easy, all the more so since the site of origin of the strain (mesenteric lymph node) is clearly suggestive. In fecal cultures, on the other hand, a confusion may easily be made with a Proteus (although Yersinia pseudotuberculosis has a negative T.D.A.). Identification will be confirmed by determining the antigenic typing. Strains isolated in man, both in France and abroad, belong to group I.
Serological diagnosis This is done by looking for agglutinating antibodies. The minimum significant titre for positivity is 1/100. Two samplings should be performed, 6 - 8 days apart, in order to ascertain the antigen titre has not varied. Administration of antibiotics does not seem to modify it. An abnormal persistence of antibodies reflects the persistence of germs in the lymph-nodes.
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Even though the post-operative course may be excellent, one cannot speak of complete recovery as long as the antigen titre remains stationary. Thus, seroagglutination possesses not only a diagnostic value but a prognostic value as well.
Pathologic diagnosis This bears almost exclusively on those mesenteric lymph-nodes where disseminated microabscesses are observed, accompanied by an epithelio'id reaction (or even by Langhans cells and sometimes caseification).
lntradermal reaction diagnosis The diagnostic interest of the intradermal reaction is particularly valuable in view of its highly specific character, whatever the serotype of the strain involved, and also because of the persistence of dermal sensitivity for years after the disease. Performing an intradermal reaction requires the injection of 1/20 to 1/10 ml of allergen in strictly intradermal fashion. The reaction can be read off after 48 hr. A positive reaction gives a red and edematous area, 1 - 2 in. in diameter. Persistence of dermal sensitivity. This lasts at least 5 - 6 years. It does not reflect a current infection, as sero-diagnosis does, but allows a retrospective diagnosis. The onset of dermal sensitivity is simultaneous with the appearance of agglutinins. The four above methods should be implemented in parallel since (a) any of the four may fail and (b) each has its own significance. EPIDEMIOLOGY OF THE DISEASE IN MAN Altogether, the quasi-totality of cases recorded so far have been observed mainly in Western and Central Europe (Switzerland, the Netherlands, Great Britain, Denmark, Belgium, Poland, Romania). Some cases have been reported from the United States, Canada, New Zealand and Africa. As new cases are reported, the geographical distribution of the disease in man appears increasingly to coincide with that of the animal disease. If we can take for a well-established fact the digestive mode of contamination, no agreement prevails about the source of the disease or its conditions of appearance. To be sure, a number of arguments are in favor of an animal origin, but this was demonstrated in only very few cases. The cat is the most likely culprit, being the most familiar animal on the one hand, and serving as the link between children and the large natural pool made up by rodents and birds on the other hand. But the frequency of the disease, in its natural form, in cats is difficult to assess: it seems to have varied, and continues to vary, over the years from one region to another. The disease was observed only exceptionally at the Toulouse National Veterinary School, whereas at the Lyon National Veterinary School, 80% of the jaundice cases observed in cats were due to Yersinia pseudotuberculosis. It would appear that the diagnosis of pseudotubereular infection in the cat is no longer pronounced by present-day practitioners, which is in contrast with the relatively high frequency of cases of the disease observed in the course of inquiries about the human disease. According to H. H. Mollaret, cats are the second largest source of contamination of children, the first being the population of small mammals (mice, guinea-pigs, hamsters) kept as home pets. Cats probably become infected through the digestive route as a result of eating rodents or birds, either sick or healthy carriers, or possibly viscera of hares and rabbits. Goret et al., 1955 [32] reported that, among the cases they had had occasion to observe, almost all the cats were good rat-catchers, that
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would feed on their prey after having killed it. By contrast, cats born and reared in apartments never caught the disease. The same observation was reported by Obwolo in 1977 1331. Even after an injection of bacilli isolated from contaminated animals, cats can remain healthy carriers for a long time (several months), harboring Yersinia pseudotuberculosis in their digestive tract. An auxiliary factor would seem to be required to trigger the disease. Also, the allergy which Goret et aL [34, 35] demonstrated in experimental infections, might be present and play an active role in the natural disease. As early as 1910, Albrecht [ 10] suspected the cat as a possible propagator of Yersinia pseudotuberculosis and the probable source of human contamination. "The patient lived in a fiat where the owner's cats had a free access to the kitchen, its utensils, dishes, plates, etc. This leads us to surmise that these cats were latent carriers of bacilli and acted as vectors of the human infection. They must have been contaminated after eating rats or mice which were infected with Malassez and Vignal's bacillus and whose feces contained the organism." Another similar case is that of a man who died of Yersinia pseudotuberculosis septicemia. For some time he had been digging work in a garden whose owner had a cat which had come down with diarrhea. Following euthanasia of this cat, Yersinia pseudotuberculosis was isolated from its lesions. In addition to these "lucky" observations, Mollaret [36] reports having come across feline pseudotuberculosis on very frequent occasions while conducting epidemiological inquiries on cases involving children: most of the time, it turned out that shortly before the child became ill, the cat had died after a diarrheic episode and without having been examined by a veterinarian. In a few cases, where the cat had died recently, an autopsy was made and Yersinia pseudotuberculosis was isolated. In some other cases, the cat was apparently in good health but repeated fecal cultures finally managed to isolate the organism in a healthy feline carrier. By repeatedly licking her genitals and/or anus and then her fur, a cat can contaminate any person who strokes her, and particularly children. Rats and mice may also be incriminated insofar as they can accede to food supplies which they can contaminate through their urine or feces. The outbreak conditions of the disease have yet to be identified: diabetes, immunodepressing drugs, alcoholism are favorable factors for septicemia. Most cases of human infection occur during the winter, i.e. cold and humid spells. But in addition to this winter maximum, a second peak can be observed between April and May, depending on the year and on the country; this second peak can perhaps be ascribed to the consumption, by humans, of fruit and vegetables soiled by traces of contaminated manure. Mesenteric adenitis is encountered mostly among young people (usually between 6 and 17), whereas enteritic forms are observed preferentially in young adults, and septicemia in old people or weakened subjects. As for the prevalence of mesenteric adenitis in males, this is more apparent than real since, anatomically, the frequency of adenitis is identical in boys and in girls; but girls seem to tolerate lymph-node disorders without clinical manifestations whereas boys exhibit more pronounced reactions. TREATMENT As in all infections due to Yersinia, whatever the strain (Y. pseudotuberculosis, Y. enterocolitica or Y. pestis), streptomycin is the antibiotic of choice, but the actual treatment,
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of course, will depend on the results of the tests assessing the sensitivity of bacteria to antibiotics. CONCLUSION S u c h is, in its m a i n features, the " s t a t e o f the a r t " r e g a r d i n g h u m a n infection by Y. pseudotuberculosis. S o m e aspects are n o w secured on firm f o u n d a t i o n s but others h a v e yet to be elucidated or c o m p l e t e d , in p a r t i c u l a r in the areas o f pathogenesis and epidemiology.
REFERENCES 1. Malassez, L. and Vignal, W., Sur le microorganisme de la tuberculose zoogl6ique. Arch. Phys. normale et pathologique 36me s6rie, tome IV, 81-105 (1884). 2. Barre, N., Louzis, C. L. and Tuffery, G., Contribution/~ l'6tude 6pid6miologique de l'infection ~ Yersinia pseudotuberculosis chez les animaux sauvages en France. Rev. Med. Vet. 128, 11, 1545-1567 (1977). 3. Bourdin, M., L'infection/~ bacille de Malassez et Vignal: Zoonose d'avenir. Th6se Doctorat V&6rinaire, Alfort (1967). 4. Masshoff, W., Eine neuartige form der mesenterialen Lymphadenitis. Dt. med. l.Vschr. 78, 532-535 (1953). 5. Knapp, W., Mesenterial lymphadenitis caused by Pasteurella pseudotuberculosis. J. Am. reed. Ass. 156, 195 (1954). 6. Girard, G., Relations 6ventuelles entre certaines ad~nites m~sent~dques aigu~s et la pseudotuberculose h "Pasteurellapseudotuberculosis" (bacille de Malassez et Vignal). Presse todd. 62, 1176-1177 (1954). 7. Ingelrans, Soots, Poupard and Vitse, Un cas d'ad6nite m6sent6rique aiguE/~ Pasteurella pseudotuberculosis. Lille Chir. 12, 201-203 (1957). 8. Mollaret, H. H., L'ad6nite m6sent&rique aigu~ /t "Pasteurella pseudotuberculosis" (bacille de Malassez et Vignal). A propos de 30 observations. II--Etude 6pid6miologique. Presse todd. 68, 1447-1450 (1960). 9. Mollaret, H. H., Une nouvelle cause possible d'6ryth6me noueux: le bacille de Malassez et Vignal (Pasteurella pseudotuberculosis)..Presse todd. 70, 1923 (1962). 10. Albrecht, H., Zur Atiologie der Enteritis follicularis suppurativa. Wien. Klin. Vy'schr. 23, 991-994 (1910). 11. Masshoff, W. and Dolle, W., t]ber eine besondere Forme der sog. mesenterialen Lymphadenopathie. "Die abscedierende reticulocytiire Lymphadenitis". Virchows ,4 rch. Path. anat. 323, 664-684 (1953). 12. Knapp, W., Pasteurella pseudotuberculosis als Erreger einer mesenterialen Lymphadenitis beim Menschen. Zbl. Bakt. I. Abt. Orig. 161,422-424 (1954). 13. Baron, H., Labbe, G. and MoUaret, H. H., Invagination intestinale et ad6nite m6sent6rique. Un cas dfi/~ une ad6nite ~.Pasteurellapseudotuberculosis. Arch.fr. Pddiat. XVIII, no 4, 512-516 (1961). 14. Lataix, P. and Perny, M., Ad6nite m6sent6rique et invagination intestinale. M~m. Acad. Chir. 87, 615, 619 (1961). 15. Labbe, G. and Chigot, P. L., Invagination intestinale et ad6nolymphite m6sent6rique. Rev. Prat. (Paris) 12, 417-424 (1962). 16. Mollaret, H. H., Invagination intestinale r6cidivante par ad6nite m6sent6rique due au Bacille de Malassez et Vignal. Presse todd. 74, 40, 2045-2046 (1966). 17. Graber, H. and Knapp, W., Die abscedierende reticulocyt~e Lymphadenitis mesenterialis (Masshoff) als Bestandteil eines enteralen Primiirkomplexes und Folge einer Infektion mit Pasteurella pseudotuberculosis. Frankfi Z. Path. 66, 399-415 (1955). 18. Graber, H., Der appendicitische Symptomenkomplex als Folge einer enteralen. Infektion mit Pasteurella pseudotuberculosis. Chirurg. 27, 401-403 (1956). 19. Mollaret, H. H., Grenet, P., Dugas, M., Iniguez, M. and Tancrede, C., La forme pseudo-tumorale de l'ad6nite m6sent6rique due au Bacille de Malassez et Vignal. Arch. Fr., b':diat. XXI, 5,521-539 (1964). 20. Morger, R., Zur "appendizitischen" form der Pasteurella pseudotuberculosis Infektion beim Kind. Praxis 51, 6, 142-144 (1962). 21. Boissi/.'re, H., Mollaret, H. H., Cagnat, R. and Correze, J. R., L'&yth6me noueux fi bacille de Malassez et Vignal. Ann. Pddiat. 41, no 29, 1293/P. 365-1299/P. 371 (1965). 22. Kerzoncuf, A., L'6ryth6me noueux ~. bacille de Malassez et Vignal. Th6se de Doctorat en M6dicine, 1967. 23. Kleibl, K. and Guiche, G., Premier cas alg6rien autochtone d'6ryth/~me polymorphe et d'6ryth/~me noueux/~ Yersinia pseudotubereulosis. Mdd. Mal. Infect. 8, 36 (1978). 24. Caillet, R., Hebert, J. P., Bognel, J. C., Hadchouel, P. and Larget-Piet, B., Septic/~mie /L Yersinia pseudotuberculosis avec arthrite r6actionnelle. Mdd. Mal. In,~. 7, 6, 308-310 (1977). 25. Lawrynowicz, AI., O Zakazenin rzekomo gruzliczem (bac. de la pseudotuberculose zoogle'ique Malassez et Vignal, B. pseudotuberculosis rodentium PfeUTer). czlowieka Polska Gaz. lek. 25, 574-577 (1925).
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26. Bouton, J. and Hall, E., Communication personnelle de H. H. Mollaret, 1962. 27. Mollaret, H. H. and Berthon, P., Une 6pid6mie due au Bacille de Malassez et Vignal. Presse todd. 70, 2570-2572 (1962). 28. Grancini, E., Sindrome oculoglandulare (congiuntivite di Parinaud) data dal "Bacterium pseudotubereulosis rodentium". (Pfeiffer). Boll. Oculist. 18, 133-163 (1939). 29. Knapp, W., Pasteurella pseudotuberculosis unter besonderer Beriicksichtigung ihrer humanmedizinischen Bedeutung. Ergebn-Mikrobiol. 26, 196-269 (1959). 30. Freland, C., Prost, A., Wallez, B., Cottin, S. and Trichereau, R., Arthrite suppur6e aigui~ ~. Yersinia pseudotuberculosis. Mdd. Mal. I~. 5, 8, 432-436 (1975). 31. Zaremba, M. L. and Los, Z., Un cas d'arthrite purulente du genou/~ Yersinia pseudotuberculosis. Mdd. Mal. Inf. 5, 10, 508-509 (1975). 32. Goret, P., Collet, P., Joubert, L. and Plier, Ch., Diagnostic exp6rimental et pathog6nie de la pseudotuberculose du chat. Bull. Soc. Sci. Vdt. Lyon. 57, 205-227 (1955). 33. Obwolo, M. J. and Gruffyd-Jones, T. J., Yersinia pseudotuberculosis in the cat. Vet. Rec. 424-425 (1977). 34. Goret, P., Joubert, L. and Pilet, Ch., Recherches exp6rimentales sur la pseudotuberculose. II.--Pseudotuberculose du chat. Diagnostic allergique exp6rimental. C. r. S~anc. Soc. Biol. 151, 2062-2064 (1957). 35. Goret, P., Joubert, L. and Pilet, Ch., Recherches exp6rimentales sur la pseudotuberculose. Ill--Infection exp~rimentale du chat. Rfle de l'allergie. C. r. S~ane. Soc. Biol. 151, 2116-2119 (1957). 36. Mollaret, H. H., Communication personneUe.
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PSEUDOTUBERCULOSIS IN MAN: POSSIBLE E P I D E M I O L O G I C A L R O L E O F THE CATS M. BOURDIN 5 Rue Eug6ne Varlin, 94450 Limeil Brevannes, France I N S E R M SCN3, Abstract--Human infection by Malassez and Vignal's bacillus (Yersinia pseudotuberculosis) can take many clinical aspects, the most frequent of which is mesenteric adenitis with pseudoappendicular syndrome, but occasionally also appearing as a tumor of the right lower abdominal quadrant. In a subsequent stage this mesenteric adenitis is often accompanied by erythema nodosum. There also exist some septicemia-like forms, which have become more and more frequent of late, always appearing on a particular terrain (predisposed persons). These various forms all correspond to contamination via the digestive route. Other, more exceptional modes of contamination may result in much rarer forms, such as ocular or pulmonary forms. Diagnosis is based on: (a) demonstrating the presence of Yersinia pseudotuberculosis, (b) serodiagnosis, (c) a positive intradermal reaction, (d) the characteristic aspect of lymph node lesions. Pseudotuberculosis is extremely frequent in animals. Many species, most of them rodents or birds, can serve as healthy carriers. This is how cats, through their access to this natural "reservoir", get contaminated and thus act as a "conveyor belt" in transmitting the disease to man.
Key words: Pseudotuberculosis, yersiniosis, Yersinia pseudotuberculosis, mesenteric, adenitis, erythema nodosum, septicemias, diagnosis, epidemiology LA PSEUDOTUBERCULOSE CHEZ L'HOMME: ROLE EPIDEMIOLOGIQUE POSSIBLE DU CHAT Resum6--L'infection humaine par le Bacille de Malassez et Vignal peut rev&ir cliniquement plusieurs aspects, le plus fr&luent, voire le plus banal est l'addnite mdsentdrique ~t symptomatologie pseudo-appendiculaire mais pouvant aussi se pr6senter comme une tumeur de lafosse iliaque droite. L "drythdme noueux est souvent associ6 dans un second temps ~ cette ad6nite m6sent6rique. I1 existe des formes septicdmiques de plus en plus fr~quentes survenant toujours sur un terrain particulier. Toutes ces formes correspondent fi une contamination par vole digestive. D'autres modes de contaminations plus exceptionnelles aboutissent h des formes beaucoup plus rarement rencontr6es: forme oculaire, forme pulmonaire. Le diagnostic est fonde, sur la mise en ~vidence de Yersinia pseudotuberculosis soit dans le ganglion soit dans le sang selon le cas, sur le sero-diagnostic, a l'aide de l'intradermoreaction, enlin par l'aspect particulier des 16sions ganglionnaires. Chez l'animal la pseudotuberculose est d'une extreme fr6quence. De nombreuses esp6ces essentiellement rongeurs et oiseaux peuvent ~tre porteurs sains. C'est en accb,dant fi ce reservoir naturel que le chat peut se contaminer et constituer ainsi le chainon assurant la transmission /~ rHomme.
Mots-clefs: Pseudotuberculose, yersiniose, Yersinia pseudotuberculosis, ad6nite m6sent6rique, erytheme noueux, septicemies, diagnostic, 6pidemiologie
INTRODUCTION P s e u d o t u b e r c u l o s i s , a y e r s i n i o s i s d u e to Yersinia pseudotuberculosis ( M a l a s s e z a n d V i g n a l ' s bacillus) w a s first d e s c r i b e d in a n i m a l s , e s p e c i a l l y g u i n e a pigs, b y M a l a s s e z a n d V i g n a l in 1883 [1]. F o r a l o n g t i m e it w a s t h o u g h t t o b e a strictly a n i m a l disease. E v e n t u a l l y Yersinia pseudotuberculosis w a s f o u n d in m a n y o t h e r species o f d o m e s t i c a n d wild a n i m a l s , as well as in b i r d s [2, 3]. 243
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The role of this bacillus in human pathology was brought to light only recently. Yersinia pseudotuberculosis official entry into human pathology took place 25 years ago, following the discoveries of the Tiibingen school [4, 51 on mesenteric adenitis. These discoveries were very quickly confirmed in many countries of Western Europe. In France, as early as 1954, Girard 161 drew the attention of the surgical community on the role played by this bacillus in mesenteric adenitis: observations by Ingelrans et al. [7], and Mollaret 181 revealed the frequency, not to say the common-place character of this syndrome. During the following years, a whole body of new knowledge accumulated rapidly and new clinical aspects were considered 191. CLINICAL STUDY The traditional classification differentiates between the general septisemic forms and the localised forms, the most frequent of which by far is mesenteric adenitis. But between these two extremes, a whole gamut of intermediate aspects exists. In this study we will consider first those forms secondary to enteral contamination, i.e. essentially mesenteric adenitis, erythemia nodosum, and the septicemic forms, as well as some other forms involving extra-mesenteric lymphatic adenitis. Then we will discuss the other forms, i.e. those secondary to non-enteral contamination: ocular forms, pulmonary forms and miscellaneous manifestations.
A. Forms secondary to enteral contamination Mesenteric adenitis This is by far the most frequent clinical form, even if it has been known for a relatively short time only: the first case was described by Albrecht [10]. It is only from 1954 onwards that mesenteric adenitis was systematically studied, thanks to the work of the Tiibingen school. In 1953, Masshoff and Dolle [11] described under the name of abscessing reticulocytic lymphadenitis a clinico-pathological picture consisting of inflammatory lymphatic lesions made up of reticulocytic proliferations preceding leucocytic infiltrations which, in turn, lead to necrosis and abscesses. In 1954, Knapp [12] succeeded in isolating Yersinia pseudotuberculosis from mesenteric lymph-nodes of children operated for mesenteric adenitis. From then on, many publications confirmed Knapp and Masshoff's discoveries and, in 1960, the first review article on French observations was written by Mollaret [8] who listed 30 cases. In its appendicular or "typical" form, mesenteric adenitis is a genuine surprise to the surgeon who operates after a diagnosis of acute appendicitis. The appendix proper is intact and a cluster of lymph nodes is discovered in the ileo-caecal area: exceptionally, only one lymph node is appended to the caecum; most of the time, the number of lymph nodes ranges from 2 or 3 to more than a dozen, their size sometimes exceeding that of an olive or even a walnut. The course is almost always benign, even without antibiotics: a mere appendectomy is sufficient to initiate a quick disappearance of the lymph-node cluster. From this rather schematic canvas, many variations have been noted, which range from: (1) severe toxic forms, to (2) nearly asymptomatic "formes frustes", detectable only inasmuch as they are systematically looked for in the brothers and sisters of an initial patient having had one of the typical forms of the disease.
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These "family"forms are practically the only ones to include a genuinely "silent" form, detectable only by means of serological diagnosis or systematic intradermal reaction. Other variants include forms with diarrhea, simulating paratyphoid fever and two other uncommon forms, namely (1) the form characterised by intussusception of the intestine, and (2) the pseudotumoral form. Intussusceptive forrns. Acute intestinal intussusception, as a revealing sign of mesenteric adenitis due to Yersinia pseudotuberculosis, is not exceptional. Several observations have been published [13, 14, 15, 16]. Pseudotumoralforms. These are frequent and their existence should be known, in view of the diagnosis problems they create. This form is not characterised by a mere increase in volume of the lymph-nodes but by a peculiar and alarming macroscopic aspect, raising a suspicion of malignancy. Numerous publications have reported this form. The "observatio princeps" was made by Albrecht, 1910 [10] cited above, and was followed by Graber and Knapp [ 171, Graber [ 18], and Mollaret et al. [19]. The circumstances causing a patient to consult are extremely varied, since the initial symptoms of the disease may resemble those of acute appendicitis or peritonitis or simply abdominal pains. But in all cases, on surgery, the findings are constant: there exists a bulky polylobated mass, frequently purplish in color, studded with numerous hemorrhagic spots, adhering to contiguous tissues and, to all appearances, giving the impression of a malignant tumor. All too often, unfortunately, on seeing this macroscopic aspect, a right hemicolectomy, based on this mere impression, is then performed whereas the fight attitude should be one of maximum conservatism. Complete recovery can be achieved without undue mutilation by a simple appendectomy, reinforced by antibiotherapy, and no need for surgically removing the lymph-node cluster other than that required for providing the material necessary for bacteriological and histological examinations.
Erythema nodosum The onset of erythema nodosum during the course of a Yersinia pseudotuberculosis infection is a very recent discovery. In 1962 Morger [20] published his observation of a young girl in whom erythema nodosum broke out in the few days following the operation she had had for mesenteric adenitis due to Yersinia pseudotuberculosis. ShOrtly afterwards, Mollaret 19] described 5 identical cases, while Boissiere et al. [21] brought forth new observations. Kerzoncuf [22] reports 52 cases of erythema nodosum, all of them observed in France, the aetiology of which was diagnosed by Mollaret at the Institut Pasteur in Paris. Finally Kleibl and Guiche [23] report the first case of autochtonous erythema nodosum observed in Algeria. This manifestation is freouent, especially among young boys, and makes its appearance during mesenteric adenitis, whether or not this latter disease has been clinically detected. The rash has a characteristic look and extends preferentially to the lower limbs, although it can occasionally spread to the forearms. Sometimes the erythema nodosum will seem to be isolated, but a well-conducted interview will retrieve the existence of a more or less discrete, painful syndrome having appeared in the preceding days or weeks. In all cases of erythema nodosum with unclear causes, it is recommended to look for a previous history of abdominal pains, and have a serologic diagnosis and an intradermal reaction performed.
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Septicemic forms These forms are more and more frequent and always appear on a specific "terrain": old age, diabetes, alcoholism, or else in young patients suffering from certain hematological diseases [24]. Such forms make up a septicopyohemic picture where, in an altogether sensitive abdomen, an enlarged and painful liver is the sign most frequently encountered. Solenomegaly, too, is frequent. A very valuable sign is afforded by manifestations of slight or marked jaundice. The course remains fatal, in spite of the treatment, in one case out of three, in view of the "terrain" over which septicemia develops.
Extra-mesenteric adenitis Superficial or deep adenopathies have been reported, usually during mesenteric adenitis and, exceptionally, in the course of generalised forms. Cervical localisations have been described by Lawrynomicz [25], Bouton and Hall [26], MoUaret and Berthon [27]. The joint occurrence of a cervical with an inguinal localisation has been reported by Ingelrans et aL [7].
B. Forms secondary to non-enteral contamination These are exceptional.
Ocular forrns This is the classical oculoglandular syndrome, known as Parinaud's syndrome, in which bacilli can be observed in cultures made from conjunctival secretions. The only two authentic cases of Parinaud's conjunctivitis are the ones described by Grancini [28] and by Knapp [291.
Pulmonary forms Although exceedingly rare, these forms should not be ignored, in view of their clinical identity with pulmonary plague. The only genuine case known to this day took place in Brussels in 1925 and was never published. The patient was a rag-peddler who died within a few days. The general clinical picture he presented led to a diagnosis of Yersinia pestis pneumonia. Only afterwards was a bacteriological study undertaken and the strain recognised as Yersiniapseudotuberculosis.
Miscellaneous manifestations Some cases of arthritis have been reported in 1975 by Freland et al. [30] and Zaremba et al. [31].
Recapitulation Apart from the appendicular form of mesenteric adenitis, all the clinical manifestations of Yersinia pseudotuberculosis infection are proteiform, rather unspecific and often deceiving. Laboratory tests are the only means of arriving at a reliable diagnosis.
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DIAGNOSIS A. Clinical diagnosis (a) Septicemic forms, even in their classical jaundice-like aspect, are not specific enough to permit a firm diagnosis. Only a blood culture will be able to identify the nature of the germ involved. (b) Mesenteric adenitis is usually discovered on surgery, the operation being performed under a diagnosis of acute appendicitis. Tumoral forms are liable to be confused with a malignant tumor, a sarcoma of the small intestine, etc. (c) Erythema nodosum will have to be distinguished from those due to tuberculosis or streptococcemia or simply to drugs. (d) Ocularforms are liable to be confused with tularemia or other forms of conjunctivitis of various origins.
Recapitulation Whatever clinical presumptions may be entertained by certain suggestive cases, resorting to laboratory tests is absolutely indispensable.
B. Laboratory investigations Four classes of methods may be used: Demonstration of the presence of the bacillus by blood or fecal cultures. Serology. Intradermal reaction. Histological examination of tissues obtained by an appendicular or lymph node biopsy.
Demonstration of the bacillus by means of a blood or fecal culture This is the choice procedure to demonstrate the role of Yersinia pseudotuberculosis. Not only is it the surest criterion but it also is the only one to provide an indication for the correct therapy to be adopted after studying the germ's sensitivity to antibiotics. Tissue sampling: most of the time this will concern a mesenteric lymph node or possibly, on autopsy of septicemic forms, the liver, the spleen or the red marrow of bones. Blood culture is imperative in the case of a septicemic form. Fecal culture is usually performed too late after surgery or after administration of antibiotics. The identification of Yersinia pseudotuberculosis is easy. This bacillus is gram-negative, motile below 30°C, non-motile above 30°C, with a rapidly-acting urease. The differential diagnosis of Yersinia pseudotuberculosis is easy, all the more so since the site of origin of the strain (mesenteric lymph node) is clearly suggestive. In fecal cultures, on the other hand, a confusion may easily be made with a Proteus (although Yersinia pseudotuberculosis has a negative T.D.A.). Identification will be confirmed by determining the antigenic typing. Strains isolated in man, both in France and abroad, belong to group I.
Serological diagnosis This is done by looking for agglutinating antibodies. The minimum significant titre for positivity is 1/100. Two samplings should be performed, 6 - 8 days apart, in order to ascertain the antigen titre has not varied. Administration of antibiotics does not seem to modify it. An abnormal persistence of antibodies reflects the persistence of germs in the lymph-nodes.
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Even though the post-operative course may be excellent, one cannot speak of complete recovery as long as the antigen titre remains stationary. Thus, seroagglutination possesses not only a diagnostic value but a prognostic value as well.
Pathologic diagnosis This bears almost exclusively on those mesenteric lymph-nodes where disseminated microabscesses are observed, accompanied by an epithelio'id reaction (or even by Langhans cells and sometimes caseification).
lntradermal reaction diagnosis The diagnostic interest of the intradermal reaction is particularly valuable in view of its highly specific character, whatever the serotype of the strain involved, and also because of the persistence of dermal sensitivity for years after the disease. Performing an intradermal reaction requires the injection of 1/20 to 1/10 ml of allergen in strictly intradermal fashion. The reaction can be read off after 48 hr. A positive reaction gives a red and edematous area, 1 - 2 in. in diameter. Persistence of dermal sensitivity. This lasts at least 5 - 6 years. It does not reflect a current infection, as sero-diagnosis does, but allows a retrospective diagnosis. The onset of dermal sensitivity is simultaneous with the appearance of agglutinins. The four above methods should be implemented in parallel since (a) any of the four may fail and (b) each has its own significance. EPIDEMIOLOGY OF THE DISEASE IN MAN Altogether, the quasi-totality of cases recorded so far have been observed mainly in Western and Central Europe (Switzerland, the Netherlands, Great Britain, Denmark, Belgium, Poland, Romania). Some cases have been reported from the United States, Canada, New Zealand and Africa. As new cases are reported, the geographical distribution of the disease in man appears increasingly to coincide with that of the animal disease. If we can take for a well-established fact the digestive mode of contamination, no agreement prevails about the source of the disease or its conditions of appearance. To be sure, a number of arguments are in favor of an animal origin, but this was demonstrated in only very few cases. The cat is the most likely culprit, being the most familiar animal on the one hand, and serving as the link between children and the large natural pool made up by rodents and birds on the other hand. But the frequency of the disease, in its natural form, in cats is difficult to assess: it seems to have varied, and continues to vary, over the years from one region to another. The disease was observed only exceptionally at the Toulouse National Veterinary School, whereas at the Lyon National Veterinary School, 80% of the jaundice cases observed in cats were due to Yersinia pseudotuberculosis. It would appear that the diagnosis of pseudotubereular infection in the cat is no longer pronounced by present-day practitioners, which is in contrast with the relatively high frequency of cases of the disease observed in the course of inquiries about the human disease. According to H. H. Mollaret, cats are the second largest source of contamination of children, the first being the population of small mammals (mice, guinea-pigs, hamsters) kept as home pets. Cats probably become infected through the digestive route as a result of eating rodents or birds, either sick or healthy carriers, or possibly viscera of hares and rabbits. Goret et al., 1955 [32] reported that, among the cases they had had occasion to observe, almost all the cats were good rat-catchers, that
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would feed on their prey after having killed it. By contrast, cats born and reared in apartments never caught the disease. The same observation was reported by Obwolo in 1977 1331. Even after an injection of bacilli isolated from contaminated animals, cats can remain healthy carriers for a long time (several months), harboring Yersinia pseudotuberculosis in their digestive tract. An auxiliary factor would seem to be required to trigger the disease. Also, the allergy which Goret et aL [34, 35] demonstrated in experimental infections, might be present and play an active role in the natural disease. As early as 1910, Albrecht [ 10] suspected the cat as a possible propagator of Yersinia pseudotuberculosis and the probable source of human contamination. "The patient lived in a fiat where the owner's cats had a free access to the kitchen, its utensils, dishes, plates, etc. This leads us to surmise that these cats were latent carriers of bacilli and acted as vectors of the human infection. They must have been contaminated after eating rats or mice which were infected with Malassez and Vignal's bacillus and whose feces contained the organism." Another similar case is that of a man who died of Yersinia pseudotuberculosis septicemia. For some time he had been digging work in a garden whose owner had a cat which had come down with diarrhea. Following euthanasia of this cat, Yersinia pseudotuberculosis was isolated from its lesions. In addition to these "lucky" observations, Mollaret [36] reports having come across feline pseudotuberculosis on very frequent occasions while conducting epidemiological inquiries on cases involving children: most of the time, it turned out that shortly before the child became ill, the cat had died after a diarrheic episode and without having been examined by a veterinarian. In a few cases, where the cat had died recently, an autopsy was made and Yersinia pseudotuberculosis was isolated. In some other cases, the cat was apparently in good health but repeated fecal cultures finally managed to isolate the organism in a healthy feline carrier. By repeatedly licking her genitals and/or anus and then her fur, a cat can contaminate any person who strokes her, and particularly children. Rats and mice may also be incriminated insofar as they can accede to food supplies which they can contaminate through their urine or feces. The outbreak conditions of the disease have yet to be identified: diabetes, immunodepressing drugs, alcoholism are favorable factors for septicemia. Most cases of human infection occur during the winter, i.e. cold and humid spells. But in addition to this winter maximum, a second peak can be observed between April and May, depending on the year and on the country; this second peak can perhaps be ascribed to the consumption, by humans, of fruit and vegetables soiled by traces of contaminated manure. Mesenteric adenitis is encountered mostly among young people (usually between 6 and 17), whereas enteritic forms are observed preferentially in young adults, and septicemia in old people or weakened subjects. As for the prevalence of mesenteric adenitis in males, this is more apparent than real since, anatomically, the frequency of adenitis is identical in boys and in girls; but girls seem to tolerate lymph-node disorders without clinical manifestations whereas boys exhibit more pronounced reactions. TREATMENT As in all infections due to Yersinia, whatever the strain (Y. pseudotuberculosis, Y. enterocolitica or Y. pestis), streptomycin is the antibiotic of choice, but the actual treatment,
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of course, will depend on the results of the tests assessing the sensitivity of bacteria to antibiotics. CONCLUSION S u c h is, in its m a i n features, the " s t a t e o f the a r t " r e g a r d i n g h u m a n infection by Y. pseudotuberculosis. S o m e aspects are n o w secured on firm f o u n d a t i o n s but others h a v e yet to be elucidated or c o m p l e t e d , in p a r t i c u l a r in the areas o f pathogenesis and epidemiology.
REFERENCES 1. Malassez, L. and Vignal, W., Sur le microorganisme de la tuberculose zoogl6ique. Arch. Phys. normale et pathologique 36me s6rie, tome IV, 81-105 (1884). 2. Barre, N., Louzis, C. L. and Tuffery, G., Contribution/~ l'6tude 6pid6miologique de l'infection ~ Yersinia pseudotuberculosis chez les animaux sauvages en France. Rev. Med. Vet. 128, 11, 1545-1567 (1977). 3. Bourdin, M., L'infection/~ bacille de Malassez et Vignal: Zoonose d'avenir. Th6se Doctorat V&6rinaire, Alfort (1967). 4. Masshoff, W., Eine neuartige form der mesenterialen Lymphadenitis. Dt. med. l.Vschr. 78, 532-535 (1953). 5. Knapp, W., Mesenterial lymphadenitis caused by Pasteurella pseudotuberculosis. J. Am. reed. Ass. 156, 195 (1954). 6. Girard, G., Relations 6ventuelles entre certaines ad~nites m~sent~dques aigu~s et la pseudotuberculose h "Pasteurellapseudotuberculosis" (bacille de Malassez et Vignal). Presse todd. 62, 1176-1177 (1954). 7. Ingelrans, Soots, Poupard and Vitse, Un cas d'ad6nite m6sent6rique aiguE/~ Pasteurella pseudotuberculosis. Lille Chir. 12, 201-203 (1957). 8. Mollaret, H. H., L'ad6nite m6sent&rique aigu~ /t "Pasteurella pseudotuberculosis" (bacille de Malassez et Vignal). A propos de 30 observations. II--Etude 6pid6miologique. Presse todd. 68, 1447-1450 (1960). 9. Mollaret, H. H., Une nouvelle cause possible d'6ryth6me noueux: le bacille de Malassez et Vignal (Pasteurella pseudotuberculosis)..Presse todd. 70, 1923 (1962). 10. Albrecht, H., Zur Atiologie der Enteritis follicularis suppurativa. Wien. Klin. Vy'schr. 23, 991-994 (1910). 11. Masshoff, W. and Dolle, W., t]ber eine besondere Forme der sog. mesenterialen Lymphadenopathie. "Die abscedierende reticulocytiire Lymphadenitis". Virchows ,4 rch. Path. anat. 323, 664-684 (1953). 12. Knapp, W., Pasteurella pseudotuberculosis als Erreger einer mesenterialen Lymphadenitis beim Menschen. Zbl. Bakt. I. Abt. Orig. 161,422-424 (1954). 13. Baron, H., Labbe, G. and MoUaret, H. H., Invagination intestinale et ad6nite m6sent6rique. Un cas dfi/~ une ad6nite ~.Pasteurellapseudotuberculosis. Arch.fr. Pddiat. XVIII, no 4, 512-516 (1961). 14. Lataix, P. and Perny, M., Ad6nite m6sent6rique et invagination intestinale. M~m. Acad. Chir. 87, 615, 619 (1961). 15. Labbe, G. and Chigot, P. L., Invagination intestinale et ad6nolymphite m6sent6rique. Rev. Prat. (Paris) 12, 417-424 (1962). 16. Mollaret, H. H., Invagination intestinale r6cidivante par ad6nite m6sent6rique due au Bacille de Malassez et Vignal. Presse todd. 74, 40, 2045-2046 (1966). 17. Graber, H. and Knapp, W., Die abscedierende reticulocyt~e Lymphadenitis mesenterialis (Masshoff) als Bestandteil eines enteralen Primiirkomplexes und Folge einer Infektion mit Pasteurella pseudotuberculosis. Frankfi Z. Path. 66, 399-415 (1955). 18. Graber, H., Der appendicitische Symptomenkomplex als Folge einer enteralen. Infektion mit Pasteurella pseudotuberculosis. Chirurg. 27, 401-403 (1956). 19. Mollaret, H. H., Grenet, P., Dugas, M., Iniguez, M. and Tancrede, C., La forme pseudo-tumorale de l'ad6nite m6sent6rique due au Bacille de Malassez et Vignal. Arch. Fr., b':diat. XXI, 5,521-539 (1964). 20. Morger, R., Zur "appendizitischen" form der Pasteurella pseudotuberculosis Infektion beim Kind. Praxis 51, 6, 142-144 (1962). 21. Boissi/.'re, H., Mollaret, H. H., Cagnat, R. and Correze, J. R., L'&yth6me noueux fi bacille de Malassez et Vignal. Ann. Pddiat. 41, no 29, 1293/P. 365-1299/P. 371 (1965). 22. Kerzoncuf, A., L'6ryth6me noueux ~. bacille de Malassez et Vignal. Th6se de Doctorat en M6dicine, 1967. 23. Kleibl, K. and Guiche, G., Premier cas alg6rien autochtone d'6ryth/~me polymorphe et d'6ryth/~me noueux/~ Yersinia pseudotubereulosis. Mdd. Mal. Infect. 8, 36 (1978). 24. Caillet, R., Hebert, J. P., Bognel, J. C., Hadchouel, P. and Larget-Piet, B., Septic/~mie /L Yersinia pseudotuberculosis avec arthrite r6actionnelle. Mdd. Mal. In,~. 7, 6, 308-310 (1977). 25. Lawrynowicz, AI., O Zakazenin rzekomo gruzliczem (bac. de la pseudotuberculose zoogle'ique Malassez et Vignal, B. pseudotuberculosis rodentium PfeUTer). czlowieka Polska Gaz. lek. 25, 574-577 (1925).
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26. Bouton, J. and Hall, E., Communication personnelle de H. H. Mollaret, 1962. 27. Mollaret, H. H. and Berthon, P., Une 6pid6mie due au Bacille de Malassez et Vignal. Presse todd. 70, 2570-2572 (1962). 28. Grancini, E., Sindrome oculoglandulare (congiuntivite di Parinaud) data dal "Bacterium pseudotubereulosis rodentium". (Pfeiffer). Boll. Oculist. 18, 133-163 (1939). 29. Knapp, W., Pasteurella pseudotuberculosis unter besonderer Beriicksichtigung ihrer humanmedizinischen Bedeutung. Ergebn-Mikrobiol. 26, 196-269 (1959). 30. Freland, C., Prost, A., Wallez, B., Cottin, S. and Trichereau, R., Arthrite suppur6e aigui~ ~. Yersinia pseudotuberculosis. Mdd. Mal. I~. 5, 8, 432-436 (1975). 31. Zaremba, M. L. and Los, Z., Un cas d'arthrite purulente du genou/~ Yersinia pseudotuberculosis. Mdd. Mal. Inf. 5, 10, 508-509 (1975). 32. Goret, P., Collet, P., Joubert, L. and Plier, Ch., Diagnostic exp6rimental et pathog6nie de la pseudotuberculose du chat. Bull. Soc. Sci. Vdt. Lyon. 57, 205-227 (1955). 33. Obwolo, M. J. and Gruffyd-Jones, T. J., Yersinia pseudotuberculosis in the cat. Vet. Rec. 424-425 (1977). 34. Goret, P., Joubert, L. and Pilet, Ch., Recherches exp6rimentales sur la pseudotuberculose. II.--Pseudotuberculose du chat. Diagnostic allergique exp6rimental. C. r. S~anc. Soc. Biol. 151, 2062-2064 (1957). 35. Goret, P., Joubert, L. and Pilet, Ch., Recherches exp6rimentales sur la pseudotuberculose. Ill--Infection exp~rimentale du chat. Rfle de l'allergie. C. r. S~ane. Soc. Biol. 151, 2116-2119 (1957). 36. Mollaret, H. H., Communication personneUe.