1. List of papers
3. Aims of the present study
4. Methodological considerations
5. Statistical methods
6. Results and general discussion (summary of the papers)
LIST OF PAPERS
l) Saebo A, Kapperud G, Lassen J, Waage J. Prevalence of antibodies to Yersinia enterocolitica
O:3 among Norwegian military recruits: Association with risk factors and clinical
manifestations. Eur J Epidemiol 1994; 10: 749-755.
ll) Saebo A, Lassen J. A survey of acute and chronic disease associated with Yersinia
enterocolitica infection. A Norwegian 10-year follow-up study on 458 hospitalized patients.
Scand J Infect Dis 1991; 23: 517-527.
lll) Saebo A, Lassen J. Acute and chronic gastrointestinal manifestations associated with
Yersinia enterocolitica infection. A Norwegian 10-year follow-up study on 458 hospitalized
patients. Ann Surg 1992; 215: 250-255.
lV) Saebo A, Lassen J. Acute and chronic liver disease associated with Yersinia enterocolitica
infection: a Norwegian 10-year follow-up study of 458 hospitalized patients. J Int Med 1992;
V) Saebo A, Lassen J. Acute and chronic pancreatic disease associated with Yersinia
enterocolitica infection: a Norwegian 10-year follow-up study of 458 hospitalized patients. J Int
Med 1992; 231: 537-541.
Vl) Saebo A, Nyland H, Lassen J. Yersinia enterocolitica infection - an unrecognized cause of
acute and chronic neurological disease? A 10-year follow-up study on 458 hospitalized
patients. Med Hypotheses 1993; 41: 282-286.
Vll) Saebo A, Elgjo K, Lassen J. Could development of malignant mesothelioma be induced by
Yersinia enterocolitica infection? Med Hypotheses 1993; 40: 275-277.
Vlll) Saebo A, Lassen J. Survival and causes of death among patients with Yersinia
enterocolitica infection. A Norwegian 10-year follow-up study on 458 hospitalized patients.
Scand J Infect Dis 1992; 24: 613-617.
The genus Yersinia of the family Enterobacteriaceae includes three well-established human
pathogens (Y. pestis, Y. pseudotuberculosis, and
Y. enterocolitica), and several non-pathogens (1, 2).
Y. pestis, the causative organism of the bubonic plague was isolated by Alexandre Yersin, in
1894 (3). Since antiquity, this microorganism has caused four great pandemics. The 14th.
century pandemic (the Black Death) may have killed a third of Europe's population; in Norway
as much as 40-50% of the population may have died (4).
Y. pseudotuberculosis (described 1884) causes epizootic disease, especially in rodents, with
necrotizing granulo matous disease of liver, spleen and lymph nodes. In humans it may cause
acute abdominal disease, septicemia, arthritis and erythema nodosum (5, 6).
Y. enterocolitica (Bacterium enterocoliticum) was first described by Scleifstein a nd Coleman
(USA) in 1939 and 1943 (7, 8). Only a few isolations were reported during the following years,
and these were labelled differently, as the species was as yet unclassified. In Europe, the
microorganism was isolated from two patients who died of generalized infection with liver
abscesses, in 1949 (9). In 1964, it was isolated from a patient who underwent surgery because of
acute terminal ileitis (10), and the same year the species name Yersinia enterocolitica was
proposed. During the follo wing years, it was isolated from humans with gastrointestinal
disease in many countries , most frequently in cooler climates (1, 11).
Y. enterocolitica is a facultative anaerobic, Gram-negative asporogenic rod that exhibit s
significant pleomorphism. It has been classified into approximately 70 serogroups on the basis
of O antigens (12) The strains pathogenic for man and animals belong to only a few
serogroups, and show distinct serogroup-biovar-phagevar combinations (1). T he
serogroup-biovar combinations commonly involved in human disease are O:3 biovar 4, O:9
biovar 2, O:8 biovar 1B, and O:5,27 biovar 2. Serogroup O:3 is the most frequently encountered
in Europe, followed by O:9. In Norway, almost exclusively serogroup O: 3 (biovar 4, phagevar
Vlll) is encountered.
Y. enterocolitica is able to multiply at temperatures approaching 0 o C, it can grow in properly
refrigerated foods, and survive in frozen foods for long periods (13).
Y. enterocolitica requ ires iron for growth, but is unable to synthesize iron-binding substances
(siderophores), and in consequence must obtain them
from other bacteria or host tissue (14). Normal human tissue iron concentrations are
growth-limiting, but individuals with ir on overload are prone to acquire disseminated infections
(15, 16, 17, 18, Notice ADDENDUM - 172).
Human serum is bactericidal against Y. enterocolitica (19); heating the serum at 56 o C abolishes
the killing, indicating involvement of compleme nt (20).
The essential pathogenic factors of Y. enterocolitica are its abilities to invade animal cells, and
to multiply within animal cells, even in macrophages (21, 22). The pathogenic serogroups of Y.
enterocolitica harbour a plasmid (small extrachromosomal piece of DNA) 40-50 megadaltons in
size, which encodes a series of proteins, several of which are important virulence factors (22).
Many strains of Y. enterocolitica produce a heat-stable enterotoxin when cultured at 25 o C
(23); and some strains even at refrigeration temperatures of 3-6 o C. (24). The enterotoxin is not
produced at normal body temperature, neither under anaerobic conditions; its relevance in
diarrheal disease has therefore been doubted (25).
Reservoir and tran smission
Y. enterocolitica is considered to be a food-borne pathogen, but only during a few outbreaks
(one in Europe) has it been isolated from suspected food sources (26, 27). The pig is the only
animal consumed by man which regularly harb ours pathogenic Y. enterocolitica (28), and its
occurrence in pork product may have been underestimated (29, 27). A high percentage of
Norwegian slaughter pigs are healthy carriers of serogroup O:3 (30).
Firm evidence for transmission by consum ption of contaminated water is lacking (28, 31), but
consumption of untreated water has recently been identified as a risk factor for infection (27).
Contamination of donor blood with Y. enterocolitica may represent a hazard in blood
transfusion ( 32).
Diagnosis of Y. enterocolitica infection
During the first days or weeks of the acute infection, Y. enterocolitica may be isolated from
stools of most patients presenting with diarrhea, or from mesenteric lymph nodes of patients w
ho are subject to laparotomy (25, 33). However, a substantial part of patients with acute
infection do not present enteritic symptoms. In these, as in patients with chronic disease,
diagnosis must rely on demonstration of a significant antibody response a gainst the
microorganism. For this purpose, tube agglutination has been widely used in the Nordic
countries. This method may be complicated by the existence of cross-reacting antigens (25, 34,
35), but the reported cross-reactions have largely been attrib uted to serogroups other than O:3,
which has been recognized as immunologically specific (36). Other methods including
enzyme-linked immunosorbent assays (ELISA) and radioimmunoassays (RIA) are now available
Acute manifestations of the Y. enterocolitica infection like abdominal pain and diarrhea,
mesenteric lymphadenitis / regional ileitis (5, 10, 37), arthritis or erythema nodosum (5, 38, 39),
and fulminant disease and septicaemia in patients with debilitating diseas es (9, 15) have been
recognized for twenty-five years. The most common acute manifestation may be a self-limited
gastroenteritis, especially in children (25, 40). The scope of the infection's manifestations has
steadily been extended, thus hepatic (5, 15, 39), pancreatic (41, 42), renal (39, 43), cardiac (5, 38,
39, 44, 45, 46), venous (47), pulmonary (48, 49), eye (5, 50), neurologic (5, 51, 52), or thyroid (53)
involvements, spontaneous abortion (5), conditions resembling sarcoidosis (54), and adverse e
ffect of iron (16, 17) have been reported.
In Norway, Y. enterocolitica is the cause of considerable morbidity. During 1982-1991, a total of
1958 bacteriologically verified cases were recorded by the Norwegian national surveillance
system. A ca se-control study, performed in the Oslo region during the period October 1988
through January 1990, detected an incidence rate of 6.4 bacteriologically confirmed
cases/100.000 population/year. Approximately 90% of the cases had acquired the infection in N
orway, and more than 95% of the infections were caused by serogroup O:3, biovar 4 (40).
Chronic manifestations. Clinical follow-up studies have documented that ankylosing
spondylitis may develop subsequently to Y. enterocolitica infection , especially in patients
presenting the histocompatibility antigen HLA-B27 (55, 56). An association between Y.
enterocolitica infection and rheumatoid arthritis has further been suggested (57, 58).
Regarding abdominal disease, several previous r eports claim that sustained or recurrent
diarrhea or abdominal pain may follow the acute Y. enterocolitica infection (5, 59, 60, 61). An
association with chronic colitis or ulcerative colitis (UC) was suggested from clinical observa
tions twenty years ago (38, 62), later were high frequencies of specific antibodies observed
among patients with UC (58) and Crohn's disease (CD) (63). In 1977, clinical observations made
me suggested the possibility of chronic liver involvement (64), and during the following years
reports of granulomatous hepatitis were added (65, 66, 67). Recently, virulent Y. enterocolitica
has been identified by immunofluorescent techniques in a patient with chronic granulomatous
hepatitis, and in patients with chronic intestinal disease (68). Acute glomerulonephritis
seemingly may progress to chronic nephropathy (69). Associations with chronic thyroid
disease (53), sarcoidosis-like conditions (54) and neurological disease (52) have been
suggested. Clinical ob servations indicating development of chronic disease are mirrored by the
demonstration of circulating immune complexes (70, 71), and deposits of immune complexes and
complement component C3 in diseased tissue (69).
AIMS OF THE PRESENT STUDY
Through a study on 755 Norwegian military recruits
( To assess the prevalence of antibodies to Y. enterocolitica O:3 among healthy young
Norwegians, and to observe possible regional differences in prevalence.
( To id entify risk factors associated with antibody activity to Y. enterocolitica.
( To study possible associations between particular clinical complaints and antibody activity to
Y. enterocolitica, as between previous appendectomy and anti body activity.
Through follow-up study on 458 hospitalized patients
( To further study frequency, clinical course and mutual relationship of acute and chronic
clinical manifestations known to be associated with the Y. entero colitica infection.
( To possibly describe previously unknown acute or chronic clinical manifestations associated
with Y. enterocolitica infection.
( To observe possible immunological aberrations associated with Y. entero-c olitica infection,
and estimate their relationship to clinical disease.
( To study the influence of the Y. enterocolitica infection on long time survival, and describe
clinical conditions associated with death.
METHODOLOGIC AL CONSIDERATIONS
In a small country like Norway, with obligate military service, military recruits constitute a
population well suited for medical research, especially prevalence and analytic epidemiological
The study was conducted at the Norwegian naval training camp in southwestern Norway.
Among 791 recruits who were enrolled for their obligate service in January 1987, 755 (95%)
participated in the study.
The 755 recruits were all healthy Nor wegian males of approximately the same age (19-26 years
old). They represented all districts of Norway, different socio-economic classes, and different
Blood samples for evaluation of antibody response to Y. enterocolitica w ere obtained from all
755 recruits within seven days after they entered the camp. In the meantime, there had been no
outbreak of gastroenteritis in the camp.
Within two weeks, the recruits answered a standardized questionnaire covering: (i)
demographic data, (ii) specific exposures, and (iii) clinical information. The questions were
precise and easily understandable.
Information on peroperative findings was obtained from hospital case records in 26 of 34
recruits with previous appendectomy.
During the 10-year period 1974-1983, Y. enterocolitica infection was diagnosed in 553
hospitalized patients, by antibody response and/or isolation of the microorganism. Excluded
were 95 patients with insufficient or missing hospit al files. Adequate clinical information was
obtained on 458 patients (202 males and 256 females) admitted to 52 different hospitals, and,
dependent on the clinical manifestations, to departments of internal medicine, surgery,
orthopedic surgery, rheumato logy, pediatrics, gynaecology and obstetrics, opthalmology,
neurology, pulmonary diseases, and dermatology.
The 458 patients constituting the material of the study were followed as a cohort prospectively
(in sense of the directional pursuit), from th e Y. enterocolitica infection, in order to observe
eventual chronic complications. However, the diagnostic methods used in the period 1974-83
were not equal to those presently available. Sophisticated methods for the demonstration of
Yersinia in diseased tissues were not accessible, and in many cases the evidence of chronic
yersiniosis was circumstantial.
Clinical data were obtained from the various departments upon the first admission, and from all
subsequent admissions. Valuabl e information was also obtained through general practitioners.
Records of death were obtained from local registraries.
At termination of the study (June, 1987), 46 patients were dead and two could not be located.
Of the remaining patients 380/410 (92. 7%) replied to a detailed clinical questionnaire,
concerning development of chronic conditions that might be attributable to yersiniosis, and
recent medical assistance or hospital admission. In case of 12/30 patients who did not answer
the questio nnaire we have complete hospital records, therefore the final clinical information is
missing in only 18/410 patients alive (4.4%).
Selected groups were more closely reexamined:
1) Twenty four patients who had been admitted to Bergen University Hospital underwent a
thorough examination including assessment of antibody response to Y. enterocolitica,
evaluation of serum levels of complement component, liver function tests, and tests for
antinuclear factor (ANA) and rheumatoid factor (RF). P atients with persisting arthralgic
complaints were examined for urethritis and for presence of the histocompatibility antigen
HLA-B27, and had radiographic examinations of ileosacral and extremity joints. Patients with
severe chronic diarrhea underwent ra diographic investigation of the small intestine,
duodenoscopy and colonoscopy, and were examined for malabsorption. Patients with elevated
liver parameters were examined for liver disease. Complement component levels were compared
with those of 32 first d egree relatives and 25 unrelated controls, without antibodies to Y.
2) Special attention was paid to patients with neurological symptoms. These patients were last
reexamined in 1991, with estimation of antibody activity to Y. enterocolitica.
3) Several patients admitted to Akershus Central Hospital have been followed for twenty years
by the author; some were also included in a previous follow-up study (60).
Totally, the information on the 458 patients of the present study constitute a database of more
than 20.000 pieces of information.
The study of clinical yersiniosis requires a large patient population, followed for a period
sufficiently long for the development of chronic disease. At present, th ese demands may be
fulfilled only by including patients from several hospitals, and by using a retrospective
approach that obviously will carry certain flaws.
In Norway, determination of antibodies to Y. enterocolitica was introduced, in 1972, b y the
National Institute of Public Health, and for several years performed almost exclusively by the
institute's laboratory. Also samples for cultivation were usually admitted to this laboratory. The
institute's records therefore constitute a unique entra nce to yersiniosis in Norway.
The material is unbiased in the respect that all patients with available hospital record were
included. However, a material constituted by hospitalized patients is selective both by nature
and severity of clinical m anifestations; the present study in consequence may concern the
more serious manifestations of the Y. enterocolitica infection.
The majority of patients were admitted to hospitals in south-eastern Norway; an observation in
concert with the reg ional distribution of IgG antibody activity observed in the prevalence
According to the complexity of the material, and to the fact that the data concerning patient
entry were documented in the past, it was found impracticable to collect a rel iable control
material with a corresponding age, sex, and geographical distribution, constituted by
individuals definitely without previous infection with Y. enterocolitica, and with a sufficiently
long follow-up period. However, the death rate of the study population was compared with the
national death rate, and the prevalences of UC and diabetes were compared with prevalences
observed in previous Norwegian studies. Serum levels of complement components of the
Bergen University Hospital patients were compared with those of control groups. Some of the
Akershus Central Hospital patients were compared with patients without antibodies to Y.
enterocolitica in a previous follow-up study (60). Clinical subgroups of the material were
compared with each other, and with themselves over time.
Diagnosis of Y.enterocolitica infection:
During the epidemiological study, diagnosis was based on an enzyme-linked immunosorbent
assay (ELISA) using lipopolysaccharide extract ed with hot phenol water as antigen (72). Net
absorbance values (absorbance in the sample minus the absorbance in the negative control) of
( 0.1 were regarded as significant. A net absorbance of ( 0.5 or an increase in the activity of at
least 30 % in two consecutive serum samples, was considered indicative of actual or recent
infection. The method has been described in Paper l. In addition to IgG activity, serum samples
were also examined for IgM and IgA activity.
During the clinical study, diagn osis of Y. enterocolitica infection was based on the following
a) isolation of Y. enterocolitica from fecal samples, and/or
b) antibody response to Y. enterocolitica as evaluated by one of the following met hods: i)
bacterial whole cell agglutination using alcohol treated bacterial cells as antigen. An
agglutination titer of ( 640, or a four-fold or greater increase of the titer in two consecutive
samples, was recognized as indicative of an actual or recent infection (1974 -1982). ii) ELISA as
described above. Serum samples were examined for both specific IgG and IgM activity. (1982
Complement components C3, C4, C3 activator and C1-INH (C1 esterase inhibitor) were
quantitated using single radial immunodiffusion with commercial plates purchased from
Behringwerke AG, Marburg an der Lahn, Germany.
Liver function tests were performed with autoanalyzer technique.
Other laboratory and clinical examinations in local hospital s were performed according to
During the epidemiological study, univariate analysis was performed with the computer
program Epi Info (Centers for Disease Control, Atlanta, USA). The signifi cance of differences
between groups was assessed using chi-square testing; Fisher's exact test was used when an
expected cell value was less than 5. Multivariate analysis on 30.000 data elements, with multiple
linear logistic regression was done with the computer program Egret (Statistics and
Epidemiology Research Corporation, Seattle, USA). All results were expressed as odds ratios
(OR) with 95% confidence intervals (CI) and two-tailed p- values.
During the clinical study, the two-sample Student's t- test, the standard error of differences
between two proportions, the chi-square test, and Fisher's exact (all two-tailed) were used for
comparison between subgroups of the material. For statistical comparison between observed
and expected survival rates w as used the log-rank or Mantel-Haenszel test, which is
considered a valid test of the null hypothesis that the survival functions of two populations are
the same. It is, in some sense, optimal if the difference arises because the mortality rate in one
gro up is a constant multiple of the corresponding rate in the other group (73).
RESULTS AND GENERAL DISCUSSION
(SUMMARY OF THE PAPERS).
Saebo A, Kapperud G, Lassen J, Waage J. Prevalence of antibodies to Yersinia enterocolitica
O:3 among Norwegian military recruits: Association with risk factors and clinical
Eur J Epidemiol 1994; 10: 749-755.
IgG antibody activity to Y. enterocolitica serogroup O:3 was detected in sera from 7.4 % of the
755 military recruits. The highest prevalence (21.4%) was found among recruits from Oslo city.
Because of the material's representative geographical distribution and high compliance, it may
give a reliable estimate of the nati onal prevalence of IgG antibodies in this age group, as of
regional differences in prevalence. As the infection may be acquired at all ages, the antibody
prevalence may increase with age. Several surveys of the prevalence of antibodies to Y.
enterocoli tica have been conducted in other European countries, but on different
subpopulations, and using a diversity of antigens and serological techniques (74). In
consequence, it is difficult to compare these results with previous observations.
In a recent Norwegian study performed in the Oslo region, 1988-1990, an incidence rate of 6.4
bacteriologically confirmed cases/100.000 population/year was observed (40). Taking into
account the high incidence observed in the younger age groups of that study, and supposing a
stable incidence and persistence of the antibody response, one could still hardly expect to
demonstrate any antibody response among the 56 Oslo city recruits (< 0.15 case). However, 12
of them had anti body activity. Regarding children and youngsters, therefore, it may be
supposed that only a few per cent of cases with acute Y. enterocolitica infection are diagnosed.
Risk factors associated with IgG antibody activity: The following ris k factors were found to be
independently associated with IgG activity in logistic regression analysis: a) receiving drinking
water from a private well, b) being a resident of Oslo city, and c) living in eastern Norway. We
failed to detect an association b etween Y. enterocolitica and contact with pigs.
The risk of receiving drinking water from a private well was clearly demonstrated by the Bergen
city observations: because of lacking municipal water supply, several small hamlets on the
outskirts of the city use private wells with stagnant water. The fact that 3/9 recruits who
received water from such wells had antibody response, and only 3/100 with other kinds of water
supply, supports previous suggestions of water as a reservoir for the microbe (28, 31, 75), and a
recent Norwegian case-control study, which identified consumption of undisinfected water as a
risk factor for yersiniosis (27). Y. enterocolitica has been isolated from water in several
investigations (31), including five Norwegian studies (76, 77, 78, 79, 80) but the majority of
strains recovered belong to avirulent serogroups. Further investigations on the occurrence of
virulent Y. enterocolitica need to be undertaken, using more sensitive and specific detection
methods like nucleic acid probes or polymerase chain reaction.
Residency of Oslo city, and living in eastern Norway were identified as independent risk factors
associated with antibody activity to Y. enterocolitica. These connections can so far not be
explained. The case-control study referred to above identified consumption of pork products as
a risk factor for yersiniosis, and it was speculated whether eating habits (e.g. eating meat raw or
rare) may differ geographically (27). Oslo and easter n Norway may have satisfactory municipal
water supply, but it should be noticed that the present study demonstrated no advantage of
water disinfection, as regards prevalence of antibodies to Y. enterocolitica. Finished Norwegian
drinking water var y considerably from district to district; these differences possibly may be
related to the epidemiology of some diseases (81).
Clinical considerations: IgG antibody activity was significantly correlated with previous
appendectomy, and with the peroperative finding of mesenteric lymphadenitis. This was not
unexpected, as mesenteric lymphadenitis, terminal ileitis, or typhlitis are common manifestations
of the acute Y.enterocolitica infection. The right iliac fossa symptoms may necessitate laparo
tomy because acute appendicitis is suspected (5, 10, 37, 82, 83, 84).
Corresponding frequencies of previous appendectomy were reported by recruits from the
eastern and the other districts of Norway, but the eastern district recruit with previous surge ry
had a significantly higher frequency of IgG antibodies (6/14 > 2/20). According to previous
reports, the proportion of patients having appendectomy with Y.enterocolitica in Europe or
North America ranges from 3.0 to 9.0 per cent (25); the high freq uency of IgG antibody among
eastern district recruits operated upon therefore is remarkable.
In the present study, five recruits with previous appendectomy complained of steatorrhea;
three of them had antibodies to Y.enterocolitica.
Statistically, however, we failed to detect an association between antibody activity and
recurrent diarrhea or persistent joint complaints. Individuals with severe complaints, of course,
would not have been enrolled for military training.
Saebo A, Lassen J. A survey of acute and chronic disease associated with Yersinia
enterocolitica infection. A Norwegian 10-year follow-up study on 458 hospitalized patients.
Scand J Infect Dis 1991; 23: 517-527.
This paper give s an extensive survey of acute and chronic disease observed among 458
patients hospitalized with Y. enterocolitica infection.
Acute symptoms: 189 patients presented with uncomplicated arthritis, and 200 with diarrhea.
These manifestations overla pped in 91 patients. 56 patients
underwent abdominal surgery. Liver involvement was observed in 54 patients (12%). Renal,
cardiac, pulmonary, pancreatic and neurologic involvement were observed with small but
significant frequencies (8-16/458 patients = 1.75%-3.5%; SD 0.61%-0.86%), and often as
components of multiorgan disease, which was observed in several patients. Other
manifestations included erythema nodosum (in 60 patients), iridocyclitis, splenomegaly, deep
venous thrombosis, thyroiditis, spon taneous abortion, chronic specific lymph node
inflammation, adverse effect of iron, and septicaemia.
Two conditions which previously have not been observed in association with Y. enterocolitica
infection deserve special attention: Acute insuli n-dependent diabetes (in two patients) is
discussed in Paper V, and development of malignant mesothelioma (in two patients) is
discussed in Paper VII. Acute gastrointestinal involvement is further discussed in Paper III,
liver involvement in Paper IV, pa ncreatic involvement in Paper V, and neurological involvement
in Paper VI. Other acute manifestation have their counterparts in previous reports (v.s.).
In addition to their acute symptoms, 64 patients had suffered from particular chronic conditions
as rheumatic disease, inflammatory bowel disease, hepatitis, thyroid disease, neurologic
disease, sarcoidosis or insulin-dependent diabetes for months or even years.
Readmissions and development of chronic disease: Among 160 patients who were readmi tted,
75 presented with arthritis, ankylosing spondylitis, or rheumatoid arthritis. 28 patients
experienced persistent diarrhea, and 38 had abdominal pain; chronic colitis was demonstrated in
four (Paper III). Chronic liver disease, in 22 patients, was as sociated with involvement of other
organs, possibly connected with development of malignant disease, and correlated with
immunological aberrations, and with an increased mortality (Paper IV).
Chronic disease of exocrine pancreas was diagnosed in four p atients, and 11 patients
developed diabetes (Paper V), six patients developed chronic neurologic disease (Paper VI),
and nine thyroid disease. Nine patients suffered from acute or chronic nephritis, and four from
cardiomyopathy. Patients of Bergen Univer sity Hospital had a lower mean serum concentration
of complement component C4, than had healthy first degree relatives and healthy controls.
At follow-up, 46 patients were dead. Survival and causes of death are discussed in Paper VIII.
In a substan tial portion of patients , acute organ involvement developed into chronic disease
over years. Therefore, we may conveniently discuss in connection acute and chronic disease of
particular organs, and compare our observations with recent contributions regar ding
pathogenesis of acute and chronic disease in yersiniosis.
Particular clinical conditions not discussed in other papers of the thesis:
Arthritis and rheumatism: Among 160 patients who were readmitted, 44 presented with uncompl
icated arthritis, and nine suffered from severe sero-negative polyarthritis. When previously
diagnosed patients were included, a total of 26 patients suffered from ankylosing spondylitis;
at least 14 of them presented the histocompatibility antigen HLA-B 27. Totally 19 patients
suffered from rheumatoid arthritis, and 11 from iridocyclitis. Development of ankylosing
spondylitis subsequently to Y. enterocolitica infection, and especially in HLA-B27 positive
patients, is well documented (55, 56); and an association with rheumatoid arthritis has been
suggested (57, 58). Our observations confirm previous observations, as nearly 10% of our
patients developed severe rheumatic disease. Also minor joint complaint may be commonly
experienced, as 149/337 que stionnaire replyers, without rheumatic disease, at follow-up
complained of arthralgia or joint swelling. Our observations support a previous contribution
suggesting that the long term prognosis of Yersinia arthritis might be less favourable than pr
eviously thought (85). Prolonged persistence of IgA antibodies to Y. enterocolitica has been
demonstrated in patients who develop reactive arthritis (86). The antibody response is directed
against both chromosomally and plasmid-encoded antigens, in dicating that the microorganism
may hide within the host for a prolonged time (86, 87, 88, 89, 90). However, only bacterial
degradation products, not whole bacteria, are present at the site of inflammation in reactive
arthritis (91). Reduced levels of ery throcyte C3b receptor may contribute to the pathogenesis
of reactive arthritis by affecting the clearance of immune complexes (92).
In a recent study on antibiotic treatment in Yersinia-associated spondyl-arthropathy,
disappearance of IgA antibo dies coincided with disappearance of virulent Y. enterocolitica in
intestinal biopsies (93).
Thyroid disease: At first admission, two patients presented with acute thyroiditis, in one
thyreotoxicosis prompted thyroid resection. Nine patie nts had thyroid disease diagnosed prior
to first admission. During the follow-up period, another nine patients developed thyroid
disease; two of them were hospitalized with acute thyroiditis. In the one, with high thyroid
antibodies, microscopy of the res ected thyroid showed Hashimoto's thyroiditis (struma
lymphomatosa); the other underwent tracheostomy because of laryngeal edema. Two of seven
patients who developed chronic thyroid disease also developed chronic liver disease. Among
the 20 patients with thyroid disease were 18 females.
Two thyroid disorders have autoimmune aetiology. In Hashimoto's thyroiditis the thyroid acini
are progressively destroyed by an autoimmune process, the gland diffusely infiltrated with
lymphocytes, and the patient becomes increasingly hypothyroid (94, 95). Graves' disease is
caused by the production of thyroid stimulating hormone (TSH) receptor autoantibodies, which
stimulate the TSH receptor to increase iodide uptake and cyclic adenosine monophosphate
(cAMP) produ ction, inducing production of excess thyroid hormones (96). A high proportion
of patients with Hashimoto's thyroiditis and Graves' disease have antibody response to Y.
enterocolitica by agglutination or ELISA technique(53, 97, 98). Significantly elevated levels of
IgG and IgA antibodies to plasmid encoded release proteins of Y. enterocolitica have been
demonstrated in such patients, and antibodies against release proteins raised in rabbits showed
specific bands on Western blots with thyro id epithelial cell homogenates (99). Y. enterocolitica
antibodies are capable of reacting with the TSH receptor (100). Conversely, Y. enterocolitica
membranes have saturable binding sites for TSH (101), and the binding of TSH to the microorg
anism is inhibited by IgG from patients with Graves' disease (102). According to a recent report,
lymphocytic thyroiditis has been induced in rats by immunizing them with Y. enterocolitica
purified membrane protein (103). However, other studies con clude that there is no unique
pattern of serological reactivity against Yersinia membranes or the release proteins in patients
with autoimmune thyroid disease (104, 105), suggesting that any causal relationship with
Grave's disease may be related t o T-cell immunity (105).
Acute and chronic nephritis: Four patients were readmitted with acute nephritis, and five
developed chronic nephritis. The finding of chronic nephritis supports observation in a
previous study, where also deposits of im mune complexes and complement C3 were
demonstrated in diseased tissue (69).
Chronic heart disease: In four males cardiomyopathy was associated with chronic liver disease;
two females presented with acute pericarditis.
Chronic complement a berrations: Twenty-four patients reexamined at Bergen University
Hospital had a significantly lowered mean serum concentration of complement component C4,
as compared with first degree relatives and healthy controls without antibody response to Y.
enterocolitica. This observation, indicating operation of the classical pathway of complement
activation, as well as the finding of generalized urticaria or angioneurotic edema in nine other
patients, are in concert with recent reports. Both the alter native pathway and the classical
pathway of complement activation are active in killing of Y. enterocolitica. However,
plasmid-bearing strains are able to inhibit complement activation, and may be protected against
its lytic action (20, 106). Compl ement components may mediate anaphylaxis by histamine
release, and may be involved in development of hemolytic anaemia and nephritis. Massive
complement activation by microbial products may launch disseminated intravascular
Saebo A, Lassen J. Acute and chronic gastrointestinal manifestations associated with Yersinia
enterocolitica infection. A Norwegian 10-year follow-up study on 458 hospitalized patients.
Ann Surg 1992; 215: 250-255.
At first admission, a substantial portion of patients presented with abdominal symptoms as
pain (184; =40%), diarrhea (200; =44%), vomiting (45, =10%), or weight loss (36; =8%). Different
age distributions were observed in subgroups with different abdominal pain localizations.
Fifty-six patients underwent emergency abdominal operations. Mesenteric lymphadenitis was
found in 23 patients, and terminal ileitis/ileitis in 20 patients. Other peroperative findings, in 13
patients, were acute a ppendicitis, acute cholecystitis, acute hepatitis, perforated duodenal
ulcer, acute colitis, intussusception, or monstrous mesenteric lymphadenitis associated with
splenomegaly and slight liver involvement. Abdominal masses were diagnosed in five patient
not operated upon; endoscopy or radiological examination revealed gastroduodenitis, terminal
ileitis, or colitis/proctitis in 13/169 patients examined.
The acute gastrointestinal manifestations observed in the present study support previous
observatio ns (5, 10, 37, 59, 60, 82, 83, 107, 108, 109, 110, 111, 112, 113, 114, 115). In addition, we
were able to demonstrate that children less than 10 years of age had a significantly higher total
frequency of diarrhea, a higher relative frequency of macroscopi cally bloody diarrhea, and a
higher frequency of vomiting than did older patients. In accordance with our observation,
bloody diarrhea was observed only in individuals less than 18 years old in a recent Norwegian
study (40). Bloody diarrhea is commonly en countered also in colonic infection by other
invasive microorganisms as Shigella, Salmonella, particular strains of E.coli, and Campylobacter
Follow-up. Among 160 readmitted patients, 38 suffered from chronic abdominal pain and 28
from chronic diarrhea. These complaint were correlated with corresponding complaints at first
admission. Chronic colitis was diagnosed in four patients, whereas another patient, with
malabsorption, had abnormal gastric, duodenal and colonic biopsies. Two patients had
pathologic Schilling's test, indicating ileal involvement. Twelve patients suffered from
unintentional weigh loss, possibly comparable with weight loss in severe systemic diseases as
tuberculosis, malignant disease, and blood disorders.
Reexamination at Bergen University Hospital disclosed abnormal duodenal biopsies in four of
five patients with severe chronic diarrhea; in all four associated with persistence of specific IgG
antibody activity, and in two with IgA activity after 9 a nd 12 years, respectively.
Questionnaire: 139/371 (37.5%) questionnaire replyers without previous inflammatory bowel
disease (IBD) complained of persistent diarrhea; 84 without bleeding and 55 with mucous or
blood. 59 patients (15.9%) experience d voluminous stools floating on water, and 39 (10.5%)
had unintentionally lost weight. There was no sex and age differences regarding frequencies of
these chronic complaints. However, patients who had been followed for 10 years or more
reported higher fre quencies of mucous or bloody diarrhea, and of weight loss, than patients
admitted later. Chronic diarrhea was significantly correlated with abdominal pain and diarrhea at
first admission. The relatively young patients who at first admission had presented with right
iliac fossa pain had a better outcome than patients admitted with diffusely located abdominal
pain, regarding subsequent mucous or bloody diarrhea, voluminous stools floating on water,
and unintentional weight loss.
The present study demon strates that gastrointestinal symptoms are very common both in
acute Y. enterocolitica infection and during the following years, and that acute and chronic
symptoms are correlated.
The Bergen University Hospital patients reflect the whole materi al regarding acute symptoms
and development of chronic complaints, and in this subpopulation we were able to demonstrate
duodenal morphological changes, and long time persistence of antibody response.
In keeping with our observations of chronic diseas e development are reports of sustained or
recurrent diarrhea, abdominal pain, weight loss, duodenal involvement, or altered ileal/intestinal
barrier function after Y. enterocolitica infection (5, 59, 60, 61, 117, 118). Prolonged persistence of
IgA antibodies (with a very short half-life) directed against a multitude of bacterial epitopes has
been demonstrated after Yersinia enteritis, indicating that the microorganism may hide within
the host (86, 87, 88, 89, 90). Virulent Y. enterocoliti ca has been demonstrated in patients with
chronic intestinal inflammations (68). Persistence of IgA antibodies may be shortened by
antibiotic treatment; the disappearance of IgA antibodies coincides with disappearance of the
microorganism in intestina l biopsies (93).
At first admission, six of our patients had suffered from UC for several years, this prevalence
exceeds previously estimated Scandinavian prevalences (119). One patient had CD. In addition,
two patients with recent acute onset of diar rhea underwent surgery; microscopy revealed UC
and CD, respectively. None of 21 previously healthy patients in whom acute terminal or
regional ileitis was demonstrated developed CD. This observation may support the observation
that patients admitted with right iliac fossa pain had the better prognosis regarding future
There is circumstantial evidence that certain microbes are associated with IBD, possibility by
launching an inflammatory response and subsequently be disintegrated, or remain in a
non-culturable form. There may be a common property of the infectious agents suggested, as
immunological capability or tissue invasiveness. Subjects who develop IBD may have a primary
or secondary impairment of the defence mechanisms preventing inte stinal infection; genetic or
environmental factors may be involved as well (120, 121).
Among other pathogens, Shigella dysenteriae, Salmonella species, Campylobacter jejuni and Y.
enterocolitica have been implicated as poss ible causative agents of IBD, particularly UC (122).
In some patients, it has been clearly shown that an acute infection precedes the first attack of
An association between Y. enterocolitica infection and chronic colitis or UC was sug gested
twenty years ago (38, 62). Later were high frequencies of specific antibodies observed among
patients with UC (58) and CD (63), and recently has persistence of virulent Y. enterocolitica
been demonstrated in patients with chronic intestinal inflammations (68). A marked increase in
responsivity of mesenteric lymph node mononuclear cells from patients with UC or CD to Y.
enterocolitica, in comparison with other enterobacteriae, has recently been demonstrated,
possibly indicating a spec ific cell-mediated immunity in IBD to Y. enterocolitica. However,
further characterization of the antigen stimulating the proliferative response is required before a
role for Y. enterocolitica in the etiopathogenesis of IBD can be proposed ( 124).
Saebo A, Lassen J. Acute and chronic liver disease associated with Yersinia enterocolitica
infection: a Norwegian 10-year follow-up study of 458 hospitalized patients. J Int Med 1992;
At first admission 54/454 patients (11.9 %) with no history of previous liver disease, presented
with acute liver involvement evinced by significantly elevated serum levels ( two-fold the 97.5%
percentile) of bilirubin and/or liver enzymes. Female s seemingly experienced more serious liver
involvement than did males: three females only had significant elevation of both bilirubin and
two enzymes, and females had the higher frequencies of elevated aspartate transferase (ASAT)
levels, and of very hi gh ASAT levels (> five-fold the 97.5% percentile). Females with liver
involvement had a higher mean age than females with normal liver function.
Two females and one male presented with substantially higher levels (4 to 5-fold) of ASAT
than of alanin e tranferase (ALAT), suggesting severe disease with cellular necrosis and
release of the mitochondrial ASAT isoenzyme. These observations were supported by the
demonstration of cellular necrosis in biopsy specimens from 2/12 patients examined; ten had
non -specific changes.
Cholecystography or choleangiography was performed in ten patients; in no case was
extrahepatic bilary obstruction demonstrated. Testing for hepatitis B antigen in ten patients
yielded negative results. Ultrasonography or scintigraph y demonstrated hepatosplenomegaly
in four patients examined. Liver involvement was associated with involvement of other organ
systems, and significantly correlated with positive tests for antinuclear antibody (ANA). Some
patients with liver involvement ex perienced multiorgan disease.
In the present study, four patients presented with chronic liver disease at the time of Y.
enterocolitica diagnosis, in one chronic granulomatous hepatitis with giant cells was
Readmissions: In 22 patients (4.9%) who were readmitted during the follow-up period, chronic
liver disease was diagnosed by liver function tests or liver biopsy. In 15 patients, the disease
might have persisted since the acute infection. In on e patient liver biop sy revealed
centrolobular hemorrhagic necrosis, in another unspecific microscopic changes progressed into
granulomatous hepatitis over three years. Again, cholecystography or endoscopic retrograde
choledochography yielded negative results in five patients examined, and scintigraphy or
computerized tomography revealed heptosplenomegaly in four patients. Chronic liver disease
was significantly correlated with positive tests for ANA and rheumatoid factor (RF). Several of
the 22 patients concomitantly suffere d from disease of other organ systems, or multiorgan
disease; thus four patients developed cardiomyopathy. A very high mortality of 10/22 (45.5%)
was observed in the chronic liver disease group, as compared with 26/426 (6.1%) among
patients with no indi cation of liver disease.
Liver involvement, often with hepatic abscesses, was first time observed in patients with
generalized Y. enterocolitica infection or septicaemia. These patients commonly suffered from
debilitating diseases as diabetes or leukemia, or iron overload caused by blood disorders or
iron therapy (9, 15, 18, 125). Later slight involvement (5, 39) or even hepatitis (64, 126, 127, 128)
have been reported, also in patients without generalized infection.
In the present study, a young man acquired Y. enterocolitica septicaemia after renal
transplantation and immunosuppression, but without liver involvement. We have no tangible
evidence of liver abscesses among our patients, but suspect this complication in a 73-years-old
male who presented with jaundice eleven months after the primary isolation of Y. enterocolitica
from fecal samples. His condition had deteriorated for six weeks, and he had lost 8 kg of weight.
Liver scintigraphy disclosed numerous cold nodules. Ta king into account his severe acute
diarrhea the last year, but quite forgetting the positive cultivation of Y. enterocolitica, this
finding was without any further ceremony recognized as representing metastases from a
supposed colonic carcinoma. Th e patient died in his home two weeks later.
Most contributions on liver involvement in acute Y. enterocolitica infection have been case
reports. However, the frequency of acute liver involvement observed in the present study may
be comparable wi th frequencies of 5/75 (6.7%) in a previous clinical study (5). According to the
size of our material, we have also been able to demonstrate sex distribution, enzyme
relationships, microscopic changes, and radiological and ultrasound findings in acute li ver
disease; these observations have no counterparts in previous publications.
In 1977, I suggested that a chronic form of liver involvement possibly might be caused by Y.
enterocolitica infection (64). In the present study, about one of twenty patients developed
chronic liver involvement with serious implications. These observation may constitute a
substantial contribution to the understanding of chronic yersiniosis. Granulomatous hepatitis
which was seen in two patients support some p revious reports (65, 66, 67, 129). This discrete
form of chronic inflammation may occur virtually de novo in response to microorganisms which
are resistant to destruction by polymorphonuclear leukocytes during the acute inflammatory
reaction. Correspondi ng granulomatous lesions were observed in a lymph node biopsy of a
patient with erythema nodosum and acute myocarditis; in three other patients "sarcoidosis"
had been diagnosed prior to first admission (Paper II).
Saebo A, Lassen J. Acute and chronic pancreatic disease associated with Yersinia
enterocolitica infection: a Norwegian 10-year follow-up study of 458 hospitalized patients. J Int
Med 1992; 231: 537-541.
Acute pancreatitis: At first ad mission, eight patients (two males and six females) presented
with serum and/or urine amylase levels elevated beyond twice the 97.5 percentile. In all,
pancreatic involvement was associated with manifestations as diarrhea, arthritis or liver
involvement e tc. Y. enterocolitica serogroup O:9 or O:3 were isolated from faecal samples in
case of two patients with antibody titers of 360 viz. 640. Six other patients, in whom cultivation
was not attempted, had titers in range 1250-2500.
Chronic pa ncreatitis. During the follow-up period, none of the patients who had experienced
acute pancreatic involvement developed chronic pancreatitis. Four other patients, however,
developed chronic disease with moderately elevated amylase levels; in the one associated with
chronic colitis. At first admission they had all presented with chronic conditions as
insulin-dependent diabetes, rheumatoid arthritis, hepatitis, or glomerulonephritis. In a male
patient with haemochromatosis chronic pancreatitis had been demonstrated by ERCP at first
Observations in the present study support previous case reports of pancreatic involvement, or
even frank pancreatitis, in association with acute Y. enterocolitica infection (5, 42, 130, 131). In
most ca ses Y. enterocolitica infection was diagnosed by antibody response, but at least in one
case the microorganism was cultivated from faecal samples (131). A previously reported patient
who developed acute pancreatitis subsequently to ileitis correspo nds well with one of our
cases (130). In a previous clinical study, Yersinia infection was diagnosed in 21/630 patients
with acute abdominal disease, by ELISA technique. Acute pancreatitis was seen in two patients
with antibodies to Y. enterocol itica O:3 (132).
In the present study 8/458 patients (1.75%) presented with acute involvement of exocrine
pancreas. This should be regarded as a minimum frequency, because most patients were not
examined for pancreatic involvement. Nevertheless, it indicates that Y. enterocolitica infection
may represent a differential diagnosis in acute pancreatitis.
Chronic pancreatic disease, resembling the conditions presented by four patients at
readmission, has previously been observed in associatio n with CD or indeterminate colitis
(133). Moreover, decreased pancreatic function has been described in UC (134), whereas acute
pancreatitis has been observed in association with CD (135). On this background, the
possibility of a nonfortutios association of IBD with pancreatitis has been supposed (133, 135).
An autoimmunologic basis may be suggested by the demonstration of autoantibodies to the
exocrine pancreas in patients with IBD (136). The fact that chronic pancreatitis In our patients
was preceded by probable autoimmune conditions may be in accordance with these reports.
Endocrine Pancreas / Diabetes mellitus. Acute insulin-dependent diabetes was diagnosed in a
female with concomitant involvement of exocrine pancreas, and in a male wit h a multiorgan
disease not including the exocrine pancreas. He subsequently developed chronic liver disease
and cardiomyopathy, from which he died.
Six patients (two males and four females) had suffered from diabetes for several years prior to
first a dmission. Two of the females had insulin-dependent diabetes. One of them suffered from
rheumatoid arthritis, and chronic colitis and pancreatitis developed subsequently. In a male
patient the disease developed into insulin-dependent diabetes during the fo llow-up period.
During the follow-up period, another two male and nine female patients developed diabetes; in
seven associated with other chronic conditions of possible autoimmune aetiology. Three had
The prevalence of di abetes among patients still alive at termination of the study was compared
with the mean prevalence of diabetes in Norway, according to four recent studies (137). A
significantly higher than expected prevalence was observed among females aged 30-54 years.
Development of insulin-dependent diabetes requires a genetically pre-disposed individual, and
an autoimmune reaction which may possibly be triggered by external factors as viruses or
toxins (138, 139). The genes involved are to a great extent located to the major
histo-compatibility complex on chromosome 6; their products are involved in
immunosurveillance and the recognition of 'self' or 'non-self' (139). The autoimmune reaction
may be present several years before the onset of clinical diabetes (139 , 140), and is supposed
to be mediated by T-lymphocytes who destroy the islet B-cells (141). Patients with insulin
dependent diabetes often suffer from other autoimmune diseases (140).
Two of our patients presented with acute insulin-dependent diabetes in association with the
acute Y. enterocolitica infection; in both the disease persisted. Also the unexpectedly high
prevalence of diabetes among females 30-55 years old; and the fact that diabetes commonly
was linked with other chronic condition s of possible autoimmune aetiology, support the
concept that infection with the immunologically competent Y. enterocolitica may initiate
diabetes. It is further remarkable that the highest incidence of diabetes in Norwegian children is
found in th e southeastern part of the country (142) where the majority of the present study
Saebo A, Nyland H, Lassen J. Yersinia enterocolitica infection - an unrecognized cause of acute
and chronic neurological disease? A 10-year follow-up study on 458 hospitalized patients.
Med Hypotheses 1993; 41: 282-286.
At first admission, eight patients (five males and three females) with acute infection presented
with neurological symptom s. Six had symptoms of CNS, as encephalitis with EEG dysrhythmia
in three patients, possible multiple sclerosis (MS) with diplopia and abnormal cerebrospinal
fluid (CSF) agarose electrophoresis in one, dizziness and nystagmus etc. in one, and headache
as sociated with peripheral pain and paraesthesias in one patient. Abnormal CSF was seen in
two of the patients with encephalitis; in case of an eight-year-old boy with positive tests for RF
and cold agglutinins CSF contained 415 mononuclear cells / mm. Two patients had symptoms
of PNS as hypaesthesia viz. polyradiculitis. Five patients had antibody titers in range 640-1250,
two had titers in range 2500-5000, and one patient with encephalitis had an extremely high titer
of 160.000. The patients additionally presented with other acute manifestations as diarrhea in
four patients, arthritis in two, liver involvement in one, and cardiac involvement with atrial
fibrillation in one patient. Five of the eight patients with acute neurological symptoms
experienced pe rsistent complaints.
During the follow-up period another six patients (two males and four females) developed
chronic neurological conditions as possible MS in one patient, EEG dysrhytmia associated with
paraesthesias and increased deep reflexes in one, Bell's palsy in one, Meniere's disease in one,
trigeminal neuralgia in one, and labyrinthitis in one patient. In five cases, the chronic
neurological condition developed with a latency of about seven years.
In 1991, antibody response was evalu ated by ELISA in 10/12 patients still alive. Eight of these
patients suffered from chronic neurological disease; six of them still had significant antibody
activity, 10-17 years after the diagnosis of yersiniosis. Five of the six patients had persistent I
gA activity, indicating chronic antigenic stimulation.
The first reports on nervous system involvement during the acute infection date from the early
seventies (5, 51). Three cases of CNS involvement have been reported in association with acute
Y. enterocolitica infection, namely two patients with meningitis (51, 143) and one with myelitis
(52). PNS involvement with abducens paralysis has been observed in one patient (144),
neurogenic amyotrophy in two (52, 145), and Guillain-Barre's synd rome in one patient (5). It has
been suggested that Y. enterocolitica may be the responsible agent of some otherwise
unexplainable neurological conditions (52).
Immunological and clinical observations in Y. enterocolitica infection may co rrespond with
observations in nervous system disease: in the inflammatory demyelinating disorders the
presence of circulating immune complexes (146, 147) and activated terminal complement
pathway (148) indicate a carrier state with microorganisms continuo usly present in the host.
Moreover, associations between MS and ankylosing spondylitis (149, 150, 151), UC (152) and
thyroid disease (153); between Guillain-Barre's syndrome and UC (154); and between peripheral
neuropathy and CD (155) have been observed. In the present study, the latency of about seven
years for development of neurological disease, and the demonstration of persistent antibody
activity in patients with chronic disease, may support the concept of an association with the Y.
Saebo A, Elgjo K, Lassen J. Could development of malignant meso-thelioma be induced by
Yersinia enterocolitica infection?
Med Hypotheses 1993; 40: 275-277.
Two out of the 458 patient s developed malignant mesothelioma of pleura viz. pericard; both
died after a few months.
Case 1. A 61-year-old woman who presented with a flu-like disease, subsequently developed a
rightsided pleural exudate, and eventually a growing tumour was observed close to the pleura
of the superior lung lobe. She died in respiratory failure.
Case 2. A 34-year-old woman diseased with precardiac pain and weight loss; leftsided pleural
exudate, venous congestion and thrombosis, and cardiac failure supervened. Thoracotomy
revealed a pericardiac tumour with pulmonary metastases; the patient died on the table.
In both cases microscopy of specimen revealed a cellular pattern consistent with malignant
mesothelioma, with partly spindle shaped, partl y more polygonal epitheloid cells.
Immunohistochemical examination (in case 1.) revealed a strong immunoreactivity for
cytokeratins (AE1/AE3), supporting the mesothelial nature of the tumour.
Development of malignant mesothelioma in association wi th Y. enterocolitica infection has
previously not been reported. Malignant mesothelioma of pleura is commonly related to
asbestos exposure, and usually encountered among males (156). In heavily exposed
populations more than 10 % of subjects may die of mesothelioma (157). The annual incidence of
pleural malignant mesothelioma among subjects without asbestos exposure is probably around
1-2 per million (158). Pericardiac mesothelioma is an extremely uncommon neoplasm as its
annual incidence is 1 per 4 0 million population (159). Asbestos is recognized as a complete
carcinogen or promotor for pleural mesothelioma (160); the mechanism of malignant
transformation may involve chromosomal damage (161). Asbestos workers and patients with
malignant mesothelio ma may have a high frequency of immune dysfunctions (162, 163), so
increased prevalences of positive tests for RF (163, 164) ANA (164) have been observed, and
an association with systemic lupus erythematosus has been reported (165). Further has
malignant pericardiac mesothelioma been observed presenting as systemic lupus
erythematosus (166); and autoimmune haemolytic anaemia has been seen in association with
malignant peritoneal mesothelioma (167).
As possible inducers of non-asbestos related pleural m alignant mesothelioma have been
suggested radiation, minerals, organic chemicals, viruses, chronic inflammation,
co-carcinogens, hereditary predisposition, and cigarette smoking (168).
In the present study, a substantial number of patients developed ch ronic conditions of
probable autoimmune aetiology, and positive tests for ANA and RF were correlated with liver
involvement with serious implications.
Our two patients with malignant mesothelioma were both females, and had not been exposed to
asbestos. Statistically, it would be very unlikely that two out of 458 patients developed
malignant mesothelioma. Hence, the association recorded should not be dismissed as
implausible, and the possibility that Y. enterocolitica infection might promote mal ignant
mesothelioma should not be disregarded.
Saebo A, Lassen J. Survival and causes of death among patients with Yersinia enterocolitica
infection. A Norwegian 10-year follow-up study on 458 hospitalized patients.
Scand J Infect Dis 1992; 24: 613-617.
At termination of the study 46 patients were dead. Two patients, who suffered from multiorgan
disease viz. CD, died in association with the acute infection; two others died from malignant
mesothelioma af ter a few months. However, also chronic disorders seemingly promoted by the
Y. enterocolitica infection might be supposed to bring a certain mortality.
The observed and expected cumulative survival rates were calculated for 10 years. For males,
the observed and expected cumulative survival rates were significantly different after one year
of observation (0.9802 < 0.9941; p < 0.025), thereafter life expectancy did not deviate from that
of the general population. For females, the devi ation of the curves was significant, and still
present at the lapse of the 10-year period (0.8980 < 0.9315; p < 0.05). Regarding the whole
material, the difference between the observed and expected cumulative survival rates remained
significant for 8 years (0.9189 < 0.9456; p < 0.025).
The event of death is unusual in acute Y. enterocolitica infection, but has been observed in
septicemia, and in fulminant abdominal disease (9, 15, 18, 108). Septicemia generally involves
patients debi litated by diseases or medical treatment (9, 15, 16, 17, 18, 108, 169, 170), and carries
a very high mortality (171). In the present study, one patient with acute myocarditis, pneumonia
and severe liver involvement died two days after admission. Another, with septicemia, was
successfully treated with gentamicin (169). In our patient with CD, Y. enterocolitica colitis was
one among several factors contributing to death. Death from malignant mesothelioma in
association with Y. enterocolitica infection has no counterpart in previous reports.
Among 42 other patients who died during the follow-up period, four died from chronic
multiorgan disease, nine from malignant disease, and two from hematological disorders. A very
high mortality of 10/22 (45.5%) was observed among patients who had developed chronic liver
disease subsequently to the infection. The event of death was also significantly correlated with
positive tests for RF, whereas the correlation between death and A NA did not reach
significance. Development of RF and ANA constitutes a general feature of diseases at the
non-organ-specific end of the autoimmune spectrum. Three of the deceased had positive tests
for both ANA and RF.
Multiorgan disease has previousl y been observed in generalized acute infection (9,15,16). The
present study demonstrates that also chronic multiorgan disease, often with fatal outcome, may
develop over several years, probably with chronic liver disease as pivot.
The significant diff erences between observed and expected cumulative survival rates in the
present study indicate that the chronic conditions associated with Y.enterocolitica infection
may exert a substantial impact on long-time survival.
In the prevalence study, IgG antibody activity to Y. enterocolitica serogroup O:3 was detected
in sera from 56 (7.4%) of 755 Norwegian military recruits; indicating that the microorganism may
be a much more common cause of infection in No rway than realized to this time. The highest
prevalence (21.4%) was found among recruits from Oslo city. Regarding geographical regions,
the prevalence detected among recruits from eastern Norway, including Oslo, was significantly
higher than the prevalen ce detected among recruits from western Norway (11.2% > 5.2%; p =
In logistic regression analysis, the following risk factors were found to be independently
associated with IgG activity: 1) receiving drinking water from a private we ll (OR) = 3.40,
p=0.004), 2) being a resident of Oslo city (OR=2.99, p=0.006), and 3) living in eastern Norway
(OR=2.25, p=0.015). The association between unsatisfactory drinking water quality and IgG
activity is very important. The interesting geograp hical impact can so far not be explained.
Seropositive recruits were more likely to report previous surgery for suspected appendicitis
than seronegative individuals (OR=4.26, p=0.0024). Among recruits with previous
appendectomy, mesenteric lymphadeniti s as the sole peroperative finding was more common in
patients with IgG activity to Y. enterocolitica O:3 (4/7) than in seronegative patients (1/19)
(p=0.01). Particular clinical complaints as recurrent diarrhoea, steatorrhea or joint co mplaints
were not associated with antibody activity.
The clinical study demonstrates that a great diversity of clinical syndromes are associated with
the Y. enterocolitica infection.
Most of the acute manifestations observed in the present study have their counterparts in
previous reports. Multiorgan disease was observed in several patients. Our observations of
malignant mesothelioma development, and of acute diabetes mellitus, represent unique
160 patient (34.9%) were readmitted during the follow-up period. A substantial number of them
suffered from persistent chronic complaints correlated with their first admission symptoms;
others developed a diversity of chronic diseases of probably autoimmune character. Chron ic
liver disease seemingly acted as the pivot of multiorgan disease development, and was
associated with immunological aberrations, with a very high mortality, and possibly with the
development of malignant disease.
At follow-up, a significantly highe r than expected prevalence of diabetes was observed among
females aged 30-54 years. In five patient with severe chronic diarrhea, as in most of those
patients who developed chronic neurological disease, significant antibody activity to Y.
enterocoliti ca was demonstrated by ELISA technique after 9-17 years. Especially the IgA
activity is important, as this immunoglobulin has a very short half-life. Its long-time persistence,
therefore, indicates chronic infection. The Bergen group of 24 patients had a significantly
lowered mean serum concentration of complement component C4, as compared with healthy
first degree relatives and unrelated controls.
The observed cumulative survival rates for female patients, and for the whole material, deviated
significantly from the expected rates for 10 and 8 years; indicating that chronic conditions
associated with Y.enterocolitica infection may exert a substantial impact on long-time survival.
Although the present investigation by no means pr ove the existence of a causal relationship
between Y. enterocolitica infection and the chronic conditions observed, it is strongly
suggestive thereof. Therefore, further studies are required to estimate the role of Y.
enterocolitica as an in ducer of chronic disease, to elucidate its reservoir and transmission, and
to organize preventive and therapeutic measures against this immunologically competent
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