Yersinia pseudotuberculosis
Authors: Thomas Butler, M.D.
Yersinia pseudotuberculosis causes zoonotic enteric infection in farm animals, wild animals, and birds. Humans acquire it by ingesting foods or water contaminated by animal feces. It causes usually mild, self-limited illnesses of mesenteric adenitis, ileitis, and diarrhea but can produce serious sepsis and abscesses in immunocompromised hosts. This infection is rarer than infection caused by the other two Yersinia pathogens Y. pestis and Y. enterocolitica. In the past decade, its genome has been elucidated through interest in this bacterium as the ancestor of the plague bacillus Y. pestis, with which it shares more than 90% of its genes (1).
MICROBIOLOGY
Characteristics
Y. pseudotuberculosis is a Gram-negative bacillus and facultative anaerobe in the family Enterobacteriaceae. It is oxidase-negative, non-lactose-fermenting, urease-positive, citrate-negative, and motile when grown at 250C but not motile when grown at 370C. Optimal growth rate is at 300C and it will grow in buffered saline at 40C. Six serotypes (I-VI) and four subtypes have been identified with O-group I accounting for approximately 80% of human cases. It produces a lipopolysaccharide (LPS) endotoxin with an O-antigenic side chain that has biological activities similar to those of other Gram-negative bacteria.
Genetics of Virulence
Y. pseudotuberculosis carries the same 70 kb virulence plasmid as the other pathogenic Yersiniae, pYV, which encodes a type III secretion system (TTSS), yersinial outer proteins (Yops), and the V antigen, which are produced in culture at 370C under growth-limiting conditions of low calcium concentrations. The TTSS uses a needle-like injectisome to insert Yops into host cells. The main effects of Yops, which are various enzymes, enzyme activators, and cytotoxins, are to inhibit phagocytosis by down-regulating cytokines and causing apoptosis of macrophages (9). Mutants of Y. pseudotuberculosis that were deficient for YopE and YopH in mice could colonize the intestine and Peyer’s patches but failed to reach the spleen and liver (16). Other mutants deficient in Yops and TTSS were unable to survive in the intestine of mice after orogastric inoculation (17). YadA is an adherence molecule encoded by the pYV plasmid that is required for survival and replication in Peyer’s patches. On the other hand,two patients have been reported whose cultures showed pYV-negaive bacteria (27). Chromosomal genes that are also essential for virulence include an invasin gene that promotes bacterial entry into M cells that that overlie Peyer’s patches (9). Mutants with genes defective for O-antigen synthesis in LPS rendering bacteria with rough colony morphology result in organisms unable to survive in the mouse intestine as well as unable to invade epithelial cells (17). A cytotoxic necrotizing factor (CNF) was shown to be secreted by growing bacteria and may target host cell GTPases (15). Additionally, a superantigenic toxin,YPMa, also called Y. pseudotuberculosis-derived mitogen, is present in 20% of European isolates and has activity in an intravenous mouse infection to accelerate mortality (3).
EPIDEMIOLOGY
A zoonotic infection, Y. pseudotuberculosis has its natural reservoirs in farm animals, wild rodents, rabbits, deer , and birds, including turkeys, ducks, geese, pigeons, pheasants, and canaries. It is transmitted among animals by the fecal-oral route. Humans become infected when they ingest fresh produce contaminated by animal feces, ingest infected meats, especially pork, and ingest unpasteurized milk or contaminated water. The infection occurs worldwide, but most cases have been reported from France and Scandinavia. Food-borne outbreaks involving grated carrots and iceberg lettuce were reported from Finland (11, 23). In outbreaks associated with carrots, produce had been stored in open containers during winter months, allowing access to rodents as well as natural cold-enrichment, and the carrots had not been washed before grating for raw consumption (10, 20). More than 500 school children developed fever and abdominal pain in these outbreaks and 5 underwent unnecessary appendectomies. Incubation periods were 4-18 days with a median of 8 days. Eating outside the home was a risk factor for infection in Finland (11). In a study of Finnish pigs, bacteria were isolated from 17% of a sample of 364 animals with more infection found in pigs raised on organic farms and on farms with more than 1,000 pigs (14). Pigs carrying this infection do not show signs of illness. Tonsils of wild boars in Sweden contained the organism in about 20% of animals (21). Tonsils of slaughtered pigs from Belgian farms contained it in 2-10% of animals (24). It is established as a significant cause of death in goats in California (6).
CLINICAL MANIFESTATIONS
The most common presentation is fever and abdominal pain or cramps (2). About half the patients have back pain and a quarter of patients have vomiting or diarrhea. The abdominal pain is often in the right lower quadrant corresponding to a clinical picture of distal ileitis and regional lymphadenitis that gives rise to the diagnostic appellation of “pseudoappendicitis.” This diagnosis leads to appendectomy in some cases, but ultrasonography and CT scanning can correctly reveal ileitis and mesenteric lymphadenitis (27). Although appendectomies are unnecessary, Y. pseudotuberculosis has been reported to cause the rare form of disease called granulomatous appendicitis (13). Another feature of this infection, occurring in half the patients, is erythema nodosum, which typically follows the onset of abdominal symptoms by about 10 days (10). Erythema nodosum is a post-infectious immunological reaction that occurs mainly in children (25). Similarly, reactive arthritis develops in a quarter of patients and is more likely in adults with the major histocompatibility complex allele HLA-B27 (25).
The infection can spread from the abdomen by way of the blood stream, especially in immunocompromised persons, to cause septicemia, liver or splenic abscesses, osteomyelitis, and septic arthritis. In a report of 27 cases in France in 2004-2005, 22 persons had bacteria isolated from blood and 5 had bacteria isolated from feces (26). Immunodeficiencies were present in 17 of these cases, including diabetes mellitus, cancer, HIV infection, cirrhosis, and kidney transplantation. Six of them died. Other reported cases of septicemia have also included patients with non-insulin-dependent diabetes mellitus and HIV infection (5, 18, 19).
Kawasaki disease, a self-limited febrile vasculitis of young children, is believed to be caused in some cases by Y. pseudotuberculosis. In a series of 452 cases in Japan, 42 children, who had positive stool cultures or elevated antibody titers, were more likely to show the potentially serious consequence of coronary artery dilatations and aneurysms (22).
LABORATORY DIAGNOSIS
Y. pseudotuberculosis can be identified in cultures by its features of being a Gram-negative bacillus that is lactose-negative, oxidase-negative, and urease-positive. It is distinguished from other enteric pathogens by further chemical reactions: negative for Voges-Proskauer, citrate, phenylalanine deaminase, ornithine decarboxylase, sucrose fermentation, and cellobiose, while positive for fermentation of rhamnose and melibiose. In stool cultures growth on MacConkey or SS agar will result in very small colonies after 24 hours at 370C, but colonies will be apparent at 48 hours. Recovery from stool specimens or contaminated environmental samples can be increased by using selective media. One of these is CIN (cefsulodin-irgasan-novobiocin) agar that contains antibiotics the bacteria are resistant to. Samples for culture can also be cold-enriched by placing them in phosphate-buffered broth and incubating at 40C for 7 or 14 days (14). Real-time PCR is an alternative method for diagnosis of infection in food (12, 21).
PATHOGENESIS
Organisms are ingested in contaminated foods, such as salads containing carrots or lettuce, or as pork, or in water. During the incubation period that averages 8 days, bacteria reach the terminal ileum and proximal colon, where they penetrate through epithelial cells overlying gut-associated lymphoid tissues including Peyer’s patches. As an intracellular infection, bacteria are taken up by macrophages, where they survive and proliferate. By using TTSS and Yops, Y. pseudotuberculosis acts to inhibit phagocytosis, allowing organisms more access to mesenteric lymph nodes and the blood stream. Results of this infection are mucosal ulcerations in the terminal ileum, less commonly ulcerations in the ascending colon, necrotic lesions in Peyer’s patches, and enlargement of mesenteric lymph nodes. The prognosis for patients with mesenteric lymphadenitis and ileitis is favorable for recovery from a self-limited infection in virtually all previously healthy persons, but patients with septicemia, who often have underlying immunocompromising illnesses, are reported to have fatal disease in about 27% of cases despite antimicrobial therapy in the hospital (26). Although acute appendicitis is not caused by Yersinae, cases of granulomatous appendicitis have been attributed to Y. pseudotuberculosis, as shown by application of PCR probes to surgical specimens (13). These tissues showed epithelioid granulomas, transmural lymphoid aggregates, giant cells, mucosal ulcerations, cryptitis, associated lymph node involvement, and absence of microabscesses in most cases. Although Y. pseudotuberculosis is not a cause of Crohn’s disease, a small percentage of acute infections have been followed by chronic symptoms that led to a diagnosis of Crohn’s disease. Additionally, patients with Crohn’s disease have a defective mucosal barrier that may predispose to yersiniosis (8).
SUSCEPTIBILITY IN VITRO AND IN VIVO
Isolates of Y. pseudotuberculosis have shown susceptibility to ampicillin, cephalosporins, tetracycline, trimethoprim-sulfamethoxazole, chloramphenicol, fluoroquinolones, and aminoglycosides. The organism is resistant to colistin. By being fully susceptible to ampicillin and first-generation cephalosporins, it differs fromY. enterocolitica, which carries beta-lactamase for resistance to ampicillin and first-generation cephalosporins.
ANTIMICROBIAL THERAPY
Treatment is not warranted in most cases of self-limited mesenteric lymphadenitis and ileitis presenting as fever and abdominal pain. Besides, the diagnosis is not available by culture at the time patients have their acute illness. Patients with septicemia, on the other hand, must be treated as promptly as possible to prevent a fatal outcome. To their benefit, most patients with septicemia will have been empirically started on an antimicrobial regimen for fever before the diagnosis of Y. pseudotuberculosis was established. Patients should receive ampicillin (100 to 200 mg/kg/day intravenously) or tetracycline, doxycycline, or aminoglycoside in standard doses for severe infections. Ofloxacin 400 mg/day and ceftriaxone 2 g/day were used successfully in a patient with septic arthritis (4). Ampicillin and gentamicin were used successfully in a patient with splenic abscesses (19). A patient with infected aortic aneurysm was cured by surgical resection followed by ceftriaxone 1 g/day and ciprofloxacin 200 mg 3 times a day intravenously (7).
ADJUNCTIVE THERAPY
Unnecessary appendectomies have been performed in patients with intestinal yersiniosis. Abdominal computed tomographic scans may reveal mesenteric lymphadenitis to rule against acute appendicitis, allowing patients appropriately not to be operated upon. Surgery, on the other hand, has been appropriate in patients with infected aneurysms and splenic abscess (7, 19). Patients with reactive arthritis benefit from treatment with non-steroidal anti-inflammatory agents, intra-articular steroid injections, and physical therapy.
ENDPOINTS OF THERAPY
In patients with septicemia, intravenous antimicrobial drugs are administered for approximately 14 days. During that time, patients should defervesce and clear symptoms of infection. If gentamicin or other aminoglycosides are used, serum concentration of antibiotic should be measured to ensure therapeutic efficacy and to avoid toxicity. Blood tests for serum creatinine and liver function are advised as are complete blood counts.
VACCINES
No vaccines are currently available.
PREVENTION
These infections are transmitted mainly by infected food. Fresh produce, such as carrots and lettuce, should be washed before consumption and should not be stored in open containers accessible to rodents. Unpasteurized milk products and uncooked or incompletely cooked meats, especially pork, should be avoided. Prolonged refrigeration of food before consumption is not advised because Yersiniae are capable of growing at 40C.
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