Pseudotuberculosis (Yersinia pseudotuberculosis Infection)

First isolated in 1883, Y pseudotuberculosis is a gram-negative bacterium that belongs to the genus Yersinia in the Enterobacteriaceae family. Along with the more common Yersinia enterocolitica, it can cause gastrointestinal infection in various wild and domestic animals. Y pseudotuberculosis appears to be cold tolerant, allowing transmission via contaminated cold-stored foods, handling of infected animal tissues, and cross-contamination during food preparation.

Y pseudotuberculosis infection occurs worldwide but appears to be most common as sporadic disease in northern Europe and Asia, primarily as a zoonotic infection of rabbits and other mammals and birds. Y pseudotuberculosis infection has been attributed to domestic pork, cattle, sheep, deer, and rabbits, which can be asymptomatically infected, as well as pet dogs, birds, and reptiles.[3]

Many Y pseudotuberculosis outbreaks have occurred in zoos, animal-holding areas, and laboratory facilities.

Even adjusting for underreporting and difficulty in microbiological isolation, Y pseudotuberculosis appears to be a relatively rare pathogen in humans. Public health data are available from Russia, where it has been a reportable disease since 1988.[4] Children appear to be 12 times more likely to become infected than adults.

The most common clinical Y pseudotuberculosis syndromes are self-limited enterocolitis and mesenteric lymphadenitis (pseudoappendicitis), but septicemia may occur in immunocompromised hosts, resulting in metastatic infection. Common metastatic sites include the liver, spleen, lungs, and joints[5] or bone, particularly among individuals with cirrhosis, diabetes, and/or hemochromatosis.[6]

A special form of Y pseudotuberculosis infection called Far East scarlet–like fever (FESLF) has been described in association with specific strains[7] of Y pseudotuberculosis in Russia and Japan that demonstrate mitogen A, which acts as a superantigen.[4] In Japan, FESLF is known as Izumi fever.

Y pseudotuberculosis is associated with postinfectious complications such as erythema nodosum, reactive arthritis, iritis, and glomerulonephritis. Y pseudotuberculosis has also been implicated in the etiology of some cases of Kawasaki disease.[8]

Because of its 97% DNA homology with the agent that causes plague, Yersinia pestis, Y pseudotuberculosis is believed to have been the progenitor of the plague bacillus and is considered a model of bacterial evolution.[9] More optimistically, a specific strain of Y pseudotuberculosis, IP32953, has been modified into a potentially promising vaccine against bubonic and pneumonic plague.[10]

Y pseudotuberculosis bears strong DNA, biochemical, and serological homology to the notorious agent of the Black Death, Y pestis, as well as a more common pathogen, Y enterocolitica. The pathogenic Yersinia species possess a wide range of chromosomal and plasmid-derived virulence factors, which allow entry, adherence, invasion, dissemination, and release from the host.[11] These include Type III Secretion system–encoded virulence plasmid pYV, the YPMa mitogen A superantigen, and the chromosomal high-pathogenicity island (HPI).

The HPI appears to be a complex of 5 genes involved in the production of an iron-siderophore yersiniabactin, which captures iron necessary and possibly rate-limiting for bacterial proliferation,[12] explaining the susceptibility among individuals with hemochromatosis or hemophilia. Other factors include YadA, which is responsible, but apparently not necessary, for invasion, the surface protein MyfA, which promotes cellular attachment, the outer proteins (Yops), which inhibit host defense by inducing apoptosis, and a chromosomal regulon (PhoP/Q), which allows bacterial survival in macrophages.

Y pseudotuberculosis is primarily a zoonotic infection of variable severity. Human infection is relatively rare, and is a foodborne illness. It usually is acquired through the ingestion of contaminated water or food or possibly cross-contamination during preparation. Y pseudotuberculosis is apparently less resistant to desiccation than Y pestis, and therefore not soil borne.[3] It appears tolerant to cold, accounting for growth in cold-stored foodstuffs. The incubation period is believed to be 4-10 days after ingestion of a reasonably large dose of bacilli.

After entry and colonization of the gastrointestinal tract, Y pseudotuberculosis bacteria stealthily invade the intestinal mucosa and undergo "quiet" replication for 36-48 hours without a measurable host response, owing to outer-protein inhibition of phagocytosis.[12] The infection then spreads to the Peyer patches and draining mesenteric lymph nodes. Y pseudotuberculosis disease typically manifests as an abscess-forming mesenteric lymphadenitis with fever and diarrhea, but can also lead to secondary perforation, intestinal obstruction, bleeding, intussusception,[13] and acute renal failure.[12]

Because the illness seems to target the terminal ileum, many cases are mistaken for appendicitis, hence the name of the organism.

Y pseudotuberculosis illness may be acute, subacute, or chronic but is usually self-limited. Bacteremia and sepsis, when it occurs, carries a high mortality rate.

In patients with underlying immunosuppressive disorders (uncontrolled diabetes mellitus, liver cirrhosis, or hemochromatosis or patients receiving immunosuppressive drugs), the bacteria may disseminate to the liver, spleen, and kidney, forming abscesses.

Postinfectious complications may include reactive arthritis, erythema nodosum, iritis, and glomerulonephritis.

Frequency

United States

The prevalence of Y pseudotuberculosis infection in the United States is unknown. It is likely underreported owing to lack of active surveillance and the need for special culture media for isolation.

International

While the distribution of Y pseudotuberculosis is worldwide, most Y pseudotuberculosis infections have been reported in countries of the northern hemisphere. Infection has been noted among domestic swine, rabbits, sheep, and deer in Italy, France, Australia, and New Zealand,[14, 4, 15, 16] with some serogroup specificity noted. Y pseudotuberculosis infection in Europe seems most prevalent in Germany, attributed to higher levels of pork consumption in that country.[12]

Animals are the major reservoir of Y pseudotuberculosis. This bacterium causes severe and, at times, lethal infections in susceptible animal species, in particular lagomorphs (hares and rabbits) during epizootics. In birds and rodents, Y pseudotuberculosis produces mild or asymptomatic infection.

Pseudotuberculosis may arise sporadically or in the form of outbreaks. Most cases are probably sporadic but likely misdiagnosed for viral enterocolitis, in part related to the labor-intensive laboratory testing for the pathogen in the stool of patients presenting with pseudotuberculosis.

Human Y pseudotuberculosis outbreaks after ingestion of contaminated milk products, undercooked or raw meat (eg, pork), fresh vegetables (carrots, lettuce), vegetable juices, and water have been reported in Canada, Finland, Russia, Japan, and New Zealand.[17] The scarlet fever–like syndrome has primarily been observed in Russia and Japan.

Most cases of pseudotuberculosis occur in winter and early spring, likely related to the enhanced growth characteristics of this pathogen in cold temperatures that occurs during long-term storage of vegetables during the winter.[12]

Mortality/Morbidity

Most Y pseudotuberculosis infections are self-limited with a low case-fatality rate. However, the uncommon septicemic form of illness that typically affects patients with underlying immunosuppressive disorders is associated with increased mortality rate (30%-40%).

Race

Y pseudotuberculosis infections appear to have no specific racial or ethnic predilection.

Sex

Y pseudotuberculosis infections are more common in men than in women. However, postinfectious complications (erythema nodosum and reactive arthritis) are more common in women.

Age

More than 75% of patients with Y pseudotuberculosis infection are aged 5-15 years.

Most pseudotuberculosis cases are either minimally symptomatic or self-limited.

More severe forms of Y pseudotuberculosis infection, such as severe mesenteric lymphadenitis and those associated with metastatic infection, respond to antibiotic therapy, and death is very rare. However, in immunocompromised patients who develop Y pseudotuberculosis bloodstream infection, the reported case fatality rate is in the range of 30%-40%.

People who prepare foods should be cautious about potential cross-contamination of foodstuffs, including baby formula, fresh vegetables, or other material stored cold, as Y pseudotuberculosis appears to be cold tolerant. It has been most commonly associated with pork products.

Symptoms caused by Y pseudotuberculosis infection include abdominal pain (often right lower quadrant location) and fever, usually with diarrhea. A 1984 series of 19 cases from Finland had the following distribution of symptoms: abdominal pain (14), fever (11), gastroenteritis (4), pseudoappendicitis (3), and none (2). Late complications of yersinial infection in this series included erythema nodosum (6), reactive arthritis (4), iritis (1), and nephritis (1).[3]

Other clinical problems associated with the enteric form of Y pseudotuberculosis infection have included terminal ileitis and intussusception, especially in children. Illness typically last 1-3 weeks, but symptoms may persist in some patients for months.

Far East scarlet fever–like syndrome, associated with specific superantigen-containing Russian and Japanese strains of Y pseudotuberculosis, has been characterized by Zalmover in 570 patients as a 6-stage illness, as follows[4, 18] :

• The incubation period of 7-10 days causes no symptoms.
• Initial onset is characterized by fever, rigors, headache, myalgia, arthralgia, asthenia, and anorexia and manifests as a red face and neck, pale nasolabial triangle, conjunctival hyperemia, coryza, and abdominal pain.
• The accrual phase occurs 3 days after symptom onset and manifests as increasing pain, fever, and the scarlet fever–like rash. Gastritis, ileitis, cholecystitis and mesenteric adenitis may occur, and right lower quadrant pain may mimic appendicitis. Hepatitis is common, as are central nervous symptoms of weakness, headache, photophobia, and vomiting.
• Remission follows, with decreased severity of symptoms.
• Recurrence and exacerbation may occur at day 8 or later and manifests as a return of pain, desquamation of skin, and increased jaundice, but absence of fever.
• Convalescence ensues with resolution of all major symptoms by day 12.

Other manifestations of Y pseudotuberculosis infection may include erythema nodosum, arthralgias, reactive arthritis, and ankylosing spondylitis.

A food history is important, as Y pseudotuberculosis infection has been associated with ingestion of contaminated food items, including fresh produce (eg, raw carrots). Physicians who suspect this disease should inquire of other persons who may have also been infected in order to document a potential point-source outbreak to public health authorities.

Physical findings caused by Y pseudotuberculosis infection may be grouped into 3 main categories—systemic, enteric, and rheumatologic. The predominant and often self-limited presentation of Y pseudotuberculosis infection is that of a febrile gastroenteritis with right lower quadrant abdominal pain.

Systemic findings may include fever, skin rash, strawberry tongue, hypotension, and lymphadenopathy.

Enteric findings include abdominal tenderness with or without rebound indicative of peritoneal involvement. Tenderness may be exquisite over McBurney point.

Rheumatologic involvement may include joint effusion, tenderness, or decreased range of movement and may be asymmetric in distribution.

Erythema nodosum lesions (often erythematous indurated tender areas on the anterior surface of the lower extremities) may be found.

Ophthalmic findings such as uveitis and conjunctivitis have also been reported.

Yersinia species can carry a wide variety of virulence factors that allow for adhesion, invasion, suppression of host response, and dissemination. Different strains carry different factors, producing a pattern of systemic, enteric, and immune-mediated responses also dependent on host susceptibility and immunologic endowment.

Most notable among strains found in eastern Eurasia is Mitogen A, which acts as a superantigen similar to those associated with toxic shock syndromes caused by Staphylococcus aureus and group A Streptococcus. To date, Y pseudotuberculosis is the only know gram-negative organism to exhibit superantigen activity.

Vital signs in patients with Y pseudotuberculosis infection may demonstrate signs of sepsis. Abdominal tenderness should be elicited, especially in the right lower quadrant.

Skin and joint examination are important for evidence of rash (erythema nodosum or scarlet fever–like rash) or arthritis.

Complications of Y pseudotuberculosis infection may include intussusception, bacteremia, septic arthritis, and disseminated infection, especially in immunocompromises or iron-overloaded patients.

Y pseudotuberculosis infection is diagnosed primarily via isolation of the organism from stool, tissue, blood, or joint fluid in patients with clinical history and manifestations suggestive of  enteritis or scarlet fever–like syndromes. The laboratory should be alerted as to the possibility of the organism in order to use special media, cold enrichment procedures, or longer monitoring of cultures.

Polymerase chain reaction (PCR) testing may be available from specialized reference or research laboratories.

Bacteriology

Y pseudotuberculosis is both aerobic and facultatively anaerobic; it is a gram-negative coccobacillus that grows slowly on blood and chocolate agar plates, forming small gray and translucent colonies at 24-72 hours. It has a good growth pattern on MacConkey or eosin-methylene blue (EMB) agar plates but is enhanced noticeably at lower temperatures (for example, 4°C cold enrichment in buffered saline) and is motile at temperatures lower than 28°C. Biochemically, it is oxidase-negative, urease-positive, and catalase-producing, and it does not ferment lactose.

Stool

Isolation of Y pseudotuberculosis from stool is difficult given the slow growth pattern and overgrowth of normal fecal flora. However, stool culture yield may be increased with cold enrichment or cefsulodin-Irgasan-novobiocin [CIN] agar.

Blood, peritoneal fluid, pharyngeal exudate, and synovial fluid

Blood, peritoneal fluid, pharyngeal exudate, and synovial fluid may yield Y pseudotuberculosis.

Serology

Numerus serological assays have been used for Yersinia infection but are neither sensitive nor specific for clinical use and not readily available, except from reference or research laboratories.

Enzyme-linked immunosorbent assay (ELISA) and agglutination tests may be obtained; the antibodies (against the O antigen) may appear soon after the onset of illness and typically wane over 2-6 months. Paired serum specimens taken 2 weeks apart that indicate a 4-fold rise in agglutinating antibodies support the diagnosis. Hemagglutination reaction tests that detect the pili (fimbriae) of either Y pseudotuberculosis or Y pestis have also been developed. Hemagglutination titers of 1:160 or higher are considered generally significant and indicative of true infection.

In patients with mesenteric lymphadenitis, CT scanning and, in some cases, ultrasonography of the abdomen and pelvis may reveal enlarged mesenteric lymph nodes and/or peritoneal findings, including appendiceal inflammation, peri-appendiceal fluid, and/or terminal ileitis.

In patients with pneumonic or septic presentations, chest radiography may reveal infiltrates.

Exploratory laparotomy is not infrequently performed in critically ill patients with prominent mesenteric lymphadenitis. Diagnostic tissue may confirm the otherwise occult diagnosis.

Although the affected appendix may appear normal, involved lymph nodes (mesenteric) typically show epithelioid granulomatous changes, lymphoid hyperplasia, coagulative necrosis, and histiocytic cell hyperplasia. Enteric lesions may be associated with crypt hyperplasia, microabscesses, and villus shortening.

Y pseudotuberculosis infection is often self-limited. However, more toxic presentations, including septic syndromes, severe dehydration, or other obscured diagnostic issues, may warrant hospitalization and empiric antibiotic therapy and supportive medical care.

Because of the rare nature of the disease, antibiotic management has not been standardized, nor has ampicillin been found effective for mild cases.[19] There has been concern about acquisition of resistance in Y pseudotuberculosis, and Y enterocolitica has been reported as resistant to ampicillin due to beta-lactamase production. Antimicrobial agents generally are not used for the treatment of enteritis or pseudoappendicitis in immunocompetent patients and do not decrease the risk for postinfectious complications.[20] Extraintestinal manifestations of infection by Y. pseudotuberculosis are susceptible to antibiotics against gram-negative bacteria[20] , such as aminoglycosides, tetracycline, cephalosporin, and ciprofloxacin[2, 20] . Antibiotic treatment typically is reserved for moderate to severe infection; however, the mortality rate for Y. pseudotuberculosis septicemia is still as high as 75%.[2]

For moderately severe Y pseudotuberculosis disease, trimethoprim-sulfamethoxazole (TMP 8 mg/kg and SMX 40 mg/kg per day in 2 divided doses) has been recommended in children, and ciprofloxacin 500 mg twice daily in adults as a 2C grade recommendation. The same author recommends ceftriaxone (2 g daily in adults, 100 mg/kg in children in 1 or 2 divided doses daily) plus gentamicin (5 mg/kg/day in 3 divided doses daily) for septicemia or severe disease.[20]  Iron is an essential element to bacterial survival and in conditions in which iron is increased, there is a predisposition to bacterial infectious diseases through both the propagation of bacteria and the modification of the immune host response.[21, 22]  Given that Yersinia pseudotuberculosis is a siderophilic bacteria[23, 24] , it probably would be prudent to discontinue iron-releasing drugs such as deferoxamine, to control hemolytic anemia, to reduce immunosuppression, and to avoid over transfusion in severely ill patients.[20]

A Y pseudotuberculosis epidemic among cattle in Australia in 1985-86 was controlled by administering tetracyclines.[25]

Exploratory laparotomy may be warranted in patients with complications, such as severe abdominal pain, including acute abdominal presentations, peritoneal findings, or, uncommonly, intussusception.

Consultation with an infectious disease specialist may be helpful. Gastroenterologists or surgeons may be required if invasive diagnostic or therapeutic interventions are warranted. For unusual Y pseudotuberculosis presentations, such as rheumatologic, dermatologic, or ocular complications, the respective consultations may be helpful.

No special diet is recommended; however, given the enteric nature of the symptoms and associated abdominal pain, diarrhea, fever, and anorexia that accompany such illness, it may be prudent to maintain the patient on nothing-by-mouth (NPO) status through the diagnostic phase of the disease and to administer intravenous fluids to prevent dehydration, as needed.

Bedrest through the acute illness is recommended. Activity as tolerated can be resumed once the enteric and systemic symptoms resolve.

Prevention of Y pseudotuberculosis infection is best accomplished by appropriate handling of pork and wild animal intestines, particularly during preparation of food that might be stored in cold temperatures.

No readily available guidelines exist for Y pseudotuberculosis infection.

In most cases, Y pseudotuberculosis infections do not require therapy with antimicrobials. However, in younger or immunosuppressed patients who are critically ill, antibiotic therapy may be prudent. Antibiotic therapy is warranted to treat severe Y pseudotuberculosis infection. Guidance via in vitro testing may be helpful; initial empiric therapy may include various antibiotics noted above.

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of the clinical setting.

Tobramycin

Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes. Dosing regimens are numerous and are adjusted based on CrCl and changes in the volume of distribution.

Gentamicin

Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes. Dosing regimens are numerous; adjust the dose based on creatinine clearance (CrCl) and changes in volume of distribution.

Trimethoprim/sulfamethoxazole (Bactrim, Bactrim DS)

Sulfamethoxazole inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid formation from para-aminobenzoic acid. Trimethoprim inhibits enzymes of the folic acid pathway by blocking dihydrofolic acid reduction to tetrahydrofolate.

Ciprofloxacin (Cipro, Cipro XR)

Ciprofloxacin is a fluoroquinolone with activity against pseudomonads, streptococci, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, and most gram-negative organisms, but with no activity against anaerobes. It inhibits bacterial deoxyribonucleic acid (DNA) synthesis and, consequently, growth.

Ceftriaxone

Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity. It has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. It arrests bacterial growth by binding to one or more penicillin-binding proteins.

Doxycycline (Acticlate, Adoxa, Doryx, Monodox, Morgidox)

Doxycycline inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. This agent interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity against susceptible bacteria.

Supportive care for patients with Y pseudotuberculosis sepsis includes general hospital acute-level care (intensive medical/surgical care may be needed, although uncommon unless the patient is severely ill) and intravenous fluids, frequent monitoring, serial examinations, radiographic studies, intravenous antibiotics, and treatment of any complicating host- or disease-related factors.

In outpatient settings or mild inpatient situations, close observation without the use of antibiotics is reasonable.

Foodborne epidemics of Y pseudotuberculosis infection can occur. Contact precautions, especially in the inpatient setting, apply to appropriate barriers (eg, gown, gloves) to exposure to enteric secretions, such as with diarrhea. Avoid ingestion of uncooked meat, contaminated water, or unpasteurized milk. Careful handwashing should follow consumption or handling of chitterlings (pork intestines).

Enteric disease may be complicated by intussusception in children. Postinfectious sequelae may include arthritis and erythema nodosum. Bacteremia and septic arthritis, osteomyelitis, and abscesses have been reported, particularly in the settings of iron overload (eg, hemophilia) and hemochromatosis.

Uncomplicated mesenteric lymphadenitis due to Y pseudotuberculosis infection is generally self-limited and commonly does not require antibiotic therapy. Septic forms of Y pseudotuberculosis infection or those associated with systemic manifestations are serious and carry a high mortality rate (often 75% despite antibiotic therapy).

Patients with Y pseudotuberculosis infection (and their families) should be familiar with forms of exposure, routes of infection, variable manifestations of the disease, difficulties in the diagnostic issues, and the potential for associated complications, including sepsis, reactive arthritis, erythema nodosum, and rare events such as cardiac or renal sequelae.