Etiology

Y. enterocolitica is a large, gram-negative coccobacillus that exhibits little or no bipolarity when stained with methylene blue and carbol fuchsin. These facultative anaerobes grow well on common culture media and are motile at 22°C but not at 37°C. Y. enterocolitica includes pathogenic and nonpathogenic members.

Epidemiology

This agent is transmitted to humans through food, water, animal contact, and contaminated blood products. Transmission can occur from mother to newborn. Y. enterocolitica appears to have a global distribution but is seldom a cause of tropical diarrhea. There is approximately 1 culture- confirmed Y. enterocolitica infection per 100,000 population/yr in the USA, and infection may be more common in Northern Europe. Cases are more common in colder months and among younger persons and boys. Most infections in children are among those <7 yr of age, with the majority among children <1 yr of age.

Natural reservoirs of Y. enterocolitica include pigs, rodents, rabbits, sheep, cattle, horses, dogs, and cats, with pigs being the major animal reservoir. Contact with feral animals or a colonized pet is a common source of human infections. Culture and molecular techniques have found the organism in a variety of foods, including vegetable juice, pasteurized milk, and carrots and in water. A source of sporadic Y. enterocolitica infections is pig offal (chitterlings). In one study, 71% of human isolates were indistinguishable from the strains isolated from pigs. Y. enterocolitica is an occupational threat to butchers. In part because of its capacity to multiply at refrigerator temperatures, Y. enterocolitica is transmitted at times by intravenous injection of contaminated fluids, including blood products.

Y. enterocolitica infections have increased, and Y. pseudotuberculosis infections have declined, leading to the suggestion that the former organism is replacing the latter in an ecologic niche. In part, the mass production of animals, development of meat factories based on chains of cold storage, and international trade of meat products and animals are believed to be the reasons for the increasing prevalence of yersiniosis in humans. There is evidence that under farm conditions pigs can be raised free of Y. enterocolitica.

Pathogenesis

The organisms most often enter by the alimentary tract and cause mucosal ulcerations in the ileum. Necrotic lesions of Peyer patches and mesenteric lymphadenitis occur. If septicemia develops, suppurative lesions can be found in infected organs. Infection can trigger reactive arthritis and erythema nodosum.

Adherence, invasion, and toxin production are established as essential mechanisms of pathogenesis. Bacterial components, some associated with the bacterial type III secretion apparatus, can actively suppress immunologic capacities, suggesting that immunosuppression can contribute to pathogenesis. Motility appears to be required for Y. enterocolitica pathogenesis. Serogroups that predominate in human illness are O:3, O:8, O:9, and O:5,27. Virulence traits are both chromosomal and plasmid encoded. Possibly because pathogenic strains require iron, patients with iron overload as in hemochromatosis, thalassemia, and sickle cell disease are at high risk for infection.

Clinical Manifestations

Disease occurs most often as enterocolitis with diarrhea, fever, and abdominal pain. Acute enteritis is more common among younger children, and mesenteric lymphadenitis that can mimic appendicitis may be found in older children and adolescents. Stools may be watery or contain leukocytes and, less commonly, frank blood and mucus. Y. enterocolitica is excreted in stool for 1-4 wk. Family contacts of a patient are often found to be asymptomatically colonized with Y. enterocolitica. Y. enterocolitica septicemia is less common and is most often found in very young children (<3 mo of age) and immunocompromised persons. Systemic infection is associated with splenic and hepatic abscesses, osteomyelitis, meningitis, endocarditis, and mycotic aneurysms. Exudative pharyngitis, pneumonia, empyema, lung abscess, and acute respiratory distress syndrome uncommonly occur. Y. enterocolitica infection in immunocompromised persons can manifest with physical and CT findings suggesting colon cancer with liver metastases.

Reactive complications include erythema nodosum, arthritis, and the uveitis rash syndrome. These manifestations may be more common in selected populations (northern Europeans), in association with HLA-B27, and in girls. Y. enterocolitica has been associated with Kawasaki disease.

Diagnosis

Y. enterocolitica is easily cultured from normally sterile sites but requires special procedures for isolation from stool, where other bacteria can outgrow it. Cold enrichment, where a sample is held in buffered saline, can result in preferential growth of Yersinia, but the procedure takes weeks. Polymerase chain reaction (PCR) and DNA microarray are more sensitive than culture with DNA microarray more sensitive and accurate than multiplex PCR. Many laboratories do not routinely perform the procedures required to detect Y. enterocolitica. Procedures targeted to this organism must be specifically requested. A history indicating contact with environmental sources of Yersinia and detection of fecal leukocytes are helpful indicators of a need to test for Y. enterocolitica. The isolation of a Yersinia from stool should be followed by tests to confirm that the isolate is a pathogen. Serodiagnosis is possible but not readily available.

Differential Diagnosis

The clinical presentation is similar to other forms of bacterial enterocolitis. The most common considerations include Shigella, Salmonella, Campylobacter, Clostridium difficile, enteroinvasive Escherichia coli, Y. pseudotuberculosis, and occasionally Vibrio diarrheal disease (Chapter 332). Amebiasis, appendicitis, Crohn disease, ulcerative colitis, diverticulitis, and pseudomembranous colitis should also be considered.

Treatment

Enterocolitis in an immunocompetent patient is a self-limiting disease, and no benefit from antibiotic therapy is established. Patients with systemic infection and very young children (in whom septicemia is common) should be treated. Many Yersinia organisms are susceptible to trimethoprim-sulfamethoxazole (TMP-SMX), aminoglycosides, 3rd-generation cephalosporins, and quinolones. TMP-SMX is the recommended empirical treatment in children, because it has activity against most strains and is well tolerated. In severe infections such as bacteremia, 3rd-generation cephalosporins with or without aminoglycosides are effective. Y. enterocolitica produces β-lactamases, which are responsible for resistance to penicillins and 1st-generation cephalosporins. Patients on deferoxamine should discontinue iron chelation therapy during treatment for Y. enterocolitica, especially if they have complicated gastrointestinal infection or extraintestinal infection.

Complications

Reactive arthritis, erythema nodosum, erythema multiforme, hemolytic anemia, thrombocytopenia, and systemic dissemination of bacteria have been reported in association with Y. enterocolitica infection. Septicemia is more common in younger children, and reactive arthritis is more common in older patients. Arthritis appears to be mediated by immune complexes, and viable organisms are not present in involved joints.

Prevention

Prevention centers on reducing contact with environmental sources of Yersinia. Breaking or sterilization of the chain from animal reservoirs to humans holds the greatest potential to reduce infections, and the techniques applied must be tailored to the reservoirs in each geographic area. There is no licensed vaccine.

Etiology

Y. pseudotuberculosis is a gram-negative aerobic and facultative anaerobic coccobacillus that does not ferment lactose; is oxidase negative, catalase producing, and urea splitting; and shares many morphologic and culture characteristics with Y. enterocolitica. It is differentiated biochemically from Y. enterocolitica on the basis of ornithine decarboxylase activity and on fermentation of sucrose, sorbitol, cellobiose, and other tests, although some overlap between species occurs. Antisera to somatic O antigens and sensitivity to Yersinia phages can also be used to differentiate the 2 species. Subspecies-specific DNA sequences that allow direct probe- and primer-specific differentiation of Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica have been described. Y. pseudotuberculosis is more closely related to Y. pestis than to Y. enterocolitica.

Epidemiology

Y. pseudotuberculosis is zoonotic, with reservoirs in wild rodents, rabbits, deer, farm animals, various birds, and domestic animals, including cats and canaries. Transmission to humans is by consumption of or contact with contaminated animals or contact with an environmental source contaminated by animals (often water). Infections are more commonly reported from Europe, in boys, and in the winter. Direct evidence of transmission of Y. pseudotuberculosis to humans by consumption of lettuce and raw carrots has been published. Y. pseudotuberculosis bacteremia is an increasingly recognized problem in HIV-infected patients.

Pathogenesis

Ileal and colonic mucosal ulceration and mesenteric lymphadenitis are hallmarks of the infection. Necrotizing epithelioid granulomas may be seen in the mesenteric lymph nodes, but the appendix is often grossly and microscopically normal. The mesenteric nodes are often the only source of isolation of the organisms. Y. pseudotuberculosis antigens bind directly to HLA class II molecules and can function as superantigens, which might account for the clinical illness resembling Kawasaki disease.

Clinical Manifestations

Pseudoappendicitis with abdominal pain, right lower quadrant tenderness, fever, and leukocytosis is the most common clinical presentation. Enterocolitis and extraintestinal spread are uncommon. Iron overload, diabetes mellitus, and chronic liver disease are often found concomitantly with extraintestinal Y. pseudotuberculosis infection. Renal involvement with tubulointerstitial nephritis, azotemia, pyuria, and glucosuria can occur.

Diagnosis

PCR of involved tissue can be used to identify the organism; isolation by culture can require an extended interval. Involved mesenteric lymph nodes removed at appendectomy can yield the organism by culture. Ultrasound examination of children with unexplained fever and abdominal pain can reveal a characteristic picture of enlarged mesenteric lymph nodes, thickening of the terminal ileum, and no image of the appendix. Y. pseudotuberculosis is rarely recovered from stool. Serologic procedures are available but not in most routine laboratories.

Differential Diagnosis

Appendicitis (most commonly), inflammatory bowel disease, and other intra-abdominal infections should be considered. Kawasaki disease, staphylococcal or streptococcal disease, leptospirosis, Stevens-Johnson syndrome, and collagen vascular diseases, including acute-onset juvenile rheumatoid arthritis, can mimic the syndrome with prolonged fever and rash. Clostridium difficile colitis, meningitis, encephalitis, enteropathic arthropathies, acute pancreatitis, sarcoidosis, toxic shock syndrome, typhoid fever, and ulcerative colitis may also be considered.

Treatment

Uncomplicated mesenteric lymphadenitis due to Y. pseudotuberculosis is a self-limited disease, and antimicrobial therapy is not required. Culture-confirmed bacteremia should be treated with an aminoglycoside, ampicillin, TMP-SMX, a 3rd-generation cephalosporin, or chloramphenicol.

Complications

An illness with presentation similar to Kawasaki disease can occur. There may be fever of 1-2 days’ duration; strawberry tongue; pharyngeal erythema; a scarlatiniform rash; cracked, red, swollen lips; conjunctivitis; sterile pyuria; periungual desquamation; and thrombocytosis. Coronary aneurysm formation has been described. Erythema nodosum and reactive arthritis can follow infection.

Prevention

Avoiding exposure to potentially infected animals and good food-handling practices can prevent infection. The sporadic nature of the disease makes application of targeted prevention measures difficult.

Etiology

Y. pestis is a gram-negative, facultative anaerobe that is a pleomorphic nonmotile, non-spore-forming coccobacillus and is a potential agent of bioterrorism (Chapter 704). The bacterium has several chromosomal and plasmid-associated factors that are essential to virulence and to survival in mammalian hosts and fleas. Y. pestis shares bipolar staining appearance with Y. pseudotuberculosis and can be differentiated by biochemical reactions, serology, phage sensitivity, and molecular techniques. The Y. pestis genome has been determined and is ~4,600,000 base pairs in size.

Epidemiology

Plague is endemic in at least 24 countries. About 3,000 cases are reported worldwide per year, with 100-200 deaths (2004). Plague is uncommon in the USA (0-40 reported cases/yr); most of these cases occur west of a line from east Texas to east Montana, with 80% of cases in New Mexico, Arizona, and Colorado. Transmission to humans is most commonly from wild animal sources, although most cases of inhalation plague reported to the Centers for Disease Control and Prevention (CDC) were associated with exposure to infected free-roaming domestic cats. The epidemic form of disease killed about 25% of the population of Europe in the Middle Ages in one of a number of epidemics and pandemics. The epidemiology of epidemic plague involves extension of infection from the zoonotic reservoirs to urban rats, Rattus rattus and Rattus norvegicus, and from fleas of urban rats to humans. Epidemics are no longer seen. Selective pressure exerted by plague pandemics in medieval Europe is hypothesized for enrichment of a deletion mutation in the gene encoding CCR5 (CCR5-Δ32). The enhanced frequency of this mutation in European populations endows about 10% of European descendants with resistance to HIV-1.

The most common mode of transmission of Y. pestis to humans is by the bite of infected fleas. Historically, most human infections are thought to have resulted from bites of fleas that acquired infection from feeding on infected urban rats. Less commonly, infection is caused by contact with infectious body fluids or tissues or inhaling infectious droplets. Sylvatic plague can exist as a stable enzootic infection or as an epizootic disease with high host mortality. Ground squirrels, rock squirrels, prairie dogs, rats, mice, bobcats, cats, rabbits, and chipmunks may be infected. Transmission among animals is usually by flea bite or by ingestion of contaminated tissue. Xenopsylla cheopis is the flea most commonly associated with transmission to humans, but >30 species of fleas have been demonstrated as vector competent, and Pulex irritans, the human flea, can transmit plague and might have been an important vector in some historical epidemics. Both sexes are similarly affected by plague, and transmission is more common in colder regions and seasons, possibly because of temperature effects on Y. pestis infections in vector fleas.

Pathogenesis

In the most common form of plague, infected fleas regurgitate organisms into a patient’s skin during feeding. The bacteria translocate to regional lymph nodes, where Y. pestis replicates, resulting in bubonic plague. In the absence of rapidly implemented specific therapy, bacteremia can occur, resulting in purulent, necrotic, and hemorrhagic lesions in many organs. Both plasmid and chromosomal genes are required for full virulence. Pneumonic plague occurs when infected material is inhaled. The organism is highly transmissible from persons with pneumonic plague and from domestic cats with pneumonic infection. This high transmissibility and high morbidity and mortality have provided an impetus for attempts to use Y. pestis as a biological weapon.

Clinical Manifestations

Y. pestis infection can manifest as several clinical syndromes; infection can also be subclinical. The 3 principal clinical presentations of plague are bubonic, septicemic, and pneumonic. Bubonic plague is the most common form and accounts for 80-90% of cases in the USA. From 2-8 days after a flea bite, lymphadenitis develops in lymph nodes closest to the inoculation site, including the inguinal (most common), axillary, or cervical region. These buboes are remarkable for tenderness. Fever, chills, weakness, prostration, headache, and the development of septicemia are common. The skin might show insect bites or scratch marks. Purpura and gangrene of the extremities can develop as a result of disseminated intravascular coagulation. These lesions may be the origin of the name Black Death. Untreated plague results in death in >50% of symptomatic patients. Death can occur within 2-4 days after onset of symptoms.

Occasionally, Y. pestis establishes systemic infection and induces the systemic symptoms seen with bubonic plague without causing a bubo (primary septicemic plague). Because of the delay in diagnosis linked to the lack of the bubo, septicemic plague carries a higher case fatality rate than bubonic plague. In some regions, bubo-free septicemic plague accounts for 25% of cases.

Pneumonic plague is the least common but most dangerous and lethal form of the disease. Pneumonic plague can result from hematogenous dissemination, or rarely as primary pneumonic plague after inhalation of the organism from a human or animal with plague pneumonia or potentially from a biological attack. Signs of pneumonic plague include severe pneumonia with high fever, dyspnea, and hemoptysis.

Plague meningitis, tonsillitis, or gastroenteritis can occur. Meningitis tends to be a late complication following inadequate treatment. Tonsillitis and gastroenteritis can occur with or without apparent bubo formation or lymphadenopathy.

Diagnosis

Plague should be suspected in patients with fever and history of exposure to small animals in endemic areas. Thus, bubonic plague is suspected in a patient with a painful swollen lymph node, fever, and prostration who has been exposed to fleas or rodents in the western USA. A history of camping or the presence of flea bites increases the index of suspicion.

Y. pestis is readily transmitted to humans by some routine laboratory manipulations. Thus, it is imperative to clearly notify a laboratory when submitting a sample suspected of containing Y. pestis. Laboratory diagnosis is based on bacteriologic culture or direct visualization using Gram, Giemsa, or Wayson stains of lymph node aspirates, blood, sputum, or exudates. Y. pestis grows slowly under routine culture conditions and best at temperatures that differ from those used for routine cultures in many clinical laboratories. ELISA and PCR are available but are not in routine clinical use. A rapid antigen test is under development. Suspected isolates of Y. pestis should be forwarded to a reference laboratory for confirmation. Special containment shipping precautions are required. Cases of plague should be reported to local and state health departments and the CDC.

Differential Diagnosis

The Gram stain of Y. pestis may be confused with Enterobacter agglomerans. Mild and subacute forms of bubonic plague may be confused with other disorders causing localized lymphadenitis and lymphadenopathy. Septicemic plague may be indistinguishable from other forms of overwhelming bacterial sepsis like tularemia and cat-scratch disease.

Pulmonary manifestations of plague are similar to those of anthrax, Q fever, and tularemia, all agents with bioterrorism and biological warfare potential. Thus, the presentation of a suspected case, and especially any cluster of cases, requires immediate reporting. Additional information on this aspect of plague and procedures can be found at www.bt.cdc.gov/agent/plague/.

Treatment

Patients in whom bubonic plague is suspected should be placed in isolation until 2 days after starting antibiotic treatment to prevent the potential spread of the disease if the patient develops pneumonia. The treatment of choice for bubonic plague historically has been streptomycin (30 mg/kg/day, maximum 2 g/day, divided every 12 hr IM for 10 days). Intramuscular streptomycin is inappropriate for septicemia because absorption may be erratic when perfusion is poor. The poor central nervous system penetration of streptomycin makes this an inappropriate drug for meningitis. Streptomycin might not be widely and immediately available. Gentamicin (children, 7.5 mg/kg IM or IV divided every 8 hr; adults, 5 mg/kg IM or IV once daily) has been shown to be as efficacious as streptomycin. Alternative treatments include doxycycline (<45 kg, 2-5 mg/kg/day every 12 hr IV, maximum 200 mg/day; not recommended for children <8 yr of age; ≥45 kg, 100 mg every 12 hr PO), ciprofloxacin (30 mg/kg/day divided every 12 hr, maximum 400 mg every 12 hr IV), and chloramphenicol (50-100 mg/kg/day IV divided every 6 hr). Meningitis is usually treated with chloramphenicol. Resistance to these agents and relapses are rare. Y. pestis is susceptible to fluoroquinolones in vitro, which is effective in treating experimental plague in animals. Y. pestis is susceptible to penicillin in vitro, but this is ineffective in treatment of human disease. Mild disease may be treated with oral chloramphenicol or tetracycline in children >8 yr of age. Clinical improvement is noted within 48 hr of initiating treatment.

Postexposure prophylaxis should be given to close contacts of patients with pneumonic plague. Antimicrobial prophylaxis is recommended within 7 days of exposure for persons with direct, close contact with a pneumonic plague patient or those exposed to an accidental or terrorist-induced aerosol. Recommended regimens include a 7-day course of tetracycline, doxycycline, or TMP-SMX. Contacts of cases of uncomplicated bubonic plague do not require prophylaxis. Y. pestis is a potential agent of bioterrorism that can require mass casualty prophylaxis (Chapter 704).

Prevention

Avoidance of exposure to infected animals and fleas is the best method of prevention of infection. In the USA, special care is required in environments inhabited by rodent reservoirs of Y. pestis and their ectoparasites. Patients with plague should be isolated if they have pulmonary symptoms, and infected materials should be handled with extreme care.