yersinia infections: centennial of the discovery of the plague bacillus

Yersinia Infections: Centennial of the Discovery of the Plague BacillusAuthor(s): Thomas ButlerSource: Clinical Infectious Diseases, Vol. 19, No. 4 (Oct., 1994), pp. 655-661Published by: Oxford University PressStable URL: http://www.jstor.org/stable/4458084 .

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655

STATE-OF-THE-ART CLINICAL ARTICLE

Yersinia Infections: Centennial of the Discovery of the Plague Bacillus Thomas Butler From the Division of Infectious Diseases, Texas Tech University Health

Science Center, Lubbock, Texas

The genus Yersinia is named after Alexandre Yersin (1863-1943). Yersin was born in Switzerland and received his medical education in Lausanne (Switzerland), Marburg (Germany), and Paris. He did research on diphtheria toxin with Emile Roux in Paris before departing in 1890 for French Indochina to work as a ship's physician. In addition to his medical work, he explored rivers and mountains in Vietnam. He discovered the plague bacillus in June 1894 while visiting Hong Kong during an epidemic of bubonic

plague. Upon his arrival, an estimated 60,000 residents of Canton and 300 residents of Hong Kong had died of the disease, and the mortality rate in hospitals was 95%. Using his microscope he described gram-negative bipolar bacilli in the buboes and blood of patients who had died of plague. He cultured the bacteria on peptone agar. He inoculated mice and guinea pigs with pulp from buboes and with cultured bacteria. After the animals died, he found bacilli in their tissues. He returned to Paris in October 1894 with pure cultures of the organisms and he revealed his findings to Emile Roux and Louis Pasteur. He published his results rapidly in the same year.

Yersin returned to Vietnam, where he spent the remainder of his life working to produce vaccines and antisera for human and animal diseases. He started a Pasteur Institute in Nha Trang and helped start a medical school in Hanoi. The

genus Yersinia was named after Yersin posthumously in the 1960s when other genera were renamed. Yersinia pestis, the plague bacillus, had been called Pasteurella pestis, Yersinia enterocolitica had been called Bacterium enterocoliticum, and Yersinia pseudotuberculosis had been called Shigella pseudotlubercu losis.

Yersinia

Pathogens and Associated Diseases

Yersinia infections are caused by gram-negative bacilli in the family Enterobacteriaceae. There are three principal

Received 16 June 1994. Portions of this manuscript have been adapted with permission from the

following textbook: Butler T. Yersinia species (including plague). In: Man- dell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases. 3rd ed. New York: Churchill Livingstone, 1990:1748-56.

Reprints or correspondence: Dr. Thomas Butler, Division of Infectious Diseases, Texas Tech University Health Science Center, Lubbock, Texas 79430.

Clinical Infectious Diseases 1994;19:655-63 ? 1994 by The University of Chicago. All rights reserved. 1058-4838/94/1904-0001 $02.00

pathogenic species: Y. enterocolitica, Y. pseudotuberculosis, and Y. pestis. All are zoonotic infections, and the major reservoirs are rodents, farm animals, and birds. Y. enterocolitica and Y. pseudotuberculosis are pathogens of human nonplague yersiniosis. The typical presentation includes fever and diarrhea or abdominal pain that may mimic appendicitis, and this enteric infection is sometimes followed by chronic arthritis. Y. pestis is the sole pathogen of human plague; the typical presentation for this disease is febrile lymphadenitis that is rapidly fatal when untreated. The results of DNA hybridization studies have indicated such close related- ness between Y. pestis and Y. pseudotuberculosis that the

plague bacillus has been renamed Y. pseudotuberculosis sub- species pestis, however, the older name Y. pestis remains in use and will be employed in this article.

Classification ofyersinia infections as nonplague yersiniosis and plague is practical because the two groups differ fun-

damentally in regard to manifestations of disease, epidemiology, and control strategies. Accordingly, this article will deal separately with nonplague yersinia infections, referred to sim- ply as yersiniosis, and Y. pestis infection, referred to as plague.

Yersiniosis

Clinical features. The alimentary tract is the portal of entry in most cases of yersiniosis; an inoculum of 109 organisms may be required to cause infection. After an incubation period of 4-7 days, this infection causes mucosal ulcerations in the terminal ileum (rarely in the ascending colon), necrotic lesions in Peyer's patches, and enlargement of mesenteric lymph nodes. In most cases, the appendix is histologi- cally normal or is mildly inflamed. Enterocolitis is the presenting feature in two-thirds of all reported cases and is associated with fever, diarrhea, and abdominal pain lasting 1-3 weeks. In serious cases, rectal bleeding and perforation of the ileum may occur. Fecal excretion of the organism may continue for weeks after symptoms have subsided. Leuko- cytes and, less commonly, blood or mucus may be present in the stool. Most patients with this syndrome are <5 years of age. Older children and young adults more often present with mesenteric adenitis and/or terminal ileitis. They have fever, right lower-quadrant pain, and leukocytosis, but they do not have diarrhea. This syndrome may be clinically indis- tinguishable from acute appendicitis and results in unneces- sary laparotomies.



656 Butler CID 1994; 19 (October)

Reactive polyarthritis, which occurs in 10%-30% of adults with Y. enterocolitica infection in Scandinavia, begins a few

days to I month after the onset of acute diarrhea and may involve the knees, ankles, toes, fingers, and wrists. In most cases, two to four joints become inflamed in rapid succession over a period of 2-14 days. Symptoms persist for more than 1 month in two-thirds of cases and for more than 4 months in one-third of cases. After 12 months, most patients are symp- tomless, but a few will have persistent low back pain, in some cases due to sacroiliitis. Most patients with arthritis due to

yersinia infection have the HLA-B27 haplotype. Ankylosing spondylitis rarely occurs. Synovial fluid examination reveals <25,000 white blood cells/mm3 with 60%-95% polymorphonuclear leukocytes. Synovial-fluid cultures are negative, but Yersinia O-polysaccharide antigen has been found in synovial leukocytes with use of immunofluorescence micros-

copy. Reiter's syndrome has also been reported. Like arthritis, this complication is much more likely to develop in individuals with the HLA-B27 antigen.

Erythema nodosum occurs in up to 30% of the Scandina- vian cases of Y. enterocolitica infection. Skin lesions appear on the patient's legs and trunk 2-20 days after the onset of fever and abdominal pain and resolve spontaneously within 1 month in most cases. Women with this manifestation out- number men by 2:1.

Recently, exudative pharyngitis has been documented as

part of the spectrum of illnesses caused by Y. enterocolitica. In one large outbreak in the United States, 8% of patients presented with acute pharyngitis and fever; none of these

patients had diarrhea. Y. enterocolitica has also been reported to cause pneumonia, empyema, and lung abscess.

Yersinia septicemia is less common and is most often re-

ported for elderly patients and for those with diabetes melli- tus, severe anemia, hemochromatosis, cirrhosis, or malig- nancy. Those with iron overload, such as thalassemic

patients who receive frequent transfusions, are at risk for septicemia. The treatment of iron-overloaded patients with des- ferrioxamine has been particularly associated with yersinia sepsis because this iron chelator enhances the growth of the

organism and also appears to inhibit polymorphonuclear leukocyte activity against the infection. Septicemic patients may develop hepatic or splenic abscesses, osteomyelitis, wound infections, or meningitis. Endocarditis and mycotic aneurysms due to Y. enterocolitica have been reported.

Agents and epidemiology. Y. enterocolitica and Y. pseudotuberculosis are gram-negative, non-lactose-fermenting, ure-

ase-positive bacilli that are motile when grown at 25?C but not at 37?C. Both organisms grow on blood agar, heart infusion agar, MacConkey agar, and Salmonella-Shigella agar at room temperature and at 37?C and in buffered saline at 4?C. Colonies often remain very small after incubation for 24 hours but are readily apparent at 48 hours. More than 50

serotypes and five biotypes of Y. enterocolitica have been described. Most strains from patients belong to serotypes 03,

08, 05, 27, and 09 and to biotypes 2, 3, and 4. Six serotypes (I-VI) and four subtypes of Y. pseudotuberculosis have been identified, with the O-group I accounting for 80% of human disease.

The virulence of the yersiniae correspond with the presence of V and W antigens, which confer dependency on calcium for growth at 37?C. Pathogenic strains are resistant to serum complement, penetrate human epithelial cells (HeLa cells) or guinea pig conjunctivae, are lethal to mice, and dem- onstrate cytotoxicity. Some of these characteristics are me- diated by a 70-kb plasmid that encodes for a secreted protein kinase and an outer membrane protein with protein tyrosine phosphatase activity. Y. enterocolitica does not produce a

siderophore for iron transport and thus grows better in the

presence of other bacteria that produce siderophores, allow-

ing the bacterium to transport iron for its own growth. Many isolates produce a heat-stable enterotoxin that is similar to the heat-stable enterotoxin produced by Escherichia coli. This enterotoxin, which is produced at 22?C but not at 37?C, is probably not an important cause of diarrhea during yersinia infection. The organisms produce a lipopolysaccha- ride endotoxin, which has biological properties similar to those of other gram-negative bacteria.

Humans become accidental hosts of Yersinia after they ingest contaminated animal products, and they do not play an important role in maintaining the organisms in nature or in their transmission (figure 1). The natural reservoirs of Y. enterocolitica include a variety of domestic and wild animal

species. The prominent hosts include pigs, rodents, rabbits, sheep, goats, cattle, horses, dogs, and cats. Y. pseudotuberculosis resides in many of the same animals, including rodents, rabbits, deer, and farm animals; however, the organism has also been found extensively in birds, including turkeys, ducks, geese, pigeons, pheasants, and canaries. Generally, animal infections with Yersinia result in asymptomatic carriage that does not produce clinical illness. On the other hand, illness in household dogs has resulted in transmission of infection to humans.

The organisms are localized in the oropharyngeal cavities and lumens of the gastrointestinal tract of the above-men- tioned animals. They are excreted into the feces, allowing fecal-oral transmission. Studies of pigs in slaughterhouses suggested that the tonsils and tongues contain Y. enterocolitica more frequently than other tissues. Pork that is uncooked or incompletely cooked is a source of infection, and raw intestines of pigs (chitterlings) have been specifically im-

plicated. The presence of Y. enterocolitica in unpasteurized milk suggests that bacteria reach the bloodstream from the intestine and are secreted into milk by mammary glands.

The ability of Y. enterocolitica to grow at 4?C means that

refrigerated meats and milk are likely sources of infection. The organisms have been isolated from lakes, streams, and

drinking water, but only a few cases of human infection have been linked to contaminated water. Epidemics of food-borne



CID 1994; 19 (October) Yersinia Infections 657

.Humans F "orl, Humans Blood Humans |'I..'no soomia-1 { H

}transfusion

T t Ingestion of incompletely Ingestion of unpasteurized cooked pork contaminated milk or pasteurized milk during slaughter by contact contaminated by unpasteurized with tonsils or feces milk or by infected persons

Animal Reservoirs:

Pigs, cows, sheep, goats, rodents, dogs, foxes, porcupines, birds

Ingestion of fecally contaminated food, water or soil;

ingestion of infected animal tissues

Figure 1. Transmission routes ofyersinioses. Wide arrows indicate common transmission, medium arrows indicate occasional transmission, and thin arrows indicate rare transmission.

disease have occurred in the United States: one was due to contaminated chocolate milk in New York; one was associated with pasteurized milk in Tennessee; one was due to contaminated bean sprouts in Pennsylvania; and epidemics associated with consumption of chitterlings during holiday festivities occurred in Atlanta and Baltimore.

Person-to-person spread of yersiniosis rarely occurs, but a few instances of intrafamilial spread and of nosocomial

spread have been reported. Contaminated blood from blood banks has been a source of Y. enterocolitica infection, result-

ing in shock and death in several cases. The donors of the contaminated blood were presumably bacteremic at the time of donation, but they were not noticeably ill. Severe disease in the recipients of the transfusions was probably due to mul-

tiplication of bacteria in the refrigerators at the blood banks.

Diagnosis and treatment. Cultures of stool, mesenteric

lymph node tissue, pharyngeal exudate, peritoneal fluid, or blood may yield Yersinia, depending on the clinical syndrome. Recovery of organisms from otherwise uncontamin- ated material such as blood, CSF, or mesenteric lymph-node tissue is not difficult, but isolation of yersiniae from feces is

hampered by the slow growth of the organism and by over-

growth of normal fecal flora. Yield of stool cultures can be increased by using cold enrichment, alkaline, or selective

cefsulodin-irgasan-novobiocin (CIN) agar, but these methods are not cost effective in routine diagnosis because most

clinically significant infections can be detected with the usual methods for culturing enteric pathogens.

Serological tests are useful in diagnosing yersinia infec-

tions, provided sera are appropriately adsorbed. Results of

serology are especially important for patients with arthritis because cultures of stool and synovial fluid are likely to be

negative. The differential diagnosis includes Lyme disease, rheumatic fever, other postinfectious arthritides, and rheuma-

tologic diseases. Tests currently being used detect antibodies that agglutinate bacteria belonging to specific serotypes. Y. enterocolitica and Y. pseudotuberculosis cross-react with each other and with other organisms such as Brucella, Vibrio, and E. coli. Y. pseudotuberculosis types II and IV cross-react with Salmonella groups B and D. Agglutinating antibodies to Y. enterocolitica appear soon after the onset of illness but generally disappear within 2-6 months. ELISA and western blots have been employed in research laboratories to further de- fine immunoglobulin class responses (IgG, IgA, and IgM) to different bacterial antigens.

Y. enterocolitica is usually susceptible in vitro to aminoglycosides, chloramphenicol, tetracycline, trimethoprim-sulfa- methoxazole (TMP-SMZ), piperacillin, third-generation cephalosporins, and fluoroquinolones. Isolates are usually resistant to penicillin; resistance to ampicillin, carbenicillin, and first-generation cephalosporins occurs frequently. The value of antimicrobial therapy in cases of enterocolitis and mesenteric adenitis is unclear, since these infections are

usually self-limited. Treatment of enterocolitis with antibiotics shortened the persistence of IgG antibodies to Yersinia to - 3 months. Patients with septicemia due to Y. enterocolitica, which is associated with a mortality of 50% despite treatment, should receive antibiotic therapy. The drug of choice for the treatment of Y. enterocolitica infection has not yet been identified, but intravenous gentamicin (5 mg/[kg. d]) in divided doses alone or combined with a third-generation cephalosporin (cefotaxime or ceftriaxone) has been suggested. Good responses have been reported with TMP-SMZ, doxycycline, and ciprofloxacin, whereas treatment failures have occurred with cefuroxime, ceftazidime, cefoperazone, and gentamicin. Therapeutic successes have been achieved with fluoroquinolones when given alone or in combination with third-generation cephalosporins or aminoglycosides. Laparotomy for suspected appendicitis should be avoided when yersiniosis is a likely diagnosis.

Y. pseudotuberculosis is usually susceptible in vitro to am-

picillin, tetracycline, chloramphenicol, cephalosporins, and

aminoglycosides. Although antibiotic therapy is probably not warranted for most patients with mesenteric adenitis, patients with septicemia should receive intravenous ampicillin (100-200 mg/[kg. d]) intramuscular streptomycin (20- 30 mg/[kg. d]), or oral or intravenous tetracycline (20-30 mg/[kg * d]) in divided doses. The mortality associated with Y. pseudotuberculosis septicemia is 75% despite administra- tion of antibiotic therapy.

Prevention. Contact with animal reservoirs should be minimized to prevent yersiniosis. Complete cooking of meats and proper pasteurization of dairy products should render




potentially contaminated foods safe for consumption. Never- theless, other approaches to reducing the frequency of contamination of uncooked foods deserve consideration. It has been proposed that abatoir workers try to prevent contact between pork and the contents of the oral cavity and intestinal tract during slaughter of pigs. Meat should not be refrigerated for prolonged periods before consumption because of the unique ability of Yersinia to multiply at 4?C.

In dairies, care must be taken to prevent contamination of milk after pasteurization. Analysis of milk-associated out- breaks in the United States revealed that pasteurization methods were adequate but that workers probably reconta- minated the milk after pasteurization. Therefore it would be

prudent to design dairy plants to insure that unpasteurized milk, as well as the workers that handle it, has no opportu- nity to be in contact with pasteurized milk. This could be

accomplished by physically separating areas where unpasteurized milk is received from those where the milk is handled after pasteurization.

The incidence of transfusion-associated yersiniosis could be reduced by screening donors for a history of recent diarrhea or fever. However, some of the donors of contaminated blood were reported to be asymptomatic. It is not practical in blood banks to culture all donated blood before it is trans- fused. Incubation of donated blood overnight before separa- tion of packed red cells has been proposed to reduce the incidence of contamination, but it is not known whether this method will be effective or feasible.

Plague

Clinical features. The most common form of plague is bubonic plague. During an incubation period of 2-8 days following the bite of an infected flea, bacteria proliferate in the regional lymph nodes. Patients are typically affected by the sudden onset of fever, chills, weakness, and headache.

Usually, after a few hours or on the next day, patients notice a bubo, which is signaled by intense pain in one anatomic

region of lymph nodes (usually the groin, axilla, or neck). Swelling increases in this area, which is so tender that the patients typically avoid any motion that would provoke dis- comfort.

The buboes of patients with plague are oval swellings that

vary from 1 to 10 cm in length and elevate the overlying skin, which may appear stretched or erythematous (figure 2). They may appear either as smooth, uniform, egg-shaped masses or as an irregular cluster of several nodes with intervening and

surrounding edema. The overlying skin is warm, and an un-

derlying, firm, nonfluctuant mass is present. The region around the lymph nodes is usually considerably edematous (either gelatinous or pitting in nature). Although infections other than plague can produce acute lymphadenitis, plague is virtually unique for the suddenness of onset of the fever and bubo, the rapid development of intense inflammation in

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Figure 2. Bubo in left femoral region of patient with plague. Re- printed with permission from: Butler T. Yersinia species (including plague). In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Princi- ples and practice of infectious diseases. 3rd ed. New York: Chur- chill Livingstone, 1990:1751.

the bubo, and the fulminant clinical course that can produce death as quickly as 2-4 days after the onset of symptoms.

The groin is the most common site of the buboes in patients with plague. Other common sites are the axillae and cervical region. A given distribution of buboes is presumed to be due to the distribution of flea bites. Body temperature is elevated (in the range of 38.5-40.0?C), and the pulse rate is increased to 1 10-140/min. The blood pressure is character-

istically low (in the range of 100/60 mm Hg), owing to ex- treme vasodilation. Lower pressures that can not be mea- sured may occur if shock ensues. The liver and spleen are often palpable and tender.

The majority of patients with bubonic plague do not have skin lesions; however, about one-fourth of the patients in Vietnam had various dermatologic findings. The most common were pustules, vesicles, eschars, or papules near the bubo or in the anatomic region of skin that is drained by the affected lymph nodes, presumably the sites of the flea bites.

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These skin lesions rarely progress to extensive cellulitis or abscesses. Ulceration, however, may lead to a large car- buncle.

Another kind of skin lesion in patients with plague is pur- pura, which is a result of the systemic disease. The purpuric lesions may become necrotic, resulting in gangrene of distal extremities, the probable basis of the epithet black death at- tributed to plague through the ages. These purpuric lesions contain vasculitic blood vessels that are occluded by fibrin thrombi, resulting in hemorrhage and necrosis.

A unique feature of plague is the development of massive bacteremia. In the early acute stages of bubonic plague, all

patients probably have intermittent bacteremia. Single blood cultures performed for Vietnamese patients at the time of

hospital admission were positive in 27% of cases. A hallmark of moribundity in cases of plague is high-density bacteremia; thus, a blood smear revealing characteristic bacilli has been used as a prognostic indicator in this disease. There are occasional cases of plague in which bacteria are inoculated and

proliferate in the body without producing a bubo. Patients

may become ill with fever and die with bacteremia but without detectable lymphadenitis. This syndrome has been termed septicemic plague, denoting plague without the for- mation of a bubo.

One of the feared complications of bubonic plague is sec-

ondary pneumonia. The infection reaches the lungs by hema-

togenous spread of bacteria from the bubo. Plague pneumonia is highly contagious via airborne transmission and is associated with a high mortality rate. It presents in patients with fever and lymphadenopathy as cough, chest pain, and often hemoptysis. Bronchopneumonia, cavities, or confluent consolidation are seen on radiographs. The sputum is usually purulent and contains plague bacilli.

Primary inhalation pneumonia is now rare but is a poten- tial threat following exposure to a patient with plague who has a cough. Recent cases in the United States were due to

exposure to infected domestic cats that had pneumonia or submandibular abscesses. Plague pneumonia is invariably fatal when antibiotic therapy is delayed for >1 day after the onset of illness.

Plague meningitis is a rarer complication and typically occurs > 1 week after the onset of bubonic plague that has been inadequately treated. It results from hematogenous spread from a bubo and is associated with a higher mortality rate than that of uncomplicated bubonic plague. There appears to be an association between buboes located in the axilla and the development of meningitis. Less commonly, plague meningitis presents as a primary infection of the me-

ninges without antecedent lymphadenitis. Plague meningitis is characterized by fever, headache, meningismus, and pleo- cytosis with a predominance of polymorphonuclear leuko-

cytes. Bacteria are frequently demonstrable on gram staining of CSF sediment.

Plague can produce pharyngitis that may resemble acute

tonsillitis. The anterior cervical lymph nodes are usually inflamed, and Y. pestis may be recovered from a throat culture or by aspiration of a cervical bubo. This is a rare form of plague that is presumed to occur after the inhalation or ingestion of plague bacilli.

Patients with plague sometimes present with prominent gastrointestinal symptoms including nausea, vomiting, diarrhea, and abdominal pain. These symptoms may appear before the bubo or, in septicemic plague, occur in the absence of a bubo, resulting in diagnostic delay.

Agents and epidemiology. Y. pestis grows aerobically on most culture media, including blood agar and MacConkey agar. It does not ferment lactose and forms small colonies on

MacConkey agar after 24 hours of incubation at 35?C. On

triple sugar iron agar, Y. pestis produces an alkaline slant and acid butt. It is nonmotile and negative for citrate utilization, urease production, and the indole reaction.

Like the other yersiniae, the plague bacillus produces V and W antigens and outer membrane proteins, which confer

dependency on calcium for growth at 37?C. Monoclonal an-

tibody to V antigen given to animals protected them from

developing plague. Other important virulence factors include the production oflipopolysaccharide endotoxin, a cap- sular envelope containing the antiphagocytic fraction I anti-

gen, the ability to absorb organic iron into the form of hemin, and the presence of the temperature-dependent enzymes co-

agulase and fibrinolysin. Throughout the world, the urban and domestic rats Rattus

rattus and Rattus norvegicus are the most important reservoirs of the plague bacillus. In sylvatic foci of plague, which are found in the United States, the important reservoirs are the ground squirrel, rock squirrel, and prairie dog. Rabbits and domestic cats are occasionally infected and can bring disease to humans. Each area ofendemicity has its own prominent host species.

The organism is transmitted among the natural animal reservoirs by flea bites or by ingestion of contaminated animal tissues (figure 3). The most efficient vector for transmission is the oriental rat flea Xenopsylla cheopis. When a flea ingests a blood meal from a bacteremic animal infected with Y. pestis, the coagulase of the organism causes the blood to clot in the flea's foregut, leading to blockage of swallowing. Y. pestis multiplies in the clotted blood. During attempts to ingest a blood meal, the flea may regurgitate thousands of organisms into an animal's skin.

Plague occurs worldwide, with most of the human cases

reported from developing countries of Asia and Africa.

During 1980-1989, 8,554 cases of human plague in 17 countries were reported to the World Health Organization. Of these cases, 981 (11%) resulted in death. The countries that reported >100 cases of plague during 1980-1989 (in descending order) were Tanzania, Vietnam, Zaire, Brazil, Madagascar, Peru, Uganda, Burma, Bolivia, the United States, and Botswana. In the United States, all the plague




Inhalation of droplets

Humans from Humans coughing

o dt of

patients

Bites of Direct handling Inhalation of rodent of respiratory fleas animal tissues secretions

(cats)

Animal Reservoirs:

Rats, ground squirrels, prairie dogs, field mice, bobcats, cats, rabbits, chipmunks, camels

Ingestion of contaminated animal tissues

Bites of fleas

Figure 3. Transmission routes of plague. Wide arrows indicate common transmission, medium arrows indicate occasional transmission, and thin arrows indicate rare transmission. Adapted with permission from: Butler T. Yersinia species (including plague). In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases. 3rd ed. New York: Churchill Living- stone, 1990: 1749.

cases occurred in the southwestern states of New Mexico, Arizona, Colorado, Utah, and California. Most of these occurred during the months of May-October, when people were outdoors and came into contact with rodents and their fleas.

Humans become accidental hosts in the natural cycle of plague when bitten by infected rodent fleas; humans appear to play no role in the maintenance of plague in nature. The infection is only rarely, during epidemics of pneumonic plague, passed directly from person to person. Humans also rarely develop infection by the direct handling of contaminated animal tissues and fluids or by inhalation of aero- solized infected fluids.

In the United States, there have been an equal number of cases in males and females. Sixty percent of cases occur in persons <20 years old. Although a majority of cases occur in whites, the attack rate among American Indians living in areas where the infection is endemic, such as Arizona, New Mexico, and Utah, is 10 times the rate observed among non- Indians living in the same states (1.4 cases/100,000 population and 0.1 cases/100,000 population, respectively).

Within these areas, risk factors associated with acquiring plague include direct contact with rodents or carnivores, the

presence of harborage and food sources for wild rodents in the immediate vicinity of the home, and, possibly, the failure to control fleas on pet dogs and cats.

Diagnosis and treatment. A bacteriologic diagnosis is

readily made in most cases by smear and culture of a bubo aspirate. To obtain the aspirate, a 20-gauge needle attached to a 10-mL syringe that contains 1 mL of sterile saline is inserted in the bubo and withdrawn several times until the saline becomes tinged with blood. Because the bubo does not contain liquid pus, it may be necessary to inject some of the saline and immediately reaspirate it. Drops of the aspirate should be placed on microscopic slides and air dried for both gram and Wayson staining. Gram staining will reveal polymorphonuclear leukocytes and gram-negative coccobacilli and bacilli ranging from 1 to 2 ,tm in length. Wayson stain is prepared by mixing 0.2 g of basic fuchsin (90% dye content) with 0.75 g of methylene blue (90% dye content) in 20 mL of 95% ethyl alcohol. This mixture is then poured slowly into 200 mL of 5% phenol. A smear, after being fixed for 2 min- utes in absolute methanol, is stained with Wayson stain for 10-20 seconds, washed with water, and dried. Y. pestis appears as a light-blue bacillus with dark-blue polar bodies; a contrasting pink counterstain will be seen on the remainder of the slide (figure 4). Smears of blood, sputum, or CSF can be handled similarly.

The aspirate, blood, and other appropriate fluid should be inoculated onto blood agar and MacConkey agar plates and into infusion broth. For definitive identification, cultures can be mailed in double containers to the Centers for Disease Control and Prevention (CDC) Plague Branch, P.O. Box 2087, Fort Collins, Colorado, 80522 (telephone: 303-221- 6450). A serological test, the passive hemagglutination test with use of fraction I antigen of Y. pestis, can be performed at

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lar bacilli characteristic of Y. pess. (Stain, Wayson; originall mag- '".'-''=.nification, X 2,800).! | | ~ 1 l l _l * * -

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Figure 4. Smear of bubo aspirate shows pleomorphic and bipolar bacilli characteristic of Y. pestis. (Stain, Wayson; original mag- nification, X 2,800).




the CDC on acute- and convalescent-phase serum. For patients with negative cultures, a fourfold or greater increase in titer of antibody to fraction I antigen of Y. pestis or a single titer of > 1:16 is presumptive evidence for a diagnosis of plague.

Early treatment of plague with antibiotics can be life sav-

ing. Untreated plague has an estimated mortality rate of >50%. Streptomycin is the drug of choice for the treatment of

plague because it reduces the case-fatality rate to - 10%. No other drug has been demonstrated to be more efficacious or less toxic. Streptomycin should be administered intramuscu-

larly in two divided daily doses totaling 30 mg/(kg d) for 10

days. The conditions of most patients improve rapidly, and

they defervesce in - 3 days. A 10-day course of streptomycin is recommended because viable bacteria have been isolated

during convalescence from buboes of patients with plague. For patients who are allergic to streptomycin or who

strongly prefer an oral agent, tetracycline is a satisfactory alternative; a dose of 2-4 g/d in four divided doses for 10

days is the usual regimen. For patients with meningitis who

require a drug with good penetration into the CSF and for

patients with profound hypotension in whom an intramuscu-

larly administered dose may be poorly absorbed, chloram-

phenicol should be administered intravenously. This regimen is given as a loading dose of 25 mg/kg, followed by 60

mg/(kg * d) in four divided doses. After clinical improvement in the patient's condition, chloramphenicol should be given orally to complete a total course of 10 days.

Other antimicrobials have been used for plague with vary- ing success. These include sulfonamides, trimethoprim-sul- famethoxazole, kanamycin, and ampicillin. These drugs all

appear either to be less effective or more toxic than streptomycin and therefore should not be chosen.

Antibiotic resistance in human isolates of Y. pestis has never been reported, and, to my knowledge, resistance dur-

ing antibiotic therapy has not emerged. Streptomycin, tetra-

cycline, and chloramphenicol given alone are clinically very effective, and relapses are exceedingly rare. Therefore, there is no rationale for using multiple antibiotics to treat plague.

The buboes usually recede without local therapy. Occa-

sionally, however, they may enlarge or become fluctuant

during the first week of treatment, necessitating incision and

drainage. The aspirated fluid should be cultured for evidence of superinfection with other bacteria, but this material is

usually sterile. Prevention. All cases of suspected plague should be re-

ported to the state Health Department and to the World Health Organization. Patients with uncomplicated infections who are promptly treated present no health hazards to other

persons. Those with cough or other signs of pneumonia must be placed in strict respiratory isolation for at least 48 hours after the institution of antibiotic therapy or until the sputum

culture is negative. Aspirates and blood samples of the bubo must be handled with gloves and with care to avoid aerosolization of these infected fluids. Laboratory workers who pro- cess the cultures should be asked to exercise precautions; however, standard bacteriologic techniques that safeguard against skin contact with cultures and aerosolization of infected fluids should be adequate.

A formalin-killed vaccine, Plague Vaccine U.S.P. (Cutter Laboratories, Berkeley, CA) is available for travelers to areas where the infection is endemic or hyperendemic, for individuals who must live and work in close contact with rodents, and for laboratory workers who must handle live Y. pestis cultures. A primary series of two injections, with a 1-3 month interval between them, is recommended for these individuals. Booster injections are given every 6 months for as long as exposure continues. In addition to vaccination, persons living in areas of endemicity should provide themselves with as much personal protection against rodents and fleas as possible, including living in ratproof houses, wearing shoes and garments that cover the legs, and applying insecticide dusts to houses. In addition, sick cats should not be handled, and dead animals should not be skinned by hunters with

ungloved hands.

Suggested Readings

Butler T. Plague and other yersinia infections. New York: Plenum, 1983. Centers for Disease Control and Prevention. Update: Yersinia enterocolitica

bacteremia and endotoxin shock associated with red blood cell transfusions-United States, 1991. MMWR Morb Mortal Wkly Rep 1991;40:176-8.

Centers for Disease Control and Prevention. Pneumonic plague-Arizona, 1992. JAMA 1992;268:2146-7.

Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med 1989;321:16- 24.

Crook LD, Tempest B. Plague. A clinical review of 27 cases. Arch Intern Med 1992; 152:1253-6.

Gayraud M, Scavizzi MR, Mollaret HH, Guillevin L, Hornstein MJ. Antibi- otic treatment of Yersinia enterocolitica septicemia: a retrospective review of 43 cases. Clin Infect Dis 1993; 17:405-10.

Granfors K, Jalkanen S, von Essen R, et al. Yersinia antigens in synovial- fluid cells from patients with reactive arthritis. N Engl J Med 1989; 320:216-21.

Hoogkamp-Korstanje JAA, de Koning J, Samsom JP. Incidence of human infection with Yersinia enterocolitica serotypes 03, 08, and 09 and the use of indirect immunofluorescence in diagnosis. J Infect Dis 1986; 153:138-41.

Hull HF, Montes JM, Mann JM. Septicemic plague in New Mexico. J Infect Dis 1987; 155:113-8.

Kihlstrom E, Foberg U, Bengtsson A, et al. Intestinal symptoms and serological response in patients with complicated and uncomplicated Yer- sinia enterocolitica infections. Scand J Infect Dis 1992;24:57-63.

Lee LA, Taylor J, Carter GP, et al. Yersinia enterocolitica 0:3: an emerging cause of pediatric gastroenteritis in the United States. J Infect Dis 1991; 163:660-3.

Tauxe RV, Vandepitte J, Wauters G, et al. Yersinia enterocolitica infections and pork: the missing link. Lancet 1987; 1:1129-32.



yersinia infections: centennial of the discovery of the plague bacillus

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