0 1991S. Karger AG, Basel M)42-9007/91/06114)018 $2.75/0
Vox Sang 1991;61:18-23
Fatal Yersinia enterocolitica (Serotype 0:5,27) Sepsis after Blood Transfusion James R. Stubbsa, Ramakrishna L. Reddyb, Steven A. Elg‘, Elizabeth H. Perryarb,Leon L. Adcock‘, Jeffrey McCullough a* ‘Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minn.; bAmerican Red Cross Blood Services, St. Paul, Minn.; “Department of Obstetrics and Gynecology, University of Minnesota Medical School, Minneapolis, Minn.; USA
Abstract. Septicemia is a rare complication of blood transfusion. This is probably primarily due to the use of sealed disposable containers for blood collection and the storage of red cell-containing components at 4°C. However, despite these measures, septicemia due to blood transfusion continues to occur. We report here a fatal case of Yersinia enterocolitica septicemia due to a contaminated unit of red cells which was collected from an apparently healthy, asymptomatic blood donor. The organism grows at cold temperature and multiplies during storage of red blood cell-containing components. Contaminated components do not show any visible abnormalities. The possibility of transfusion-transmitted Y. enterocolitica should be considered in patients who have symptoms of sepsis or shock following transfusion.
Introduction Septicemia has become a rare complication of blood transfusion. Bacterial contamination was responsible for only 2 of 113 transfusion-related fatalities reported to the Food and Drug Administration (FDA) between April 3, 1976 and December 31, 1979. Both patients died of gramnegative endotoxemia. The implicated units were whole blood in one case and cryoprecipitate in the other [I]. Honig and Bove [2] report on two additional transfusion-related fatalities resulting from bacterial contamination of blood products which occurred between 1976 and 1978. The use of sealed disposable blood collection systems and the storage of whole blood and red blood cells at 4°C are probably the most important factors limiting the incidence of bacteremia. However, despite these standard measures to minimize bacterial contamination and growth in blood products, septicemia due to blood transfusion, though quite rare, continues to be a worrisome source of morbidity and mortality. Nine deaths due to posttransfusion sepsis were recorded by the FDA between January 1980 and December 1983. Six of these deaths were associated with platelet products [3]. Four episodes of bacterial sepsis related to contaminated platelet concentrates occurred in a 3-month period in 1985 [4]. These cases closely followed the adopted practice
of 7-day room temperature storage of platelets in December 1984. All 4 cases involved pooled platelet concentrates with at least one unit stored at room temperature for 5 days or longer. These cases prompted a return to 5-day room temperature storage for platelets. A separate case of transfusion-related sepsis resulting from platelets reported by Heal et al. [3] proposed that a state of low-grade asymptomatic bacteremia (Salmonella) can occur in some donors. Since 1979, at least 26 cases of gram-negative bacterial sepsis associated with whole-blood or red blood cell transfusion have been published. Yersinia enterocolitica was identified in 15 of these cases [ 5 ] . The Centers for Disease Control (CDC) recently reported on 7 episodes in which transfused red blood cells were contaminated with Y. enterocolitica. One of those 7cases was caused by serotype 0:5,27 [5]. We report here another case of fatal endotoxemia caused by a unit of red cells contamined with Y. enterocolitica serotype 0:5,27.
Case History A 53-year-old, para 1-0-0-1woman underwent a pre-radiation therapy surgical staging procedure for squamous cell carcinoma of the cervix on October 4,1989. Cefoxitin therapy was started following the operation as a matter of routine postoperative care. The patient’s
19
Y. enterocolitica Sepsis after Blood Transfusion
course was uneventful until the third postoperative day. At that time her hemoglobin was 86 gh and two units of packed red blood cells were ordered to be transfused. Approximately 30 min into the transfusion of the first unit (80-100 ml transfused), the patient developed chills, tachycardia and tachypnea. Her temperature increased from 37°C before transfusion to 39.2”C. The transfusion was stopped, microbial cultures were obtained, and the packed-cell unit was returned to the blood bank. Her temperature rose to 40°C. She became hypotensive (blood pressure: 76/48), tachycardic with poor respiratory function, and soon became unconscious. Her chest x ray showed bilateral pulmonary infiltrates. Antimicrobial therapy, consisting of cefotaxime, vancomycin and metronidazole was started. She underwent tracheal intubation and invasive cardiac monitoring was instituted. The patient remained febrile in spite of multiple negative cultures of blood, urine, and catheter sites. Candida albicans was isolated in urine later in her course and this was treated with bladder irrigations of amphotericin B. Management in the surgical intensive-care unit included treatment with dobutamine, dopamine, crystalloid, colloid, and blood products. Intravenous antibiotics included cefoxitin, cefotaxime, gentamicin, vancomycin, metronidazole, and imipenem. The patient became anuric and hemodialysis was initiated on the 24th postoperative day. Liver failure followed with a peak bilirubin of 478.8 pmolfl. On postoperative day 32, an intraperitoneal hemorrhage developed requiring multiple blood transfusions. Due to the patient’s deteriorating condition and poor prognosis, the family elected to withdraw supportive care. She expired 37 days after the transfusion.
Methods A transfusion reaction investigation, performed the same day as the reported reaction, consisted of a recheck for clerical errors, visual inspection of the unit for evidence of hemolysis, discoloration, gas bubbles or clots, a complete cross-match including direct antiglobulin test, and gram stain and microbial culture of the unit and attached segments. Previous donations by the donor of the implicated unit were reviewed for causes of deferral and for any adverse outcomes of transfused products. The donor health history was carefully re-examined, and information was collected on the presence of illness in any employee involved in the handling of the unit from collection to transfusion. All records pertaining to the collection, processing, shipment, and disposition of all components made from the implicated donation were reviewed to disclose any deviation from normal blood bank procedures. The donor was interviewed for details of any illness in the 2 months prior and any time after the donation. Questions were asked regarding recent dental procedures and family history of hemochromatosis. The donor was also questioned about travel, diet, and exposure to animals in the months prior to donation. Specific inquiry was made regarding the possible ingestion of untreated water, unpasteurized dairy products and raw or undercooked meat. Information regarding illness among the donor’s household members and other close contacts was collected. The CDC Hospital Infections Program was notified of the case on October 12,1989, and the following specimens were sent to the Nosocomial Infections Laboratory: the packed red cell unit, sample segments from the red cell unit, the patient’s pre-reaction (10-7-89) and postreaction (10-9-89) plasma, donor blood for microbial culture, endotox-
in level and agglutinin titer (10-16-89),throat swab and rectal swab from the donor (10-16-89), the hospital Y.enterocolitica isolate, and an aliquot from the donated plasma unit which was recalled. A unit of blood was collected from the donor on December 12,1989 for microbial culture and endotoxin assay. The unit was processed as an Adsol unit. Microbial cultures were performed following 2, 5 and 7 weeks of storage at 4°C. Following the last culture, the unit was sent to the CDC for endotoxin studies.
Results The transfusion reaction workup showed no clerical errors, no evidence of hemolysis, and a compatible crossmatch. The red cell unit and administration set had no visually detectable abnormalities. Gram stain of the red cell unit revealed rare/few gram-negative rods. Bacterial culture of the unit was positive within 12 h for Y enterocolitica. The unit of blood was drawn on September 11, 1989 by the St. Paul Regional Blood Services of the American Red Cross and thus had been stored for 26 days at the time of transfusion. The donor was a 47-year-old male school teacher from the Minneapolis-St. Paul metropolitan area. He was a regular cytomegalovirus-negative blood donor who had donated 6 times previously since November 1987 with no reported recipient complications. He had been deferred once previously due to elevated blood pressure. He was feeling well on the day of donation. He did not give a history of diarrhea, fever, headache, pharyngitis, abdominal pain, erythema nodosum, or arthritis in the months preceding or after the implicated donation. There was no diarrhea or other gastrointestinal problem in the donor’s family before or after the donation. He had no other known infectious exposures. There was no family history of hemochromatosis and the donor had not had recent dental work. He had no known exposure to farm animals or wild animals, and his eating habits were not unusual. The donor was taking one teaspoon of psyllium hydrophilic mucilloid daily for constipation. He was on no other medications. Further retrospective questioning revealed that the donor had streaks of blood in his stool once in July 1989 and once in August 1989. There was no history of hemorrhoids. He had no symptoms related to these incidents, and he did not seek medical attention. Other components prepared from the original unit of whole blood included a platelet concentrate, which was transfused into another patient uneventfully, and liquid plasma which was sent for fractionation and subsequently recalled. High concentrations of Y enterocolitica (1.38 x lo8CFU/ ml) and endotoxin (9,100 ng/ml) were found in the red cell
StubbslReddylElg/Perry/AdcockMcCullough
20
unit. The serotype of the Y. enterocolitica was 0:5,27. Sample segments from the red cell unit and the blood sample collected from the donor on 10-16-89 showed no microbial growth and no detectable endotoxin. The patient’s prereaction and post-reaction plasma specimens had no detectable endotoxin. The plasma recalled from the implicated donation was negative for endotoxin as well. The donor throat and rectal swabs showed normal flora with no Y. enterocolitica or other pathogens isolated. Y. enterocolitica agglutinin titers performed on the recalled plasma and on plasma collected from the donor on 10-16-89revealed a titer of 1:128 in both specimens. Blood cultures performed on the follow-up donor unit at 2, 5 and 7 weeks were negative. There was no endotoxin detected in this unit.
Discussion
Y. enterocolitica is a gram-negative coccoid bacillus of the family Enterobacteriaceae. The organism is a facultative anaerobe, and it has been isolated from humans essentially worldwide. However, it appears to be found most frequently in cooler climates [6]. The true incidence and prevalence of Y. enterocolitica are not known. A Canadian study found that Y. enterocolitica was recovered from the stool cultures of 2.8% of 6,364 children with diarrhea who where tested over a 15-month period. In the same study, not a single Y. enterocolitica isolate was found among 545 children without gastroenteritis who had stool cultures. The duration of excretion of the organism in the stool ranged from 14 to 97 days (mean 42 days) [7]. Studies of patients with enteritis performed in Italy and the Netherlands have isolated Y.enterocolifica in 1.4 and 2.9%, respectively [8, 91. In contrast, a study performed in Detroit, Mich., failed to isolate Y. enterocolitica from stool cultures in 1,262patients with diarrhea between May and November 1977 [lo]. Y enterocolitica has been isolated from a variety of animal reservoirs. Swine are recognized as an important animal reservoir for pathogenic Y. enterocolitica in Europe and Japan [ll-131. Animal products may also harbor the organism [6,13,14]. Other reservoirs include lakes [W], streams [6, 161, well water [17, 181, soil [6], and vegetables [6]. A human carrier state has never been documented. The transmission of Y. enterocolitica to humans has occurred primarily by the ingestion of contaminated foods [14, 191, water [16], and milk [20]. Products in which Y. enterocolitica has been isolated include raw milk [21,22], whipped cream [6], cheese curds [22], ice cream [6], beef [6], lamb [6], poultry
[6], and especially pork [6, 14,19,23,24]. Direct transmission from dogs [25-271, cats [28], and swine [29, 301 to humans by a fecal-oral or oral-oral route has been proposed [16]. Person-to-person transmission has been suggested in reports of sequential onset of illness in family members [27, 28, 31, 321 and nosocomially acquired infections [33-351. Y enterocolitica of the serotypes 0:3,0:8, and 0:9 are the most frequently reported as causes of human disease and bacteremia worldwide [9, 36, 371. However, serotype 0:5,27 is known to cause disease in humans [23, 381. In the recent report of 7 cases of transfusion-associated Y. enterocolitica sepsis from the CDC, 1case was caused by serotype 0:5,27. Of the remaining cases, 4 were caused by organisms of serotype 0:3, and 1 case each was caused by serotypes 0:1,2,3 and 0:20 [5]. Y. enterocolitica infection gives rise to a variety of clinical manifestations. The most common presentation, enterocolitis, often occurs in young children and is characterized by diarrhea, low-grade fever, abdominal pain, and vomiting. Leukocytes and erythrocytes may be present in the stool. Gross blood is evident in the stools of up to 25% of patients. Most cases of Y. enterocolitica enterocolitis are self-limited. Y. enterocolitica infection may present as pseudoappendicular syndrome, which is clinically similar to appendicitis. The syndrome occurs most often in older children and young adults. Involvement of extraintestinal sites, either in association with or independent of gastrointestinal involvement, may also occur. Pharyngitis, with or without associated lymphadenopathy, leads a long list of extraintestinal infections. The most common delayed manifestations of Y. enterocolitica infection are polyarticular arthritis and erythema nodosum. The arthritis typically begins 1-2 weeks after the onset of gastrointestinal symptoms and usually persists for 1-4 months; however, prolonged symptoms may occur in some patients. The HLA-B27 histocompatibility antigen is present in approximately 80% of patients that develop reactive arthropathy [39]. Bacteremia associated with Y. enterocolitica infection is currently thought to occur most often in patients who have a predisposing underlying disease or are in an iron-overloaded state [40-43]. Examples include patients with cirrhosis [44, 451, hemochromatosis [44, 451, acute iron poisoning [40, 44, 461, transfusion-dependent disorders [41, 42, 44, 451, diabetes mellitus [44,47]. alcoholism [44], and malnutrition [44,45]. Patients receiving deferoxamine [4042, 461 or immunosuppressive therapy [39] are also predisposed to bacteremia. The reported case fatality rate of Y enferocolitica bacteremia in these susceptible groups is 3450% [44,45]. It is apparent upon review of the published cases of transfusion-associated Y enterocolirica sepsis
21
Y. enterocolitica Sepsis after Blood Transfusion
that a state of transient bacteremia may occur in some people without symptoms, and unfortunately some of these people may donate blood during the bacteremic period [48-511. The incidence of asymptomatic Y. enferocolifica bacteremia is unknown. The pH range in which Y enterocolifica is able to grow is between 5.0 and 9.0. The optimal pH range for growth is between 7.0 and 8.0. The organism grows well at 4°C with dextrose as its carbon source [39]. Stenhouse and Milner [48] inoculated a fresh unit of ACD whole blood with 80 CFU/ml of Y. enterocolifica and stored it at 4°C. After 21 days there were 5 x 10' CFU/ml with no visible signs of contamination in the blood bag. Iron is an essential growth factor for most bacteria and Y. enterocolitica is no exception [39]. Endotoxin is produced by most clinical isolates of Y enterocolitica [38]. In vitro studies have shown an absence of endotoxin production at temperatures exceeding 30°C [52]. Thus, it is apparent that prolonged storage of red blood cells at 4°C provides an environment suitable for the growth of large numbers of Y. enterocolitica. It is likely that these storage conditions also allow production of endotoxin in contaminated units. All reported transfusion reactions due to blood components contaminated with Y. enterocolifica have involved red blood cell-containing units stored for more than 21 days. The symptoms, signs, and findings in this particular case of transfusion-related Y. enterocolitica sepsis are consistent with cases previously reported. The patient quickly developed symptoms compatible with endotoxic shock from a unit of red blood cells with high concentrations of Y. enferocolitica and endotoxin. The high level of endotoxin found in this unit most likely served as the trigger for the severe reaction that ultimately led to a fatal outcome. Y enterocolitica was never isolated from the recipient's blood following the transfusion. Two of the 7 patients with transfusion-associated Y enferocoliticasepsis reported by the CDC also had negative blood cultures during or following the transfusion of contaminated red blood cells [5]. In this case, the blood donor apparently had asymptomatic bacteremia at the time of his 9-11-89 blood donation. Agglutinin studies performed on blood samples from 9-1189 and 10-16-89 revealed donor exposure to Y. enferocolifica. Prospective screening revealed that the donor met all standard criteria as an acceptable blood donor. Retrospective study of the donor was positive only for the history of asymptomatic blood-streaked stools in the 2 months prior to donation. The bacteremia was likely transient as evidenced by negative blood culture and endotoxin results following two subsequent blood collections from the donor (10-16-89 and 12-12-89).
Y. enterocolitica sepsis, although rare, is clearly a complication of transfusion therapy. The best method of prevention of this complication is unclear at this time. Contaminated units do not show any grossly visible abnormalities. Mass screening of donors either by culture or agglutinin titers at the time of donation does not seem practical due to the low incidence of this complication. The CDC reports that culturing of blood from attached tubing segments has not been helpful [5]. Gram stain examination of a red cell unit prior to issue is not commonly done due to the questionable sensitivity of the test. Careful screening to exclude donors with recent gastrointestinal abnormalities might be an appropriate practice. However, the degree of gastrointestinal abnormality required for exclusion, how long a person must be free of abnormality prior to donation, and how long a donor must be deferred from donation, are all unclear.
Summary This case is an example of a tragic outcome of transfusion therapy despite the fact that the donated unit of red blood cells met all current acceptable criteria for transfusion. Physicians caring for patients who receive transfusions should be aware that contamination of red blood cells and whole blood with Y. enferocolifica may occur on rare occasions. This is another reason why unnecessary blood transfusion should be avoided. The possibility of transfusion-transmitted Y. enterocolifica should be considered in patients who have symptoms of sepsis or shock following transfusion. Prompt administration of appropriate antibiotics and therapy for endotoxic shock may improve the likelihood of the patient surviving. Contamination of blood products with Y. enferocolifica is another potential adverse effect of transfusion.
Acknowledgement The authors thank Lee A. Bland, M.A., M.P.H., Nosocomial Infections Laboratory, Hospital Infections Program, CDC, Atlanta, Ga., for performing microbial cultures, serotyping, endotoxin levels and agglutinin titers for Y.enterocolidca.
References 1 Myhre BA: Fatalities from blood transfusion. JAMA 1980; 244:1333-1335. 2 Honig CL, Bove JR: Transfusion-associated fatalities: Review of Bureau of Biologics reports 1976-1978. Transfusion 1980;20:653661.
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3 Heal JM, Jones ME, Forey J, Chaudhry A, Stricof RL: Fatal Salmonella septicemia after platelet transfusion. Transfusion 1987;27:2-5. 4 Braine HG, Kickler TS,Charache P, Ness PM, Davis J, Reichart C, Fuller AK: Bacterial sepsis secondary to platelet transfusion: An adverse effect of extended storage at room temperature. Transfusion 1986;26:391-393. 5 Tipple MA, Bland LA, Murphy JJ, Arduino MJ, Panlilio AL, Farmer JJ 111, Tourault MA, Macpherson CR, Menitove JE, Grindon AJ, Johnson PS, Strauss RG, Bufill JA, Ritch PS, Archer JR, Tablan OC, Jarvis WR: Sepsis associated with transfusion of red cells contaminated with Yersinia enterocolitica. Transfusion 1990;30:207-213. 6 Mollaret HH, Bercovier H , Alonso JM: Summary of the data received at the WHO Reference Center for Yersinia enterocolitica. Contrib Microbiol Immunol 1979;5:174-184. 7 Marks MI, Pai CH, Lafleur L, Lackman L, Hammerberg 0: Yersinia enterocolitica gastroenteritis: A prospective study of clinical, bacteriologic, and epidemiologic features. J Pediatr 1980;96: 26-3 1. 8 Mingrone MG, Fantasia M, Figura N, Guglielmetti P: Characteristics of Yersiniu enterocolitica isolated from children with diarrhea in Italy. J Clin Microbiol 1987;25:1301-1304. 9 Hoogkamp-Korstanje JA, de Koning J , Samsom JP: Incidence of human infection with Yersinia enterocolitica serotypes 0:3,0:8,and 0:9 and the use of indirect immunofluorescence in diagnosis. J Infect Dis 1986;153:138-141. 10 Dajani AS, Maurer MJ: Is Yersinia enterocolitica gastroenteritis a Canadian disease? J Pediatr 1980;97:165-166. 11 Wauters G: Carriage of Yersinia enterocolitica serotype 3 by pigs as a source of human infection. Contrib Microbiol Immunol 1979; 5 ~249-252. 12 Pedersen KB: Occurrence of Yersinia enterocolifica in the throat of swine. Contrib Microbiol Immunol 1979;5:253-256. 13 Asakawa Y, Akahane S, Shiozawa K, Honma T: Investigations of source and route of Yersinia enterocolitica infection. Contrib Microbiol Immunol 1979;5:115-121. 14 Lee LA, Gerber AR, Lonsway DR, Smith JD, Carter GP, Puhr ND, Parrish CM, Sikes RK, Finton RJ, Tauxe RV: Yersinia enterocolificu 0:3 infections in infants and children, associated with the household preparation of chitterlings. New Engl J Med 1990; 322:984-987. 15 Harvey S, Greenwood JR, Pickett MJ, Mah RA: Recovery of Yersinia enterocolifica from streams and lakes of California. Appl Environ Microbiol 1976;32:352-354. 16 Keet EE: Yersinia enterocoliticu septicemia: Source of infection and incubation period identified. NY State J Med 1974;74:2226 2230. 17 Thompson JS, Gravel MJ: Family outbreak of gastroenteritis due to Yersinia enterocoliticaserotype 0:3 from well water. Can J Microbiol 1986;32:700-701. 18 Lassen J: Yersinia enterocolitica in drinking water. Scand J Infect Dis 1972;4:125-127. 19 Tauxe RV, Vandepitte J, Wauters G , Martin SM, Goossens V, De Mol P, Van Noyen R, Thiers G: Yersinia enterocolifica infections and pork: The missing link. Lancet 1987;1:1129-1132. 20 Black RE, Jackson RJ, Tsai T, Medvesky M, Shayegani M, Feeley JC, MacLeod KIE, Wakelee AM: Epidemic Yersinia enterocolitica infection due to contaminated chocolate milk. New Engl J Med 1978;298:7679.
Stu bbslReddy/Elg/Perry/Adcock/McCullough
21 Francis DW, Spaulding PL, Lovett J: Enterotoxin production and thermal resistance of Yersiniu enterocoliticu in milk. Appl Environ Microbiol 1980;40:174-176. 22 Schiemann DA: Association of Yersiniaenterocolitica with the manufacture of cheese and occurrence in pasteurized milk. Appl Environ Microbiol 1978;36:274-277. 23 Maruyama T Yersinia enterocolitica infection in humans and isolation of the microorganism from pigs in Japan. Contrib Microbiol Immunol 1987;9:48-55. 24 Shiozawa K, Akiyama M, Sahara K, Hayashi M, Nishina T, Murakami M, Asakawa Y Pathogenicity of Yersinia enterocolitica biotype 3B and 4, serotype 0:3 isolates from pork samples and humans. Contrib Microbiol Immunol 1987;9:30-40. 25 Wilson HD, McCormick JB, Feeley JC: Yersinia enterocolitica infection in a 4-month-old infant associated with infection in household dogs. J Pediatr 1976;89:767-769. 26 Boemi G , Chiesa C, DiLorenzo M, Patti G , Marrocco G , Midulla M.: Yersinia enterocolitica peritonitis. Gastroenterology 1985; 89:927-928. 27 Gutman LT, Ottesen EA, Quan TJ, Noce PS, Katz SL: An interfamilial outbreak of Yersinia enterocolitica enteritis. New Engl J Med 1973;288: 1372-1377. 28 Ahvonen P: Human yersiniosis in Finland. 11. Clinical features. Ann Clin Res 1972;4:3948. 29 Rabson AR, Koornhof HJ, Notman J, Maxwell WG: Hepatosplenic abcesses due to Yersinia enterocolitica. Br Med J 1972;4:341. 30 Ahvonen P, Rossi T Familial occurrence of Yersinia enterocolitica infection and acute arthritis. Acta Paediatr Scand 1970;206(suppl):121-122. 31 Martin T, Kasian GF, Stead S: Family outbreak of yersiniosis. J Clin Microbiol 1982;16:622-626. 32 Fukushima H, Ito Y, Saito K, Kuroda K, Inoue J, Tsubokura M, Otsuki K: Intrafamilial cases of Yersinia enterocolitica appendicitis. Microbiol Immunol 1981;25:71-73. 33 Toivanen P, Toivanen A , Olkkonen L, Aantaa S: Hospital outbreak of Yersinia enterocolitica infection. Lancet 1973;i:801-803. 34 Ratnam S, Mercer E, Picco B, Parsons S, Butler R: A nosocomial outbreak of diarrheal disease due to Yersiniu enterocolitica serotype 0 3 , biotype 1. J Infect Dis 1982;145:242-247. 35 McIntyre M, Nnochiri E: A case of hospital-acquiried Yersinia enterocolitica gastroenteritis. J Hosp Infect 1986;7:299-301. 36 Van Noyen R, Vandepitte J, Wauters G , Selderslaghs R: Yersinia enterocolitica: Its isolation by cold enrichment from patients and healthy subjects. J Clin Pathol 1981;34:1052-1056. 37 Kay BA, Wachsmuth K, Gemski P, Feeley JC, Quan TJ, Brenner DJ: Virulence and phenotypic characterization of Yersinia enferocolitica isolated from humans in the United States. J Clin Microbiol 1983;17:12&138. 38 Pai CH, Mors V, Toma S: Prevalence of enterotoxigenicity in human and nonhuman isolates of Yersinia enterocolifica. Infect Immun 1978;22:334-338. 39 Cover TL, Aber RC: Yersiniu enterocolitica. New Engl J Med 1989;321:16-24. 40 Mofenson HC, Caraccio TR, Sharieff N: Iron sepsis: Yersinia enterocolitica septicemia possibly caused by an overdose of iron. New Engl J Med 1987;316:1092-1093. 41 Gallant T, Freedman MH, Vellend H, Francombe WH: Yersinia sepsis in patients with iron overload treated with deferoxamine. New Engl J Med 1986;314:1643. 42 Chiu HY, Flynn DM, Hoffbrand AV, Politis D: Infection with
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43
44
45 46
47
48 49
Yersinia enterocolitica in patients with iron overload. Br Med J 1986;292:97. Boelaert JR, van Landuyt HW, Valcke YJ, Cantinieaux B, Lornoy WF, Vanherweghem JL, Moreillon P, Vandepitte JM: The role of iron overload in Yersiniu enterocoliticaand Yersinia pseudotuberculosis bacteremia in hemodialysis patients. J Infect Dis 1987; 156:384-387. Bouza E, Dominguez A, Meseguer M, Buzon L, Boixeda D, Revillo MJ, de Rafael L, Martinez-Beltran J: Yersinia enterocoliticu septicemia. Am J Clin Pathol 1980;74:404-409. Rabson AR, Hallett AF, Koornhof HJ: Generalized Yersinia enterocolitica infection. J Infect Dis 1975;131:447451. Melby K, Slordahl S , Gutteberg TJ, Nordbo SA: Septicaemia due to Yersiniu enterocolitica after oral overdoses of iron. Br Med J 1982;285:467468. Foberg U, Fryden A, Kihlstrom E, Persson K, Weiland 0: Yersinia enterocoliticu septicemia: Clinical and microbiological aspects. Scand J Infect Dis 1986;18:269-279. Stenhouse MA, Milner LV Yersiniu enterocoliticu: A hazard in blood transfusion. Transfusion 1982;22:396-398. Bjune G, Ruud TE, Eng J: Bacterial shock due to transfusion with Yersiniu enterocoliticu infected blood. Scand J Infect Dis 1984; 16:411-412.
50 Collins PS, Salander JM, Youkey JR, Elliott BM, Collins GJ Jr, Donohue HJ,Rich NM: Fatal sepsis from blood contaminated with Yersinia enterocolitica: A case report. Milit Med 1985;150:689-692. 51 Wright DC, Selss IF, Vinton KJ, Pierce RN: Fatal Yersinia enterocolitica sepsis after blood transfusion. Arch Pathol Lab Med 1985;109:1040-1042. 52 Pai CH, Mors U: Production of enterotoxin by Yersinia enterocoliticu. Infect Immunol1978;19:90&911.
Received: October 15, 1990 Accepted: December 28,1990 James R. Stubbs, MD Department of Laboratory Medicine and Pathology University of Minnesota Medical School Box 198 UMHC, D2ll Mayo Building 420 Delaware Street SE Minneapolis, MN 55455 (USA)
Vox Sang 1991;61:18-23
Fatal Yersinia enterocolitica (Serotype 0:5,27) Sepsis after Blood Transfusion James R. Stubbsa, Ramakrishna L. Reddyb, Steven A. Elg‘, Elizabeth H. Perryarb,Leon L. Adcock‘, Jeffrey McCullough a* ‘Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minn.; bAmerican Red Cross Blood Services, St. Paul, Minn.; “Department of Obstetrics and Gynecology, University of Minnesota Medical School, Minneapolis, Minn.; USA
Abstract. Septicemia is a rare complication of blood transfusion. This is probably primarily due to the use of sealed disposable containers for blood collection and the storage of red cell-containing components at 4°C. However, despite these measures, septicemia due to blood transfusion continues to occur. We report here a fatal case of Yersinia enterocolitica septicemia due to a contaminated unit of red cells which was collected from an apparently healthy, asymptomatic blood donor. The organism grows at cold temperature and multiplies during storage of red blood cell-containing components. Contaminated components do not show any visible abnormalities. The possibility of transfusion-transmitted Y. enterocolitica should be considered in patients who have symptoms of sepsis or shock following transfusion.
Introduction Septicemia has become a rare complication of blood transfusion. Bacterial contamination was responsible for only 2 of 113 transfusion-related fatalities reported to the Food and Drug Administration (FDA) between April 3, 1976 and December 31, 1979. Both patients died of gramnegative endotoxemia. The implicated units were whole blood in one case and cryoprecipitate in the other [I]. Honig and Bove [2] report on two additional transfusion-related fatalities resulting from bacterial contamination of blood products which occurred between 1976 and 1978. The use of sealed disposable blood collection systems and the storage of whole blood and red blood cells at 4°C are probably the most important factors limiting the incidence of bacteremia. However, despite these standard measures to minimize bacterial contamination and growth in blood products, septicemia due to blood transfusion, though quite rare, continues to be a worrisome source of morbidity and mortality. Nine deaths due to posttransfusion sepsis were recorded by the FDA between January 1980 and December 1983. Six of these deaths were associated with platelet products [3]. Four episodes of bacterial sepsis related to contaminated platelet concentrates occurred in a 3-month period in 1985 [4]. These cases closely followed the adopted practice
of 7-day room temperature storage of platelets in December 1984. All 4 cases involved pooled platelet concentrates with at least one unit stored at room temperature for 5 days or longer. These cases prompted a return to 5-day room temperature storage for platelets. A separate case of transfusion-related sepsis resulting from platelets reported by Heal et al. [3] proposed that a state of low-grade asymptomatic bacteremia (Salmonella) can occur in some donors. Since 1979, at least 26 cases of gram-negative bacterial sepsis associated with whole-blood or red blood cell transfusion have been published. Yersinia enterocolitica was identified in 15 of these cases [ 5 ] . The Centers for Disease Control (CDC) recently reported on 7 episodes in which transfused red blood cells were contaminated with Y. enterocolitica. One of those 7cases was caused by serotype 0:5,27 [5]. We report here another case of fatal endotoxemia caused by a unit of red cells contamined with Y. enterocolitica serotype 0:5,27.
Case History A 53-year-old, para 1-0-0-1woman underwent a pre-radiation therapy surgical staging procedure for squamous cell carcinoma of the cervix on October 4,1989. Cefoxitin therapy was started following the operation as a matter of routine postoperative care. The patient’s
19
Y. enterocolitica Sepsis after Blood Transfusion
course was uneventful until the third postoperative day. At that time her hemoglobin was 86 gh and two units of packed red blood cells were ordered to be transfused. Approximately 30 min into the transfusion of the first unit (80-100 ml transfused), the patient developed chills, tachycardia and tachypnea. Her temperature increased from 37°C before transfusion to 39.2”C. The transfusion was stopped, microbial cultures were obtained, and the packed-cell unit was returned to the blood bank. Her temperature rose to 40°C. She became hypotensive (blood pressure: 76/48), tachycardic with poor respiratory function, and soon became unconscious. Her chest x ray showed bilateral pulmonary infiltrates. Antimicrobial therapy, consisting of cefotaxime, vancomycin and metronidazole was started. She underwent tracheal intubation and invasive cardiac monitoring was instituted. The patient remained febrile in spite of multiple negative cultures of blood, urine, and catheter sites. Candida albicans was isolated in urine later in her course and this was treated with bladder irrigations of amphotericin B. Management in the surgical intensive-care unit included treatment with dobutamine, dopamine, crystalloid, colloid, and blood products. Intravenous antibiotics included cefoxitin, cefotaxime, gentamicin, vancomycin, metronidazole, and imipenem. The patient became anuric and hemodialysis was initiated on the 24th postoperative day. Liver failure followed with a peak bilirubin of 478.8 pmolfl. On postoperative day 32, an intraperitoneal hemorrhage developed requiring multiple blood transfusions. Due to the patient’s deteriorating condition and poor prognosis, the family elected to withdraw supportive care. She expired 37 days after the transfusion.
Methods A transfusion reaction investigation, performed the same day as the reported reaction, consisted of a recheck for clerical errors, visual inspection of the unit for evidence of hemolysis, discoloration, gas bubbles or clots, a complete cross-match including direct antiglobulin test, and gram stain and microbial culture of the unit and attached segments. Previous donations by the donor of the implicated unit were reviewed for causes of deferral and for any adverse outcomes of transfused products. The donor health history was carefully re-examined, and information was collected on the presence of illness in any employee involved in the handling of the unit from collection to transfusion. All records pertaining to the collection, processing, shipment, and disposition of all components made from the implicated donation were reviewed to disclose any deviation from normal blood bank procedures. The donor was interviewed for details of any illness in the 2 months prior and any time after the donation. Questions were asked regarding recent dental procedures and family history of hemochromatosis. The donor was also questioned about travel, diet, and exposure to animals in the months prior to donation. Specific inquiry was made regarding the possible ingestion of untreated water, unpasteurized dairy products and raw or undercooked meat. Information regarding illness among the donor’s household members and other close contacts was collected. The CDC Hospital Infections Program was notified of the case on October 12,1989, and the following specimens were sent to the Nosocomial Infections Laboratory: the packed red cell unit, sample segments from the red cell unit, the patient’s pre-reaction (10-7-89) and postreaction (10-9-89) plasma, donor blood for microbial culture, endotox-
in level and agglutinin titer (10-16-89),throat swab and rectal swab from the donor (10-16-89), the hospital Y.enterocolitica isolate, and an aliquot from the donated plasma unit which was recalled. A unit of blood was collected from the donor on December 12,1989 for microbial culture and endotoxin assay. The unit was processed as an Adsol unit. Microbial cultures were performed following 2, 5 and 7 weeks of storage at 4°C. Following the last culture, the unit was sent to the CDC for endotoxin studies.
Results The transfusion reaction workup showed no clerical errors, no evidence of hemolysis, and a compatible crossmatch. The red cell unit and administration set had no visually detectable abnormalities. Gram stain of the red cell unit revealed rare/few gram-negative rods. Bacterial culture of the unit was positive within 12 h for Y enterocolitica. The unit of blood was drawn on September 11, 1989 by the St. Paul Regional Blood Services of the American Red Cross and thus had been stored for 26 days at the time of transfusion. The donor was a 47-year-old male school teacher from the Minneapolis-St. Paul metropolitan area. He was a regular cytomegalovirus-negative blood donor who had donated 6 times previously since November 1987 with no reported recipient complications. He had been deferred once previously due to elevated blood pressure. He was feeling well on the day of donation. He did not give a history of diarrhea, fever, headache, pharyngitis, abdominal pain, erythema nodosum, or arthritis in the months preceding or after the implicated donation. There was no diarrhea or other gastrointestinal problem in the donor’s family before or after the donation. He had no other known infectious exposures. There was no family history of hemochromatosis and the donor had not had recent dental work. He had no known exposure to farm animals or wild animals, and his eating habits were not unusual. The donor was taking one teaspoon of psyllium hydrophilic mucilloid daily for constipation. He was on no other medications. Further retrospective questioning revealed that the donor had streaks of blood in his stool once in July 1989 and once in August 1989. There was no history of hemorrhoids. He had no symptoms related to these incidents, and he did not seek medical attention. Other components prepared from the original unit of whole blood included a platelet concentrate, which was transfused into another patient uneventfully, and liquid plasma which was sent for fractionation and subsequently recalled. High concentrations of Y enterocolitica (1.38 x lo8CFU/ ml) and endotoxin (9,100 ng/ml) were found in the red cell
StubbslReddylElg/Perry/AdcockMcCullough
20
unit. The serotype of the Y. enterocolitica was 0:5,27. Sample segments from the red cell unit and the blood sample collected from the donor on 10-16-89 showed no microbial growth and no detectable endotoxin. The patient’s prereaction and post-reaction plasma specimens had no detectable endotoxin. The plasma recalled from the implicated donation was negative for endotoxin as well. The donor throat and rectal swabs showed normal flora with no Y. enterocolitica or other pathogens isolated. Y. enterocolitica agglutinin titers performed on the recalled plasma and on plasma collected from the donor on 10-16-89revealed a titer of 1:128 in both specimens. Blood cultures performed on the follow-up donor unit at 2, 5 and 7 weeks were negative. There was no endotoxin detected in this unit.
Discussion
Y. enterocolitica is a gram-negative coccoid bacillus of the family Enterobacteriaceae. The organism is a facultative anaerobe, and it has been isolated from humans essentially worldwide. However, it appears to be found most frequently in cooler climates [6]. The true incidence and prevalence of Y. enterocolitica are not known. A Canadian study found that Y. enterocolitica was recovered from the stool cultures of 2.8% of 6,364 children with diarrhea who where tested over a 15-month period. In the same study, not a single Y. enterocolitica isolate was found among 545 children without gastroenteritis who had stool cultures. The duration of excretion of the organism in the stool ranged from 14 to 97 days (mean 42 days) [7]. Studies of patients with enteritis performed in Italy and the Netherlands have isolated Y.enterocolifica in 1.4 and 2.9%, respectively [8, 91. In contrast, a study performed in Detroit, Mich., failed to isolate Y. enterocolitica from stool cultures in 1,262patients with diarrhea between May and November 1977 [lo]. Y enterocolitica has been isolated from a variety of animal reservoirs. Swine are recognized as an important animal reservoir for pathogenic Y. enterocolitica in Europe and Japan [ll-131. Animal products may also harbor the organism [6,13,14]. Other reservoirs include lakes [W], streams [6, 161, well water [17, 181, soil [6], and vegetables [6]. A human carrier state has never been documented. The transmission of Y. enterocolitica to humans has occurred primarily by the ingestion of contaminated foods [14, 191, water [16], and milk [20]. Products in which Y. enterocolitica has been isolated include raw milk [21,22], whipped cream [6], cheese curds [22], ice cream [6], beef [6], lamb [6], poultry
[6], and especially pork [6, 14,19,23,24]. Direct transmission from dogs [25-271, cats [28], and swine [29, 301 to humans by a fecal-oral or oral-oral route has been proposed [16]. Person-to-person transmission has been suggested in reports of sequential onset of illness in family members [27, 28, 31, 321 and nosocomially acquired infections [33-351. Y enterocolitica of the serotypes 0:3,0:8, and 0:9 are the most frequently reported as causes of human disease and bacteremia worldwide [9, 36, 371. However, serotype 0:5,27 is known to cause disease in humans [23, 381. In the recent report of 7 cases of transfusion-associated Y. enterocolitica sepsis from the CDC, 1case was caused by serotype 0:5,27. Of the remaining cases, 4 were caused by organisms of serotype 0:3, and 1 case each was caused by serotypes 0:1,2,3 and 0:20 [5]. Y. enterocolitica infection gives rise to a variety of clinical manifestations. The most common presentation, enterocolitis, often occurs in young children and is characterized by diarrhea, low-grade fever, abdominal pain, and vomiting. Leukocytes and erythrocytes may be present in the stool. Gross blood is evident in the stools of up to 25% of patients. Most cases of Y. enterocolitica enterocolitis are self-limited. Y. enterocolitica infection may present as pseudoappendicular syndrome, which is clinically similar to appendicitis. The syndrome occurs most often in older children and young adults. Involvement of extraintestinal sites, either in association with or independent of gastrointestinal involvement, may also occur. Pharyngitis, with or without associated lymphadenopathy, leads a long list of extraintestinal infections. The most common delayed manifestations of Y. enterocolitica infection are polyarticular arthritis and erythema nodosum. The arthritis typically begins 1-2 weeks after the onset of gastrointestinal symptoms and usually persists for 1-4 months; however, prolonged symptoms may occur in some patients. The HLA-B27 histocompatibility antigen is present in approximately 80% of patients that develop reactive arthropathy [39]. Bacteremia associated with Y. enterocolitica infection is currently thought to occur most often in patients who have a predisposing underlying disease or are in an iron-overloaded state [40-43]. Examples include patients with cirrhosis [44, 451, hemochromatosis [44, 451, acute iron poisoning [40, 44, 461, transfusion-dependent disorders [41, 42, 44, 451, diabetes mellitus [44,47]. alcoholism [44], and malnutrition [44,45]. Patients receiving deferoxamine [4042, 461 or immunosuppressive therapy [39] are also predisposed to bacteremia. The reported case fatality rate of Y enferocolitica bacteremia in these susceptible groups is 3450% [44,45]. It is apparent upon review of the published cases of transfusion-associated Y enterocolirica sepsis
21
Y. enterocolitica Sepsis after Blood Transfusion
that a state of transient bacteremia may occur in some people without symptoms, and unfortunately some of these people may donate blood during the bacteremic period [48-511. The incidence of asymptomatic Y. enferocolifica bacteremia is unknown. The pH range in which Y enterocolifica is able to grow is between 5.0 and 9.0. The optimal pH range for growth is between 7.0 and 8.0. The organism grows well at 4°C with dextrose as its carbon source [39]. Stenhouse and Milner [48] inoculated a fresh unit of ACD whole blood with 80 CFU/ml of Y. enterocolifica and stored it at 4°C. After 21 days there were 5 x 10' CFU/ml with no visible signs of contamination in the blood bag. Iron is an essential growth factor for most bacteria and Y. enterocolitica is no exception [39]. Endotoxin is produced by most clinical isolates of Y enterocolitica [38]. In vitro studies have shown an absence of endotoxin production at temperatures exceeding 30°C [52]. Thus, it is apparent that prolonged storage of red blood cells at 4°C provides an environment suitable for the growth of large numbers of Y. enterocolitica. It is likely that these storage conditions also allow production of endotoxin in contaminated units. All reported transfusion reactions due to blood components contaminated with Y. enterocolifica have involved red blood cell-containing units stored for more than 21 days. The symptoms, signs, and findings in this particular case of transfusion-related Y. enterocolitica sepsis are consistent with cases previously reported. The patient quickly developed symptoms compatible with endotoxic shock from a unit of red blood cells with high concentrations of Y. enferocolitica and endotoxin. The high level of endotoxin found in this unit most likely served as the trigger for the severe reaction that ultimately led to a fatal outcome. Y enterocolitica was never isolated from the recipient's blood following the transfusion. Two of the 7 patients with transfusion-associated Y enferocoliticasepsis reported by the CDC also had negative blood cultures during or following the transfusion of contaminated red blood cells [5]. In this case, the blood donor apparently had asymptomatic bacteremia at the time of his 9-11-89 blood donation. Agglutinin studies performed on blood samples from 9-1189 and 10-16-89 revealed donor exposure to Y. enferocolifica. Prospective screening revealed that the donor met all standard criteria as an acceptable blood donor. Retrospective study of the donor was positive only for the history of asymptomatic blood-streaked stools in the 2 months prior to donation. The bacteremia was likely transient as evidenced by negative blood culture and endotoxin results following two subsequent blood collections from the donor (10-16-89 and 12-12-89).
Y. enterocolitica sepsis, although rare, is clearly a complication of transfusion therapy. The best method of prevention of this complication is unclear at this time. Contaminated units do not show any grossly visible abnormalities. Mass screening of donors either by culture or agglutinin titers at the time of donation does not seem practical due to the low incidence of this complication. The CDC reports that culturing of blood from attached tubing segments has not been helpful [5]. Gram stain examination of a red cell unit prior to issue is not commonly done due to the questionable sensitivity of the test. Careful screening to exclude donors with recent gastrointestinal abnormalities might be an appropriate practice. However, the degree of gastrointestinal abnormality required for exclusion, how long a person must be free of abnormality prior to donation, and how long a donor must be deferred from donation, are all unclear.
Summary This case is an example of a tragic outcome of transfusion therapy despite the fact that the donated unit of red blood cells met all current acceptable criteria for transfusion. Physicians caring for patients who receive transfusions should be aware that contamination of red blood cells and whole blood with Y. enferocolifica may occur on rare occasions. This is another reason why unnecessary blood transfusion should be avoided. The possibility of transfusion-transmitted Y. enterocolifica should be considered in patients who have symptoms of sepsis or shock following transfusion. Prompt administration of appropriate antibiotics and therapy for endotoxic shock may improve the likelihood of the patient surviving. Contamination of blood products with Y. enferocolifica is another potential adverse effect of transfusion.
Acknowledgement The authors thank Lee A. Bland, M.A., M.P.H., Nosocomial Infections Laboratory, Hospital Infections Program, CDC, Atlanta, Ga., for performing microbial cultures, serotyping, endotoxin levels and agglutinin titers for Y.enterocolidca.
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48 49
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Received: October 15, 1990 Accepted: December 28,1990 James R. Stubbs, MD Department of Laboratory Medicine and Pathology University of Minnesota Medical School Box 198 UMHC, D2ll Mayo Building 420 Delaware Street SE Minneapolis, MN 55455 (USA)
