Escherichia coli O157:H7, other verotoxin-producing E coli and the hemolytic uremic syndrome in childhood

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1 CON SEN SUS STATE MENT Escherichia coli O157:H7, other verotoxin-producing E coli and the hemolytic uremic syndrome in childhood THE PAST DEC ADE, VEROTOXIN- PRODUCING ESCHERI CHIA coli IN (VTEC) have emerged as im por tant gas tro in tes ti nal patho - gens for in di vidu als of all ages, but with an in creased in ci - dence and se ver ity of ill ness in young chil dren and the eld erly (1). The most fre quently iden ti fied VTEC se ro type, E coli 0157:H7, is strongly as so ci ated with hemo lytic ure mic syn - drome (HUS), a lead ing cause of acute re nal fail ure in child - hood (2-6). Be cause Can ada has one of the high est re ported rates of VTEC in fec tion in the world, the pur pose of this state - ment, pre pared by the In fec tious Dis eases and Im mu ni za tion Com mit tee of the Ca na dian Pae di at ric So ci ety, the Ca na dian As so cia tion of Pe di at ric Neph rolo gists and the Ca na dian Pae di at ric Kid ney Dis ease Re search Cen tre, is to pro vide rec om men da tions for early di ag no sis of VTEC in in fants and chil dren, for pre vent ing or in ter rupt ing the spread of VTEC, and for early di ag no sis and man age ment of HUS in or der to mini - mize the im pact of VTEC. BACKGROUND AND NOMENCLATURE VTEC are so named be cause of their abil ity to pro duce one or more exo tox ins (VT-1, VT-2, VT-2 vari ant) that have cy to - pathic ef fects on vero cells (Af ri can green mon key kid ney cells). VTEC af fect other cell lines as well (7-9). VT-1 is also known as shiga- like toxin be cause of its struc tural and func - tional simi lar ity to the toxin pro duced by Shigella dys en te riae 1. In con trast to some of the other causes of gas tro en teri tis, VTEC cause dis ease not by lo cal in va sion of the gut mu cosa but by the di rect ac tion of vero toxin on cer tain cells. Vero tox - ins bind to a spe cific gly colipid re cep tor, Gb3, found on en do - the lial cells of blood ves sels, smooth mus cle cells, re nal en do the lial cells and red blood cells (10-12). Once bound, vero tox ins in hibit in tra cel lu lar pro tein syn the sis, thereby Correspondence and reprints: Canadian Paediatric Kidney Disease Research Centre, 401 Smyth Road, Ottawa, Ontario K1H 8L1. Telephone (613) caus ing cell death. Be cause the struc ture of Gb3 is iden ti cal to that of the Pk an ti gen in the P blood group sys tem, it is not sur pris ing that P blood group status ap pears to in flu ence the risk of de vel op ing HUS af ter VTEC in fec tion (13-14). VTEC that pro duce VT-2 alone or in com bi na tion with VT-1 are more com monly as so ci ated with HUS than are or gan isms that pro - duce VT-1 alone (15,16). HOW ARE E COLI O157:H7 AND OTHER VTEC INFECTIONS IDENTIFIED? VTEC in clud ing E coli O157:H7 re quire spe cial meth ods for de tec tion in the labo ra tory. Mi cro bi ol ogy labo ra to ries can screen for E coli O157:H7 by in ocu lat ing stool speci mens onto Mac Con key me dium con tain ing sor bi tol in stead of lac - tose (17). If this screen ing stool cul ture is nega tive, O157:H7 and other VTEC can be iden ti fied via meth ods avail able in ref - er ence labo ra to ries, such as de tec tion of free fe cal vero toxin, de tec tion of vero toxin genes through po lymerase chain re ac - tion am pli fi ca tion (18) or se ro logi cal re sponses to vero tox ins or the lipo poly sac cha ride of E coli O157 (19). Pro longed ex cre tion of E coli O157:H7 in stools is un com - mon, and the rate of re cov ery of E coli O157:H7 from an in - fected in di vid ual falls af ter the sixth day of ill ness (20,21). There fore, stool sam ples should be ob tained as early in the clini cal ill ness as pos si ble. A nega tive cul ture from a stool ob - tained af ter the sixth day of ill ness does not ex clude the pos si - bil ity of E coli O157:H7 in fec tion. Fur ther more, a nega tive cul ture for O157:H7 at any point does not ex clude the pos si - bil ity of in fec tion by other VTEC se ro types. HOW COMMON IS E COLI O157:H7 INFECTION? In many re gions of Can ada, E coli 0157:H7 is the sec ond most com mon bac te rial patho gen found in stools sub mit ted to clini cal labo ra to ries, fal ling just be hind Cam py lo bac ter spe - cies (22). Dur ing the warmer sum mer months, the preva lence in creases suf fi ciently to move E coli 0157:H7 into first place (23). E coli 0157:H7 is also more com mon among in di vidu als CAN J INFECT DIS VOL 6 NO 2 MARCH/APRIL

2 Con sen sus state ment with blood in their stools (23,24). Data on non- O157 VTEC are sparse, but a re cent study of stool speci mens sub mit ted to a chil dren s hos pi tal in Se at tle found non- O157 VTEC to be more com mon than Yersinia or Shigella spe cies (25). HOW IS VTEC INFECTION ACQUIRED? Be cause cat tle are fre quently colo nized with VTEC, foods of bo vine ori gin are an im por tant source of hu man VTEC in fec tion (26,27). Dur ing the slaugh ter of cat tle, in tes ti nal VTEC can con tami nate the sur face of meat. These sur face con tami - nants can then be dis trib uted through out the meat when it is ground, and can sur vive to cause hu man dis ease if cook ing time and tem pera ture are in ade quate. In ves ti ga tions us ing as says for vero toxin have shown preva lence rates for VTEC of 36.4% in re tail ground beef and 10.6% in re tail ground pork speci mens (28,29). Most re ported epi dem ics of E coli O157:H7 gas tro en teri tis have oc curred af ter in ges tion of un der cooked ground beef, but out breaks have been linked to un pas teur ized milk, cheese, yo ghurt, cold cuts, po ta toes, con tami nated wa ter and per son to per son spread (1,30-36). Out breaks of HUS have also been re ported af ter ex po sure to fresh ap ple juice and un - pas teur ized ap ple ci der (37,38). Prepa ra tion of food on a sur - face that has been con tami nated (for ex am ple, by juices from thaw ing meat) can in crease the risk of VTEC in fec tion. While ap pro pri ate em pha sis has been placed on food con - tami na tion as the source of E coli 0157:H7, per son to per son spread has been im pli cated in day care and nurs ing home out - breaks of E coli O157:H7 in fec tion (31,34) as well as in sec on - dary trans mis sion in house holds (39). In chil dren with spo radic HUS, re cent work also sug gests that ac qui si tion of in - fec tion may be more com monly at trib ut able to per son to per - son spread than to di rect in ges tion of con tami nated foods (40). Thus, once in tro duced into a fam ily, closed group, or com mu nity through con tami nated food or wa ter, VTEC in fec - tion has the po ten tial to spread widely as a re sult of per son to per son trans mis sion. HOW ARE VTEC INFECTION AND HUS RECOGNIZED CLINICALLY? Gas tro in tes ti nal in fec tion with E coli O157:H7 most com - monly be gins with a crampy, wa tery di ar rhea af ter an in cu ba - tion pe riod of three to four days (range one to 10 days) (1). In fec tion may also prog ress to bloody di ar rhea with stools con tain ing amounts of blood rang ing from streaks to grossly visi ble blood. The pro por tion of pa tients who go on to de velop bloody di ar rhea is un known be cause those with non - bloody di ar rhea are less likely to have stool cul tures per - formed. In clini cal se ries, bloody stools are ob served in over 75% of pa tients and usu ally are evi dent one to three days af - ter the on set of ill ness (41). Half the pa tients also have vom it - ing, but only about one- third de velop fe ver. In the ma jor ity of pa tients, symp toms usu ally re solve af ter a week. More se vere mani fes ta tions of this ill ness in clude in tus sus cep tion, rec tal pro lapse, hemo lytic ane mia and HUS or throm botic throm bo - cy topenic pur pura (1). HUS typi cally ap pears abruptly five to nine days af ter the on set of gas tro in tes ti nal symp toms but can oc cur as early as one to two days af ter di ar rhea be gins. HUS is rec og nized by the rapid de vel op ment of hemo lytic ane mia, throm bo cy - topenia and evi dence of acute re nal in jury, in con junc tion with vari able de grees of cen tral nerv ous sys tem dys func tion (in - clud ing leth argy, sei zures or coma) (42). It is now clear that HUS can also oc cur in a sub clini cal form, in which re nal in jury es capes rec og ni tion be cause the child con tin ues to pro duce urine, and in an in com plete form, in which pa tients have hemo lytic ane mia or throm bo cy topenia with out evi dence of acute re nal in jury (43,44). HOW DOES HUS DEVELOP? The clini cal fea tures of HUS are thought to be ini ti ated by the di rect ef fect of vero toxin on re nal en do the lial cells (45), which re sults in cell swel ling, lo cal in tra vas cu lar co agu la tion with plate let ag gre ga tion, me chani cal dam age to red blood cells and re duc tion in glom eru lar fil tra tion (46). Oxi da tive dam age to red blood cells may play a role in the de vel op ment of the hemo lytic ane mia (47). HOW OFTEN IS HUS RECOGNIZED FOLLOWING VTEC INFECTION? In Can ada, HUS is rela tively com mon, with an over all in ci - dence of 1.44/100,000 chil dren un der 15 years of age and a peak in ci dence of 3.11/100,000 chil dren un der five (4). This trans lates into ap proxi mately 75 to 90 epi sodes of HUS among Ca na dian chil dren each year. Eighty per cent of HUS epi sodes oc cur be tween April and Sep tem ber, cor re spond ing to the sea sonal pat tern of VTEC in fec tion in Can ada (per sonal com - mu ni ca tion). The risk of HUS in chil dren brought to medi cal at ten tion for E coli O157:H7 in fec tion is ap proxi mately 8 to 10%. Al though HUS is seen at all ages, the eld erly and chil dren younger than age five have an in creased risk, as do those with a more se - vere gas tro in tes ti nal pro drome (48). None the less, 20 to 25% of pa tients have no visi ble evi dence of bloody stools in the two weeks be fore pre sent ing with HUS (4). HOW SHOULD VTEC INFECTION BE TREATED? At pres ent, treat ment of VTEC in fec tion is pri mar ily sup por - tive. An timo til ity drugs are to tally con tra in di cated, not only be - cause they in ter fere with rec og ni tion of de hy dra tion, but also be cause they may pro long the time of ex po sure to vero toxin and thereby in crease the risk of HUS (49). The role of an ti bi ot ics in the man age ment of VTEC in fec tion is un clear. A small pro spec tive pla cebo con trolled study to evalu ate the ef fect of trimethoprim- sulfamethoxazole in chil - dren with proven E coli 0157:H7 in fec tion did not show a sta - tis ti cally sig nifi cant ef fect of treat ment on pro gres sion of symp toms, fe cal patho gen ex cre tion or in ci dence of HUS (50). How ever, in vi tro evi dence in di cates that vero toxin pro duc tion or re lease is in creased af ter ex po sure to an ti bi ot ics (51), sug - gest ing that an ti mi cro bial ther apy in vivo may not be bene fi - cial. 106 CAN J INFECT DIS VOL 6 NO 2 MARCH/APRIL 1995

3 E coli and HUS HOW IS HUS TREATED? If HUS is sus pected, the child should be re ferred to a cen tre with a spe cial ist skilled in the man age ment of these pa tients. Al though large bo luses of oral or in tra ve nous flu ids are usu - ally in di cated in de hy drated chil dren with olig uria, the same ther apy for olig uric chil dren with HUS can be dis as trous be - cause of the po ten tial for over hy dra tion, hy pona tre mia and sei zures. Cur rent treat ment for the child with HUS con sists of care ful fluid ad mini stra tion dur ing pe ri ods of olig uria or anuria, ju di cious blood prod uct re place ment, treat ment of elec tro lyte dis tur bances, con trol of sei zures and hy per ten sion and, when nec es sary, di aly sis (52). Early spe cial ized medi cal care has been re spon si ble in part for the re duc tion in HUS mor tal ity from 100% in 1955 to 2.6% among Ca na dian chil dren in (4). HUS re mains a se ri ous ill ness, with up to 50% of af fected chil dren in some cen tres re ceiv ing ei ther peri to neal di aly sis or he mo dialy sis and with a mean length of di aly sis of 14 days. Sev eral stud ies have dem on strated long term mor bid ity fol - low ing HUS, in clud ing pro gres sive re duc tions in re nal func tion in some chil dren af ter dis charge from hos pi tal (53-55) and, less com monly, per ma nent cen tral nerv ous sys tem dys func - tion rang ing from men tal re tar da tion and hemi pare sis to learn ing dis abili ties (56,57). PREVENTION Meas ures that can ef fec tively pre vent hu man VTEC in fec - tion have not been stud ied ex ten sively. Ac tive im mu ni za tion is not yet avail able. Pro posed meth ods of re duc ing the rate of ex po sure to VTEC in clude re duc ing con tami na tion of meat in slaugh ter houses and meat proc ess ing plants, and ir ra di at ing meat (58), as well as en sur ing proper food stor age, food prepa ra tion and cook ing both at home and in the com mer cial food in dus try. An in creased fo cus on hand wash ing once in - fec tion is iden ti fied within fami lies may re duce in tra fa mil ial trans mis sion. To pre vent fur ther spread in day care out breaks, Be longia and col leagues (59) recom mend that all chil dren with E coli 0157:H7 gas troen teri tis be ex cluded from day care un til two se rial stool cul tures ob tained at least 48 h apart are nega tive. This strat egy has not yet been com pared with co - hort ing of in fected chil dren. Whether HUS can be pre vented in pa tients with known VTEC in fec tion is the sub ject of in ten sive study. WHY SHOULD WE ATTEMPT TO IDENTIFY THOSE WITH VTEC INFECTION? Early di ag no sis of VTEC gas tro en teri tis is im por tant in or der to, first, avoid un nec es sary di ag nos tic pro ce dures and in cor - rect di ag no ses in those with bloody di ar rhea; sec ond, alert the care giver to the pos si bil ity of HUS de vel op ing; third, pro vide the im pe tus for stress ing hy gi enic meas ures so that per son to per son trans mis sion or fur ther food con tami na tion can be re - duced; and fourth, re port to pub lic health of fi cials in a timely man ner so any con tami nated food source can be dis cov ered and in fec tion con trol meas ures in sti tuted. RECOMMENDATIONS A) Pub lic health: 1. VTEC including E coli O157:H7 are nationally notifiable, but early reporting to the local public health authorities must be encouraged so outbreaks can be contained. 2. Until further information is available, we recommend that children with E coli O157:H7 in institutional settings or daycares be isolated or excluded until two consecutive stools are culture-negative. 3. Individuals with E coli O157:H7 infection who are employed preparing food should be excluded from work until their stool cultures are negative. B) Labo ra tory: 4. To promote identification of VTEC infection, we recommend that clinical microbiology laboratories use the MacConkey-sorbitol procedure to screen for E coli O157:H7 whenever a stool specimen is cultured for bacterial pathogens. C) Phy si cian: 5. We recommend that all children with bloody diarrhea have stool specimens submitted to a microbiology laboratory that is equipped to screen for E coli O157:H7. 6. We recommend that all children with nonbloody diarrhea have stool specimens screened for E coli O157:H7 whenever there has been exposure to undercooked ground beef or unpasteurized milk, or close contact with an individual with suspected or documented VTEC infection. 7. Antimotility agents should not be used with suspected or proven VTEC gastroenteritis and are not recommended in any other type of gastroenteritis in children. 8. There are no data available to support the use of antibiotics in cases of VTEC gastroenteritis. 9. To improve the early detection of HUS among children with proven VTEC gastroenteritis, we recommend that physicians consider performing a urinalysis, an examination of the peripheral smear, a complete blood count and a serum creatinine assay seven to 10 days after the onset of diarrhea. If there are any abnormalities on these tests, the child should be discussed with a specialist familiar with HUS. In the case of the child in whom HUS is strongly suspected, the tests should be done immediately and, if they are abnormal, the child should be referred to a pediatrician (and preferably a pediatric nephrologist) even if VTEC infection is not yet proven. CAN J INFECT DIS VOL 6 NO 2 MARCH/APRIL

4 Con sen sus state ment IN FOR MA TION FOR SHAR ING WITH PAR ENTS AND FAMI LIES HAM BURGER DIS EASE OR BAR BE CUE SYN DROME VTEC GAS TRO EN TERI TIS Ham burger dis ease or bar be cue syn drome is the com mon name for one type of food poi son ing that is caused by a germ known as vero toxi genic Escheri chia coli, E coli O157:H7, or VTEC. The germ causes ill ness by pro duc ing a toxin (ie, a poi son) that can break down the lin ing of the in tes tines and in some cases dam age the kid neys. Where do VTEC come from? Most out breaks of VTEC gas tro en teri tis have oc curred af ter con sump tion of un der cooked con tami nated ground beef (ham - burger) but out breaks have also been re ported af ter con sump tion of un pas teur ized milk, cheese or yo ghurt, cold cuts, un pas teur - ized ap ple juice or ci der, or wa ter con tami nated with the germ. The germ can also be spread from one in fected per son to an - other. VTEC in fec tion is more com mon in the spring and sum mer than in the win ter. What are the symp toms? The in fected per son typi cally has the fol low ing symp toms: Severe stomach cramps and bloody diarrhea occur one to eight days after consumption of contaminated food. In some cases, the diarrhea is watery without blood. Dehydration due to loss of fluid is common. Fever, if present, is usually mild. The illness usually lasts seven to 10 days. Most people recover without any problems but the disease can have serious effects especially in young children and the elderly. A very serious complication in young children is a type of kidney failure called hemolytic uremic syndrome (HUS). How can the dis ease be treated? Anyone with symptoms of bloody diarrhea, severe vomiting, bad abdominal cramps or a decrease in urination during a diarrheal illness should see their doctor. Antidiarrheal medication should not be taken. The benefit of antibiotic treatment is uncertain. Drinking small frequent amounts of clear fluids can help prevent dehydration. How can the dis ease be pre vented? To mini mize the risk of in fec tion: Always wash hands BEFORE handling food, AFTER handling raw meat products, AFTER toilet use and AFTER changing a diaper. Clean and sanitize utensils and kitchen work surfaces BEFORE and AFTER use. NEVER prepare ready to eat foods such as sandwiches or salads on any counter used for the preparation of raw meats UNLESS the surface has been cleaned and sanitized. Place ground meat on the lowest rack in the refrigerator to avoid meat juices spilling onto other food. When barbecuing or cooking ground meats such as hamburger, pork or chicken patties, COOK THE MEAT THOROUGHLY AT THE CENTRE. Meat and juices should be brown, not pink or red check to make sure. NEVER ORDER OR ACCEPT UNDERCOOKED ground meat products in an eating establishment Do NOT drink unpasteurized milk, apple juice or apple cider, and do not eat unpasteurized cheese. KEEP COLD FOOD COLD (less than 4 C) and HOT FOODS HOT (above 60 C) Fur ther in for ma tion on safe food han dling can be ob tained from your lo cal health de part ment REF ER ENCES 1. Griffin PM, Tauxe RV. The epidemiology of infections caused by Escherichia coli O157:H7, other enterohemorrhagic E coli, and the associated hemolytic uremic syndrome. Epidemiol Rev 1991;13: Karmali MA, Steele BT, Petric M, Lim C. Sporadic cases of haemolytic-uremic syndrome associated with faecal cytotoxin-producing Escherichia coli in stools. Lancet 1983;i: Kleanthous H, Smith HR, Scotland SM, et al. Haemolytic uraemic syndromes in the British Isles, : association with verocytotoxin-producing Escherichia coli. Part 2: microbiologic aspects. Arch Dis Child 1990;65: Rowe PC, Orrbine E, Wells GA, McLaine PN, and the CPKDRC coinvestigators. The epidemiology of hemolytic uremic syndrome in Canadian children from 1986 to J Pediatr 1991;119: Bitzan M, Moebius E, Ludwig K, Muller-Wiefel DE, Heesemann J, Karch H. High incidence of serum antibodies to Escherichia coli O157 lipopolysaccharide in children with hemolytic-uremic syndrome. J Pediatr 1991;119: Kaplan BS, Trompeter RS, Moake JL, eds. Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura. New York: Marcel Dekker, Konowalchuk J, Speirs JI, Stavric S. Vero response to a cytotoxin of Escherichia coli. Infect Immun 1977;18: O Brien AD, Tesh VL, Donohue-Rolfe A, et al. Shiga toxin: biochemistry, genetics, mode of action, and role in pathogenesis. Curr Top Microbiol 1992;180: Karmali MA. Infection by verocytotoxin-producing Escherichia coli. Clin Microbiol Rev 1989;2: Lingwood CA, Law H, Richardson S, et al. Glycolipid binding of purified and recombinant Escherichia coli produced verotoxin in vitro. J Biol Chem 1987;262: Waddell T, Head S, Petric M, Cohen A, Lingwood C. Globotriosyl ceramide is specifically recognized by the Escherichia coli 108 CAN J INFECT DIS VOL 6 NO 2 MARCH/APRIL 1995

5 E coli and HUS verocytotoxin 2. Biochem Biophys Res Commun 1988;152: Kasai K, Galton J, Terasaki PI, et al. Tissue distribution of the P k antigen as determined by a monoclonal antibody. J Immunogenetics 1985;12: Taylor CM, Milford DV, Rose PE, Roy TCF, Rowe B. The expression of blood group P1 in post-enteropathic haemolytic uraemic syndrome. Pediatr Nephrol 1990;4: Newburg DS, Chaturvedi P, Lopez EL, Devoto S, Fayad A, Cleary TG. Susceptibility to hemolytic-uremic syndrome relates to erythrocyte glycosphingolipid patterns. J Infect Dis 1993;168: Scotland SM, Willishaw GA, Smith HR, Rowe B. Properties of strains of Escherichia coli belonging to serogroup O157 with special reference to production of Vero cytotoxins VT 1 and VT 2. Epidemiol Infect 1987;99: Ostroff SM, Tarr PI, Neill MA, Lewis JH, Hargrett-Bean N, Kobayashi JM. Toxin genotypes and plasmid profiles as determinants of systemic sequelae in Escherichia coli O157:H7 infections. J Infect Dis 1989;160: March SB, Ratnam S. 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6 Con sen sus state ment 51. Walterspiel JN, Ashkenazi S, Morrow AL, Cleary TG. Effect of subinhibitory concentrations of antibiotics on extracellular Shiga-like toxin I. Infection 1992;20: Siegler RL. Management of hemolytic uremic syndrome. J Pediatr 1988;112: Van Dyck M, Proesmans W, Depraetere M. Hemolytic uremic syndrome in childhood: renal function ten years later. Clin Nephrol 1988;29: O Regan S, Blais N, Russo P, Pison CF, Rousseau E. Hemolytic uremic syndrome: glomerular filtration rate, 6 to 11 years later measured by 99m Tc DTPA plasma slope clearance. Clin Nephrol 1989;32: Perelstein EM, Grunfeld BG, Simsolo RB, Gimenez MI, Gianantonio CA. Renal functional reserve compared in haemolytic uraemic syndrome and single kidney. Arch Dis Child 1990;65: Upadhyaya K, Barwick K, Fishaut M, et al. The importance of non-renal involvement in hemolytic-uremic syndrome. Pediatrics 1980;65: Schlieper A, Rowe PC, Orrbine E, et al. Sequelae of haemolytic uraemic syndrome. Arch Dis Child 1992;67: Mossel DAA, Struijk CB. Food-borne illness 1993: updating Wilson s triad. Lancet 1993;342: Belongia EA, Osterholm MT, Soler JT, Ammend DA, Braun JE, MacDonald KL. Transmission of Escherichia coli O157:H7 infection in Minnesota child day-care facilities. JAMA 1993;269: Pe ter C Rowe MD FRCPC De part ment of Pe di at rics Johns Hop kins Uni ver sity School of Medi cine Bal ti more, Mary land, USA In fec tious Dis eases and Im mu ni za tion Com mit tee Mem bers: Don ald Clogg (di rec tor re spon si ble), Al berta Chil dren s Hos pi tal, Cal gary, Al berta; Noni E Mac Don ald (chair), De part ment of Pe di at rics, Chil dren s Hos pi tal of East ern On tario, Ot tawa, On tario; Gil les Delage, Ad joint médi cal, Serv ice de trans fu sion de sang de la Croix- Rouge ca na di - enne, Cen tre de Mon tréal, Mon tréal, Qué bec; Scott Halp erin, De - part ment of Pe di at rics, IWK Chil dren s Hos pi tal, Hali fax, Nova Sco tia; Taj Ja davji, De part ment of Pe di at rics, Al berta Chil dren s Hos pi tal, Cal gary, Al berta; Su san King, Di vi sion of In fec tious Dis ease, The Hos pi tal for Sick Chil dren, To - ronto, On tario; Bar bara Law, Pe di at ric In fec tious Dis eases, Uni ver - sity of Mani toba, Win ni peg, Mani toba; Marc Le bel, Dépar te ment de Pédia trie, Hôpi tal Sainte- Justine, Mon tréal, Qué bec. Con sult ants: Ron ald Gold, Di vi sion of In fec tious Dis ease, The Hos pi tal for Sick Chil dren, To ronto, On tario; Vic tor Marches sault, De part ment of Pe di at rics, Chil dren s Hos pi tal of East ern On tario, Ot tawa, On tario. Li ai sons: Pub lic Health, Jac - que line Carl son, Dis ease Con trol and Epi de mi ol ogy, Pub lic Health Branch, To ronto, On tario; Comité d im mu ni sa tion du Qué bec, Pi erre Dery, Cen tre hos pi tal ier de l U ni ver sité La val, Ste- Foy, Qué bec; Ameri can Acad - emy of Pe di at rics, Dan Granoff, St Louis, Mis souri; Cen tre for Vac - cine Evalua tion, David Scheifele, Di vi sion of In fec tious Dis eases, Re search Cen tre, BC s Chil dren s Hos pi tal, Van cou ver, Brit ish Co lum bia; Epi de mi ol ogy, John Wa ters, Al berta Health, Com mu ni ca ble Dis ease Con trol, Ed mon ton, Al berta Ac know ledge ments: We thank the fol low ing for their valu able ad - vice about the manu script: Ca na dian Pae di at ric Kid ney Dis ease Re search Cen tre, Pe ter McLaine, Elaine Orr bine, Terry Klas sen, Chil dren s Hos pi tal of East ern On tario, Ot tawa, On - tario; Ca na dian As so cia tion of Pae di at ric Neph rolo gists, Brian Steele, McMas ter Uni ver sity, Ham il ton, On tario, Doug las Mat sell, Chil dren s Hos pi tal of West ern On tario, Lon don, On tario; Hermy Lior, Na tional Labo ra tory for En teric Patho gens, Labo - ra tory Cen tre for Dis ease Con trol, Ot tawa, On tario; Glen Arm - strong, De part ment of Medi cal Mi cro bi ol ogy and In fec tious Dis eases, Uni ver sity of Al berta, Ed mon ton, Al berta 110 CAN J INFECT DIS VOL 6 NO 2 MARCH/APRIL 1995

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