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NewsJune, 2007

Lessons from China 's Streptococcussuis Outbreak: The Risk for Humans

By Marcelo Gottschalk, D VM, PhD ,and Mariela Segura, MSc, PhD

IntroductionStreptococcus suis infections are considered a major

worldwide problem in the swine industry, particularlyduring the past 15 years . The natural habitat ofS. suisin pigs is the upper respiratory tract, mainly the tonsilsand nasal cavities, and the genital and alimentary tracts.The most important clinical feature associated with S.suis is meningitis . I However, other pathologies havealso been described, such as arthritis, endocarditis,pneumonia, and septicemia with sudden death. AlthoughS. suis is considered mainly a swine pathogen, it has beenincreasingly isolated from a wide range of mammalianspecies (including humans) and from birds, which maysuggest new concepts on some epidemiological aspectsof the infection. Although recognized for more than 30years, S. suis infections in humans have been consideredto be sporadic and of low incidence. However, thisdisease has probably been underestimated due mainly to amisidentification of strains isolated from humans in manycountries, especially in North America. A recent importanthuman S. suis outbreak in China (summer 2005) attracte dconsiderable public and scientific interest. In this shortpaper, we summarize features of the infection in huma~s

and the main characteristics of the China outbreak, whichwe were directly involved in investigating.

The infection in humansFrom the first description in Denmark in 1968 to

early 2005, around 200 human cases of S. suis infectionhave been reported) ,3 S. suis infections in humans areobserved more frequently in intensive pig farming areasor where people live in close contact with pigs. Caseshave been reported in The Netherlands, Denmark, Italy,Germany, Belgium, United Kingdom, France, Spain ,Sweden, Ireland, Austria, Hungary, Hong Kong, Croatia,Japan, Singapore, Taiwan , New Zealand, and Argentina.Mysteriously, only a few cases have been reported inCanada and none in USA (up to early 2005, see below).

In general, S. suis disease is considered a rare eventin humans ; however, it has been reported to be "o ne

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of the major causes of meningitis in adults in HongKong."4 Most cases are caused by serotype 2 strains;but cases due to serotype 4 (one case) , serotype 14(two cases) and serotype I (two cases; serotype notconfirmed since the strains were lost: J. Kopic , per­sonal communication, 2004) strains have also beenobserved. In humans, S. suis usually produces a purulentor non-purulent meningitis. I In addition, endocarditis,cellulitis, rhabdomyolysis, arthritis, pneumonia, andendopthalmitis have also been reported. Arthriti saffects various joints, including hips, elbows, wrists ,sacroiliac, spine, and thumb) In most cases, arthritisreflects genera lized septicemia caused by S. suis, Severecases of sepsis with shock, multiple organ failure,dissemi nated intravascular coagulation, and associatedpurpura fulminans, which lead to death within hours,have also been described. It has been demonstrated thatS. suis has important inflammatory capacities.5,6

One of the most striking features of the infectionis the consequence of deafness following S. suismeningitis. In fact, the recorded incidence of deafnessfollowing S. suis infection is consistently higher thanthat for other meningitis-causing bacteria and canreach 50 percent and 65 percent in Europe and Asia,respectively.3 The reason for this is unknown. Thedeafness (unilateral or bilateral) has been mainly hightone and is frequently associated with vertigo . Earlyadministration of antibiotics does not appear to haveany influence on subsequent hearing loss. No cases ofdeafness have been reported in non-meningitis cases ofhuman S. suis infection.

Epidemiology of the infection and riskfactors

It has been suggested that the routes of entry ofthe organism in humans might be a small cut in the skin(although in some cases no wound was detected), thenasopharynx (with positive isolation from tonsils ofabattoir workers), or the gastrointestinal tract (diarrheaas a prodromal symptom is sometimes observed). Theincubation period ranges from a few hours to two days .3

Although not all facets of the epidemiology ofS.suis infections in humans have been elucidated, it is ap­parent that nearly all cases of infection in man can

be ascribed to a high degree of expos ure to unprocessed 15 years of interval, has been reported. 12 The second andpig meat or to close contact with pigs.7 Since most patients fatal episode was considered as a re-infection rather than aacquire the disease after occup ational exposure to pigs recurre nce of the previous infection, confirming the absenceor pork products, the preponderance of adult males is of immunity after the previous infection and the utmostreadily explained. Manifestation of disea se in pigs is not importance of continuous prevention in exposed workers.a prerequisite for infections in peop le in contact with Despite the low incidence ofS. suis infection in hu-pigs, since most animals are colonized by S. suis without mans , some preventive measures may be justified due to theprese nting clinical signs. In addi tion to pigs , wild boars high rate of contamination of pigs with this microorganism.may also be a source of S. suis infection for hunters and People in close occupational contact with pigs or porkpoachers in countries where these animals are present. In meat should pay spec ial attention. Most infected personsthe United Kingdom and France, this infection was listed are probab ly healt hy carriers; however, in situationsas an Industrial Disease in 1983 and 1995, respectively. of stress or immunodeficiency, S. suis may become anAs mentioned above, most cases of infected people are opportunistic pathogen. The environment can act as apig farmers , abattoir workers, persons transporting pork source of infection, and S. suis can survive in dust, manure ,meat, meat inspectors, and butchers. From stud ies of and pig carcasses for days or even weeks under optimalcontamination of hands and knives, it was concluded that conditions . Moreover, S. suis can survive in water for 10eviscerators involved in removing the larynx and lungs from minutes at 60°C, making the scalding process in abattoirsthe carcasses have a significantly higher risk of exposure to a possible source of contamination. Some researchersS. suis than other abattoir workers. Finally, one documented recommend prompt first-aid for injuries in meat handlers tocase of a veterinary surgeo n has been reported.8 In very rare reduce the risk ofS. suis infections, but others consider thiscases, there was no apparent connection with exposure to recommendation questionable because evident skin lesionspigs or pork products. have only been reported in some cases and the route of entry

Information about the occurrence and frequency of of the pathogen remains unclear. Therefore, it is difficult tohuman colonization by S. suis is scarce, with most data recommend effective prevention measures for employees incoming from abattoir workers. In New Zealand, relatively the food product industry.high antibody titers against S. suis serotype 2 were reportedin people with occupational contact within the pig industry.9 What happened in China in the summer

of2005?However, these data should be taken with caution since no1------s-o-ta-n-r-a-rCIizeo serological test to etect . S lIlS antloooi-es- - - - - From mid-Jul y-to theend-of-Augu!'t~OO5,a total-Bf- --

215 cases of human S. suis infections, 66 of which wereexists . It seems evident that high exposure to S. suis maylead to a colonization of the upper respiratory tract without laboratory confirmed, were reported in Sichuan, China. Allany health consequences. Only in some cases , clinical infections occurred in backyard farmers who were directly

exposed during the slaughtering process of pigs that haddisease may follow. Splenectomy and, to a lesser extent,alcoholism have been suggested as important predisposing died of unknown causes or been killed for food because theyfactors for the development of serious S. suis disease. I0, II were ill. Sixty-one farmers (28 percent) had streptococcalIn fact, the fatality rate for S. suis infectio n after toxic shock syndrome; 38 (62 percent) died. The othersplenectomy seems to be around 80 percent. It has even illnesses reported were sepsi s (24 percent) and meningitisbeen sugges ted that individuals who have had a splenectomy (48 percent) or both . The high death ratio was of concern;

prohibiting backyard slaughtering ended the outbreak.13shou ld be excl uded from the meat trade or pig farms. InIn addition to its size and the associated high mortal­

general , S. suis isolates from humans are phenotypically andgenotypically simi lar to those recovered from pigs. ity, this outbreak is unique in that a large proportion of

patients were victims of a "toxic shock-like syndrome"Therapy and prevention of infection in (TSLS). To date, streptococcal toxic shock, as per consensushumans definition, has been limited to disease caused by the group

S. suis strains recovered from humans proved to be A strep tococc us, S. pyogenes, with some sporadic reportssensitive to penicillin in all instances except for one penicil - of other (nongroup A) beta-haemolytic streptococci . S. suislin-tolerant strain . Therefore, intravenous penicillin G has has rarely been associated with TSLS , although some casesbeen a successful treatment in most cases . Since at least with well described hypotension and multi-organ failuretwo relapse cases have occurred after two or four weeks of have been reported. Epidemiologically, all cases of humantreatment, treatment should be applied for a relati vely long disease in the recent outbreak were linked to exposure toperiod (at least 6 wee ks). Ampici llin and chloramphenicol, pigs, and skin as the route of entry was reported in mostsometimes combined with an aminoglycoside, can also be cases . Interestingly, a similar but less extended outbreak ofused . As previously mentioned, hearing loss and vestibular S. suis serotype 2 was described in the same region in 1998.disturbances are frequently observed sequelae that are This outbreak was reported only in Chinese journals, and itsunrelated to antibiotic use. existence was unknown in the Occident. At least some of the

S. suis vaccines for humans do not exist as yet. Interest - human cases in the S. suis outbreak in Sichuan province iningly, a recurrent septic shock due to S. suis serotype 2, with 1998 may have been related to ingestion of contaminated

- - ,-

food, but this wa s not the case in the 2005 outbreak. Farmersin Sichuan province have close contact with their pigs;humans and anima ls often share the same accommodationsand animals are slaughtered at home. Furthermore, it iscommon practice to slaughter and eat diseased animals.Thus, in addition to inoculation and airborne transmissionfrom infect ed pig s, foodborne transmission by infected porkmay hav e also contributed to this outbreak. 13

Very little information about the pig outbreak in 2005 isavailable. It has been reported that 600 pigs died of S. suis ,and the outbreak was rapidly controlled through use of anautogenous vaccine. Interestingly, large production systemswere not affected, probably due to biosecurity measuresadopted in these herds. Many que stions, most of themstill unresol ved , arise from this experience. For example,if close contact with pig s is a millenary habitude of theChinese population in Sichuan province, why have onl y twooutbreak s been observed? If all affected animals originatedfrom back yard production systems, how can we explainthe transmi ssion of infec tion between villages, whichsometimes ex ist hundreds of kilometers apart? Why did theoutbreak suddenly app ear and then suddenly disappear?Why was septic shock or TSL S mainl y obse rved? How canwe explain the el imination of the infection in pigs followingthe use of an autogenous vaccine (bacterin) even thoughsuch vaccines usually offer limited protection? Is it possiblethat a strain of higher virulence was respons ible for theseoutbreaks?

A collaborative team composed of people from mylaboratory and the CDC in Beijing, China, studied thestrains responsible for the outbreak. Only one clone wasresponsible for all diagnosed cl inical cases.14The sameclone was iso lated from diseased pig s that were slaughteredby people that became ill. The same clone wa s alsoresponsible for the outbreak in 1998, but the strain seems tobe different from other strains isolated in oth er pro vinces ofChina. Interestingly, the same clone was isolated some yearsago from a TSLS case in Hong Kong. So, this leads to thequestion, is this clone more viru lent than "normal" virulentstrains? Thus far, we have no indication that this is true .Although the strain is slightly more toxic, normal virulencemarkers (typical of those found in European and other Asianstrains) were found. No supe rantigen activity (typical ofbacterial species that induce toxic-shock syndrome) wasidentified , and there wa s no indication of higher cytokineinduction (such as TNF-a). In other words, we have no clearindication wh eth er thi s strain is more pathogenic to humans .We can only perform further research on these strains inChina because Chinese authorities have not yet ass ented tosend them to laboratori es abroad.

Could this kind of outbreak happen in Canada!USA?

We do not th ink so. Although the infection is wid elydistributed in the pig population, a relatively low numberof human cases have been reported in North America. First ,human-pig contact on a daily basis is completel y different inour countries . In addition, ill animals are not

usually con sumed, and minimal biosecurity measures wouldprevent transmission . The low incidence of disease in NorthAmerica is also probably due to a low level of colonizationof human mucosa by thi s pathogen and/or a relatively lowsusceptibility of healthy person s in contact with pigs todevelop the disease. However, there is a serious diagnosticproblem in laboratories working in human medicine. Eve nthough S. suis field isolates readily grow on media employedfor culturing meningitis-causing bacteria, many laboratoriesare not aware of this microorganism, and it is usuallymisidentified as enterococci , Streptococcus pneumoniae,Streptococcus bovis, viridans group streptococc i, or eve nListeria. In many cases, the initial Gram stain diagnosisof the cerebrospinal fluid specimen is pneumococcalmeninigitis. We believe that this the only explanation forthe lack of reports of human cases up to 2005 in the UnitedStates, wh ere S. suis is one of the most important swi nepathogens. A few months after the Chinese outbreak, thefirst report on a human case in USA wa s publ ished.H Th isis a clear indication that the dis ease ex isted previously butwas probably misidentified . The Chinese experience hasbeen at least very instructive, and more human cases willprobably be reported in the next months. Veterinar iansshould be aw are that a low but real risk may be presentduring manipulation of S. s uis-diseased anima ls that mightshed a high number of this zoonotic etiological agent.

Refere nces1. Higgins, R., M. Gottschalk. 2005. Streptococcal diseases. In:

Straw, B. E., D'Allairc, S., Mengeling, W. L., Taylor, D. J.(eds.). Diseases ofSwine. Iowa State University Press. 9thEdition. Ames, pp 769-783.

2. Perch, B., P. Kristjansen, K. Skadhauge. 1968. Group Rstreptococci pathogenic for man. Two cases of meningitis andone fatal case of sepsis. Acta path microbiol scandinav. 74:69­76.

3. Donsakul, K, D. Charungthai, R. Witoonpanich. 2003.Streptococcus suis: Clinical features and diagnostic pitfalls.Southeast Asian J Trop Med Public Health. 34:154-158.

4. Chau, P.Y.,c.Y. Huang, R. Kay. 1983. Streptococcus suismeningitis. An important underdiagnosed disease in HongKong. Med J Aust. 1:414-41 7.

5. Gottschalk, M., M. Segura. 2000. The pathogenesis of themeningitis caused by Streptoco ccus suis : The unresolvedquestions. Vet Microbiol. 76:259-272.

6. Segura, M., G. Vanier, D. Al Numani, S. Lacouture, M. Olivier,M. Gottschalk. 2006. Proinflammatory cytokine and chemokinemodulation by Streptococcus suis in a whole-blood culturesystem. FEMS Immunol Med Microbiol. 47:92-106.

7. Lutticken, R., N. Temme, E. Hahn, E. W. Bartelheimer. 1986.Meningitis caused by Streptococcus suis : Case report andreview of the literature. Infection. 14:1 81-185.

8. Walsh, B., A. E. Williams, J. Satsangi. 1992. Streptococcus suistype 2 : Pathogenesis and clinical disease. Rev Med Microbiol.3:65-71.

9. Robertson I. D., D. K. Blackmore. 1989. Occupational exposureto Streptococcus suis type 2. Epidemiol Infect. 103:157-16

10. Watkins, E. J., P. Brooksby, M. S. Schweiger, S. M. Enright.2001. Septicaemia in a pig-farm worker. The Lancet. 357:38.

II . Gallagher, F. Streptococcus suis infection and splenectomy.200 I.The Lancet. 1131 -1132.

12. Francois, 8 ., V. Gissot, M. C. Ploy, P. Vignon. 1998. Recurrentseptic shock due to Streptococcus suis. J Clin Microbiol.36:2395.

13. Tang, J., C. Wang, Y. Feng, W. Yang, H. Song , Z. Chen, H. Yu,X. Pan, X. Zhou, H. Wang, 8. Wu, H. Wang, H. Zhao, Y. Lin,J. Vue, Z. Wu, X. He, F. Gao , A. Khan, J. Wang, G. Zhao, Y.Wang, X. Wang, Z. Chen, G. Gao . 2006 . Streptococcal toxicshock syndrome caused by Streptococcus suis serotype 2.PLoS Med. 3:187.

14. Yc, c.. X. Zlm, H. Jing , H. Du, M. Segura, H. Zheng, 8. Kan,L. Wang, X. 8ai, Y. Zhou, Z. Cui, S. Zhang, D. Jin, N. Sun,X. Luo, J. Zhang, Z. Gong, X. Wang , L. Wang, H. Sun , Z.Li, Q. Sun, H. Liu, 8 . Dong , C. Ke, H. Yuan, H. Wang, K.Tian, Y. Wang, M. Gottschalk, J. Xu. 2006 . Streptococcussuis sequence type 7 outbreak, Sichuan, China. Emerg InjectDis.12: 1203-1208.

Gottschalk is with Groupe de Recherche surles Maladies du Pore(GREMIP) and the Centre de Recherche en Injectiologie Porcine(CRIP). Faculte de medecine veterinaire , Universite de Montreal,

St-Hyacinthe. Quebec. Canada.Segura is with McGill UniversityHealth Centre Research Institute, Montreal General Hospital,

Montreal, Quebec, Canada

- Submitted by Morgan Morrow

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