Introduction

Streptococcus suis infections are considered a major worldwide problem in the swine industry, particularly during the past 15 years. The natural habitat of S. suis in pigs is the upper respiratory tract, mainly the tonsils and nasal cavities, and the genital and alimentary tracts. The most important clinical feature associated with S. suis is meningitis. However, other pathologies have also been described, such as arthritis, endocarditis, pneumonia, and septicemia with sudden death. Although S. suis is considered mainly a swine pathogen, it has been increasingly isolated from a wide range of mammalian species (including humans) and from birds, which may suggest new concepts on some epidemiological aspects of the infection. Although recognized for more than 30 years, S. suis infections in humans have been considered to be sporadic and of low incidence. However, this disease has probably been underestimated due mainly to a misidentification of strains isolated from humans in many countries, especially in North America. A recent important human S. suis outbreak in China (summer 2005) attracted considerable public and scientific interest. In this short paper, we summarize features of the infection in humans and the main characteristics of the China outbreak, which we were directly involved in investigating.

The infection in humans

From the first description in Denmark in 1968 to early 2005, around 200 human cases of S. suis infection have been reported.^2,3 S. suis infections in humans are observed more frequently in intensive pig farming areas or where people live in close contact with pigs. Cases have 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 in Canada and none in USA (up to early 2005, see below). In general, S. suis disease is considered a rare event in humans; however, it has been reported to be “one of the major causes of meningitis in adults in Hong Kong.”⁴ Most cases are caused by serotype 2 strains; but cases due to serotype 4 (one case), serotype 14 (two cases) and serotype 1 (two cases; serotype not confirmed since the strains were lost: J. Kopic, personal communication, 2004) strains have also been observed. In humans, S. suis usually produces a purulent or non-purulent meningitis. In addition, endocarditis, cellulitis, rhabdomyolysis, arthritis, pneumonia, and endopthalmitis have also been reported. Arthritis affects various joints, including hips, elbows, wrists, sacroiliac, spine, and thumb.³ In most cases, arthritis reflects generalized septicemia caused by S. suis. Severe cases of sepsis with shock, multiple organ failure, disseminated intravascular coagulation, and associated purpura fulminans, which lead to death within hours, have also been described. It has been demonstrated that S. suis has important inflammatory capacities.^5,6 One of the most striking features of the infection is the consequence of deafness following S. suis meningitis. In fact, the recorded incidence of deafness following S. suis infection is consistently higher than that for other meningitis- causing bacteria and can reach 50 percent and 65 percent in Europe and Asia, respectively.³ The reason for this is unknown. The deafness (unilateral or bilateral) has been mainly high tone and is frequently associated with vertigo. Early administration of antibiotics does not appear to have any influence on subsequent hearing loss. No cases of deafness have been reported in non-meningitis cases of human S. suis infection.

Epidemiology of the infection and risk factors

It has been suggested that the routes of entry of the organism in humans might be a small cut in the skin (although in some cases no wound was detected), the nasopharynx (with positive isolation from tonsils of abattoir workers), or the gastrointestinal tract (diarrhea as a prodromal symptom is sometimes observed). The incubation period ranges from a few hours to two days.³ Although not all facets of the epidemiology of S. 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 exposure to unprocessed pig meat or to close contact with pigs.⁷ Since most patients acquire the disease after occupational exposure to pigs or pork products, the preponderance of adult males is readily explained. Manifestation of disease in pigs is not a prerequisite for infections in people in contact with pigs, since most animals are colonized by S. suis without presenting clinical signs. In addition to pigs, wild boars may also be a source of S. suis infection for hunters and poachers in countries where these animals are present. In the United Kingdom and France, this infection was listed as an Industrial Disease in 1983 and 1995, respectively. As mentioned above, most cases of infected people are pig farmers, abattoir workers, persons transporting pork meat, meat inspectors, and butchers. From studies of contamination of hands and knives, it was concluded that eviscerators involved in removing the larynx and lungs from the carcasses have a significantly higher risk of exposure to S. suis than other abattoir workers. Finally, one documented case of a veterinary surgeon has been reported.⁸ In very rare cases, there was no apparent connection with exposure to pigs or pork products. Information about the occurrence and frequency of human colonization by S. suis is scarce, with most data coming from abattoir workers. In New Zealand, relatively high antibody titers against S. suis serotype 2 were reported in people with occupational contact within the pig industry.⁹ However, these data should be taken with caution since no standardized serological test to detect S. suis antibodies exists. It seems evident that high exposure to S. suis may lead to a colonization of the upper respiratory tract without any health consequences. Only in some cases, clinical disease may follow. Splenectomy and, to a lesser extent, alcoholism have been suggested as important predisposing factors for the development of serious S. suis disease.^10,11 In fact, the fatality rate for S. suis infection after splenectomy seems to be around 80 percent. It has even been suggested that individuals who have had a splenectomy should be excluded from the meat trade or pig farms. In general, S. suis isolates from humans are phenotypically and genotypically similar to those recovered from pigs.

Therapy and prevention of infection in humans

S. suis strains recovered from humans proved to be sensitive to penicillin in all instances except for one penicillin- tolerant strain. Therefore, intravenous penicillin G has been a successful treatment in most cases. Since at least two relapse cases have occurred after two or four weeks of treatment, treatment should be applied for a relatively long period (at least 6 weeks). Ampicillin and chloramphenicol, sometimes combined with an aminoglycoside, can also be used. As previously mentioned, hearing loss and vestibular disturbances are frequently observed sequelae that are unrelated to antibiotic use. S. suis vaccines for humans do not exist as yet. Interestingly, a recurrent septic shock due to S. suis serotype 2, with 15 years of interval, has been reported.¹² The second and fatal episode was considered as a re-infection rather than a recurrence of the previous infection, confirming the absence of immunity after the previous infection and the utmost importance of continuous prevention in exposed workers. Despite the low incidence of S. suis infection in humans, some preventive measures may be justified due to the high rate of contamination of pigs with this microorganism. People in close occupational contact with pigs or pork meat should pay special attention. Most infected persons are probably healthy carriers; however, in situations of stress or immunodeficiency, S. suis may become an opportunistic pathogen. The environment can act as a source of infection, and S. suis can survive in dust, manure, and pig carcasses for days or even weeks under optimal conditions. Moreover, S. suis can survive in water for 10 minutes at 60°C, making the scalding process in abattoirs a possible source of contamination. Some researchers recommend prompt first-aid for injuries in meat handlers to reduce the risk of S. suis infections, but others consider this recommendation questionable because evident skin lesions have only been reported in some cases and the route of entry of the pathogen remains unclear. Therefore, it is difficult to recommend effective prevention measures for employees in the food product industry.

What happened in China in the summer of 2005?

From mid-July to the end of August 2005, a total of 215 cases of human S. suis infections, 66 of which were laboratory confirmed, were reported in Sichuan, China. All infections occurred in backyard farmers who were directly exposed during the slaughtering process of pigs that had died of unknown causes or been killed for food because they were ill. Sixty-one farmers (28 percent) had streptococcal toxic shock syndrome; 38 (62 percent) died. The other illnesses reported were sepsis (24 percent) and meningitis (48 percent) or both. The high death ratio was of concern; prohibiting backyard slaughtering ended the outbreak.¹³ In addition to its size and the associated high mortality, this outbreak is unique in that a large proportion of patients were victims of a “toxic shock-like syndrome” (TSLS). To date, streptococcal toxic shock, as per consensus definition, has been limited to disease caused by the group A streptococcus, S. pyogenes, with some sporadic reports of other (nongroup A) beta-haemolytic streptococci. S. suis has rarely been associated with TSLS, although some cases with well described hypotension and multi-organ failure have been reported. Epidemiologically, all cases of human disease in the recent outbreak were linked to exposure to pigs, and skin as the route of entry was reported in most cases. Interestingly, a similar but less extended outbreak of S. suis serotype 2 was described in the same region in 1998. This outbreak was reported only in Chinese journals, and its existence was unknown in the Occident. At least some of the human cases in the S. suis outbreak in Sichuan province in 1998 may have been related to ingestion of contaminated food, but this was not the case in the 2005 outbreak. Farmers in Sichuan province have close contact with their pigs; humans and animals often share the same accommodations and animals are slaughtered at home. Furthermore, it is common practice to slaughter and eat diseased animals. Thus, in addition to inoculation and airborne transmission from infected pigs, foodborne transmission by infected pork may have also contributed to this outbreak.¹³ Very little information about the pig outbreak in 2005 is available. It has been reported that 600 pigs died of S. suis, and the outbreak was rapidly controlled through use of an autogenous vaccine. Interestingly, large production systems were not affected, probably due to biosecurity measures adopted in these herds. Many questions, most of them still unresolved, arise from this experience. For example, if close contact with pigs is a millenary habitude of the Chinese population in Sichuan province, why have only two outbreaks been observed? If all affected animals originated from backyard production systems, how can we explain the transmission of infection between villages, which sometimes exist hundreds of kilometers apart? Why did the outbreak suddenly appear and then suddenly disappear? Why was septic shock or TSLS mainly observed? How can we explain the elimination of the infection in pigs following the use of an autogenous vaccine (bacterin) even though such vaccines usually offer limited protection? Is it possible that a strain of higher virulence was responsible for these outbreaks? A collaborative team composed of people from my laboratory and the CDC in Beijing, China, studied the strains responsible for the outbreak. Only one clone was responsible for all diagnosed clinical cases.¹⁴ The same clone was isolated from diseased pigs that were slaughtered by people that became ill. The same clone was also responsible for the outbreak in 1998, but the strain seems to be different from other strains isolated in other provinces of China. Interestingly, the same clone was isolated some years ago from a TSLS case in Hong Kong. So, this leads to the question, is this clone more virulent than “normal” virulent strains? Thus far, we have no indication that this is true. Although the strain is slightly more toxic, normal virulence markers (typical of those found in European and other Asian strains) were found. No superantigen activity (typical of bacterial species that induce toxic-shock syndrome) was identified, and there was no indication of higher cytokine induction (such as TNF-a). In other words, we have no clear indication whether this strain is more pathogenic to humans. We can only perform further research on these strains in China because Chinese authorities have not yet assented to send them to laboratories abroad.

Could this kind of outbreak happen in Canada/USA?

We do not think so. Although the infection is widely distributed in the pig population, a relatively low number of human cases have been reported in North America. First, human-pig contact on a daily basis is completely different in our countries. In addition, ill animals are not usually consumed, and minimal biosecurity measures would prevent transmission. The low incidence of disease in North America is also probably due to a low level of colonization of human mucosa by this pathogen and/or a relatively low susceptibility of healthy persons in contact with pigs to develop the disease. However, there is a serious diagnostic problem in laboratories working in human medicine. Even though S. suis field isolates readily grow on media employed for culturing meningitis-causing bacteria, many laboratories are not aware of this microorganism, and it is usually misidentified as enterococci, Streptococcus pneumoniae, Streptococcus bovis, viridans group streptococci, or even Listeria. In many cases, the initial Gram stain diagnosis of the cerebrospinal fluid specimen is pneumococcal meninigitis. We believe that this the only explanation for the lack of reports of human cases up to 2005 in the United States, where S. suis is one of the most important swine pathogens. A few months after the Chinese outbreak, the first report on a human case in USA was published.¹⁴ This is a clear indication that the disease existed previously but was probably misidentified. The Chinese experience has been at least very instructive, and more human cases will probably be reported in the next months. Veterinarians should be aware that a low but real risk may be present during manipulation of S. suis-diseased animals that might shed a high number of this zoonotic etiological agent.

References

1. Higgins, R., M. Gottschalk. 2005. Streptococcal diseases. In: Straw, B. E., D’Allaire, S., Mengeling, W. L., Taylor, D. J. (eds.). Diseases of Swine. Iowa State University Press. 9th Edition. Ames, pp 769-783.
2. Perch, B., P. Kristjansen, K. Skadhauge. 1968. Group R streptococci pathogenic for man. Two cases of meningitis and one fatal case of sepsis. Acta path microbiol scandinav. 74:69- 76.
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 suis meningitis. An important underdiagnosed disease in Hong Kong. Med J Aust. 1:414-417.
5. Gottschalk, M., M. Segura. 2000. The pathogenesis of the meningitis caused by Streptococcus suis: The unresolved questions. Vet Microbiol. 76:259-272.
6. Segura, M., G. Vanier, D. Al Numani, S. Lacouture, M. Olivier, M. Gottschalk. 2006. Proinflammatory cytokine and chemokine modulation by Streptococcus suis in a whole-blood culture system. FEMS Immunol Med Microbiol. 47:92-106.
7. Lütticken, R., N. Temme, E. Hahn, E. W. Bartelheimer. 1986. Meningitis caused by Streptococcus suis: Case report and review of the literature. Infection. 14:181-185.
8. Walsh, B., A. E. Williams, J. Satsangi. 1992. Streptococcus suis type 2 : Pathogenesis and clinical disease. Rev Med Microbiol. 3:65-71.
9. Robertson I. D., D. K. Blackmore. 1989. Occupational exposure to 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.
11. Gallagher, F. Streptococcus suis infection and splenectomy. 2001. The Lancet. 1131-1132.
12. Francois, B., V. Gissot, M. C. Ploy, P. Vignon. 1998. Recurrent septic 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, B. Wu, H. Wang, H. Zhao, Y. Lin, J. Yue, Z. Wu, X. He, F. Gao, A. Khan, J. Wang, G. Zhao, Y. Wang, X. Wang, Z. Chen, G. Gao. 2006. Streptococcal toxic shock syndrome caused by Streptococcus suis serotype 2. PLoS Med. 3:187.
14. Ye, C., X. Zhu, H. Jing, H. Du, M. Segura, H. Zheng, B. Kan, L. Wang, X. Bai, 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, B. Dong, C. Ke, H. Yuan, H. Wang, K. Tian, Y. Wang, M. Gottschalk, J. Xu. 2006. Streptococcus suis sequence type 7 outbreak, Sichuan, China. Emerg Infect Dis. 12:1203-1208.

Further Reading