Streptococcus suis Meningitis: Epidemiology,Clinical Presentation and Treatment

Abstract

Streptococcus suis, a prevalent porcine pathogen, may sporadically cause infections in humans, and has recently emerged as a cause of zoonoses in some professionals. The aim of this article was to review available data on epidemiology, etiopathogenesis, diagnostics, and management of the most common form of S. suis infection, purulent meningitis. Literature data show that S. suis is an important etiological factor of purulent meningitis, especially in subjects being occupationally exposed to contact with pigs and/or pork meat. Owing to growing incidence of S. suis meningitis, a history of such exposure should be verified in each patient presenting with typical meningeal symptoms. Whenever S. suis was confirmed as the etiological factor of purulent meningitis, therapeutic protocol should be adjusted appropriately, to avoid patient's exposure to potentially ototoxic antimicrobial agents and corticosteroids. Considering the biphasic character of S. suis meningitis and its frequently atypical outcome, all individuals with this condition should be optimally supervised by a multidisciplinary team, including an ENT specialist.

Introduction

S treptococcus suis, a prevalent porcine pathogen, may sporadically cause infections in humans, and has recently emerged as a cause of zoonoses in some professionals. Patients infected with S. suis typically present with meningitis, arthritis, and/or sepsis. Main risk groups for S. suis infection are subjects being occupationally exposed to pigs and/or pork, for example, farmers, butchers, meat sellers, foresters, and hunters.

The aim of this article was to review available data on epidemiology, etiopathogenesis, diagnostics, and management of the most common form of S. suis infection, purulent meningitis.

Microbiology of S. suis

S. suis is a heterogeneous Gram-positive bacterium. This facultative anaerobe, spherical or ovoid in shape, typically presents in pairs or as short chains. Another specific feature of S. suis is the presence of alpha hemolysis on selective media enriched with horse blood (Staats et al. 1997, Feng et al. 2014). The lack of growth in 6.5% NaCl agar, negative result of Voges-Proskauer test, and synthesis of acid from trehalose or salicin are sufficient to consider an alpha-hemolytic Gram-positive coccus as a S. suis isolate (Goyette-Desjardins et al. 2014, Okura et al. 2016). However, more accurate identification requires additional biochemical tests: for arginine dihydrolase (positive result), production of acid from lactose, sucrose, and inulin (positive result) and synthesis of acid from glycerol, mannitol, and sorbitol (negative result) (Goyette-Desjardins et al. 2014, Okura et al. 2016).

S. suis is a very common swine pathogen, isolated from upper airways (predominantly tonsils and nasal cavity), gastrointestinal tract, and genitals of pigs. Markedly less often, S. suis may be also isolated from other species like horses, dogs, and cats. Apparently, some porcine strains of S. suis have evolved and become potent human pathogens, as well (Staats et al. 1997, Gottschalk and Segura 2000, Huang et al. 2005).

Although to this date, a total of 35 various serotypes of S. suis have been identified based on the heterogeneity of their capsular antigens, it is serotype 2 (SS2) that plays a crucial role in the pathogenesis of human infections (Gottschalk et al. 2007, Wertheim et al. 2009). Other serotypes, less often isolated from humans, are SS1, SS4, SS5, SS14, SS16, and SS24 (Arends and Zanen 1988, Mai et al. 2008, Nghia et al. 2008, Haleis et al. 2009, Kerdsin et al. 2009, 2011, Gustavsson and Ramussen 2014). However, this serotype-based classification raises some controversies. Some authors who documented the presence of “S. suis-like strains,” which although satisfied the previously mentioned biochemical taxonomic criteria, were shown to be genetically distinct entities (Hill et al. 2005, Tien le et al. 2013, Ishida et al. 2014, Baig et al. 2015, Nomoto et al. 2015, Okura et al. 2016). Hence, molecular methods have been used increasingly to ultimately confirm the identity of presumable S. suis isolates (see, Okura et al. 2016). Using a molecular approach, namely multilocus sequence typing, SS2, the most common cause of human infections among S. suis serotypes, has been classified into at least 16 sequence types (STs), some of which form clonal complexes (King et al. 2002, Goyette-Desjardins et al. 2014).

A number of S. suis virulence factors have been identified to date. They can be classified into four main categories: (1) surface/secreted elements, (2) enzymes/proteases, (3) transcription factors/regulatory systems, and (4) transporters/secretion systems (Feng et al. 2014). Based on the profile of their virulence factors, S. suis strains are classified as highly pathogenic, weakly pathogenic (hypovirulent), and nonpathogenic (avirulent) (Feng et al. 2014). The most prominent and best characterized virulence factors of S. suis are surface and secreted elements: capsular polysaccharides, muramidase-released protein, and a 38 kDa surface protein, suilysin (SLY) (Wilson et al. 2007). Although the list of confirmed and putative virulence factors is extensive (see, Fittipaldi et al. 2012, Segura et al. 2017) and at least 37 of them are claimed to be “critical,” the role of many still has not been verified appropriately.

Epidemiology of S. suis Infections

S. suis was first identified as an etiological factor of human infections in 1968 (Wertheim et al. 2009), and since then a total of ∼1600 cases of zoonoses caused by this pathogen have been reported in ∼30 countries in Europe (Austria, Belgium, Croatia, Denmark, France, Germany, Greece, Hungary, Ireland, Italy, the Netherlands, Poland, Portugal, Spain, Sweden, and United Kingdom), Asia (China, Hong Kong, India, Japan, Korea, Laos, Philippines, Singapore, Taiwan, Thailand, and Vietnam), North America (Canada and United States), South America (Argentina, Chile, and French Guiana), Australia, and New Zealand (Shneerson et al. 1980, Robertson 1986, Yen et al. 1994, Kay et al. 1995, Michaud et al. 1996, Staats et al. 1997, Spiss et al. 1999, GeffnerSclarsky et al. 2001, Kopić et al. 2002, Ibaraki et al. 2003, Rosenkranz et al. 2003, Teekakirikul and Wiwanitkit 2003, Suankratay et al. 2004, Huang et al. 2005, Hui et al. 2005, Lopreto et al. 2005, Willenburg et al. 2006, Yu et al. 2006, Gottschalk et al. 2007, Camporese et al. 2007, Lun et al. 2007, Lee et al. 2008, Ma et al. 2008, Mai et al. 2008, Manzin et al. 2008, van de Beek et al. 2008, Fittipaldi et al. 2009, Wertheim et al. 2009a, 2009b, Feng et al. 2010, Huh et al. 2011, Nghia et al. 2011, Demar et al. 2013, Koch et al. 2013, Zalas-Wiecek et al. 2013). Although a majority of these cases were sporadic infections, two outbreaks of S. suis SS2 epidemics were reported from China (Huang et al. 2005, Ye et al. 2006, Yu et al. 2006, Lun et al. 2007, Feng et al. 2009, 2010, Ma et al. 2009), and this bacterium was shown to occur endemically in Thailand and Vietnam (Teekakirikul and Wiwanitkit 2003, Suankratay et al. 2004, Mai et al. 2008, Wertheim et al. 2009a, 2009b, Kerdsin et al. 2009, 2011, Nghia et al. 2011, Ngo et al. 2011). All this points to S. suis as a potential public health threat.

Relatively more frequent occurrence of human S. suis infections in Asian countries points to a potential geographical tropism of this pathogen that probably should be attributed not only to the specific climate but also to the leading role of pork industry and popularity of pork dishes in this area (see Risk Factors, Risk Groups, and Routes of Infection section) (Feng et al. 2014). Most European cases of S. suis infections in humans were reported from the Netherlands (n = 41), the United Kingdom (n = 15), and Denmark (n = 12), and zoonoses caused by this pathogen occurred only sporadically in the remaining countries (Wertheim et al. 2009a). One specific feature of the European isolates of S. suis is their predilection to the meninges and frequent involvement in the etiology of purulent meningitis (Feng et al. 2014). S. suis infections have been relatively rarely documented in the United States and Canada, two potent players in the global swine market (Donsakul et al. 2003, Heidt et al. 2005, Gottschalk et al. 2007). Recent evidence suggests that the latter phenomenon may be at least partially explained by different structure of the Northern American S. suis STs. Although most S. suis found in Asia and Europe were highly virulent ST1 isolates, the intermediate-virulence ST25 and ST28 strains seem to prevail in the United States and Canada (Goyette-Desjardins et al. 2014, Athey et al. 2015).

Risk Factors, Risk Groups, and Routes of Infection

Literature evidence suggests that the principal risk group for S. suis infection are individuals exposed to pigs and pork meat, usually in an occupational setting. The following groups can be identified as particularly predisposed to S. suis infection: farmers, slaughterhouse workers, butchers, and meat sellers (Dupas et al. 1992, Staats et al. 1997, Charland et al. 2000, Lalonde et al. 2000). However, there is also evidence of occupational S. suis infection in which wild boars were the source of the pathogen, for example, for foresters and hunters (Rosenkranz et al. 2003). The susceptibility to infection does not seem to be age and sex specific, as zoonoses caused by S. suis were reported in 30- to 70-year-old subjects, both men and women (Feng et al. 2014).

The aim of a case–control study conducted in Vietnam (Nghia et al. 2011) was to identify the risk factors for S. suis meningitis using a subset of 100 patients with this type of infection and a group of matched hospital (n = 303) and community controls (n = 300). The study identified consumption of dishes containing undercooked, raw pork, swine intestines, and porcine blood, occupational exposure to pigs and pork, and presence of skin injuries while dealing with pigs and pig meat as independent risk factors for S. suis infection (Nghia et al. 2011). According to some authors, the incidence of S. suis zoonoses is higher in summer (Ma et al. 2008). Others showed that swine industry workers constitute up to 60% of patients infected with this pathogen (Hui et al. 2005), and researchers from the Netherlands demonstrated that occupational exposure to pigs is associated with up to 1000-fold increase in the risk for S. suis infection (Halaby et al. 2000). However, there are also published reports on the occurrence of S. suis infections in subjects who have never had any contact with swine or consumed the “high-risk” raw pork dishes (Kopić et al. 2002, Manzin et al. 2008, van de Beek et al. 2008, Fittipaldi et al. 2009).

Nevertheless, the abovementioned findings, as well as the evidence from many published case reports, imply that typically S. suis zoonoses result from a wound infection or ingestion of pork contaminated with this pathogen. This was also confirmed in a recent meta-analysis based on three studies with a total of 1454 cases reported, which identified raw pork consumption, exposure to pigs or pork, pig-related occupation, and male sex as significant risk factors for S. suis infection (Rayanakorn et al. 2018).

Regarding the route of transmission, a growing body of evidence suggests that S. suis can be an airborne pathogen. S. suis was shown to survive in feces for up to 104 days (Clifton-Hadley and Enright 1984), and an airborne transmission of this pathogen has been demonstrated in experimental studies in pigs (Berthelot-Herault et al. 2001, Madsen et al. 2001). Those findings were more recently confirmed by Bonifait et al. (2014), who detected S. suis in the aerosol from the swine confinement buildings and in the nasal swabs from 58% of pork producers, taken before the work shift.

Purulent Meningitis as the Most Common Form of S. suis Infection in Humans

According to literature, the most common forms of zoonotic S. suis infections are meningitis and sepsis (Suankratay et al. 2004, Wertheim et al. 2009b). The first reported case of S. suis meningitis was diagnosed in Denmark in 1968 (Staats et al. 1997). Since then, meningitis was shown to be the most common presentation of this infection in both Europe and Asia (84.6% and 75.2%, respectively), and sepsis turned out to be the second most common of S. suis-related zoonoses (15.4% and 18.6%, respectively) (Huang et al. 2005). Other, less often reported clinical forms of S. suis infection include enteritis, arthritis, endocarditis, pneumonia (predominantly an opportunistic one), spondylodiscitis, endophthalmitis, uveitis, and peritonitis (Huang et al. 2005). Also in a large retrospective analysis of patients from Hong Kong hospitalized owing to S. suis infection, primary clinical manifestations were meningitis (48%), sepsis (38%), and endocarditis (14%) (Ma et al. 2008).

S. suis can be also an etiological factor of streptococcal toxic shock-like syndrome (STSLS). A few cases of STSLS caused by S. suis have been described in various countries thus far, primarily in pig farmers (Gomez et al. 2014, Yamanaka et al. 2015, Mancini et al. 2016, Kim et al. 2018). According to literature, this condition, characterized by shock, multiorgan failure, rapidly progressive soft-tissue infection, and high fatality, may be caused by some S. suis isolates that release more proinflammatory cytokines than others (Ye et al. 2009).

Usually, S. suis infection starts with the typical meningeal signs, such as fever, headache, nausea, and vomiting, and neurological symptoms, such as dizziness, balance disorders, and limb trembling. The results of central nervous system imaging are normal in most cases. The diagnosis of purulent meningitis can be confirmed based on cerebrospinal fluid (CSF) examination and CSF and blood culturing. Most patients respond well to broad-spectrum intravenous antibiotics such as penicillin, ampicillin, amikacin, or cefotaxime. Usually a spectacular improvement of general and neurological status is observed within a few days/week of such treatment. However contrary to purulent meningitis of other etiologies, infections caused by S. suis show a tendency to relapse (Dupas et al. 1992, Bronstein et al. 1995, Grebe et al. 1997).

Literature data imply that S. suis meningitis is characterized by prolonged, biphasic course with frequent incidence of cerebellar ataxia and deafness (sometimes irreversible) (Dupas et al. 1992, Bronstein et al. 1995, Grebe et al. 1997). Exacerbation of the symptoms is usually observed after 2–3 weeks of first-line antibiotic therapy. Clinical manifestation of relapsing S. suis meningitis varies. According to the authors of one review article, a considerable proportion of patients with S. suis meningitis (50.5% from Europe and 51.9% from Asia) develop deafness after a temporary improvement of their clinical status (Huang et al. 2005), and data from other centers imply that the prevalence of secondary deafness in subjects with S. suis meningitis may be even higher, up to 80% (Kay et al. 1995, Mai et al. 2008, Wertheim et al. 2009a). The authors of another review article showed that hearing loss in S. suis meningitis is sensorineural, involves high-frequency range, and can be profound (>80 dB) (Wertheim et al. 2009a). Either one or both ears can be affected. Although it may sometimes resolve over time, typically the hearing loss is permanent. In a study conducted in Vietnam, 66.4% of adult patients with S. suis meningitis presented with mild-to-severe hearing loss at the time of hospital discharge, as compared with 47.7% six months thereafter (Feng et al. 2014). Sometimes, hearing loss may be associated with vestibular dysfunction, for example, ataxia (Feng et al. 2014).

Despite considerable prevalence, still little is known on the etiopathogenesis of hearing impairment observed at later stages of S. suis meningitis. According to one theory, the loss of hearing is associated with purulent internal otitis, resulting from damage of cochlear tissues by SLY, a previously mentioned toxin of S. suis (Kay 1991). However, this theory has not been confirmed in humans thus far (Spiss et al. 1999). The authors of a Vietnamese study (Mai et al. 2008) identified independent risk factors for hearing impairment during the course of S. suis meningitis based on the retrospective analysis of 151 patients with this condition. Severe deafness at hospital discharge was associated with patients >50 years of age, infection with a strain carrying the epf gene and dexamethasone therapy, but not with bacterial DNA load in the CSF (Mai et al. 2008).

Therapeutic Implications and Preventive Measures

Some authors claimed on efficient control of the first-phase infection with broad-spectrum antimicrobials, such as penicillin, ampicillin, and ceftriaxone (Huang et al. 2005, Ma et al. 2008, Huh et al. 2011). However, frequent occurrence of hearing impairment in subjects with S. suis meningitis implies that potentially ototoxic agents, such as aminoglycoside antibiotics, should be used with extreme caution in this group. Moreover, some evidence suggests that a growing proportion of S. suis strains involved in purulent meningitis may show multidrug resistance (Hoa et al. 2011). Although this seems to be an issue mainly in countries with high incidence of S. suis infections, it should not be neglected, especially after a study conducted in New Zealand showed high ratio of local farmers and meat inspectors being seropositive to S. suis SS2 (Dickie et al. 1987, Coolen et al. 1989), which points to the likely presence of subclinical infections.

Finally, steroid use requires careful analysis; while steroids are an important element of successful therapy of bacterial meningitis, they are also a risk factor for secondary hearing loss.

Apart from the control of S. suis infection, equally important is primary prevention, specifically use of appropriate protective devices (e.g., gloves) by personnel exposed to contact with pigs and pork, especially when the skin integrity is breached, and also a thorough veterinary control of slaughtered animals and adherence to all general sanitary and hygienic standards are followed.

Conclusion

Literature data show that S. suis is an important etiological factor of purulent meningitis, especially in subjects being occupationally exposed to contact with pigs and/or pork meat. Owing to growing incidence of S. suis meningitis, a history of such exposure should be verified in each patient presenting with typical meningeal symptoms. Whenever, S. suis was confirmed as the etiological factor of purulent meningitis, therapeutic protocol should be adjusted appropriately to avoid patient's exposure to potentially ototoxic antimicrobial agents and corticosteroids. Considering the biphasic character of S. suis meningitis and its frequently atypical outcome, all individuals with this condition should be optimally supervised by a multidisciplinary team, including an ENT specialist.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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