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Streptococcus agalactiae infections and clinical relevance in adults, Thailand
Journal Pre-proof Streptococcus agalactiae infections and clinical relevance in adults, Thailand
Wantana Paveenkittiporn, Ratchadabhorn Ungcharoen, Anusak Kerdsin PII:
S0732-8893(19)31119-8
DOI:
https://doi.org/10.1016/j.diagmicrobio.2020.115005
Reference:
DMB 115005
To appear in:
Diagnostic Microbiology & Infectious Disease
Received date:
8 November 2019
Revised date:
2 January 2020
Accepted date:
26 January 2020
Please cite this article as: W. Paveenkittiporn, R. Ungcharoen and A. Kerdsin, Streptococcus agalactiae infections and clinical relevance in adults, Thailand, Diagnostic Microbiology & Infectious Disease(2020), https://doi.org/10.1016/ j.diagmicrobio.2020.115005
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© 2020 Published by Elsevier.
Journal Pre-proof
Streptococcus agalactiae infections and clinical relevance in adults, Thailand
Wantana Paveenkittiporna, Ratchadabhorn Ungcharoen b, Anusak Kerdsin b*
a
National Institute of Health, Department of Medical Sciences, Ministry of Public Health,
Thailand Faculty of Public Health, Kasetsart University Chalermphrakiat Sakon Nakhon Province
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b
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Campus, Sakon Nakhon, Thailand
*Correspondence: Anusak Kerdsin, Faculty of Public Health, Kasetsart University
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Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon 47000, Thailand,
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Email: [email protected]
Running title: S. agalactiae infection in Thailand
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Type of Article: Original Article
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Keywords: Streptococcus agalactiae; Group B streptococcus; Serotype; Sepsis; Urinary tract infection (UTI)
Word count of text: 2,391
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Journal Pre-proof Abstract Streptococcus agalactiae is an important pathogen that causes infections in neonates and adults especially infections in nonpregnant adults is increasing worldwide. Of 1,736 S. agalactiae isolates from individual throughout Thailand demonstrated that serotypes III (46.4%) and V (21%) were the most common serotypes. Human cases (56.5% female and 43.5% male) could be found all year round with the peak occurring more frequently during the rainy season (May–October). The mortality rate of S. agalactiae infections
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was 11.6% and serotype III was the most common serotype involved. Serotype III was strongly significantly (p-value <0.001) correlated with meningitis (odds ratio; OR = 26.72), sepsis (OR = 5.56), and septic arthritis (OR = 22.79). Serotype V was more
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associated with urinary tract infection than other serotypes. (p-value 0.005; OR = 2.32).
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Word count: 128
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Journal Pre-proof 1. Background Streptococcus agalactiae or Lancefield group B Streptococcus (GBS) is an important pathogen that causes infections in neonates and adults. The most common clinical manifestations of S. agalactiae in neonatal infection are meningitis and sepsis which are in contrast to the main clinical manifestations in adults such as bacteremia, soft tissue infection, and pneumonia (Morozumi et al. 2016). S. agalactiae isolates can be classified into 10 different serotypes (Ia, Ib, and II to IX), with serotypes Ia, II, III, and V
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being the predominant causes of human diseases (Imperi et al. 2012). In particular, the serotypes Ia, III, and V most commonly cause neonatal infections, with serotype III being the main serotype recovered from patients of all age groups, including nonpregnant adults
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(Kerdsin et al. 2017; Ippolito et al. 2010; Madrid et al. 2017; Farley 2001).
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The epidemiology of S. agalactiae disease has been well described in high-
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income contexts but less well studied in low- to middle-income contexts (Madrid et al., 2017). Rates of maternal invasive S. agalactiae infections in the US vary by States, with
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rates ranging from 0.1 per 1,000 deliveries to 0.8 per 1,000 deliveries, while nonpregnant
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adults, incidence was from 3.6 cases/100,000 persons in 1990 to 7.3 cases/100,000 persons in 2007, based on surveillance in 10 US States (Raabe and Shane, 2019).
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Invasive S. agalactiae annually affects 25 per 100,000 adults ages 65 and older in the US (Raabe and Shane, 2019). The yearly cost of delivery and treatment of newborns with GBS infection was $41,875±6,823 (El Helali et al., 2019). In UK, the economic cost of S. agalactiae infections in infants was £6,144.7 higher among cases than among non-S. agalactiae controls (Schroeder et al., 2009). S. agalactiae infections are increasing, particularly in elderly persons with underlying diseases such as diabetes, cardiovascular disease, and cancer (Farley 2001). In this study, we characterized 1,736 S. agalactiae isolates from an individual patient throughout Thailand to reveal serotype distribution, demographic data, and clinical manifestations in adults. 5
Journal Pre-proof 2. Objectives The aim of this study was to characterize 1,736 S. agalactiae isolates throughout Thailand to reveal serotype distribution, demographic data, and clinical manifestations in adults. 3. Study design 3.1. Bacterial isolates, identification and serotyping In total, 1,736 S. agalactiae isolates from individual case were characterized in
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this study and were collected from 25 tertiary hospitals located in the North (n=6), Northeast (n=6), East (n=3), South (n=5), and Central (n=5) Thailand during January
prospective study) as shown in Figure 1.
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2014 to June 2016 under the Vaccine Preventable Infections Surveillance Program (a
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Conventional biochemical tests described elsewhere were used to confirm S.
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agalactiae identification (Facklam 2002). Briefly, the organisms were cultured on sheep blood agar for 18-24 hours at 37 oC plus 5% CO2 and then tested for Gram’s stain,
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catalase production, bacitracin susceptibility, CAMP reaction, hippurate hydrolysis,
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Voges-Proskauer reaction, arginine deamination, esculin hydrolysis, starch hydrolysis, and production of acid in sorbitol and trehalose (Facklam 2002). Species identification
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was interpreted using the identification key/table described elsewhere (Facklam 2002). In addition, S. agalactiae isolates were confirmed using multiplex PCR as previously described (Kerdsin et al. 2017). All S. agalactiae isolates recovered in this study were initially serotyped using a PCR assay, as described by elsewhere (Imperi et al. 2010). 3.2. Human cases and statistical analyses The complete medical records of 1,394 cases were reviewed by the physicians in charge. Any incomplete or unavailable medical records were excluded in this study. The clinical manifestations of S. agalactiae infections were divided into seven categories: 5
Journal Pre-proof skin infections, central nervous system infections, urinary-reproductive system infections, bone/joint infections, blood infection, respiratory tract infections, and other (Table 1). The case definitions of these clinical presentations were determined according to criteria described elsewhere (Musher & Thorner, 2014; Kerdsin et al., 2018; Kranz et al., 2018; Ramakrishnan et al., 2015). Correlation of the clinical characteristics and serotypes were analyzed using the Logistic regression in the Stata version 12.0 software (StataCorp, College Station, TX, USA). Data were considered significant at p < 0.001.
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4. Results 4.1. Serotype distribution of S. agalactiae isolates
Of the 1,736 isolates, multiplex PCR revealed 805 isolates of serotype III (46.4%),
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365 isolates of serotype V (21%), 248 isolates of serotype II (14.3%), 118 isolates of
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serotype VI (6.8%), 96 isolates of serotype Ia (5.5%), 57 isolates of serotype Ib (3.3%),
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31 isolates of serotype VII (1.8%), 12 isolates of serotype IV (0.7%), and 4 isolates that were untypable (0.2%) (Table 1).
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4.2. Geographic and monthly distribution
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Of the 1,736 isolates, 648 (37.3%) were recovered from patients in the northern region, 537 (31%) from patients in the central region, 316 (18.2%) from those in the
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northeastern region, 45 (2.6%) from those in the east region, and 190 (10.9%) from those in the southern region (Figure 1). The isolations dates of S. agalactiae as well as their relationship with temperature or rainfall were shown in Figure 2. These data suggested that human cases could be found all year round and the peak occurred more frequently during the rainy season, May–October of each year. 4.3. Clinical features of S. agalactiae infections As shown in Table 1, S. agalactiae isolates were recovered from 980 females (56.5%) and 756 males (43.5%). The bacterium was isolated from 54 (3.1%) young
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Journal Pre-proof children (≤ 5 y.o), 7 (0.4%) children (6-10 y.o), 47 (2.7%) old children (11-19 y.o), 916 (52.8%) adults (20-60 y.o), and 712 (41%) elderly (≥61 y.o), respectively. Of 1,736 cases, 847 (48.8%) had an underlying condition including alcoholism (n=23; 2.7%), cirrhosis (n=28; 3.3%), diabetes mellitus (n=581; 68.6%), and hypertension (n=215; 25.4%) as shown in Table 1. The mortality rate of S. agalactiae infections in our study was 11.6% (201 cases), with serotype III (49.7%; 100 cases) being the most common serotype for this outcome (Table 1).
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Of 1,736 cases, 1,394 (80.3%) cases had a complete diagnosis or clear clinical manifestations. Most of these patients had a urinary tract infection (UTI; n=417; 29.9%), followed by sepsis (n=287; 20.6%), infected diabetic foot/ulcer (n=157; 11.3%), septic
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arthritis (n=149; 10.7%), and meningitis (n=120; 8.6%), respectively (Table 1).
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As shown in Table 1, UTI cases (n=417) were mainly caused by serotype V
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isolates (n=143; 34.3%), followed by serotype III (n=97; 23.3%) and II (n=69; 16.5%). On the other hand, serotype III isolates were major causes of 76% sepsis (n=218/287),
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92% septic arthritia/arthritis (n= 137/149), and 95% meningitis (n=114/120), respectively.
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Infected diabetic foot/ulcer (n=157) was caused by serotype V isolates (n=55; 35%), followed by serotype II (n=33; 21%) and III (n=30; 19.1%), respectively. It is interesting
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that serotype V was the common serotype for UTI and infected diabetic foot/ulcer, whereas serotype III was the dominant serotype of sepsis, septic arthritis, and meningitis (Table 1). Correlations of serotypes and clinical presentation were shown in Table 2. Serotype III has a broad spectrum of diseases, it was strongly significantly correlated to meningitis, sepsis, and septic arthritis with a higher odds ratio (OR). Serotype V was significantly associated with meningitis, sepsis, and septic arthritis (p < 0.001) but this serotype had a very low odds ratio (Table 2). UTI showed possible correlation to serotype V (p = 0.005, OR = 2.32) as shown in Table 2. Both serotype III and serotype V was 5
Journal Pre-proof significantly associated with patients with diabetes mellitus (p < 0.001); however, serotype V (OR = 1.89) had a higher odds ratio to diabetes mellitus than did serotype III (OR = 0.36) as shown in Table 2. 5. Discussion We characterized humans S. agalactiae isolates throughout Thailand to reveal serotype distribution, demographic data, and clinical manifestations. A recent study in Thailand reported that serotype III (87.15%) was the most common serotype, followed by
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serotype Ia (5.24%) and V (3.81%), respectively (Kerdsin et al. 2017). In other studies, serotype III was the most frequent serotype isolated from humans in the USA (Ippolito et
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al. 2010), Sweden (GudjÓnsdÓttir et al. 1988), South Africa (Madzivhandila et al. 2011),
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Gabon (Belard et al. 2015), China (Lu et al. 2016), Taiwan (Wang et al. 2015), and Japan (Morozumi et al. 2014; Chang et al. 2014). Our study demonstrated that serotypes III and
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V were the most common serotypes in adults. In the Japanese study, serotype III and V
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were the common serotypes detected in all genders and age-groups, especially adults and the elderly (Morozumi et al. 2016). According to previous study, adults were the most
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commonly infected group by these serotypes compared to the other age-groups (Kerdsin
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et al. 2017). Other studies revealed that infants, pregnant women, or adults were mostly infected or colonized with serotype III or Ia (Madrid et al. 2017; Russell et al. 2017; Pinto et al. 2018). A trivalent conjugate vaccine (serotypes Ia/Ib/III) has completed phase 2 clinical trials, and a pentavalent vaccine (Ia/Ib/II/III/V) is in development (Seale et al. 2016). According to the serotype distribution in this study, coverage of the pentavalent vaccine is higher than that of the trivalent vaccine and the former would be a more promising vaccine for prevention of S. agalactiae infections in Thailand. A previous study demonstrated that 64.6% of patients had underlying medical conditions with diabetes in the majority (Chaiwarith et al. 2011). Concordant to our
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Journal Pre-proof study, diabetes mellitus (68.6%) was the main predisposing condition. A retrospective study in Thailand revealed mortality of S. agalactiae infections was 14.6% (Chaiwarith et al. 2011). In our study the mortality rate was 11.6%, with serotype III was the main serotype for mortality. The study in Japan indicated the mortality rate was 10.2% for all ages and was highest in patients with serotype VI (Morozumi et al. 2016). Most of patients in our study had a UTI followed by sepsis. These results were in contrast to the previous study in Thailand, where septicemia was the most common condition when S.
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agalactiae was detected, followed by meningitis and septic arthritis (Kerdsin et al. 2017; Chaiwarith et al. 2011). It seems that UTI is correlated to serotype V (p = 0.005, OR = 2.32) in this study. This was different from previous reports that revealed serotypes did
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not correlate significantly to clinical manifestations (Morozumi et al. 2016; Yoon et al.
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2015). Another study demonstrated that serotype III and V were more frequently isolated
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from UTI cases than from controls; especially serotypes III was the only type that was more frequently associated with acute disease than other serotypes (Ulett et al., 2009). In
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this study serotype V was more associated to UTI than other serotypes. Different capsular
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types might influence the development of UTI. In addition, age, gender, host susceptibility, and predisposing conditions may play as related factors contributing to
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UTI due to this serotype.
In the United States, the incidence of S. agalactiae disease in adults was 7.3 cases per 100,000 population in 2007 (Skoff et al. 2009). The incidence of invasive disease was approximately 7 cases per 100,000 nonpregnant adults, with the highest incidence among adults 65 years of age and older (20 to 25 cases per 100,000) (Farley 2001; Raabe and Shane, 2019). A systematic review estimated that the pooled incidence of invasive S. agalactiae disease in infants was 0.49 per 1,000 live births (95% confidence interval [CI], 0.43–0.56), and was highest in Africa (1.12) and lowest in Asia (0.30) (Madrid et al. 2017). The incidence of neonatal sepsis was 8.7 (95% CI; 7.0–10.8) cases per 1,000 live 5
Journal Pre-proof births in Portugal (Pinto et al. 2018). Although the incidence rate of invasive neonatal S. agalalctiae disease in Thailand was reported at 0.2 per 1,000 live births (Villanueva-Uy et al. 2015), the incidence rate of S. agalactiae infection in adults is still unknown. Therefore, epidemiological studies are necessary to further investigate the implication of infections caused by S. agalactiae and its serotypes as well as its genotypes i.e., sequence type, antibiotic susceptibility, and resistant genes. Noted that evidence on the impact of climate on human to bacterial infections is
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very limited. Our study revealed that peak of S. agalactiae human infected cases occurred during the rainy season (May-Oct) which has high humidity, compared with cold season (Dec-Feb) which has low humid in our study regions. Studies in Thailand also revealed
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the similarity that S. agalactiae infections including arthritis occurred between May and
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November, a rainy season (Chaiwarith et al., 2011; Louthrenoo et al., 2014; Ruksasakul
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et al., 2019). A study in Barcelona, Spain indicated that risks of GBS colonization was increased in higher ambient temperatures and humidity (Dadvand et al., 2001). Another
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study in Iran showed that invasive GBS infection commonly occurred in moist and cold
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weather (Shayanfar et al., 2012). In US, S. agalactiae infections in nonpregnant adults were more prevalent in a late summer (Phares et al., 2008). Reasons for seasonal
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variability of S. agalactiae infections are not yet understood, but environmental conditions such as humidity and temperature which could influence the growth, spread and virulence of S. agalactiae as well as the host defense mechanisms, might be possible factors. A limitation of this study was the usage of multiplex PCR to serotype S. agalactiae isolates which provides no information on the expression of capsule. Although, PCR or molecular serotyping assay could overcome the typing of nontypeable strains using antisera-based agglutination. Nonetheless, serotyping by antisera agglutination could reveal possible vaccine coverage or vaccine failures as well as planning for future 5
Journal Pre-proof vaccine development. We suggest that serotyping using the combination of antisera agglutination and multiplex PCR should be included in epidemiological and surveillance studies of S. agalactiae in order to correctly identify or to confirm their serotypes. Another limitation is the low-count bacteriuria of UTI cases used as exclusion criteria in this study. As low-count of bacteria in urine is sometimes associated with acute infection. A previous study reported that semi-quantitative bacteriuria counts were not useful in the differential diagnosis of UTI caused by S. agalactiae (Tan et al., 2012). A cut-off values
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commonly used such as ≥105 CFU/ml and ≥104 CFU/ml is insensitive for the diagnosis of acute UTI from S. agalactiae, therefore, cut-off of ≥103 CFU/ml might be appropriate (Tan et al., 2012).
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In conclusion, this study demonstrated that serotypes III and V were the most
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common serotypes isolated from S. agalactiae infections in adults in Thailand. Serotype
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III was significantly associated with a broad spectrum of diseases whereas serotype V was more associated with UTI than other serotypes. Physicians should aware of S.
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agalactiae infection in patients with underlying medical conditions such as diabetes
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mellitus who present meningitis septicemia, septic arthritis, and UTI.
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Ethical approval: This study was reviewed and approved by the Ethics Review Board (ERB) of the Ministry of Public Health, Thailand. The medical records were reviewed by attending physicians at the hospital using the clinical case record form approved by the ERB. The ERB waived requirement for informed consent as the study satisfied the conditions of the policy statement on ethical conduct for research involving humans. This study was conducted according to the principles expressed in the Declaration of Helsinki.
Conflict of Interest: The authors declare that they have no conflict of interest.
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Journal Pre-proof Funding: This work was supported by grants from Thailand MOPH-US CDC Collaboration, 2014-2016.
Author contributions Design the study: WP and AK Performed lab-work: WP and AK Statistics analysis: RU
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Wrote the manuscript: AK, WP, RU. All authors read and approved the manuscript.
Acknowledgements
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We would like to thank Dr. Charatdao Bunthi, Division of Global Health
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Protection, Thailand Ministry of Public Health–US Centers for Disease Control and
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Prevention Collaboration for critical review of manuscript and thank Kasetsart University
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Figure legends Figure 1. Study sites and distribution of Streptocoocus agalatiae serotypes in each region in Thailand.
Figure 2. Seasonal distribution of the cases, temperature, and rainfall from 2014 to 2016 in Thailand.
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Author Statements On behalf of all authors, I would like to statement the role of authors in the following; 1. Wantana
Paveenkittiporn:
Conceptualization,
Resource,
Investigation,
Methodology, Writing - original draft, and Writing - review & editing 2. Ratchadabhorn Ungcharoen: Methodology, Formal analysis
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3. Anusak Kerdsin: Conceptualization, Investigation, Methodology, Formal analysis,
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Writing - original draft, and Writing - review & editing
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Journal Pre-proof Table 1. S. agalactiae serotype distribution among isolates recovered from human patients in Thailand
1 1 4 55 35
6
6
2 26 23
5 134 103
31 4 22 414 334
1 8 3
8 1 8 200 148
70 26
39 18
137 111
408 397
9 3
216 149
10
34
100
1
36
74
41
195
619
11
300
14
6
19
86
29
42 8 44
1 21 3 32
6 6 112 32 92
14 15 149 117 510
1 5 184 36 139
11
4
1
3
33 7 3 6
30 6 12 3
1
1
114
69 1
97 2 9 1 5
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III
2
157 (11.3) 24 (1.7) 31 (2.2) 15 (1.1)
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Spondylodiscitis/Osteomyelitis
II
8
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Unknown Underlying conditions Alcoholism Cirrhosis Diabetes mellitus Hypertension None Type of Infection Skin and subcutaneous infection Infected diabetic ulcer Infected wound Cellulitis Necrotizing fasciitis CNS infection Meningitis Urinary reproductive system infection Urinary tract infection Urethritis Nephritis/pyelonephritis Vaginosis Pelvic inflammatory disease Bloodstream infection Sepsis Sepsis with focal sign Infective endocarditis Bone/joint infection Septic arthritis/Arthritis
Ib
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Alive
Serotype IV
Ia
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Age group (year) Young child (<5) Children (6-10) Old children (11-19) Adult (20-60) Elderly (>60) Sex Female Male Outcome Died
All (%) 1736 54 (3.1) 7 (0.4) 47 (2.7) 916 (52.8) 712 (41) 1736 980 (56.5) 756 (43.5) 1736 201 (11.6) 1366 (78.7) 169 (9.7) 1736 23 (1.3) 28 (1.6) 581 (33.5) 215 (12.4) 889 (51.2) 1394
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Characteristic
120 (8.6)
7 1 4
3 1
V
55 7 8 3 4
417 (29.9) 5 (0.4) 13 (0.9) 10 (0.7) 21 (1.5)
31 1 1 1 2
19
3
1 4
287 (20.6) 26 (1.9) 10 (0.7)
7 4
6 1 1
25 5 1
218 9 8
149 (10.7)
1
3
137
3
4
10
9
23 (1.6) 5
1
3
1
143 1 2 2 4
2
24 3
Journal Pre-proof Respiratory tract infection Pneumonia Bacteremic pneumonia Other Spontaneous bacterial peritonitis
45 (3.2) 29 (2.1)
6 1
1
15 3
12 13
1
6
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Underlying conditions
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Parameter
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Diabetes mellitus
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Hypertension
p-value, OR (95% CI)
Serotype III
serotype V
<0.001,
<0.001,
0.33 (0.25-0.44)
1.92 (1.46-2.51)
0.317
0.920
1.15 (0.87-1.51)
1.01 (0.77-1.34)
0.467,
0.943,
0.68 (0.24-1.91)
1.03 (0.39-2.71)
0.004,
0.005,
0.65 (0.48-0.87)
2.32 (1.09-4.91)
<0.001,
<0.001
5.56 (4.05-7.64)
0.27 (0.17-0.43)
<0.001,
<0.001,
26.72 (12.14-58.77)
0.13 (0.04-0.36)
<0.001,
<0.001,
22.79 (11.95-43.46)
0.07 (0.02-0.23)
Type of infections
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Infected diabetic ulcer
Urinary tract infection
Sepsis
Meningitis
Septic arthritis
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1 8 1
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12 (0.9)
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Journal Pre-proof Bacteremic pneumonia Table 2. Associati
0.401,
0.541,
1.39 (0.63-3.06)
1.30 (0.56-3.04)
0.217,
0.217,
0.49 (0.16-1.50)
0.39 (0.08-1.73)
Pneumonia
on between
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S. agalactiae serotype III and V and clinical manifestations
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Figure 1
Figure 2
Wantana Paveenkittiporn, Ratchadabhorn Ungcharoen, Anusak Kerdsin PII:
S0732-8893(19)31119-8
DOI:
https://doi.org/10.1016/j.diagmicrobio.2020.115005
Reference:
DMB 115005
To appear in:
Diagnostic Microbiology & Infectious Disease
Received date:
8 November 2019
Revised date:
2 January 2020
Accepted date:
26 January 2020
Please cite this article as: W. Paveenkittiporn, R. Ungcharoen and A. Kerdsin, Streptococcus agalactiae infections and clinical relevance in adults, Thailand, Diagnostic Microbiology & Infectious Disease(2020), https://doi.org/10.1016/ j.diagmicrobio.2020.115005
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© 2020 Published by Elsevier.
Journal Pre-proof
Streptococcus agalactiae infections and clinical relevance in adults, Thailand
Wantana Paveenkittiporna, Ratchadabhorn Ungcharoen b, Anusak Kerdsin b*
a
National Institute of Health, Department of Medical Sciences, Ministry of Public Health,
Thailand Faculty of Public Health, Kasetsart University Chalermphrakiat Sakon Nakhon Province
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b
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Campus, Sakon Nakhon, Thailand
*Correspondence: Anusak Kerdsin, Faculty of Public Health, Kasetsart University
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Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon 47000, Thailand,
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Email: [email protected]
Running title: S. agalactiae infection in Thailand
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Type of Article: Original Article
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Keywords: Streptococcus agalactiae; Group B streptococcus; Serotype; Sepsis; Urinary tract infection (UTI)
Word count of text: 2,391
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Journal Pre-proof Abstract Streptococcus agalactiae is an important pathogen that causes infections in neonates and adults especially infections in nonpregnant adults is increasing worldwide. Of 1,736 S. agalactiae isolates from individual throughout Thailand demonstrated that serotypes III (46.4%) and V (21%) were the most common serotypes. Human cases (56.5% female and 43.5% male) could be found all year round with the peak occurring more frequently during the rainy season (May–October). The mortality rate of S. agalactiae infections
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was 11.6% and serotype III was the most common serotype involved. Serotype III was strongly significantly (p-value <0.001) correlated with meningitis (odds ratio; OR = 26.72), sepsis (OR = 5.56), and septic arthritis (OR = 22.79). Serotype V was more
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associated with urinary tract infection than other serotypes. (p-value 0.005; OR = 2.32).
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Word count: 128
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Journal Pre-proof 1. Background Streptococcus agalactiae or Lancefield group B Streptococcus (GBS) is an important pathogen that causes infections in neonates and adults. The most common clinical manifestations of S. agalactiae in neonatal infection are meningitis and sepsis which are in contrast to the main clinical manifestations in adults such as bacteremia, soft tissue infection, and pneumonia (Morozumi et al. 2016). S. agalactiae isolates can be classified into 10 different serotypes (Ia, Ib, and II to IX), with serotypes Ia, II, III, and V
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being the predominant causes of human diseases (Imperi et al. 2012). In particular, the serotypes Ia, III, and V most commonly cause neonatal infections, with serotype III being the main serotype recovered from patients of all age groups, including nonpregnant adults
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(Kerdsin et al. 2017; Ippolito et al. 2010; Madrid et al. 2017; Farley 2001).
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The epidemiology of S. agalactiae disease has been well described in high-
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income contexts but less well studied in low- to middle-income contexts (Madrid et al., 2017). Rates of maternal invasive S. agalactiae infections in the US vary by States, with
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rates ranging from 0.1 per 1,000 deliveries to 0.8 per 1,000 deliveries, while nonpregnant
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adults, incidence was from 3.6 cases/100,000 persons in 1990 to 7.3 cases/100,000 persons in 2007, based on surveillance in 10 US States (Raabe and Shane, 2019).
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Invasive S. agalactiae annually affects 25 per 100,000 adults ages 65 and older in the US (Raabe and Shane, 2019). The yearly cost of delivery and treatment of newborns with GBS infection was $41,875±6,823 (El Helali et al., 2019). In UK, the economic cost of S. agalactiae infections in infants was £6,144.7 higher among cases than among non-S. agalactiae controls (Schroeder et al., 2009). S. agalactiae infections are increasing, particularly in elderly persons with underlying diseases such as diabetes, cardiovascular disease, and cancer (Farley 2001). In this study, we characterized 1,736 S. agalactiae isolates from an individual patient throughout Thailand to reveal serotype distribution, demographic data, and clinical manifestations in adults. 5
Journal Pre-proof 2. Objectives The aim of this study was to characterize 1,736 S. agalactiae isolates throughout Thailand to reveal serotype distribution, demographic data, and clinical manifestations in adults. 3. Study design 3.1. Bacterial isolates, identification and serotyping In total, 1,736 S. agalactiae isolates from individual case were characterized in
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this study and were collected from 25 tertiary hospitals located in the North (n=6), Northeast (n=6), East (n=3), South (n=5), and Central (n=5) Thailand during January
prospective study) as shown in Figure 1.
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2014 to June 2016 under the Vaccine Preventable Infections Surveillance Program (a
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Conventional biochemical tests described elsewhere were used to confirm S.
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agalactiae identification (Facklam 2002). Briefly, the organisms were cultured on sheep blood agar for 18-24 hours at 37 oC plus 5% CO2 and then tested for Gram’s stain,
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catalase production, bacitracin susceptibility, CAMP reaction, hippurate hydrolysis,
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Voges-Proskauer reaction, arginine deamination, esculin hydrolysis, starch hydrolysis, and production of acid in sorbitol and trehalose (Facklam 2002). Species identification
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was interpreted using the identification key/table described elsewhere (Facklam 2002). In addition, S. agalactiae isolates were confirmed using multiplex PCR as previously described (Kerdsin et al. 2017). All S. agalactiae isolates recovered in this study were initially serotyped using a PCR assay, as described by elsewhere (Imperi et al. 2010). 3.2. Human cases and statistical analyses The complete medical records of 1,394 cases were reviewed by the physicians in charge. Any incomplete or unavailable medical records were excluded in this study. The clinical manifestations of S. agalactiae infections were divided into seven categories: 5
Journal Pre-proof skin infections, central nervous system infections, urinary-reproductive system infections, bone/joint infections, blood infection, respiratory tract infections, and other (Table 1). The case definitions of these clinical presentations were determined according to criteria described elsewhere (Musher & Thorner, 2014; Kerdsin et al., 2018; Kranz et al., 2018; Ramakrishnan et al., 2015). Correlation of the clinical characteristics and serotypes were analyzed using the Logistic regression in the Stata version 12.0 software (StataCorp, College Station, TX, USA). Data were considered significant at p < 0.001.
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4. Results 4.1. Serotype distribution of S. agalactiae isolates
Of the 1,736 isolates, multiplex PCR revealed 805 isolates of serotype III (46.4%),
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365 isolates of serotype V (21%), 248 isolates of serotype II (14.3%), 118 isolates of
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serotype VI (6.8%), 96 isolates of serotype Ia (5.5%), 57 isolates of serotype Ib (3.3%),
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31 isolates of serotype VII (1.8%), 12 isolates of serotype IV (0.7%), and 4 isolates that were untypable (0.2%) (Table 1).
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4.2. Geographic and monthly distribution
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Of the 1,736 isolates, 648 (37.3%) were recovered from patients in the northern region, 537 (31%) from patients in the central region, 316 (18.2%) from those in the
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northeastern region, 45 (2.6%) from those in the east region, and 190 (10.9%) from those in the southern region (Figure 1). The isolations dates of S. agalactiae as well as their relationship with temperature or rainfall were shown in Figure 2. These data suggested that human cases could be found all year round and the peak occurred more frequently during the rainy season, May–October of each year. 4.3. Clinical features of S. agalactiae infections As shown in Table 1, S. agalactiae isolates were recovered from 980 females (56.5%) and 756 males (43.5%). The bacterium was isolated from 54 (3.1%) young
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Journal Pre-proof children (≤ 5 y.o), 7 (0.4%) children (6-10 y.o), 47 (2.7%) old children (11-19 y.o), 916 (52.8%) adults (20-60 y.o), and 712 (41%) elderly (≥61 y.o), respectively. Of 1,736 cases, 847 (48.8%) had an underlying condition including alcoholism (n=23; 2.7%), cirrhosis (n=28; 3.3%), diabetes mellitus (n=581; 68.6%), and hypertension (n=215; 25.4%) as shown in Table 1. The mortality rate of S. agalactiae infections in our study was 11.6% (201 cases), with serotype III (49.7%; 100 cases) being the most common serotype for this outcome (Table 1).
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Of 1,736 cases, 1,394 (80.3%) cases had a complete diagnosis or clear clinical manifestations. Most of these patients had a urinary tract infection (UTI; n=417; 29.9%), followed by sepsis (n=287; 20.6%), infected diabetic foot/ulcer (n=157; 11.3%), septic
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arthritis (n=149; 10.7%), and meningitis (n=120; 8.6%), respectively (Table 1).
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As shown in Table 1, UTI cases (n=417) were mainly caused by serotype V
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isolates (n=143; 34.3%), followed by serotype III (n=97; 23.3%) and II (n=69; 16.5%). On the other hand, serotype III isolates were major causes of 76% sepsis (n=218/287),
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92% septic arthritia/arthritis (n= 137/149), and 95% meningitis (n=114/120), respectively.
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Infected diabetic foot/ulcer (n=157) was caused by serotype V isolates (n=55; 35%), followed by serotype II (n=33; 21%) and III (n=30; 19.1%), respectively. It is interesting
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that serotype V was the common serotype for UTI and infected diabetic foot/ulcer, whereas serotype III was the dominant serotype of sepsis, septic arthritis, and meningitis (Table 1). Correlations of serotypes and clinical presentation were shown in Table 2. Serotype III has a broad spectrum of diseases, it was strongly significantly correlated to meningitis, sepsis, and septic arthritis with a higher odds ratio (OR). Serotype V was significantly associated with meningitis, sepsis, and septic arthritis (p < 0.001) but this serotype had a very low odds ratio (Table 2). UTI showed possible correlation to serotype V (p = 0.005, OR = 2.32) as shown in Table 2. Both serotype III and serotype V was 5
Journal Pre-proof significantly associated with patients with diabetes mellitus (p < 0.001); however, serotype V (OR = 1.89) had a higher odds ratio to diabetes mellitus than did serotype III (OR = 0.36) as shown in Table 2. 5. Discussion We characterized humans S. agalactiae isolates throughout Thailand to reveal serotype distribution, demographic data, and clinical manifestations. A recent study in Thailand reported that serotype III (87.15%) was the most common serotype, followed by
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serotype Ia (5.24%) and V (3.81%), respectively (Kerdsin et al. 2017). In other studies, serotype III was the most frequent serotype isolated from humans in the USA (Ippolito et
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al. 2010), Sweden (GudjÓnsdÓttir et al. 1988), South Africa (Madzivhandila et al. 2011),
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Gabon (Belard et al. 2015), China (Lu et al. 2016), Taiwan (Wang et al. 2015), and Japan (Morozumi et al. 2014; Chang et al. 2014). Our study demonstrated that serotypes III and
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V were the most common serotypes in adults. In the Japanese study, serotype III and V
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were the common serotypes detected in all genders and age-groups, especially adults and the elderly (Morozumi et al. 2016). According to previous study, adults were the most
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commonly infected group by these serotypes compared to the other age-groups (Kerdsin
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et al. 2017). Other studies revealed that infants, pregnant women, or adults were mostly infected or colonized with serotype III or Ia (Madrid et al. 2017; Russell et al. 2017; Pinto et al. 2018). A trivalent conjugate vaccine (serotypes Ia/Ib/III) has completed phase 2 clinical trials, and a pentavalent vaccine (Ia/Ib/II/III/V) is in development (Seale et al. 2016). According to the serotype distribution in this study, coverage of the pentavalent vaccine is higher than that of the trivalent vaccine and the former would be a more promising vaccine for prevention of S. agalactiae infections in Thailand. A previous study demonstrated that 64.6% of patients had underlying medical conditions with diabetes in the majority (Chaiwarith et al. 2011). Concordant to our
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Journal Pre-proof study, diabetes mellitus (68.6%) was the main predisposing condition. A retrospective study in Thailand revealed mortality of S. agalactiae infections was 14.6% (Chaiwarith et al. 2011). In our study the mortality rate was 11.6%, with serotype III was the main serotype for mortality. The study in Japan indicated the mortality rate was 10.2% for all ages and was highest in patients with serotype VI (Morozumi et al. 2016). Most of patients in our study had a UTI followed by sepsis. These results were in contrast to the previous study in Thailand, where septicemia was the most common condition when S.
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agalactiae was detected, followed by meningitis and septic arthritis (Kerdsin et al. 2017; Chaiwarith et al. 2011). It seems that UTI is correlated to serotype V (p = 0.005, OR = 2.32) in this study. This was different from previous reports that revealed serotypes did
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not correlate significantly to clinical manifestations (Morozumi et al. 2016; Yoon et al.
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2015). Another study demonstrated that serotype III and V were more frequently isolated
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from UTI cases than from controls; especially serotypes III was the only type that was more frequently associated with acute disease than other serotypes (Ulett et al., 2009). In
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this study serotype V was more associated to UTI than other serotypes. Different capsular
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types might influence the development of UTI. In addition, age, gender, host susceptibility, and predisposing conditions may play as related factors contributing to
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UTI due to this serotype.
In the United States, the incidence of S. agalactiae disease in adults was 7.3 cases per 100,000 population in 2007 (Skoff et al. 2009). The incidence of invasive disease was approximately 7 cases per 100,000 nonpregnant adults, with the highest incidence among adults 65 years of age and older (20 to 25 cases per 100,000) (Farley 2001; Raabe and Shane, 2019). A systematic review estimated that the pooled incidence of invasive S. agalactiae disease in infants was 0.49 per 1,000 live births (95% confidence interval [CI], 0.43–0.56), and was highest in Africa (1.12) and lowest in Asia (0.30) (Madrid et al. 2017). The incidence of neonatal sepsis was 8.7 (95% CI; 7.0–10.8) cases per 1,000 live 5
Journal Pre-proof births in Portugal (Pinto et al. 2018). Although the incidence rate of invasive neonatal S. agalalctiae disease in Thailand was reported at 0.2 per 1,000 live births (Villanueva-Uy et al. 2015), the incidence rate of S. agalactiae infection in adults is still unknown. Therefore, epidemiological studies are necessary to further investigate the implication of infections caused by S. agalactiae and its serotypes as well as its genotypes i.e., sequence type, antibiotic susceptibility, and resistant genes. Noted that evidence on the impact of climate on human to bacterial infections is
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very limited. Our study revealed that peak of S. agalactiae human infected cases occurred during the rainy season (May-Oct) which has high humidity, compared with cold season (Dec-Feb) which has low humid in our study regions. Studies in Thailand also revealed
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the similarity that S. agalactiae infections including arthritis occurred between May and
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November, a rainy season (Chaiwarith et al., 2011; Louthrenoo et al., 2014; Ruksasakul
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et al., 2019). A study in Barcelona, Spain indicated that risks of GBS colonization was increased in higher ambient temperatures and humidity (Dadvand et al., 2001). Another
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study in Iran showed that invasive GBS infection commonly occurred in moist and cold
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weather (Shayanfar et al., 2012). In US, S. agalactiae infections in nonpregnant adults were more prevalent in a late summer (Phares et al., 2008). Reasons for seasonal
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variability of S. agalactiae infections are not yet understood, but environmental conditions such as humidity and temperature which could influence the growth, spread and virulence of S. agalactiae as well as the host defense mechanisms, might be possible factors. A limitation of this study was the usage of multiplex PCR to serotype S. agalactiae isolates which provides no information on the expression of capsule. Although, PCR or molecular serotyping assay could overcome the typing of nontypeable strains using antisera-based agglutination. Nonetheless, serotyping by antisera agglutination could reveal possible vaccine coverage or vaccine failures as well as planning for future 5
Journal Pre-proof vaccine development. We suggest that serotyping using the combination of antisera agglutination and multiplex PCR should be included in epidemiological and surveillance studies of S. agalactiae in order to correctly identify or to confirm their serotypes. Another limitation is the low-count bacteriuria of UTI cases used as exclusion criteria in this study. As low-count of bacteria in urine is sometimes associated with acute infection. A previous study reported that semi-quantitative bacteriuria counts were not useful in the differential diagnosis of UTI caused by S. agalactiae (Tan et al., 2012). A cut-off values
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commonly used such as ≥105 CFU/ml and ≥104 CFU/ml is insensitive for the diagnosis of acute UTI from S. agalactiae, therefore, cut-off of ≥103 CFU/ml might be appropriate (Tan et al., 2012).
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In conclusion, this study demonstrated that serotypes III and V were the most
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common serotypes isolated from S. agalactiae infections in adults in Thailand. Serotype
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III was significantly associated with a broad spectrum of diseases whereas serotype V was more associated with UTI than other serotypes. Physicians should aware of S.
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agalactiae infection in patients with underlying medical conditions such as diabetes
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mellitus who present meningitis septicemia, septic arthritis, and UTI.
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Ethical approval: This study was reviewed and approved by the Ethics Review Board (ERB) of the Ministry of Public Health, Thailand. The medical records were reviewed by attending physicians at the hospital using the clinical case record form approved by the ERB. The ERB waived requirement for informed consent as the study satisfied the conditions of the policy statement on ethical conduct for research involving humans. This study was conducted according to the principles expressed in the Declaration of Helsinki.
Conflict of Interest: The authors declare that they have no conflict of interest.
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Journal Pre-proof Funding: This work was supported by grants from Thailand MOPH-US CDC Collaboration, 2014-2016.
Author contributions Design the study: WP and AK Performed lab-work: WP and AK Statistics analysis: RU
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Wrote the manuscript: AK, WP, RU. All authors read and approved the manuscript.
Acknowledgements
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We would like to thank Dr. Charatdao Bunthi, Division of Global Health
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Protection, Thailand Ministry of Public Health–US Centers for Disease Control and
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Prevention Collaboration for critical review of manuscript and thank Kasetsart University
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Figure legends Figure 1. Study sites and distribution of Streptocoocus agalatiae serotypes in each region in Thailand.
Figure 2. Seasonal distribution of the cases, temperature, and rainfall from 2014 to 2016 in Thailand.
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Journal Pre-proof
Author Statements On behalf of all authors, I would like to statement the role of authors in the following; 1. Wantana
Paveenkittiporn:
Conceptualization,
Resource,
Investigation,
Methodology, Writing - original draft, and Writing - review & editing 2. Ratchadabhorn Ungcharoen: Methodology, Formal analysis
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3. Anusak Kerdsin: Conceptualization, Investigation, Methodology, Formal analysis,
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Writing - original draft, and Writing - review & editing
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Journal Pre-proof Table 1. S. agalactiae serotype distribution among isolates recovered from human patients in Thailand
1 1 4 55 35
6
6
2 26 23
5 134 103
31 4 22 414 334
1 8 3
8 1 8 200 148
70 26
39 18
137 111
408 397
9 3
216 149
10
34
100
1
36
74
41
195
619
11
300
14
6
19
86
29
42 8 44
1 21 3 32
6 6 112 32 92
14 15 149 117 510
1 5 184 36 139
11
4
1
3
33 7 3 6
30 6 12 3
1
1
114
69 1
97 2 9 1 5
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III
2
157 (11.3) 24 (1.7) 31 (2.2) 15 (1.1)
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Spondylodiscitis/Osteomyelitis
II
8
na
Unknown Underlying conditions Alcoholism Cirrhosis Diabetes mellitus Hypertension None Type of Infection Skin and subcutaneous infection Infected diabetic ulcer Infected wound Cellulitis Necrotizing fasciitis CNS infection Meningitis Urinary reproductive system infection Urinary tract infection Urethritis Nephritis/pyelonephritis Vaginosis Pelvic inflammatory disease Bloodstream infection Sepsis Sepsis with focal sign Infective endocarditis Bone/joint infection Septic arthritis/Arthritis
Ib
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Alive
Serotype IV
Ia
re
Age group (year) Young child (<5) Children (6-10) Old children (11-19) Adult (20-60) Elderly (>60) Sex Female Male Outcome Died
All (%) 1736 54 (3.1) 7 (0.4) 47 (2.7) 916 (52.8) 712 (41) 1736 980 (56.5) 756 (43.5) 1736 201 (11.6) 1366 (78.7) 169 (9.7) 1736 23 (1.3) 28 (1.6) 581 (33.5) 215 (12.4) 889 (51.2) 1394
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Characteristic
120 (8.6)
7 1 4
3 1
V
55 7 8 3 4
417 (29.9) 5 (0.4) 13 (0.9) 10 (0.7) 21 (1.5)
31 1 1 1 2
19
3
1 4
287 (20.6) 26 (1.9) 10 (0.7)
7 4
6 1 1
25 5 1
218 9 8
149 (10.7)
1
3
137
3
4
10
9
23 (1.6) 5
1
3
1
143 1 2 2 4
2
24 3
Journal Pre-proof Respiratory tract infection Pneumonia Bacteremic pneumonia Other Spontaneous bacterial peritonitis
45 (3.2) 29 (2.1)
6 1
1
15 3
12 13
1
6
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Underlying conditions
re
Parameter
na
Diabetes mellitus
ur
Hypertension
p-value, OR (95% CI)
Serotype III
serotype V
<0.001,
<0.001,
0.33 (0.25-0.44)
1.92 (1.46-2.51)
0.317
0.920
1.15 (0.87-1.51)
1.01 (0.77-1.34)
0.467,
0.943,
0.68 (0.24-1.91)
1.03 (0.39-2.71)
0.004,
0.005,
0.65 (0.48-0.87)
2.32 (1.09-4.91)
<0.001,
<0.001
5.56 (4.05-7.64)
0.27 (0.17-0.43)
<0.001,
<0.001,
26.72 (12.14-58.77)
0.13 (0.04-0.36)
<0.001,
<0.001,
22.79 (11.95-43.46)
0.07 (0.02-0.23)
Type of infections
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Infected diabetic ulcer
Urinary tract infection
Sepsis
Meningitis
Septic arthritis
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1 8 1
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12 (0.9)
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Journal Pre-proof Bacteremic pneumonia Table 2. Associati
0.401,
0.541,
1.39 (0.63-3.06)
1.30 (0.56-3.04)
0.217,
0.217,
0.49 (0.16-1.50)
0.39 (0.08-1.73)
Pneumonia
on between
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S. agalactiae serotype III and V and clinical manifestations
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Figure 1
Figure 2