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Lyme borreliosis (LB), the most common tick-borne disease in Europe, is endemic to southern coastal Norway. LB commonly presents as erythema migrans, which can disseminate, resulting in more severe disease such as Lyme neuroborreliosis or arthritis. In Norway, public health LB surveillance is conducted via mandatory reporting of laboratory-confirmed disseminated cases. From 2012 to 2022, Norway's surveillance-reported incidence of laboratory-confirmed disseminated LB increased by 78%. Although surveillance provides estimates of the incidence of disseminated LB, this study sought to estimate the incidence of symptomatic LB to better understand Norway's LB disease burden. Two studies were identified that, when combined, estimated an LB seroprevalence of 6.8% in the general adult population in southern Norway. Utilizing data from these seroprevalence studies, public health surveillance, and results from literature searches indicating that 37% of seroconverted LB cases are symptomatic and that the duration of LB antibody detection ranges from 10 to 20 years, we estimated that there were 315-630 symptomatic LB cases per 100,000 adult population in five southern coastal counties in Norway in 2022 and 24-48 cases of symptomatic LB for every public health surveillance-reported LB case in adults in these five counties in Norway., (© 2024 The Author(s). APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

lyme disease (LD) is the most common vector-borne disease in the United States, with 476,000 cases estimated each year. It is unclear how LD risk factors vary by residential setting. We conducted a case-control study on LD risk by rural, urban, and suburban residential settings. Individuals from 15 high-incidence states and the District of Columbia in the Optum Research Database were identified as cases (LD medical claim) or controls (no LD medical claim, matched by county of residence and census block group population density). Participants were surveyed about LD history, outdoor activities, and residential characteristics. The final analytic dataset had 750 LD cases and 965 controls. Residence in a rural setting had increased LD risk (OR 1.41, 95% CI 1.16, 1.72). In multivariable analyses, activities associated with LD were hiking/walking/running or having an occupation in forests, wooded areas, or areas of tall grass (all respondents), and spending time in a yard (rural and urban residents only). Public health interventions can help prevent LD in high-incidence jurisdictions by reinforcing the nearuniversal LD risk for rural residents, and highlighting activities that lead to increased LD risk for those in areas with less ubiquitous tick exposure like in urban and suburban settings., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Objectives: To better understand the Lyme borreliosis (LB) burden in Europe, we aimed to estimate the incidence of symptomatic Borrelia burgdorferi sensu lato (Bbsl) infections after adjusting public health LB surveillance data for under-detection of symptomatic Bbsl infections., Methods: Data from seroprevalence studies and estimates of the symptomatic proportion and duration of antibody detection in Bbsl-infected individuals, derived from reviews of the published literature, were used to adjust public health LB surveillance data to estimate the incidence of symptomatic Bbsl infection in nine European countries from 2018-2022., Results: The prevalence of anti-Bbsl antibodies ranged from 2.3% in Romania to 9.4% in Germany. Under-detection multipliers varied across surveillance systems; using 10-year duration of antibody detection, multipliers were 2.4-10.5 in countries reporting all LB cases and 54.6-722.2 in countries reporting only Lyme neuroborreliosis cases. The incidence of symptomatic Bbsl infection adjusted for under-detection was highest in Finland, Germany, Norway, Poland, and Switzerland, intermediate in the Czech Republic and Denmark, and lowest in Ireland and Romania., Conclusions: Adjustment of LB surveillance for under-detection found a high incidence of symptomatic Bbsl infection in several European countries. Differences in LB surveillance systems should be considered when comparing surveillance data between countries and when estimating LB disease burden., Competing Interests: Declaration of competing interest Frederick J. Angulo, Gordon Brestrich, Emily Colby, Andrew Vyse, L. Hannah Gould, Kate Halsby, Patrick H. Kelly, Jennifer C. Moïsi, Andreas Pilz, Madiha Shafquat, and James H. Stark are employees of Pfizer and may hold stock or stock options. Per-Eric Lindgren has been an external scientific advisor to Valneva, Pfizer, and Bavarian-Nordic A/S., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Lyme borreliosis (LB), caused by Borrelia burgdorferi sensu lato (Bbsl), is the most common tick-borne disease in Europe. Although public health surveillance for LB has been conducted in Romania since 2007, the extent of under-detection of Bbsl infections by LB surveillance has not been estimated. We therefore estimated the under-detection of symptomatic Bbsl infections by LB surveillance to better understand the LB burden in Romania., Methods: The number of incident symptomatic Bbsl infections were estimated from a seroprevalence study conducted in six counties (population 2.3 M) and estimates of the symptomatic proportion and duration of persistence of anti-Bbsl immunoglobulin G (IgG) antibodies. The number of incident symptomatic Bbsl infections were compared with the number of surveillance-reported LB cases to derive an under-detection multiplier, and then the under-detection multiplier was applied to LB surveillance data to estimate the incidence of symptomatic Bbsl infection from 2018 to 2023., Results: We estimate that there were 1968 individuals with incident symptomatic Bbsl infection in the six counties where the seroprevalence study was conducted in 2020, compared with the 187 surveillance-reported LB cases, resulting in an under-detection multiplier of 10.5 (i.e., for every surveillance-reported LB case, there were 10.5 symptomatic incident Bbsl infections). The incidence of symptomatic Bbsl infection in the six counties was 86.9/100,000 population in 2023, similar to the incidence in 2018-2020 (86.0) and higher than in 2021-2022 (40.3)., Conclusions: There is a higher incidence of symptomatic Bbsl infection than is reported through public health surveillance for LB in Romania. Additional efforts are needed to strengthen disease prevention and address the important public health problem of LB., (© 2024. The Author(s).)

Background: Tick-borne encephalitis (TBE) is caused by the tick-borne encephalitis virus (TBEV). TBEV infection can cause symptoms of central nervous system (CNS) inflammation and result in severe consequences including death. TBE is an increasing health threat in the Czech Republic and elsewhere in Europe. In 2020, 23% of 3734 TBE cases reported to the European Centre for Disease Prevention and Control were from the Czech Republic. TBE vaccination is universally recommended in the Czech Republic, but a full analysis of TBE vaccine effectiveness (VE) in the Czech Republic has not been published. Methods: TBE is a notifiable disease in the Czech Republic with mandatory reporting of cases ( i.e., laboratory-confirmed TBEV infected patient with symptoms of CNS inflammation) and vaccination history to public health authorities. TBE VE was estimated using the screening method utilizing public health surveillance data from 2018 to 2022 and online household surveys of the general population on TBE vaccine uptake conducted in 2019-2022. Results: In 2018-2022, 3648 TBE cases were reported in the Czech Republic; 98.1% (3105/3166) of TBE cases with known vaccination history were unvaccinated. Among 42,671 persons surveyed from the general population who had known TBE vaccination history, 66.5% were unvaccinated. VE against TBE was 97.6% (95% confidence interval 95.7-98.7). When stratified by age group, VE was 97.1% (88.4-99.3) in 1-15 years of age, 97.9% (95.3-99.0) in 16-59 years of age, and 96.9% (90.5-99.0) in ≥60 years of age. TBE vaccination averted an estimated 1020 TBE cases in the Czech Republic from 2018 to 2022. Conclusions: This first published study with a full analysis of TBE VE in the Czech Republic showed that vaccination was highly effective for the prevention of TBE including in children, an age group with increasing TBE disease burden. Vaccination averted hundreds of TBE cases and hospitalizations despite the relatively low compliance with TBE vaccine recommendations. To prevent additional TBE cases in the Czech Republic, enhanced efforts to increase TBE vaccine uptake are needed.

The European Centre for Disease Prevention and Control (ECDC) defines a case of tick-borne encephalitis (TBE) as an infection by the TBE virus (TBEV) with clinical manifestations of central nervous system inflammation (e.g., meningitis, encephalitis). To better understand the TBE surveillance landscape, online searches were conducted to determine if cases of TBE, TBEV infection, acute meningitis or encephalitis, or viral meningitis or encephalitis were subject to statutory reporting in European countries in 2023. In countries with statutory reporting, notification responsibility and available information on surveillance-reported cases were determined. The number of TBE cases reported to ECDC were compared with the number of cases recorded in national surveillance reports. Of 44 countries of the Europe Region of the United Nations, 37 (84 %) mandated statutory reporting of cases of TBE, TBEV infection, or acute/viral meningitis/encephalitis. Twenty-six (87 %) of 30 countries with identified surveillance reports recorded TBE cases in 2020-2023. Of these countries, 17 (65 %) required TBE reporting by clinicians and laboratories, 5 (19 %) by clinicians only, and 4 (15 %) by laboratories only. Twenty-four countries reported on TBE cases to ECDC in 2020; however, surveillance for TBE in Europe is heterogeneous. Standardization of TBE surveillance would enhance the understanding of TBE disease burden in Europe., Competing Interests: Declaration of competing interest Frederick J. Angulo, Kate Halsby, Alexander Davidson, Andreas Pilz, James H. Stark, and Jennifer C. Moïsi are employees of Pfizer and may hold stocks or stock options., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Borrelia burgdorferi sensu lato (Bb) are a complex of bacteria genospecies that can cause Lyme disease (LD) in humans after the bite of an infected Ixodes spp. vector tick. In Canada, incidence of LD is increasing in part due to the rapid geographic expansion of Ixodes scapularis across the southcentral and eastern provinces. To better understand temporal and spatial (provincial) prevalence of Bb infection of I. scapularis and how tick surveillance is utilized in Canada to assess LD risk, a literature review was conducted. Tick surveillance studies published between January 1975 to November 2023, that measured the prevalence of Bb in I. scapularis via "passive surveillance" from the public citizenry or "active surveillance" by drag or flag sampling of host-seeking ticks in Canada were included for review. Meta-analyses were conducted via random effects modeling. Forty-seven articles, yielding 26 passive and 28 active surveillance studies, met inclusion criteria. Mean durations of collection for I. scapularis were 2.1 years in active surveillance studies (1999-2020) and 5.5 years by passive surveillance studies (1990-2020). Collectively, data were extracted on 99,528 I. scapularis nymphs and adults collected between 1990-2020 across nine provinces, including Newfoundland & Labrador (33 ticks) and Alberta (208 ticks). More studies were conducted in Ontario (36) than any other province. Across nine provinces, the prevalence of Bb infection in I. scapularis collected by passive surveillance was 14.6% with the highest prevalence in Nova Scotia at 20.5% (minimum studies >1). Among host-seeking I. scapularis collected via active surveillance, Bb infection prevalence was 10.5% in nymphs, 31.9% in adults, and 23.8% across both life stages. Host-seeking I. scapularis nymphs and adults from Ontario had the highest Bb prevalence at 13.6% and 34.8%, respectively. Between 2007-2019, Bb infection prevalence in host-seeking I. scapularis was positively associated over time (p<0.001) which is concurrent with a ∼25-fold increase in the number of annually reported LD cases in Canada over the same period. The prevalence of Bb-infection in I. scapularis has rapidly increased over three decades as reported by tick surveillance studies in Canada which coincides with increasing human incidence for LD. The wide-ranging distribution and variable prevalence of Bb-infected I. scapularis ticks across provinces demonstrates the growing need for long-term standardized tick surveillance to monitor the changing trends in I. scapularis populations and best define LD risk areas in Canada., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PHK, YT, QY, MS, AD, MM, AG, KH, FJA, JM and JHS are employees of Pfizer and may hold shares and/or stock options in the company. The other authors have no potential conflict of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Clostridioides difficile infection (CDI) is an important cause of morbidity and mortality worldwide. Data from public health surveillance systems are important for estimating country-level CDI burden. CDI surveillance can be population-based or hospital-based. Population-based surveillance results in overall estimates of CDI incidence (cases per 100,000 population-per-year), and hospital-based surveillance results in estimates of hospital-based CDI incidence (cases per 10,000 patient-days) or CDI admission rates (cases per 1,000 admissions). We sought to better understand temporal trends in CDI incidence reported in publicly available surveillance data worldwide and describe varying surveillance methods. We identified 13 countries in Europe, North America, and Oceania with publicly available population-based and/or hospital-based CDI surveillance data in online reports and/or dashboards. Additional countries in Europe, in particular, also conduct hospital-based CDI surveillance. Inconsistent CDI case definitions and surveillance approaches between countries limit the interpretability of multi-country comparisons. Nonetheless, publicly available CDI surveillance data enabled us to compare CDI incidence among countries with population-based and/or hospital-based surveillance systems and to describe trends in CDI incidence within countries over time. The highest CDI incidence is in the United States. While there have been recent declines in CDI incidence in all countries, the CDI burden remains high, and the need persists for CDI prevention strategies in communities and healthcare settings., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Frederick J. Angulo, Melissa Furtado, Elisa Gonzalez, Pingping Zhang, Patrick H. Kelly, and Jennifer C. Moïsi are employees of Pfizer and hold stock and stock options in Pfizer Inc., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Lyme disease (LD), caused by the spirochete Borrelia burgdorferi, is the most common vector-borne disease in the United States. Although most surveillance-reported cases are in people who are White, data suggest worse outcomes among people from racial and ethnic minority groups., Methods: We conducted a systematic literature review to describe racial disparities in LD. We described the epidemiology of LD by race and ethnicity, including clinical presentation at diagnosis, and summarised the literature on knowledge, attitudes and practices related to LD and ticks by race and ethnicity., Results: Overall, the incidence and prevalence of LD were 1.2-3.5 times higher in White persons than in persons who identified as Asian or Pacific Islander and 4.5-6.3 times higher in White persons than in persons who identified as Black. Across multiple studies, people from racial and ethnic minority groups were more likely than White people to have disseminated manifestations of LD, including neurological manifestations and arthritis, and less likely to have erythema migrans. People from racial and ethnic minority groups were also more likely to report disease onset in the fall and less likely to report disease onset in the summer. Possible reasons for these disparities include lack of recognition of the disease in people with darker skin tones, lack of knowledge of disease risk for some groups and differences in exposure risk., Conclusions: Taken together, these results reinforce that all people residing in high-incidence areas are at risk of LD, regardless of race or ethnicity. Future prevention measures should be broadly targeted to reach all at-risk populations., (© 2024 The Authors. Zoonoses and Public Health published by Wiley‐VCH GmbH.)

Despite the availability of tick-borne encephalitis (TBE) vaccines, the incidence of TBE is increasing. To understand the historical patterns of infection, we conducted a global meta-analysis of studies before December 2023 reporting human antibody prevalence against TBEV (TBE virus) among general or high-risk population groups stratified by country, collection year, serological method, and vaccination status. Pooled data were compared within groups over time by random-effects modeling. In total, 2403 articles were retrieved; 130 articles published since 1959 were included. Data were extracted from 96 general populations (117,620 participants) and 71 high-risk populations (53,986 participants) across 33 countries. Germany had the most population groups (21), and Poland had the most participants (44,688). Seven serological methods were used; conventional IgG/IgM ELISAs were the most common (44%). Four studies (1.7%) used NS1-ELISA serology. Between 1956-1991 and 1992-2022, anti-TBEV seroprevalence remained at ~2.75% across all population groups from "high-risk" areas ( p = 0.458) but decreased within general populations (1.7% to 1%; p = 0.001) and high-risk populations (5.1% to 1.3%; p < 0.001), possibly due to differences in the study methodologies between periods. This global summary explores how serological methods can be used to assess TBE vaccination coverage and potential exposure to TBEV or measure TBE burden and highlights the need for standardized methodology when conducting TBE seroprevalence studies to compare across populations.

Background: Lyme borreliosis (LB) remains a public health concern in France despite improved patient management and medical care. Stay-at-home restrictions during the COVID-19 pandemic, which affected participation in outdoor recreational activities and disrupted access to health care services, may have impacted the risk of developing LB. Methods: We analyzed data from two general practitioner networks in France (Sentinel Network and an electronic medical records database [EMR]) and the national hospital discharge database to describe LB epidemiology in 2020-2021 and compare it to previous years. Google Trends' search volume was used to evaluate the association between the population's interest in LB and the evolving epidemiology. Results: Annual LB incidence rates in primary care decreased from 104 cases/100,000 population in 2018 to 71/100,000 in 2021 and from 82/100,000 to 60/100,000 according to Sentinel Network and EMR, respectively. Google Trends' search volume for "Lyme" followed a similar trend, one year earlier. Annual hospitalizations were stable from 2012-2019 (1.6/100,000 on average) and declined to 1.3/100,000 in 2020 and 1.1/100,000 in 2021. This decline was observed primarily in adults ( e.g., 3.4/100,000 in 2017-2019 to 1.8/100,000 in 2020-2021 for 70-79 years of age). Changes in regional incidence rates in primary care from 2017-2019 to 2020-2021 ranged from -75% to 208%. Hospitalizations decreased in all regions except in Bretagne. Conclusions: The estimated LB incidence decreased in 2020 and 2021 compared with previous years but this change may not be related to COVID-19. The incidence decrease observed in primary care could result from reduced population interest in LB, leading to lower care-seeking behavior. The decrease in LB hospitalizations may be explained by changes in clinical practice. Surveillance systems are critical to understand the evolution of LB epidemiology. However, external factors impacting incidence estimates should be considered.

Background: Tick-borne encephalitis (TBE) is an infectious disease caused by the tick-borne encephalitis virus (TBEV) in patients with symptoms of central nervous system (CNS) inflammation. More than 25 European countries have one or more TBE-endemic areas. Although two TBE vaccines, FSME-IMMUN® and Encepur®, are commonly used in Europe, there are no published reviews of the real-world effectiveness of TBE vaccines in Europe or elsewhere., Methods: We searched PubMed for TBE vaccine effectiveness (VE) articles and extracted information on country, study design, study period, study population, number of TBEV-infected cases, number of participants, and VE against TBEV infection and outcomes., Results: We identified 13 studies, conducted in Austria, the Czech Republic, Latvia, Germany, and Switzerland, published in 2003-2023. One study was a cohort investigation of a milk-borne outbreak. In the other studies, 11 (91.7%) used the screening method and two (16.7%) used a case-control design (one study used both). TBE vaccines were highly effective (VE estimates >92%) against TBEV infection in all age groups. Vaccines were also highly protective against mild infections (i.e., infections in patients without symptoms of CNS inflammation), and against infections resulting in TBE and hospitalization. Vaccines were also highly protective against the most serious outcomes such as hospitalization greater than 12 days. Product-specific VE estimates were also high, though limited data were available. Studies in Austria, the Czech Republic, Latvia, and Switzerland estimated that TBE vaccines prevented >1,000 TBE cases a year, avoiding many hospitalizations and deaths, in these countries combined., Conclusions: Published VE studies demonstrate a high real-world effectiveness of the commercially available TBE vaccines in Europe. Although cases averted have been estimated in only four countries, TBE vaccination prevents thousands of cases in Europe each year. To prevent life-threatening TBE, TBE vaccine uptake and compliance with the vaccination schedule should be increased in residents of, and travelers to, TBE-endemic countries in Europe., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Frederick J. Angulo reports a relationship with Pfizer Inc that includes: employment and equity or stocks. Pingping Zhang reports a relationship with Pfizer Inc that includes: employment and equity or stocks. Kate Halsby reports a relationship with Pfizer Inc that includes: employment and equity or stocks. Patrick Kelly reports a relationship with Pfizer Inc that includes: employment and equity or stocks. Andreas Pilz reports a relationship with Pfizer Inc that includes: employment and equity or stocks. Harish Madhava reports a relationship with Pfizer Inc that includes: employment and equity or stocks. Jennifer C. Moisi reports a relationship with Pfizer Inc that includes: employment and equity or stocks. Luis Jodar reports a relationship with Pfizer Inc that includes: employment and equity or stocks., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Lyme borreliosis (LB), the most common tick-borne disease in Europe, is endemic to Poland. Despite public health surveillance with mandatory reporting of LB cases by physicians and laboratories, many symptomatic LB cases are not included in surveillance in Poland. We estimated the extent of the under-ascertainment of symptomatic LB cases via surveillance in the Polish province of Lublin to better understand Poland's LB burden. The number of incident symptomatic LB cases in Lublin in 2010 was estimated from two seroprevalence studies conducted among adults in Lublin, as well as estimates of the proportion of asymptomatic LB cases and the duration of LB antibody persistence. The estimated number of incident symptomatic LB cases was compared to the number of surveillance-reported cases in Lublin to derive an under-ascertainment multiplier. This multiplier was applied to the number of surveillance-reported cases in 2021 to estimate the number and population-based incidence of symptomatic LB cases in Lublin in 2021. We estimate that there are 5.9 symptomatic LB cases for every surveillance-reported LB case in Lublin. Adjusting for under-ascertainment, the estimated number of symptomatic LB cases in Lublin in 2021 was 6204 (population-based incidence: 467.6/100,000). After adjustment for under-ascertainment, the incidence of symptomatic LB in Lublin, Poland, is high.

Background: First recognized in children in the United States, Lyme borreliosis (LB) is the most prevalent tickborne illness in North America and Europe. However, the incidence of LB in children, including geographic variation and difference from that in adults, is incompletely described., Methods: We compiled surveillance data from public health agency websites reporting age-stratified LB case data, which was combined with census data to derive incidence estimates. Additional incidence estimates were obtained through a systematic literature review., Results: We identified 18 surveillance systems and 15 published studies for derivation of LB incidence in children. National incidence of >10 cases in children per 100,000 per year were estimated for the United States and parts of Eastern, Western and Northern Europe. However, there was substantial variation in incidence among countries in some European regions. National incidence estimates from the literature largely aligned with estimates from surveillance. Surveillance-reported pediatric incidence was lower than adult incidence in adults in 8 countries, similar to adult incidence in 3 countries, and higher than adult incidence in 1 country. Among all pediatric age strata, the 5-9 years of age stratum had the highest proportion of pediatric cases in most countries., Conclusions: As pediatric LB represents a substantial proportion of overall LB incidence across countries in Europe and North America, LB prevention and control efforts should target pediatric as well as adult populations. However, better data are needed to fully characterize the difference in incidence across geographic regions., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Tick-borne encephalitis (TBE) is an infection by the tick-borne encephalitis virus (TBEV) with symptoms of central nervous system inflammation. TBE is endemic in Latvia and other parts of Europe. TBE vaccination is recommended for children in Latvia. TBE vaccine effectiveness (VE) was estimated in Latvia, a country with high TBE incidence, providing the first VE estimates against a range of TBEV infection outcomes in children 1-15 years-of-age., Methods: Rīga Stradinš University conducted nationwide surveillance for suspected TBE cases. Serum and cerebrospinal fluid were ELISA tested for TBEV-specific IgG and IgM antibodies. A fully vaccinated child was an individual who had received the 3-dose primary series and appropriately timed boosters. The proportion of laboratory-confirmed TBE cases fully vaccinated (PCV) was determined from interviews and medical records. The proportion of the general population fully vaccinated (PPV) was determined from national surveys conducted in 2019 and 2020. TBE VE in children 1-15 years-of-age was estimated using the screening method: VE = 1 - [PCV/(1 - PCV)/PPV/(1 - PPV)]., Results: From 2018 to 2020, surveillance identified 36 TBE cases in children 1-15 years-of-age; all were hospitalized, 5 (13.9%) for >12 days. Of the TBE cases, 94.4% (34/36) were unvaccinated compared with 43.8% of children in the general population. VE against TBE hospitalization in children 1-15 years-of-age was 94.9% (95% confidence interval 63.1-99.3). In 2018-2020, vaccination in children 1-15 years-of-age averted 39 hospitalized TBE cases., Conclusion: Pediatric TBE vaccines were highly effective in preventing TBE in children. Increasing TBE vaccine uptake in children is essential to maximize the public health impact of TBE vaccination., Competing Interests: D.Z. declares a research grant within the Research Collaboration to Rīga Stradinš University (employer) from Pfizer Vaccines. Z.F. declares editorial support for the manuscript by Pfizer. L.R.H., C.B., P.Z., F.J.A., W.E., A.G., J.C.M., and L.J. are employees of Pfizer Inc. and hold stock and stock options in Pfizer Inc. The other authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Although Clostridioides difficile infection (CDI) incidence is high in the United States, standard-of-care (SOC) stool collection and testing practices might result in incidence overestimation or underestimation. We conducted diarrhea surveillance among inpatients >50 years of age in Louisville, Kentucky, USA, during October 14, 2019-October 13, 2020; concurrent SOC stool collection and CDI testing occurred independently. A study CDI case was nucleic acid amplification test‒/cytotoxicity neutralization assay‒positive or nucleic acid amplification test‒positive stool in a patient with pseudomembranous colitis. Study incidence was adjusted for hospitalization share and specimen collection rate and, in a sensitivity analysis, for diarrhea cases without study testing. SOC hospitalized CDI incidence was 121/100,000 population/year; study incidence was 154/100,000 population/year and, in sensitivity analysis, 202/100,000 population/year. Of 75 SOC CDI cases, 12 (16.0%) were not study diagnosed; of 109 study CDI cases, 44 (40.4%) were not SOC diagnosed. CDI incidence estimates based on SOC CDI testing are probably underestimated.

Background: Lyme borreliosis (LB) is the most common tick-borne disease in Europe. To inform European intervention strategies, including vaccines under development, we conducted a systematic review for LB incidence. Methods: We searched publicly available surveillance data reporting LB incidence in Europe from 2005 to 2020. Population-based incidence was calculated as the number of reported LB cases per 100,000 population per year (PPY), and high LB risk areas (incidence >10/100,00 PPY for 3 consecutive years) were estimated. Results: Estimates of LB incidence were available for 25 countries. There was marked heterogeneity in surveillance systems (passive vs. mandatory and sentinel sites vs. national), case definitions (clinical, laboratory, or both), and testing methods, limiting comparison across countries. Twenty-one countries (84%) had passive surveillance; four (Belgium, France, Germany, and Switzerland) used sentinel surveillance systems. Only four countries (Bulgaria, France, Poland, and Romania) used standardized case definitions recommended by European public health institutions. Among all surveillance systems and considering any case definition for the most recently available years, national LB incidences were highest in Estonia, Lithuania, Slovenia, and Switzerland (>100 cases/100,000 PPY), followed by France and Poland (40-80/100,000 PPY), and Finland and Latvia (20-40/100,000 PPY). Incidences were lowest in Belgium, Bulgaria, Croatia, England, Hungary, Ireland, Norway, Portugal, Romania, Russia, Scotland, and Serbia (<20/100,000 PPY). At the subnational level, highest LB incidences (>100/100,000 PPY) were observed in areas of Belgium, Czech Republic, France, Germany, and Poland. Overall, on average 128,888 cases are reported annually. An estimated 202/844 million (24%) persons in Europe reside in areas of high LB incidence and 202/469 million (43.2%) persons reside in areas of high LB incidence among countries with surveillance data. Conclusion: Our review showed substantial variability in reported LB incidence across and within European countries, with highest incidences reported from the Eastern, Northern (Baltic states and Nordic countries), and Western Europe surveillance systems. Standardization of surveillance systems, including wider implementation of common case definitions, is urgently needed to interpret the range of differences in LB incidence observed across European countries.

Background: Lyme borreliosis (LB), a tick bite-transmitted infection caused by Borrelia burgdorferi sensu lato ( Bbsl ) complex spirochetes, is the most common tickborne disease in Europe. Studies in European countries have reported LB seroprevalence (prevalence of antibodies to Bbsl infection) and diagnostic strategies used for testing. We conducted a systematic literature review to summarize contemporary LB seroprevalence in Europe. Methods: PubMed, Embase, and CABI Direct (Global Health) databases were searched from 2005 to 2020 to identify studies reporting LB seroprevalence in European countries. Reported single-tier and two-tier test results were summarized; algorithms (standard or modified) were used to interpret final test results from studies that used two-tier testing. Results: The search yielded 61 articles from 22 European countries. Studies used a range of diagnostic testing methods and strategies (48% single-tier, 46% standard two-tier, and 6% modified two-tier). In 39 population-based studies, of which 14 were nationally representative, seroprevalence estimates ranged from 2.7% (Norway) to 20% (Finland). There was substantial heterogeneity among studies in terms of design, cohort types, periods sampled, sample sizes, and diagnostics, which limited cross-study comparisons. Nevertheless, among studies that reported seroprevalence in persons with greater exposure to ticks, LB seroprevalence was higher among these groups than in the general population (40.6% vs. 3.9%). Furthermore, among studies that used two-tier testing, general population LB seroprevalence was higher in Western Europe (13.6%) and Eastern Europe (11.1%) than in Northern Europe (4.2%) and Southern Europe (3.9%). Conclusion: Despite variations in LB seroprevalence between and within European subregions and countries, high seroprevalence was observed in certain geographic regions and particular risk groups, suggesting significant disease burden and supporting the need for improved, targeted public health interventions such as vaccination. Harmonized approaches to serologic testing and more nationally representative seroprevalence studies are needed to better understand the prevalence of Bbsl infection in Europe.

Introduction: Clostridioides difficile infection (CDI) is a recognized global threat especially for vulnerable populations. It is of particular concern to healthcare providers as it is found in both hospital and community settings, with severe courses, frequent recurrence, high mortality and substantial financial impact on the healthcare system. The CDI burden in Germany has been described and compared by analysing data from four different public databases., Methods: Data on hospital burden of CDI have been extracted, compared, and discussed from four public databases for the years 2010-2019. Hospital days due to CDI were compared to established vaccine preventable diseases, such as influenza and herpes zoster, and also to CDI hospitalisations in the United States (US)., Results: All four databases reported comparable incidences and trends. Beginning in 2010, population-based hospitalised CDI incidence increased to a peak of > 137/100,000 in 2013. Then, incidence declined to 81/100,000 in 2019. Hospitalised patients with CDI were predominantly > 50 years of age. The population-based incidence of severe CDI was between 1.4 and 8.4/100,000 per year. Recurrence rates were between 5.9 to 6.5%. More than 1,000 CDI deaths occurred each year, with a peak of 2,666 deaths in 2015. Cumulative CDI patient days (PD) were between 204,596 and 355,466 each year, which exceeded cumulated PD for influenza and herpes zoster in most years, though year-to-year differences were observed. Finally, hospitalized CDI incidence was higher in Germany than in the US, where the disease is well recognized as a public health threat., Conclusions: All four public sources documented a decline in CDI cases since 2013, but the disease burden remains substantial and warrants continued attention as a severe public health challenge., (© 2023. The Author(s).)

Background: Lyme borreliosis (LB) is the most common tick-borne disease in Europe, but the burden of disease is incompletely described. Methods: We conducted a systematic review across PubMed, EMBASE, and CABI Direct (Global Health) databases, from January 1, 2005, to November 20, 2020, of epidemiological studies reporting incidence of LB in Europe (PROSPERO, CRD42021236906). Results: The systematic review yielded 61 unique articles describing LB incidence (national or subnational) in 25 European countries. Substantial heterogeneity in study designs, populations sampled, and case definitions restricted data comparability. The European Union Concerted Action on Lyme Borreliosis (EUCALB)-published standardized LB case definitions were used by only 13 (21%) of the 61 articles. There were 33 studies that provided national-level LB incidence estimates for 20 countries. Subnational LB incidence was available from an additional four countries (Italy, Lithuania, Norway, and Spain). The highest LB incidences (>100 cases per 100,000 population per year [PPY]) were reported in Belgium, Finland, the Netherlands, and Switzerland. Incidences were 20-40/100,000 PPY in the Czech Republic, Germany, Poland, and Scotland and <20/100,000 PPY in Belarus, Croatia, Denmark, France, Ireland, Portugal, Russia, Slovakia, Sweden, and the United Kingdom (England, Northern Ireland, and Wales); markedly higher incidences were observed at the subnational level (up to 464/100,000 PPY in specific local areas). Conclusions: Although countries in Northern (Finland) and Western (Belgium, the Netherlands, and Switzerland) Europe reported the highest LB incidences, high incidences also were reported in some Eastern European countries. There was substantial subnational variation in incidence, including high incidences in some areas of countries with low overall incidence. This review, complemented by the incidence surveillance article, provides a comprehensive view into LB disease burden across Europe that may guide future preventive and therapeutic strategies-including new strategies on the horizon.

Clostridioides difficile infection (CDI) often manifests as diarrhea, particularly in adults of older age or with underlying comorbidities. However, only severe cases are notifiable in Germany. Moreover, failure to collect a stool specimen from inpatients with diarrhea or incomplete testing may lead to underdiagnosis and underreporting of CDI. We assessed the frequency of diarrhea, stool specimen collection, and CDI testing to estimate CDI underdiagnosis and underreporting among hospitalized adults. In a ten-day point-prevalence study (2019-2021) of nine hospitals in a defined area (Muenster/Coesfeld, North Rhine-Westphalia, Germany), all diarrhea cases (≥ 3 loose stools in 24 h) among adult inpatients were captured via medical record screening and nurse interviews. Patient characteristics, symptom onset, putative origin, antibiotic consumption, and diagnostic stool sampling were collected in a case report form (CRF). Diagnostic results were retrieved from the respective hospital laboratories. Among 6998 patients screened, 476 (7%) diarrhea patients were identified, yielding a hospital-based incidence of 201 cases per 10,000 patient-days. Of the diarrheal patients, 186 (39%) had a stool sample collected, of which 160 (86%) were tested for CDI, meaning that the overall CDI testing rate among diarrhea patients was 34%. Toxigenic C. difficile was detected in 18 (11%) of the tested samples. The frequency of stool specimen collection and CDI testing among hospitalized diarrhea patients was suboptimal. Thus, CDI incidence in Germany is likely underestimated. To assess the complete burden of CDI in German hospitals, further investigations are needed., (© 2022. The Author(s).)

Objectives: Clostridioides difficile infection (CDI) burden is not well-characterized in Japan. Therefore, we conducted a population-based, hospitalized CDI incidence study, compared the results with standard-of-care (SOC) CDI testing, and generalized the results for nationwide incidence estimates., Methods: Surveillance identified inpatients ≥50 years-of-age with diarrhea in nine Tokyo hospitals from December 17, 2018-March 30, 2020. A CDI case was defined as a patient with a PCR-positive/cell cytotoxicity neutralization assay (CCNA)-positive stool or a PCR-positive stool and pseudomembranous colitis (PMC). Incidence estimates were adjusted for the hospitalization share of participating hospitals and, in the sensitivity analysis, for missing CDI test results. SOC specimen collection and CDI testing occurred independently., Results: Surveillance during 318 840 patient-days identified 4633 inpatients with diarrhea. Sixty-three CDI cases were identified; 11 (17·5%) had PMC, eight (12·7%) recurrent CDI, and nine (14·3%) died. The hospitalized CDI incidence was 97/100 000 population per year (PPY) in persons ≥50 years-of-age and, in the sensitivity analysis, 324/100 000 PPY. The incidence was 170 and 481/100 000 PPY in persons ≥65 and ≥85 years-of-age, respectively; these estimates increased to 569 and 1609/100 000 PPY in the sensitivity analysis, respectively. There were 12 primary SOC CDI cases in persons ≥50 years-of-age (18/100 000 PPY)., Conclusions: The CDI incidence was high in older adults, with severe clinical consequences. SOC specimen collection and testing under-estimated CDI burden. There are >57 000 hospitalized CDI cases per year in Japan in persons ≥50 years-of-age. Public health interventions are needed to reduce the CDI burden in Japan., Competing Interests: Declaration of competing interest Shuhei Ito, Elisa Gonzalez, Pingping Zhang, Michael Pride, Sharon Gray, Nadia Minarovic, Frederick J. Angulo, Jennifer C. Moïsi, and Luis Jodar are employees of Pfizer Inc. Shuhei Ito, Elisa Gonzalez, Pingping Zhang, Michael Pride, Sharon Gray, Frederick J. Angulo, Jennifer C. Moïsi, and Luis Jodar hold stock and stock options in Pfizer Inc. Pfizer Inc. provided support for medical writing and article publication. Kazuhiro Tateda declares consulting fees from Pfizer for Advisory Board participation and payment from Pfizer for presentations. Junro Ishida and Satoshi Yoshizumi declare no competing interests., (Copyright © 2022 The Pfizer, The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study aimed to determine the stool specimen collection and Clostridioides difficile (C. difficile) testing frequency from inpatients and long-term care facility (LTCF) residents with new-onset diarrhea., Methods: A cross-sectional study was conducted in all wards of 9 adult hospitals (3532 beds) and 14 LTCFs (1205 beds) in Louisville, Kentucky to identify new-onset diarrhea (≥3 loose stools in the past 24 h and not present in the preceding 24 h) among Louisville adults via electronic medical record review, nurse interviews, and patient interviews during a 1-2 week observation period in 2018-2019., Results: Among Louisville-resident inpatients, 167 patients with 9731 inpatient-days had new-onset diarrhea (1.7/100 inpatient-days). Stool specimens were collected from 32% (53/167); 12 (23%) specimens were laboratory-confirmed for C. difficile infection (CDI) (12.3 cases/10,000 inpatient-days). Among LTCF residents, 63 with 10,402 LTCF resident-days had new-onset diarrhea (0.6/100 LTCF resident-days). Stool specimens were collected from 32% (20/63); 9 (45%) specimens were laboratory-confirmed for CDI (8.6 cases/10,000 LTCF resident-days)., Conclusions: New-onset diarrhea was common among inpatients and LTCF residents. Only one-third of patients with new-onset diarrhea had a stool specimen collected and tested for C. difficile-indicative of a potential CDI underdiagnosis-although, further studies are needed to confirm the extent of CDI underdiagnosis., Competing Interests: Declaration of Competing Interest Senén Peña Oliva, Ruth Carrico, Stephen Furmanek, and Julio Ramirez report no conflicts of interest relevant to this article. Frederick J. Angulo, Joann Zamparo, Elisa Gonzalez, Sharon Gray, Kimbal D. Ford, David Swerdlow, and Jennifer C. Moïsi are full-time employees of Pfizer and hold stock or stock options in Pfizer, Inc., (Copyright © 2022 The Pfizer and The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Streptococcus agalactiae or group B Streptococcus (GBS) has emerged as an important cause of invasive disease in adults, particularly among the elderly and those with underlying comorbidities. Traditionally, it was recognised as an opportunistic pathogen colonising and causing disease in pregnant women, neonates, and young infants. Reasons for the upsurge of invasive GBS (iGBS) among the elderly remain unclear, although it has been related to risk factors such as underlying chronic diseases, immunosenescence, impaired inflammatory response, and spread of virulent clones. Antibiotics are successfully as treatment or prophylaxis against iGBS. Several candidate vaccines against iGBS are under development., Objectives: To conduct a systematic review of the current literature on invasive GBS in order to determine disease incidence and case fatality ratio (CFR) among non-pregnant adults. Additionally, information on risk factors, clinical presentation, serotype distribution, and antimicrobial resistance was also retrieved., Methods: Between January and June 2020, electronic searches were conducted in relevant databases: MEDLINE, EMBASE, Global Health, and SCOPUS. Studies were included in the systematic review if they met the inclusion/exclusion criteria. The authors assessed the selected studies for relevance, risk of bias, outcome measures, and heterogeneity. Meta-analyses on incidence and CFR were conducted after evaluating the quality of methods for assessment of exposure and outcomes., Results: Pooled estimates of iGBS incidence in non-pregnant adults 15 years and older were 2.86 cases per 100.000 population (95% CI, 1.68-4.34). Incidence rates in older adults were substantially higher, 9.13 (95%CI, 3.53-17.22) and 19.40 (95%CI, 16.26-22.81) per 100.000 population ≥50 and ≥ 65 years old, respectively. Incidence rates ranged from 0.40 (95% CI, 0.30-0.60) in Africa to 5.90 cases per 100.000 population (95% CI, 4.30-7.70) in North America. The overall CFR was and 9.98% (95% CI, 8.47-11.58). CFR was highest in Africa at 22.09% (95% CI, 12.31-33.57). Serotype V was the most prevalent serotype globally and in North America accounting for 43.48% (n = 12926) and 46,72% (n = 12184) of cases, respectively. Serotype Ia was the second and serotype III was more prevalent in Europe (25.0%) and Asia (29.5%). Comorbidities were frequent among non-pregnant adult iGBS cases. Antimicrobial resistance against different antibiotics (i.e., penicillin, erythromycin) is increasing over time., Conclusions: This systematic review revealed that iGBS in non-pregnant adults has risen in the last few years and has become a serious public health threat especially in older adults with underlying conditions. Given the current serotype distribution, vaccines including serotypes predominant among non-pregnant adults (i.e., serotypes V, Ia, II, and III) in their formulation are needed to provide breadth of protection. Continued surveillance monitoring potential changes in serotype distribution and antimicrobial resistance patterns are warranted to inform public health interventions., Competing Interests: All authors are employees of Pfizer and may hold stock options. Pfizer supported the work.

Background: Burkina Faso, a country in Africa's meningitis belt, introduced 13-valent pneumococcal conjugate vaccine (PCV13) in October 2013, with 3 primary doses given at 8, 12 and 16 weeks of age. To assess whether the new PCV13 program controlled pneumococcal carriage, we evaluated overall and serotype-specific colonization among children and adults during the first 3 years after introduction., Methods: We conducted 2 population-based, cross-sectional, age-stratified surveys in 2015 and 2017 in the city of Bobo-Dioulasso. We used standardized questionnaires to collect sociodemographic, epidemiologic, and vaccination data. Consenting eligible participants provided nasopharyngeal (all ages) and oropharyngeal (≥5 years only) swab specimens. Swab specimens were plated onto blood agar either directly (2015) or after broth enrichment (2017). Pneumococci were serotyped by conventional multiplex polymerase chain reaction. We assessed vaccine effect by comparing the proportion of vaccine-type (VT) carriage among colonized individuals from a published baseline survey (2008) with each post-PCV survey., Results: We recruited 992 (2015) and 1005 (2017) participants. Among children aged <5 years, 42.8% (2015) and 74.0% (2017) received ≥2 PCV13 doses. Among pneumococcal carriers aged <1 year, VT carriage declined from 55.8% in 2008 to 36.9% in 2017 (difference, 18.9%; 95% confidence interval, 1.9%-35.9%; P = .03); among carriers aged 1-4 years, VT carriage declined from 55.3% to 31.8% (difference, 23.5%; 6.8%-40.2%; P = .004); and among participants aged ≥5 years, no significant change was observed., Conclusion: Within 3 years of PCV13 implementation in Burkina Faso, we documented substantial reductions in the percentage of pneumococcal carriers with a VT among children aged <5 years, but not among persons aged ≥5 years. More time, a change in the PCV13 schedule, or both, may be needed to better control pneumococcal carriage in this setting., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Pneumococcal disease is a major public health concern globally and particularly in Burkina Faso, where the 13-valent pneumococcal conjugate vaccine (PCV13) was introduced nationwide into the routine immunization schedule in 2013. The aim of this study was to evaluate vaccine impact on all-cause pneumonia hospitalizations among children <5 years of age., Methods: Hospitalization data covering a 10-year period (January 1, 2009-December 31, 2018) were collected retrospectively in four rural district hospitals, using medical records to extract data on relevant variables. Using an interrupted time-series design and segmented regression, the effectiveness and impact of PCV13 on the rates of pneumonia hospitalization were estimated. Severe acute malnutrition and unintentional injury were used as control conditions., Results: Vaccine effectiveness was found to be 34% (95% confidence interval (CI) 16-49%, p=0.001), 24% (95% CI 2-41%, p=0.032), and 50% (95% CI 30-64%, p<0.001) against all-cause pneumonia among children <5 years, <2 years, and 2-4 years of age, respectively. By October 2018, PCV13 introduction had led to an absolute reduction in the pneumonia hospitalization rate of 348 cases per 100000 person-years among children <5 years of age. No decline was observed for the control conditions., Conclusions: These estimates point to a substantial public health impact of PCV13 against pneumonia hospitalization among children aged <5 years in Burkina Faso., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Respiratory syncytial virus (RSV) is the most common pathogen associated with acute lower respiratory tract infections in young children. RSV is also a major viral pathogen causing severe lung disease in the adult population, particularly among the elderly. We conducted a review of adult RSV studies published from January 1970 to February 2017 to determine the burden of disease among adults worldwide. There were no restrictions on health care setting or definition of RSV infection. A total of 1530 published studies were identified, 95 of which were included in this review. The incidence rates of hospitalised RSV acute respiratory tract infection (ARI) in adults >65 years old ranged from 7.3 to 13.0/105 population in Africa and Asia and from 190 to 254/105 population in the USA. Higher incidence rates (195-1790/105 population) were observed in adults ≥50 years old for outpatient or emergency visits in the USA. Of all ARI patients, RSV accounted for 1-10% in adults and 2-14% in patients with chronic diseases or transplantation. Given the limitations in the existing data, significant efforts should be made to generate evidence on the burden of RSV infections in adults and to estimate the potential impact of future preventive interventions.

Background: Many African countries have introduced pneumococcal conjugate vaccine (PCV) into their routine immunization program to reduce the burden of morbidity and death that results from Streptococcus pneumoniae infection, yet immunogenicity and reactogenicity data from the region are limited for the 2 available PCV products., Methods: We conducted a randomized trial of 13-valent PCV (PCV13) in Bobo-Dioulasso, Burkina Faso. Infants received 3 doses of PCV at 6, 10, and 14 weeks of age or at 6 weeks, 14 weeks, and 9 months of age; toddlers received 2 doses 2 months apart or 1 dose beginning at 12 to 15 months of age; and children received 1 dose between 2 and 4 years of age. We measured each participant's serotype-specific serum immunoglobulin G concentration and opsonophagocytic activity before and after vaccination. For each age group, we compared immune responses between study arms and between the standard schedule in our study and the PCV13-licensing trials., Results: In total, 280 infants, 302 toddlers, and 81 children were assigned randomly and underwent vaccination; 268, 235, and 77 of them completed follow-up, respectively. PCV13 resulted in low reactogenicity in all the study arms. The vaccine elicited a strong primary immune response in infants after 2 or more doses and in children aged 1 to 4 years after 1 dose. Infants who received a booster dose exhibited a robust memory response. Immunogenicity was higher than or comparable to that observed in the PCV13-licensing trials for a majority of serotypes in all 3 age groups., Conclusions: PCV13 has a satisfactory immunogenicity and reactogenicity profile in this population. Our findings will help support decision making by countries regarding their infant and catch-up vaccination schedules., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: During 2014, 4 regions in Togo within the African meningitis belt implemented vaccination campaigns with meningococcal serogroup A conjugate vaccine (MACV). From January to July 2016, Togo experienced its first major Neisseria meningitidis serogroup W (NmW) outbreak. We describe the epidemiology, response, and management of the outbreak., Methods: Suspected, probable, and confirmed cases were identified using World Health Organization case definitions. Through case-based surveillance, epidemiologic and laboratory data were collected for each case. Cerebrospinal fluid specimens were analyzed by polymerase chain reaction, culture, or latex agglutination. Vaccination campaigns were conducted in affected districts., Results: From January 11 to July 5, 2016, 1995 suspected meningitis cases were reported, with 128 deaths. Among them, 479 (24.0%) were confirmed by laboratory testing, and 94 (4.7%) and 1422 (71.3%) remained as probable and suspected cases, respectively. Seven epidemic districts had cumulative attack rates greater than 100 per 100 000 population. Of the confirmed cases, 91.5% were NmW; 39 of 40 available NmW isolates were sequence type-11/clonal complex-11., Conclusions: This outbreak demonstrates that, although high coverage with MACV has reduced serogroup A outbreaks, large meningococcal meningitis outbreaks due to other serogroups may continue to occur; effective multivalent meningococcal conjugate vaccines could improve meningococcal disease prevention within meningitis belt populations., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Streptococcus pneumoniae serotype 3 remains a significant cause of morbidity and mortality worldwide, despite inclusion in the 13-valent pneumococcal conjugate vaccine (PCV13). Serotype 3 increased in carriage since the implementation of PCV13 in the USA, while invasive disease rates remain unchanged. We investigated the persistence of serotype 3 in carriage and disease, through genomic analyses of a global sample of 301 serotype 3 isolates of the Netherlands3-31 (PMEN31) clone CC180, combined with associated patient data and PCV utilization among countries of isolate collection. We assessed phenotypic variation between dominant clades in capsule charge (zeta potential), capsular polysaccharide shedding, and susceptibility to opsonophagocytic killing, which have previously been associated with carriage duration, invasiveness, and vaccine escape. We identified a recent shift in the CC180 population attributed to a lineage termed Clade II, which was estimated by Bayesian coalescent analysis to have first appeared in 1968 [95% HPD: 1939-1989] and increased in prevalence and effective population size thereafter. Clade II isolates are divergent from the pre-PCV13 serotype 3 population in non-capsular antigenic composition, competence, and antibiotic susceptibility, the last of which resulting from the acquisition of a Tn916-like conjugative transposon. Differences in recombination rates among clades correlated with variations in the ATP-binding subunit of Clp protease, as well as amino acid substitutions in the comCDE operon. Opsonophagocytic killing assays elucidated the low observed efficacy of PCV13 against serotype 3. Variation in PCV13 use among sampled countries was not independently correlated with the CC180 population shift; therefore, genotypic and phenotypic differences in protein antigens and, in particular, antibiotic resistance may have contributed to the increase of Clade II. Our analysis emphasizes the need for routine, representative sampling of isolates from disperse geographic regions, including historically under-sampled areas. We also highlight the value of genomics in resolving antigenic and epidemiological variations within a serotype, which may have implications for future vaccine development., Competing Interests: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. AS has received assistance to attend scientific meetings and honoraria for lecturing funded from Pfizer and from GlaxoSmithKline, and Participated in Advisory Board of GlaxoSmithKline and Pfizer. WPH has consulted for Antigen Discovery Inc. JCM is employed by Pfizer, Inc. This does not alter our adherence to all PLOS Pathogens policies on sharing data and materials. The other authors have declared that no competing interests exist.

Streptococcus pneumoniae (Spn) is a leading cause of community-acquired pneumonia (CAP), yet existing diagnostic tools remain inadequate. We aimed to evaluate laboratory and radiological methods for detecting pneumococcal aetiology in CAP patients and to estimate Spn prevalence in this group. All-aged patients hospitalized with clinically defined CAP in northern Togo were enrolled during 2010-2013. Latent class analysis pooled results of semi-automated blood culture (SABC), whole blood lytA real-time polymerase chain reaction (rt-PCR), serum C-reactive protein (CRP), and chest radiography (CXR) and categorized patients as likely pneumococcal or non-pneumococcal CAP. We enrolled 1684 patients; 1501 had results for all tests. CXR, SABC, lytA rt-PCR and CRP >71·2 mg/l had sensitivities of 94% [95% confidence interval (CI) 87-100], 13% (95% CI 10-16), 17% (95% CI 14-21) and 78% (95% CI 75-80), and specificities of 88% (95% CI 84-93), 100% (95% CI 99-100), 97% (95% CI 96-99) and 77% (95% CI 75-79), respectively. Pneumococcal attributable proportion was 34% (95% CI 32-37), increasing with age and in men. We estimated that Spn caused one third of CAP. Whole blood lytA rt-PCR was more sensitive than SABC; both had low sensitivity and high specificity. Conversely CXR was highly sensitive and reasonably specific; it could be a useful tool for epidemiological studies aiming to define Spn pneumonia incidence across all ages.

Background: S. pneumoniae is a leading cause of meningitis morbidity and mortality in the African meningitis belt, but little is known of its contribution to the burden of pneumonia in the region. We aimed to estimate the incidence of pneumococcal disease in children and adults in northern Togo, before the introduction of pneumococcal conjugate vaccine (PCV)., Methods and Findings: From May 1st 2010 to April 30th 2013, we systematically enrolled all hospitalized patients meeting a case definition of suspected meningitis or clinical pneumonia, residing in Tone or Cinkasse districts, northern Togo and providing informed consent. We collected clinical data and tested biological specimens according to standardized procedures, including bacteriology and PCR testing of cerebro-spinal fluid for meningitis patients and blood cultures and whole blood lytA PCR for pneumonia patients. Chest X-rays (CXR) were interpreted using the WHO methodology. We included 404 patients with meningitis (104 <5 years of age) and 1550 with pneumonia (251 <5 years) over the study period. Of these, 78 (19%) had pneumococcal meningitis (13 <5 years), 574 (37%) had radiologically-confirmed pneumonia (83 <5 years) and 73 (5%) had culture-confirmed pneumococcal pneumonia (2 <5 years). PCV13 serotypes caused 79% (54/68) of laboratory-confirmed pneumococcal meningitis and 83% (29/35) of culture-confirmed pneumococcal pneumonia. Serotype 1 predominated in meningitis (n = 33) but not in pneumonia patients (n = 1). The incidence of pneumococcal disease was 7.5 per 100,000 among children <5 years of age and 14.8 in persons 5 years of age and above in the study area. When considering CXR-confirmed and blood PCR-positive pneumonia cases as likely pneumococcal, incidence estimates increased to 43.7 and 66.0 per 100,000 in each of these age groups, respectively. Incidence was at least 3-fold higher when we restricted the analysis to the urban area immediately around the study hospitals., Conclusions: Our findings highlight the important role of S. pneumoniae as a meningitis and pneumonia-causing pathogen in the African meningitis belt. Pneumococcal disease incidence in our population was substantially lower than expected from global models; we hypothesize that poor access to hospital care led us to substantially underestimate the burden of disease. Surveillance is ongoing and will enable an evaluation of PCV impact, providing novel, high quality data from the region., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: BG, HT, BMNL, JCM work for AMP and receive research funding from Pfizer and GSK, manufacturers of pneumococcal conjugate vaccines. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Ongoing surveillance is critical to assessing pneumococcal conjugate vaccine (PCV) impact over time. However, robust prospective studies are difficult to implement in resource-poor settings. We evaluated retrospective use of routinely collected data to estimate PCV impact in Rwanda., Methods: We collected data from admission registers at five district hospitals on children age <5yearsadmitted for suspected meningitis and pneumonia during 2002-2012. We obtained clinical and laboratory data on meningitis from sentinel surveillance at the national reference hospital in Kigali. We developed multivariable logistic regression models to estimate PCV effectiveness (VE) against severe pneumonia and probable bacterial meningitis and Poisson models to estimate absolute rate reductions. Haemophilus influenzae type b vaccine was introduced in January 2002, PCV7 in April 2009 and PCV13 in August 2011., Results: At the district hospitals, the severe pneumonia and suspected meningitis hospitalization rates decreased by 70/100,000 and 11/100,000 children for 2012 compared to baseline, respectively. VE against severe pneumonia calculated from logistic regression was 54% (95% CI 42-63%). In Kigali, from 2002 to 2012, annual suspected meningitis cases decreased from 170 pre-PCV7 to 40 post-PCV13 and confirmed pneumococcal meningitis cases from 7 to 0. VE against probable bacterial meningitis was 42% (95% CI -4% to 68%)., Conclusion: In a resource-poor African setting, analysis of district hospital admission logbooks and routine sentinel surveillance data produced results consistent with more sophisticated impact studies conducted elsewhere. Our findings support applying this methodology in other settings and confirm the benefits of PCV in Rwanda., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

During 2010-2014, we enrolled 511 patients with suspected bacterial meningitis into surveillance in 2 districts of northern Togo. We identified 15 persons with Streptococcus suis infection; 10 had occupational contact with pigs, and 12 suffered neurologic sequelae. S. suis testing should be considered in rural areas of the African meningitis belt.

Prior antibiotic use, contamination, limited blood volume, and processing delays reduce yield of blood cultures for detection of Streptococcus pneumoniae. We performed immunochromatographic testing (ICT) on broth from incubated blood culture bottles and real-time lytA polymerase chain reaction (PCR) on broth and whole blood and compared findings to blood culture in patients with suspected bacteremia. We selected 383 patients in Mali and 586 patients in Thailand based on their blood culture results: 75 and 31 were positive for pneumococcus, 100 and 162 were positive for other pathogens, and 208 and 403 were blood culture negative, respectively. ICT and PCR of blood culture broth were at least 87% sensitive and 97% specific compared with blood culture; whole blood PCR was 75-88% sensitive and 96-100% specific. Pneumococcal yields in children < 5 years of age increased from 2.9% to 10.7% in Mali with > 99% of additional cases detected by whole blood PCR, and from 0.07% to 5.1% in Thailand with two-thirds of additional cases identified by ICT. Compared with blood culture, ICT and lytA PCR on cultured broth were highly sensitive and specific but their ability to improve pneumococcal identification varied by site. Further studies of these tools are needed before widespread implementation., (© The American Society of Tropical Medicine and Hygiene.)

Background: Many surface proteins thought to promote Streptocococcus pneumoniae virulence have recently been discovered and are currently being considered as future vaccine targets. We assessed the prevalence of 16 virulence genes among 435 S. pneumoniae invasive isolates from France and the "African meningitis belt" region, with particular focus on serotype 1 (Sp1), to compare their geographical distribution, assess their association with site of infection and evaluate their potential interest as new vaccine candidates., Methods: Detection by PCR of pspA (+families), pspC (+pspC.4), pavA, lytA, phtA,B,D,E, nanA,B,C, rrgA (Pilus-1), sipA (Pilus-2), pcpA and psrp was performed on all isolates, as well as antibiotic resistance testing and MLVA typing (+MLST on 54 representative strains). Determination of ply alleles was performed by sequencing (Sp1 isolates)., Results: MLVA and virulence genes profiles segregated Sp1 isolates into 2 groups that followed continent distribution. The ply allele 5 and most of the genes that were variable (nanC, Pilus-2, psrp, pcpA, phtD) were present in the French Sp1 isolates (PMEN clone Sweden(1)-28, ST306) but absent from the African ones. Whereas all African Sp1 isolates clustered into a single MLST CC (CC217), MLVA distinguished two CCs that followed temporal evolution. Pilus-2 and psrp were more prevalent in bacteraemic pneumonia yielded isolates and phtB in meningitis-related isolates. Considering vaccine candidates, phtD was less prevalent than anticipated (50%) and pcpA varied importantly between France and Africa (98% versus 34%). Pilus-1 was carried by 7-11% of isolates and associated with β-lactams resistance., Conclusions: Most virulence genes were carried by the European ST306 clone but were lacking on Sp1 isolates circulating in the African meningitis belt, where a more serious pattern of infection is observed. While virulence proteins are now considered as vaccine targets, the geographical differences in their prevalence could affect the efficacy expected from future vaccines.

Streptococcus pneumoniae serotype 1 (Sp1) constitutes an important cause of seasonal endemic meningitis in all age groups in the African meningitis belt. Despite a higher meningitis incidence, the Burkinabé population has an Sp1-specific antibody seroprevalence similar to that reported in the United Kingdom (UK). We aimed to establish whether the opsonophagocytic activity (OPA) of pneumococcal IgG naturally present in Burkina Faso differs from that seen in individuals in the UK and to compare the OPAs generated by natural and vaccine-induced immunity. Samples collected from pneumococcal vaccine-naive Burkinabé and UK subjects were matched for age (1 to 39 years) and anti-Sp1 IgG level, analyzed for OPA to 3 S. pneumoniae serotypes (1, 5, and 19A), and compared to postvaccine samples. Furthermore, the Burkinabé samples were assessed for IgG avidity and serotype-specific IgM concentrations. One hundred sixty-nine matched serum samples from both populations were selected. A greater proportion of Burkinabé subjects aged 1 to 19 years had functional Sp1 activity (OPA ≥ 8) compared to UK subjects (12% versus 2%, P < 0.001); however, the proportions were similar among adults (9%). The correlation between Sp1 IgG concentration and OPA was good (P < 0.001), but many individuals had nonfunctional IgG, which was not related to avidity. While the Sp1 IgM concentrations correlated with OPA, not all of the function in serum samples with low IgG could be attributed to IgM. Finally, vaccine-induced Sp1-specific IgG was more functional than equivalent amounts of naturally occurring IgG. In conclusion, despite a substantially higher pneumococcal meningitis incidence, no decreased functional immunity to Sp1 could be evidenced in the Burkinabé population compared to that in the population from the UK. Furthermore, the naturally induced antibodies were less functional than vaccine-induced antibodies., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

We evaluated pneumococcal serotype/group distribution using polymerase chain reaction (PCR) testing on cerebrospinal fluid collected from patients from Burkina Faso and Togo who presented for care during 2007-2009. We identified 282 pneumococcal meningitis cases based on PCR, latex agglutination, or culture, of which 206 underwent serotyping. Serotype 1 was identified for 18% of serotyped cases from patients aged <5 years and 66% of those aged ≥5 years. The 13-valent and 10-valent pneumococcal conjugate vaccines (PCV-13 and PCV-10) contain 53% of serotypes identified among children age <5 years and 76-77% among persons aged ≥5 years. Pneumococcal meningitis was highly seasonal regardless of serotype. Data from this study emphasize the potential usefulness of PCVs among older children and adults., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We conducted a prospective pilot study over a 1-year period in New Caledonia in preparation for the Pneumonia Research for Child Health (PERCH) project. The pathogens associated with hospitalized lower respiratory infections in children were identified through the use of culture of induced sputum and blood, urinary antigen detection, polymerase chain reaction (PCR) on respiratory specimens, and serology on paired sera. Respiratory viruses were detected on respiratory specimens by immunofluorescence and PCR, and by serology on paired sera. Pathogens were detected in 87.9% of the 108 hospitalized cases. Viruses represented 81.6% of the 152 pathogens detected. Respiratory syncytial virus and rhinovirus were the most frequent, accounting for 32.2% and 24.3% of the pathogens identified, respectively. Only 26.3% of 99 induced sputum specimens collected were determined to be of good quality, which may be a consequence of the collection method used.

As a case-control study of etiology, the Pneumonia Etiology Research for Child Health (PERCH) project also provides an opportunity to assess the risk factors for severe pneumonia in hospitalized children at 7 sites. We identified relevant risk factors by literature review and iterative expert consultation. Decisions for inclusion in PERCH were based on comparability to published data, analytic plans, data collection costs and logistic feasibility, including interviewer time and subject fatigue. We aimed to standardize questions at all sites, but significant variation in the economic, cultural, and geographic characteristics of sites made it difficult to obtain this objective. Despite these challenges, the depth of the evaluation of multiple risk factors across the breadth of the PERCH sites should furnish new and valuable information about the major risk factors for childhood severe and very severe pneumonia, including risk factors for pneumonia caused by specific etiologies, in developing countries.

To develop a case definition for the Pneumonia Etiology Research for Child Health (PERCH) project, we sought a widely acceptable classification that was linked to existing pneumonia research and focused on very severe cases. We began with the World Health Organization's classification of severe/very severe pneumonia and refined it through literature reviews and a 2-stage process of expert consultation. PERCH will study hospitalized children, aged 1-59 months, with pneumonia who present with cough or difficulty breathing and have either severe pneumonia (lower chest wall indrawing) or very severe pneumonia (central cyanosis, difficulty breastfeeding/drinking, vomiting everything, convulsions, lethargy, unconsciousness, or head nodding). It will exclude patients with recent hospitalization and children with wheeze whose indrawing resolves after bronchodilator therapy. The PERCH investigators agreed upon standard interpretations of the symptoms and signs. These will be maintained by a clinical standardization monitor who conducts repeated instruction at each site and by recurrent local training and testing.

Objective: To explore excess paediatric mortality after discharge from Kilifi District Hospital, Kenya, and its duration and risk factors., Methods: Hospital and demographic data were used to describe post-discharge mortality and survival probability in children aged < 15 years, by age group and clinical syndrome. Cox regression models were developed to identify risk factors., Findings: In 2004-2008, approximately 111,000 children were followed for 555,000 person-years. We analysed 14,971 discharges and 535 deaths occurring within 365 days of discharge. Mortality was higher in the post-discharge cohort than in the community cohort (age-adjusted rate ratio, RR: 7.7; 95% confidence interval, CI: 6.6-8.9) and declined little over time. An increased post-discharge mortality hazard was found in children aged < 5 years with the following: weight-for-age Z score < -4 (hazard ratio, HR: 6.5); weight-for-age Z score > -4 but < -3 (HR: 3.4); hypoxia (HR: 2.3); bacteraemia (HR: 1.8); hepatomegaly (HR: 2.3); jaundice (HR: 1.8); hospital stay > 13 days (HR: 1.8). Older age was protective (reference < 1 month): 6-23 months, HR: 0.8; 2-4 years, HR: 0.6. Children with at least one risk factor accounted for 545 (33%) of the 1655 annual discharges and for 39 (47%) of the 83 discharge-associated deaths., Conclusion: Hospital admission selects vulnerable children with a sustained increased risk of dying. The risk factors identified provide an empiric basis for effective outpatient follow-up.

Objective: To explore the relationship between homestead distance to hospital and access to care and to estimate the sensitivity of hospital-based surveillance in Kilifi district, Kenya., Methods: In 2002-2006, clinical information was obtained from all children admitted to Kilifi District Hospital and linked to demographic surveillance data. Travel times to the hospital were calculated using geographic information systems and regression models were constructed to examine the relationships between travel time, cause-specific hospitalization rates and probability of death in hospital. Access to care ratios relating hospitalization rates to community mortality rates were computed and used to estimate surveillance sensitivity., Findings: The analysis included 7200 admissions (64 per 1000 child-years). Median pedestrian and vehicular travel times to hospital were 237 and 61 minutes, respectively. Hospitalization rates decreased by 21% per hour of travel by foot and 28% per half hour of travel by vehicle. Distance decay was steeper for meningitis than for pneumonia, for females than for males, and for areas where mothers had less education on average. Distance was positively associated with the probability of dying in hospital. Overall access to care ratios, which represent the probability that a child in need of hospitalization will have access to care at the hospital, were 51-58% for pneumonia and 66-70% for meningitis., Conclusion: In this setting, hospital utilization rates decreased and the severity of cases admitted to hospital increased as distance between homestead and hospital increased. Access to hospital care for children living in remote areas was low, particularly for those with less severe conditions. Distance decay was attenuated by increased levels of maternal education. Hospital-based surveillance underestimated pneumonia and meningitis incidence by more than 45% and 30%, respectively.

Streptococcus pneumoniae is a common cause of community-acquired pneumonia (CAP) but existing diagnostic tools have limited sensitivity and specificity. We enrolled adults undergoing chest radiography at three Indian Health Service clinics in the Southwestern United States and collected acute and convalescent serum for measurement of PsaA and PspA titres and urine for pneumococcal antigen detection. Blood and sputum cultures were obtained at the discretion of treating physicians. We compared findings in clinical and radiographic CAP patients to those in controls without CAP. Urine antigen testing showed the largest differential between CAP patients and controls (clinical CAP 13%, radiographic CAP 17%, control groups 2%). Serological results were mixed, with significant differences between CAP patients and controls for some, but not all changes in titre. Based on urine antigen and blood culture results, we estimated that 11% of clinical and 15% of radiographic CAP cases were due to pneumococcus in this population.

We conducted a vaccine coverage survey in Kilifi District, Kenya in order to identify predictors of childhood immunization. We calculated travel time to vaccine clinics and examined its relationship to immunization coverage and timeliness among the 2169 enrolled children (median age: 12.5 months). 86% had vaccine cards available, >95% had received three doses of DTP-HepB-Hib and polio vaccines and 88% of measles. Travel time did not affect vaccination coverage or timeliness. The Kenyan EPI reaches nearly all children in Kilifi and delays in vaccination are few, suggesting that vaccines will have maximal impact on child morbidity and mortality., (Copyright 2010 Elsevier Ltd. All rights reserved.)