Transplacental transfer efficiency of maternal antibodies against influenza A(H1N1)pdm09 virus and dynamics of naturally acquired antibodies in Chinese children: a longitudinal, paired mother-neonate cohort study.

BACKGROUND: The 2009 pandemic H1N1 influenza A virus (A(H1N1)pdm09 virus) evolves rapidly and has continued to cause severe infections in children since its emergence in 2009. We aimed to characterise the kinetics of maternally and naturally acquired antibodies against historical A(H1N1)pdm09 strains and to assess the extent to which the response to heterologous strains following infection or vaccination affects observed A(H1N1)pdm09 strain-specific antibody titres in a Chinese paediatric population. METHODS: In this retrospective study, we used residual serum samples from 528 mother-neonate pairs from a non-interventional, longitudinal cohort study in southern China conducted from Sept 20, 2013, to Aug 24, 2018, from six local hospitals in Anhua County, Hunan Province, China. Mother-neonate pairs were eligible for inclusion if the neonates were born after Sept 20, 2013, and their mothers had resided in the study sites for at least 3 months. We tested samples with a haemagglutination inhibition (HAI) assay to measure antibody levels against three historical A(H1N1)pdm09 strains that were antigenically similar to the strains that circulated during the 2009 pandemic (A/Hunan-Kaifu/SWL4204/2009 [SWL4204/09 strain], A/Hunan-Daxiang/SWL1277/2016 [SWL1277/16 strain], and A/Hunan-Yanfeng/SWL185/2018 [SWL185/18 strain]). We also determined the seroprevalence, geometric mean titres (GMTs), transfer ratio of maternal antibodies, and the dynamics of maternally and naturally acquired antibodies in children, from birth to 3 years of age. FINDINGS: 1066 mother-neonate pairs were enrolled in the original cohort between Sept 20, 2013, and Oct 14, 2015. Of these, 528 pairs (523 mothers, 528 neonates) were selected for the present study. The median age of the mothers was 25 years (IQR 23 to 29). 291 (55%) of 528 children were boys and 237 (45%) were girls, and most children (452 [86%]) were breastfed before the age of 6 months. The GMTs and the seroprevalence for the SWL4204/09 strain were higher than those for the SWL1277/16 and SWL185/18 strains among mothers (GMTs: 10·4 [95% CI 9·8 to 11·1] vs 9·3 [8·7 to 9·8] vs 8·0 [7·5 to 8·4], p<0·0001; seroprevalence: 11·1% [95% CI 8·5 to 14·1] vs 6·9% [4·9 to 9·4] vs 4·6% [3·0 to 6·8], p=0·0003) and among neonates (GMTs: 10·7 [10·0 to 11·5] vs 9·4 [8·8 to 10·0] vs 8·1 [7·6 to 8·6], p<0·0001; seroprevalence: 13·4% [10·7 to 16·7] vs 8·7% [6·5 to 11·5] vs 6·1% [4·2 to 8·5], p=0·0002). Regardless of the A(H1N1)pdm09-specific strain, maternal antibodies could be transferred efficiently via the placenta (mean transfer ratios: 1·10 for SWL4204/09 vs 1·09 for SWL1277/16 vs 1·06 for SWL185/18; p=0·93). The A(H1N1)pdm09 strain-specific antibodies waned below the protective threshold of 1:40 within 2 months after birth. After maternal antibody waning, there were periodic increases and decreases in HAI antibody titres against three A(H1N1)pdm09 strains, and such increases were all significantly associated with a higher immune response to heterologous strains. Vaccination against the SWL4204/09 strain was associated with a poor response to the SWL185/18 strain (ß-0·20, 95% CI -0·28 to -0·13; p<0·0001). INTERPRETATION: Our findings suggest low pre-existing immunity against influenza A(H1N1)pdm09 virus among unvaccinated Chinese adult female and paediatric populations. This evidence, together with the rapid decay of maternal antibodies and the observed cross-reactivity among different A(H1N1)pdm09 strains, highlights the importance of accelerating maternal and paediatric influenza vaccination in China. FUNDING: The Key Program of the National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Long-term measles antibody profiles following different vaccine schedules in China, a longitudinal study.

Characterizing the long-term kinetics of maternally derived and vaccine-induced measles immunity is critical for informing measles immunization strategies moving forward. Based on two prospective cohorts of children in China, we estimate that maternally derived immunity against measles persists for 2.4 months. Following two-dose series of measles-containing vaccine (MCV) at 8 and 18 months of age, the immune protection against measles is not lifelong, and antibody concentrations are extrapolated to fall below the protective threshold of 200 mIU/ml at 14.3 years. A catch-up MCV dose in addition to the routine doses between 8 months and 5 years reduce the cumulative incidence of seroreversion by 79.3-88.7% by the age of 6 years. Our findings also support a good immune response after the first MCV vaccination at 8 months. These findings, coupled with the effectiveness of a catch-up dose in addition to the routine doses, could be instrumental to relevant stakeholders when planning routine immunization schedules and supplemental immunization activities.

Seroepidemiology of enterovirus A71 infection in prospective cohort studies of children in southern China, 2013-2018.

Enterovirus A71 (EV-A71)-related hand, foot, and mouth disease (HFMD) imposes a substantial clinical burden in the Asia Pacific region. To inform policy on the introduction of the EV-A71 vaccine into the National Immunization Programme, we investigated the seroepidemiological characteristics of EV-A71 in two prospective cohorts of children in southern China conducted between 2013 and 2018. Our results show that maternal antibody titres declined rapidly in neonates, with over half becoming susceptible to EV-A71 at 1 month of age. Between 6 months and 2 years of age, over 80% of study participants were susceptible, while one third remained susceptible at 5 years old. The highest incidence of EV-A71 infections was observed in children aged 5-6 months. Our findings support EV-A71 vaccination before 6 months for birth cohorts in southern China, potentially with a one-time catch-up vaccination for children 6 months-5 years old. More regionally representative longitudinal seroepidemiological studies are needed to further validate these findings.

The transfer of maternal antibodies and dynamics of maternal and natural infection-induced antibodies against coxsackievirus A16 in Chinese children 0-13 years of age: a longitudinal cohort study.

BACKGROUND: A major hand-foot-and-mouth disease (HFMD) pathogen, coxsackievirus A16 (CVA16), has predominated in several of the last 10 years and caused the largest number of HFMD outbreaks between 2011 and 2018 in China. We evaluated the efficacy of maternal anti-CVA16 antibody transfer via the placenta and explored the dynamics of maternal and natural infection-induced neutralizing antibodies in children. METHODS: Two population-based longitudinal cohorts in southern China were studied during 2013-2018. Participants were enrolled in autumn 2013, including 2475 children aged 1-9 years old and 1066 mother-neonate pairs, and followed for 3 years. Blood/cord samples were collected for CVA16-neutralizing antibody detection. The maternal antibody transfer efficacy, age-specific seroprevalence, geometric mean titre (GMT) and immune response kinetics were estimated. RESULTS: The average maternal antibody transfer ratio was 0.88 (95% CI 0.80-0.96). Transferred maternal antibody levels declined rapidly (half-life: 2.0 months, 95% CI 1.9-2.2 months). The GMT decayed below the positive threshold (8) by 1.5 months of age. Due to natural infections, it increased above 8 after 1.4 years and reached 32 by 5 years of age, thereafter dropping slightly. Although the average duration of maternal antibody-mediated protection was < 3 months, the duration extended to 6 months on average for mothers with titres ≥ 64. CONCLUSIONS: Anti-CVA16 maternal antibodies are efficiently transferred to neonates, but their levels decline quickly. Children aged 0-5 years are the main susceptible population and should be protected by CVA16 vaccination, with the optimal vaccination time between 1.5 months and 1 year of age.

Outcomes and prognostic factors in 70 non-survivors and 595 survivors with COVID-19 in Wuhan, China.

Since the first outbreak of coronavirus disease 2019 (COVID-19) occurred in December 2019, more than 51 million cases had been reported globally. We aimed to identify the risk factors for in-hospital fatal outcome and severe pneumonia of this disease. This is a retrospective, multicentre study, which included all confirmed cases of COVID-19 with definite outcomes (died or discharged) hospitalized between 1 January and 4 March 2020 in Wuhan. Of all 665 patients included, 70 died and 595 discharged (including 333 mild and 262 severe cases). Underlying comorbidity was more commonly observed among deaths (72.9%) than mild (26.4%) and severe (61.5%) survivors, with hypertension, diabetes and cardiovascular as dominant diseases. Fever and cough were the primary clinical magnifications. Older age (≥65 years) (OR = 3.174, 95% CI = 1.356-7.755), diabetes (OR = 2.540, 95% CI = 0.995-6.377), dyspnoea (OR = 7.478, 95% CI = 3.031-19.528), respiratory failure (OR = 10.528, 95% CI = 4.484-25.829), acute cardiac injury (OR = 25.103, 95% CI = 9.057-76.590) and acute respiratory distress syndrome (OR = 7.308, 95% CI = 1.501-46.348) were associated with in-hospital fatal outcome. In addition, older age (OR = 2.149, 95% CI = 1.424-3.248), diabetes (OR = 3.951, 95% CI = 2.077-7.788), cardiovascular disease (OR = 3.414, 95% CI = 1.432-8.799), nervous system disease (OR = 4.125, 95% CI = 1.252-18.681), dyspnoea (OR = 31.944, 95% CI = 18.877-92.741), achieving highest in-hospital temperature of >39.0°C (OR = 37.450, 95% CI = 7.402-683.403) and longer onset of illness to diagnosis (≥9 days) were statistically associated with higher risk of developing severe COVID-19. In conclusion, the potential risk factors forolder age, diabetes, dyspnoea, respiratory failure, acute cardiac injury and acute respiratory distress syndrome could help clinicians to identify patients with poor prognosis at an early stage.

Genetic Variation of Multiple Serotypes of Enteroviruses Associated with Hand, Foot and Mouth Disease in Southern China.

Enteroviruses (EVs) species A are a major public health issue in the Asia-Pacific region and cause frequent epidemics of hand, foot and mouth disease (HFMD) in China. Mild infections are common in children; however, HFMD can also cause severe illness that affects the central nervous system. To molecularly characterize EVs, a prospective HFMD virological surveillance program was performed in China between 2013 and 2016. Throat swabs, rectal swabs and stool samples were collected from suspected HFMD patients at participating hospitals. EVs were detected using generic real-time and nested reverse transcription-polymerase chain reactions (RT-PCRs). Then, the complete VP1 regions of enterovirus A71 (EV-A71), coxsackievirus A16 (CVA16) and CVA6 were sequenced to analyze amino acid changes and construct a viral molecular phylogeny. Of the 2836 enrolled HFMD patients, 2,517 (89%) were EV positive. The most frequently detected EVs were CVA16 (32.5%, 819), CVA6 (31.2%, 785), and EV-A71 (20.4%, 514). The subgenogroups CVA16_B1b, CVA6_D3a and EV-A71_C4a were predominant in China and recombination was not observed in the VP1 region. Sequence analysis revealed amino acid variations at the 30, 29 and 44 positions in the VP1 region of EV-A71, CVA16 and CVA6 (compared to the respective prototype strains BrCr, G10 and Gdula), respectively. Furthermore, in 21 of 24 (87.5%) identified EV-A71 samples, a known amino acid substitution (D31N) that may enhance neurovirulence was detected. Our study provides insights about the genetic characteristics of common HFMD-associated EVs. However, the emergence and virulence of the described mutations require further investigation.

The transfer and decay of maternal antibodies against enterovirus A71, and dynamics of antibodies due to later natural infections in Chinese infants: a longitudinal, paired mother-neonate cohort study.

BACKGROUND: Since 1997, epidemics of hand, foot, and mouth disease associated with enterovirus A71 (EV-A71) have affected children younger than 5 years in the Asia-Pacific region, including mainland China. EV-A71 vaccines have been licensed for use in children aged 6-71 months in China, but not for infants younger than 6 months. We aimed to assess the dynamics of maternal EV-A71 antibodies to inform choice of potential vaccination strategies to protect infants younger than 6 months, because they have a substantial burden of disease. METHODS: We did a longitudinal cohort study with mother-neonate pairs in local hospitals in southern China during 2013-18. We collected cord blood from neonates and venous blood from mothers at delivery. We followed up and collected blood samples from the children at ages 2, 4, 6, 12, 24, and 36 months and tested for the presence of neutralising antibodies against EV-A71 with virus neutralisation assays. Seropositivity, or protective titre, was defined as a neutralisation antibody titre of 16 or higher. We estimated the seroprevalence, geometric mean titre (GMT), and transfer ratio of maternal antibodies. We used a binomial distribution to derive the 95% CIs of seroprevalence. Seropositivity between mothers and neonates was compared by use of an agreement (κ), while GMTs were compared by use of paired Student's t tests. FINDINGS: Between Sept 20, 2013, and Oct 14, 2015, 1054 mothers with 1066 neonates were enrolled. The EV-A71 GMT was similar among pairs of neonates (22·7, 95% CI 20·8-24·9) and mothers (22·1, 95% CI 20·2-24·1; p=0·20). The mean transfer ratio of maternal antibodies was 1·03 (95% CI 0·98-1·08). Although 705 (66%) of 1066 neonates acquired protective concentrations of EV-A71 antibodies from mothers, these declined rapidly, with a half-life of 42 days (95% CI 40-44). The time to loss of protective immunity was extended to 5 months in neonates with mothers who had titres of 128 or higher. By age 30 months, 28% of children had become seropositive because of natural infection. INTERPRETATION: EV-A71 maternal antibodies were efficiently transferred to neonates, but declined quickly to below the protective threshold, particularly among those whose mothers had low antibody titres. Our findings suggest that maternal vaccination could be explored to provide neonatal protection against EV-A71 through maternal antibodies. Catch-up vaccination between ages 6 months to 5 years could provide protection to the approximately 30-90% of children that have not had natural EV-A71 infection by that age. FUNDING: National Science Fund for Distinguished Young Scholars, National Natural Science Foundation of China.

Molecular strategy for the direct detection and identification of human enteroviruses in clinical specimens associated with hand, foot and mouth disease.

BACKGROUND: Diseases caused by human enteroviruses (EVs) are a major global public health problem. Thus, the effective diagnosis of all human EVs infections and the monitoring of epidemiological and ecological dynamic changes are urgently needed. METHODS: Based on two comprehensive virological surveillance systems of hand, foot and mouth disease (HFMD), real-time PCR and nested RT-PCR (RT-snPCR) methods based on the enteroviral VP1, VP4-VP2 and VP4 regions were designed to directly detect all human EVs serotypes in clinical specimens. RESULTS: The results showed that the proposed serotyping strategy exhibit very high diagnostic efficiency (Study 1: 99.9%; Study 2: 89.5%), and the variance between the study was due to inclusion of the specific Coxsackie virus A6 (CVA6) real-time RT-PCR and VP4 RT-snPCR in Study 1 but not Study 2. Furthermore, only throat swabs were collected and analyzed in Study 2, whereas in Study 1, if a specific EV serotype was not identified in the primary stool sample, other sample types (rectal swab and throat swab) were further tested where available. During the study period from 2013 to 2018, CVA6 became one of the main HFMD causative agents, whereas the level of enterovirus A71 (EV-A71) declined in 2017. CONCLUSION: The findings of this study demonstrate the appropriate application of PCR methods and the combination of biological sample types that are useful for etiological studies and propose a molecular strategy for the direct detection of human EVs in clinical specimens associated with HFMD.

Correction: Clinical features of 2041 human brucellosis cases in China.

[This corrects the article DOI: 10.1371/journal.pone.0205500.].

Epidemiology of Norovirus Outbreaks Reported to the Public Health Emergency Event Surveillance System, China, 2014⁻2017.

We conducted a retrospective analysis of norovirus outbreaks reported to the National Public Health Emergency Event Surveillance System (PHEESS) in China from January 1, 2014 to December 31, 2017. We reviewed all acute gastroenteritis outbreaks (n = 692) submitted to PHEESS to identify the frequency, seasonality, geographic distribution, setting, and transmission mode of outbreaks due to norovirus. A total of 616 norovirus outbreaks resulting in 30,848 cases were reported. Among these outbreaks, 571 (93%) occurred in school settings including 239 (39%) in primary schools, 136 (22%) in childcare facilities, and 121 (20%) in secondary schools. The majority of outbreaks (63%) were due to person-to-person transmission, followed by multiple modes of transmission (11%), foodborne (5%) and waterborne (3%) transmission. These findings highlight the importance of improving hand hygiene and environmental disinfection in high-risk settings. Developing a standard and quantitative outbreak reporting structure could improve the usefulness of PHEESS for monitoring norovirus outbreaks.

Prevalence of rotavirus and rapid changes in circulating rotavirus strains among children with acute diarrhea in China, 2009-2015.

BACKGROUND: Rotavirus is a leading cause of morbidity and mortality in young children worldwide. In China, the universal immunization of children with the rotavirus vaccine has not been introduced, and the two globally distributed vaccines (RotaTeq and Rotarix) are not licensed in the country. We aim to determine the prevalence and strain diversity of rotavirus in children with diarrhea aged ≤ five years across China. MATERIALS AND METHODS: Sentinel-based surveillance of acute diarrhea was conducted at 213 participating hospitals in China from January 1, 2009, through December 31, 2015. Group A rotavirus (RVA) was tested by using enzyme-linked immunosorbent assays, and G- and P-genotype of RVA were tested by RT-PCR methods. RESULTS: Of 33,616 children with diarrhea, 10,089 (30%) were positive for RVA; RVA-associated diarrhea was identified in 2247 (39.5%, n = 2247/5685) inpatients and 7842 (28.1%, n = 7842/27931) outpatients. Children living in low-middle-income regions suffered from the highest burden of rotavirus, with 40.7% of diarrhea cases attributed to rotavirus infection, followed by 31.3% in upper-middle-income and 11.2% in high-income regions. The majority of children (88.9%, n = 8976/10089) who tested positive for RVA were children aged ≤ 2 years. The seasonal peak of RVA was in the winter. Among all 2533 RVA strains genotyped, five strain combinations, G9P[8], G3P[8], G1P[8], G2P[4] and G3P[4], contributed to 71.3% (1807/2533) of the RVA-associated diarrhea cases. The predominant strain of RVA has rapidly evolved from G3P[8] and G1P[8] to G9P[8] in the recent years, with the proportion of G9P[8] having increased remarkably from 3.4% in 2009 to 60.9% in 2015. CONCLUSIONS: The burden of diarrhea attributed to rotavirus is high in China, highlighting the potential value of vaccination. The rapid shift of RVA strains highlights the importance of conducting rotavirus surveillance to ensure that currently marketed vaccines provide protective efficacy against the circulating strains.

A Spatio-Temporal Modeling Framework for Surveillance Data of Multiple Infectious Pathogens with Small Laboratory Validation Sets.

Many surveillance systems of infectious diseases are syndrome-based, capturing patients by clinical manifestation. Only a fraction of patients, mostly severe cases, undergo laboratory validation to identify the underlying pathogen. Motivated by the need to understand transmission dynamics and associate risk factors of enteroviruses causing the hand, foot and mouth disease (HFMD) in China, we developed a Bayesian spatio-temporal modeling framework for surveillance data of infectious diseases with small validation sets. A novel approach was proposed to sample unobserved pathogen-specific patient counts over space and time and was compared to an existing sampling approach. The practical utility of this framework in identifying key parameters was assessed in simulations for a range of realistic sizes of the validation set. Several designs of sampling patients for laboratory validation were compared with and without aggregation of sparse validation data. The methodology was applied to the 2009 HFMD epidemic in southern China to evaluate transmissibility and the effects of climatic conditions for the leading pathogens of the disease, enterovirus 71 and Coxsackie A16.

Epidemiological features and spatial clusters of hand, foot, and mouth disease in Qinghai Province, China, 2009-2015.

BACKGROUND: Hand, Foot, and Mouth Disease (HFMD) is most frequently caused by Enterovirus71 (EV-A71) or Coxsackie virus A16 (CV-A16), infants and young children are at greatest risk. Describing the epidemiology of HFMD can help develop and better target interventions, including the use of pediatric EV-A71 vaccination. METHODS: We obtained data from the national surveillance system for HFMD cases with onset dates from 2009 to 2015. We defined probable cases as patient with skin papular or vesicular rashes on the hands, feet, mouth, or buttocks and confirmed cases as patients with the above symptoms along with laboratory-based enterovirus detection. We generated overall and age-specific annual incidence rates and described the temporal variability and seasonality of HFMD in Qinghai Province. We identified spatial clustering of HFMD incidence at the county level using the Local Indicator of Spatial Associationand an alpha level of 0.05. RESULTS: During the study period, 14,480 HFMD probable or confirmed cases were reported in Qinghai Province. Of the 2158 (14.9%) with laboratory confirmation, 924 (42.6%) were caused by CV-A16 and 830 (38.2%) were caused by EV-A71. The majority (89%) of all case-patients were ≤ 5 years of age and male (61.5%). The overall mean annual HFMD incidence rate was 36.4 cases per 100,000 populations, while the incidence rate for children ≤5 years of age was 379.5 cases per 100,000. Case reports peaked during the months of May through July. HFMD was predominantly caused by EV-A71, except in 2010 and 2014 when CV-A16 was the predominant causative agent. High incidence rates of HFMD were clustered (Moran's I = 0.59, P < 0.05) in the eastern region of the province. CONCLUSION: HFMD remains an important cause of childhood disease in Qinghai Province, occurring in an acyclical pattern of increased incidence, primarily due to CV-A16 circulation every three years. Incidence is also seasonal and tends to spatially cluster in the eastern region of the province. Since approximately 40% of confirmed HFMD cases were due to EV-A71, EV-A71 vaccination is likely to have a positive impact on the HFMD disease burden. Routine analysis of local surveillance data is crucial for describing disease occurrence and changes in etiology.

Population based hospitalization burden of laboratory-confirmed hand, foot and mouth disease caused by multiple enterovirus serotypes in Southern China.

BACKGROUND: Hand, foot and mouth disease (HFMD) is spread widely across Asia, and the hospitalization burden is currently not well understood. Here, we estimated serotype-specific and age-specific hospitalization rates of HFMD in Southern China. METHODS: We enrolled pediatric HFMD patients admitted to 3/3 county-level hospitals, and 3/23 township-level hospitals in Anhua county, Hunan (CN). Samples were collected to identify enterovirus serotypes by RT-PCRs between October 2013 and September 2016. Information on other eligible, but un-enrolled, patients were retrospectively collected from the same six hospitals. Monthly numbers of all-cause hospitalizations were collected from each of the 23 township-level hospitals to extrapolate hospitalizations associated with HFMD among these. RESULTS: During the three years, an estimated 3,236 pediatric patients were hospitalized with lab-confirmed HFMD, and among these only one case was severe. The mean hospitalization rate was 660 (95% CI: 638-684) per 100,000 person-years for lab-confirmed HFMD, with higher rates among CV-A16 and CV-A6 associated HFMD (213 vs 209 per 100,000 person-years), and lower among EV-A71, CV-A10 and other enterovirus associated HFMD (134, 39 and 66 per 100,000 person-years respectively, p<0.001). Children aged 12-23 months had the highest hospitalization rates (3,594/100,000 person-years), followed by those aged 24-35 months (1,828/100,000 person-years) and 6-11 months (1,572/100,000 person-years). Compared with other serotypes, CV-A6-associated hospitalizations were evident at younger ages. CONCLUSIONS: Our study indicates a substantial hospitalization burden associated with non-severe HFMD in a rural county in southern China. Future mitigation policies should take into account the disease burden identified, and optimize interventions for HFMD.

Clinical features of 2041 human brucellosis cases in China.

BACKGROUND: Human brucellosis has become a major public health problem in China. However, the available clinical data on brucellosis cases are limited. METHODS: We retrospectively reviewed medical charts of 2041 patients with confirmed human brucellosis and prospectively recorded their outcomes by telephone interview. These patients were admitted to the Sixth People's Hospital of the Xinjiang Uygur Autonomous region between 1st January and 31st December 2014. Data on these patients were collected from hospital medical records. RESULTS: Many patients presented with fatigue (67%), fever (64%), arthralgia (63%) and sweating (54%). High erythrocyte sedimentation rate (ESR) (69%), high C-reactive protein (CRP) (39%), high alanine aminotransferase (ALT) (33%) and high aspartate aminotransferase (AST) (20%) were the most common laboratory findings, especially in acute patients. There was evidence of focal involvement in 90% of patients. A total of 61.5% of brucellosis patients recovered. Multivariate logistic regression analyses suggested that the risk factors key to unfavorable prognosis were: age≥45 years (OR = 1.75, 95% CI 1.36-2.24), back pain (OR = 1.50, 95% CI 1.16-1.94) and joint tenderness (OR = 1.73, 95% CI 1.13-2.65). The increasing duration of the illness increased the risk of poor prognosis. CONCLUSION: Patients with brucellosis showed different characteristics in different clinical stages. In China, the chronicity rate of human brucellosis is high. The risk of poor prognosis is increased in patients aged 45 years or older, patients who have had brucellosis for a substantial period of time, and patients with back pain or joint tenderness. The clinical management of brucellosis should be improved to include sensitive diagnostic methods for subacute and chronic brucellosis.

Emerging Enteroviruses Causing Hand, Foot and Mouth Disease, China, 2010-2016.

Coxsackievirus A6 emerged as one of the predominant causative agents of hand, foot and mouth disease epidemics in many provinces of China in 2013 and 2015. This virus strain accounted for 25.9% of mild and 15.2% of severe cases in 2013 and 25.8% of mild and 16.9% of severe cases in 2015.

Prolonged Evolution of Virus-Specific Memory T Cell Immunity after Severe Avian Influenza A (H7N9) Virus Infection.

Since 2013, influenza A H7N9 virus has emerged as the most common avian influenza virus subtype causing human infection, and it is associated with a high fatality risk. However, the characteristics of immune memory in patients who have recovered from H7N9 infection are not well understood. We assembled a cohort of 45 H7N9 survivors followed for up to 15 months after infection. Humoral and cellular immune responses were analyzed in sequential samples obtained at 1.5 to 4 months, 6 to 8 months, and 12 to 15 months postinfection. H7N9-specific antibody concentrations declined over time, and protective antibodies persisted longer in severely ill patients admitted to the intensive care unit (ICU) and patients presenting with acute respiratory distress syndrome (ARDS) than in patients with mild disease. Frequencies of virus-specific gamma interferon (IFN-γ)-secreting T cells were lower in critically ill patients requiring ventilation than in patients without ventilation within 4 months after infection. The percentages of H7N9-specific IFN-γ-secreting T cells tended to increase over time in patients ≥60 years or in critically ill patients requiring ventilation. Elevated levels of antigen-specific CD8+ T cells expressing the lung-homing marker CD49a were observed at 6 to 8 months after H7N9 infection compared to those in samples obtained at 1.5 to 4 months. Our findings indicate the prolonged reconstruction and evolution of virus-specific T cell immunity in older or critically ill patients and have implications for T cell-directed immunization strategies.IMPORTANCE Avian influenza A H7N9 virus remains a major threat to public health. However, no previous studies have determined the characteristics and dynamics of virus-specific T cell immune memory in patients who have recovered from H7N9 infection. Our findings showed that establishment of H7N9-specific T cell memory after H7N9 infection was prolonged in older and severely affected patients. Severely ill patients mounted lower T cell responses in the first 4 months after infection, while T cell responses tended to increase over time in older and severely ill patients. Higher levels of antigen-specific CD8+ T cells expressing the lung-homing marker CD49a were detected at 6 to 8 months after infection. Our results indicated a long-term impact of H7N9 infection on virus-specific memory T cells. These findings advance our understanding of the dynamics of virus-specific memory T cell immunity after H7N9 infection, which is relevant to the development of T cell-based universal influenza vaccines.

Outcomes following severe hand foot and mouth disease: A systematic review and meta-analysis.

BACKGROUND: Hand, foot and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) is associated with acute neurological disease in children. This study aimed to estimate the burden of long-term sequelae and death following severe HFMD. METHODS: This systematic review and meta-analysis pooled all reports from English and Chinese databases including MEDLINE and Wangfang on outbreaks of clinically diagnosed HFMD and/or laboratory-confirmed EV-A71 with at least 7 days' follow-up published between 1st January 1966 and 19th October 2015. Two independent reviewers assessed the literature. We used a random effects meta-analysis to estimate cumulative incidence of neurological sequelae or death. Studies were assessed for methodological and reporting quality. PROSPERO registration number: 10.15124/CRD42015021981. FINDINGS: 43 studies were included in the review, and 599 children from 9 studies were included in the primary analysis. Estimated cumulative incidence of death or neurological sequelae at maximum follow up was 19.8% (95% CI:10.2%, 31.3%). Heterogeneity (Iˆ2) was 88.57%, partly accounted for by year of data collection and reporting quality of studies. Incidence by acute disease severity was 0.00% (0.00, 0.00) for grade IIa; 17.0% (7.9, 28.2) for grade IIb/III; 81.6% (65.1, 94.5) for grade IV (p = 0.00) disease. CONCLUSIONS: HFMD with neurological involvement is associated with a substantial burden of long-term neurological sequelae. Grade of acute disease severity was a strong predictor of outcome. Strengths of this study include its bilingual approach and clinical applicability. Future prospective and interventional studies must use rigorous methodology to assess long-term outcomes in survivors. FUNDING: There was no specific funding for this study. See below for researcher funding.

Spectrum of Enterovirus Serotypes Causing Uncomplicated Hand, Foot, and Mouth Disease and Enteroviral Diagnostic Yield of Different Clinical Samples.

Background: Hand, foot, and mouth disease (HFMD) represents a substantial disease burden in the Western Pacific region. We investigated the spectrum of causative enteroviruses of HFMD, and evaluated different clinical samples' diagnostic yield for enteroviruses. Methods: We enrolled pediatric patients hospitalized for HFMD among 6 hospitals in Anhua County, Hunan Province, China between October 2013 and September 2016. Throat swabs and stool samples (or rectal swabs) were collected to detect the enterovirus serotypes by real-time reverse-transcription polymerase chain reaction (PCR) or nested PCR. Results: Among the 2836 patients, only 1 developed severe illness. Seventeen serotypes were identified in 2401 patients (85%), with the most frequently detected being CV-A16 (29% [814]), CV-A6 (28% [784]), EV-A71 (17% [491]), CV-A10 (4% [114]), and CV-A4 (2% [53]). Children were younger in CV-A6, CV-A10, and CV-A4 infections (median, 12 months; interquartile range [IQR], 12-24 months) than EV-A71 and CV-A16 infections (median, 24 months; IQR, 12-36 months; P < .05). The predominant enterovirus serotype shifted between CV-A16 and CV-A6 during the 3 years. Stool had a higher diagnostic yield (89%) than rectal (77%) and throat swabs (74%). Detection rates reached 93% when testing stools followed by throat swabs if stools were negative, and 89% when testing rectal swabs followed by throat swabs if rectal swabs were negative. Conclusions: Our results provide a virological benchmark for future surveillance and diagnostics. Continuous comprehensive virological surveillance is essential, especially after implementation of the EV-A71 vaccine in China, to monitor serotype replacement and the vaccine's impact.