Li-Yuan Wang

Clinical progression and predictors of death in patients with severe fever with thrombocytopenia syndrome in China

BACKGROUND Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease of which the clinical progression and factors related to death are still unclear. OBJECTIVE To identify the clinical progression of SFTS and explore predictors of fatal outcome throughout the disease progress. STUDY DESIGN A prospective study was performed in a general hospital located in Xinyang city during 2011-2013. Confirmed SFTS patients were recruited and laboratory parameters that were commonly evaluated in clinical practice were collected. The clinical progression was determined based on analysis of dynamic profiles and Friedmans test. At each clinical stage, the laboratory features that could be used to predict fatal outcome of SFTS patients were identified by stepwise discriminant analysis. RESULTS Totally 257 survivors and 54 deceased SFTS patients were recruited and the data of 11 clinical and laboratory parameters along their entire disease course were consecutively collected. Three clinical stages (day 1-5 post onset, day 6-11 post onset and day 12 to hospital discharge) were determined based on distinct clinical parameters evaluations. Multivariate discriminant analysis at each clinical stage disclosed the indicators of the fatal outcome as decreased platelet counts at early stage, older age and increased AST level at middle stage, and decreased lymphocyte percentage and increased LDH level at late stage. CONCLUSIONS The significant indicators at three clinical stages could be used to assist identifying the patients with high risk of death. This knowledge might help to perform supportive treatment and avoid fatality.

Severe fever with thrombocytopenia syndrome bunyavirus-related human encephalitis

BACKGROUND Severe Fever with Thrombocytopenia Syndrome (SFTS) is an emerging infectious disease caused by a novel bunyavirus. Until recently, SFTSV-associated encephalitis remained largely uninvestigated. METHODS We made clinical investigation on SFTS patients who experienced encephalitis in one reference hospital in Henan Province from 2011 to 2013 to identify the risk factors for encephalitis occurrence and their fatal outcome development. RESULTS Altogether 538 SFTS patients were included and 19.1% of them developed encephalitis. Fatal outcome occurred in 44.7% of the encephalitis patients. The risk factors associated with encephalitis occurrence and death included older age, longer delay between disease onset and hospital admission, pre-existing diabetes and myalgias, as well as the laboratory evaluations of higher virus load on admission, decreased WBC, PLT count, lymphocyte percentage and ALB, elevated neutrophils percentage, AST, ALT, LDH, CK, ALP, GGT, BUN and CREA. These parameters could be used as potential predictors referring to severe SFTS cases. One SFTSV strain was isolated from cerebrospinal fluid sample. Cytokine/chemokine assay revealed that blood EOTAXIN, IFN-γ, IL-15, IL-6, IP-10, TNF-α were remarkably elevated before clinical deterioration in the confirmed encephalitis patient. CONCLUSIONS SFTSV is capable of infecting the central nervous system and screening for SFTSV in encephalitis of unknown reason should be performed in SFTS endemic regions. The encephalitis occurrence and fatal outcome could be potentially predicted by clinical and laboratory evaluations.

Prevalence of enteroviruses in children with and without hand, foot, and mouth disease in China

BackgroundTo determine the prevalence of human enteroviruses (HEVs) among healthy children, their parents, and children with hand, foot, and mouth disease (HFMD).MethodsWe conducted a case–control study that included throat samples from 579 children with HFMD and from 254 healthy controls. Throat samples from 49 households (98 parents and 53 healthy children) were also analyzed. Phylogenetic analysis was carried out to study genetic relationships of EV71 strains.ResultsThe HEV positive rate in HFMD patients was significantly higher than that in healthy controls (76.0% vs. 23.2%, P < 0.001). The EV71 (43.7% vs. 15.0%, P < 0.001), CVA16 (18.0% vs. 2.8%, P < 0.001), and CVA10 (5.7% vs. 0.8%, P = 0.001) serotypes were significantly overrepresented in HFMD patients in comparison to healthy children. Other HEV serotypes were detected with comparable frequency in cases and controls. The HEV positive rate in severe HFMD patients was significantly higher than that in mild group (82.1% vs. 73.8%, P = 0.04). The EV71 (55.0% vs. 39.7%, P = 0.001) and CVA16 (11. 9% vs. 20.0%, P = 0.024) positive rate differed significantly between severe and mild HFMD patients. Other HEV serotypes were detected with comparable frequency between severe and mild HFMD patients. Among 49 households, 22 households (44.9%) had at least 1 family member positive for HEV. Children had significantly higher HEV positive rate than adult (28.3% vs. 14.3%, P = 0.037). The HEV positive rate was similar between mothers and fathers (12.24% vs. 16.32%, P = 0.56). The VP1 sequences of EV71 from HFMD patients and healthy children were nearly identical and all were clustered in the same clade, C4a.ConclusionsOur study demonstrated the co-circulation of multiple HEV serotypes in children with and without HFMD during epidemic. Our study deserves the attention on HFMD control.

Genetic diversity of Bartonella quintana in macaques suggests zoonotic origin of trench fever

Bartonella quintana is a bacterium that causes a broad spectrum of diseases in humans including trench fever. Humans were previously considered to be the primary, if not the only, reservoir hosts for B. quintana. To identify the animal reservoir and extend our understanding of the ecological and evolutionary history of B. quintana, we examined blood samples from macaques and performed multilocus sequence typing (MLST) analysis. We demonstrated the prevalence of B. quintana infection was common in macaques from main primate centres in mainland China. Overall, 18.0% (59/328) of rhesus macaques and 12.7% (39/308) of cynomolgus macaques were found to be infected with B. quintana by blood culture and/or polymerase chain reaction. The infection was more frequently identified in juvenile and young monkeys compared with adult animals. In contrast with the relatively low level of sequence divergence of B. quintana reported in humans, our investigation revealed much higher genetic diversity in nonhuman primates. We identified 44 new nucleotide variable sites and 14 novel sequence types (STs) among the B. quintana isolates by MLST analysis. Some STs were found only in cynomolgus macaques, while some others were detected only in rhesus macaques, suggesting evidence of host‐cospeciation, which were further confirmed by phylogenetic analysis and Splits decomposition analysis. Our findings suggest that trench fever may primarily be a zoonotic disease with macaques as the natural hosts.

Molecular Epidemiology of Human Rhinovirus in Children with Acute Respiratory Diseases in Chongqing, China

Human rhinovirus-C (HRV-C) has been increasingly detected in patients with acute respiratory diseases (ARDs). Prolonged surveillance was performed on children with ARD to investigate the molecular epidemiology and clinical characteristics of HRV in Chongqing, China. Nasopharyngeal aspirates (NPA) were collected from hospitalized children with ARD during 2009–2012. HRV-C was genotyped by sequencing the VP4/VP2 coding region. Among the 1,567 NPAs obtained, 223 (14.2%) were HRV positive, and 75.3% of these 223 NPAs were co-infected with other viruses. HRV-A (54.7%) and HRV-C (39.9%) accounted for the majority of HRV infections. Logistic regression models demonstrated significant associations between HRV-A, HRV-C, and asthma attacks, as well as between HRV-C and wheezing. A phylogenetic tree showed that HRV-C2 was the predominant type of HRV-C, followed by HRV-C43, HRV-C1, and HRV-C17. Three novel genotypes were proposed on the basis of a low identity with the known HRVs. Our results showed that HRV-A and HRV-C were the predominant types of HRV infection, and HRV-C showed a high genetic variation in Chongqing, China. HRV infection was associated with asthma attacks and wheezing; furthermore, HRV infections played a minor role in causing severe pneumonia. This knowledge provides information for the prevention and control of HRV associated with ARDs.

The Severe Fever with Thrombocytopenia Syndrome Bunyavirus (SFTSV) Antibody in a Highly Endemic Region from 2011 to 2013: A Comparative Serological Study

A seropositive rate of 6.59% was determined in the highly endemic region for severe fever with thrombocytopenia syndrome. A significant correlation was observed between case incidence and seroprevalence on temporal and geographic levels. Seroprevalence was comparable in the last 3 years, indicating a stable and ongoing circulation of the infection.

The prospective evaluation of viral loads in patients with severe fever with thrombocytopenia syndrome

BACKGROUND Severe fever with thrombocytopenia syndrome (SFTS), caused by novel bunyavirus (SFTSV) is a potentially fatal disease that was first identified in China. Person to person transmission through contact with blood or body fluids was considered as an important infection route. OBJECTIVES The study is designed to investigate the longitudinal viral loads following SFTSV infection and to identify factors affecting viral shedding in SFTS patients. METHODS A prospective, observational study was performed on 208 laboratory-confirmed SFTSV infected patients in Xinyang, Henan Province. Sequential serum samples were collected on admission and during the hospitalization for quantification of SFTSV RNA by real-time RT-PCR. RESULTS The viral RNA was undetectable in 55.6% of the patients on admission into the hospital, becoming detectable in most cases until three days and attained maximum level on six days after disease onset. This was followed by an obvious decrease thereafter, but maintained detectable for over 20 days. Viral load was independently predictable of severe disease outcome throughout the hospitalization. Viral load of >10(7)copies/mL was predictable of fatal outcome. The serum levels of PLT, WBC, LDH, AST and CK were significantly associated with viral loads level. CONCLUSIONS The diagnosis of SFTSV infection based on PCR test should be performed at least three days after disease onset. Peaking viral loads were attained around six days after disease, posing a highest risk of human-to-human transmission.

Severe fever with thrombocytopenia syndrome in children: a case report

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel bunyavirus (SFTSV) in China. Humans of all ages living in endemic areas have high risk of acquiring SFTS. Most clinical data so far have been from adults and no clinical study was available from children yet. The present study identified four SFTSV infected children through hospital based surveillance. A prospective observational study was performed to obtain their clinical and laboratory characteristics.Case presentationThe patients’ age ranged from 4–15 years old and two were male. On hospitalization, fever, malaise and gastrointestinal syndromes were the most commonly presenting symptoms. Hemorrhagic symptoms or neurological manifestation was not recorded in any of the four pediatric patients. Hematological abnormalities at admission into hospital included leucopenia (4 cases), thrombocytopenia (1 case) and bicytopenia (1 case). The abnormal parameters included elevated aminotransferase (1 case), alanine transaminase (2 case), and lactate dehydrogenase (3 case). Laboratory parameters indicative of renal damage was not observed during the hospitalization. All the patients recovered well without sequelae being observed.ConclusionCompared with adults, pediatric patients with SFTSV infection seem to have less vague subjective complaints and less aggressive clinical course. Thrombocytopenia is suggested to be used less rigorously in recognizing SFTSV infection in pediatric patients, especially at early phase of disease.

Common adverse events associated with ribavirin therapy for Severe Fever with Thrombocytopenia Syndrome

Severe Fever with Thrombocytopenia Syndrome (SFTS) is associated with high mortality rate, for which antiviral therapy with ribavirin was recommended. Based on our previous study, no visible effect of ribavirin therapy in improving clinical outcome was observed. Here we have accumulated the sample size to 634, and by performing prospective observation on the clinical progress and laboratory parameters, we found a significantly higher incidence of anemia and hyperamylasemia in patients who received ribavirin therapy in comparison with those who received no therapy. Generalized estimating equation model disclosed a significant effect on hemoglobin reduction and blood amylase augmentation from ribavirin administration. The occurrence of anemia and hyperamylasemia was associated with SFTS patients receiving ribavirin therapy, which might be adverse event of this drug administration. The recommendation of ribavirin for treating SFTS should be applied with caution.

Epidemiological and clinical features of laboratory-diagnosed severe fever with thrombocytopenia syndrome in China, 2011–17: a prospective observational study

BACKGROUND Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with an increasing case number and extensive geographical expansion, raising concerns locally and globally; however, the description of its clinical features needs to be addressed by large studies. We aimed to determine all the clinical features of SFTS in a large population of patients in an endemic area. METHODS In this prospective observational study, data were collected on patients admitted to the Peoples Liberation Army Hospital in Xinyang, Henan Province, China, with laboratory-diagnosed SFTS. Demographic, clinical, laboratory, and treatment data were collected for each patient, and patients were followed up within 2 weeks after discharge or discontinuation of treatment. The association between each demographic, clinical, and laboratory variable with a fatal outcome was assessed. A clinical scoring model was designed for the early prediction of a fatal outcome, and the effect of treatment on outcome was analysed. FINDINGS Between April 1, 2011, and Oct 31, 2017, 2096 patients with laboratory-confirmed SFTS were admitted. Mean age at admission was 61·4 years (SD 12·2) and 1239 (59%) patients were female. The case fatality rate (CFR) was 16·2% (95% CI 14·6-17·8). A higher risk was associated with being male (unadjusted odds ratio [OR] 1·45, 95% CI 1·15-1·83; p=0·002), older age (for a 10-year increase, unadjusted OR 1·82, 95% CI 1·62-2·04; p<0·0001), longer delay in admission (for every extra day taken before admission to hospital, unadjusted OR 1·18, 1·12-1·24; p<0·0001), presence of diarrhoea (adjusted OR 1·44, 1·12-1·87; p=0·005) or dyspnoea (adjusted OR 8·35, 5·97-11·69; p<0·0001), and development of haemorrhagic signs (adjusted OR 2·79, 95% CI 2·18-3·57; p<0·0001) or neurological symptoms (adjusted OR 30·26, 21·39-42·81; p<0·0001). Laboratory variables that were associated with death included abnormal concentrations of lactate dehydrogenase, aspartate aminotransferase, and blood urea nitrogen, and abnormal neutrophil percentage, which together with age and neurological symptoms were combined in the clinical scoring system. A total score of more than 8 was the optimal threshold to predict risk of death for patients who were evaluated within 6 days after symptom onset (area under the curve 0·879, 95% CI 0·855-0·902). For all participants, viraemia was a strong predictor of fatal outcome (all p<0·0001). Ribavirin therapy was effective in reducing CFR from 6·25% (15 of 240 participants) to 1·16% (two of 173 participants), but only in patients with a viral load below 1×106 copies per mL (hazard ratio 9·72, 95% CI 1·30-72·87; p=0·027). INTERPRETATION The changing epidemiological features and high CFR of SFTS underscore the necessity of continued surveillance. Early prediction of fatal outcome can be attained by monitoring of clinical and laboratory data. Ribavirin should be applied early, with best results achieved before the viral load reaches 1 × 106 copies per mL. FUNDING National Natural Science Foundation of China.