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The positive rate of detecting the HEV71- (●) and CVA16-specific (○) IgM as a function of time after the onset of symptoms.
Source publication
Hand-foot-and-mouth disease (HFMD) is caused mainly by the human enterovirus type 71 (HEV71) and the Coxsackievirus A group type 16 (CVA16). Large outbreaks of disease have occurred frequently in the Asia-Pacific region. Reliable methods are needed for diagnosis of HFMD in children. IgM-capture ELISA, with its notable advantages of convenience and...
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In recent years, enterovirus A71 (EV-A71) infection has become a major global public health problem, especially for infants and young children. The results of epidemiological research show that EV-A71 infection can cause acute hand, foot, and mouth disease (HFMD) and complications of the nervous system in severe cases, including aseptic pediatric m...
SETD3 is an essential host factor for the replication of a variety of enteroviruses that specifically interacts with viral protease 2A. However, the interaction between SETD3 and the 2A protease has not been fully characterized. Here, we use X-ray crystallography and cryo-electron microscopy to determine the structures of SETD3 complexed with the 2...
The emerging human enterovirus 71 (EV71) represents a growing threat to public health, and no vaccine or specific antiviral is currently available. Human intravenous immunoglobulin (IVIG) is clinical used in treating severe EV71 infections. However, the discovery of antibody dependent enhancement (ADE) of EV71 infection illustrates the complex role...
Enterovirus A71 (EV-A71), coxsackievirus A16 (CV-A16), and CV-A10 belong to the main prevailing types causing hand-foot-and-mouth disease. Since EV-A71 monovalent vaccine does not confer cross-protection, developing a multivalent vaccine is essential. In this study, a trivalent chimeric virus-like particle of EV-A71 (EV-A71-VLPCHI3) was constructed...
Enterovirus A71 (EV-A71) causes hand, foot, and mouth disease associated with neurological complications in young children. Currently, there is no specific treatment for EV-A71 infection due to the inadequate information on viral biology and neuropathogenesis. Among enteroviruses, nonstructural 3A protein mediates the formation of replication organ...
Citations
... After the decay of maternal antibody, the seroprevalence was similar between CVA16 and EV-A71 within 4 months to 3-year-old children (unpublished study), although the EV-A71 GMT was higher than the CVA16 GMT. A similar pattern was also observed in previous studies [31][32][33], showing that EV-A71 might elicit stronger neutralizing antibody responses than CVA16. The capsid proteins of the two viruses have approximately 20% sequence differences, as well as antigenic variation caused by the different surface structures of the two viruses, which may explain this phenomenon [34]. ...
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.
... Previous studies have reported that serological cross-reactivity occurs when enterovirus IgM is detected by ELISA. However, Zhang et al. in a study using RT-PCR as the reference method, obtained overall ELISA specificities similar to ours and comparatively higher than those of other studies, in which the specificity ranged from 72.1% to 90.0% (Xu et al., 2010;Lin et al., 2011;Yu et al., 2012;Aw-Yong et al., 2016;Zhang et al., 2016). This may be because Zhang T. et al. and our group used the same ELISA kit, while that used in the other studies had a number of deficiencies other than the cross-reactivity in IgM detection. ...
Hand, foot and mouth disease (HFMD) is a major public health problem among children in the Asia-Pacific region. The optimal specimen for HFMD virological diagnosis remains unclear. Enterovirus A71 (EV-A71) neutralizing antibody titres detected in paired sera were considered the reference standard for calculating the sensitivity, specificity, positive and negative predictive value of throat swabs, rectal swabs, stool, blood samples and cerebrospinal fluid (CSF) by RT-PCR or ELISA assay. In this study, clinical samples from 276 HFMD patients were collected for analysing the sensitivity of different kind of specimens. Our results showed that stool had the highest sensitivity (88%, 95% CI: 74%–96%) and agreement with the reference standard (91%). The order of diagnostic yield for EV-A71 infection was stool sample ≥ rectal swab > throat swab > blood sample > CSF sample, and using a combination of clinical samples improved sensitivity for enterovirus detection. The sensitivity of ELISA for IgM antibody detection in sterile-site specimens was significantly higher than that of RT-PCR (serum/plasma: 62% vs. 2%, CSF: 47% vs. 0%) (P < 0.002). In conclusion, our results suggest that stool has the highest diagnostic yield for EV-A71-infected HFMD. If stool is unavailable, rectal swabs can be collected to achieve a similar diagnostic yield. Otherwise, throat swabs may be useful in detecting positive samples. Although IgM in blood or CSF is diagnostically accurate, it lacks sensitivity, missing 40%–50% of cases. The higher proportion of severe cases and shorter interval between onset and sampling contributed to the increase in congruency between clinical testing and the serological reference standard.
... However, no studies have systematically defined the acute and convalescence phases of enterovirus infection. Previous studies performed according to experience without much evidence have defined various periods, such as 03 d (11,14,15), 05 d (16), 07 d (17,18) or 24 d (19) after onset, as the acute stage. Researchers have collected convalescent sera at 716 d (11,19), 1430 d (16), 46 wk (20) or 2 mo (14) after onset. ...
... Their results showed that the seropositive percentage changed from 60% for EV-A71 and 27% for CVA16 at enrollment (<3 d after onset) to 100% at the second serum collection (within 714 d after enrollment), and the corresponding GMTs of EV-A71 patients increased from 38 to 295 and were lower for CVA16 (which increased from 10 to 141), similar to our results (11). The differences in the positive percentage of IgM during the course of infection with EV-A71 and CVA16 were also consistent with our finding of an increase in the seropositive percentage (17). In addition, the kinetics for the anti-CVA16 IgM response decreased after 20 wk, similar to those in our study. ...
... After adjusting for age and clinical severity, the number of EV-A71infected patients was still higher than that of CVA16 patients. These results suggest that EV-A71 might elicit stronger NAb responses than CVA16, and a similar pattern was also observed in previous studies (11,12,17). This difference is probably due to the ∼20% sequence difference in the capsid proteins of the two viruses and the antigenic variation caused by the different surface structures of the two viruses (28). ...
Hand, foot, and mouth disease (HFMD), which is mainly caused by coxsackievirus A16 (CVA16) or enterovirus A71 (EV-A71), poses a serious threat to children's health. However, the long-term dynamics of the neutralizing Ab (NAb) response and ideal paired-serum sampling time for serological diagnosis of CVA16-infected HFMD patients were unclear. In this study, 336 CVA16 and 253 EV-A71 PCR-positive HFMD inpatients were enrolled and provided 452 and 495 sera, respectively, for NAb detection. Random-intercept modeling with B-spline was conducted to characterize NAb response kinetics. The NAb titer of CVA16 infection patients was estimated to increase from negative (2.1, 95% confidence interval [CI]: 1.4-3.3) on the day of onset to a peak of 304.8 (95% CI: 233.4-398.3) on day 21 and then remained >64 until 26 mo after onset. However, the NAb response level of EV-A71-infected HFMD patients was much higher than that of CVA16-infected HFMD patients throughout. The geometric mean titer was significantly higher in severe EV-A71-infected patients than in mild patients, with a 2.0-fold (95% CI: 1.4-3.2) increase. When a 4-fold rise in titer was used as the criterion for serological diagnosis of CVA16 and EV-A71 infection, acute-phase serum needs to be collected at 0-5 d, and the corresponding convalescent serum should be respectively collected at 17.4 (95% CI: 9.6-27.4) and 24.4 d (95% CI: 15.3-38.3) after onset, respectively. In conclusion, both CVA16 and EV-A71 infection induce a persistent humoral immune response but have different NAb response levels and paired-serum sampling times for serological diagnosis. Clinical severity can affect the anti-EV-A71 NAb response.
... El aislamiento del virus tiene baja sensibilidad, pero alta especificidad 1,3 . Las pruebas ELISA detectan anticuerpos IgM en un porcentaje elevado de pacientes y son pruebas económicas 9,10 . Actualmente el método de elección es la PCR, teniendo una especificidad y sensibilidad del 100% en LCR y 88% en suero y orina combinados 11 , pero con la limitación que solo puede realizarse en laboratorios de alta complejidad. ...
Resumen La Enfermedad mano pie boca es una patología exantemática viral muy contagiosa, de predominio en la edad pediátrica. Sus agentes etiológicos más frecuentes son los virus Coxsackie y Enterovirus. Se caracteriza clínicamente por la presencia de fiebre, erosiones en mucosa bucal y exantema máculo vesicular en regiones acrales. Generalmente se autolimita, pero puede presentar complicaciones severas con compromiso neurológico, pulmonar y cardíaco. Se han observado brotes mundiales, por lo que actualmente es considerada un problema de salud pública emergente, tanto en poblaciones pediátricas como adultos. Se presentan casos de pacientes adultos inmunocompetentes con transmisión intrafamiliar de Coxsackie B, sin complicaciones severas. Estos casos muestran la importancia de la prevención para evitar brotes epidémicos, además de destacar la presentación infrecuente en adultos inmunocompetentes.
... Virus isolation, neutralization tests and nucleic acid amplification are commonly used for the detection and diagnosis of EV71 and CA16 [9,10]. Virus isolation and neutralization are not rapid and accurate enough because of complex procedures and low specificities and sensitivities. ...
Background:
Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the two main etiological agents of Hand, Foot and Mouth Disease (HFMD). Simple and rapid detection of EV71 and CA16 is critical in resource-limited settings.
Methods:
Duplex real time reverse-transcription recombinase aided amplification (RT-RAA) assays incorporating competitive internal amplification controls (IAC) and visible RT-RAA assays combined with lateral flow strip (LFS) for detection of EV71 and CA16 were developed respectively. Duplex real time RT-RAA assays were performed at 42 °C within 30 min using a portable real-time fluorescence detector, while LFS RT-RAA assays were performed at 42 °C within 30 min in an incubator. Recombinant plasmids containing conserved VP1 genes were used to analyze the sensitivities of these two methods. A total of 445 clinical specimens from patients who were suspected of being infected with HFMD were used to evaluate the performance of the assays.
Results:
The limit of detection (LoD) of the duplex real time RT-RAA for EV71 and CA16 was 47 copies and 38 copies per reaction, respectively. The LoD of the LFS RT-RAA for EV71 and CA16 were both 91 copies per reaction. There was no cross reactivity with other enteroviruses. Compared to reverse transcription-quantitative PCR (RT-qPCR), the clinical diagnostic sensitivities of the duplex real time RT-RAA assay were 92.3% for EV71 and 99.0% for CA16, and the clinical diagnostic specificities were 99.7 and 100%, respectively. The clinical diagnostic sensitivities of the LFS RT-RAA assay were 90.1% for EV71 and 94.9% for CA16, and the clinical diagnostic specificities were 99.7 and 100%, respectively.
Conclusions:
The developed duplex real time RT-RAA and LFS RT-RAA assays for detection of EV71 and CA16 are potentially suitable in primary clinical settings.
... We included the HFMD surveillance data of 29 provinces of mainland China collected during January 1, 2008-December 31, 2015. We excluded data from Hunan and Hubei Provinces from this study because (since 2010 for Hunan Province and 2012 for Hubei Province) most of the hospitals in these provinces reported EV-A71 infection on the basis of EV-A71 IgM antibody detection assays, which are unreliable tests (15)(16)(17). ...
Using China’s national surveillance data on hand, foot and mouth disease (HFMD) for 2008–2015, we described the epidemiologic and virologic features of recurrent HFMD. A total of 398,010 patients had HFMD recurrence; 1,767 patients had 1,814 cases of recurrent laboratory-confirmed HFMD: 99 reinfections of enterovirus A71 (EV-A71) with EV-A71, 45 of coxsackievirus A16 (CV-A16) with CV-A16, 364 of other enteroviruses with other enteroviruses, 383 of EV-A71 with CV-A16 and CV-A16 with EV-A71, and 923 of EV-A71 or CV-A16 with other enteroviruses and other enteroviruses with EV-A71 or CV-A16. The probability of HFMD recurrence was 1.9% at 12 months, 3.3% at 24 months, 3.9% at 36 months, and 4.0% at 38.8 months after the primary episode. HFMD severity was not associated with recurrent episodes or time interval between episodes. Elucidation of the mechanism underlying HFMD recurrence with the same enterovirus serotype and confirmation that HFMD recurrence is not associated with disease severity is needed. © 2018, Centers for Disease Control and Prevention (CDC). All rights reserved.
... The role of the dentist is important, as he/she is one of the professionals who must help with diagnosis when the patient seeks professional advice for painful oral lesions. Another diagnostic method studied recently by Yu et al. is the use of IgM ELISA in EV71 and CVA16 infections to correctly identify the virus causing the disease in patients [36]. ...
... The cross-reactivity with other non-EV-A71 Enteroviruses was reported to be 11.4% [34]. Good sensitivity for early stage EV-A71 IgM detection at 95.7% in an 'in house' IgM-capture ELISA assay was again confirmed in the study by Yu et al. (2012) However, for the sera derived from 134 EV-A71 infected patients, significant cross-reactivity towards Coxsackievirus CV-A 16 IgM was observed in 28.2% of the 206 clinical samples. For the 119 sera derived from 16 infected patients, CV-A16 IgM was detected only in 69.7% of clinical samples, while cross reactivity towards EV-A71 IgM was present in 30.3% of samples. ...
... For the 119 sera derived from 16 infected patients, CV-A16 IgM was detected only in 69.7% of clinical samples, while cross reactivity towards EV-A71 IgM was present in 30.3% of samples. The EV-A71 IgM was also detected in 14 of 49 sera infected with other Enteroviruses [35]. Despite the cross-reactivity being reported by several studies, EV-A71 IgM ELISA kits have been marketed by a few commercial companies. ...
... A serological test such as enzyme-linked immunosorbent assay (ELISA) is an alternative as results can be obtained in 2-3 hours and most diagnostic laboratories will have access to the equipment, and IgM can be detected early in EV-A71 infection (Zhao et al., 2011). The use of two commercially available EV-A71 IgM kits, EV-A71 IgM-capture ELISA and EV-A71 IgM-colloidal gold immunochromatographic assay (GICA), have been reported in China (Xu et al., 2010;Yu et al., 2012;Wang et al., 2015) but it is critical to evaluate assays in different geographical settings, where there may be potential differences in circulating EV-A71 genotype and patient immune responses. In this study, we evaluated the performances of these two commercial assays in serum samples collected from HFMD patients in Malaysia. ...
... There are very few commercial EV-A71 IgM diagnostic kits available. In this study, we compared EV-A71 IgM-capture ELISA and IgM GICA assays in Malaysian patients, and found sensitivity rates (78.4% and 75.7%, respectively) that were lower than the 93.6% and 94.1% (IgM-capture ELISA), and 93.3% (IgM-GICA) reported earlier in China (Xu et al., 2010;Yu et al., 2012, Wang et al., 2015. One possible reason might be the varying detection of antibodies resulting from different circulating EV-A71 genotypes found in Malaysia and China. ...
... When testing serum from children with HFMD, the assays showed specificity rates of 80.8% and 76.9% for the IgM-capture ELISA and IgM GICA, respectively. These specificity rates were lower than the 88.6% reported by Xu et al. (2010), but higher than the 69.6% reported for the IgM-capture ELISA by Yu et al. (2012) and the 50% for the IgM GICA reported by Wang et al. (2015). The PPV rates of 74.4% (ELISA) and 70.0% ...
Hand, foot and mouth disease (HFMD) is a common childhood infection caused by many enteroviruses, including enterovirus A71 (EV-A71). As EV-A71 is associated with severe neurological disease, early diagnosis is critical for clinical and public health management. In developing countries such as Malaysia, laboratory capacity to carry out EV-A71 IgM detection is greater than that of the gold standard methods of virus culture or molecular detection. This study evaluated two diagnostic kits, EV-A71 IgM-capture enzyme-linked immunosorbent (ELISA) and EV-A71 IgM-colloidal gold immunochromatographic assay (GICA), which had previously only been assessed in China. The assays were tested with 89 serum samples from patients with suspected HFMD. The sensitivity, specificity, positive predictive value, and negative predictive value rates were 78.4%, 80.8%, 74.4%, and 84.0%, respectively, for the IgM-capture ELISA, and 75.7%, 76.9%, 70.0%, and 81.6% for the IgM GICA. These performance measures were similar between the two assays. Concordance between the two assays was 91.1%. The sensitivity rates were lower than those previously reported, likely because the multiple circulating EV-A71 genotypes in Malaysia differ from the C4 subgenotype found in China and used in the assays. Both assays had low false positive rates (12.5% and 16.7% for ELISA and GICA, respectively) when tested on sera from patients confirmed to have enteroviruses. Both diagnostic kits are suitable for early diagnosis of HFMD caused by EV-A71 in Malaysia, but confirmation with culture or PCR is still important.
... The role of the dentist is important, as he/she is one of the professionals who must help with diagnosis when the patient seeks professional advice for painful oral lesions. Another diagnostic method studied recently by Yu et al. is the use of IgM ELISA in EV71 and CVA16 infections to correctly identify the virus causing the disease in patients [36]. ...
Background
To report an uncommon case of hand, foot and mouth disease, (HFMD) in an immunocompetent adult; a highly infectious disease, characterized by the appearance of vesicles on the mouth, hands and feet, associated with coxsackieviruses and enteroviruses; including a literature review. Case reportA 23 year Caucasian male with no medical or surgical history, no allergies, was not taking any medication and smoked ten cigarettes a day, suffering from discomfort in the oral cavity; itching, burning and pain when swallowing associated with small erythematous lesions located on the hard palate, and small ulcers in tonsillar pillars and right buccal mucosa. Mild fever of 37.8 °C and general malaise. The patient reported he had had contact with a child diagnosed with HFMD. From his background and symptoms, the patient was diagnosed with HFMD. Following symptomatic treatment, the symptoms remitted in 7 days. MethodsA literature review in MEDLINE (PubMed). The inclusion criteria were for studies on humans over the last 5 years, using the keywords HFMD. ResultsWe found 925 articles, which were subsequently reduced to 52 documents after applying the inclusion criteria. Maculopapular lesions were found on hands and feet. Conclusions
Dentists may have a key role diagnosing the disease. A surveillance system to predict future outbreaks, encourage early diagnosis, put appropriate public health measures in place and research vaccine development is vitally important in order to control the disease.
