Penny Lewthwaite

Virology, epidemiology, pathogenesis, and control of enterovirus 71

First isolated in California, USA, in 1969, enterovirus 71 (EV71) is a major public health issue across the Asia-Pacific region and beyond. The virus, which is closely related to polioviruses, mostly affects children and causes hand, foot, and mouth disease with neurological and systemic complications. Specific receptors for this virus are found on white blood cells, cells in the respiratory and gastrointestinal tract, and dendritic cells. Being an RNA virus, EV71 lacks a proofreading mechanism and is evolving rapidly, with new outbreaks occurring across Asia in regular cycles, and virus gene subgroups seem to differ in clinical epidemiological properties. The pathogenesis of the severe cardiopulmonary manifestations and the relative contributions of neurogenic pulmonary oedema, cardiac dysfunction, increased vascular permeability, and cytokine storm are controversial. Public health interventions to control outbreaks involve social distancing measures, but their effectiveness has not been fully assessed. Vaccines being developed include inactivated whole-virus, live attenuated, subviral particle, and DNA vaccines.

Clinical features, diagnosis, and management of enterovirus 71

Although poliomyelitis has been mostly eradicated worldwide, large outbreaks of the related enterovirus 71 have been seen in Asia-Pacific countries in the past 10 years. This virus mostly affects children, manifesting as hand, foot, and mouth disease, aseptic meningitis, poliomyelitis-like acute flaccid paralysis, brainstem encephalitis, and other severe systemic disorders, including especially pulmonary oedema and cardiorespiratory collapse. Clinical predictors of severe disease include high temperature and lethargy, and lumbar puncture might reveal pleocytosis. Many diagnostic tests are available, but PCR of throat swabs and vesicle fluid, if available, is among the most efficient. Features of inflammation, particularly in the anterior horns of the spinal cord, the dorsal pons, and the medulla can be clearly seen on MRI. No established antiviral treatment is available. Intravenous immunoglobulin seems to be beneficial in severe disease, perhaps through non-specific anti-inflammatory mechanisms, but has not been tested in any formal trials. Milrinone might be helpful in patients with cardiac dysfunction.

A cohort study to assess the new WHO Japanese encephalitis surveillance standards

Objective To assess the field-test version of the new WHO Japanese encephalitis (JE) surveillance standards. Methods We applied the clinical case definition of acute encephalitis syndrome (AES), laboratory diagnostic criteria and case classifications to patients with suspected central nervous system (CNS) infections in southern Viet Nam. Findings Of the 380 patients (149 children) recruited with suspected CNS infections, 296 (96 children) met the AES case definition. 54 children were infected with JE virus (JEV), of whom 35 (65%) had AES, giving a sensitivity of 65% (95% CI: 56–73) and specificity of 39% (95% CI: 30–48). Nine adults with JEV presented with AES. 19 JEV-infected children missed by surveillance included 10 with acute flaccid paralysis, two with flaccid hemiparesis and six with meningism only. Altering the case definition to include limb paralysis and meningism improved sensitivity to 89% (95% CI: 83–95), while reducing specificity to 23% (95% CI: 15–30). Six children that did not have AES on admission had reduced consciousness after admission. Cerebrospinal fluid (CSF) analysis diagnosed seven patients negative on serum analysis. Five patients with neurological manifestations of dengue infection had JEV antibodies in serum and would have been misdiagnosed had we not tested for dengue antibodies in parallel. Conclusion Children infected with JEV that presented with acute limb paralysis or neck stiffness only were missed by the surveillance standards, although some of them subsequently became encephalopathic. A footnote in the surveillance standards drawing attention to these presentations would be helpful. An acute CSF sample is more sensitive and specific than an acute serum sample.

Current use and development of vaccines for Japanese encephalitis

Background: Japanese encephalitis (JE) is a significant cause of human morbidity and mortality throughout Asia. Vaccines for JE have been available for many years and their use has been effective in reducing the incidence of JE disease in several countries but, as disease incidence has decreased, concerns regarding adverse events following immunisation have increased. Objective: To review existing JE vaccines and new candidates in advanced preclinical or clinical evaluation. Methods: The review primarily covers published and some unpublished literature from the past decade describing current use of approved JE vaccines in various parts of the world, and advanced development and clinical testing of alternative vaccine candidates. Results/conclusion: There is a clear need for additional licensing of existing or new JE vaccines. Several promising candidates are currently in use or completing clinical trials.

The incidence of acute encephalitis syndrome in Western industrialised and tropical countries

BackgroundAs part of efforts to control Japanese encephalitis (JE), the World Health Organization is producing a set of standards for JE surveillance, which require the identification of patients with acute encephalitis syndrome (AES). This review aims to provide information to determine what minimum annual incidence of AES should be reported to show that the surveillance programme is active.MethodsA total of 12,436 articles were retrieved from 3 databases; these were screened by title search and duplicates removed to give 1,083 papers which were screened by abstract (or full paper if no abstract available) to give 87 papers. These 87 were reviewed and 25 papers identified which met the inclusion criteria.ResultsCase definitions and diagnostic criteria, aetiologies, study types and reliability varied among the studies reviewed. Amongst prospective studies reviewed from Western industrialised settings, the range of incidences of AES one can expect was 10.5–13.8 per 100,000 for children. For adults only, the minimum incidence from the most robust prospective study from a Western setting gave an incidence of 2.2 per 100,000. The incidence from the two prospective studies for all age groups was 6.34 and 7.4 per 100,000 from a tropical and a Western setting, respectively. However, both studies included arboviral encephalitis, which may have given higher rather than given higher] incidence levels.ConclusionIn the most robust, prospective studies conducted in Western industrialised countries, a minimum incidence of 10.5 per 100,000 AES cases was reported for children and 2.2 per 100,000 for adults. The minimum incidence for all ages was 6.34 per 100,000 from a tropical setting. On this basis, for ease of use in protocols and for future WHO surveillance standards, a minimum incidence of 10 per 100,000 AES cases is suggested as an appropriate target for studies of children alone and 2 per 100,000 for adults and 6 per 100,000 for all age groups.

Gastrointestinal parasites in the immunocompromised.

Purpose of review Parasites and other infections have many effects on the gastrointestinal tract of individuals who are immunocompromised. Few reviews focus on parasitic infections, which are covered here. Recent findings The review first examines recent advances in our understanding of the taxonomy, diagnosis and treatment of pathogens such as cryptosporidia, cyclospora, isospora and microsporidia, which are recognized causes of diarrhoea in the immunocompromised, and discusses possible links between amoebiasis and HIV. The complex interactions of both intact and abnormal immune systems with helminth infections such as hookworm and strongyloidiasis, and with trematode infections such as schistosomiasis, are receiving increasing attention. These are discussed, together with the novel concept of using live helminths to treat inflammatory bowel disease. Summary Parasitic infections remain a significant problem for immunocompromised individuals in resource-poor settings, and further work is needed to develop accessible diagnostic tests and to improve our understanding and management of their pathogenic effects. New concepts about the interactions of helminths with host immunity suggest the need for collection of further epidemiological and clinical data to unravel the complexities of such immunological interactions.

Chikungunya Virus and Central Nervous System Infections in Children, India

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus best known for causing fever, rash, arthralgia, and occasional neurologic disease. By using real-time reverse transcription–PCR, we detected CHIKV in plasma samples of 8 (14%) of 58 children with suspected central nervous system infection in Bellary, India. CHIKV was also detected in the cerebrospinal fluid of 3 children.

The Epidemiology, Clinical Features, and Long-Term Prognosis of Japanese Encephalitis in Central Sarawak, Malaysia, 1997–2005

BACKGROUND Japanese encephalitis is a major public health problem in Asia. However, there is little data on the long-term outcome of Japanese encephalitis survivors. METHODS We prospectively evaluated children with serologically confirmed Japanese encephalitis over an 8.3-year period. The patients were assessed and their outcomes were graded with a functional outcome score at hospital discharge and at follow-up appointments. We examined how patient outcome at hospital discharge compared with that at long-term follow-up visits, when changes in outcome occurred, and the prognostic indicators of the eventual outcome. RESULTS One hundred and eighteen patients were recruited into the study, and 10 (8%) died during the acute phase of illness. At hospital discharge, 44 (41%) of the 108 patients who survived had apparent full recovery; 3 (3%) had mild, 28 (26%) had moderate, and 33 (31%) had severe neurological sequelae. Eighty six of the 108 patients were followed up for a median duration of 52.9 months (range, 0.9-114.9 months). During follow-up, 31 patients experienced improvement, but 15 patients experienced deterioration in their outcome grade. In most cases, assessment during the first 3-6 months after hospital discharge was predictive of the long-term outcome. More than one-half of the patients continued to experience neuropsychological sequelae and behavioral disorders. A combination of poor perfusion, Glasgow coma score < or =8, and > or =2 witnessed seizures predicted a poor long-term outcome with 65% sensitivity and 92% specificity. CONCLUSIONS Neurological assessment of Japanese encephalitis survivors at hospital discharge does not predict long-term outcome. Seizures and shock are treatable risk factors for a poor outcome at hospital discharge and at long-term follow-up visits.

Human Parvovirus 4 as Potential Cause of Encephalitis in Children, India

To investigate whether uncharacterized infectious agents were associated with neurologic disease, we analyzed cerebrospinal fluid specimens from 12 children with acute central nervous system infection. A high-throughput pyrosequencing screen detected human parvovirus 4 DNA in cerebrospinal fluid of 2 children with encephalitis of unknown etiology.

Enterovirus 75 encephalitis in children, Southern India

Recent outbreaks of enterovirus in Southeast Asia emphasize difficulties in diagnosis of this infection. To address this issue, we report 5 (4.7%) children infected with enterovirus 75 among 106 children with acute encephalitis syndrome during 2005–2007 in southern India. Throat swab specimens may be useful for diagnosis of enterovirus 75 infection.