Clinical features and management of individuals admitted to hospital with monkeypox and associated complications across the UK: a retrospective cohort study.

BACKGROUND: The scale of the 2022 global mpox (formerly known as monkeypox) outbreak has been unprecedented. In less than 6 months, non-endemic countries have reported more than 67 000 cases of a disease that had previously been rare outside of Africa. Mortality has been reported as rare but hospital admission has been relatively common. We aimed to describe the clinical and laboratory characteristics and outcomes of individuals admitted to hospital with mpox and associated complications, including tecovirimat recipients. METHODS: In this cohort study, we undertook retrospective review of electronic clinical records and pathology data for all individuals admitted between May 6, and Aug 3, 2022, to 16 hospitals from the Specialist and High Consequence Infectious Diseases Network for Monkeypox. The hospitals were located in ten cities in England and Northern Ireland. Inclusion criteria were clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing. Patients admitted solely for isolation purposes were excluded from the study. Key outcomes included admission indication, complications (including pain, secondary infection, and mortality) and use of antibiotic and anti-viral treatments. Routine biochemistry, haematology, microbiology, and virology data were also collected. Outcomes were assessed in all patients with available data. FINDINGS: 156 individuals were admitted to hospital with complicated mpox during the study period. 153 (98%) were male and three (2%) were female, with a median age of 35 years (IQR 30-44). Gender data were collected from electronic patient records, which encompassed full formal review of clincian notes. The prespecified options for data collection for gender were male, female, trans, non-binary, or unknown. 105 (71%) of 148 participants with available ethnicity data were of White ethnicity and 47 (30%) of 155 were living with HIV with a median CD4 count of 510 cells per mm3 (IQR 349-828). Rectal or perianal pain (including proctitis) was the most common indication for hospital admission (44 [28%] of 156). Severe pain was reported in 89 (57%) of 156, and secondary bacterial infection in 82 (58%) of 142 individuals with available data. Median admission duration was 5 days (IQR 2-9). Ten individuals required surgery and two cases of encephalitis were reported. 38 (24%) of the 156 individuals received tecovirimat with early cessation in four cases (two owing to hepatic transaminitis, one to rapid treatment response, and one to patient choice). No deaths occurred during the study period. INTERPRETATION: Although life-threatening mpox appears rare in hospitalised populations during the current outbreak, severe mpox and associated complications can occur in immunocompetent individuals. Analgesia and management of superimposed bacterial infection are priorities for patients admitted to hospital. FUNDING: None.

Rapid qualitative analysis in a mixed-methods evaluation of an infection prevention intervention in a UK hospital setting during the COVID-19 pandemic: A discussion of the CLEAN study methodology.

The COVID-19 pandemic created an urgent need for high-quality rapid research. One clinical challenge was how to minimise the risk of transmission in the hospital setting. The CLEAN study conducted a rapid evaluation of the potential utility of a spray-based disinfectant in a hospital setting. The study was undertaken between December 2020 and March 2021 and involved the implementation of the spray in 10 different clinical areas in one UK teaching hospital. A mixed-methods approach was adopted (including observations, surveys, and qualitative interviews) informed by the theories for understanding the implementation of new healthcare technologies. The evaluation found that while the spray had a number of perceived benefits when added to existing disinfection processes, other factors limited its potential utility. These findings informed a number of recommendations for future adoption within hospital settings. This paper describes and reflects on the rapid methodology that allowed us to undertake the study and deliver results in a short space of time. We experienced a number of pressures during set-up and fieldwork due to the challenging conditions caused by the pandemic, and the methodological approach had to evolve throughout the study because of the changing clinical context. The involvement of clinicians from the research setting as full members of the research team was key to the rapid delivery of the research. They provided an essential link to the implementation environment, and their experiential knowledge of the setting added an important perspective to the analysis. Balancing their involvement with their clinical roles was challenging, however, as was coordinating a large and diverse team of interviewers in such a short space of time. Overall, the study highlighted the value of rapid research to inform urgent healthcare decisions in a pandemic. Although our experience suggests that conducting such research requires some practical and methodological trade-offs, we found that there were also numerous benefits of using rapid methods and identified various opportunities to ensure their robustness.

SARS-CoV-2 diagnostics: Towards a more comprehensive approach to routine patient testing.

The SARS-CoV-2 pandemic has provided the stimulus for the rapid development of a variety of diagnostic testing methods. Initially these were deployed as screening tools to evidence spread of the virus within populations. The recent availability of vaccines against the virus and the need to better understand the parameters of post-infection protective immunity requires development of methods, suitable for use in the routine diagnostic laboratory, capable of characterising the viral immune response in greater detail. Such methods need to consider both cellular and humoral immunity. Toward this aim we have investigated use of a commercial multiplex assay (COVID Plus Assay, One Lambda), providing assessment of the SARS-CoV-2 response at structural level, and developed an in-house cell stimulation assay using commercially available viral peptides (Miltenyi). This paper reports our experience in use of these methods in extended investigation of a cohort of healthcare workers with prior screening results indicative of viral infection. The antibody response generated is shown to be both qualitatively and quantitatively different in different individuals. Similarly a recall response to SARS-CoV-2 antigen involving the T cell compartment can be readily demonstrated in recovered individuals but is of variable magnitude.

Long-term clinical outcomes in survivors of severe acute respiratory syndrome and Middle East respiratory syndrome coronavirus outbreaks after hospitalisation or ICU admission: A systematic review and meta-analysis.

OBJECTIVE: To determine long-term clinical outcomes in survivors of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronavirus infections after hospitalization or intensive care unit admission. DATA SOURCES: Ovid MEDLINE, EMBASE, CINAHL Plus, and PsycINFO were searched. STUDY SELECTION: Original studies reporting clinical outcomes of adult SARS and MERS survivors 3 months after admission or 2 months after discharge were included. DATA EXTRACTION: Studies were graded using the Oxford Centre for Evidence-Based Medicine 2009 Level of Evidence Tool. Meta-analysis was used to derive pooled estimates for prevalence/severity of outcomes up to 6 months after hospital discharge, and beyond 6 months after discharge. DATA SYNTHESIS: Of 1,169 identified studies, 28 were included in the analysis. Pooled analysis revealed that common complications up to 6 months after discharge were: impaired diffusing capacity for carbon monoxide (prevalence 27%, 95% confidence interval (CI) 15­45%); and reduced exercise capacity (mean 6-min walking distance 461 m, CI 450­473 m). The prevalences of post-traumatic stress disorder (39%, 95% CI 31­47%), depression (33%, 95% CI 20­50%) and anxiety (30%, 95% CI 10­61) beyond 6 months after discharge were considerable. Low scores on Short-Form 36 were identified beyond 6 months after discharge. CONCLUSION: Lung function abnormalities, psychological impairment and reduced exercise capacity were common in SARS and MERS survivors. Clinicians should anticipate and investigate similar long-term outcomes in COVID-19 survivors.

'More than devastating'-patient experiences and neurological sequelae of Japanese encephalitis§.

BACKGROUND: Japanese encephalitis (JE), caused by the mosquito-borne JE virus, is a vaccine-preventable disease endemic to much of Asia. Travellers from non-endemic areas are susceptible if they travel to a JE endemic area. Although the risk to travellers of JE is low, the consequences may be severe. METHODS: Here, we describe three cases of JE in British travellers occurring in 2014-15. In addition, we report, through interviews with survivors and their families, personal experiences of life after JE. RESULTS: Three cases of JE were diagnosed in British travellers in 2014/15. One was acquired in Thailand, one in China and one in either Thailand, Laos or Cambodia. All three patients suffered severe, life-threatening illnesses, all were admitted to intensive care units and required medical evacuation back to the UK. One patient suffered a cardiac arrest during the acute stage but made a good recovery. The other two patients remain significantly paralysed and ventilator dependent. All three cases had clear indications for vaccination, and all have been left with life-changing neurological sequelae. CONCLUSIONS: Travel health providers should be aware of the severity of JE, as well as the risk, allowing travellers to make fully informed decisions on JE vaccination.

Human T cell responses to Japanese encephalitis virus in health and disease.

Japanese encephalitis (JE) virus (JEV) is an important cause of encephalitis in children of South and Southeast Asia. However, the majority of individuals exposed to JEV only develop mild symptoms associated with long-lasting adaptive immunity. The related flavivirus dengue virus (DENV) cocirculates in many JEV-endemic areas, and clinical data suggest cross-protection between DENV and JEV. To address the role of T cell responses in protection against JEV, we conducted the first full-breadth analysis of the human memory T cell response using a synthetic peptide library. Ex vivo interferon-γ (IFN-γ) responses to JEV in healthy JEV-exposed donors were mostly CD8(+) and targeted nonstructural (NS) proteins, whereas IFN-γ responses in recovered JE patients were mostly CD4(+) and targeted structural proteins and the secreted protein NS1. Among patients, a high quality, polyfunctional CD4(+) T cell response was associated with complete recovery from JE. T cell responses from healthy donors showed a high degree of cross-reactivity to DENV that was less apparent in recovered JE patients despite equal exposure. These data reveal divergent functional CD4(+) and CD8(+) T cell responses linked to different clinical outcomes of JEV infection, associated with distinct targeting and broad flavivirus cross-reactivity including epitopes from DENV, West Nile, and Zika virus.

A preliminary randomized double blind placebo-controlled trial of intravenous immunoglobulin for Japanese encephalitis in Nepal.

BACKGROUND: Japanese encephalitis (JE) virus (JEV) is a mosquito-borne flavivirus found across Asia that is closely related to West Nile virus. There is no known antiviral treatment for any flavivirus. Results from in vitro studies and animal models suggest intravenous immunoglobulin (IVIG) containing virus-specific neutralizing antibody may be effective in improving outcome in viral encephalitis. IVIG's anti-inflammatory properties may also be beneficial. METHODOLOGY/PRINCIPAL FINDINGS: We performed a pilot feasibility randomized double-blind placebo-controlled trial of IVIG containing anti-JEV neutralizing antibody (ImmunoRel, 400mg/kg/day for 5 days) in children with suspected JE at two sites in Nepal; we also examined the effect on serum neutralizing antibody titre and cytokine profiles. 22 children were recruited, 13 of whom had confirmed JE; 11 received IVIG and 11 placebo, with no protocol violations. One child (IVIG group) died during treatment and two (placebo) subsequently following hospital discharge. Overall, there was no difference in outcome between treatment groups at discharge or follow up. Passive transfer of anti-JEV antibody was seen in JEV negative children. JEV positive children treated with IVIG had JEV-specific neutralizing antibody titres approximately 16 times higher than those treated with placebo (p=0.2), which was more than could be explained by passive transfer alone. IL-4 and IL-6 were higher in the IVIG group. CONCLUSIONS/SIGNIFICANCE: A trial of IVIG for JE in Nepal is feasible. IVIG may augment the development of neutralizing antibodies in JEV positive patients. IVIG appears an appealing option for JE treatment that warrants further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01856205.

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.

Disability from Japanese encephalitis in Cambodia and Viet Nam.

A cohort of Japanese encephalitis (JE) survivors in Cambodia and Viet Nam were assessed at least 4 months after hospital discharge in order to understand the extent of disability after JE. We used a simple assessment tool which focuses on the impact on daily life. In total, 64 disability assessments were conducted: 38 in Cambodia and 26 in Viet Nam. In Cambodia, 4 (11%) children had severe sequelae, suggesting the children would likely be dependent, 15 (39%) had moderate sequelae and 17 (45%) had mild sequelae. In Viet Nam, two (8%) persons had severe sequelae, five (19%) had moderate sequelae and eight (31%) had mild sequelae. In many JE-endemic areas there are no multi-disciplinary teams with sophisticated equipment to assess patients after JE disease. This assessment tool can assist with patient management and generate data to support the need for programmes to prevent disease and improve outcomes for survivors.

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.

Tumefactive demyelination-an unusual neurological presentation of HIV.

We describe 3 individuals infected with human immunodeficiency virus with unusual focal brain syndromes; magnetic resonance imaging revealed "open-ring" pattern space occupying lesions. After deterioration while the patients were receiving anti-Toxoplasma therapy, brain biopsy was performed, which revealed aggressive demyelination consistent with tumefactive demyelination. Treatment with high-dose steroids resulted in complete recovery in all cases.

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.

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.

Disability after encephalitis: development and validation of a new outcome score.

OBJECTIVE: To develop a simple tool for assessing the severity of disability resulting from Japanese encephalitis and whether, as a result, a child is likely to be dependent. METHODS: A new outcome score based on a 15-item questionnaire was developed after a literature review, examination of current assessment tools, discussion with experts and a pilot study. The score was used to evaluate 100 children in Malaysia (56 Japanese encephalitis patients, 2 patients with encephalitis of unknown etiology and 42 controls) and 95 in India (36 Japanese encephalitis patients, 41 patients with encephalitis of unknown etiology and 18 controls). Inter- and intra-observer variability in the outcome score was determined and the score was compared with full clinical assessment. FINDINGS: There was good inter-observer agreement on using the new score to identify likely dependency (Kappa = 0.942 for Malaysian children; Kappa = 0.786 for Indian children) and good intra-observer agreement (Kappa = 1.000 and 0.902, respectively). In addition, agreement between the new score and clinical assessment was also good (Kappa = 0.906 and 0.762, respectively). The sensitivity and specificity of the new score for identifying children likely to be dependent were 100% and 98.4% in Malaysia and 100% and 93.8% in India. Positive and negative predictive values were 84.2% and 100% in Malaysia and 65.6% and 100% in India. CONCLUSION: The new tool for assessing disability in children after Japanese encephalitis was simple to use and scores correlated well with clinical assessment.

Evaluation of two commercially available ELISAs for the diagnosis of Japanese encephalitis applied to field samples.

OBJECTIVE: To compare two commercially available kits, Japanese Encephalitis-Dengue IgM Combo ELISA (Panbio Diagnostics) and JEV-CheX IgM capture ELISA (XCyton Diagnostics Limited), to a reference standard (Universiti Malaysia Sarawak - Venture Technologies VT ELISA). METHODS: Samples were obtained from 172/192 children presenting to a site in rural India with acute encephalitis syndrome. RESULTS: Using the reference VT ELISA, infection with Japanese encephalitis virus (JEV) was confirmed in 44 (26%) patients, with central nervous system infection confirmed in 27 of these; seven patients were dengue seropositive. Of the 121 remaining patients, 37 (31%) were JEV negative and 84 (69%) were JEV unknown because timing of the last sample tested was <10 day of illness or unknown. For patient classification with XCyton, using cerebrospinal fluid alone (the recommended sample), sensitivity was 77.8% (59.2-89.4) with specificity of 97.3% (90.6-99.2). For Panbio ELISA, using serum alone (the recommended sample), sensitivity was 72.5% (57.2-83.9) with specificity of 97.5% (92.8-99.1). Using all available samples for patient classification, sensitivity and specificity were 63.6% (95% CI: 48.9-76.2) and 98.4% (94.5-99.6), respectively, for XCyton ELISA and 75.0% (59.3-85.4) and 97.7% (93.3-99.2) for Panbio ELISA. CONCLUSION: The two commercially available ELISAs had reasonable sensitivities and excellent specificities for diagnosing JEV.

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.