Late Ebola virus relapse causing meningoencephalitis: a case report.

BACKGROUND: There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13.2). METHODS: A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. FINDINGS: On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23.7) than plasma (31.3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. INTERPRETATION: Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors for cases of relapsed infection. The potential for these cases to initiate new transmission chains is a serious public health concern. FUNDING: Royal Free London NHS Foundation Trust.

An association between pulmonary Mycobacterium avium-intracellulare complex infections and biomarkers of Th2-type inflammation.

BACKGROUND: The rising incidence of pulmonary Mycobacterium avium-intracellulare complex (MAI) infection is unexplained but parallels the growing world-wide epidemic of allergic disease. We hypothesized an association between pulmonary MAI infection and Th2-type immune responses as seen in allergy. METHODS: Biomarkers of patient Th2-type immune responses (peripheral blood eosinophil counts and serum IgE levels) were compared between patients with positive pulmonary samples for tuberculosis and non-tuberculous mycobacterial (NTM) infection. A further comparison of clinical characteristics, including respiratory co-morbidities, and biomarkers, was conducted between patients culturing MAI NTM and those culturing NTM other than MAI. RESULTS: Patients culturing NTM from pulmonary samples had significantly higher peripheral blood eosinophil levels than those culturing Mycobacterium tuberculosis. Furthermore, patients culturing MAI compared to those culturing NTM other than MAI had higher eosinophil counts (mean 0.29x109/L vs 0.15x109/L, p = 0.010) and IgE levels (geometric mean 138kU/L vs 47kU/L, p = 0.021). However there was no significant difference in the frequency of asthma between the two NTM groups. CONCLUSIONS: There is an association between biomarkers of Th2-type immune responses and pulmonary MAI. Prospective and translational research could identify the direction of causation; and so determine whether our finding may be utilized within future management strategies for MAI.

Febrile illness in healthcare workers caring for Ebola virus disease patients in a high-resource setting.

Ebola virus disease (EVD) patients treated in high-resource facilities are cared for by large numbers of healthcare staff. Monitoring these healthcare workers (HCWs) for any illness that may represent transmission of Ebola virus is important both for the individuals and to minimise the community risk. International policies for monitoring HCWs vary considerably and their effectiveness is unknown. Here we describe the United Kingdom (UK) experience of illness in HCWs who cared for three patients who acquired EVD in West Africa. Five of these 93 high-level isolation unit (HLIU) HCWs presented with fever within 21 days of working on the unit; one of these five presented outside of the UK. This article discusses different approaches to monitoring of HCW symptom reporting. The potential impact of these approaches on HLIU staff recruitment, including travel restrictions, is also considered. An international surveillance system enhancing collaboration between national public health authorities may assist HLIU HCW monitoring in case they travel.

Thromboelastography in the Management of Coagulopathy Associated With Ebola Virus Disease.

Here, we describe the first use of thromboelastography (TEG) in the management of 2 cases of Ebola virus disease. Early in their illness, both patients had evidence of a consumptive coagulopathy. As this resolved, TEG demonstrated that both developed a marked hypercoagulable state, which was treated with low-molecular-weight heparin.

Variation in C - reactive protein response according to host and mycobacterial characteristics in active tuberculosis.

BACKGROUND: The C - reactive protein (CRP) response is often measured in patients with active tuberculosis (TB) yet little is known about its relationship to clinical features in TB, or whether responses differ between ethnic groups or with different Mycobacterium tuberculosis (M.tb) strain types. We report the relationship between baseline serum CRP prior to treatment and disease characteristics in a metropolitan population with TB resident in a low TB incidence region. METHODS: People treated for TB at four London, UK sites between 2003 and 2014 were assessed and data collected on the following characteristics: baseline CRP level; demographics (ethnicity, gender and age); HIV status; site of TB disease; sputum smear (in pulmonary cases) and culture results. The effect of TB strain-type was also assessed in culture-positive pulmonary cases using VNTR typing data. RESULTS: Three thousands two hundred twenty-two patients were included in the analysis of which 72 % had a baseline CRP at or within 4 weeks prior to starting TB treatment. CRP results were significantly higher in culture positive cases compared to culture negative cases: median 49 mg/L (16-103 mg/L) vs 19 mg/L (IQR 5-72 mg/L), p = <0.001. In those with pulmonary disease, smear positive cases had a higher CRP than smear negative cases: 67 mg/L (31-122 mg/L) vs 24 mg/L (7-72 mg/L), p < 0.001. HIV positive cases had higher baseline CRPs than HIV negative cases: 75 mg/L (26-136 mg/L) vs 37 mg/L (10-88 mg/L), p <0.001. Differing sites of disease were associated with differences in baseline CRP: locations that might be expected to have a high mycobacterial load (e.g. pulmonary disease and disseminated disease) had a significantly higher CRP than those such as skin, lymph node or CNS disease, where the mycobacterial load is typically low in HIV negative subjects. In a multivariable log-scale linear regression model adjusting for host characteristics and M.tb strain type, infection with the East African Indian strain was associated with significantly lower baseline-CRP (fold-change in CRP 0.51 (0.34-0.77), p < 0.01). CONCLUSIONS: Host and mycobacterial factors are strongly associated with baseline CRP response in tuberculosis. This analysis suggests that there are important differences in innate immune response according to ethnicity, Mtb strain type and site of disease. This may reflect differing mycobacterial loads or host immune responses.

Decreasing cost effectiveness of testing for latent TB in HIV in a low TB incidence area.

Testing for latent tuberculosis infection (LTBI) in HIV-infected persons in low tuberculosis (TB) incidence areas is often recommended. Using contemporary, clinical data, we report the yield and cost-effectiveness of testing all HIV attendees, two current UK strategies and no LTBI testing. Economic modelling was performed utilising 10-year follow up data from a large HIV clinical cohort. Outcomes were numbers of cases of active TB and incremental cost per quality-adjusted life year (QALY) gained. Between 2000 and 2010, 256 people were treated for TB/HIV co-infection. 72 (28%) occurred ≥3 months after HIV diagnosis and may have been prevented by LTBI testing. Between 2000 and 2005, the incremental cost per QALY gained for the British HIV Association (BHIVA) and UK National Institute of Care Excellence (NICE) strategies, and testing all clinic attendees was €6270, €6998 and €33,473, respectively. These rose to €9332, €32,564 and €74,067, respectively, between 2005 and 2010. Probabilistic sensitivity analysis suggested that at a threshold of €24,000 per additional QALY, the most cost-effective strategies would be NICE or testing all in 2000-2005 and BHIVA during 2005-2010. Both UK testing regimens missed cases but are cost-effective compared with no testing. Using recent data, they all became more expensive, suggesting that alternative or more targeted TB testing strategies must be considered.

Occupational hazard in an immunosuppressed patient.

A 60-year-old male liver transplant recipient presented to his local hospital with left-sided partial seizures following a few days of generalised headache. He had undergone transplantation for primary sclerosing cholangitis 4 years earlier and maintained on tacrolimus monotherapy immunosuppression. He had no other comorbidities of note and worked as an arable farmer. At last follow-up, he had been well with preserved graft function and afternoon trough tacrolimus levels of 2-4 ng/mL. Over the preceding 4 weeks, he had been investigated locally for weight loss and a productive cough, where CT of the chest showed calcified mediastinal and hilar lymphadenopathy. Bronchoscopy samples were negative for acid-fast bacilli and he had been empirically treated for assumed community acquired pneumonia. Initial seizure management was with intravenous diazepam and phenytoin. On transfer to our centre, he was noted to be dysarthric with persisting 4/5 left upper limb weakness and nystagmus to all extremes of gaze. Blood tests were significant for mild anaemia (haemoglobin 90 g/L) and elevated C reactive protein (134 mg/L). The peripheral white cell count was 6.6×109/L. Biochemical liver graft function was normal and the 8am trough tacrolimus level was low at 2 ng/mL. CT head revealed bilateral ring enhancing cerebral lesions with surrounding vasogenic oedema but no mass effect. On MRI these exhibited restricted diffusion and marked perilesional oedema, suggestive of infection. Cerebrospinal fluid (CSF) analysis was as follows: white cell count <1/mm3, protein 0.57 g/L (normal range <45 g/L) and glucose 3 mmol/L (paired plasma glucose 4.8 mmol/L). Testing for virological causes via PCR, toxoplasma serology and blood and CSF cultures, including for tuberculosis, were all negative. Whole body positron emission tomography-CT demonstrated uptake in numerous peritoneal and intramuscular lesions as well as right-sided cervical lymphadenopathy, which was sampled with fine needle aspiration. Microscopy revealed a filamentous, beading and branching Gram-positive bacillus that was partially acid-fast, subsequently speciated as Nocardia farcinica.

Improved treatment completion for tuberculosis patients: The case for a dedicated social care team.

OBJECTIVES: The increasing social needs of people with Tuberculosis (TB), and the poor adherence to anti-TB therapy (ATT) associated with homelessness, drug or alcohol abuse, and prison history, led us to introduce a social care team (SCT) to support patient engagement with care within this low TB incidence setting. METHODS: Using a risk assessment, patients with social risk factors (SRF) for non-adherence to ATT are identified and a referral made to the SCT, who then provide intensive casework support for areas including homelessness, housing, benefits, debt and immigration. Retrospective data analysis of the social care database from 2017 to 2019 was conducted. Patients who were (n = 170) and were not referred to the SCT (n = 734) were compared. RESULTS: Patients referred were significantly more likely to complete treatment for TB than those not (88.2% versus 77.7% respectively, p = 0.0025), irrespective of receipt of Directly/Video Observed Therapy and adjusting for confounders. CONCLUSIONS: This paper demonstrates important evidence for the positive impact of a dedicated SCT within a TB service, and these improved treatment outcomes provide a strong argument for development of similar SCTs within UK TB services and similar healthcare settings.

Cost effectiveness of testing HIV infected individuals for TB in a low TB/HIV setting.

OBJECTIVES: Guidelines recommend routine testing for latent TB infection (LTBI) in people living with HIV. However there are few cost-effectiveness studies to justify this in contemporary high resource, low TB/HIV incidence settings. We sought to assess the uptake, yield and cost-effectiveness of testing for latent and active TB. METHODS: Adults attending an ambulatory HIV clinic in London, UK were prospectively recruited by stratified selection and tested for TB infection using symptom questionnaires, chest radiograph (CXR), tuberculin skin test (TST), T-Spot.TB and induced sputum. From this, 30 testing strategies were compared in a cost-effectiveness model including probabilistic sensitivity analysis using Monte Carlo simulation. RESULTS: 219 subjects were assessed; 95% were using antiretroviral therapy (ART). Smear negative, culture positive TB was present in 0.9% asymptomatic subjects, LTBI in 9%. Only strategies testing those from subSaharan Africa with a TST or interferon gamma release assay (IGRA) with or without CXR, or testing those from countries with a TB incidence of >40/100,000 with TST alone were cost-effective using a £30,000/QALY threshold. CONCLUSIONS: Cost-effectiveness analysis in an adult HIV cohort with high ART usage suggests there is limited benefit beyond routine testing for latent TB in people from high and possibly medium TB incidence settings.

Detection of mycobacterial antigen responses in lung but not blood in HIV-tuberculosis co-infected subjects.

Forty-seven HIV-infected adults had broncho-alveolar lavage stimulated with purified protein derivate of Mycobacterium tuberculosis. Eighteen of 19 (95%) with tuberculosis co-infection had interferon-gamma synthetic CD4 lymphocyte responses > 1% versus three of 28 (11%) without (P < 0.0001). Lung response was unrelated to blood CD4 cell count. BAL HIV tuberculosis responses were similar in 25 HIV-uninfected tuberculosis patients. Responses in matched blood samples were often undetectable. Therefore, immunological tuberculosis assays seem less affected by HIV co-infection when lung-based.

Does immune reconstitution syndrome promote active tuberculosis in patients receiving highly active antiretroviral therapy?

OBJECTIVES: To assess whether highly active anti-retroviral therapy (HAART) contributes to the presentation of active tuberculosis (TB). DESIGN: Retrospective single-centre cohort study. METHODS: A total of 111 HIV-infected individuals with active TB were identified at an urban teaching hospital between February 1997 and April 2004. Those receiving HAART at the time of TB diagnosis were assessed. RESULTS: Nineteen of 111 (17%) were receiving HAART when TB developed. Within this group there appeared to be two distinct populations. Thirteen of 19, 12 from ethnic or social groups with high background rates of TB, developed disease a median of 41 days (range, 7-109) after starting HAART ('early TB' group). In six of 19 ('late TB' group), TB occurred a median of 358 days after HAART initiation (range, 258-598). The 'early TB' group had lower CD4 cell counts when starting HAART in comparison with the 'late TB' group (median; 87 versus 218 x 10 cells/l; P = 0.04); however no difference was observed in the rate of change of CD4 cell count (P = 0.5) or HIV load. Paradoxical reaction rate in the 'early TB' group was significantly greater than in the 'late-TB' group (62 versus 0%, P = 0.02) and greater than in a similar control population who started HAART while taking anti-TB therapy (62 versus 30%, P = 0.05). CONCLUSIONS: These data suggest anti-HIV treatment may amplify the presentation of active TB. This has implications for antiretroviral programmes in countries with high TB rates and warrants prospective investigation of a larger cohort.

The relationship between CD4 cell count nadirs and the toxicity profiles of antiretroviral regimens.

BACKGROUND: It has been suggested that a lower pre-highly active antiretroviral therapy (HAART) CD4 count nadir may lead to a greater risk of experiencing HAART-related toxicity. We investigated the relationship between the pre-HAART CD4 count nadir, HAART and the occurrence of laboratory-defined toxicities. METHODS: Previously antiretroviral-naive individuals starting HAART at the Royal Free Hospital, London, UK, were included. Drug discontinuation, increases in total cholesterol (by > 1 mmol/l), alanine aspartate transferase/ alanine aminotransferase (AST/ALT) (by >2.5 times the upper limit of normal), bilirubin (by > 2.5 times the upper limit of normal), triglycerides (by > 1 mmol/l) and decreases in haemoglobin (by > 2 g/dl) were assessed. RESULTS: 377/847 (45%) individuals starting HAART stopped at least one antiretroviral within the first 48 weeks. Lower CD4 nadirs were not associated with a greater rate of discontinuing antiretrovirals (adjusted hazard ratio (HR)=1.04 per 100 cells/mm3 higher; 95% confidence intervals (CI) 0.99 - 1.10; P = 0.15). 70/297 (24%), 39/192 (20%) and 73/358 (20%) with a CD4 cell nadir of 0-100, 100-200 and 200+ cells/mm3, respectively, stopped for toxicity reasons; 11/297 (4%), 5/192 (3%) and 3/358 (11%) stopped for reasons of insufficient efficacy; 63/297 (21%), 33/192 (17%) and 80/358 (22%) stopped for other reasons (P = 0.1). Reasons for stopping were similar between CD4 nadir groups. Lower CD4 nadirs were not associated with an increased risk of hypercholesterolaemia, anaemia, hypertriglyceridaemia or increases in AST/ALT but were associated with increased incidence of hyperbilirubinaemia (HR=0.67 per 100 cells/mm3 higher; 95% CI 0.49-0.92; P = 0.01). DISCUSSION: Lower CD4 nadirs were not found to be associated either with discontinuing an antiretroviral or with a higher risk of toxicity, except for an increased risk of experiencing an increase in bilirubin levels.