Thomas Fletcher

Caring for Critically Ill Patients with Ebola Virus Disease. Perspectives from West Africa

The largest ever Ebola virus disease outbreak is ravaging West Africa. The constellation of little public health infrastructure, low levels of health literacy, limited acute care and infection prevention and control resources, densely populated areas, and a highly transmissible and lethal viral infection have led to thousands of confirmed, probable, or suspected cases thus far. Ebola virus disease is characterized by a febrile severe illness with profound gastrointestinal manifestations and is complicated by intravascular volume depletion, shock, profound electrolyte abnormalities, and organ dysfunction. Despite no proven Ebola virus-specific medical therapies, the potential effect of supportive care is great for a condition with high baseline mortality and one usually occurring in resource-constrained settings. With more personnel, basic monitoring, and supportive treatment, many of the sickest patients with Ebola virus disease do not need to die. Ebola virus disease represents an illness ready for a paradigm shift in care delivery and outcomes, and the profession of critical care medicine can and should be instrumental in helping this happen.

Doing Today's Work Superbly Well — Treating Ebola with Current Tools

Its possible to save many patients who have Ebola virus disease, since supportive care is also specific care for EVD and in all likelihood reduces mortality. Yet many patients in West Africa continue to die for lack of the opportunity to receive such basic care.

Ebola virus disease and critical illness

As of 20 May 2016 there have been 28,646 cases and 11,323 deaths resulting from the West African Ebola virus disease (EVD) outbreak reported to the World Health Organization. There continue to be sporadic flare-ups of EVD cases in West Africa.EVD presentation is nonspecific and characterized initially by onset of fatigue, myalgias, arthralgias, headache, and fever; this is followed several days later by anorexia, nausea, vomiting, diarrhea, and abdominal pain. Anorexia and gastrointestinal losses lead to dehydration, electrolyte abnormalities, and metabolic acidosis, and, in some patients, acute kidney injury. Hypoxia and ventilation failure occurs most often with severe illness and may be exacerbated by substantial fluid requirements for intravascular volume repletion and some degree of systemic capillary leak. Although minor bleeding manifestations are common, hypovolemic and septic shock complicated by multisystem organ dysfunction appear the most frequent causes of death.Males and females have been equally affected, with children (0–14 years of age) accounting for 19xa0%, young adults (15–44 years) 58xa0%, and older adults (≥45xa0years) 23xa0% of reported cases. While the current case fatality proportion in West Africa is approximately 40xa0%, it has varied substantially over time (highest near the outbreak onset) according to available resources (40–90xa0% mortality in West Africa compared to under 20xa0% in Western Europe and the USA), by age (near universal among neonates and high among older adults), and by Ebola viral load at admission.While there is no Ebola virus-specific therapy proven to be effective in clinical trials, mortality has been dramatically lower among EVD patients managed with supportive intensive care in highly resourced settings, allowing for the avoidance of hypovolemia, correction of electrolyte and metabolic abnormalities, and the provision of oxygen, ventilation, vasopressors, and dialysis when indicated. This experience emphasizes that, in addition to evaluating specific medical treatments, improving the global capacity to provide supportive critical care to patients with EVD may be the greatest opportunity to improve patient outcomes.

Diagnosis of Febrile Illnesses other than Ebola Virus Disease at an Ebola Treatment Unit in Sierra Leone

Abstract Patients with febrile illnesses presenting to an Ebola treatment unit in Sierra Leone had a wide range of diagnoses other than Ebola virus disease. Rapid diagnostic tests were useful in confirming these diagnoses, reducing the length of patient stay with valuable consequences. These alternative diagnoses should assist in future planning.

Being ready to treat Ebola virus disease patients.

As the outbreak of Ebola virus disease (EVD) in West Africa continues, clinical preparedness is needed in countries at risk for EVD (e.g., United States) and more fully equipped and supported clinical teams in those countries with epidemic spread of EVD in Africa. Clinical staff must approach the patient with a very deliberate focus on providing effective care while assuring personal safety. To do this, both individual health care providers and health systems must improve EVD care. Although formal guidance toward these goals exists from the World Health Organization, Medecin Sans Frontières, the Centers for Disease Control and Prevention, and other groups, some of the most critical lessons come from personal experience. In this narrative, clinicians deployed by the World Health Organization into a wide range of clinical settings in West Africa distill key, practical considerations for working safely and effectively with patients with EVD.

Evidence-based guidelines for supportive care of patients with Ebola virus disease

The 2013-16 Ebola virus disease outbreak in west Africa was associated with unprecedented challenges in the provision of care to patients with Ebola virus disease, including absence of pre-existing isolation and treatment facilities, patients reluctance to present for medical care, and limitations in the provision of supportive medical care. Case fatality rates in west Africa were initially greater than 70%, but decreased with improvements in supportive care. To inform optimal care in a future outbreak of Ebola virus disease, we employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to develop evidence-based guidelines for the delivery of supportive care to patients admitted to Ebola treatment units. Key recommendations include administration of oral and, as necessary, intravenous hydration; systematic monitoring of vital signs and volume status; availability of key biochemical testing; adequate staffing ratios; and availability of analgesics, including opioids, for pain relief.

Tuberculin Skin Testing and Treatment Modulates Interferon-Gamma Release Assay Results for Latent Tuberculosis in Migrants

Background Identifying latent tuberculosis infection (LTBI) in people migrating from TB endemic regions to low incidence countries is an important control measure. However, no prospective longitudinal comparisons between diagnostic tests used in such migrant populations are available. Objectives To compare commercial interferon (IFN)-gamma release assays (IGRAs) and the tuberculin skin test (TST) for diagnosing LTBI in a migrant population, and the influence of antecedent TST and LTBI treatment on IGRA performance. Materials and Methods This cohort study, performed from February to September 2012, assessed longitudinal IGRA and TST responses in Nepalese military recruits recently arrived in the UK. Concomitant T-SPOT.TB, QFT-GIT and TST were performed on day 0, with IGRAs repeated 7 and 200 days later, following treatment for LTBI if necessary. Results 166 Nepalese recruits were prospectively assessed. At entry, 21 individuals were positive by T-SPOT.TB and 8 individuals by QFT-GIT. There was substantial agreement between TST and T-SPOT.TB positives at baseline (71.4% agreement; κu200a=u200a0.62; 95% CI:0.44–0.79), but only moderate concordance between positive IGRAs (38.1% agreement; κu200a=u200a0.46; 95% CI:0.25–0.67). When reassessed 7 days following TST, numbers of IGRA-positive individuals changed from 8 to 23 for QFT-GIT (pu200a=u200a0.0074) and from 21 to 23 for T-SPOT.TB (pu200a=u200a0.87). This resulted in an increase in IGRA concordance to substantial (64.3% agreement; κu200a=u200a0.73; 95% CI:0.58-0.88). Thus, in total on day 0 and day 7 after testing, 29 out of 166 participants (17.5%) provided a positive IGRA and of these 13 were TST negative. Two hundred days after the study commenced and three months after treatment for LTBI was completed by those who were given chemoprophylaxis, 23 and 21 participants were positive by T-SPOT.TB or QFT-GIT respectively. When individual responses were examined longitudinally within this population 35% of the day 7 QFT-GIT-positive, and 19% T-SPOT.TB-positive individuals, were negative by IGRA. When the change in the levels of secreted IFN-γ was examined after chemoprophylaxis the median levels were found to have fallen dramatically by 77.3% from a pre-treatment median concentration of IFN-γ 2.73 IU/ml to a post-treatment median concentration IFN-γ 0.62 (pu200a=u200a0.0002). Conclusions This study suggests differences in the capacity of commercially available IGRAs to identify LTBI in the absence of antecedent TST and that IGRAs, in the time periods examined, may not be the optimal tests to determine the success of chemoprophylaxis for LTBI.

Screening for latent tuberculosis and gastrointestinal parasite infections in Gurkha recruits: research driving policy change

Nepalese Gurkha soldiers are recruited from a country endemic for a number of infectious diseases, including tuberculosis and gastrointestinal parasites. This article describes a prospective cohort study which investigated screening strategies for these infections among Gurkha recruits arriving in the UK to begin basic training. Several recommendations were made as a result of the study which were supported for early implementation and subsequently fully adopted. Military screening and treatment policies have been directly influenced by this research which also has translational application to similar migrant civilian populations.

Immunological correlates of mycobacterial growth inhibition describe a spectrum of tuberculosis infection

A major contribution to the burden of Tuberculosis (TB) comes from latent Mycobacterium tuberculosis infections (LTBI) becoming clinically active. TB and LTBI probably exist as a spectrum and currently there are no correlates available to identify individuals with LTBI most at risk of developing active disease. We set out to identify immune parameters associated with ex vivo mycobacterial growth control among individuals with active TB disease or LTBI to define the spectrum of TB infection. We used a whole blood mycobacterial growth inhibition assay to generate a functional profile of growth control among individuals with TB, LTBI or uninfected controls. We subsequently used a multi-platform approach to identify an immune signature associated with this profile. We show, for the first time, that patients with active disease had the greatest control of mycobacterial growth, whilst there was a continuum of responses among latently infected patients, likely related to the degree of immune activation in response to bacillary load. Control correlated with multiple factors including inflammatory monocytes, activated and atypical memory B cells, IgG1 responses to TB-specific antigens and serum cytokines/chemokines. Our findings offer a method to stratify subclinical TB infections and the future potential to identify individuals most at risk of progressing to active disease and benefit from chemoprophylaxis.

Born to be wild

Antisocial behaviour in adolescence can be associated with ill health in the form of self-harm, drug abuse, and mental disorders, and may presage criminal activity later in life. This is a worldwide problem with far-reaching social and economic implications, for individuals as well as for society as a whole. There are both genetic and environmental risk factors associated with antisocial behaviour, and recent research appears to show a substantial genetic eff ect on the likelihood of an individual becoming a persistent off ender. This is potentially a controversial fi nding, and some will inevitably draw the conclusion that individuals who commit crimes do so not of their own errant free will but because they have been genetically programmed to do so. But before we accept this startling conclusion the paper needs careful scrutiny. James Barnes and co-workers studied people who had participated in a longitudinal survey of adolescent health in the USA. The authors compared the self-reported behaviour of adolescents, in particular twins, siblings, and other relatives, assessing frequency of antisocial behaviours—ranging from unruly conduct in public to drug dealing—over a 6-year period during the transition from adolescence to young adulthood. The results yielded a heritability statistic of 56–70%, suggesting that most of the diff erences in an individual’s reported antisocial behaviour could be ascribed to genetics. This seems a high degree of heritability, and it should be remembered that misleading associations are not unknown in individual genetic studies. Indeed, environmental and genetic eff ects are not independent—nature and nurture are interrelated, and infl uence each other substantially. Large numbers of genes, possibly thousands, are likely to have small but cumulative eff ects on behaviour, and might only manifest in antisocial behaviour when combined with environmental factors. Just as individuals genetically predisposed to addiction are not guaranteed to abuse drugs, the law-breakers of the future are likely to be made rather than born antisocial. It is highly unlikely that future research will be able to identify a hypothetical gene or genes conferring criminality on unfortunate recipients, so genetics will probably not be able to improve crime detection and prevention for the maintenance of law and order. Barnes and colleages’ study does, however, highlight the need to study environmental and behavioural associations with ill health in adolescents in order to shape health and social policies. The importance of tackling poverty, drug use, and child maltreatment as risk factors for crime has never been clearer.