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[Editorial] Disease, disability, and demography—a world in transition

In today’s Lancet, the Global Burden of Disease (GBD) Study 2013 Collaborators report a major study on 301 acute and chronic diseases and injuries, and consequent years lived with disability, in the vast majority of the world’s countries. Drawing on an enormous dataset and applying state-of-the-art statistical analyses, the exercise aims to understand diseases and their effects on people in all regions of the world, and the changes over time, to inform medical practice and public health policy. As Rifat Atun notes in an accompanying Comment, “a radical rethink of health systems” worldwide will be needed to rise to the challenges of multimorbidity and disability.

Fourth University of Queensland measles case confirmed

A vaccination clinic will be set up at the University of Queensland (UQ) after a fourth measles case was confirmed.

The student attended lectures at the St Lucia campus last week with another student who had contracted the illness.

They also had visited a pub and a shopping centre when they were unaware they were infectious.

The person visited:

  • University of Queensland, St Lucia, Tuesday 11/8 & Wednesday 19/8
  • Indooroopilly Shopping Centre Thursday 13/8
  • The Royal Exchange Hotel Saturday 15/8
  • Taringa Day & Night Medical Centre evening of Sunday 16/8

Metro North Public Health Unit will set up a vaccination clinic at UQ’s St Lucia Campus this week and students who live in the university’s colleges are urged to get vaccinated if they’re unsure of their status.

Queensland Health has put out an alert telling students and others who were in the above premises to be alert for measles symptoms.

This is the fourth Queensland measles alert in the last month. The first was from a UQ student who contracted the disease overseas in July.

Latest news:

 

[Perspectives] The social history of ISIS-2: the early history

For almost half a century epidemiological science has occupied a leading position in the development of preventive medicine. This status is all the more remarkable since it was not until the 1940s that the modern field of epidemiology was recognised as a medical discipline. The most important breakthrough in the history of cancer epidemiology was the carcinogenic effect of tobacco, a discovery to which Austin Bradford Hill and Richard Doll made a major contribution in 1950. Collectively, Bradford Hill and Doll laid the foundations for the rapid development of epidemiology by showing how the old science that had focused on infectious diseases could be reconfigured for non-communicable diseases.

[Comment] A global perspective on hypertension: a Commission

Despite extensive knowledge about how to prevent and treat hypertension, it has been the number one killer in the world for more than 10 years. Elevated blood pressure is the principal risk factor for cardiovascular diseases worldwide,1,2 affecting one billion individuals globally.2 It is the cause of 54% of strokes and 47% cases of ischaemic heart disease, and is responsible for 7·6 million premature deaths per year (ie, 13·5% of all deaths worldwide) and 92 million disability-adjusted life-years.

Biosimilar drugs – should doctors be concerned?

In June, the Australian Parliament passed legislation allowing prescribed biological medicines to be substituted with biosimilar drugs when they are dispensed by pharmacists.

Under the change, the Pharmaceutical Benefits Advisory Committee (PBAC) will assess on a case-by-case basis whether a specific biological medicine can be safely switched for a biosimilar by a pharmacist. As for all prescribed medicines, doctors can still control what medicine is dispensed to their patients by marking ‘do not substitute’ on the prescription.

Is pharmacist substitution of biologicals a good thing? Or will this pose risks to patient health? And what are biological and biosimilar medicines anyway?

The AMA is satisfied with the regulatory arrangements introduced for biosimilars, but it is important that doctors are aware of the potential implications for their patients. Here’s a summary of the key facts.

What are biologicals?

A biological medicine is made from a living organism, typically extracted from a human cell or tissue-based system. Biologicals include:

  • hormones used to treat hormone deficiencies, e.g. insulin for diabetes;
  • monoclonal antibodies for the treatment of autoimmune diseases and cancers;
  • blood products, e.g. for the treatment of haemophilia;
  • immunomodulators, e.g. beta-interferon for multiple sclerosis;
  • enzymes, e.g. to remove blood clots; and
  • vaccines to prevent a number of diseases.

The manufacturing process for biologicals is complex and sensitive to variations because of the nature of the biological substances used and modified. Subtle variations of a biological substance exist between batch preparations from the same manufacturer.

What is a biosimilar?

A biosimilar is not a generic biological medicine.

A biosimilar medicine is highly similar to a biological medicine that has already been approved but for which the patent has expired. Unlike a generic medicine, which is made from the same chemical compounds and has the same chemical structure as the original brand medicine, a biosimilar is not a generic copy of the reference biological medicine.

While a biosimilar’s manufacture is based on the same active ingredient as the original biological, by their nature they cannot be identical.

Before a biosimilar can be approved for sale in Australia, any differences between the biosimilar and its reference medicine must have been shown not to affect quality, safety or efficacy through a robust clinical trial process.

Biosimilars, like generic medicines, will be significantly cheaper than the original biological medicine, although not to the same extent given the higher costs needed to invest in clinical trials, manufacturing and post-approval monitoring programs.

There are already biosimilar versions of medicines listed on the Pharmaceutical Benefits Scheme (PBS) being prescribed to patients.

What are the issues?

Biologicals are more likely to cause an immune reaction than chemical medicines.

In turn, small changes in the manufacturing process or composition of a biological may result in the emergence of immune reactions, even if the agent had previously been well tolerated. For example, in one instance a minor alteration in the manufacturing process of erythropoietin alpha triggered acquired pure red blood cell aplasia in a small cohort of patients.

It is therefore important that effective adverse event reporting mechanisms are in place to ensure that any patterns of adverse events are quickly identified and tracked to the specific biological brand.

Because of the documented variability between biologicals and biosimilars, it is conceivable that adverse reactions may increase with substitution.

Some consumer groups and pharmaceutical companies have argued that allowing biologicals to be switched at the dispensing point will make it more difficult to identify the specific brand if an adverse event occurs.

Government regulation

The Therapeutic Goods Administration (TGA) will remain the regulatory body responsible for assessing and approving a biosimilar as a safe and equally effective treatment compared to another medicine before it can be sold in Australia. The TGA is currently reviewing its assessment guidelines.

Once the biosimilar has been approved by the TGA, the PBAC will also consider if the biosimilar medicine should be listed to allow substitution by a pharmacist under the PBS.

The PBAC has stated that it will not recommend a biosimilar as suitable for substitution unless it is sure of its equal safety and effectiveness.

The PBAC’s assessment will include consideration of whether there is available data to support safe switching between the original product and the biosimilar product, and whether it can be safely substituted by a pharmacist at the point of dispensing.

Examples of biosimilar brands available in Australia include:

  • Aczicrit, Grandicrit and Novicrit with the active substance epoetin lambda – all have been approved by the TGA but only Novicrit is listed on the PBS; and
  • Nivestim, Tevagrastim and Zarzio with the active substance filgrastim – all have been approved by the TGA and all are listed on the PBS.

No biosimilar has yet been approved for substitution by a pharmacist.

What should doctors do?

  • When prescribing biological medicines, doctors should ensure they mark the prescription as ‘do not substitute’ if they have any concerns about the impact on their patients of switching to another brand;
  • doctors should discuss this decision with their patients so that patients are also aware they must not allow their pharmacist to substitute the medicine;
  • doctors who find out that a pharmacist has substituted a medicine ignoring the ‘do not substitute’ mark on the prescription should report the behaviour. Under PBS related legislation, this can attract a $2000 fine or 12 months in gaol. Report breaches to the Department of Human Services by phoning 132 290 or emailing pbs@humanservices.gov.au;
  • Any suspected adverse event should be reported to the TGA:

The AMA welcomes members’ views on this issue to president@ama.com.au. Member comments help inform AMA advice and activities.

 

Fascioliasis in Australian travellers to Bali

Clinical record

Case 1

A 50-year-old woman presented with mild right upper quadrant (RUQ) pain 2 weeks after returning from Bali. This progressed over 1 month to severe epigastric pain, fever and rigors. She recalled eating mixed salad vegetables while in Bali. On ultrasound, multiple liver lesions were found and a diagnosis of pyogenic liver abscess was made. An infectious diseases (ID) physician was consulted. Her eosinophil count was raised (1.3 × 109/L [18%]; reference interval, 0.02–0.5 × 109/L). Microscopy of multiple stool samples did not show ova, cysts or parasites. Serological testing was positive for Fasciola hepatica (IgG optical density [OD], 3.0), and negative for Entamoeba spp. Hydatid antibodies were detected at a low titre (1 : 256) (this was considered to be a cross-reaction as confirmatory testing was negative). She had a good clinical response to oral triclabendazole 750 mg per month for 3 months.

Case 2

A 44-year-old woman developed diarrhoea during her stay in Bali, on a background of psoriatic arthropathy treated with leflunomide. While in Bali she frequently ate salads and uncooked vegetables. Her eosinophil count was normal (0.4 × 109/L [9%]). She developed RUQ pain 1–2 months after her return, and computed tomography (CT) imaging at 4 months showed a multifocal liver lesion with associated duct dilatation. She underwent a hemihepatectomy for presumed malignancy. Histopathological tests were non-diagnostic. An ID physician was consulted. Serological testing for F. hepatica was positive (IgG OD, 1.6). She was clinically cured with oral triclabendazole 750 mg monthly for 2 months.Clinical and diagnostic features of these two and four other cases are summarised in the Table, and selected images are shown in Figures A and B.

Fascioliasis is a foodborne infection caused by liver flukes Fasciola hepatica and F. gigantica. Transmission occurs from herbivores to humans via ingestion of cysts (metacercariae) present on water plants (classically watercress; see Box) or in contaminated water.1 Fascioliasis affects some of the world’s poorest communities. In the developed world, cases are mainly described in returned travellers, but infection may occur locally through ingestion of imported or locally grown vegetables.2

There are two distinct clinical phases of infection. The parenchymal liver phase is caused by larval migration through the liver, typically 6–9 weeks after infection. Clinically, this manifests as fever, RUQ pain, and eosinophilia. The ductal phase occurs as flukes enter the bile ducts and may cause obstructive jaundice or cholangitis.

Diagnosis among patients in this case series was delayed, with an average time from clinical presentation to diagnosis of 5.2 months. The patients we describe suffered considerable morbidity related to invasive investigations, surgery and delay in targeted antihelmintic therapy.

Radiological findings are often non-specific for fascioliasis. Ultrasonography and CT images often show poorly circumscribed lesions during the liver parenchymal phase.3

Once fascioliasis was considered in the diagnosis, fasciola serology was ordered and confirmed the diagnosis in all cases. The sensitivity and specificity using enzyme-linked immunosorbent assay (ELISA) based on excretory-secretory antigen both exceed 95%.4 Results of serological testing may become positive 2–4 weeks after infection, preceding the presence of eggs in the stool. Serological testing is useful in travellers, but is of little use in residents of endemic areas, as it is difficult to differentiate past from present infection. Cross-reactivity with other helminths (as illustrated by these cases) is well recognised.5 We suspect these cases represent F. gigantica infection with antibodies being detected by the commercial ELISA based on F. hepatica antigens. In Australia, serological testing is only available at the Institute for Clinical Pathology and Medical Research in Westmead.

Normal eosinophil count cannot be used to exclude parasitic aetiology. Eosinophilia is more likely to be present during the parenchymal phase, however the eosinophil count may be normal in up to 50% of chronic cases.2 Stool microscopy did not yield positive results before treatment in these patients. It is not useful in the acute phase of illness, as the pre-patent period (time from infection to shedding of ova in the faeces by mature adult worms) is 4 months (Box).

Differentiating fascioliasis from other parasitic conditions is important, as the recommended management is specific. Triclabendazole in two separate treatments of 10 mg/kg per treatment is well tolerated and single dose cure rates exceed 80%.6,7 Resistance in humans has not yet been described. This drug is difficult to obtain in Australia for human use, and can either be imported or acquired through veterinary supply. Prescription requires Special Access Scheme approval and hospital ethics approval for use in humans.

Human cases of fascioliasis acquired in Bali have not previously been reported (Putra AA, Senior Veterinary Epidemiologist, Disease Investigation Centre, Denpasar, Bali, personal communication, 10 Dec 2013). These six patients were diagnosed between 2011–2014. Indonesia is the second most common destination for Australian travellers, with 1.01 million journeys in the 2013–14 financial year. This is a 266% trend change compared with the 2003–04 financial year.8 There are likely to be further cases affecting locals and tourists. Five of the six patients were women, perhaps reflecting a female preference for fresh salad. Women from endemic areas are recognised to be at higher risk than men, owing to exposure to contaminated water during washing and meal preparation.9 Two patients (Case 2 and Case 6) in this series were immunosuppressed, both receiving leflunomide for psoriatic arthritis. As co-exposed family members did not appear to contract fascioliasis, their immunosuppressed state may have contributed to their susceptibility.

The lack of human cases among locals in Bali to date may represent underdiagnosis, underreporting or perhaps a cultural difference in consumption of uncooked vegetables.

These patients are likely to have been infected with F. gigantica (rather than F. hepatica), as this is the predominant species in tropical regions, and up to 40% of Bali cattle are reportedly infected with F. gigantica (Putra AA, Senior Veterinary Epidemiologist, Disease Investigation Centre, Denpasar, Bali, personal communication, 10 Dec 2013). Species differentiation is possible based on the morphology of ova and worms, isoenzyme analysis or molecular techniques. F. hepatica could conceivably be transmitted by goats, but its prevalence in Bali is unknown.

Fascioliasis should be considered when a patient presents with RUQ pain, a poorly circumscribed lesion on imaging, eosinophilia (useful if present) and appropriate exposure history. A detailed travel and dietary history and an increased awareness of parasitic causes are important in facilitating timely referral to an infectious diseases or microbiology service for assistance with diagnosis and management.

Lessons from practice

  • A detailed travel history should be obtained to assist in the differential diagnosis of liver lesions.
  • Eosinophilia is suggestive of a parasitic cause of liver lesions; however, its absence does not rule this out.
  • Serological testing is required to diagnose fascioliasis in a returned traveller.

Figure


A: Case 3; CT image showing multiloculated hepatic lesions (arrow), central cystic changes and necrosis. B: Case 2; CT image showing irregular lesions (arrows) through both left and right hepatic lobes.

Table

Characteristic

Case 1

Case 2

Case 3

Case 4

Case 5

Case 6


Age in years, sex

50, female

44, female

48, female

45, female

37, female

58, male

Symptoms on presentation

RUQ pain, fever

Diarrhoea, RUQ pain

RUQ pain, fever

Diarrhoea, RUQ pain

RUQ pain, fever

Malaise, fever

Exposure

Watercress

Fresh salad

Watercress

Watercress

Fresh salad

Fresh salad

Travel destination

Bali

Bali

Bali

Bali, Java

Bali

Bali

Presumptive diagnosis

Pyogenic liver abscess

Malignancy

Malignancy

Pyogenic liver abscess

Pyogenic liver abscess

Pyogenic liver abscess

Initial eosinophil count (absolute, %)

1.3 × 109/L, 18%

0.4 × 109/L, 9%

1.1 × 109/L, 17%

2.4 × 109/L, 32%

0.0 × 109/L, 0

1.2 × 109/L, 26%

Liver biopsy

Not done

Chronic inflammation

No malignancy

No malignancy

Three, non-diagnostic

Degenerate inflammatory cells

Stool microscopy for ova, cysts and parasites

Negative

Negative

Negative

Negative

Negative

Negative

F. hepatica serology

Positive (IgG OD, 3.0)

Positive (IgG OD, 1.6)

Positive (IgG OD, 2.3)

Positive (IgG OD, 2.8)

Positive (IgG OD, 1.3)

Positive (IgG OD, 23.9)

Other positive serology (considered to be cross-reactivity)

Hydatid, low titre

Nil

Strongyloides, Angiostrongylus, low titre

Nil

Strongyloides, low titre

Schistosoma, low titre

Time to diagnosis once medical attention sought

3 months

4 months

4 months

6 months

2 months

12 months

Treatment

Triclabendazole 750 mg immediately, repeat at 1, 2 months

Triclabendazole 750 mg immediately, repeat at 1 month

Triclabendazole 500 mg daily for 2 days

Triclabendazole 750 mg immediately, repeat at 1 month

Triclabendazole 500 mg daily for 2 days

Triclabendazole 1 g immediately, repeat at 1, 2 months

Outcome at 24 months

Clinically well

Clinically well

Clinically well

Clinically well

Clinically well

Recently diagnosed


Life cycle of Fasciola species*


Fasciola eggs are released in the biliary ducts and faeces (1). Eggs embryonate in water (2), releasing miracidia (3), which invades the intermediate host, the snail (4). Parasites undergo development in the snail (sporocysts 4a, rediae 4b) maturing into cercariae (4c) which are released from the snail (5) and encyst as metacercariae on aquatic vegetation or other surfaces. Domestic or wild ruminants and humans can become infected by ingesting vegetation containing metacercariae (6). Metacercariae excyst in the duodenum (7), migrate through the intestinal wall, the peritoneal cavity, and the liver parenchyma into the biliary ducts, where they develop into adult flukes during a 3–4 month maturation period (8).

*Reproduced (diagram) and adapted (text) with permission from the Centers for Disease Control and Prevention.1

Perspectives from the field: Ebola response in Sierra Leone

On Christmas Day 2014, I started a 6-week placement at the Australian-flagged Ebola Treatment Centre, managed by Aspen Medical, in Freetown, Sierra Leone. I joined about 30 doctors, nurses, environmental health officers, and management and support staff from across Australia and New Zealand, working alongside 120 Sierra Leoneans.

A societal disaster

The West African Ebola virus disease (EVD) outbreak is a medical and societal disaster. Most patients die, leaving devastated families and communities. EVD spreads by interpersonal contact, so the community prevention message is “Avoid Body Contact” — ABC. However, body contact makes us human, and the ABC protocol is freakish in all cultures. Dramatic community-wide behaviour change is needed to control an EVD outbreak.

The EVD outbreak is occurring in West African countries already devastated by ecological, economic and governance crises. Access to food is limited; many people require food aid. Schools have closed, and a generation may never reach their potential. Health care services have collapsed — deaths from malaria, tuberculosis, HIV and diarrhoea will far exceed deaths from EVD.1

Challenges in the Ebola Treatment Centre

Outbreaks of EVD are brutal. The Ebola Treatment Centre assists in controlling the outbreak by isolating patients with EVD infection. A razor wire fence surrounds the treatment centre. Incinerators spew smoke as contaminated clothes, bedding, food and personal belongings are burnt. Controlled access to the treatment centre, and its white, green and red zones, prevents spread of the disease within the centre.

Survivors of Ebola virus disease leave their mark on this special wall at the Freetown Ebola Treatment Centre as they return home free of the disease. Image courtesy of Aspen Medical
.

Clean gloves are part of the personal protective equipment (PPE) used every time anyone enters the red zone of an Ebola Treatment Centre. For tasks that do not require dexterity, thick gloves are used. All PPE is carefully removed on exiting the red zone, and the gloves are washed in chlorine and dried in the sun for reuse. Image courtesy of Aspen Medical.

Inside the Ebola Treatment Centre, personal protective equipment (PPE) is conspicuous. This equipment is required for entry to the red zone and is donned under supervision. Scrubs, boots, overalls, double gloves, an apron, an N95 mask, a hood and goggles must cover the entire body. The PPE soon becomes hot and goggles fog up, so time in the red zone is limited to 60 minutes. Patient care is restricted by these time limitations and by the PPE itself, which impairs communication and makes the stethoscope useless. Frequent chlorine spraying damages the available medical equipment.

Personal reflections

Despite the Ebola Treatment Centre’s restrictions and the lack of specific treatment for EVD, the work was satisfying. We offered symptom relief, particularly fluids and opiates, along with compassion, counselling and support. We witnessed life and death and celebrated each EVD survivor. The placement gave me insights into how health determinants can be so cruel, yet individuals so inspiring.

Ethical considerations in the management of Ebola virus disease

The current Ebola virus disease (EVD) outbreak in West Africa is the largest since the disease was first described in 1976. By the end of March this year, it had caused more than 10 000 deaths, including 495 among health care workers (HCWs).1,2 Twenty-four patients with EVD have been admitted to hospitals in high-income countries.3 The nurses who were infected while looking after Thomas Duncan in Dallas, Texas, highlighted the risk of transmission of EVD to HCWs, even in well resourced hospitals. HCWs in Australia were quick to compare this with an outbreak of severe acute respiratory syndrome (SARS) in a Toronto hospital in 2003, when a single case led to an epidemic in which nearly half the cases occurred in HCWs.4

The public response after a doctor who became infected while treating patients with EVD in Africa returned to the United States, and the ostracising of HCWs at the hospital where he was treated, reflected community concerns about EVD.5 The unpredictable nature of EVD, the infection of carers and the high case-fatality rate in Africa have generated fear of the disease.

HCWs have raised concerns about appropriate clinical management of patients with EVD and the need for a clear ethical framework to guide decision making.6 While there are general management guidelines for patients with EVD, including strict isolation, appropriate use of personal protective equipment (PPE) and prompt correction of fluid and electrolyte loss, uncertainty surrounds many aspects of care, including the extent to which supportive care can be provided and the circumstances under which it should be discontinued.

Here, we focus on two ethical questions regarding the critical care of patients with EVD in an Australian setting. The first is whether it is ethically appropriate in some circumstances for HCWs to decline to care for patients with EVD. The second question concerns how treatment decisions should be made regarding limitation of therapy for patients with EVD. Similar questions have been asked in the context of other infectious diseases, including SARS, where provision of care put HCWs at significant risk, and in the early stages of the AIDS epidemic, when the risk to HCWs was minimal.7,8

Is it ever ethically appropriate to decline to care for patients with Ebola virus disease?

Questions regarding the critical care of patients with EVD will not be resolved simply by recourse to the concept of futility.9 The frequently quoted EVD case-fatality rate of 60%–90% now appears excessive, as Médecins sans Frontières have reported case-fatality rates in Guinea of 25% (among 21 patients treated in Telimele) and 37% (among 59 confirmed cases in Donka).10 Of the 24 patients managed in Western countries so far, five (21%) have died, all of whom were seriously ill on admission to hospital.3 These data favour an aggressive approach to treatment.

However, the lack of definitive therapy and the devastating effects of infection are sobering realities that counterbalance the argument for aggressive therapy and complicate the dilemma faced by clinicians. Emergency department, infectious diseases, laboratory and intensive care personnel are exposed to higher risk than other HCWs. Nurses, in particular, spend long periods in contact with patients and are therefore most vulnerable. Although the risks to HCWs cannot be easily quantified, they can be minimised to acceptable levels with protocols, training, optimal staffing ratios, appropriate use of PPE and integrated teamwork. The key question for HCWs and policymakers becomes one of defining what constitutes an acceptable level of risk, and what obligations HCWs have to care for patients with high-risk illnesses.11

Health professionals have codes of conduct that identify the concept of duty of care but provide no guidance as to how it applies in situations involving significant personal risk.12 HCWs must personally decide how to balance their duty to a highly infectious patient against their duty to protect themselves. While such decisions are often seen as binary — HCWs have either a “duty to treat” or a “right to refuse” — in fact, they are highly complex. These decisions are subject to multiple influences, including how clinicians perceive the risk of exposure to EVD and how well they tolerate risk in general; how they prioritise their own family responsibilities; how well they trust their colleagues, the hospital as an organisation and the PPE provided; and how they perceive their professional, ethical and legal responsibilities to their patients and employer.1315

Data on willingness to treat patients with high-risk illnesses show interesting patterns. Among 1000 physicians surveyed in the US, 80% indicated willingness to care for patients with an unknown but lethal illness, but only about 20% felt prepared to do so.15 Psychometric data in risk perception demonstrate that what appears to be a neutral, unbiased and professional risk assessment will be affected by cognitive heuristics, which can produce systematic distortions in thinking.16 Scientific experts also display such thinking, and retrospective assessments of responses to crisis events routinely identify “over-reactions”.

Ethical considerations relating to providing supportive therapy for patients with EVD appear straightforward. There is an obligation to treat patients with therapies that provide the greatest likely benefit, with manageable risks to staff and the institution. However, this expectation is not unlimited: it also depends on whether adequate resources are provided to allow staff to work in the safest possible environment. Employers have a responsibility to provide these resources and could not ethically compel staff to care for patients if doing so exposed them to avoidable personal risk.17 However, whether they could do so in these circumstances would depend on how “adequate resources” and “avoidable risk” were defined.

While some staff might prefer not to care for a patient with EVD because of a perceived high level of personal risk, experience in the current EVD outbreak and previous epidemics, notably SARS, suggests that HCWs rarely refuse if provided with adequate information, training, resources and rosters. Nevertheless, a small number of HCWs may need to be excused from caring for patients with EVD because of underlying medical or psychological factors.

How should treatment decisions for patients with Ebola virus disease be made?

As therapies for a seriously ill patient become progressively more invasive, the relative benefits diminish while the risk to carers increases. For patients with EVD, aerosol-generating procedures, such as mechanical ventilation, place HCWs at increased risk. However, compared with non-invasive ventilation, placement of an endotracheal tube and closed-circuit ventilation decrease the risk, particularly in patients with haemoptysis.

In other circumstances, the benefit to the patient of aggressive supportive care may be more difficult to determine. Dialysis, for example, poses several challenges. Independent of the prognosis of acute renal failure in the setting of severe EVD,18 it would seem unethical not to offer dialysis. While treatment protocols for renal replacement therapy have been developed,19 the risks of individual therapies have not been quantified. However, patients with EVD have been treated experimentally with plasmapheresis and continuous renal replacement therapy, without any reports of cross-infection.20

While the clinical obligations of HCWs are aligned to maximise therapeutic options for patients, this is not necessarily the case for other aspects of care. Despite detailed protocols for risk assessment and safe collection, transport and laboratory testing of specimens from patients with EVD, laboratory investigations and blood transfusion are often limited to point-of-care modalities and uncross-matched donor supplies, respectively. The relevant protocols involve strict precautions, comparable with those for clinical management of patients with EVD.21 Although transmission of EVD in laboratory settings has only been documented when breaches of protocol have occurred,2224 laboratory directors may be unwilling to subject staff to any perceived risk or to incur potential disruption to the rapid throughput of routine specimens. However, protocols that restrict laboratory testing limit investigative and therapeutic options available to clinicians and potentially compromise patient outcomes. We contend that the ethical obligations of frontline clinical staff to provide patient care should also apply to laboratory staff.

Imaging for patients with EVD is also restricted, usually to bedside radiography or ultrasonography, and it is unlikely that a patient would be considered for a major surgical intervention or cross-sectional imaging under current institutional protocols. These protocols require that, once admitted, a patient with EVD should remain in the ultra-isolation unit until fully recovered. This requirement is based on the potential risk, however small, to staff, patients or the public from exposure to a patient with EVD being transported within the hospital.

Invasive or aggressive interventions would be contraindicated, as they would be for any patient, if continued care of a patient with EVD were judged to be futile. However, the potential increased risk to HCWs would add weight to an otherwise marginal decision to cease active intervention. Compassionate palliation would then be indicated. For example, a patient with EVD who has a massive haemorrhage could pose an enormous risk to HCWs. Likewise, cardiopulmonary resuscitation, which may be performed as a last resort for patients with other illnesses, would be inappropriate for patients with EVD. Recent ethical debate in the US about the role of cardiopulmonary resuscitation in patients with EVD canvassed the problem of inevitable delay because of the requirement for resuscitation teams to don PPE, but cautioned that an automatic “do not resuscitate” order may not be appropriate in the US.25

How can clinicians resolve these dilemmas?

Ethical debate during the SARS epidemic resulted in a broad consensus that HCWs have a duty to treat patients with infectious diseases, but that this duty is not absolute and is dependent on the degree of risk to which HCWs are exposed, their capacity to protect themselves from the risk, their skills and expertise, and the specific circumstances.11

Situations may arise where a decision not to treat or not to escalate therapy is justifiable because of unmanageable risk, despite all available resources. In such situations, where it is difficult to extricate the ethical obligations owed to patients from those owed to staff, and decisions may be contestable, it is crucial that the decision-making process is transparent, ethically and clinically rigorous, and acceptable to all stakeholders. These conditions are likely to be met if decisions are not made by a single clinician at the bedside but are based on a clear institutional policy or advice from an expert advisory group.

For clinicians, the answers to many of these ethical questions will be clarified as experience in the care of patients with EVD in Western hospitals grows. Just as it did in the setting of HIV and SARS, the hysteria associated with EVD is likely to settle over time and as effective therapeutic options become available. In the interim, it is imperative to develop an approach that facilitates rigorous, evidence-based and ethically justifiable decision making. In this way, we can optimise clinical care, maintain the integrity and efficient functioning of the health system, and reduce stigma and professional and public anxiety.

While issues relating to other infectious diseases, such as extremely drug-resistant tuberculosis and virulent respiratory viral infections, have been debated,26 particularly difficult questions arise in relation to the critical care of patients with EVD, due to its severity, the absence of proven therapies and the risk to HCWs. The key concern is ensuring that no patient is denied therapy that should be provided, while preventing unnecessary risk to staff. It is possible that these may represent intersecting priorities, and the balance would, of necessity, favour preventing infections in staff.

These dilemmas can be resolved with an approach that includes a predetermined, institutionally endorsed process for assessing difficult clinical scenarios as they arise. This process should be transparent and consistent, with clear policies and governance structures to provide the optimal balance between ensuring a patient with EVD receives appropriate care and that staff are not placed at unnecessary risk.

[Comment] UK Biobank comes of age

UK Biobank is the most ambitious national initiative aiming to improve the prevention, diagnosis, and treatment of diseases. The baseline information obtained between 2006 and 2010 from 500 000 adults encompasses a vast range of characteristics, including sociodemographic information, physical measures, health and lifestyle factors, medical history, and blood measurements.1 The participants have been followed up for mortality for an average of 5 years. The wealth of data from UK Biobank is available to researchers worldwide, after an approved application.

[Comment] Interleukin-17 inhibition: a route to psoriasis clearance?

Interleukin 17 is involved in the inflammatory cascade in several immune-mediated and inflammatory diseases such as psoriasis, psoriatic arthritis, and ankylosing spondylitis. It is, therefore, not surprising that intense development of several specific inhibitory drugs followed identification of the five members of the interleukin-17 family, among which interleukin 17A is so far the best characterised regarding its inflammatory effects.1